Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial

Background: Rucaparib, a poly(ADP-ribose) polymerase inhibitor, has anticancer activity in recurrent ovarian carcinoma harbouring a BRCA mutation or high percentage of genome-wide loss of heterozygosity. In this trial we assessed rucaparib versus placebo after response to second-line or later platinum-based chemotherapy in patients with high-grade, recurrent, platinum-sensitive ovarian carcinoma. Methods: In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited patients from 87 hospitals and cancer centres across 11 countries. Eligible patients were aged 18 years or older, had a platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma, had received at least two previous platinum-based chemotherapy regimens, had achieved complete or partial response to their last platinum-based regimen, had a cancer antigen 125 concentration of less than the upper limit of normal, had a performance status of 0–1, and had adequate organ function. Patients were ineligible if they had symptomatic or untreated central nervous system metastases, had received anticancer therapy 14 days or fewer before starting the study, or had received previous treatment with a poly(ADP-ribose) polymerase inhibitor. We randomly allocated patients 2:1 to receive oral rucaparib 600 mg twice daily or placebo in 28 day cycles using a computer-generated sequence (block size of six, stratified by homologous recombination repair gene mutation status, progression-free interval after the penultimate platinum-based regimen, and best response to the most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary outcome was investigator-assessed progression-free survival evaluated with use of an ordered step-down procedure for three nested cohorts: patients with BRCA mutations (carcinoma associated with deleterious germline or somatic BRCA mutations), patients with homologous recombination deficiencies (BRCA mutant or BRCA wild-type and high loss of heterozygosity), and the intention-to-treat population, assessed at screening and every 12 weeks thereafter. This trial is registered with ClinicalTrials.gov, number NCT01968213; enrolment is complete. Findings: Between April 7, 2014, and July 19, 2016, we randomly allocated 564 patients: 375 (66%) to rucaparib and 189 (34%) to placebo. Median progression-free survival in patients with a BRCA-mutant carcinoma was 16·6 months (95% CI 13·4–22·9; 130 [35%] patients) in the rucaparib group versus 5·4 months (3·4–6·7; 66 [35%] patients) in the placebo group (hazard ratio 0·23 [95% CI 0·16–0·34]; p<0·0001). In patients with a homologous recombination deficient carcinoma (236 [63%] vs 118 [62%]), it was 13·6 months (10·9–16·2) versus 5·4 months (5·1–5·6; 0·32 [0·24–0·42]; p<0·0001). In the intention-to-treat population, it was 10·8 months (8·3–11·4) versus 5·4 months (5·3–5·5; 0·36 [0·30–0·45]; p<0·0001). Treatment-emergent adverse events of grade 3 or higher in the safety population (372 [99%] patients in the rucaparib group vs 189 [100%] in the placebo group) were reported in 209 (56%) patients in the rucaparib group versus 28 (15%) in the placebo group, the most common of which were anaemia or decreased haemoglobin concentration (70 [19%] vs one [1%]) and increased alanine or aspartate aminotransferase concentration (39 [10%] vs none). Interpretation: Across all primary analysis groups, rucaparib significantly improved progression-free survival in patients with platinum-sensitive ovarian cancer who had achieved a response to platinum-based chemotherapy. ARIEL3 provides further evidence that use of a poly(ADP-ribose) polymerase inhibitor in the maintenance treatment setting versus placebo could be considered a new standard of care for women with platinum-sensitive ovarian cancer following a complete or partial response to second-line or later platinum-based chemotherapy. Funding: Clovis Oncology

A standard protocol to report discrete stage-structured demographic information

Stage-based demographic methods, such as matrix population models (MPMs), are powerful tools used to address a broad range of fundamental questions in ecology, evolutionary biology and conservation science. Accordingly, MPMs now exist for over 3000 species worldwide. These data are being digitised as an ongoing process and periodically released into two large open-access online repositories: the COMPADRE Plant Matrix Database and the COMADRE Animal Matrix Database. During the last decade, data archiving and curation of COMPADRE and COMADRE, and subsequent comparative research, have revealed pronounced variation in how MPMs are parameterized and reported. Here, we summarise current issues related to the parameterisation and reporting of MPMs that arise most frequently and outline how they affect MPM construction, analysis, and interpretation. To quantify variation in how MPMs are reported, we present results from a survey identifying key aspects of MPMs that are frequently unreported in manuscripts. We then screen COMPADRE and COMADRE to quantify how often key pieces of information are omitted from manuscripts using MPMs. Over 80% of surveyed researchers (n = 60) state a clear benefit to adopting more standardised methodologies for reporting MPMs. Furthermore, over 85% of the 300 MPMs assessed from COMPADRE and COMADRE omitted one or more elements that are key to their accurate interpretation. Based on these insights, we identify fundamental issues that can arise from MPM construction and communication and provide suggestions to improve clarity, reproducibility and future research utilising MPMs and their required metadata. To fortify reproducibility and empower researchers to take full advantage of their demographic data, we introduce a standardised protocol to present MPMs in publications. This standard is linked to www.compa dre-db.org, so that authors wishing to archive their MPMs can do so prior to submission of publications, following examples from other open-access repositories such as DRYAD, Figshare and Zenodo. Combining and standardising MPMs parameterized from populations around the globe and across the tree of life opens up powerful research opportunities in evolutionary biology, ecology and conservation research. However, this potential can only be fully realised by adopting standardised methods to ensure reproducibility

The role of left ventricular deformation in the assessment of microvascular obstruction and intramyocardial haemorrhage

In the setting of acute ST-elevation myocardial infarction (STEMI), it remains unclear which strain parameter most strongly correlates with microvascular obstruction (MVO) or intramyocardial haemorrhage (IMH). We aimed to investigate the association of MVO, IMH and convalescent left ventricular (LV) remodelling with strain parameters measured with cardiovascular magnetic resonance (CMR). Forty-three patients with reperfused STEMI and 10 age and gender matched healthy controls underwent CMR within 3-days and at 3-months following reperfused STEMI. Cine, T2-weighted, T2*-imaging and late gadolinium enhancement (LGE) imaging were performed. Infarct size, MVO and IMH were quantified. Peak global longitudinal strain (GLS), global radial strain (GRS), global circumferential strain (GCS) and their strain rates were derived by feature tracking analysis of LV short-axis, 4-chamber and 2-chamber cines. All 43 patients and ten controls completed the baseline scan and 34 patients completed 3-month scans. In multivariate regression, GLS demonstrated the strongest association with MVO or IMH (beta = 0.53, p 20%). Baseline GLS also demonstrated the strongest diagnostic performance in predicting adverse LV remodelling (AUC = 0.79; 95% CI 0.60–0.98; p = 0.03). Post-reperfused STEMI, baseline GLS was most closely associated with the presence of MVO or IMH. Baseline GLS was more strongly associated with adverse LV remodelling than other CMR parameters

Aggression in Low Functioning Children and Adolescents with Autistic Disorder

BACKGROUND: Parents, caregivers and mental health professionals have often reported violence and aggression in children or adolescents with autistic disorder. However, most of these observations derived from anecdotal reports, and studies on frequency and characterization of aggression in autism remain limited. Our objective was to better characterize and understand the different types of aggressive behaviors displayed by a large group of individuals with autism in different observational situations. METHODOLOGY/FINDINGS: The study was conducted on 74 children and adolescents with autism and 115 typically developing control individuals matched for sex, age and pubertal stage. Other-Injurious Behaviors (OIB) were assessed in three observational situations (parents at home, two caregivers at day-care, a nurse and a child psychiatrist during blood drawing) using validated scales. The frequency of OIB was significantly higher in individuals with autism compared to typically developing control individuals during the blood drawing (23% vs. 0%, P<0 .01). The parents observed significantly less OIB in their children than caregivers (34% vs. 58%, P<0.05). In addition, the most frequent concurrent behaviors occurring just before the appearance of OIB in individuals with autism were anxiety-related behaviors and excitation according to the parental as well as the caregiver observation. CONCLUSIONS/SIGNIFICANCE: The results suggest that in a stressful situation, such as the blood drawing, individuals with autism release their stress through behaviors such as OIB, whereas typically developing individuals regulate and express their stress through cognitive skills such as mental coping strategies, symbolization skills with representation and anticipation of the stressful situation, social interaction and verbal or non-verbal communication. The findings underline also the key role of the environment in assessing OIB and developing therapeutic perspectives, with an individual who modulates his/her behavior according to the environment, and an environment that perceives this behavior and reacts to it with different tolerance thresholds according to the observers

Loss of Myotubularin Function Results in T-Tubule Disorganization in Zebrafish and Human Myotubular Myopathy

Myotubularin is a lipid phosphatase implicated in endosomal trafficking in vitro, but with an unknown function in vivo. Mutations in myotubularin cause myotubular myopathy, a devastating congenital myopathy with unclear pathogenesis and no current therapies. Myotubular myopathy was the first described of a growing list of conditions caused by mutations in proteins implicated in membrane trafficking. To advance the understanding of myotubularin function and disease pathogenesis, we have created a zebrafish model of myotubular myopathy using morpholino antisense technology. Zebrafish with reduced levels of myotubularin have significantly impaired motor function and obvious histopathologic changes in their muscle. These changes include abnormally shaped and positioned nuclei and myofiber hypotrophy. These findings are consistent with those observed in the human disease. We demonstrate for the first time that myotubularin functions to regulate PI3P levels in a vertebrate in vivo, and that homologous myotubularin-related proteins can functionally compensate for the loss of myotubularin. Finally, we identify abnormalities in the tubulo-reticular network in muscle from myotubularin zebrafish morphants and correlate these changes with abnormalities in T-tubule organization in biopsies from patients with myotubular myopathy. In all, we have generated a new model of myotubular myopathy and employed this model to uncover a novel function for myotubularin and a new pathomechanism for the human disease that may explain the weakness associated with the condition (defective excitation–contraction coupling). In addition, our findings of tubuloreticular abnormalities and defective excitation-contraction coupling mechanistically link myotubular myopathy with several other inherited muscle diseases, most notably those due to ryanodine receptor mutations. Based on our findings, we speculate that congenital myopathies, usually considered entities with similar clinical features but very disparate pathomechanisms, may at their root be disorders of calcium homeostasis

Impaired Executive Function Mediates the Association between Maternal Pre-Pregnancy Body Mass Index and Child ADHD Symptoms

Increasing evidence suggests exposure to adverse conditions in intrauterine life may increase the risk of developing attention-deficit/hyperactivity disorder (ADHD) in childhood. High maternal pre-pregnancy body mass index (BMI) has been shown to predict child ADHD symptoms, however the neurocognitive processes underlying this relationship are not known. The aim of the present study was to test the hypothesis that this association is mediated by alterations in child executive function.A population-based cohort of 174 children (mean age = 7.3 ± 0.9 (SD) yrs, 55% girls) was evaluated for ADHD symptoms using the Child Behavior Checklist, and for neurocognitive function using the Go/No-go task. This cohort had been followed prospectively from early gestation and birth through infancy and childhood with serial measures of maternal and child prenatal and postnatal factors. Maternal pre-pregnancy BMI was a significant predictor of child ADHD symptoms (F((1,158)) = 4.80, p = 0.03) and of child performance on the Go/No-go task (F((1,157)) = 8.37, p = 0.004) after controlling for key potential confounding variables. A test of the mediation model revealed that the association between higher maternal pre-pregnancy BMI and child ADHD symptoms was mediated by impaired executive function (inefficient/less attentive processing; Sobel Test: t = 2.39 (± 0.002, SEM), p = 0.02).To the best of our knowledge this is the first study to report that maternal pre-pregnancy BMI-related alterations in child neurocognitive function may mediate its effects on ADHD risk. The finding is clinically significant and may extrapolate to an approximately 2.8-fold increase in the prevalence of ADHD among children of obese compared to those of non-obese mothers. These results add further evidence to the growing awareness that neurodevelopmental disorders such as ADHD may have their foundations very early in life

Nutrition, mental health and violence: from pregnancy to postpartum Cohort of women attending primary care units in Southern Brazil - ECCAGE study

<p>Abstract</p> <p>Background</p> <p>Woman's nutritional status, before and during pregnancy, is a strong determinant of health outcomes in the mother and newborn. Gestational weight gain and postpartum weight retention increases risk of overweight or obesity in the future and they depend on the pregestational nutritional status and on food consumption and eating behavior during pregnancy. Eating behavior during pregnancy may be the cause or consequence of mood changes during pregnancy, especially depression, which increases likelihood of postpartum depression. In Brazil, a study carried out in the immediate postpartum period found that one in three women experienced some type of violence during pregnancy. Violence and depression are strongly associated and both exposures during pregnancy are associated with increased maternal stress and subsequent harm to the infant. The main objectives of this study are: to identify food intake and eating behaviors patterns; to estimate the prevalence of common mental disorders and the experience of violence during and after pregnancy; and to estimate the association between these exposures and infant's health and development.</p> <p>Methods/Design</p> <p>This is a cohort study of 780 pregnant women receiving care in 18 primary care units in two cities in Southern Brazil. Pregnant women were first evaluated between the 16^thand 36^thweek of pregnancy at a prenatal visit. Follow-up included immediate postpartum assessment and around the fifth month postpartum. Information was obtained on sociodemographic characteristics, living circumstances, food intake, eating behaviors, mental health and exposure to violence, and on infant's development and anthropometrics measurements.</p> <p>Discussion</p> <p>This project will bring relevant information for a better understanding of the relationship between exposures during pregnancy and how they might affect child development, which can be useful for a better planning of health actions aiming to enhance available resources in primary health care.</p

On the Determinants of Currency Crises: The Role of Model Uncertainty

We tackle explicitly the issue of model uncertainty in the framework of binary variable models of currency crises. Using Bayesian model averaging techniques, we assess the robustness of the explanatory variables proposed in the recent literature for both static and dynamic models. Our results indicate that the variables belonging to the set of macroeconomic fundamentals proposed by the literature are very fragile determinants of the occurrence of currency crises. The results improve if the crisis index identifies a crisis period (defined as the period up to a year before a crisis) instead of a crisis occurrence. In this setting, the extent of real exchange rate misalignment and financial market indicators appear as robust determinants of crisis periods