Association between cord blood 25-hydroxyvitamin D concentrations and respiratory tract infections in the first 6 months of age in a Korean population: a birth cohort study (COCOA)

PurposePrevious studies suggest that the concentration of 25-hydroxyvitamin D [25(OH)D] in cord blood may show an inverse association with respiratory tract infections (RTI) during childhood. The aim of the present study was to examine the influence of 25(OH)D concentrations in cord blood on infant RTI in a Korean birth cohort.MethodsThe levels of 25(OH)D in cord blood obtained from 525 Korean newborns in the prospective COhort for Childhood Origin of Asthma and allergic diseases were examined. The primary outcome variable of interest was the prevalence of RTI at 6-month follow-up, as diagnosed by pediatricians and pediatric allergy and pulmonology specialists. RTI included acute nasopharyngitis, rhinosinusitis, otitis media, croup, tracheobronchitis, bronchiolitis, and pneumonia.ResultsThe median concentration of 25(OH)D in cord blood was 32.0 nmol/L (interquartile range, 21.4 to 53.2). One hundred and eighty neonates (34.3%) showed 25(OH)D concentrations less than 25.0 nmol/L, 292 (55.6%) showed 25(OH)D concentrations of 25.0-74.9 nmol/L, and 53 (10.1%) showed concentrations of ≥75.0 nmol/L. Adjusting for the season of birth, multivitamin intake during pregnancy, and exposure to passive smoking during pregnancy, 25(OH)D concentrations showed an inverse association with the risk of acquiring acute nasopharyngitis by 6 months of age (P for trend=0.0004).ConclusionThe results show that 89.9% of healthy newborns in Korea are born with vitamin D insufficiency or deficiency (55.6% and 34.3%, respectively). Cord blood vitamin D insufficiency or deficiency in healthy neonates is associated with an increased risk of acute nasopharyngitis by 6 months of age. More time spent outdoors and more intensified vitamin D supplementation for pregnant women may be needed to prevent the onset of acute nasopharyngitis in infants

Inducible Deletion of Protein Kinase Map4k4 in Obese Mice Improves Insulin Sensitivity in Liver and Adipose Tissues

Studies in vitro suggest that mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) attenuates insulin signaling, but confirmation in vivo is lacking since Map4k4 knockout is lethal during embryogenesis. We thus generated mice with floxed Map4k4 alleles and a tamoxifen-inducible Cre/ERT2 recombinase under the control of the ubiquitin C promoter to induce whole-body Map4k4 deletion after these animals reached maturity. Tamoxifen administration to these mice induced Map4k4 deletion in all tissues examined, causing decreased fasting blood glucose concentrations and enhanced insulin signaling to AKT in adipose tissue and liver but not in skeletal muscle. Surprisingly, however, mice generated with a conditional Map4k4 deletion in adiponectin-positive adipocytes or in albumin-positive hepatocytes displayed no detectable metabolic phenotypes. Instead, mice with Map4k4 deleted in Myf5-positive tissues, including all skeletal muscles tested, were protected from obesity-induced glucose intolerance and insulin resistance. Remarkably, these mice also showed increased insulin sensitivity in adipose tissue but not skeletal muscle, similar to the metabolic phenotypes observed in inducible whole-body knockout mice. Taken together, these results indicate that (i) Map4k4 controls a pathway in Myf5-positive cells that suppresses whole-body insulin sensitivity and (ii) Map4k4 is a potential therapeutic target for improving glucose tolerance and insulin sensitivity in type 2 diabetes

Pulmonary Hypertension Associated with Use of Phentermine

Weight-control drugs (known as anorexigens) such as fenfluramine have been linked with pulmonary hypertension in previous reports. In our case, a 29 year old woman was admitted for shortness of breath and was diagnosed with pulmonary hypertension. Three months ago, she had been taking phentermine for five weeks. Other factors that might have contributed to the development of pulmonary hypertension were excluded. With treatment, her symptoms improved. This is the first case that can suggest a possible connection between phenermine single medication with pulmonary hypertension. Phentermine has been considered a relatively safe drug to treat obesity, and further investigation is needed to decide the safety and dosage of phentermine

Short-term protein intake increases fractional synthesis rate of muscle protein in the elderly: meta-analysis

The precise effects of protein intake on fractional synthesis rate (FSR) of muscle protein are still under debate. The sample size of these studies was small and the conclusions in young and elderly subjects were inconsistent. To assess the effect of dietary protein intake on the FSR level, we conducted a meta-analysis of controlled protein intake trials. Random-effects models were used to calculate the weighted mean differences (WMDs). Ten studies were included and effects of short-term protein intake were evaluated. In an overall pooled estimate, protein intake significantly increased the FSR (20 trials, 368 participants; WMD: 0.025%/h; 95%CI: 0.019-0.031; P < 0.0001). Meta-regression analysis suggested that the protein dose was positively related to the effect size (regression coefficient = 0.108%/h; 95%CI: 0.035, 0.182; P = 0.009). A subgroup analysis indicated that protein intake significantly increased FSR when the protein dose was ≤ 0.80 g/kg BW (16 trials, 308 participants; WMD: 0.027%/h; 95%CI: 0.019-0.031; P < 0.0001), but did not affect FSR when the protein dose was > 0.80 g/kg BW (4 trials, 60 participants; WMD: 0.016%/h; 95%CI: 0.004-0.029; P = 0.98). In conclusion, this study is the first integrated results showing that a short-term protein intake is effective at improving the FSR of muscle protein in the healthy elderly as well as young subjects. This beneficial effect seems to be dose-dependent when the dose levels of protein range from 0.08 to 0.80 g/kg BW

Humanity's Last Exam

Benchmarks are important tools for tracking the rapid advancements in large language model (LLM) capabilities. However, benchmarks are not keeping pace in difficulty: LLMs now achieve over 90\% accuracy on popular benchmarks like MMLU, limiting informed measurement of state-of-the-art LLM capabilities. In response, we introduce Humanity's Last Exam (HLE), a multi-modal benchmark at the frontier of human knowledge, designed to be the final closed-ended academic benchmark of its kind with broad subject coverage. HLE consists of 3,000 questions across dozens of subjects, including mathematics, humanities, and the natural sciences. HLE is developed globally by subject-matter experts and consists of multiple-choice and short-answer questions suitable for automated grading. Each question has a known solution that is unambiguous and easily verifiable, but cannot be quickly answered via internet retrieval. State-of-the-art LLMs demonstrate low accuracy and calibration on HLE, highlighting a significant gap between current LLM capabilities and the expert human frontier on closed-ended academic questions. To inform research and policymaking upon a clear understanding of model capabilities, we publicly release HLE at https://lastexam.ai

Humanity's Last Exam

Benchmarks are important tools for tracking the rapid advancements in large language model (LLM) capabilities. However, benchmarks are not keeping pace in difficulty: LLMs now achieve over 90\% accuracy on popular benchmarks like MMLU, limiting informed measurement of state-of-the-art LLM capabilities. In response, we introduce Humanity's Last Exam (HLE), a multi-modal benchmark at the frontier of human knowledge, designed to be the final closed-ended academic benchmark of its kind with broad subject coverage. HLE consists of 3,000 questions across dozens of subjects, including mathematics, humanities, and the natural sciences. HLE is developed globally by subject-matter experts and consists of multiple-choice and short-answer questions suitable for automated grading. Each question has a known solution that is unambiguous and easily verifiable, but cannot be quickly answered via internet retrieval. State-of-the-art LLMs demonstrate low accuracy and calibration on HLE, highlighting a significant gap between current LLM capabilities and the expert human frontier on closed-ended academic questions. To inform research and policymaking upon a clear understanding of model capabilities, we publicly release HLE at https://lastexam.ai

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase&nbsp;1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation&nbsp;disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age&nbsp; 6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score&nbsp; 652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc&nbsp;= 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N&nbsp;= 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in&nbsp;Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in&nbsp;Asia&nbsp;and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

A reference map of the human binary protein interactome.

Global insights into cellular organization and genome function require comprehensive understanding of the interactome networks that mediate genotype-phenotype relationships(1,2). Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. With approximately 53,000 protein-protein interactions, HuRI has approximately four times as many such interactions as there are high-quality curated interactions from small-scale studies. The integration of HuRI with genome(3), transcriptome(4) and proteome(5) data enables cellular function to be studied within most physiological or pathological cellular contexts. We demonstrate the utility of HuRI in identifying the specific subcellular roles of protein-protein interactions. Inferred tissue-specific networks reveal general principles for the formation of cellular context-specific functions and elucidate potential molecular mechanisms that might underlie tissue-specific phenotypes of Mendelian diseases. HuRI is a systematic proteome-wide reference that links genomic variation to phenotypic outcomes

Vision, challenges and opportunities for a Plant Cell Atlas

With growing populations and pressing environmental problems, future economies will be increasingly plant-based. Now is the time to reimagine plant science as a critical component of fundamental science, agriculture, environmental stewardship, energy, technology and healthcare. This effort requires a conceptual and technological framework to identify and map all cell types, and to comprehensively annotate the localization and organization of molecules at cellular and tissue levels. This framework, called the Plant Cell Atlas (PCA), will be critical for understanding and engineering plant development, physiology and environmental responses. A workshop was convened to discuss the purpose and utility of such an initiative, resulting in a roadmap that acknowledges the current knowledge gaps and technical challenges, and underscores how the PCA initiative can help to overcome them.</jats:p