Rare and common variants associated with alcohol consumption identify a conserved molecular network.

Background: Genome-wide association studies (GWAS) have identified hundreds of common variants associated with alcohol consumption. In contrast, genetic studies of alcohol consumption that use rare variants are still in their early stages. No prior studies of alcohol consumption have examined whether common and rare variants implicate the same genes and molecular networks, leaving open the possibility that the two approaches might identify distinct biology.

Genome-wide association studies of coffee intake in UK/US participants of European ancestry uncover cohort-specific genetic associations.

Coffee is one of the most widely consumed beverages. We performed a genome-wide association study (GWAS) of coffee intake in US-based 23andMe participants (N = 130,153) and identified 7 significant loci, with many replicating in three multi-ancestral cohorts. We examined genetic correlations and performed a phenome-wide association study across hundreds of biomarkers, health, and lifestyle traits, then compared our results to the largest available GWAS of coffee intake from the UK Biobank (UKB; N = 334,659).

Multi-ancestry meta-analysis of tobacco use disorder identifies 461 potential risk genes and reveals associations with multiple health outcomes.

Tobacco use disorder (TUD) is the most prevalent substance use disorder in the world. Genetic factors influence smoking behaviours and although strides have been made using genome-wide association studies to identify risk variants, most variants identified have been for nicotine consumption, rather than TUD. Here we leveraged four US biobanks to perform a multi-ancestral meta-analysis of TUD (derived via electronic health records) in 653,790 individuals (495,005 European, 114,420 African American and 44,365 Latin American) and data from UK Biobank (n = 898,680).

Rare and Common Variants Associated with Alcohol Consumption Identify a Conserved Molecular Network.

Genome-wide association studies (GWAS) have identified hundreds of common variants associated with alcohol consumption. In contrast, rare variants have only begun to be studied for their role in alcohol consumption. No studies have examined whether common and rare variants implicate the same genes and molecular networks.

Multi-ancestry meta-analysis of tobacco use disorder prioritizes novel candidate risk genes and reveals associations with numerous health outcomes.

Tobacco use disorder () is the most prevalent substance use disorder in the world. Genetic factors influence smoking behaviors, and although strides have been made using genome-wide association studies () to identify risk variants, the majority of variants identified have been for nicotine consumption, rather than TUD. We leveraged five biobanks to perform a multi-ancestral meta-analysis of TUD (derived via electronic health records, ) in 898,680 individuals (739,895 European, 114,420 African American, 44,365 Latin American).

Aligning Semantic Interoperability Frameworks with the FOXS Stack for FAIR Health Data.

Background: FAIR Guiding Principles present a synergy with the use cases for digital health records, in that clinical data need to be found, accessible within a range of environments, and data must interoperate between systems and subsequently reused. The use of HL7 FHIR, openEHR, IHE XDS, and SNOMED CT (FOXS) together represents a specification to create an open digital health platform for modern health care applications.

Objectives: To describe where logical FOXS components align to the European Open Science Cloud Interoperability Framework (EOSC-IF) reference architecture for semantic interoperability.

Predicted leukocyte telomere length and risk of germ cell tumours.

Background: Genetically predicted leukocyte telomere length (LTL) has been evaluated in several studies of childhood and adult cancer. We test whether genetically predicted longer LTL is associated with germ cell tumours (GCT) in children and adults.

Methods: Paediatric GCT samples were obtained from a Children's Oncology Group study and state biobank programs in California and Michigan (N = 1413 cases, 1220 biological parents and 1022 unrelated controls).

Utilising the FOXS Stack for FAIR Architected Data Access.

A FOXS stack assembles HL7 FHIR, openEHR, IHE XDS and SNOMED CT as an operational clinical data platform to build digital systems. This paper analyses its applicability for FAIR-enabled medical research based on a summary of key principles. It highlights the benefit of the blended approach to operational technology stacks for health systems, and a need for industry standard technologies to enable greater semantic coherence for primary/secondary data use.

openEHR Based Contextual Problem List.

The problem list is a key facet of the digital patient record that has historically been difficult to curate. This paper presents an implementation of a contextual problem list using openEHR. It describes the modelling approach, key model elements, and how these are assembled to underpin a Problem Oriented Medical Record.

Defining the Contextual Problem List.

The Problem Oriented Medical Record (POMR) is considered a key charting method to support clinical care. Although not uniformly represented amongst digital health systems, this paper presents a clinical model to represent multiple clinical perspectives from a single problem list. The contextual problem list model is defined according to primary diagnosis, comorbidities and problems arising from the primary condition.

Discovery of the 3-Imino-1,2,4-thiadiazinane 1,1-Dioxide Derivative Verubecestat (MK-8931)-A β-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor for the Treatment of Alzheimer's Disease.

Verubecestat 3 (MK-8931), a diaryl amide-substituted 3-imino-1,2,4-thiadiazinane 1,1-dioxide derivative, is a high-affinity β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor currently undergoing Phase 3 clinical evaluation for the treatment of mild to moderate and prodromal Alzheimer's disease. Although not selective over the closely related aspartyl protease BACE2, verubecestat has high selectivity for BACE1 over other key aspartyl proteases, notably cathepsin D, and profoundly lowers CSF and brain Aβ levels in rats and nonhuman primates and CSF Aβ levels in humans. In this annotation, we describe the discovery of 3, including design, validation, and selected SAR around the novel iminothiadiazinane dioxide core as well as aspects of its preclinical and Phase 1 clinical characterization.

Peat bog wildfire smoke exposure in rural North Carolina is associated with cardiopulmonary emergency department visits assessed through syndromic surveillance.

Background: In June 2008, burning peat deposits produced haze and air pollution far in excess of National Ambient Air Quality Standards, encroaching on rural communities of eastern North Carolina. Although the association of mortality and morbidity with exposure to urban air pollution is well established, the health effects associated with exposure to wildfire emissions are less well understood.

Objective: We investigated the effects of exposure on cardiorespiratory outcomes in the population affected by the fire.

Mathematical modeling to define optimum operating room staffing for pediatric patients in trauma centers.

Background: Adult trauma centers (TCs) in the United States may be verified with an on-call operating room team if the performance improvement program shows no adverse outcome. Using queuing and simulation methodology, this study attempts to add a volume guideline for injured children.

Methods: Data from 63 verified TCs identified demographic factors including specific information regarding the first pediatric trauma-related operation done between 11 pm and 7 am each month for 1 year.

Comparison of methods for analysis of functional observation battery (FOB) data.

Introduction: Different methods for the analysis of behavioral observation data were compared to evaluate how the interpretation of a data set may depend on the analysis method employed.

Methods: Three methods of analysis were used to evaluate the same four sets of rodent behavioral FOB data: (1) evaluation by a trained behavioral toxicologist (ToxRev); (2) Kruskal-Wallis statistical analysis of variance for nonparametric data followed by Wilcoxon pairwise tests (KW) and (3) Cochran-Mantel-Haenszel statistical analysis of variance for nonparametric data followed by Wilcoxon pairwise tests (CMH). The FOB consisted of 9 behavioral, 10 neurologic and 7 autonomic parameters that were evaluated following administration of either vehicle or diazepam (1 or 4 mg/kg; 1, 2 or 5 mg/kg) to male and female rats.

Electronic patient record evaluation in community mental health.

Background: Deployment of electronic patient records (EPRs) is one of the primary goals of national NHS information technology (IT) initiatives. However, many systems come into disrepute through poor planning or design flaws, and media scrutiny focuses on these problems rather than the potential gains.

Objective: To evaluate the deployment of an EPR in a community mental health setting.

Early life programming of innate fear and fear learning in adult female rats.

The early rearing environment can impact on emotional reactivity and learning later in life. In this study the effects of neonatal maternal separation (MS) on innate fear and fear learning were assessed in the adult female rat. Pups were subjected to MS (360 min), brief handling (H; 15 min), or animal facility rearing (AFR) on post-natal days 2-14.

Increasing research capacity at the New England School of Acupuncture through faculty and student research training initiatives.

Few complementary and alternative medicine (CAM) institutions require their students to undergo substantive training in research literacy and conduct, and well-developed programs to train CAM institution faculty in research are virtually non-existent. As part of a National Center for Complementary and Alternative Medicine (NCCAM) initiative to increase research capacity at CAM institutions, the New England School of Acupuncture (NESA), in collaboration with the Harvard Medical School (HMS) Osher Institute, was awarded a Developmental Center for Research on Complementary and Alternative Medicine (DCRC) grant. This article discusses a number of initiatives that we designed and implemented to train NESA students, faculty members, and alumni in the foundations of clinical research and to stimulate interest in both participating in research and receiving additional research training.

Thyroid hormone, glucocorticoids, and prolactin at the nexus of physiology, reproduction, and toxicology.

A symposium at the 2003 Annual Meeting of the Society of Toxicology brought together an expert group of endocrinologists to review how non-reproductive hormones can affect the endocrine system. This publication captures the essence of those presentations. Paul Cooke and Denise Holsberger recapitulate the evidence of how thyroid hormones affect male and female reproduction, and reproductive development.

A prospective double-blind study of nasal sumatriptan versus IV ketorolac in migraine.

We conducted a study to compare the efficacy in migraine headache of nasal sumatriptan and intravenous ketorolac. The study was a prospective, double-blind study done with a convenience sample of 29 patients presenting to the emergency department (ED) with acute migraine. Patients received either 20 mg of nasal sumatriptan or 30 mg of intravenous ketorolac.

Dietary exposure to genistein increases vasopressin but does not alter beta-endorphin in the rat hypothalamus.

Genistein is a plant-derived estrogenic isoflavone commonly found in soy-based products such as soymilk and soy-based dietary supplements for treating menopausal symptoms, for example. Vasopressin is a neurosecretory nonapeptide synthesized primarily in neurons of the hypothalamus and secreted into the bloodstream from the posterior lobe of the pituitary. The endogenous opiate peptide beta-endorphin is synthesized both in neurons of the hypothalamus and in pituitary cells, primarily of the neurointermediate lobe.

Quantitative three-dimensional reconstruction: feasibility for studies of sexually dimorphic hypothalamic development in rats.

The adult rat brain develops through an interplay of neuronal proliferation with programmed cell death. Sensory stimulation, as well as growth factors and steroids, may alter the balance between these competing processes. "Endocrine disrupters" (EDs) may do the same by mimicry or modulation of endogenous hormones.