The relationship between maternal methadone dose at delivery and neonatal outcome: Methodological and design considerations

Compared to untreated opioid dependence, methadone maintenance treatment of opioid-dependent pregnant women has been found to be associated with better maternal and neonatal outcomes. Secondary analysis of data from 73 maternal and neonatal participants in the MOTHER study (H. E. Jones et al., New England Journal of Medicine, 2010) found no relationship between maternal methadone dose at delivery and any of 9 neonatal outcomes – peak neonatal abstinence syndrome (NAS) score, total amount of morphine needed to treat NAS, duration of neonatal hospital stay, duration of treatment for NAS, estimated gestational age at delivery, Apgar score at 5 minutes, and neonatal head circumference, length, and weight at birth. These results are consistent with a recent systematic review and meta-analysis (B. J. Cleary et al., Addiction, 2010) and extend findings to outcomes other than NAS. Methodological and design issues that might have adversely impacted the ability of researchers to establish the existence or non-existence of these relationships are considered

Outcome reporting in neonates experiencing withdrawal following opioid exposure in pregnancy: a systematic review

BackgroundNeonatal withdrawal secondary to in utero opioid exposure is a growing global concern stressing the psychosocial well-being of affected families and scarce hospital resources. In the ongoing search for the most effective treatment, randomized controlled trials are indispensable. Consistent outcome selection and measurement across randomized controlled trials enables synthesis of results, fostering the translation of research into practice. Currently, there is no core outcome set to standardize outcome selection, definition and reporting. This study identifies the outcomes currently reported in the literature for neonates experiencing withdrawal following opioid exposure during pregnancy.MethodsA comprehensive literature search of MEDLINE, EMBASE and Cochrane Central was conducted to identify all primary research studies (randomized controlled trials, clinical trials, case-controlled studies, uncontrolled trials, observational cohort studies, clinical practice guidelines and case reports) reporting outcomes for interventions used to manage neonatal abstinence syndrome between July 2007 and July 2017. All “primary” and “secondary” neonatal outcomes were extracted by two independent reviewers and were assigned to one of OMERACT’s core areas of “pathophysiological manifestation”, “life impact”, “resource use”, “adverse events”, or “death”.ResultsForty-seven primary research articles reporting 107 “primary” and 127 “secondary” outcomes were included. The most frequently reported outcomes were “duration of pharmacotherapy” (68% of studies, N = 32), “duration of hospital stay” (66% of studies, N = 31) and “withdrawal symptoms” (51% of studies, N = 24). The discrepancy between the number of times an outcome was reported and the number of articles was secondary to the use of composite outcomes. Frequently reported outcomes had heterogeneous definitions or were not defined by the study and were measured at different times. Outcomes reported in the literature to date were mainly assigned to the core areas “pathophysiologic manifestations” or “resource use”. No articles reported included parent or former patient involvement in outcome selections.ConclusionsInconsistent selection and definition of primary and secondary outcomes exists in the present literature of pharmacologic and nonpharmacologic interventions for managing opioid withdrawal in neonates. No studies involved parents in the process of outcome selection. These findings hinder evidence synthesis to generate clinically meaningful practice guidelines. The development of a specific core outcome set is imperative

A core outcome set for neonatal abstinence syndrome: Study protocol for a systematic review, parent interviews and a Delphi survey

Background: The prevalence of neonatal abstinence syndrome (NAS) is increasing globally resulting in an increased incidence of adverse neonatal outcomes and health system costs. Evidence regarding the effectiveness of NAS prevention and management strategies is very weak and further research initiatives are critically needed to support meta-analysis and clinical practice guidelines. In NAS research, the choice of outcomes and the use of valid, responsive and feasible measurement instruments are crucial. There is currently no consensus and evidence-based core outcome set (COS) for NAS. Methods/design: The development of the NAS-COS will include five stages led by an international Multidisciplinary Steering Committee: (1) qualitative interviews with parents/families and a systematic review (SR) to identify items for inclusion in a COS. The SR will also identify participants for the Delphi survey, (2) a three-round Delphi survey to gain expert opinion on the importance of health outcomes influencing NAS management decisions, (3), a consensus meeting to finalize the items and definitions with experts and COS users, (4) feasibility and pilot testing, development of the COS and explanatory document and (5) implementation planning. Discussion: Since standardized outcome measurement and reporting will improve NAS clinical research consistency, efficacy and impact, this COS will reflect the minimum set of health outcomes which should be measured in trials evaluating interventions for preventing or treating NAS

Ruptured idiopathic hepatic artery pseudoaneurysm causing portal vein thrombosis with portal hypertension and variceal bleeding

Portal vein thrombosis (PVT) is an important cause of noncirrhotic portal hypertension. Noncancerous extrinsic compression of portal vein to drive PVT formation is rare, but important to identify. A 64-year-old female with idiopathic hepatic artery pseudoaneurysm (HAPA) rupture 7 months prior presented with acute-onset hematemesis and melena and was found to have prehepatic portal hypertensive variceal bleeding. Her HAPA-related retroperitoneal hematoma had resulted in portal vein compression, thrombosis, and cavernous transformation despite prompt stent graft placement across the ruptured HAPA, and required definitive treatment by transjugular intrahepatic portosystemic shunt creation with portal vein reconstruction utilizing a trans-splenic access. This case highlights the importance of interval abdominal imaging and hypercoagulability screening for noncirrhotic patients at-risk for PVT, which identified the patient as a heterozygous carrier of Factor V Leiden

Neonatal outcomes and their relationship to maternal buprenorphine dose during pregnancy

Buprenorphine pharmacotherapy for opioid-dependent pregnant women is associated with maternal and neonatal outcomes superior to untreated opioid dependence. However, the literature is inconsistent regarding the possible existence of a dose-response relationship between maternal buprenorphine dose and neonatal clinical outcomes

International Network for Comparison of HIV Neutralization Assays: The NeutNet Report II

BACKGROUND: Neutralizing antibodies provide markers for vaccine-induced protective immunity in many viral infections. By analogy, HIV-1 neutralizing antibodies induced by immunization may well predict vaccine effectiveness. Assessment of neutralizing antibodies is therefore of primary importance, but is hampered by the fact that we do not know which assay(s) can provide measures of protective immunity. An international collaboration (NeutNet) involving 18 different laboratories previously compared different assays using monoclonal antibodies (mAbs) and soluble CD4 (Phase I study). METHODS: In the present study (Phase II), polyclonal reagents were evaluated by 13 laboratories. Each laboratory evaluated nine plasmas against an 8 virus panel representing different genetic subtypes and phenotypes. TriMab, a mixture of three mAbs, was used as a positive control allowing comparison of the results with Phase I in a total of nine different assays. The assays used either uncloned virus produced in peripheral blood mononuclear cells (PBMCs) (Virus Infectivity Assays, VIA), or Env (gp160)-pseudotyped viruses (pseudoviruses, PSV) produced in HEK293T cells from molecular clones or from uncloned virus. Target cells included PBMC and genetically engineered cell lines in either single- or multiple-cycle infection format. Infection was quantified by using a range of assay read-outs including extra- or intra-cellular p24 antigen detection, luciferase, beta-galactosidase or green fluorescent protein (GFP) reporter gene expression. FINDINGS: Using TriMab, results of Phase I and Phase II were generally in agreement for six of the eight viruses tested and confirmed that the PSV assay is more sensitive than PBMC (p = 0.014). Comparisons with the polyclonal reagents showed that sensitivities were dependent on both virus and plasma. CONCLUSIONS: Here we further demonstrate clear differences in assay sensitivities that were dependent on both the neutralizing reagent and the virus. Consistent with the Phase I study, we recommend parallel use of PSV and VIA for vaccine evaluation

‘‘Beet-ing’’ the Mountain: A Review of the Physiological and Performance Effects of Dietary Nitrate Supplementation at Simulated and Terrestrial Altitude

Exposure to altitude results in multiple physiological consequences. These include, but are not limited to, a reduced maximal oxygen consumption, drop in arterial oxygen saturation, and increase in muscle metabolic perturbations at a fixed sub-maximal work rate. Exercise capacity during fixed work rate or incremental exercise and time-trial performance are also impaired at altitude relative to sea-level. Recently, dietary nitrate (NO3-) supplementation has attracted considerable interest as a nutritional aid during altitude exposure. In this review, we summarise and critically evaluate the physiological and performance effects of dietary NO3- supplementation during exposure to simulated and terrestrial altitude. Previous investigations at simulated altitude indicate that NO3- supplementation may reduce the oxygen cost of exercise, elevate arterial and tissue oxygen saturation, improve muscle metabolic function, and enhance exercise capacity/ performance. Conversely, current evidence suggests that NO3- supplementation does not augment the training response at simulated altitude. Few studies have evaluated the effects of NO3- at terrestrial altitude. Current evidence indicates potential improvements in endothelial function at terrestrial altitude following NO3- supplementation. No effects of NO3- supplementation have been observed on oxygen consumption or arterial oxygen saturation at terrestrial altitude, although further research is warranted. Limitations of the present body of literature are discussed, and directions for future research are provided

A communal catalogue reveals Earth's multiscale microbial diversity

Our growing awareness of the microbial world's importance and diversity contrasts starkly with our limited understanding of its fundamental structure. Despite recent advances in DNA sequencing, a lack of standardized protocols and common analytical frameworks impedes comparisons among studies, hindering the development of global inferences about microbial life on Earth. Here we present a meta-analysis of microbial community samples collected by hundreds of researchers for the Earth Microbiome Project. Coordinated protocols and new analytical methods, particularly the use of exact sequences instead of clustered operational taxonomic units, enable bacterial and archaeal ribosomal RNA gene sequences to be followed across multiple studies and allow us to explore patterns of diversity at an unprecedented scale. The result is both a reference database giving global context to DNA sequence data and a framework for incorporating data from future studies, fostering increasingly complete characterization of Earth's microbial diversity.Peer reviewe

A communal catalogue reveals Earth’s multiscale microbial diversity

Our growing awareness of the microbial world’s importance and diversity contrasts starkly with our limited understanding of its fundamental structure. Despite recent advances in DNA sequencing, a lack of standardized protocols and common analytical frameworks impedes comparisons among studies, hindering the development of global inferences about microbial life on Earth. Here we present a meta-analysis of microbial community samples collected by hundreds of researchers for the Earth Microbiome Project. Coordinated protocols and new analytical methods, particularly the use of exact sequences instead of clustered operational taxonomic units, enable bacterial and archaeal ribosomal RNA gene sequences to be followed across multiple studies and allow us to explore patterns of diversity at an unprecedented scale. The result is both a reference database giving global context to DNA sequence data and a framework for incorporating data from future studies, fostering increasingly complete characterization of Earth’s microbial diversity

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe