Simultaneous release of a hydroxy-methylglutaryl coenzyme A reductase inhibitor and a glycoprotein IIb/IIIa antagonist from a thermoresponsive NiPAAm/NtBAAm copolymer system.

While deployment of intracoronary stents has been shown to reduce restenosis, stenting can also damage the endothelial was eluted during this period. Xemilofiban release was measured in terms of its ability to inhibit platelet adhesion, using a microfluidic system. To investigate the influence of location and hydrophobicity on elution of bioactivity, three separate systems were employed. While elution of anti-adhesive activity from the system containing xemilofiban-loaded matrices was more dramatic in the short term, a more sustained level of inhibition was achieved when xemilofiban had been incorporated into microgels. All samples investigated for anti-adhesive activity also decreased human coronary artery smooth muscle cell proliferation. Therefore xemilofiban has potential as an agent for preventing in-stent thrombosis. Our study has demonstrated the feasibility of using this novel matrix/microgel system to regulate simultaneous release of both agents in bioactive concentratio

Effect of fixed-dose subcutaneous reslizumab on asthma exacerbations in patients with severe uncontrolled asthma and corticosteroid sparing in patients with oral corticosteroid-dependent asthma : results from two phase 3, randomised, double-blind, placebo-controlled trials

BACKGROUND: Reslizumab 3 mg/kg administered intravenously is approved for the treatment of severe eosinophilic asthma. We assessed the safety and efficacy of subcutaneous reslizumab 110 mg in two trials in patients with uncontrolled severe asthma and increased blood eosinophils. The aim was to establish whether subcutaneous reslizumab 110 mg can reduce exacerbation rates in these patients (study 1) or reduce maintenance oral corticosteroid dose in patients with corticosteroid-dependent asthma (study 2). METHODS: Both studies were randomised, double-blind, placebo-controlled, phase 3 studies. Entry criteria for study 1 were uncontrolled severe asthma, two or more asthma exacerbations in the previous year, a blood eosinophil count of 300 cells per μL or more (including no more than 30% patients with an eosinophil count <400 cells/μL), and at least a medium dose of inhaled corticosteroids with one or more additional asthma controllers. Patients in study 2 had severe asthma, a blood eosinophil count of 300 cells per μL or more, daily maintenance oral corticosteroid (prednisone 5-40 mg, or equivalent), and high-dose inhaled corticosteroids plus another controller. Patients were randomly assigned (1:1) to subcutaneous reslizumab (110 mg) or placebo once every 4 weeks for 52 weeks in study 1 and 24 weeks in study 2. Patients and investigators were masked to treatment assignment. Primary efficacy outcomes were frequency of exacerbations during 52 weeks in study 1 and categorised percentage reduction in daily oral corticosteroid dose from baseline to weeks 20-24 in study 2. Primary efficacy analyses were by intention to treat, and safety analyses included all patients who received at least one dose of study treatment. These studies are registered with ClinicalTrials.gov, NCT02452190 (study 1) and NCT02501629 (study 2). FINDINGS: Between Aug 12, 2015, and Jan 31, 2018, 468 patients in study 1 were randomly assigned to placebo (n=232) or subcutaneous reslizumab (n=236), and 177 in study 2 to placebo (n=89) or subcutaneous reslizumab (n=88). In study 1, we found no significant difference in the exacerbation rate between reslizumab and placebo in the intention-to-treat population (rate ratio 0·79, 95% CI 0·56-1·12; p=0·19). Subcutaneous reslizumab reduced exacerbation frequency compared with placebo in the subgroup of patients with blood eosinophil counts of 400 cells per μL or more (0·64, 95% CI 0·43-0·95). Greater reductions in annual exacerbation risk (p=0·0035) and longer time to first exacerbation were observed for patients with higher trough serum reslizumab concentrations. In study 2, we found no difference between placebo and fixed-dose subcutaneous reslizumab in categorised percentage reduction in daily oral corticosteroid dose (odds ratio for a lower category of oral corticosteroid use in the reslizumab group vs the placebo group, 1·23, 95% CI 0·70-2·16; p=0·47). The frequency of adverse events and serious adverse events with reslizumab were similar to those with placebo in both studies. INTERPRETATION: Fixed-dose (110 mg) subcutaneous reslizumab was not effective in reducing exacerbation frequency in patients with uncontrolled asthma and increased blood eosinophils (≥300 cells/μL), or in reducing the daily maintenance oral corticosteroid dose in patients with oral corticosteroid-dependent severe eosinophilic asthma. Higher exposures than those observed with 110 mg subcutaneous reslizumab are required to achieve maximal efficacy. FUNDING: Teva Branded Pharmaceutical Products R&D

Understanding interannual, decadal level variability in paralytic shellfish poisoning toxicity in the Gulf of Maine : the HAB Index

Author Posting. © The Author(s), 2013. This is the author's version of the work. It is posted here by permission of Elsevier for personal use, not for redistribution. The definitive version was published in Deep Sea Research Part II: Topical Studies in Oceanography 103 (2014): 264-276, doi:10.1016/j.dsr2.2013.09.018.A major goal in harmful algal bloom (HAB) research has been to identify mechanisms underlying interannual variability in bloom magnitude and impact. Here the focus is on variability in Alexandrium fundyense blooms and paralytic shellfish poisoning (PSP) toxicity in Maine, USA, over 34 years (1978 – 2011). The Maine coastline was divided into two regions - eastern and western Maine, and within those two regions, three measures of PSP toxicity (the percent of stations showing detectable toxicity over the year, the cumulative amount of toxicity per station measured in all shellfish (mussel) samples during that year, and the duration of measurable toxicity) were examined for each year in the time series. These metrics were combined into a simple HAB Index that provides a single measure of annual toxin severity across each region. The three toxin metrics, as well as the HAB Index that integrates them, reveal significant variability in overall toxicity between individual years as well as long-term, decadal patterns or regimes. Based on different conceptual models of the system, we considered three trend formulations to characterize the long-term patterns in the Index – a three-phase (mean-shift) model, a linear two-phase model, and a pulse-decline model. The first represents a “regime shift” or multiple equilibria formulation as might occur with alternating periods of sustained high and low cyst abundance or favorable and unfavorable growth conditions, the second depicts a scenario of more gradual transitions in cyst abundance or growth conditions of vegetative cells, and the third characterizes a ”sawtooth” pattern in which upward shifts in toxicity are associated with major cyst recruitment events, followed by a gradual but continuous decline until the next pulse. The fitted models were compared using both residual sum of squares and Akaike’s Information Criterion. There were some differences between model fits, but none consistently gave a better fit than the others. This statistical underpinning can guide efforts to identify physical and/or biological mechanisms underlying the patterns revealed by the HAB Index. Although A. fundyense cyst survey data (limited to 9 years) do not span the entire interval of the shellfish toxicity records, this analysis leads us to hypothesize that major changes in the abundance of A. fundyense cysts may be a primary factor contributing to the decadal trends in shellfish toxicity in this region. The HAB Index approach taken here is simple but represents a novel and potentially useful tool for resource managers in many areas of the world subject to toxic HABs.Research support provided through the Woods Hole Center for Oceans and Human Health, National Science Foundation (NSF) Grants OCE- 1128041 and OCE-1314642; and National Institute of Environmental Health Sciences (NIEHS) Grant 1-P50-ES021923-01, the ECOHAB Grant program through NOAA Grants NA06NOS4780245 and NA09NOS4780193, the MERHAB Grant program through NOAA Grant NA11NOS4780025, the PCMHAB Grant program through NOAA Grant NA11NOS4780023, and funding through the states of ME, NH, and MA. Funding for J.L. Martin was provided by Fisheries and Oceans Canada

Hickey MM, Lam JC, Bezman NA, Rathmell WK, Simon MC.. von Hippel-Lindau mutation in mice recapitulates Chuvash polycythemia via hypoxia-inducible factor-2alpha signaling and splenic erythropoiesis. J Clin Invest 117: 3879-3889

The R200W mutation in the von Hippel-Lindau (VHL) tumor suppressor protein (pVHL) is unique in that it is not associated with tumor development, but rather with Chuvash polycythemia, a heritable disease characterized by elevated hematocrit and increased serum levels of erythropoietin and VEGF. Previous studies have implicated hypoxia-inducible factor-1alpha (HIF-1alpha) signaling in this disorder, although the effects of this mutation on pVHL function are not fully understood. In order to explore the mechanisms underlying the development of this polycythemia, we generated mice homozygous for the R200W mutation (Vhl(R/R)). Vhl(R/R) mice developed polycythemia highly similar to the human disease. The activity of HIF proteins, specifically the HIF-2alpha isoform, was upregulated in ES cells and tissues from Vhl(R/R) mice. Furthermore, we observed a striking phenotype in Vhl(R/R) spleens, with greater numbers of erythroid progenitors and megakaryocytes and increased erythroid differentiation of Vhl(R/R) splenic cells in vitro. These findings suggest that enhanced expression of key HIF-2alpha genes promotes splenic erythropoiesis, resulting in the development of polycythemia in Vhl(R/R) mice. This mouse model is a faithful recapitulation of this VHL-associated syndrome and represents a useful tool for studying polycythemias and investigating potential therapeutics

A Neutralizing Human Monoclonal Antibody Protects against Lethal Disease in a New Ferret Model of Acute Nipah Virus Infection

Nipah virus is a broadly tropic and highly pathogenic zoonotic paramyxovirus in the genus Henipavirus whose natural reservoirs are several species of Pteropus fruit bats. Nipah virus has repeatedly caused outbreaks over the past decade associated with a severe and often fatal disease in humans and animals. Here, a new ferret model of Nipah virus pathogenesis is described where both respiratory and neurological disease are present in infected animals. Severe disease occurs with viral doses as low as 500 TCID50 within 6 to 10 days following infection. The underlying pathology seen in the ferret closely resembles that seen in Nipah virus infected humans, characterized as a widespread multisystemic vasculitis, with virus replicating in highly vascular tissues including lung, spleen and brain, with recoverable virus from a variety of tissues. Using this ferret model a cross-reactive neutralizing human monoclonal antibody, m102.4, targeting the henipavirus G glycoprotein was evaluated in vivo as a potential therapeutic agent. All ferrets that received m102.4 ten hours following a high dose oral-nasal Nipah virus challenge were protected from disease while all controls died. This study is the first successful post-exposure passive antibody therapy for Nipah virus using a human monoclonal antibody

Linking world bank development indicators and outcomes of congenital heart surgery in low-income and middle-income countries: Retrospective analysis of quality improvement data

Objective Many low-income and middle-income countries (LMICs) struggle to provide the health services investment required for life-saving congenital heart disease (CHD) surgery. We explored associations between risk-adjusted CHD surgical mortality from 17 LMICs and global development indices to identify patterns that might inform investment strategies. Design Retrospective analysis: country-specific standardised mortality ratios were graphed against global development indices reflective of wealth and healthcare investment. Spearman correlation coefficients were calculated. Setting and participants The International Quality Improvement Collaborative (IQIC) keeps a volunteer registry of outcomes of CHD surgery programmes in low-resource settings. Inclusion in the IQIC is voluntary enrolment by hospital sites. Patients in the registry underwent congenital heart surgery. Sites that actively participated in IQIC in 2013, 2014 or 2015 and passed a 10% data audit were asked for permission to share data for this study. 31 sites in 17 countries are included. Outcome measures In-hospital mortality: standardised mortality ratios were calculated. Risk adjustment for in-hospital mortality uses the Risk Adjustment for Congenital Heart Surgery method, a model including surgical risk category, age group, prematurity, presence of a major non-cardiac structural anomaly and multiple congenital heart procedures during admission. Results The IQIC registry includes 24 917 congenital heart surgeries performed in children less than 18 years of age. The overall in-hospital mortality rate was 5.0%. Country-level congenital heart surgery standardised mortality ratios were negatively correlated with gross domestic product (GDP) per capita (r=-0.34, p=0.18), and health expenditure per capita (r=-0.23, p=0.37) and positively correlated with under-five mortality (r=0.60, p=0.01) and undernourishment (r=0.39, p=0.17). Countries with lower development had wider variation in mortality. GDP per capita is a driver of the association between some other measures and mortality. Conclusions Results display a moderate relationship among wealth, healthcare investment and malnutrition, with significant variation, including superior results in many countries with low GDP per capita. These findings provide context and optimism for investment in CHD procedures in low-resource settings. © 2019 BMJ Publishing Group Limited

A case series of familial ARID1B variants illustrating variable expression and suggestions to update the ACMG criteria

ARID1B is one of the most frequently mutated genes in intellectual disability (~1%). Most variants are readily classified, since they are de novo and are predicted to lead to loss of function, and therefore classified as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines for the interpretation of sequence variants. However, familial loss-of-function variants can also occur and can be challenging to interpret. Such variants may be pathogenic with variable expression, causing only a mild phenotype in a parent. Alternatively, since some regions of the ARID1B gene seem to be lacking pathogenic variants, loss-of-function variants in those regions may not lead to ARID1B haploinsufficiency and may therefore be benign. We describe 12 families with potential loss-of-function variants, which were either familial or with unknown inheritance and were in regions where pathogenic variants have not been described or are otherwise challenging to interpret. We performed detailed clinical and DNA methylation studies, which allowed us to confidently classify most variants. In five families we observed transmission of pathogenic variants, confirming their highly variable expression. Our findings provide further evidence for an alternative translational start site and we suggest updates for the ACMG guidelines for the interpretation of sequence variants to incorporate DNA methylation studies and facial analyses

Phenotypic expansion in DDX3X - a common cause of intellectual disability in females

De novo variants in DDX3X account for 1-3% of unexplained intellectual disability (ID) cases and are amongst the most common causes of ID especially in females. Forty-seven patients (44 females, 3 males) have been described. We identified 31 additional individuals carrying 29 unique DDX3X variants, including 30 postnatal individuals with complex clinical presentations of developmental delay or ID, and one fetus with abnormal ultrasound findings. Rare or novel phenotypes observed include respiratory problems, congenital heart disease, skeletal muscle mitochondrial DNA depletion, and late-onset neurologic decline. Our findings expand the spectrum of DNA variants and phenotypes associated with DDX3X disorders

MED27 Variants Cause Developmental Delay, Dystonia, and Cerebellar Hypoplasia

The Mediator multiprotein complex functions as a regulator of RNA polymerase II-catalyzed gene transcription. In this study, exome sequencing detected biallelic putative disease-causing variants in MED27, encoding Mediator complex subunit 27, in 16 patients from 11 families with a novel neurodevelopmental syndrome. Patient phenotypes are highly homogeneous, including global developmental delay, intellectual disability, axial hypotonia with distal spasticity, dystonic movements, and cerebellar hypoplasia. Seizures and cataracts were noted in severely affected individuals. Identification of multiple patients with biallelic MED27 variants supports the critical role of MED27 in normal human neural development, particularly for the cerebellum. ANN NEUROL 2021Peer reviewe