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LONG-TERM TREATMENT WITH APIXABAN OF PARTICIPANTS FOLLOWING CONCLUSION OF AVERROES Abstract: Background: AVERROES, a randomized trial in high‐risk patients with atrial fibrillation, unsuitable for vitamin K antagonist therapy, demonstrated the efficacy and safety of apixaban compared to aspirin for stroke prevention. As AVERROES was concluding, the long‐term open‐label extension (LTOLE) study was initiated to allow AVERROES patients to receive, or continue to receive, apixaban until it became locally available. Methods: Major efficacy and safety outcomes occurring during LTOLE were prospectively reported, including stroke or systemic embolism, and major bleeding. An analysis that included all patient years of apixaban treatment, occurring from the start of AVERROES to the end of LTOLE, was also performed. Results: Of the 5,599 patients enrolled in AVERROES, 3,275 patients were enrolled in the LTOLE. Patients enrolled in LTOLE were younger than those not enrolling (mean age 69±9 vs. 71±10 years); with lower mean CHADS score, (2.0±1.0 vs. 2.2±1.1). There were 177 patients in LTOLE (5.4%), who received reduced apixaban dose of 2.5 mg bid. Mean follow up duration in LTOLE was 2.8 years; maximum 7.8 years. The rate of stroke or systemic embolism during LTOLE was 1.0% per year (compared to 1.6% per year for apixaban treated patients during AVERROES study); and the rate of major bleeding was 1.2% per year (compared to 1.4% per year for apixaban treated patients during AVERROES). After adjustment for imbalances in patient variables, event rates during LTOLE remained as low as, or lower than, those seen in patients receiving apixaban during AVERROES. In the analysis including all patient years of apixaban treatment, either during AVERROES, during LTOLE or both, 4,412 patients received apixaban. The longest continuous duration of apixaban treatment was 9.5 years; with annual event rates of 1.2% per year for stroke or systemic embolism, 0.3% per year for hemorrhagic stroke and 1.2% per year for major bleeding. Conclusion: During the long‐term extension of AVERROES, rates of stroke or systemic embolism, and of major bleeding, in patients receiving apixaban remained as low as those observed during apixaban treatment in AVERROES. These data suggest that the long term use of apixaban is effective and safe.

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Secondary Outcomes From the Child/Adolescent Anxiety Multimodal Study: implications for Clinical Practice Abstract: Controlled evaluations comparing medication, cognitive‐behavioral therapy (CBT), and their combination in the treatment of youth anxiety have predominantly focused on global ratings by independent evaluators. Such ratings are resource intensive, may be of limited generalizability, and do not directly inform our understanding of treatment responses from the perspective of treated families. We examined outcomes from the perspective of treated youth and parents in the Child/Adolescent Anxiety Multimodal Study. Participants (N = 488; ages 7‐17 years) who had a primary diagnosis of separation, social, and/or generalized anxiety disorder were randomly assigned to a treatment condition in the Child/Adolescent Anxiety Multimodal Study trial. Linear mixed‐effects and analysis of covariance models examined parent‐ and youth‐reported anxiety symptoms, impact of anxiety, broader internalizing and externalizing psychopathology, depressive symptoms, and family burden throughout the 12‐week acute treatment phase and 6‐month follow‐up. At Week 12, combination treatment showed superiority over placebo, sertraline, and CBT with regard to parent‐reported youth anxiety symptoms, and sertraline and CBT as monotherapies showed superiority over placebo with regard to parent‐reported youth anxiety. Combination therapy and sertraline also showed Week 12 superiority over placebo with regard to parent‐reported internalizing psychopathology, and superiority over placebo and CBT with regard to parent‐reported impact of anxiety, family burden, and youth depressive symptoms. By Week 36, parent reports of many youth outcomes were comparable across active conditions. Youth measures tracked parent measures on many outcomes. Findings were drawn on brief, readily available questionnaires that in conjunction with clinician measures can inform patient‐centered care and collaborative decision making.Copyright © 2017, © 2017 Society of Clinical Child & Adolescent Psychology.

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Efficacy and safety of relugolix in black men with advanced prostate cancer: a subgroup analysis from the randomized, phase 3 HERO study versus leuprolide Abstract: Background: Prostate cancer disproportionately impacts Black men, with a higher incidence and worse outcomes relative to other races (Siegel DA, MMWR Morb Mortal Wkly Rep. 2020;69:1473). In the international phase 3 HERO study, relugolix, the once‐daily oral GnRH receptor antagonist, demonstrated superior continuous suppression of testosterone to castrate levels through week 48 compared to leuprolide (96.7% for relugolix vs. 88.8% of men receiving leuprolide; Shore N, NEJM 2020; 382:2187) in men with advanced prostate cancer (APC). To further characterize the results from this trial in black men a subgroup analysis of HERO was undertaken. Methods: HERO was a phase 3 randomized, open‐label, study to evaluate relugolix vs. leuprolide in 930 treated men with APC. The subgroup analyzed included all Black men enrolled in the HERO study. Assessments analyzed included sustained testosterone suppression to castrate levels (<50 ng/dL) from day 29 through 48 weeks, early testosterone suppression to castrate levels (day 4 and day 15), PSA response (>50% decrease) at day 15 with confirmation at day 29, profound castration rate (<20 ng/dL) at day 15, and FSH level at the end of week 24. Results: Of the 930 men (relugolix: 622; leuprolide: 308) randomized and treated in HERO, 30 (4.8%) and 16 (5.2%) Black men were enrolled in the relugolix and leuprolide groups, respectively. Most men in this subgroup were from North America (82.6%) and ≤75 years old (89.1%), with a median age of 66 years. More Black men in the relugolix group had metastatic disease at study entry (30% vs. 25%), prior androgen deprivation therapy (13.3% vs. 6.3%), and prior prostatectomy (53.3% vs. 18.8%). Median PSA (12.8 vs. 16.0 ng/ml) and median testosterone levels (375.2 vs. 419.2 ng/dL) were lower at baseline for relugolix vs leuprolide. Of the Black men who received relugolix, 93.3% (95% confidence interval [CI], 75.9% to 98.3%) maintained castration through 48 weeks, as compared with 93.3% (95% CI, 61.3 to 99.0) of men receiving leuprolide (difference: 0% [95% CI, ‐15.5% to 15.5]). Testosterone suppression to castrate levels at day 4 (53% vs 0%), castrate levels at day 15 (97% vs 13%), and profound castration rates on day 15 (67% vs 6%) were greater with relugolix vs leuprolide. PSA response at day 15 was 83.3% with relugolix and 6.3% with leuprolide. At the end of week 24, median FSH levels were 1.75 IU/L for relugolix and 3.72 IU/L for leuprolide. Incidence of all grade adverse events were 96.7% vs 87.5% and grade ≥3 adverse events were 16.7% vs 25.0% in the relugolix and leuprolide groups, respectively. Conclusions: In this HERO study subgroup analysis, relugolix was effective and generally well tolerated in a cohort of Black men, consistent with the relugolix results in the overall population. Given the limited size of the subgroup, additional research is warranted in this population.

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Efficacy and safety of foslevodopa/foscarbidopa versus oral carbidopa/levodopa in advanced parkinson's disease patients: design of a phase 3, randomized, double-blind, double-dummy, active controlled 12-week trial Abstract: Objective: Efficacy and Safety of Foslevodopa/Foscarbidopa Versus Oral Carbidopa/Levodopa in Advanced Parkinson's Disease Patients: Design of a Phase 3, Randomized, Double‐Blind, Double‐Dummy, Active Controlled 12‐Week Trial Background: As PD progresses, oral drug regimens may become insufficient for symptom control. Foslevodopa/foscarbidopa, formally known as ABBV‐951, is a new soluble formulation of carbidopa and levodopa prodrugs being developed for the treatment of advanced PD delivered as a CSCI via a portable external pump. Design/Methods: This phase 3, randomized, double‐blind, double‐dummy, parallel‐group, active‐controlled, multicenter study includes patients (≥30 years) whose motor symptoms are no longer adequately controlled by their current therapy and experience a minimum daily average of 2.5h of "Off" time per day (with a minimum of 2.0h each day). The study is comprised of a screening period, and an oral CD/LD stabilization period, followed by randomization into the 12‐week double‐blind treatment period. Patients will receive either 24‐hour/day CSCI of foslevodopa/foscarbidopa plus oral placebo or 24‐hour/day CSCI of placebo solution plus oral CD/LD. Assessments include the change from baseline to Week 12 in "On" and "Off" times from PD Diaries, MDS‐UPDRS scores, quality of life, sleep symptoms, and PD symptoms measured using a wearable device. Local and systemic safety and tolerability will be assessed using the Infusion Site Evaluation Scale and adverse event monitoring. Results: This study will enroll approximately 130 advanced PD patients from an estimated 80 sites in the United States and Australia (clinicaltrials.gov ID: NCT04380142) Conclusions: This study will provide important data on the safety and efficacy of foslevodopa/foscarbidopa, a potentially new advanced treatment option, delivered 24‐hour/day via CSCI versus oral CD/LD in advanced PD patients.

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Short-course antimicrobial therapy for paediatric respiratory infections (SAFER): a multicentre, randomized, controlled, blinded, noninferiority trial Abstract: Background: Community‐acquired pneumonia (CAP) is a common occurrence in childhood; consequently, evidence‐based recommendations for its treatment are required. The study objective was to determine if, in previously healthy children presenting to the emergency department (ED), 5 days of high‐dose amoxicillin led to noninferior rates of clinical cure at 14‐21 days post‐enrolment compared with 10 days of high‐dose amoxicillin. Methods: The SAFER study was a multicentre, randomized, parallel‐group, multiple‐ blinded, controlled, noninferiority study, enrolling between 2012‐2014 (single centre pilot) and then 2016‐2019 (follow‐up main study). Children aged 6 months ‐ 10 years with all of the following were eligible: fever within 48h; a respiratory symptom/ sign; a chest radiograph consistent with pneumonia as per the emergency MD; and a primary diagnosis of CAP. Children were excluded if they required hospitalization, had any medical comorbidities, or if they were already receiving beta‐lactam antibiotic therapy. The intervention of interest was 5 days of high‐dose amoxicillin followed by 5 days placebo. The control (standard care) arm received 5 days of high‐dose amoxicillin followed by a different formulation of 5 days of high‐dose amoxicillin. The primary outcome was clinical cure at 14‐21 days post‐enrolment. The pre‐set noninferiority margin was 0.075 less than the clinical cure risk difference (1‐sided 97.5% CI). Results: Of the 281 participants, 119 (42%) were female; the median age was 2.6 y (25‐75%ile 1.6‐4.9 y). There were 140 randomized to short‐course treatment and 141 to standard care. Clinical cure at 14‐21 days was observed in 108/126 (86%) in the short‐course arm and in 106/126 (84%) in the standard‐care arm (risk difference 0.023, lower limit of 1‐sided 97.5%CI ‐0.061). There were no participants who, after finishing amoxicillin, later deteriorated and required hospitalization for progressive CAP. Conclusion: Short‐course antibiotic therapy was noninferior to standard care for the treatment of previously healthy children with non‐severe CAP diagnosed in Canadian EDs. Clinical practice guidelines should recommend no more than 5 days of amoxicillin for paediatric pneumonia management, in accordance with antimicrobial stewardship principles.

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Effect of anacetrapib on ABCA1-specific cholesterol efflux capacity: a substudy of the define trial Abstract: Background: Impaired reverse cholesterol transport is associated with increased atherosclerosis. Cholesterol efflux from macrophages (CEC) is the initial step of reverse cholesterol transport and is inversely associated with cardiovascular disease (CVD). Anacetrapib is the only cholesterylester transfer protein (CETP) inhibitor that not only raised HDL‐C levels but also reduced CVD. However, the effect of anacetrapib on ABCA1‐specific CEC among those with CVD is unknown. Objective: To determine the effect of anacetrapib on ABCA1‐specific CEC in those with CVD. Methods: This study included 574 participants randomly selected from the DEFINE trial, a randomized placebo‐controlled trial of anacetrapib in participants with coronary heart disease on statin therapy. CEC was measured at baseline and at the 24‐week follow up visit using J774 macrophages, BODIPY fluorescent cholesterol, and apolipoprotein B‐depleted plasma. CEC was normalized to efflux elicited by pooled human plasma and by Apo AI 100mcg/mL. Multivariable adjusted linear regression analyses were performed to evaluate the independent associations of anacetrapib and lipids on CEC. Results: Similar to the total DEFINE cohort, anacetrapib was associated with increased HDL‐C and Apo AI and reduced Apo B and LDL‐C compared to the placebo group. In the placebo group, change in CEC was positively associated with increased Apo AI and Apo B but not HDL‐C. Anacetrapib was associated with increased CEC at follow up regardless of normalization method after adjustment for baseline CEC, co‐variates, and changes in lipids (30% increase; Figure 1). Conclusions: Among patients with coronary disease, anacetrapib at a dose linked to improved CVD outcomes also significantly increased ABCA1‐specific CEC. Increases in CEC are linked more to changes in apolipoprotein levels than cholesterol levels. (Figure Presented).

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Influence of genetic polymorphisms on the response to tramadol and ibuprofen in patients with moderate-to-severe pain Abstract: The aim of this study was to evaluate the impact of several polymorphisms on the analgesic effect of ibuprofen and tramadol. We analysed 81 patients with moderate‐to‐severe pain after dental surgery who randomly received ibuprofen arginine 400 mg or tramadol 50 mg for pain control. Patients recorded their pain intensity on a Visual Analogue Scale (VAS) to a maximum of 6 hours. We analysed 32 variants in metabolizing enzymes (cytochrome P450 (CYP), COMT), transporters (ABCB1, SLC22A1) and receptors (OPRM1, PTGS2) using the custom SNP‐array platform PharmArray.¹ Regarding ibuprofen, CYP2C8 PM experienced significant lower VAS reduction at 6 h (P = 0.02). Conversely, although it was not significant (P = 0.07), CYP2C9 PM presented a better response, possibly as a consequence of higher ibuprofen concentrations. There was no association between CYP2B6, CYP2C19, CYP2D6, CYP3A5 and PTGS2 and the response to ibuprofen. Regarding tramadol, the only subject who was CYP2D6 UM experienced a higher VAS reduction at 1 h, which could be explained as CYP2D6 mediates the formation of O‐desmethyltramadol, which has a higher mu‐opioid receptor affinity than tramadol. The only CYP2D6 PM subject experienced a late response (no reduction at 1 h) due to the lower formation of O‐desmethyltramadol. Patients carrying ABCB1 minor alleles showed a greater response, along with patients carrying OPRM1 118G allele (P = 0.049). Patients with lack of SLC22A1 active alleles experienced a worse response to tramadol. In summary, several polymorphisms have an impact in the efficacy of ibuprofen and tramadol in patients with acute pain. However, further research is needed with larger sample size to confirm our results.

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Remote ischemic preconditioning preceding coronary artery bypass grafting reduces the volume of ischemic brain lesions Abstract: Introduction: Neurological sequelae following cardiac surgery impact quality of life, mortality and health resource utilization. We hypothesized that remote ischemic preconditioning (RIPC) prior to CABG harbors a neuroprotective effect. Methods: In this randomized trial 70 CABG patients were assigned to undergo RIPC or a sham procedure. Structural brain MRI was complemented with resting state functional MRI to gain a whole‐brain data‐driven global connectivity analysis. A postoperative decrease of one standard deviation in neurocognitive tests was considered abnormal. Paired neurocognitive and MRI data were acquired pre‐and postoperatively. Results: Two patients in each group didn't have postoperative MRIs and were excluded. There were a total of 11 new brain ischemic lesions in 8 patients in the RIPC group, and 25 new lesions in 7 patients in the control group (8/33 (24%) vs. 7/33 (21%) P=1.0, mean ischemic volume 191±92 vs. 2588±5105 mm , P=0.004). A total of 99 individual neurocognitive tests were performed in each group. The reduction in abnormal test results in the RIPC group was below the threshold of statistical significance (8/99 (8%) vs. 17/99 (17%); P=0.085). There were no major adverse cardiac and cerebrovascular events in either group. Thirty‐three patients had resting state functional MRI datasets of sufficient quality to undergo analysis. Interaction effects in bilateral primary visual cortex regions, driven by both the effects of surgery and RIPC, were noted (Figure 1). RIPC was associated with postoperative global brain connectivity elevations. Contrariwise, attenuation of connectivity was noted in the control group. Conclusions: New, clinically silent, ischemic brain lesions after CABG are frequently detected on brain MRI. While the overall incidence of new ischemic brain lesions did not differ between the groups, RIPC significantly reduced their mean volume. RIPC also impacted global brain connectivity within primary visual regions.

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Ustekinumab treatment effectiveness in clinical practice-a multicentre retrospective review of long-term outcomes in Crohn's disease Abstract: Background: Recently published data demonstrated the efficacy of Ustekinumab (USK) in the treatment of moderate‐severe Crohn's disease. This study aimed to evaluate the Irish experience of USK 2011‐2016 Methods: A retrospective multicentre analysis of patients treated with USK was performed via the INITiative network, a national collaborative IBD research network. Data collected from 5 centres included patient and disease characteristics, surgical history, concomitant therapies, induction and escalation of therapy, surgery post‐treatment and sustained benefit at 12 months. Results: 59 patients were included; data available n=54. Patient and disease characteristics as per Table 1. [Table Presented] Median duration of follow‐up post‐treatment = 17.4 months. 32/54 patients (59.3%) had prior Crohn's‐related surgery; 28% pa‐tients had >1 surgical procedure. All patients had been treated with >1 anti‐TNF agent. 32 patients (35%) had failed therapy with 3 anti‐TNF agents. Various induction regimens were utilised. All patients received sub‐cutaneous (sc) induction; median cumulative induction dose=225mg (range 135‐270mg). 29.6% (n=16) were taking concomitant im‐munomodulators and 27.8% (n=15) concomitant steroids at induction. Most patients received 90mg maintenance dose; median interval of 8 weeks (range: 2‐8weeks). In 17 cases (31.5%) USK therapy was escalated, usually by increasing dose frequency. Of those patients who were escalated 13 (76.5%) had a sustained clinical benefit at 12 months. 12 month follow‐up data is available for 44 patients; 10 patients continue USK with treatment duration <12 months. The median treatment duration=359 days (IQR 101‐956 days). 25/44 (56.8%) had sustained benefit at 12 months; 18 patients (72%) continued USK at the time of last follow‐up. 23 patients had endoscopic assessment before and after induction therapy. 39% (n=9) demonstrated improvement; 5 patients achieved mucosal healing. 13/54 patients (24%) had surgery while on USK; n=9 within 12 months of induction. In a logistic regression model, failing to respond to 3 anti‐TNF agents (primary non‐response, loss of response, adverse event) was signif‐icantly associated with requiring surgery in the 12 months post‐induction (p=0.017). Conclusions: In this study, USK provided sustained benefit at 12 months to >50% patients with medically‐refractory Crohn's disease. These data suggest that induction therapy with sc USK may be an alternative to iv induction. As with anti‐TNF therapy, dose optimi‐sation appears to be critical in inducing and maintaining response.

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Inverse association between carbohydrate consumption and plasma adropin concentrations in humans Abstract: Objective: The role of metabolic condition and diet in regulating circulating levels of adropin, a peptide hormone linked to cardiometabolic control, is not well understood. In this study, weight loss and diet effects on plasma adropin concentrations were examined. Methods: This report includes data from (1) a weight loss trial, (2) an evaluation of acute exercise effects on mixed‐meal (60% kcal from carbohydrates) tolerance test responses, and (3) a meta‐analysis to determine normal fasting adropin concentrations. Results: Distribution of plasma adropin concentrations exhibited positive skew and kurtosis. The effect of weight loss on plasma adropin concentrations was dependent on baseline plasma adropin concentrations, with an inverse association between baseline and a decline in concentrations after weight loss (Spearman's rho = ‐0.575; P < 0.001). When ranked by baseline plasma adropin concentrations, only values in the upper quartile declined with weight loss. Plasma adropin concentrations under the main area of the bell curve correlated negatively with habitual carbohydrate intake and plasma lipids. There was a negative correlation between baseline values and a transient decline in plasma adropin during the mixed‐meal tolerance test. Conclusions: Plasma adropin concentrations in humans are sensitive to dietary macronutrients, perhaps due to habitual consumption of carbohydrate‐rich diets suppressing circulating levels. Very high adropin levels may indicate cardiometabolic conditions sensitive to weight loss.

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Everolimus and early calcineurin inhibitor withdrawal is associated with superior renal function: 5-year follow-up of the randomized protect liver transplantation study Abstract: Purpose: At the end of the 12‐month (M) PROTECT core study (NCT00378014), de novo liver transplant recipients (LTxR) who switched from a calcineurin inhibitor (CNI) based immunosuppression to a CNI free everolimus (EVR) based regimen showed numerically better renal function. The renal function benefit with EVR group was maintained up to 3 years post LTx. Here we present the 5‐year follow‐up data from the PROTECT study. Methods: PROTECT was an open‐label, parallel‐group, randomized controlled study in which LTxR received basiliximab and CNI‐based immunosuppression with/without corticosteroids. Between Week 4 and 8, patients were randomized 1:1 to receive EVR or continue CNI. In the EVR group, CNI was completely withdrawn after 8 weeks. Patients who completed core study were asked to enter the extension study and continue their randomized treatment. Key endpoints included change in renal function measured by estimated glomerular filtration rate (eGFR) by Cockcroft‐Gault (CG), efficacy failure (composite of biopsy‐proven acute rejection [BPAR], graft loss, death, or loss to follow‐up), and incidence of adverse events (AEs) and serious AEs (SAEs). Results: A total of 81 patients entered the extension study (41, EVR group; 40, CNI group). At M59 post randomization, the adjusted mean eGFR was significantly higher in the EVR vs CNI group, with a benefit of 12.4 mL/min using CG [95%CI: 1.2; 23.6; P=0.0301]. In the extension period, 3 deaths occurred (EVR, 1; CNI, 2). There were no cases of graft loss. Two BPAR occurred in the EVR group. SAEs occurred in 26 (63.4%) and 28 (70.0%) of the patients in the EVR and CNI group, respectively. The most commonly reported AEs were incisional hernia, nasopharyngitis, peripheral edema, diarrhea, and back pain. Conclusion: In comparison to CNI based immunosuppressive treatment EVR‐based CNI free immunosuppression resulted in better renal function and comparable patient and graft outcomes after 5 years follow‐up. (Table presented) .

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Cognitive-behavioral therapy and educational counseling for chronic pain and opioid dependence Abstract: Aims: To examine the efficacy of cognitive behavioral therapy (CBT) and educational counseling (EC)‐the educational component of CBT augmented by additional psychoeducation on chronic pain and addiction‐for co‐occurring chronic low‐back pain and opioid dependence (POD). Methods: 90 POD patients received a standard protocol of buprenorphine/naloxone (BUP/NLX) and were assigned to: physician management (PM) alone, consisting of six 10‐15 min medically focused sessions; PM plus psychologist‐delivered CBT (10 sessions over 12 weeks); or PM plus nurse‐delivered EC (10 sessions over 12 weeks). Primary outcomes were pain interference, pain intensity, and percentage of opioid‐negative urines. Results: The majority were men (68%), Caucasian (89%), and never married (60%). Completion rates (>90%) and PM attendance (mean of 5.6 of 6 planned sessions) did not vary across conditions. There was a significant overall decrease in average pain interference from 4.6 at baseline to 3.4 at month 3 (p < .05) and a significant interaction between condition and time (p < .05), favoring PM plus CBT or EC over PM alone: The mean (SD) reductions in pain interference (scored on 0‐10 scales) in the CBT, EC, and PM alone groups were 1.7 (1.7), 1.4 (1.6), and 0.6 (1.6), respectively. Pain intensity decreased over time (p < .05) but did not differ by group nor was there a significant interaction with group by time. Overall, the proportion of urine samples indicating nonmedical opioid use decreased from 100% at baseline to 31% (95% CI 23‐40%) at month 1, 36% (95% CI 27‐46%) at month 2, and 39% (95% CI 30‐50%) at month 3. Covarying for nonmedical opioid use during BUP/NLX induction, there was a significant interaction between counseling and time (p < .05): reductions from baseline were sustained in both CBT and EC groups, while nonmedical opioiduse increased in the PM alone group. Conclusions: Our findings support the efficacy of PM enhanced by CBT or EC for patients with POD treated with BUP/NLX.

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Symptom clusters among MS-flash clinical trial participants Abstract: Objective: Women experience multiple co‐occurring symptoms (symptom clusters) during the menopausal transition and early postmenopause. Although symptom clusters have been identified among community‐dwelling populations, to date there have been no studies of participants in clinical trials necessitating inclusion for hot flashes. Our objective was to identify symptom clusters using standardized measures completed by MS‐FLASH clinical trial participants at baseline including: hot flashes, sleep disruption, mood and pain symptoms. Design: All women randomized to interventions and controls from MS FLASH studies 1‐3 (N=806) were included. Scores from standardized measures obtained at baseline included: Hot Flash Daily Interference Scale (HFDIS) scores, Insomnia Severity Index (ISI) scores, Patient Health Questionnaire (PHQ 9) measure of depressed mood, Generalized Anxiety Disorder (GAD), Pittsburgh Sleep Quality Inventory (PSQI), and Brief Pain Inventory PEG scale scores. Latent class analysis was used to identify clusters of symptoms using standardized scale scores and cut points. Results: Using the BIC criterion, three clusters provided the optimal solution. Cluster 1 (n=259) included women with no or moderate pain, little anxiety, no depression, poor sleep quality, sub‐threshold or moderate insomnia, and a range of hot flash daily interference. Cluster 2 (n=147) included women with no or moderate pain, mild or sometimes moderate anxiety, mild or moderate depression, poor sleep quality, sub‐threshold or moderate insomnia, and higher scores on hot flash interference. Cluster 3 (n=400) included women with no or some moderate pain, little anxiety, no depression, good or fair sleep quality, no insomnia, and low hot flash interference. Conclusion: Women meeting hot flash frequency criteria for inclusion in clinical trials exhibit multiple co‐occurring symptoms that cluster into identifiable groups. Consideration of effects of therapeutic agents on multiple co‐occurring symptoms will be important to enhance treatment outcomes and minimize adverse effects on other symptoms.

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Rosiglitazone improves c-reactive protein and liver function in impaired glucose tolerance but not coronary artery calcification or exercise function Abstract: Type 2 diabetes (T2D) increases cardiovascular (CV) risk and decreases functional exercise capacity. We and others have reported that rosiglitazone (RO) improves functional exercise capacity and endothelial function in T2D and decreases coronary artery calcium (CAC), a CV disease surrogate. Impaired glucose tolerance (IGT) is associated with excess CV risk and progression to T2D. We tested the impact of RO on functional exercise capacity and CAC in 40 subjects with IGT randomized to RO or placebo (PL) for 18 months. VO2 peak, VO2 kinetics and CAC were assessed. Despite randomization, BMI and fasting insulin differed between groups at baseline, and a hemoglobin A1c (A1c) difference approached significance. Paired analyses within each group demonstrated decreased 2 hr glucose on RO but not PL. Insulin increased and A1c trended up on PL but not RO. C‐reactive protein (CRP) and liver function tests (LFTs) decreased in the RO group only. No change was observed in VO2 peak or VO2 kinetics in either group. CAC trended upward with no difference between groups but this study was limited by small sample size. In summary, RO resulted in benefits in glucose metabolism and improved CRP and LFTs. However, in contrast to effects in T2D, RO does not appear to improve exercise capacity or decrease CAC in IGT in this small cohort. (Table presented).

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Comparison of the effects of terlipressin, somatostatin, and octreotide when combined with endoscopic treatment in acute gastroesophageal variceal bleeding: a multicenter prospective randomized controlled trial Abstract: Background and Aims: Vasoactive drugs, including terlipressin, somatostatin, and octreotide, are recommended to be started as soon as possible in suspected variceal bleeding, even before diagnostic endoscopy. However, it is unclear whether the hemostatic effect and safety is comparable among terlipressin, somatostatin, and octreotide in patients with variceal bleeding. The aim of this study was to compare the hemostatic effect and safety among terlipressin, somatostatin, and octreotide when combined with endoscopic treatment in patients with acute variceal bleeding. Methods: This prospective, randomized, controlled trial was conducted in 11 hospitals in Korea. Patients with liver cirrhosis and significant upper gastrointestinal bleeding were initially treated with terlipressin, somatostatin, or octreotide after randomization. Afterward, patients with non‐variceal bleeding on endoscopy were excluded. Primary endpoint was 5‐day success rate, defined as hemostasis without rebleeding or mortality within 5 days. Patients with hepatocellular carcinoma and portal vein invasion or contraindications to vasoactive drugs were excluded. Results: A total of 1034 patients with liver cirrhosis were treated with vasoactive drugs after randomization; 209 patients were excluded because of bleeding from non‐variceal origin on endoscopy. Another 33 patients who were diagnosed as hepatocellular carcinoma with portal vein invasion and 12 patients with follow‐up duration of less than 5 days were excluded. Finally, 780 patients with variceal bleeding were enrolled in the study: 261 patients in terlipression group, 259 patients in somatostatin group, and 260 patients in octreotide group. Hemostasis failed in 90 patients (11.5%) and 62 of 90 patients (68.9%) died within 5 days. Among 690 patients with successful hemostasis, rebleeding was developed in 29 patients (4.2%) and 2 of 29 patients (6.9%) died within 5 days. Additional 2 patients died within 5 days from liver failure. Five‐day success rate was 84.5%: it did not differ significantly among terlipressin group (86.2%), somatostatin group (83.4%), and octreotide group (83.8%, P = 0.636). Adverse events were noted in 14 patients (1.8%): the incidence of adverse events did not differ among three groups (P = 0.933). Conclusion: The hemostatic effects and safety was comparable among terlipressin, somatostatin, and octreotide when combined with endoscopic treatment in patients with acute gastroesophageal variceal bleeding.

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Physical therapy for persistent postpartum stress urinary incontinence: a seven year follow-up study Abstract: Hypothesis / aims of study The aim of this study was to evaluate the effect of intensive, eight‐week physical therapy programs, with and without deep abdominal muscle training, on persistent postpartum SUI seven years post‐treatment. Study design, materials and methods: This was a prospective, single‐blind randomized controlled trial. Fifty‐seven postnatal women with clinically‐demonstrated persistent SUI three months or more after delivery participated in eight weeks of either pelvic floor muscle training (PFMT) alone (28) or with deep abdominal muscle training (PFMT+Tra) (29). Both groups had a pelvic floor or pelvic floor/abdominal exercise program to follow at home, once a day, five days a week, in addition to a weekly physical therapy session for the eight‐week period. Physical therapy sessions for the PFMT group consisted of a 15‐minute period of electrical stimulation followed by 25 minutes of PFMT exercises. The PFMT+Tra group received an additional 10‐minute session of deep abdominal muscle exercises (1). Seven year post‐treatment, participants were contacted by telephone and invited to participate in a follow‐up study. They were asked to do a 20‐minute pad test with standardized volume and complete three incontinence‐specific questionnaires: the Urogenital Distress Inventory questionnaire (UDI), the Incontinence Impact Questionnaire (IIQ) and the Visual Analog Scale (VAS) with a blinded outcome assessor. Kruskal‐Wallis tests were used to compare follow‐up participants to non‐follow‐up participants in regard to baseline characteristics. Outcome measures at the 7‐year follow‐up for PFMT and PFMT+Tra groups were compared using Mann‐Whitney U test. Finally, both groups were combined to compare baseline, posttreatment and 7‐year follow‐up scores for all outcome measure. A non‐parametric Friedman rank tests was used and if the test was significant, post‐hoc comparisons were calculated to compare paired outcomes. Results: Thirty‐five of the initial 57 participants (61.4%) agreed to the follow‐up, of which twenty‐six (45.6%) took the 20‐minute pad test (12 PFMT and 14 PFMT+Tra) and 35 (61.4%) completed the questionnaires (18 PFMT and 17 PFMT+Tra). Among the 22 nonfollow‐up participants, 10 had changed phone numbers, 11 did not want to participate and 1 had moved to another city. The baseline clinical characteristics of the follow‐up participants and non‐follow‐up participants were not significantly different; nor did they differ between PFMT and PFMT‐Tra participants enrolled in the follow‐up study, except for UDI and IIQ (p <0.029). Outcome‐measure comparisons between PFMT and PFMT +Tra at seven years were thus calculated for pad test and VAS only. Pad test scores and VAS scores for the PFMT group were not statistically different than those of PFMT+ Tra group at seven years (U=79.5; p =0.08 and U= 108; p= 0.14). When combining both treatment groups, a total of 14/26 (53%) participants were still continent according to the pad test at seven years. Comparisons of the combined treatment group between baseline, post‐treatment and seven years for all outcome measures are presented in Table 1. Interpretation of results: Seven years after following an intensive eight‐week physical therapy program for persistent postpartum SUI, there were no statistically significant differences in the pad test and VAS scores between PFMT group and PFMT +Tra group. When combining both treatment groups together, one woman out of two was still continent according to pad testing. Incontinencespecific signs, symptoms and quality of life remained better than before treatment although not as good as immediately after. An observed reduction of the effect of physical therapy over time, was not unexpected, especially as only 19/35 (54 %) of the participants continued to practice PFM exercises regularly. In spite of the worsening of all outcomes at the 7‐year follow‐up compared to immediately after treatment, pad test, IIQ and VAS outcomes were still significantly better than at baseline. Concluding message: According to this small follow‐up RCT, the addition of deep abdominal training does not appear to further improve the outcome of PFM training in the long term. However, benefits of physical therapy for persistent postpartum SUI, although not as important as immediately after the intervention, seemed to be present seven years post‐treatment. Further research with larger groups, is required in order to compare the long‐term impact of PFMT programs, as well as whether and how post‐treatment benefits can be maintained. (Table Presented).

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Supraphysiologic Testosterone Increases Proactive Aggression in the Power-to-Take Game Abstract: Identifying the mechanisms that compel prosocial and antisocial behaviors is essential when seeking to develop effective social policies. While selfishness is ever present, in many situations cooperation is the norm. Testosterone increases a variety of antisocial behaviors but can also induce cooperation and honesty. We tested whether testosterone influences taking money from others, a measure of proactive aggression. We administered synthetic testosterone to participants (N = 163) in a double‐blind placebo‐controlled study before they made decisions in the power‐to‐take (PTT) game in which participants can take resources controlled by another while the other person can destroy resources so they are not taken. Three measures of testosterone were obtained from blood samples before and after drug administration to assess parametric effects. The data showed that an average 62% increase in total testosterone had no effect on average taking or destroying decisions in the PTT game. But taking money from others increased linearly in participants with supraphysiologic levels of testosterone. At the same time, testosterone improved participants’ moods and those with positive affect destroyed fewer resources. Our results show that testosterone should be viewed as a nuanced modulator of social interactions rather than the cause of antisocial behaviors

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Clinical and radiographical performance of implants placed with simultaneous guided bone regeneration using resorbable and non-resorbable membranes after 22-24 years, a prospective, controlled clinical trial Abstract: AIM: The aim was to evaluate the performance of implants placed with simultaneous guided bone regeneration (GBR) using resorbable or non‐resorbable membranes compared to implants placed in pristine bone without bone regeneration after an observation period of 22‐24 years. MATERIAL AND METHODS: The patient cohort of this clinical trial was treated from 1994 to 1996. Dehiscence defects were treated with GBR by either using resorbable collagen membranes (BG) or non‐resorbable ePTFE membranes (GT). Implants placed in pristine bone served as a control (CT). Clinical parameters, marginal bone levels and technical outcomes were evaluated following restoration placement and at the present follow‐up. A 3D radiographic analysis was conducted in order to assess buccal and oral bone dimensions. Implant survival was assessed with Kaplan‐Meier analysis and a frailty model (level of significance 5%). RESULT(S): Out of the originally 72 patients (mean age 75.4+/‐15.70 years) with 265 implants, 39 patients with 147 implants were included in study after a median period of 23.5 years. Implant survival was 89.3% in group BG (n= 100), 90.2% in group GT (n= 37), and 93.8% in group CT (n= 105), without significant differences (Frailty proportional hazard model p=0.79). Smoking had a negative effect on survival (p=0.0122). Mean vertical marginal bone levels were ‐2.3+/‐1.4mm (BG, n= 59), ‐3.0+/‐1.5mm (GT, n= 21) and ‐2.3+/‐1.6mm (CT, n=52). The vertical buccal bone levels were ‐3.0+/‐1.9mm (BG, n= 57), ‐3.5+/‐2.2mm (GT, n= 21) and ‐2.6+/‐1.8mm (CT, n= 49), without significant differences. CONCLUSION(S): Implant placement with GBR procedures provides treatment outcomes with favorable implant survival rates (89.3%‐93.8%) after 23.5 years. Smoking, however, affected implant survival negatively.Copyright This article is protected by copyright. All rights reserved.

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A Comparative Study of Glycopyrollate and Ondansetron for the Control of Post Operative Nausea and Vomiting Following General Anaesthesia Abstract: Background : Postoperative nausea and vomiting (PONV) is a common distressing problem in patients undergoing surgery under general anaesthesia which requires frequent medical interventions. Objectives : Primary objective was to find out the efficacy of glycopyrrolate & ondansetron in prevention of PONV in patients undergoing surgery under general anaesthesia. Methods: This was a prospective, randomized, placebo controlled study conducted in Victoria & Bowring hospital. Study subjects were randomly assigned into three groups of 10 patients each. Group G received inj Glycopyrrolate 0.2 mg i.v, Group O received inj. Ondansetron 8 mg i.v, Group N will receive 1 ml normal saline i.v, just before induction of anaesthesia with Inj.Fentanyl & inj. propofol. Incidence of nausea & vomiting was assessed for 24 hrs after surgery. Results: Out of 30 patients 12 (40%) patients had nausea and vomiting in the postoperative period i.e Three (10%) patients in group G, two (6.67%) in group O & seven (23.34%) in group N. Incidence of nausea was compared between glycopyrrolate & saline (OR= 0.214, CI= 0.02‐1.8, P= 0.164), Ondansetron & saline (OR= 0.0938, CI= 0.007‐ 1.2, P= 0.07). Whereas occurrence of vomiting between Glycopyrrolate & saline (OR= 0.14, CI= 0.01‐1.9, P= 0.14), Ondansetron & saline (OR= 0.12, CI= 0.009‐ 1.7, P= 0.12). Conclusions: Our study showed that prophylactic use of ondansetron is discreetly effective in the prevention of PONV. As this is an on‐going study the results are being awaited.

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More precise dosing of acenocoumarol for better control in patients aged above 80 years, a randomized controlled pilot study Abstract: Background: Many elderly patients are confined to treatment with vitamin K antagonists (VKA) instead of direct oral anticoagulants (DOACs). However, quality of VKA treatment declines with age. At the same time, the average VKA dose requirement decreases with age. This increases the day‐to‐ day variation in VKA dose. Aims: To obtain information on the effect size for, and feasibility of a full scale trial to assess whether more precise dosing of acenocoumarol increases the quality of VKA treatment in elderly patients. Methods: In this pilot study we randomized 80 patients aged 80 and above who used 0.5‐2.0 mg acenocoumarol daily to either regular dosing in 1.0 mg acenocoumarol increments, or more precise dosing with 0.5 mg increments. We compared changes in time in therapeutic range (TTR) and International Normalised Ratio (INR) variability (VGR) between the two treatment groups, in the six month before and six months during study period. In addition changes in anticoagulation‐related quality of life were assessed using PACT‐Q. Results: Patients were aged 84±3 years. Overall baseline TTR was 61% (± 19.2). TTR had improved in both groups, but somewhat more in the intervention group (3.4%, 9.0 vs 5.6; 95% CI ‐3.7 to 10.5). The INR variability also improved, slightly more in the 0.5 mg group. PACT‐Q convenience remained constant in time and did not differ between groups. PACT‐Q satisfaction decreased, almost equally, in both groups. Four dosing errors related to dose increments occurred, three in the intervention and one in the control group. Conclusions: Although more precise dosing of acenocoumarol leads to a slightly better quality of anticoagulation, this effect is too small to convey a relevant clinical benefit. We will not proceed with a full scale RCT. Notably, the overall decrease in treatment satisfaction should be considered when performing future anticoagulation studies in this population.

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Multifidis peripheral nerve stimulation randomized controlled trial Abstract: Introduction: ReActiv8‐B is an international, multicenter, prospective, randomized, sham‐controlled, blinded clinical trial with one‐way crossover, conducted under an IDE from the FDA (clinicaltrials. gov/show/NCT02577354). The study, performed at 26 investigational sites in the United States, Australia and Europe, is intended to evaluate safety and efficacy of a novel implantable neurostimulator for adults with Chronic Low Back Pain (CLBP) and no prior spine surgery. The therapeutic target is the multifidus muscle which normally provides functional stability to the lumbar spine. Fundamental to the therapeutic effect is arthrogenic multifidus inhibition, and the associated segmental instability and possible atrophy. Bilateral electrical stimulation of the L2 dorsal ramus medial branch elicits episodic contractions of the deep multifidi, thus overriding underlying inhibition. Reactivation of motor control and restoration of functional stability is the hypothesized mechanism of action. Materials and Methods: Key eligibility criteria included debilitating CLBP despite medical management with at least pain medications and physical therapy in patients who were not candidates for spine surgery. Subjects were implanted and randomized to 'Treatment' (stimulation eliciting multifidus contractions) or 'Sham‐Control' (subthreshold stimulation). All subjects were blinded and self‐administered two 30‐minute “stimulation” sessions daily. After primary endpoint assessment, subjects in the 'Sham‐Control' group crossed‐over to 'Treatment'. The primary endpoint was a comparison of responder rates at 120 days post‐randomization. A 'Responder' is a subject with ≥30% reduction from baseline in Average LBP VAS (VAS), without any increase in pain medication or muscle relaxants in the two weeks prior to primary outcome assessment. Results: At baseline (N=204), LBP duration was 14±11 years, age 47±9 years, VAS 7.3±0.7 and Oswestry Disability Index (ODI) 39±10. Most subjects (80%) were regularly using back pain medications, including opioids (37%). In the intent‐to‐treat cohort, the difference in responder rates was not significant at 120 days (56% vs. 47%). After exclusion of the 6 subjects who increased pain medication for reasons unrelated to back pain (prespecified analysis), 'Treatment' was superior to 'Sham‐Control' (61% vs. 47%). Secondary endpoints and supporting analyses also showed statistically significant differences. Matched one‐year data was available for 116 subjects. VAS improved from 7.3±0.8 to 3.0±2.5 and ODI from 38±10 to 19±14. • § 64% reported ≥50% VAS improvement • § 52% remitters (VAS≤2.5) • § 44% (22/50) eliminated (28%) or reduced (16%) opioid use • § 70% reported ≥15‐point improvement on ODI The safety profile is favorable compared to other neurostimulation modalities. Conclusion: The totality of data supports the validation of ReActiv8 as a viable therapy.

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Comparison of focal impulse and rotor modulation ablation (FIRM) only versus second-generation cyroballoon ablation in patients with paroxysmal atrial fibrillation Abstract: Background: Rotors have been postulated to be a major driver of atrial fibrillation (AF). Initial studies demonstrated, that focal impulse and rotor modulation (FIRM) might be an effective therapy for the treatment of paroxysmal AF (PAF). However, data about FIRM‐guided ablation strategies without PVI is sparse. Objective: To compare the safety and efficacy of FIRM‐guided catheter ablation (without PVI; FIRM arm) and second generation cryoballoon (CB2, CB2 arm) based PVI in patients with paroxysmal atrial fibrillation (PAF) and de‐novo catheter ablation of AF. Methods: In this retrospective single‐center study patients with PAF undergoing de‐novo ablation of PAF between February 2016 and January 2017 were enrolled. Patients treated with FIRM‐guided AF ablation as a standalone therapy without PVI were included and compared with patients undergoing CB2 based PVI. All patients in the FIRM arm were part of the randomized multicenter FIRMAP AF trial (results of this trial will be presented at this meeting). In patients undergoing FIRM‐guided ablation, 3D electroanatomical mapping of both atria was performed. Rotor mapping using FIRM technology was conducted in spontaneous or induced AF. The procedural endpoint was the elimination of all rotors and focal impulses; no PVI was performed in those patients. In the CB2 arm, CB based PVI with the procedural endpoint of isolation of all veins was performed. Procedural data and arrhythmia‐free survival after 12 months were compared. Results: FIRM‐guided and CB2 based AF ablation was performed in 22 and 86 patients, respectively. Follow up was completed in 20 and 79 patients LA diameter differed between groups. Otherwise, baseline characteristics did not differ between the FIRM group (mean age 60±11 years, 59.1% males) and the CB2 group (mean age 62±13, 62.4% male). Arrhythmia‐free survival including a 90‐day blanking period was 25.0% (15/20) in the FIRM group and 86.1% (11/79) in the CB2 PVI group (p=0.000; Figure 1). Procedure duration was significantly longer in the FIRM group (152 [120; 176] minutes) compared to the CB2 PVI group (122 [110; 145] minutes) (p=0.031), whereas radiation dose was lower in the FIRM group (1266 [1027; 2281] cGy cm2 vs. 3020 [1677; 4215] cGy cm2). Adverse events (groin complications) occurred in 1 patient (1.2%) in the CB2 PVI group and 5 patients (22.7%) in the FIRM group. Conclusion: De novo ablation of PAF using a FIRM‐guided AF ablation only (without PVI) is associated with poor arrhythmia‐free survival after 12 months compared to CB2 PVI. These results underline the importance of PVI as the first‐line approach in catheter ablation of AF.

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Forearm bone mineral density and fracture incidence in postmenopausal women with osteoporosis: results from the ACTIVE xtend phase 3 trial Abstract: Wrist fractures are the most common fracture of the upper extremity and are associated with increased subsequent fracture risk in women with postmenopausal osteoporosis. Most wrist fractures occur at the ultradistal (UD) radius. Abaloparatide (ABL) is a selective activator of the PTH1 receptor signaling pathway that stimulates bone formation. In the ACTIVE phase 3 study, 18 months of ABL significantly increased bone mineral density (BMD) at the UD radius and maintained BMD at the 1/3 distal radius vs placebo (PBO) and teriparatide (TPTD). BMD effects were associated with a trend for numerically lower wrist fracture incidence for ABL vs TPTD (P=0.052). Women receiving ABL or PBO in ACTIVE were offered enrollment in the ACTIVExtend extension study in which both groups received 24 months of open‐label alendronate (ALN) 70 mg/wk for a total of 43 months (18 months ABL or PBO, 1 month for reconsent, 24 months ALN). Our objective was to determine the efficacy of ABL followed by ALN (ABL/ALN) vs PBO/ALN on BMD at the UD radius over 43 months. Forearm BMD data (ACTIVE baseline and month 43) were measured for 213 and 233 women in ABL/ALN and PBO/ALN groups, respectively. BMD was centrally analyzed and adjusted for machine differences. DXA scanner and baseline BMD were included as covariates. Wrist fracture event rates were estimated for the ACTIVExtend ITT population (558 ABL/ALN; 581 PBO/ALN) by KM method. Over the 18 months of the ACTIVE trial, BMD of the UD radius decreased in the placebo group but increased with ABL; these increases were maintained over the ALN extension (Figure). There were 15 women with wrist fractures in the ABL/ALN group (KM estimate: 2.8%) and 20 in the PBO/ALN group (3.6%). Although the number of wrist fractures was low, these fractures were numerically lower with ABL/ALN vs PBO/ALN (HR=0.77, 95% CI [0.39, 1.50], P=NS). In conclusion, the BMD gains at the UD radius following treatment with ABL were maintained over the subsequent 24 months of treatment with ALN. Wrist fracture risk was numerically lower with ABL/ALN vs PBO/ALN. These results, together with previous ACTIVE analyses, suggest that BMD of the UD radius, which is rich in trabecular bone, may be a better predictor of wrist fracture than the 1/3 distal radius. (Figure Presented) .

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Nalbuphine pretreatment for prevention of etomidate induced myoclonus: a prospective, randomized and double-blind study Abstract: Background and Aims: Etomidate induced myoclonus (EM) is a common and hazardous sequel. Premedication with a number of opioids has been shown to effectively attenuate EM. However, there is no reported literature evaluating the effect of nalbuphine pretreatment on EM. The present study was designed to evaluate the efficacy of 0.2 mg/kg nalbuphine intravenous (IV) pretreatment for prevention of EM. Material and Methods: This prospective randomized double‐blind and placebo controlled study was conducted in a medical college associated tertiary hospital. One hundred patients undergoing elective surgeries under general anesthesia were randomly allocated to one of two groups to receive: 10 ml of normal saline (Group I) or 0.2 mg/kg nalbuphine in 10 ml of normal saline (Group II) 150 s before injection etomidate 0.3 mg/kg administered IV over 20 s. The patients were assessed for the presence and severity of etomidate induced vascular pain (EP) and EM while injecting etomidate and for the next 2 min, respectively. The patients were monitored for sedation, nausea/vomiting, headache, dizziness, and respiratory depression for 24 h postoperatively. Student's t‐test, Chi‐square test, or Fisher exact test were used wherever appropriate and P < 0.05 was considered statistically significant. Results and Conclusion: Both the groups were comparable with respect to demographic characteristics. Nalbuphine pretreatment significantly reduced the incidence (20% vs. 72%; respiratory rate = 0.294, 95% confidence interval: 0.160‐0.496, P < 0.01) and severity of EM without any significant increase in the incidence of adverse effects. Nalbuphine 0.2 mg/kg IV pretreatment significantly reduces the incidence and severity of EM with side‐effect profile comparable to saline placebo.

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Efficacy of autologous expanded bone marrow derived mesenchymal stem cells (AXBM-MSC) in the treatment of patients with Chron's disease who have failed to standard therapy: an open-label, randomized controlled clinical trial phase II Abstract: Crohn's disease is a severe and progressive auto inflammatory/autoimmune disease with major complications like fistula, ulcers and cancer. The current treatments include immune suppressors and anti TNF‐blockers produced adverse effects. We aim to evaluate the efficacy of axBM‐MSC by mesenteric artery infusion. This single‐center, randomized, open‐label, controlled clinical recruited 26 patients with resistance and not response to the current treatments including anti TNF‐blockers, treated by our multidisciplinary surgical medical team with the use of axBM‐MSC expanded and cultured in vitro during 1 month and subsequently supraselective infusion in the total colonic area by endovascular catheterism in superior and inferior mesenteric artery to accurate the arrival of the cells to the colonic tissue. The changes were statistically significant compared with the control group without intervention. After one month of the treatment several changes in the patients was documented like decrease in the number of diarrhea episodes, bloodiness, pain and CDAI score. The treated patients showed absence of ulcerations and lesions of colitis activity in the colonoscopy and the pathological study. Several important changes in the systemic cytokines patterns are fund, like upregulation of IL‐10, TGF‐B, and IL‐6 and downregulation of IFN‐gamma. The autoantibodies like ANAS and ASCAS was negative between 3 to 6 months after the therapy with complete remission after 3 months and maintained until six years then documented in the first patients treated. We conclude that autologous expanded and endovascular infused Mesenchymal Stem Cells offer a safety opportunity of immune regulation and tissue regeneration in Crohn's Disease.

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Double-blind, randomised, placebo-controlled three-way crossover clinical investigation to evaluate the beneft of IQP-VV-102 in reducing postprandial glucose level in overweight Caucasian subjects Abstract: Introduction: IQP‐VV‐102, which contains a proprietary grape extract (grape marc) and L‐arabinose, has been proven to promote weight loss in overweight and obese individuals. In this study we evaluated the effect of IQP‐VV‐102 on reducing postprandial glucose (PPG) AUC levels. Methods: 30 overweight, but otherwise healthy Caucasians (BMI 25‐ 29.9kg/m2), both male and female, aged 18 ‐ 60 years were randomly allocated to verum and placebo in a single‐dose crossover design, with 3‐day washout periods. Two doses of IQP‐VV‐102 were investigated ‐ 1290mg (V1) and 2580mg (V2) ‐ together with placebo control (P). Blood sampling for PPG, insulin and triglycerides were performed afer shortly taking each of the respective investigational products followed by the test meal ‐ marked as 0 mins ‐ and subsequently at 15, 30, 45, 60, 90, 120 and 180 mins. Results: Tere were statistically signifcant diferences for in total PPG AUC levels at 120mins, both between the V2 group and the P group (p = 0.0028), and between the V1 and P groups (p = 0.037). IQP‐VV‐102 also reduced postprandial insulin AUC levels signifcantly (p < 0.05 for = “ both=” doses=“ at=” 120=“ mins=” compared=“ to=” pla‐cebo=“ ‐0=” 05‐=”> Tere were no clinically relevant changes in safety laboratory parameters and no adverse effects. 100% of the subjects rated the tolerability of the products with good or very good. Conclusion: IQP‐VV‐102 favourably afects PPG levels and insulin response. In addition to promoting weight loss, the results here suggest that IQP‐VV‐102 may have important clinical value in reducing PPG level without augmenting insulin responses.

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Clearance of vancomycin-resistant Enterococcus concomitant with administration of a microbiota-based drug targeted at recurrent Clostridium difficile infection Abstract: Background. Vancomycin‐resistant Enterococcus (VRE) is a major healthcare‐associated pathogen and a well known complication among transplant and immunocompromised patients. We report on stool VRE clearance in a post hoc analysis of the Phase 2 PUNCH CD study assessing a microbiota‐based drug for recurrent Clostridium difficile infection (CDI). Methods. A total of 34 patients enrolled in the PUNCH CD study received 1 or 2 doses of RBX2660 (microbiota suspension). Patients were requested to voluntarily submit stool samples at baseline and at 7, 30, and 60 days and 6 months after the last administration of RBX2660. Stool samples were tested for VRE using bile esculin azide agar with 6 μg/mL vancomycin and Gram staining. Vancomycin resistance was confirmed by Etest. Results. VRE status (at least 1 test result) was available for 30 patients. All stool samples for 19 patients (63.3%, mean age 61.7 years, 68% female) tested VRE negative. Eleven patients (36.7%, mean age 75.5 years, 64% female) were VRE positive at the first test (baseline or 7‐day follow‐up). Of these patients, 72.7%, n = 8 converted to negative as of the last available follow‐up (30 or 60 days or 6 months). Of the other 3: 1 died (follow‐up data not available); 1 patient remained positive at all follow‐ups; 1 patient retested positive at 6 months with negative tests during the interim. Conclusions. Although based on a small sample size, this secondary analysis demonstrated the possibility of successfully converting a high percentage of VRE‐positive patients to negative in a recurrent CDI population with RBX2660.

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Corneal collagen crosslinking and intracorneal ring segments: simultaneous vs sequential surgery Abstract: Purpose : Intacs® (implantable intracorneal ring segments (ICRS)) and corneal collagen crosslinking (CXL) are used for the treatment of keratoconus and corneal ectasia. In previous work, using symmetric 350μm segments, we found no clinical difference between sequential and simultaneous treatment. In this prospective randomized controlled clinical trial, we compare the 6‐months clinical outcomes of eyes with one 450μm Intacs® segment placed, CXL performed simultaneously or 3 months later. Methods : 26 eyes of 18 patients (19 eyes in the simultaneous group, and 7 eyes in the sequential group) received one 450μm segment of Intacs® (Addition Technology Inc, Illinois, USA) followed by CXL. The first group had Intacs® placed followed by CXL on the same day (simultaneous group), and the second group received Intacs® followed by CXL 3 months later (sequential group). Principal outcomes included uncorrected distance visual acuity (UCDVA) and best‐corrected distance visual acuity (BCDVA), maximum and average keratometry (K), inferior‐superior (I‐S) ratio, and point of maximum fiattening, as measured by the Pentacam (Oculus Inc, Wetzlar, Germany). Results : UCDVA improved by ‐0.28 ± 0.28 LogMAR (P < 0.01) and ‐0.2 ± 0.43 LogMAR (P = 0.41) in the simultaneous and sequential group, respectively. BCDVA improved by ‐0.07 ± 0.12 LogMAR (P = 0.065) and ‐0.16 ± 0.12 LogMAR (P = 0.056) in the simultaneous and sequential group, respectively. With regards to topography, average K fiattened by ‐1.67 ± 1.07D (P < 0.01) and ‐3.72 ± 3.33D (P = 0.054), and maximum K fiattened by ‐3.01 ± 2.09D (P < 0.01) and ‐5.78 ± 4.45D (P = 0.034) in the simultaneous and sequential group, respectively. The I‐S ratio improved by ‐4.9 ± 2.24D (P < 0.01) in the simultaneous group, and by ‐6.05 ± 4.47D (P = 0.03) in the sequential group. The point of maximum fiattening fiattened by ‐8.0 ± 2.64D compared to ‐11.68 ± 5.65D. There was no statistically significant difference between the simultaneous and sequential group with regards to all of the primary outcomes (P = 0.66, P =0.18, P = 0.24, P = 0.2, P = 0.60, P = 0.18). Conclusions : Intacs®, with a single 450μm segment, followed by corneal collagen crosslinking, performed sequentially or simultaneously, appear to have similar efficacy.

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Stopping Tenofovir Disoproxil Fumarate (TDF) treatment after long term virologic suppression in HBeAg-negative CHB: week 48 interim results from an ongoing randomized, controlled trial (“FINITE CHB”) Abstract: Background and Aims: Long‐term effective NUC therapy may lead to partial restoration of HBV‐specific T cell functions. Stopping therapy in HBV‐DNA suppressed HBeAg‐negative patients may lead to initial viral rebound and hepatic flare followed by HBsAg clearance. We investigated HBsAg kinetics after controlled stopping of long‐term TDF therapy. Methods: Subjects on effective TDF therapy for at least 4 years were randomized to either stop or to continue TDF for 144 weeks (advanced fibrosis/cirrhosis excluded). Primary endpoint is HBsAg loss at W144. TDF could be restarted in case of clinically significant hepatitis B flares. Results: 45 subjects were randomized in this open‐label study at 13 sites in Germany. 21 Stop‐TDF and 21 Continue‐TDF subjects completed W48 (n = 3 withdrew consent‐ data excluded). At W48, Continue‐TDF subjects maintained viral suppression, stable ALT, none lost HBsAg. 19 of 21 Stop‐TDF subjects had early (first 12 weeks) substantial HBV DNA rebound (median 205, 380 IU/mL, [Q1 59, 995 IU/mL; Q3: 444, 147 IU/mL]) accompanied by ALT elevations (median 106 IU/mL; [Q1 76 IU/ml; Q3 233 IU/mL]). 2 subjects had minimal HBV DNA rebound (max 259 IU/mL) and normal ALT; both had HBsAg levels 1 log (n = 5, median ‐1.62 log) compared those with decline. Conclusion: Stopping TDF in chronic HBV HBeAg negative long‐term suppressed subjects with defined restarting criteria appears to be safe and led to a significantly greater early HBsAg decline as compared to continued TDF monotherapy. HBsAg loss was observed so far in two subjects (9.5%). If necessary, TDF can be effectively restarted. Lower HBsAg level at BL seems to be a predictive factor for HBsAg decline.

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Peroperative enteral nutrition with arginine-omega-3 fatty acids and ribonucleic acid and glutamin supplemented diet could improve postoperative recovery in lung cancer patients Abstract: Rationale: The purpose of this study was to evaluate the effect of peroperative immunonutrition pharmaceutics diet versus standard enteral nutrition on postoperative recovery of patients with lung cancer. Methods: A retrospective, controlled clinical study was conducted from January 2012 to March 2014 in the Department of Thoracic Surgery, Pamukkale University, School of Medicine. Patients with lung cancer undergoing elective surgery were divided into an immunonutrition group (n=32) and a control group (n=30). Patients in the immunonutrition group received oral supplementation containing arginine, omega‐3 fatty acids, RNA and glutamin for 7 days prior to surgery and for 15 days after surgery. Patients in the control group received no artificial nutrition and were allowed to consume regular food before surgery. Postoperative complications, surgical site infections, and the days of postoperative hospitalization were measured. Results: No significant differences between the 2 groups were noted for the body mass index, total protein, albumin, hemoglobin, surgical methods, operation time, or volume of intraoperative bleeding. The incidence of postoperative complications was significantly lower and the days of postoperative hospitalization were significantly decreased in the immunonutrition group (P<0.05). Conclusion: Peroperative enteral immunonutrition improves postoperative recovery in lung cancer patients.

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Social media and diabetes: can we improve glucose control in adolescents on pump therapy? One year experience Abstract: Background and aims: To evaluate results from social media (Skype and Facebook) and Carelink as tools to improve diabetes control in diabetic adolescents on Medtronic PRT (insulin pump with glucose sensor).Materials and methods: A total of 78 adolescents with type 1 diabetes, ages 14‐23, were randomized in two groups: Regular visits (Group 1)‐ 40 type 1 diabetes patients were treated using standard medical protocol with regular visits at clinic, where data was downloaded at the clinic and intervention (pump settings‐basal bolus insulin, education) were given to the patient and Internet visits (Group 2)‐ 38 type 1 diabetes patients were treated using Carelink personal program (Medtronic Diabetes), where the data was downloaded by the patient at home and interventions (same as group 1) were given via Skype (sound and video) and Facebook (written reports and chats). A1C was obtained before and every three months during the study in one year period..Results: Regular visits were 2.4±1.3 per patient/ month in group 1 and Internet visits were 2.6±1.6 per patient/month retrospectively. There was significantly improvement in both groups (group 1 and 2 retrospectively, 7.45 ±0.9% and 7.68 ±1.1% on beginning with 6.22 ±0.8 % and 6.09 ±1.0%, p< 0.05) at the end of the study. The significant improvement was performed in the first six months and continued to maintain in the following months. Internet visits were more preferable by the patients.Conclusion: This brief trial suggests that type 1 diabetes adolescents prefer to communicate with their health care providers using social networks, where new technologies can improve diabetes control same as regular clinic visits.

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Heralding cerebellar mutism: evidence for pre-surgical language impairment as primary risk factor in posterior fossa surgery Abstract: The aim of this study is to identify possible risks factors for the occurrence of cerebellar mutism syndrome (CMS) in children with posterior cranial fossa tumours. Children diagnosed with posterior fossa tumours consecutively admitted to our institution between 2006 and 2008 were the subjects of this prospective study. Besides standard neurological and radiological evaluations, all children underwent thorough neuropsychological assessments at admission and following surgery. Children under two or older than 16 years of age and those with a severe pre‐operative clinical condition precluding neuropsychological assessment were excluded. Thirty‐four children met the inclusion criteria. They were divided into two groups. Group I consisted of 23 children with normal language on admission and group II had 11 children showing pre‐operative language impairment (PLI). PLI was observed in 11 children (32.4%: group II). Post‐operatively, seven out of 34 children developed CMS (20.6%), all of them belonging to group II. In group II, indeed, the incidence of CMS was 63%. No case ofCMS was observed in group I. PLI regressed after the operation in three out of the four subjects belonging to group II who did not develop CMS. PLI remained unchanged in the last child of this group. Posterior fossa tumour resection can have different effects on children with pre‐existing language impairment (PLI). PLI can be considered a subclinical state of CMS in some children with posterior fossa tumour. However, in some children with PLI, the tumour resection may improve the linguistic abilities, as well as the other neurocognitive performances. In the present series, children with normal pre‐operative language function did not develop post‐operative mutism. Springer Science+Business Media, LLC 2010.

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The effect of antibiotic irrigation of surgical incisions in prevention of surgical site infection Abstract: Background: surgical site infection is one of the most common post operative complications alongside with sepsis, cardiovascular, pulmonary and thromboembolic complications. The development of surgical site infection is related to three factors: the degree of microbial contamination of the wound during surgery, the duration of the procedure, and host factors such as diabetes, malnutrition, obesity, immune suppression, and a number of other underlying disease states. The purpose of this study was to evaluate the effects of topical cephazolin in controlling infection of the site of surgery after non‐laparoscopic cholecystecomy. Methods: One hundred and two of patients referred to the outpatient clinic of Imam Khomeini Hospital from fall 2005 to fall 2006 non‐laparoscopic cholecystectomy enrolled in a randomized clinical trial. All patients underwent the same procedure of anesthesia and surgery and they were randomly assigned into two groups of cases with irrigation of the site of surgery with 1g of topical Cephazolin prior to the termination of the operation‐and controls. Cephazolin is a first generation cephalosporin which binds penicillin binding protein and is a potent cell wall synthesis inhibitor. The patients were followed up for six weeks for symptoms and signs of infection including discharge of the wound; and presence of pain, warmness, swelling and erythema of the wound. Results: There were no significant differences between two study groups regarding mean age, duration of operation, and sex. There was no significant difference in the incidence of infection of the site of surgery (11.8% in both groups with p=0.99) between two groups. Conclusion: Analyzing the collected data confirms that prophylactic use of topical cephazolin was unable to decrease the risk of infection of the site of surgery in patients undergoing non‐laparascopic cheolecystectomy.

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Effects of ruxolitinib cream on pruritus and sleep in atopic dermatitis: 52-week pooled results from two phase III studies Abstract: Atopic dermatitis (AD) is a highly pruritic, inflammatory skin disease. Quality of life can be significantly reduced by pruritus and sleep disturbances. Ruxolitinib cream is a topical formulation of ruxolitinib, a selective Janus kinase (JAK)1/JAK2 inhibitor. In two phase III randomized AD studies of identical design [TRuEAD1 (NCT03745638) and TRuE‐AD2 (NCT03745651)], ruxolitinib cream was well tolerated and demonstrated significant improvement vs. vehicle in itch and sleep (TRuE‐AD1) at week 8. In these studies, patients aged ≥ 12 years with AD for ≥ 2 years, an Investigator's Global Assessment score of 2 or 3, and 3‐20% affected body surface area (excluding scalp) were randomized (2: 2: 1) to twice‐daily 0 75% ruxolitinib cream, 1 5% ruxolitinib cream, or vehicle cream for an 8‐week, double‐blind, vehicle‐ controlled period (VC) (continuous treatment). Patients subsequently continued in a double‐blind, long‐term safety period (LTS) (as‐needed treatment) up to week 52. Patients initially randomized to ruxolitinib cream remained on their regimen during the LTS; patients initially on vehicle were rerandomized (1: 1) to either ruxolitinib cream strength. During the LTS, patients treated areas with active AD only, stopped treatment 3 days after lesion clearance, and restarted treatment upon recurrence. Here, the effects of ruxolitinib cream on itch and sleep during the LTS are reported using pooled results from the two studies. Itch and sleep were assessed using questions 1 and 2 of the Patient‐Oriented Eczema Measure (POEM Q1 and Q2), in which patients reported the number of days/nights of itchy skin or disturbed sleep owing to eczema in the past week, respectively. Sleep‐related impairment and sleep disturbance were also assessed using items 8a and 8b of the Patient‐Reported Outcomes Measurement Information System (PROMIS), with a recall period of 24 h for the VC and 7 days for the LTS. Of 1249 randomized patients, 1072 (85 8%) continued into the LTS; 1031 were evaluated for efficacy (0 75% ruxolitinib cream, n = 409; 1 5% ruxolitinib cream, n = 428; vehicle to 0 75% ruxolitinib cream, n = 98; vehicle to 1 5% ruxolitinib cream, n = 96). Median age was 33 0 years (range 12‐85), 61 7% of patients were female, 70 3% were white, and 22 8% were black. At week 8, the proportions of patients reporting no days of itch per POEM Q1 were 27 7%, 32 7%, 9 2%, and 9 5% for 0 75% ruxolitinib cream, 1 5% ruxolitinib cream, vehicle to 0 75% ruxolitinib cream, and vehicle to 1 5% ruxolitinib cream, respectively. During as‐needed application of ruxolitinib cream in the LTS, itch relief was maintained for patients who remained in the 0 75%/1 5% ruxolitinib cream groups (week 52: 28 0%/36 2% reported no days of itch). In the vehicle to 0 75%/1 5% ruxolitinib cream groups, more patients reported no days of itch at week 52 (36 1%/43 2%) vs. week 8. The proportions of patients reporting no nights of disturbed sleep per POEM Q2 at week 8 were 64 9%, 71 8%, 48 0%, and 41 1% for 0 75% ruxolitinib cream, 1 5% ruxolitinib cream, vehicle to 0 75% ruxolitinib cream and vehicle to 1 5% ruxolitinib cream, respectively. At week 52, patients who remained in the 0 75%/1 5% ruxolitinib cream groups maintained undisturbed sleep (74 5% for both groups). More patients who switched from vehicle to as‐needed 0 75%/1 5% ruxolitinib cream reported no nights of disturbed sleep at week 52 (73 6%/ 80 2%) vs. week 8. At baseline, PROMIS sleep‐related impairment mean scores were 17 3, 17 4, 17 0, and 16 6 for 0 75% ruxolitinib cream, 1 5% ruxolitinib cream, vehicle to 0 75% ruxolitinib cream, and vehicle to 1 5% ruxolitinib cream, respectively. Overall, scores had decreased slightly in the ruxolitinib cream groups by the beginning of the LTS, indicating less impairment (15 2, 15 2, 16 0, 16 7), and decreased slightly in all groups to week 52 (14 4, 14 4, 14 8, 13 8). PROMIS sleep disturbance mean scores at baseline were 18 9, 19 2, 18 2, and 18 9; had decreased slightly in the ruxolitinib cream groups by the beginning of the LTS (17 4, 17 4, 18 8, 19 6) and were maintained or slightly decreased in all groups to week 52 (16 8, 17 2, 17 0, 16 2). In summary, itch and sleep were improved with ruxolitinib cream, and these improvements were maintained for 44 weeks with as‐needed ruxolitinib cream use. Patients who switched from vehicle to ruxolitinib cream at week 8 had similar itch and sleep scores at week 52 to patients initially randomized to ruxolitinib cream.

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Cilostazol for Intermittent Claudication Abstract: Study design: A review of the Cochrane Vascular Specialized Register, CENTRAL, MEDLINE, Embase, CINAHL, and AMED databases, and the World Health Organization International Clinical Trials Registry Platform and trials registries on November 9, 2020. Key findings: Participants taking cilostazol had higher initial claudication distance and absolute claudication distance compared with those taking placebo, along with a possible improvement of quality of life (16 double‐blind, randomized controlled trials). There was no difference detected between cilostazol and pentoxifylline for improving initial claudication or absolute claudication distance (5 double‐blind, randomized controlled trials). The most commonly reported adverse events of cilostazol were headache, gastrointestinal symptoms, and palpitations. Conclusion: Cilostazol has been shown to improve walking distance in people with intermittent claudication, but there was no difference between cilostazol and pentoxifylline for improving walking distance. Participants taking cilostazol had higher odds of experiencing headache. Commentary: Cilostazol (Pletal) is a phosphodiesterase‐III inhibitor, which has vasodilatory, antiplatelet, and antithrombotic actions. The suggested dose of cilostazol for intermittent claudication is 100 mg taken orally twice daily. Cilostazol is contraindicated in patients with congestive heart failure and those with renal or hepatic impairment. One reason why I enjoy reviewing articles for JVS Vantage Point is that I continually learn new things. When I was a vascular surgery fellow and young attending, I could have sworn I learned that several randomized trials proved cilostazol (Pletal) not only improved claudication compared with placebo but also compared with pentoxifylline (Trental). During my career, I never prescribed Trental for claudication, and I don’t know anyone else who did either. But this review of the literature seems to suggest that Trental is as good as Pletal, but the latter is more likely to cause headaches. I wonder what percent of vascular surgeons offer Pletal to patients with claudication before offering intervention. I do. It makes me feel better knowing that I’ve exhausted all conservative treatments, along with emphasizing smoking cessation and an exercise regimen and prescribing aspirin and a statin, before performing an endovascular or surgical procedure that could cause complications.

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Is It Realistic to Stop Prednisone in Early Rheumatoid Arthritis? A Subanalysis from the BeSt and IMPROVED Studies Abstract: Background/Purpose: Glucocorticoids are widely used in the treatment of rheumatoid arthritis (RA) patients. It is internationally recommended to taper and stop glucocorticoids as rapidly as clinically feasible, but there are little data regarding this strategy. In two previous clinical trials (BeSt and IMPROVED) patients were treated with methotrexate (MTX) and a temporary course of oral prednisone (60 mg/day, tapered in 7 weeks to 7.5 mg/day). If the treatment target (TT, DAS≤2.4 in BeSt, DAS< 1.6 in IMPROVED) was achieved, prednisone was stopped, but in case of flare it was restarted. We present percentages of successful stopping and looked for potential predictors. Methods: 508 early RA patients were recruited for the BeSt study, from those 133 patients were randomized into the third arm of treatment (MTX+Sulfasalazin+Prednisone). 610 early RA or undifferentiated arthritis patients were enrolled into the IMPROVED study, all receiving MTX+Prednisone. Disease Activity Score was measured each 3 and 4 months, respectively. Stepwise tapering was slow in BeSt (prednisone tapered only after repeated treatment target achieved, earliest stop at week 35) and more rapid in IMPROVED (prednisone stop as soon as treatment target achieved, earliest at week 16), with a restart in case of flare 3 (BeSt) or 4 months (IMPROVED) after stop, respectively. Percentages still on treatment target after stopping of prednisone were compared in BeSt and IMPROVED. Univariable logistic regression was performed to identify potential predictors of successful stopping. Predictors with p< 0.2 were included in multivariable logistic regression analyses. Results: In the BeSt study, 67/133 (50%) could stop initial prednisone due to sustained low disease activity (Figure 1). After prednisone stop, 51/67 (76%) patients remained on TT, but 18 flared. In the IMPROVED study, 387/610 (63%) patients stopped prednisone because of DAS‐remission at 4 months (Figure 1). Of those, 269/387 (70%) remained on TT after stopping prednisone, while 112 flared. Baseline patient and disease characteristics between patients who did or did not flare after prednisone stop in both studies are shown in Table 1. In the BeSt study, DAS at previous visit was an independent predictor for successful secondary stopping of prednisone (p=0.005, Table 2). In the IMPROVED multivariable testing showed female gender and lower DAS at previous visit as independent predictors of successful secondary stopping prednisone (p< 0.03) Fulfilling the 2010 classification criteria for RA was not associated with the outcome after PRD stop (Table 2). Conclusion: In these treat‐to‐target studies, where initial co‐treatment with prednisone was stopped after the treatment target was (repeatedly, in BeSt) achieved, a lower DAS at the visit before stopping, was predictive of remaining on treatment target without flare. In IMPROVED, female patients also could more often successfully stop prednisone. Successful stopping of initial co‐treatment with prednisone appears to be irrespective of treatment duration and treatment target. The data suggest that in patients with early RA the duration of temporary 'bridging' treatment of prednisone should be individually timed.

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The effect of standard versus longer intestinal bypass on GLP-1 regulation and glucose metabolism in patients with type 2 diabetes undergoing Roux-en-Y gastric bypass Abstract: BACKGROUND: Roux‐en‐Y gastric bypass (RYGB) characteristically enhances post‐prandial levels of glucagon‐like peptide (GLP)‐1, a mechanism that is believed to contribute to its glucose‐lowering effects. This enhancement is thought to be triggered by bypass of food to distal parts of the small intestine with higher densities of Lcells. Consistent with this hypothesis, modifications of RYGB with increased length of intestinal bypass have been proposed to further enhance GLP‐1 response and improve control of type 2 diabetes mellitus (T2DM). METHODS: In this mechanistic study, we compared a 'standard limb' RYGB (50‐cm biliopancreatic limb length) vs. 'long limb' RYGB (150‐cm biliopancreatic limb length) in patients with T2DM and obesity. Fifty‐three participants were randomised at 1:1 ratio to these interventions in a double‐blinded manner. They underwent meal tolerance tests to measure glucose excursions and insulin secretion, and hyperinsulinaemic euglycaemic clamps with stable isotopes to measure insulin sensitivity pre‐operatively, at 2 weeks after the surgery and at matched 20% total body weight loss. RESULTS: Forty‐eight participants completed the trial. There were statistically significant decreases in fasting and post‐prandial glucose concentrations, increase in insulin and GLP‐1 secretion, insulin sensitivity and reduction in HbA1c and weight within groups. However, there were no significant differences between groups in any of these parameters. CONCLUSION: These findings challenge mainstream hypotheses of GLP‐1 regulation after RYGB in humans and instead suggest that gastric and proximal intestinal mechanisms triggered by their anatomic configuration might be responsible for the postprandial enhancement of GLP‐1.

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Associations Between Parental Beliefs About Adolescence, Parent-Teen Communication, And Psychological Well-Being Abstract: Purpose: Prior research suggests that parental perceptions of adolescence as a period of ‘storm and stress’ are associated with more parent‐teen conflict, less involved parenting, and more problem behaviors in youth. In the present study, we examined whether parental beliefs about adolescence were associated with parents’ and adolescents’ psychological well‐being. Additionally, we hypothesized that parent‐teen communication (PTC) would mediate the association between parental beliefs about adolescence and psychological well‐being. Methods: We used baseline data from a randomized controlled trial on strength‐based parenting (registered clinical trial #NCT03496155). The participants were 61 parent‐teen dyads (adolescents aged 13 to 15 years) who were scheduled to attend the adolescent’s well child visit in a diverse, urban pediatric primary care practice. Parents completed the Beliefs about Adolescents scale to measure beliefs related to whether “typical” adolescents are risk takers, moody, friendly, or prosocial. Parents and teens separately completed the Parent‐Adolescent Communication Scale (measuring general PTC) and the Flourishing Scale (measuring psychological well‐being). All analyses were performed in SPSS and controlled for youth age, sex, and race. PROCESS Macro was used to test independent associations between variables and to test PTC as a mediator; the Sobel test was used to confirm statistical significance of any mediating effects. Results: Nearly half (47%) of the youth were male; 67% were Black/African American, 19% were Caucasian, and 12% were multiracial. The extent to which parents perceived adolescents to be risk takers or moody was not associated with parent or adolescent psychological well‐being. However, parents’ perceptions of adolescents as friendly and prosocial were associated with higher psychological well‐being in both parents (β for friendly= 0.08, p<0.01; β for prosocial= 0.13, p<0.001) and adolescents (β for friendly= 0.11, p< 0.05; β for prosocial= 0.11, p<0.05). Parents’ perceptions of adolescents as friendly and prosocial were also associated with better PTC (according to parent report only; β for friendly=0.17, p<0.05 and β for prosocial=0.24, p<0.01). Parents’ report of better PTC was, in turn, associated with better psychological well‐being in parents (β=0.23, p<0.001) and adolescents (β=0.18, p<0.05). Further analyses indicated that parent report of PTC was a significant mediator of the association between parents’ perceptions of adolescents as friendly and prosocial and parent well‐being (Sobel test for friendly= 2.10, p<0.05; Sobel test for prosocial= 2.30, p<0.05). Parent report of PTC did not mediate the relationship between parental beliefs about adolescents and adolescent well‐being. Conclusions: Positive parental beliefs about adolescence (i.e., believing that typical teens are friendly and prosocial) were associated with better psychological well‐being in both parents and adolescents. For parent psychological well‐being, these associations appeared to be mediated by parents’ perceptions of better PTC. Efforts to help parents think more positively about adolescents may have a beneficial impact on the parent‐teen relationship and psychological well‐being for parents and adolescents. Future prospective research is needed to examine longitudinal relationships between parental beliefs, PTC, and psychological well‐being among both parents and adolescents and to inform intervention development. Sources of Support: John Templeton Foundation; Maternal & Child Health Bureau

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Extending the verifiability approach framework: the effect of initial questioning Abstract: The verifiability approach (VA) is a lie‐detection tool that examines reported checkable details. Across two studies, we attempt to exploit liar's preferred strategy of repeating information by examining the effect of questioning adult interviewees before the VA. In Study 1, truth tellers (n = 34) and liars (n = 33) were randomly assigned to either an initial open or closed questioning condition. After initial questioning, participants were interviewed using the VA. In Study 2, truth tellers (n = 48) and liars (n = 48) were interviewed twice, with half of each veracity group randomly assigned to either the Information Protocol (an instruction describing the importance of reporting verifiable details) or control condition. Only truth tellers revised their initial statement to include verifiable detail. This pattern was most pronounced when initial questioning was open (Study 1) and when the information protocol was employed (Study 2). Thus, liar's preferred strategy of maintaining consistency between statements appears exploitable using the VA.

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A dual intervention in geriatric patients to prevent drug-related problems and improve discharge management Abstract: Background Drug‐related problems (DRPs) endanger geriatric patients' safety. Especially a follow‐up treatment with increased number of care transitions is a critical time for patients. Objective This study aimed at optimising medication therapy and the transfer of medication‐related information to ambulatory care in geriatric rehabilitation patients. Setting German geriatric rehabilitation centre (GRC). Method A prospective, controlled intervention study was performed. Patients in the control group (CG) received standard care, those in the intervention group (IG) an additional dual pharmaceutical intervention: (i) medication review to optimise in‐hospital medication and (ii) improvement of discharge letters for optimising transfer of medication‐related information. Main outcome measure (i) Number of patients with at least one DRP at discharge and (ii) predefined quality criteria for the discharge letters. Results 150 patients were enrolled in CG and 163 in IG. (i) At discharge, 126 (84%) patients in the CG were affected by at least one DRP. In the IG, the number of affected patients decreased to 64 (39%, P < 0.05). (ii) In comparison to discharge letters in the CG, predefined quality criteria were improved in the IG. Following differences were measured (CG vs. IG, each P < 0.05): active ingredient indicated (60 vs. 99%), brand name indicated (60 vs. 96%), explanation of medication changes (47 vs. 68%), visualisation of explanations next to the discharge medication (26 vs. 91%) and recommended therapy duration for short‐term medications (49 vs. 84%). Conclusion DRPs and incomplete discharge letters affected many patients. The dual intervention improved in‐hospital medication therapy and optimised the transfer of medication‐related information.Copyright © 2018, Springer International Publishing AG, part of Springer Nature.

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Longitudinal intrinsic functional connectivity changes in preclinical Alzheimer's disease: a two-year follow up study Abstract: Background: Although previous cross sectional studies demonstrated intrinsic functional connectivity (FC) changes in the preclinical Alzheimer's disease (AD), effects of amyloid burden in FC changes are still not yet clear on the longitudinal basis Methods: Sixty four florbetaben (FBB) amyloid PET defined NIA‐AA preclinical AD subjects (stage 1 (N= 31) and stage2/3 (N=33)) and 32 healthy control subjects (stage 0) completed resting state functional magnetic resonance imaging (fMRI) scans. FC changes were examined for three networks of interest (default mode network (DMN), salience network (SN), and central executive network (CEN)) using independent component analysis during a 2‐year follow‐up. We also analyzed the group by amyloid retention with FC changes in the three networks. Results: Longitudinal analysis showed that the DMN of the stage 1 subjects showed significantly increased FC compared to the stage 0 and 2/3 subjects. On the other hand, stage 2/3 subjects showed decreased FC compared to stage 0 and 1 subjects. The FC of the CEN showed significantly decreased in the stage 1 and increased in stage 2/3 during the follow up periods. There were no longitudinal FC changes in SN in all subjects. In addition, there were significant group x FBB amyloid retention level interaction with FC changes in the posterior DMN. Conclusions:Our results of aberrant DMN FC changes and distinctive interaction patterns might reflect a biphasic trajectory of changes in FC in preclinical AD subjects. These changes might have clinical implications as surrogate markers of efficacy in clinical trials of the disease modifying agents.

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Allergic rhinitis Abstract: Allergic rhinitis is one of the most common chronic diseases in childhood. The International Study of Asthma and Allergies in Childhood reported an average prevalence rhinitis of 8.5% among 6‐7‐year‐old children, and 14.6% for 13‐14 year‐old children1. The burden of allergic rhinitis to individual patients and the society is often underestimated, and there is a general lack of data on the risk factors and phenotypes of rhinitis in childhood and adolescence2. Diagnosis of Allergic Rhinitis The diagnosis of allergic rhinitis is based upon clinical history, including type, duration and frequency of symptoms and exacerbating factors2. Most children and teenagers with rhinitis experience upper respiratory symptoms including nasal blockage, itching, watery rhinorrhea and sneezing, but some may present atypically with cough or snoring. It is worth noting that despite often troublesome symptoms, rhinitis is often ignored, and only a minority of symptomatic children have appropriate diagnosis and management plans3. Examination of nose is essential in the diagnosis of rhinitis, and should always been carried out2. Atopic sensitization can be ascertained using skin prick tests or measurement of allergen‐specific serum IgE. However, both these tests can be positive in the absence of any symptoms, and positive skin test or IgE does not confirm the expression of rhinitis symptoms upon allergen exposure. In allergen‐driven rhinitis, symptoms have to be seen in association with allergen exposure2. The data which demonstrated that quantification of atopic sensitization by using the titer of sIgE antibodies or the size of skin prick test wheals increases the specificity of these tests in relation to the presence and severity of rhinitis4 have in recent years changed the way we interpret the results of IgE and skin tests, with a move from dichotomization (positive/negative test) to quantification (IgE titer and skin test wheal size)2. Measuring sensitization to allergen components (component‐resolved diagnostics) may more be informative than standard tests using whole allergen extracts. However, the potential value of component resolved diagnosis in the diagnosis of rhinitis needs to be established before it can be considered for the routine use in clinical practice2. Other investigations may be required to evaluate other possible diagnoses (e.g. measurement of nasal mucociliary clearance, nasal nitric oxide, nasal endoscopy, acoustic rhinometry etc.). Management Management strategy for allergic rhinitis should include avoidance of relevant allergens when possible2. Oral and intranasal antihistamines and intranasal corticosteroids are the first‐line treatment of allergic rhinitis, with intranasal corticosteroids having the greatest efficacy. Add‐on treatments may include oral leukotriene receptor antagonist and intranasal cromoglycate2. In patients with allergic rhinitis over the age of five years who are inadequately controlled using standard pharmacological treatment, allergen‐specific immunotherapy can be helpful and should be considered. Allergic Rhinitis and Asthma Presence and Severity Amongst school‐age children, allergic rhinitis frequently co‐exists with asthma3, and it often precedes asthma development5. There is a mounting body of evidence that patients with both asthma and rhinitis have more severe lower respiratory symptoms compared to those with asthma alone. For example, amongst adult patients with asthma, those with comorbid rhino‐sinusitis have considerably poorer quality of life, and chronic rhinitis is an important co‐morbidity of severe asthma6. Similarly, in children with asthma, allergic rhinitis has an adverse impact on asthma control7; in addition, children and adolescents with moderate/severe asthma who are treated with inhaled corticosteroids and have concurrent allergic have increased use of emergency care services compared to patients without rhinitis8. Among children with asthmarecruited from the hospital asthma clinic, the presence of allergic rhinitis has been shown to have a significant adverse effect on asthma control, evenwhen asthma was considered adequately controlled7. In a population‐based study, we have demonstrated that amongst children with asthma, the presence of rhinitis has significant adverse effect on asthma severity9. Among asthmatic children, those with rhinitis had more frequent wheeze attacks (2.4‐fold increase in risk), more severe attacks of wheezing associated with speech limitations (3.4‐fold increase in risk), more frequent visits to the family doctor (9.5‐fold increase in risk) and greater school absenteeism because of asthma (9‐fold increase in risk)9. Can Treatment of Allergic Rhinitis Improve Asthma Control? In a study from the Netherlands, treatment of allergic rhinitis with intranasal corticosteroid reduced the adverse effect of rhinitis on asthma severity and control7. Similarly, in our study described above, adjusting for the use of antihistamines did not change the association between rhinitis and asthma severity, but adjusting for the use of intranasal corticosteroid resulted in a small, but consistent reduction in risk9. These observations are consistent with findings in a retrospective cohort of older children and adults, which showed that among patients with both asthma and rhinitis, those who were treated for allergic rhinitis were significantly less likely to visit emergency departments or be hospitalized than those who were not treated10. The results of the above studies suggest (but do not prove) that amongst children with both asthma and rhinitis, appropriate treatment of rhinitis with intranasal corticosteroids may improve asthma control. The definitive answer can only be obtained in appropriately designed randomized controlled trials; however, there are as yet no such longterm trials in children. It is however of note that a 4‐week study among children with mild/moderate asthma and intermittent allergic rhinitis has shown that intranasal corticosteroid may improve exerciseinduced bronchospasm11. In contrast, a double‐blind randomized cross‐over trial amongst adults with asthma and persistent allergic rhinitis did not demonstrate any steroid sparing effect of adding intranasal corticosteroid to low dose inhaled corticosteroids on lower airway outcomes12. Recent meta‐analysis of 18 studies assessing the effect of intranasal corticosteroid on asthma outcomes in patients with allergic and comorbid asthma concluded that intranasal corticosteroid may improve some lower airway outcomes, but that further studies are needed to confirm the role of intranasal corticosteroid sprays as therapy for asthma outcomes13. In conclusion, allergic rhinitis is common, and is an important comorbidity of childhood asthma. All children with asthma should be assessed for the presence of rhinitis, and appropriately treated to alleviate both upper and lower respiratory symptoms.

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Randomised controlled trial of avocado-soybean unsapomfiable (piascledine) effect on structure modification in hip osteoarthritis: the eradias study Abstract: Objective: To assess the ability of avocado‐soybean unsaponifiable‐ Expanscience (ASU‐E) to slow radiographic progression in symptomatic hip osteoarthritis (OA). Methods: Prospective, randomised, double blind, parallel group, placebo controlled 3 year trial. Patients with symptomatic (painful 1 year, Lequesne Index between 3 and 10) hip OA (American College of Rheumatology criteria) and a minimum joint space width (JSW) of the target hip between 1 and 4 mm on a pelvic radiograph were randomly assigned to 300 mg/day ASU‐E or placebo. Standing pelvis, target hip anteroposterior (AP) and oblique views were taken annually. The primary outcome was JSW change at year 3, measured at the narrowest point on pelvic or target hip AP view (manual measure using a 0.1 mm graduated magnifying glass). The full analysis dataset (FAS) included all patients having at least two successive radiographs. An analysis of covariance Mixed Model for Repeated Measurements with Missing at Random (for missing data) was performed to compare adjusted 3 year JSW changes (primary outcome) and the percentages of 'progressors∗ (JSW losse 0.5 mm) between groups. Results: 399 patients were randomised (345 kept in the FAS), aged 62 (35 ‐ 84) years, 54 % women, mean body mass index 27 (SD 4) kg/m2, mean symptom duration 4 (SD 5) years, 0‐100 normalised Lequesne Index 30 (SD 9) and global pain visual analogue scale 37 (SD 23) mm. Mean baseline JSW was 2.8 (0.9) mm. There was no significant difference on mean JSW loss (‐0.638 mm vs ‐0.672 mm, p = 0.72, in the ASU‐E and placebo groups, respectively) but there were 20 % less progressors in the ASU‐E than in the placebo group (40 % vs 50 %, respectively, p = 0.040). No difference was observed on clinical outco‐mes. Safety was excellent Conclusions: 3 year treatment with ASU‐E reduces the percentage of JSW progressors, indicating a potential structure modifying effect in hip OA to be confirmed, and the clinical relevance requires further assessment. Trial registration number on ClinicalTrial.gov NCT01062737.

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PCN7 Analysis of Individual-Level Association of Progression-Free Survival (PFS) and Time to Treatment Failure (TTF) with Overall Survival (OS) for Previously Untreated Advanced Renal Cell Carcinoma Patients in the CheckMate 214 Trial Abstract: Objectives: To determine the association between overall survival (OS) and two other endpoints, progression‐free survival (PFS) and time to treatment failure (TTF), for patients with previously untreated advanced renal cell carcinoma. We used individual patient data from the intent‐to‐treat population (n=1096) in the CheckMate 214 study. Methods: Exploratory landmark analyses assessed whether early progression status and earlier switch to next line of therapy by clinically meaningful timepoints predict subsequent survival. In parallel, correlation analyses using copula (Clayton, Plackett, and Hougaard) functions and Poisson modeling explored individual‐level associations using the 42‐month follow‐up data, where the strength of association was measured by Kendall’s τ. For both landmark and correlation analyses, experiments examined the sensitivity of the results using data from the intermediate/poor‐risk patients only and 30‐month follow‐up. Results: In landmark analyses, patients who progressed by 3, 6, and 12 months were at higher risk of death versus those who did not progress by corresponding landmark timepoints, with hazard ratios (HR) adjusted for age, gender, Karnofsky performance status, and IMDC risk score being 3.18 (95% CI: 2.57‐3.93), 3.70 (95% CI: 3.01‐4.53), and 3.71 (95% CI: 2.88‐4.78), respectively. Similarly, with respect to TTF status by 3, 6, and 12 months, HRs were 3.39 (95% CI: 2.55‐4.51), 2.93 (95% CI: 2.39‐3.60), and 3.12 (95% CI: 2.52‐3.87), respectively. TTF yielded slightly higher Kendall’s than PFS (0.50 vs 0.48) in nearly all copula and Poisson models. These findings were similar for the intent‐to‐treat population at the 30‐month follow‐up and for the intermediate/poor‐risk patients. Conclusions: Patients in the CheckMate 214 trial who progressed or changed medication early on were at substantially higher risk of death than those who had not. Both intermediate endpoints showed moderate correlation to OS. Future research can analyze the association between the two pairs of endpoints with alternative measures and/or longer‐term follow‐up data.

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Early versus late sustained low efficiency dialysis in critically ill cirrhotics with septic shock and acute kidney injury-interim analysis of an open label randomized controlled trial-NCT02937961 Abstract: Background: Renal dialysis is a key to management of acute kidney injury (AKI) in the intensive care unit (ICU). Critically ill cirrhotics (CIC) pose a management challenge due to severe and progressive metabolic derangements and the ideal timing of initiation of dialysis in the absence of life‐threatening complications in CIC is not known. We compared the safety and efficacy of early (EG) versus late group (LG) SLED in CIC presenting with septic shock and AKI. Methods: CIC with septic shock and AKI after initial fluid resuscitation were randomized to EG {SLED initiated within 6‐12 hours of presentation} or LG {SLED initiated once the patient met absolute criteria; i.e. refractory hyperkalemia,metabolic acidosis, fluid overload, uremia or anuria >24 hours} and clinical outcomes and adverse events compared. Results: Thirty‐three CIC(aged 47±9.6 yr, 88% males, 87% alcohol‐related) were randomized. Pneumonia (58%) and spontaneous bacterial peritonitis (18%) were common. Baseline demographic and renal parameters were comparable including lactate(mg/dl)[3.1±2.1 vs 3.6±2.3], MELD[ 33.2±6.7 vs 33.6±7.6] and SOFA scores[12.1±1.2 vs 13.1±4.4]. Median time to dialysis (hours)was 7(IQR 6‐8) in EG and 24(22‐48) in LG (p<0.001). Patients in the EG at 24 hours had higher serum bicarbonate [22.9±3.4 vs.18±3.6,p=0.002 ], lower potassium [4.3±0.66 vs. 3.8±0.36,p=0.019 ], CVP (10.7±0.7 vs.12±2, p=0.04] and phosphate levels [3.45±0.64 vs.4.08±1.24] than LG respectively. Mortality at 28‐days [53% vs. 44%; p=0.6] was similar, however, fewer deaths occurred in EG due to renal failure[0% vs. 36%;p=0.08]. A lower(p<0.05)incidence of intradialytic hypotension (IDH) [7%vs50%], higher urea reduction ratio[78% vs.18%;],lactate clearance [P=0.04], improvement in SOFA scores(by 2 points) at 48 hours[57% vs. 8%] and reversal of shock [59% vs.18%] was noted in the EG than LG. A greater frequency of recovery of renal functions [57% vs. 7%; p=0.006] was noted in EG which also translated into improved 28‐day survival [0.03, HR 0.31, 0.10‐0.93] after adjusting for the baseline SOFA score. Conclusion: Critically ill cirrhotics with septic shock and severe AKI have a high short‐term mortality. Dialysis within 12 hours can avert serious metabolic complications, decrease incidence of IDH and deaths due to renal failure. A higher frequency of recovery of renal functions and reduced AKI related mortality could be achieved by early initiation of SLED in CICs.

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Sildenafil reduces pulmonary vascular resistance in single ventricular physiology Abstract: Background High pulmonary vascular resistance (PVR) may be a risk factor for early and late mortality in both Glen shunt and Fontan operation patients. Furthermore, PVR may increase long after the Fontan operation. Whether pulmonary vasodilators such as phosphodiesterase 5 inhibitors can decrease PVR in patients with single ventricular physiology remains undetermined. Methods and results This was a prospective, multicenter study. Patients with single ventricular physiology who have a PVR index higher than 2.5 Wood units.m2 (WU) were enrolled. Cardiac catheterization was performed before and after administration of sildenafil in all patients. After the Fontan operation, a six minute walk test (6 MWT) was also performed. A total of 42 patients were enrolled. PVR was significantly decreased in each stage of single ventricular physiology after sildenafil administration: from 4.3 +/‐ 1.5 WU to 2.1 +/‐ 0.6 WU (p < 0.01) in patients before a Glenn shunt, from 3.2 +/‐ 0.5 WU to 1.6 +/‐ 0.6 WU (p < 0.001) in patients after a Glenn shunt, and from 3.9 +/‐ 1.7 WU to 2.3 +/‐ 0.8 WU (p < 0.001) in patients after Fontan. In patients after Fontan, the 6 MWT increased from 416 +/‐ 74 m to 485 +/‐ 72 m (p < 0.01), and NYHA functional class improved significantly (p < 0.05) after sildenafil administration. No major side effects were observed in any patients. Conclusions Sildenafil reduced PVR in patients with single ventricle physiology. Sildenafil increased exercise capacity and improved NYHA functional class in patients after a Fontan operation. This implies that pulmonary vasodilation is a potential therapeutic target in selected patients with elevated PVR with single ventricle physiology. Long‐term clinical significance warrants further study.

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Effect of low dose rocuronium in preventing ventilation leak for flexible laryngeal mask airway during radical mastectomy Abstract: The flexible laryngeal mask airway (FLMA) is becoming more and more popular in general anesthesia during surgery of head, neck and upper chest. But very limited information has been published about whether muscle relaxant was necessary or not for anesthesia with FLMA. To investigate whether low‐dose muscle relaxant is necessary in preventing ventilation leak of FLMA in radical mastectomy, forty‐eight female patients undergoing radical mastectomy were enrolled in the study. They were randomly divided into low‐dose muscle relaxant (LD‐MR) group and non‐muscle relaxant (non‐MR) group. All the included patients received total intravenous anesthesia (with propofol, fentanyl and remifentanil) and controlled mechanical ventilation with FLMA during the surgery. Patients in LD‐MR group received 0.4 mg/kg rocuronium during anesthesia induction, while patients in non‐MR group received equivalent volumes of physiological saline. Insertion time was shorter in LD‐MR group than that in non‐MR group (P < 0.05). Peak airway pressures and ventilation leak volumes at 10, 20 and 30 minutes were lower in LD‐MR group than those in non‐MR group (P < 0.05). No difference was found between LD‐MR and non‐MR group in terms of emergence time, FLMA extraction time, and maximum tidal volumes before FLMA extraction. The results show that low‐dose rocuronium could reduce the ventilation leak for mechanical ventilation with FLMA during radical mastectomy without prolonging the emergence time.

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Vascular response to lipid-lowering therapy in diabetes versus non-diabetes patients: serial optical coherence tomography and intravascular ultrasound study Abstract: Background: Diabetes (DM) is a risk factor for recurrent ischemic events in patients with coronary artery disease. However, the difference in vascular response to statin therapy between patients with and without DM is largely unknown. Methods: From a randomized trial (NCT01023607), we identified 97 lipid‐rich plaques from 69 patients who were randomized to receive atorvastatin 60mg, rosuvastatin 10mg or atorvastatin 20mg. Serial OCT and IVUS imaging were performed at baseline, 6‐month, and 12‐month. We compared the fibrous cap thickness (FCT) and mean lipid arc by OCT, and the percent atheroma volume (PAV) by IVUS between patients with and without DM. Results: The baseline characteristics were comparable between patients with DM (n=34) and without DM (n=35) other than the prevalence of smoker (32.4% vs. 62.9%, P=0.01). The baseline FCT (61.4 ± 16.2 vs. 60.8 ± 20.7, μm, P=0.87), mean lipid arc (177.2 ± 47.0° vs. 172.5 ± 56.1°, P=0.66) and PAV (56.6 ± 9.46 vs. 53.9 ± 9.17, P=0.16) were also similar between the two groups. At 12‐month, PAV was significantly greater in DM than in non‐DM (57.1 ± 8.63 vs. 52.6 ± 9.29, P=0.02), while the FCT and lipid arc remain similar between the two groups (Figure). Conclusion: In DM patients with coronary artery disease, PAV became greater compared to non‐DM patients despite of the 12‐month statin therapy. This result may partly explain the worse outcome in DM patients despite statin therapy. (Figure presented) .

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Topical tranexamic acid as a promising treatment for melasma Abstract: Background: In recent times, tranexamic acid (TA) is claimed to have whitening effects especially for ultraviolet‐induced hyperpigmentation including melasma. The aim of our study was to evaluate the efficacy and safety of topical solution of TA and compare it with combined solution of hydroquinone and dexamethasone as the gold standard treatment of melasma in Iranian women. Materials and Methods: This was a double‐blind split‐face trial of 12 weeks which was conducted in Isfahan, Iran. Fifty Iranian melasma patients applied topical solution of 3% TA on one side of the face, and topical solution of 3% hydroquinone + 0.01% dexamethasone on the other side two times a day. The Melasma Area and Severity Index (MASI) and the side effects were evaluated at baseline and every 4 weeks before and after photographs to be compared by a dermatologist were taken. The patient satisfaction was documented at week 12. Results: A repeated measurement analysis was used to evaluate the changes in the MASI score before and after treatments. A significant decreasing trend was observed in the MASI score of both groups with no significant difference between them during the study (P < 0.05). No differences were seen in patients’ and investigator’s satisfaction of melasma improvement between two groups (P < 0.05). However, the side effects of hydroquinone + dexamethasone were significantly prominent compared with TA (P = 0.01). Conclusion: This study’s results introduce the topical TA as an effective and safe medication for the treatment of melasma.

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Comparison with two types of training in dependent's elderly person Abstract: This study compared two types of training in 22 senior subjects of an EHPAD service. Subjects were randomized to either one of two groups, the "strength" or the "aerobic" group. Sixteen subjects participated to all sessions and were included in the statistical analysis. The "strength" group underwent analytical musculature exercises in room and the "aerobic" group underwent continuous and intermittent walking sessions in a lane. The duration of specific training was 5 weeks. Each population was evaluated pre‐ and post‐training using two tests: the "30s‐chair‐stand test", evaluated inferior limbs power, and maximal speed evaluation after 8 minutes intermittent walk. Results indicate a statistically significant improvement in the two parameters evaluated after training, without any effect of the type of training. Level of evidence Level II. © 2013 Elsevier Masson SAS.

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Efficacy and safety of balugrastim compared with pegfilgrastim in patients with breast cancer who are receiving chemotherapy Abstract: Background: Recombinant granulocyte colony‐stimulating factors (G‐CSFs) stimulate the proliferation and differentiation of neutrophils. Balugrastim is a long‐acting G‐CSF composed of a genetic fusion between recombinant human serum albumin and G‐CSF. The objective of this study was to compare the efficacy and safety of balugrastim and pegfilgrastim in patients with histologically or cytologically confirmed breast cancer who were scheduled to receive doxorubicin and docetaxel. Methods: In this double‐blind, randomized, active‐comparator, noninferiority trial, patients with ≥1.5×109 neutrophils per liter, and ≥100×109 platelets per liter were randomly assigned to subcutaneous injections of balugrastim 40 mg (n=153) or pegfilgrastim 6 mg (n= 151). The primary efficacy end point was the duration of severe neutropenia during cycle 1 for the population of patients who did not have major protocol violations. Results: The mean duration of severe neutropenia in cycle 1 was 1.1 days in the balugrastim group and 1.0 days in the pegfilgrastim group (95% CI for difference between groups, ‐0.13 to 0.37). Fiftyeight percent of patients in the balugrastim group and 59 % in the pegfilgrastim group had severe neutropenia during cycle 1 (95% CI for difference between groups, ‐11.98 to 10.41 %). Twenty percent of patients in the balugrastim group and 19 % in the pegfilgrastim group had adverse events that the investigator considered to be related to study medication. Six and seven patients, respectively, had serious adverse events. Conclusions: The results of this study support the non‐inferiority of balugrastim versus pegfilgrastim, demonstrating that both compounds have comparable efficacy. There were no unexpected safety events.

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Cognitive, neuroendocrine, and symptom change in PTSD treatment of OEF/OIF veterans Abstract: Background: While effective psychotherapies for the treatment of PTSD exist (Foa et al, 2008), the biological and cognitive mechanisms involved in effective treatment have received little empirical attention. The current study provides an examination of changes in cortisol and changes in trauma related cognitions in relation to PTSD symptoms during PTSD treatment. Methods: Veterans and active duty Service Members (N=36) were randomly assigned to receive 10‐12 weekly sessions of either Prolonged Exposure Therapy (PE) or Present Centered Therapy (PCT). Twenty two patients completed treatment and 14 dropped out or were withdrawn. Pre, mid, and post treatment data on these returnees will be presented. Several different challenge tasks, targeting the fear response system, have been included to examine processes involved in treatment change. The current analyses will examine cortisol response to awakening and cognitive changes over treatment. Results: Returnee average age was 32 (SD=7.6). Fifty‐five percent were married. Most served in Iraq (86%), but a significant minority serve in Afghanistan (22%; some served in both). Returnees report moderately severe PTSD at pre treatment on the Clinician Administered PTSD Scale (M=78.6, SD=11.7). Preliminary results were examined on the first 15 completers. To examine whether changes in cortisol response to awakening were related to treatment response or treatment condition, two repeated measures ANOVAs were conducted. PE but not PCT leads to a normalization of cortisol awakening response among those veterans receiving PE such that the PE group has a higher AUC than the PCT group, F (1,14)=11.1, p=005. Further, responders demonstrated a normalization of cortisol response to awakening such that at post treatment the difference in cortisol response to awakening approaches significance, t (14)=‐1.88, p=.08. In order to examine the relationships between change in each of these factors, standardized residual gain scores were calculated for each variable (cognition, cortisol RTA, PTSD severity score) and correlational analyses conducted. Changes in negative thoughts about the self, the world, and self blame correlated highly with reductions in PTSD severity [Self, r (28)=.70, p o.0001; World, r (28)=.38, p=.04; self‐blame, r (28)=.52, p=.005]. The poster will include mediational analyses (Baron & Kenny, 1986) examining the potential mediation of the relationship between cognitive change and PTSD change by change in cortisol response to awakening. All data is collected and final cortisol assays are being conducted. Poster will present final cortisol data. Discussion: Change in trauma related cognitions are related to change in PTSD symptoms accounting for about half of the variance in reduction of PTSD with treatment. Changes in cortisol response to awakening are related to response to PTSD treatment with a normalization of cortisol response to awakening occurring over the course of effective PTSD treatment. Implications of these findings for the identification of potential treatment mechanisms will be discussed.

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COMPUTER VISION MEASUREMENT OF DISEASE SEVERITY DISTRIBUTION OUTPERFORMS TRADITIONAL ENDOSCOPIC SCORING FOR DETECTING THERAPEUTIC RESPONSE IN A CLINICAL TRIAL OF USTEKINUMAB FOR ULCERATIVE COLITIS Abstract: BACKGROUND: Endoscopic scoring is a cornerstone of disease assessment in ulcerative colitis (UC). Novel computer vision methods may provide a more sensitive measure of endoscopic activity, potentially improving therapeutic efficacy assessment compared to conventional scoring. METHODS: Endoscopic video from subjects completing through week 44 of the phase‐three randomized placebo (PBO) controlled trial of ustekinumab (UST) for UC (UNIFI) underwent novel computer vision analysis. Pre‐trained neural networks were used to detect UC severity, ulceration, and erythema at the frame‐level. A fully automated anatomic positional neural network provided colon location data within videos and was fused with disease severity data to generate novel UC disease distribution scores (Figure 1). Disease distribution scores were compared to conventional Mayo endoscopic scoring (MES) for detecting therapeutic effect at study completion and the change between pre‐ and posttreatment. Endoscopic activity measurement differences between treatments were assessed using the Student's t‐test, with therapeutic effect measured using Cohen's d values. Projected sample size estimates based on endoscopic effect detected assumed a power of 0.8 and alpha of 0.05. RESULTS: 362 subjects from UNIFI met selection criteria, including 276 standarddose UST and 86 PBO users. At study completion mean MES scores were significantly lower for UST (1.36, SD 1.07) compared to PBO (1.72, SD 1.19, p=0.014). Mean novel disease severity distribution scores at week 44 were also significantly lower for UST (493, SD 344) compared to PBO (651, SD 440, p=0.003). The detected endoscopic healing effect size was greater using disease severity distribution scores (d=0.40) compared to conventional MES scoring (d=0.31). Examining the change in endoscopic activity between week 0 and 44, mean MES change was significantly greater for UST (1.34, SD 1.06) vs. PBO (0.97, SD 1.11, p=0.007). Alternatively, disease distribution scoring again captured an improved separation of therapeutic change for UST (455, SD 451) vs. PBO (252, SD 474, p=0.0006). Disease distribution measures better detected the change in endoscopic activity between UST and PBO, with an effect of d=0.44 compared to the effect assessed with traditional MES of d= 0.34. Using novel endoscopic disease distribution measures, the projected sample size estimated to detect a therapeutic difference between UST compared to PBO was reduced 39.4% from 274 to 166 subjects. CONCLUSIONS: Computer vision enabled endoscopic disease distribution measures better detects the significant therapeutic effect of UST over PBO in UC compared to traditional endoscopic scoring instruments. Objective computeraided activity measures may improve efficiency in clinical trials and therapeutic disease monitoring in the care of UC. (Figure Presented) Figure 1. Disease Severity Distribution Scoring for UC Using Novel Computer Vision Methods. Shown is an example of the endoscopic disease severity distribution score for ulcerative colitis. Automated location inference is used to plot normal (green), mild (yellow), moderate (pink), and severe (red) disease activity (score values 0,1,2,3) at standardized relative intervals along the length of the colon and aggregated for a cumulative disease severity score. The clinical non‐responder exhibited minimal change during the study and was assigned placebo (+161). The clinical responder assigned to ustekinumab had a reduction of cumulative endoscopic activity (‐1044).

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Impact of antibullying educational program on psychological adjustment among preparatory school victims Abstract: School bullying is a global problem confronting the international community that has been existed in public and private schools for years with a negative impact on the psychosocial wellbeing of victims that have limited social skills ability, thus anti bullying educational program including social skills training and bullying related knowledge may limit the negative consequences of school bullying. The present study aimed to evaluate the impact of antibullying educational program on psychological adjustment among preparatory school victims. A purposive sample of 50 students detected from preparatory school screening for school bullying victims, aged between 11‐15 years old, were randomly divided into study and control group. The study conducted in preparatory school at kom Hamada, Al beheira governorate. The effect of the program was measured using two tools psychological adjustment (PA), composed of 16 items and program related knowledge using pre and post test that composed of 17 items. Results of the current study revealed that there is a statistical significant difference between study and control group in relation to psychological adjustment and program related knowledge for all items at post test and follow up test where p<0.05. Thus to conclude that School‐based anti‐bullying programs that involve social skills learning produce modest positive outcomes in reducing bullying and victimization that in turn enhance psychological adjustment of victims.

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Umbralisib plus ublituximab (U2) is superior to obinutuzumab plus chlorambucil (O+Chl) in qqpatients with treatment-naïve (TN) and relapsed/ refractory (R/R) chronic lymphocytic leukemia (CLL): results from the phase 3 unity-CLL study Abstract: Background: Umbralisib is an oral, once‐daily, novel, kinase inhibitor of PI3Kd and casein kinase‐1epsilon (CK1e) that is pharmacologically distinct from other PI3K inhibitors, as it is highly selective for the delta isoform. Ublituximab is a novel anti‐CD20 monoclonal antibody glycoengineered for enhanced antibody‐dependent cellular cytotoxicity that targets a unique epitope on CD20. The umbralisib and ublituximab combination, U2, has been well‐tolerated and has demonstrated promising activity in heavily pre‐treated CLL patients. Herein, results are presented for the randomized, multicenter, Phase 3 UNITY‐CLL trial (NCT02612311), which evaluated U2 vs. Obinutuzumab plus Chlorambucil (O+Chl) in patients with treatment naïve (TN) and relapsed/refractory (R/R) CLL. Methods: Patients ≥18 years of age with TN or R/R CLL requiring treatment per iwCLL criteria with adequate organ function and ECOG PS ≤2 were eligible. Stratification factors included treatment status (TN vs. R/R) and del(17p) status. Patients were initially randomized 1:1:1:1 to receive U2, O+Chl, umbralisib monotherapy, or ublituximab monotherapy. Following the establishment of contribution comparing U2 to the single agents, patients were randomized 1:1 to U2 or O+Chl. Umbralisib was given orally at 800mg once daily until progression or removal from treatment for other reasons. Ublituximab was administered intravenously at 900mg on Days 1/2 [split 150/750mg], 8, and 15 of Cycle 1, Day 1 of Cycles 2‐6, and on Day 1 every 3 cycles after Cycle 6. O was given intravenously at 1000mg on Days 1/2 [split 100/900], 8, and 15 of Cycle 1, and Day 1 of Cycles 2‐6. Chl was given orally at 0.5 mg/kg on Day 1 and 15 of Cycles 1‐6. Each cycle was 28 days. The primary endpoint was the independent review committee (IRC)‐assessed progression‐free survival (PFS) of U2 vs. O+Chl. Key secondary endpoints included IRC‐assessed overall response rate (ORR), complete response (CR), undetectable minimal residual disease (uMRD), duration of response (DOR), and safety (assessed from the first dose until 30 days after the last dose of study medication in each arm) as well as contribution of umbralisib and ublituximab to the U2 combination. Results: From February 2016 to October 2017, 421 patients were randomized to the U2 (n=210) or O+Chl (n=211) arms. The median age was 67 years (range, 36‐91) and 66% were male; 57% of patients (n=240) were treatment‐naïve; 43% (n=181) had R/R CLL (median number of prior treatments =1); 10% had del(17p), 20% del(11q), and 56% were IgHV unmutated. Demographics were well‐balanced between treatment arms. At a median follow‐up of 36.2 months, U2 significantly prolonged PFS vs. O+Chl (median 31.9 vs. 17.9 months; HR 0.546, 95% CI 0.413‐0.720, p<0.0001; Figure 1). Estimated 24‐month PFS rates with U2 and O+Chl were 60.8 and 40.4%, respectively. PFS improvement with U2 vs. O+Chl was consistent across all subgroups examined including treatment‐naïve patients (median 38.5 vs. 26.1 months; HR [95% CI]; 0.482 [0.316‐0.736]); relapsed/refractory patients (median 19.5 vs. 12.9 months; HR [95% CI]; 0.601 [0.415‐0.869]); and by IGHV status (unmutated HR [95% CI]; 0.482 [0.340‐0.684]; mutated HR [95% CI] 0.877 [0.459‐1.677]).IRC‐assessed ORR was higher with U2 (83.3%; 95% CI, 78.1‐88.6%) vs. O+Chl (68.7%; 95% CI, 62.2‐75.2%; p<0.001). Among previously treated subjects, 26 (6%) received prior ibrutinib (14 on U2, 12 on O+Chl), with an ORR of 57% observed for U2 compared to 25% for O+Chl in this population. Minimal residual disease data are currently being analyzed. The median treatment duration was 23 months for U2 (range, 0.1‐49 months) and 5 months (range, 0.1‐7 months) for O+Chl. G3/4 AEs of interest regardless of causality (U2 vs. O+Chl) included neutropenia (30.6 vs. 34.7%), thrombocytopenia (3.4 vs. 13.1%), diarrhea (12.1 vs. 2.5%), infusion‐related reaction (1.9 vs. 3.5%), elevated AST/ ALTs (8.3 vs. 2%), colitis (3.4 vs. 0%) and pneumonitis (2.9 vs. 0%). AEs led to treatment discontinuation in 34 patients (16.5%) on U2 and 16 patients (7.6%) on O+Chl. Conclusions: UNITY‐CLL is the first randomized Phase 3 study in CLL of a PI3Ki vs. chemoimmunotherapy, and the first randomized study of a PI3Ki in treatment‐naive CLL. U2 exhibited a well‐tolerated safety profile and significantly improved PFS vs. standard of care chemoimmunotherapy in patients with treatment‐naive and relapsed/refractory CLL.

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Controlled hypotension for FESS: a randomised double-blinded comparison of magnesium sulphate and dexmedetomidine Abstract: Background and Aims: Intense bleeding during general anaesthesia (GA) is the major limitation during functional endoscopic sinus surgery (FESS). This study was aimed to compare the efficacy of dexmedetomidine and magnesium sulphate (MgSO4)for controlled hypotension in FESS. Methods: Sixty eight patients undergoing FESS were randomised to receive either dexmedetomidine 1 μg/kg over 10 min followed by infusion at 0.2 to 0.7 μg/kg/h (Group D) or MgSO440 mg/kg over 10 min followed by an infusion at 10 to 15 mg/kg/h (Group M). Anaesthesia and infusion rates for study drugs were maintained with sevoflurane to keep MAP between 60‐70 mmHg throughout the surgery. The time to reach the target MAP, the number of patients requiring a minimum and maximum infusion doses of study drugs were noted. Results: The mean time to achieve target mean arterial pressure (MAP) was less in group D (10.59 ± 2.04) as compared with (21.32 ± 4.65 min) group M (P < 0.001). The target MAP was achieved between 5‐15 min in 73.52% patients (Group D) with an infusion dose of 0.2‐0.4 μg/kg/h of dexmedetomidine without the use of sevoflurane, while 82.35% patients in group M required 4% sevoflurane along with >12‐15 mg/kg/hr infusion of MgSO4to achieve target MAP in 10‐20 min. Conclusion: Dexmedetomidine is superior to MgSO4in achieving target MAP in lesser time with minimum infusion dose.

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Development and validation of a novel scoring index (C-reactive protein, age, race, and tumor size) to predict renal functional decline post partial nephrectomy Abstract: Background: Functional decline is a sequelae of extirpative renal surgery with potential for significant morbidity. We utilized pre‐operative patient demographics, C‐reactive protein, and tumor size to design and validate a novel scoring index to predict functional decline post partial nephrectomy. Methods: A multi‐institutional dataset was utilized for analysis of patients with pre‐operative estimated glomerular filtration rate (eGFR) > 60mL/min/1.73m2 by CKD‐EPI equation. Multivariable analysis (MVA) was carried out for potential variables associated with development of post‐operative chronic kidney disease (CKD) stage IIIB at last follow‐up (eGFR < 45 mL/min/1.73m2). Significant variables were included in the predictive model and assigned an index score based on odds ratio. Receiver‐operating‐characteristic (ROC) analysis was employed to evaluate predictive validity, and bootstrapping technique was utilized to validate the model. Results: 924 patients were analyzed. 826 patients had post‐operative eGFR > 45, while 111 patients had eGFR. Factors on MVA independently associated with increased risk of development of eGFR < 45 included age 65+ (OR = 2.6, p < 0.001), African‐American race (OR = 2.3, p = 0.006), C‐reactive protein level > 0.5mg/dL (OR = 5.3, p < 0.001), and tumor size > 4 cm (OR = 1.458, p = 0.189). For CART (C‐reactive protein, Age, Race, Tumor size) score, the following values were assigned: age ( < 65 = 1, age > 65 = 3), race (non‐African‐American = 1, African‐American = 2), tumor size ( < 4 = 1, > 4cm = 2), and CRP ( < 0.5mg/dL = 1, > 0.5mg/dL = 4). Analysis demonstrated 2.6% (12/469) of patients with a low (4‐6) score had de novo eGFR < 45 postoperatively, while 35% (41/117) of patients with a high (10‐11) score had de novo eGFR < 45. ROC analysis revealed AUC of 0.778, and ROC bootstrapping validation of 95 randomly selected patients revealed an AUC of 0.808. Conclusions: CART score represents a novel composite score that significantly predicts development of eGFR < 45 after surgery. This scoring system may assist in patient counseling and clinical decision making, as well as an impetus to improve outcomes in at‐risk patient subgroups.

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Functional Status, Quality of Life and Ventricular Tachyarrhythmias Improve with Right Ventricular Pacing Compared to Biventricular Pacing in LVAD Patients Abstract: Purpose: Cardiac resynchronization therapy (CRT) and left ventricular assist devices (LVAD) independently improve outcomes in heart failure patients, but the effects of combining these therapies remain unknown. We present the full study cohort of the first prospective study evaluating outcomes with right ventricular (RV) vs biventricular (BiV) pacing in LVAD patients. Methods: We performed a prospective, randomized, crossover study. LVAD patients with previously implanted CRT devices were randomized to RV or BiV pacing for 7 days. After data collection, the pacing mode was switched for an additional 7 days. Ambulatory step count (by Fitbit Zip device), 6 minute walk test (6MWT) distance, Kansas City Cardiomyopathy Questionnaire (KCCQ‐12) scores, arrhythmia burden, ICD lead function, and echocardiographic data were collected with each pacing mode. Results: 30 patients were enrolled, with a mean age of 61 years, 67% male, and median duration of LVAD support of 343 days. During RV pacing, mean daily step count was 21% higher compared to BiV pacing (2177 vs. 1798 steps, p = 0.001). With RV pacing, there was a 9% higher 6MWT distance (313 vs. 288 m, p = 0.003). KCCQ‐12 score was significantly higher with RV pacing (45.8 vs 43.7, p = 0.02). There were significantly fewer patients with ventricular tachyarrhythmia episodes with RV pacing (8% vs 19%, p=0.04); one patient had 4 episodes of sustained ventricular tachycardia requiring anti‐tachycardia pacing during BiV pacing. No significant difference was observed in lead impedance between RV and BiV pacing with the right atrial, right ventricular, and left ventricular leads. Conclusion: In the first prospective randomized study comparing variable pacing in LVAD patients, RV pacing was associated with significantly improved functional status, quality of life, and ventricular tachyarrhythmia burden compared to BiV pacing. We recommend turning off LV lead pacing in patients on LVAD support with CRT devices.

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A study of the effectiveness of group play therapy upon the theory of mind in preschool children Abstract: Theory of mind is a one of the most important issues of social cognition topics and whereas it is a prerequisite for understanding the social environment and involvement in social behavior competitive, it has been considered during the last decades in the field of psychology. In this regard, the purpose of this study was to evaluate the effectiveness of group play therapy on levels of childrenin preschool's theory of mind. Materials and Methods The present study, was a Quasi‐experimental study design with pre‐test and post‐test and control groups which for this purpose 30 students selected by cluster random sampling and random assignment to experimental and control groups, respectively. 38‐item test of theory of mind was used as a tool to obtain data.Package of six sessions of play therapy was administered to the experimental group. Data were analyzed using descriptive and inferential statistics covariance. Results The results showed that there was a significant difference between the experimental and control groups in terms of levels of theory of mind test.Follow up test after one month, showed the stability of results. Conclusions According to data obtained from this study can be concluded that the play therapy promotes children's theory of mind levels and since training activities were based on cognitive‐behavioral and there is a close relationship between social cognition and doing group play, visible impact on the promotion of children's theory of mind test levels can be explained.

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Effect of a bilberry extract (BILBERON®)-containing diet on the improvement of eye fatigue-related symptoms (II) - A randomized, double-blind, placebo-controlled, parallel-group comparison study Abstract: Objective: In recent years, it has been reported that the ingestion of bilberry extract improves visual function. However, few clinical studies have investigated the efficacy of bilberry extract for the improvement of eye fatigue‐related symptoms that are induced by visual display terminals (VDT). Therefore, we examined the safety and efficacy of bilberry extract (BILBERON®) in the treatment of VDT‐induced eye fatigue‐related symptoms. Methods: In this human trial, healthy adult subjects with subjective eye fatigue who were exposed to VDT work for over 4 h/day were recruited. The subjects were randomly divided into two groups (n = 10 for the test product group and n = 11 for the placebo group) and orally ingested either 160 mg/day of BILBERON® or the placebo capsule for 6 weeks. The VDT was loaded on the examination days before and after the 6‐week ingestion period. A Schirmer's test was performed before the VDT load to assess eye dryness, and the following investigations were performed before and after the VDT load: miosis frequency (MF), near point pupil diameter (NPD), and far point pupil diameter (FPD) examination to determine the accommodative function, critical flicker frequency (CFF) to assess eye fatigue, and a Likert scale questionnaire to assess subjective symptoms. Results: Significant improvements were observed in the MF, variation between NPD and FPD, ratio of Schirmer value and subjective symptoms, including an eye fatigue sensation and a neck and shoulder stiffness sensation, of the test product group after the 6‐week ingestion period compared to those of the placebo group. Moreover, the CFF (red light), as a measure of eye fatigue, was less in the placebo group compared to that of the test product group, which suggests that the accumulative eye fatigue was suppressed in the test product group. Discussion Healthy subjects with subjective eye fatigue showed improvements in their VDT‐induced eye fatigue‐related symptoms, including accommodative function, eye fatigue, eye dryness, subjective symptoms of eye fatigue sensation, and neck and shoulder stiffness sensation, following an ingestion of 160 mg/day bilberry extract (BILBERON®) for 6 weeks. In addition, the test product appeared to be safe under the conditions employed in the present study.

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Drug interactions in communitydwelling people screened positive for dementia: results of the DelpHi study Abstract: Background: Older people with polypharmacy run a higher risk of drug interactions. However, little is known about the prevalence of drug interactions in community‐dwelling people screened positive for dementia. This analysis aimed to determine (1) the active agent‐related prevalence of drug interactions and (2) the socio‐demographic and clinical variables associated with total number of drug interactions. Methods: The DelpHi‐MV study (Dementia: life‐and person‐centered help in Mecklenburg‐Western Pomerania) is a general practitioner (GP)‐based cluster‐randomized controlled intervention trial to implement and evaluate an innovative concept of collaborative dementia care management in the primary care setting in Germany. Medication reviews of n=446 study participants were conducted by pharmacists based on the comprehensive baseline assessment that included a computer‐based home medication assessment. Results: Of the n=446 patients, a total of 155 (35%) had at least one potential drug interaction of moderate severity, 14 (3%) had at least one clinically relevant drug interaction, and 11 (2%) had at least one inappropriate combination of drugs with food. Total number of drugs taken (OR 1.26) and support with medication (OR 2.09) were associated with drug interactions. The most frequent specific drug interactions will be presented and discussed. Conclusion: The present analysis underlined that a comprehensive medication review has the potential to improve the pharmacotherapy in community‐dwelling people living with dementia is of major importance.

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Peanut-specific immunoglobulin levels following SCIT-treatment with a chemically modified, aluminum hydroxide adsorbed peanut extract (HALMPE1) in peanut allergic patients Abstract: Background: Currently, there is no effective disease modifying treatment for peanut allergy available. Therefore, a chemically modified, aluminum hydroxide adsorbed peanut extract (HAL‐MPE1) for subcutaneous administration has been developed. In a phase I study, evaluating the safety and tolerability of SCIT‐treatment with HAL‐MPE1 in subjects with peanut allergy, changes in peanut specific immunoglobulin levels and basophil histamine release were assessed. Method: In a randomized, double blind, placebo controlled, single‐centre, Phase I study 17 Caucasian subjects (mean age: 20.9±2.6 years, 53% female), with a history of systemic reactions after peanut ingestion, a positive food challenge test and an Ara h 2 IgE > 0.7 kU/l, were randomized to receive 15‐20 weekly incremental doses of either HAL‐MPE1 (11 subjects) or placebo (6 subjects). At baseline and end of study IgE, IgG and IgG4 to peanut extract, peanut allergens (Ara h 1, Ara h 2, Ara h 3, Ara h 6, Ara h 8, Ara h 9) and basophil histamine release were determined. Results: Increased IgG and IgG4 levels specific for peanut extract, Ara h 1, Ara h 2, Ara h 3, Ara h 6 were observed following active treatment as compared to placebo, whereas no clear changes in Ara h 8 and Ara h 9 specific IgG and IgG4 levels were observed compared to placebo. No clear pattern in IgE levels specific for peanut extract and peanut allergens (Ara h 1, Ara h 2, Ara h 3, Ara h 6, Ara h 8, Ara h 9) was observed. Furthermore, a trend towards a difference in basophil histamine release between the placebo group and the active treatment group was observed. Conclusion: The results indicate that subcutaneous administration of HAL‐MPE1 is capable of inducing immunological changes following 4‐5 months of weekly dose escalations.

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Determination of the most appropriate method for extrapolating overall survival data from a placebo-controlled clinical trial of lenvatinib for progressive, radioiodine-refractory differentiated thyroid cancer Abstract: Background: Cost‐effectiveness models for the treatment of long‐term conditions often require information on survival beyond the period of available data. Objectives: This paper aims to identify a robust and reliable method for the extrapolation of overall survival (OS) in patients with radioiodine‐refractory differentiated thyroid cancer receiving lenvatinib or placebo. Methods: Data from 392 patients (lenvatinib: 261, placebo: 131) from the SELECT trial are used over a 34‐month period of follow‐up. A previously published criterion‐based approach is employed to ascertain credible estimates of OS beyond the trial data. Parametric models with and without a treatment covariate and piecewise models are used to extrapolate OS, and a holistic approach, where a series of statistical and visual tests are considered collectively, is taken in determining the most appropriate extrapolation model. Results: A piecewise model, in which the Kaplan‐Meier survivor function is used over the trial period and an extrapolated tail is based on the Exponential distribution, is identified as the optimal model. Conclusion: In the absence of long‐term survival estimates from clinical trials, survival estimates often need to be extrapolated from the available data. The use of a systematic method based on a priori determined selection criteria provides a transparent approach and reduces the risk of bias. The extrapolated OS estimates will be used to investigate the potential long‐term benefits of lenvatinib in the treatment of radioiodine‐refractory differentiated thyroid cancer patients and populate future cost‐effectiveness analyses.

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Effects of therapeutic massage on metabolic control indicators in patients with type II diabetes Abstract: Objectives: Diabetes is a growing epidemic, resulting in significant mortality and morbidity. Individuals diagnosed with diabetes can improve their clinical outcomes through good metabolic control. Considering the fact that achieving metabolic control is very difficult, use of complementary treatments, in addition to regular medicines, is recommended. Therapeutic massage is a complementary treatment method, the effects of which on diabetic patients have been rarely studied. This study aimed to evaluate the effects of massage on metabolic control indicators in patients with type II diabetes. Materials and Methods: In this randomized clinical trail, 50 women with type II diabetes were divided into case and control groups via randomized blocking method. The case group received 10 sessions of 30‐min therapeutic massage, while the control group received usual care. Inter‐group and intra‐group changes in the level of metabolic control indicators (e.g., glycated hemoglobin, lipid profile, blood pressure and body mass index) were evaluated by paired t‐test and multivariate analysis of variance. Results: Changes in glycated hemoglobin [7.18 (0.14) vs. 8.06(0.22)] (p<0.01), systolic blood pressure [104.61 (3.25) vs. 118.35 (3.26)] (p=0.001), diastolic pressure [68.47(1.34) vs. 77.47 (2.21)] (p=0.001) and body mass index [28.47 (0.85) vs. 29.34(0.85)] (p=0.001) were significant in the case group. The multivariate analysis of variance showed a significant difference between the groups in terms of mean changes in glycated hemoglobin (p=0.001), systolic pressure (p=0.001), diastolic pressure (p=0.001) and body mass index (p=0.008). The lipid profile was not significantly different between the groups, either before or after the intervention. Conclusion: Therapeutic massage could lead to improvements in metabolic control indicators in patients with type II diabetes.

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Bimatoprost 0.01% or 0.03% in patients with glaucoma or ocular hypertension previously treated with latanoprost: two randomized 12-week trials Abstract: Background: The purpose of this study was to evaluate the intraocular pressure (IOP)‐lowering efficacy and safety of bimatoprost 0.01% or 0.03% as monotherapy in patients treated with latanoprost 0.005% monotherapy who require additional IOP lowering for their ocular hypertension or open‐angle glaucoma. Methods: Two prospective, investigator‐masked, randomized, parallel‐group, multicenter studies enrolled patients with baseline IOP $20 mmHg after $30 days of latanoprost 0.005% monotherapy. Patients were randomized to 12 weeks of study treatment (study 1, bimatoprost 0.01% once daily or bimatoprost 0.01% once daily plus brimonidine 0.1% three times daily; study 2, bimatoprost 0.03% once daily or bimatoprost 0.03% once daily plus fixed‐combination brimonidine 0.2%/timolol 0.5% twice daily). Patient evaluations at weeks 4 and 12 included IOP at 8 am, 10 am, and 4 pm and safety assessments. Results in the monotherapy study arms (bimatoprost 0.01% or 0.03%) are presented. Results: Latanoprost‐treated baseline mean diurnal IOP (± standard error of the mean) was 22.2±0.3 mmHg and 22.1±0.4 mmHg in the bimatoprost 0.01% and bimatoprost 0.03% treatment arms, respectively (P=0.957). In both treatment arms, mean (± standard error of the mean) reduction in IOP from latanoprost‐treated baseline was statistically significant at each time point at both follow‐up visits (P,0.001), ranging from 3.7±0.4 (17.0%) mmHg to 4.4±0.4 (19.9%) mmHg with bimatoprost 0.01% and from 2.8±0.5 (12.8%) mmHg to 3.9±0.5 (16.7%) mmHg with bimatoprost 0.03%. Mean percentage IOP reduction from latanoprost‐treated baseline was numerically greater with bimatoprost 0.01% than with bimatoprost 0.03% throughout follow‐up. The incidence of conjunctival hyperemia of mild or greater severity increased from latanoprost baseline after 12 weeks of treatment only in the bimatoprost 0.03% treatment arm. Conclusion: Many patients who do not reach their target IOP on latanoprost can achieve additional IOP lowering and maintain monotherapy by replacing latanoprost with bimatoprost. Reductions in IOP from latanoprost baseline were larger with bimatoprost 0.01% than with bimatoprost 0.03%, and bimatoprost 0.01% had a more favorable tolerability profile. © 2014 Arora et al.

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Prospective randomized controlled trial with crossover of endoscopic ultrasound fine needle aspiration (EUS-FNA) using 22g procore and 22g echotip needle for solid pancreatic mass: the “picore” study Abstract: Aim: To compare the diagnostic accuracy of EUS‐FNA between the novel22G Procore ™ (P) and the 22G EchoTip ® (ET) for solid pancreatic mass. Patients and Methods: It was a prospective multicentric study (17 centers). EUS‐FNA were performed for patients with pancreatic solid mass, using ET (2 passes) and P (1 pass) (Cook Medical Inc., Limerick, Ireland). The randomization was used to define the order use of needles in the tumor. The main objective was to compare the diagnostic accuracy of the two needles. The final diagnosis of malignancy/benignancy was based on surgical histology, FNA under CT or clinical follow up with repeated imaging examinations during at least 6 months. Secondary end points included the morbidity, ease of EUS‐FNA, needle dysfunction, cyto‐histological quality (Visual analogical scale, modified Mair score), number of non assessable sampling and weight of material obtained. Samples were immersed in the Cytolyt. A mono layer cell pellet of 20 mm was prepared and then stained (Papanicolaou). The remainder of the sample was embedded in paraffin, cut at different levels, stained by HES, PAS and alcian blue with any immunohistochemical study. Reading was centralized by 2 independent expert pathologists blinded to the randomization and diagnosis with third reading in case of discordance. Results: 80 patients (49 men, 67.1 ± 11.1 years [41‐86]) were included. The final diagnosis was in favor of malignancy in 89% of cases with adenocarcinoma (n=63, 79%), endocrine lesions (n=6, 8%) and metastases of lung cancer (n=2, 2%). A benign histology was raised for 9 patients (5 chronic pancreatitis). The lesions were mostly unique (n = 76, 95%), located in the head and uncus (n=48, 60%). No EUS‐FNA failure was observed with both needles. EUS‐FNA was inconclusive in 7 patients with ET and in 13 patients with P. Sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy were respectively for the 22G P : 88.6%, 50%, 100%, 100% and 83.7%, and for 22G ET : 92.8%, 50%, 83.3%, 97% and 87.5% (p=ns). Ease of EUS‐FNA was considered significantly higher with the 22G P (7.01 vs. 6.65 VAS, p =.05). Only one slight bleeding was observed with a 22G ET (p=ns). The weight of the sample was significantly higher with the ET (0.37 g vs. 0.27 g, p=.01). The mean histological VAS and the Mair score were significantly higher for the ET (respectively 5.02 vs. 3.97, p=.0007 and 6.41 vs. 6.21, p=.0458). Both pathologist experts found the overall quality of samples significantly better for ET (expert 1, p=.009 and expert 2, p=.002). Conclusion: Diagnostic accuracy of EUS‐FNA for pancreatic solid mass using 22G P (one pass) and ET (2 passes) are comparable. Overall histological quality of samples obtained with the 22G ET is better compared to the 22G P. safety profile is identical with easier EUS‐FNA when using 22G P.

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Immediate and delayed SWL for ureteral stones: late period success rates Abstract: OBJECTIVE: To investigate the effect on success rates after 3 SWL sessions of immediate or delayed SWL for ureteral stones. METHODS: Patients who applied with renal colic and who have single, radiopaque ureteric stone of 5 to 20mm size were included in the study. Patients were randomized into two groups, such that, immediate and delayed SWL treatments were scheduled within 24 hours and 3 to 7 days from referral, respectively. Stone free status was assessed with plain abdominal radiograph and noncontrast computed tomography on the 3rd day after SWL session. In controls, the patients who did not show any piece of stone were defined as stone‐free. Stones with ≤ 4mm in diameter were considered as clinically insignificant residual fragments (CIRF), while bigger stones were accepted as residual stone. To the patients, who had residual stone supplemental SWL session was performed. To the cases, who had residual stone maximum 3 SWL sessions were performed and the differences between the groups were investigated. RESULTS: Patients, 32 in the immediate and 31 in the delayed SWL group, were included in the study after randomization. The average stone size before SWL was similar between the groups, the average size of stones were 8.12 and 8.8mm (p = 0,375) in the immediate and delayed SWL groups, respectively. In the comparison between 2 SWL groups after 3 SWL sessions, the stone‐free rate has been found similar, statistically (p = 0.414). CONCLUSIONS: Immediate or delayed application of SWL seems not to affect the success rates for ureteral stone cases which require multiple sessions.

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International phase III study of chlorambucil versus fludarabine as initial therapy for Waldenstrom macroglobulinaemia and related disorders Abstract: Waldenstrom macroglobulinaemia (WM) and related‐disorders (splenic marginal zone lymphoma: MZL, and non‐IgM lymphoplasmacytic lymphoma: LPL) are rare diseases with very few randomised trials having been reported. The WM1 study was a prospective randomised open‐label study that compared the efficacy of chlorambucil at a dose of 8 mg/m2 (6 mg/m2 for those > 75 years) for 10 days every 28 to a maximum of 12 cycles with oral fludarabine at a dose of 40 mg/m2 (30 mg/m2 for those > 75 years) for 5 days every 28 to a maximum of 6 cycles. Primary endpoints were response and duration of response; secondary endpoints were improvement in hematological parameters, toxicity and OS. 416 patients were enrolled between 07/01‐12/09 and 414 received at least one course of chemotherapy. There were 337 WM, 34 MZL and 43 LPL with a median age of 68 years (40‐89). Patients received a median of 9 cycles of chlorambucil and 6 cycles of fludarabine. 88% of patients are evaluable for response with an overall response rate (CR and PR) of 54.2% with fludarabine and 43.8% with chlorambucil (p=0.05). The CR rate was low at 3.6% overall. Age, IgM concentration, haematological parameters, albumin and B2M did not predict for response. The median follow up is currently 32.5 months and fludarabine is associated with a superior outcome with PFS and TTF of 36.4 and 38.3 months compared to 27.1 and 19.5 months for chlorambucil (p=0.01 for PFS, p=0.001 for TTF). There is currently no difference in OS but the ISSWM was informative. Fludarabine was associated with a higher incidence of grade IV anaemia (12.1% v 6.9%) and neutropenia (13.6% v 3.5%). We would conclude that fludarabine appears superior to chlorambucil but with the advent of monoclonal antibody combinations and agents such as bortezomib the optimal primary therapy in WM remains unclear.

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Health-Related Quality-of-Life Analysis From the Phase 3 CLEAR Trial of Lenvatinib + Pembrolizumab or Everolimus Versus Sunitinib for Patients With Advanced Renal Cell Carcinoma Abstract: INTRODUCTION AND OBJECTIVES: Lenvatinib + pembrolizumab (L+P) improved progression‐free survival, overall survival, and objective response rate versus sunitinib as first‐line treatment of patients with advanced renal cell carcinoma (aRCC). We report a secondary objective of CLEAR comparing the impact of L+P or lenvatinib + everolimus (L+E) versus sunitinib on health‐related quality‐of‐life (HRQoL). METHODS: Patients (N=1069) were randomly assigned (1:1:1) to receive lenvatinib 20mg orally daily + pembrolizumab 200mg intravenously once every 3 weeks; lenvatinib 18mg + everolimus 5mg orally daily; or sunitinib 50mg orally daily (4 weeks on/2 weeks off). HRQoL was assessed per FKSIDRS, EORTC QLQ‐C30, and EuroQoL EQ‐5D‐3L, at baseline, on day 1 of subsequent 3‐week cycles starting with cycle 2, and at the off‐treatment visit. HRQoL analyses (unless otherwise noted) were based on data from randomized patients with any HRQoL data who received ≥1 dose of study treatment. No adjustments for multiple testing or estimation were used; statistics are nominal and descriptive. RESULTS: For comparisons of L+P versus sunitinib, overall changes from baseline at mean follow‐up (week 46) favored L+P with significant differences between treatments for EORTC QLQ‐C30 physical functioning (least‐squares mean difference [LSMD][95% CI]: 3.01[0.48,5.54]) and fatigue (‐2.80[‐5.52,‐0.08]), dyspnea (‐2.79[‐5.33,‐0.25]), and constipation (‐2.19[‐4.19,‐0.18]). LSMD of the FKSI‐DRS total score was 0.2(‐0.4,0.7). Of 18 scales assessing L+P versus sunitinib, 14 had no significant differences in LSMD comparisons. The L+P arm was favored over sunitinib for time to first deterioration (TTD) for EORTC QLQ‐C30 physical functioning (HR[95%CI]: 0.81[0.68,0.98], dyspnea (0.79[0.64,0.97]), appetite loss (0.82[0.68,0.98]), and EQ‐5D VAS 7‐point minimally important difference (0.83[0.70,0.99]). Of 19 scales assessing L+P versus sunitinib, 15 had no significant differences in TTD comparisons. Overall, L+E resulted in similar or worse LSMDs and TTD versus sunitinib. CONCLUSIONS: Compared with sunitinib, patients in L+P group had similar or better symptoms and HRQoL.

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Feasibility of conducting a randomized, placebo-controlled study assessing whether omega-3 fatty acids prevent gout flares when starting urate-lowering treatment Abstract: OBJECTIVE: The aim was to test the feasibility of a randomized controlled trial exploring whether omega‐3 fatty acid supplementation limits gout flares during treat‐to‐target urate‐lowering treatment (T2T‐ULT).METHODS: Adults with at least one gout flare in the past 12 months and serum urate (SU) ≥360 μmol/l were recruited from general practices (primary method) and randomly assigned 1:1 to receive omega‐3 fatty acid supplementation (4 g/day) or placebo for 28 weeks. At week 5, participants began T2T‐ULT. The primary outcome was drop‐out rate. Secondary outcomes were recruitment rate, outcome data completeness, the number, severity and duration of gout flares between weeks 5 and 28, and study drug compliance.RESULTS: Ninety‐five per cent of randomized participants (n = 60) completed all study visits. The primary method recruitment rate was 2.2%. Fifty and 42 participants achieved SU < 360 and 300 μmol/l (6 and 5 mg/dl), respectively. The number of gout flares [median (interquartile range): active 1 (0‐2) and placebo 1 (0‐2)], flare duration [mean (s.d.): active 7.00 (4.52) days and placebo 7.06 (8.14) days] and time to first flare [hazard ratio (95% CI) 0.97 (0.50, 1.86)] were comparable between both arms. Study drug compliance was high and comparable in both arms [median (interquartile range) returned capsule count: active 57 (26‐100) and placebo 58 (27‐154)]; red blood cell omega‐3 fatty acid index increased twofold in the active arm and remained unchanged in the control arm.CONCLUSION: The study demonstrated feasibility and provided useful metrics for conducting a community‐based gout flare prophylaxis trial.STUDY REGISTRATION: ISRCTN; https://www.isrctn.com/; ISRCTN79392964.

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Additive effect of androgens and estrogens on pubertal growth acceleration Abstract: Objective: The influence of androgens and estrogens on growth is complex, and understanding their relative roles is important for optimizing the treatment of children with various disorders of growth and puberty. Design: We examined the proportional roles of androgens and estrogens in the regulation of pubertal growth in boys with constitutional delay of growth and puberty (CDGP). The study compared 6‐month low‐dose intramuscular testosterone (T) treatment (1 mg/kg/month) (n=14) with peroral letrozole (Lz) treatment (2.5 mg/day) (n=14) which inhibits conversion of androgens to estrogen. Patients: Boys with CDGP were recruited to a randomized, controlled, open‐label trial between 2013 and 2017 (NCT01797718)1. Measurements: The patients were evaluated at 0‐, 3‐, and 6‐month visits, and morning blood samples were drawn. Linear regression models were used for data analyses. Results: In the T‐group, serum testosterone concentration correlated with serum estradiol concentration at the beginning of the study and at 3 months, whereas in the Lz‐group the sex steroids correlated only at baseline. Association between serum T level and growth velocity differed between the T‐ and Lz‐groups, as each nmol/l increase in serum T increased growth velocity 2.6 times more in the former group. Serum T was the best predictor of growth velocity in both treatment groups. In the Lz‐group, adding serum estradiol to the model significantly improved the growth estimate. Only the boys with serum estradiol above 10 pmol/l had a growth velocity above 8 cm/year. Conclusions: During puberty promoting treatment with T or aromatase inhibitor Lz, growth response is tightly correlated with serum T level. A threshold level of estrogen appears to be needed for optimal growth rate that corresponds to normal male peak height velocity of puberty. Serum T one week after the injection and serum T and estradiol 3 months after aromatase inhibitor treatment onset can be used as biomarkers for treatment response in terms of growth.

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Role of radiotherapy and dose-densification of R-chop in primary mediastinal B-cell lymphoma: a subgroup analysis of the unfolder trial of the German lymphoma alliance (GLA) Abstract: Background: Primary mediastinal B‐cell lymphoma (PMBCL) is a distinct entity of aggressive lymphoma, which typically presents in young patients (pts) with a bulky mediastinal mass. Therapy is based on R‐CHOP or similar regimens. The role of treatment intensification and consolidative radiotherapy (RT) is controversial, because data from randomized trials are rare. Aims: In a planned PMBCL‐subgroup analysis from the UNFOLDER trial we investigated the role of treatment intensification and RT. Methods: The UNFOLDER trial included 18‐60 year‐old pts (aaIPI = 0 with Bulk [≥7.5 cm] or aaIPI = 1) qualifying for radiotherapy to Bulk or extralymphatic involvement (E). Pts were randomized in a 2 x 2 factorial design to 6xR‐CHOP‐14 or 6x‐R‐CHOP‐21 without or with RT (39.6 Gy) to Bulk and E. Primary endpoint was event‐free survival (EFS), secondary endpoints were progression‐free (PFS) and overall survival (OS). Response was evaluated by the Internat Standardized Response Criteria (Cheson 1999). Results: 131 PMBCLs were included with a median age of 34 years, 54% were female, 79% had elevated LDH > UNV and 24% had E. 82 pts were assigned to RT (R‐CHOP‐21: 43; R‐CHOP‐14: 39) and 49 to no RT (R‐CHOP‐21: 27, R‐CHOP‐14: 22). 96% (79/82) of pts assigned to RT received RT per protocol and 5 pts in the no RT arm received unplanned RT (4 after PR and 1 after CR/CRu). RT related toxicity with grade > = 3 was found for nausea (2%), oesophagitis/dysphagia (6%), larynx (2%), skin local (2%) and infection (2%). Responses for pts assigned to RT vs no RT were CR/CRu 94% vs 84%, PR 2% vs 10%, PD 2% vs 4%. With a median observation time of 63 months the pooled 3 year rates were for EFS 88% (95% CI: 82‐93), for PFS 93% (95% CI: 89‐97) and for OS 97% (95% CI: 94‐100). 3‐year EFS was superior for pts assigned to RT (94% vs 78%; p = 0.007), mostly due to events caused by initiation of RT (n = 5) in the no RT arm. In an as‐treated‐ analysis the difference between the RT and the no RT arm was not significant (p = 0.136). Regarding PFS and OS no difference between the RT and the no RT arm was detected (PFS: 95% (95% CI: 90‐100) vs 90% (95% CI: 81‐98), p = 0.253; OS: 98% (95% CI: 94‐100) vs 96% (95% CI: 90‐100), p = 0.636). Dose‐densification of R‐CHOP‐21 by R‐CHOP‐14 did neither improve EFS, PFS nor OS. Not any event was observed within the patient group with aaIPI 0. Within the group of pts with aaIPI 1 two‐fold elevated LDH and E‐involvement were significant independent risk factors in a multivariate analysis, (HR[LDH>2ULN]EFS = 4.5 [95%CI: 1.5‐13.4], p = 0.006 and HR[E involv]EFS = 3.6 [95%CI: 1.2‐11.0], p = 0.027; HR[LDH>2ULN]PFS = 7.9 [1.8‐34.8], p = 0.007 and HR[E involv]PFS = 3.3 [0.7‐14.5], p = 0.117). Only 4 pts died (all of them with LDH>2ULN). So far two secondary carcinomas have been observed, both in the R‐CHOP‐21+RT arm. Summary/Conclusion: To our knowledge, this is the largest series of PMBCLs so far, which have been treated in a prospective, randomized trial in the Rituximab era. The results reveal no differences in outcome between R‐CHOP‐14 vs R‐CHOP‐21. Pts assigned to RT had a superior EFS mostly due to a higher PR rate in the no RT arm triggering RT, with no differences in PFS and OS. The results suggest a benefit of RT only for pts, who are responding to R‐CHOP with PR according to Internat Standardized Response Criteria (Cheson 1999). Testing RT in PET‐positive residual tumors in a randomized trial can solve the question, while RT in PET‐negative pts is studied in the ongoing randomized IELSG 37 trial. Our results indicate a very favorable 3‐year OS of 96% in PMBCL pts treated with R‐CHOP.

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Derivation of “specific population who could benefit from Rosuvastatin”: a secondary analysis on randomised controlled trial to uncover novel value of Rosuvastatin for precise treatment of ARDS Abstract: Introduction: The high heterogeneity of ARDS contributes to paradoxical conclusions from previous investigations of rosuvastatin for ARDS. Identification of the population (phenotype) who could benefit from rosuvastatin is a novel exploration for precise treatment of ARDS. Methods: The patient population for this analysis consisted of unique patients with ARDS enrolled in the SAILS trial (Rosuvastatin vs. Placebo). Phenotypes were derived using consensus k means clustering applied to routinely available clinical variables within 6 hours of hospital presentation before receiving placebo or rosuvastatin. Kaplan‐ Meier statistic was used to estimate the 90 day cumulative mortality for screening specific population who could benefit from rosuvastatin, with cut‐off value as P < 0.05. Results: The derivation cohort included 585 patients with ARDS. Of the 4 derived phenotypes, phenotype 3 was identified as “specific population who could benefit from rosuvastatin” since rosuvastatin resulted in a significant reduction in 90 day cumulative mortality for ARDS (hazard ratio [HR] 0.29 [95% CI 0.09, 0.93]; P = 0.027). Meanwhile, there were no significant differences in baseline characteristics between those assigned to rosuvastatin and those assigned to placebo. Additionally, rosuvastatin markedly improved the free of cardiovascular failure (10.08 ± 3.79 in Rosuvastatin group vs 7.31 ± 4.94 in Placebo group, P = 0.01) and coagulation abnormality (13.65 ± 1.33 vs 12.15 ± 3.77, P = 0.02) to day 14 in phenotype 3. Patients classified as phenotype 3 exhibited but not limited to the relative higher platelet count (390.05 ± 79.43×10∧9/L), lower CRP (20.23 ± 11.99μg/L) and Creat (1.42 ± 1.08 mg/dl), compared with patients classified as other phenotypes. Besides that, rosuvastatin seemed to increase 90 day mortality for patients in phenotype 4 (HR 2.76[95% CI 0.09, 9.93], P = 0.076), with its adverse effect on the reduction of free of renal failure to day 14(4.70 ± 4.99 vs 10.17 ± 4.69, P = 0.01). Patients in phenotype 4 showed a relative severe illness baseline features particularly renal failure. Conclusion: This secondary analysis of SAILS trial identified the specific population who can benefit from rosuvastatin using machine learning applied to clinical variables at the time of hospital presentation, which uncovered a novel value of rosuvastatin for the treatment of ARDS, with validation clinical trials to be warranted to assess these further.

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Axonal integrity in primary and secondary progressive multiple sclerosis: a baseline subgroup analysis of sex, age, and disease severity from the phase III SPI2 study Abstract: Objective: We used proton magnetic resonance spectroscopy (MRS) to measure potential differences in axonal integrity between primary and secondary progressive multiple sclerosis (PPMS, SPMS) in a cohort of patients from the SPI2 study. Background: SPI2 is a phase III trial investigating the safety and efficacy of MD1003 (high‐dose biotin) in patients with PPMS and SPMS. Here, we assess at baseline the impact of sex, age, disability status, and type of progressive MS on the ratio of total N‐acetyl groups (NA) to creatine (Cr), a marker of neuroaxonal integrity, measured by MRS. Design/Methods: SPI2 inclusion required documented, relapse‐free, disability progression in expanded disability status scale (EDSS) over 2 years. MRS data from a central brain single voxel positioned on the body of the corpus callosum were obtained at participating centers having the necessary capabilities. Spectra were analyzed and NA/Cr computed centrally. Results: As of July 2018, 642 pts with PPMS or SPMS were randomised 1:1 to MD1003 300 mg/day or placebo. The MRS analysis included 422 patients: 60% had SPMS, 52.6% were females, and 65.9% had EDSS>5. The mean NA/Cr ratio was significantly higher (P<0.05) in females versus males within patients with PPMS. We observed a trend toward a higher mean NA/Cr ratio in female patients with PPMS versus female patients with SPMS, and a trend toward a lower mean NA/Cr ratio in male patients with PPMS versus male patients with SPMS. There were no differences in NA/Cr between SPMS and PPMS linked to patient age. Baseline NA/Cr was not correlated with EDSS. Conclusions: MRS measures of brain neuronal integrity were higher in female patients with PPMS than in male patients with PPMS. Whether neuronal degeneration differs in PPMS between men and women, and between PPMS and SPMS patients warrants further study.

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An exploration of the shared experiences and personal impact of a progressive resistance training programme, for young people with cerebral palsy: a qualitative analysis Abstract: Introduction: While resistance training is often delivered as part of rehabilitation for young people with cerebral palsy (CP), little is known about the experience and impact of resistance training on those delivering and receiving the programme. The aim of this work was to explore the personal experiences and overall impact of participating in a resistance training programme among young people with CP and physiotherapists. Patients and Methods: This study was conducted as part of a large, multi‐centre, randomized controlled trial to determine the feasibility, acceptability, and efficacy of resistance training for adolescents with cerebral palsy (STAR Trial). Participants who were randomized to the progressive resistance training arm of the trial, in addition to the physiotherapists running the programme, were invited to take part in a 1:1 semi‐structured, interview. Data was analysed using a multistage process known as the Framework approach. Results: Thirty‐two young people with CP (age 10‐19y, GMFCS levels I‐III) and 13 physiotherapists participated. The following five overarching themes relating to participants' personal experiences and the overall impact of the programme were developed: physical impact, sense of achievement, social impact, long‐term prioritization, and long‐term integration of resistance training. The active and progressive nature of the 10‐week programme was fundamental to the physical, social, and psychological beneficial impact of the programme, and motivated participants to continue the programme. Conclusion: This study shows that progressive resistance training has a positive impact on young people with CP, which goes beyond physical benefits.

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A mixed-methods feasibility study exploring the cultural adaptation of walk with ease to the United Kingdom Abstract: Background/Purpose: The Arthritis Foundation's Walk With Ease (WWE) is an evidence‐based 6 week community‐based walking program for adults with arthritis delivered in instructor‐led or self‐directed format. It has been shown to improve physical function, pain, stiffness and fatigue. WWE is also a Centers for Disease Control and Prevention‐recommended physical activity (PA) program. In recent years, WWE has been scaled‐up and expanded to communities across the United States (US), yet is little known outside North America. This study aimed to examine the relevance, acceptability and feasibility of WWE in a United Kingdom (UK) context, where walking for pleasure and transport is culturally embedded. Methods: This 4 phase study was carried out in collaboration with community and patient partners: 1) Cultural adaptation; 2) WWE program; 3) Qualitative enquiry; 4) Future planning. Recruitment was primarily via invitation letter to persons registered in selected Aberdeen primary care practices. Eligible (≥18 years, doctor diagnosed arthritis (confirmed or selfreport), and self‐reported joint symptoms in last 30 days, BMI ≥ 25 kg/m2, and <150 min/week of moderate/vigorous PA) and consented participants were randomised into 2 groups: WWE program or usual care. Descriptive statistics explored physical performance measures (PPM), symptoms and beliefs using physical performance assessment and survey data collected at baseline and post‐6 week program. Participants' experiences of WWE were explored via video ethnography and narrative interviews, and analysed thematically. Results: Of 149 participants, the majority were women (70%) aged 60 years (76%). OA was most prevalent (66%), followed by back pain (54%) and RA (13%); most also had at least 1 non‐arthritis condition (79%). Among participants, 97 received the WWE program: 52 chose instructor‐led; 45 chose self‐directed. Follow‐up was 80.4% at 6‐weeks; 82.5% at 18‐weeks. Average walk attendance across 5 walking groups was 63% (11.5/18 walks). Nearly all (99%) would recommend WWE to family or friends and 81% reported they were satisfied with the program. At 6 weeks, about half reported being at least moderately better in physical health (47%) and emotional well‐being (53%). Within both WWE formats, statistically significant differences representing improvement were observed at 6 weeks from baseline for PPM, symptoms and beliefs (table). Qualitatively, participants described liking and using the WWE guidebook but wanted a foldable exercise leaflet and expanded online resources. Positive experiences were reported, with emergent themes of improved motivation, mental health and social well‐being. Conclusion: Findings indicate that WWE is a relevant and acceptable walking program in a UK context. Wider implementation of this evidence‐based program may benefit the physical health and well‐being of people with arthritis. (Table Presented).

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Long-term effect of elagolix on bone mineral density in women with endometriosis-associated pain Abstract: Introduction: To evaluate the long‐term effect of elagolix, an oral, non‐peptide GnRH antagonist, on bone mineral density (BMD) in two 6‐month (M) extension studies (Elaris EM‐III and IV) of the pivotal, 6M, phase 3 studies (12M overall treatment with 150mg once daily [QD] or 200mg twice daily [BID]). Methods: Women with moderate/severe endometriosis‐associated pain and a baseline BMD Z‐score.‐1.5 were randomized to receive elagolix in the pivotal studies and continued elagolix treatment in the extension studies (treated: Elaris EM‐III, n=287; Elaris EM‐IV, n=282). Total hip BMD was measured by dual energy X‐ray absorp‐tiometry and reviewed/evaluated by a blinded central reader. Baseline was before dosing in pivotal studies. Results: After 6M of elagolix treatment in the pivotal studies, the proportion of women with a decrease in total hip BMD $8% ranged 0‐1.1% across doses/studies; these women were not eligible for extension study. Following 12M treatment, the proportion of women with a total hip BMD decrease from baseline $8% was 1.8% (n=2) at 150mg QD and 0.9% (n=1) at 200mg BID in Elaris EM‐III and 0% (n=0) at 150mg QD and 4.6% (n=5) at 200mg BID in Elaris EM‐IV. For total hip, the mean BMD Z‐score at extension‐M6 was within the normal range of‐2.0 to +2.0 across doses/studies; no women had a total hip BMD Z‐score #‐2. Conclusion: In women with endometriosis‐associated pain, long‐term elagolix treatment was associated with decreases in total hip BMD, while the mean total hip BMD Z‐score was within the normal range and no women had a total hip BMD Z‐score #‐2.

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Prenatal use of aspirin and acetaminophen Abstract: INTRODUCTION: Acetaminophen is widely used in pregnancy for pain management. Recently published data indicates that in‐utero acetaminophen exposure may be associated with greater odds that the resulting child will develop ADHD. Aspirin may be a suitable alternative to pain management in the first and second trimesters. METHODS: A systematic review of English language publications using the search terms, “salicylates, pregnancy,” “congenital defects, aspirin,” acetaminophen and ADHD'' was conducted to describe perinatal outcome of in utero acetaminophen and aspirin exposure studies showing only third trimester adverse effects were excluded. RESULTS: The search found the following publications. 1 case report, 1 meta‐analysis, 2 systematic reviews, 1 case control, 1 randomized controlled trial, 4 retrospective cohort and 2 prospective cohort studies. Aspirin use during the first trimester was associated with increased risk of miscarriage and gastroschisis. There appears to be a comparable risk of cryptorchidism with both aspirin and acetaminophen use in the second trimester. The increased risk of miscarriage was significant only when the analgesic agent was taken at the time of conception. However, the increased risk of gastroschisis was heterogeneous, in the absence of controls for numerous confounders, may not be clinically significant. CONCLUSION: Prior to use of pain relievers during pregnancy, a thorough discussion of the known and potential risks versus the benefits of available analgesic agents should be followed by shared decision making when considering analgesic options. This has ethical and public health implications, given the reports that have associated in‐utero acetaminophen exposure with an increased risk of ADHD.

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Deltamethrin resistance in Aedes aegypti results in treatment failure in Merida, Mexico Abstract: The operational impact of deltamethrin resistance on the efficacy of indoor insecticide applications to control Aedes aegypti was evaluated in Merida, Mexico. A randomized controlled trial quantified the efficacy of indoor residual spraying (IRS) against adult Ae. aegypti in houses treated with either deltamethrin (to which local Ae. aegypti expressed a high degree of resistance) or bendiocarb (to which local Ae. aegypti were fully susceptible) as compared to untreated control houses. All adult Ae. aegypti infestation indices during 3 months post‐spraying were significantly lower in houses treated with bendiocarb compared to untreated houses (odds ratio <0.75; incidence rate ratio < 0.65) whereas no statistically significant difference was detected between the untreated and the deltamethrin‐treated houses. On average, bendiocarb spraying reduced Ae. aegypti abundance by 60% during a 3‐month period. Results demonstrate that vector control efficacy can be significantly compromised when the insecticide resistance status of Ae. aegypti populations is not taken into consideration. Copyright © 2017 Public Library of Science. All Rights Reserved.

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Clinical and electrophysiological correlates of absent somatosensory evoked potentials after post-anoxic brain damage: a multicentre cohort study Abstract: Introduction: Multimodal assessment is recommended for prognostication of coma after cardiac arrest (CA). Bilateral absence of cortical response (N20) to somatosensory evoked potentials (SSEPs) has very high predictive value for poor prognosis, however the exact correlates of absent N20 with other clinical, electrophysiological and biochemical outcome prognosticators are unclear. Objective: The aim of this study was to evaluate clinical and electrophysiological characteristics of patients with absent N20. Methods: Retrospective analysis of institutional databases (2007‐ 2014) in three academic ICUs including all adult comatose CA patients treated with targeted temperature management (TTM, for 24 hours) who underwent multimodal assessment including SSEPs (48‐72 hours after CA) as part of standard care. Additional data included clinical examination (absence of pupillary reflexes, absent or posturing motor response and myoclonus on day 2‐3), EEG (absence of reactivity to painful stimuli; presence of a malignant pattern, such as burst‐suppression or suppressed background; seizures or status epilepticus) during the first 48 hours and peak NSE levels over the first 72 hours from CA. Neurological outcome was assessed at 3 months using the Cerebral Performance Categories (3‐5 = poor outcome; 1‐2 = good outcome). Results: A total of 532 patients with SSEPs data were analyzed, of whom 143 (27 %) had bilateral absent N20 (N20ABS); 198 (37 %) patients had a good outcome and all had present N20 (N20+). Median time to SSEPs was 72 [IQRs: 48‐72] hours after arrest. In N20ABS patients, the occurrence of absent pupillary reflexes (74 % vs. 17 % in N20+; p < 0.001), absent or extension motor response (94 % vs. 38 %; p < 0.001), myoclonus (38 % vs. 8 %; p < 0.001) malignant EEG patterns (51 % vs. 21 %; p < 0.001) and non‐reactive EEG (90 % vs. 32 %; p < 0.001) was more frequent than others; also higher NSE (77.2 [37.5‐120.9] ‐ n = 64 vs. 21.0 mcg/L [14.9‐32.7] ‐ n = 238; p < 0.001] was found in N20ABS patients. N20ABS was concomitantly associated with at least one EEG finding (non‐reactive background, seizures or malignant pattern) and one clinical sign (bilateral absence of pupillary reflexes or myoclonus) of poor prognosis in 112/143 (78 % vs. 58/389 (15 %) in N20+, p < 0.001). Conclusions: Our data confirm that bilateral absence of N20 reflects severe post‐anoxic cerebral damage and therefore frequently correlates with concordant clinical and EEG signs of poor outcome. However, our study also identified a subset of patients with discordant signs, in whom clinical examination and/or EEG were reactive despite bilaterally absent N20. Our findings raise further questions on outcome prognostication after CA and underline the importance of multimodal assessment in this setting.

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Correction: FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): a post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomised open-label phase 3 trial (The Lancet Oncology (2016) 17(10) (1426–1434) (S1470204516302698) (10.1016/S1470-2045(16)30269-8)) Abstract: Stintzing S, Modest DP, Rossius L,et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE‐3): a post‐hoc analysis of tumour dynamics in the final RAS wild‐type subgroup of this randomised open‐label phase 3 trial. Lancet Oncol 2016; 17: 1426–34—In the appendix, page 9, supplementary table 3, the values for ORR ‘central independent review board’ should have read ‘113/157 (72·0%)’ and for the Difference ‘3/157 (1·9%)’ in the FOLFIRI plus cetuximab group. This correction has been made to the online version as of Oct 31, 2016.

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Results from phase 2 trial ongoing expansion stage of SL-401 in patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN) Abstract: Background: SL‐401 is a targeted therapy directed to the interleukin‐3 receptor (CD123), a target overexpressed on blastic plasmacytoid dendritic cell neoplasm (BPDCN) and other hematologic malignancies. BPDCN is an aggressive hematologic malignancy of unmet medical need that often presents in bone marrow and skin, and may also involve lymph nodes and viscera. Long‐term outcomes after treatment with chemotherapy have been very poor, with median overall survival from diagnosis of ∼12 months, highlighting the need for novel therapies. Results from the Phase 2 trial of SL‐401 in patients with BPDCN are reported here. Methods:This multicenter, single‐arm Phase 2 trial of patients with BPDCN includes a lead‐in (stage 1) and expansion (stage 2). In stage 1, patients with BPDCN or relapsed or refractory (r/r) AML received SL‐401 as a daily IV infusion at 7, 9, 12, or 16 ug/kg/day for days 1‐5 of a 21 day cycle. In stage 2, patients with BPDCN receive SL‐401 at the dose determined in stage 1. Results: As of 7/25/16, 29 patients with BPDCN have received SL‐401, including 16 first‐line and 10 relapsed/refractory (r/r) adults and 3 pediatric patients (under compassionate use). The 26 adult patients (9+17 in stages 1&2) received SL‐401 at 7 ug/kg (n=3 [stage 1]) or 12 ug/kg (n=23 [6+17 in stages 1&2]). The median adult age was 69 years (range: 29‐82 years). In stage 1, 12 ug/kg was the highest tested dose for BPDCN; MTD was not reached in BPDCN. Results in AML (r/r) patients will be reported separately. The most common treatment‐related AEs, all grades, were transient transaminase elevation (54%) and hypoalbuminemia (38%). Transient thrombocytopenia was also noted (19%). The most common ≥ Grade 3 treatment‐related AEs were transient transaminase elevation (42%) and thrombocytopenia (19%). Two stage 1 patients developed capillary leak syndrome (CLS): gr 5 (7 ug/kg) and gr 4 (12 ug/kg). Safety precautions, including monitoring of albumin levels and body weight, were successfully implemented to minimize risk of severe CLS, which has not occurred in patients with BPDCN since adoption. Twenty‐one of 26 adult patients were evaluable for response (response assessment from 3 recently treated patients are pending; 1 patient was discontinued for as yet unspecified reasons; and 1 patient treated at 7 ug/kg was not evaluable for response due to AE); median follow‐up for evaluable patients was 6.9 months (range: 0.6‐17.6 months). An 86% (18/21) ORR was observed in evaluable adult BPDCN patients. ORR in evaluable patients was 100% (14/14) in first‐ line and 57% (4/7) in r/r BPDCN. Of these, 92% (11/12) of first‐line patients treated at 12 ug/kg had a CR (n=8) or clinical CR (CRc: a CR in non‐skin organs with gross reduction in cutaneous lesions and residual microscopic skin disease) (n=3). 75% (9/12) of these patients remain progression free for 3+ to 16+ months (ongoing), including 4 patients who remain on SL‐401 in remission (for 3+ to 12+ months [up to 16+ cycles], ongoing) and 5 additional patients who experienced a major response on SL‐401 (3 CR, 1 CRc, 1 PR) and were then successfully bridged to stem cell transplant (SCT; 3 auto‐SCT and 2 allo‐SCT) and all remain progression free for 3+ to 16+ months (ongoing) since first SL‐401 dose. Notably, a patient with r/r BPDCN was recently bridged to allo‐SCT following CRc on SL‐401. Conclusions: SL‐401 demonstrates robust single agent activity in BPDCN, including 86% ORR in all‐lines, with multiple CRs, in evaluable patients. Six patients, including 1 r/r patient, have proceeded to SCT after achieving a major response from SL‐401, and an additional 7 patients remain on SL‐401 for up to 12+ months, ongoing. The SL‐401 side effect profile remains manageable, and no unexpected AEs have emerged with increased treatment duration, drug exposure, and patient enrollment. Response duration, progression‐free and overall survival data continue to be encouraging and updated data will be presented.

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Efficacy of IPX066, an extended-release formulation of carbidopa-levodopa, in advanced Parkinson's disease patients with troublesome dyskinesia Abstract: Objective: Evaluate the efficacy of IPX066 in advanced Parkinson's disease (PD) patients with troublesome dyskinesia. Background: IPX066 is an extended‐release formulation of carbidopa‐levodopa (CD‐LD) designed to provide a rapid increase in plasma LD concentrations similar to immediate‐release CD‐LD, but with sustained stable concentrations to allow a dosing interval of every 6 hours. IPX066 has demonstrated improvements in PD motor symptoms in early and advanced PD. Methods: IPX066 was administered for 13 weeks in a double‐blind, parallel‐group study vs. immediate‐release CD‐LD (IR) in advanced PD patients (randomized N=393). This posthoc analysis compared the cohort of patients who entered the study with any reported “on” time with troublesome dyskinesia, by patient diary (IPX066, n=44; IR, n=35). Efficacy measures included patient diaries and Unified Parkinson's disease Rating Scale (UPDRS) Parts II (activities of daily living)+III (motor score). Results: At baseline, these patients had a mean (SD) “on” time with troublesome dyskinesia of 1.7 (1.3) hr and 1.9 (1.6) hr, and mean “off” time of 5.3 (1.8) hr and 5.5 (1.7) hr, for IPX066 and IR groups, respectively. Baseline UPDRS Parts II+III scores were 30.3 (14.9) for IPX066 and 34.1 (14.8) for IR. At the end of the 13‐week treatment period, IPX066 treatment produced a significantly greater improvement in UPDRS Parts II+III scores (‐4.9 [10.5] points) compared to IR, which worsened by +1.6 (10.4) points (P<.001). IPX066 treatment also produced a greater decrease in “off” time (‐1.4 [2.8] hr) compared to the IR group (‐0.7 [2.9] hr), although this was not statistically significant (P=.13). Both groups showed less “on” time with troublesome dyskinesia at the end of treatment, ‐0.4 (1.9) hr for IPX066 and ‐0.8 (2.2) hr for IR (P=.40). Conclusions: Advanced PD patients with troublesome dyskinesia at baseline demonstrated significantly greater improvement in UPDRS Parts II+III scores and numerically greater improvement in “off” time after treatment with IPX066 compared to IR. These improvements were not accompanied by increased “on” time with troublesome dyskinesia in either treatment group.

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Effectiveness of hepatitis C virus (HCV) testing for persons born during 1945-1965-summary results from three randomized controlled trials Abstract: PURPOSE: CDC and the U.S. Preventive Services Taskforce recommend 1‐time HCV testing for persons born during 1945‐1965 (birth cohort). We present summary results from 3 independent trials to determine the relative probability of identifying HCV infections using birth cohort (BC) testing versus current screening protocol. METHODS: From December 2012 to February 2014, we conducted HCV (BC) testing trials at 3 large primary care healthcare centers using variations of the randomized controlled trial design. Across centers, patients born during 1945‐1965 with no clinical documentation of prior HCV test or infection were randomly assigned (individually or in defined clusters) to receive a 1‐time HCV test (intervention) or the prevailing screening protocol (control). In trial #1, we individually assigned patients to receive letters with invitations for BC testing. For trial #2, we assigned clinics to implement BC testing with provider Best Practice Alert. In trial #3, we assigned clinics to perform BC testing with trained recruiters; mid‐trial, intervention and control arms were switched such that each clinic served as its own control. Analysis was by intention‐to‐treat with patient as the unit of inference. We estimated the risk ratio (RR) of identifying patients with HCV antibody or RNA positive results (HCV+) using BC testing versus control for each trial, with adjustment for correlated data. We applied meta‐analysis to summarize individual risk ratios into a pooled effect estimate. RESULTS: In trial #1, 9,000 patients were allocated to BC (n=3,000) or control (n=6,000) in a 1:2 ratio, and 8,992 patients (BC=2,996; control=5,996) were included in the analysis. The RR of identifying HCV+ patients using BC testing versus control was 8.0 (95%CI 1.7‐37.7). In trial #2, 10 clinics were assigned to BC (n=5) or control (n=5) in a 1:1 ratio; data from 13,481 patients (BC=8,313 control=5,168) were analyzed. HCV+ patients were 3 times more likely to be identified using BC testing versus control (RR 3.1, 95%CI 1.2‐8.2). In trial #3, 4 clinics were assigned to both BC (n=4) and control (n=4) over 2 different time periods (crossover); data for 14,966 patients (BC=4,608; control=10,358) were analyzed. BC testing was 5 times more likely to identify HCV+ patients compared with control (RR 5.2, 95%CI 2.8‐9.5); period had no significant effect on outcome (p=0.20). Pooled RR of identifying HCV+ patients using BC testing versus control was 4.8 (95%CI 2.9‐7.8). CONCLUSIONS: HCV testing of persons born during 1945‐1965 without prior ascertainment of HCV risk was 5 times more effective in identifying persons with previous or current HCV infection compared with standard of care.

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The risk of severe treatment-related adverse events is significantly lower in children compared with adults when treated with SQ-standardised grass allergy immunotherapy tablets: post hoc analysis of seven clinical trials Abstract: Background: Allergy immunotherapy tablets (AIT) is a safe and more convenient alternative to subcutaneous specific immunotherapy treatment. However, severe adverse events occur infrequently. Pooled safety data from one phase II/III and six phase III clinical trials (five in adults, two in children 5‐17 years of age) with SQ‐standardised grass AIT (Phleum pratense 75 000 SQ‐T/ 2800 BAU) were analysed. Method: All trials were randomised, doubleblind, placebo‐controlled multi‐centre trials. Subjects suffered from grass pollen induced allergic rhinoconjunctivitis with or without asthma, had positive skin prick test and specific IgE to Phleum pratense. Subjects received once‐daily sublingual treatment with grass AIT or placebo for approximately 24 weeks. The five adult trials comprised 2095 treated subjects (AIT = 1060, placebo = 1035) and the two children trials comprised 597 treated subjects (AIT = 301, placebo = 296). Adverse events were assessed by the investigator as treatmentrelated (possible or probable) or unlikely related, and for seriousness. Application siterelated events were defined as adverse events in relation to the oral cavity. Result: In the adult trials, 71% of AITtreated subjects reported treatment‐related adverse events compared with 24% for placebo. In the children trials the corresponding numbers were 63% for AIT and 27% for placebo. Of the AIT‐treated subjects, two children (0.7%) and 32 adults (3.0%) experienced severe treatment‐related events. The odds for severe treatment‐related events was 4.7 times lower in children compared with adults (odds‐ratio with CI95%: 0.22 [0.025 0.85], P = 0.019). Two AIT‐treated children (0.7%) and 18 adults (1.7%) experienced severe treatment‐ related events that were application site‐related. The odds for having severe related application site adverse events was 2.6 times lower in children compared with adults (odds‐ratio with CI95%: 0.39 [0.04;1.63], P = 0.27, not statistically significant). No serious treatment‐related adverse events were reported. Conclusion: This pooled analysis of over 2000 subjects in seven clinical trials shows that the risk of experiencing severe treatment‐ related adverse events was significantly lower in children compared with adults when treated with SQ‐standardised grass AIT. This analysis provides evidence that grass AIT is an important and safe immunotherapy treatment option in children with grass pollen induced allergic rhinoconjunctivitis.

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Long-term outcome of ligasure haemorrhoidectomy vs. Conventional diathermy for IV-degree haemorrhoids: a prospective randomized trial Abstract: Background Milligan‐Morgan operation is still considered the treatment of choice for IV‐degree haemorrhoids: it is frequently associated with significant postoperative pain and prolonged hospital stay. Many instruments were conceived to reduce these complications, such as the LigaSureTM (LS) system, a combination of radiofrequency and pressure that seems mainly effective where a large tissue demolition is required. This prospective randomized study is designed to compare the effectiveness and long‐term outcome of LigaSureTM haemorrohidectomy with conventional diathermy (CD) in patients with IV‐degree haemorrhoids. Methods Seventy‐eight patients with IV‐degree haemorrhoids were randomly assigned to two different surgical treatments (conventional diathermy vs. LigaSureTM haemorrhoidectomy). They were evaluated on the basis of the following main outcomes: mean operative time, postoperative pain, day of discharge early, and late complications. The time of recovery of work was also assessed. All patients had a minimum follow‐up of 2 years (range 24‐36). All data were statistically evaluated. Results Forty patients were treated by conventional diathermy, 38 by LigaSureTM. The mean operative time was significantly shorter in LS, such as postoperative pain, mainly lower on the third and fourth postoperative day; moreover pain disappeared earlier in LS than CD. The time off‐work was shorter in LS, while there was no difference in hospital stay and overall complications rate. Conclusions This randomized prospective controlled trial confirms, according to other large trials in literature, the benefits of the LigaSureTM haemorrhoidectomy over conventional diathermy when a large tissue demolition is required, supporting the use of this device as treatment of choice in IV degree haemorrhoids; as the procedure is only more expensive than conventional operation. Even if compared to stapled haemorrhoidopexy (± pile/s excision), that is a conceptually different operation, LigaSure haemorrhoidectomy is safe, cheaper, and longterm effective.

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AN EXPLORATORY COMBINED MACHINE LEARNING AND PHARMACOGENOMIC APPROACH TO PRECISION TREATMENT OF AUD WITH ZONISAMIDE Abstract: Purpose: We aimed to advance precision medicine by identifying a profile of likely responders (LRs) to zonisamide from clinical trial data using a combined machine learning and pharmacogenomic approach. Methods: Clinical trial participants with alcohol use disorder (AUD) were genotyped with the Illumina PsychArray, and quality control was performed in PLINK v1.9. Imputations were made through the Michigan Imputation Server using the Haplotype Reference Consortium reference panel. For genetically defined European Americans (EAs) (N = 132), summary statistics from four previously published GWAS traits, e.g., drinks per week (DPW), and time to relapse (TR), were used to calculate polygenic risk scores (PRS) using PRScs. PRS variables were combined with demographic and other baseline phenotypic variables (craving, depression, etc.) in Random Forest (RF) analysis of 196 total participants (85% EAs, 38% women). The algorithm, performed in R, first identified a predictive classifier of LRs using a criterion of ≥40% actual reduction of heavy drinking during treatment in zonisamide treated participants. The resulting RF model was used to obtain predicted probabilities of being a LR for those randomized to zonisamide and counterfactually for those randomized to placebo. If the predicted probability was >50%, the subject was considered to be a LR to zonisamide (whether randomized to zonisamide or placebo) and tests of causal superiority comparing actual outcomes of zonisamide to placebo were performed using a Binomial Score test. Results: Based on out of bag measures, the RF model was very accurate in identifying LRs among patients randomized to zonisamide. Two PRS, (DPW and TTR), were identified as the most important features in predicting LR status with alcohol craving being the third most predictive. Without the PRS, the RF AUC dropped substantially to 0.767. LRs had higher polygenic risk for alcohol intake, lower polygenic risk for earlier relapse, and higher craving at baseline. Zonisamide was causally superior to placebo in LRs (score statistic = 2.802, p = 0.005). Conclusions: The RF model has good accuracy and is potentially clinically useful in determining whether a prospective patient is a LR to zonisamide prior to treatment. There are substantial causal benefits of treatment with zonisamide for patients predicted to be LRs. This approach warrants further research.

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Brief systemic therapy in people exposed to a recent highly stressful event: a randomised controlled trial Abstract: Background: Highly stressful events can have harmful effects on people's well‐being and mental health. Objective: To evaluate the efficacy of a preventive intervention protocol based on Brief Systemic Therapy oriented to people who recently experienced a highly stressful event. Method: Seventy‐five people participated, 39 were in the experimental group and 36 in the control group. A quantitative design with two groups (experimental and control) and two time points (pre‐and post‐intervention) was used for data analysis. A six‐month follow‐up was added to the experimental group. The protocol was structured in four sessions and aimed to impact on posttraumatic symptoms, posttraumatic growth, ruminative response and coping strategies. Results: An increase in posttraumatic growth, deliberate rumination, problem‐focused coping, and positive reinterpretation was observed in the experimental group. In contrast, there was only a nonsignificant trend in reduced posttraumatic symptomatology and in seeking social support. Conclusions: These results contribute to the development of Brief Systemic Therapy and support its usefulness in preventive intervention with people exposed to a highly stressful event.

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Immediate and Short-term Effects of Straw Phonation in Air or Water on Vocal Fold Vibration and Supraglottic Activity of Adult Patients with Voice Disorders Visualized with Strobovideolaryngoscopy: a Pilot Study Abstract: Purpose The first purpose of this study was to investigate and compare the short‐term effects after a semi‐occluded vocal tract (SOVT) therapy session consisting of straw phonation (SP) in air or water on vocal fold vibration and supraglottic activity of adult patients with voice disorders, visualized with strobovideolaryngoscopy (SVL). The second purpose of this study was to investigate and compare immediate changes in the patients’ vocal fold vibration and supraglottic activity during SP in air or water, visualized with SVL. Methods Twelve adult patients with voice disorders (eight women and four men, mean age 52 years) were assigned randomly to one of two study groups: SP in air or SP in water. Immediately before and after a therapy session of 15 min, participants underwent a rigid SVL to determine the short‐term effects of the SP session. At the posttherapy examination, flexible SVL while performing SP was added to determine the effects occurring during SP. The visual‐perceptual ratings were performed blindly and in random order by three laryngologists, using the Voice‐Vibratory Assessment with Laryngeal Imaging rating form for stroboscopy. Results Short‐term effects after SP: After the SP‐in‐air session, the supraglottic mediolateral compression decreased significantly. The SP‐in‐water session led to significantly increased left vibrational amplitude. Immediate effects during SP: During SP in air, a significantly increased left amplitude and mucosal wave, and significantly decreased mediolateral supraglottic activity, were found. SP in water tended to decrease the vibrational amplitude during performance of the task. A trend toward higher anteroposterior supraglottic compression was observed during both SP in air and water, being more prominent in the latter. Conclusion SP in air led to less false vocal fold adduction and consequently less hyperfunction. The small increment in anteroposterior supraglottic activity during SP in air and water might be related to epilarynx narrowing, an economic phenomenon associated with SOVT exercises. The effects on vibrational amplitude were rather ambiguous. The small reduction in amplitude during SP in water is expected to diminish vocal fold impact stress and therefore creates an ideal basis for voice therapy. The increment in amplitude and mucosal wave during SP in air might indicate insufficient supraglottic pressure to obtain the favorable effects of semi‐occlusion. Whether or not the rise in amplitude after the SP‐in‐water session is due to voice efficiency or voice fatigue remains unknown. Future larger‐scale investigation in subgroups of voice patients is needed to explore these hypotheses.

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Effect of a postcard immunisation reminder in hospital outpatients: a randomised controlled trial Abstract: Background: Missed immunisation opportunities occur at hospital outpatient visits. The Australian Childhood Immunisation Register (ACIR) identifies children <7 years not up‐to‐date with routine immunisations, but is under‐utilised in hospitals. Aims: To determine whether a randomly assigned postcard‐size immunisation reminder, provided at the clinic visit for 'not up‐to‐date' children, could facilitate catch‐up immunisation within 3 and 12 months. Methods: All children <7 years attending the Royal Children's Hospital (RCH) outpatients and not up‐to‐date according to ACIR were identified. Exclusion criteria included attending an immunosuppression clinic or allied‐health appointment. On alternate days, rotating weekly, immunisation reminder postcards were distributed to identified parents and the clinic doctor. The postcard also highlighted the RCH Immunisation Drop‐in Centre as a place to discuss immunisations. Individual ACIR records were reviewed again 3 and 12 months post the initial visit. Results: Between 28 February ‐ 25 August 2008, 1563 children were flagged by ACIR [332 misclassified; 102 allied health clinics; 15 immunosuppression clinic], leaving 1114 study participants [648 control; 466 intervention group]. At 3 months 26.5% (123/464) were up‐to‐date in the intervention group, 0.4% greater than controls [Odds ration (OR) 1.02 (95% confidence intervals (CI) 0.77; 1.36), P = 0.88]. At 12 months 31.2% (144/462) were up‐to‐date in the intervention group, controls 31.1% (OR 1.00 [95% CI 0.77; 1.31] P = 0.98). In univariate analysis medical appointments versus surgical were 1.6% more likely to be up‐to‐date at 3 months (P = 0.65). 27 patients attended the Drop‐in Centre; 10 had ACIR records updated and 65% (11/17) requiring vaccines had them administered. Conclusion: The postcard reminder did not provide additional benefit regarding up‐to‐date status. The ability to link outpatient appointments with immunisation outcomes was established. The proposed introduction of electronic health records will provide new opportunities to act on ACIR status within healthcare appointments.

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Gonadotropin-releasing hormone agonist versus expectant management for treating multiple leiomyomas after myomectomy: the study protocol for a multicentre, prospective, randomised controlled clinical trial Abstract: Introduction Leiomyoma recurrence is a major concern for long‐term myomectomy management, especially for multiple leiomyomas. Gonadotropin‐releasing hormone agonist (GnRHa) is one of the most effective medications to reduce the volume of fibroids and the uterus. However, its role in preventing recurrence after conservative surgery remains unclear. At present, there is no randomised clinical trial determining the efficacy of GnRHa treatment for preventing multiple leiomyomas recurrence after myomectomy. Methods and analysis We are conducting a phase IV randomised controlled trial in women aged 18‐45 undergoing myomectomy for multiple leiomyomas. After surgery, women whose pathological result confirms multiple leiomyomas are randomised in a 1:1 ratio into an observation or GnRHa group. The primary outcome is the recurrence of either clinical symptoms or fibroids on imaging. Patients will be assessed for adverse events during the follow‐up. Ethics and dissemination The study was approved by the Medical Ethics Committee of the Tongji Hospital Affiliated with the Tongji Medical College of Huazhong University of Science and Technology (TJ‐IRB20180311) according to the submitted study protocol (V.1.0, 10 November 2017) and informed consent (V.1.0, 10 November 2017). The results will be presented at domestic and international conferences and published in peer‐reviewed journals.

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Integrated Chinese and western medicine for acute guillain-barré syndrome treatment Abstract: Guillain‐Barré syndrome (GBS) is a worldwide demyelinating polyradiculopathy and polyneuropathy. Currently, there is no specific drug for GBS, and established treatment is generally based on immune‐modulating treatment with plasma exchange or intravenous immunoglobulin in combination with supportive care. This study aimed to investigate the efficiency of integrated Chinese and Western medicine for acute GBS treatment. We enrolled 73 subjects, and randomly divided them into two groups: 35 cases in the traditional Chinese medicine (TCM) group, and 28 in the Control group. The Control group was treated with the common Western medicine for one month; and the TCM group was administrated with one month of common treatment combined with TCM medication. Compared to the controls, TCM significantly enhanced the treatment efficiency in symptom expression, including the TCM syndrome score, the activity of daily living score, Hughes functional score and sensory dysfunction assessment. The total effective rate of the TCM group was 94.29%, significantly better than controls (78.59%). Moreover, TCM provide better improvement in motor nerve conduction functions (distal motor latency and motor conduction velocity) and sensory nerve conduction functions (sensory conduction velocity and sensory nerve action potential) in median nerve, ulnar nerve, and common fibular nerve. When combined with TCM administration, the GBS treatment could acquire better outcomes.

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Acceptability to parents of a baby-led approach to introducing solids Abstract: In Baby‐Led Weaning (BLW), infants are offered foods they can pick up and feed themselves from the start of complementary feeding. Infants who are fully BLW are not spoonfed at all by their parents, feeding themselves all their foods instead. The Baby‐Led Introduction to SolidS (BLISS) study was a randomised controlled trial of the effect of a modified version of BLW5 on infant growth, iron status, and risk of choking, and provides an opportunity to investigate parents' experiences of using a baby‐led approach to infant feeding. Complementary feeding methods are usually chosen by parents, so it is important to ascertain whether parents find a baby‐led method of introducing solids acceptable if they are assigned to follow it. This is both to determine whether it would be feasible to randomise them to follow BLW in future randomised controlled trials and because, if beneficial effects of BLW are shown, policy makers need to know whether parents would find it acceptable to follow BLW. The aim of this analysis was to determine the acceptability to parents of a baby‐led approach to complementary feeding when their infant was 7 to 12 months of age. In total, 206 participants were randomised to Control (n = 101) or BLISS (n = 105) groups in the third trimester of pregnancy. When the infants were 7, 8, 9, and 12 months of age, questionnaires were administered to determine parents' happiness and frustration with their feeding method, and attitudes regarding its convenience, mess, and expense. Food cost was estimated using supermarket prices linked to a 3‐day weighed diet record collected at 7 months of age. Both groups reported high levels of happiness and convenience, but also reported finding complementary feeding very frustrating. There were two significant differences between the groups ‐ the BLISS group reported less messiness, and were more likely to perceive their method as expensive. The actual food cost per day was not statistically significantly different between the two groups (NZ$1.70 for BLISS, NZ$1.90 for Controls). In conclusion, parents did not find a baby‐led approach to introducing solids any less acceptable than control parents found standard infant feeding. It is, therefore, feasible to run studies where parents are randomised to follow a baby‐led approach to complementary feeding and, should health advantages to BLW be identified, parents are likely to find BLW acceptable to follow.

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Recruitment to the randomised iron deficiency anaemia management pilot (RAINDroP) Abstract: Introduction: The RAINDroP study is a pilot randomised clinical trial investigating the possible benefits of replacing oral iron therapy with intravenous iron in the treatment of iron deficiency anemia. One of the primary outcomes is recruitment rates, and the aim is to use multiple channels to maximise the pool of potential participants. Method: Recruitment to the study is running in parallel in primary and secondary care utilising support from both primary care and ageing research networks to facilitate screening. Broad inclusion/exclusion criteria have been applied, to include co‐morbidities that would be expected within the eligible population. Four sites have been selected for the study, two in Scotland and two in England. Study posters, a website and local press will also be used to boost recruitment A secure Patient Management System (PMS) incorporating central mailing designed by the Health Informatics Centre at Dundee University is core to the administration of this multiple recruitment strategy. Where potential participants are identified their details will be securely uploadedto the PMS which can then be accessed by study staff at the relevant site. Timing of Potential Results: The trial is due to end in January 2020, with a review of recruitment carried out in May 2019. Potential Relevance and Impact: There is a significant population prescribed oral iron for iron deficiency anaemia but there is a lack of evidence to show the benefit of this intervention. The RAINDroP study aims to identify the most effective methods of recruitment and inform the design and sample size calculation for a future definitive trial. The impact for patients with Iron deficiency anaemia could be a change to the treatment pathway which will include improved quality of life and physical outcomes along with reduced side effect profile should IV iron prove to be the best intervention.

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Compressive strength of three all-ceramic chairside CAD/CAM onlays Abstract: BACKGROUND: The use of chairside computer aided design/computer aided manufacture (CAD/CAM) system is a convenient way to fabricate porcelain onlays that have been widely used in clinical practice. Different chairside CAD/CAM all‐ceramic materials have different physical and chemical properties, which make a certain difficulty in clinical selection. There are few studies on compressive strength of chairside CAD/CAM porcelain onlays at home and abroad. OBJECTIVE: To investigate the fracture strength of onlay restorations with different chairside CAD/CAM all‐ceramic materials. METHODS: Thirty onlay specimens of isolated teeth were prepared in the study. These specimens were randomly divided into three groups: CEREC Blocs group, IPS e.max CAD group and Lava Ultimate group. In each group, 10 specimens were randomized into two subgroups: bonding group (dual‐curing resin adhesive) and unbonded group. Afterwards, these specimens were subjected to vertical compressive loading; the maximum force at fracture and patterns of failure were recorded. RESULTS AND CONCLUSION: (1) In these groups, the maximum fracture strength was (313.22±56.00) MPa for IPS e.max CAD bonding group; the minimum fracture strength was (15.85±5.20) MPa for CEREC Blocs unbonded group. The fracture strength of IPS e.max CAD was higher than that of the other five groups (P < 0.05). The fracture strength of the bonding group was greater than that of the unbonded group (P < 0.05). There was no significant difference in the fracture strength of the Lava Ultimate and CEREC Blocs groups. (2) In the unbonded group, only fractured porcelain pieces were detected. In the bonding group, fracture of porcelain pieces was often accompanied by tooth fractures. The tooth fracture rate of the bonding group was greater than that of the unbonded group (P < 0.05). There was no significant difference in the failure mode between all‐ceramic materials (P > 0.05). (3) Under the condition of this study, the highest fracture strength was found with the IPS e.max CAD material in the three kinds of CAD/CAM all ceramic materials.

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Comparing the effectiveness of sponge cooling and ice packs methods on controlling the patients’ fever in intensive care units: a randomized clinical trial Abstract: Introduction: Fever is a common problem in intensive care unit. Therefore, this study aimed to compare the effectiveness of two methods of sponge cooling with ice packs on controlling of patients’ fever in intensive care units. Method: This is a randomized clinical trial, which conducted on 60 patients hospitalized in intensive care units in Valie‐Asr hospital in 2017. Patients randomly allocated into two groups of sponge cooling and ice packs based on blocking method. The patients were under intervention up to 3 hours. Changes in body temperature every 15 minutes in both groups were recorded. Results: The average of age in the group of sponge cooling was 41.87 ± 13.92 and in the group ice packs was 41.7 ± 14.48. Two groups have no significant differences on age, sex, and length of stay in hospital before intervention. After 3 hours of intervention, the mean body temperature in the group of sponge cooling was 37.71 ± 0.44°C and in the group of ice pack was 37.80 ± 0.48°C. This means that reducing the body temperature is the same in both groups and they had no significant difference. The consecutive measurements of body temperatures in both groups significantly have declined (P = 0.0001). Conclusion: Both methods of sponge cooling and ice packs were effective on fever of the patients. As chills and inconvenience were less in sponge cooling group, this method recommended for reducing fever in ICU.

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Decompression Surgery Alone Versus Decompression Plus Fusion in Symptomatic Lumbar Spinal Stenosis: a Swiss Prospective Multi-center Cohort Study with 3 Years of Follow-up Abstract: STUDY DESIGN.: Retrospective analysis of a prospective, multicenter cohort study. OBJECTIVE.: To estimate the added effect of surgical fusion as compared to decompression surgery alone in symptomatic lumbar spinal stenosis patients with spondylolisthesis. SUMMARY OF BACKGROUND DATA.: The optimal surgical management of lumbar spinal stenosis patients with spondylolisthesis remains controversial. METHODS.: Patients of the LSOS with confirmed DLSS and spondylolisthesis were enrolled in this study. The outcomes of this study were Spinal Stenosis Measure (SSM) symptoms (score range 1‐5, best‐worst) and function (1‐4) over time, measured at baseline, 6, 12, 24 and 36 months follow‐up. In order to quantify the effect of fusion surgery as compared to decompression alone and number of decompressed levels, we used mixed effects models and accounted for the repeated observations in main outcomes (SSM symptoms and SSM function) over time. In addition to individual patients' random effects, we also fitted random slopes for follow‐up time points and compared these two approaches with Akaike's Information Criterion (AIC) and the chi‐squared test. Confounders were adjusted with fixed effects for age, gender, BMI, diabetes, CIRS musculoskeletal disorders and duration of symptoms. RESULTS.: One hundred and thirty‐one patients undergoing decompression surgery alone (n?=?85) or decompression plus fusion surgery (n?=?46) were included in this study. In the multiple mixed effects model the adjusted effect of fusion versus decompression alone surgery on SSM symptoms was 0.06 (95% confidence interval, CI: ‐0.16 to 0.27) and ‐0.07 (95% CI: ‐0.25 to 0.10) on SSM function, respectively. CONCLUSIONS.: Among the patients with degenerative lumbar spinal stenosis and spondylolisthesis our study confirms that in the two groups, decompression alone and decompression plus fusion, patients distinctively benefited from surgical treatment. When adjusted for confounders, fusion surgery was not associated with a more favorable outcome in both SSM scores as compared to decompression alone surgery.Level of Evidence: 3 Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Curative effect analysis of hepatoprotection by Jianganle particle combined with western medicine treatment on antituberculotic drug induced liver injury Abstract: Background: The research aimed to curative effect of hepatoprotection by Jianganle particle combined with diammonium glycyrrhizinate and tiopronin treatment on antituberculotic drug induced liver injury. Methods: 36 cases were randomly divided into two groups, 18 patients were treated with diammonium glycyrrhizinate and tiopronin as control group, at the same time 18 patients were treated with Jianganle particle combined with glycyrrhizinate and tiopronin as treatment group. The liver function such as TBIL, DBIL, AST, ALT, ALP, GGT, and PT were observed before and after treatment. Result: After treatment, the liver function index of the treatment group was decreased significantly (P<0.05). There is obvious differences between the two groups of clinical efficacy (P<0.05). Conclusion: The clinical curative effect is remarkable by Jianganle particle combined with glycyrrhizinate and tiopronin treatment on antituberculotic drug induced liver injury.

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The effect of testosterone therapyon muscle mass, bone mass and haemoglobin in hypogonadal men with cirrhosis Abstract: Background and Aims: Low testosterone and sarcopenia are common in men with cirrhosis and both are associated with adverse outcome. The effect of testosterone therapy on body composition has not previously been investigated in this population. Methods: We conducted a 12 month double‐blinded, randomised, placebo‐controlled trial of intramuscular testosterone decanoate in 101 men with established cirrhosis and low serum testosterone (total testosterone <12 nmol/L or free testosterone <230 pmol/L). Total body composition was quantified using dual‐energy X‐ray absorptiometry. Results: Appendicular lean muscle mass was significantly higher in the active group compared to placebo at 12 months (mean adjusted difference (MAD) 1.69 kg, CI 0.40‐2.97 kg, p = 0.021). Total lean mass was similarly higher in the active group (MAD 4.74 kg, CI 1.75‐ 7.74 kg, p = 0.008). Fat mass was lower in the actively treated group (MAD‐4.34 kg, CI‐2.04 to ‐6.64 kg, p < 0.001). Bone mineral density was significantly higher at the femoral neck and total bone mass were both significantly higher in the active group (MAD in T score 0.287 points, CI 0.140‐0.4340.140‐0.434, p < 0.001; (MAD in bone mass 0.08 kg, CI 0.01‐0.15 kg, p = 0.009). Haemoglobin was significantly higher in actively treated patients (MAD 10.2 g/L, CI 1.50‐18.9 g/L, p = 0.041) and HbA1c was lower (MAD ‐0.35%, CI ‐0.05 to ‐0.54, p = 0.028). No serious adverse effects were reported. There were more deaths on placebo (25.5%) than active treatment (16%) but this was not significant (p = 0.352). Conclusions: Testosterone therapy in men with cirrhosis and low baseline testosterone levels safely improves muscle mass, bone mass and haemoglobin, and reduces fat mass and HbA1c. This is a promising new therapy for systemic complications of cirrhosis that targets a specific hormonal imbalance in men with cirrhosis. (Figure Presented).

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Evaluation of anesthesia profile in pediatric patients after inguinal hernia repair with caudal block or local wound infiltration Abstract: AIM: The aim of this study is to evaluate anesthesia and recovery profile in pediatric patients after inguinal hernia repair with caudal block or local wound infiltration. MATERIAL AND METHODS: In this prospective interventional clinical study, the anesthesia and recovery profile was assessed in sixty pediatric patients undergoing inguinal hernia repair. Enrolled children were randomly assigned to either Group Caudal or Group Local infiltration. For caudal blocks, Caudal Group received 1 ml/kg of 0.25% bupivacaine; Local Infiltration Group received 0.2 ml/kg 0.25% bupivacaine. Investigator who was blinded to group allocation provided postoperative care and assessments. Postoperative pain was assessed. Motor functions and sedation were assessed as well. RESULTS: The two groups did not differ in terms of patient characteristic data and surgical profiles and there weren’t any hemodynamic changes between groups. Regarding the difference between groups for analgesic requirement there were two major points ‐ on one hand it was statistically significant p < 0.05 whereas on the other hand time to first analgesic administration was not statistically significant p = 0.40. There were significant differences in the incidence of adverse effects in caudal and local group including: vomiting, delirium and urinary retention. CONCLUSIONS: Between children undergoing inguinal hernia repair, local wound infiltration insures safety and satisfactory analgesia for surgery. Compared to caudal block it is not overwhelming. Caudal block provides longer analgesia, however complications are rather common.

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