Showing papers by "Indiana University published in 2016"

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.

Sharing and community curation of mass spectrometry data with Global Natural Products Social Molecular Networking

Abstract: The potential of the diverse chemistries present in natural products (NP) for biotechnology and medicine remains untapped because NP databases are not searchable with raw data and the NP community has no way to share data other than in published papers. Although mass spectrometry (MS) techniques are well-suited to high-throughput characterization of NP, there is a pressing need for an infrastructure to enable sharing and curation of data. We present Global Natural Products Social Molecular Networking (GNPS; http://gnps.ucsd.edu), an open-access knowledge base for community-wide organization and sharing of raw, processed or identified tandem mass (MS/MS) spectrometry data. In GNPS, crowdsourced curation of freely available community-wide reference MS libraries will underpin improved annotations. Data-driven social-networking should facilitate identification of spectra and foster collaborations. We also introduce the concept of 'living data' through continuous reanalysis of deposited data.

REVEL: An Ensemble Method for Predicting the Pathogenicity of Rare Missense Variants

Abstract: The vast majority of coding variants are rare, and assessment of the contribution of rare variants to complex traits is hampered by low statistical power and limited functional data. Improved methods for predicting the pathogenicity of rare coding variants are needed to facilitate the discovery of disease variants from exome sequencing studies. We developed REVEL (rare exome variant ensemble learner), an ensemble method for predicting the pathogenicity of missense variants on the basis of individual tools: MutPred, FATHMM, VEST, PolyPhen, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP, SiPhy, phyloP, and phastCons. REVEL was trained with recently discovered pathogenic and rare neutral missense variants, excluding those previously used to train its constituent tools. When applied to two independent test sets, REVEL had the best overall performance (p −12 ) as compared to any individual tool and seven ensemble methods: MetaSVM, MetaLR, KGGSeq, Condel, CADD, DANN, and Eigen. Importantly, REVEL also had the best performance for distinguishing pathogenic from rare neutral variants with allele frequencies

The rise of social bots

Abstract: Today's social bots are sophisticated and sometimes menacing. Indeed, their presence can endanger online ecosystems as well as our society.

Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study

Abstract: Summary Background Limited evidence exists to show that adding a third agent to platinum-doublet chemotherapy improves efficacy in the first-line advanced non-small-cell lung cancer (NSCLC) setting. The anti-PD-1 antibody pembrolizumab has shown efficacy as monotherapy in patients with advanced NSCLC and has a non-overlapping toxicity profile with chemotherapy. We assessed whether the addition of pembrolizumab to platinum-doublet chemotherapy improves efficacy in patients with advanced non-squamous NSCLC. Methods In this randomised, open-label, phase 2 cohort of a multicohort study (KEYNOTE-021), patients were enrolled at 26 medical centres in the USA and Taiwan. Patients with chemotherapy-naive, stage IIIB or IV, non-squamous NSCLC without targetable EGFR or ALK genetic aberrations were randomly assigned (1:1) in blocks of four stratified by PD-L1 tumour proportion score ( 2 every 3 weeks followed by pembrolizumab for 24 months and indefinite pemetrexed maintenance therapy or to 4 cycles of carboplatin and pemetrexed alone followed by indefinite pemetrexed maintenance therapy. The primary endpoint was the proportion of patients who achieved an objective response, defined as the percentage of patients with radiologically confirmed complete or partial response according to Response Evaluation Criteria in Solid Tumors version 1.1 assessed by masked, independent central review, in the intention-to-treat population, defined as all patients who were allocated to study treatment. Significance threshold was p Findings Between Nov 25, 2014, and Jan 25, 2016, 123 patients were enrolled; 60 were randomly assigned to the pembrolizumab plus chemotherapy group and 63 to the chemotherapy alone group. 33 (55%; 95% CI 42–68) of 60 patients in the pembrolizumab plus chemotherapy group achieved an objective response compared with 18 (29%; 18–41) of 63 patients in the chemotherapy alone group (estimated treatment difference 26% [95% CI 9–42%]; p=0·0016). The incidence of grade 3 or worse treatment-related adverse events was similar between groups (23 [39%] of 59 patients in the pembrolizumab plus chemotherapy group and 16 [26%] of 62 in the chemotherapy alone group). The most common grade 3 or worse treatment-related adverse events in the pembrolizumab plus chemotherapy group were anaemia (seven [12%] of 59) and decreased neutrophil count (three [5%]); an additional six events each occurred in two (3%) for acute kidney injury, decreased lymphocyte count, fatigue, neutropenia, and sepsis, and thrombocytopenia. In the chemotherapy alone group, the most common grade 3 or worse events were anaemia (nine [15%] of 62) and decreased neutrophil count, pancytopenia, and thrombocytopenia (two [3%] each). One (2%) of 59 patients in the pembrolizumab plus chemotherapy group experienced treatment-related death because of sepsis compared with two (3%) of 62 patients in the chemotherapy group: one because of sepsis and one because of pancytopenia. Interpretation Combination of pembrolizumab, carboplatin, and pemetrexed could be an effective and tolerable first-line treatment option for patients with advanced non-squamous NSCLC. This finding is being further explored in an ongoing international, randomised, double-blind, phase 3 study. Funding Merck & Co.

Modular Brain Networks

Abstract: The development of new technologies for mapping structural and functional brain connectivity has led to the creation of comprehensive network maps of neuronal circuits and systems. The architecture of these brain networks can be examined and analyzed with a large variety of graph theory tools. Methods for detecting modules, or network communities, are of particular interest because they uncover major building blocks or subnetworks that are particularly densely connected, often corresponding to specialized functional components. A large number of methods for community detection have become available and are now widely applied in network neuroscience. This article first surveys a number of these methods, with an emphasis on their advantages and shortcomings; then it summarizes major findings on the existence of modules in both structural and functional brain networks and briefly considers their potential functional roles in brain evolution, wiring minimization, and the emergence of functional specialization...

A Critical Review and Best-Practice Recommendations for Control Variable Usage

Abstract: The use of control variables plays a central role in organizational research due to practical difficulties associated with the implementation of experimental and quasi-experimental designs. As such, we conducted an in-depth review and content analysis of what variables, and why such variables are controlled for, in 10 of the most popular research domains (task performance, organizational citizenship behaviors, turnover, job satisfaction, organizational commitment, employee burnout, personality, leader‒member exchange, organizational justice, and affect) in organizational behavior/human resource management (OB/HRM) and applied psychology. Specifically, we examined 580 articles published from 2003 to 2012 in AMJ, ASQ, JAP, JOM, and PPsych. Results indicate that, across research domains with clearly distinct theoretical bases, the overwhelming majority of the more than 3,500 controls identified in our review converge around the same simple demographic factors (i.e., gender, age, tenure), very little effort is made to explain why and how controls relate to focal variables of interest, and control variable practices have not changed much over the past decade. To address these results, we offer best-practice recommendations in the form of a sequence of questions and subsequent steps that can be followed to make decisions on the appropriateness of including a specific control variable within a particular theoretical framework, research domain, and empirical study. Our recommendations can be used by authors as well as journal editors and reviewers to improve the transparency and appropriateness of practices regarding control variable usage.

Many-body localization in a quantum simulator with programmable random disorder

Abstract: Interacting quantum systems are expected to thermalize, but in some situations in the presence of disorder they can exist in localized states instead. This many-body localization is studied experimentally in a small system with programmable disorder. When a system thermalizes it loses all memory of its initial conditions. Even within a closed quantum system, subsystems usually thermalize using the rest of the system as a heat bath. Exceptions to quantum thermalization have been observed, but typically require inherent symmetries1,2 or noninteracting particles in the presence of static disorder3,4,5,6. However, for strong interactions and high excitation energy there are cases, known as many-body localization (MBL), where disordered quantum systems can fail to thermalize7,8,9,10. We experimentally generate MBL states by applying an Ising Hamiltonian with long-range interactions and programmable random disorder to ten spins initialized far from equilibrium. Using experimental and numerical methods we observe the essential signatures of MBL: initial-state memory retention, Poissonian distributed energy level spacings, and evidence of long-time entanglement growth. Our platform can be scaled to more spins, where a detailed modelling of MBL becomes impossible.

Early role of vascular dysregulation on late-onset Alzheimer’s disease based on multifactorial data-driven analysis

Abstract: Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD-abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions.

Scaling laws predict global microbial diversity

Abstract: Scaling laws underpin unifying theories of biodiversity and are among the most predictively powerful relationships in biology. However, scaling laws developed for plants and animals often go untested or fail to hold for microorganisms. As a result, it is unclear whether scaling laws of biodiversity will span evolutionarily distant domains of life that encompass all modes of metabolism and scales of abundance. Using a global-scale compilation of ∼35,000 sites and ∼5.6⋅106 species, including the largest ever inventory of high-throughput molecular data and one of the largest compilations of plant and animal community data, we show similar rates of scaling in commonness and rarity across microorganisms and macroscopic plants and animals. We document a universal dominance scaling law that holds across 30 orders of magnitude, an unprecedented expanse that predicts the abundance of dominant ocean bacteria. In combining this scaling law with the lognormal model of biodiversity, we predict that Earth is home to upward of 1 trillion (1012) microbial species. Microbial biodiversity seems greater than ever anticipated yet predictable from the smallest to the largest microbiome.

Hearing impairment and cognitive energy: the Framework for Understanding Effortful Listening (FUEL)

Abstract: The Fifth Eriksholm Workshop on “Hearing Impairment and Cognitive Energy” was convened to develop a consensus among interdisciplinary experts about what is known on the topic, gaps in knowledge, the use of terminology, priorities for future research, and implications for practice. The general term cognitive energy was chosen to facilitate the broadest possible discussion of the topic. It goes back to Titchener (1908) who described the effects of attention on perception; he used the term psychic energy for the notion that limited mental resources can be flexibly allocated among perceptual and mental activities. The workshop focused on three main areas: (1) theories, models, concepts, definitions, and frameworks; (2) methods and measures; and (3) knowledge translation. We defined effort as the deliberate allocation of mental resources to overcome obstacles in goal pursuit when carrying out a task, with listening effort applying more specifically when tasks involve listening. We adapted Kahneman’s seminal (1973) Capacity Model of Attention to listening and proposed a heuristically useful Framework for Understanding Effortful Listening (FUEL). Our FUEL incorporates the well-known relationship between cognitive demand and the supply of cognitive capacity that is the foundation of cognitive theories of attention. Our FUEL also incorporates a motivation dimension based on complementary theories of motivational intensity, adaptive gain control, and optimal performance, fatigue, and pleasure. Using a three-dimensional illustration, we highlight how listening effort depends not only on hearing difficulties and task demands but also on the listener’s motivation to expend mental effort in the challenging situations of everyday life.

BotOrNot: A System to Evaluate Social Bots

Abstract: While most online social media accounts are controlled by humans, these platforms also host automated agents called social bots or sybil accounts. Recent literature reported on cases of social bots imitating humans to manipulate discussions, alter the popularity of users, pollute content and spread misinformation, and even perform terrorist propaganda and recruitment actions. Here we present BotOrNot, a publicly-available service that leverages more than one thousand features to evaluate the extent to which a Twitter account exhibits similarity to the known characteristics of social bots. Since its release in May 2014, BotOrNot has served over one million requests via our website and APIs.

MicrobeJ, a tool for high throughput bacterial cell detection and quantitative analysis

Abstract: Single-cell analysis of bacteria and subcellular protein localization dynamics has shown that bacteria have elaborate life cycles, cytoskeletal protein networks and complex signal transduction pathways driven by localized proteins. The volume of multidimensional images generated in such experiments and the computation time required to detect, associate and track cells and subcellular features pose considerable challenges, especially for high-throughput experiments. There is therefore a need for a versatile, computationally efficient image analysis tool capable of extracting the desired relationships from images in a meaningful and unbiased way. Here, we present MicrobeJ, a plug-in for the open-source platform ImageJ(1). MicrobeJ provides a comprehensive framework to process images derived from a wide variety of microscopy experiments with special emphasis on large image sets. It performs the most common intensity and morphology measurements as well as customized detection of poles, septa, fluorescent foci and organelles, determines their subcellular localization with subpixel resolution, and tracks them over time. Because a dynamic link is maintained between the images, measurements and all data representations derived from them, the editor and suite of advanced data presentation tools facilitates the image analysis process and provides a robust way to verify the accuracy and veracity of the data.

The increasing importance of atmospheric demand for ecosystem water and carbon fluxes

Abstract: US Department of Energy; National Science Foundation (NSF) [DEB 1552747]; NSF [DEB 1552976, EF 1241881, EAR 125501, EAR 155489]; NOAA/GFDL-Princeton University Cooperative Institute for Climate Science

Psychosocial Care for People With Diabetes: A Position Statement of the American Diabetes Association

Abstract: Complex environmental, social, behavioral, and emotional factors, known as psychosocial factors, influence living with diabetes, both type 1 and type 2, and achieving satisfactory medical outcomes and psychological well-being. Thus, individuals with diabetes and their families are challenged with complex, multifaceted issues when integrating diabetes care into daily life. To promote optimal medical outcomes and psychological well-being, patient-centered care is essential, defined as “providing care that is respectful of and responsive to individual patient preferences, needs, and values and ensuring that patient values guide all clinical decisions” (1). Practicing personalized, patient-centered psychosocial care requires that communications and interactions, problem identification, psychosocial screening, diagnostic evaluation, and intervention services take into account the context of the person with diabetes (PWD) and the values and preferences of the PWD. This article provides diabetes care providers with evidence-based guidelines for psychosocial assessment and care of PWD and their families. Recommendations are based on commonly used clinical models, expert consensus, and tested interventions, taking into account available resources, practice patterns, and practitioner burden. Consideration of life span and disease course factors (Fig. 1) is critical in the psychosocial care of PWD. This Position Statement focuses on the most common psychological factors affecting PWD, including diabetes distress and psychological comorbidities, while also considering the needs of special populations and the context of care. Figure 1 Psychosocial care for PWD: life and disease course perspectives. *With depressed mood, anxiety, or emotion and conduct disturbance. **Personality traits, coping style, maladaptive health behaviors, or stress-related physiological response. \***|Examples include changing schools, moving, job/occupational changes, marriage or divorce, or experiencing loss. #### Recommendations

Genetic drift, selection and the evolution of the mutation rate

Abstract: Mutation is the source of genetic diversity on which natural selection acts, therefore understanding the rates of mutations is crucial for understanding evolutionary trajectories. In this Opinion article, the authors discuss how emerging experimental mutation-rate data from genome-wide sequencing studies, combined with population-genetic theory, can provide unifying explanations for the diversity in mutation rates between species and across genomic locations.

Role of the ACE2/Angiotensin 1-7 Axis of the Renin-Angiotensin System in Heart Failure.

Abstract: Heart failure (HF) remains the most common cause of death and disability, and a major economic burden, in industrialized nations. Physiological, pharmacological, and clinical studies have demonstrated that activation of the renin-angiotensin system is a key mediator of HF progression. Angiotensin-converting enzyme 2 (ACE2), a homolog of ACE, is a monocarboxypeptidase that converts angiotensin II into angiotensin 1-7 (Ang 1-7) which, by virtue of its actions on the Mas receptor, opposes the molecular and cellular effects of angiotensin II. ACE2 is widely expressed in cardiomyocytes, cardiofibroblasts, and coronary endothelial cells. Recent preclinical translational studies confirmed a critical counter-regulatory role of ACE2/Ang 1-7 axis on the activated renin-angiotensin system that results in HF with preserved ejection fraction. Although loss of ACE2 enhances susceptibility to HF, increasing ACE2 level prevents and reverses the HF phenotype. ACE2 and Ang 1-7 have emerged as a key protective pathway against HF with reduced and preserved ejection fraction. Recombinant human ACE2 has been tested in phase I and II clinical trials without adverse effects while lowering and increasing plasma angiotensin II and Ang 1-7 levels, respectively. This review discusses the transcriptional and post-transcriptional regulation of ACE2 and the role of the ACE2/Ang 1-7 axis in cardiac physiology and in the pathophysiology of HF. The pharmacological and therapeutic potential of enhancing ACE2/Ang 1-7 action as a novel therapy for HF is highlighted.

Trends in Care Practices, Morbidity, and Mortality of Extremely Preterm Neonates, 1993-2012

Abstract: Obstet Gynecol Surv 2016;71(1):7–9Since the 1990s, there have been considerable changes in care for mothers in preterm labor and for extremely preterm infants. The Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network has monitored changes in this

SARC‐F: a symptom score to predict persons with sarcopenia at risk for poor functional outcomes

Abstract: Background A brief, inexpensive screening test for sarcopenia would be helpful for clinicians and their patients. To screen for persons with sarcopenia, we developed a simple five-item questionnaire (SARC-F) based on cardinal features or consequences of sarcopenia. Methods We investigated the utility of SARC-F in the African American Health (AAH) study, Baltimore Longitudinal Study of Aging (BLSA), and National Health and Nutrition Examination Survey (NHANES). Internal consistency reliability for SARC-F was determined using Cronbach's alpha. We evaluated SARC-F factorial validity using principal components analysis and criterion validity by examining its association with exam-based indicators of sarcopenia. Construct validity was examined using cross-sectional and longitudinal differences among those with high (≥4) vs. low (<4) SARC-F scores for mortality and health outcomes. Results SARC-F exhibited good internal consistency reliability and factorial, criterion, and construct validity. AAH participants with SARC-F scores ≥ 4 had more Instrumental Activity of Daily Living (IADL) deficits, slower chair stand times, lower grip strength, lower short physical performance battery scores, and a higher likelihood of recent hospitalization and of having a gait speed of <0.8 m/s. SARC-F scores ≥ 4 in AAH also were associated with 6 year IADL deficits, slower chair stand times, lower short physical performance battery scores, having a gait speed of <0.8 m/s, being hospitalized recently, and mortality. SARC-F scores ≥ 4 in the BLSA cohort were associated with having more IADL deficits and lower grip strength (both hands) in cross-sectional comparisons and with IADL deficits, lower grip strength (both hands), and mortality at follow-up. NHANES participants with SARC-F scores ≥ 4 had slower 20 ft walk times, had lower peak force knee extensor strength, and were more likely to have been hospitalized recently in cross-sectional analyses. Conclusions The SARC-F proved internally consistent and valid for detecting persons at risk for adverse outcomes from sarcopenia in AAH, BLSA, and NHANES.

Global Disorders of Sex Development Update since 2006: Perceptions, Approach and Care

Abstract: The goal of this update regarding the diagnosis and care of persons with disorders of sex development (DSDs) is to address changes in the clinical approach since the 2005 Consensus Conference, since knowledge and viewpoints change. An effort was made to include representatives from a broad perspective including support and advocacy groups. The goal of patient care is focused upon the best possible quality of life (QoL). The field of DSD is continuously developing. An update on the clinical evaluation of infants and older individuals with ambiguous genitalia including perceptions regarding male or female assignment is discussed. Topics include biochemical and genetic assessment, the risk of germ cell tumor development, approaches to psychosocial and psychosexual well-being and an update on support groups. Open and on-going communication with patients and parents must involve full disclosure, with the recognition that, while DSD conditions are life-long, enhancement of the best possible outcome improves QoL. The evolution of diagnosis and care continues, while it is still impossible to predict gender development in an individual case with certainty. Such decisions and decisions regarding surgery during infancy that alters external genital anatomy or removes germ cells continue to carry risk.

β-Lactams and β-Lactamase Inhibitors: An Overview

Abstract: β-Lactams are the most widely used class of antibiotics. Since the discovery of benzylpenicillin in the 1920s, thousands of new penicillin derivatives and related β-lactam classes of cephalosporins, cephamycins, monobactams, and carbapenems have been discovered. Each new class of β-lactam has been developed either to increase the spectrum of activity to include additional bacterial species or to address specific resistance mechanisms that have arisen in the targeted bacterial population. Resistance to β-lactams is primarily because of bacterially produced β-lactamase enzymes that hydrolyze the β-lactam ring, thereby inactivating the drug. The newest effort to circumvent resistance is the development of novel broad-spectrum β-lactamase inhibitors that work against many problematic β-lactamases, including cephalosporinases and serine-based carbapenemases, which severely limit therapeutic options. This work provides a comprehensive overview of β-lactam antibiotics that are currently in use, as well as a look ahead to several new compounds that are in the development pipeline.

Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects of LPA

Abstract: Genome-wide association studies have identified numerous loci linked with complex diseases, for which the molecular mechanisms remain largely unclear. Comprehensive molecular profiling of circulating metabolites captures highly heritable traits, which can help to uncover metabolic pathophysiology underlying established disease variants. We conduct an extended genome-wide association study of genetic influences on 123 circulating metabolic traits quantified by nuclear magnetic resonance metabolomics from up to 24,925 individuals and identify eight novel loci for amino acids, pyruvate and fatty acids. The LPA locus link with cardiovascular risk exemplifies how detailed metabolic profiling may inform underlying aetiology via extensive associations with very-low-density lipoprotein and triglyceride metabolism. Genetic fine mapping and Mendelian randomization uncover wide-spread causal effects of lipoprotein(a) on overall lipoprotein metabolism and we assess potential pleiotropic consequences of genetically elevated lipoprotein(a) on diverse morbidities via electronic health-care records. Our findings strengthen the argument for safe LPA-targeted intervention to reduce cardiovascular risk.

Vitamin D supplementation for women during pregnancy

Abstract: Background Vitamin D deficiency or insufficiency is thought to be common among pregnant women. Vitamin D supplementation during pregnancy has been suggested as an intervention to protect against adverse pregnancy outcomes. Objectives To examine whether oral supplements with vitamin D alone or in combination with calcium or other vitamins and minerals given to women during pregnancy can safely improve maternal and neonatal outcomes. Search methods We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (23 February 2015), the International Clinical Trials Registry Platform (31 January 2015), the Networked Digital Library of Theses and Dissertations (28 January 2015) and also contacted relevant organisations (31 January 2015). Selection criteria Randomised and quasi-randomised trials with randomisation at either individual or cluster level, evaluating the effect of supplementation with vitamin D alone or in combination with other micronutrients for women during pregnancy. Data collection and analysis Two review authors independently i) assessed the eligibility of studies against the inclusion criteria ii) extracted data from included studies, and iii) assessed the risk of bias of the included studies. Data were checked for accuracy. The quality of the evidence was assessed using the GRADE approach. Main results In this updated review we included 15 trials assessing a total of 2833 women, excluded 27 trials, and 23 trials are still ongoing or unpublished. Nine trials compared the effects of vitamin D alone versus no supplementation or a placebo and six trials compared the effects of vitamin D and calcium with no supplementation. Risk of bias in the majority of trials was unclear and many studies were at high risk of bias for blinding and attrition rates. Vitamin D alone versus no supplementation or a placebo Data from seven trials involving 868 women consistently show that women who received vitamin D supplements alone, particularly on a daily basis, had higher 25-hydroxyvitamin D than those receiving no intervention or placebo, but this response was highly heterogeneous. Also, data from two trials involving 219 women suggest that women who received vitamin D supplements may have a lower risk of pre-eclampsia than those receiving no intervention or placebo (8.9% versus 15.5%; risk ratio (RR) 0.52; 95% CI 0.25 to 1.05, low quality). Data from two trials involving 219 women suggest a similar risk of gestational diabetes among those taking vitamin D supplements or no intervention/placebo (RR 0.43; 95% CI 0.05, 3.45, very low quality). There were no clear differences in adverse effects, with only one reported case of nephritic syndrome in the control group in one study (RR 0.17; 95% CI 0.01 to 4.06; one trial, 135 women, low quality). Given the scarcity of data for this outcome, no firm conclusions can be drawn. No other adverse effects were reported in any of the other studies. With respect to infant outcomes, data from three trials involving 477 women suggest that vitamin D supplementation during pregnancy reduces the risk preterm birth compared to no intervention or placebo (8.9% versus 15.5%; RR 0.36; 95% CI 0.14 to 0.93, moderate quality). Data from three trials involving 493 women also suggest that women who receive vitamin D supplements during pregnancy less frequently had a baby with a birthweight below 2500 g than those receiving no intervention or placebo (RR 0.40; 95% CI 0.24 to 0.67, moderate quality). In terms of other outcomes, there were no clear differences in caesarean section (RR 0.95; 95% CI 0.69 to 1.31; two trials; 312 women); stillbirths (RR 0.35 95% CI 0.06, 1.99; three trials, 540 women); or neonatal deaths (RR 0.27; 95% CI 0.04, 1.67; two trials, 282 women). There was some indication that vitamin D supplementation increases infant length (mean difference (MD) 0.70, 95% CI -0.02 to 1.43; four trials, 638 infants) and head circumference at birth (MD 0.43, 95% CI 0.03 to 0.83; four trials, 638 women). Vitamin D and calcium versus no supplementation or a placebo Women who received vitamin D with calcium had a lower risk of pre-eclampsia than those not receiving any intervention (RR 0.51; 95% CI 0.32 to 0.80; three trials; 1114 women, moderate quality), but also an increased risk of preterm birth (RR 1.57; 95% CI 1.02 to 2.43, three studies, 798 women, moderate quality). Maternal vitamin D concentration at term, gestational diabetes, adverse effects and low birthweight were not reported in any trial or reported only by one study. Authors' conclusions New studies have provided more evidence on the effects of supplementing pregnant women with vitamin D alone or with calcium on pregnancy outcomes. Supplementing pregnant women with vitamin D in a single or continued dose increases serum 25-hydroxyvitamin D at term and may reduce the risk of pre-eclampsia, low birthweight and preterm birth. However, when vitamin D and calcium are combined, the risk of preterm birth is increased. The clinical significance of the increased serum 25-hydroxyvitamin D concentrations is still unclear. In light of this, these results need to be interpreted with caution. Data on adverse effects were lacking in all studies. The evidence on whether vitamin D supplementation should be given as a part of routine antenatal care to all women to improve maternal and infant outcomes remains unclear. While there is some indication that vitamin D supplementation could reduce the risk of pre-eclampsia and increase length and head circumference at birth, further rigorous randomised trials are required to confirm these effects.

Does the presence of independent and female directors impact firm performance? A multi-country study of board diversity

Abstract: This study empirically analyzes whether gender diversity enhances boards of directors’ independence and efficiency. Using data from 3,876 public firms in 47 countries and controlling for a wide set of corporate governance mechanisms, we find that firms with more female directors have higher firm performance by market (Tobin’s Q) and accounting (return on assets) measures. The results also suggest that external independent directors do not contribute to firm performance unless the board is gender diversified. These results hold with respect to different estimation models and robustness tests. Overall, our findings provide evidence that the female directors enhance boards of directors’ effectiveness. Finally, we find that firms that are concerned with board independence, and that firms in more complex environments are more likely to have gender-balanced boards.

Hybridization and extinction.

Abstract: Hybridization may drive rare taxa to extinction through genetic swamping, where the rare form is replaced by hybrids, or by demographic swamping, where population growth rates are reduced due to the wasteful production of maladaptive hybrids. Conversely, hybridization may rescue the viability of small, inbred populations. Understanding the factors that contribute to destructive versus constructive outcomes of hybridization is key to managing conservation concerns. Here, we survey the literature for studies of hybridization and extinction to identify the ecological, evolutionary, and genetic factors that critically affect extinction risk through hybridization. We find that while extinction risk is highly situation dependent, genetic swamping is much more frequent than demographic swamping. In addition, human involvement is associated with increased risk and high reproductive isolation with reduced risk. Although climate change is predicted to increase the risk of hybridization-induced extinction, we find little empirical support for this prediction. Similarly, theoretical and experimental studies imply that genetic rescue through hybridization may be equally or more probable than demographic swamping, but our literature survey failed to support this claim. We conclude that halting the introduction of hybridization-prone exotics and restoring mature and diverse habitats that are resistant to hybrid establishment should be management priorities.