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Anaphylaxis guidelines recommend intramuscular adrenaline, commonly 300 μg administered using an auto-injector device. However, overweight/obese patients may require a higher adrenaline dose for adequate cardiovascular (CV) response. This study evaluated the pharmacokinetics (PK) and pharmacodynamic (PD) CV profiles after a single 500 μg adrenaline injection via Anapen auto-injector in healthy normal weight males and otherwise healthy, overweight or obese females.In this exploratory open-label, single-centre study, 54 healthy volunteers aged 18-50 years received a single 500 μg adrenaline injection (Anapen auto-injector) in the thigh (antero-lateral middle third [18 males] or antero-inferior third [36 females]). Assessments included depot depth (ultrasonography), plasma adrenaline levels (liquid chromatography-tandem mass spectrometry) and heart rate (HR; ECG Holter monitor).Ultrasonography showed that 82.4% of normal weight males received intramuscular injections; all overweight and obese females received subcutaneous injections. Anapen injection produced rapid increases in circulating adrenaline levels and significant increases in systolic blood pressure (SBP) and HR. Second peak plasma adrenaline concentrations (CA 500 μg adrenaline injection via Anapen produced rapid PK/PD changes in normal weight, overweight and obese subjects, irrespective of intramuscular or subcutaneous injection, and was well tolerated.

PURPOSE: Anti-Müllerian hormone (AMH) and antral follicle count (AFC) are correlated with the ovarian response, but their reliability and reproducibility are questionable. This large multicenter study describes their distribution, inter-cycle and inter-center variability, and their correlation. METHODS: A total of 25,854 IVF cycles among 15,219 patients were selected in 12 ART centers. Statistical distribution of AMH and AFC was studied by using the Kolmogorov–Smirnov test and Shapiro goodness of fit test. The reproducibility of AFC and AMH was measured using a mixed model regressing the logarithmic transformation of AFC with age. RESULTS: The distribution of AMH and AFC was characterized by a wide dispersion of values, twice more important for AFC, and a logarithmic distribution. The faster decline in AMH than in AFC with age suggests that their correlation changes with age. AMH and AFC showed a very low proportion of concordance in the range of expected poor responders according to Bologna cutoffs. The heterogeneity for AMH and AFC across centers was small, but much larger across patients within each center. Concerning the patients with several successive cycles, the reproducibility for AMH seemed much better than for AFC. Comparing respective performances of AMH and AFC for the prediction of ovarian response depended on the local conditions for measuring these indicators and on the reproducibility of results improved over time. CONCLUSION: Distribution of AMH and AFC was characterized by the wide dispersion of values, and a logarithmic distribution. Establishing cutoffs or a direct relationship AMH/AFC without considering age seems hazardous. Correlation between AMH and AFC was very poor in the range of poor responders.

Background and objective Excessive daytime sleepiness (EDS) and fatigue are major complaints in patients with obstructive sleep apnoea (OSA) syndrome. Pitolisant is an orally active selective histamine H3 receptor (H3R) antagonist/inverse agonist, which enhances histaminergic transmissions in the brain and thereby elicits strong wake-promoting effects. This article assesses the efficacy and safety of pitolisant 20 mg in patients with OSA, based on existing randomised controlled studies. Methods An individual patient data (IPD) meta-analytical two-level (study-patient) hierarchical model was used assuming a random treatment effect. The Epworth Sleepiness Scale (ESS) and Oxford Sleep Resistance (OSleR) tests were co-primary endpoints. Results A total of 512 patients, including 384 treated with pitolisant and 128 with placebo, were included in the analysis. Compared with placebo, pitolisant reduced mean ESS by − 3.1 (95% CI [− 4.1; − 2.1]; p < 0.001) and improved OSleR by 1.18 (1.02; 1.35, p = 0.022); 30% more patients had reduced fatigue (risk ratio [RR] = 1.3, [1.11; 1.53]), p = 0.001) and 46% more patients had improved Clinical Global Impression (CGI) (RR = 1.46 [1.12; 1.89], p = 0.005). No significant differences in safety endpoints were found. These results proved homogeneous across studies and subgroups of the population. Conclusion The results provide evidence of a significant benefit of pitolisant in improving EDS and fatigue, irrespective of baseline conditions. Supplementary Information The online version contains supplementary material available at 10.1007/s40261-021-01104-8.

AIM: To study the effect of metformin on plasma levels of arginine, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), indicators of the nitric oxide pathway.MATERIALS AND METHODS: In this post hoc analysis of the HOME trial, we analysed plasma levels of arginine, ADMA and SDMA during the 4.3-year follow-up (comparing the effects of metformin versus placebo on top of insulin therapy). Statistical analysis was performed with a mixed model approach, in which simultaneously constant treatment effects were estimated, as well as time-dependent treatment effects.RESULTS: We found that metformin compared with placebo did not affect ADMA or SDMA plasma levels but rapidly decreased arginine plasma levels and hence the arginine to ADMA ratio. The constant treatment effect on ADMA was 0.99 (95% CI 0.97, 1.00) relative to placebo and the time-dependent treatment effect was 1.00 (95% CI 1.00, 1.01). By contrast, the constant treatment effect on arginine was 0.86 (95% CI 0.84, 0.88), with only a minimal time-dependent change of 1.01 (95% CI 1.00, 1.01).CONCLUSIONS: The potential benefits of metformin on endothelial function cannot be explained by a decrease in ADMA or by improved global arginine availability. The clinical significance of the decreased arginine plasma levels is not clear and can be harmful or beneficial, depending on the mechanism involved. However, a potential effect of metformin on the nitric oxide pathway is not restricted to the studied metabolites.

STUDY QUESTION Can the Poor Responder Outcome Prediction (PROsPeR) score identify live birth outcomes in subpopulations of patients with poor ovarian response (POR) defined according to the ESHRE Bologna criteria (female age, anti-Müllerian hormone (AMH), number of oocytes retrieved during the previous cycle (PNO) after treatment with originator recombinant human follitropin alfa? SUMMARY ANSWER The PROsPeR score discriminated the probability of live birth in patients with POR using observational data with fair discrimination (AUC ≅ 70%) and calibration, and the AUC losing less than 5% precision compared with a model developed using the observational data. WHAT IS KNOWN ALREADY Although scoring systems for the likelihood of live birth after ART have been developed, their accuracy may be insufficient, as they have generally been developed in the general population with infertility and were not validated for patients with POR. The PROsPeR score was developed using data from the follitropin alfa (GONAL-f; Merck KGaA, Darmstadt, Germany) arm of the Efficacy and Safety of Pergoveris in Assisted Reproductive Technology (ESPART) randomized controlled trial (RCT) and classifies women with POR as mild, moderate or severe, based upon three variables: female age, serum AMH level and number of oocytes retrieved during the previous cycle (PNO). STUDY DESIGN, SIZE, DURATION The external validation of the PROsPeR score was completed using data derived from eight different centres in France. In addition, the follitropin alfa data from the ESPART RCT, originally used to develop the PROsPeR score, were used as reference cohort. The external validation of the PROsPeR score l was assessed using AUC. A predetermined non-inferiority limit of 0.10 compared with a reference sample and calibration (Hosmer–Lemeshow test) were the two conditions required for evaluation. PARTICIPANTS/MATERIALS, SETTING, METHODS The observational cohort included data from 8085 ART treatment cycles performed with follitropin alfa in patients with POR defined according to the ESHRE Bologna criteria (17.6% of the initial data set). The ESPART cohort included 477 ART treatment cycles with ovarian stimulation performed with follitropin alfa in patients with POR. MAIN RESULTS AND THE ROLE OF CHANCE The external validation of the PROsPeR score to identify subpopulations of women with POR with different live birth outcomes was shown in the observational cohort (AUC = 0.688; 95% CI: 0.662, 0.714) compared with the ESPART cohort (AUC = 0.695; 95% CI: 0.623, 0.767). The AUC difference was −0.0074 (95% CI: −0.083, 0.0689). This provided evidence, with 97.5% one-sided confidence, that there was a maximum estimated loss of 8.4% in discrimination between the observational cohort and the ESPART cohort, which was below the predetermined margin of 10%. The Hosmer–Lemeshow test did not reject the calibration when comparing observed and predicted data (Hosmer–Lemeshow test = 1.266688; P = 0.260). LIMITATIONS, REASONS FOR CAUTION The study was based on secondary use of data that had not been collected specifically for the analysis reported here and the number of characteristics used to classify women with POR was limited to the available data. The data were from a limited number of ART centres in a single country, which may present a bias risk; however, baseline patient data were similar to other POR studies. WIDER IMPLICATIONS OF THE FINDINGS This evaluation of the PROsPeR score using observational data supports the notion that the likelihood of live birth may be calculated with reasonable precision using three readily available pieces of data (female age, serum AMH and PNO). The PROsPeR score has potential to be used to discriminate expected probability of live birth according to the degree of POR (mild, moderate, severe) after treatment with follitropin alfa, enabling comparison of performance at one centre over time and the comparison between centres. STUDY FUNDING/COMPETING INTEREST(S) This analysis was funded by Merck KGaA, Darmstadt, Germany. P.L. received grants from Merck KGaA, outside of the submitted work. N.M. reports grants, personal fees and non-financial support from Merck KGaA outside the submitted work. T.D.H. is Vice President and Head of Global Medical Affairs Fertility, Research and Development at Merck KGaA, Darmstadt, Germany. P.A. has received personal fees from Merck KGaA, Darmstadt, Germany, outside the submitted work. C.R. has received grants and personal fees from Gedeon Richter and Merck Serono S.A.S., France, an affiliate of Merck KGaA, Darmstadt, Germany, outside the submitted work. P.S. reports congress support from Merck Serono S.A.S., France (an affiliate of Merck KGaA, Darmstadt, Germany), Gedeon Richter, TEVA and MDS outside the submitted work. C.A., J.P., G.P. and R.W. declare no conflict of interest. TRIAL REGISTRATION NUMBER N/A

The benefit of LH supplementation (LHS) over sole use of FSH during controlled ovarian stimulation (COS) remains controversial. Meta-analyses have provided some evidence that the benefit of LHS is limited to women with poor ovarian response (POR). This study aimed to assess the effectiveness of LHS on cumulative live birth rate (CLBR) in POR using a large controlled study in a real-world context.This retrospective multicentre controlled study used data from registries at 12 French ART centres. All instances of POR undergoing ovarian stimulation and treated with follitrophin-alfa (FSH-α) with or without lutrophin-α were selected following an intention-to-treat principle. POR was defined according to the ESHRE Bologna criteria, and classified into three categories (Mild, Moderate and Severe) according to the Poor Responder Outcome Prediction (PROsPeR) score. The primary end-point was the CLBR associated with fresh and frozen embryos originating from the same ovarian stimulation.A total of 9787 instances of ovarian stimulation (5218 LHS, 4569 FSH-α only) were analysed, 33.0%, 52.4% and 14.6% being allocated to the Mild, Moderate and Severe PROsPeR categories, respectively. Using a mixed logistic model and adjusting for matched subclasses and baseline POR severity, it was found that the benefit of LHS compared with use of FSH alone differed between baseline severity categories (interaction test, P = 0.007): a significant benefit of LHS for CLBR was found for patients in the Moderate (14.3% versus 11.3%, odds ratio [OR] = 1.37, 95% confidence interval [CI] 1.07-1.75, risk ratio [RR] = 1.29, P = 0.013) and Severe (9.8% versus 4.4%, OR = 2.40, 95% CI- 1.48-3.89, RR = 1.89, P 0.001) categories, but not for the Mild category (18.8% versus 19.6%, OR = 0.95, 95% CI 0.78-1.15, RR = 0.95, P = 0.60).LHS has a significant effect on increasing CLBR in moderately and severely poor ovarian responders.

Introduction: Early prediction of survival without bronchopulmonary dysplasia (BPD) at 36 weeks of postmenstrual age remains challenging for infants born extremely preterm. We aimed to provide a new predictive model including variables available only at or soon after birth based on the literature and existing models. Methods: We conducted a systematic review to identify all variables considered to be significant predictors of BPD and survival at birth in extremely preterm infants. We then assessed the external validity of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network BPD estimator on the PREMILOC cohort, a recent French study with a large sample of extremely preterm infants and a vast number of variables at baseline. Finally, we attempted to improve this model by testing the added value of other early predictors reported in previous studies. Results: Restricted to baseline predictors, the NICHD Neonatal Research Network BPD estimator confirmed its calibration and fair discrimination (area under the receiver operating characteristic [auROC] [95% CI] = 0.73 [0.68–0.77] when used with a published model and auROC [95% CI] = 0.77 [0.73–0.81] when fitted to the PREMILOC dataset). We were able to improve the discriminatory power by adding candidate variables at birth associated with BPD in previous studies. The modified best predicting model included gestational age at birth, birthweight, respiratory support at baseline, gender, center effect, and multiple pregnancy as baseline predictors. This model showed significantly better discrimination (auROC [95% CI] = 0.85 [0.82–0.88]) and better confirmed calibration (Hosmer-Lemeshow test, p = 0.45). Conclusion: This new model, based on 6 early predictors, appears to improve the prediction soon after birth of BPD-free survival in extremely preterm infants.

Introduction: Pitolisant a Histamin H3-receptor inverse agonist waking agent for Excessive Daytime Sleepines (EDS) treatment in narcolepsy showed efficacy on EDS in Obstructive Sleep Apnea (OSA) patients with EDS treated respectively with and without Continuous Positive Airway Pressure (CPAP). Objective: Its efficacy and safety at 20mg/day was evaluated through an Individual patient data meta-analysis vs placebo.Methods: Epworth Sleep Scale (ESS) and Oxford Sleep Resistance (Osler) tests were co-primary endpoints tested at 0.025 significance and Fatigue (Pichot Scale) was secondary. Results: A significant mean ESS reduction of -3.06([95%CI -4.1,-2.02], Pl 0.001) was found with Pitolisant versus placebo and 81% more patients decreased final ESS to less than 10 (RR= 1.81 [95%CI 1.36, 2.39], pl 0.001). The Osler Final/Baseline was also 18% better (ratio=1.18[95%CI 1.02,1.35], P=0.022). A clinically meaningful EDS effect of Pitolisant measured by the aggregate Z-score on ESS and Osler was 0.71([0.46, 0.97], Pl 0.001). Finally, a significant mean Pichot Fatigue reduction of -1.23([-2.29,0.18], P=0.022) was found. These effects were shown invariant across various subgroups of the population (age,gender,work conditions). Finally these effects were not impacted as to whether or not CPAP was used. Side effect incidence was similar in both groups. Conclusions: These results confirm pitolisant efficacy on EDS and Fatigue symptoms in sleepy OSA patients versus placebo, evaluated by the ESS, Osler, EDS Z-score and Pichot Fatigue, irrespective of CPAP use. Bioprojet sponsored this analysis. CC is an employee of bioprojet pharma. JLP, YD, VA, were investigators, PL received honoraria from bioprojet.

Background: Spasmolytic agents are an attractive first line treatment option for irritable bowel syndrome (IBS). Pinaverium bromide (pinaverium) has antispasmodic effects on gastrointestinal smooth muscle and can relieve major IBS symptoms, but an up-to-date meta-analysis comparing the efficacy of pinaverium with placebo is lacking. The aim is to perform a systematic review and meta-analysis to assess the efficacy of pinaverium compared with placebo for IBS treatment. Methods: All placebo-controlled trials evaluating pinaverium for IBS treatment were included, up to October 2019. Treatment efficacy was evaluated by overall patient IBS symptoms. Individual symptoms were also evaluated. The effect of pinaverium versus placebo was expressed as standardized mean difference (SMD) and risk ratio (RR). Odds ratio (OR) and number needed to treat (NNT) were also calculated. Results: Eight studies were included for analysis. Pinaverium treatment had a beneficial effect on overall IBS symptom relief with a positive SMD of 0.64 [95% confidence interval (CI) 0.45–0.82, p Conclusion: Pinaverium is superior to placebo for the treatment of IBS symptoms, irrespective of patient age or gender, study publication year, sample size, or MQS. The NNT in this meta-analysis is amongst the lowest for studies and meta-analyses of antispasmodics versus placebo in IBS.

Background The administration of adrenaline is a life-saving intervention for anaphylactic reactions. However, it has been questioned whether the needle length of the autoinjectors is sufficient to achieve genuine intramuscular delivery and optimal bioavailability. Objective To assess the adequacy of Anapen, which has a relatively short needle length (10.5 mm), through a comparison of the depot localization, plasma pharmacokinetics, and cardiovascular responses of adrenaline delivered via Anapen versus a prefilled syringe with a 25.4-mm needle, which is generally used for intramuscular injections. Methods This randomized, open-label, crossover study compared the impact of adrenaline administration at 2 sites in the thigh of 18 normal weight male volunteers, using either Anapen or the prefilled syringe; in addition, we studied the treatment of 12 overweight women with Anapen. The depot depth was measured by ultrasonography, plasma adrenaline level was evaluated by ultra performance liquid chromatography-mass spectrometry (UPLC-MS), and heart rates were measured using a Holter monitor. Results Intramuscular injections were given with both devices at both thigh sites in nonobese men, but not in overweight women. Adrenaline levels showed a double peak, with parallel changes in the heart rate. The first peak, of potential vital importance in anaphylaxis treatment, occurred at approximately 10 minutes postinjection, with maximum concentration and area under the curve significantly higher with Anapen than with prefilled syringes; the magnitude of the second peak did not differ among the various conditions. Unexpectedly, in overweight women treated with Anapen, the magnitude of the first peak was similar to that observed in men, despite the injection being subcutaneous, and the overall bioavailability was enhanced. Conclusions Needle length and intramuscular injection are not absolute requirements for autoinjector efficacy, but the monitoring of injection location, biphasic adrenaline levels, and cardiovascular responses is important for the assessment of their therapeutic relevance in anaphylaxis.

Aim: To determine the influence of polymorphisms on the effects of metformin on HbA1c, daily dose of insulin and metformin plasma concentration. Methods: In a post hoc analysis of a 4.3 year placebo-controlled randomized trial with 390 patients with Type 2 diabetes already on insulin, we analyzed the influence of polymorphisms in genes coding for ATM and the transporters OCT1 and MATE1. Outcome measures were a combined HbA1c + daily dose of insulin Z score and metformin plasma concentrations. Results: rs11212617 (ATM) was associated with an improved Z score and a lower metformin plasma concentration. In addition, the major allele of rs2289669 (MATE1) was also associated with an improved Z score. Conclusion: The ATM SNP rs11212617 significantly affected the effect of metformin and metformin plasma concentration. Further research is needed to determine the clinical importance of these findings, in particular the effects on metformin plasma concentration.

Aims To study the effects of metformin, as compared to placebo, on serum levels of vitamin D (25-hydroxyvitamin D [25(OH)D]) in patients with advanced type 2 diabetes.Materials and Methods In the HOME trial, a randomized placebo-controlled trial, 390 insulin-treated patients with type 2 diabetes were treated with 850 mg metformin or placebo thrice daily for 52 months. In a post-hoc analysis, we examined changes in the combined levels of 25(OH)D-2 and 25(OH)D-3 at 4 and 16 months during the study.Results Mean combined 25(OH)D at baseline was 68.2 nmoL/L (95% confidence interval [CI]: 65.5-71.1). In mixed model analysis, metformin, as compared to placebo, had no effect on 25(OH)D levels during 16 months (coefficient: 1.002 per month, multiplicative model; 95% CI: 0.998-1.006, P=.30). Metformin was associated with a small increase of 25(OH)D-2 (coefficient: 1.012 per month; 95% CI: 1.003-1.021, P=.008). However, 25(OH)D-2 is only a very small fraction (3%) of 25(OH)D. Seasonal variation had the biggest impact on 25(OH)D levels. Vitamin B12 levels were not associated with the levels of 25(OH)D.Conclusion Metformin had no effect on serum 25(OH)D during 16 months in the setting of a clinical randomized controlled trial in patients with type 2 diabetes. Our results show that metformin doesn't lead to vitamin D deficiency.

In this trial, 390 insulin-treated patients with type 2 diabetes were randomized to either placebo or metformin. Fasting levels of glucose, insulin and C peptide were determined at baseline, after 4 months and yearly thereafter for 4 years to assess fasting estimates of beta cell function. The primary endpoint was the fasting C peptide-to-glucose ratio (FCPGR) and secondary measures were the disposition index (DI) and the fasting C peptide (FCP). We analysed the results with a general linear mixed model. Baseline FCPGR was 5.27 (95% CI, 4.83 - 5.71). Compared to placebo, FCPGR increased in the metformin group with 1.48 (95% CI, 1.09 - 1.87, P

Aims: Metformin treatment is associated with a decrease of serum vitamin B12, but whether this reflects tissue B12 deficiency is controversial. We studied the effects of metformin on serum levels of methylmalonic acid (MMA), a biomarker for tissue B12 deficiency, and on onset or progression of neuropathy.Methods: In the HOME trial, 390 insulin-treated patients with type 2 diabetes were treated with metformin or placebo for 52 months. In a post hoc analysis, we analyzed the association between metformin, MMA and a validated Neuropathy Score (NPS).Results: Metformin vs placebo increased MMA at the end of the study (95%CI: 0.019 to 0.055, p = 0.001). Mediation analysis showed that the effect of metformin on the NPS consisted of a beneficial effect through lowering HbAlc (-0.020 per gram year) and an adverse effect through increasing MMA (0.042 per gram year), resulting in a non-significant net effect (0.032 per gram year, 95% CI: -0.121 to 0.182, p = 034).Conclusion: Metformin not only reduces serum levels of B12, but also progressively increases serum MMA. The increase of MMA in metformin users was associated with significant worsening of the NPS. These results provide further support that metformin-related B12 deficiency is clinically relevant. Monitoring of B12 in users of metformin should be considered. (C) 2017 Elsevier Inc. All rights reserved.

Metformin prevents weight gain in patients with type 2 diabetes (T2D). However, the mechanisms involved are still unknown. In this post hoc analysis of the HOME trial, we aimed to determine whether metformin affects energy intake. Patients with T2D were treated with 850 mg metformin or received placebo added to insulin (1-3 times daily) for 4.3 years. Dietary intake was assessed at baseline, after 1 year and after 4.3 years, according to the dietary history method. Among the 310 included participants, 179 (93 placebo, 86 metformin) completed all 3 dietary assessments. We found no significant difference in energy intake after 4.3 years between the groups (metformin vs placebo: -31.0 kcal/d; 95% CI, -107.4 to 45.4; F-value, 1.3; df = 415; P = .27). Body weight in placebo users increased significantly more than in metformin-users during 4.3 years (4.9 ± 4.9 vs 1.1 ± 5.2 kg; t test: P ≤ .001). Linear mixed models did not show a significant effect of energy intake as explanation for the difference in weight gain between the groups (F-value, 0.1; df = 1; P = .82). In conclusion, the prevention of weight gain by metformin cannot be explained by reduced energy intake.

International audience; Background: Domains encompassing emotional disorders in relapsing-remitting MS (RRMS) patients are still unclear.Methods: We performed a 24-month, multicenter, single-arm, prospective study. RRMS patients started IFN-β treatment at baseline. The primary endpoint was lack of emotional control, measured using the "Echelle d'HumeurDépressive" (EHD) scale three times at baseline and at 10 post-treatment visits. Secondary endpoints were emotional blunting, irritability, fatigue, depression and anxiety. A linear mixed covariance model assessed change from baseline on an intention-to-treat basis, under the assumption of no mood disorder effect (one-sided 97.5% level), in which autoregressive type of autocorrelation was tested.Results: Out of 79 recruited patients, 70 were analyzed: 80% female; mean (SD) age, 37.0 (11.5) years. Mean (SD) lack of emotional control score at baseline and Month 24 was 12.7 (4.4) and 12.6 (5.5), respectively, versus 10.1 (3.2) in a healthy control population matched for age and sex. Stepwise analysis identified younger age, male sex and antidepressant use as significant predictors of higher lack of emotional control values.Conclusions: Based on 24 months of prospective follow-up, the results of this study highlights a broad spectrum of emotional disorders in the MS population at the time of disease modifying drugs initiation but no major IFN-β-related emotional disorders (mood dyscontrol, anxiety, depression) were observed. However, sporadic occurrences of severe mood disorders and suicidality cannot be excluded.

Research question Can previous reports of a decreased probability of success in stimulated IVF cycles with premature rise of progesterone, as determined by progesterone concentration on HCG day (PHCG), be confirmed? Design Retrospective, observational, single-centre cohort study conducted on 5447 IVF and intracytoplasmic (ICSI) cycles carried out among 2192 patients between 2009 and 2015, with conventional ovarian stimulation. This large database was used to develop a non-linear mixed prognosis model of live birth rate (LBR) incorporating PHCG as a predictor. Results In addition to known predictors (age, body mass index, anti-Mullerian hormone, type of infertility), PHCG was associated with a linear effect (OR 0.78 per Log[PHCG]ng/ml, 95% CI 0.611 to 0.997, P = 0.047) combined with a strong quadratic effect (OR 0.585 per Log2(PHCG)ng/ml, 95% CI 0.444 to 0.775, P Conclusions Evidence is provided of an important negative effect of PHCG at lower and higher values, independent of oocyte number, thus defining appropriate ranges for fresh embryo transfer or freeze-all strategy. In poor responders, premature progesterone rise may be ignored, thus avoiding unnecessary cancellations or embryo freezing. Conversely, in higher responders, the negative effect of progesterone elevation is more pronounced, suggesting that freeze-all policy should be applied more widely.

The Outcome study examines the fate of 4083 patients beginning IVF in 41 IVF centres, between January 2010 and December 2013. Cumulative live birth rate per patient (CLBR), the best reflection of IVF efficacy, is rarely presented in publications as it requires long-term follow-up, including all successive cycles, and pregnancies outcome. Analysis of international publications shows an average CLBR of 41.6 % and a drop-out rate of 49.5 %, both greatly varying by country and IVF centres. Because of the frequency with which patients change centre (8%), the Outcome study distinguishes patients with a past history of IVF in another centre (CLBR = 47.2 %) and patients undergoing their first true cycle (CLBR = 56.4 %). Survival techniques by Competing Risk, intended to take account of drop-out and lost to follow-up, assessed the overall CLBR as being 65.4 %. Differences in performance between centres are considerable for both CLBR (32–64%) and Performance Index, taking account of the number of cycles required to achieve a pregnancy (2–5). Multiple variance logistic regression analysis shows that the indicators influencing performance are age, parity, number of oocytes, smoking habit and overweight. These indicators are independent each other and are influencing performance in a high significant way. After adjusting for these indicators, the differences between centres are reduced but remain large and very significant. No centre appears to have specific expertise in the management of patients with adverse indicators. The Outcome study therefore confirms that the large differences in performance between centres are not explained by a difference in the treated population.

Objectif Pitolisant (P), agent eveillant agoniste inverse des recepteurs H3 (histamine) est un traitement de la somnolence diurne excessive (SDE) de la narcolepsie. La synthese de son efficacite, sa tolerance a 20 mg versus placebo (pl) est demontree via une meta-analyse des donnees individuelles patient a partir de 2 etudes chez des patients souffrant d’Apnee Obstructive du Sommeil (SAOS) presentant une SDE residuelle (SDEr) traites ou non par Pression Positive Continue (PPC). Methodes Les score d’Epworth (ESS) et test d’OSleR (OSL) etaient les criteres d’evaluation principaux, le z-score (ESS + OSL), la fatigue (score de Pichot), la reponse au traitement(RT), les principaux criteres secondaires. Resultats Une reduction significative de l’ESS -3,06([95 %CI -4,1,-2,0], p 0 et amelioration OSL) confirma la superiorite de P : ratio RR P20/PCB = 1,81[95 %CI 1,36, 2,39], p Conclusion Ces resultats prouvent l’efficacite de P sur la somnolence et la fatigue mesures par l’ESS, OSleR, Z-score et score de Pichot chez des patients SAOS somnolents avec ou sans PPC.

Background Abnormalities in brain structure and function can occur several decades prior to the onset of cognitive decline. It is in the preceding decades that an intervention is most likely to be effective, when informed by an understanding of factors contributing to the disease prodrome. Few studies, however, have sufficient longitudinal data on relevant risks to determine the optimum targets for interventions to improve cognition in aging. In this article we examine the timing and exposure of factors contributing to verbal memory performance in later life. Methods 387 participants from the population-based Women's Healthy Ageing Project, mean age at baseline of 49.6 years (range: 45–55 years), had complete neuropsychiatric assessments, clinical information, physical measures, and biomarkers collected at baseline, with at least three follow-up visits that included at least one cognitive reassessment. Mixed linear models were conducted to assess the significance of risk factors on later-life verbal memory. We explored the influence of early, contemporaneous, and cumulative exposures. Results Younger age and better education were associated with baseline memory test performance (CERAD). Over the 20 years of study follow-up, cumulative mid- to late-life physical activity had the strongest effect on better later life verbal memory (0.136 [0.058, 0.214]). The next most likely contributors to verbal memory in late life were the negative effect of cumulative hypertension (−0.033 [−0.047, −0.0.18] and the beneficial effect of HDL cholesterol (0.818 [0.042, 1.593]). Conclusions Findings suggest that midlife interventions focused on physical activity, hypertension control, and achieving optimal levels of HDL cholesterol will help maintain later-life verbal memory skills.

Objectif Deux symptomes caracterisent la narcolepsie : la somnolence diurne excessive (SDE) evaluee par le score d’Epworth (ESS), le test de Maintien de l’Eveil (TME) et les crises de cataplexie (CC). Des analyses multi-traitement (TT) comparatives des TT furent faites sur la SDE, les CC et la tolerance via une MAR. Methodes La MAR fut faite selon les guidelines et la selection des etudes cliniques randomises (ECR) fut definie par tous les ECR chez les patients narcoleptiques (PN) evaluant > 1 TT et le placebo (pl). Des meta-analyses univariees furent faites sur SDE, TME et CC, puis des meta-analyses multivariees avec des Z-scores. L’index de tolerance (IT) etait le taux des effets indesirables (EI). Ensuite, avec le Z-score efficacite (SDE et CC) et l’IT fut calcule l’index benefice/risque (IBR). Resultats Modafinil (MDF), oxybate de sodium (SXB) et pitolisant (P) sont efficaces sur la SDE ; P et SXB sont efficaces sur les CC. Quatorze ECR furent eligibles et 6 TT consideres : MDF (200–400 mg/j), SXB a 6 g/j (SXB6) et 9 g/j (SXB9), P jusqu’a 20 mg/j (P20) et jusqu’a 40 mg/j (P40) et pl. SXB9, MDF et P40 etaient significativement meilleurs que pl sur ESS, TME et CC. Selon les P-scores et les parametres d’efficacite, l’effet-TT observe le plus eleve fut P40 puis SXB9 et MDF. Le meilleur profil de tolerance fut P puis MDF et SXB6 et SXB9 avec taux d’EI eleve. Le meilleur IBR observe fut pour P40. Conclusion Cette meta-analyse en reseau montre que chez les PN, pitolisant jusqu’a 40 mg/j possede l’index benefice/risque le plus eleve en tenant compte de l’efficacite globale (SDE et CC) et de la tolerance.

Study Objectives Randomized controlled trials (RCTs) that compared the safety and efficacy of medical treatments for narcolepsy were analyzed using network meta-analysis. Methods The RCTs in narcolepsy were searched. Network meta-analysis compared efficacy and safety of multiple treatments, multi-arm studies, and multi-criteria treatment decisions, based on a random model that assumed heterogeneity between studies, with corrections for multi-arm studies. Results Fourteen RCTs, three drug treatments, and six doses were identified: sodium oxybate (6 and 9 g/d), modafinil (between 200 and 400 mg/d), and pitolisant (up to 20 and up to 40 mg/d). Significant heterogeneity (>50%) between studies was found in 12/14 studies for almost all endpoints, but between-design consistency was present. For ESS and MWT, sodium oxybate 9 g/d, modafinil, and pitolisant up to 40 mg/d had similar efficacy. Pitolisant 40 mg/d and sodium oxybate 9 g/d in two nightly doses had similar efficacy in reducing cataplexy. A good safety profile characterized by a TEAE incidence risk ratio (IRR)

ObjectiveTo evaluate the safety and efficacy of cholecalciferol in patients with relapsing-remitting MS (RRMS).MethodsIn this double-blind, placebo-controlled parallel-group, 2-year study, 181 patients with RRMS were randomized 1:1. Key inclusion criteria were a low serum 25-hydroxy vitamin D (25OHD) concentration (ResultsThe primary end point was not met. In patients who completed the 2-year follow-up (45 with cholecalciferol and 45 with placebo), all efficacy parameters favored cholecalciferol with an ARR reduction (p = 0.012), less new hypointense T1-weighted lesions (p = 0.025), a lower volume of hypointense T1-weighted lesions (p = 0.031), and a lower progression of EDSS (p = 0.026). The overall rate of adverse events was well balanced between groups.ConclusionsAlthough the primary end point was not met, these data suggest a potential treatment effect of cholecalciferol in patients with RRMS already treated with interferon beta-1a and low serum 25OHD concentration. Together with the good safety profile, these data support the exploration of cholecalciferol treatment in such patients with RRMS.Clinicaltrials.gov identifierNCT01198132.Classification of evidenceThis study provides Class II evidence that for patients with RRMS and low serum 25OHD, cholecalciferol did not significantly affect ARRs.

RESEARCH QUESTION: A number of live-birth predictive models are available, and despite clinical interest these are rarely used owing to poor performance. In addition, no predictive models specifically for poor ovarian responders (POR) are available. The aim of the current project was to develop a clinically applicable tool for predicting live birth for PORs receiving recombinant human FSH [r-hFSH]. DESIGN: A model was developed to predict live birth in PORs receiving r-hFSH, using data from the ESPART trial. Initially, two models were developed separately: one for patients with data from a previous assisted reproductive technology (ART) cycle and one for ART treatment-naïve patients. Subsequently, the simplified Poor Responder Outcome Prediction (PROsPeR) concept was derived. RESULTS: PROsPeR considers three predictors and categorizes PORs into three scores, with predicted the live-birth rate divided by three with each worsening category. When adequately calibrated, a discrimination score up to area under the receiver operating characteristic (AUCROC) (95% CI) of 0.84 (0.79 to 0.88) was observed, which is superior to previously published models. Lower discriminations were observed when the PROsPeR model was used to evaluate the patients who received both r-hFSH and recombinant human LH in the ESPART study (AUCROC [95% CI] 0.66 [0.61 to 0.71]) and when all the patients included in the ESPART study were evaluated (AUCROC [95% CI] 0.68 [0.61 to 0.72]). CONCLUSIONS: This model, specific to PORs receiving r-hFSH, constitutes the best compromise between precision and simplicity, and is suitable for routine practice. ispartof: REPRODUCTIVE BIOMEDICINE ONLINE vol:37 issue:1 pages:43-52 ispartof: location:Netherlands status: published

A number of health and lifestyle factors are thought to contribute to cognitive decline associated with age but cannot be easily modified by the individual patient. We identified 12 individually-modifiable interventions that can be implemented during midlife or later with the potential to ameliorate cognitive aging. For 10 of these, we used PubMed databases for a systematic review of long-duration (at least six months), randomized controlled trials in midlife and older adults without dementia or mild cognitive impairment with objective measures of neuropsychological performance. Using network meta-analysis, we performed a quantitative synthesis for global cognition (primary outcome) and episodic memory (secondary outcome). Of 1038 publications identified by our search strategy, 24 eligible trials were included in the network meta-analysis. Results suggested that the Mediterranean diet supplemented by olive oil and tai chi exercise may improve global cognition, and the Mediterranean diet plus olive oil and soy isoflavone supplements may improve memory. Effect sizes were no more than small (standardized mean differences 0.11 to 0.22). Cognitive training may have cognitive benefit as well. Most individually modifiable risk factors have not yet been adequately studied. We conclude that some interventions that can be self-initiated by healthy midlife and older adults may ameliorate cognitive aging.

We assessed the predictive value added by Anti-Mullerian Hormone (AMH) to currently validated live birth (LB) prediction models.Based on recent data from our center, we compared the external validity of the Templeton Model (TM) and its recent improvement (TMA) to select our model of reference. The added predictive value of AMH was assessed in testing the likelihood ratio significance and the Net Reclassification Index (NRI). The surrogate utility of AMH was tested by conducting an exploratory stepwise logistic regression.Based on 715 cycles, the original TM had poor performances (auROC C = 0.61 [0.58, 0.66], improving by fitting TM to our data (C = 0.71[0.66, 0.75]. TMA fitting proved better (C = 0.76; 95 %CI: 0.71, 0.80) and was selected as model of reference. Adding AMH to TMA or TM had no effect on discrimination (C = 0.76; 95 %CI: 0.72, 0.80), the likelihood ratio test was significant (p = 0.023), but the NRI was not (6.7 %; p = 0.055). A stepwise exploratory logistic regression identified the effects of age, previous IVF resulting in LB, time trend and AMH, leading to a prediction model reduced to four predictors (C = 0.75 [0.70, 0.81]).The added predictive value of AMH is limited. A possible surrogate/simplifying effect of AMH was found in eliminating 9/13 predictors from the model of reference. We conclude that whereas AMH does not add significant predictive value to the existing model, it contributes to simplifying the equation to reliable, easy to collect, and available in all databases predictors: age, AMH, time trend and female previous fertility history.

International audience; Aims:The prevalence of insomnia ranges from 36% to 91% in alcohol-dependent patients and may persist after alcohol withdrawal. Acamprosate has been shown to decrease insomnia in abstinent patients. Based on a large clinical trial database, the aim of the present study is to assess the efficacy of acamprosate in reducing insomnia, and if indeed it does reduce insomnia, to better understand its action mechanism.Short Summary:The aim of the study is to confirm the efficacy of acamprosate to reduce insomnia using an individual patient data meta-analysis. Twelve studies were found including 3508 patients. After a 6-month follow-up, the mean insomnia decrease over baseline was -26% and -45% for the placebo and acamprosate groups, respectively (P < 0.001).Methods:An individual patient data meta-analysis selected all the randomized trials of acamprosate in which insomnia was documented. Our main endpoint was insomnia change after a 6-month follow-up, measured by the validated Short Sleep Index (SSI) derived from the Hamilton Depression and Anxiety Scale. The meta-analysis was conducted using a two-level multilevel (patient/trial) mixed model with random treatment effect, random study effect and adjusting for baseline severity covariates.Results:Twelve studies were found including 3508 patients, 59.8% of whom were suffering from insomnia (95% CI 58.1-61.4). Psychiatric history, severe addiction, living alone and abnormal gamma-GT levels were found to be the risk factors of insomnia. After 6 months, the mean SSI decrease over baseline was -26% and -45% for placebo and acamprosate, respectively (treatment effect = 19%, 12.5-25.5; P < 0.001). By using a univariate mediation model, we found that the mediating effect of abstinence on insomnia accounted for 55.7% of the overall effect of acamprosate on insomnia reduction.Conclusions:Insomnia is prevalent among alcohol-dependent patients. It decreases spontaneously with abstinence but more frequently with acamprosate treatment.

Objectives Vascular disease remains a leading cause of death. There are several vascular risk factors identified that can mitigate development of disease in ageing. We examine reported rates of modifiable risk factors in women responding to an online health questionnaire advertised by popular media. Methods A sample of 26 620 women aged over 18 was examined in 2015 with a cross-sectional health questionnaire. The questionnaire included self-reported health, mood, lifestyle and vascular risk factors. Results There remains high rates of modifiable risk factors present in women. The vast majority of women (80%) reported not eating enough fruit and vegetables. Compared to the guidelines for health, the majority did not perform enough weekly physical activity (70%) and more than half the participants were overweight (54%). Sufficient fruit, vegetables, fish, legumes and physical activity were reported in less than 30% of women! Conclusions Women continue to report low rates of physical activity, fruit and vegetable intake and higher BMI than recommended for good health, despite worldwide health promotion activities aimed at changing these lifestyle factors. Programs to support healthy living need to be reviewed and revised to reduce the burden of vascular disease and dementia in women. Previous guidelines are not having the important impact they should, particularly in women.

International audience; BACKGROUND:Histaminergic neurons are crucial to maintain wakefulness, but their role in cataplexy is unknown. We assessed the safety and efficacy of pitolisant, a histamine H3 receptor inverse agonist, for treatment of cataplexy in patients with narcolepsy.METHODS:For this randomised, double-blind, placebo-controlled trial we recruited patients with narcolepsy from 16 sleep centres in nine countries (Bulgaria, Czech Republic, Hungary, Macedonia, Poland, Russia, Serbia, Turkey, and Ukraine). Patients were eligible if they were aged 18 years or older, diagnosed with narcolepsy with cataplexy according to version two of the International Classification of Sleep Disorders criteria, experienced at least three cataplexies per week, and had excessive daytime sleepiness (defined as an Epworth Sleepiness Scale score ≥12). We used a computer-generated sequence via an interactive web response system to randomly assign patients to receive either pitolisant or placebo once per day (1:1 ratio). Randomisation was done in blocks of four. Participants and investigators were masked to treatment allocation. Treatment lasted for 7 weeks: 3 weeks of flexible dosing decided by investigators according to efficacy and tolerance (5 mg, 10 mg, or 20 mg oral pitolisant), followed by 4 weeks of stable dosing (5 mg, 10 mg, 20 mg, or 40 mg). The primary endpoint was the change in the average number of cataplexy attacks per week as recorded in patient diaries (weekly cataplexy rate [WCR]) between the 2 weeks of baseline and the 4 weeks of stable dosing period. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01800045.FINDINGS:The trial was done between April 19, 2013, and Jan 28, 2015. We screened 117 patients, 106 of whom were randomly assigned to treatment (54 to pitolisant and 52 to placebo) and, after dropout, 54 patients from the pitolisant group and 51 from the placebo group were included in the intention-to-treat analysis. The WCR during the stable dosing period compared with baseline was decreased by 75% (WCRfinal=2·27; WCRbaseline=9·15; WCRfinal/baseline=0·25) in patients who received pitolisant and 38% (WCRfinal=4·52; WCRbaseline=7·31; WCRfinal/baseline=0·62) in patients who received placebo (rate ratio 0·512; 95% CI 0·43-0·60, p

Treatment of steroid-resistant acute graft-versus-host disease (GVHD) remains an unmet clinical need. Inolimomab, a monoclonal antibody to CD25, has shown encouraging results in phase 2 trials. This phase 3 randomized, open-label, multicenter trial compared inolimomab vs usual care in adult patients with steroid-refractory acute GVHD. Patients were randomly selected to receive treatment with inolimomab or usual care (the control group was treated with antithymocyte globulin [ATG]). The primary objective was to evaluate overall survival at 1 year without changing baseline allocated therapy. A total of 100 patients were randomly placed: 49 patients in the inolimomab arm and 51 patients in the ATG arm. The primary criteria were reached by 14 patients (28.5%) in the inolimomab and 11 patients (21.5%) in the ATG arms, with a hazard ratio of 0.874 (P = .28). With a minimum follow-up of 1 year, 26 (53%) and 31 (60%) patients died in the inolimomab and ATG arms, respectively. Adverse events were similar in the 2 arms, with fewer viral infections in the inolimomab arm compared with the ATG arm. The primary end point of this randomized phase 3 trial was not achieved. The lack of a statistically significant effect confirms the need for development of more effective treatments for acute GVHD. This trial is registered to https://www.clinicaltrialsregister.eu/ctr-search/search as EUDRACT 2007-005009-24.

The efficacy of racecadotril (RC), an intestinal antisecretory drug acting via an enkephalinase inhibition, was reviewed in paediatric acute diarrhoea but not yet in adults. Objective: To estimate the effectiveness of RC in the symptomatic treatment of acute diarrhoea in adults. Data Sources: A systematic review of MedLine, Cochrane Controlled Trials Register, DARE, and Embase (up to November 2013). Additional studies were identified by contacting clinical experts and the manufacturer. Study Selection and Appraisal: Randomized Controlled Trials performed in adults suffering from acute diarrhoea using RC in one treatment arm. Independent extraction of articles using predefined data fields, and methodological quality measurement assessment. All randomised trials performed in adults suffering from acute diarrhoea with RC as the studied group. Statistics: The main efficacy endpoint was diarrhoea duration defined as time to recovery compared between groups by survival techniques and converted into hazard ratio (HR). We exclusively used a random-effect meta-analytic model. Constipation proportion was the main safety endpoint, evaluated between treatments by the Relative Risks (RR). Results: Twelve randomised trials (2619 patients) met inclusion criteria. Duration of diarrhoea was much shorter in the RC group, the proportion of patients having recovered at any time of the treatment period was 65% higher in the RC group, compared with placebo (HR = 1.65 [1.38-1.97], p p = 0.24, n = 1618). The proportions of constipated patients were similar in the RC and placebo groups 0.95 [0.24-3.68], p = 0.97), however, about 3 times more constipated patients were found in the loperamide group compared with the RC group (RR = 0.34 [0.22-0.51], p to placebo, RC is characterized by a clinically relevant earlier remission of diarrhoea. When compared to loperamide, diarrhoea duration was similar, however, significantly fewer secondary constipation adverse effects were observed.

Racecadotril is an antidiarrhoeal drug with a pure intestinal antisecretory mechanism of action. Aim: To assess racecadotril efficacy, whatever its dose, versus placebo in adult acute diarrhoea. Methods: Individual Patient Data meta-analysis following multilevel mixed models testing of the significance of the treatment effect adjusted for baseline covariates. Diarrhoea duration was the common main criteria. Results: Four randomized clinical trials (n = 669) were identified with raw data. The clinical global impression evaluated at baseline by the physician was found to be the essential predictor influencing the outcome. As compared to placebo, the 100 mg dose, the minimum effective dose, induced a 80% increase of the recovered patient proportion at anytime (Hazard Ratio = 1.8 [1.3, 2.5], p < 0.001), a 60% increase of the responder proportion i.e. recovery within 3 days (p < 0.001), a 47% reduction of abdominal pain and nausea and an overall 33% decrease of sick days (p < 0.001). In conclusion, as compared to placebo, racecadotril induced several significant effects, such as reducing the diarrhoea duration, the number of stools and associated symptoms, leading to less lost productivity.