Safety and Tolerability of SRX246, a Vasopressin 1a Antagonist, in Irritable Huntington\u27s Disease Patients-A Randomized Phase 2 Clinical Trial.

SRX246 is a vasopressin (AVP) 1a receptor antagonist that crosses the blood-brain barrier. It reduced impulsive aggression, fear, depression and anxiety in animal models, blocked the actions of intranasal AVP on aggression/fear circuits in an experimental medicine fMRI study and demonstrated excellent safety in Phase 1 multiple-ascending dose clinical trials. The present study was a 3-arm, multicenter, randomized, placebo-controlled, double-blind, 12-week, dose escalation study of SRX246 in early symptomatic Huntington\u27s disease (HD) patients with irritability. Our goal was to determine whether SRX246 was safe and well tolerated in these HD patients given its potential use for the treatment of problematic neuropsychiatric symptoms. Participants were randomized to receive placebo or to escalate to 120 mg twice daily or 160 mg twice daily doses of SRX246. Assessments included standard safety tests, the Unified Huntington\u27s Disease Rating Scale (UHDRS), and exploratory measures of problem behaviors. The groups had comparable demographics, features of HD and baseline irritability. Eighty-two out of 106 subjects randomized completed the trial on their assigned dose of drug. One-sided exact-method confidence interval tests were used to reject the null hypothesis of inferior tolerability or safety for each dose group vs. placebo. Apathy and suicidality were not affected by SRX246. Most adverse events in the active arms were considered unlikely to be related to SRX246. The compound was safe and well tolerated in HD patients and can be moved forward as a candidate to treat irritability and aggression

Genome-Wide Gene-Environment Study Identifies Glutamate Receptor Gene GRIN2A as a Parkinson's Disease Modifier Gene via Interaction with Coffee

Our aim was to identify genes that influence the inverse association of coffee with the risk of developing Parkinson's disease (PD). We used genome-wide genotype data and lifetime caffeinated-coffee-consumption data on 1,458 persons with PD and 931 without PD from the NeuroGenetics Research Consortium (NGRC), and we performed a genome-wide association and interaction study (GWAIS), testing each SNP's main-effect plus its interaction with coffee, adjusting for sex, age, and two principal components. We then stratified subjects as heavy or light coffee-drinkers and performed genome-wide association study (GWAS) in each group. We replicated the most significant SNP. Finally, we imputed the NGRC dataset, increasing genomic coverage to examine the region of interest in detail. The primary analyses (GWAIS, GWAS, Replication) were performed using genotyped data. In GWAIS, the most significant signal came from rs4998386 and the neighboring SNPs in GRIN2A. GRIN2A encodes an NMDA-glutamate-receptor subunit and regulates excitatory neurotransmission in the brain. Achieving P2df = 10−6, GRIN2A surpassed all known PD susceptibility genes in significance in the GWAIS. In stratified GWAS, the GRIN2A signal was present in heavy coffee-drinkers (OR = 0.43; P = 6×10−7) but not in light coffee-drinkers. The a priori Replication hypothesis that “Among heavy coffee-drinkers, rs4998386_T carriers have lower PD risk than rs4998386_CC carriers” was confirmed: ORReplication = 0.59, PReplication = 10−3; ORPooled = 0.51, PPooled = 7×10−8. Compared to light coffee-drinkers with rs4998386_CC genotype, heavy coffee-drinkers with rs4998386_CC genotype had 18% lower risk (P = 3×10−3), whereas heavy coffee-drinkers with rs4998386_TC genotype had 59% lower risk (P = 6×10−13). Imputation revealed a block of SNPs that achieved P2df<5×10−8 in GWAIS, and OR = 0.41, P = 3×10−8 in heavy coffee-drinkers. This study is proof of concept that inclusion of environmental factors can help identify genes that are missed in GWAS. Both adenosine antagonists (caffeine-like) and glutamate antagonists (GRIN2A-related) are being tested in clinical trials for treatment of PD. GRIN2A may be a useful pharmacogenetic marker for subdividing individuals in clinical trials to determine which medications might work best for which patients

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

National trends in total cholesterol obscure heterogeneous changes in HDL and non-HDL cholesterol and total-to-HDL cholesterol ratio : a pooled analysis of 458 population-based studies in Asian and Western countries

Background: Although high-density lipoprotein (HDL) and non-HDL cholesterol have opposite associations with coronary heart disease, multi-country reports of lipid trends only use total cholesterol (TC). Our aim was to compare trends in total, HDL and nonHDL cholesterol and the total-to-HDL cholesterol ratio in Asian and Western countries. Methods: We pooled 458 population-based studies with 82.1 million participants in 23 Asian and Western countries. We estimated changes in mean total, HDL and non-HDL cholesterol and mean total-to-HDL cholesterol ratio by country, sex and age group. Results: Since similar to 1980, mean TC increased in Asian countries. In Japan and South Korea, the TC rise was due to rising HDL cholesterol, which increased by up to 0.17 mmol/L per decade in Japanese women; in China, it was due to rising non-HDL cholesterol. TC declined in Western countries, except in Polish men. The decline was largest in Finland and Norway, at similar to 0.4 mmol/L per decade. The decline in TC in most Western countries was the net effect of an increase in HDL cholesterol and a decline in non-HDL cholesterol, with the HDL cholesterol increase largest in New Zealand and Switzerland. Mean total-to-HDL cholesterol ratio declined in Japan, South Korea and most Western countries, by as much as similar to 0.7 per decade in Swiss men (equivalent to similar to 26% decline in coronary heart disease risk per decade). The ratio increased in China. Conclusions: HDL cholesterol has risen and the total-to-HDL cholesterol ratio has declined in many Western countries, Japan and South Korea, with only a weak correlation with changes in TC or non-HDL cholesterol.Peer reviewe

Repositioning of the global epicentre of non-optimal cholesterol

High blood cholesterol is typically considered a feature of wealthy western countries(1,2). However, dietary and behavioural determinants of blood cholesterol are changing rapidly throughout the world(3) and countries are using lipid-lowering medications at varying rates. These changes can have distinct effects on the levels of high-density lipoprotein (HDL) cholesterol and non-HDL cholesterol, which have different effects on human health(4,5). However, the trends of HDL and non-HDL cholesterol levels over time have not been previously reported in a global analysis. Here we pooled 1,127 population-based studies that measured blood lipids in 102.6 million individuals aged 18 years and older to estimate trends from 1980 to 2018 in mean total, non-HDL and HDL cholesterol levels for 200 countries. Globally, there was little change in total or non-HDL cholesterol from 1980 to 2018. This was a net effect of increases in low- and middle-income countries, especially in east and southeast Asia, and decreases in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe. As a result, countries with the highest level of non-HDL cholesterol-which is a marker of cardiovascular riskchanged from those in western Europe such as Belgium, Finland, Greenland, Iceland, Norway, Sweden, Switzerland and Malta in 1980 to those in Asia and the Pacific, such as Tokelau, Malaysia, The Philippines and Thailand. In 2017, high non-HDL cholesterol was responsible for an estimated 3.9 million (95% credible interval 3.7 million-4.2 million) worldwide deaths, half of which occurred in east, southeast and south Asia. The global repositioning of lipid-related risk, with non-optimal cholesterol shifting from a distinct feature of high-income countries in northwestern Europe, north America and Australasia to one that affects countries in east and southeast Asia and Oceania should motivate the use of population-based policies and personal interventions to improve nutrition and enhance access to treatment throughout the world.Peer reviewe

Worldwide trends in underweight and obesity from 1990 to 2022: a pooled analysis of 3663 population-representative studies with 222 million children, adolescents, and adults

Background Underweight and obesity are associated with adverse health outcomes throughout the life course. We estimated the individual and combined prevalence of underweight or thinness and obesity, and their changes, from 1990 to 2022 for adults and school-aged children and adolescents in 200 countries and territories. Methods We used data from 3663 population-based studies with 222 million participants that measured height and weight in representative samples of the general population. We used a Bayesian hierarchical model to estimate trends in the prevalence of different BMI categories, separately for adults (age ≥20 years) and school-aged children and adolescents (age 5–19 years), from 1990 to 2022 for 200 countries and territories. For adults, we report the individual and combined prevalence of underweight (BMI &lt;18·5 kg/m2) and obesity (BMI ≥30 kg/m2). For school&#x2;aged children and adolescents, we report thinness (BMI &lt;2 SD below the median of the WHO growth reference) and obesity (BMI &gt;2 SD above the median). Findings From 1990 to 2022, the combined prevalence of underweight and obesity in adults decreased in 11 countries (6%) for women and 17 (9%) for men with a posterior probability of at least 0·80 that the observed changes were true decreases. The combined prevalence increased in 162 countries (81%) for women and 140 countries (70%) for men with a posterior probability of at least 0·80. In 2022, the combined prevalence of underweight and obesity was highest in island nations in the Caribbean and Polynesia and Micronesia, and countries in the Middle East and north Africa. Obesity prevalence was higher than underweight with posterior probability of at least 0·80 in 177 countries (89%) for women and 145 (73%) for men in 2022, whereas the converse was true in 16 countries (8%) for women, and 39 (20%) for men. From 1990 to 2022, the combined prevalence of thinness and obesity decreased among girls in five countries (3%) and among boys in 15 countries (8%) with a posterior probability of at least 0·80, and increased among girls in 140 countries (70%) and boys in 137 countries (69%) with a posterior probability of at least 0·80. The countries with highest combined prevalence of thinness and obesity in school-aged children and adolescents in 2022 were in Polynesia and Micronesia and the Caribbean for both sexes, and Chile and Qatar for boys. Combined prevalence was also high in some countries in south Asia, such as India and Pakistan, where thinness remained prevalent despite having declined. In 2022, obesity in school-aged children and adolescents was more prevalent than thinness with a posterior probability of at least 0·80 among girls in 133 countries (67%) and boys in 125 countries (63%), whereas the converse was true in 35 countries (18%) and 42 countries (21%), respectively. In almost all countries for both adults and school-aged children and adolescents, the increases in double burden were driven by increases in obesity, and decreases in double burden by declining underweight or thinness. Interpretation The combined burden of underweight and obesity has increased in most countries, driven by an increase in obesity, while underweight and thinness remain prevalent in south Asia and parts of Africa. A healthy nutrition transition that enhances access to nutritious foods is needed to address the remaining burden of underweight while curbing and reversing the increase in obesit

Heterogeneous contributions of change in population distribution of body mass index to change in obesity and underweight NCD Risk Factor Collaboration (NCD-RisC)

From 1985 to 2016, the prevalence of underweight decreased, and that of obesity and severe obesity increased, in most regions, with significant variation in the magnitude of these changes across regions. We investigated how much change in mean body mass index (BMI) explains changes in the prevalence of underweight, obesity, and severe obesity in different regions using data from 2896 population-based studies with 187 million participants. Changes in the prevalence of underweight and total obesity, and to a lesser extent severe obesity, are largely driven by shifts in the distribution of BMI, with smaller contributions from changes in the shape of the distribution. In East and Southeast Asia and sub-Saharan Africa, the underweight tail of the BMI distribution was left behind as the distribution shifted. There is a need for policies that address all forms of malnutrition by making healthy foods accessible and affordable, while restricting unhealthy foods through fiscal and regulatory restrictions

Polymer-Clay Nanocomposites of Linear Low Density Polyethylene (LLDPE) and Polyoxymethylene (Pom)

Polymer-clay nanocomposites involving a blend of two otherwise incompatible thermoplastic polymers were prepared and investigated for the effects of the addition of organically modified clay. Linear low density polyethylene (LLDPE) with melt index (MI) of 20 g/10 min and density of 0.925 g/cm3 and polyoxymethylene (POM) with melt volume rate (MVR) of 8 cm3/10min at 190 °C and density of 1.41 g/cm3 at several composition ratios (70/30, 50/50, 30/70) were melt mixed with 5% Cloisite 15A and 5% Cloisite 30B, respectively and their blends were characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). The LLDPE/POM (70/30) blend nanocomposites incorporating Cloisite 15A showed co-continuous morphology according to the SEM images, while those with Cloisite 30B showed some limited levels of compatibility. Further, Cloisite 15A improved the melting temperature of LLDPE and POM by 2.51°C and 2.61°C from 122.41°C and 161.02°C respectively, while Cloisite 30B had no significant effect on LLDPE melting temperature and increased melting temperature of POM by 2.09°C. As for the LLDPE/POM (30/70) blends, Cloisite 15A made the two originally incompatible phases indistinguishable, while the blends containing Cloisite 30B showed a significant decrease in the domain sizes. However, the blend samples without organoclay incorporation did not exhibit any compatibility and the dispersed phase was totally segregated. TGA results showed that addition of Cloisite 15A decreased POM degradation temperature (originally 365.49°C) by 72.09°C while Cloisite 30B lowered the degradation temperature of POM by 92.43°C. There was no significant change observed in PE degradation temperature. The clay compatibility with one or both polymers is shown to make significant difference in blend morphology and compatibilization mechanisms of the polymer-clay nanocomposites are phenomenologically explained in this paper which makes us one step closer to recognize clay as a general compatiblizer. There are very few published studies about LLDPE/POM blends which make this paper more significant; LLDPE in a blend with high percentage of POM could make POM processing much easier, and on the other hand blending a POM with LLDPE could improve mechanical properties of LLDPE