The beneficial effect of prophylactic hydrocortisone treatment in extremely preterm infants improves upon adjustment of the baseline characteristics.

BACKGROUND: Prophylactic low-dose hydrocortisone (HC) was found to improve survival without bronchopulmonary dysplasia (BPD) in extremely preterm infants. However, appropriately adjusting for baseline risks of BPD or death might substantially increase the precision of the HC effect size. METHODS: We conducted a secondary analysis of the PREMILOC trial. The treatment effect was evaluated on the primary endpoint through a covariance analysis ANCOVA, adjusting for the baseline covariates using a mixed linear model. Several sensitivity analyses were conducted to assess the potential heterogeneity of the treatment effect across centers and subpopulations. RESULTS: The interaction between treatment group and baseline risk for BPD or death was not statistically significant (p = 0.498). After adjusting for the patient's probability of BPD-free survival using baseline predictors alone, the HC treatment exhibited a highly significant effect (OR [95% CI] = 2.053 [1.602-2.501], p = 0.002), with a number needed to treat NNT [95% CI] = 5.8 [4.1-23.0]. Despite a weak interaction with sex, we found a lack of heterogeneity in the treatment effect across specific subpopulations. CONCLUSIONS: In the PREMILOC trial, the beneficial effect of prophylactic HC versus placebo on BPD-free survival in extremely preterm neonates was found to be greater when adjusted to baseline risks of BPD or death. REGISTRATION NUMBERS: EudraCT number 2007-002041-20, ClinicalTrial.gov number NCT00623740. IMPACT: Prophylactic low-dose hydrocortisone (HC) provided past evidence of a beneficial effect in improving survival without BPD in infants born extremely preterm. Adjustment for baseline risks of BPD or death might substantially increase the precision of the HC effect size. The beneficial effect of prophylactic HC vs placebo on BPD-free survival in extremely preterm neonates was found to be greater when adjusted to baseline risks of BPD or death. We evidenced a lack of heterogeneity in the treatment effect in specific subpopulations despite some weak interaction with sex.

Predicting the ovarian response: towards a determinant model and implications for practice.

OBJECTIVE: To improve the reliability of prediction models for ovarian response to stimulation in ART. DESIGN: A multicenter retrospective cohort study. SETTING: Twelve reproductive centers. PATIENTS: A total of 25,854 controlled ovarian stimulations between 2005 and 2016, including cycles cancelled for inadequate response, were included. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Precision of the prediction of the number of oocytes at ovarian pickup and of cancellation rate for poor ovarian response. RESULTS: Both AMH and antral follicle count exhibit a non-linear effect on the oocyte yield, with a linear relationship after log-transformation. After adjustment for age, BMI, and center, ovarian response observed in a previous stimulation was found to be the best predictor, followed by AMH and AFC. The zero-inflated binomial negative model showed that predictors of cycle cancellation and number of oocytes at retrieval were different, and assimilating cancellation to zero oocyte greatly reduces the determination of the model. Our model was characterized by the best ever reached determination (R2=0.505 for non-naïve women, 0.313 for all the women) and provided evidence of a very strong difference among centers. The results can be easily converted in the prediction of response levels (poor-medium-good-high). Finally, in case of partial report of the above predictors, we show that the univariate prediction based on the best predictor provides a good approximation. CONCLUSION(S): A substantial improvement of the ovarian response prediction is possible in modelling the possible cancellation decision, followed by the oocyte retrieval itself, according to an appropriate model based on previous stimulation and non-linear effects of AMH and AFC.

Bioavailability and cardiovascular effects of adrenaline administered by Anapen 500 µg auto-injector in healthy volunteers.

AIMS: 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. METHODS: 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). RESULTS: 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 (Cmax2 ) were reduced, and time to Cmax2 increased in overweight and obese females compared with males with normal body mass index; area under the curve (0-240 min) (AUC(0-240) ) was increased in overweight and obese females. Obese females had reduced maximal SBP values compared with normal weight males or overweight females; overweight and obese females had markedly different HR time courses compared with normal weight males. CONCLUSION: A 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.

Metformin and high-sensitivity cardiac troponin I and T trajectories in type 2 diabetes patients: a post-hoc analysis of a randomized controlled trial.

BACKGROUND: Metformin has favorable effects on cardiovascular outcomes in both newly onset and advanced type 2 diabetes, as previously reported findings from the UK Prospective Diabetes Study and the HOME trial have demonstrated. Patients with type 2 diabetes present with chronically elevated circulating cardiac troponin levels, an established predictor of cardiovascular endpoints and prognostic marker of subclinical myocardial injury. It is unknown whether metformin affects cardiac troponin levels. The study aimed to evaluate cardiac troponin I and T trajectories in patients with diabetes treated either with metformin or placebo. METHODS: This study is a post-hoc analysis of a randomized controlled trial (HOME trial) that included 390 patients with advanced type 2 diabetes randomized to 850 mg metformin or placebo up to three times daily concomitant to continued insulin treatment. Cardiac troponin I and T concentrations were measured at baseline and after 4, 17, 30, 43 and 52 months. We evaluated cardiac troponin trajectories by linear mixed-effects modeling, correcting for age, sex, smoking status and history of cardiovascular disease. RESULTS: This study enrolled 390 subjects, of which 196 received metformin and 194 received placebo. In the treatment and placebo groups, mean age was 64 and 59 years; with 50% and 58% of subjects of the female sex, respectively. Despite the previously reported reduction of macrovascular disease risk in this cohort by metformin, linear mixed-effects regression modelling did not reveal evidence for an effect on cardiac troponin I and cardiac troponin T levels [- 8.4% (- 18.6, 3.2), p = 0.150, and - 4.6% (- 12, 3.2), p = 0.242, respectively]. A statistically significant time-treatment interaction was found for troponin T [- 1.6% (- 2.9, - 0.2), p = 0.021] but not troponin I concentrations [- 1.5% (- 4.2, 1.2), p = 0.263]. CONCLUSIONS: In this post-hoc analysis of a 4.3-year randomized controlled trial, metformin did not exert a clinically relevant effect on cardiac troponin I and cardiac troponin T levels when compared to placebo. Cardioprotective effects of the drug observed in clinical studies are not reflected by a reduction in these biomarkers of subclinical myocardial injury. Trial registration ClinicalTrials.gov identifier NCT00375388.

Effect of metformin on arginine and dimethylarginines in patients with advanced type 2 diabetes: A post hoc analysis of a randomized trial.

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.

Reliability of AMH and AFC measurements and their correlation: a large multicenter study.

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.

Effect of recombinant LH supplementation on cumulative live birth rate compared with FSH alone in poor ovarian responders: a large, real-world study.

RESEARCH QUESTION: 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. DESIGN: 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. RESULTS: 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). CONCLUSION: LHS has a significant effect on increasing CLBR in moderately and severely poor ovarian responders.

A phase 3 randomized trial comparing inolimomab vs usual care in steroid-resistant acute GVHD.

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.

Both high and low HCG day progesterone concentrations negatively affect live birth rates in IVF/ICSI cycles.

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-Müllerian 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 < 0.001) resulting into a parabolic reverse-U curve. A significant interaction (P = 0.038) was found between PHCG and number of oocytes if three or less, but the effect of PHCG remains modest. For higher oocyte numbers, LBR rapidly increases with number of retrieved oocytes; however, LBR becomes more sensitive to PHCG as the number of oocytes increases. Higher live birth prognoses occur for optimal PHCG but are sharply reduced for lower or higher PHCG. 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.

Predicting live birth for poor ovarian responders: the PROsPeR concept.

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.

Metformin and ß-cell function in insulin-treated patients with type 2 diabetes: A randomized placebo-controlled 4.3-year trial.

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 < 0.001). The DI showed comparable results with a treatment effect of 1.50 (95% CI, 1.17 - 1.83; P < 0.001). FCP also increased in the metformin group but did not reach statistical significance vs placebo (0.034 nmol, 95% CI, -0.005 - 0.072; P = 0.085). Treatment with metformin vs placebo, added to insulin in patients with type 2 diabetes, improves long-term estimates of beta cell function in the fasting state.

Metformin-associated prevention of weight gain in insulin-treated type 2 diabetic patients cannot be explained by decreased energy intake: A post hoc analysis of a randomized placebo-controlled 4.3-year trial.

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.

Long-term treatment with metformin in type 2 diabetes and vitamin D levels: A post-hoc analysis of a randomized placebo-controlled trial.

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)D2 and 25(OH)D3 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)D2 (coefficient: 1.012 per month; 95% CI: 1.003-1.021, P = .008). However, 25(OH)D2 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.

Insomnia in Alcohol-Dependent Patients: Prevalence, Risk Factors and Acamprosate Effect: An Individual Patient Data Meta-Analysis.

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.

Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-α and -δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening.

BACKGROUND & AIMS: Elafibranor is an agonist of the peroxisome proliferator-activated receptor-α and peroxisome proliferator-activated receptor-δ. Elafibranor improves insulin sensitivity, glucose homeostasis, and lipid metabolism and reduces inflammation. We assessed the safety and efficacy of elafibranor in an international, randomized, double-blind placebo-controlled trial of patients with nonalcoholic steatohepatitis (NASH). METHODS: Patients with NASH without cirrhosis were randomly assigned to groups given elafibranor 80 mg (n = 93), elafibranor 120 mg (n = 91), or placebo (n = 92) each day for 52 weeks at sites in Europe and the United States. Clinical and laboratory evaluations were performed every 2 months during this 1-year period. Liver biopsies were then collected and patients were assessed 3 months later. The primary outcome was resolution of NASH without fibrosis worsening, using protocol-defined and modified definitions. Data from the groups given the different doses of elafibranor were compared with those from the placebo group using step-down logistic regression, adjusting for baseline nonalcoholic fatty liver disease activity score. RESULTS: In intention-to-treat analysis, there was no significant difference between the elafibranor and placebo groups in the protocol-defined primary outcome. However, NASH resolved without fibrosis worsening in a higher proportion of patients in the 120-mg elafibranor group vs the placebo group (19% vs 12%; odds ratio = 2.31; 95% confidence interval: 1.02-5.24; P = .045), based on a post-hoc analysis for the modified definition. In post-hoc analyses of patients with nonalcoholic fatty liver disease activity score ≥4 (n = 234), elafibranor 120 mg resolved NASH in larger proportions of patients than placebo based on the protocol definition (20% vs 11%; odds ratio = 3.16; 95% confidence interval: 1.22-8.13; P = .018) and the modified definitions (19% vs 9%; odds ratio = 3.52; 95% confidence interval: 1.32-9.40; P = .013). Patients with NASH resolution after receiving elafibranor 120 mg had reduced liver fibrosis stages compared with those without NASH resolution (mean reduction of 0.65 ± 0.61 in responders for the primary outcome vs an increase of 0.10 ± 0.98 in nonresponders; P < .001). Liver enzymes, lipids, glucose profiles, and markers of systemic inflammation were significantly reduced in the elafibranor 120-mg group vs the placebo group. Elafibranor was well tolerated and did not cause weight gain or cardiac events, but did produce a mild, reversible increase in serum creatinine (effect size vs placebo: increase of 4.31 ± 1.19 µmol/L; P < .001). CONCLUSIONS: A post-hoc analysis of data from trial of patients with NASH showed that elafibranor (120 mg/d for 1 year) resolved NASH without fibrosis worsening, based on a modified definition, in the intention-to-treat analysis and in patients with moderate or severe NASH. However, the predefined end point was not met in the intention to treat population. Elafibranor was well tolerated and improved patients' cardiometabolic risk profile. ClinicalTrials.gov number: NCT01694849.

Predictive Factors for Verbal Memory Performance Over Decades of Aging: Data from the Women's Healthy Ageing Project.

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.

Improving the quality of life of multiple sclerosis patients through coping strategies in routine medical practice.

Multiple sclerosis (MS) has a major impact on quality of life (QoL). Coping strategies which may influence QoL have not been identified. Furthermore, there is no coping scale designed to measure coping in MS patients and concise enough for routine medical practice. We used 46 items and 7 coping dimensions; we successively reduced the minimum number of dimensions through confirmatory factor analysis (CFA) and Rasch modelling. The resulting scale was submitted to psychometric validation via an independent cross-sectional analysis. After administration to 331 MS patients, we eliminated 10 of the 46 initial items; a CFA iterative algorithm identified a positive coping (PC) group and a negative coping (NC) group; an iterative reduction algorithm led to a final 10 items questionnaire, which was tested in an independent, new cross-sectional sample of 457 patients. Psychometric tests, including the Rasch model and CFA, successfully validated the scale, confirming the two dimensions and the absence of differential item functioning. The correlation between coping and QoL increased to 0.59 and 0.62 for NC and PC, respectively, compared with 0.33 found with existing scales. Our findings justify a one-dimensional overall coping scale (PC + NC). The effect of coping on QoL can be evaluated simply by adding together a positive and a negative coping strategy, for which we developed a short 10-item scale, which can be considered as an effective means of measuring the impact of coping on QoL and is ideal in routine medical practice.

To what extent does Anti-Mullerian Hormone contribute to a better prediction of live birth after IVF?

OBJECTIVE: We assessed the predictive value added by Anti-Mullerian Hormone (AMH) to currently validated live birth (LB) prediction models. METHODS: 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. RESULTS: 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]). CONCLUSION: 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.

Recombinant human follicle-stimulating hormone (r-hFSH) plus recombinant luteinizing hormone versus r-hFSH alone for ovarian stimulation during assisted reproductive technology: systematic review and meta-analysis.

BACKGROUND: The potential benefit of adding recombinant human luteinizing hormone (r-hLH) to recombinant human follicle-stimulating hormone (r-hFSH) during ovarian stimulation is a subject of debate, although there is evidence that it may benefit certain subpopulations, e.g. poor responders. METHODS: A systematic review and a meta-analysis were performed. Three databases (MEDLINE, Embase and CENTRAL) were searched (from 1990 to 2011). Prospective, parallel-, comparative-group randomized controlled trials (RCTs) in women aged 18-45 years undergoing in vitro fertilization, intracytoplasmic sperm injection or both, treated with gonadotrophin-releasing hormone analogues and r-hFSH plus r-hLH or r-hFSH alone were included. The co-primary endpoints were number of oocytes retrieved and clinical pregnancy rate. Analyses were conducted for the overall population and for prospectively identified patient subgroups, including patients with poor ovarian response (POR). RESULTS: In total, 40 RCTs (6443 patients) were included in the analysis. Data on the number of oocytes retrieved were reported in 41 studies and imputed in two studies. Therefore, data were available from 43 studies (r-hFSH plus r-hLH, n=3113; r-hFSH, n=3228) in the intention-to-treat (ITT) population (all randomly allocated patients, including imputed data). Overall, no significant difference in the number of oocytes retrieved was found between the r-hFSH plus r-hLH and r-hFSH groups (weighted mean difference -0.03; 95% confidence interval [CI] -0.41 to 0.34). However, in poor responders, significantly more oocytes were retrieved with r-hFSH plus r-hLH versus r-hFSH alone (n=1077; weighted mean difference +0.75 oocytes; 95% CI 0.14-1.36). Significantly higher clinical pregnancy rates were observed with r-hFSH plus r-hLH versus r-hFSH alone in the overall population analysed in this review (risk ratio [RR] 1.09; 95% CI 1.01-1.18) and in poor responders (n=1179; RR 1.30; 95% CI 1.01-1.67; ITT population); the observed difference was more pronounced in poor responders. CONCLUSIONS: These data suggest that there is a relative increase in the clinical pregnancy rates of 9% in the overall population and 30% in poor responders. In conclusion, this meta-analysis suggests that the addition of r-hLH to r-hFSH may be beneficial for women with POR.

Sexual function in the late postmenopause: a decade of follow-up in a population-based cohort of Australian women.

INTRODUCTION: There is a paucity of longitudinal studies assessing sexual function of women in the late postmenopause. AIM: This study aims to describe sexual function of women in the late postmenopause and to investigate change from early postmenopause. METHODS: Cross-sectional analysis of 2012/13 and longitudinal analysis from 2002/04 of the population based, Australian cohort of the Women's Healthy Ageing Project, applying validated instruments: Short Personal Experience Questionnaire (SPEQ), Female Sexual Distress Scale (FSDS), Hospital Anxiety and Depression Scale, Geriatric Depression Scale, and California Verbal Learning Test. MAIN OUTCOME MEASURES: Sexual activity, SPEQ, and FSDS. RESULTS: Two hundred thirty women responded (follow-up rate 53%), mean age was 70 years (range 64-77), 49.8% were sexually active. FSDS scores showed more distress for sexually active women (8.3 vs. 3.2, P<0.001). For 23 (23%) sexually active and for five (7%) inactive women, the diagnosis of female sexual dysfunction could be made. After adjustment, available partner (odds ratio [OR] 4.31, P<0.001), no history of depression (OR 0.49, P=0.036), moderate compared with no alcohol consumption (OR 2.43, P=0.019), and better cognitive function score (OR1.09, P=0.050) were significantly predictive for sexual activity. Compared with early postmenopause, 18% more women had ceased sexual activity. For women maintaining their sexual activity through to late postmenopause (n=82), SPEQ and FSDS scores had not changed significantly, but frequency of sexual activity had decreased (P=0.003) and partner difficulties had increased (P=0.043). [Correction added on 10 July 2014, after first online publication: Mean age of respondents was added.] CONCLUSIONS: In late postmenopause, half of the women were sexually active. Most important predictors were partner availability and no history of depression. However, being sexually active or having a partner were associated with higher levels of sexual distress. Compared with early postmenopause, sexual function scores had declined overall but were stable for women maintaining sexual activity. Further research into causes of sexual distress and reasons for sexual inactivity at this reproductive stage is warranted.