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Safety, pharmacokinetics and proof-of-mechanism of an oral bruton's tyrosine kinase inhibitor HM71224 in healthy adult volunteers Abstract: Background: HM71224 is an orally available, irreversible and highly selective small molecule inhibiting Bruton's Tyrosine Kinase (BTK) which plays key roles in B‐cell receptor (BCR) and Fc receptor (FcR) signaling cascades and B cell development and activation. HM71224 showed strong efficacy in mice and rat collagen induced arthritis models, dose‐proportional pharmacokinetic (PK) profile and acceptable tolerability in healthy male volunteers. Therefore, HM71224 may provide a new therapeutic option for active rheumatoid arthritis (RA). We hereby report updated data from the first in man clinical study with HM71224 (NCT01765478). Objectives: To evaluate safety, tolerability, PK and pharmacodynamics (PD) of HM71224 following once daily or twice daily multiple ascending dose (MAD) in healthy volunteers. Methods: MAD part was performed in a randomized, double‐blind, placebocontrolled design in which subjects were administered HM 71224 once daily (10 mg ∼120mg) or twice daily (5mg ∼ 60mg) for 14 days. Adverse events (AEs) were monitored throughout the study. Blood samples were collected to measure HM71224/metabolites concentration and explore PD effect such as BTK occupancy. Results: HM71224 showed good safety profile up to once daily MAD of 80 mg HM71224. No drug‐related serious AEs were reported in twice daily MAD dosing. Following multiple ascending administration of HM71224, exposure in plasma (Cmax and AUC0‐t) increased approximately dose‐proportionally. BTK occupancy was increased with blood concentration of parent HM71224 and above 90 percent of BTK occupancy was achieved at a trough level with 20 mg twice daily MAD. Conclusions: HM71224 is being developed as a BTK inhibitor for RA treatment. HM71224 demonstrated well‐tolerated safety profile in HVs and desirable PK and PD properties supporting sustained target inhibition. Phase 2 study will be initiated in active RA patients soon.

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Periprocedural outcomes of prophylactic protamine administration for reversal of heparin after cryoballoon ablation of atrial fibrillation Abstract: Purpose: The aim of this study was to investigate the efficacy and the safety of prophylactic use of protamine in a series of heparinized patients having undergone cryoballoon (CB) ablation for atrial fibrillation (AF). Methods: From October 2013 to January 2014, 54 consecutive patients received protamine after CB ablation to neutralize unfractionated heparin (UFH) effects. They were prospectively included in this study and compared to a control group of 53 patients who underwent CB ablation without receiving protamine. Results: A total of 54 consecutive patients (33 male, 61 %; mean age, 58 + 12 years) were included. Twenty‐one patients (39 %) presented with hypertension, 17 (31 %) with dyslipidemia, and 4 (7 %) with diabetes. Five patients (9 %) had a previous episode of ischemic stroke. Mean protamine dose was 68 + 22 mg. No adverse reaction to protamine was observed. Among patients having received protamine, one (2 %) experienced a cardiac tamponade requiring non‐surgical drainage. No patient having undergone protamine administration experienced vascular complications. Conversely, the group of patients not treated with protamine had a significantly higher incidence of vascular complications as compared to patients having undergone protamine infusion (11 vs 0 %, p = 0.01). Conclusions: Reversing effects of UFH by the means of protamine administration appears to be safe after CB ablation for AF. It can allow in‐laboratory sheath removal with potentially less vascular complications and no increase of thromboembolic risk. Larger randomized studies are needed in order to confirm our findings.

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A phase II randomized trial of lapatinib with either vinorelbine or capecitabine as first- and second-line therapy for HER2 overexpressing metastatic breast cancer (MBC) Abstract: Background: Lapatinib (L) is approved for the treatment of human epidermal growth factor receptor 2 (HER2) positive MBC in combination with capecitabine (C) following progression after trastuzumab, anthracyclines and taxanes. Vinorelbine (V) is an important chemotherapy option in MBC. This randomized, open‐label, multicenter phase II study (NCT01013740 ) evaluated the efficacy and safety of L with either V or C in women with HER2+ MBC. The analysis of progression‐free survival (PFS) and safety showed comparable rates of efficacy and tolerability between the 2 arms (Janni et al, SABCS 2012). Here we report the results of the overall survival (OS) and crossover analyses. Methods: Patients with MBC who had received 1 chemotherapy regimen in the metastatic setting were randomized 2:1 to either L 1250 mg orally once daily (QD) continuously + V 20 mg/m2 intravenously on days 1 and 8, every 3 weeks, or L 1250 mg orally QD continuously + C 2000 mg/m2/day orally in 2 doses, 12 hours apart on days 1‐14 every 3 weeks. Patients were stratified by prior receipt of therapy for MBC and site of metastatic disease. The primary endpoint was PFS. Other endpoints included OS, overall response rate and safety. Patients progressing on one treatment arm were given the option of crossover to the other arm. All analyses were conducted with a descriptive intent only. The control arm of L+C was included in the study design to validate the patient population and lend support to the activity of L+V. Results: 112 patients were randomized in the study; 37 to the L+C arm and 75 to the L+V arm. The median OS in the L+C arm was 19.4 months [95% CI: 16.4‐27.2] and 24.3 months [95% CI: 16.4‐NE] in the L+V arm. At the time of analysis 42 patients had crossed over; 29 patients to L+C and 13 to L+V. Median PFS after crossover was 4 months [95% CI: 2.1‐5.8] in the L+C arm and 3.2 months [95% CI: 1.7‐5.1] in the L+V arm. Conclusions: L+V has shown consistent median OS with that reported in the pivotal study of L+C. The exploratory analysis of patients retreated with L after progression on L supports the biological rationale for maintaining HER2 suppression in HER2+ patients with progression on prior lines of anti‐HER2 agents.

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Diagnostic value of serum adenosine deaminase levels in sputum smear negative pulmonary tuberculosis patients in Nepalese population Abstract: Objective: To assess the levels of adenosine deaminase (ADA) in serum in patients with sputum smear negative pulmonary tuberculosis (SNPTB) and to compare it with serum ADA levels in patients with non‐tuberculous pulmonary disease ‐ chronic obstructive pulmonary disease (COPD) and with healthy control group and to explore its validity as a diagnostic marker in serum in SNPTB patients. Methods: Three groups of study populations were made. Group I: SNPTB ‐ 142 cases, Group II: non‐tubercular pulmonary disease ‐ COPD ‐ 40 cases, Group III: healthy controls ‐ 80 cases. Serum samples were collected and ADA assay was done by the method of Guisti and Galanti. Results: ADA levels (Mean±SD, U/L) in the three groups were as follows: Group I: 42.26±21.22, Group II: 23.31±8.22, Group III: 18.88±6.67. Difference between Group I and Group III was statistically significant (P < 0.0001). The test showed a high specificity 91.25% (95% confidence interval ‐ CI 83.00 ‐ 95.7) and a sensitivity of 83.10% (95% CI 76.08‐88.37) in Group I. Positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio and accuracy in Group I were 94.00%, 69.52%, 9.49, 0.18 and 82.43% respectively. Conclusions: Overall assessment of the use of serum ADA levels as a diagnostic biochemical marker in smear‐negative pulmonary tuberculosis patients showed promising results. Studies with a larger population group are required to validate its use as a routine diagnostic test in these cases. © 2012 Asian Pacific Tropical Biomedical Magazine.

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Effectiveness of video-based home exercise for osteoarthritis of the knee: a randomized controlled trial Abstract: Purpose: Several systematic reviews conclude that exercise therapy has beneficial effects on pain and physical function of the population with osteoarthritis (OA) of the knee. However, its positive post‐treatment effects on pain and physical function declined over time. Exercise adherence has been shown to be an important predictor of long‐term outcome in exercise therapy. Video media can be an effective means of delivering exercise instruction. Therefore, use of a home exercise video could enhance adherence to prescribed exercise program. No published research to date has investigated the effectiveness of a home exercise video for patients with knee OA. The purpose of this study was to investigate the effects of video‐based home exercise on pain, physical function and quality of life in patients with knee OA in comparison with those of conventional quadriceps exercise. Methods: One hundred seven subjects, aged 50 years or older with knee pain and radiographic evidence of OA (Kellgren‐Lawrence Grade 2, 3, or 4) were randomized to a video‐based exercise group or a control group. Subjects in the video‐based exercise group received a digital video disk‐based program encompassing eight types of muscle stretching, active ROM exercises, and muscle strengthening. Initially, they watched the video alongside a physiotherapist. They were then given a 30‐min exercise video to take home and use it during home exercise, reinforced at a clinic visit 4 weeks later. Subjects in the control group received detailed verbal and hands‐on instruction in a home‐based program of a conventional quadriceps exercise program initially, reinforced at a clinic visit 4 weeks later. Subjects in both groups were evaluated after 3 and 6 months and compared with the baseline scores. Measured outcomes were self‐reported exercise adherence collected from diaries, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), 8‐Item Short‐Form Health Survey (SF‐8), pain during walking with the visual analog scale (VAS), and the body mass index (BMI). Results: Concerning exercise adherence, subjects in the video‐based exercise group performed the prescribed exercise 5.3 times (SD 1.9) and 5.0 times (SD 2.0) in a week at 3 and 6 months, while those in the control group performed the prescribed exercise 3.9 times (SD 2.1) and 3.7 times (SD 2.4), respectively. The numbers of times in the video‐based exercise group were significantly higher than those in the control group (3 months: p<0.008, 6 months: p<0.017). The video‐based exercise group showed significant improvements in WOMAC, SF‐8 physical component summary, and VAS scores at 3 months; improvements were still evident at 6 months, while there were no significant improvements in scores of SF‐8 mental component summary. In addition, the video‐based exercise group showed significant reduction of BMI at 3 and 6 months, but the control group not. The improvements at each period in WOMAC, SF‐8 physical component summary, and VAS scores were significantly greater in the video‐based exercise group than in the control group, while we failed to find significant differences in the amount of BMI loss between these two groups. Conclusions: Video‐based home exercise can enhance adherence to prescribed exercise program and produce substantial improvements in pain, physical function and quality of life in patients with knee OA.

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Evaluation of prednisolone and prednisolone sodium succinate concentrations in human plasma and inner ear perilymph during cochlear implantation 24 h after intratympanic injection Abstract: Background: The use of intratympanic (IT) steroids has drastically increased over the past 10–15 years to manage many otological pathologies. Objectives: This study aimed to compare the concentrations of prednisolone and prednisolone sodium succinate (SS) in the plasma and inner ear perilymph of participants who underwent cochlear implantation 24 h after IT injection. Materials and methods: It was a prospective comparative randomized study. Twenty participants received an IT injection of prednisolone SS ∼24 h before the cochlear implantation. The other five participants received an IT saline injection and represented the control group. Perilymph and blood were sampled during the cochlear implantation surgery. Results: Both prednisolone and prednisolone SS were still present in perilymph ∼24 h after the IT administration. Only prednisolone was present in the blood plasma of seven participants (35%). Conclusion: IT injection of prednisolone SS resulted in high perilymph concentrations of prednisolone and prednisolone SS, which could stay in the perilymph for at least 24 h. Using a mini‐endoscope during the IT injection may effectively detect barriers infront of the round window membrane, increasing the drug concentration in the inner ear. Significance: IT injection is an effective method for delivering prednisolone to the inner ear.

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Real-world efficacy and safety of mycophenolate mofetil in active moderate-to-sight-threatening thyroid eye disease Abstract: Purpose: There is no universal consensus on second‐line agents for the treatment of moderate/severe to sight‐threatening thyroid eye disease (TED) to maintain remission after first‐line intravenous methylprednisolone (IVMP). This study investigates the efficacy and safety of mycophenolate mofetil (MMF) in TED patients in a real‐world setting and over a longer period than previous randomized controlled trials. Methods: A retrospective cohort study of TED patients with active moderate/severe to sight‐threatening TED seen over a 4‐year period. Data collected were visual acuity (VA), Clinical Activity Score (CAS), Gorman Diplopia scores, MMF dosing and side effects at 24, 52 and 78 weeks. Clinical efficacy was defined as an absence of relapse: no decline in best corrected LogMAR VA, no need for further steroids, no increase in CAS of ≥2. Results: Out of 23 patients, 20 patients were included in this study. 10% (2/20) stopped MMF before 24 weeks. Median duration of MMF treatment was 76 weeks (1–140 weeks). 55% (11/20) had dysthyroid optic neuropathy (DON). In those with active moderate‐severe TED without DON, clinical efficacy was seen in 100% (8/8) at 24 weeks, 87.5% (7/8) at 52 weeks, and 83.3% (5/6) at 78 weeks, with CAS decreasing from a baseline of 2.78±1.99 to 0.50±0.58 at 24 weeks, 0.50±0.82 at 52 weeks and 1.00±1.30 at 78 weeks. In DON, improvements were seen in 90% (9/10) at 24 weeks, 100% (7/7) at 52 weeks and 100% (4/4) at 78 weeks, with significantly reduced CAS scores from 2.55±1.54 to 0.83±1.27, 1.00 ±1.17 and 0.63±0.95 at 24, 52 and 78 weeks, respectively. Gorman score, VA and soft tissue inflammation parameters also improved throughout. There were two significant side effects over the treatment period. Conclusion: MMF appears to be an effective and safe second‐line immunosuppressive agent. Further studies aimed at elucidating optimal dosing regimens and ideal treatment duration will prove helpful.

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Genetic aspects associated with the seed per pod trait in soybean Abstract: Numerical traits related to yield have different sensitivity to the environment, being the seed per pod (SPP) one of the most stable, providing an opportunity to increase it genetically if lines with high SPP were available. The SPP is a weighted mean that depends on the relative quantity of pods with different number of 2‐, 3‐, and 4‐seeds (2SP, 3SP, and 4SP, respectively). In our Laboratory, lines with SPP > 3.7 (i.e., with +70% 4SP) were developed. In the Argentine market there are no soybean commercial varieties with high % 4SP. The aim of this study was to characterize genetic aspects related to SPP and associated traits such as pod number per plant (PNP), seed number per plant (SNP), % 2SP, % 3SP and % 4SP, and their possible association, during the growing seasons (GS): 2015/16 and 2016/17. A set of 131 recombinant inbred lines (RIL) derived from the cross of two experimental lines: one with SPP = 3.53 (54% 4SP) and the other with SPP = 2.25 (0% 4SP), were used. The RIL population with their parents, hybrids and their reciprocals were planted in a single‐line plot of 2 m in length and 0.52 m in width, in a randomized complete block design with three replications. Six plants of each inbred line (genotype) were phenotyped at full maturity for SPP, PNP, SNP and the % of 2SP, 3SP and 4SP. All the screened traits showed variability in the RIL. Mean values for each trait in both GS were: SPP = 2.8 (range: 2.0‐3.9); PNP = 68 (range: 13‐187); SNP = 189 (range: 20‐532); % 2SP = 32% (range: 0‐100%); % 3SP = 55% (range: 0‐91%); % 4SP = 13% (range: 0‐78%). For variance components, genotype explained >85% of the total variation for SPP, as well as % of 2SP, 3SP, and 4SP. Conversely, genotype only explain <5% of the total variation for PNP and SNP. These results show high narrow sense heritability values (h 2 ) for SPP, % 2SP, % 3SP and % 4SP (h 2 > 0.95); and low heritability for PNP and SNP (h 2 < 0.23). Correlation coefficients among the different traits were: SPP and % 4SP (r = 0.9, P < 0.01); PNP and SNP (r = 0.9, P < 0.01); SPP and PNP (r = ‐0.1, P < 0.01). Results proved the strong genetic regulation and limited environmental influence that presents the SPP trait, providing the possibility to improve it through the increase in the % 4SP. Additionally, even though SNP is highly associated with PNP, the low correlation between PNP and SPP proved the lack of tradeoff between these two components. Thus, the positive effect of incorporating the high % 4SP trait on SPP will be maintained regardless of variations in PNP.

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Effect of 52 weeks of mirikizumab on inflammatory bowel disease questionnaire scores in patients with moderately to severely active crohn's disease Abstract: Introduction: Mirikizumab (miri; IL‐23p19 antibody) is a humanized, IgG4 monoclonal antibody specifically targeting the p19 subunit of IL23. Miri has demonstrated clinical efficacy in Phase 2 trials in psoriasis and ulcerative colitis and resulted in significant improvements in health‐related quality of life (HRQoL) as measured by the inflammatory bowel disease questionnaire (IBDQ) after 12 weeks of induction treatment in a Phase 2 trial (SERENTIY; NCT02891226) in patients with moderate‐to‐severely active Crohn's disease (CD). The Week 52 IBDQ results are reported here. Aims & Methods: Maintenance period aims were to evaluate the longterm efficacy and safety of miri administered over one year. Patients with moderate‐to‐severe CD were randomized 2:1:1:2 across 4 treatment arms (PBO, 200, 600, 1000mg miri, administered intravenously (IV) at Weeks 0, 4, 8). Patients who received miri and achieved ≥ 1 point improvement at Week 12 in Simple Endoscopic Score for Crohn's Disease (SES‐CD) were re‐randomized 1:1 into double‐blind maintenance to continue IV treatment assignment (IV‐C; N=41) or to 300mg miri SC (SC; N=46). IBDQ score change from baseline (induction phase), IBDQ response, and IBDQ remission were assessed through Week 52. Group comparisons for IBDQ score change from baseline were done using an ANCOVA model with IBDQ score baseline and response status as covariates. Results: Baseline demographics and disease characteristics as well as Week 52 IBDQ outcomes are provided (Table 1). Among the Week 12 miri induction endoscopic improvers, IBDQ response rates at Week 52 were 75.6% (31/41) and 80.4% (37/46) and IBDQ remission rates were 65.9% (27/41) and 67.4% (31/46) in the IV‐C and SC groups, respectively. The change from baseline in IBDQ was similar in both groups, with a total change of 64.3 and 66.4 points in the IV‐C and SC groups, respectively. Changes from baseline in IBDQ at Week 52 were significantly higher for patients who achieved PRO response (decrease in SF or AP ≥30% and no worse than baseline) and PRO remission (SF ≤2.5 and AP ≤1 and no worse than baseline) at Week 52 (64.0 and 70.3) versus those who did not achieve these endpoints (37.8 and 45.6; p< 0.001 in both cases). Conclusion: These data affirm the sustained efficacy of miri in producing meaningful improvements in HRQoL as measured by the IBDQ through 52 weeks of treatment.

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Brain responses to emotional stimuli after eicosapentaenoic acid and docosahexaenoic acid treatments in major depressive disorder: toward personalized medicine with anti-inflammatory nutraceuticals Abstract: N‐3 polyunsaturated fatty acid supplements improve the symptoms of major depressive disorder (MDD) in randomized‐controlled trials and meta‐analyses, with the higher efficacy from anti‐inflammatory eicosapentaenoic acid (EPA) than brain‐dominant docosahexaenoic acid (DHA). To investigate the specific brain mechanisms of the anti‐inflammatory anti‐depressant nutraceutical compounds, we recruited 24 MDD subjects in this double‐blind, head‐to‐head study with a 12‐week EPA or DHA treatment (clinical trial registration number: NCT03871088). The depression severity was assessed by Hamilton depression rating scale (HAM‐D). Brain responses to emotional stimuli were measured by a 3‐Tesla MRI. The correlation between HAM‐D scores and brain responses also were tested. Compared to 18 healthy controls, the brain responses of untreated 24 MDD patients mainly revealed hypoactivity in the regions associated with emotion perception and emotion control when processing positive emotion. After treatment, more remitted MDD patients have been observed in the EPA as compared to the DHA groups. In addition, the EPA, but not DHA, treatment revealed increased activity in the regions associated with emotion perception and cognitive control when processing positive emotion. The correlation analysis further revealed negative correlation between HAM‐D scores and brain responses in cognitive control regions. The results of this study may imply the compensatory brain responses of cognitive and emotion controls by EPA but not DHA and underpin personalized medicine with anti‐inflammatory nutraceuticals toward depression treatments.

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Impacts of citrulline malate supplementation on the fatigue in multiple sclerosis Abstract: Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of central nervous system and fatigue is one of the most common symptoms in multiple sclerosis.As a result, patient's daily affairs deteriorate obviously by fatigue. Citrulline Malate supplementation and Amantadin are two drugs that used for attenuating of fatigue./this study designed to evaluate Citrulline Malate utilization efficacy in MS patients./To investigate the impacts of Citrulline Malate on the fatigue in MS/In this double‐blind randomized clinical trial a total number of 90 MS patients referring to neurology clinic who complain of fatigue were enrolled in study .The patients were randomly assigned into groups for at least one month therapy: Amantadin alone users as group 1, concomitant use of Amantadin and Citrulline Malate as group 2 and Citrulline Malate alone users as group 3. Patient's fatigue intensity was measured using fatigue severity scale (FSS) questionnaire./ There were no statistically significant differences among groups regarding to age, sex, living place, and duration of MS disease as well as marital status and education levels of participants. Statistically significant diminish in the rates of the patients fatigue based on the Fatigue Severity Scale (FSS) were found among patients who used Citrulline Malate or concomitant users of Amantadin and Citrulline Malate in comparison with Amantadin alone users (P‐value < 0.0001)./According to our findings, Citrulline Malate possess a significant property for fatigue handling in MS patients .

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Everolimus with reduced calcineurin inhibitor exposure in de novo kidney transplant recipients: infection and wound healing outcomes from the transform study Abstract: Background: Post‐transplant (Tx) infections affect graft and patient survival. The protective effect of early introduction of everolimus (EVR) against viral infections has repeatedly been shown in kidney transplant recipients (KTxRs). However, including mTOR inhibitors (mTORi) into immunosuppressive regimen immediately after Tx was questioned because of their anti‐proliferative properties and potential effects on the wound healing process. Here we report 12 months (M) results on the incidence of infections and wound healing in KTxRs receiving EVR + reduced calcineurin inhibitor (rCNI) vs. mycophenolic acid (MPA) + Standard CNI (sCNI) regimen from the TRANSFORM study. Methods: TRANSFORM (NCT01950819) is a 24M, multicenter, open‐label, 2‐arm study in which de novo KTxRs were randomized (1:1) within 24 h post‐Tx to receive either EVR+rCNI (N = 1022) or MPA+sCNI (N = 1015), with induction and steroids. Here we show outcomes on infections and on wound healing events (WHE). Results: The overall infection rate was lower with EVR+rCNI than MPA+sCNI regimen (52.0% vs. 59.8%). The overall incidence of CMV infections was significantly lower with EVR+rCNI vs. MPA+sCNI regimen (3.6% vs. 13.3%, p < 0.001) The overall rates of BKV infection reported as adverse event were also significantly lower in EVR+rCNI vs. MPA+sCNI arm (4.3% vs. 8.0%, p < 0.001). The overall incidence of WHE was comparable between the groups (EVR+rCNI vs. MPA+sCNI: 39.0% vs. 33.7%). Conclusions: M12 results from TRANSFORM, the largest KTx study to date, confirmed the benefit of early EVR introduction in preventing viral infection in de novo KTxRs and confirmed its safe profile with comparable risk of WHE between the EVR+rCNI and MPA+sCNI groups.

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Tolerability of inhaled N-chlorotaurine-a phase I clinical study Abstract: N‐chlorotaurine (NCT), an endogenous antiseptic applicable to different body regions was tested on its tolerability upon inhalation in humans. This was a double‐blind and randomized study with a parallel test (1% NCT) and control group (0.9% NaCl as placebo) in two Austrian centers, the hospitals Natters and Vöcklabruck. Healthy, full age volunteers were included, 12 in each center. Exactly the half of each group was treated in each center. One inhalation (single dose 1.2 ml each, inhaled for 10 min) was done on every day on 5 consecutive days using an AKITA JET nebulizer. Primary criterion of evaluation was the forced expiratory volume in the first second (FEV1). Secondary criteria were subjective sensations, further lung function parameters such as airway resistance, physical examination, and blood analyses (gases, electrolytes, organ function values, pharmacokinetic parameters taurine and methionine, immune parameters). All included 15 females and 9 males completed the treatment and the control examinations according to the study protocol. FEV1 and all other objective parameters remained unchanged and constant during the treatment and in control examinations 1 week and 3 months after the treatment. Subjective mild sensations with a higher frequency in the test group were chlorine taste (P <0.01) and occasional tickle in the throat (P = 0.057). Taurine, methionine, neopterin, tryptophan, and kynurenine plasma concentrations did not change within 60 min after inhalation or later on. Inhaled NCT is well tolerated with only mild, topical and transitory subjective side effects.

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The teen bypass equipoise sleeve trial (teen-best): a randomised controlled trial of gastric bypass versus sleeve gastrectomy for adolescents with severe obesity dragons' den meets shark tank (proposals for randomized controlled trials) Abstract: Background and rationale for the RCT, including existing literature reviews Six to seven percent of children in Western Europe have obesity (1), many experiencing life‐changing and life‐shortening comorbidities (2), which begin in adolescence (3) and may progress more rapidly when onset is in youth (4). Where non‐surgical therapies fail (5), surgical treatments are well established in adults (6). In addition to our published reviews (2,3,6), we and another group have recently reported the long‐term safety and efficacy of adolescent gastric bypass (7, 8). Gastric bypass has been the procedure of choice, but has recently been overtaken in popularity by sleeve gastrectomy, despite an absence of long‐term outcome data in adolescents. With limited evidence permitting direct comparison between these procedures, a clear knowledge gap, coupled with genuine clinical equipoise prevents evidence‐based recommendation to eligible adolescents. Overall aim in PICO (Patients, Intervention, Comparator, Outcomes) format In adolescents eligible for bariatric surgery, is sleeve gastrectomy non‐inferior to gastric bypass, in terms of achieving a 10% total bodyweight loss and the relative incidence of additional surgical intervention, 3 years after surgery? Trial design (selection and recruitment of patients, timing of randomization, details of the intervention) Multicenter randomised controlled trial across two centralised units; one in the Netherlands and one in Sweden. The protocol will be specifically designed to be deliverable across a broad range of healthcare systems worldwide and, upon successful initiation, further centres will be invited to conduct additional satellite trials, resulting in sufficient aggregate power to examine prospectively identified secondary outcomes, which require larger cohorts for sufficient power. Inclusion/exclusion: Meeting all US (9) and European (10) criteria, including:‐Aged 14‐18 years, BMI >40 KG/M2 with comorbidity, or>35 KG/M2 with serious comorbidity (e.g. T2DM). Randomisation:‐Independent, computerised, on day of surgery. Interventions:‐Standardised techniques agreed by lead surgeons (7, 8).‐Performed by a bariatric surgeon, accompanied by a paediatric surgeon. Primary outcomes: At 3 years after surgery: 1.Successful (>10%) total bodyweight loss. 2.Additional surgical intervention rate. 246 Chosen as both relevant and deliverable outcomes within the Netherlands and Sweden across a 3‐year recruitment phase. A sample size of 116 patients/arm will permit detection of non‐inferiority for TBW loss, with a margin of <‐0.1 in success rate (alpha=0.05, 1‐beta=0.9, nB=99), allowing a 15% dropout (85/arm required for additional surgical intervention). Secondary outcomes: Prospectively determined by a Delphi expert consensus process, which we are currently undertaking to develop a Core Outcome Set specific to adolescent bariatric surgery, as recently determined in adults (11). All outcomes will be assessed in line with our previous study (7), by a dedicated research nurse within each country, at 30 days and 6, 12, 24, 36, 60 and 120 months.

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Late breaking abstract-is there a role for cardiopulmonary exercise testing in identifying COPD patients most likely to respond to morphine? Abstract: Introduction: Opioids are rarely prescribed for breathlessness in advanced COPD due, in part, to an inability to predict which patient (s) will respond. Objectives: To determine the acute effect of immediate release oral morphine (M) on exertional breathlessness and exercise endurance time (EET) and to also identify predictors of the acute response to M in patients with advanced COPD and refractory breathlessness. Methods: Twenty adults with COPD (FEV1=35±9%predicted) underwent constant‐load cardiopulmonary cycle exercise testing (CPET) after single‐dose ingestion of M (0.1mg/kg) or placebo (P). Opioid responders (R) were identified as patients reporting a >1 Borg unit decrease in breathlessness during constant‐load CPET at isotime after ingestion of M vs. P. Results: In all 20 patients, M decreased isotime breathlessness by 1.2±0.4 Borg units and increased EET by 2.5±0.9 min vs. P (both p<0.05). Baseline patient characteristics, including FEV1 %predicted, plethysmographic lung volumes, cardiorespiratory fitness, and mMRC and CAT scores, were not significantly different between R (n=11) and nonresponders (NR, n=9). In contrast to NR, EET increased by 3.6±1.3 min and isotime breathlessness decreased by 2.3±0.6 Borg units after ingestion of M vs. P within R (both p<0.01). A higher percentage of R vs. NR identified intolerable breathlessness as the primary reason for stopping incremental CPET: 82 vs. 33% (p=0.03). Conclusions: The locus of symptom‐limitation on laboratory‐based CPET may help to identify patients with advanced COPD most likely to achieve clinically meaningful relief of exertional breathlessness in response to morphine.

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Phase I/II randomized trial of GM.CD40L vaccine plus/minus CCL21 in advanced lung adenocarcinoma: final results Abstract: Background: Our GM.CD40L vaccine (an allogeneic tumor cell‐based vaccine generated from human bystander cell line) recruits and activates dendritic cells, which then migrate to regional lymph nodes, where T‐cell activation occurs, leading to systemic tumor cell killing. The CCL21 chemokine helps to recruit T cells and leads to enhanced T‐cell responses. The GM.CD40L.CCL21 combination has demonstrated additive effects in NSCLC mouse models. Methods: We initiated a phase I/II randomized study with plans to evaluate GM.CD40L (Arm A; n = 32) vs. GM.CD40L.CCL21 (Arm B; n = 35) in patients with lung adenocarcinoma who had failed first‐line therapy. Primary endpoints were safety/tolerability of Arm B in phase I and progression‐free survival (PFS) in phase II; secondary endpoints included anti‐tumor immune responses/T‐cell responses by ELISpot assay on PBMC and tissue correlates. Intradermal vaccines were administered every 14 days for 3 doses and then monthly X3. A two‐stage minimax design with a 10% type I and II error rate was used. Results: Between 4/2012 and 1/2016, in phase I, 3 patients were treated with GM.CD40L.CCL21 (no dose‐limiting toxicities occurred), followed by enrollment of 37 patients in Arm A and 33 patients in Arm B. Including those in phase I, median age was 66/67 years; females: 47.5%/57.5%; PS1: 66%/66%, median prior regimens: 2.5/3 for Arm A vs. Arm B. Most common toxicities for Arm A vs. Arm B were injection site reaction (30%/46%) and fatigue (22%/20%). Median PFS/OS for Arm A vs. B was 2.4/9.3 vs. 3.1/9.4 months (p = 0.44/0.54). Of patients evaluable for efficacy per RECIST v1.1, 48% vs. 38% had stable disease and 52% vs. 62% had progressive disease for Arm A vs. Arm B, respectively. All 9 patients who remained on treatment after progression demonstrated confirmed progression on subsequent scans and treatment was stopped. Blood and tissue correlate studies are underway. Conclusions: GM.CD40L.CCL21 vaccine was well tolerated but did not clearly improve outcomes over the GM.CD40L vaccine. In a heavily pretreated, unselected NSCLC population, the median OS of GM.CD40L vaccine was similar to single‐agent nivolumab. A clinical trial of anti‐PD1 plus/minus GM.CD40L is planned.

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The effects of ginger on fasting blood sugar, hemoglobin A1c, and lipid profiles in patients with type 2 diabetes Abstract: Background: Lipid and glycemic abnormalities are prevalent in diabetes leading to long term complications. Use of safe and natural foods instead of medications is now considered by many scientists. Objectives: This study aimed at determining the effect of ginger on lipid and glucose levels of patients with type 2 diabetes mellitus. Methods: In a double‐blind placebo‐controlled trial, 50 patients with type 2 diabetes were randomly allocated to 2 groups of intervention (n = 25) and placebo (n = 25). Each patient received 2000 mg per day of ginger supplements or placebo for 10 weeks. Serum levels of fasting blood sugar (FBS), total cholesterol (TC), triacylglycerol (TG), low density lipoprotein cholesterol (LDL‐C), high density lipoprotein cholesterol (HDL‐C),andglycosylated hemoglobin (HbA1C) were analyzed. Daily dietary intakesandanthropometric parameters were also determined. Results: Data from 45 patients were analyzed (23 patients in the ginger group and 22 patients in the control group) at the end of the study. Ginger consumption significantly reduced serum levels of fasting blood glucose (‐26.30 ± 35.27 vs. 11.91 ± 38.58 mg/dl; P = 0.001) and hemoglobin A1C (‐0.38 ± 0.35 vs. 0.22 ± 0.29 %; P < 0.0001) compared to the placebo group. Ginger consumption also reduced the ratio of LDL‐C/HDL‐C (2.64 ± 0.85 vs. 2.35 ± 0.8; P = 0.009). However, there was no significant change in serum concentrations of triglycerides, total cholesterol, LDL‐C, and HDL‐C due to the ginger supplements. Conclusions: The current results showed that ginger could reduce serum levels of fasting blood glucose and hemoglobin A1C in patients with diabetes.

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Mathematical Modeling of Free Thyroxine Concentrations During Methimazole Treatment for Graves’ Disease: development and Validation of a Computer-Aided Thyroid Treatment Method Abstract: Background: Methimazole (MMI) is the first‐line treatment for patients with Graves’ disease (GD). While there are empirical recommendations for initial MMI doses, there is no clear guidance for subsequent MMI dose titrations. We aimed to (a) develop a mathematical model capturing the dynamics of free thyroxine (FT4) during MMI treatment (b), validate this model by use of numerical simulation in comparison with real‐life patient data (c), develop the software application Digital Thyroid (DigiThy) serving either as a practice tool for treating virtual patients or as a decision support system with dosing recommendations for MMI, and (d) validate this software framework by comparing the efficacy of its MMI dosing recommendations with that from clinical endocrinologists. Methods: Based on concepts of automatic control and by use of optimization techniques, we developed two first order ordinary differential equations for modeling FT4 dynamics during MMI treatment. Clinical data from patients with GD derived from the outpatient clinic of Endocrinology at the Medical University of Graz, Austria, were used to develop and validate this model. It was subsequently used to create the web‐based software application DigiThy as a simulation environment for treating virtual patients and an autonomous computer‐aided thyroid treatment (CATT) method providing MMI dosing recommendations. Results: Based on MMI doses, concentrations of FT4, thyroid‐stimulating hormone (TSH), and TSH‐receptor antibodies (TRAb), a mathematical model with 8 patient‐specific constants was developed. Predicted FT4 concentrations were not significantly different compared to the available consecutively measured FT4 concentrations in 9 patients with GD (52 data pairs, p=0.607). Treatment success of MMI dosing recommendations in 41 virtually generated patients defined by achieved target FT4 concentrations preferably with low required MMI doses was similar between CATT and usual care. Statistically, CATT was significantly superior (p<0.001). Conclusions: Our mathematical model produced valid FT4 predictions during MMI treatment in GD and provided the basis for the DigiThy application already serving as a training tool for treating virtual patients. Clinical trial data are required to evaluate whether DigiThy can be approved as a decision support system with automatically generated MMI dosing recommendations.

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EQUIP INTERIM RESULTS: a PHASE 1B STUDY EVALUATING ITOLIZUMAB IN SUBJECTS WITH MODERATE-TO-SEVERE UNCONTROLLED ASTHMA Abstract: Introduction: CD6 is a co‐stimulatory receptor predominantly expressed on T cells; its ligand, ALCAM, is expressed on antigen presenting, epithelial and endothelial cells. The CD6/ALCAM pathway is elevated in severe asthmatics and is implicated in Th2 and Th1/Th17 driven responses. Itolizumab is a humanized IgG1 monoclonal antibody that binds CD6 and blocks ALCAM interaction to inhibit T cell activation and trafficking. Methods: EQUIP is a randomized (3:1), placebo‐controlled, Phase 1b study evaluating safety, pharmacokinetics, pharmacodynamics, and clinical activity of itolizumab in adult patients with moderate/severe uncontrolled asthma requiring moderate/high‐dose inhaled corticosteroids (FEV1 [predicted] between 40‐90%, reversibility documented within 2 years, and ACQ‐6 ≥ 1.5). Treated subjects received 5 doses of itolizumab SC Q2weeks (Cohorts: 0.8 mg/kg ‐ 3.2 mg/kg). Results: Cohort 1 (0.8 mg/kg, n=9); mean age: 52, 33% female, 78% white, mean FEV1: 2.1L (61% predicted), ACQ‐6: 2.5 (range 1.8‐3.5). By Day 29, mean ACQ‐6 declined to 1.5 with no change in FEV1. Cohort 2 (1.6 mg/kg) enrollment is ongoing. Itolizumab was well tolerated, with no SAEs reported. 100% of subjects reported an AE, mostly mild /moderate injection‐site reactions and decreased lymphocyte count (without clinical sequelae), with no notable changes in vital signs/clinical labs. One AE of lymphopenia resulted in drug discontinuation. While itolizumab accumulated in serum with multiple doses, a significant decrease in CD6 cell surface expression was observed after the first dose and sustained thereafter (Figure). Conclusion: Itolizumab 0.8 mg/kg SC Q2W resulted in pronounced CD6 decreases in uncontrolled asthma subjects, supporting continued evaluation of itolizumab in asthma. [Formula presented]

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Higher rates of paroxysmal atrial fibrillation in stroke of undetermined etiology after 12 months Abstract: Background And Aims: Detection of paroxysmal atrial fibrillation (pAF) results in oral anticoagulation for secondary stroke prevention. In a subgroup of stroke patients with unknown etiology, the ESUS‐concept (“embolic stroke of undetermined stroke”) has been established. Two large randomized trials recently failed to show a benefit of oral anticoagulation among all ESUS‐patients. To strengthen the concept of pAF as one major underlying cause for ESUS, detection rates of pAF between ESUS and No‐ESUS patients were compared. Methods: Within the open‐label randomised multi‐center prospective Find‐AFrandomised‐study (NCT01855035), assessing prolonged and enhanced Holter‐monitoring in acute ischemic stroke patients ≥60 years without history of atrial fibrillation or significant extra‐ or intracranial artery stenosis, patients were screened for eligibility of adapted ESUS criteria. ESUS‐patients were compared to No‐ESUS‐patients with respect to detection of pAF during follow‐up. Results: of 393 patients, 251 (63.9%) fulfilled diagnostic workup to assess for ESUS (lesion depiction on imaging, TTE/TEE, ≥24h Holter‐ECG‐monitoring). Among these ESUS‐eligible patients, 125 were classified as ESUS‐patients. The two groups did not differ significantly with respect to baseline characteristics or intensified Holter‐ECG‐monitoring. pAF was detected in 11 after 6 and in 13 ESUS‐patients after 12 months as opposed to 5 patients in the No‐ESUS group after 6 and 12 months (p=0.177 and p=0.048, respectively). Conclusions: ESUS patients were found to have a significantly higher rate of pAF after 12 months. This underlines the necessity for complete stroke work‐up diagnostics to correctly identify ESUS‐patients and initiate intensified rhythm monitoring to increase rates of pAF detection resulting in a shift of secondary stroke prevention.

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Comparison of intraarticular bupivacaine-dexmedetomidine and bupivacaine-magnesium sulfate for postoperative analgesia in arthroscopic meniscectomy: a randomized controlled clinical trial Abstract: Background: Arthroscopic meniscus surgery can lead to pain at various levels. In this study, we aimed to compare, in patients undergoing arthroscopic meniscectomy under spinal anesthesia, the efficacy of the combination of magnesium sulfate and dexmedetomidine with local anesthetics administered intraarticularly for postoperative pain management Methods: This prospective, randomized, controlled, double‐blind study comprised of 52 patients who were randomly assigned into two groups depending on the combination injected intraarticularly at the end of the procedure: bupivacaine and dexmedetomidine (group D) or bupivacaine and magnesium sulfate (group M). Perioperative data, postoperative visual analog scale (VAS) scores, and total analgesic consumption were recorded. Clinical trial registration: NCT03479216 Results: No statistically significant differences were found in mobilization times, rescue analgesic times, and non‐steroidal anti‐inflammatory consumption. The maximum mean VAS values at rest and during movement in group D were measured at the 6th hour while in group M peaked at the 8th hour. Conclusion: Both intraarticular dexmedetomidine and magnesium sulfate, in combination with bupivacaine, have simi‐lar effects on reducing postoperative pain in arthroscopic knee surgery. HIPPOKRATIA 2019, 23(2): 51‐57.

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Accuracy of wrist-worn heart rate monitors for chronotropic assessment in atrial fibrillation Abstract: Introduction: Wrist‐worn fitness and heart rate (HR) monitors are increasingly popular. Previous studies in healthy participants with sinus rhythm (SR) have yielded variable results depending on HR, activity levels and device tested. A paucity of data exists on their accuracy in atrial fibrillation (AF) in ambulatory patients. Purpose: We sought to assess the HR accuracy of 2 commercially available smart watches (Fitbit Charge HR [FB] and AppleWatch Series 3 [AW]) compared with Holter monitoring in an ambulant patient cohort. Methods: Patients aged >18 years referred for 24‐hour Holter monitoring were prospectively recruited. The Holter monitor was the criterion measure. Each patient was randomly allocated to either a FB or AW along with their Holter monitor. The study protocol was approved by the institutional review board. Statistical analysis: Pearson (r) correlation coefficients and Bland‐Altman comparison with 95% limits of agreement (LoA) were evaluated to assess criterion validity and agreement between the smart watch and Holter ECGHR. Bias was the calculated mean difference between the smart watch and ECG‐HR. A ± 10‐beat different between Holter‐HR and SW‐HR was used as a clinically relevant range to establish the accuracy of HR estimation by SW. Results: Across all devices, 53,288 hear rate values were recorded from 32 patients. Twenty six patients were in persistent AF and six were in SR. Twelve patients wore the FB while 20 wore the AW. In the FB arm, nice patient were in persistent AF and three in SR. In the AW arm, persistent AF was the rhythm in seventeen and SR in three. Patients in SR demonstrated overall strong agreement compared to Holter monitoring (Mean Bias <1 beat, LoA ‐11 to 11 beats) and a correlation coefficient of 0.87 (p<0.001). In AF, both devices underestimated HR measurements (Overall Bias ‐9 beats, LoA ‐41 to 23, r=0.60, p<0.001). The AW had lower bias and narrower LoA compared to FB (‐5 beats vs ‐13 beats, LoA ‐31 to 21 beats vs ‐50 to 22 beats). Using a ± 10‐beat range against ECG‐HR for clinical accuracy, both the AW and FB performed satisfactorily in SR with 95.2% of AW and 92.2% of FB HR readings considered valid. In AF, however, the AW‐HR readings were within the ± 10‐beat threshold in 76.5% of the time compared with only 56.1% of FB readings. Conclusion: In ambulatory patients, smart watches were accurate in HR estimation when compared to Holter monitor in SR; however tended to underestimate HR in AF. Further improvements in device technology are needed before the widespread consumer adoption of this nascent technology for chronotropic assessment in arrhythmias.

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Effect of Intervention Nursing on Radiation Pneumonia Caused by Radiotherapy of Thoracic Tumor Abstract: Objective:To investigate the effect of nursing on radiation pneumonia caused by radiotherapy of thoracic tumors. Methods:One hundred patients with radiation pneumonia (≥ grade 2) caused by thoracic tumor radiotherapy in our hospital between January 2018 and January 2019 were enrolled. Fifty patients were randomly selected as the observation group, and the other 50 patients were taken as the control group. The control group got routine nursing. The observation group was added with psychological guidance, respiratory care, dietary intervention, health education and other nursing interventions. Compare the clinical effects of the two groups. Results:There were 40 cases cured and 7 cases effective in the observation group, and the total effective rate was 94%. In the control group, there were 30 cases cured and 12 cases effective, and the total effective rate was 84%. There were statistically significant differences between the two groups (χ2=5.067, P=0.028). The satisfaction rate of the patients in the observation group was 100%, in which 42 patients were very satisfied. In the control group, the satisfaction rate was 94%, and 25 patients were very satisfied. The differences were also statistically significant between the two groups (χ2=5.073, P=0.025). Conclusion:Interventional care can effectively improve the effective rate of patients with radiotherapy‐caused pneumonia.

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Performance of two alternative treatments for cervical pre-cancer against standard gas-based cryotherapy Abstract: Objective: Gas‐based cryotherapy, the standard treatment for cervical pre‐cancer in low‐resource settings, is problematic due to the need for cryogenic gas. To develop alternative treatments, we compared depth of necrosis (DON) and patient pain associated with gas‐based cryotherapy, CryoPen® (a gasless cryotherapy device), and thermoablation. Methods: Subjects were 126 women aged 25‐65 scheduled for hysterectomy for indications other than cervical pathology. Patients were randomly assigned to five arms: single‐freeze CO2 cryotherapy (Arm A), double‐freeze CO2 cryo‐therapy (Arm B), single‐freeze CryoPen (Arm C), double‐freeze CryoPen (Arm D), and thermoablation applied at 100 °C for 40 seconds (Arm E). Pain was reported verbally on a scale of 0 (no pain) to 10 (worst pain). The deepest necrosis point in cervical samples was measured and recorded. Results: Mean DON (in mm) achieved by all treatments was above our predetermined benchmark of 3.5: A = 4.9 (SD = 2.0), B = 5.6 (SD = 1.3), C = 4.9 (SD = 1.6), D = 4.5 (SD = 1.2), E = 4.1 (SD = 1.1). Reported pain levels ranged from 1‐8 and mean pain per treatment was A = 1.7 (SD = 0.8), B = 2.2 (SD = 1.0), C = 2.5 (SD = 1.4), D = 2.5 (SD = 1.4), and E = 3.4 (SD = 1.7). Conclusions: CryoPen® and thermoablation achieved non‐inferior DON to standard cryotherapy. Pain levels were tolerable for all treatments, although somewhat higher with thermoablation. Quality control is underway and results will be updated accordingly. These new treatments are potentially viable alternatives to the current standard of care.

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A propensity score analysis of two methods of hepatic vascular occlusion in hepatectomy Abstract: Background The key points in hepatectomy are reducing blood loss and preservation of hepatic function. The aim of this study was to compare the perioperative outcomes of partial hepatectomy using two techniques of hepatic vascular inflow occlusion. Materials and methods A total of 1817 patients were selected from our multi‐institutional hepatectomy database in China and classified into two groups: the hemihepatic inflow occlusion (HIO) group (n = 1693) and the ipsilateral portal vein branch occlusion (IPVBO) group (n = 124). Propensity score matching of patients in a ratio of 1:1 was conducted. The primary outcome was intraoperative blood loss. Secondary outcomes were postoperative liver function, postoperative morbidity and mortality, and duration of hospital stay after surgery. Results After propensity score matching, there were 124 patients in the IPVBO group and the HIO group, respectively. There were no significant differences between the two groups regarding intraoperative blood loss, blood transfusion requirement, operating time, postoperative morbidity and mortality, and duration of hospital stay after surgery (P > 0.05). However, The IPVBO group was associated with significantly lower peak in postoperative ALT level than the HIO group (P < 0.05). Conclusions The results indicated that IPVBO did not lead to more intraoperative blood loss compared with HIO, and it decreased the peak of postoperative ALT level. In terms of postoperative morbidity and mortality, duration of hospital stay after surgery, IPVBO was also equal to HIO. Thus, IPVBO could be an alternative method of hepatic inflow occlusion. Copyright © 2017 Elsevier Inc.

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Effect of enoxaparin sodium on the coagulation function of patients with nonsmall cell lung cancer Abstract: Objective: To investigate the effect of enoxaparin sodium on the coagulation function of patients with non‐small cell lung cancer. Methods: From Jan, 2014 to Jan, 2016, 100 patients with non‐small cell lung cancer admitted to our hospital were prospectively studied and were randomly assigned into the study group or the control group, 50 cases in each group. During the study period, the study group was treated by enoxaparin sodium for anticoagulation therapy, while the control group was treated by the rivaroxaban for anticoagulation therapy. The incidence of toxic side effects, reaction time (tR), kenetics of clot development time (tK), maximum amplitude (tMA), coagulation index (CI) and time to maximum amplitude (tTMA) of the two groups were observed and compared. Results: There were no significant differences in the tK, tMA and tTMA between the two groups before and after the anticoagulation therapy (P>0.05). There was yet no significant difference in the tR between the two groups before anticoagulation[(6.82±0.82) vs. (6.85±0.88), P=0.860]. Compared with the control group, the level of tR in the study group was significantly increased after coagulation therapy[(8.94±1.26) vs. (7.83±1.08), P=0.000]. No significant difference in CI was observed between the two groups before anticoagulation[(1.34±0.46) vs. (1.38±0.52), P=0.685], However, after anticoagulation, the CI was significantly decreased in the study group, as compared with the control group [(‐0.84±0.43) vs. (‐0.23±0.56), P=0.000]. During the treatment, no bleeding occurred in the two groups, while one patient in the control group suffered from deep venous thrombosis. There was no significant difference in the incidence of nausea, vomiting, neutropenia, anemia, thrombocytopenia and increased transaminase between the two groups (P>0.05). Conclusion: Both enoxaparin sodium and rivaroxaban were effective in preventing the thrombosis in the patients with non‐small cell lung cancer after operation, and enoxaparin sodium had better efficacy.

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Rapid viral response (RVR) as a predictor of treatment failure in hepatitis C virus (HCV) patients receiving ledipasvir and sofosbuvir (LDV/SOF): a retrospective case-control analysis Abstract: Background. New HCV therapies report cure rates of ∼90% but are costly. Rapid viral response, defined as undetectable viral load at 4 weeks, is predictive of treatment failure with some previous HCV therapies. Limited data exists evaluating the role of RVR in new therapy options, including LDV/SOF. Methods. A pilot, single‐center, retrospective case‐control analysis of adult patients treated with LDV/SOF from 10 October 2013 to 19 December 2015 was conducted. Included patients had a viral load obtained between weeks 3‐6 of therapy (RVR) and between weeks 12‐16 after the end of therapy (SVR). Identified patients with SVR failure (viral load detectable) constituted the case population. The control population was randomly selected in a 1:4 case/control ratio from all identified SVR successes. The primary outcome was SVR failure. Variables with a p <0.2 in univariate analysis were included in the regression model. Results. Twelve SVR failures were identified. Forty‐eight of 144 SVR successes were randomly selected for inclusion (1:4 case/control). Table 1 presents demographic information. Overall failure rate was 8.33%. Results of univariate analysis are shown in Table 2. Previous treatment failure, H2RA use, and CrCl >90 mL/minute were included in the regression model, along with RVR per protocol. Nagelkerke's R2 for the model was 0.312. CrCl >90 mL/minute was independently associated with treatment failure (odds ratio, 7.27; 95% CI, 1.33 to 39.72; p = 0.022); H2RA use approached significance but was limited by few patients taking H2RAs. Conclusion. Patients with CrCl >90 mL/minute were 7.27 times more likely to fail SVR than patients with CrCl < 90 mL/minute. A possible explanation is that patients with CrCl >90 mL/minute do not maintain adequate drug exposure for viral clearance. Further evaluation of increased CrCl and H2RA use with SVR failure utilizing a larger sample size is warranted. (Table Presented) .

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Comparison of short-term outcomes between two sacrospinous suture capture devices : a randomised controlled trial Abstract: Introduction: Sacrospinous Fixation is a procedure for mid‐compartment apical suspension in pelvic organ prolapse surgery with high success rates. The approach by traditional wide dissection has been well documented. The literature is lacking however with regard to newer devices on the market that use less extensive dissection to perform this procedure. Objective: The objective of this study was to compare the short term efficacy of the Fixt® with the Capio Slim®. This short term assessment was defined as the 6 week period after the surgical procedure. Methods: A randomised controlled trial was carried out comparing the Boston Scientific's Capio Slim® (control) and Bard's Fixt® (intervention) for bilateral sacrospinous fixation in women with mid‐compartment prolapse requiring surgery and who met the study criteria. The primary outcome was time (in seconds) to successful bilateral suspension suture placements. Secondary outcomes examined were used to assess short‐term safety and efficacy of the devices at the time of the procedure and at the 6 week follow‐up. Results: Of the 51 women recruited to the trial, 27 were randomised to the Capio slim® control arm and 24 women to the Fixt ® intervention arm of the trial. Analysis was carried out by intention to treat. Most of the demographic characteristics and pre‐operative prolapse questionnaire scores of participants in the two arms of the trial were similar. The mean pre‐operative POP‐Q point C was +1.185 (±3.990) in the Capio Slim® group and +1.458 (±4.452) in the Fixt® group (p value 0.8182). When comparing the Capio Slim® and Fixt® devices in this non‐inferiority trial, no significant difference was found in the primary outcome, i.e. time (in seconds) to bilateral sacrospinous suture placements. The median time for the Capio Slim® was 170.5 (105‐642) seconds and 222 (112‐848) seconds with the Fixt® (p value of 0.3513). No significant difference was found in the secondary outcomes examined. This related to the number of throws required until a successful suture is placed (median of 1 throw on each side in both arms); adverse events intra‐operatively and postoperatively; post‐operative subjective pain assessments, post‐operative symptoms and levels of satisfaction (both arms median score 5 out of 5). Improvement of POP‐Q point C at 6 weeks was comparable with mean improvement of 7.96 cm with the Capio Slim® and 7.63 cm with the Fixt® (p value 0.7849). No statistical difference was found in the incidence of post‐operative buttock pain related to pudendal nerve entrapment requiring release of the suspension suture (ROS incidence 7 % Capio Slim®, 8 % Fixt®). Conclusions: Non‐inferiority between the Capio Slim® and Fixt ® device was proven when comparing short‐term outcomes in terms of their safety and efficacy. The anterior approach to the sacrospinous fixation was also shown to be an effective procedure for mid‐compartment prolapse. Long‐term trials are needed to assess the success of procedures performed with the above devices beyond 6 weeks. (Table Presented).

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The double-blind studyof isolated and combined use of tranexamic acid and epidural anesthesia in scoliosis surgery Abstract: Aims: To assess the effectiveness of tranexamic acid (TA) and in combination with epidural anesthesia (EA) on perioperative blood loss and hemostasis/fibrinolysis in scoliosis surgery. A prospective, randomized, double‐blind study of four techniques for perioperative analgesia during scoliosis surgery. Method: The study included 115 patients, aged from 15 to 18 years. All patients were divided into 4 groups. Thoracic epidural anesthesia with 0.75% ropivacaine and fentanil and general anesthesia with sevoflurane were used in group 1 and group 2 and only general anesthesia with sevoflurane and fentanil was used in group 3 and group 4. Tranexamic acid was administered in group 1 and group 3 before skin incision ‐ a bolus of 15 mg / kg followed by IV infusion of 2 mg/kg/hour up to the end of surgery. Results: The main effect of reducing intraoperative blood loss by 65%(524ml, p=0.001)was obtained in group 1 as compared with group 3. In patients without epidural anesthesia using of TA has decreased blood loss to 29.7% (p=0.01) comparing with group 4. The use of EA without TA has reduced intraoperative blood loss to 50% (730 ml, p=0.005). The use of EA contributed to limit the changes in biochemical data of hemostasis/fibrinolysis system during surgery; while hypercoagulated changes dominated in group 4. There were no complications in all groups. Conclusion: The main blood saving effect of EA conclude in redistribution of blood flow. The suppression of fibrinolysis is an added without impacting significantly on the amount of perioperative blood loss and transfusion requirements.

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CGRP monoclonal antibody LY2951742 for the prevention of migraine: a Phase 2, Randomized, double-blind, placebo-controlled study Abstract: OBJECTIVE: We evaluated the efficacy and safety of LY2951742, a fully humanized monoclonal antibody to Calcitonin Gene Related Peptide for migraine prevention. BACKGROUND: Migraine remains poorly treated with few effective preventive medications available. DESIGN/ METHODS: Subjects with 4‐14 migraine headache days (MHD) per month were enrolled in a double‐blind, randomized, 12‐week placebo‐controlled trial of biweekly subcutaneous injections of LY2951742 (150 mg) versus placebo. The primary endpoint was the change in number of MHD per 28 day period assessed at 12 weeks; secondary end points were the change in headache days, migraine attacks, and responder rate. RESULTS: A total of 217 subjects were randomized and received LY2951742 (107) or placebo (110). The mean change in MHD at 12 weeks when compared to baseline was ‐4.2 (62.5% decrease) vs. ‐3.0 (42.3% decrease) for LY2951742 and placebo respectively (p,0.003). LY2951742 was superior to placebo for all secondary endpoints including headache days ‐4.9 vs. ‐3.7 (p,0.0117), migraine attacks ‐3.1 vs. ‐2.3 (p,0.0051), and responder rate 70% vs. 45% (OR 2.88 [CI 1.78 to 4.69]). An exploratory endpoint of complete responders (100% reduction in MHD) was 33.3% vs. 17.3% for LY2951742 and placebo respectively. Adverse events seen more frequently with LY2951742 than placebo included injection site pain, upper respiratory tract infections, and abdominal pain. CONCLUSION: In subjects with frequent migraine headache, treatment with LY2951742 resulted in a significant decrease in the number of migraine headache days, headache days, and migraine attacks when compared to placebo. LY2951742 was safe and well tolerated. The safety and robust efficacy results in this study are promising and justify the conduct of larger, randomized, placebo‐controlled, phase 3 studies and the expression of cautious optimism that a new era of mechanismbased migraine prevention is beginning.

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