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/* * Copyright 2010-2013 Amazon.com, Inc. or its affiliates. All Rights Reserved. * * Licensed under the Apache License, Version 2.0 (the "License"). * You may not use this file except in compliance with the License. * A copy of the License is located at * * http://aws.amazon.com/apache2.0 * * or in the "license" file accompanying this file. This file is distributed * on an "AS IS" BASIS, WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either * express or implied. See the License for the specific language governing * permissions and limitations under the License. */ #import "SimpleDBMissingParameterException.h" @implementation SimpleDBMissingParameterException @synthesize boxUsage; -(id)initWithMessage:(NSString *)theMessage { if (self = [super initWithMessage:theMessage]) { } return self; } -(void)setPropertiesWithException:(AmazonServiceException *)theException { [super setPropertiesWithException:theException]; if ([theException.additionalFields valueForKey:@"BoxUsage"] != nil) { self.boxUsage = [AmazonSDKUtil convertStringToNumber:[theException.additionalFields valueForKey:@"BoxUsage"]]; } } -(NSString *)description { NSMutableString *buffer = [[NSMutableString alloc] initWithCapacity:256]; [buffer appendString:@"{"]; [buffer appendString:[[[NSString alloc] initWithFormat:@"BoxUsage: %@,", boxUsage] autorelease]]; [buffer appendString:[super description]]; [buffer appendString:@"}"]; return [buffer autorelease]; } -(void)dealloc { [boxUsage release]; [super dealloc]; } @end

Various non-informational, non-programmable nanoparticles have been known in the art, such as those disclosed in Zhang, et al., Science 272:1777-1779, 1996; LaRue et al., Macromolecules 39:309-314, 2006; Ishihara et al., Chem. Eur. J. 13:4560-4570, 2007; Kim et al., Angew. Chem., Int. Ed 46:5779-5782, 2007; Li et al., Macromolecules 41:6605-6607, 2008; Roy et al., Chem. Commun. 2106-2108, 2009; and Fernyhough et al., Soft Matter 5:1674-1682, 2009. There is a need in the art for micelles that are capable of changing morphology in a predictable or programmable way. Provided herein are solutions to these and other problems in the art.

Kaltbrunn railway station Kaltbrunn railway station is a railway station situated in the municipality of Kaltbrunn in the Swiss canton of St. Gallen. It is located on the Uznach to Wattwil line, close to the western portal of the long Ricken Tunnel. The station is served by hourly St. Gallen S-Bahn service S4, which operates in both directions around a loop via Wattwil, St. Gallen, Sargans, Ziegelbrücke and Uznach. References Category:Railway stations in the canton of St. Gallen Category:Swiss Federal Railways stations

Q: Bold Font in Linux Re-Edit of the question for clarification: Blender only has one font and it doesn't turn bold. Any way to make easily make it bold? So, I am using the RC1 release of 2.8 right now to make a logo for a possible client, but it looks like Blender only comes with a single font and it doesn't turn to bold. The logo includes bold font so I am wondering if there is any way to achieve this easily. Maybe another downloadeable font from somewhere else? Perhaps access to the fonts included in Linux? A: Different fonts can be loaded in the font tab which is shown below. Once you have selected the desired font files you can format the text. You can change the formatting by switching to edit mode. Then you can select the text by moving the cursor with the left and right arrow keys to a desired position, now press and hold the shift key and move to the end position of the selection using the arrow keys. Once you have a selection the font menu allows to change the formatting. A: While blender includes one font with its installation, you can use almost any font you can find. The most common font formats you find will be postscript, truetype or opentype. Look at the list of formats supported by Freetype. Almost every website offering downloadable fonts offers a format that you can use with blender regardless of which system you are running. You can save these fonts anywhere and open them in blender. Linux has several packages of different fonts available to install that can easily be found by most programs, unfortunately blender doesn't look in these standard font directories, we need to open specific font files. To find the location of installed fonts, open a terminal and type fc-list to get a list of paths, font name and available styles.

Q: Page transitions, depending on URL This code fades each page out, before going to the URL's destination. However, there are some instances where the user doesn't go to a new page, but goes to a PDF in the browser, or it opens the default mail application. On Safari it seems, if you go to an external site (www.twitter.com) and press the back button, the .wrapper is still faded out. (Perhaps a cache thing?) function fadeAndGo(x) { $(x).click(function (e) { e.preventDefault(); var href = this.href; $('.wrapper').fadeOut(function(){ window.location = href; }); // $('.wrapper').delay()fadeIn(); }); } fadeAndGo('a'); Is it possible to either: Fade out, only if the URL does not contain 'PDF, mailto', or is an external link? Fade in after a certain amount of time (it faded out, but faded back in after a couple of seconds, in case it was a PDF/mailto). A: Try this: function fadeAndGo(x) { $(x).click(function (e) { e.preventDefault(); var href = $(this).attr("href"); if (!/PDF|mailto/gi.test(href)) { $('.wrapper').fadeOut(function () { window.location = href; }).delay(2000).fadeIn(); } else { window.location = href; } }); } fadeAndGo('a');

Frederick Lohden Frederick Charles Lohden OBE (13 June 1871 – 13 April 1954) was an English sportsman who played rugby union as a forward at international level for England in a single game during the 1893 Home Nations Championship. After retiring from playing sport he became a sports administrator, most notably as the chairman of the Lawn Tennis Association. Personal history Lohden was born in Hartlepool in the north of England on 13 June 1871 to Jacob and Mary Lohden, and christened at Christ Church, Hartlepool on 12 July of that year. He attended Durham School as a youth, completing his education in France and Germany. In 1898 he was married to Margaret Emily Marshall of Broadwater, Sussex. With the outbreak of the First World War, Lohden, who already had military experience, was promoted to Lieutenant in the 4th Durham Volunteer Artillery. He later joined the East Surrey Regiment. In 1917 he was transferred to the Ministry of Shipping and was placed in charge of Standard Steamers, Russian Steamers and Oilers. He was awarded the Order of the British Empire in the 1919 New Year Honours for his work for the Ministry of Shipping. He later moved to Cheam on the border between London and Surrey where he worked as a shipping broker. Lohden later became the mayor of Sutton and Cheam, and was also made a Justice of the Peace. Sporting history Lohden showed promise as a sportsman while a youth, making the Durham School rugby XV while still a 15-year-old, the biggest forward in his team. On his return from education in mainland Europe he joined Hartlepool Rovers, and by the age of 19 he was selected to play at county level for Durham. By the 1892/93 season he was playing for one of England's premier clubs, Blackheath. While representing Blackheath he came to the attention of the English selectors and was chosen for the South of England team in the trials of the England squad. He was given his first and only cap in the opening game of the 1893 Home Nations Championship against Wales at the Cardiff Arms Park. The game started well for the English side, opening a 7–0 lead in the first half, one of the two tries scored by Lohden. A further England try at the start of the second half appeared to give England an overwhelming lead only to see an historic Welsh comeback, led by their talismanic captain Arthur Gould, which snatched victory from England in the final minutes. Although Lohden never played for England again, a series of minor injuries ending his career by 1896, he was selected for invitational tourists the Barbarians in 1893, and also represented Surrey county. After retiring from playing he kept up his connection with the sport of rugby by being elected onto the Durham County Rugby Union committee, serving them from 1896 to 1902. As well as rugby, Lohden was a keen sports shooter, and won the Baltic Exchange 'miniature' Championship for three years running. On returning to civilian life after the war, Lohden became increasingly active in the world of racket sports. A skillful badminton player he represented Surrey County playing in four consecutive London Badminton doubles finals in 1920. This was followed by the title of Veteran's Doubles Champion of England in 1921. That year Lohden also set up the Surrey Badminton Association, becoming their first honorary secretary. In 1907 Lohden put his sporting administrative abilities to further use when he was elected to the Surrey branch of the Lawn Tennis Association. He progressed to becoming the organisations chairman, and then in 1911 he joined the Council of the LTA. In 1933 he became chairman of the LTA and the year later its vice-president. References Bibliography Category:1871 births Category:1954 deaths Category:Rugby union forwards Category:English rugby union players Category:England international rugby union players Category:Barbarian F.C. players Category:Blackheath F.C. players Category:Sportspeople from Hartlepool Category:Officers of the Order of the British Empire Category:People educated at Durham School Category:British Army personnel of World War I Category:East Surrey Regiment officers Category:Tennis in the United Kingdom

Association of Chief Police Officers The Association of Chief Police Officers (ACPO), officially The Association of Chief Police Officers of England, Wales and Northern Ireland, was a not-for-profit private limited company that for many years led the development of policing practices in England, Wales, and Northern Ireland. Established in 1948, ACPO provided a forum for chief police officers to share ideas and coordinate their strategic operational responses, and advised government in matters such as terrorist attacks and civil emergencies. ACPO coordinated national police operations, major investigations, cross-border policing, and joint law enforcement. ACPO designated Senior Investigative Officers for major investigations and appointed officers to head ACPO units specialising in various areas of policing and crime reduction. ACPO was led by Chief Constable Sir Hugh Orde, QPM, who was, until 2009, the Chief Constable of the Police Service of Northern Ireland. He was elected as president by fellow members of ACPO in April 2009. ACPO was funded by Home Office grants, profits from commercial activities and contributions from the 44 police authorities in England, Wales, and Northern Ireland. Following the Parker Review into ACPO, it was replaced in 2015 by a new body, the National Police Chiefs' Council, set up under a police collaboration agreement under Section 22A of the Police Act 1996. Background UK policing sprang from local communities in the 1800s. Since the origins of policing, chief officers have regularly associated to discuss and share policing issues. Although ACPO as now recognised was formed in 1948, records of prior bodies go back to the early 1900s. The UK retains a decentralised model of policing based around the settlement which emerged from the Royal Commission on the work of the Police in 1962. ACPO continued to provide a forum for chief officers across 44 local police forces and 13 national areas across England, Wales and Northern Ireland, and provided local forces with agreed national policies and guidelines. ACPO failed to convince its sponsors to contribute to its survival and in May 2011 the BBC reported that ACPO would run out of money in February 2012 without extra funding. ACPO was half-funded by the Home Office and half by 44 police authorities. A third of police authorities refused to pay in 2010 and another third were undecided. The Association of Police Authorities said the withdrawal of funding by police authorities was "partly due to a squeeze on their income". ACPO was due to wind up formally in April 2015. Constitutional status Over time, demands for coordination across the police service increased as society changed, for example to take account of new developments in international terrorism and organised crime, or roles such as monitoring offenders on release from prison or working with young people to divert them from crime. In 1997 ACPO was incorporated as a private company limited by guarantee. As a private company, ACPO was not subject to freedom of information legislation. It was not a staff association; the staff association for senior police officers was a separate body, the Chief Police Officers Staff Association (CPOSA). The change in structure from a "band of volunteers" to a limited company allowed the organisation to employ staff, enter into contracts for accommodation and publish accounts. A number of options were considered for the status of ACPO, including charitable status, but all were discounted. Chief Constables and Commissioners are responsible for the direction and control of policing in their force areas. Although a national body and recognized by the government for consultation, ACPO had no powers of its own, nor any mandate to instruct chief officers. However, the organisation allowed chief officers to form a national policy rather than replicate the work in each of their forces. For example, after the 1980–81 riots in 27 British cities including in St. Pauls and Brixton ACPO began to prepare the Public Order Manual of Tactical Operations and Related Matters. Police forces began training in its tactics late in 1983. Membership ACPO was not a staff association. It acted for the police service, not its members. The separate Chief Police Officers Staff Association acts for chief officers. ACPO was composed of the chief police officers of the 44 police forces in England & Wales and Northern Ireland, the Deputy Chief Constable and Assistant Chief Constable of 42 of those forces and the Deputy Commissioner, Assistant Commissioner, Deputy Assistant Commissioner and Commanders of the remaining two - the Metropolitan Police and City of London Police. Certain senior non-police staff and senior members of national police agencies and certain other specialised and non-geographical forces in the UK, the Isle of Man and the Channel Islands were also members. As of March 2010 there were 349 members of ACPO. The membership elected a full-time President, who held the office of Chief Constable under the Police Reform Act 2002. ACPO bodies ACPO was responsible for several ancillary bodies, which it either funded or which received Home Office funding but which reported to ACPO: ACPO Criminal Records Office The ACPO Criminal Records Office (ACRO) was set up in 2006 in response to a perceived gap in the police service's ability to manage criminal records and in particular to improve links to biometric data. The initial aim of ACRO was to provide operational support relating to criminal records and associated biometric data, including DNA and fingerprint recognition. It also issues police certificates, for a fee, needed to obtain immigration visas for countries including Australia, Belgium, Canada, Cayman Islands, New Zealand, South Africa and the United States. The organization continues under the style "ACRO Criminal Records Office" under the control of Hampshire Constabulary. ACPO Vehicle Crime Intelligence Service The Association of Chief Police Officers Vehicle Crime Intelligence Service (AVCIS), later the National Vehicle Crime Intelligence Service (NAVCIS), was managed by ACPO, and was responsible for combating organised vehicle crime and the use of vehicles in crime. National Community Tension Team The National Community Tension Team (NCTT) was an ACPO body which monitored religious, racial, or other tensions within communities, and provided liaison between police forces and community organisations. National Counter Terrorism Security Office The National Counter Terrorism Security Office was funded by, and reported to, ACPO and advised the British government on its counter terrorism strategy. Police National Information and Co-ordination Centre ACPO was responsible for coordinating the national mobilisation of police resources at times of national need through the Police National Information and Co-ordination Centre (PNICC), which it set up in 2003. This included ensuring policing resilience during major events such as emergency response to serious flooding or the investigation of a terrorist attack. PNICC sat alongside the government in COBR (Cabinet Office Briefing Room) to advise on national issues. PNICC also handled support to overseas crises involving UK nationals. It employed three full-time staff, with other staff seconded to it as needed and is funded by contributions from each of the police forces. Counter Terrorism Internet Referral Unit The Counter Terrorism Internet Referral Unit (CTIRU) was set up in 2010 by ACPO (and run by the Metropolitan Police) to remove unlawful terrorist material content from the Internet with a focus on UK based material. The December 2013 report of the Prime Minister's Extremism task force said that it would "work with internet companies to restrict access to terrorist material online which is hosted overseas but illegal under UK law" and "work with the internet industry to help them in their continuing efforts to identify extremist content to include in family-friendly filters" which would likely involve lobbying ISPs to add the CTIRU list to their filters without the need for additional legislation. National Wildlife Crime Unit The National Wildlife Crime Unit is a national police unit that gathers intelligence on wildlife crime and provides analytical and investigative support to law enforcement agencies. Controversies Freedom of information ACPO had been criticised as being unaccountable to Parliament or the public by virtue of its limited company status. In October 2009 Sir Hugh Orde stated that ACPO would be "more than happy" to be subject to the Freedom of Information Act. On 30 March 2010, the Ministry of Justice announced that ACPO would be included under the FOI Act from October 2011. In its response, the organisation stated that "Although organisations cannot voluntarily comply with the Act, a large proportion of ACPO's work is public already or available under FOI through any police force". In January 2011 its website still said it: "is unable to do is to respond to requests for information under the Act. The organisation is too small and there are too few members of staff to be able to conduct the necessary research and to compile the responses". From November 2011, however, FOI requests could be made to ACPO. Confidential Intelligence Unit In February 2009, the Mail on Sunday highlighted the involvement of ACPO in setting up the "Confidential Intelligence Unit" as a specialised unit to monitor left-wing and right-wing political groups throughout the UK. Commercial activities The February 2009 Mail on Sunday investigation also highlighted other activities of the ACPO including selling information from the Police National Computer for £70 despite it costing them only 60p to access it, marketing "police approval" logos to firms selling anti-theft devices and operating a separate private firm offering training to speed camera operators. Apartments The organisation was criticised in February 2010 for allegedly spending £1.6 million per year from government anti-terrorist funding grants on renting up to 80 apartments in the centre of London which were reported as being empty most of the time. The organisation responded that it had reviewed this policy and would reduce the number of apartments. Undercover activities As a result of The Guardian articles with regards to the activities and accusations of PC Mark Kennedy of the National Public Order Intelligence Unit within the National Extremism Tactical Co-ordination Unit, and the collapse of the subsequent trial of six activists, a number of initiatives and changes were announced: Acknowledging that "something had gone very wrong" in the Kennedy case to the Home Affairs Select Committee, Home Office minister Nick Herbert stated that ACPO would lose control of three teams involved in tackling domestic extremism. Herbert announced that the units would be transferred to the Metropolitan Police, with acting commissioner Tim Godwin confirming that this would occur at the earliest possible timescale. Her Majesty's Inspectorate of Constabulary announced that Bernard Hogan-Howe would lead an investigation into ACPO, to assess whether undercover operations had been "authorised in accordance with law" and "proportionate". The Association of Police Authorities said it was ending its annual £850,000 grant to ACPO. DNA database ACPO has supervised the creation of one of the world's largest per-capita DNA databases, containing the DNA profiles of more than one million innocent people. ACPO's guidelines that these profiles should only be deleted in "exceptional circumstances" were found to be unlawful by the UK Supreme Court in May 2011. They were found to be incompatible with the European Convention on Human Rights, following the ruling by the European Court of Human Rights in S and Marper v United Kingdom. On 1 May 2012, the Protection of Freedoms Act 2012 completed its passage through Parliament and received Royal Assent. To date, ACPO has not reissued revised guidelines to replace its unlawful DNA exceptional procedure. Big Brother Watch, in a report of June 2012, concludes that despite the Protection of Freedoms Act, the retention of DNA in England and Wales remains an uncertain and illiberal regime. Fake uniforms During the summer of 2011, Hugh Orde, then president of the ACPO, was seen wearing a dark blue police-style uniform with ACPO insignia, and was accused of wearing a fake uniform. Senior police officers claimed that the uniform was not that of any police force in the country but "closely resembled" the uniform worn by former Metropolitan Police Commissioner, Paul Stephenson. Sam Leith, an author, journalist and literary editor of The Spectator, mocked Orde's decision "to wear this Gadaffi-style pretend uniform on television", and suggested it was "a subliminal pitch for the Met Commissioner's job." Brian Paddick, at the time the Police Commander for the London Borough of Lambeth, said: "It's unusual for the president of ACPO to appear in all these interviews in uniform. He is sending a clear signal: how would I look in the commissioner's uniform?" One officer noted: "If anything, Hugh should be wearing the uniform of the Police Service of Northern Ireland because that's where he served. But their uniform is green, not the dark blue he currently wears." An ACPO spokesperson stated that the "Police Reform Act 2002 states that the President of the Association of Chief Police Officers holds the rank of chief constable. Not being a member of a particular force, the President wears a generic police uniform". Parker Review In 2013, an independent review of ACPO by General Sir Nick Parker was published. It recommended that ACPO be replaced by a new body, in the interests of greater transparency and cost effectiveness. On the basis of these recommendations, a new organization, the National Police Chiefs' Council, was set up to replace ACPO, which it did on 1 April 2015. Notable members Commander Christine Jones (Metropolitan Police), lead on mental health issues References External links Association of Chief Police Officers website (archived link from March 2015) Category:Law enforcement in England and Wales Category:Law enforcement in Northern Ireland Category:Organizations established in 1948 Category:British intelligence agencies Category:Privately held companies of the United Kingdom Category:Counter-intelligence agencies Category:1948 establishments in the United Kingdom Category:2015 disestablishments in the United Kingdom Category:Law enforcement-related professional associations

Q: Classic vs universal Google analytics and loss of historical data I'm keen to use some of the new features in Google Universal Analytics. I have an old site though that I don't want to lose the historical data for. The comparisons with historical data are interesting for example. However Google doesn't appear to allow you to change a property from the classic code to the new code. Am I missing something? I'm surprised this isn't a bigger issue for many other users. A: Edit: Google just announced the upgrade path to universal analytics: We just launched the Google Analytics Upgrade Center, an easy, two-step process to upgrade your classic Analytics accounts to Universal Analytics. From their upgrade instructions: Step 1: Transfer your property from Classic to Universal Analytics. We’ve developed a new tool to transfer your properties to Universal Analytics that we will be slowly enabling in the admin section of all accounts. In the coming weeks, look for it in your property settings. Step 2: Re-tag with a version of the Universal Analytics tracking code. After completing Step 1, you’ll be able to upgrade your tracking code, too. Use the analytics.js JavaScript library on your websites, and Android or iOS SDK v2.x or higher for your mobile apps. Our goal is to enable Universal Analytics for all Google Analytics properties. Soon all Google Analytics updates and new features will be built on top of the Universal Analytics infrastructure. To make sure all properties upgrade, Classic Analytics properties that don’t initiate a transfer will be auto-transferred to Universal Analytics in the coming months. Google will support upgrading and migrating data to the universal analytics, but that upgrade process is not ready yet. From their help document: In the coming months, look for documentation to help you upgrade your existing Google Analytics web properties and data to UA.

Visual attention to features by associative learning. Expecting a particular stimulus can facilitate processing of that stimulus over others, but what is the fate of other stimuli that are known to co-occur with the expected stimulus? This study examined the impact of learned association on feature-based attention. The findings show that the effectiveness of an uninformative color transient in orienting attention can change by learned associations between colors and the expected target shape. In an initial acquisition phase, participants learned two distinct sequences of stimulus-response-outcome, where stimuli were defined by shape ('S' vs. 'H'), responses were localized key-presses (left vs. right), and outcomes were colors (red vs. green). Next, in a test phase, while expecting a target shape (80% probable), participants showed reliable attentional orienting to the color transient associated with the target shape, and showed no attentional orienting with the color associated with the alternative target shape. This bias seemed to be driven by learned association between shapes and colors, and not modulated by the response. In addition, the bias seemed to depend on observing target-color conjunctions, since encountering the two features disjunctively (without spatiotemporal overlap) did not replicate the findings. We conclude that associative learning - likely mediated by mechanisms underlying visual object representation - can extend the impact of goal-driven attention to features associated with a target stimulus.

ABC News’ Good Morning America outstripped NBC News’ Today by 761,000 viewers and 279,000 news demo viewers the week of April 7. It’s GMA‘s seventh consecutive week on top of the morning infotainment show race in both metrics, and its largest demo margin in three months. GMA has ranked No. 1 in overall audience for 89 of the past 93 weeks, and No. 1 in the news demo for 25 of this season’s 29 weeks to date. Today meanwhile, boasted it finished first with the younger, 18-49 year old age bracket, for the 42nd consecutive week. Today is on top of the ratings in the daypart with men 25-54 this season, NBC noted — as well as adults, men and women 18-49. Today has posted seven consecutive months of ratings growth in total viewers, and both the 25-54 and 18-49 demos which NBC says is the show’s biggest ratings uptick since ’97. For the week, GMA clocked 5.617 million viewers — 2.212 million in the demo. Today logged 4.856 million viewers — 1.933 million in the demo. GMA bested CBS This Morning‘s 3.041 million viewers — 956,000 in the news demo. 8 Comments now if they would only get rid of Roker and Daly, maybe I would watch again. Also replace Hall in the 9 o’clock hour. She is awful. GIVE ME MY GEIST BACK B stock • on Apr 17, 2014 8:54 am I love GMA but they really need to get rid of the music that you have to listen to even when the anchors are talking…. So annoying….off today and excited to watch but had to turn channel because the music is too loud and so annoying… George even asked for the music to be turned down! Bill • on Apr 17, 2014 8:54 am who cares Carol Dehart • on Apr 17, 2014 8:54 am I miss Sam and josh very much. Congrats over you numbers. Please have Sarah on more edna • on Apr 17, 2014 8:54 am I love GMA, but I miss Sam and Josh. Carla • on Apr 17, 2014 8:54 am Format is fantastic – notice Today ditched there ugly sofa for the “round table.” Nothing like GMA comradery! Little late Today producers! Greatly miss Gosh and Sam. Not so keen w/Ginger – maybe trying too hard, not found her “nitch.” Only complaint? Too much Estrogen on the show! Enjoy success GMA! Barrack • on Apr 17, 2014 8:54 am I love, The new Weather Person…….Sam was great, but it was good that he moved on. Ginger is fresh and of course the storm chaser! Lara, has done well in her position. I did not think anyone could take Dianne’s place she has done very well. Now as for Josh, well he did not stay long enough to matter. Easy to replace. Robin is a fixture, so is George. The rest just compliment them. Ohhhhhh and Stahan wow that will be awesome!! Go GMA!! Sixto • on Apr 17, 2014 8:54 am Thanks God that people are discarding Lauer and in the future Al Roker as hosts of Today. People are being conscientious that Lauer is pucking and that Al is passe with the same phrase over and over and over “now lets see whats happening in your neck of the woods” .

Q: How to make a field in a table reference to another table in MySQL/MariaDB? Say I'm setting up an small database with just 2 tables: feeds and feeditems. In one table I'd store the feedname and url, with an ID as unique key. In the second table I'd like to store some info coming from feed items (in example: date, title, url of the item and feedname). But instead of storing the feed name, I'd like to reference this feed field to the ID of that feed in the first table. Thanks A: this a quick example of how to achieve your requirement... CREATE TABLE IF NOT EXISTS `feeds` ( `Feed_ID` int(11) NOT NULL, `Feed_Name` varchar(32) NOT NULL, `Feed_Url` varchar(255) NOT NULL, PRIMARY KEY (`Feed_ID`) ) CREATE TABLE IF NOT EXISTS `feeditems` ( `FeedItem_ID` int(11) NOT NULL, `Feed_ID` int(11) NOT NULL, `FeedItem_Date` datetime NOT NULL, `FeedItem_Title` varchar(255) NOT NULL, `FeedItem_Url` varchar(255) NOT NULL, `FeedItem_Name` varchar(255) NOT NULL, PRIMARY KEY (`FeedItem_ID`), FOREIGN KEY (`Feed_ID`) REFERENCES `feeds`(`Feed_ID`) ON DELETE CASCADE )

Irinotecan (CPT-11, Campto®) -- a semisynthetic, water-soluble derivative of the plant alkaloid camptothecin -- is the standard of care in the treatment of advanced colorectal cancer when 5-fluorouracil (5-FU)-based therapy has failed ([Cunningham *et al*, 2001](#bib5){ref-type="other"}). Phase II trials have demonstrated objective response rates of 16--27% in pretreated patients, with stabilisation of disease in a further 40--60% of patients ([Rougier *et al*, 1997](#bib13){ref-type="other"}; [Van Cutsem *et al*, 1999](#bib17){ref-type="other"}). Median overall survival rates of up to 10 months are achievable when irinotecan is used in relapsed/refractory colorectal cancer ([Shimada *et al*, 1993](#bib15){ref-type="other"}; [Rothenberg *et al*, 1996](#bib12){ref-type="other"}, [1999](#bib11){ref-type="other"}; [Pitot *et al*, 1997](#bib10){ref-type="other"}; [Rougier *et al*, 1997](#bib13){ref-type="other"}; [Van Cutsem *et al*, 1999](#bib17){ref-type="other"}). Two European phase III trials investigating the efficacy and safety of irinotecan, following 5-FU failure in advanced colorectal cancer, have demonstrated significant improvements in survival compared with best supportive care and 5-FU ([Cunningham *et al*, 1998](#bib6){ref-type="other"}; [Rougier *et al*, 1998](#bib14){ref-type="other"}). The main adverse events accompanying treatment with irinotecan in these trials were diarrhoea, neutropenia, fatigue, nausea and vomiting. Although 350 mg m^−2^ as an intravenous infusion every 3 weeks is the standard recommended dosage of irinotecan, pharmacokinetic parameters of irinotecan-lactone and the active metabolite SN-38-lactone vary between individuals ([Xie *et al*, 2002](#bib18){ref-type="other"}). This may be attributed to differences in the levels of the enzymes that metabolise irinotecan, notably carboxylesterase for SN-38. Furthermore, the variable interindividual patient exposure to SN-38 has been identified as an important determinant of toxicity ([Mathijssen *et al*, 2002](#bib8){ref-type="other"}). At the same time, there is convincing evidence of a dose--response relationship, and therefore a rationale for increasing doses when possible. In a phase I trial by [Abigerges *et al* (1995)](#bib1){ref-type="other"}, there were two recommended doses: 350 mg m^−2^ without high-dose loperamide and 600 mg m^−2^ with high-dose loperamide. With the exception of one responder treated at 260 mg m^−2^, all objective responses were observed at dose levels above 350 mg m^−2^. [Merrouche *et al* (1997)](#bib9){ref-type="other"} provided further support for this from a phase I trial in which an increased tumour response was seen at an irinotecan dose level of 500 mg m^−2^. Thus, these data suggest that a fixed-dose strategy for administration of irinotecan may not be optimal for all patients, thereby comprising treatment. The interindividual variability in pharmacokinetic parameters and dose--response relationship provided the rationale for investigating a dose optimisation strategy for irinotecan ([Chabot *et al*, 1995](#bib4){ref-type="other"}). The present study investigated different strategies, using doses of irinotecan up to 500 mg m^−2^, as single-agent therapy in the treatment of patients with metastatic colorectal cancer resistant to 5-FU. METHODS ======= Patients -------- Eligibility criteria included metastatic, histologically proven adenocarcinoma of the colon or rectum progressing on 5-FU-based chemotherapy (adjuvant and/or palliative); administration of ⩽2 5-FU-based regimens in the adjuvant setting or ⩽1 in the palliative setting; World Health Organization (WHO) performance status (PS) of ⩽2; adequate haematological, renal and hepatic function. Exclusion criteria included prior treatment with topoisomerase-I inhibitors; evidence of central nervous system metastases; prior history of chronic diarrhoea; current infection; or any other serious illness or medical condition. Study design and conduct ------------------------ This was a prospective, randomised, multicentre, open-label, phase II study. The study was conducted in accordance with the Declaration of Helsinki (Hong Kong revision, 1989) and with the approval of the Ethics Committee (Institutional Review Board) at each participating centre. Written informed consent was obtained from each patient prior to his or her enrolment into the trial. An independent Monitoring Committee regularly assessed the safety and efficacy issues and reviewed the conduct of the study if needed. An External Response Review Committee (ERRC) assessed tumour responses without knowledge of the randomisation arm. The aim of the study was to determine the optimal dosing strategy in terms of efficacy and safety of single-agent irinotecan (by individual dose optimisation based on patient tolerance to treatment, or optimisation based on specific baseline risk factors) in the treatment of 5-FU-resistant patients with metastatic colorectal cancer. The primary efficacy endpoint was the overall response rate. ### Dosing scenarios Patients were randomised to one of three groups (A, B and C (outlined below)), each group receiving irinotecan as a 30 min intravenous infusion scheduled every 21 days. This dosing interval could be extended to a maximum of 35 days in the event of persistent toxicity to allow satisfactory recovery from the previous cycle. Doses \<250 mg m^−2^ or \>500 mg m^−2^ were not used in this study; patients who exhibited significant toxicity at 250 mg m^−2^ were withdrawn from the study. Group A was the reference group in which a fixed dose of 350 mg m^−2^ of irinotecan was administered on Day 1. In subsequent cycles, the dose of irinotecan could be decreased (but not increased) according to the presence of significant toxicity at this dose. Groups B and C investigated dosing scenarios to select patients for whom the higher dose of irinotecan (500 mg m^−2^) could be optimally used. Patients randomised to Group B received irinotecan at a starting dose of 250 mg m^−2^ followed by increasing doses (350 and 500 mg m^−2^) depending on the tolerance observed in the preceding cycle. In the event of significant toxicity, dose reductions were implemented. In Group C, the irinotecan dose was based on protocol-defined toxicity risk factors identified at baseline: grade 3--4 neutropenia (bilirubin \>70% upper limit of normal (UNL), haemoglobin \<12 g dl^−1^, \>3 organs involved) and/or grade 3--4 diarrhoea (PS⩾1, creatinine \>70% UNL ([Freyer *et al*, 2000](#bib7){ref-type="other"})). Patients could be started at an irinotecan dose of 500 mg m^−2^ in the absence of toxicity risk factors. The starting dose of irinotecan was 350 mg m^−2^ in patients with one risk factor or one factor from each group, and 250 mg m^−2^ for patients with \>2 risk factors or two factors from the same group. The dose was not escalated, but could be reduced to 250 mg m^−2^ in the event of significant treatment-emergent toxicity. Concomitant treatments and follow-up ------------------------------------ Antiemetic drugs were administered as premedication to irinotecan infusions. Atropine was permitted for acute anticholinergic symptoms and loperamide (or similar) for delayed diarrhoea. In addition, preventative oral antibiotic therapy (e.g. an oral fluoroquinolone) was administered to patients with persistent (\>48 h) grade 4 diarrhoea or for diarrhoea associated with grade 3--4 neutropenia or fever. No granulocyte-colony-stimulating factor (G-CSF) support was allowed. All patients were followed until disease progression, unacceptable toxicity or death occurred, or the patient chose to withdraw from the trial. In all cases, in each group where toxicity necessitated a dose reduction, delay or study treatment termination, the patient was followed up until the event had resolved. Efficacy, safety and pharmacokinetic evaluations ------------------------------------------------ Tumour response rate, the primary efficacy end point, was measured according to WHO criteria and evaluated by the ERRC. Response was defined as complete (CR) plus partial (PR) response and as tumour growth control in terms of stabilisation of disease (PR plus no change/stable disease). Secondary efficacy variables were the duration of response and disease stabilisation, time to progression (TTP), time to treatment failure (TTF) and overall survival. The duration of response was measured from the first day of infusion of irinotecan to the first date that disease progression was noted or to the date of death for any reason. Time to progression was calculated from the date of randomisation to the first documented date of progression or the date of death for any reason. Time to treatment failure was the period between the date of randomisation and the date of tumour progression or treatment discontinuation for any reason. Survival was defined as the time between randomisation and death. Efficacy evaluations were performed using intent-to-treat (ITT) and per-protocol (eligible and evaluable) patient populations. The safety population comprised all patients who had started at least one infusion of study treatment. Safety was assessed according to the National Cancer Institute Common Toxicity Criteria or, if this was not applicable, graded as mild, moderate, severe or life threatening. The safety analysis was based on the worst grade by patient and by cycle. Deaths during the trial and up to 30 days from the last infusion were recorded. Pharmacokinetic evaluations were performed using a population approach ([Chabot *et al*, 1995](#bib4){ref-type="other"}; [Canal *et al*, 1996](#bib3){ref-type="other"}). At 30 min prior to infusion, and at 5 min and 3--4 h postinfusion (an additional sample was collected at 24 h postinfusion in some cases), three 5 ml blood samples (plus one predrug sample) were taken for analysis at the first cycle of chemotherapy for Groups A and C, and at the first, second and third cycles for Group B. Plasma levels of irinotecan and SN-38 were measured using reverse-phase high-performance liquid chromatography with camptothecin as an internal standard. Peak plasma concentration (*C*~max~) and the area under the plasma concentration--time curve (AUC) were calculated for both irinotecan and SN-38. In addition, total body clearance was calculated for irinotecan, and the time to reach *C*~max~ (*t*~max~) as well as the AUC normalised to l mg of irinotecan (AUC~N~) were calculated for SN-38. A three- and two-compartment model was used for irinotecan and SN-38, respectively. Statistical considerations -------------------------- Using the hypothesis that the response rate in Groups B and C would be 20%, a total of 64 patients in each of these groups were required to yield a confidence interval (CI) band of ⩽20%. For the reference group (Group A), the number of subjects randomised was half that of Groups B and C. The 95% CIs were estimated for response, using the exact method. Confidence intervals on median values were estimated using the method described by Brookmeyer and Crowley ([Simon *et al*, 1985](#bib16){ref-type="other"}). Descriptive statistics only were used for the pharmacokinetic parameters in each group. RESULTS ======= Patients -------- A total of 164 patients entered the study: 36 in Group A, 62 in Group B and 66 in Group C ([Table 1](#tbl1){ref-type="table"}). The majority of patients (⩾97%) had received surgery and 20--30% had received radiotherapy and/or prior adjuvant chemotherapy. Based on the assessment of baseline risk factors previously described, 23 (35%) patients in Group C were assigned to receive a starting dose of 250 mg m^−2^ irinotecan, 37 (56%) patients to 350 mg m^−2^ and six (9%) patients to 500 mg m^−2^. A total of 144 (88%) patients (31, 51 and 62 in Groups A, B and C, respectively) were eligible and evaluable for the efficacy analyses. Nine patients were ineligible due to major protocol violations (\>1 line of palliative chemotherapy, and past or concurrent history of neoplasm other than colorectal adenocarcinoma in one patient) and 12 patients (not mutually exclusive) were nonevaluable for response. Early discontinuation because of adverse events rendered eight patients nonevaluable. Extent of exposure to irinotecan -------------------------------- The median dose intensity of irinotecan was similar in the three arms: 114.21 mg m^−2^ week^−1^ (95% CI 76.14--119.21) in Group A, 101.36 mg m^−2^ week^−1^ (95% CI 68.22--158.17) in Group B and 106.69 mg m^−2^ week^−1^ (95% CI 67.11--170.93) in Group C. However, the median cumulative dose was higher in Group A (1948.80 mg m^−2^) than in Groups B (1564.26 mg m^−2^) and C (1326.77 mg m^−2^), possibly due to the longer median treatment time in this group (18 weeks, compared with 16 and 13 weeks in Groups B and C, respectively). The percentage of cycles delivered at doses of 250, 350 and 500 mg m^−2^ were as follows: 3, 92 and 0% (as this was not an option) in Group A; 41, 30 and 27% in Group B; and 33, 51 and 8% in Group C. A few cycles in each group were given at intermediate doses or at doses above 525 mg m^−2^. In Group B, the only dose escalation option, 63% of patients had at least one dose escalation from the 250 mg m^−2^ start dose. More than 80% of patients in each group did not require dose reduction. A total of 36--40% of patients experienced a cycle delay ([Table 2](#tbl2){ref-type="table"}). Although the majority of dose reductions in each group were made for treatment-related reasons (mostly nonhaematological adverse events across all arms), the majority of cycle delays occurred for reasons unrelated to treatment. Efficacy -------- ### Response rate In the total (ITT) patient population (*n*=164), the overall response rates were 8, 13 and 9% in Groups A, B and C, respectively ([Table 3](#tbl3){ref-type="table"}). There were no CRs. Tumour growth control rates were higher in Groups A and B and the rates of progressive disease were lower, compared with Group C ([Table 3](#tbl3){ref-type="table"}). The pattern of response across the groups was maintained in the per-protocol (eligible and evaluable) patient population (*n*=144), with overall response rates (no CR) of 10, 16 and 10% in Groups A, B and C, respectively. Corresponding tumour growth control rates were 61, 65 and 53%. Responses occurred at all dose levels ([Table 3](#tbl3){ref-type="table"}). However, there were only two responses at the 250 mg m^−2^ dose of irinotecan, both in Group C. Although it is difficult to interpret the data based on the small patient numbers in this study, they suggest that starting patients on a dose of 250 mg m^−2^ was not beneficial. The median duration of response and TTP were significantly longer in Groups A and B compared with Group C (*P*=0.030) ([Table 3](#tbl3){ref-type="table"}). Despite a trend towards a shorter TTF and median overall survival in Group C, there were no significant differences across the arms for these parameters. Safety and tolerability ----------------------- All patients were evaluable for safety. At least one adverse event was reported in all patients. However, grade 3--4 adverse events possibly or probably related to the study treatment were reported in less than half of the patients in each group ([Table 4](#tbl4){ref-type="table"}). Most of these were related to haematological or gastrointestinal (GI) events ([Table 4](#tbl4){ref-type="table"}). Grade 3--4 neutropenia with fever or infection was infrequent. Although anaemia was common, it was infrequently reported at grade 3--4 level of severity ([Table 4](#tbl4){ref-type="table"}). Diarrhoea was the most common GI event, occurring in 85% of patients, although grade 3--4 diarrhoea was less frequent (31, 21 and 27% in Groups A, B and C, respectively) ([Table 4](#tbl4){ref-type="table"}). There were no significant between-group differences for any of the adverse events reported. In addition, analysis of adverse events at the different dose levels showed no consistent evidence that toxicity increased with increasing dosage. There was no difference between the three treatment groups for the number of patients reporting ⩾1 grade 3--4 adverse event considered to be possibly or probably treatment-related (Group A, 42%; Group B, 48%; Group C, 49%). Overall, 74 serious adverse events considered possibly or probably related to study medication occurred in 39 patients. Treatment discontinuations -------------------------- At the designated study end date, 159 (96.95%). patients had discontinued treatment (Group A, 97%; Group B, 95%; Group C, 99%) ([Table 5](#tbl5){ref-type="table"}). Disease progression resulted in proportionately fewer discontinuations in Group B (57%) than in Groups A (72%) and C (80%), and included fatalities arising from progressive disease (one patient in each of Groups A and B, and two patients in Group C). There was also one fatality: a case of aspiration pneumonia secondary to vomiting in a patient in Group B receiving the first cycle of irinotecan 250 mg m^−2^. Five (42%) of the patients who discontinued treatment from Group B were receiving the 250 mg m^−2^ dose option during cycle 1 at the time of withdrawal. Adverse events leading to discontinuations are listed in [Table 5](#tbl5){ref-type="table"}. Pharmacokinetic parameters -------------------------- The principal pharmacokinetic parameters for irinotecan and SN-38 measured in 29 assessable patients are presented in [Table 6](#tbl6){ref-type="table"}. The mean total body clearance values of irinotecan were similar across all three groups and no relevant differences in dose-normalised exposure were seen. Exposure to irinotecan and SN-38 increased proportionally over the 250--500 mg m^−2^ irinotecan dose range. In the population pharmacokinetic analysis, exposure to irinotecan appeared to be increased in patients with PS 1 or 2, and in patients with high alkaline phosphate levels. DISCUSSION ========== The results of this phase II study confirm the activity of single-agent irinotecan in patients with metastatic colorectal cancer who have failed previous therapy with 5-FU. All three treatment strategies investigated were active and demonstrated acceptable tolerability patterns. Although almost all patients in the study had ⩾1 adverse event, less than half of the patients in each treatment strategy had grade 3--4 toxicity. The main aim of this study was to determine the optimal irinotecan dosing regimen for the treatment of this population, with the primary end point being response rate. The highest overall response rate was seen in patients in Group B (13%). In this group, four (21%) of the 19 patients receiving irinotecan 500 mg m^−2^ achieved a response. There was little difference in the overall response rates in Groups A and C (8 and 9%, respectively). An interesting observation in this study was the relatively higher rate of progressive disease in Group C (44%) compared with Groups A and B (36 and 31%). None of the differences in response rate between the groups were statistically significant. It is worth mentioning that the response rate observed in Group A was unusually low, and less than that seen in published studies of similar populations of patients treated with the same schedule ([Rougier *et al*, 1997](#bib13){ref-type="other"}; [Van Cutsem *et al*, 1999](#bib17){ref-type="other"}). This may be due to changes in first-line treatment that have occurred in recent years; compared with patients treated in earlier studies, those in the present study may have been more heavily pretreated with 5-FU and oxaliplatin in the first-line setting, thus making them more chemotherapy resistant. Despite the lower response rate in Group A, it is within the CIs of previous studies and so can be considered representative. The lack of a significant difference in overall response rates between the groups may reflect the fact that the median dose intensity of irinotecan delivered was relatively constant across the three groups, despite a proportion of patients in Groups B (34%) and C (9%) receiving an irinotecan dose of 500 mg m^−2^. This finding is probably due mainly to the fact that a disproportionate number of patients (more than one-third) in each of Groups B and C never received a dose of more than 250 mg m^−2^, and so were possibly underdosed. The likelihood of underdosing in Groups B and C is supported by the observation that only 6% of patients in Group A required dose reduction from 350 to 250 mg m^−2^. There were no significant differences between Groups A and B in TTP or overall survival. This may be due to an insufficient powering of the study and/or too small a difference in response rates. A previous meta-analysis conducted in patients with advanced colorectal cancer reported that only large differences in response rate correspond to a significant difference in TTP ([Buyse *et al*, 2000](#bib2){ref-type="other"}). Both TTP and duration of response were significantly shorter in Group C than in Groups A and B, and there was also a trend for a shorter overall survival in this group. The relatively poor efficacy seen in Group C may have been due to a combination of underdosing (i.e. a significant number of patients receiving irinotecan 250 mg m^−2^) and the small number of patients who received the high dose of irinotecan (500 mg m^−2^) (six patients or 9%). There was a trend towards a better safety profile in Group B. Grade 3--4 neutropenia was 31% in Group B, 47% in A and 44% in Group B. Similarly, there was less grade 3--4 diarrhoea in Group B as compared with Groups A and C (21 *vs* 31 and 27%, respectively), despite 34% of patients receiving the highest irinotecan dose. We cannot exclude the contribution to this difference of imbalances in gender ratio (more male patients in Group B) and PS (more patients with PS=0 in Group B). However, it is possible that the results reflect the aim of the strategy adopted in Group B, which was to avoid subjecting patients to higher doses than they were able to tolerate. Indeed 10 out of 12 patients in Group B who withdrew from the study due to treatment-related adverse events received the lowest dose of irinotecan (250 mg m^−2^) and therefore would not have tolerated an increased dose of irinotecan. However, it should also be noted that severe toxicity leading to treatment discontinuation occurred more frequently in Group B despite the low dose given to all patients in the first cycle. In Group C, despite the strategy of basing the initial irinotecan dose on predetermined risk factors, patients administered the 250 mg m^−2^ dose demonstrated higher rates of grade 3--4 anaemia and diarrhoea compared with those receiving the 350 and 500 mg m^−2^ doses. This study demonstrates that intrapatient dose escalation based on toxicity in the preceding cycle dose, as practised in Group B, is feasible. Although the increase in the response rate over the whole group was modest compared with the standard irinotecan dose, clinical benefit may be seen in those patients who are able to receive 350 and 500 mg m^−2^, which, in this study, was associated with a response rate of 25 and 21%, respectively. The findings of our study in pretreated patients are in agreement with those of a nonrandomised study in previously untreated patients ([Ychou *et al*, 2002](#bib19){ref-type="other"}): the greater proportion of patients who are able to receive the higher dose and the higher response rate achieved in the latter study compared with our study is probably a reflection of interstudy differences in the starting dose, dose escalation guidelines and in the study population (previous treatment compared with no previous treatment). In contrast with the feasibility of the strategy in Group B, the use of dose optimisation according to the baseline risk characteristics identified in our study protocol (as practised in Group C) appeared not to be an appropriate approach. This may be because the risk characteristics identified were not valid in this setting or that the algorithm for dose assignment was not relevant. Further investigation is required to clarify this. In conclusion, the data from our randomised phase II study suggest that individual dose optimisation based on toxicity in the preceding cycle is feasible and merits further investigation. Increasing the dose of irinotecan to 500 mg m^−2^ can be of benefit in selected patients. It will be necessary to identify the most appropriate starting dose, as the dose of 250 mg m^−2^ used in this study was possibly too conservative. Data from pharmacogenomic research are likely to be useful in the future for identifying the most appropriate starting dose of irinotecan for individual patients. The following additional investigators contributed to this study: F Cavalli (Switzerland), A Etxeberria (Spain), C Focan (Belgium), H Honegger (Switzerland), R Mathijs (Belgium), M Pestalozzi (Switzerland), M Symann (Belgium) and A Tres (Spain). ###### Patient demographics and baseline characteristics   **Treatment group** ---------------------------------------------------------------------------- --------------------------- --------------------------- ---------------------------- Number of patients (*n*); randomised (eligible and evaluable) 36 (31) 62 (51) 66 (62) Gender; male : female (%) 50 : 50 71 : 29 62 : 38 Age in years; median (range) 60 (29--71) 59 (33--70) 60 (30--70) Weight loss at baseline in relation to usual body weight (% of population)  ⩽5% 88.9 85.5 87.9  \>5% 5.6 4.8 3.0  Unknown 5.6 9.7 9.1  Mean loss (kg) 1.1 0.9 1.0 WHO PS  Median 1 0 1  0 (%) 50.0 59.7 45.5  1 (%) 44.4 35.5 53.0  2 (%) 5.6 4.8 1.5 Primary tumour location  Colon 63.9 66.1 66.7  Rectum 36.1 33.9 33.3 Number of organs with metastatic involvement; median (range) 2 (1--3) 2 (1--3) 2 (1--4) Synchronous metastases (%) 41.7 59.7 56.1 Sites of metastatic disease (%)  Liver 69.4 79.0 80.3  Liver alone 48.0 53.1 37.7  Liver and other organs 52.0 46.9 62.3  Lung 41.7 30.6 31.8  Peritoneum 11.1 4.8 13.6  Lymph nodes 11.1 21.0 22.7  Colon 0 6.5 1.5  All others^a^ 27.8 22.6 30.3 Median (range) time to randomisation (months) from  First diagnosis 18.1 (4.7--82.3) (*n*=35) 12.7 (3.0--76.3) (*n*=61) 12.6 (3.2--160.1) (*n*=66)  First metastasis 9.1 (0.0--54.7) (*n*=35) 9.0 (0.6--42.7) (*n*=62) 8.1 (0.1--51.6) (*n*=65) Prior anticancer treatment (% of patients)  Surgery 97.2 98.4 97.0  Radiotherapy 30.6 21.0 22.7  Adjuvant chemotherapy 33.3 25.8 21.2 At least one symptom at baseline (% of patients) 72.2 62.9 77.3 At least one abnormal laboratory value at baseline (% of patients) 97.2 95.2 93.9 Soft tissue, bone, adrenal, pelvis, abdomen, pleura, retroperitoneum, spleen, mediastinum, skin. WHO, World Health Organization. ###### Extent of exposure to irinotecan   **Treatment group** ----------------------------------------------------------- --------------------------- ----------------------------- --------------------------- Number of patients exposed 36 62 66 Number of treatment cycles 216 370 333 Median (range) number of cycles 6 (1--24) 5 (1--21) 4 (1--15) Median (range) treatment duration (weeks) 18 (3--78) 16 (3--64) 13 (3--46) Cycles by dose (% of cycles)^a^  250 mg m^−2^ 3 41 33  350 mg m^−2^ 92 30 51  500 mg m^−2^ --- 27 8 Median actual dose intensity (mg m^−2^ week^−1^) (95% CI) 114.21 (76.14--119.21) 101.36 68.22--158.17) 106.69 (67.11--170.93) Median cumulative dose (mg m^−2^) (95% CI) 1948.80 (314.65--8373.08) 1564.26 (247.52--10 100.00) 1326.77 (249.73--4899.13) At least one dose increase (% of patients) --- 63 --- At least one dose reduction^b^  % of patients 17 15 17  % of cycles 4 3 5 At least one cycle delayed^b^  % of patients 36 40 36  % of cycles 19 15 15 Some cycles were administered at intermediate doses. For any reason (see text). ###### Efficacy results **Parameter** **Group A (*n*=36)** **Group B (*n*=62)** **Group C (*n*=66)** ***P*-value^a^** --------------------------------------------------- ---------------------- ---------------------- ---------------------- ------------------ Overall response rate, % (95% CI)^b^ 8 (1.8--22.5) 13 (5.7--23.9) 9 (3.4--18.7)   Overall response rate, % (95% CI)^b^ Per protocol 10 (2.0--25.8) 16 (7.0--28.6) 10 (3.6--19.9)    250 mg m^−2^ ^c^ --- (0/16) 0% (2/20) 10% NC  350 mg m^−2^ ^c^ (3/31) 10% (4/16) 25% (4/36) 11% NC  500 mg m^−2^ ^c^ --- (4/19) 21% (0/6) 0% NC Tumour growth control rate (%) 58% 60% 50% NC Progressive disease (%) 36% 31% 44% NC Median duration of response (months) 6.4 6.6 4.3 0.03 Median TTP (months) 4.1 4.2 3.0 0.019 Median TTF (months) 3.7 3.4 2.5 NS Median overall survival (months) 12.5 12.1 10.9 NS Results are presented for the ITT population, unless otherwise stated. A *vs* C and B *vs* C. There were no CRs. Response rate is expressed as a percentage of patients treated at that dose level as their highest dose in each group. CI, confidence interval; NC, not calculated; NS, not significant. ###### Adverse events **Grade 3--4 adverse events^a^** **Treatment group: *n* (% of patients)** ----------------------------------------------------------- ------------------------------------------ --------- --------- At least one grade 3--4 adverse event^a^ 15 (42) 30 (48) 32 (48) Haematological  Leukopenia 9 (25) 15 (24) 21 (32)  Neutropenia 17 (47) 19 (31) 29 (44)  Anaemia 3 (8) 1 (2) 5 (8)  Infection (grade 3--4 neutropenia present) 2 (6) 0 2 (3)  Fever without infection (grade 3--4 neutropenia present) 0 2 (3) 3 (5) Gastrointestinal (GI)  Vomiting 5 (14) 10 (16) 6 (9)  Diarrhoea 11 (31) 13 (21) 18 (27)  Nausea 4 (11) 7 (11) 7 (11)  All other GI events^b^ 5 (14) 5 (8) 4 (6) Other adverse events  Fatigue 3 (8) 7 (11) 8 (12)  Fever (grade 3--4 neutropenia absent) 0 1 (2) 3 (5)  Infection (grade 3--4 neutropenia absent) 2 (6) 1 (2) 3 (5) Possibly or probably related to study treatment. Anorexia, five (3%) cases; cholinergic syndrome, three (2%) cases; GI pain, two (1%) cases; dehydration, three (2%) cases; stomatitis, one (1%) case. ###### Patient discontinuations   **Treatment group: *n* (% of patients)** --------------------------------------------------- ------------------------------------------ --------- --------- No. of patients still on treatment at cutoff date 1 (3) 3 (5) 1 (2) Total treatment discontinuations 35 (97) 59 (95) 65 (99) *Nonfatal reasons* Progressive disease 25 (69) 34 (55) 51 (77) Treatment-related adverse event 2 (6) 12 (19) 6 (9) Adverse events leading to discontinuation^a^  Fatigue 1 (3) 3 (5) 2 (3)  Vomiting 1 (3) 3 (5) 2 (3)  Diarrhoea --- 4 (7) 2 (3)  Nausea --- 2 (3) 2 (3)  Neutropenia --- 2 (3) 1 (2)  Febrile neutropenia --- 2 (3) ---  Neutropenic infection 1 (3) --- ---  Infection --- --- 2 (3)  Fever (infection absent) --- 1 (2) --- All other nonfatal events^b^ --- 5 (8) 1 (2)  Patient refusal 1 (3) 4 (7) 1 (2)  Other 6 (17) 7 (11) 4 (6) *Fatal reasons* Death due to treatment-related adverse events --- 1 (2) --- Death due to progressive disease 1 (3) 1 (2) 2 (3) Cardio-respiratory failure --- --- 1 (2) Not mutually exclusive. Patients may have discontinued treatment for more than one adverse event reason. Group B: aggravation reaction, two (3%) cases; anorexia, one (2%) case; dehydration, one (2%) case; small bowel obstruction, one (2%) case. Group C: anorexia, one (2%) case. ###### Pharmacokinetic profiles of irinotecan and SN-38 at different doses of irinotecan   **Arm A** **Arm B** **Arm C** ------------------------ ------------------- -------------------- -------------------- ------------------- ------------------- ------------------- Cycle 1 1 2 3 1 1 No. of patients 6 13 8 5 5 5 Dose (*n*) (mg m^−2^) 350 250 350 300 (1)/500 (4) 250 350 *Irinotecan* Infusion duration (h) 0.5--1.5 0.5--1.5 0.5--1.0 0.5--1.1 0.5--1.6 0.5--1.1 *C*~max~ (mg l^−1^) 5.88 (4.79--9.18) 4.55 (3.05--5.87) 6.12 (5.33--6.70) 8.40 (4.57--8.62) 3.61 (3.26--4.56) 7.13 (5.10--7.79) AUC (mg h l^−1^) 32.7 (14.3--36.4) 20.5 (11.6--30.9) 27.8 (20.4--39.2) 44.7 (28.0--50.6) 19.7 (15.3--29.0) 33.4 (22.9--46.3) Clearance (l h m^−2^) 9.3 (8.4--21.3) 10.6 (7.0--18.9) 10.9 (8.2--14.9) 9.1 (5.9--15.6) 10.6 (7.53--14.4) 9.03 (6.55--13.3) *SN-38* Median *t*~max~ (h) 0.7 (0.6--1.5) 0.6 (0.5--1.6) 0.6 (0.5--1.0) 0.7 (0.6--1.1) 1.5 (0.6--1.6) 1.0 (0.6--1.1) *C*~max~ (μg l^−1^) 61.9 (33.5--86.7) 49.7 (24.0--138.0) 58.7 (38.0--168.0) 80.7 (34.9--97.3) 40.6 (33.9--962) 67.9 (50.2--135) AUC (μg h l^−1^) 668 (362--1110) 676 (324--1140) 960 (546--1300) 1420 (609--1610) 595 (403--903) 768 (579--1395) AUC~N~^a^ (μg h l^−1^) 1.9 (1.1--2.9) 2.4 (1.3--5.0) 2.6 (1.6--4.4) 2.6 (1.3--5.1) 2.0 (1.5--3.2) 2.5 (1.5--4.4) Normalised to 1 mg irinotecan dose. Data are expressed as median (95% CI) unless otherwise stated. AUC, area under the plasma concentration--time curve; *C*~max~, maximum plasma concentration; *t*~max~, time to reach maximum plasma concentration.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Most organisms rely on an innate immune system as their first line of defense against infection. Within the innate immune system, the Toll-like receptors (TLRs), a family of evolutionarily ancient receptors found on the surface of many cell types, are critical for pathogen recognition outside the cell. About 12 TLRs recognize structures specific to pathogens, such as bacterial cell wall components, bacterial filament proteins, or certain types of nucleic acid. This recognition event initiates a signal inside the cell, which induces the rapid secretion of antimicrobial and inflammatory proteins. Inside the cell, the NOD proteins and RNA helicases such as MDA5 recognize similar pathogen-associated structures to those recognized by TLRs. Remarkably, given the structural diversity of the structures that they recognize, all TLRs and NODs rely on a "leucine-rich repeat" (LRR) domain to recognize pathogen-associated structures. The overall goal of our research program on innate immune sensors is to understand how they recognize conserved molecular patterns in pathogens, and how this recognition is translated into an innate immune response. Our structural approach will provide unique insights into these important processes. First, we aim to determine the structure of one or more TLR-ligand complexes, by X-ray crystallography. Alternative crystallization targets are NOD-ligand or helicase-RNA complexes. We propose to use novel protein expression techniques to maximize protein yields. Our structures will likely define novel principles of molecular recognition. By revealing the conformational changes associated with ligand binding, the structures will provide insight on how pathogen recognition is translated into a signal in the cell that elicits an immune response. Our work will also guide efforts to design synthetic agonists or antagonists with immunomodulatory properties. Such compounds would have a wide range of medical applications, particularly as vaccine adjuvants or anti-inflammatory therapeutics.

The prior art has proposed various methods and apparatus to produce composite materials. U.S. Pat. No. 2,931,082 to Brennan discloses a casting method and apparatus wherein a composite metal article is formed by continuously casting molten metal against a longitudinally moving base such as a metal strip or the like. In Brennan, a strip is disposed between the material being cast and a rotating casting wheel. U.S. Pat. No. 5,077,094 to McCall et al. discloses a process for applying a metal coating to a metal strip substrate. In this process, a melt pool of a metal coating material is deposited on a casting surface of the substrate material and rapidly cooled to form the coated metal strip. U.S. Pat. No. 4,224,978 to Klein discloses a twin roll casting method and apparatus for forming a composite material. In this method, a material having a mechanical strength and melting point substantially higher than that of aluminum is plated on at least one face of a continuously cast aluminum core material. Referenced in this patent is French Patent No. 1,364,758 which describes in principle a continuous casting method in which still liquid metal is introduced between two cooled work rolls and in which a metal plating strip is interposed between the liquid metal and the work rolls. The metal plating strip is thus plated onto the continuously cast material. This French patent discloses plating an aluminum blank with a strip of aluminum. In the prior art, it is also known to provide a brazing sheet comprising a core of an aluminum alloy and a brazing material, i.e. a coating of a lower melting point filler metal. Typically, the coatings are roll bonded to one or both sides of the core sheet during fabrication. Brazing sheet can then be formed without removing the coating, assembled, fluxed and brazed without placing additional filler metal at a joint site. In one type of roll bonding, the brazing material is bonded to a core material at an ingot stage. The bonded ingot must then be hot rolled to brazing sheet thicknesses, typically 0.125". This hot rolling step is conducive to the formation of surface oxides which impair the quality of the brazing sheet and can adversely affect brazing performance. Alternatively, the filler metal can be produced by casting into an ingot form and rolled to a thin gauge liner stock. After rolling, the wrought filler metal can be roll bonded to the aluminum core material using conventional techniques. This method requires numerous annealing and surface preparation steps to prepare the thin gauge liner stock for bonding. The core material may vary depending on the application. AA3003 or AA6951 aluminum alloys are typical examples of core materials. The brazing filler metals can also vary depending on the desired use, usually comprising an AA4XXX-type aluminum alloy. Besides the drawbacks noted above concerning excessive surface oxides in hot rolled brazing sheet and the additional processing steps of annealing and surface cleaning for wrought liner stock, prior art methods of making brazing sheet lack the ability to vary the cladding or filler metal composition for a given core material. In response to the drawbacks and disadvantages of the prior art discussed above, a need has developed to provide an improved method for making twin roll cast composite materials offering flexibility in choice of composition, cost effectiveness and energy efficiency. In response to this need, the present invention provides a method for making a twin roll cast clad material having an acceptable structure and quality in combination with low operating and capital costs and the ability to utilize different brazing filler materials with a single core material.

HaberkipCollege or work? Gap year or victory lap? And how should a young person choose among the multitude of programs offered through universities, colleges or a combination of both?Those are just some of the questions faced by today’s high school graduates.In... College or work? Gap year or victory lap? And how should a young person choose among the multitude of programs offered through universities, colleges or a combination of both?Those are just some of the questions faced by today’s high school graduates.In... College or work? Gap year or victory lap? And how should a young person choose among the multitude of programs offered through universities, colleges or a combination of both? Those are just some of the questions faced by today’s high school graduates. In an era of tough competition for jobs, the rise of precarious employment and the disappearance of a linear path from school to work, teaching kids career and life planning is more important than ever. But a new report from People for Education says Ontario students aren’t getting what they need from the province’s careers strategy, introduced over a three-year period beginning in 2013. Principals surveyed by the research and advocacy group cited problems implementing the plan, a shortage of guidance counsellors and lack of teacher training to help students at all levels. “The bottom line is it’s been hard for schools to implement this policy, which is a laudable policy, it’s something we need to be doing in our schools,” said Annie Kidder, executive director of People for Education. “We need to be thinking about the now multiple paths that our kids are going to end up being on as they grow up.” “The evidence tells us now you’re probably going to have multiple jobs in multiple different areas and also multiple paths even through your education.” So helping them understand themselves and their interests even as young students is key to making sure they have the tools to navigate a complex path. The Ontario strategy includes such mandatory components as: portfolios for every student from kindergarten to Grade 12 to help them reflect on their interests, strengths, learning and later career possibilities; career and life-planning committees in every school; and professional development for teachers to help them integrate career and life planning into the classroom. It is also linked to the existing 40 hours of mandatory community volunteering for high school students and the compulsory Grade 10 careers course. The survey of 1,100 principals found: Mandatory career and life-planning committees were in place in only 15 per cent of elementary schools and 39 per cent of high schools. And of those, only 8 per cent of secondary schools included community members. Thirty-four per cent of elementary and 56 per cent of secondary schools reported that every student had a career/life-planning portfolio. Teacher training on career and life planning was available at fewer than one in four elementary schools and 40 per cent of high schools. While high school guidance counsellors are the primary staff members responsible for student portfolios and planning, 16 per cent of secondary schools don’t have a full-time guidance counsellor. The average ratio is one counsellor for every 380 students — in line with what provincial funding provides — but one in 10 schools struggles with a ratio of 600 students per teacher. Principals said two years of education labour disputes interfered with the new strategy, but also blamed lack of technology support, workload issues, and a lack of overall understanding of the policy. “While lots of them talked about how great the policy was, an equal number talked about how difficult it was to implement,” says Kidder. She cited “initiative exhaustion” among teachers and administrators following a stream of new education strategies ranging from math to well-being to experiential learning, which can leave staff overwhelmed. And she called for better integration of the career and life lessons with all school subjects. For Bruce Lawson of the Counselling Foundation of Canada, making the most of the provincial strategy is key. And he says despite the challenges addressed in the report, it is one of the best in the country. By the time today’s elementary students graduate, at least one third of the occupations open to them will be jobs that don’t currently exist, says Lawson, president of the foundation, which promotes career planning and development. For kindergarten students, it amounts to more than half. “Given how the world is changing at such a rapid pace, we really need to equip young people with the skills, competency and resilience to be able to navigate the 21st-century workplace.” The Toronto Star and thestar.com, each property of Toronto Star Newspapers Limited, One Yonge Street, 4th Floor, Toronto, ON, M5E 1E6. You can unsubscribe at any time. Please contact us or see our privacy policy for more information. Our editors found this article on this site using Google and regenerated it for our readers.

<?php /* * THIS SOFTWARE IS PROVIDED BY THE COPYRIGHT HOLDERS AND CONTRIBUTORS * "AS IS" AND ANY EXPRESS OR IMPLIED WARRANTIES, INCLUDING, BUT NOT * LIMITED TO, THE IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR * A PARTICULAR PURPOSE ARE DISCLAIMED. IN NO EVENT SHALL THE COPYRIGHT * OWNER OR CONTRIBUTORS BE LIABLE FOR ANY DIRECT, INDIRECT, INCIDENTAL, * SPECIAL, EXEMPLARY, OR CONSEQUENTIAL DAMAGES (INCLUDING, BUT NOT * LIMITED TO, PROCUREMENT OF SUBSTITUTE GOODS OR SERVICES; LOSS OF USE, * DATA, OR PROFITS; OR BUSINESS INTERRUPTION) HOWEVER CAUSED AND ON ANY * THEORY OF LIABILITY, WHETHER IN CONTRACT, STRICT LIABILITY, OR TORT * (INCLUDING NEGLIGENCE OR OTHERWISE) ARISING IN ANY WAY OUT OF THE USE * OF THIS SOFTWARE, EVEN IF ADVISED OF THE POSSIBILITY OF SUCH DAMAGE. * * This software consists of voluntary contributions made by many individuals * and is licensed under the LGPL. For more information, see * <http://www.doctrine-project.org>. */ namespace Doctrine\ORM\Internal\Hydration; use Doctrine\DBAL\Connection; /** * Hydrator that produces flat, rectangular results of scalar data. * The created result is almost the same as a regular SQL result set, except * that column names are mapped to field names and data type conversions take place. * * @author Roman Borschel <[email protected]> * @since 2.0 */ class ScalarHydrator extends AbstractHydrator { /** @override */ protected function _hydrateAll() { $result = array(); $cache = array(); while ($data = $this->_stmt->fetch(\PDO::FETCH_ASSOC)) { $result[] = $this->_gatherScalarRowData($data, $cache); } return $result; } /** @override */ protected function _hydrateRow(array $data, array &$cache, array &$result) { $result[] = $this->_gatherScalarRowData($data, $cache); } }

package network // Copyright (c) Microsoft and contributors. All rights reserved. // // Licensed under the Apache License, Version 2.0 (the "License"); // you may not use this file except in compliance with the License. // You may obtain a copy of the License at // http://www.apache.org/licenses/LICENSE-2.0 // // Unless required by applicable law or agreed to in writing, software // distributed under the License is distributed on an "AS IS" BASIS, // WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied. // // See the License for the specific language governing permissions and // limitations under the License. // // Code generated by Microsoft (R) AutoRest Code Generator. // Changes may cause incorrect behavior and will be lost if the code is regenerated. import ( "context" "github.com/Azure/go-autorest/autorest" "github.com/Azure/go-autorest/autorest/azure" "github.com/Azure/go-autorest/tracing" "net/http" ) // VpnSitesClient is the network Client type VpnSitesClient struct { BaseClient } // NewVpnSitesClient creates an instance of the VpnSitesClient client. func NewVpnSitesClient(subscriptionID string) VpnSitesClient { return NewVpnSitesClientWithBaseURI(DefaultBaseURI, subscriptionID) } // NewVpnSitesClientWithBaseURI creates an instance of the VpnSitesClient client. func NewVpnSitesClientWithBaseURI(baseURI string, subscriptionID string) VpnSitesClient { return VpnSitesClient{NewWithBaseURI(baseURI, subscriptionID)} } // CreateOrUpdate creates a VpnSite resource if it doesn't exist else updates the existing VpnSite. // Parameters: // resourceGroupName - the resource group name of the VpnSite. // vpnSiteName - the name of the VpnSite being created or updated. // vpnSiteParameters - parameters supplied to create or update VpnSite. func (client VpnSitesClient) CreateOrUpdate(ctx context.Context, resourceGroupName string, vpnSiteName string, vpnSiteParameters VpnSite) (result VpnSitesCreateOrUpdateFuture, err error) { if tracing.IsEnabled() { ctx = tracing.StartSpan(ctx, fqdn+"/VpnSitesClient.CreateOrUpdate") defer func() { sc := -1 if result.Response() != nil { sc = result.Response().StatusCode } tracing.EndSpan(ctx, sc, err) }() } req, err := client.CreateOrUpdatePreparer(ctx, resourceGroupName, vpnSiteName, vpnSiteParameters) if err != nil { err = autorest.NewErrorWithError(err, "network.VpnSitesClient", "CreateOrUpdate", nil, "Failure preparing request") return } result, err = client.CreateOrUpdateSender(req) if err != nil { err = autorest.NewErrorWithError(err, "network.VpnSitesClient", "CreateOrUpdate", result.Response(), "Failure sending request") return } return } // CreateOrUpdatePreparer prepares the CreateOrUpdate request. func (client VpnSitesClient) CreateOrUpdatePreparer(ctx context.Context, resourceGroupName string, vpnSiteName string, vpnSiteParameters VpnSite) (*http.Request, error) { pathParameters := map[string]interface{}{ "resourceGroupName": autorest.Encode("path", resourceGroupName), "subscriptionId": autorest.Encode("path", client.SubscriptionID), "vpnSiteName": autorest.Encode("path", vpnSiteName), } const APIVersion = "2018-10-01" queryParameters := map[string]interface{}{ "api-version": APIVersion, } preparer := autorest.CreatePreparer( autorest.AsContentType("application/json; charset=utf-8"), autorest.AsPut(), autorest.WithBaseURL(client.BaseURI), autorest.WithPathParameters("/subscriptions/{subscriptionId}/resourceGroups/{resourceGroupName}/providers/Microsoft.Network/vpnSites/{vpnSiteName}", pathParameters), autorest.WithJSON(vpnSiteParameters), autorest.WithQueryParameters(queryParameters)) return preparer.Prepare((&http.Request{}).WithContext(ctx)) } // CreateOrUpdateSender sends the CreateOrUpdate request. The method will close the // http.Response Body if it receives an error. func (client VpnSitesClient) CreateOrUpdateSender(req *http.Request) (future VpnSitesCreateOrUpdateFuture, err error) { var resp *http.Response resp, err = autorest.SendWithSender(client, req, azure.DoRetryWithRegistration(client.Client)) if err != nil { return } future.Future, err = azure.NewFutureFromResponse(resp) return } // CreateOrUpdateResponder handles the response to the CreateOrUpdate request. The method always // closes the http.Response Body. func (client VpnSitesClient) CreateOrUpdateResponder(resp *http.Response) (result VpnSite, err error) { err = autorest.Respond( resp, client.ByInspecting(), azure.WithErrorUnlessStatusCode(http.StatusOK, http.StatusCreated), autorest.ByUnmarshallingJSON(&result), autorest.ByClosing()) result.Response = autorest.Response{Response: resp} return } // Delete deletes a VpnSite. // Parameters: // resourceGroupName - the resource group name of the VpnSite. // vpnSiteName - the name of the VpnSite being deleted. func (client VpnSitesClient) Delete(ctx context.Context, resourceGroupName string, vpnSiteName string) (result VpnSitesDeleteFuture, err error) { if tracing.IsEnabled() { ctx = tracing.StartSpan(ctx, fqdn+"/VpnSitesClient.Delete") defer func() { sc := -1 if result.Response() != nil { sc = result.Response().StatusCode } tracing.EndSpan(ctx, sc, err) }() } req, err := client.DeletePreparer(ctx, resourceGroupName, vpnSiteName) if err != nil { err = autorest.NewErrorWithError(err, "network.VpnSitesClient", "Delete", nil, "Failure preparing request") return } result, err = client.DeleteSender(req) if err != nil { err = autorest.NewErrorWithError(err, "network.VpnSitesClient", "Delete", result.Response(), "Failure sending request") return } return } // DeletePreparer prepares the Delete request. func (client VpnSitesClient) DeletePreparer(ctx context.Context, resourceGroupName string, vpnSiteName string) (*http.Request, error) { pathParameters := map[string]interface{}{ "resourceGroupName": autorest.Encode("path", resourceGroupName), "subscriptionId": autorest.Encode("path", client.SubscriptionID), "vpnSiteName": autorest.Encode("path", vpnSiteName), } const APIVersion = "2018-10-01" queryParameters := map[string]interface{}{ "api-version": APIVersion, } preparer := autorest.CreatePreparer( autorest.AsDelete(), autorest.WithBaseURL(client.BaseURI), autorest.WithPathParameters("/subscriptions/{subscriptionId}/resourceGroups/{resourceGroupName}/providers/Microsoft.Network/vpnSites/{vpnSiteName}", pathParameters), autorest.WithQueryParameters(queryParameters)) return preparer.Prepare((&http.Request{}).WithContext(ctx)) } // DeleteSender sends the Delete request. The method will close the // http.Response Body if it receives an error. func (client VpnSitesClient) DeleteSender(req *http.Request) (future VpnSitesDeleteFuture, err error) { var resp *http.Response resp, err = autorest.SendWithSender(client, req, azure.DoRetryWithRegistration(client.Client)) if err != nil { return } future.Future, err = azure.NewFutureFromResponse(resp) return } // DeleteResponder handles the response to the Delete request. The method always // closes the http.Response Body. func (client VpnSitesClient) DeleteResponder(resp *http.Response) (result autorest.Response, err error) { err = autorest.Respond( resp, client.ByInspecting(), azure.WithErrorUnlessStatusCode(http.StatusOK, http.StatusAccepted, http.StatusNoContent), autorest.ByClosing()) result.Response = resp return } // Get retrieves the details of a VPNsite. // Parameters: // resourceGroupName - the resource group name of the VpnSite. // vpnSiteName - the name of the VpnSite being retrieved. func (client VpnSitesClient) Get(ctx context.Context, resourceGroupName string, vpnSiteName string) (result VpnSite, err error) { if tracing.IsEnabled() { ctx = tracing.StartSpan(ctx, fqdn+"/VpnSitesClient.Get") defer func() { sc := -1 if result.Response.Response != nil { sc = result.Response.Response.StatusCode } tracing.EndSpan(ctx, sc, err) }() } req, err := client.GetPreparer(ctx, resourceGroupName, vpnSiteName) if err != nil { err = autorest.NewErrorWithError(err, "network.VpnSitesClient", "Get", nil, "Failure preparing request") return } resp, err := client.GetSender(req) if err != nil { result.Response = autorest.Response{Response: resp} err = autorest.NewErrorWithError(err, "network.VpnSitesClient", "Get", resp, "Failure sending request") return } result, err = client.GetResponder(resp) if err != nil { err = autorest.NewErrorWithError(err, "network.VpnSitesClient", "Get", resp, "Failure responding to request") } return } // GetPreparer prepares the Get request. func (client VpnSitesClient) GetPreparer(ctx context.Context, resourceGroupName string, vpnSiteName string) (*http.Request, error) { pathParameters := map[string]interface{}{ "resourceGroupName": autorest.Encode("path", resourceGroupName), "subscriptionId": autorest.Encode("path", client.SubscriptionID), "vpnSiteName": autorest.Encode("path", vpnSiteName), } const APIVersion = "2018-10-01" queryParameters := map[string]interface{}{ "api-version": APIVersion, } preparer := autorest.CreatePreparer( autorest.AsGet(), autorest.WithBaseURL(client.BaseURI), autorest.WithPathParameters("/subscriptions/{subscriptionId}/resourceGroups/{resourceGroupName}/providers/Microsoft.Network/vpnSites/{vpnSiteName}", pathParameters), autorest.WithQueryParameters(queryParameters)) return preparer.Prepare((&http.Request{}).WithContext(ctx)) } // GetSender sends the Get request. The method will close the // http.Response Body if it receives an error. func (client VpnSitesClient) GetSender(req *http.Request) (*http.Response, error) { return autorest.SendWithSender(client, req, azure.DoRetryWithRegistration(client.Client)) } // GetResponder handles the response to the Get request. The method always // closes the http.Response Body. func (client VpnSitesClient) GetResponder(resp *http.Response) (result VpnSite, err error) { err = autorest.Respond( resp, client.ByInspecting(), azure.WithErrorUnlessStatusCode(http.StatusOK), autorest.ByUnmarshallingJSON(&result), autorest.ByClosing()) result.Response = autorest.Response{Response: resp} return } // List lists all the VpnSites in a subscription. func (client VpnSitesClient) List(ctx context.Context) (result ListVpnSitesResultPage, err error) { if tracing.IsEnabled() { ctx = tracing.StartSpan(ctx, fqdn+"/VpnSitesClient.List") defer func() { sc := -1 if result.lvsr.Response.Response != nil { sc = result.lvsr.Response.Response.StatusCode } tracing.EndSpan(ctx, sc, err) }() } result.fn = client.listNextResults req, err := client.ListPreparer(ctx) if err != nil { err = autorest.NewErrorWithError(err, "network.VpnSitesClient", "List", nil, "Failure preparing request") return } resp, err := client.ListSender(req) if err != nil { result.lvsr.Response = autorest.Response{Response: resp} err = autorest.NewErrorWithError(err, "network.VpnSitesClient", "List", resp, "Failure sending request") return } result.lvsr, err = client.ListResponder(resp) if err != nil { err = autorest.NewErrorWithError(err, "network.VpnSitesClient", "List", resp, "Failure responding to request") } return } // ListPreparer prepares the List request. func (client VpnSitesClient) ListPreparer(ctx context.Context) (*http.Request, error) { pathParameters := map[string]interface{}{ "subscriptionId": autorest.Encode("path", client.SubscriptionID), } const APIVersion = "2018-10-01" queryParameters := map[string]interface{}{ "api-version": APIVersion, } preparer := autorest.CreatePreparer( autorest.AsGet(), autorest.WithBaseURL(client.BaseURI), autorest.WithPathParameters("/subscriptions/{subscriptionId}/providers/Microsoft.Network/vpnSites", pathParameters), autorest.WithQueryParameters(queryParameters)) return preparer.Prepare((&http.Request{}).WithContext(ctx)) } // ListSender sends the List request. The method will close the // http.Response Body if it receives an error. func (client VpnSitesClient) ListSender(req *http.Request) (*http.Response, error) { return autorest.SendWithSender(client, req, azure.DoRetryWithRegistration(client.Client)) } // ListResponder handles the response to the List request. The method always // closes the http.Response Body. func (client VpnSitesClient) ListResponder(resp *http.Response) (result ListVpnSitesResult, err error) { err = autorest.Respond( resp, client.ByInspecting(), azure.WithErrorUnlessStatusCode(http.StatusOK), autorest.ByUnmarshallingJSON(&result), autorest.ByClosing()) result.Response = autorest.Response{Response: resp} return } // listNextResults retrieves the next set of results, if any. func (client VpnSitesClient) listNextResults(ctx context.Context, lastResults ListVpnSitesResult) (result ListVpnSitesResult, err error) { req, err := lastResults.listVpnSitesResultPreparer(ctx) if err != nil { return result, autorest.NewErrorWithError(err, "network.VpnSitesClient", "listNextResults", nil, "Failure preparing next results request") } if req == nil { return } resp, err := client.ListSender(req) if err != nil { result.Response = autorest.Response{Response: resp} return result, autorest.NewErrorWithError(err, "network.VpnSitesClient", "listNextResults", resp, "Failure sending next results request") } result, err = client.ListResponder(resp) if err != nil { err = autorest.NewErrorWithError(err, "network.VpnSitesClient", "listNextResults", resp, "Failure responding to next results request") } return } // ListComplete enumerates all values, automatically crossing page boundaries as required. func (client VpnSitesClient) ListComplete(ctx context.Context) (result ListVpnSitesResultIterator, err error) { if tracing.IsEnabled() { ctx = tracing.StartSpan(ctx, fqdn+"/VpnSitesClient.List") defer func() { sc := -1 if result.Response().Response.Response != nil { sc = result.page.Response().Response.Response.StatusCode } tracing.EndSpan(ctx, sc, err) }() } result.page, err = client.List(ctx) return } // ListByResourceGroup lists all the vpnSites in a resource group. // Parameters: // resourceGroupName - the resource group name of the VpnSite. func (client VpnSitesClient) ListByResourceGroup(ctx context.Context, resourceGroupName string) (result ListVpnSitesResultPage, err error) { if tracing.IsEnabled() { ctx = tracing.StartSpan(ctx, fqdn+"/VpnSitesClient.ListByResourceGroup") defer func() { sc := -1 if result.lvsr.Response.Response != nil { sc = result.lvsr.Response.Response.StatusCode } tracing.EndSpan(ctx, sc, err) }() } result.fn = client.listByResourceGroupNextResults req, err := client.ListByResourceGroupPreparer(ctx, resourceGroupName) if err != nil { err = autorest.NewErrorWithError(err, "network.VpnSitesClient", "ListByResourceGroup", nil, "Failure preparing request") return } resp, err := client.ListByResourceGroupSender(req) if err != nil { result.lvsr.Response = autorest.Response{Response: resp} err = autorest.NewErrorWithError(err, "network.VpnSitesClient", "ListByResourceGroup", resp, "Failure sending request") return } result.lvsr, err = client.ListByResourceGroupResponder(resp) if err != nil { err = autorest.NewErrorWithError(err, "network.VpnSitesClient", "ListByResourceGroup", resp, "Failure responding to request") } return } // ListByResourceGroupPreparer prepares the ListByResourceGroup request. func (client VpnSitesClient) ListByResourceGroupPreparer(ctx context.Context, resourceGroupName string) (*http.Request, error) { pathParameters := map[string]interface{}{ "resourceGroupName": autorest.Encode("path", resourceGroupName), "subscriptionId": autorest.Encode("path", client.SubscriptionID), } const APIVersion = "2018-10-01" queryParameters := map[string]interface{}{ "api-version": APIVersion, } preparer := autorest.CreatePreparer( autorest.AsGet(), autorest.WithBaseURL(client.BaseURI), autorest.WithPathParameters("/subscriptions/{subscriptionId}/resourceGroups/{resourceGroupName}/providers/Microsoft.Network/vpnSites", pathParameters), autorest.WithQueryParameters(queryParameters)) return preparer.Prepare((&http.Request{}).WithContext(ctx)) } // ListByResourceGroupSender sends the ListByResourceGroup request. The method will close the // http.Response Body if it receives an error. func (client VpnSitesClient) ListByResourceGroupSender(req *http.Request) (*http.Response, error) { return autorest.SendWithSender(client, req, azure.DoRetryWithRegistration(client.Client)) } // ListByResourceGroupResponder handles the response to the ListByResourceGroup request. The method always // closes the http.Response Body. func (client VpnSitesClient) ListByResourceGroupResponder(resp *http.Response) (result ListVpnSitesResult, err error) { err = autorest.Respond( resp, client.ByInspecting(), azure.WithErrorUnlessStatusCode(http.StatusOK), autorest.ByUnmarshallingJSON(&result), autorest.ByClosing()) result.Response = autorest.Response{Response: resp} return } // listByResourceGroupNextResults retrieves the next set of results, if any. func (client VpnSitesClient) listByResourceGroupNextResults(ctx context.Context, lastResults ListVpnSitesResult) (result ListVpnSitesResult, err error) { req, err := lastResults.listVpnSitesResultPreparer(ctx) if err != nil { return result, autorest.NewErrorWithError(err, "network.VpnSitesClient", "listByResourceGroupNextResults", nil, "Failure preparing next results request") } if req == nil { return } resp, err := client.ListByResourceGroupSender(req) if err != nil { result.Response = autorest.Response{Response: resp} return result, autorest.NewErrorWithError(err, "network.VpnSitesClient", "listByResourceGroupNextResults", resp, "Failure sending next results request") } result, err = client.ListByResourceGroupResponder(resp) if err != nil { err = autorest.NewErrorWithError(err, "network.VpnSitesClient", "listByResourceGroupNextResults", resp, "Failure responding to next results request") } return } // ListByResourceGroupComplete enumerates all values, automatically crossing page boundaries as required. func (client VpnSitesClient) ListByResourceGroupComplete(ctx context.Context, resourceGroupName string) (result ListVpnSitesResultIterator, err error) { if tracing.IsEnabled() { ctx = tracing.StartSpan(ctx, fqdn+"/VpnSitesClient.ListByResourceGroup") defer func() { sc := -1 if result.Response().Response.Response != nil { sc = result.page.Response().Response.Response.StatusCode } tracing.EndSpan(ctx, sc, err) }() } result.page, err = client.ListByResourceGroup(ctx, resourceGroupName) return } // UpdateTags updates VpnSite tags. // Parameters: // resourceGroupName - the resource group name of the VpnSite. // vpnSiteName - the name of the VpnSite being updated. // vpnSiteParameters - parameters supplied to update VpnSite tags. func (client VpnSitesClient) UpdateTags(ctx context.Context, resourceGroupName string, vpnSiteName string, vpnSiteParameters TagsObject) (result VpnSitesUpdateTagsFuture, err error) { if tracing.IsEnabled() { ctx = tracing.StartSpan(ctx, fqdn+"/VpnSitesClient.UpdateTags") defer func() { sc := -1 if result.Response() != nil { sc = result.Response().StatusCode } tracing.EndSpan(ctx, sc, err) }() } req, err := client.UpdateTagsPreparer(ctx, resourceGroupName, vpnSiteName, vpnSiteParameters) if err != nil { err = autorest.NewErrorWithError(err, "network.VpnSitesClient", "UpdateTags", nil, "Failure preparing request") return } result, err = client.UpdateTagsSender(req) if err != nil { err = autorest.NewErrorWithError(err, "network.VpnSitesClient", "UpdateTags", result.Response(), "Failure sending request") return } return } // UpdateTagsPreparer prepares the UpdateTags request. func (client VpnSitesClient) UpdateTagsPreparer(ctx context.Context, resourceGroupName string, vpnSiteName string, vpnSiteParameters TagsObject) (*http.Request, error) { pathParameters := map[string]interface{}{ "resourceGroupName": autorest.Encode("path", resourceGroupName), "subscriptionId": autorest.Encode("path", client.SubscriptionID), "vpnSiteName": autorest.Encode("path", vpnSiteName), } const APIVersion = "2018-10-01" queryParameters := map[string]interface{}{ "api-version": APIVersion, } preparer := autorest.CreatePreparer( autorest.AsContentType("application/json; charset=utf-8"), autorest.AsPatch(), autorest.WithBaseURL(client.BaseURI), autorest.WithPathParameters("/subscriptions/{subscriptionId}/resourceGroups/{resourceGroupName}/providers/Microsoft.Network/vpnSites/{vpnSiteName}", pathParameters), autorest.WithJSON(vpnSiteParameters), autorest.WithQueryParameters(queryParameters)) return preparer.Prepare((&http.Request{}).WithContext(ctx)) } // UpdateTagsSender sends the UpdateTags request. The method will close the // http.Response Body if it receives an error. func (client VpnSitesClient) UpdateTagsSender(req *http.Request) (future VpnSitesUpdateTagsFuture, err error) { var resp *http.Response resp, err = autorest.SendWithSender(client, req, azure.DoRetryWithRegistration(client.Client)) if err != nil { return } future.Future, err = azure.NewFutureFromResponse(resp) return } // UpdateTagsResponder handles the response to the UpdateTags request. The method always // closes the http.Response Body. func (client VpnSitesClient) UpdateTagsResponder(resp *http.Response) (result VpnSite, err error) { err = autorest.Respond( resp, client.ByInspecting(), azure.WithErrorUnlessStatusCode(http.StatusOK, http.StatusCreated), autorest.ByUnmarshallingJSON(&result), autorest.ByClosing()) result.Response = autorest.Response{Response: resp} return }

Gordhan asks for fresh thinking Business News / 9 July 2012, 4:48pm SAPA Cape Town 141010 Finance Minister, Pravin Gordhan briefing parliment on the annal business report.South African Finance Minister Pravin Gordhan said on Thursday the world was heading towards a "currency war" unless developed nations gave ground in negotiations at the Group of 20 (G20). picture : neil baynes Gordhan told the 16th World Economic History Congress in Stellenbosch there was an imbalance between the locus of production and that of growth, and between political beliefs and the predominant reality. “The question is, is there an epochal transition, are we seeing a new configuration of political and social power?” Gordhan said history was essential to understanding society, but the challenge was to turn these insights into practice. “What we learnt from Karl Marx is that philosophers interpret the world. However the point is to change it.” When Gordhan became finance minister in 2009, much was made of his early affiliation to the SA Communist Party, but he said he was a no longer a member and had explored Marxism as a set of humanist values. - Sapa

Located in the Mohawk Valley of New York State just outside of Schenectady, Pathways Nursing and Rehabilitation Center is a Sentosa Care affiliated facility. Sentosa Care is an organization formed to service and assist affiliated nursing facilities in fulfilling their commitment to quality healthcare. The long-term FHA financing for Pathways carries a 30-year term at a low, fixed rate, and enables Sentosa Care to invest significant capital in upgrading the facility’s existing spaces and amenities, as well as construct a newly planned vent unit and upgrade the pediatric unit. “It’s especially gratifying to us at Greystone that we are able to provide capital to a facility like Pathways that provides care to difficult cases in their specialty units,” said Mr. Levine. “We truly value the trust Sentosa Care has in us to provide financing for their facilities and will continually work to exceed their expectations.”

Jabal Omar 'Jabal Omar (جبل عمر ) is a neighbourhood located in Makkah, Saudi Arabia south of the Al Haram district. Description Jabal Omar is named for the hill Mount Omar that traditionally stood on the southern outskirts of Mecca and currently consists of a group of old housing units that were built randomly over the years. There are currently no facilities in the Jabal Omar area, especially sanitation facilities. However, in late 2006, a clearance program was begun in Jabal Omar to provide the necessary space for the establishment of the Jabal Omar project. Jabal Omar is in the Sub Municipality of Ajyad (بلدية أجياد). References Category:Neighborhoods of Mecca

The Difference Between Botox and Dermal Fillers Written by CG Cosmetic on February 19, 2015 CG Cosmetic understands the difficulties that come with aging. Everyone has days where they look in the mirror and are concerned with what they see. Whether or not you see deep lines and wrinkles, or fine lines, aging is inevitable. The question then, is what can you do about these signs of aging? Perhaps the most common solution people have heard of is Botox. However, Botox is not the only option. While CG Cosmetic offers Botox procedures, we also offer Dermal Fillers. Botox Most men and women have heard about celebrities using Botox to rejuvenate their skin and appear more youthful, but Botox isn’t just for celebrities. Botox has provided amazing and effective results that are also safe and convenient for many individuals. Facial lines and wrinkles often occur because of the way your muscles work underneath your skin. Overtime, as muscles tense due to making repeated facial expressions, your skin creates lines and wrinkles. Botox works by gently relaxing the muscles in your face, softening the wrinkles and leaving you with long-lasting smooth skin. CG Cosmetic patients have described their Botox experience as quick and painless, with most appointments taking less than one hour. Call to set up an appointment with our expert Botox specialist, Dr. Mayra Diaz, who has been in private practice for over 25 years. Dermal Fillers CG Cosmetic also specializes in Dermal Fillers. Different from Botox, dermal fillers work by lifting and plumping up skin, replacing collagen lost by the natural aging process. In addition to gently filling the skin, most dermal fillers also stimulate skin to encourage it to produce more collagen on its own. Dermal fillers are a great way to fix lines and wrinkles in the face, but they are also used for lip augmentations, creating fuller, plumper lips. It is important to fully research all of your options for cosmetic surgery before making a decision about what is right for you. Start your research with a call to CG Cosmetic and talk to a specialist by scheduling a free consultation: 305-446-7277.

'use strict'; angular.module("ngLocale", [], ["$provide", function($provide) { var PLURAL_CATEGORY = {ZERO: "zero", ONE: "one", TWO: "two", FEW: "few", MANY: "many", OTHER: "other"}; function getDecimals(n) { n = n + ''; var i = n.indexOf('.'); return (i == -1) ? 0 : n.length - i - 1; } function getVF(n, opt_precision) { var v = opt_precision; if (undefined === v) { v = Math.min(getDecimals(n), 3); } var base = Math.pow(10, v); var f = ((n * base) | 0) % base; return {v: v, f: f}; } $provide.value("$locale", { "DATETIME_FORMATS": { "AMPMS": [ "Dinda", "Dilolo" ], "DAY": [ "Lumingu", "Nkodya", "Nd\u00e0ay\u00e0", "Ndang\u00f9", "Nj\u00f2wa", "Ng\u00f2vya", "Lubingu" ], "MONTH": [ "Ciongo", "L\u00f9ishi", "Lus\u00f2lo", "M\u00f9uy\u00e0", "Lum\u00f9ng\u00f9l\u00f9", "Lufuimi", "Kab\u00e0l\u00e0sh\u00ecp\u00f9", "L\u00f9sh\u00eck\u00e0", "Lutongolo", "Lung\u00f9di", "Kasw\u00e8k\u00e8s\u00e8", "Cisw\u00e0" ], "SHORTDAY": [ "Lum", "Nko", "Ndy", "Ndg", "Njw", "Ngv", "Lub" ], "SHORTMONTH": [ "Cio", "Lui", "Lus", "Muu", "Lum", "Luf", "Kab", "Lush", "Lut", "Lun", "Kas", "Cis" ], "fullDate": "EEEE d MMMM y", "longDate": "d MMMM y", "medium": "d MMM y HH:mm:ss", "mediumDate": "d MMM y", "mediumTime": "HH:mm:ss", "short": "d/M/y HH:mm", "shortDate": "d/M/y", "shortTime": "HH:mm" }, "NUMBER_FORMATS": { "CURRENCY_SYM": "FrCD", "DECIMAL_SEP": ",", "GROUP_SEP": ".", "PATTERNS": [ { "gSize": 3, "lgSize": 3, "maxFrac": 3, "minFrac": 0, "minInt": 1, "negPre": "-", "negSuf": "", "posPre": "", "posSuf": "" }, { "gSize": 3, "lgSize": 3, "maxFrac": 2, "minFrac": 2, "minInt": 1, "negPre": "-", "negSuf": "\u00a4", "posPre": "", "posSuf": "\u00a4" } ] }, "id": "lu-cd", "pluralCat": function (n, opt_precision) { var i = n | 0; var vf = getVF(n, opt_precision); if (i == 1 && vf.v == 0) { return PLURAL_CATEGORY.ONE; } return PLURAL_CATEGORY.OTHER;} }); }]);

Dominik Brunner - Nordketten Check out from go-shred.com on Vimeo. Home is where your heart is! Our heart, our office and our home is Innsbruck right now. One of the most amazing cities in the world! Probably the only SPOT where you can get to the slopes in less then 15 minutes. Certainly you ask Sadly this year K.O.T. Gruam was boycotted by bad weather, misunderstanding and lack of snow. But still some warriors showed up for chilling and grilling under the Dragon tent (thank you Dragon so much for keeping us dry). Near the bonfire amazing stories were told about the past weeks here in Nor

Q: extjs data reader reading data from nested object of an xml reponse I have xml file with following structure <root> <o1> <p1></p1> <p2></p2> <p3></p3> <o2> <p1></p1> <o3> <p2></p2> <p3></p3> </o3> <o2> </o1> </root> I want the model to be loaded only with the p1 p2 and p3 for o1. But the model gets populated with the values inside o2 and o3 instead. In the reader that I have configured, the root is 'root' and record is o1. I even tried setting the implicitIncludes property of the reader to false. Please help. A: I think this is because of the Ext.DomQuery.selectNode() method that is used in the conversion function of the model which probably starts parsing from the innermost node and returns the first occurence... I solved this by overriding the getResponseData() method of the reader. In the overridden method, I removed the inner node of the xml response document i.e. the o2 node and then passed on the document to the readRecords() method as the natural flow is. Though kind of a workaround but it is fine for me as the inner node is not needed my case.

Q: Download OS X App Store updates to update multiple Macs I have two MacBook Airs, but I have very limited bandwidth. I would prefer to download updates once and then copy them onto all the other MacBook Airs. How can I download App Store updates once to update multiple Macs? A: There are two types of update. OS X software updates are updates for the OS and OS components (e.g. iTunes). These used to be delivered through a separate software update app, but since the introduction of the Mac App Store, the OS X updates have been combined with Mac App Store updates in the Updates tab of the Mac App Store. However, the CLI tool remains, giving you more flexibility in Terminal and allow the downloading of updates without installing them, perfect for copying to other machines before the installation takes place. You can download OS X updates without installing them (which would automatically remove them) so you can copy them, using the following command: softwareupdate -dav The 10.9.4 update is distributed externally, outside of the Mac App Store; the Mac App Store just provides the UI for the installation process. Conversely, for Mac App Store apps, you need OS X Server's Caching service, as the apps are 'non-transferrable' and the app receipt must match the Apple ID that downloaded the app for the app to be updated in the future. However, if you're using the same Apple ID, or don't care about updating the app from the second machine, update the app normally then copy the .app bundle from /Applications to the other Macs as necessary.

Q: MySQL replication: "Houston, We've Got a Problem" I ran into a problem with our replication server. Essentially, we have 2 databases (database1 and database2). Master server has both. Slave has only database1. There is a Replicate_Do_DB: database1 set in CHANGE MASTER TO configuration. Now what happened is - we are using code igniter, and one of the programers created database2 and started inserting info into it. Code igniter sets a default database to database1. Now the result is for every query he produced - I get an error on SHOW SLAVE STATUS\G: Error 'Table 'database2.tbl40' doesn't exist' on query. Default database: 'database1'. Query: 'INSERT INTO `database2`.`tbl40` (`date`, `day`) VALUES ('2011-04-26', '2011-04-26')' So essentially, I he fixed the problem afterwards, but the replication doesn't work as there is around 1000 queries that will produce that error for replication server. My question is - is there some way to clear queries like that from the binlog? Or I need to write a script that will do a SET GLOBAL SQL_SLAVE_SKIP_COUNTER = 1; for every query that produces and error ? A: If you really don't care about that table, you can use pt-slave-restart on the slave and have it skip those problems. I would be conservative about running it and make sure that you are only skipping queries for the table/database that you don't care about or at least for only a specific error. You didn't post what the error code was in the output from SHOW SLAVE STATUS, but I suspect it is error 1146. For example, this will skip all errors for 1146: pt-slave-restart -u root -p pass --error-numbers 1146 Or, you could try skipping all errors that reference that table pt-slave-restart -u root -p pass --error-text 'database2' Another way to do this would be to set replicate-ignore-db=database2 and restart MySQL on the slave, but there are some caveats to how that works that you should read about in the documentation A: I think the bigger problem here is your default database context was database1. Thats's why your slave tried to execute the update on database2 since it was specified in database2.table format. Basically it's not safe to user db.table syntax with wildcards or you find yourself in the situation you did. If you're wanting to use the wildcard do or ignores it's generally safer to always specify your default db using "use" and execute the query in that context.

The VC-2 video compression standard is an open free-use video-decoding standard contributed by British Broadcasting Corporation (BBC) to the Society of Motion Picture and Television Engineers (SMPTE) standard. The VC-2 standard uses discrete-wavelet-transform (DWT) and interleaved exponential-Golomb (IEG) variable-length-encoding to achieve the desired video compression. Originally designed to compete with the prevailing H.264 standard, it is expected that DWT results in fewer blocky artifacts than the prevailing discrete-cosine-transform (DCT)-based systems. To achieve the low-delay requirement in a serial data interface (SDI) transmission system, SMPTE standardized two low-delay profiles, which include the level-64 using the (2, 2) DWT, and the level-65, using the overlapped (5, 3) DWT. It has been shown that in order to fit a high definition (HD) video into a standard definition SDI (SD-SDI) payload with excellent video quality, the level-65 compression is required. The VC-2 level-65 is a subset of the low-delay profile with the following attributes: 1. 4:2:2 10-bit sampling with supported resolutions 1920×1080i29.97, 1920×1080i25, 1280×720p59.94, 1280×720p50. 2. The codec uses only Low-Delay Profile. 3. The codec uses only the LeGall (5, 3) wavelet transform (wavelet index=1). 4. The wavelet depth is exactly 3 levels. 5. The slice size is fixed to be 16 (horizontal)×8 (vertical) in luminance and 8 (horizontal)×8 (vertical) in chrominance. Conventionally, overlapped DWT is used in the JPEG-2000 standard which is used extensively in digital cameras and medical imaging systems. In the literature, there are many publications on how to reduce the implementation complexity of 2-D DWT. A common property of this technology is that JPEG-2000 based implementation uses an external frame-buffer memory for processing the on-chip DWT/IDWT data. Thus, such publications have primarily focused on how to: minimize the read and write access to the external memory; reduce the on-chip internal memory; speed up data processing; and choose a scan scheme to minimize the memory usage. However, an external memory typically increases costs associated with the chip package size and power consumption, as well as the overall system complexity and bill-of-material (BOM) costs.

Executive and Special Sessions Thursday July, 26 2018 Executive and Special Sessions Thursday July, 26 2018 The Devils Lake Water Improvement District Board will be holding an Executive Session immediately followed by a Special Session (per ORS 192.640) at 10:00 a.m., Thursday July 26, 2018. This meeting will be held at Oregon Coast Community College Room 108, located at 3788 SE High School Dr. in Lincoln City, Oregon. The purpose of this meeting is to discuss and finalize the contract for installation of the lake bottom aeration system All whom are interested are encouraged to attend this public meeting. Devils Lake in Lincoln City, Oregon is a naturally shallow, coastal lake. It is uniquely placed in the world sitting on the Pacific coast edge of the North American Continent, intersecting the 45th parallel, the mark half way between the equator and the North Pole. Devils Lake is managed by the Devils Lake Water Improvement District.

Q: Social buttons and changing attributes using EmberJS I'm trying to have two social buttons (facebook & twitter) on my website using EmberJS. I'm binding the URL of those buttons to an attribute url (for example). The problem is that the attribute url is changing, and the buttons are not reloading. I did a spin-off of this article on the EmberJS: http://emberjs.com/guides/cookbook/helpers_and_components/creating_reusable_social_share_buttons/ Updated to the last EmberJS version (1.3.1), and added a "change text" button. Try changing the text for the text button, and you'll see that the button is not reloading. Link to the jsbin: http://emberjs.jsbin.com/izOtIYi/1/edit (watch the console too) I think it's because Twitter is messing with the Metamorph system. How can I bypass this? I'm sure someone faced this before. The strangest thing is that it's working well with facebook like button. Thanks ! A: The issue is that when you load the twitter widget it parses the <a> and then replaces it with an <iframe>. So even when you update the text property it doesnt reload the button. One way to work around it would be to rerender the view when the text changes this would cause the iframe to be removed and a new a tag to be added. I fixed up the jsbin to update the button when the text changes http://emberjs.jsbin.com/izOtIYi/8/edit I got put the logic which rerenders the button into the component to make it more reusable. The button will flash whenever the text is changed because its actually removing the existing button and creating a new button each time the text changes.

package com.android.inputmethodcommon; class InputMethodSettingsInterface { } class InputMethodSettingsImpl { int mContext; int mImi; int mImm; int mSubtypeEnablerIcon; int mSubtypeEnablerIconRes; int mSubtypeEnablerTitle; int mSubtypeEnablerTitleRes; int mInputMethodSettingsCategoryTitle; int mInputMethodSettingsCategoryTitleRes; int mSubtypeEnablerPreference; } class InputMethodSettingsFragment { int mSettings; } class InputMethodSettingsActivity { int mSettings; }

<?xml version="1.0" encoding="utf-8"?> <LinearLayout xmlns:android="http://schemas.android.com/apk/res/android" android:layout_width="match_parent" android:layout_height="match_parent" android:background="@color/appBackground" android:foreground="?android:attr/selectableItemBackground" android:gravity="center_vertical" android:orientation="horizontal" android:paddingBottom="15dp" android:paddingLeft="10dp" android:paddingRight="10dp" android:paddingTop="15dp"> <ImageView android:id="@+id/song_item_img" android:layout_width="50dp" android:layout_height="50dp" android:layout_weight="0" /> <LinearLayout android:layout_width="match_parent" android:layout_height="wrap_content" android:layout_marginStart="15dp" android:layout_weight="1" android:orientation="vertical"> <TextView android:id="@+id/song_item_name" android:layout_width="wrap_content" android:layout_height="wrap_content" android:singleLine="true" android:textColor="#000" android:textSize="16sp" /> <TextView android:id="@+id/song_item_artist" android:layout_width="wrap_content" android:layout_height="wrap_content" android:singleLine="true" android:textColor="#989898" android:textSize="14sp" /> </LinearLayout> <ImageView android:id="@+id/song_item_menu" android:layout_width="wrap_content" android:layout_height="wrap_content" android:layout_marginRight="5dp" android:layout_weight="0" android:background="@drawable/unbounded_ripple" android:foregroundTint="#434343" android:padding="5dp" android:src="@drawable/abc_ic_menu_moreoverflow_mtrl_alpha" android:theme="@style/Theme.AppCompat.Light" /> </LinearLayout>

Q: Is there a way to get a list of the currently addedtostage events in JavaScript without jQuery? I am wondering if there is a way to get a list of the currently addedtostage events in JavaScript without jQuery? I want to know this because I want to remove these events later. I looked around on stackoverflow but I couldn't find an answer without jQuery. I tried: Event.observers.each(function(item) { if(item[0] == element) { console.log(item[2]) } }); I also looked at List all javascript events wired up on a page using jquery Thanks A: as far as I know since eventListenerList haven't been included in DOM 3 there is still no way to actually do it natively in js. if it's just for debuging you can use tool such as visual event (http://www.sprymedia.co.uk/article/Visual+Event ) which know how majors libs suscribe events and how to read in it.

Q: Is it necessary to install Yoast for a website which is installed inside an existing WordPress installation folder? I am setting up a new website inside an already installed WordPress website folder (e.g., www.example.com/newsite/). I am using the Yoast SEO plugin for my old website (www.example.com). Is it necessary to install the Yoast SEO plugin for /newsite again, and go through Google Authorization Code and Search Console too? A: If you are setting up a separate WordPress site (meaning no multisite) and you want to use Yoast SEO then, yes, you will have to install the plugin again. The new site has no way of using the existing copy in your old site. You also have to register it as a separate entity for Google. I am not sure what your plan is but I would not recommend hosting a new site in a folder inside an existing domain. If you want it to rank properly, it should have its own domain. Aside from that, I would also place both sites in separate folders alongside one another instead of nesting one inside the other.

Olefin cyclopropanation via carbene transfer catalyzed by engineered cytochrome P450 enzymes. Transition metal-catalyzed transfers of carbenes, nitrenes, and oxenes are powerful methods for functionalizing C=C and C-H bonds. Nature has evolved a diverse toolbox for oxene transfers, as exemplified by the myriad monooxygenation reactions catalyzed by cytochrome P450 enzymes. The isoelectronic carbene transfer to olefins, a widely used C-C bond-forming reaction in organic synthesis, has no biological counterpart. Here we report engineered variants of cytochrome P450(BM3) that catalyze highly diastereo- and enantioselective cyclopropanation of styrenes from diazoester reagents via putative carbene transfer. This work highlights the capacity to adapt existing enzymes for the catalysis of synthetically important reactions not previously observed in nature.

Maroš Ferenc Maroš Ferenc (born 19 February 1981, in Prešov) is a Slovak football goalkeeper who currently plays for 1. FC Tatran Prešov. References Category:1981 births Category:Living people Category:Slovak footballers Category:Association football goalkeepers Category:1. FC Tatran Prešov players Category:AS Trenčín players Category:MEAP Nisou players Category:MFK Zemplín Michalovce players Category:FC Eindhoven players Category:Slovak Super Liga players Category:Sportspeople from Prešov

Introduction {#sec1} ============ Acute aortic dissection (AAD) is a relatively uncommon medical emergency with a high mortality after symptom onset. The mortality of acute type A aortic dissection increases by 1--2% per hour during the first 48 h if no treatment is received \[[@cit0001]\]. Meanwhile, other common causes of acute chest pain, such as acute myocardial infarction (AMI) and pulmonary embolism (PE), also require rapid differentiation from AAD due to their critical and lethal characteristics \[[@cit0002]\]. However, the misdiagnosis rate of AAD has been reported to be approximately 30% on initial evaluation \[[@cit0003], [@cit0004]\]. Currently, noninvasive imaging modalities, including enhanced computed tomography (CT), transesophageal echocardiography (TEE) and magnetic resonance imaging (MRI), have been developed to improve the diagnosis of AAD, but these imaging modalities are expensive, time-consuming and unavailable at the bedside. Therefore, a rapid, cheap, reliable and sensitive laboratory test is urgently needed to diagnose AAD. D-dimer, the degradation product of cross linked fibrin, is significantly elevated in AAD patients \[[@cit0005]--[@cit0008]\] and has been suggested for use as a complementary marker to rule out AAD \[[@cit0005]--[@cit0007], [@cit0009]--[@cit0011]\]. However, in real-world clinical practice, AAD, PE and AMI are all thrombogenic diseases with high mortality, and whether the D-dimer level is helpful for differentiating these diseases remains to be elucidated. We therefore conducted a prospective cohort study to evaluate the validity and reliability of D-dimer level for differentiating AAD from other types of acute chest pain, including PE, AMI, unstable angina (UA), and other uncertain diagnoses of chest pain. Material and methods {#sec2} ==================== Study population {#sec2.1} ---------------- A single-center, prospective cohort study was conducted in Fuwai Hospital (the National Center for Cardiovascular Diseases in China) from January 2009 to January 2010. A series of consecutive patients with acute chest pain who presented to the emergency department (ED) of Fuwai Hospital within 24 h of symptom onset were enrolled in a prospective manner. Baseline clinical characteristics such as sex, age, Stanford types of AAD, intervals from onset of symptoms to hospital admission, medical histories, baseline parameters of physical examinations and laboratory tests including C-reactive protein (CRP), imaging examinations, in-hospital managements, ED diagnosis and discharge diagnosis were recorded according to pre-designed case report forms. The study protocols were approved by the appropriate institutional review boards of Fuwai Hospital and complied with the Declaration of Helsinki. All subjects provided written informed consent. D-dimer test and diagnosis {#sec2.2} -------------------------- Plasma D-dimer levels were measured using a stago-evolution device (France) in patients with chest pain immediately following admission. The results collected are expressed in micrograms per milliliter. The effective detection range of the assay is 0.22--20 µg/ml. Diagnoses of AAD and PE were confirmed by aorta or pulmonary angiography with multi-detector CT scan. Acute myocardial infarction was confirmed by acute chest pain, elevated cardiac-enzyme levels (cardiac troponin I or T, or the MB fraction of creatine kinase exceeded the 99^th^ percentile upper reference limit), documented findings of a new ST segment elevation/depression or a new T wave inversion on electrocardiography, and/or with evidence of obstructive coronary artery on angiography. Unstable angina was confirmed by chest pain, ST segment depression or T wave changes with evidence of obstructive coronary artery on angiography, but without the elevation of cardiac enzymes. Statistical analysis {#sec2.3} -------------------- Continuous variables are presented as mean ± SD or median and interquartile range according to whether they follow Gaussian distributions. Categorical data are presented as numbers and proportions. Baseline characteristics between groups were compared using Student's *t* test or the nonparametric Mann-Whitney test for continuous data and the χ^2^ test for categorical data. Receiver-operating characteristic (ROC) curves were constructed to calculate the sensitivity for AAD. The area under the curve (AUC) was calculated. A *p-*value \< 0.05 was considered statistically significant. The statistical calculations were performed with SPSS 19.0 (SPSS Inc., Chicago, Illinois, USA). Results {#sec3} ======= A total of 790 patients were enrolled, including 202 AAD, 43 PE, 315 AMI, 136 UA, and 94 cases with other uncertain diagnoses. Of the 202 AAD patients confirmed by CT angiography, 119 (58.9%) were Stanford type A AAD cases and 83 (41.0%) were Stanford type B AAD cases. Patient demographics and baseline characteristics are shown in [Table I](#t0001){ref-type="table"}. Compared to the patients with other causes of chest pain, AAD patients were more likely to be younger and male and tended to have concomitant hypertension but rarely have diabetes mellitus (all *p* \< 0.001). ###### Baseline characteristics of AAD patients and non-AAD (PE, UA, AMI, and uncertain diagnosis) Parameter AAD (*n* = 202) Non-AAD *P*-value ------------------------------------ ----------------- ----------- ------------ ------------ ----------- ---------- Age \[years\] 51 ±12 55 ±17 61 ±12 60 ±12 54 ±17 \< 0.001 Male, *n* (%) 169 (83.7) 21 (48.8) 102 (75.0) 254 (80.6) 65 (69.1) \< 0.001 Systolic blood pressure \[mm Hg\] 141 ±31 129 ±21 138 ±23 128 ±23 133 ±23 \< 0.001 Diastolic blood pressure \[mm Hg\] 80 ±21 81 ±10 87 ±57 79 ±14 81 ±14 0.535 Heart rate \[beats per minute\] 81 ±19 87 ±17 72 ±13 76 ±18 80 ±28 \< 0.001 Body mass index \[kg/m^2^\] 24.6 ±3.2 25.7 ±3.7 26.7 ±4.2 25.5 ±3.4 26.2 ±4.9 0.450 Creatinine kinases \[U/l\] 269 ±544 85 ±61 97 ±84 497 ±688 109 ±105 \< 0.001 Fasting blood glucose \[mmol/l\] 7.5 ±1.9 6.3 ±1.6 7.4 ±3.1 8.4 ±3.4 7.1 ±2.7 \< 0.001 Hypertension, *n* (%) 133 (65.8) 13 (31.0) 86 (63.2) 161 (51.3) 42 (46.2) \< 0.001 Diabetes mellitus, *n* (%) 5 (2.5) 2 (4.8) 31 (22.8) 68 (21.7) 13 (14.3) \< 0.001 Hypercholesterolemia, *n* (%) 18 (8.9) 3 (7.1) 34 (25.0) 75 (24.0) 13 (14.3) \< 0.001 Stroke, *n* (%) 10 (5.0) 2 (4.8) 13 (9.6) 33 (10.5) 7 (7.7) 0.471 Smoker, n (%) 64 (31.7) 7 (16.7) 31 (22.8) 105 (33.5) 18 (19.8) 0.060 Drinker, *n* (%) 21 (10.4) 0 (0.0) 6 (4.4) 14 (4.5) 6 (6.6) 0.110 AAD -- acute aortic dissection, PE -- pulmonary embolism, UA -- unstable angina, AMI -- acute myocardial infarction. The D-dimer level was elevated (\> 0.50 µg/ml) in 190 (94.1%) AAD patients. The D-dimer level in AAD patients was approximately 9-fold higher than that in non-AAD patients (median: 4.19 vs. 0.45 µg/ml, *p* \< 0.05). [Figure 1](#f0001){ref-type="fig"} shows the D-dimer level in patients with different causes of chest pain. The D-dimer level was significantly higher in patients with AAD than in patients with UA (median: 0.38 µg/ml, *p* \< 0.001), AMI (median: 0.45 µg/ml, *p* \< 0.001) and other uncertain diagnoses (median: 0.44 µg/ml, *p* \< 0.001), but it was comparable with that of PE patients (median: 2.72 µg/ml, *p* = 0.065). Similarly, the D-dimer level in PE patients was significantly higher than that in patients with UA, AMI, or other uncertain diagnoses (all *p* \< 0.001). Moreover, patients with type A AAD had higher D-dimer levels than those with type B AAD (median: 4.64 vs. 4.0 µg/ml, *p* = 0.022). {#f0001} [Figure 2](#f0002){ref-type="fig"} shows the ROC for patients with AAD versus non-AAD patients. The AUC value was 0.90 (95% CI: 0.87--0.93) for patients with AAD vs. all non-AAD patients. The AUC value was 0.59 (95% CI: 0.5--0.68) vs. PE, 0.91 (95% CI: 0.88--0.94) vs. AMI, 0.95 (95% CI: 0.93--0.97) vs. UA, and 0.93 (95% CI: 0.91--0.96) vs. patients with other uncertain diagnoses. Moreover, the best cut-off value of D-dimer for predicting PE was 1.14 µg/ml by ROC analysis with an AUC of 0.79 (95% CI: 0.74--0.84). The sensitivity and specificity were 88.4% and 71.2%, respectively. {#f0002} The diagnostic performance at the cutoff level of 0.5 µg/ml was analyzed. At this cutoff level, the sensitivity was 94.0% and the specificity was 56.8% for AAD compared to non-AAD patients; the negative and positive likelihood ratio were 0.10 and 2.18, respectively with a positive predictive value of 42.6% and a negative predictive value of 96.6%. The specificity was 4% for PE, 56% for AMI, 72.9% for UA, and 65.1% for uncertain diagnostic cases ([Table II](#t0002){ref-type="table"}). ###### Diagnostic performance of D-dimer at the cutoff level of 0.5 µg/ml Variable Sensitivity (%) Specificity (%) Youden's index PPV (%) NPV (%) PLR NLR ----------- ----------------- ----------------- ---------------- --------- --------- ------ ------ AAD 94.0 Non-AAD: 56.8 0.51 42.6 96.6 2.18 0.10  PE 4.0 --0.02 81.1 14.2 0.97 1.25  AMI 56.0 0.49 57.5 93.5 2.11 0.12  UA 72.9 0.67 83.7 89.2 3.48 0.08 Uncertain 65.1 0.56 86.3 83.3 1.44 0.09 PLR -- positive likelihood ratio, NLR -- negative likelihood ratio, PPV -- positive predictive value, NPV -- negative predictive value, AAD -- acute aortic dissection, PE -- pulmonary embolism, UA -- unstable angina, AMI -- acute myocardial infarction. Discussion {#sec4} ========== The present study demonstrated a significantly higher admission D-dimer level in patients with AAD within 24 h after symptom onset than those with AMI, UA, and other uncertain diagnoses. At the widely used cutoff level of 0.5 µg/ml, a favorable negative likelihood ratio of 0.10 and negative predictive value of 96.6% were found in patients with AAD. However, the D-dimer level was not significantly different between patients with AAD and PE. Our study suggests that a plasma D-dimer test within 24 h of symptom onset may be helpful for differentiating AAD and PE from other causes of acute chest pain. Acute aortic dissection is a catastrophic medical emergency, which requires early and accurate diagnosis and treatment. Imaging modalities, including enhanced CT and MRI, can facilitate an accurate diagnosis. However, these methods are limited due to unavailability at the bedside and their time-consuming nature, and they are not cost effective for routine screening. Thus, a rapid and reliable biomarker is urgently needed. Previous studies have evaluated several biomarkers for AAD, such as the smooth muscle myosin heavy chain \[[@cit0012]--[@cit0014]\], the BB-isozyme of creatine kinase \[[@cit0015]\], and calponin \[[@cit0016]\]. However, none of these markers have been adopted into routine clinical practice due to their inability to meet the requirements of a 'gold standard' biomarker including having adequate sensitivity and specificity in addition to a favorable time course of release that covers a time window necessary for nonambiguity in the clinical setting \[[@cit0017]\]. D-dimer is a fibrin fragment seen in coagulopathic disorders, and measurements are routinely used for the exclusion of venous thromboembolic diseases and PE \[[@cit0018]--[@cit0020]\]. In recent years, multiple studies have confirmed that D-dimer is elevated in AAD, and several studies have assessed its diagnostic value for AAD. However, at a defined cutoff value, the sensitivity and specificity of D-dimer for the diagnosis of AAD have been reported to vary, possibly due to different assay methods used in different studies. Generally, when a cutoff value of 0.5 µg/ml is used, the sensitivity and negative predictive value can reach almost 100% with a specificity of 54--68.6% \[[@cit0005], [@cit0009]\], and the specificity can be increased to 73% when the cutoff value is 0.626 µg/ml \[[@cit0006]\]. Shimony *et al.* \[[@cit0021]\] recently performed a meta-analysis of D-dimer to diagnose AAD and found that at a cutoff value of 0.5 µg/ml, the sensitivity and negative predictive value were 0.97 and 0.96, respectively. However, the specificity and positive predictive value were low, 0.56 and 0.60, respectively. Moreover, the negative likelihood ratio showed an excellent discriminative ability (0.06), whereas the positive likelihood ratio did not (2.43). They concluded that a plasma D-dimer level \< 0.5 µg/ml was a useful screening tool to identify patients who do not have AAD. Therefore, the plasma D-dimer level may thus be used to identify subjects who are unlikely to benefit from further aortic imaging. Our results were consistent with this study, suggesting that the cutoff value of D-dimer \< 0.5 µg/ml, which is widely used for excluding PE \[[@cit0022]\], is also applicable for the exclusion of AAD. However, the D-dimer level in patients with AAD is not always elevated, and several studies \[[@cit0023], [@cit0024]\], including ours, have observed this phenomenon. Hazui *et al.* \[[@cit0025]\] proposed that younger patients with a short dissection length and a thrombosed false lumen without ulcer-like projections may have false-negative D-dimer results. Therefore, patients who present classic characteristics of AAD but have a negative D-dimer test should receive further aortic imaging. Due to its non-specific characteristics, an elevated D-dimer level is also seen in patients with other morbidities such as PE, AMI, UA, and other diseases. Therefore, further investigation is necessary to clarify whether D-dimer tests can differentiate AAD from other diseases that presented with elevated D-dimer levels. Suzuki *et al.* \[[@cit0026]\] reported that when the cutoff level was 1.6 µg/ml, D-dimer was a useful tool for differentiating AAD from AMI, angina or other ischemic heart diseases within the first 6 h, and when the cutoff value was 0.8 or 0.9 µg/ml, the D-dimer level could differentiate AAD from AMI \[[@cit0027]\]. Sakamoto *et al.* \[[@cit0028]\] also found that a cutoff value of 0.5 µg/ml was effective for distinguishing AAD and PE from AMI, with a sensitivity of 68% and a specificity of 90%. Although their results were mostly consistent with ours, the cutoff values used in these studies were different and the obtained D-dimer levels in various causes of acute chest pain varied greatly. One possible explanation for this variation was the different measurement equipment and the test strip used. Therefore, a standard and unified detection protocol may improve the heterogeneity of measurement, making the detection value more reliable. Additionally, the D-dimer level was elevated in both AAD and PE patients, with no significant difference in our study, consistent with the findings of Sakamoto *et al.* \[[@cit0028]\] and Eggebrecht *et al.* \[[@cit0006]\]. Given the high mortality of the two morbidities, immediate contrast CT imaging or tissue Doppler imaging \[[@cit0029]\] may be good choices to differentiate AAD from PE. In the setting of AMI/UA, rupture of atherosclerotic plaques causes thrombopoiesis and activates fibrin degradation, leading to D-dimer formation. Therefore, D-dimer is elevated in patients with AMI/UA but not in patients with stable angina and healthy controls \[[@cit0030], [@cit0031]\]. Although the D-dimer level does not directly reflect the degree of myocardial damage, it has been confirmed that an elevated D-dimer level is a strong predictor of mortality in patients with AMI/UA \[[@cit0032], [@cit0033]\]. Therefore, the D-dimer level is not only a useful tool for the differentiation of diagnoses, but it also plays an important role in the prognostic evaluation for some cardiovascular diseases. Some limitations of the present study need to be addressed. First, although our study shows good prediction for AAD with the D-dimer level at the cutoff of 0.5 µg/ml, the specificity is low (56.8%). Indeed, D-dimer as a diagnostic biomarker of AAD did have some limitations due to the relatively high false positive rate. Therefore, for patients with a D-dimer level \> 0.5 µg/ml, the D-dimer level should be combined with other diagnostic tests, especially imaging tests, for an accurate diagnosis of AAD. Second, the small sample size of PE patients may affect the statistical power. Furthermore, the difference in D-dimer levels was not evaluated between patients with ST-segment elevation AMI and non-ST-segment elevation AMI. Therefore, further large, prospective, multi-center studies are needed. In conclusion, the D-dimer level within 24 h after symptom onset might be helpful for differentiating patients with suspected AAD from other causes of chest pain. The first two authors contributed equally to this study. We wish to thank the patients for their participations in our study, and we are also grateful to other clinical doctors and nurses for their help in the study. This work was supported by a grant (81170286) from the National Natural Science Foundation of China to Dr. Fan Xiaohan. Conflict of interest ==================== The authors declare no conflict of interest.

--- abstract: 'In state space models, smoothing refers to the task of estimating a latent stochastic process given noisy measurements related to the process. We propose an unbiased estimator of smoothing expectations. The lack-of-bias property has methodological benefits: independent estimators can be generated in parallel, and confidence intervals can be constructed from the central limit theorem to quantify the approximation error. To design unbiased estimators, we combine a generic debiasing technique for Markov chains with a Markov chain Monte Carlo algorithm for smoothing. The resulting procedure is widely applicable and we show in numerical experiments that the removal of the bias comes at a manageable increase in variance. We establish the validity of the proposed estimators under mild assumptions. Numerical experiments are provided on toy models, including a setting of highly-informative observations, and a realistic Lotka-Volterra model with an intractable transition density.' author: - | Pierre E. Jacob[^1]\ Department of Statistics, Harvard University\ Fredrik Lindsten and Thomas B. Schön\ Department of Information Technology, Uppsala University bibliography: - 'Biblio.bib' title: '**Smoothing with Couplings of Conditional Particle Filters**' --- \#1 [*Keywords:*]{} couplings, particle filtering, particle smoothing, debiasing techniques, parallel computation. Introduction\[sec:introduction\] ================================ Goal and content ---------------- In state space models, the observations are treated as noisy measurements related to an underlying latent stochastic process. The problem of smoothing refers to the estimation of trajectories of the underlying process given the observations [@cappe:ryden:2004]. For finite state spaces and linear Gaussian models, smoothing can be performed exactly. In general models, numerical approximations are required, and many state-of-the-art methods are based on particle methods [@douc:moulines:2014; @kantas2015particle]. Following this line of work, we propose a new method for smoothing in general state space models. Unlike existing methods, the proposed estimators are unbiased, which has direct benefits for parallelization and for the construction of confidence intervals. The proposed method combines recently proposed conditional particle filters [@andrieu:doucet:holenstein:2010] with debiasing techniques for Markov chains [@glynn2014exact]. Specifically, we show in Section \[sec:unbiasedsmoothing\] how to remove the bias of estimators constructed with conditional particle filters, in exchange for an increase of variance; this variance can then be controlled with tuning parameters, and arbitrarily reduced by averaging over independent replicates. The validity of the proposed approach relies on the finiteness of the computational cost and of the variance of the proposed estimators, which we establish under mild conditions in Section \[sec:newsmoother:theory\]. Methodological improvements are presented in Section \[sec:newsmoother:practical\], and comparisons with other smoothers in Section \[sec:comparison\]. Numerical experiments are provided in Section \[sec:numerics\], and Section \[sec:discussion\] concludes. Smoothing in state space models \[sec:intro:smoothing\] ------------------------------------------------------- The latent stochastic process $(x_{t})_{t\geq 0}$ takes values in $\mathbb{X}\subset \mathbb{R}^{d_x}$, and the observations $(y_t)_{t\geq 1}$ are in $\mathbb{Y}\subset \mathbb{R}^{d_y}$ for some $d_x,d_y \in\mathbb{N}$. A model specifies an initial distribution $m_0(dx_{0}|\theta)$ and a transition kernel $f(dx_{t}| x_{t-1},\theta)$ for the latent process. We will assume that we have access to deterministic functions $M$ and $F$, and random variables $U_t$ for $t\geq 0$, such that $M(U_0,\theta)$ follows $m_0(dx_0|\theta)$ and $F(x_{t-1},U_t,\theta)$ follows $f(dx_t|x_{t-1},\theta)$; we refer to these as random function representations of the process [see @diaconis1999iterated]. Conditionally upon the latent process, the observations are independent and their distribution is given by a measurement kernel $g(dy_{t}| x_{t},\theta)$. The model is parameterized by $\theta\in\Theta\subset \mathbb{R}^{d_\theta}$, for $d_\theta\in\mathbb{N}$. Filtering consists in approximating the distribution $p(dx_{t}| y_{1:t},\theta)$ for all times $t\geq 1$, whereas smoothing refers to the approximation of $p(dx_{0:T}|y_{1:T},\theta)$ for a fixed time horizon $T$, where for $s,t\in\mathbb{N}$, we write $s:t$ for the set $\{s,\ldots,t\}$, and $v_{s:t}$ for the vector $(v_s,\ldots,v_t)$. The parameter $\theta$ is hereafter fixed and removed from the notation, as is usually done in the smoothing literature [see Section 4 in @kantas2015particle]; we discuss unknown parameters in Section \[sec:discussion\]. Denote by $h$ a test function from $\mathbb{X}^{T+1}$ to $\mathbb{R}$, of which we want to compute the expectation with respect to the smoothing distribution $\pi(dx_{0:T})=p(dx_{0:T}|y_{1:T})$; we write $\pi(h)$ for $\int_{\mathbb{X}^{T+1}} h(x_{0:T}) \pi(dx_{0:T})$. For instance, with $h:x_{0:T}\mapsto x_t$ where $t\in 0:T$, $\pi(h)$ is the smoothing expectation $\mathbb{E}[x_t|y_{1:T}]$. Postponing a discussion on existing smoothing methods to Section \[sec:comparison\], we first describe the conditional particle filter [CPF, @andrieu:doucet:holenstein:2010], which is a variant of the particle filter [@doucet:defreitas:gordon:2001]. Given a “reference” trajectory $X = x_{0:T}$, a CPF generates a new trajectory $X^\prime = x_{0:T}^\prime$ as described in Algorithm \[alg:conditional-particle-filter\], which defines a Markov kernel on the space of trajectories; we will write $x^\prime_{0:T} \sim \text{CPF}(x_{0:T},\cdot)$. This Markov kernel leaves $\pi$ invariant and ergodic averages of the resulting chains consistently estimate integrals with respect to $\pi$, under mild conditions [@andrieu:doucet:holenstein:2010; @ChopinS:2015; @LindstenDM:2015; @andrieuvihola2013uniform; @kuhlenschmidt2018stability; @Lee2018ccbpf]. We denote by $(X^{(n)})_{n\geq 0}$ a chain starting from a path $X^{(0)}$, and iterating through $X^{(n)}\sim\text{CPF}(X^{(n-1)},\cdot)$ for $n\geq 1$. 1. 2. <!-- --> 1. 2. 3. <!-- --> 1. 2. In step 2.1. of Algorithm \[alg:conditional-particle-filter\], the resampling distribution $r(da^{1:N-1}|w^{1:N})$ refers to a distribution on $\{1,\ldots,N\}^{N-1}$ from which “ancestors” are drawn according to particle weights. The resampling distribution is an algorithmic choice; specific schemes for the conditional particle filter are described in @ChopinS:2015. Here we will use multinomial resampling throughout. In step 2.3., “normalize the weights” means dividing them by their sum. Instead of bootstrap particle filters [@gordon:salmon:smith:1993], where particles are propagated from the model transition, more sophisticated filters can readily be used in the CPF procedure. For instance, performance gains can be obtained with auxiliary particle filters [@pitt1999filtering; @johansen2008note], as illustrated in Section \[sec:numerics:hiddenar\]. In presenting algorithms we focus on bootstrap particle filters for simplicity. When the transition density is tractable, extensions of the CPF include backward sampling [@whiteleycommentonpmcmc; @LindstenS:2013] and ancestor sampling [@LindstenJS:2014], which is beneficial in the proposed approach as illustrated in Section \[sec:numerics:hiddenar\]. The complexity of a standard CPF update is of order $NT$, and the memory requirements are of order $T + N\log N$ [@jacob2015path]. The proposed method relies on CPF kernels but is different from Markov chain Monte Carlo (MCMC) estimators: it involves independent copies of unbiased estimators of $\pi(h)$. Thus it will be amenable to parallel computation and confidence intervals will be constructed in a different way than with standard MCMC output [e.g. Chapter 7 in @gelman2010handbook]; see Section \[sec:comparison\] for a comparison with existing smoothers. Debiasing Markov chains \[sec:debiasing\] ----------------------------------------- We briefly recall the debiasing technique of @glynn2014exact, see also @McLeish:2011 [@Rhee:Glynn:2012; @vihola2015unbiased] and references therein. Denote by $(X^{(n)})_{n\geq 0}$ and $({\tilde{X}}^{(n)})_{n\geq 0}$ two Markov chains with invariant distribution $\pi$, initialized from a distribution $\pi_0$. Assume that, for all $n\geq 0$, $X^{(n)}$ and ${\tilde{X}}^{(n)}$ have the same marginal distribution, and that $\lim_{n\to\infty} \mathbb{E}[h(X^{(n)})] = \pi(h)$. Writing limit as a telescopic sum, and swapping infinite sum and expectation, which will be justified later on, we obtain $$\begin{aligned} \pi(h) &= \mathbb{E}[h(X^{(0)})] + \sum_{n=1}^\infty \mathbb{E}[h(X^{(n)}) - h(\tilde{X}^{(n-1)})] = \mathbb{E}[h(X^{(0)}) + \sum_{n=1}^\infty (h(X^{(n)}) - h(\tilde{X}^{(n-1)}))].\end{aligned}$$ Then, if it exists, the random variable $H_0 = h(X^{(0)}) + \sum_{n=1}^\infty (h(X^{(n)}) - h(\tilde{X}^{(n-1)}))$, is an unbiased estimator of $\pi(h)$. Furthermore, if the chains are coupled in such a way that there exists a time $\tau$, termed the *meeting time*, such that $X^{(n)}={\tilde{X}}^{(n-1)}$ almost surely for all $n\geq \tau$, then $H_0$ can be computed as $$H_0 = h(X^{(0)}) + \sum_{n=1}^{\tau - 1} (h(X^{(n)}) - h(\tilde{X}^{(n-1)})). \label{eq:RGestimator}$$ We refer to $H_0$ as a Rhee–Glynn estimator. Given that the cost of producing $H_0$ increases with $\tau$, it will be worth keeping in mind that we would prefer $\tau$ to take small values with large probability. The main contribution of the present article is to couple CPF chains and to use them in a Rhee–Glynn estimation procedure. Section \[sec:newsmoother:theory\] provides guarantees on the cost and the variance of $H_0$ under mild conditions, and Section \[sec:newsmoother:practical\] contains alternative estimators with reduced variance and practical considerations. Unbiased smoothing \[sec:unbiasedsmoothing\] ============================================ Coupled conditional particle filters \[sec:ccpf\] ------------------------------------------------- Our goal is to couple CPF chains $(X^{(n)})_{n\geq 0}$ and $({\tilde{X}}^{(n)})_{n\geq 0}$ such that the meeting time has finite expectation, in order to enable a Rhee–Glynn estimator for smoothing. A coupled conditional particle filter (CCPF) is a Markov kernel on the space of pairs of trajectories, such that $(X^\prime,{\tilde{X}}^\prime)\sim \text{CCPF}((X,{\tilde{X}}), \cdot)$ implies that $X^\prime\sim \text{CPF}(X, \cdot)$ and ${\tilde{X}}^\prime \sim \text{CPF}({\tilde{X}}, \cdot)$. Algorithm \[alg:coupled-conditional-particle-filter\] describes CCPF in pseudo-code, conditional upon $X = x_{0:T}$ and ${\tilde{X}}= {\tilde{x}}_{0:T}$. Two particle systems are initialized and propagated using common random numbers. The resampling steps and the selection of trajectories at the final step are performed jointly using couplings of discrete distributions. To complete the description of the CCPF procedure, we thus need to specify these couplings (for steps 2.1. and 3.1. in Algorithm \[alg:coupled-conditional-particle-filter\]). With the Rhee–Glynn estimation procedure in mind, we aim at achieving large meeting probabilities $\mathbb{P}(X^\prime = {\tilde{X}}^\prime | X,{\tilde{X}})$, so as to incur short meeting times on average. 1. 2. 3. <!-- --> 1. 2. 3. <!-- --> 1. 2. Coupled resampling \[sec:couplingparticlesystems\] -------------------------------------------------- The temporal index $t$ is momentarily removed from the notation: the task is that of sampling pairs $(a,{\tilde{a}})$ such that $\mathbb{P}(a=j)=w^{j}$ and $\mathbb{P}({\tilde{a}}=j)={\tilde{w}}^{j}$ for all $j\in 1:N$; this is a sufficient condition for CPF kernels to leave $\pi$ invariant [@andrieu:doucet:holenstein:2010]. A joint distribution on $\{1,\ldots,N\}^{2}$ is characterized by a matrix $P$ with non-negative entries $P^{ij}$, for $i,j\in\{ 1,\ldots,N\}$, that sum to one. The value $P^{ij}$ represents the probability of the event $(a,{\tilde{a}}) = (i,j)$. We consider the set $\mathcal{J}(w,{\tilde{w}})$ of matrices $P$ such that $P\mathds{1}=w$ and $P^{\mathsf{T}}\mathds{1}={\tilde{w}}$, where $\mathds{1}$ denotes a column vector of $N$ ones, $w = w^{1:N}$ and ${\tilde{w}}= {\tilde{w}}^{1:N}$. Matrices $P\in \mathcal{J}(w,{\tilde{w}})$ are such that $\mathbb{P}(a=j)=w^{j}$ and $\mathbb{P}({\tilde{a}}=j)={\tilde{w}}^{j}$ for $j\in 1:N$. Any choice of probability matrix $P\in\mathcal{J}(w,{\tilde{w}})$, and of a way of sampling $(a,{\tilde{a}})\sim P$, leads to a *coupled* resampling scheme. In order to keep the complexity of sampling $N$ pairs from $P$ linear in $N$, we focus on a particular choice. Other choices of coupled resampling schemes are given in @deligiannidis2015correlated [@jacob2016coupling; @sen2018coupling], following earlier works such as @pitt2002smooth [@lee2008towards]. We consider the *index-coupled* resampling scheme, used by @ChopinS:2015 in their theoretical analysis of the CPF, and by @jasra2015multilevel in a multilevel Monte Carlo context, see also Section 2.4 in @jacob2016coupling. The scheme amounts to a maximal coupling of discrete distributions on $\{1,\ldots,N\}$ with probabilities $w^{1:N}$ and ${\tilde{w}}^{1:N}$, respectively. This coupling maximizes the probability of the event $\{a = \tilde{a}\}$ under the marginal constraints. How to sample from a maximal coupling of discrete distributions is described e.g. in @lindvall2002lectures. The scheme is intuitive at the initial step of the CCPF, when $x_0^j = {\tilde{x}}_0^j$ for all $j=1,\ldots,N-1$: one would want pairs of ancestors $(a_0,{\tilde{a}}_0)$ to be such that $a_0 = {\tilde{a}}_0$, so that pairs of resampled particles remain identical. At later steps, the number of identical pairs across both particle systems might be small, or even null. In any case, at step 2.2. of Algorithm \[alg:coupled-conditional-particle-filter\], the same random number $U_{t}^j$ is used to compute $x^j_{t}$ and ${\tilde{x}}^j_{t}$ from their ancestors. If $a_{t-1}^j = {\tilde{a}}_{t-1}^j$, we select ancestor particles that were, themselves, computed with common random numbers at the previous step, and we give them common random numbers again. Thus this scheme maximizes the number of consecutive steps at which common random numbers are used to propagate each pair of particles. We now discuss why propagating pairs of particles with common random numbers might be desirable. Under assumptions on the random function representation of the latent process, using common random numbers to propagate pairs of particles results in the particles contracting. For instance, in an auto-regressive model where $F(x,U,\theta) = \theta x + U$, where $\theta \in (-1,1)$ and $U$ is the innovation term, we have $|F(x,U,\theta) - F({\tilde{x}},U,\theta)| = |\theta| |x-{\tilde{x}}|$, thus a pair of particles propagated with common variables $U$ contracts at a geometric rate. We can formulate assumptions directly on the function $x\mapsto \mathbb{E}_U[F(x,U,\theta)]$, such as Lipschitz conditions with respect to $x$, after having integrated $U$ out, for fixed $\theta$. Discussions on these assumptions can be found in @diaconis1999iterated, and an alternative method that would not require them is mentioned in Section \[sec:discussion\]. Rhee–Glynn smoothing estimator \[sec:rgsmoothing\] -------------------------------------------------- We now put together the Rhee–Glynn estimator of Section \[sec:debiasing\] with the CCPF algorithm of Section \[sec:ccpf\]. In passing we generalize the Rhee–Glynn estimator slightly by starting the telescopic sum at index $k\geq 0$ instead of zero, and denote it by $H_k$; $k$ becomes a tuning parameter, discussed in Section \[sec:newsmoother:practical\]. The procedure is fully described in Algorithm \[alg:rheeglynnsmoother\]; CPF and CCPF refer to Algorithms \[alg:conditional-particle-filter\] and \[alg:coupled-conditional-particle-filter\] respectively. By convention the sum from $k+1$ to $\tau-1$ in the definition of $H_k$ is set to zero whenever $k+1>\tau-1$. Thus the estimator $H_k$ is equal to $h(X^{(k)})$ on the event $\{k+1>\tau-1\}$. Recall that $h(X^{(k)})$ is in general a biased estimator of $\pi(h)$, since there is no guarantee that a CPF chain reaches stationarity within $k$ iterations. Thus the term $\sum_{n=k+1}^{\tau - 1}(h(X^{(n)}) - h({\tilde{X}}^{(n-1)}))$ acts as a bias correction. 1. 2. 1. 2. 3. At step 1. of Algorithm \[alg:rheeglynnsmoother\], the paths $X^{(0)}$ and ${\tilde{X}}^{(0)}$ can be sampled independently or not from $\pi_0$. In the experiments we will initialize chains independently and $\pi_0$ will refer to the distribution of a path randomly chosen among the trajectories of a particle filter. Theoretical properties\[sec:newsmoother:theory\] ================================================ We give three sufficient conditions for the validity of Rhee–Glynn smoothing estimators. \[assumption:upperbound\] The measurement density of the model is bounded from above: there exists $\bar{g} < \infty$ such that, for all $y\in \mathbb{Y}$ and $x\in\mathbb{X}$, $g(y | x) \leq \bar{g}$. \[assumption:couplingmatrix\] The resampling probability matrix $P$, with rows summing to $w^{1:N}$ and columns summing to ${\tilde{w}}^{1:N}$, is such that, for all $i\in \{1,\ldots,N\}$, $P^{ii} \geq w^i {\tilde{w}}^i$. Furthermore, if $w^{1:N} = {\tilde{w}}^{1:N}$, then $P$ is a diagonal matrix with entries given by $w^{1:N}$. \[assumption:mixing\] Let $(X^{(n)})_{n \geq 0}$ be a Markov chain generated by the conditional particle filter and started from $\pi_0$, and $h$ a test function of interest. Then $\mathbb{E}\left[h(X^{(n)})\right] \xrightarrow[n\to \infty]{} \pi(h)$. Furthermore, there exists $\delta > 0$, $n_0 < \infty$ and $C<\infty$ such that, for all $n\geq n_0$, $\mathbb{E}\left[h(X^{(n)})^{2+\delta}\right]\leq C$. The first assumption is satisfied for wide classes of models where the measurements are assumed to be some transformation of the latent process with added noise. However, it would not be satisfied for instance in stochastic volatility models where it is often assumed that $Y|X=x\sim \mathcal{N}(0, \exp(x)^2)$ or variants thereof [e.g. @fulop2013efficient]. There, the measurement density would diverge when $y$ is exactly zero and $x\to -\infty$. A similar assumption is discussed in Section 3 of @whiteley2013stability. One can readily check that the second assumption always holds for the index-coupled resampling scheme. The third assumption relates to the validity of MCMC estimators generated by the CPF algorithm, addressed under general assumptions in @ChopinS:2015 [@LindstenDM:2015; @andrieuvihola2013uniform]. Our main result states that the proposed estimator is unbiased, has a finite variance, and that the meeting time $\tau$ has tail probabilities bounded by those of a geometric variable, which implies in particular that the estimator has a finite expected cost. Under Assumptions \[assumption:upperbound\] and \[assumption:couplingmatrix\], for any initial distribution $\pi_0$, any number of particles $N\geq 2$ and time horizon $T\geq 1$, there exists $\varepsilon>0$, which might depend on $N$ and $T$, such that for all $n\geq 2$, $$\mathbb{P}(\tau > n) \leq (1-\varepsilon)^{n-1},$$ and therefore $\mathbb{E}[\tau]<\infty$. Under the additional Assumption \[assumption:mixing\], the Rhee–Glynn smoothing estimator $H_k$ of Algorithm \[alg:rheeglynnsmoother\] is such that, for any $k\geq 0$, $\mathbb{E}[H_k] = \pi(h)$ and $\mathbb{V}[H_k] < \infty$. \[thm:finitevariance\] The proof is in Appendices \[sec:proof:intermed\] and \[sec:proof:unbiased\]. Some aspects of the proof, not specific to the smoothing setting, are similar to the proofs of Theorem 1 in @rhee:phd, Theorem 2.1 in @McLeish:2011, Theorem 7 in @vihola2015unbiased, and results in @glynn2014exact. It is provided in univariate notation but the Rhee–Glynn smoother can estimate multivariate smoothing functionals, in which case the theorem applies component-wise. Improvements and tuning \[sec:newsmoother:practical\] ===================================================== Since $H_\ell$ is unbiased for all $\ell\geq 0$, we can compute $H_\ell$ for various values of $\ell$ between two integers $k\leq m$, and average these estimators to obtain $H_{k:m}$ defined as $$\begin{aligned} \label{eq:timeaverage} H_{k:m} & = \frac{1}{m-k+1}\sum_{n = k}^m \{h(X^{(n)}) + \sum_{\ell = n + 1}^{\tau - 1} (h(X^{(\ell)}) - h({\tilde{X}}^{(\ell-1)}))\} \nonumber \\ &= \frac{1}{m-k+1}\sum_{n = k}^m h(X^{(n)}) + \sum_{n =k + 1}^{\tau - 1} \frac{\min(m-k+1, n-k)}{m-k+1} (h(X^{(n)}) - h({\tilde{X}}^{(n-1)})).\end{aligned}$$ The term $(m-k+1)^{-1} \sum_{n = k}^m h(X^{(n)})$ is a standard ergodic average of a CPF chain, after $m$ iterations and discarding the first $k-1$ steps as burn-in. It is a biased estimator of $\pi(h)$ in general since $\pi_0$ is different from $\pi$. The other term acts as a bias correction. On the event $\tau - 1< k+1$ the correction term is equal to zero. As $k$ increases the bias of the term $(m-k+1)^{-1} \sum_{n = k}^m h(X^{(n)})$ decreases. The variance inflation of the Rhee–Glynn estimator decreases too, since the correction term is equal to zero with increasing probability. On the other hand, it can be wasteful to set $k$ to an overly large value, in the same way that it is wasteful to discard too many iterations as burn-in when computing MCMC estimators. In practice we propose to choose $k$ according to the distribution of $\tau$, which can be sampled from exactly by running Algorithm \[alg:rheeglynnsmoother\], as illustrated in the numerical experiments of Section \[sec:numerics\]. Conditional upon a choice of $k$, by analogy with MCMC estimators we can set $m$ to a multiple of $k$, such as $2k$ or $5k$. Indeed the proportion of discarded iterations is approximately $k/m$, and it appears desirable to keep this proportion low. We stress that the proposed estimators are unbiased and with a finite variance for any choice of $k$ and $m$; tuning $k$ and $m$ only impacts variance and cost. For a given choice of $k$ and $m$, the estimator $H_{k:m}$ can be sampled $R$ times independently in parallel. We denote the independent copies by $H_{k:m}^{(r)}$ for $r\in 1:R$. The smoothing expectation of interest $\pi(h)$ can then be approximated by $\bar{H}_{k:m}^R = R^{-1}\sum_{r=1}^R H_{k:m}^{(r)}$, with a variance that decreases linearly with $R$. From the central limit theorem the confidence interval $[\bar{H}_{k:m}^R + z_{\alpha/2} \hat{\sigma}^R/\sqrt{R}, \bar{H}_{k:m}^R + z_{1-\alpha/2} \hat{\sigma}^R/\sqrt{R}]$, where $\hat{\sigma}^R$ is the empirical standard deviation of $(H_{k:m}^{(r)})_{r=1}^R$ and $z_a$ is the $a$-th quantile of a standard Normal distribution, has $1-\alpha$ asymptotic coverage as $R\to \infty$. The central limit theorem is applicable as a consequence of Theorem \[thm:finitevariance\]. The variance of the proposed estimator can be further reduced by Rao–Blackwellization. In Eq. , the random variable $h(X^{(n)})$ is obtained by applying the test function $h$ of interest to a trajectory drawn among $N$ trajectories, denoted by say $x_{0:T}^k$ for $k=1,\ldots,N$, with probabilities $w_T^{1:N}$; see step 3 in Algorithms \[alg:conditional-particle-filter\] and \[alg:coupled-conditional-particle-filter\]. Thus the random variable $\sum_{k=1}^N w_T^{k}h(x_{0:T}^{k})$ is the conditional expectation of $h(X^{(n)})$ given the trajectories and $w_T^{1:N}$, which has the same expectation as $h(X^{(n)})$. Thus any term $h(X^{(n)})$ or $h({\tilde{X}}^{(n)})$ in $H_{k:m}$ can be replaced by similar conditional expectations. This enables the use of all the paths generated by the CPF and CCPF kernels, and not only the selected ones. As in other particle methods the choice of the number of particles $N$ is important. Here, the estimator $\bar{H}_{k:m}^R$ is consistent as $R\to \infty$ for any $N\geq 2$, but $N$ plays a role both on the cost and of the variance of each $H^{(r)}_{k:m}$. We can generate unbiased estimators for different values of $N$ and compare their costs and variances in preliminary runs. The scaling of $N$ with the time horizon $T$ is explored numerically in Section \[sec:numerics:hiddenar\]. If possible, one can also employ other algorithms than the bootstrap particle filter, as illustrated in Section \[sec:numerics:hiddenar\] with the auxiliary particle filter. Comparison with existing smoothers \[sec:comparison\] ===================================================== The proposed method combines elements from both particle smoothers and MCMC methods, but does not belong to either category. We summarize advantages and drawbacks below, after having discussed the cost of the proposed estimators. Each estimator $H_{k:m}$ requires two draws from $\pi_0$, here taken as the distribution of a trajectory selected from a particle filter with $N$ particles. Then, the estimator as described in Algorithm \[alg:rheeglynnsmoother\] requires a draw from the CPF kernel, $\tau-1$ draws from the CCPF kernel, and finally $m-\tau$ draws of the CPF kernel on the events $\{m>\tau\}$. The cost of a particle filter and of an iteration of CPF is usually dominated by the propagation of $N$ particles and the evaluation of their weights. The cost of an iteration of CCPF is approximately twice larger. Overall the cost of $H_{k:m}$ is thus of order $C(\tau,m,N) = N\times (3+2(\tau-1)+\max(0,m-\tau))$, for fixed $T$. The finiteness of the expected cost $\mathbb{E}[C(\tau,m,N)]$ is a consequence of Theorem \[thm:finitevariance\]. The average $\bar{H}_{k:m}^R$ satisfies a central limit theorem parametrized by the number of estimators $R$, as discussed in Section \[sec:newsmoother:practical\]; however, since the cost of $H_{k:m}$ is random, it might be more relevant to consider central limit theorems parametrized by computational cost, as in @glynn1992asymptotic. The asymptotic inefficiency of the proposed estimators can be defined as $\mathbb{E}[C(\tau,m,N)]\times\mathbb{V}[H_{k:m}]$, which can be approximated with independent copies of $H_{k:m}$ and $\tau$, obtained by running Algorithm \[alg:rheeglynnsmoother\]. State-of-the-art particle smoothers include fixed-lag approximations [@kitagawa2001monte; @cappe:ryden:2004; @olsson2008sequential], forward filtering backward smoothers [@GodsillDW:2004; @del2010forward; @douc2011sequential; @taghavi2013adaptive], and smoothers based on the two-filter formula [@briers2010smoothing; @kantas2015particle]. These particle methods provide consistent approximations as $N\to\infty$, with associated mean squared error decreasing as $1/N$ [Section 4.4 of @kantas2015particle]; except for fixed-lag approximations for which some bias remains. The cost is typically of order $N$ with efficient implementations described in @fearnheadwyncolltawn2010 [@kantas2015particle; @olsson2017efficient], and is linear in $T$ for fixed $N$. Parallelization over the $N$ particles is mostly feasible, the main limitation coming from the resampling step [@murray2015parallel; @lee2015forest; @whiteley2016role; @paige2014asynchronous; @murray2016anytime]. The memory cost of particle filters is of order $N$, or $N\log N$ if trajectories are kept [@jacob2015path], see also @Koskela2018. Assessing the accuracy of particle approximations from a single run of these methods remains a major challenge; see @lee2015variance [@olsson2017numerically] for recent breakthroughs. Furthermore, we will see in Section \[sec:numerics:unlikely\] that the bias of particle smoothers cannot always be safely ignored. On the other hand, we will see in Section \[sec:numerics:pz\] that the variance of particle smoothers can be smaller than that of the proposed estimators, for a given computational cost. Thus, in terms of mean squared error per unit of computational cost, the proposed method is not expected to provide benefits. The main advantage of the proposed method over particle smoothers lies in the construction of confidence intervals, and the possibility of parallelizing over independent runs as opposed to interacting particles. Additionally, a user of particle smoothers who would want more precise results would increase the number of particles $N$, if enough memory is available, discarding previous runs. On the other hand, the proposed estimator $\bar{H}_{k:m}^R$ can be refined to arbitrary precision by drawing more independent copies of $H_{k:m}$, for a constant memory requirement. Other popular smoothers belong to the family of MCMC methods. Early examples include Gibbs samplers, updating components of the latent process conditionally on other components and on the observations [e.g. @carter1994gibbs]. The CPF kernel described in Section \[sec:intro:smoothing\] can be used in the standard MCMC way, averaging over as many iterations as possible [@andrieu:doucet:holenstein:2010]. The bias of MCMC estimators after a finite number of iterations is hard to assess, which makes the choice of burn-in period difficult. Asymptotically valid confidence intervals can be produced in various ways, for instance using the CODA package [@plummer2006coda]; see also @vats2018strong. On the other hand, parallelization over the iterations is intrinsically challenging with MCMC methods [@rosenthal2000parallel]. Therefore the proposed estimators have some advantages over existing methods, the main drawback being a potential increase in mean squared error for a given (serial) computational budget, as illustrated in the numerical experiments. Numerical experiments\[sec:numerics\] ===================================== We illustrate the tuning of the proposed estimators, their advantages and their drawbacks through numerical experiments. All estimators of this section employ the Rao–Blackwellization technique described in Section \[sec:newsmoother:practical\], and multinomial resampling is used within all filters. Hidden auto-regressive model\[sec:numerics:hiddenar\] ----------------------------------------------------- Our first example illustrates the proposed method, the impact of the number of particles $N$ and that of the time horizon $T$, and the benefits of auxiliary particle filters. We consider a linear Gaussian model, with $x_{0}\sim\mathcal{N}\left(0,1\right)$ and $x_{t}=\eta x_{t-1}+\mathcal{N}\left(0,1\right)$ for all $t \geq 1$, with $\eta=0.9$. We assume that $y_{t}\sim\mathcal{N}\left(x_{t},1\right)$ for all $t \geq 1$. We first generate $T = 100$ observations from the model, and consider the task of estimating all smoothing means, which corresponds to the test function $h: x_{0:T}\mapsto x_{0:T}$. With CPF kernels using bootstrap particle filters, with $N = 256$ particles and ancestor sampling [@LindstenJS:2014], we draw meeting times $\tau$ independently, and represent a histogram of them in Figure \[fig:ar1:meetings\]. Based on these meeting times, we can choose $k$ as a large quantile of the meeting times, for instance $k = 10$, and $m$ as a multiple of $k$, for instance $m = 2k = 20$. For this choice, we find the average compute cost of each estimator to approximately equal that of a particle filter with $28\times 256$ particles, with a memory usage equivalent to $2\times 256$ particles. How many of these estimators can be produced in a given wall-clock time depends on available hardware. With $R=100$ independent estimators, we obtain $95\%$ confidence intervals indicated by black error bars in Figure \[fig:ar1:smoothingmeans\]. The true smoothing means, obtained by Kalman smoothing, are indicated by a line. The method is valid for all $N$, which prompts the question of the optimal choice of $N$. Intuitively, larger values of $N$ lead to smaller meeting times. However, the meeting time cannot be less than $2$ by definition, which leads to a trade-off. We verify this intuition by numerical simulations with $1,000$ independent runs. For $N=16$, $N=128$, $N=256$, $N=512$ and $N=1,024$, we find average meeting times of $97$, $15$, $7$, $4$ and $3$ respectively. After adjusting for the different numbers of particles, the expected cost of obtaining a meeting is approximately equivalent with $N=16$ and $N=512$, but more expensive for $N=1,024$. In practice, for specific integrals of interest, one can approximate the cost and the variance of the proposed estimators for various values of $N$, $k$ and $m$ using independent runs, and use the most favorable configuration in subsequent, larger experiments. Next we investigate the effect of the time horizon $T$. We expect the performance of the CPF kernel to decay as $T$ increases for a fixed $N$. We compensate by increasing $N$ linearly with $T$. Table \[table:effecthorizon\] reports the average meeting times obtained from $R=500$ independent runs. We see that the average meeting times are approximately constant or slightly decreasing over $T$, implying that the linear scaling of $N$ with $T$ is appropriate or even conservative, in agreement with the literature [e.g. @huggins2015sequential]. The table contains the average meeting times obtained with and without ancestor sampling [@LindstenJS:2014]; we observe significant reductions of average meeting times with ancestor sampling, but it requires tractable transition densities. Finally, for the present model we can employ an auxiliary particle filter, in which particles are propagated conditionally on the next observation. Table \[table:effecthorizon\] shows a significant reduction in expected meeting time. The combination of auxiliary particle filter and ancestor sampling naturally leads to the smallest expected meeting times. A hidden auto-regressive model with an unlikely observation {#sec:numerics:unlikely} ----------------------------------------------------------- We now illustrate the benefits of the proposed estimators in an example taken from @ruiz2016particle where particle filters exhibit a significant bias. The latent process is defined as $x_{0}\sim\mathcal{N}\left(0,0.1^{2}\right)$ and $x_{t}=\eta x_{t-1}+\mathcal{N}\left(0,0.1^{2}\right)$; we take $\eta=0.9$ and consider $T=10$ time steps. The process is observed only at time $T=10$, where $y_{T}=1$ and we assume $y_{T}\sim\mathcal{N}\left(x_{T},0.1^{2}\right)$. The observation $y_{T}$ is unlikely under the model. Therefore the filtering distributions and the smoothing distributions have little overlap, particularly for times $t$ close to $T$. This toy model is a stylized example of settings with highly-informative observations [@ruiz2016particle; @del2015sequential]. We consider the task of estimating the smoothing mean $\mathbb{E}[x_9|y_{10}]$. We run particle filters for different values of $N$, $10,000$ times independently, and plot kernel density estimators of the distributions of the estimators of $\mathbb{E}[x_9|y_{10}]$ in Figure \[fig:unlikely:pf\]. The dashed vertical line represents the estimand $\mathbb{E}[x_9|y_{10}]$, obtained analytically. We see that the bias diminishes when $N$ increases, but that it is still significant with $N=16,384$ particles. For any fixed $N$, if we were to ignore the bias and produce confidence intervals using the central limit theorem based on independent particle filter estimators, the associated coverage would go to zero as the number of independent runs would increase. In contrast, confidence intervals obtained with the proposed unbiased estimators are shown in Figure \[fig:unlikely:rg\]. For each value of $N$, the average meeting time was estimated from $100$ independent runs (without ancestor sampling), and then $k$ was set to that estimate, and $m$ equal to $k$. Then, $R=10,000$ independent estimators were produced, and confidence intervals were computed as described in Section \[sec:newsmoother:practical\]. This leads to precise intervals for each choice of $N$. The average costs associated with $N=128$, $N=256$, $N=512$ and $N=1024$ were respectively matching the costs of particle filters with $3814$, $4952$, $9152$ and $13,762$ particles. To conclude, if we match computational costs and compare mean squared errors, the proposed method is not necessarily advantageous. However, if the interest lies in confidence intervals with adequate coverage, the proposed approach comes with guarantees thanks to the lack of bias and the central limit theorem for i.i.d. variables. Prey-predator model \[sec:numerics:pz\] --------------------------------------- Our last example involves a model of plankton–zooplankton dynamics taken from @jones2010bayesian, in which the transition density is intractable [@breto2009time; @jacob2015sequential]. The bootstrap particle filter is still implementable, and one can either keep the entire trajectories of the particle filter, or perform fixed-lag approximations to perform smoothing. On the other hand, backward and ancestor sampling are not implementable. The hidden state $x_t = (p_t, z_t)$ represents the population size of phytoplankton and zooplankton, and the transition from time $t$ to $t+1$ is given by a Lotka–Volterra equation, $$\frac{dp_t}{dt} = \alpha p_t - c p_t z_t , \quad \text{and}\quad \frac{dz_t}{dt} = e c p_t z_t -m_l z_t -m_q z_t^2,$$ where the stochastic daily growth rate $\alpha$ is drawn from $\mathcal{N}(\mu_\alpha,\sigma_\alpha^2)$ at every integer time $t$. The propagation of each particle involves solving the above equation numerically using a Runge-Kutta method in the `odeint` library [@ahnert2011odeint]. The initial distribution is given by $\log p_0 \sim \mathcal{N}(\log 2 , 1)$ and $\log z_0 \sim \mathcal{N}(\log 2, 1)$. The parameters $c$ and $e$ represent the clearance rate of the prey and the growth efficiency of the predator. Both $m_l$ and $m_q$ parameterize the mortality rate of the predator. The observations $y_t$ are noisy measurements of the phytoplankton $p_t$, $\log y_t \sim \mathcal{N}(\log p_t, 0.2^2)$; $z_t$ is not observed. We generate $T = 365$ observations using $\mu_\alpha = 0.7, \sigma_\alpha = 0.5$, $c = 0.25$, $e = 0.3$, $m_l = 0.1$, $m_q = 0.1$. We consider the problem of estimating the mean population of zooplankton at each time $t\in0:T$, denoted by $\mathbb{E}[z_t|y_{1:T}]$, given the data-generating parameter. The distribution of meeting times obtained with $N=4,096$ particles over $R=1,000$ experiments is shown in Figure \[fig:pz:meetings\]. Based on this graph, we choose $k=7$, $m=2k=14$, and produce $R=1,000$ independent estimators of the smoothing means $\mathbb{E}[z_t|y_{1:T}]$. We compute the smoothing means with a long CPF chain, taken as ground truth. We then compute the relative variance of our estimators, defined as their variance divided by the square of the smoothing means. We find the average cost of the proposed estimator to be equivalent to that of a particle filter with $78,377$ particles. To approximately match the cost, we thus run particle filters with $2^{16}=65,536$ particles, with and without fixed-lag smoothing with a lag of $10$. The resulting relative variances are shown in Figure \[fig:pz:relvar\]. We see that the proposed estimators yield a larger variance than particle filters, but that the difference is manageable. Fixed-lag smoothing provides significant variance reduction, particularly for earlier time indices. We can also verify that the bias of fixed-lag smoothing is negligible in the present example; this would however be hard to assess with fixed-lag smoothers alone. Discussion\[sec:discussion\] ============================ The performance of the proposed estimator is tied to the meeting time. As in @ChopinS:2015, the coupling inequality [@lindvall2002lectures] can be used to relate the meeting time with the mixing of the underlying conditional particle filter kernel. The proposed approach can be seen as a framework to parallelize CPF chains and to obtain reliable confidence intervals over independent replicates. Any improvement in the CPF directly translates into more efficient Rhee–Glynn estimators, as we have illustrated in Section \[sec:numerics:hiddenar\] with auxiliary particle filters and ancestor sampling. The methods proposed e.g. in @SinghLM:2017 [@del2015sequential; @guarniero2015iterated; @gerber2015sequential; @heng2017controlled] could also be used in Rhee–Glynn estimators, with the hope of obtaining shorter meeting times and smaller variance. We have considered the estimation of latent processes given known parameters. In the case of unknown parameters, joint inference of parameters and latent processes can be done with MCMC methods, and particle MCMC methods in particular [@andrieu:doucet:holenstein:2010]. Couplings of generic particle MCMC methods could be achieved by combining couplings proposed in the present article with those described in @jacob2017unbiased for Metropolis–Hastings chains. Furthermore, for fixed parameters, coupling the particle independent Metropolis–Hastings algorithm of @andrieu:doucet:holenstein:2010 would lead to unbiased estimators of smoothing expectations that would not require coupled resampling schemes (see Section \[sec:couplingparticlesystems\]). The appeal of the proposed smoother, namely parallelization over independent replicates and confidence intervals, would be shared by perfect samplers. These algorithms aim at the more ambitious task of sampling exactly from the smoothing distribution [@leedoucetperfectsimulation]. It remains unknown whether the proposed approach could play a role in the design of perfect samplers. We have established the validity of the Rhee–Glynn estimator under mild conditions, but its theoretical study as a function of the time horizon and the number of particles deserves further analysis [see @Lee2018ccbpf for a path forward]. Finally, together with Fisher’s identity [@douc:moulines:2014], the proposed smoother provides unbiased estimators of the score for models where the transition density is tractable. This could help maximizing the likelihood via stochastic gradient ascent. **Acknowledgements.** The authors thank Marco Cuturi, Mathieu Gerber, Jeremy Heng and Anthony Lee for helpful discussions. This work was initiated during the workshop on *Advanced Monte Carlo methods for complex inference problems* at the Isaac Newton Institute for Mathematical Sciences, Cambridge, UK held in April 2014. We would like to thank the organizers for a great event which led to this work. Intermediate result on the meeting probability \[sec:proof:intermed\] ===================================================================== Before proving Theorem \[thm:finitevariance\], we introduce an intermediate result on the probability of the chains meeting at the next step, irrespective of their current states. The result provides a lower-bound on the probability of meeting in one step, for coupled chains generated by the coupled conditional particle filter (CCPF) kernel. Let $N\geq 2$ and $T\geq 1$ be fixed. Under Assumptions \[assumption:upperbound\] and \[assumption:couplingmatrix\], there exists $\varepsilon>0$, depending on $N$ and $T$, such that $$\forall X \in \mathbb{X}^{T+1}, \quad \forall {\tilde{X}}\in \mathbb{X}^{T+1}, \quad \mathbb{P}(X' = {\tilde{X}}' | X, {\tilde{X}}) \geq \varepsilon,$$ where $(X',{\tilde{X}}') \sim \text{CCPF}((X,{\tilde{X}}), \cdot)$. Furthermore, if $X = {\tilde{X}}$, then $X' = {\tilde{X}}'$ almost surely. \[lemma:meetingprobability\] The constant $\varepsilon$ depends on $N$ and $T$, and on the coupled resampling scheme being used. Lemma \[lemma:meetingprobability\] can be used, together with the coupling inequality [@lindvall2002lectures], to prove the ergodicity of the conditional particle filter kernel, which is akin to the approach of @ChopinS:2015. The coupling inequality states that the total variation distance between $X^{(n)}$ and ${\tilde{X}}^{(n-1)}$ is less than $2\mathbb{P}(\tau > n)$, where $\tau$ is the meeting time. By assuming ${\tilde{X}}^{(0)}\sim\pi$, ${\tilde{X}}^{(n)}$ follows $\pi$ at each step $n$, and we obtain a bound for the total variation distance between $X^{(n)}$ and $\pi$. Using Lemma \[lemma:meetingprobability\], we can bound the probability $\mathbb{P}(\tau > n)$ from above by $(1-\varepsilon)^n$, as in the proof of Theorem \[thm:finitevariance\] below. This implies that the computational cost of the proposed estimator has a finite expectation for all $N\geq 2$ and $T\geq 1$. *Proof of Lemma \[lemma:meetingprobability\]*. We write ${{\mathbb{P}}_{x_{0:t},\tilde x_{0:t}}}$ and ${{\mathbb{E}}_{x_{0:t},\tilde x_{0:t}}}$ for the conditional probability and expectation, respectively, with respect to the law of the particles generated by the CCPF procedure conditionally on the reference trajectories up to time $t$, $(x_{0:t}, \tilde x_{0:t})$. Furthermore, let $\mathcal{F}_t$ denote the filtrations generated by the CCPF at time $t$. We denote by $x_{0:t}^k$, for $k\in1:N$, the surviving trajectories at time $t$. Let $I_t \subseteq 1:N-1$ be the set of common particles at time $t$ defined by $I_t = \{j \in 1:N-1 : x_{0:t}^j = \tilde x_{0:t}^j \}$. The meeting probability can then be bounded by: $$\begin{gathered} {{\mathbb{P}}_{x_{0:T},\tilde x_{0:T}}}(x_{0:T}^\prime = \tilde x_{0:T}^\prime) = {{\mathbb{E}}_{x_{0:T},\tilde x_{0:T}}}\left[{\mathds{1}}\!\left(x_{0:T}^{b_T} = \tilde x_{0:T}^{\tilde{b}_T} \right)\right] \geq \sum_{k=1}^{N-1} {{\mathbb{E}}_{x_{0:T},\tilde x_{0:T}}}[{\mathds{1}}\!\left(k \in I_T\right) P_T^{kk}] \\ = (N-1){{\mathbb{E}}_{x_{0:T},\tilde x_{0:T}}}[{\mathds{1}}\!\left(1\in I_T \right) P_T^{11}] \geq \frac{N-1}{ (N\bar{g})^2} {{\mathbb{E}}_{x_{0:T},\tilde x_{0:T}}}[{\mathds{1}}\!\left(1\in I_T \right) g_T(x_T^1) g_T(\tilde x_T^1)],\end{gathered}$$ where we have used Assumptions \[assumption:upperbound\] and \[assumption:couplingmatrix\]. Now, let $\psi_t : {\mathbb{X}}^t \mapsto {\mathbb{R}}_+$ and consider $$\begin{aligned} \label{eq:crude:h} {{\mathbb{E}}_{x_{0:t},\tilde x_{0:t}}}[{\mathds{1}}\!\left( 1\in I_t \right) \psi_t(x_{0:t}^1) \psi_t(\tilde x_{0:t}^1)] = {{\mathbb{E}}_{x_{0:t},\tilde x_{0:t}}}[{\mathds{1}}\!\left( 1\in I_t \right) \psi_t(x_{0:t}^1)^2],\end{aligned}$$ since the two trajectories agree on $\{1\in I_t\}$. We have $$\begin{aligned} {\mathds{1}}\!\left( 1\in I_t \right) \geq \sum_{k=1}^{N-1} {\mathds{1}}\!\left(k\in I_{t-1} \right) {\mathds{1}}\!\left(a_{t-1}^1 = \tilde a_{t-1}^1 = k \right),\end{aligned}$$ and thus $$\begin{gathered} \label{eq:crude:h2} {{\mathbb{E}}_{x_{0:t},\tilde x_{0:t}}}[{\mathds{1}}\!\left( 1\in I_t \right) \psi_t(x_{0:t}^1)^2] \\ \geq {{\mathbb{E}}_{x_{0:t},\tilde x_{0:t}}}[\sum_{k=1}^{N-1} {\mathds{1}}\!\left(k\in I_{t-1} \right) {{\mathbb{E}}_{x_{0:t},\tilde x_{0:t}}}[ {\mathds{1}}\!\left(a_{t-1}^1 = \tilde a_{t-1}^1 = k \right) \psi_t(x_{0:t}^1)^2 \mid \mathcal{F}_{t-1} ]] \\ = (N-1){{\mathbb{E}}_{x_{0:t},\tilde x_{0:t}}}[{\mathds{1}}\!\left(1\in I_{t-1} \right) {{\mathbb{E}}_{x_{0:t},\tilde x_{0:t}}}[ {\mathds{1}}\!\left(a_{t-1}^1 = \tilde a_{t-1}^1 = 1 \right) \psi_t(x_{0:t}^1)^2 \mid \mathcal{F}_{t-1} ]].\end{gathered}$$ The inner conditional expectation can be computed as $$\begin{gathered} \label{eq:cruce:h2-inner} {{\mathbb{E}}_{x_{0:t},\tilde x_{0:t}}}[ {\mathds{1}}\!\left(a_{t-1}^1 = \tilde a_{t-1}^1 = 1 \right) \psi_t(x_{0:t}^1)^2 \mid \mathcal{F}_{t-1} ] \\ =\sum_{k,\ell=1}^N P_{t-1}^{k\ell} {\mathds{1}}\!\left(k=\ell=1\right) \int \psi_t((x_{0:t-1}^k, x_t ))^2 f(dx_t|x_{t-1}^k) \\ = P_{t-1}^{11} \int \psi_t((x_{0:t-1}^1, x_t))^2 f(dx_t|x_{t-1}^1) \\ \geq \frac{g_{t-1}(x_{t-1}^1) g_{t-1}(\tilde x_{t-1}^1) }{(N\bar{g})^2} \left( \int \psi_t((x_{0:t-1}^1, x_t )) f(dx_t|x_{t-1}^1) \right)^2,\end{gathered}$$ where we have again used Assumptions \[assumption:upperbound\] and \[assumption:couplingmatrix\]. Note that this expression is independent of the final states of the reference trajectories, $(x_t, \tilde x_t)$, which can thus be dropped from the conditioning. Furthermore, on $\{1\in I_{t-1}\}$ it holds that $x_{0:t-1}^1 = \tilde x_{0:t-1}^1$ and therefore, combining Eqs. – we get $$\begin{gathered} {{\mathbb{E}}_{x_{0:t},\tilde x_{0:t}}}[{\mathds{1}}\!\left( 1\in I_t \right) \psi_t(x_{0:t}^1) \psi_t(\tilde x_{0:t}^1)] \\ \geq \frac{(N-1)}{(N\bar{g})^2}{{\mathbb{E}}_{x_{0:t-1},\tilde x_{0:t-1}}}\Big[{\mathds{1}}\!\left(1\in I_{t-1} \right) g_{t-1}(x_{t-1}^1) \int \psi_t((x_{0:t-1}^1, x_t )) f(dx_t|x_{t-1}^1) \\ \times g_{t-1}(\tilde x_{t-1}^1) \int \psi_t((\tilde x_{0:t-1}^1, x_t )) f(dx_t|\tilde x_{t-1}^1) \Big].\end{gathered}$$ Thus, if we define for $t=1,\ldots,T-1$, $\psi_t(x_{0:t}) = g_t(x_t) \int \psi_{t+1}(x_{0:t+1}) f(dx_{t+1}|x_t)$, and $\psi_T(x_{0:T}) = g_T(x_T)$, it follows that $$\begin{aligned} {{\mathbb{P}}_{x_{0:T},\tilde x_{0:T}}}(x_{0:T}^\prime= \tilde x_{0:T}^\prime) &\geq \frac{(N-1)^{\mathsf{T}}}{(N\bar{g})^{2T}} {{\mathbb{E}}_{x_{0},\tilde x_{0}}}[{\mathds{1}}\!\left(1\in I_1 \right) \psi_1(x_1^1)\psi_1(\tilde x_1^1)] \\ &= \frac{(N-1)^{\mathsf{T}}}{(N\bar{g})^{2T}} {{\mathbb{E}}_{x_{0},\tilde x_{0}}}[\psi_1(x_1^1)^2] \geq \frac{(N-1)^{\mathsf{T}}}{(N\bar{g})^{2T}} Z^2 > 0,\end{aligned}$$ where $Z > 0$ is the normalizing constant of the model, $Z=\int m_0(dx_0) \prod_{t=1}^{\mathsf{T}}g_t(x_t) f(dx_t|x_{t-1})$. This concludes the proof of Lemma \[lemma:meetingprobability\]. For any fixed $T$, the bound goes to zero when $N\to \infty$. The proof fails to capture accurately the behaviour of $\varepsilon$ in Lemma \[lemma:meetingprobability\] as a function of $N$ and $T$. Indeed, we observe in the numerical experiments of Section \[sec:numerics\] that meeting times decrease when $N$ increases. Proof of Theorem \[thm:finitevariance\] \[sec:proof:unbiased\] ============================================================== The proof is similar to those presented in @rhee:phd, in @McLeish:2011, @vihola2015unbiased, and @glynn2014exact. We can first upper-bound $\mathbb{P}\left(\tau>n\right)$, for all $n\geq2$, using Lemma \[lemma:meetingprobability\] [e.g. @williams1991probability exercise E.10.5]. We obtain for all $n\geq2$, $$\mathbb{P}\left(\tau>n\right)\leq\left(1-\varepsilon\right)^{n-1}.\label{eq:meetingtime:survival2}$$ This ensures that $\mathbb{E}[\tau]$ is finite; and that $\tau$ is almost surely finite. We then introduce the random variables $Z_{m}=\sum_{n=0}^{m} \Delta^{(n)}$ for all $m\geq 1$. Since $\tau$ is almost surely finite, and since $\Delta^{(n)} = 0$ for all $n \geq \tau$, then $Z_m\to Z_\tau = H_0$ almost surely when $m\to\infty$. We prove that $(Z_m)_{m\geq 1}$ is a Cauchy sequence in $L_2$, i.e. $\sup_{m'\geq m} \mathbb{E}\left[ (Z_{m'} - Z_m)^2 \right]$ goes to $0$ as $m\to\infty$. We write $$\begin{aligned} \label{eq:zcauchy} \mathbb{E}[(Z_{m'} - Z_m)^2] &= \sum_{n = m + 1}^{m'}\sum_{\ell = m + 1}^{m'} \mathbb{E}[\Delta^{(n)}\Delta^{(\ell)}].\end{aligned}$$ We use Cauchy-Schwarz inequality to write $(\mathbb{E}[\Delta^{(n)}\Delta^{(\ell)}])^2 \leq \mathbb{E}[(\Delta^{(n)})^2]\mathbb{E}[(\Delta^{(\ell)})^2]$, and we note that $(\Delta^{(n)})^2= \Delta^{(n)}\mathds{1}(\tau>n)$. Together with Hölder’s inequality with $p=1+\delta/2$, and $q=(2+\delta)/\delta$, where $\delta$ is as in Assumption \[assumption:mixing\], we can write $$\begin{aligned} \mathbb{E}\left[(\Delta^{(n)})^{2}\right] & \leq\mathbb{E}\left[(\Delta^{(n)})^{2+\delta}\right]^{1/(1+\delta/2)}\left(\left(1-\varepsilon\right)^{\delta/(2+\delta)}\right)^{n-1}.\end{aligned}$$ Furthermore, using Assumption \[assumption:mixing\] and Minkowski’s inequality, we obtain the bound $$\begin{aligned} \forall n\geq n_0, \qquad & \mathbb{E}\left[(\Delta^{(n)})^{2+\delta}\right]^{1/(1+\delta/2)}\leq C_{1},\end{aligned}$$ where $C_1$ is independent of $n$. The above inequalities lead to the terms $\mathbb{E}[\Delta^{(n)}\Delta^{(\ell)}]$ being upper bounded by an expression of the form $C_1 \eta^n \eta^\ell$, where $\eta \in (0,1)$. Thus we can compute a bound on Eq. , by computing geometric series, and finally conclude that $(Z_m)_{m \geq 1}$ is a Cauchy sequence in $L_2$. By uniqueness of the limit, since $(Z_m)_{m \geq 1}$ goes almost surely to $H_0$, $(Z_m)_{m \geq 1}$ goes to $H_0$ in $L_2$. This shows that $H_0$ has finite first two moments. We can retrieve the expectation of $H_0$ by $$\mathbb{E}Z_{m}=\sum_{n=0}^{m}\mathbb{E}[\Delta^{(n)}]=\mathbb{E}\left[h(X^{(m)})\right] \xrightarrow[m\to \infty]{} \pi(h),$$ according to Assumption \[assumption:mixing\]. This concludes the proof of Theorem \[thm:finitevariance\] for $H_k$ with $k=0$, and a similar reasoning applies for any $k\geq 0$. [^1]: The authors gratefully acknowledge the Swedish Foundation for Strategic Research (SSF) via the projects *Probabilistic Modeling and Inference for Machine Learning* (contract number: ICA16-0015) and ASSEMBLE (contract number: RIT15-0012), the Swedish Research Council (VR) via the projects *Learning of Large-Scale Probabilistic Dynamical Models* (contract number: 2016-04278) and *NewLEADS - New Directions in Learning Dynamical Systems* (contract number: 621-2016-06079), and the National Science Foundation through grant DMS-1712872.

The establishment of a radioactive waste disposal facility in Western Australia for low level waste. The Radiation Health Section of the Health Department of Western Australia has been a repository for unwanted radioactive sources for many years. They had been placed in the radioactive store located on the Queen Elizabeth II Medical Centre Campus. After a collection period of more than 20 years the storage facilities of the Radiation Health Section were nearing capacity. A decision was made to relocate these sources into a permanent near surface burial facility. Following extensive community consultation and site investigations, waste originating in Western Australia was disposed of at Mt Walton (East), 80 km North East of Koolyanobbing, Western Australia in November 1992.

Mucosal involvement is a risk factor for poor clinical outcomes and relapse in patients with pemphigus treated with rituximab. Many studies have reported the outcome of rituximab use in pemphigus but studies regarding the clinical risk factors for poor clinical outcomes or relapse are lacking. To clarify the risk factors for poor clinical outcomes or relapse in patients with pemphigus treated with rituximab, a retrospective chart analysis was performed on patients with pemphigus who were treated with rituximab in the dermatology clinic of Seoul National University Hospital. Forty patients with pemphigus were treated with rituximab, of which 39 (97.5%) experienced remission and 19 (48.7%) experienced relapse. Patients with mucosal lesions demonstrated poor clinical outcomes. The risk for relapse was 4.626 (confidence interval: 1.126-19.001, p = .034) times higher in patients with mucosal lesions than in those without lesions. In patients with pemphigus treated with rituximab, the presence of mucosal lesions resulted in poor clinical outcomes and frequent recurrence.

If you or your colleagues still "dump" static data from line-of-business systems into a tool like Excel to manipulate, analyze, or present it; or if you have colleagues who re-key data from Office tools like Word and Excel into line-of-business systems for processing, read on:

I'm pretty sure I'm gonna get a tattoo on my ass shaped like Rainbow Dashes cutie mark and than I'm gonna cut out every piece of clothing I have into that sign so I can walk down the street with a cutie mark. I've had an idea. Coats matching the mane 6 and some extra ponies with the inside color the hair and the outside the ponies' coat color, with their cutie mark in the bottom left or right side on the back. With Rainbow Dash's, the elastic fabric that's on the end of the sleeves and on the waist of the coat can be rainbow colored, with the inside color matching her eyes. Oh and the zipper handle being something they enjoy, for example, Pinkie Pie's would be a cupcake, Twilight's a book, and Applejack's an apple. Sound good?

This application claims the benefit of Korean Application No. 98-54151, filed Dec. 10, 1998, in the Korean Patent Office, the disclosure of which is incorporated herein by reference. 1. Field of the Invention The present invention relates to a fluid jetting apparatus and a process for manufacturing the same, and more particularly, to a fluid jetting apparatus for a print head which is employed in output apparatuses such as an ink-jet printer, a facsimile machine, etc. to jet fluid through a nozzle, and a manufacturing process thereof. 2. Description of the Related Art A print head is a part or a set of parts which are capable of converting output data into a visible form on a predetermined medium using a type of printer. Generally, such a print head for an ink jet printer, and the like, uses a fluid jetting apparatus which is capable of jetting the predetermined amount of fluid through a nozzle to an exterior of a fluid chamber holding the fluid by applying a physical force to the fluid chamber. According to methods for applying physical force to the fluid within the fluid chamber, the fluid jetting apparatus is roughly grouped into a piezoelectric system and a thermal system. The piezoelectric system pushes out the ink within the fluid chamber through a nozzle through an operation of a piezoelectric element which is mechanically expanded in accordance with a driving signal. The thermal system pushes the fluid through the nozzle by means of bubbles which are produced from the fluid within the fluid chamber by the heat generated by an exothermic body. Recently, also, a thermal compression system has been developed, which is an improved form of the thermal system. The thermal compression system is for jetting out the fluid by driving a membrane by instantly heating a vaporizing fluid which acts as a working fluid. FIG. 1 is a vertical sectional view of a fluid jetting apparatus according to a conventional thermal compression system. The fluid jetting apparatus of the thermal compression system includes a heat driving part 10, a membrane 20, and a nozzle part 30. A substrate 11 of the heat driving part 10 supports the heat driving part 10 and the whole structure that will be constructed later. An insulated layer 12 is diffused on the substrate 11. An electrode 14 is made of a conductive material for supplying an electric power to the heat driving part 10. An exothermic body 13 is made of a resistive material having a predetermined resistance for expanding a working fluid by converting electrical energy into heat energy. Working fluid chambers 16 and 17 contain the working fluid, to maintain a pressure of the working fluid which is heat expanded, are connected by a working fluid introducing passage 18, and are formed within a working fluid barrier 15. Further, the membrane 20 is a thin layer which is adhered to an upper portion of the working fluid barrier layer 15 and working; fluid chambers 16 and 17 to be moved upward and downward by the pressure of the expanded working fluid. The membrane 20 includes a polyimide coated layer 21 and a polyimide adhered layer 22. Jetting fluid chambers 37 and 38 are chambers which are formed to enclose the jetting fluid. When the pressure is transmitted to the jetting fluid through the membrane 20, the jetting fluid is jetted only through a nozzle 35 formed in a nozzle plate 34. Here, the jetting fluid is the fluid which is pushed out of the jetting fluid chambers 37 and 38 in response to the driving of the membrane 20, and is finally jetted to the exterior. A jetting fluid introducing passage 39 connects the jetting fluid chambers 37 and 38. The jetting fluid chambers 37 and 38 and the jetting fluid introducing passage 39 are formed in a jetting fluid barrier layer 36. The nozzle 35 is an orifice through which the jetting fluid held using the membrane 20 and the jetting fluid chambers 37 and 38 is emitted to the exterior. Another substrate 31 (see FIGS. 4A and 4B) of the nozzle part 30 is temporarily employed for constructing the nozzle part 30, and should be removed before the nozzle part 30 is assembled. FIG. 2 shows a process for manufacturing the fluid jetting apparatus according to a conventional roll method. As shown in FIG. 2, the nozzle plate 34 is transferred from a feeding reel 51 to a take-up reel 52. In the process of transferring the nozzle plate 34 from the feeding reel 51 to the take-up reel 52, a nozzle is formed in the nozzle plate 34 by laser processing equipment 53. After the nozzle is formed, air is jetted from an air blower 54 so as to eliminate extraneous substances attached to the nozzle plate 34. Next, an actuator chip 40, which is laminated on a substrate to the jetting fluid barrier, is bonded with the nozzle plate 34 by a tab bonder 55, and accordingly, the fluid jetting apparatus is completed. The completed fluid jetting apparatuses are wound around the take-up reel 52 to be preserved, and then sectioned in pieces in the manufacturing process for the print head. Accordingly, each piece of the fluid jetting apparatuses is supplied into the manufacturing line of a printer. The process for manufacturing the, fluid jetting apparatus according to the conventional thermal compression system will be described below with reference to the construction of the fluid jetting apparatus shown in FIG. 1. FIGS. 3A and 3B are views for showing a process for manufacturing the heat driving part and FIG. 3C is a view for showing a process for manufacturing the membrane on the heat driving part of the conventional fluid jetting apparatus. FIGS. 4A to 4C are views for showing the process for manufacturing the nozzle part. In order to manufacture the conventional fluid jetting apparatus, the heat driving part 10 and the nozzle part 30 should be manufactured separately. Here, the heat driving part 10 is completed as the separately-made membrane 20 is adhered to the working fluid barrier layer 15 of the heat driving part 10. After that, by reversing and adhering the separately-made nozzle part 30 to the membrane 20, the fluid jetting apparatus is completed. FIG. 3A shows a process for diffusing the insulated layer 12 on the substrate 11 of the heat driving part 10, and for forming an exothermic body 13 and an electrode 14 on the insulated layer 12 in turn. Referring to FIG. 3B, working fluid chambers 16 and 17 and a working fluid passage 18 are formed by performing an etching process of the working fluid barrier layer 15 through a predetermined mask patterning. More specifically, the heat driving part 10 is formed as the insulated layer 12, the exothermic body 13, the electrode 14, and the working fluid barrier layer 15 are sequentially laminated on the substrate 11 (which is a silicon substrate). In such a situation, the working fluid chambers 16 and 17 (which are filled with the working fluid to be expanded by heat, are formed on an etched portion of the working fluid barrier layer 15. The working fluid is introduced through the working fluid introducing passage 18. FIG. 3C shows a process for adhering the separately-made membrane 20 to the upper portion of the completed heat driving part 10. The membrane 20 is a thin diaphragm, which is to be driven toward the jetting fluid chamber 37 (see FIG. 1) by the working fluid which is heated by the exothermic body 13. FIG. 4A shows a process for manufacturing a nozzle 35 using the laser processing equipment 53 (shown in FIG. 2) after an insulated layer 32 and the nozzle plate 34 are sequentially formed on a substrate 31 of the nozzle part 30. FIG. 4B shows a process for forming the jetting fluid barrier layer 36 on the upper portion of the construction shown in FIG. 4A, and jetting fluid chambers 37 and 38 and the fluid introducing passage by an etching process through a predetermined mask patterning. FIG. 4C shows a process for exclusively separating the nozzle part 10 from the substrate 31 of the nozzle part 30. The nozzle part 30 includes the jetting fluid barrier layer 36 and the nozzle plate 34. On the etched portion of the jetting fluid barrier layer 36, the jetting fluid chambers 37 and 38 filled with the fluid to be jetted are formed. The jetting fluid such as an ink, or the like, is introduced through the jetting fluid introducing passage 39 (see FIG. 1) for introduction of the jetting fluid. The nozzle 35 is formed on the nozzle plate 34 to be interconnected with the jetting fluid chamber 37, so that the fluid is jetted through the nozzle 35. The nozzle part 30 is manufactured by the processes that are shown in FIGS. 4A to 4C. First, the nozzle plate 34 inclusive of the nozzle 35, is formed on the substrate 31 having the insulated layer 32 through an electroplating process. Next, the jetting fluid barrier layer 36 is laminated thereon, and the jetting fluid chambers 37 and 38 and the jetting fluid introducing passage 39 are formed through a lithographic process. Finally, as the insulated layer 32 and the substrate 31 are removed, the nozzle part 30 is completed. The completed nozzle part 30 is reversed, and then adhered to the membrane 20 of a membrane, heat driving part assembly which has been assembled beforehand. More specifically, the jetting fluid barrier 36 of the nozzle part 30 is adhered to the polyimide coated layer 21 of the membrane 20. The operation of the fluid jetting apparatus according to the thermal compression system will be described below with reference to the construction shown in FIG. 1. First, an electric power is supplied through the electrode 14, and an electric current flows through the exothermic body 13 connected to the electrode 14. Since the exothermic body 13 generates heat due to its resistance, the fluid within the working fluid chamber 16 is subjected to a resistance heating, and the fluid starts to vaporize when the temperature thereof exceeds a predetermined temperature. As the amount of the vaporized fluid increases, the vapor pressure accordingly increases. As a result, the membrane 20 is driven upward. More specifically, as the working fluid undergoes a thermal expansion, the membrane 20 is pushed upward in a direction indicated by the arrow in FIG. 1. As the membrane 20 is pushed upward, the fluid within the jetting fluid chamber 37 is jetted out toward an exterior through the nozzle 35. Then, when the supply of electric power is stopped, the resistance heating of the exothermic body 13 is no longer generated. Accordingly, the fluid within the working fluid chamber 16 is cooled to a liquid state, so that the volume thereof decreases and the membrane 20 recovers its original shape. Meanwhile, a conventional material of the nozzle plate 34 is mainly made of nickel, but the trend in using the material of a polyimide synthetic resin has increased recently. When the nozzle plate 34 is made of the polyimide synthetic resin, it is fed in a reel type. The fluid jetting apparatus is completed by the way a chip laminated from the silicon substrate to the jetting fluid barrier layer 36 is bonded on the nozzle plate 34 fed in the reel type. According to the conventional fluid jetting apparatus and its manufacturing process, however, since the heat driving part, the membrane, and the nozzle part have to be separately made before such are adhered to each other by three adhering processes, the productivity has been decreased. Further; since the adhesion between the heat driving part and the membrane, and between the membrane and, the nozzle part are often unreliable, the working fluid and the jetting fluid often leak, so that a fraction defective has been increased, and the reliability and quality of the fluid jetting apparatus has been deteriorated. The present invention has been made to overcome the above-described problems of the prior art, and accordingly it is an object of the present invention to provide a fluid jetting apparatus and a manufacturing process thereof capable of improving the reliability, quality and the productivity of the fluid jetting apparatus by sequentially laminating a heat driving part, a membrane, and a nozzle part to form the fluid jetting apparatus, instead of adhering the same to each other. Additional objects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention. The above and other objects are accomplished by a method of manufacturing a fluid jetting apparatus according to the present invention, including: (1) forming a heat driving part having a sacrificial layer; (2) forming a membrane on the heat driving part which includes the sacrificial layer; (3) forming a nozzle part on the membrane; and (4) removing the sacrificial layer. The step (1) includes: (i) forming an electrode and an exothermic body on a substrate; (ii) laminating a working fluid barrier on the electrode and the exothermic body, and forming a working fluid chamber in the working fluid barrier; (iii) forming a protective layer on the working fluid barrier, the electrode, and the exothermic body; (iv) forming a sacrificial layer on the protective layer and within the working fluid chamber at the same height as the working fluid barrier. Further, the step (1) may otherwise include: (i) forming an electrode and an exothermic body on a substrate; (ii) forming a plane layer on the substrate at the same height as the electrode and the exothermic body combined; (iii) laminating a protective layer on the electrode and the plane layer; (iv) laminating the working fluid barrier on the protective layer, and forming a working fluid chamber in the working fluid barrier; and (v) forming the sacrificial layer on the protective layer and within an interior of the working fluid chamber at the same height as the working fluid barrier. The step (2) is performed through a spin coating process. The step (3) includes: (i) laminating a jetting fluid barrier on the membrane, and forming a jetting fluid chamber in the jetting fluid barrier; and (ii) laminating a nozzle plate on the jetting fluid barrier, and forming a nozzle in the nozzle plate. The nozzle plate is laminated through a process for laminating a dry film. The above and other objects of the present invention may further be achieved by providing a fluid jetting apparatus including a heat driving part which generates a driving force, a nozzle part having a jetting fluid chamber interconnected to an exterior of the fluid jetting apparatus through a nozzle, and a membrane which transmits the driving force generated from the heat driving part to the nozzle part, wherein the heat driving part comprises: an electrode and an exothermic body formed on a substrate; a plane layer formed on the substrate at the same height as the electrode and the exothermic body combined; a protective layer laminated on the plane layer; and a working fluid barrier laminated on the protective layer, and provided with the working fluid chamber for holding a working fluid which is expanded by the exothermic body to generate the driving force.

Event Description Professor Bill Lee, Former Director of the Centre for Nuclear Engineering, Imperial College London Speakers include: Dr Dan Poulter MP Tim Yeo, Chairman, New Nuclear Watch Europe (NNWE) Nick Butler, Energy Commentator, Financial Times Peter Atherton, Associate, Cornwall Energy New Nuclear Watch Europe (NNWE) invites you to attend our upcoming Parliamentary Briefing on The future of nuclear energy in Europe following Brexit, due to be held in the House of Commons, London, on the 14 March 2017 at 16.00. The event will focus on the opportunities and challenges facing the nuclear energy sector across Europe following Brexit. With the UK moving forward with a pipeline of new nuclear build projects, most recently with the CGN-EDF Hualong 1 application for GDA approval, this event will bring together leading policymakers, industry, academics and commentators to discuss how Europe can continue to be a global leader in nuclear energy development. NNWE intends to promote discussion on the need for a Pan-European, or EU+, policy framework when discussing new nuclear build. With Brexit likely to occur in 2019, and the recent announcement that the UK will be pulling out of the Euratom Treaty, NNWE envisages the development of an Organisation for Nuclear Cooperation and Development in Europe, to continue and further enhance nuclear cooperation. The latest EU PINC report highlights that 105GWe of new nuclear generation will be needed by 2050 – roughly 100 new reactors – to meet existing demand and climate change targets. However, only eighteen nuclear power plants are in development, planned, or proposed within the European Union itself. Whereas ninety-five reactors are planned throughout our EU neighbours – including Belarus, Russia, Switzerland, Turkey, Ukraine and now the UK. NNWE believes an organisation is needed to drive the future of nuclear energy development across Europe and help us reach the ambitious 2050 target. Agenda (subject to change) Time Description 16.00 Registration and light refreshments 16.15 Introduction Dr Dan Poulter MP Professor Bill Lee, Former Director of the Centre for Nuclear Engineering, Imperial College London NNWE was established at the end of 2014 under the chairmanship of Tim Yeo (former UK Member of Parliament and Chair of the House of Commons Energy and Climate Change Select Committee) and is an interest group which aims to ensure nuclear power is recognised as an important and desirable way for European governments to meet the long-term security needs of their countries.

Tetsuya Nakashima Tetsuya Nakashima (中島哲也) (born 1959) is a Japanese film director. He was born in Fukuoka, attending high school in Chikushino. Nakashima was given the Best Director award at the 2005 Yokohama Film Festival for his film Kamikaze Girls. His 2010 film Confessions was selected as the Japanese entry for the Best Foreign Language Film at the 83rd Academy Awards and made the final shortlist in January 2011. He was originally slated to direct an adaptation of the hit manga Attack on Titan, but in December 2012 he left the project due to differences with the rest of the production team. Filmography Bakayaro! I'm Plenty Mad (1988) (segment 2) Happy-Go-Lucky (1997) Beautiful Sunday (1998) Kamikaze Girls (2004) Rolling Bomber Special (2005) Memories of Matsuko (2006) Paco and the Magical Picture Book (2008) Confessions (2010) The World of Kanako (2014) It Comes (2018) References External links Category:1959 births Category:Living people Category:Japanese film directors Category:People from Fukuoka Prefecture

Q: Corona sdk Get Sim Card Details I'm creating an Application using Corona sdk with Lua Language, can anyone help me with getting Sim Card details such as, mobile Number, pin no .. etc Thank you A: Corona provides system.getInfo() for getting device-specific information. I dont think you can find the mobile Number, but there is some info you can get. You can get more details in the docs You probably will find deviceID useful: On iOS, "deviceID" returns a "unique" id for the device. Per Apple's policies, on iOS 6 and later, "deviceID" returns a MD5 hash of the device's "identifierForVendor" (see below); on iOS 5 it returns a MD5 of a GUID (Globally Unique Identifier) that is unique for each app install. On Android, if your app uses the "android.permission.READ_PHONE_STATE" permission, the following will be returned: IMEI for GSM phones. MEID or ESN for CDMA phones. The operating system's unique ID for devices that are not phones. If your Android app does not use the "android.permission.READ_PHONE_STATE" permission, then the operating system's unique ID will be returned for all devices. Note that the operating system's unique ID may change after re-installing the operating system on the device.

1. Field of the Invention The invention relates generally to a device that attaches to a telephone for the purpose of lifting up the receiver end of a telephone handset (hook-switching). 2. Description of the Prior Art Many of the newest telephone systems that are coming out on the market have what is called electronic hook-switching. This is basically a button, that when pressed, will give a dial tone for a telephone headset. This is a very convenient option for people who use telephone headsets, but the problem still remains that there are literally millions of telephones on the market that do not have this option. Until now, the only option that people have had to alleviate this problem is to physically pick up the handset every time the telephone rings, and place the headset off to the side of the telephone base. This procedure is time and space consuming. Another method that is commonly used when getting a dial tone, is to balance the telephone handset just up and to the side of the telephone""s hook-switch. The major problem with this solution is that if accidently bumped or moved, the handset will fall back into place and one will hang up the line. The present invention overcomes the prior art practices by providing a mechanical handset lift for lifting the receiver end of a telephone handset off the hook-switch and pivoting the handset about the microphone end, but leaving the handset centrally positioned over and about the telephone body. The general purpose of the present invention is to provide a mechanical device for lifting the receiver end of a telephone handset off the telephone hook-switch to allow electrical operation of a remote handset receiver/mouthpiece while still leaving the handset placed over and about the telephone base unit. According to one object of the present invention, there is provided a vertically oriented base for mounting to the side of a telephone base. A moveable pivot shaft extends through an upper region of the vertically oriented base end, which includes a lift rod secured to one end of the pivot shaft and a lift rod lever handle secured to the opposite end of the pivot shaft. A stop shaft limits the over center travel of the lift rod lever handle and the lift rod to allow on hook or off hook positioning of a telephone handset receiver. According to an alternate embodiment of the present invention, there is provided a vertical base member with a lift rod and lift lever secured about the base member in positive locked alignment and also having rotational stops aligned on a surface of the vertical base member. One significant aspect and feature of the present invention is mechanical handset lift that will mechanically lift up the receiver end of a telephone handset off the hook-switch so that a dial tone may be obtained for the telephone headset in use. Another significant aspect and feature of the present invention is a mechanical handset lift which will lift the receiver end of a telephone handset off the hook-switch so as to allow a user to use either the telephone handset or a telephone headset. A further significant aspect and feature of the present invention is a mechanical handset lift which will lift the receiver end of a telephone handset off the hook-switch and which will result in the environment on a person""s desk being less cluttered due to the absence of a telephone handset lying off to the side of the telephone base while the telephone handset is in use. Yet another significant aspect and feature of the present invention is a mechanical handset lift that will mechanically lift up the receiver end of a telephone handset in such a manner that will greatly increase the chances of not accidentally hanging up the telephone while a telephone headset is in use. Another significant aspect and feature of the present invention is a lift rod and lift rod handle in positive angular engagement with each other about a base unit. Another significant aspect and feature of the present invention is stops which define rotational movement of the lift rod and lift rod handle with respect to the base of a telephone. Having thus described the embodiments of the present invention, it is the principal object hereof to provide a mechanical handset lift. The present invention relates to a mechanical handset lift device that will enable the telephone user to enable and disable the telephone""s hook-switch capabilities without the inconvenience of picking up the telephone and placing it on the desk. Currently, the only means to do this is by placing the telephone handset on and off the hook-switch. The problems that arrive from this method are 1) one has to physically pick up the handset every time the telephone rings, 2) one has to lay the handset on the desk (for many people this takes up just too much room), 3) if the telephone allows one to balance the handset off to the right side of the hook switch, one may bump the telephone, and accidentally hang up. The invention uses the handset""s own mold to accomplish the goal of hook-switching, and allows the handset to be used as well. The present invention also creates an environment where it is virtually impossible to accidently hand up the telephone. This is a very common problem when the telephone is balanced to the side of the hook-switch. It is an object of the present invention to provide a device that will enable a telephone handset operator to use both the telephone handset or headset conveniently, without the problems that are currently plaguing the telephone headset industry.

Seven rare rhinos spotted in Indonesian jungle August 9, 2012 in Biology / Ecology In this undated photo released by Leuser International Foundation, a Sumatran rhino roams at Gunung Leuser National Park in Aceh province, Indonesia. A conservationist from the foundation said Thursday, Aug. 9, 2012 that seven of the world's rarest rhinoceroses were photographed at the national park. It is the first sighting there in 26 years. (AP Photo/Leuser International Foundation) NO SALES Seven Sumatran rhinos have been captured on hidden cameras in an Indonesian national park where the critically endangered species was feared extinct, a conservationist said Thursday. The Sumatran rhino had not been sighted in the Mount Leuser National Park on the northern tip of Sumatra for 26 years, the project's team leader Tarmizi of the Leuser International Foundation said. "This discovery can allay doubts over the rhino's presence in the park," Tarmizi told AFP, adding he hoped the discovery would encourage more efforts to conserve the species. Images of the rhinos were captured by 28 infrared cameras set up between June 2011 and April this year and confirmed six female and one male rhino appearing in 1,000 photo frames. The Sumatran rhino population has dropped 50 percent over the past 20 years, and there are now believed to be fewer than 200 left in the world. The rhinos are commonly targeted by poachers and rampant illegal logging has destroyed much of their habitat.

Notice # 01-184 May 31, 2001 TO: All NYMEX Division Members and Member Firms FROM: Neal L. Wolkoff, Executive Vice President RE: Reminder on Use of Money Market Funds as Original Margin Deposits on the NYMEX Division DATE: May 31, 2001 =========================================================== This Notice is a reminder regarding certain rule changes and related policy guidelines that will go into effect on June 1, 2001 for the NYMEX Division. The rule changes going into effect on June 1, 2001 on the NYMEX Division allow shares of certain money market mutual funds to be acceptable for purposes of original margin deposits. Corresponding rule changes for the COMEX Division have also been approved by the NYMEX Board of Directors and filed with the CFTC; the changes for the COMEX Division will be implemented at a later date. Rule Amendments The amendments generally require that in order to be used for such purpose, a money market fund must be approved by the NYMEX Board and also must comply with CFTC Regulation ? 1.25. For purposes of original margin, the Exchange's Clearing House will value such money market fund shares at 95% of their market value. In addition, a Clearing Member's participation in any approved fund or any group of approved funds offered by the same issuer shall be limited to the greater of $250,000 or 25% of the Clearing Member's total original margin obligations. Finally, no more than 25% of the total assets of an approved money market mutual fund may be used to meet original margin obligations at the Exchange. Exchange Policy on Money Market Funds The NYMEX Board of Directors also recently adopted three additional guidelines that will be applicable to such funds. First, until further notice from the Exchange, the Board has determined to limit the number of money market funds available for this purpose to ten. Second, the Board will require that henceforth each fund applying for such status must have a minimum value of $5 billion. Finally, each fund further must provide for same day payment if notification is made by 3:00 p.m. on that day. If you have any questions concerning this change, please contact Bernard Purta, Senior Vice President, Regulatory Affairs and Operations, at (212) 299- 2380; Arthur McCoy, Vice President, Financial Surveillance Section, NYMEX Compliance Department, at (212) 299-2928; or Joseph Sanguedolce, Director, Financial Surveillance Section, NYMEX Compliance Department, at (212) 299-2855. AMENDMENTS TO NYMEX RULE 9.05 ("MARGINS") (Asterisks indicate additions; brackets indicate deletions.) Rule 9.05. MARGINS * * * * (E) Clearing Members may meet original margin calls by depositing: *(4) Shares in a money market mutual fund that complies with CFTC Regulation ?1.25 and that has been approved by the Board, subject to the following conditions: (i) for purposes of original margin, such shares will be valued at 95% of market value; (ii) a Clearing Member's participation in any approved fund or any group of approved funds offered by the same issuer shall be limited to the greater of $250,000 or 25% of the Clearing Member's total original margin obligations; (iii) no more than 25% of the total assets of an approved money market mutual fund may be used to meet original margin obligations at the Exchange.* [Shares of Brown Brothers Harriman & Co. Common Settlement Fund, valued at 95% of market value.] __________________________________________________ Please click on the link below to indicate you have received this email. "http://208.206.41.61/email/[email protected]&refdoc=(01-184)" Note: If you click on the above line and nothing happens, please copy the text between the quotes, open your internet browser, paste it into the web site address and press Return.

Management of ventricular tachycardia in the ablation era: results of the European Heart Rhythm Association Survey. Patients with sustained ventricular tachycardia (VT) are at risk of sudden death. Treatment options for VT include antiarrhythmic drug therapy, insertion of an implantable cardioverter-defibrillator, and catheter ablation. Evidence on indications for VT ablation, timing, ablation strategies, and periprocedural management is sparse. The aim of this European Heart Rhythm Association (EHRA) survey was to evaluate clinical practice regarding management of VT among the European countries. An electronic questionnaire was sent to members of the EHRA Electrophysiology Research Network. Responses were received from 88 centres in 12 countries. The results have shown that management of VTs is very heterogeneous across the participating centres. Indications, periprocedural management, and ablation strategies vary substantially. This EP Wire survey has revealed that catheter ablation is the first-line therapy for the treatment of recurrent monomorphic stable VT in patients without structural heart disease as well as in patients with ischaemic cardiomyopathy and impaired left ventricular ejection fraction in the majority of centres. Furthermore, in patients with ischaemic cardiomyopathy and the first episode of monomorphic VT, most centres (62.0%) performed catheter ablation. On the contrary, in patients with non-ischaemic cardiomyopathy, amiodarone (41.4%) and catheter ablation (37.1%) are used in a very similar proportion. Ablation strategies, endpoints, and post-ablation antithrombotic management vary substantially among European centres.

Is there a ProductHunt without the “selection process”? - hoodoof i.e. a site that actually shows what&#x27;s new, not just what ProductHunt thinks we should see is new? ====== ledil [http://www.produktfang.de](http://www.produktfang.de) I'm the author of produktfang. We aggregate new apps and show them on the front page ... there is no "community" that decides what should be shown or not like in producthunt. ------ getdavidhiggins [http://urli.st/](http://urli.st/) Lots of products can be found on URLIST. It's basically product hunt, except not sabotaged by trends and a karma system

Q: Scale down numbers with known max min to new max min in PHP Let's say I have this array of numbers: $arr = [100, 60, 30, 22, 1] and it's based off a 1 - 100 range. And I want it based of a 1 - 5 range. I have found this answer here: How to scale down a range of numbers with a known min and max value which details: Array.prototype.scaleBetween = function(scaledMin, scaledMax) { var max = Math.max.apply(Math, this); var min = Math.min.apply(Math, this); return this.map(num => (scaledMax-scaledMin)*(num-min)/(max-min)+scaledMin); } But I am not sure how I would translate that to PHP/Laravel. A: Not sure if this are the correct results, but it does what you described: $arr = [100, 60, 30, 22, 1]; function scale(array $array, float $min, float $max): array { $lowest = min($array); $highest = max($array); return array_map(function ($elem) use ($lowest, $highest, $min, $max) { return ($max - $min) * ($elem - $lowest) / ($highest - $lowest) + $min; }, $array); } echo json_encode(scale($arr, 1, 10)); // [10,6.363636363636363,3.6363636363636362,2.909090909090909,1]

Background ========== Polysaccharide-rich fungi and plants have been employed for centuries by cultures around the world for their dietary and medicinal benefits \[[@B1]-[@B5]\]. Often thought to merely support normal bowel function and blood glucose and lipid levels \[[@B6]-[@B8]\], certain polysaccharides have attracted growing scientific interest for their ability to exert marked effects on immune system function, inflammation and cancers \[[@B9]-[@B11]\]. Many of these chemically and structurally diverse, non- to poorly-digestible polysaccharides have been shown to beneficially affect one or more targeted cellular functions *in vitro*\[[@B11]-[@B16]\], but much of the *in vivo*literature consists of studies in which polysaccharides were injected \[[@B1],[@B2]\]. For clinicians and scientists interested in immunologic effects following dietary intake, the value of such studies is uncertain. Polysaccharides that elicit effects *in vitro*or by injection may be ineffective or have different effects when taken orally \[[@B17]\]. We thus decided to conduct a systematic review to evaluate the specific immunologic effects of dietary polysaccharide products on rodents and human subjects. Methods ======= Literature review ----------------- Studies were identified by conducting electronic searches of PubMed and Google Scholar from their inception to the end of October 2009. The reference lists of the selected articles were checked for additional studies that were not originally found in the search. Study selection and data extraction ----------------------------------- The following search terms were combined with the term polysaccharide: dietary AND immune, or oral AND immune, or dietary AND inflammation, or oral AND inflammation. When specific polysaccharides or polysaccharide-rich plants and fungi were identified, further searches were conducted using their names with the same search terms. Studies were selected based on the following inclusion criteria: 1\. Rodent or human studies 2\. The presence of test group and control group (using either placebo, crossover, sham, or normal care) 3\. Studies reporting statistically significant immunomodulatory effects 4\. English language 5\. Studies published up to October 2009. Two researchers (JER, EDN) reviewed the list of unique articles for studies that fit the inclusion criteria. Uncertainties over study inclusion were discussed between the researchers and resolved through consensus. Searches were then conducted to obtain specific polysaccharide product information: safety (using the search terms: toxicity, NOAEL, LD~50~), composition and structure, and disposition. Quality assessment ------------------ Each study was assessed as to whether or not it reported a significant outcome measure for the polysaccharide intervention group. Results ======= A total of 62 rodent publications (Tables [1](#T1){ref-type="table"}, [2](#T2){ref-type="table"} and [3](#T3){ref-type="table"}) and 15 human publications (Table [4](#T4){ref-type="table"}) were deemed appropriate for inclusion in this review. Available structural and compositional information for these immunomodulatory polysaccharides are provided in Table [5](#T5){ref-type="table"} and safety information is provided in Table [6](#T6){ref-type="table"}. The majority of animal studies explored models in which animals were injected or implanted with cancer cells or tumors, were healthy, or were exposed to carcinogens. Other studies investigated immunodeficient, exercise-stressed, aged animals, or animals exposed to inflammatory agents, viruses, bacterial pathogens, pathogenic protozoa, radiation or mutagens. Human studies assessed immunomodulatory effects in healthy subjects, or patients with cancers, seasonal allergic rhinitis or aphthous stomatitis. Because of the limited number of human studies, we included some promising open-label controlled trials. Human study durations ranged from four days to seven years; daily doses ranging from 100-5,400 mg were reported to be well-tolerated. ###### Immunomodulatory Glucan Extracts: Oral Animal Studies ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ Source Extract Animal Dose/day Duration of study Treatment Effects Reference ------------------------------------- ---------------------------------- --------------------------------------------------------------------------- ---------------------------------------------------------------------- ------------------- ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ ------------ *Agaricus*\ α-1,6 and\ 8-week ♀ C3H/He mice (5/group) 100 mg/kg IG every 3 days 1 month Healthy animals ↑ \#s splenic T lymphocytes (Thy1.2, CD4+ and CD8+) \[[@B24]\] (*A. blazei*) *subrufescens* α-1,4 glucans Aqueous 7-9-week ♂ Balb/cByJ mice (40/group) 1 ml 0.45N, 0.6N, or 3N aqueous extract 2 months All doses ↑ serum IgG levels, CD3+ T cell populations and PML phagocytic activity \[[@B22]\] 7-9-week male Balb/cByJ mice (40/group) 1 ml 0.45N, 0.6N, or 3N aqueous extract 10 weeks IP injection of OVA at 4 weeks 0.6N and 3N ↑ levels of OVA-specific serum IgG 28 days post-immunization; all doses ↑ delayed-type hypersensitivity and TNF-α secreted from splenocytes at 10 weeks; 0.6N ↑ splenocyte proliferation at 10 weeks 5-6 -week ♀ BALB/cHsdOla mice (8/group × 2) One 200 μl extract day 1, orogastric intubation 1 week Injected IP fecal solution day 2 ↓ CFU in blood of mice with severe peritonitis & improved overall survival rate in all peritonitis groups \[[@B46]\] 6-week BALB/c nu/nu mice (7/group) 2.5 mg extract days 20-41, drinking water 41 days Injected SC Sp-2 myeloma cells day 1 ↓ tumor size & weight after 21 days treatment \[[@B65]\] Aqueous, acid treated 6-week ♀ C57BL/6 mice (10/group) 20, 100 or 500 μg/ml, drinking water 9 days Injected IP human ovarian cancer cells day 1 500 μg/ml ↓ tumor weight \[[@B66]\] 20, 100 or 500 μg/ml, drinking water 3 weeks Injected IV murine lung cancer (3LL) cells 100 & 500 μg/ml ↓ \#s metastatic tumors Aqueous, with 200 ng/day\ 6-week ♀ BALB/c mice (10/group) 200 ng days 5-21 3 weeks Injected Meth A tumor cells day 1 ↓ tumor size & weight \[[@B23]\] β-glucan 2 weeks Injected Meth A tumor cells ↑ cytotoxic T lymphocyte activity & spleen cell IFN-α protein 300 mg 5 days Healthy animals ↑ splenic NK cell activity *Avena*spp. β-glucans (particulate) 6-7 -week ♀ C57BL/6 mice (7/group) 3 mg every 48 h, days 1-3 1 month Oral *E. vermiformis*oocytes day 10 ↓ *E. vermiformis*fecal oocyte \#s; increased intestinal anti-merozoite IgA; ↓ \# of IL-4-secreting MLN cells \[[@B42]\] 3 mg on alternating days, days 1-10 22 days Injected IP *Eimeria vermiformis*day 10 ↓ *E. vermiformis*fecal oocyte \#s; ↑ anti-merozoite intestinal IgA \[[@B43]\] β-glucans (soluble) 4-week ♂ CD-1 mice (24/group) 0.6 mg/ml 68% β-glucan, drinking water 1 month Resting or exercise-stressed (days 8-10) animals administered HSV-1 IN\ ↓ morbidity in resting and exercise-stressed animals; ↓ mortality in exercise-stressed animals; pre-infection, ↑ Mø anti-viral resistance in resting and exercise-stressed animals \[[@B38]\] day 10 \~3.5 mg days\ Resting or exercise-stressed (days 5-10) animals administered HSV-1 IN\ Pre-infection, ↑ Mø antiviral resistance in resting animals \[[@B41]\] 1-10, drinking water day 10 4-week ♂ CD-1 mice (10/group) 0.6 mg/ml 68% β-glucan, drinking water 10 days Resting animals or animals exposed to a bout of fatiguing exercise days 8-10 or moderate exercise days 5-10, injected IP with thioglycollate on day 10 ↑ neutrophil mobilization in resting & moderately exercised animals; ↑ neutrophil respiratory burst activity in resting and fatiguing exercised animals \[[@B37]\] 4-week ♂ CD-1 mice (19-30/group) 0.8 mg/ml 50% β-glucan, days\ 1 month Resting or exercise-stressed (days 8-10) animals administered IN clodronate-filled liposomes to deplete Mø days 8 & 14 & infected IN with HSV-1 day 10 ↓ morbidity, mortality, symptom severity in exercise-stressed animals, without Mø depletion \[[@B40]\] 1-10, drinking water 4-week ♂ CD-1 mice (20/group) Resting or exercise-stressed (days 8-10) animals administered HSV-1 IN day 10 ↓ morbidity in exercise-stressed & resting animals; ↓ mortality in exercise-stressed animals \[[@B39]\] *Ganoderma lucidum* Aqueous 7-week ♂ CD-1 mice (26/group) 5% of diet 5 months Injected IM DMH once a week, weeks 1-10 ↓ aberrant crypt foci per colon, tumor size, cell proliferation, nuclear staining of β-catenin \[[@B69]\] 4-8-week BALB/c mice (10/group) 50, 100 or 200 mg/kg, oral 10 days Injected SD Sarcoma 180 cells ↓ of tumor weight was dose dependent: 27.7, 55.8, 66.7%, respectively \[[@B67]\] *Ganoderma lucidum*(mycelia) Aqueous 7-week ♂ F344/Du Crj rats (16/group) 1.25% or 2.5% of diet 6 months Injected SC AOM once a week, weeks2-5 Both doses ↓ colonic adenocarcinoma incidence; 2.5% ↓ total tumor incidence; both doses ↓ nuclear staining of β-catenin and cell proliferation \[[@B68]\] *Ganoderma tsugae* Aqueous 8-week ♀ BALB/cByJNarl mice (14/group) 0.2-0.4% of diet (young fungi); 0.33 or 0.66% of diet (mature fungi) 5 weeks Injected IP OVA days 7, 14, 21; aerosolized OVA twice during week 4 In splenocytes, both doses of both extracts ↑ IL-2 and IL-2/IL-4 ratios, 0.2% young extract and 0.66% mature extract ↓ IL-4; in Mø, 0.66% mature extract ↑ IL-1β, both doses of both extracts ↑ IL-6 \[[@B53]\] *Grifola frondosa* D fraction Mice: 1) ICR, 2) C3H/HeN, 3) CDF~1~(10/group) 1.5 mg every other day, beginning day 2 13 days Implanted SC: 1) Sarcoma-180, 2) MM-46 carcinoma, or 3) IMC carcinoma cells ↓ tumor weight & tumor growth rate: 1) 58%, 2) 64%, and 3) 75%, respectively \[[@B71]\] 5-week ♂ BALB/c mice (10/group) 2 mg,\ 45 days Injected in the back with 3-MCA, day 1 ↓ (62.5%) \# of animals with tumors; ↑ H~2~0~2~production by plasma Mø; ↑ cytotoxic T cell activity \[[@B72]\] days 15-30 *Hordeum vulgare* β-1,3;1,4 or β-1,3;1,6-D-glucans Athymic nu/nu mice\ 40 or 400 μg IG for 4 weeks 31 weeks Mice with human xenografts (SKMel28 melanoma, A431 epidermoid carcinoma, BT474 breast carcinoma, Daudi lymphoma, or LAN-1 neuroblastoma) ± mAb (R24, 528, Herceptin, Rituximab, or 3F8, respectively) therapy twice weekly 400 μg + mAb ↓ tumor growth & ↑ survival; higher MW ↓ tumor growth rate for both doses \[[@B75]\] (4-12/group) β-1,3;1,4-D-glucans Athymic BALB/c mice 4, 40, or 400 μg for 3-4 weeks 1 month Mice with neuroblastoma (NMB7, LAN-1, or SK-N-ER) xenografts, ± 3F8 mAb therapy twice weekly 40 and 400 μg doses + mAB ↓ tumor growth; 400 μg dose ↑ survival. Serum NK cells required for effects on tumor size \[[@B76]\] C57BL/6 WT and CR3-deficient mice (10/group) 0.4 mg for 3 weeks 100 days Injected SC RMA-S-MUC1 lymphoma cells day 1 ± IV 14.G2a or anti-MUC1 mAb every 3rd day ±mAB ↓ tumor diameter; ↑ survival \[[@B73]\] β-glucans ♀ Fox Chase ICR immune-deficient (SCID) mice (9/group) 400 μg days 1-29 50 days Mice with human (Daudi, EBV-BLCL, Hs445, or RPMI6666) lymphoma xenografts, ± Rituximab mAb therapy twice weekly +mAB ↓ tumor growth and ↑ survival \[[@B74]\] *Laminaria digitata* Laminarin ♂ ICR/HSD mice (3/group) 1 mg 1 day Healthy animals ↑ Mø expression of Dectin-1 in GALT cells; ↑ TLR2 expression in Peyer\'s patch dendritic cells \[[@B29]\] ♂ Wistar rats (7/group) 5% of diet days 1-4, 10% of diet days 5-25 26 days Injected IP *E. coli*LPS day 25 ↓ liver ALT, AST, and LDH enzyme levels; ↑ ED2-positive cells, .↓ peroxidase-positive cells in liver; ↓ serum monocytes, TNF-α, PGE2, NO~2~ \[[@B44]\] *Lentinula edodes* SME 6-week nude mice 0.1 ml water with10% SME/10 g body weight days 1-19, 33-50 50 days Injected SC prostate cancer (PC-3) cells day 1 ↓ tumor size \[[@B80]\] β-glucans ♀ 3- and 8-week BALB/c mice (15/group) 50, 100 or 250 μg 1-2 weeks Healthy animals 250 μg dose ↑ spleen cell IL-2 secretion \[[@B27]\] ♀ 3- and 8-week BALB/c mice (15/group) 50, 100 or 250 μg 1-2 weeks Injected murine mammary carcinoma (Ptas64) cells into mammary fat pads 2 weeks before treatment ↓ tumor weight Lentinan 6-week ♂ Wistar-Imamichi specific-pathogen free rats (10/group) 1 mg twice weekly 1-2 months Healthy animals ↑ T cell \#s, helper-cell \#s & helper/suppressor ratio, ↓ suppressor cell level at 4, but not 8 weeks \[[@B26]\] 5-6-week ♂\ 3 mg, days 1-7 3 weeks Injected SC K36 murine lymphoma cells day 7 ↓ tumor weight; ↑ tumor inhibition rate (94%) \[[@B82]\] pre-leukemic AKR mice (10/group) 5-6-week athymic mice (10/group) 5 weeks Injected SC colon cancer (LoVo and SW48, SW480 and SW620, or SW403 and SW1116) cells day 7 ↓ tumor weight, ↑ tumor inhibition rate (\>90%) ♂ AKR mice 3 mg 1 day Pre-leukemic mice ↑ serum IFN-α and TNF-α, peak at 4 h and then back to normal at 24 h; ↑ IL-2 and IL-1α, peak at 2 h and back to normal at 24 h; ↑ CD3+ T, CD4+ T, CD8+ T, B lymphocytes \[[@B81]\] *Phellinus linteus* Aqueous, alcohol-precipitated 6-7-week C57BL/6 mice (10-50/group) 200 mg/kg in drinking water 1 month Healthy animals ↑ production and secretion of IFN-γ by con A stimulated T cells \[[@B32]\] *Saccharomyces cerevisiae* Scleroglucan ♂ ICR/HSD mice (3/group) 1 mg one day before challenge (day 1) 6 days IV *Staphylococcus aureus*or *Candida albicans*day 2 ↑ long-term survival \[[@B29]\] β-1,3;1,6 glucans (particulate) 3 and 8-week ♀ BALB/c mice (15/group) 50, 100 or 250 μg 1-2 weeks Injected murine mammary carcinoma (Ptas64) cells into mammary fat pads 2 weeks before treatment ↓ tumor weight \[[@B27]\] β-1,3-glucan Healthy animals All 3 doses ↑ phagocytic activity of blood monocytes & neutrophils & ↑ spleen cell IL-2 secretion WT or CCD11b^-/-^C57BL/6 mice (2/group) 0.4 mg for 3 weeks 100 days Injected SC RMA-S-MUC1 lymphoma cells ± 14.G2a or anti-MUC1 mAb IV injection every 3^rd^day ↓ tumor diameter when included with mAb; ↑ survival with and without mAb \[[@B73]\] C57BL/6mice (4/group) 25 mg 1 week Healthy animals ↑ \# intestinal IELs; ↑ \# TCRαβ+, TCR γδ+, CD8+, CD4+, CD8αα+, CD8αβ+ T cells in IELs; ↑ IFN-γ mRNA expression in IELs and spleen \[[@B28]\] *Sclerotinia sclerotiorum* SSG 6-8-week specific pathogen-free ♂ CDF~1~mice (3/group) 40 or 80 mg/kg days 1-10 2 weeks Healthy animals 10 mg dose ↑ acid phosphatase activity of peritoneal Mø (day 14) \[[@B30]\] 40, 80 or 160 mg/kg days 2-6 35 days Implanted SC Metha A fibrosarcoma cells day 1 80 mg dose ↓ tumor weight 6-8-week specific pathogen-free ♂ CDF~1~mice (10/group) 40, 80 or 160 mg/kg days 2-11 Injected ID IMC carcinoma cells day 1 6-8-week specific-pathogen free ♂ mice of BDF1 and C57BL/6 mice (7/group) 0.5, 1, 2, or 4 mg days 1-10 2-3 weeks Injected IV Lewis lung carcinoma (3LL) cells 2 mg ↓ \# of 3LL surface lung nodules at 2 weeks \[[@B83]\] *Sclerotium rofsii* Glucan phosphate ♂ ICR/HSD mice (3/group) 1 mg 1 day Healthy animals ↑ systemic IL-6; ↑ Mø expression of Dectin-1 in GALT cells; ↑ TLR2 expression in dendritic cells from Peyer\'s patches \[[@B29]\] *Trametes*(*Coriolus*) *versicolor* PSP 6-8-week ♂ BALB/c mice (10/group) 35 μg days 5-29 in drinking water 29 days Implanted SC Sarcoma-180 cells day 1 ↓ tumor growth & vascular density \[[@B94]\] ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ ###### Immunomodulatory Non-Glucan Extracts: Oral Animal Studies ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Extract Source Animal Oral dose/day Duration Treatment Significant effects Reference ---------------------------------------------------------------------- ------------------------------------------------------------------ ------------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------------- ---------- ---------------------------------------------------------------------------------------------------------------------- ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ------------- Fucoidans *Cladosiphon okamuranus Tokida* 8-week ♀ BALB/c mice, 10/group 0.05% w/w of diet 56 days DSS-induced UC ↓ disease activity index and myeloperoxidase activity; ↓ \# of B220-positive colonic B cells; ↓ colonic MLN IFN-γ and IL-6 and ↑ IL-10 and TGF-β; ↓ colonic IgG; ↓ colonic epithelial cell IL-6, TNF-α, and TLR4 mRNA expression \[[@B49]\] *Undaria pinnatifida* 5-week ♀ BALB/c mice (10-12/group) 5 mg, days 1-14 or 7-14 2 weeks Injected HSV into cornea day 7 ↓ facial herpetic lesions; ↑ survival, particularly in pre-treated animals \[[@B45]\] 10 mg 1 week Administered\ ↑ plasma NK cell activity 5-fluorouracil Injected SC HSV ↑ cytotoxic splenic T lymphocyte activity 0.1 or 0.5 mg 3 weeks Injected IP HSV Both doses ↑ serum neutralizing Ab titers, weeks 2 and 3 6-week ♂ ddY mice (5/group) 50, 100, 200 400 or\ 3 weeks Injected with Ehrlich carcinoma in back day 14 200-500 mg/kg ↓ tumor growth \[[@B116]\] 500 mg/kg\ days 1-28 6-week ♂ BALB/c mice (8/group) 40 mg/kg alternating days\ 19 days Injected IP Meth A fibrosarcoma day 1 ↓ tumor growth 7-19 Furanose (COLD-FX^®^) *Panax quinquefolium* Weanling ♂ SD rats (10/group) 450 or\ 1 week Healthy animals Both doses ↑ spleen Il-2 and IFN-γ production following ConA or LPS stimulation; ↓ proportion of total MLN and Peyer\'s patch CD3+ cells & activated T cells; high dose ↑ spleen cell IL-1β production following 48 h ConA stimulation. \[[@B33]\] 900 mg/kg in food Galacto-mannan (partially hydrolyzed guar gum) *Cyamopsis tetragonolobus* 10-week ♀ BALB/c mice,\ 5% of diet 3 weeks DSS-induced UC at beginning of\ ↓ disease activity index scores, ↓ colonic mucosal myeloperoxidase activity & lipid peroxidation; ↓ colonic TNF-α protein levels & mRNA expression up regulated by DSS exposure \[[@B50]\] 11-15/group week 3 Galacto-mannans\ 8-month- SD rats, 5/group 5% of diet 3 weeks Older animals ↓ serum IgG; ↑ MLN lymphocyte IgA, IgM and IgG production \[[@B36]\] (guar gum) Glucomannan (KS-2) *Lentinula edodes* DD1 mice (10-20/group) 140 mg/kg days\ 50 days Injected IP Ehrlich ascites tumor cells day 1 ↑ survival \[[@B84]\] 2-13 0.1, 1, 10, or 100 mg/kg dose days 2-13 100 days Injected Sarcoma-180 tumor cells\ 1, 10, and 100 mg/kg doses ↑ survival day 1 Heteroglycan (ATOM) *A. subrufescens* Mice (10/group): 1) 5-week ♂ Swiss/NIH; 6 week- ♀ DS mice; 3) 8-week ♀ BALB/c nude; 4) 5-week C3H/HcN 100 or\ 8 weeks Implanted SC 1) Sarcoma-180, 2) Shionogi carcinoma 42, 3) Meth A fibrosarcoma, or 4) Ehrlich ascites carcinoma cells Both doses ↓ Sarcoma-180 tumor size at 4 weeks & ↑ survival; 300 mg/kg ↑ peritoneal macrophage and C3-positive cells; 300 mg/kg ↓ Shionogi and Meth A tumor sizes at 4 weeks. Both doses ↑ survival of Ehrlich ascites mice \[[@B93]\] 300 mg/kg\ days 2-11 Heteroglycan (LBP~3p~) *Lycium barbarum* ♂ Kunming mice (10/group) 5, 10 or\ 10 days Injected SC Sarcoma-180 cells 5 & 10 mg/kg ↑ thymus index; all doses ↓ weight, ↓ lipid peroxidation in serum, liver and spleen & ↑ spleen lymphocyte proliferation, cytotoxic T cell activity, IL-2 mRNA \[[@B91]\] 20 mg/kg Heteroglycan (PNPS-1) *Pholiota nameko* SD rats (5/group) 100, 200 or 400 mg/kg days 1-8 8 days Implanted SC cotton pellets in scapular region\ ↓ granuloma growth positively correlated with dose: 11%, 18% and 44%, respectively \[[@B55]\] day 1 Heteroglycan (PG101) *Lentinus lepideus* 8-10-week ♀ BALB/c mice (3/group) 10 mg 24 days 6 Gy gamma irradiation ↑ colony forming cells, granulocyte CFUs/Mø, erythroid burst-forming units, and myeloid progenitor cells in bone marrow; induced proliferation of granulocyte progenitor cells in bone marrow; ↑ serum levels of GM-CSF, IL-6, IL-1β \[[@B92]\] Mixed poly-saccharides (Ambrotose^®^or Advanced Ambrotose^®^powders) *Aloe barbadensis*, *Larix*spp, and other plant poly-saccharides ♂ SD rats (10/group) 37.7 or 377 mg/kg Ambrotose^®^powder or 57.4 or 574 mg/kg Advanced Ambrotose^®^powder 2 weeks 5% DSS in drinking water beginning day 6 574 mg/kg Advanced Ambrotose powder ↓ DAI scores; 377 mg/kg Ambrotose complex & both doses Advanced Ambrotose powder ↑ colon length and ↓ blood monocyte count \[[@B52]\] Pectin *Pyrus pyrifolia* 6-8-week ♂ BALB/c mice (11/group) 100 μg\ 22 days Injected IP OVA day 7, provoked with OVA aerosol day 21 bronchial fluid:↓ IFN-γ & ↑ IL-5; splenic cells: ↑ IFN-γ, ↓ IL-5; normalized pulmonary histopathological changes; ↓ serum IgE \[[@B54]\] days 1-7 Pectins (bupleurum 2IIc) *Bupleurum falcatum* 6-8-week ♀ specific-pathogen-free C3H/HeJ mice 250 mg/kg 1 week Healthy animals ↑ spleen cell proliferation \[[@B35]\] Pectins (highly methoxylated) *Malus*spp. 8-month- SD rats (5/group) 5% of diet vs. cellulose control 3 weeks Older animals ↑ MLN lymphocyte IgA & IgG \[[@B36]\] Pectins Citrus spp. 5-week ♀ F344 rats (30/group) 15% of diet 34 weeks Injected SC AOM once a week, weeks 4-14 ↓ colon tumor incidence \[[@B86]\] *Malus*spp. 5-week ♀ BALB/c mice (6/group) 5% of diet 2 weeks Healthy animals ↑ fecal IgA and MLN CD4+/CD8+ T lymphocyte ratio & IL-2 & IFN-γ secretion by ConA-stimulated MLN lymphocytes \[[@B51]\] 5-week ♀ BALB/c mice (6/group) 5% of diet days 5-19 vs. cellulose control 19 days DSS-induced UC days 1-5 Significantly increased MLN lymphocytes IgA, and significantly decreased IgE; significantly decreased ConA-stimulated IL-4 and IL-10 4-week ♂ Donryu rats (20-21/group) 20% of diet 32 weeks Injected SC AOM once a week,\ ↓ colon tumor incidence \[[@B85]\] weeks 2-12 4-week ♂ Donryu rats (19-20/group) 10 or 20% of diet 32 weeks Injected SC AOM once a week,\ Both doses ↓ colon tumor incidence; 20% ↓ tumor occupied area & ↓ portal blood and distal colon PGE~2~ \[[@B90]\] weeks 2-12 Pectins (modified) Citrus spp. 2-4-month BALB/c mice (9-10/group) 0.8 or 1.6 mg/ml drinking water,\ 20 days Injected SC with 2 × 2 mm section of human colon-25 tumor on day 1 Both doses ↓ tumor size \[[@B87]\] days 8-20 NCR nu/nu mice (10/group) 1% (w/v) drinking water 16 weeks Orthotopically injected human breast carcinoma cells (MDA-MB-435) into mammary fat pad on day 7 ↓ tumor growth rate & volume at 7 weeks, lung metastases at 15 weeks, \# of blood vessels/tumor at 33 days post-injection \[[@B89]\] NCR nu/nu mice (10/group) 1% (w/v) drinking water 7 weeks Injected human colon carcinoma cells (LSLiL6) into cecum on day 7 ↓ tumor weights and metastases to the lymph nodes and liver SD rats (7-8/group) 0.01%, 0.1% or 1.0% wt/vol of drinking water, days 4-30 1 month Injected SC MAT-LyLu rat prostate cancer cells 0.1% and 1.0% ↓ lung metastases; 1.0% ↓ lymph node disease incidence \[[@B88]\] ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ###### Immunomodulatory Polysaccharide-Rich Plant Powders: Oral Animal Studies ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Source Animal Oral dose/day Duration Treatment Significant effects Reference ------------------------------------------------------ ----------------------------------------------------------------- --------------------------------------------------------- ----------- ------------------------------------------------------------------------------------------------------------------------------ ---------------------------------------------------------------------------------------------------------------------------------------------------------- ------------ *Agaricus*(*A. blazei*) *subrufescens*(fruit bodies) 6-week ♂ C57BL/6, C3H/HeJ and BALB/c mice (3/group) 16, 32 or 64 mg 2 weeks Healthy animals 32 and 64 mg ↑ liver mononuclear cell cytotoxicity \[[@B25]\] *Grifola frondosa* 6-week ♀ ICR mice (10-15/group) 5% of diet 36 weeks Oral N-butyl-N\'-butanolnitrosamine daily for first 8 weeks ↓ \#s of animals with bladder tumors; ↓ tumor weight; ↑ peritoneal Mø chemotactic activity, splenic lymphocyte blastogenic response & cytotoxic activity \[[@B70]\] *Laminaria angustata* Weanling SD rats (58/group) 5% of diet 26 weeks IG DMBA, beginning of week 5 ↑ time to tumor development and ↓ \# of adenocarcinomas in adenocarcinoma-bearing animals \[[@B77]\] *Lentinula*(*Lentinus*) *edodes* 6-week ♀ ICR mice (10-17/group) 5% of diet 36 weeks Oral BBN daily for first 8 weeks ↓ \# of animals with bladder tumors; ↓ tumor weight; ↑ Mø chemotactic activity, splenic lymphocyte blastogenic response, cytotoxic activity \[[@B70]\] 7-8 -week ♂ Swiss mice (10/group) 1%, 5% or 10% of diet of 4 different lineages days 1-15 16 days Injected IP N-ethyl-N-nitrosourea day 15 All 3 doses of one lineage and the 5% dose of two other lineages ↓ \#s of micronucleated bone marrow polychromatic erythrocytes \[[@B79]\] *Lentinula edodes*(fruit bodies) 5-week ♀ ICR mice\ 10%, 20% or 30% of diet 25 days Injected IP Sarcoma-180 ascites All 3 doses ↓ Sarcoma-180 tumor weight \[[@B78]\] (14/group × 2) Mice: 1) CDF~1~; 2) C3H; 3) BALB/c; 4,5) C57BL/6N (9/group × 3) 20% of diet 25 days Injected SC 1) IMC carcinoma, 2) MM-46 carcinoma, 3) Meth-A fibrosarcoma, 4) B-16 melanoma, or 5) Lewis lung carcinoma cells ↓ growth of MM-46, B-16, Lewis lung, and IMC tumors; ↑ lifespan in Lewis lung and MM-46 animals ICR mice (14/group × 2) 20% of diet days 1-7, days 7-31 or days 14-31 31 days Injected IP Sarcoma-180 ascites ↓ tumor weight & growth when fed days 7-31 or 14-31 Mice: 1) CDF~1~; 2) C3 H (5/group × 4) 20% of diet 7-12 days Injected SC: 1) IMC carcinoma or 2) MM-46 carcinoma cells ↑ spreading rate of activated Mø ↑ phagocytic activity *Phellinus linteus* 4-week ♂ ICR mice (10/group) 2 mg 1 month Healthy animals ↓ serum & splenocyte IgE production; ↑ proportion of splenic CD4^+^T cells & splenocyte IFN-γ production \[[@B31]\] *Pleurotus ostreatus* 6-week ♀ ICR mice\ 5% of diet 36 weeks Oral BBN daily for first 8 weeks ↓ \#s of animals with bladder tumors; ↓ tumor weight; ↑ plasma Mø chemotactic activity, splenic lymphocyte blastogenic response, cytotoxic activity \[[@B70]\] (10-20/group) ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ###### Immunomodulatory Polysaccharide Products: Oral Human Studies ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Extract Source Study design Population N (experimental/control) Dose/day Dura-tion Significant effects Reference -------------------------------- ---------------------------------- ---------------------------------------------- ---------------------------------------------------------------------------------- -------------------------------------- ---------------------------------------------------------------------- ------------------------- ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ------------ Arabino-galactans *Larix occidentalis* Randomized, double-blind, placebo-controlled Healthy adults 8/15 4 g 6 weeks ↑ % CD8+ lymphocytes & blood lymphocyte proliferation \[[@B18]\] Arabino-galactans (ResistAid™) Healthy adults given pneumococcal vaccinations day 30 21/24 4.5 g 72 days ↑ plasma IgG subtypes \[[@B19]\] Fucoidans *Undaria pinnatifida*sporophylls Randomized, single-blind, placebo-controlled Healthy adults 25 (75% fucoidan, 6 (10% fucoidan)/6 3 g 12 days 75% fucoidan: ↓ \#s blood leukocytes, lymphocytes\' ↑ plasma stromal derived factor-1, IFN-γ, CD34+ cells; ↑ % CXCR4-expressing CD34+ cells \[[@B21]\] Furanose extract (Cold-FX^®^) *Panax quinque-folium* Randomized, double-blind, placebo-controlled Healthy older adults given influenza immunization at the end of week 4 22/21 400 mg 4 months During weeks 9-16, ↓ incidence of acute respiratory illness, symptom duration \[[@B20]\] Glucans *Agaricus subru-fescens* Randomized, double-blind, placebo-controlled Cervical, ovarian or endometrial cancer patients receiving 3 chemotherapy cycles 39/61 5.4 g (estimated) 6 weeks ↑ NK cell activity, ↓ chemotherapy side effects \[[@B64]\] Glucans\ Not identified Placebo-controlled Recurrent aphthous stomatitis patients 31/42 20 mg 20 days ↑ PBL lymphocyte proliferation,↓ Ulcer Severity Scores \[[@B48]\] (β-1,3;1,6) Glucans\ *S. cerevisiae* Randomized, double-blind, placebo-controlled Adults with seasonal allergic rhinitis 12/12 20 mg 12 weeks 30 minutes after nasal allergen provocation test, nasal lavage fluid: ↓ IL-4, IL-5, % eosinophils, ↑ IL-12 \[[@B47]\] (β-1,3;1-6) Glucans (PSK) *Trametes versicolor* Randomized, controlled Patients with curatively resected colorectal cancer receiving chemotherapy 221/227 200 mg 3-5 years ↑ disease-free survival and overall survival \[[@B56]\] Controlled Post-surgical colon cancer patients receiving chemotherapy 123/121 3 g for 4 weeks, alternating with 10 4-week courses of chemo-therapy 7 years ↑ survival from cancer deaths; no difference in disease-free or overall survival \[[@B57]\] Post-surgical colorectal cancer patients receiving chemotherapy 137/68 3 g daily 2 years ↑survival in stage III patients; ↓ recurrence in stage II & III patients \[[@B58]\] Post-surgical gastric cancer patients receiving chemotherapy 124/129 3 g for 4 weeks, alternating with 10 4-week courses of chemo-therapy 5-7 years ↑ 5-year disease-free survival rate, overall 5-year survival \[[@B59]\] Pre-surgical gastric or colorectal cancer patients 16 daily; 17 every other day/13 3 g daily or on alternate days before surgery \<14 days or 14-36 days ≥14 day treatment: ↑ peripheral blood NK cell activity, PBL cytotoxicity, proportion of PBL helper cells; ↓ proportion of PBL inducer cells; \<14 day treatment: ↑ PBL response to PSK and Con A, proportion of regional node lymphocyte suppressor cells \[[@B62]\] Randomized, double-blind, placebo-controlled Post-surgical stage III-IV colorectal cancer patients 56/55 3 g for 2 months, 2 g for 22 months, 1 g thereafter 8-10 years ↑ remission & survival rates \[[@B61]\] Controlled Post-surgical stage III gastric cancer patients receiving chemotherapy 32/21 3 g 1 year ↑ survival time \[[@B60]\] Glucans (PSP) *Trametes versicolor* Randomized, double-blind, placebo-controlled Conventionally-treated stage III-IV non-small cell lung cancer patients 34/34 3.06 g 1 month ↑ blood IgG & IgM, total leukocyte and neutrophil counts, % body fat; ↓ patient withdrawal due to disease progression \[[@B63]\] ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ###### Immunomodulatory Polysaccharide Products: Composition and Structure -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Source Category Features MW Monosaccharide composition Reference ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ----------------------------------------- ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ ------------------------------------------------------------------------ ------------------------------------------------------------------------------------------------------------------------------- -------------------------------------------- *Agaricus subrufescens*(*A. blazei*) Extract β-1,6-D-glucan 10,000 NA \[[@B66]\] *Agaricus subrufescens*(fruit body) Extract α-1,6- and α-1,4 glucans with β-1,6-glucopyranosyl backbone (629.2 mcg/mg polysaccharides, 43.5 mcg/mg protein) 170,000 glucose \[[@B24]\] α-1,4 glucans & β-1,6 glucans with β-1,3 side branches; α-1,6 glucans; β-1,6; 1-3 glucans, β-1,4 glucans; β-1,3 glucans; β-1,6; α-1,3 glucans; riboglucans, galactoglucomannans, β-1,2; β-1,3 glucomannans NA glucose, mannose, galactose, ribose \[[@B25],[@B117],[@B118]\] *Agaricus subrufescens*(mycelia) Extract (ATOM) β-1,6-D-glucan, protein complex, 5% protein 100,000-1,000,000 glucose, mannose, galactose, ribose \[[@B93]\] *Aloe barbadensis*(leaf gel) Whole tissue Dry weight: 10% polysaccharides; acemannan, aloemannan, aloeride, pectic acid, galactans, arabinans, glucomannans average 2,000,000 mannose, glucose, galactose, arabinose, xylose, rhamnose \[[@B119],[@B120]\] Extract (aloemannan) neutral partially acetylated glucomannan, mainly β-1,4-mannans \>200,000 mannose, glucose \[[@B121]\] Extract (aloeride) NA 4,000,000-7,000,000 37% glucose, 23.9% galactose, 19.5% mannose, 10.3% arabinose \[[@B122]\] Extract (acemannan) β-1,4 acetylated mannan 80,000 mannose \[[@B123]\] *Aloe barbadensis*, (leaf gel), *Larix*sp. (bark), *Anogeissus latifolia*(bark), *Astragalus gummifer*(stem), *Oryza sativa*(seed), *glucosamine* Extracts (Ambrotose^®^powder) β-1,4 acetylated mannan, arabinogalactans, polysaccharide gums, rice starch, 5.4% protein 57.3% ≥ 950,000; 26.4% \< 950,000 and ≥80,000; 16.3% ≤ 10,000 mannose, galactose, arabinose, glucose, galacturonic acid, rhamnose, xylose, fructose, fucose, glucosamine, galacturonic acid (unpublished data, Mannatech Incorporated) *Aloe barbadensis*(leaf gel), *Larix*sp. (bark), *Undaria pinnatifida*(frond), *Anogeissus latifolia*(bark), *Astragalus gummifer*(stem), *Oryza sativa*(seed), *glucosamine* Extracts (Advanced Ambrotose^®^powder) β-1,4 acetylated mannan, arabinogalactans, polysaccharide gums, fucoidans, rice starch, 6% protein, 1% fatty acids 13% = 1,686,667; 46% = 960,000 30% \<950,000 and ≥70,000; 11% ≤ 10,000 *Avena*spp. (seed endosperm) Extract β-1,3;1,4 particulate (1-3 μ) glucans 1,100,000 glucose \[[@B43]\] *Avena*spp. (seed) Extract β-1,4,1,3 particulate glucans (linear chains of β-D-glycopyranosyl units; 70% β 1-4 linked) 2,000,000 NA \[[@B41],[@B124]\] *Buplerum falcatum*(root) Extract (bupleuran 2IIc) 6 linked galactosyl chains with terminal glucuronic acid substituted to β-galactosyl chains NA galactose, glucuronic acid, rhamnose \[[@B35]\] Citrus spp. (fruit) Extract α-1,4-linked partially esterified D-anhydrogalacturonic acid units interrupted periodically with 1,2-rhamnose 70,000-100,000 galactose, galacturonic acid, arabinose, glucose, xylose, rhamnose \[[@B125]\] *Cladosiphon okamuranus*(frond) Extract α-1,3-fucopyranose sulfate 56,000 fucose:glucuronic acid (6.1:1.0) \[[@B126]\] *Cordyceps sinensis*(mycelia) Extract β-1,3-D-glucan with 1,6-branched chains NA NA \[[@B127]\] *Cyamopsis tetragonolobus*(seed) Extract (guar gum) Main chain of β-1,4-mannopyranosyl units with α-galactopyranosyl units 220,000 mannose, galactose \[[@B36],[@B128]\] Extract (partially-hydrolyzed guar gum) NA 20,000 mannose, galactose \[[@B50]\] *Flammulina velutipes* Extract NA NA glucose, mannose, galactose \[[@B117]\] *Flammulina velutipes*(fruit body) Extract β-1,3 glucan NA glucose \[[@B129]\] *Ganoderma lucidum* Whole tissue Linear β-1,3-glucans with varying degrees of\ 400,000-1,000,000 glucose, galactose, mannose, xylose, uronic acid \[[@B130]\] D-glucopyranosyl branching, β-glucan/protein complexes, heteropolysaccharides Extract NA 7,000-9,000 NA \[[@B67]\] *Ganoderma lucidum*(fruit body) Extract NA 7,000-9,000 NA β-linked heteroglycan peptide 513,000 fructose, galactose, glucose, rhamnose, xylose (3.167:\ \[[@B15]\] 0.556:6.89:0.549:3.61) *Ganoderma tsugae* Extract 55.6% carbohydrates (12.5% polysaccharides); 12% triterpenes, 1.7% sodium, 0.28% protein, 0% lipid NA NA \[[@B53]\] *Ginkgo biloba*(seed) Extract 89.7% polysaccharides NA glucose, fructose, galactose, rhamnose \[[@B131]\] *Grifola frondosa* Whole tissue β-1,3; 1, 6-glucans, α-glucans, mannoxyloglucans, xyloglucans, mannogalactofucans NA glucose, fucose, xylose, mannose, galactose \[[@B117]\] *Grifola frondosa*(fruit body) Extract\ β-1,6-glucan with β-1,3 branches, 30% protein NA glucose \[[@B132]\] (D fraction) Extract\ β-1,6-D-glucan with α-1,4 branches, 35% protein 550,000-558,000 glucose (X fraction) *Hordeum*spp. (seed) Extract β-1,3;1,4-and β-1,3;1,6-D-glucans 45,000-404,000 glucose \[[@B75]\] Primarily linear β-1,3;1,4- glucans NA glucose \[[@B124]\] *Laminaria*spp.\ Extract (laminarin) β-1,3;1-6 glucan 7,700 glucose \[[@B29]\] (frond) β-1,3 glucan with some β-1,6 branches and a small amount of protein 4,500-5,500 glucose \[[@B44]\] Extract Fucoidan NA NA \[[@B133]\] *Larix occidentalis*(bark) Extract β-1,3;1,6-D-galactans with arabinofuranosyl and arabinopyranosyl side chains 19,000-40,000 galactose:arabinose (6:1), uronic acid \[[@B128],[@B134]\] *Lentinula edodes* Extract (SME) β-1,3-glucans (4-5%), α-1,4-glucan (8-10%), protein (11-14%) NA glucose \[[@B80]\] Extract β-glucan 1,000 glucose \[[@B27]\] Whole tissue Linear β-1,3-glucans, β-1,4;1,6-glucans, heterogalactan NA glucose, galactose, mannose, fucose, xylose \[[@B135]\] Extract (lentinan) β-1,3-glucan with 2 β-1,6 glucopyranoside branchings for every 5 β-1,3-glucopyranoside linear linkages 500,000 glucose \[[@B136]\] *Lentinula edodes*(fruit body)\ Extract (lentinan) Neutral β-1,3-D glucan with two β-1,6 glucoside branches for every five β-1,3 units 400,000-800,000 glucose \[[@B137]\] *Lentinula edodes* Extract\ Peptide units and mannan connected by α-glycosidic bonds 60,000-90,000 mannose, glucose (KS-2) *Lentinula edodes*(mycelia or fruit body) Extract Triple helical β-1,3-D glucan with β-1,6 glucoside branches 1,000,000 glucose \[[@B3]\] *Lentinula edodes*(mycelia) Extract\ 44% sugars, 24.6% protein \~1,000,000 xylose, arabinose, glucose, galactose, mannose, fructose \[[@B3]\] (LEM) Extract (PG101) 72.4% polysaccharides, 26.2% protein, 1.4% hexosamine NA 55.6% glucose, 25.9% galactose, 18.5% mannose \[[@B138]\] *Lycium barbarum* Whole tissue α-1,4;1,6-D-glucans, lentinan, β-1,3;1,6 heteroglucans, heterogalactans, heteromannans, xyloglucans NA glucose, galactose, mannose, xylose \[[@B139]\] *Lycium barbarum*(fruit body) Extract\ 88.36% sugars, 7.63% protein 157,000 galactose, glucose, rhamnose, arabinose, mannose, xylose (molar ratio of 1:2.12:1.25:1.10:1.95:1.76) \[[@B91]\] (LBP~3p~) *Panax quinquefolium*(root) Extract Poly-furanosyl-pyranosyl saccharides NA arabinose, galactose, rhamnose, galacturonic acid, glucuronic acid \[[@B33]\] NA NA glucose, mannose, xylose \[[@B140]\] Extract\ 90% poly-furanosyl-pyranosyl-saccharides NA furanose \[[@B20]\] (Cold-fX^®^) *Phellinus linteus*(fruit body) Extract α- and β-linked 1,3 acidic proteoglycan with 1,6 branches 150,000 glucose, mannose, arabinose, xylose \[[@B141]\] *Phellinus linteus*(mycelia) Extract 83.2% polysaccharide (4.4% β-glucan), 6.4% protein, 0.1% fat NA glucose \[[@B142]\] *Pholiota nameko*(fruit body) Extract (PNPS-1) NA 114,000 mannose, glucose, galactose, arabinose, xylose (molar ratio of 1:8.4:13.6:29.6:6.2) \[[@B55]\] *Pleurotus ostreatus*(mycelia) Extract β-1,3;1,6-D-glucans 316,260 glucose \[[@B143]\] *Saccharomyces cerevisiae* Extract (WGP) Particulate β-1,3;1,6-D-glucan NA glucose \[[@B144]\] Extract β-glucans with β-1,6 branches with a β-1,3 regions NA glucose \[[@B124]\] Extract\ soluble β-1,3-D-glucan with β-1,3 side chains attached with β-1,6 linkages 20,000 glucose \[[@B145]\] (SBG) *Sclerotinia sclerotiorum*(mycelia) Extract\ β-1,3-D-glucan, \<1% protein (\>98% polysaccharide) NA glucose \[[@B83]\] (SSG) *Sclerotium rofsii* Extract (scleroglucan) β-1,3;1,6 glucan 1,000,000 glucose \[[@B29]\] *Trametes versicolor*(fruit body) Extract\ α-1,4, β-1,3 glucans, 10% peptides 100,000 glucose, arabinose, mannose, rhamnose \[[@B146]\] (PSP) *Trametes versicolor*(mycelia) Extract\ β-1,4;1,3;1,6-D-glucans, protein 94,000 glucose (74.6%), mannose (15.5%), xylose (4.8%), galactose (2.7%), fucose (2.4%) \[[@B137],[@B147]\] (PSK) *Undaria pinnatifida*(sporophyll) Extract Galactofucan sulfate 9,000 fucose:galactose 1.0:1.1 \[[@B148]\] Galactofucan sulfate 63,000 fucose:galactose:gluc-uronic acid (1.0:1.0:0.04) \[[@B149]\] β-1,3-galactofucan sulphate 38,000 fucose, galactose \[[@B150]\] Unidentified source Extract (modified citrus pectin) NA 10,000 galactose, rhamnose, uronic acid \[[@B125]\] Extract (highly methoxylated pectin) NA 200,000 NA \[[@B36]\] -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ###### Safety of Immunomodulatory Polysaccharide Products Following Oral Intake ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ Category Source Test group Test Design Results Equivalent human dose\* Reference ------------------- ----------------------------------------------------------- ---------------------------------------------------- --------------------------------- ------------------------------------------------------------------------------------- -------------------------------------------------------------------------------------------------------------------------------------------------------------- ------------------------- ------------------------------------ Arabino-galactans *Argemone mexicana*(arabinogalactan protein) Pregnant rats Develop-mental toxicity 250, 500, or 1,00 mg/kg, gestational days 5-19 No developmental toxicity: NOAEL = 1 g/kg 68 g \[[@B151]\] ♀ and ♂ rats Fertility 250, 500, or 1,00 mg/kg, 1 month No effects on reproduction: NOAEL = 1 g/kg Fucoidans *Undaria pinnatifi*da Rats Subchronic toxicity 1.35 g/kg, 1 month No evidence of toxicity 91.8 g \[[@B152]\] Galacto-mannans *Cyamopsis tetragonolobus* Adolescent and adult ♂ rats Subchronic and chronic toxicity 8% of diet, 6-67 weeks No evidence of toxicity 8% of diet \[[@B153]\] Rats Acute toxicity One 7.06 g/kg dose: observed 2 weeks LD~50~= 7.06 g/kg 480 g \[[@B96]\] Subchronic and chronic toxicity 1, 2, 4, 7.5 or 15% of diet, 3 months All doses ↓ ♀ BW; 7.5-15% ↓ ♂ BW; 15% ↓ bone marrow cellularity; ↓ kidney and liver weights 1-15% of diet 19 adults with hypercholesterol-emia 18 g/day, 1 year Short-term gastric bloating/loose stools, in 8 subjects, resolved in 7-10 days; 2 withdrew because of diarrhea. No toxicity for 13 subjects completing study 18 g \[[@B154]\] 16 Type II diabetics 26.4-39.6 g/day, 6 months No effects on hematologic, hepatic, or renal function 39.9 g \[[@B155]\] 18 Type II diabetics 30 g/day, 4 months 30 g *Cyamopsis tetragonolobus*(partially hydrolyzed guar gum) Mice & rats Acute toxicity One 6 g/kg dose; observed\ LD~50~\> 6 g/kg \>408 g \[[@B156]\] 2 weeks Rats Subchronic toxicity 0.2, 1.0 or 5% of diet, 13 weeks No evidence of toxicity 5% of diet 0.5 or 2.5 g/kg, 1 month NOAEL \> 2.5 g/kg \>170 g \[[@B157]\] *S. typhimurium* Mutagenicity Ames test Not mutagenic NA Glucans *Agaricus subrufescens*(aqueous extract) Rats Subchronic toxicity 0.63, 1.25, 2.5 or 5% of diet, 3 months NOAEL = 5% of diet 5% of diet \[[@B158]\] 3 women with advanced cancers Case reports Specific identity of products, doses, and durations of intake unknown Severe hepatotoxicity; two patients died NA \[[@B97]\] *Agaricus subrufescens*(freeze dried powder) 24 normal adults and 24 adults with liver problems Subchronic toxicity 3 g, 4 months No evidence of toxicity 3 g \[[@B159]\] *Ganoderma lucidum*\ Elderly woman Case report 1 year *G. lucidum*(and another unidentified product, initiated one month previous) Elevated liver enzymes and liver tissue damage NA \[[@B98]\] (supplement) *Grifola frondosa*(powder) Rats Acute toxicity One 2 g/kg dose No evidence of toxicity 136 g \[[@B160]\] *Lentinula edodes*(powder) 10 adults Safety 4 g/day for 10 weeks; repeated\ 50% of subjects experienced blood eosinophilia, ↑ eosinophil granule proteins in serum and stool, ↑GI symptoms 4 g \[[@B99]\] 3-6 months later *Lentinula edodes*\ Nude mice Safety 10% of diet days 1-18, 33-50 No adverse events 10% of diet \[[@B80]\] (SME) 61 men with prostate cancer 0.1 g/kg, 6 months No adverse events 6.8 g *Lentinus lepideus*(PG101) Female mice Subchronic toxicity 0.5 g/kg, 24 days No evidence of toxicity 34 g \[[@B92]\] *Phellinus linteus*\ Rats Acute toxicity One 5 g/kg dose; observed\ LD~50~\> 5 g/kg 349 g \[[@B161]\] (crude extract) 2 weeks *Pleurotus ostreatus*(aqueous extract) Mice Acute toxicity One 3 g/kg dose; observed\ LD~50~\> 3 g/kg \>204.g \[[@B100]\] 1 day Subacute toxicity 319 mg/kg, 1 month Hemorrhages in intestine, liver, lung, kidney; inflammation and microabscesses in liver 21.7 g *Saccharomyces cerevisiae*(particulate glucan \[WGP\]) Rats Acute toxicity One 2 g/kg, observed 2 weeks LD~50~\> 2 g/kg \>136 g \[[@B144]\] Subchronic toxicity 2, 33.3 or 100 mg/kg, 3 months NOAEL = 100 mg/kg 6.80 g Heteroglycans *Trametes versicolor*\ Rats Subchronic toxicity 1.5, 3.0 or 6.0 mg/kg, 2 months No evidence of toxicity 408 mg \[[@B162]\] (PSP) Rats & monkeys Subchronic and chronic toxicity 100-200X equivalent human dose, 6 months No evidence of toxicity NA *Trametes versicolor*\ Humans with colon cancer Safety 3 g/day, up to 7 years No significant adverse events 3 g \[[@B57]\] (PSK) Humans with colorectal cancer 3 g/day, 2 years 3 g \[[@B58]\] Mannans *Aloe vera*gel Dogs Acute toxicity Fed one 32 g/kg; observed 2 weeks LD50 \> 32 g/kg \>2,176 g Bill Pine, personal communi-cation Rats One 21.5 g/kg; observed 2 weeks LD50 \> 10 g/kg \>680 g ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ \*150 lb adult A number of studies in healthy human adults demonstrated immune stimulating effects of oral polysaccharides. Arabinogalactans from *Larix occidentalis*(Western larch) were shown in RCTs to increase lymphocyte proliferation and the number of CD8+ lymphocytes \[[@B18]\] and to increase the IgG subtype response to pneumococcal vaccination \[[@B19]\]. A furanose extract from *Panax quiquefolium*(North American ginseng) was shown in an RCT of healthy older adults to decrease the incidence of acute respiratory illness and symptom duration \[[@B20]\]. Finally, an RCT of healthy adults consuming *Undaria pinnatifida*(wakame) fucoidans found both immune stimulating and suppressing effects, including increased stromal-derived factor-1, IFN-g, CD34+ cells and CXCR4-expressing CD34+ cells and decreased blood leukocytes and lymphocytes \[[@B21]\]. Studies in healthy animals showed a number of immune stimulating effects of various glucan products from *Agaricus subrufescens (A. blazei)*(aqueous extracts \[[@B22]\], aqueous extracts with standardized β-glucans \[[@B23]\], α-1,6 and α-1,4 glucans \[[@B24]\], and whole plant powders \[[@B25]\]); *Lentinula edodes*(shiitake) (lentinan \[[@B26]\] and β-glucans \[[@B27]\]); *Saccharomyces cerevisiae*(β-1,3-glucans \[[@B27],[@B28]\]); *Laminaria digitata*(laminarin \[[@B29]\]); *Sclerotium rofsii*(glucan phosphate \[[@B29]\]); *Sclerotinia sclerotiorum*(SSG \[[@B30]\]); and *Phellinus linteus*(powder \[[@B31]\] and aqueous, alcohol-precipitated extract \[[@B32]\]). A furanose extract from *P. quiquefolium*and pectins from *Buplerum falcatum*and *Malus*(apple) spp. have also been shown to enhance immune function in healthy young animals \[[@B33]-[@B35]\]. *Cyamopsis tetragonolobus*galactomannan (guar gum) or highly methoxylated pectin feeding exerted numerous stimulating effects on antibody production in older animals \[[@B36]\]. Evidence for the effectiveness of oral polysaccharides against infection and immune challenges has been mainly demonstrated in animals. Immune stimulating effects have been shown in resting and exercise-stressed animals with thioglycollate, clodronate, or HSV-1 injections fed *Avena*(oat) spp. soluble glucans \[[@B37]-[@B41]\]; animals injected with or fed *E. vermiformis*and fed *Avena*spp. particulate glucans \[[@B42],[@B43]\]; animals with *E. coli*injections fed *L. digitata*glucans (laminarin) \[[@B44]\]; animals with HSV injections fed *U. pinnatifida*fucoidans \[[@B45]\]; animals with *Staphylococcus aureus*or *Candida albicans*injections fed *S. cerevisiae*glucans (scleroglucan) \[[@B29]\]; and animals with fecal solution injections fed an aqueous extract of *A. subrufescens*(*A. blazei*Murrill) \[[@B46]\]. Additional controlled human and animal studies have shown anti-inflammatory and anti-allergy effects of some polysaccharide products. In an RCT of adults with seasonal allergic rhinitis, *S. cerevisiae*β-1,3;1-6 glucans decreased IL-4, IL-5 and percent eosinophils, and increased IL-12 in nasal fluid \[[@B47]\], while a placebo-controlled study of patients with recurrent aphthous stomatitis (canker sores) consuming β-1,3;1-6 glucans found increased lymphocyte proliferation and decreased Ulcer Severity Scores \[[@B48]\]. Animal models of inflammatory bowel disease have shown anti-inflammatory effects of *Cladosiphon okamuranus*Tokida fucoidans \[[@B49]\], *Cyamopsis tetragonolobus*galactomannans \[[@B50]\], *Malus*spp. pectins \[[@B51]\], and mixed polysaccharide supplements \[[@B52]\]. Animals challenged with ovalbumin have demonstrated anti-inflammatory/allergy effects of *A. subrufescens*aqueous extracts \[[@B22]\], an aqueous extract *of Ganoderma tsugae*\[[@B53]\], and *Pyrus pyrifolia*pectins \[[@B54]\]. Anti-inflammatory effects have also been seen in animals with cotton pellet implantations fed a *Pholiota nameko*heteroglycan (PNPS-1) \[[@B55]\]. *Trametes versicolor*glucans have demonstrated anti-cancer effects in humans. In two RCTs and five controlled trials, PSK from *T. versicolor*mycelia increased survival of advanced stage gastric, colon and colorectal cancer patients \[[@B56]-[@B62]\] with one study showing increased immune parameters (including blood NK cell activity, leukocyte cytotoxicity, proportion of helper cells and lymphocyte suppressor cells) \[[@B62]\]. An RCT of advanced stage lung cancer patients consuming PSP from *T. versicolor*fruit bodies found increased IgG and IgM antibodies and total leukocyte and neutrophil counts, along with a decrease in the number of patients withdrawing from the study due to disease progression \[[@B63]\]. An RCT of ovarian or endometrial cancer patients consuming *A. subrufescens*glucans showed increased NK cell activity and fewer chemotherapy side effects \[[@B64]\]. In numerous animal models of cancer, a wide range of polysaccharides have shown anti-tumorogenic effects. Glucan products sourced from *A. subrufescens*demonstrating anti-cancer activities in animal models include an aqueous extract \[[@B65]\], an aqueous, acid-treated extract \[[@B66]\], and an aqueous extract with standardized levels of β-glucans \[[@B23]\]. Anti-cancer effects have been reported following intake of aqueous extracts of *G. lucidum*\[[@B67]-[@B69]\]; the powder and D fraction of *G. frondosa*\[[@B70]-[@B72]\]; *Hordeum vulgare*β-glucans \[[@B73]-[@B76]\]; *Laminaria angustata*powder \[[@B77]\]; *Lentinula edodes products*(powders \[[@B70],[@B78],[@B79]\], SME \[[@B80]\], β-glucans \[[@B27]\], and lentinan \[[@B81],[@B82]\]); *Pleurotus ostreatus*powder \[[@B70]\], *Saccharomyces cerevisiae*particulate β-1,3;1,6 and β-1,3glucans\[[@B27],[@B73]\]; and a glucan from *Sclerotinia sclerotiorum*(SSG) \[[@B30],[@B83]\]. A glucomannan from *L. edodes*(KS-2) improved survival of animals with cancer cell injections \[[@B84]\]; apple and citrus pectins have exerted anti-cancer effects, including decreased tumor incidence \[[@B85]-[@B90]\]. Finally, heteroglycans from *Lycium barbarum*(LBP~3p~), *Lentinus lepidus*(PG101) and A. *subrufescens*(ATOM) demonstrated a number of immune stimulating effects in animal cancer models \[[@B91]-[@B93]\]. Interestingly, only one animal study has been performed using glucans from *T. versicolor*(PSP): animals with cancer cell implantations showed decreased tumor growth and vascular density \[[@B94]\]. Most polysaccharide products appear to be safe, based on NOAEL, acute and/or chronic toxicity testing in rodents (Table [6](#T6){ref-type="table"}). As would be expected, powders, extracts and products that have not been fully characterized pose the most concerns. Other than for aloe vera gel, which was shown in a small human trial to increase the plasma bioavailability of vitamins C and E \[[@B95]\], the impact of polysaccharide intake on the absorption of nutrients and medications is not known. While one rat toxicity study raised concerns when guar gum comprised 15% of the daily diet \[[@B96]\], the product was safe in humans studies when 18-39.6 g/day was consumed for up to a year (Table [4](#T4){ref-type="table"}). Product contamination may explain three case reports of hepatotoxicity and/or death following intake of an *A. subrufescens*aqueous extract \[[@B97]\]. Seven animal studies reporting positive immunologic effects of *A. subrufescens*extracts in healthy animals or animals with cancers found no evidence of toxicity (Tables [1](#T1){ref-type="table"} and [2](#T2){ref-type="table"}). In humans, six weeks of *A. subrufescens*glucans intake was safe for cancer patients, and four months of 3 g/day intake by 24 healthy adults and 24 adults with liver disease reported no evidence of toxicity (Table [4](#T4){ref-type="table"}). Another case report associated liver toxicity with *G. lucidum*intake, but the elderly subject also took an unidentified product a month previous to her admission for testing \[[@B98]\]. Three animal studies reported immunologic benefits and no adverse effects following intake of *G. lucidum*aqueous extracts; in one study intake was 5% of the diet for 5 months (Table [1](#T1){ref-type="table"}). While adverse effects were also reported in a study in which 10 adults consumed 4 g/day *L. edodes*powder for 10 weeks \[[@B99]\], immunologic animal studies reported no ill effects of either *L. edodes*powder (5 studies, up to 5% of the diet up to nine months) or extract (7 studies, up to 40 days intake) (Tables [1](#T1){ref-type="table"} and [3](#T3){ref-type="table"}). Finally, while intake of 319 mg/kg of an aqueous extract of *P. ostreatus*by mice for 1 month caused hemorrhages in multiple tissues \[[@B100]\], there was no reported toxicity when mice consumed the mushroom powder as 5% of their diet for nine months (Table [3](#T3){ref-type="table"}). While ≥1 gram/day of *T. versicolor*glucan products were safely consumed by cancer patients for up to 10 years, the long-term effects of ingestion of the other polysaccharide products discussed in this review is also not known. Discussion ========== The majority of studies that qualified for inclusion in this review employed models investigating immune stimulation; fewer explored anti-inflammatory effects. Animal studies reported immune system effects in the gut, spleen, bone marrow, liver, blood, thymus, lungs, and saliva; controlled human studies reported evidence of immune stimulation in the blood, anti-inflammatory effects in nasal lavage fluid and improved survival in cancer patients. The literature is highly heterogenous and is not sufficient to support broad structure/function generalizations. For the limited number of studies that investigated well-characterized, isolated products (primarily glucan products), effects can be unequivocally attributed to polysaccharides. Such associations are certainly more tenuous when considering product powders or products obtained by extraction methods designed to isolate polysaccharides, but without complete compositional analyses. Dietary polysaccharides are known to impact gut microbial ecology \[[@B101],[@B102]\], and advances in microbial ecology, immunology and metabolomics indicate that gut microbiota can impact host nutrition, immune modulation, resistance to pathogens, intestinal epithelial development and activity, and energy metabolism \[[@B103]-[@B107]\]. Other than fucoidans, the polysaccharides discussed in this review appear to be at least partially degraded by bacterial enzymes in the human digestive tract (Table [7](#T7){ref-type="table"}). Arabinogalactans, galactomannans, a glucan (laminarin), glucomannans, and mixed polysaccharide products (Ambrotose^®^products) have been shown to be metabolized by human colonic bacteria. Orally ingested fucoidans, glucans and mannans (or their fragments) have been detected in numerous tissues and organs throughout the body \[[@B73],[@B108],[@B109]\], (Carrington Laboratories, personal communication). We know of no study that has determined the specific identity of orally-ingested polysaccharide end products in animal or human tissues. ###### Fate of Immunomodulatory Polysaccharide Products Following Oral Intake -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Category Product Metabol-ized by human gut bacteria? Study type Fate\ References (method: tissues detected) ------------------------------- --------------------------------------------------------------------------------- ------------------------------------- ------------ ------------------------------------------------------------------------------------------------------------------- --------------------------------------------------- Arabinogalactans *Larix*spp. yes *in vitro* NA \[[@B163]-[@B169]\] Fucoidans *Undaria pinnatifida* no *in vitro* Ab: human plasma \[[@B108],[@B170]\] Galactomannans *Cyamopsis tetragonolobus*(partially hydrolyzed guar gum) yes *in vivo* NA \[[@B171]\] *Cyamopsis tetragonolobus*(guar gum) yes *in vitro* NA \[[@B167]\] Glucans *Hordeum vulgare* NA *in vivo* Fluorescein-labeled: mouse Mø in the spleen, bone marrow, lymph nodes \[[@B73]\] *Laminaria digitata*(laminarin) yes *in vitro* NA \[[@B29],[@B170],[@B172]\] *Sclerotium rofsii*(scleroglucan) glucan phosphate, *Laminaria*spp. (laminarin) NA *in vivo* Alexa Fluor 488-labeled: mouse intestinal epithelial cells, plasma, GALT \[[@B29]\] *Saccharomyces cervisiae*(particulate) NA *in vivo* Fluorescein-labeled: mouse macrophage in the spleen, bone marrow, lymph nodes \[[@B73]\] *Trametes versicolor*\ NA *in vivo* ^14^C-labeled: rat and rabbit serum; mouse GI tract, bone marrow, salivary glands, liver, brain, spleen, pancreas \[[@B173]\] (PSK) Mannans *Aloe barbadensis*(aloemannan) yes *in vitro* FITC-labeled: mouse, GI tract \[[@B121],[@B174]\] *Aloe barbadensis*\ yes *in vitro* NA \[[@B163]\] (gel powder) *Aloe barbadensis*(acemannan) NA *in vivo* ^14^C-labeled: dog systemic, particularly liver, bone marrow, gut, kidney, thymus, spleen (Carrington Laboratories, personal communication) Mixed polysaccharide products Ambrotose complex^®^, Advanced Ambrotose^®^powder yes *in vitro* NA \[[@B163],[@B175]\] Pectins NA yes *in vitro* NA \[[@B165]-[@B167],[@B176]\] *Buplerum falcatum*(bupleuran 2IIc) NA *in vivo* Ab bound: mouse Peyer\'s patch, liver \[[@B109]\] -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- One can only speculate upon the mechanisms by which the polysaccharides discussed in this review influence immunologic function, particularly when one considers the exceedingly complex environment of the GI tract. It is possible that fragments of polysaccharides partially hydrolyzed by gut bacteria may either bind to gut epithelia and exert localized and/or systemic immune system effects, or be absorbed into the bloodstream, with the potential to exert systemic effects. Current studies investigating the link between the bioconversion of dietary polysaccharides, their bioavailability and their downstream effects on the host metabolism and physiology are utilizing metabolomic and metagenomic approaches that can detect and track diverse microbial metabolites from immunomodulatory polysaccharides \[[@B103]\]. These and other innovative approaches in the field of colonic fermentation are providing novel insights into gut microbial-human mutualism \[[@B110],[@B111]\], its impact on regulating human health and disease, and the importance of dietary modulation \[[@B112]-[@B115]\]. Additional RCTs of well-characterized products are needed to more completely understand the immunomodulatory effects and specific applications of oral polysaccharides. Such studies will need to better investigate the optimal timing and duration for polysaccharide ingestion. That is, should they be consumed continuously, before, at the time of, or after exposure to a pathogen or environmental insult? Only a few studies have actually investigated the impact of timing of polysaccharide intake to achieve optimal benefits. Daily feeding with some polysaccharides appears to result in tolerance (and diminished benefits); this has been demonstrated for some mushroom β-glucans \[[@B3],[@B26]\]. For those polysaccharides whose immunologic effects are dependent on their prebiotic activities, regular feeding would be presumed necessary. Conclusions =========== The dietary polysaccharides included in this review have been shown to elicit diverse immunomodulatory effects in animal tissues, including the blood, GI tract, and spleen. In controlled human trials, polysaccharide intake stimulated the immune system in the blood of healthy adults, dampened the allergic response to a respiratory inflammatory agent, and improved survival in cancer patients. Additional RCTs of well-characterized products are needed to more completely understand the immunomodulatory effects and specific applications of oral polysaccharides List of abbreviations ===================== ♀: female; ♂: male; Ab: antibody; AIDS: autoimmune deficiency syndrome; AOM: azoxymethane; BBN: N-butyl-N\'-butanolnitrosamine; BLCL: Burkitt\'s Lymphoma Cell Line; BW: body weight; CBC: complete blood count; CD: cluster of differentiation; CFU: colony forming unit; ConA: concanavalin A; CXCR: CXC chemokine receptor; DMBA: 7,12-dimethylbenz*(a)*anthracene; DMH: N-N\'-dimethylhydrazine; DMN: dimethylhydrazine; DSS: dextran sulfate sodium; EBV: Epstein-Barr virus; GALT: gut-associated lymphoid tissue; GI: gastrointestinal; H~2~0~2:~hydrogen peroxide; HSV: herpes simplex virus; ICR: imprinting control region; ID: intradermal; IEL: intraepithelial lymphocytes; IFN-λ: interferon gamma; IG: intragastric; IgA: immunoglobulin A; IgE: immunoglobulin E; IgG: immunoglobulin G; IgM: immunoglobulin M; IL: interleukin; IMC: invasive micropapillary carcinoma; IN: intranasally; IP: intraperitoneal; IV: intravenous; LPS: lipopolysaccharide; Mø: macrophage; mAb: monoclonal antibody; 3-MCA: methylcholanthrene; MLN: mesenteric lymph nodes; MM-46 carcinoma: mouse mammary carcinoma; MW: molecular weight; NK: natural killer; NOAEL: no observable adverse effect level; OVA: ovalbumin; PBL: peripheral blood leukocytes; PBMC: peripheral blood mononuclear cells; PHA: phytohaemagglutinin; PMA: phorbol 12-myristate 13-acetate; PML: polymorphonuclear lymphocyte; RCT: randomized, controlled trial; RNA: ribonucleic acid; SC: subcutaneous; SD rats: Sprague Dawley; TCR: T cell receptor; TLR: toll like receptor; TNF-α: tumor necrosis factor alpha; UC: ulcerative colitis; WT: wild type. Competing interests =================== The authors are employees of the Research & Development Department at Mannatech, Incorporated, which sells two of the polysaccharide products (Ambrotose^®^powder and Advanced Ambrotose^®^powder) discussed in this review. Authors\' contributions ======================= JER and EDN conducted literature searches and wrote the manuscript. RAS provided technical guidance. All authors read and approved the final manuscript. Acknowledgements ================ The authors would like to thank Barbara K. Kinsey, Ward Moore and Mrs. Jennifer Aponte for their assistance with the preparation of this manuscript, and Dr. Azita Alavi and Mrs. Christy Duncan for their editorial assistance.

Long Beach Film Festival - Now Accepting Films & Screenplays From: Robin Duarte Subject: Long Beach Film Festival - Now Accepting Films & Screenplays Date: Fri, 19 Jul 2002 15:13:14 -0800 Filmmakers & Screenwriters (please forward to interested parties): The Long Beach Film Festival is now accepting screenplays and films (short, documentary & feature) in all formats. The winners' work will be reviewed by a committee of established production companies. This is a great way to get exposure and even discovered in Hollywood. The festival is being held onboard the renowned Queen Mary in Long Beach, California (30 miles from Hollywood). The dates of the festival are September 13 - 22, 2002. You can view an 8 x 10 flyer here: http://www.longbeachfilmfestival.com/poster.html A 20% discount has been set up for students and independent filmmakers. The discounted submission prices are as follows: ORIGINAL PRICE DISCOUNTED PRICE Short Film $45 $36 Feature Film $60 $48 Screenplay $50 $40 To take advantage of these discounted prices, simply include a printout of this email with the submission form and legibly write 'email discount' on the payment check. The submission forms can be found here: http://www.longbeachfilmfestival.com/entry.htm All submissions must be received by August 15th, 2002. We look forward to receiving your work. Robin Duarte http://www.longbeachfilmfestival.com

994 A.2d 1040 (2010) 202 N.J. 43 STATE v. McCARY. Supreme Court of New Jersey. May 19, 2010. Petition for Certification Denied.

Metrics and proxies for stringency of regulation of plant water status (iso/anisohydry): a global data set reveals coordination and trade-offs among water transport traits. Plants operate along a continuum of stringency of regulation of plant water potential from isohydry to anisohydry. However, most metrics and proxies of plant iso/anisohydric behavior have been developed from limited sets of site-specific experiments. Understanding the underlying mechanisms that determine species' operating ranges along this continuum, independent of site and growing conditions, remains challenging. We compiled a global database to assess the global patterns of metrics and proxies of plant iso/anisohydry and then explored some of the underlying functional traits and trade-offs associated with stringency of regulation that determines where species operate along the continuum. Our results showed that arid and semi-arid biomes were associated with greater anisohydry than more mesic biomes, and angiosperms showed marginally greater anisohydry than gymnosperms. Leaf water potential at the turgor loss point (Ψtlp) and wood density were the two most powerful proxies for ranking the degree of plant iso/anisohydry for a wide range of species and biomes. Both of these simple traits can be easily and rapidly determined, and therefore show promise for a priori mapping and understanding of the global distribution pattern of the degree of plant iso/anisohydry. Generally, the most anisohydric species had the most negative values of Ψtlp and highest wood density, greatest resistance to embolism, lowest hydraulic capacitance and lowest leaf-specific hydraulic conductivity of their branches. Wood density in particular appeared to be central to a coordinated series of traits, trade-offs and behaviors along a continuum of iso/anisohydry. Quantification of species' operating ranges along a continuum of iso/anisohydry and identification of associated trade-offs among functional traits may hold promise for mechanistic modeling of species-specific responses to the anticipated more frequent and severe droughts under global climate change scenarios.

Spain is the EU country where most people live in apartments Eurostat spends a good amount of money in producing statistics about almost any activity within the EC and offers very valuable information about the construction industry. This time it has produced an array of figures about where the European likes to live. I am not one for statistics I must confess, but as I have mentioned in many other articles we do obtain a lot of useful information especially for those of us involved in the construction industry. Spain tops the ranking According to the latest data from the European Statistical Office (Eurostat), Spain tops the ranking of countries in the European Union (EU) where the highest percentage of population lives in an apartment: 66.5% of Spaniards live in this type of building compared to 33.1% it does in a house. The figure is striking especially when compared with other neighbouring countries. In France, for example, the ratio is almost reversed: seven out of 10 French lives in a house for three out of 10 in apartments. The difference is even greater if we take the number of UK, the country with the highest percentage of population living in households: 84.7% versus 14.4% living in a flat (0.9% of those interviewed answered with another category called "other"). The closest country to Spain with apartments as the most widespread living accommodation is Latvia (65.1%), followed by Lithuania (58.4%) and Greece (56.9%), in that order. The result of the average of the EU countries also marks a clear dissimilarity with the Spanish context: six out of 10 Europeans live in a house opposite the remaining four does so in an apartment; more than 2.5 points of difference from the Spanish proportion. There are more home owners in Spain than in other European countries. Another interesting figure from Eurostat study on the conditions and characteristics of housing in the EU is about ownership, all data shown here are obtained from 2014. In this respect, nearly eight out of 10 Spaniards (78.8%) own the property in which they live, 8.7% more than the European average. For rent they are somewhat below the average: 21.2% versus 29.9% for the European Community. Why is the apartment so quintessential to the Spanish people and why are they so prone to this property regime? The reasons can be explained by three factors: the historical, economic and sociological. From inside the castle wall to the apartment block. Let’s start from the beginning. We have to roll back to the turbulent middle ages, when wars determined the pattern of urban settlements. The cities were walled, the ground was very limited and already at that time housing needed to be built in height. It was also the same in other countries, but in those countries wars did not last centuries as in Spain. More recently, we had the rural exodus: Farmers left the countryside and moved on to the city. In Spain this happened not long ago just in the decades of the 60’s to the 80’s. People migrated to cities and property developers sorted the problem out with a quick construction method: the block of flats. Today, vertical construction has been widely accepted because it is greener and more resource-efficient. Spain is an increasingly empty country where it is increasingly easy to build horizontally. Still remember that, despite everything, the Spaniards hardly see the good side of an ecological construction and tend to seek the villas from a prestigious point of view. Property developers take control. The role of the economy and the current situation of crisis arising from the bursting of the housing bubble, are some of the explanations that make almost seven out of 10 Spaniards to live in apartments. There has been a very uneven economy and there are the selected few who control the sale of development land. The property developer gets more economic benefit from building in height because they can make more profit. A conservative family orientated society. The Spanish idiosyncrasies explain the property ownership regime being most widespread among the Spanish people on one hand, and developments been built around the block of flats on the other. The Spaniards are very conservative and fear and loath financial investments. You only have to read recent news to see what happened to those who tried buying complicated financial products that they didn’t understand. In general people have always seen the brick as a solid long term investment, unlike financial products. They are also conservative in its family structure. There is less geographical mobility than other countries and historically people have bought a house because they did not anticipate moving for work reasons for a long time. Having said that, due to the current crisis there a good percentage of the working population ready to move anywhere, even abroad for a stable job position. This has impacted directly on the sale of properties, now the tendency has changed to rent. However, figures for rental in this country still far from European countries more oriented in that direction. As shown in Eurostat study, Germany with 52.5%, Austria with 57.2% and Denmark with 63.3%, are the countries where most people opt for the lease in detriment of an ownership regime.

Q: Disciplining: what to do when kid starts hiding his mischief? We try to set well-defined/predictable and not-to-harsh consequences for mischief of our 4.5-year-old: timeouts, taking away toys, refusing to play, skipping story-time, etc., but no physical punishment, long solitary timeouts or excessive shouting. Afterwards we usually talk about why the mischief was followed with a consequence. Sometimes, our child will freak out at the threat of such a discipline measure, that they beg one parent not to tell the other parent about the mischief, in hopes of skipping or lessening the measure of discipline he's threatened by. Think: "Ok, that's it, there's no story-time, you'll just go to sleep by yourself" "Please don't tell mommy, please, please " It seems that such a response is a direct result of our discipline measures. The child is starting to hide the mischief even when it could be hazardous or too minor to have consequences. We fear raising a child who will be afraid to tell their parents about any problems/mistakes/issues they are faced with, and would like to build a trusting relationship with them. Are there any well-known/established recommendations on how to approach disciplining a child, so that they do not develop this fear-of-consequence attitude that is beginning to appear in our child? A: I think this seems normal at this point. You're avoiding the major problem areas here by not having long lasting punishments. More than likely your child is simply embarrassed. She recognizes that she misbehaved, and doesn't want mommy to know she misbehaved, because it's embarrassing. A good way to approach this when it happens is to simply point out that it's not something with long term consequences. Get her to focus on improving her "next time" if she wants mommy's approval. If she says "don't tell mommy", you can redirect with "Well, if you want this not to happen when mommy does bedtime, how can we work on making better choices next time?", for example. Move her quietly off of 'embarrassment' to 'solution-oriented'. Realistically, every child will hide something, sometimes, whether from embarrassment or from punishment avoidance. Giving her a loving environment where you help her make better choices rather than having significant punishments is the best approach, and being understanding when she does hide things is also appropriate. Rather than punishing the 'not telling', as some do, I suggest when you do discover something that wasn't told, you talk to her about why she didn't tell you, and talk about the potential consequences of not telling you - not punishment, but what bad things could happen (she or someone else could get hurt, the house could be damaged, etc.), and lightly talk about things like trustworthiness (though if she really is embarrassed by this, it's something to tread lightly around, as that risks more problems I worry with a child who's perhaps not high in the self confidence area).

Cast metal bases as an economical alternative for the severely resorbed mandible. Resorption of the alveolar ridge is a common problem in edentulous patients and can compromise the stability and function of dentures. Resorption and its consequences can be minimized when strategically placed implants are used; however, this option is financially out of reach for many patients. The article discusses a more cost-effective alternative (metalbased dentures) for patients with ridge resorption. In certain environments, like a dental school, where patients are looking for solutions to their dental problems at a reasonable price, cast metal bases can be a feasible economical alternative for edentulous patients. Both cases presented here demonstrated a significant improvement in stability, phonation, and mastication.

Pancreatic trauma: Management and literature review. Pancreatic injury is an uncommon event often difficult to diagnose at an early stage. After abdominal trauma, the surgeon must always be aware of the possibility of pancreatic trauma due to the complications associated with missed pancreatic injuries. Due to its retroperitoneal position, asociated organs and vascular injuries are almost always present, which along with frequent extra abdominal injuries explain the high morbidity and mortality. The aim of this study is to present a concise description of the incidence of these injuries, lesional mechanisms, recommended diagnostic methods, therapeutic indications including nonoperative management, endoscopy and surgery, and an analysis of pancreas-specific complications and mortality rates in these patients based on a 60-year review of the literature, encompassing 6,364 patients. Due to pancreatic retroperitoneal position, asociated organs and vascular injuries are almost always present, which along with frequent extraaabdominal injuries explain the high morbidity and mortality of these patients.

[Patterns of Candida esophagitis in cancer and AIDS patients: histopathological study of 23 patients]. Candida oesophagitis is a common concomitant disease in neutropenic cancer patients after chemotherapie as well as in HIV-patients. In order to characterize the features of oesophagitis in each population, we reviewed the medical history and pathology records of 23 patients (18 cancer-patients, 5 HIV-patients) with culture and autopsy-proven Candida oesophagitis. Histopathological patterns of morphology, invasion, angioinvasion and inflammation were evaluated. Virtually all patients, 17/18 cancer- and 5/5 HIV-patients, had a history of previous mucosal candidosis or candidemia. There was a significant difference histopathologically in depth of invasion of the Candida-organisms between cancer and HIV-patients. Only in HIV-patients organisms were observed within the muscularis propria and the adventitia (2/5 vs 0/18; p = 0.04). The frequency of angioinvasion (12/18 vs 3/5) was similar in both groups. Neutropenia (< 500/microliter) was present in 12 (68%) of 18 cancer patients vs 0/5 HIV-patients (p = 0.01). Correspondingly there was a significant higher PMN/MN ratio in the oesophageal inflammatory infiltrate in HIV-patients, reflecting chemotherapy-induced neutropenia in cancer patients (p = 0.02). Oesophageal candidosis in HIV-patients may be highly invasive despite the presence of neutrophils. These findings suggest an impaired inflammatory response of HIV-patients to invasive candidosis, leading to impaired mucosal host defence.

TMBA 166 (LBP142) – The Hiring Golden Triangle Happy Valentines Day from the fellas at The Lifestyle Business Podcast. Everybody’s back together this week to bring you some love. Ian has determined Tokyo to be his favorite Asian city and Dan has returned from some business (and pleasure) in the Philippines. Dan and Ian discuss hiring, when to use interns vs. VA’s vs. professionals and how this can have a profound impact on your business’ growth. They have also been getting an incredible amount of emails, reviews and feedback from everybody so the fellas take some time to answer your most pressing questions, concerns and confessions. To Hire or Not to Hire… How you can scientifically determine the best time to hire your first employee.

Kengo Ota is a Japanese football player for Grulla Morioka. Career After attending Osaka University of Health and Sport Sciences, Ota joined Grulla Morioka in January 2018. Club statistics Updated to 30 August 2018. References External links Profile at J. League Profile at Iwate Grulla Morioka Category:1995 births Category:Living people Category:Osaka University of Health and Sport Sciences alumni Category:Association football people from Kanagawa Prefecture Category:Japanese footballers Category:J3 League players Category:Iwate Grulla Morioka players Category:Association football defenders

Q: Multiple lock owners in SQL Server 2014 I've encountered a deadlock on SQL Server 2014, and created a deadlock report using extended events. Below is an excerpt from the report. What does it mean for objectlock(objid="554979041") to have multiple owners (namely, process14f3f2108 and processf32b5848 (twice)). I understand how a lock may have multiple waiters, but what does it mean to have multiple owners? I thought that a lock could only be owned by a single process, and that all other processes interested in the lock would have to wait for the lock. What am I missing? <deadlock> ... content deleted ... <resource-list> <keylock hobtid="72057633537982464" dbid="15" objectname="BasketHeader" indexname="UX_BasketHeader_BasketID_Account" id="lock2d9b59f80" mode="X" associatedObjectId="72057633537982464"> <owner-list> <owner id="process203dad848" mode="X" /> </owner-list> <waiter-list> <waiter id="process14f3f2108" mode="RangeS-U" requestType="wait" /> </waiter-list> </keylock> <objectlock lockPartition="0" objid="554979041" subresource="FULL" dbid="15" objectname="BasketItem" id="lock1e64cbc80" mode="IX" associatedObjectId="554979041"> <owner-list> <owner id="process14f3f2108" mode="IX" /> !!! OWNER 1 </owner-list> <waiter-list> <waiter id="processf32b5848" mode="X" requestType="convert" /> </waiter-list> </objectlock> <objectlock lockPartition="0" objid="554979041" subresource="FULL" dbid="15" objectname="BasketItem" id="lock1e64cbc80" mode="IX" associatedObjectId="554979041"> <owner-list> <owner id="processf32b5848" mode="IX" /> !!! OWNER 2 <owner id="processf32b5848" mode="X" requestType="convert" /> !!! OWNER 3 </owner-list> <waiter-list> <waiter id="process203dad848" mode="IX" requestType="wait" /> </waiter-list> </objectlock> </resource-list> </deadlock> A: The processes use and request different types of locks on the tables Exclusive (X) Shared (S) Intent exclusive (IX) Intent shared (IS) Shared with intent exclusive (SIX) And the compatability matrix looks like this: (X) (S) (IX) (IS) (SIX) (X) ✗ ✗ ✗ ✗ ✗ (S) ✗ ✓ ✗ ✓ ✗ (IX) ✗ ✗ ✓ ✓ ✗ (IS) ✗ ✓ ✓ ✓ ✓ (SIX) ✗ ✗ ✗ ✓ ✗ process203dad848 (A) has a X (exclusive) lock on the BasketHeader table and is requesting an IX (Intent Exclusive) lock on the BasketItem table process14f3f2108 (B) has an IX (Intent Exclusive) lock on BasketItem and is waiting to get a RangeS-U on BasketHeader. processf32b5848 (C) has an IX lock on BasketItem and is waiting for it to be turned into a X lock As you can see on the table above IX locks are compatible so seeing two of those on the BasketItem table is perfectly normal. The RangeS-U makes this interesting as range locks only happen when you are running transactions if you are using serializable isolation level Whats happening is that (A) holds an exclusive lock on BasketHeader and is waiting for an IntentExclusive lock on BasketItem. (B) is running in serializable isolation level and and is waiting for getting an exclusive Shared lock on BasketHeader and holds an IntentExclusive lock on BasketItem While (C) is Converting its IX lock to X lock. (B) who is running in serializable will not be able to continue unless it gets its RangeS-U on BasketHeader and will not yield for (C). (A) cannot continue until it can get its lock on BasketItem and there you have your deadlock

Guard youths from alcopops 9:55 AM, May 8, 2013 Written by Dylan Goodman OPINION Attending any high school means you hear a lot about what everyone is doing - from after-school activities to alcohol. One of the major problems are alcopops - alcoholic drinks marketed toward youths that are easy to mistake as juice, soda or energy drinks because of their packaging and taste. I attend Asheville High School and work with Youth Empowered Solutions, a youth advocacy group that focuses on everything from youth obesity to substance abuse. We've worked before on labeling alcopops with stickers that remind adults not to purchase the products for youths and help distinguish the ...

In cranes, cargo-handling machinery or construction machinery, such as excavators for example, hydraulic quick couplings are widely used for the purpose of coupling structural components which have to be separated or reset for a specific use of for transport. The structural components are in most cases connected mechanically by quick-change systems, the coupling of the power transmission lines, especially those with large cross sections, being associated with considerable expenditure in terms of energy and in terms of time. One object of the present application is to make available a hydraulic quick coupling which on the one hand reduces the expenditure of energy and time and on the other hand avoids contamination of the hydraulic fluid by using individual couplings free from leakage oil. According to the one embodiment, the object is achieved by a hydraulic quick coupling. The coupling includes two interacting quick-coupling parts which are arranged respectively on the structural components that are to be connected or separated. One quick-coupling part has at least one guide bolt which can engage in a centering bore of the quick-coupling part lying opposite it, each quick-coupling part being provided with coupling plugs or coupling sleeves for the connection of the hydraulic lines, and at least one quick-coupling part being arranged movably on one structural component in order to connect or separate the two quick-coupling parts. Preferred embodiments are set out in the dependent claims following on from the main claim. Accordingly, one quick-coupling part can preferably be arranged fixedly on one structural component, while the other quick-coupling part is arranged movably on the second structural component. Particularly advantageously, at least one of the quick-coupling parts is spring-mounted in a support frame. In this way, the coupling can be kept free from forces acting on the structural components. The quick-coupling part spring-mounted in the support frame can, together with said support frame, be mounted movably on the structural component. At least one lock can be provided via which the quick-coupling parts can be locked to one another in the coupled state. The lock can secure the at least one guide bolt driven into the corresponding at least one centering bore. The movable quick-coupling part can sit displaceably on a linear guide. As has already been mentioned, the support frame in which the quick-coupling part is spring-mounted can also be guided on this linear guide. The movable quick-coupling part is advantageously displaceable via a piston/cylinder arrangement. To lock the quick-coupling parts in the coupled state, it is also possible for the coupled position to be fixed, for example, by a permanent pressure load of the piston/cylinder arrangement or by suitable shut-off valves. Advantageously, the movable quick-coupling part spring-mounted in the support frame can be fixed in its opened position by a guide. The guide can comprise a guide means, for example, a guide bolt which engages in the coupling sleeve in the opened position of the quick-coupling part. In this position, the guide means, that is to say for example a guide bolt, permits guiding of the spring-mounted quick-coupling part in such a way that the forces acting on the latter can be taken up. When attaching the quick-coupling part, that is to say when moving it into the closed position, the quick-coupling part moves with its centering bore onto the guide bolt of the other quick-coupling part lying opposite it. In the coupled position, the guide means, that is to say for example the guide bolt, frees the corresponding coupling sleeve. The securing of the quick-coupling part is taken over by the guide bolt of the opposite quick-coupling part. To provide a possibility of also being able to couple structural components which are angled about their bolted point, at least one of the two quick-coupling parts is arranged on a pivotable support bracket. The support bracket can be pivoted by its own piston/cylinder arrangement. The quick-coupling part arranged on the support bracket can in addition be driven along the support bracket and moved to and fro along the lengthwise guide with another piston/cylinder arrangement. In this way, the quick-coupling parts can also be coupled in an angled position.

/*####################################################### * Copyright (c) 2014 Jeff Martin * Copyright (c) 2015 Pedro Lafuente * Copyright (c) 2017-2019 Gregor Santner * * Licensed under the MIT license. * You can get a copy of the license text here: * https://opensource.org/licenses/MIT ###########################################################*/ package other.writeily.ui; import android.app.Dialog; import android.os.Bundle; import android.support.annotation.NonNull; import android.support.v4.app.DialogFragment; import android.support.v7.app.AlertDialog; import android.text.TextUtils; import net.gsantner.markor.R; import net.gsantner.markor.util.AppSettings; import java.io.Serializable; public class WrConfirmDialog extends DialogFragment { public static final String FRAGMENT_TAG = "WrConfirmDialog"; private static final String EXTRA_TITLE = "EXTRA_TITLE"; private static final String EXTRA_MESSAGE = "EXTRA_MESSAGE"; public static final String EXTRA_DATA = "EXTRA_DATA"; private Serializable _data; private ConfirmDialogCallback[] _callbacks; private String _summary; public static WrConfirmDialog newInstance(String title, String message, Serializable data, ConfirmDialogCallback... callbacks) { WrConfirmDialog confirmDialog = new WrConfirmDialog(); Bundle args = new Bundle(); args.putSerializable(EXTRA_DATA, data); args.putString(EXTRA_TITLE, title); args.putString(EXTRA_MESSAGE, message); confirmDialog.setArguments(args); confirmDialog.setCallbacks(callbacks); return confirmDialog; } public void setCallbacks(ConfirmDialogCallback[] callbacks) { _callbacks = callbacks; } @Override @NonNull public Dialog onCreateDialog(Bundle savedInstanceState) { String title = getArguments().getString(EXTRA_TITLE); String message = getArguments().getString(EXTRA_MESSAGE); _data = getArguments().getSerializable(EXTRA_DATA); AlertDialog.Builder dialogBuilder; boolean darkTheme = AppSettings.get().isDarkThemeEnabled(); dialogBuilder = new AlertDialog.Builder(getActivity(), darkTheme ? R.style.Theme_AppCompat_Dialog : R.style.Theme_AppCompat_Light_Dialog); dialogBuilder.setTitle(title); if (!TextUtils.isEmpty(message)) { dialogBuilder.setMessage(message); } dialogBuilder.setPositiveButton(getString(android.R.string.ok), (dialog, which) -> { if (_callbacks != null) { for (ConfirmDialogCallback cdc : _callbacks) { if (cdc != null) { cdc.onConfirmDialogAnswer(true, _data); } } } }); dialogBuilder.setNegativeButton(getString(R.string.cancel), (dialog, which) -> { dialog.dismiss(); for (ConfirmDialogCallback cdc : _callbacks) { cdc.onConfirmDialogAnswer(false, _data); } }); return dialogBuilder.show(); } public interface ConfirmDialogCallback { void onConfirmDialogAnswer(boolean confirmed, Serializable data); } }

Review Transcript: October is finally in full swing, giving us four (count them: FOUR) movies in one week, one of which is the latest in supernatural horror: Sinister. Truth be told, this is a pretty solid horror movie overall, and gives a fresh spin on the idea of “found footage” movies! It’s brought to us by the producer of Paranormal Activity and Insidious, but doesn’t suffer from some of the issues that both of these had. Paranormal Activity suffered from being regarded as either incredibly boring or weird and somewhat tense until everything comes to a head at the end. Insidious on the other hand, had a very strong and refreshingly scary feel to it that took a major nosedive in the third act. Sinister manages to maintain a consistent tone to its horror that builds over time…you know, like a proper movie should. It never quite reaches the heights of terror that either movie achieved when at their best, but is a strong effort that’s overall enjoyable. Of all the characters involved, the most intriguing is easily Ellison Oswalt, played by Ethan Hawke. He’s a true crime writer with a desire to write his best book ever, and the desire quickly turns to an obsession, as the last time he achieved fame was a decade ago with his first book. This obsession drives him to not only move to the same town where the grisly deaths of a family occurred, but into their house where they were murdered! Now it’s obvious that Sinister is a horror movie, but…the first act of the movie could very well be the first act of a crime thriller along the same lines as Red Dragon (a great movie that should be seen if you haven’t already). This provides the audience a good portrayal of the mental and physical toll that the story takes on Ellison, as well as the family dynamics and how his obsessions affect his wife and children. Although a successfully scary film, there are two issues that were hard for me to ignore. The first is that the actors playing Ellison’s children, Ashley and Trevor, were less than impressive. It’s no surprise for kid actors to not give great performances, but the daughter’s deadpan performance was incredibly distracting. Then again, my disappointment could be from comparing these kids to Pierce Gagnon, the kid from Looper. The second and most jarring issue is Sinister’s reliance upon loud music and sounds for many of its scares, like Insidious. Or as my friend the Film Phage put it: “LOUD NOISES!” Despite the annoyingly influential LOUD NOISES…*ahem*…despite the annoyingly influential loud noises and music however, these elements are used in a way that lead to an effectively creepy and unnerving movie. Sure it’s a manipulative tool, but a tool that is used really well. While Sinister may let down horror purists by relying too much on occasional jump-scares and way too many LOUD NOISES, it is a horror movie that most audiences will enjoy. It will legitimately scare, or at the very least creep out many viewers, while some might leave the theater terrified. I give Sinister: 8/10. I’m Papa Kenn, and I’ll see you next review. Fair Use: All copyrighted material used under Fair Use. If you are a copyright holder and believe your material has been used unfairly, please contact me at: [email protected]

There is a philosophy that says that if something is unobservable -- unobservable in principle -- it is not part of Science...By that standard, most of the universe has no scientific reality -- it's just a figment of our imaginations. ~ Leonard Susskind,~

Q: Silverlight resource constructor always return to internal When I modify my resource file (.resx) add text or modify, the constructor of my resource always go to internal and after that, when I run my silverlight I have an error in my binding XAML. Is there a way to avoid this scenario? I need to go in the designer of my resource and put the constructor to public to solve the problem I use my resource like this in my xaml file <UserControl.Resources> <resources:LibraryItemDetailsView x:Key="LibraryItemDetailsViewResources"></resources:LibraryItemDetailsView> </UserControl.Resources> <TextBlock FontSize="12" FontWeight="Bold" Text="{Binding Path=FileSelectedText3, Source={StaticResource LibraryItemDetailsViewResources}}"></TextBlock> A: Another way to do this without code changes is as below. Worked well for me. http://guysmithferrier.com/post/2010/09/PublicResourceCodeGenerator-now-works-with-Visual-Studio-2010.aspx A: You can create a public class that exposes the resources through a property: public class StringsWrapper { private static LibraryItemDetailsView _view = null; public LibraryItemDetailsView View { get { if (_view == null) { _view = new LibraryItemDetailsView(); } return _view; } } } Then in your XAML you can access your resource: <UserControl.Resources> <StringsWrapper x:Key="LibraryItemDetailsViewResources"></StringsWrapper> </UserControl.Resources> <TextBlock FontSize="12" FontWeight="Bold" Text="{Binding Path=View.FileSelectedText3, Source={StaticResource LibraryItemDetailsViewResources}}"></TextBlock> This way the resx constructor can be internal!

MARVIN T. BURTON, JR. Defendant Below, Appellant, v. STATE OF DELAWARE, Plaintiff Below, Appellee. No. 335, 2008 Supreme Court of Delaware. Submitted: January 28, 2009. Decided: March 4, 2009. Before STEELE, Chief Justice, JACOBS and RIDGELY, Justices. ORDER JACK B. JACOBS, Justice. This 4th day of March 2009, upon consideration of the briefs of the parties and the record in this case, it appears to the Court that: 1. Marvin Burton, the defendant below, appeals from the denial by the Superior Court of a Rule 61 motion for post-conviction relief. On appeal, Burton argues that the trial court erroneously denied that motion which was based, in part, on a claim of ineffective assistance of counsel. Given the serious nature of the charges, the fact that Burton's Rule 61 motion was filed pro se, and that the alleged new evidence has not yet been considered by the Superior Court, we remand for further proceedings limited to Burton's ineffective assistance of counsel claim. 2. Burton was arrested on October 6, 2004, and indicted on October 25, 2004 on charges of First Degree Rape, Second Degree Rape and Second Degree Unlawful Sexual Contact. Burton's daughter, the alleged victim, who was eleven years old at the relevant times, claimed that on at least three occasions Burton had sexually abused and raped her. All three incidents allegedly occurred while the victim was staying at Burton's parents' house in 2004, with the two most serious incidents allegedly occurring in August 2004. Trial began on August 8, 2005. On August 11, 2005 Burton was convicted on all charges. 3. Because of prior convictions for Third Degree Burglary and Third Degree Unlawful Sexual Intercourse, the State moved to declare Burton an habitual offender under 11 Del. C. § 4214.[1] On October 28, 2005, the Superior Court declared Burton an habitual offender and sentenced him to life in prison for each of the two Rape charges, plus two additional years imprisonment for the Unlawful Sexual Contact charge. The Superior Court also imposed special conditions, including a no contact order and sex offender registration. 4. After sentencing, defense counsel filed a notice of appeal on Burton's behalf and a motion to withdraw pursuant to Supreme Court Rule 26(c). The State filed a motion to affirm. After reviewing the record, this Court determined that Burton's appeal was "wholly without merit and devoid of any arguably appealable issue" and granted the motion to affirm.[2] 5. On August 16, 2007 Burton moved pro se for post-conviction relief, raising multiple claims including ineffective assistance of counsel.[3] Burton alleged that his trial counsel was incompetent, failed to interview and subpoena key defense witnesses, and did not allow Burton to testify. On September 4, 2007, trial counsel filed a sworn letter memorandum responding to that motion. Trial counsel explained that he did not mislead Burton or refuse to allow him to testify. Rather, he advised Burton not to take the stand for the strategic purpose of avoiding cross-examination on Burton's prior convictions. After receiving that advice, Burton agreed and chose not to testify. Trial counsel further explained that he did, in fact, contact most of the witnesses Burton claimed were not interviewed or subpoenaed, and found that those witnesses either could not provide the testimony Burton claimed, or that they had no information helpful to Burton's defense. 6. On June 3, 2008, the Superior Court denied Burton's motion without a hearing, finding that Burton's arguments were all without merit.[4] On June 30, Burton filed a notice of appeal, pro se, and on August 14, appellate counsel entered an appearance on his behalf. 7. Although Burton advanced numerous claims of error in his motion for post-conviction relief, on appeal he advances only one—that the Superior Court erred by denying his claim of ineffective assistance of counsel. Moreover, Burton limits that claim to the contention that trial counsel was ineffective by failing to contact, properly interview and subpoena material witnesses, and also by refusing to allow Burton to testify at trial.[5] 8. The State has moved to strike certain affidavits and information included in Burton's appendix that were not part of the record on appeal. These affidavits include: (i) a statement by Marvin Burton, Sr. "that he was not contacted, interviewed or subpoenaed concerning the fact that the alleged victim . . . did not live in our residence from late July through September 2004"; and (ii) a statement by Stacie Brittingham (Burton's sister) that she was not interviewed before the day of trial concerning her testimony, and that the alleged victim did not live in her parent's residence from late July through September 2004 and that that issue was not raised in questioning during her testimony at trial. Also included was a statement by Eric Morris that (i) "he was not contacted, interviewed or called as a witness concerning the fact that the alleged victim . . . did not live at Marvin Burton, Sr. and Vivian Burton's residence from late July through September 2004;" and that (ii) "I would also have testified that [the alleged victim] lived with me approximately 3 weeks during the end of July and August 2004 and she stayed with other individuals until the month of September 2004. . . ." 9. As a general matter, the record on appeal may not be supplemented by affidavits relating facts and circumstances that were not fairly presented to the trial court,[6] and we will not consider such supplemental affidavits. For new evidence to be considered, a party should file a motion to remand to the trial court to determine the facts in light of their new evidence.[7] Here, however, Burton moved for post-conviction relief pro se, without the evidence having been considered by the Superior Court. In such circumstances, some leeway should be granted if, in the interests of justice, the new evidence ought to be considered.[8] For that purpose a remand is appropriate. NOW, THEREFORE, IT IS ORDERED that this matter is remanded to the Superior Court for further proceedings limited to the ineffective assistance of counsel claim. Jurisdiction is not retained. NOTES [1] See generally 11 Del. C. § 4214 (providing for sentencing as an habitual criminal). [2] Burton v. State, 907 A.2d 145, 2006 WL 2434914, at *1 (Del. 2006) (Table). [3] Burton claimed that: (1) the indictment was illegal; (2) a Batson violation had occurred; (3) a juror had misled the Superior Court during voir dire; (4) a juror drank alcohol during the trial; (5) Burton was not allowed to testify; (6) Burton was not allowed to call witnesses; (7) prosecutorial misconduct occurred; (8) his sentence was illegal; (9) his trial counsel was ineffective; and (10) his trial counsel failed to interview and call material witnesses. See State v. Burton, 2008 WL 2359717 (Del. Super. Ct. June 3, 2008). [4] See State v. Burton, 2008 WL 2359717, at *1-6. [5] "Appellant's counsel has reviewed all of the allegations set forth in the Rule 61 Motion and is limiting argument in this opening brief to the fact that [trial counsel] was ineffective by failing to contact, properly interview and subpoena material witnesses for the disputed allegations made by the alleged victim as well as allowing the Appellant to testify during his trial." [6] Sup. Ct. R. 8; Merritt v. State, 219 A.2d 258, 260 (Del. 1966); Draper v. State, 146 A.2d 796, 800 (Del. 1958); see also Gateley v. Gateley, 832 A.2d 1251, 2003 WL 22282584, at *2 n.7 (Del. Oct. 1, 2003) (Table) (declining to review documents presented for the first time on appeal). [7] Compare Merritt, 219 A.2d at 260 (remanding the case with authority and instructions to ascertain the facts) with Draper, 146 A.2d at 800 (refusing to consider new evidence on appeal). [8] See Yancey v. Nat'l Trust Co., Ltd., 712 A.2d 476, 1998 WL 309819 (Del. May 19, 1998) (Table) (Del. 1998) (noting that some degree of leniency should be granted for pro se appeals); see also In re Estate of Hall, 882 A.2d 761, 2005 WL 2473791 (Del. Aug. 26, 2005) (Table) (noting that we allow pro se litigants some leeway).

1953 Kent State Golden Flashes football team The 1953 Kent State Golden Flashes football team was an American football team that represented Kent State University in the Mid-American Conference (MAC) during the 1953 college football season. In their eighth season under head coach Trevor J. Rees, the Golden Flashes compiled a 7–2 record (3–1 against MAC opponents), finished in a tie for third place in the MAC, and outscored all opponents by a combined total of 250 to 103. The team's statistical leaders included Lou Mariano with 816 rushing yards, Don Burke with 577 passing yards, and Gino Gioia with 84 receiving yards. Fullback Jim Cullom and offensive tackle Al Kilgore were selected as first-team All-MAC players. References Kent State Category:Kent State Golden Flashes football seasons Kent State football

Training in youth-friendly service provision improves nurses' competency level in the Great Lakes Region. This survey investigates whether relevant training and availability of guidelines improve self-reported competencies of nurses in the provision of youth-friendly sexual and reproductive health services in South-Kivu Province in the Democratic Republic of the Congo, Burundi, and Rwanda. A quantitative baseline survey was conducted among nurses in randomly selected health facilities. Nurses providing youth-friendly sexual and reproductive health services were asked to self-rate their competencies with regards to technical knowledge, clinical, and communication skills. In South-Kivu, Burundi, and Rwanda, 135, 131, and 99 nurses were interviewed, respectively. Overall differences of service and guideline availability and self-rated competencies can be observed between the three countries. In two countries, more than one in five nurses considered themselves to be only somewhat or not confident to counsel young people. Nurses from Rwanda showed the highest level of competencies followed by Burundi and South-Kivu. Lack of training in youth-friendly health services or family planning showed significant associations with reporting feeling somehow or not competent. The lack of training, supervision, and guidelines expressed by the nurses is of great concern. Competency-based training in youth-friendly health services is an important approach in improving nurses' competency level.

Oh, Boo-Hoo, Hillary But Hillary’s is not the caricatured, bitchy, ball-breaking toughness that their enemies like to attribute to her. She has almost always been much more thoughtful than they granted. It is more like a kind of military rigor: reading the landscape, seeing the obstacles, recognizing which ones are malevolent or malign, and taking expedient action accordingly. Whatever, Skippy. We know better and socialists/communists have you all afoul. Like this: LikeLoading... Related This entry was posted on June 4, 2007 at 2:03 am and is filed under Character. You can follow any responses to this entry through the RSS 2.0 feed. You can leave a response, or trackback from your own site. 4 Responses to “Oh, Boo-Hoo, Hillary” Where is the G-damn f**king flag? I want the G-damn f**king flag up every f**king morning at f**king sunrise.” (From the book “Inside The White House” by Ronald Kessler, p. 244 – Hillary to the staff at the Arkansas Governor’s mansion on Labor Day, 1991) “You sold out, you mother f**ker! You sold out!” From the book “Inside” by Joseph Califano, p. 213 – Hillary yelling at Democrat lawyer. “It’s been said, and I think it’s accurate, that my husband was obsessed by terrorism in general and al-qaida in particular.” (Hillary telling a post-9/11 world what a ‘great’ commander in chief her husband was; Dateline, NBC 4/16/2004.) “I have to admit that a good deal of what my husband and I have learned [about Islam] has come from our daughter.” (TruthInMedia.org 8/8/1999 – Hillary at a White House function, proudly tells some Muslim groups she is gaining a greater appreciation of Islam because Chelsea was then taking a class on the “religion of peace”) “F**k off! It’s enough that I have to see you shit-kickers every day, I’m not going to talk to you too!! Just do your G*damn job and keep your mouth shut.” (From the book “American Evita” by Christopher Anderson, p. 90 – Hillary to her State Trooper bodyguards after one of them greeted her with “Good morning.” “You f**king idiot.” (From the book “Crossfire” p. 84 – Hillary to a State Trooper who was driving her to an event.) “If you want to remain on this detail, get your f**king ass over here and grab those bags!” (From the book “The First Partner” p. 259 – Hillary to a Secret Service Agent who was reluctant to carry her luggage because he wanted to keep his hands free in case of an incident.) “Get f**ked! Get the f**k out of my way!!! Get out of my face!!!” (From the book “Hillary’s Scheme” p. 89 – Hillary’s various comments to her Secret Service detail agents.) “Stay the f**k back, stay the f**k away from me! Don’t come within ten yards of me, or else! Just f**king do as I say, Okay!!!?” (From the book “Unlimited Access”, by Clinton FBI Agent in Charge, Gary Aldrige, p. 139 – Hillary screaming at her Secret Service detail.) Hillary represents “What’s wrong with America….always blaming someone for his or her perceptions and actions , rather than assuming responsibility” and the scaring part is, Americans have supported the Clintons. She has been and is,… a total fraud WILLING TO SAY ANYTHING TO GET ELECTED. She is about as ‘warm’ as a cold blooded rattlesnake.

Fidel Antonio Vargas Fidel Antonio Vargas (born 28 July 1992) is a Cuban canoeist who won a silver medal in the K-2 200 m event at the 2015 Pan American Games, together with Reiner Torres. He competed in the individual 200 m at the 2016 Summer Olympics, but failed to reach the final. References Category:1992 births Category:Living people Category:Cuban male canoeists Category:Olympic canoeists of Cuba Category:Canoeists at the 2016 Summer Olympics Category:Place of birth missing (living people) Category:Pan American Games medalists in canoeing Category:Pan American Games silver medalists for Cuba Category:Canoeists at the 2015 Pan American Games

Given the potential pharmacological and physiological diversity arising from heterodimerization of opioid receptors, an important challenge in opioid research is the development of selective tools for the investigation of such phenotypic opioid receptors. Selective pharmacological tools that can span the divide between cultured cells and in vivo systems would clarify the functional roles and localization of heterodimeric opioid receptors in experimental animals. Thus, the broad, long-term objectives of this research are to develop ligands with selectivity for heterodimeric opioid receptors as tools to study the functional roles of physically associated opioid receptors in the central nervous system. The long-term goal is to use the information obtained from such studies to develop superior analgesics that are devoid of tolerance and dependence. [unreadable] [unreadable] The specific aims of the present application include the synthesis and biological evaluation of ligands that are selective for opioid receptor heterodimers. Based on reports of heterodimeric opioid receptors in cultured cells and on the large body of literature that implicates interaction between mu and kappa opioid receptors and mu and NK1, CCK2, ORL1, and CB1 receptors in vivo, a total of ten series of compounds will be synthesized. Eight of the proposed series are bivalent ligands that will include mu and kappa opioid pharmacophores or a mu agonist pharmacophore combined with NK1, CCK2, ORL1, or CB1 antagonist pharmacophores. The pharmacophores in each of these bivalent series will be linked to each other through spacers containing 12-22 atoms. The antagonist non-opioid pharmacophores were selected because interaction between mu opioid receptors and the above receptors have been reported to modulate antinociception, tolerance and/or dependence. The corresponding series of monovalent ligands with matching spacers and matching pharmacophores will be synthesized as controls. There will be 11 compounds in each of these 16 series. The remaining two series will be structurally related to 6'-GNTI which has been reported to produce analgesia in mice by selectively targeting spinal delta-kappa opioid receptor heterodimers. Because analgesia of 6'-GNTI is mediated spinally, such compounds should not possess the supraspinal side-effects generally associated with clinically employed analgesics. As a second approach to development of spinally-selective analgesics, the Pl/s library of ~1000 opiates will undergo Flexstation screening on cultured cells containing coexpressed and singly expressed delta and kappa opioid receptors. Target compounds and screening hits will be tested in cultured cells and in behavioral tests in mice that include evaluation of tolerance and physical dependence. [unreadable] [unreadable] [unreadable]

2/(x/2). Suppose -5*r + 4*h + 43 = -187, -h + q = 0. Is 35 a factor of r? False Let r be ((-32)/(-20))/(2/5). Suppose -4*a = 3*m + 33, 0 = 3*a - r*a - 3*m - 6. Is 2/(-1)*a/1 a multiple of 16? False Suppose 4*b + 3*k = 8019, -392*b + 3*k - 4011 = -394*b. Is 12 a factor of b? True Suppose -5*g = -4*z + 117, g - 6*g - 3*z = 131. Suppose 22*u - 2*m + 10 = 20*u, u = -3*m + 3. Let f = u - g. Is f a multiple of 22? True Let v = 0 - 6. Suppose -426 = 5*s - 2*w, 2*w + 171 = -2*s + 3*w. Let n = v - s. Is n a multiple of 26? True Let z be 4/(-12) - (-22)/(-6). Let j(n) = 4*n**2 + 5*n + 1. Let m be j(z). Suppose -95 = -5*a + m. Is 26 a factor of a? False Suppose -2*j + 3*t - t = 2, -2*t - 4 = -5*j. Let d(w) = 0*w**3 + 6*w**2 + 0*w**3 + 6*w - 22*w**j + w**3. Does 17 divide d(16)? False Let b(i) = i**2 - 4*i + 3. Let k be b(3). Suppose -648 = -w + 2*w + 3*c, k = -2*w + 4*c - 1316. Is (-4)/10 - w/10 a multiple of 23? False Suppose 4*b - 3*b = 5*g - 2042, b - 814 = -2*g. Is 34 a factor of g? True Let x(k) = -100*k**3 + 10*k**2 + 9*k - 1. Does 10 divide x(-1)? True Let j(h) = 9*h + 28. Is j(4) a multiple of 64? True Let z = -3510 + 5478. Is 93 a factor of z? False Let t(k) = 4*k**2 + 5*k - 153. Is 18 a factor of t(-17)? True Let d be ((-6)/(-4))/(5/60). Let b = 21 - d. Does 25 divide 18/7*7*b? False Let w(p) = -218*p + 116. Does 52 divide w(-4)? True Let c(g) = -6*g + 24. Let n be c(8). Is 2/2 - n - 3 - 1 a multiple of 5? False Let w(t) be the third derivative of -13*t**4/24 + 19*t**3/6 - 6*t**2. Let k be w(-15). Suppose -218 - k = -4*a. Is a a multiple of 18? True Let c be 10*(-4)/8*176/(-10). Let k = -71 + c. Is k even? False Suppose -9*i + 140 = i. Suppose 0 = 5*j - 2*x - 3*x - 185, j = -4*x + 22. Let n = j - i. Is n a multiple of 5? True Let c = 1189 - -603. Does 14 divide c? True Let z = 90 + 211. Suppose y + 4*y = -4*b - 287, 3*b - z = 5*y. Let i = 105 + y. Is i a multiple of 24? False Let m = 12 + -7. Suppose 41 + 47 = 2*r + 4*i, -3*r + m*i = -77. Is r a multiple of 11? False Suppose 6*q - 10*q + 2508 = 0. Suppose 4*o = q + 317. Is 48 a factor of o? False Let w = 5 + -11. Let a(j) = j**2 + j. Let y be a(-6). Let h = w + y. Does 24 divide h? True Is (-3)/(-6) + 22673/158 a multiple of 18? True Is (-1 - -4)/(1*33/1804) a multiple of 4? True Let i(l) = -10*l - 2. Let j(x) = 10*x + 1. Let c(k) = 4*i(k) + 5*j(k). Let r = 160 - 157. Is 7 a factor of c(r)? False Let v(r) = 4*r**3 + 3*r**2 + 17. Is 5 a factor of v(5)? False Suppose 3*c + 25 = 34. Suppose -3*b = b + 3*f - 665, 4*f = -c*b + 490. Is 22 a factor of b? False Suppose 0 = 179*u - 182*u + 414. Is u even? True Suppose -73*c - 756 = -79*c. Is 7 a factor of c? True Let w = -34 + 46. Is w/(-27)*-123 + (-1)/(-3) a multiple of 11? True Suppose -4*w - 4*t - 420 = w, -2*t = 3*w + 254. Let q = -26 - w. Is 11 a factor of q? False Suppose 12*h = 16*h - 3740. Is h a multiple of 10? False Let t = -343 - -525. Is t a multiple of 14? True Suppose -z + 0 + 3 = 0. Does 11 divide ((-51)/z + -1)*(-5)/2? False Let z be (-1)/10 + 38538/180. Let s = z + -114. Does 10 divide s? True Suppose -111*n + 3*x - 1809 = -112*n, -n + 4*x + 1788 = 0. Does 83 divide n? False Let f be 2*(-3)/(-24) - (-13)/(-4). Does 10 divide 5 - f - -1*2? True Suppose 245 = 2*h + 77. Suppose -2 = 2*y - 3*p + 54, -p = 4*y + h. Is ((-10)/(-10))/((-2)/y) a multiple of 11? True Does 14 divide 4/((-12)/3) - (-1054 + 3)? True Suppose 0 = 55*g - 61*g + 1272. Is g a multiple of 3? False Let u = 27 + 7. Let c = u + -9. Suppose 47 + c = 2*f. Is 23 a factor of f? False Let h = 93 - 72. Let s be 2/(-2 - -1) + 4. Suppose f + h = s*f. Is 15 a factor of f? False Let c(d) = -7*d**3 + 7*d**2 - 4*d + 8. Let v(k) = k**3. Let x(o) = -c(o) - 6*v(o). Is 20 a factor of x(7)? True Let r = 16 + -12. Suppose -c - 3*c + 49 = 3*u, r*c - 31 = 3*u. Let f = c - -26. Is f a multiple of 12? True Suppose -5*c + 0*c - 15 = 0. Let k = c - -28. Let q = k + 7. Does 23 divide q? False Let a(v) = -v**2 + 6*v + 22. Let r be a(10). Is 196 - (r/7 + (-12)/(-21)) a multiple of 22? True Let q(k) = k. Let b be q(4). Suppose -3*h - 2*j = -4*h + 231, -b*h + 3*j = -949. Is h a multiple of 28? False Suppose 5*x - 4*b - 8 = 0, -4*x = -3*b + 7*b - 28. Suppose 12 = x*z - 60. Is 9 a factor of z? True Let s be (-2)/5 + 874/10. Suppose -60 = -7*j + s. Does 21 divide j? True Suppose 2 = 2*j - 10. Let y = 26 - j. Is y a multiple of 13? False Is 972 + 4 - -6 - -10 a multiple of 32? True Let g(t) = t**3 - 5*t**2 + 5*t - 3. Let q be g(4). Let m be q/(-2*1/(-6)). Does 14 divide (-1)/(129/(-42) + m)? True Let z(a) = 4*a**2 + 4*a - 3. Let s be z(-7). Let t = s - 19. Is 15 a factor of t? False Let h be 0 - -4 - (-2)/1. Suppose -h = 4*k - 2*k. Does 11 divide (423/(-3))/(-3) + k? True Let r be -2 - (2 + -2 + (-4 - 44)). Let l = r - 6. Is l a multiple of 5? True Suppose 31*k + 1200 = 36*k. Is k a multiple of 12? True Suppose -t + m = -5*t + 5961, 0 = 4*t + 3*m - 5963. Does 10 divide t? True Let f(r) = -132*r + 96. Is f(-2) a multiple of 53? False Suppose -5*c + 3161 = 161. Is c a multiple of 57? False Let k(p) be the second derivative of p**5/20 + p**4/12 + p**3/6 + 30*p**2 - 4*p. Let o be k(0). Suppose o = 3*u + 2*u. Is u a multiple of 9? False Let m = -138 + 143. Let k = m - -9. Is 2 a factor of k? True Let q = 125 + 115. Is 30 a factor of q? True Suppose -91*o = -10*o - 2187. Is o a multiple of 17? False Let l be (6/15)/(7/1890). Let w be (-2)/(-4) + 238/(-4). Let o = w + l. Is o a multiple of 15? False Let b = 72 - 255. Is ((-2)/(-3))/((-2)/b) a multiple of 17? False Let d(k) be the second derivative of k**5/24 - 5*k**4/12 - k**3 + 8*k. Let m(c) be the second derivative of d(c). Is 5 a factor of m(8)? True Suppose 0 = -2*o - 3*o - 5*f + 1660, -2*o + 652 = -4*f. Is o a multiple of 33? True Suppose -7 = h - 5*k, 4*k = -5*h + 9*k + 25. Does 6 divide (632/(-12))/(-2) + h/(-6)? False Let z = -1551 - -2225. Let u = 78 - 81. Does 17 divide z/10 + u/(-5)? True Let y(s) be the first derivative of 49*s**2/2 + 7*s + 2. Does 7 divide y(1)? True Let h(o) = o**2 - 21*o + 27. Suppose 14 - 110 = -4*t. Is 25 a factor of h(t)? False Let u be -81 + -2*(-1)/(-2). Let i(a) = 5*a + 12. Let q be i(-11). Let r = q - u. Is r a multiple of 14? False Let n(h) = 2*h**2 + 2*h - 1. Suppose -8*y + 4*y = -24. Let q = -8 + y. Is n(q) a multiple of 2? False Let r = 60 - 107. Let s = 167 + r. Is 12 a factor of s? True Does 19 divide 1/(-2) + (-2548)/(-8)? False Suppose 0*l = -5*l. Suppose -5*q = l, 2*w + 0*q - q - 58 = 0. Is 6 a factor of w/3 - 2/(-6)? False Suppose -n = -6*n. Suppose n = 3*o - 7*o + 108. Suppose -38 - o = -5*r. Does 3 divide r? False Suppose -19*o = -54*o + 22750. Does 65 divide o? True Suppose -l - 3 + 4 = 0. Let z(c) be the second derivative of 4*c**5/5 - c**3/2 + c**2 + 53*c. Is 15 a factor of z(l)? True Let t = 68 + -65. Suppose j - 104 = 4*l, 0 = t*j + 5*l - l - 376. Does 9 divide j? False Let q = -27 - 18. Let o = 29 - q. Suppose 3*p - p = o. Does 15 divide p? False Let u(l) = -l + 360. Does 18 divide u(0)? True Let c = 1276 + -1133. Is c a multiple of 14? False Suppose -105*b + 47*b = -11020. Is b even? True Let z be 387/6*14/21. Let j = 13 + z. Is j a multiple of 8? True Let b be ((-22)/(-33))/((-2)/33). Does 6 divide b/2*-6 + 0/3? False Let b(c) = c + 204. Is 3 a factor of b(48)? True Let v be 89 + (-7)/(105/(-6))*5. Let r = 134 - v. Is r a multiple of 29? False Suppose -5*v - 120 = 3*v. Suppose 5*d = -5*p + 4*d + 128, 4*d = -p + 37. Let k = v + p. Is k a multiple of 2? True Let z be (-1016)/12 + 1/(-3). Let t = 55 + z. Let s = 21 - t. Is s a multiple of 10? False Let p = -227 - -375. Is p a multiple of 17? False Let b = -15 + 14. Let t(u) = -15*u**2 - u - 2. Let p be t(b). Let j = 27 + p. Is j a multiple of 8? False Let v(i) = -i**3 + 3*i**2 - 4. Let h be v(4). Let g = 1 - h. Is 5 a factor of g? False Let a(b) = 62*b**2 - 2*b. Does 8 divide a(-1)? True Let f(k) = 6*k**2 - 2*k - 4. Let d be f(-3). Suppose 4*s + w - d = -w, -3*s + 3*w = -42. Suppose -4*v + 126 = -s. Is 10 a factor of v? False Let f be (1 - 0)/(3 + -2). Does 14 divide (f*-1)/((-9)/126)? True Let b(i) = 2*i**3 + 3*i - 7. Let j be 8/3 - (-13)/39. Is b(j) a multiple of 28? True Let x = 119 + 247. Is 65 a factor of x? False Let j = -1257 + 1800. Does 48 divi

Q: How to check if file exist when downloading from FTP I'm downloading from FTP server and I don't know exactly how to check if file already exist. What I want to do is that I retrieve filname from FTP server and then compare it with all files in folder. If file already exists then it compares next FTP filename with all files in folder and so on. I already did comparison and it's working if all files from folder have same name as files on FTP server but if I add some older file then it downloads all files once again and I don't want that. Here is my scratch code: String[] names = client.listNames(); File folder = new File("c:\\test\\RTR_ZIP\\"); String[] filename = folder.list(); for (;i<names.length;i++) { name = names[i]; exists=false; if (name.contains(".zip")) { if (filename.length == 0) { new_file = new FileOutputStream("C:\\test\\RTR_ZIP\\" + name); client.retrieveFile(name, new_file); j++; exists=true; } else { for (;k<filename.length;k++) { name = names[i]; i++; name1=filename[k]; // CHECK IF FILE EXISTS if (!name.equals(name1)) { new_file = new FileOutputStream("C:\\test\\RTR_ZIP\\" + name); client.retrieveFile(name, new_file); j++; exists=true; } } }//else }//if contains .zip }//for Thanks in advance. A: If your ftp server supports XCRC command it could be possible to compare checksum (CRC32) of local and remote file. You could iterate all files in the folder and compare its crc with local one. import java.io.File; import java.io.IOException; import java.net.SocketException; import java.util.Scanner; import org.apache.commons.io.FileUtils; import org.apache.commons.net.ftp.FTPClient; public class DownloadFile { private FTPClient client = new FTPClient(); public void connect() throws SocketException, IOException { client.connect("127.0.0.1"); client.login("user", "password"); } public boolean hasXCRCSupport() throws IOException { client.sendCommand("feat"); String response = client.getReplyString(); Scanner scanner = new Scanner(response); while(scanner.hasNextLine()) { String line = scanner.nextLine(); if(line.contains("XCRC")) { return true; } } return false; } public boolean isSameFile() throws IOException { if(hasXCRCSupport()) { File file = new File("D:/test.txt"); String localCRC = Integer.toHexString((int) FileUtils.checksumCRC32(file)).toUpperCase(); client.sendCommand("XCRC /test.txt"); String response = client.getReplyString().trim(); System.out.println(response); if(response.endsWith(localCRC)) { return true; } } return false; } public void logout() throws IOException { client.logout(); } public static void main(String[] args) throws SocketException, IOException { DownloadFile downloadFile = new DownloadFile(); downloadFile.connect(); if(downloadFile.isSameFile()) { System.out.println("remote file is same as local"); } downloadFile.logout(); } }

Risk factors for conversion to laparotomy during laparoscopic management of an ectopic pregnancy. To identify risk factors for conversion to laparotomy during laparoscopic management of ectopic pregnancy. A retrospective chart review of patients who underwent laparoscopy for treatment of ectopic pregnancy, during a 32-month period (6/1999-2/2002), at the University of Miami Jackson Memorial Hospital. We identified 229 patients; 201 had a successful laparoscopy (non-converted group) and 28 who were converted to laparotomy (converted group). Variables analyzed between the two groups were demographic data, patient-related risk factors available to the surgeon prior to the surgery (previous laparotomy, previous laparoscopy, history of PID, history of endometriosis, diameter of ectopic pregnancy as measured by ultrasound, amount of free fluid on ultrasound, BMI), and surgeons' experience. Out of the 229 laparoscopies, 28 were converted to laparotomy (12.2%). The rate of conversion was significantly higher for less experienced compared to experienced surgeon (OR = 6.1, 95% CI = 2.35-15.88). Significantly more women had a BMI > 30 kg/m2 in the converted group compared to the non-converted group (42% vs. 14%; OR = 4.28, 95% CI = 1.7-10.75) and the converted group had significantly higher rate of large free fluid reported on ultrasound compared to the non-converted group (21.42% vs. 7.46%; OR = 3.38, 95% CI = 1.04-10.61). Less experienced surgeon, BMI > 30 kg/m2, and large amount of free fluid on ultrasound increase the risk of conversion to laparotomy during laparoscopic management of ectopic pregnancy.

ChatSua ChatSua () is a Thai film based on a work by "Orawun" (lyu Sresawek). It was premièred on June 18, 1958, at Sala Chalermkrung Royal Theatre and Sala Chalermbure Royal Theatre. The film was directed by Prateb Gomonpis. It is a sequel to the 1956 film PraiKuarng. The film was the screen debut of Mitr Chaibancha, as Wai Sukda, and stars Rewadee Sewilai, Win Wunchai, Narmkern bunnuk, Praphasee Satornkid, Naiyana TanomSub, Usanee Isaranun, NoppaMad Sirisopon, Punga Suttirin, Porn Paroch, Pramin Jarujarit, Sail Poonsai, Sompong pongmitr, Sukon Kueawleam and Lortok. The film has grossed over 800,000 baht. The critical response was mostly favourable. References Category:Thai films Category:1958 films

Q: Conditional formatting: making cells colorful is it possible to do the following: loc1 <- c("Aa", "Aa", "aa", "Aa") loc2 <- c("aa", "aa", "aa", "AA") loc3 <- c("aa", "Aa", "aa", "aa") gen <- data.frame(loc1, loc2, loc3) loc1g <- c(0.01, 0.5, 1, 0.75) loc2g <- c(0.2, 0.1, 0.2, 0.6) loc3g <- c(0.8, 0.8, 0.55, 1) pval <- data.frame(loc1g, loc2g, loc3g) I want to print to a file to gen dataframe such way that is conditionally formatted by the pval dataframe. Means than (row1, col1) of gen color depends upon pvale (row1, col1). The following are color coding: 0 to 0.3 is "red" text color 0.31 to 0.7 is "yellow" > 0.7 is "red" gen[1,1] will be "Aa" printed in red text color and so on.... appreciated your help. EDITS: I am more interested in printing not plotting in graph. If I can save output as MS excel and open in MSEXCEL it would be great. I can also be other types of text editors format that can read color coded text. As my orginal data matrix should be of a dimension of 1000 x 1000 or even more. I would like to quicky know unlying p-value for each gen categories. A: Sounds like you want to mimic Excel. Here are a couple examples: x = 1:ncol(pval) y = 1:nrow(pval) # Colored backgrounds dev.new(width=4, height=4) image(x, y, t(as.matrix(pval)), col = c('red', 'yellow', 'red'), breaks = c(0, 0.3, 0.7, 1), xaxt='n', yaxt='n', ylim=c(max(y)+0.5, min(y)-0.5), xlab='', ylab='') centers = expand.grid(y, x) text(centers[,2], centers[,1], unlist(gen)) # Colored text dev.new(width=4, height=4) image(x,y, matrix(0, length(x), length(y)), col='white', xaxt='n', yaxt='n', ylim=c(max(y)+0.5, min(y)-0.5), xlab='', ylab='') pvals = unlist(pval) cols = rep('red', length(pvals)) cols[pvals>0.3 & pvals<=0.7] = 'yellow' text(centers[,2], centers[,1], unlist(gen), col=cols) grid(length(x),length(y)) A: Giving a POC-like answer which is using an ugly loop and not the most beatiful design: Loading eg. the xlxs package to be able to write to Excel 2007 format: library(xlsx) Let us create a workbook and a sheet (see the manual!): wb <- createWorkbook() sheet <- createSheet(wb, "demo") Define some styles to use in the spreadsheet: red <- createCellStyle(wb, fillBackgroundColor="tomato", fillForegroundColor="yellow", fillPattern="BIG_SPOTS") yellow <- createCellStyle(wb, fillBackgroundColor="yellow", fillForegroundColor="tomato", fillPattern="BRICKS1") And the ugly loop which is pasting each cell to the spreadsheet with appropriate format: for (i in 1:nrow(pval)) { rows <- createRow(sheet, rowIndex=i) for (j in 1:ncol(pval)) { cell.1 <- createCell(rows, colIndex=j)[[1,1]] setCellValue(cell.1, gen[i,j]) if ((pval[i,j] < 0.3) | (pval[i,j] > 0.7)) { setCellStyle(cell.1, red) } else { setCellStyle(cell.1, yellow) } } } Saving the Excel file: saveWorkbook(wb, '/tmp/demo.xls') Result: demo.xls Alternative solution with package ascii: ascii.data.frame() can export data frames to a bunch of formats with the ability of adding some formatting. E.g. exporting to pandoc, first define the styles of each cells to an array with the same dimensions as pval: style <- matrix('d', dim(pval)[1], dim(pval)[2]) style[pval < 0.3 | pval > 0.7] <- 's' Set the desired output: options(asciiType = "pandoc") And export the data frame: > ascii(gen, style=cbind('h', style)) **loc1** **loc2** **loc3** --- ---------- ---------- ---------- 1 Aa **aa** **aa** 2 **Aa** **aa** Aa 3 **aa** aa **aa** 4 **Aa** **AA** **aa** --- ---------- ---------- ---------- With ascii::Report you could easily convert it it pdf, odt or html. Just try it :) Small demo with HTML output: result r <- Report$new() r$add(section("Demo")) r$add(ascii(gen, style=cbind('h', style))) options(asciiType = "pandoc") r$backend <- "pandoc" r$format <- "html" r$create() And odt output: result r$format <- "odt" r$create()

Immunohistochemical study of delta and mu opioid receptors on synaptic glomeruli with substance P-positive central terminals in chicken dorsal horn. In an attempt to clarify the mechanism underlying the regulation of the release of substance P (SP) from the central axon terminals of the synaptic glomeruli in lamina II of the dorsal horn, we examined the expression patterns of delta and mu opioid receptors (DOR and MOR) in relation to those of enkephalin (ENK) and SP in the synaptic glomeruli. DOR, MOR, ENK and SP immunoreactivities in lamina II of the dorsal horn in the chicken were examined by confocal laser scanning and electron microscopies. DOR immunoreactivity was localized in both SP-positive central terminals and peripheral elements, while MOR immunoreactivity was only localized in the peripheral elements of the synaptic glomeruli. Both of the peripheral DOR- and MOR-immunoreactive elements were shown to be vesicle-containing dendrites by electron microscopy. Dual immunohistochemistry indicated that DOR, MOR and ENK immunoreactivities were located in distinct peripheral elements. On the basis of present results, the possible roles of DOR and MOR in the regulation of the release of SP from the central axon terminals in the synaptic glomeruli are discussed.

Sand Ridge State Forest Sand Ridge State Forest is a conservation area located in the U.S. state of Illinois. Containing , it is the largest state forest in Illinois. It is located in northern Mason County. The nearest town is Manito, Illinois and the nearest numbered highway is U.S. Highway 136. It is located on a low bluff, or "sand ridge", overlooking the Illinois River, hence the name. The sand ridge is believed to be an artifact of the post-glacial Kankakee Torrent. The Sand Ridge State Forest largely dates back to 1939, when the state of Illinois purchased parcels of submarginal sandy farmland for conservation purposes. The Civilian Conservation Corps planted pine trees on much of the land. Today, the state forest contains of dryland oak-hickory woodlands, of pine woodlands, and of open fields and sand prairies. Endemic species include the prickly pear cactus, Opuntia, more familiar to Mexicans and residents of the U.S. Southwest. The Sand Ridge State Forest contains the Clear Lake Site, an archeological site listed on the National Register of Historic Places. Current status In the 2010s, Sand Ridge is managed by the Illinois Department of Natural Resources (IDNR) as open space for active recreational purposes, especially whitetail deer hunting. Revis Hill Prairie, also located within Mason County, is operated by IDNR as a disjunct area of Sand Ridge State Forest. In early 2012, Sand Ridge State Forest lost about to a fire caused by a man burning brush in high winds which sparked the trees. External links Illinois DNR Sand Ridge State Forest site Category:1939 establishments in Illinois Category:Civilian Conservation Corps in Illinois Category:Illinois River Category:Illinois state forests Category:Protected areas established in 1939 Category:Protected areas of Mason County, Illinois

C-Track E-Filing The Supreme Court of Nevada Appellate Case Management System C-Track, the browser based CMS for Appellate Courts Case Search Participant Search

Q: unable to display array result I got the following array. now I get the single records but when is their array records then it doesn't work. I tried with OR condition but it doesn't work. $this->db->get_where('genre',array('genre_id'=>$row['genre_id']))->row()->name; //I get Follwoing Records Array( [0] => Array ( [movie_id] => 7 [title] => Raaz [genre_id] => 8 // it display the name [actors] => [] [trailer_url] => https://drive.google.com/ ) [1] => Array ( [movie_id] => 8 [title] => Tribute [genre_id] => ["2","5","20"] // it doesn't display the name [actors] => [] [trailer_url] => https://drive.google.com/ ) I tried the following code $this->db->get_where('genre',array('genre_id'=>$row['genre_id']))->row()->name; above code works for 0 index but it doesn't work 1 index array A: You can use where_in but you can't use it with get_where, you need to use alternate here instead of get_where: Example: You can alternate here like: $this->db->select('name'); $this->db->from('genre'); if(is_array($row['genre_id'])){ // if result is in array $this->db->where_in('genre_id',$row['genre_id']); } else{ // for single record. $this->db->where('genre_id',$row['genre_id']); } $query = $this->db->get(); print_r($query->result_array()); // will generate result in an array Edit: After debugging, you are getting this value ["2","5","20"] as a string, so you can modify this code: $genreID = intval($row['genre_id']); // if($genreID > 0){ $this->db->where('genre_id',$row['genre_id']); } else{ $genreID = json_decode($row['genre_id'],true); $this->db->where_in('genre_id',$genreID); } CI Query Builder

The overall goal of this project is to determine the role of bone marrow (BM) stem/progenitor cells in regulating fibrocyte homeostasis in the mammalian inner ear. It is well established that specific subpopulations of inner ear fibrocytes are actively involved in the generation of electrochemical gradients essential to normal auditory function. Injury to or loss of these cells resulting from ototoxins, noise-trauma, genetic defects and aging is associated with a range of hearing and balance disorders. These highly specialized fibrocytes undergo continuous replacement throughout life and their turnover rate has been shown to increase with injury and decrease with age. However, it is not known whether this self renewal is mediated by a resident population of adult stem/progenitor cells or through some other mechanism. New data provided here document that cells derived from BM have the capacity to engraft and differentiate towards ion transport fibrocyte phenotypes in the mouse inner ear. These data also suggest that BM may provide a continuous source of stem/progenitor cells for fibrocyte turnover in the inner ear but this remains unproven. Three Specific Aims are designed to address these important issues. Aim 1 will evaluate the relative ability of two highly purified populations of BM stem/progenitor cells to engraft and differentiate into fibrocytes in the normal inner ear. Aim 2 will investigate the potential of BM stem/progenitor cells to replace fibrocytes or other inner ear cell types damaged by chemical injury, genetic mutations or aging. Aim 3 seeks to develop and optimize procedures for the direct introduction of BM stem/progenitor cells into the inner ear. The experimental design incorporates mouse BM transplantation and parabiosis models employing donor cells that express high levels of EGFP, allowing their tracking with immunological and histochemical procedures. Given the increasing evidence that defects or injuries to inner ear fibrocytes are associated with a wide range of hearing and balance disorders, it is important to obtain further knowledge about the derivation of these cells and the mechanisms mediating their turnover and replacement in both the normal, traumatized and aging inner ear. Such knowledge will be essential in the design of therapeutic strategies for the treatment of inner ear disorders associated with injury or destruction of specialized populations of inner ear fibrocytes. [unreadable] [unreadable] [unreadable]

Work It Work It But it was Melissa Fleis' royal-blue cowl-neck frock that earned her the win. Rightfully so. "I want to do away with typical 'office clothes,'" Fleis says, echoing a popular sentiment among so many busy ladies. "Working women today are looking for that edge in life and the workplace. I want to help them achieve it." Fleis, however, who had yet to win a challenge in the season, was shocked to have landed on top. Alex Wynne in top by Raul Osorio and skirt by Sonjia Williams; Lacee Teel in the winning dress by Melissa Fleis.

An exploration of patient safety culture in Kuwait hospitals: a qualitative study of healthcare professionals' perspectives. Patient safety culture (PSC) represents a key component of the quality of care offered by healthcare professionals. Therefore, it is crucial to understand the factors that influence the implementation of a safe culture. This study explored the knowledge and attitudes of healthcare professionals in Kuwait towards the factors that might affect the PSC. A qualitative study using semi-structured interviews with healthcare professionals was conducted between February and June 2018 at two major hospitals in Kuwait. Both hospitals had been accredited and have been applying the safety programmes recommended by the Kuwaiti Ministry of Health. Participants were purposively selected where 20 healthcare professionals were interviewed. The interviewees comprised of six physicians, six clinical pharmacists, six nurses and two members of the patient safety committee. Inclusion criteria involved healthcare professionals who had more than 1-year clinical experience, have interest in patient safety and had a good level of English. Interviews were audio-recorded and transcribed verbatim. Thematic analysis of the interview transcripts was conducted to identify the emergent themes. Thematic analysis of the interviews yielded three major themes related to 'management', 'regulations and policies' and 'healthcare professionals'. Management issues included managerial support, resources, safety environment and staff training. Regulations and policies highlighted issues related to policies and procedures and incident reporting system. Healthcare professionals' theme covered factors related to knowledge, communication and teamwork among healthcare professionals. This study gave insight into how healthcare professionals perceive the current PSC in Kuwait. Despite their positive attitudes and knowledge towards patient safety, various barriers were reported that hinder optimal PSC. These barriers were related to support, staffing, resources and response to error.

Q: What is the advantage of using a digital signature over simple asymmetric encryption? If you're sending me a message, you can: a) Encrypt the message using your private key, and I can decrypt is using your public key. b) You can create a digital signature of your message, and then send the signature along with the un-encrypted message. My two questions are: 1) I read somewhere that in the (a) scenario, if your encrypted message is tampered with en route, I won't be able to decrypt it using your public key. Is this the case? I thought I'd be able to apply your public key to any message, tampered-with or not, and if it's been tampered with, the message might just be gibberish or something. 2) What is the advantage of (b) over (a)? Given that the encrypted message in (a) and the digital signature in (b) are both encrypted using the same private key, in what way is the security provided by (b) better? A: These misconceptions come from people trying to explain digital signatures to the layperson. Once someone understands the concept of asymmetric encryption, a common way to explain signatures is "encryption with private key", but in reality there is no such thing (for a very technical explanation, see here). You're far better off thinking of asymmetric encryption and digital signatures as two entirely separate things. You've come across some of the many problems with this explanation. If someone did try to send you a message "encrypted" with their private key and it was tampered with, you are correct that you would be able to "decrypt" it, but it would be gibberish. In practice though, messages are too long to be encrypted or signed directly with asymmetric cryptography. When encrypting, a symmetric key is usually generated and used to encrypt the data, then that key is encrypted asymmetrically with the recipient's public key. Likewise, when signing, the message is first passed through a digest algorithm (cryptographic hash) to remove any structure in the data and to output a small digest that is then signed with the private key. Even if you only have a very short message to sign though, you must still pass it through a hash, otherwise an attacker may be able to forge signatures on random messages algebraically related to yours. Since correct signing requires some sort of hashing to be used, the signature obviously can't be reversed to the original message, so the message also has to be sent separately to the recipient (consequently your (a) scenario isn't even possible). Often, messages are signed with the sender's private key, then encrypted with a random symmetric key, which itself is then encrypted with the recipient's public key.

Introduction ============ Phytogenic feed additives (PFA) have attracted a lot of attention in recent years. When used in diets, these substances exhibit antioxidative properties and antimicrobial activity, improve nutrient absorption, and could ultimately improve animal performance ([@bib26]; [@bib30]; [@bib37]). PFA are less toxic, have fewer side effects, and are residue-free compared with synthetic feed additives, and are thought to be ideal feed additives in animal production ([@bib25]). Therefore, many phytogenic compounds have been recommended for use as feed additives. Fenugreek (*Trigonella foenum-graecum* L) belongs to the Leguminosae family and is cultivated predominantly in India, West Asia, the Mediterranean, North Africa, and Canada ([@bib29]). The seeds are generally used for condiments in various food preparations, are regarded to have great nutritive value and restorative properties, and have been used in folk medicine for centuries for their hypoglycemic, anthelmintic, antibacterial, antiinflammatory, antipyretic, and antimicrobial properties ([@bib49]; [@bib7]; [@bib50]). The major active components of fenugreek seeds are 4-hydroxyisoleucine, trigonelline, galactomannan with flavonoids, carotenoids, coumarins, and saponins, which confer pharmacological activity and beneficial effects ([@bib46]; [@bib7]). Recently, the modes of PFA action in vivo, including aromatic plants, plant extracts, their single active components, or their blended additives, have been investigated in several studies ([@bib54]; [@bib6]; [@bib37]; [@bib38]). However, in laying hens, a comparatively small number of studies have investigated the effects of fenugreek seed on production performance and egg quality. Therefore, in this study, an attempt was made to evaluate the fenugreek seed as natural growth promoter in laying hen diets. The evaluation included biochemical changes in egg production, egg quality, blood profiles, cecal microflora, and excreta noxious gas emission. Materials and Methods ===================== Ethical Considerations ---------------------- The experimental protocols describing the management and care of animals were reviewed and approved by the Animal Care and Use Committee of Dankook University. Experimental Design, Animals, and Housing ----------------------------------------- A total of 384, 26-week-old (Hyline-brown) laying hens were used in this 6-week trial. Laying hens were randomly assigned to one of three treatments with eight replicates (16 hens/replicate). The experimental treatments were: control, basal diet (FSE 0%); fenugreek seed extract (FSE) 0.05%, basal diet + 0.05% FSE; FSE 0.1%, basal diet + 0.1% FSE. The FSE used in our study was Nutrifen^®^ (Emerald Seed Products Ltd., Avonlea, Canada), which contains ≥ 15.0 mg/g saponin. Nutrifen^®^ was composed of 3584 kcal/kg ME, 10.4% moisture, 28.0% CP, 9.9% crude fiber, 10.4% crude fat, and 4.6% crude ash. It also contained macrominerals as follows; 0.34% calcium, 0.28% sulfur, 0.74% phosphorus, 0.26% magnesium, 36.2 mg/kg zinc, 21.4 mg/kg manganese, and 36.2 mg/kg iron. Laying hens were provided ad libitum access to water and feed. All the diets were formulated in mash form to meet or exceed the [@bib36] nutrition requirement ([Table 1](#T1){ref-type="table"}). Treatment additives were included in the diet by replacing the same amount of corn. Laying hens were allowed to adjust to the environment for 5 days prior to beginning the feeding trial, during which they were fed a basal diet. They were raised in an ambient-regulated house, in which the temperature was maintained below 23°C and the light regime was set on a 16:8-light: dark cycle throughout the entire experiment. Birds were individually reared in adjacent steel cages fitted with a nipple drinker, feeder, and an egg collecting plate. ###### Formula and chemical composition of basal diet (as-fed basis) Item (%) -------------------------------------------------------- ------------- Ingredients   Corn 50.40   Soybean meal (CP 46%) 18.70   Wheat grain 10.00   Corn gluten meal   2.00   Wheat bran   5.00   Animal fat   4.40   Limestone   7.50   Dicalcium phosphate (P 18%)   1.40   Salt   0.30   [dl]{.smallcaps}-Met (50%)   0.10   Vitamin premix[^1^](#tf1){ref-type="table-fn"}   0.10   Trace mineral premix[^2^](#tf2){ref-type="table-fn"}   0.10   Total 100 Calculated values   ME (kcal/kg) 2,904         CP (%) 15.02   Lys (%)   0.78   Met + Cys (%)   0.65   Ca (%)   3.25   P (%)   0.61 Provided per kilogram of premix: 125,000 IU vitamin A; 2,500 IU vitamin D~3~; 10 mg vitamin E; 2 mg vitamin K~3~; 1 mg vitamin B~1~; 5 mg vitamin B~2~; 1 mg vitamin B~6~; 15 mg vitamin B~12~; 500 mg folic acid; 35,000 mg niacin; 10,000 mg Ca-Pantothenate and 50 mg biotin. Provided per Kg of diet: 8 mg Mn (as MnO~2~); 60 mg Zn (as ZnSO~4~); 5mg Cu (as CuSO~4~·5H~2~O); 40mg Fe (as FeSO~4~·7H~2~O); 0.3 mg Co (as CoSO~4~·5H~2~O); 1.5 mg I (as KI), and 0.15 mg Se (as Na~2~SeO~3~·5H~2~O). Laying Production, Performance, and Egg Quality ----------------------------------------------- The hen-day egg production and egg weights were recorded daily, while feed consumption was measured weekly. The feed conversion ratio was calculated as the feed consumption per hen divided by egg weight per day per hen. For each treatment, 40 normal eggs (five eggs/cage) were collected randomly at 32 weeks and used to determine the egg quality. Eggshell color scores were determined using an eggshell color fan on a 1--15 scale (1=light to 15=dark brown) by a single trained evaluator. Haugh units, albumen height, and yolk color were determined, using an egg multi tester (Touhoku Rhythm Co., Ltd., Tokyo, Japan). Eggshell breaking strength was evaluated, using an Eggshell force gauge, model II (Robotmation Co., Ltd., Tokyo, Japan), and eggshell thickness was measured, using a dial pipe gauge (Ozaki Mfg. Co., Ltd., Tokyo, Japan). Blood Profile ------------- At the end of the experiment, 16 laying hens were randomly selected from each treatment (two hens/replication) and blood samples were taken from the jugular vein by a sterilized syringe with needle. Then, the samples were transferred to either a vacuum or K3EDTA vacuum tube (Becton Dickinson Vacutainer Systems, FranklinLakes, NJ, USA). The blood samples were centrifuged at 2000×g at 4°C for 15 min to separate the serum. High-density lipoprotein (HDL), low-density lipoprotein (LDL), and total cholesterol, and immunoglobulin G (IgG) concentrations in the serum were then analyzed using an automatic biochemistry blood analyzer (HITACHI747, Tokyo, Japan). Whole blood samples from the K~3~EDTA vacuum tube were analyzed immediately to determine the white blood cells (WBC), red blood cells (RBC), and lymphocyte concentrations using an automatic blood analyzer (ADVIA 120, Bayer, Tarrytown, NY, USA). Cecal Microflora ---------------- At the end of the experiment, samples of cecal contents were collected from 16 laying hens randomly selected from each treatment, then placed on ice for transportation to the laboratory, where analyses were immediately performed using the method described by [@bib51]. One-gram of pooled cecal content sample was diluted 1:9 (wt/vol) with phosphate buffer saline solution (PBS; 0.1M, pH 7.0). Then, 10-fold serial dilutions (10^−3^ to 10^−6^) of cecal content samples were generated with PBS and placed onto Mac-Conkey (Difco Laboratories, Detroit, MI, USA) and *Lactobacillus*-Rogosa agar plates (Difco Laboratories) to isolate the *Escherichia coli* and *Lactobacillus*, respectively. The *Lactobacillus*-Rogosa and MacConkey agar plates were then incubated for 24 h at 37°C under anaerobic and aerobic conditions, respectively. After incubation, *Lactobacillus* and *E. coli* colonies were counted immediately using a colony counter, and are reported as colony-forming units (CFU) log~10~ per g. Excreta Noxious Gas Emission ---------------------------- Fresh excreta from laying hens were collected from eight cages per treatment to determine excreta noxious gas emission according to the method described by [@bib11]. Excreta samples (300 g) were stored in 2-L plastic boxes. The samples were allowed to ferment for 1 day at room temperature (28°C). After the fermentation period, the gases that formed were determined using a Gastec (model GV-100) gas sampling pump (Gastec Corp., Gastec detector tube No. 3L and 3La for ammonia; No. 4LL and 4LK for hydrogen sulfide; No. 70 and 70L for total mercaptan, Gastec Corp, detector tube, Ayase, Japan) from approximately 5 cm above the excreta samples. Statistical Analysis -------------------- Data were statistically analyzed via ANOVA using the GLM procedure of SAS (SAS Inst. Inc., Cary, NC) for a randomized complete block design. The linear and quadratic effects of FSE among treatments were analyzed using a contrast statement. The mean values and standard error of means (SEM) were reported. Probability values less than 0.05 were considered significant. Results ======= Egg Production Performance -------------------------- Laying hens fed diets supplemented with FSE during weeks 27--32 showed significant differences in egg weight compared with those fed the control treatment, as dietary FSE increased from 0.05 to 0.1% (linear, *P*=0.012). However, throughout the experimental period, there was no significant difference in egg production, feed intake, and feed conversion in laying hens fed different levels of FSE in their diet ([Table 2](#T2){ref-type="table"}). ###### The effects of dietary fenugreek seed extract (FSE) on productivity in laying hens[^1^](#tf3){ref-type="table-fn"} FSE, % SEM[^2^](#tf4){ref-type="table-fn"} *P*-value ---------------------- -------- ------------------------------------- ----------- ------ ------- ------- Egg production, % 96.0 97.9 96.5 1.21 0.677 0.115 Egg weight, g 63.1 64.2 66.4 0.89 0.012 0.642 Feed intake, g 115 115 117 1.93 0.659 0.698 Feed conversion, g:g 1.833 1.797 1.757 0.02 0.052 0.952 Each treatment mean represents 8 replicates (16 hens/replicate). Standard error of mean Egg Quality ----------- Eggshell breaking strength and eggshell thickness were found to be increased in the FSE groups compared with the control group (linear *P*\<0.05). As the dietary levels of FSE increased, a linear increase in the intensity of yolk color was observed (*P*=0.001). There was no significant difference in eggshell color, Haugh units, or albumen height of laying hens fed different levels of FSE in their diet ([Table 3](#T3){ref-type="table"}). ###### The effects of dietary fenugreekseed extract (FSE) on egg quality in laying hens[^1^](#tf5){ref-type="table-fn"} FSE, % SEM[^2^](#tf6){ref-type="table-fn"} *P*-value -------------------------------------- -------- ------------------------------------- ----------- ------ ------- ------- Eggshell color 11.25 11.35 11.3 0.19 0.855 0.752 Eggshell breaking strength, kg/cm^2^ 4.390 4.483 4.661 0.06 0.012 0.588 Eggshell thickness, mm^−2^ 35.41 36.36 36.73 0.43 0.038 0.304 Haugh unit 82.52 83.03 82.62 1.41 0.959 0.788 Albumen height, mm 7.55 7.84 7.68 0.19 0.635 0.355 Yolk color 7.0 7.1 7.8 0.14 0.001 0.091 Each treatment mean represents 40 replicates (5 eggs/replicate). Standard error of mean Blood Profiles -------------- Serum levels of HDL-cholesterol were elevated in the FSE treatment group compared with the control group (linear, *P*=0.017). The total cholesterol concentration decreased as dietary FSE increased in laying hens compared with laying hens fed the control diet (linear, *P*=0.042). However, serum LDL-cholesterol and IgG levels were not affected by the addition of FSE. Furthermore, FSE treatment had no significant effect on WBC, RBC, or lymphocytes ([Table 4](#T4){ref-type="table"}). ###### The effect of dietary fenugreekseed extract (FSE) on blood profiles in laying hens[^1^](#tf7){ref-type="table-fn"} FSE, % SEM[^2^](#tf8){ref-type="table-fn"} *P*-value ------------------------------- -------- ------------------------------------- ----------- -------- ------- ------- White blood cells, 10^3^/*µl* 27.0 27.3 31.5 3.92 0.365 0.636 Red blood cells, 10^6^/*µl* 2.3 2.6 2.3 0.15 0.906 0.141 Lymphocyte, % 70.4 60.7 66.2 9.92 0.745 0.495 HDL-cholesterol, mg/dL 33 41 44 2.05 0.017 0.503 LDL-cholesterol, mg/dL 63 62 61 6.24 0.848 0.987 Total cholesterol, mg/dL 222 172 184 11.14 0.042 0.067 Immunoglobulin G, mg/dL 446 469 452 106.45 0.968 0.883 Each treatment mean represents 16 replicates (2 hens/replicate). Standard error of mean Cecal Microflora ---------------- FSE supplementation linearly increased *Lactobacillus* numbers in the cecum, compared with the control treatment (*P*=0.012). Cecal *E. coli* decreased quadratically as dietary FSE increased (*P*=0.010) ([Table 5](#T5){ref-type="table"}). ###### The effects of dietary fenugreekseed extract (FSE) on cecal microbiota in laying hens[^1^](#tf9){ref-type="table-fn"} FSE, % SEM[^2^](#tf10){ref-type="table-fn"} *P*-value -------------------------------- -------- -------------------------------------- ----------- ------ ------- ------- *Lactobacillus*, log~10~ cfu/g 6.98 7.33 7.42 0.10 0.012 0.298 *E. coil*, log~10~ cfu/g 6.57 6.14 6.37 0.08 0.151 0.010 Each treatment mean represents 16 replicates (2 hens/replicate). Standard error of mean Excreta Noxious Gas Emissions ----------------------------- Excreta ammonia emissions were decreased as dietary FSE supplementation increased (linear, *P*=0.020). However, FSE supplementation did not affect total mercaptan and hydrogen sulfide emissions, compared with the control treatment ([Table 6](#T6){ref-type="table"}). ###### The effects of dietary fenugreekseed extract (FSE) on excreta gas emission in laying hens[^1^](#tf11){ref-type="table-fn"} FSE, % SEM[^2^](#tf12){ref-type="table-fn"} *P*-value ----------------------- -------- -------------------------------------- ----------- ------ ------- ------- Total mercaptan, ppm 1.4 0.9 1.0 0.17 0.058 0.134 Ammonia, ppm 48 33 30 4.40 0.020 0.277 Hydrogen sulfide, ppm 2.4 2.4 2.4 0.07 0.987 0.892 Each treatment mean represents 8 replicates (16 hens/replicate). Standard error of mean Discussion ========== Laying performance of the FSE-treated groups did not significantly differ over 27--32 weeks in our study. PFA has been investigated in numerous studies on poultry with varying responses, depending upon the plant species, disease challenges, and different environmental conditions used. Results have also varied depending on the specific plant-derived compound used, or stress type ([@bib15]; [@bib22]; [@bib10]; [@bib12]). Several studies have reported that dietary supplementation with extracts of some plants increased egg production, feed conversion ratio, and egg weight in laying hens ([@bib48]; [@bib35]; [@bib41]). Recent reports have also suggested an improvement in the early growth performance of broilers and pigs, when supplemented with FSE ([@bib28]; [@bib39]). In contrast, previous studies have shown that neither PFA nor FSE exhibited significant effects on feed intake, feed efficiency, and/or egg production of laying hens ([@bib8]; [@bib16]; [@bib3]). Growth responses of broilers, or the egg production performance of laying hens supplemented with PFA remain controversial, and the mechanism of FSE action on poultry performance has not yet been clearly established. Our finding suggests that FSE had no direct beneficial effect on egg production, feed intake, or feed conversion. However, a significant improvement in egg weight, eggshell strength, and eggshell thickness was observed when FSE was included in the diet. The results of our study were similar to those reported recently by [@bib19], who showed significant effects on the eggshell thickness, eggshell weight, and specific gravity between control and fenugreek powder groups. [@bib40] reported that fenugreek seeds in the diet may enhance nutrient absorption due to greater villus height and crypt depth, thereby improving intestinal health. Similarly, [@bib5] found that the apparent ileal digestibility of crude ash, calcium, and phosphorus increased linearly with increasing dose of PFA in the diet. Moreover, fenugreek seeds naturally contain high levels of minerals, including calcium, iron, and zinc ([@bib27]). The beneficial effect on egg weight, eggshell breaking strength, and eggshell thickness might be attributable to favorable alterations in the intestinal environment and function, which may have increased intestinal calcium absorption. Therefore, FSE may help calcium utilization for egg-shell formation, although no significant differences were observed in egg production performance between the FSE groups and the control. In our study, the addition of FSE increased the intensity of the yolk color. Fenugreek seeds are also widely used as a spice and food colorant in food preparations because of their light yellow-brown color ([@bib13]). An increase in the intensity of yolk color is likely to be due to the action of the yellow color agent present in FSE on the yolk following the addition of FSE. Thus, FSE could be supplied as a component of pigment in the diets in order to influence egg yolk yellowness. Serum lipid metabolites in relation to PFA and their extracts have been extensively studied. The addition of PFA could affect serum triglyceride and cholesterol concentrations and effectively prevent the progress of hypercholesterolemia and cholesterol accumulation in the liver induced by a high cholesterol diet in rats ([@bib20]). PFA also significantly decreased blood lipid fractions and increased high-density lipoprotein in poultry ([@bib1]). Results obtained in the present study show that FSE increases serum HDL-cholesterol, and decreases total cholesterol, regardless of LDL-cholesterol levels. Some studies have indicated that fenugreek seeds have hypocholesterolemic activity, which may reduce the risk of heart disease ([@bib42]; [@bib31]). Saponins, which are a major active constituent of the fenugreek seeds, have beneficial effects on blood cholesterol and triglyceride concentrations in rats, rabbits, and humans ([@bib34]; [@bib43]; [@bib2]). Additionally, non-starch polysaccharides, which provide the major soluble fiber content in fenugreek seeds, include galactomannan ([@bib9]), which has been reported to reduce blood lipids ([@bib53]; [@bib44]). The presence of these compounds in particular could increase the viscosity of the digested food and decrease serum total cholesterol levels by inhibiting bile salt reabsorption in the small intestine ([@bib32]). Therefore, the decreased concentration of blood lipid metabolites observed in the present study due to the inclusion of dietary FSE may be related to the saponins or galactomannan fiber content in FSE. Several PFAs have long been recognized for their antimicrobial actions against major pathogens including coccidium and fungi ([@bib21]; [@bib52]). An in vitro study by [@bib18] found that carvacrol and thymol inhibited the growth of *E. coli, Clostridium perfringens*, and *Salmonella* strains. [@bib24] reported that in vitro, essential oils including basil, lemon balm, marjoram, oregano, rosemary, sage, and thyme, strongly inhibited the growth of *B. cereus, P. aeruginosa, E. coli*, and *L. monocytogenes*. In an in vivo study, [@bib23] demonstrated that the herb extracts were largely associated with reduced cecal *Bacteroides* spp., enterococci, and *E. coli* numbers, but increased numbers of bifidobacteria and lactobacilli, relative to the control and antibiotic groups in chickens. In addition, [@bib55] noted that a fenugreek diet caused higher *Lactobacillus* and *Clostridium* concentrations and lower *Escherichia, Hafnia*, and *Shigella* concentrations in the small intestine of piglets. Many investigators have reported an antibacterial effect of fenugreek seeds ([@bib14]; [@bib4]; [@bib33]). Such an effect seems to be related to the presence of certain molecular compounds, usually in the form of secondary metabolites, such as flavonoids, saponins, and phenolic compounds ([@bib14]). In our study, laying hens fed the FSE diets had a higher population of cecal *Lactobacillus* and a lower population of *E. coli*. Therefore, decreased cecal *E. coli* counts in laying hens fed dietary FSE may be explained by the antibacterial activity of FSE against different pathogenic bacteria. These effects of FSE on cecal microflora have led to a reduction in ammonia gas emission in laying hen excreta. In other words, a positive effect of FSE is exerted by suppressing harmful cecal *E. coli*, and favoring beneficial *Lactobacillus*, which may be reflected in the ammonia gas emissions of the excreta. This result is in line with the reports of [@bib47] and [@bib45], who determined that supplemental PFA decreased noxious gas emission, including ammonia concentrations, in pigs and laying hens. Furthermore, decreased levels of excreta ammonia gas found in the FSE groups may be associated with intestinal pH. [@bib17] observed that supplementation of quail diets with PFA (thyme and black seed essential oils) significantly decreased intestinal pH. Similarly, [@bib55] indicated that fenugreek seed reduced the pH in the cecum and colon of piglets, due to an increase in the number of lactate-producing bacteria or their relevant metabolic activity. Therefore, the decrease in ammonia gas emission observed in excreta following the addition of FSE to laying hen diets is thought to be induced by the maintenance of beneficial microbiota or a reduction in intestinal pH. In conclusion, based on these findings, FSEs are a valuable natural feed additive for laying hens, particularly with regard to egg weight, egg quality, serum cholesterol, cecal lactobacilli number and excreta ammonia gas emission.

// Copyright 2004-present Facebook. All Rights Reserved. #include "SamplingProfilerJniMethod.h" #include <JavaScriptCore/JSProfilerPrivate.h> #include <jschelpers/JSCHelpers.h> #include <jni.h> #include <string> using namespace facebook::jni; namespace facebook { namespace react { /* static */ jni::local_ref<SamplingProfilerJniMethod::jhybriddata> SamplingProfilerJniMethod::initHybrid(jni::alias_ref<jclass>, jlong javaScriptContext) { return makeCxxInstance(javaScriptContext); } /* static */ void SamplingProfilerJniMethod::registerNatives() { registerHybrid( {makeNativeMethod("initHybrid", SamplingProfilerJniMethod::initHybrid), makeNativeMethod("poke", SamplingProfilerJniMethod::poke)}); } SamplingProfilerJniMethod::SamplingProfilerJniMethod(jlong javaScriptContext) { context_ = reinterpret_cast<JSGlobalContextRef>(javaScriptContext); } void SamplingProfilerJniMethod::poke( jni::alias_ref<JSPackagerClientResponder::javaobject> responder) { if (!JSC_JSSamplingProfilerEnabled(context_)) { responder->error("The JSSamplingProfiler is disabled. See this " "https://fburl.com/u4lw7xeq for some help"); return; } JSValueRef jsResult = JSC_JSPokeSamplingProfiler(context_); if (JSC_JSValueGetType(context_, jsResult) == kJSTypeNull) { responder->respond("started"); } else { JSStringRef resultStrRef = JSValueToStringCopy(context_, jsResult, nullptr); size_t length = JSStringGetLength(resultStrRef); char buffer[length + 1]; JSStringGetUTF8CString(resultStrRef, buffer, length + 1); JSStringRelease(resultStrRef); responder->respond(buffer); } } } }

We now require registration to download high resolution fan art. Please take a few seconds to register absolutely free! Click here now. (Registering will also let you tell this artist how much you enjoy their work in the comments below.) Here's the picture I made. Ducky edited it and made the lines cleaner so it'd look better than before. It's a heartless!!! A sad one. Isn't it cute?

UK Commission concludes international patent laws hinder access to medicines in developing countries. On 12 September 2002, the UK Commission on Intellectual Property Rights, an independent body established in May 2001 by the British government, released its report analyzing the impact of international agreements on patents. The report, Integrating Intellectual Property Rights and Developmental Policy, makes 55 recommendations "aimed at aligning [intellectual property] protection with the goal of reducing poverty".

Q: Free Software for Partition Manager Free Software for the Partition Manager on Windows XP/vista? A: Try GParted Live. You can create a Boot CD and use that to work with partitions. A: Windows Vista now has a built in partition manager. You can access it like this: Go to Control Panel / Administrative Tools / Computer Management. Then go down to Storage / Disk Management. That brings up your drives. Now you can just select a partition within a drive. Right click it and you'll have options to Shrink, Extend or Delete it. The former two show a popup detailing what size you'd like. More info here. A: Easeus Partition Master is an excellent tool, and the Home version is free! It has a bunch of useful features. I've been using it for a little while, and still cannot believe they give it away for free. You should definitely try it out.

--- abstract: 'We analytically derive the upper bound on the overall efficiency of single-photon generation based on cavity quantum electrodynamics (QED), where cavity internal loss is treated explicitly. The internal loss leads to a tradeoff relation between the internal generation efficiency and the escape efficiency, which results in a fundamental limit on the overall efficiency. The corresponding lower bound on the failure probability is expressed only with an “internal cooperativity," introduced here as the cooperativity parameter with respect to the cavity internal loss rate. The lower bound is obtained by optimizing the cavity external loss rate, which can be experimentally controlled by designing or tuning the transmissivity of the output coupler. The model used here is general enough to treat various cavity-QED effects, such as the Purcell effect, on-resonant or off-resonant cavity-enhanced Raman scattering, and vacuum-stimulated Raman adiabatic passage. A repumping process, where the atom is reused after its decay to the initial ground state, is also discussed.' author: - 'Hayato Goto,$^1$ Shota Mizukami,$^2$ Yuuki Tokunaga,$^3$ and Takao Aoki$^2$' title: 'Fundamental Limit on the Efficiency of Single-Photon Generation Based on Cavity Quantum Electrodynamics' --- *Introduction*. Single-photon sources are a key component for photonic quantum information processing and quantum networking [@Kimble2008a]. Single-photon sources based on cavity quantum electrodynamics (QED) [@Eisaman2011a; @Rempe2015a; @Kuhn2010a; @Law1997a; @Vasilev2010a; @Maurer2004a; @Barros2009a; @Kuhn1999a; @Duan2003a] are particularly promising, because they enable deterministic emission into a single mode, which is desirable for low-loss and scalable implementations. Many single-photon generation schemes have been proposed and studied using various cavity-QED effects, such as the Purcell effect [@Eisaman2011a; @Rempe2015a; @Kuhn2010a], on-resonant [@Kuhn2010a; @Law1997a; @Vasilev2010a] or off-resonant [@Maurer2004a; @Barros2009a] cavity-enhanced Raman scattering, and vacuum-stimulated Raman adiabatic passage (vSTIRAP) [@Eisaman2011a; @Rempe2015a; @Kuhn2010a; @Vasilev2010a; @Kuhn1999a; @Duan2003a; @Maurer2004a]. The overall efficiency of single-photon generation based on cavity QED is composed of two factors: the internal generation efficiency $\eta_{\mathrm{in}}$ (probability that a photon is generated inside the cavity) and the escape efficiency $\eta_{\mathrm{esc}}$ (probability that a generated photon is extracted to a desired external mode). The upper bounds on $\eta_{\mathrm{in}}$, based on the cooperativity parameter $C$ [@Rempe2015a], have been derived for some of the above schemes [@Rempe2015a; @Kuhn2010a; @Law1997a; @Vasilev2010a]. $C$ is inversely proportional to the total cavity loss rate, $\kappa=\kappa_{\mathrm{ex}}+\kappa_{\mathrm{in}}$, where $\kappa_{\mathrm{ex}}$ and $\kappa_{\mathrm{in}}$ are the external and internal loss rates, respectively [@comment-loss]. Note that $\kappa_{\mathrm{ex}}$ can be experimentally controlled by designing or tuning the transmissivity of the output coupler. Thus, $\eta_{\mathrm{in}}$ is maximized by setting $\kappa_{\mathrm{ex}}$ to a small value so that $\kappa \approx \kappa_{\mathrm{in}}$. However, a low $\kappa_{\mathrm{ex}}$ results in a low escape efficiency $\eta_{\mathrm{esc}}=\kappa_{\mathrm{ex}}/\kappa$, which limits the channelling of the generated photons into the desired mode. There is therefore a *tradeoff* relation between $\eta_{\mathrm{in}}$ and $\eta_{\mathrm{esc}}$ with respect to $\kappa_{\mathrm{ex}}$, and $\kappa_{\mathrm{ex}}$ should be optimized to maximize the overall efficiency. This tradeoff relation has not been examined in previous studies, where the internal loss rate $\kappa_{\mathrm{in}}$ has not been treated explicitly. Additionally, previous studies on the photon-generation efficiency have not taken account of a repumping process, where the atom decays to the initial ground state via spontaneous emission and is “reused" for cavity-photon generation [@Barros2009a]. In this paper, we analytically derive the upper bound on the overall efficiency of single-photon generation based on cavity QED, by taking into account both the cavity internal loss and the repumping process. We use the model shown in Fig. \[fig-system\], which is able to describe most of the previously proposed generation schemes, with or without the repumping process, in a unified and generalized manner. In particular, we show that the lower bound on the failure probability for single-photon generation, $P_F$, for the case of no repumping, is given by [@comment-on-Goto; @Goto2008a; @Goto2010a] $$\begin{aligned} P_F \ge \frac{2}{\displaystyle 1+\sqrt{1+2C_{\mathrm{in}}}} \approx \sqrt{\frac{2}{C_{\mathrm{in}}}}, \label{eq-PF}\end{aligned}$$ where we have introduced the “internal cooperativity," $$\begin{aligned} C_{\mathrm{in}}= \frac{g^2}{2\kappa_{\mathrm{in}} \gamma }, \label{eq-Cin}\end{aligned}$$ as the cooperativity parameter with respect to $\kappa_{\mathrm{in}}$ instead of $\kappa$ for the standard definition, $C=g^2/(2\kappa \gamma )$ [@Rempe2015a]. The approximation in Eq. (\[eq-PF\]) holds when $C_{\mathrm{in}} \gg 1$. The lower bound on $P_F$ in Eq. (\[eq-PF\]) is obtained when $\kappa_{\mathrm{ex}}$ is set to its optimal value, $$\begin{aligned} \kappa_{\mathrm{ex}}^{\mathrm{opt}} \equiv \kappa_{\mathrm{in}} \sqrt{1+2C_{\mathrm{in}}}, \label{eq-optimal-kex}\end{aligned}$$ and is simply expressed as $2\kappa_{\mathrm{in}}/\kappa^{\mathrm{opt}}$, where $\kappa^{\mathrm{opt}} \equiv \kappa_{\mathrm{in}} + \kappa_{\mathrm{ex}}^{\mathrm{opt}}$ [@comment-kex]. Note that the experimental values of $(g,\gamma,\kappa_{\mathrm{in}})$ determine which regime the system should be in: the Purcell regime ($\kappa \gg g \gg \gamma$), the strong-coupling regime ( $g \gg (\kappa, \gamma)$), or the intermediate regime ($\kappa \approx g \gg \gamma$). The remainder of this paper is organized as follows. First, we show that the present model is applicable to various cavity-QED single-photon generation schemes. Next, we provide the basic equations for the present analysis. Using these equations, we analytically derive an upper bound on the success probability, $P_S=1-P_F$, of single-photon generation. From here, we optimize $\kappa_{\mathrm{ex}}$ and derive Ineq. (\[eq-PF\]). We then briefly discuss the condition for typical optical cavity-QED systems. Finally, the conclusion and outlook are presented. *Model*. As shown in Fig. \[fig-system\], we consider a cavity QED system with a $\Lambda$-type three-level atom in a one-sided cavity. The atom is initially prepared in $|u\rangle$. The $|u\rangle$-$|e\rangle$ transition is driven with an external classical field, while the $|g\rangle$-$|e\rangle$ transition is coupled to the cavity. This system is general enough to describe most of the cavity QED single-photon generation schemes. For instance, by first exciting the atom to $|e\rangle$ with a resonant $\pi$ pulse (with time-dependent $\Omega$), or fast adiabatic passage (with time-dependent $\Delta_u$), the atom is able to decay to $|g\rangle$ with a decay rate enhanced by the Purcell effect [@Purcell1946a], generating a single photon. Here, the Purcell regime is assumed. [@Rempe2015a; @Kuhn2010a; @Eisaman2011a]. Another example is where the atom is weakly excited with small $\Omega$ and a cavity photon is generated by cavity-enhanced Raman scattering. Here, $\kappa \gg g$ is assumed in the on-resonant case ($\Delta_e=\Delta_u=0$) [@Kuhn2010a; @Law1997a; @Vasilev2010a], while $\Delta_e \gg g$ is assumed in the off-resonant case ($\Delta_u=0$) [@Barros2009a; @Maurer2004a]. A third example is based on vSTIRAP [@Rempe2015a; @Eisaman2011a; @Kuhn2010a; @Vasilev2010a; @Kuhn1999a; @Duan2003a; @Maurer2004a], where $\Omega$ is gradually increased, and where the strong-coupling regime \[$g \gg (\kappa, \gamma)$\] and small detunings ($|\Delta_e|, |\Delta_u| \ll g$) are assumed. *Basic equations*. The starting point of our study is the following master equation describing the cavity-QED system: $$\begin{aligned} \dot{\rho} =& \mathcal{L} \rho, ~ \mathcal{L} =\mathcal{L}_{\mathcal{H}} + \mathcal{J}_u + \mathcal{J}_g + \mathcal{J}_o + \mathcal{J}_{\mathrm{ex}} + \mathcal{J}_{\mathrm{in}}, \label{eq-master} \\ \mathcal{L}_{\mathcal{H}} \rho =& -\frac{i}{\hbar} \left( \mathcal{H} \rho - \rho \mathcal{H}^{\dagger} \right),~ \mathcal{H}=H -i\hbar \left( \gamma \sigma_{e,e} + \kappa a^{\dagger} a \right), \nonumber \\ H =& \hbar \Delta_e \sigma_{e,e} + \hbar \Delta_u \sigma_{u,u} \nonumber \\ &+ i\hbar \Omega (\sigma_{e,u} - \sigma_{u,e} ) + i\hbar g (a \sigma_{e,g} - a^{\dagger} \sigma_{g,e} ), \label{eq-Hamiltonian} \\ \mathcal{J}_{u} \rho =& 2 \gamma r_u \sigma_{u,e} \rho \sigma_{e,u},~ \mathcal{J}_{g} \rho = 2 \gamma r_g \sigma_{g,e} \rho \sigma_{e,g}, \nonumber \\ \mathcal{J}_{o} \rho =& 2 \gamma r_o \sigma_{o,e} \rho \sigma_{e,o},~ \mathcal{J}_{\mathrm{ex}} \rho = 2 \kappa_{\mathrm{ex}} a \rho a^{\dagger},~ \mathcal{J}_{\mathrm{in}} \rho = 2 \kappa_{\mathrm{in}} a \rho a^{\dagger}, \nonumber\end{aligned}$$ where $\rho$ is the density operator describing the state of the system; the dot denotes differentiation with respect to time; $H$ is the Hamiltonian for the cavity-QED system; $a$ and $a^{\dagger}$ are respectively the annihilation and creation operators for cavity photons; $|o\rangle$ is, if it exists, a ground state other than $|u\rangle$ and $|g\rangle$; $r_u$, $r_g$, and ${r_o=1-r_u-r_g}$ are respectively the branching ratios for spontaneous emission from $|e\rangle$ to $|u\rangle$, $|g\rangle$, and $|o\rangle$; and $\sigma_{j,l}=|j\rangle \langle l|$ ($j,l=u, g, e, o$) are atomic operators. In the present work, we assume no pure dephasing [@comment-dephasing]. The transitions corresponding to the terms in Eqs. (\[eq-master\]) and (\[eq-Hamiltonian\]) are depicted in Fig. \[fig-transition\], where the second ket vectors denote cavity photon number states. Once the state of the system becomes $|g\rangle |0\rangle$ or $|o\rangle |0\rangle$ by quantum jumps, the time evolution stops. Among the quantum jumps, $\mathcal{J}_{\mathrm{ex}}$ corresponds to the success case where a cavity photon is emitted into the external mode, and the others result in failure of emission. Taking this fact into account, we obtain the following formal solution of the master equation [@Carmichael]: $$\begin{aligned} \rho_c (t) =& \mathcal{V}_{\mathcal{H}}(t,0) \rho_0 + \int_0^t \! dt' \mathcal{J}_{\mathrm{ex}} \mathcal{V}_{\mathcal{H}} (t',0) \rho_0 \nonumber \\ &+ \int_0^t \! dt' \mathcal{V}_c (t,t') \mathcal{J}_u \mathcal{V}_{\mathcal{H}} (t',0) \rho_0, \label{eq-rho-c}\end{aligned}$$ where $\rho_c$ denotes the density operator conditioned on no quantum jumps of $\mathcal{J}_g$, $\mathcal{J}_o$, and $\mathcal{J}_{\mathrm{in}}$, $\rho_0 = |u\rangle |0\rangle \langle u| \langle 0|$ is the initial density operator, and $\mathcal{V}_{\mathcal{H}}$ and $\mathcal{V}_c$ are the quantum dynamical semigroups defined as follows: $$\begin{aligned} \frac{d}{dt} \mathcal{V}_{\mathcal{H}}(t,t') = \mathcal{L}_{\mathcal{H}}(t) \mathcal{V}_{\mathcal{H}}(t,t'),~ \frac{d}{dt} \mathcal{V}_c(t,t') = \mathcal{L}_c(t) \mathcal{V}_c(t,t'), \nonumber\end{aligned}$$ where $\mathcal{L}_c =\mathcal{L}_{\mathcal{H}} + \mathcal{J}_u + \mathcal{J}_{\mathrm{ex}}$ is the Liouville operator for the conditioned time evolution. Note that $\rho_c(t) = \mathcal{V}_c(t,0) \rho_0$. The trace of $\rho_c$ decreases from unity for ${t>0}$. This decrease corresponds to the failure probability due to $\mathcal{J}_g$, $\mathcal{J}_o$, and $\mathcal{J}_{\mathrm{in}}$ [@Carmichael; @Plenio1998a]. Note that $\rho_{\mathcal{H}}(t)=\mathcal{V}_{\mathcal{H}}(t,0) \rho_0$ can be expressed with a state vector as follows: $$\begin{aligned} \rho_{\mathcal{H}}(t)= |\psi (t) \rangle \langle \psi (t)|,~ i\hbar |\dot{\psi} \rangle = \mathcal{H} |\psi \rangle,~ |\psi (0) \rangle = |u \rangle |0 \rangle. \nonumber\end{aligned}$$ Setting $|\psi \rangle = \alpha_u |u \rangle |0 \rangle + \alpha_e |e \rangle |0 \rangle + \alpha_g |g \rangle |1 \rangle$, the non-Hermitian Schrödinger equation is given by $$\begin{aligned} & \dot{\alpha_u}= -i\Delta_u \alpha_u -\Omega \alpha_e, \label{eq-alpha-u} \\ & \dot{\alpha_e}= -(\gamma + i \Delta_e) \alpha_e + \Omega \alpha_u + g \alpha_g, \label{eq-alpha-e} \\ & \dot{\alpha_g}= -\kappa \alpha_g - g \alpha_e. \label{eq-alpha-g}\end{aligned}$$ Using the state vector and the amplitudes, Eq. (\[eq-rho-c\]) becomes $$\begin{aligned} \rho_c (t) =& |\psi (t) \rangle \langle \psi (t)| + 2 \kappa_{\mathrm{ex}} \int_0^t \! dt' |\alpha_g (t')|^2 |g \rangle |0 \rangle \langle g| \langle 0| \nonumber \\ &+ 2 \gamma r_u \int_0^t \! dt' |\alpha_e (t')|^2 \mathcal{V}_c (t,t') \rho_0. \label{eq-rho-c-2}\end{aligned}$$ *Upper bound on success probability*. A successful photon generation and extraction event is defined by the condition that the final atom-cavity state is $|g\rangle|0\rangle$, and that the quantum jump $\mathcal{J}_{\mathrm{ex}}$ has occurred. The success probability, $P_S$, of the single-photon generation is therefore formulated by $P_S = \langle g| \langle 0| \rho_c(T) |g \rangle |0 \rangle$ for a sufficiently long time $T$. Using Eq. (\[eq-rho-c-2\]), we obtain $$\begin{aligned} P_S =& 2 \kappa_{\mathrm{ex}} \int_0^T \! dt |\alpha_g (t)|^2 \nonumber \\ &+ 2 \gamma r_u \int_0^T \! dt |\alpha_e (t)|^2 \langle g| \langle 0| \mathcal{V}_c (T,t) \rho_0 |g \rangle |0 \rangle. \label{eq-PS-formula}\end{aligned}$$ Here we assume the following inequality: $$\begin{aligned} \langle g| \langle 0| \mathcal{V}_c (T,t) \rho_0 |g \rangle |0 \rangle \le \langle g| \langle 0| \mathcal{V}_c (T,0) \rho_0 |g \rangle |0 \rangle = P_S. \label{eq-Vc}\end{aligned}$$ This assumption is natural because $\mathcal{V}_c (t,t')$ should be designed to maximize $P_S$ [@comment-Vc]. Thus we obtain $$\begin{aligned} P_S \le \frac{2 \kappa_{\mathrm{ex}} I_g} {\displaystyle 1-2 \gamma r_u I_e}, \label{eq-PS-inequality}\end{aligned}$$ where ${I_g = \int_0^T \! dt |\alpha_g (t)|^2}$ and ${I_e = \int_0^T \! dt |\alpha_e (t)|^2}$. The two integrals, $I_g$ and $I_e$, can be evaluated as follows. First, we have $$\begin{aligned} \frac{d}{dt} \langle \psi |\psi \rangle = -2\gamma |\alpha_e|^2 - 2\kappa |\alpha_g|^2 ~\Rightarrow~ 2\gamma I_e + 2\kappa I_g \approx 1, \label{eq-norm}\end{aligned}$$ where ${\langle \psi (0)|\psi (0) \rangle =1}$ and ${\langle \psi (T)|\psi (T) \rangle \approx 0}$ have been used assuming a sufficiently long time $T$. Next, using Eq. (\[eq-alpha-g\]), we obtain $$\begin{aligned} & I_e = \int_0^T \! dt \frac{|\dot{\alpha_g}(t) + \kappa \alpha_g (t)|^2}{g^2} \nonumber \\ &= \int_0^T \! dt \frac{|\dot{\alpha_g}(t)|^2 + \kappa^2 |\alpha_g (t)|^2}{g^2} + \frac{\kappa}{g^2} \left[ |\alpha_g(T)|^2 - |\alpha_g(0)|^2 \right] \nonumber \\ &\approx \frac{I'_g}{g^2} +\frac{\kappa^2}{g^2} I_g, \label{eq-Ie}\end{aligned}$$ where we have used ${|\alpha_g(0)|^2=0}$ and ${|\alpha_g(T)|^2\approx 0}$ and have set ${I'_g = \int_0^T \! dt |\dot{\alpha}_g (t)|^2}$. Using Eqs. (\[eq-norm\]) and (\[eq-Ie\]), we obtain $$\begin{aligned} I_g &= \frac{C}{\kappa (1+2C)} \left( 1- \frac{I'_g}{\kappa C} \right), \label{eq-Ig-result} \\ I_e &= \frac{1}{2\gamma} \left[ 1- \frac{2C}{1+2C} \left( 1- \frac{I'_g}{\kappa C} \right) \right]. \label{eq-Ie-result}\end{aligned}$$ Substituting Eqs. (\[eq-Ig-result\]) and (\[eq-Ie-result\]) into Ineq. (\[eq-PS-inequality\]), the upper bound on $P_S$ is finally obtained as follows: $$\begin{aligned} P_S &\le \frac{\kappa_{\mathrm{ex}}}{\kappa} \frac{2C}{1+2C} \frac{\displaystyle 1-\frac{I'_g}{\kappa C}} {\displaystyle 1-r_u + r_u \frac{2C}{1+2C} \left( 1-\frac{I'_g}{\kappa C} \right)} \nonumber \\ &\le \left( 1- \frac{\kappa_{\mathrm{in}}}{\kappa} \right) \left( 1- \frac{1}{1+2C} \right) \sum_{n=0}^{\infty} \left( \frac{r_u}{1+2C} \right)^n, \label{eq-PS}\end{aligned}$$ where we have used $0\le 1 - I'_g/(\kappa C) \le 1$ [@comment-Ig]. The equality approximately holds when the system varies slowly and the following condition holds: $$\begin{aligned} \frac{1}{\kappa} \int_0^T \! dt |\dot{\alpha_g}(t)|^2 \ll C.\end{aligned}$$ The upper bound on the success probability given by Ineq. (\[eq-PS\]) is a unified and generalized version of previous results [@Kuhn2010a; @Law1997a; @Vasilev2010a; @comment-storage; @Gorshkov2007a; @Dilley2012a], which did not treat explicitly internal loss, detunings, or repumping. The upper bound has a simple physical meaning. The first factor is the escape efficiency $\eta_{\mathrm{esc}}$. The product of the second and third factors is the internal generation efficiency $\eta_{\mathrm{in}}$. Each term of the third factor represents the probability that the decay from $|e \rangle$ to $|u \rangle$ occurs $n$ times. Note that $\eta_{\mathrm{in}}$ is increased by the repumping process. So far, the photons generated by repumping after decay to $|u\rangle$ are counted, as in some experiments [@Barros2009a]. However, such photons may have time delays or different pulse shapes from photons generated without repumping, and are therefore not useful for some applications, such as photonic qubits. If the photons generated by repumping are not counted, we should consider the state conditioned further on no quantum jump of $\mathcal{J}_u$. In this case, the upper bound on the success probability is obtained by modifying Ineq. (\[eq-PS\]) with $r_u=0$. The contribution of the repumping to $P_S$, denoted by $P_{\mathrm{rep}}$, is given by the second term in the right-hand side of Eq. (\[eq-PS-formula\]). Using Eqs. (\[eq-Ie-result\]) and (\[eq-PS\]), we can derive an upper bound on $P_{\mathrm{rep}}$ as follows: $$\begin{aligned} P_{\mathrm{rep}} \le 2\gamma r_u I_e P_S &\le \frac{\kappa_{\mathrm{ex}}}{\kappa} \frac{2C}{1+2C} \sum_{n=1}^{\infty} \left( \frac{r_u}{1+2C} \right)^n \nonumber \\ &= \frac{\kappa_{\mathrm{ex}}}{\kappa} \frac{2C}{1+2C} \frac{r_u}{1+2C-r_u}. \label{eq-Prepump}\end{aligned}$$ Thus, the contribution of the repumping is negligible when $C \gg 1$ or when $r_u \ll 1$. *Fundamental limit on single-photon generation based on cavity QED*. The reciprocal of the upper bound on $P_S$ is simplified as $$\begin{aligned} \left( 1 + \frac{\kappa_{\mathrm{in}}}{\kappa_{\mathrm{ex}}} \right) \left[ 1 + \frac{1-r_u}{2C_{\mathrm{in}}} \left( 1 + \frac{\kappa_{\mathrm{ex}}}{\kappa_{\mathrm{in}}} \right) \right].\end{aligned}$$ This can be easily minimized with respect to $\kappa_{\mathrm{ex}}$, which results in the following lower bound on $P_F$: $$\begin{aligned} P_F \ge \frac{2}{\displaystyle 1+\sqrt{1+2C_{\mathrm{in}}/(1-r_u)}}, \label{eq-PF-ru}\end{aligned}$$ where the lower bound is obtained when $\kappa_{\mathrm{ex}}$ is set to $$\begin{aligned} \kappa_{\mathrm{ex}}^{\mathrm{opt}} \equiv \kappa_{\mathrm{in}} \sqrt{1+2C_{\mathrm{in}}/(1-r_u)}. \label{eq-optimal-kex-ru}\end{aligned}$$ In the case of no repumping, Eqs. (\[eq-PF-ru\]) and (\[eq-optimal-kex-ru\]) are modified by $r_u=0$. This leads to Ineq. (\[eq-PF\]) and Eq. (\[eq-optimal-kex\]). The approximate lower bound in Ineq. (\[eq-PF\]) can be derived more directly from Ineq. (\[eq-PS\]) (${r_u=0}$) using the arithmetic-geometric mean inequality as follows: $$\begin{aligned} P_F \ge \frac{\kappa_{\mathrm{in}}}{\kappa} + \frac{1}{2C+1} -\frac{\kappa_{\mathrm{in}}}{\kappa} \frac{1}{2C+1} \approx \frac{\kappa_{\mathrm{in}}}{\kappa} + \frac{\kappa \gamma}{g^2} \ge \sqrt{\frac{2}{C_{\mathrm{in}}}}, \nonumber\end{aligned}$$ where ${\kappa_{\mathrm{in}} \ll \kappa}$ and ${C \gg 1}$ have been assumed. Note that $\kappa$ is cancelled out by multiplying the two terms [@comment-arithmetic-geometric]. *Typical optical cavity-QED systems*. In optical cavity-QED systems where a single atom or ion is coupled to a single cavity mode [@Law1997a; @Vasilev2010a; @Barros2009a; @Maurer2004a; @Kuhn1999a; @Duan2003a], the cavity-QED parameters are expressed as follows [@Rempe2015a]: $$\begin{aligned} g &= \sqrt{\frac{\mu_{g,e}^2 \omega_{g,e}}{2\epsilon_0 \hbar A_{\mathrm{eff}} L}}, \label{eq-g} \\ \kappa_{\mathrm{in}} &= \frac{c}{2L} \alpha_{\mathrm{loss}}, \label{eq-kappa-in} \\ r_g \gamma &= \frac{\mu_{g,e}^2 \omega_{g,e}^3}{6 \pi \epsilon_0 \hbar c^3}, \label{eq-gamma}\end{aligned}$$ where $\epsilon_0$ is the permittivity of vacuum, $c$ is the speed of light in vacuum, $\mu_{g,e}$ and $\omega_{g,e}$ are the dipole moment and frequency of the $|g\rangle$-$|e\rangle$ transition, respectively, $L$ is the cavity length, $A_{\mathrm{eff}}$ is the effective cross-section area of the cavity mode at the atomic position, and $\alpha_{\mathrm{loss}}$ is the one-round-trip cavity internal loss. Substituting Eqs. (\[eq-g\])–(\[eq-gamma\]) into the definition of $C_{\mathrm{in}}$, we obtain $$\begin{aligned} \frac{2C_{\mathrm{in}}}{1-r_u} &= \frac{1}{\alpha_{\mathrm{loss}}} \frac{1}{r_A} \frac{r_g}{1-r_u} \le \frac{1}{\alpha_{\mathrm{loss}}} \frac{1}{r_A}, \label{eq-Cin-formula}\end{aligned}$$ where $\lambda = 2\pi c/\omega_{g,e}$ is the wavelength corresponding to $\omega_{g,e}$, $r_A=A_{\mathrm{eff}}/\sigma$ is the ratio of the cavity-mode area to the atomic absorption cross section ${\sigma = 3\lambda^2/(2\pi)}$, and the inequality comes from $r_g/(1-r_u) \le 1$. (The equality holds when ${r_o=0}$.) Note that the cavity length $L$ and the dipole moment $\mu_{g,e}$ are cancelled out. From Ineq. (\[eq-PF-ru\]), it turns out that the single-photon generation efficiency is limited only by the one-round-trip internal loss, ${\alpha_{\mathrm{loss}}}$, and the area ratio, $r_A$, even when counting photons generated by repumping. *Conclusion and outlook*. By analytically solving the master equation for a general cavity-QED model, we have derived an upper bound on the success probability of single-photon generation based on cavity QED in a unified way. We have taken cavity internal loss into account, which results in a tradeoff relation between the internal generation efficiency and the escape efficiency with respect to the cavity external loss rate $\kappa_{\mathrm{ex}}$. By optimizing $\kappa_{\mathrm{ex}}$, we have derived a lower bound on the failure probability. The lower bound is inversely proportional to the square root of the internal cooperativity $C_{\mathrm{in}}$. This gives the fundamental limit of single-photon generation efficiency based on cavity QED. The optimal value of $\kappa_{\mathrm{ex}}$ has also been given explicitly. The repumping process, where the atom decays to the initial ground state via spontaneous emission and is reused for cavity-photon generation has also been taken into account. For typical optical cavity-QED systems, the lower bound is determined only by the one-round-trip internal loss and the ratio between the cavity-mode area and the atomic absorption cross section. This result holds even when the photons generated by repumping are counted. The lower bound is achieved in the limit that the variation of the system is sufficiently slow. When the short generation time is desirable, optimization of the control parameters will be necessary. This problem is left for future work. Acknowledgments {#acknowledgments .unnumbered} =============== The authors thank Kazuki Koshino, Donald White and Samuel Ruddell for their useful comments. This work was supported by JST CREST Grant Number JPMJCR1771, Japan. [19]{} H. J. Kimble, Nature **453**, 1023 (2008). M. D. Eisaman, J. Fan, A. Migdall, and S. V. Polyakov, Rev. Sci. Instrum. **82**, 071101 (2011), and references therein. A. Reiserer and G. Rempe, Rev. Mod. Phys. **87**, 1379 (2015). A. Kuhn and D. Ljunggren, Contemp. Phys. **51**, 289 (2010). C. K. Law and H. J. Kimble, J. Mod. Opt. **44**, 2067 (1997). G. S. Vasilev, D. Ljunggren, and A. Kuhn, New J. Phys. **12**, 063024 (2010). H. G. Barros, A. Stute, T. E. Northup, C. Russo, P. O, Schmidt, and R. Blatt, New J. Phys. **11**, 103004 (2009). C. Maurer, C. Becher, C. Russo, J. Eschner, and R. Blatt, New J. Phys. **6**, 94 (2004). A. Kuhn, M. Hennrich, T. Bondo, and G. Rempe, Appl. Phys. B **69**, 373 (1999). L.-M. Duan, A. Kuzmich, and H. J. Kimble, Phys. Rev. A **67**, 032305 (2003). The external loss is due to the extraction of cavity photons to the desired external mode via transmission of the mirror, while the internal loss is due to undesirable scattering and absorption inside the cavity. It is notable that similar lower bounds on failure probabilities, inversely proportional to $\sqrt{C_{\mathrm{in}}}$, have been derived for quantum gate operations based on cavity QED [@Goto2008a; @Goto2010a]. This fact implies that $C_{\mathrm{in}}$ should be regarded as a figure of merit of cavity-QED systems for quantum applications. In Refs. [@Goto2008a; @Goto2010a], the critical atom number [@Rempe2015a], which is the inverse of the cooperativity, was used instead of the internal cooperativity. Note that in Ref. [@Goto2008a], $\kappa$ should be interpreted as $\kappa_{\mathrm{in}}$ because in this case the external field is unnecessary and we can set $\kappa_{\mathrm{ex}}=0$. H. Goto and K. Ichimura, Phys. Rev. A **77**, 013816 (2008). H. Goto and K. Ichimura, Phys. Rev. A **82**, 032311 (2010). Interestingly, this optimal value of $\kappa_{\mathrm{ex}}$ is exactly the same as that for a quantum gate operation in Ref. [@Goto2010a]. E. M. Purcell, Phys. Rev. **69**, 681 (1946). Pure dephasing may degrade single-photon efficiency, and therefore not affect the upper bound on the efficiency. In typical optical cavity-QED systems where a single atom or ion is coupled to a single cavity mode [@Law1997a; @Vasilev2010a; @Barros2009a; @Maurer2004a; @Kuhn1999a; @Duan2003a], pure dephasing is actually negligible. H. J. Carmichael, in *An Open Systems Approach to Quantum Optics*, edited by W. Beiglböck, Lecture Notes in Physics Vol. m18, (Springer-Verlag, Berlin, 1993). M. B. Plenio and P. L. Knight, Rev. Mod. Phys. **70**, 101 (1998). If $\langle g| \langle 0| \mathcal{V}_c (T,t) \rho_0 |g \rangle |0 \rangle > \langle g| \langle 0| \mathcal{V}_c (T,0) \rho_0 |g \rangle |0 \rangle$, then we should use $\mathcal{V}_c (T,t)$ for the single-photon generation, instead of $\mathcal{V}_c (T,0)$. Note that $I'_g \ge 0$ by definition and $1 - I'_g/(\kappa C) \ge 0$ because $I_g \ge 0$, by definition, in Eq. (\[eq-Ig-result\]). Interestingly, it is known that photon storage with cavity-QED systems without internal loss also has a similar upper bound, $2C/(2C+1)$, on the success probability [@Gorshkov2007a; @Dilley2012a]. This, together with the results for quantum gate operations [@Goto2008a; @Goto2010a], implies the universality of the upper bound. A. V. Gorshkov, A. André, M. D. Lukin, and A. S. S[ø]{}rensen, Phys. Rev. A **76**, 033804 (2007). J. Dilley, P. Nisbet-Jones, B. W. Shore, and A. Kuhn, Phys. Rev. A **85**, 023834 (2012). A similar technique has been applied to the derivation of an upper bound on the success probability of a quantum gate operation based on cavity QED [@Goto2008a].

Q: Pod spec lint fail validation: no known class method for selector I'm trying to create a pod, my framework is building fine and I have no problem using it projects, but when I am trying to convert it into a pod and run pod spec lint to validate it it fails, and gives me the following error: - ERROR | [iOS] xcodebuild: SimpleCameraFramework/SimpleCameraFramework/AVCaptureSession+Safe.m:28:67: error: no known class method for selector 'safeCastFromObject:' In this file I have no compiler error, I have exposed the category in the umbrella header, so I really don't see where the problem is... Any idea? A: I found out the problem, for some reason the pod doesn't work with the precompiled header, if I remove it and import the .h file directly in AVCaptureSession+Safe, it works...

Cryopreserved (frozen) Donor vials are available to individual Client(s)/Recipient(s), within the United States and Worldwide to achieve Assisted Reproduction. BioGenetics Corporation was established in 1980 to become the first commercial sperm bank in the United States located in New Jersey. BioGenetics respects the current medical standards and ethics set forth by the: American Society for Reproductive Medicine (ASRM) American Society of Andrology (ASA) The American Association of Tissue Banks (AATB) The American Urological Association (AUA) and all related scientific associations as well as regulatory government agencies that may impact Reproductive Cell and Tissue Banking. BioGenetics is FDA Registered BioGenetics is licensed by The New Jersey State Department of Health as a Laboratory under CLIA The New York State Department of Health as a Reproductive Cell & Tissue Bank BioGenetics Corporation operates under the direction of Albert Anouna, President and CEO. Mr. Anouna holds a B.Sc. and is certified as a High Complexity Laboratory Director (HCLD). Mr. Anouna is a member of the following professional and scientific organizations: American Society for Reproductive Medicine (ASRM) American Association of Tissue Banks (AATB) American Society of Andrology (ASA) American Association for Clinical Chemists (AACC) American Association of Bioanalysts (AAB) International Society for Environmental and Biological Repositories (ISBER) International Society for Cellular Therapy (ISCT) The BioGenetics Corporation staff includes a Medical Director, a consulting Pathologist, Geneticist, an Embryologist, several Phlebotomists, Medical Technologists, Laboratory Technicians as well as Administrative support personnel.

Manhattan Airport Foundation The Manhattan Airport Foundation is a parody advocacy organization lobbying, as part of a hoax, for the development of an international airport replacing Central Park between 59th Street and 110th Street in Manhattan. The Foundation claims to have been founded in 2006 and that it is composed of members of civic, environmental and community groups as well as elected officials and city and state agencies. The Foundation states that their proposed 'Manhattan International Airport' would be the largest public works project to be undertaken in New York since the creation of Central Park. Once built, the Airport would provide a much needed international air hub offering vital transportation access to individuals living and working in the center of Manhattan. See also Aviation in the New York metropolitan area References External links The Manhattan Airport Foundation website Curbed Monogocoro Gothamist Treehugger U.S. News & World Report Category:Hoaxes in the United States Category:Parodies Category:Central Park

Q: How to measure g using a metre stick and a ball Can I measure the value of g using only a metre stick and a ball? I am not supposed to use a stopwatch and that has been the problem. NOTE: I do not know if a solution exists or not. A: No you can't. You can see this because you are only given things that can define a units of length and mass (the meterstick and the ball), so you need something that can define the unit of time. If there was another process, nongravitational, with which you could define a unit of time, then you can find g relative to this unit of time, but absent such a thing, you can only define the unit of time by dropping something or measuring something oscillate in gravity, and then you are stuck.

Cardiotoxicity among adult survivors suffered from childhood malignancies. Late cardiotoxicity following treatment of malignancy diseases has been long established. Cancer therapeutics-related cardiac dysfunction (CTRCD), acute arrhythmias, pericardial disease, valvopathies and early atherosclerotic Cardiovascular Disease (CVD), are the clinical presentations of cardiotoxicity. Although these clinical modalities can affect adults treated for malignancies, they are more common to present in the pediatric survivors as improvement of prognosis, nowadays exists. Studies have shown that CVD can present earlier than thirty years, post treatment. If adding on this the early and late effect of cardiotoxicity on the developing in childhood cardiovascular system, we are then faced with a new Risk Factor (RF) for CVD. Anthracyclines and its derivatives have served for over fifty years as the road model of studding early, mid and late term cardiotoxicity. Today a vast number of chemical agents are used, many of them with very good results in treating the existing malignancies. Unfortunate, little or even less are known on their potential mechanism of derived cardiotoxicity when used by their own or combined with others and/or radiotherapy (RT). The 2013 existing guidelines by ACC/AHA on surveillance of the cardiovascular health of oncology survivors, are mostly addressing early cardiac adverse effects and CTRCD. Little is mentioned about the development of early CVD, its subclinical diagnosis, prevention and the need of early intervention before clinical events are present. The aim of this paper is to review the exist knowledge and practice on this condition with growing numbers of survivors facing the risk of early atherosclerotic CVD.

Stone flaming Stone flaming or thermaling is the application of high temperature to the surface of stone to make it look like natural weathering. The sudden application of a torch to the surface of stone causes the surface layer to expand and flake off, exposing rough stone. Flaming works well on granite, because granite is made up of minerals with differing heat expansion rates. Process After removing a rock from a quarry, the rock is sliced into multiple flat slabs using a diamond gang saw. The saw leaves flat surfaces with circular marks. Flaming is done by wetting, and then running an oxygen-acetylene or oxygen-propane torch over the surface. As seen in both photos, the torch is usually kept at a 45 degree angle to the stone. Alternatives Alternative techniques for creating a rough surface on sawed stone include: bush hammering sandblasting hydrofinishing See also References External links Stone surfaces, photos of various surface treatments Palowy Stone, photos of stone flaming Understanding Flagstone: Sawcut, Thermaled, and Chiseled Edges Photos of hydrofinishing Category:Stonemasonry