Hypoglycaemic stimulation of macrophage cytokine release is suppressed by AMP-activated protein kinase activation.

Aims: Acute hypoglycaemia promotes pro-inflammatory cytokine production, increasing the risk for cardiovascular events in diabetes. AMP-activated protein kinase (AMPK) is regulated by and influences the production of pro-inflammatory cytokines. We sought to examine the mechanistic role of AMPK in low glucose-induced changes in the pro-inflammatory cytokine macrophage migration inhibitory factor (MIF), which is elevated in people with diabetes.

Detection and characterization of copy-number variants from exome sequencing in the DDD study.

Purpose: Structural variants such as multiexon deletions and duplications are an important cause of disease but are often overlooked in standard exome/genome sequencing analysis. We aimed to evaluate the detection of copy-number variants (CNVs) from exome sequencing (ES) in comparison with genome-wide low-resolution and exon-resolution chromosomal microarrays (CMAs) and to characterize the properties of de novo CNVs in a large clinical cohort.

Methods: We performed CNV detection using ES of 9859 parent-offspring trios in the Deciphering Developmental Disorders (DDD) study and compared them with CNVs detected from exon-resolution array comparative genomic hybridization in 5197 probands from the DDD study.

Exploring concussion prevalence, knowledge and reporting behaviours in women playing rugby union in the United Kingdom.

Objectives: The aim of this study was to capture information regarding concussion prevalence, knowledge, and reporting behaviors in women rugby players across all competitive levels in the UK. We also investigated whether these outcomes were influenced by the prevailing concussion awareness programme (HEADCASE).

Measures: Two hundred and thirty players from elite (Premiership), Championship, British Universities, and College Sport and club level completed ( = 133) or partially completed ( = 97) a mixed-methods online questionnaire.

Early-life challenge enhances cortisol regulation in zebrafish larvae.

The hypothalamic-pituitary-adrenal (HPA) axis in mammals and the hypothalamic-pituitary-interrenal (HPI) axis in fish are open systems that adapt to the environment during development. Little is known about how this adaptation begins and regulates early stress responses. We used larval zebrafish to examine the impact of prolonged forced swimming at 5 days post-fertilization (dpf), termed early-life challenge (ELC), on cortisol responses, neuropeptide expression in the nucleus preopticus (NPO), and gene transcript levels.

Quantitative Sensory Testing - From bench to bedside.

The methodology of Quantitative Sensory Testing (QST) comprises standardized testing procedures, which provide information of the integrity of the somatosensory nervous system. Over the years, different protocols have been established, which utilize similar but distinct testing procedures. They pursue the same overall objective to identify loss or gain of function of the respective sensory parameter to better understand the degree of abnormal nervous function and thereby improve patient care in the long-term.

Pathogenic PDE12 variants impair mitochondrial RNA processing causing neonatal mitochondrial disease.

Pathogenic variants in either the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired mitochondrial function. Within this group, an increasing number of families have been identified, where Mendelian genetic disorders implicate defective mitochondrial RNA biology. The PDE12 gene encodes the poly(A)-specific exoribonuclease, involved in the quality control of mitochondrial non-coding RNAs.

The Genomic Signature and Transcriptional Response of Metal Tolerance in Brown Trout Inhabiting Metal-Polluted Rivers.

Industrial pollution is a major driver of ecosystem degradation, but it can also act as a driver of contemporary evolution. As a result of intense mining activity during the Industrial Revolution, several rivers across the southwest of England are polluted with high concentrations of metals. Despite the documented negative impacts of ongoing metal pollution, brown trout (Salmo trutta L.

The effectiveness and usability of online, group-based interventions for people with severe obesity: a systematic review and meta-analysis.

Long wait times, limited resources, and a lack of local options mean that many people with severe obesity cannot access treatment. Face-to-face group-based interventions have been found effective and can treat multiple people simultaneously, but are limited by service capacity. Digital group interventions could reduce wait times, but research on their effectiveness is limited.

Widening the phenotypic spectrum caused by pathogenic variants in individuals with neonatal diabetes.

Introduction: Biallelic variants are a rare cause of isolated pancreatic agenesis and neonatal diabetes (NDM) without exocrine pancreatic insufficiency, with 17 cases reported in the literature.

Research Design And Methods: To determine the phenotypic variability caused by this rare genetic aetiology, we investigated 19 individuals with NDM resulting from biallelic disease-causing variants.

Results: Of the 19 individuals, 8 (42%) were confirmed to have exocrine insufficiency requiring replacement therapy.

Type 1 diabetes genetic risk contributes to phenotypic presentation in monogenic autoimmune diabetes.

Disease-causing variants in key immune homeostasis genes can lead to monogenic autoimmune diabetes. Some individuals carrying disease-causing variants do not develop autoimmune diabetes, even though they develop other autoimmune disease. We aimed to determine whether type 1 diabetes polygenic risk contributes to phenotypic presentation in monogenic autoimmune diabetes.

Microbiota and cognitive impairment: Current challenges and future perspectives.

Recent studies indicate that gut microbiota may play a crucial role in cognitive function. Individuals with cognitive impairment tend to have fewer beneficial gut bacteria and lower microbial diversity. Therefore, gut microbiota could be a potential biomarker for cognitive vulnerability.

Usefulness of FFR-CT to exclude haemodynamically significant lesions in high-risk NSTE-ACS.

Background: Coronary computed tomography angiography (CCTA) and fractional flow reserve (FFR) derived from CCTA (FFR-CT) may provide a means of reducing unnecessary invasive coronary angiography (ICA) in patients with suspected non-ST-elevation acute coronary syndromes (NSTE-ACS).

Aims: The aim of this study was to evaluate the capacity of FFR-CT and CCTA to rule out significant lesions in high-risk NSTE-ACS patients, using ICA with invasive FFR as the gold standard.

Methods: High-risk NSTE-ACS patients admitted to 4 European centres were enrolled in this single-arm, prospective core lab-adjudicated study.

DINGO: increasing the power of locus discovery in maternal and fetal genome-wide association studies of perinatal traits.

Perinatal traits are influenced by fetal and maternal genomes. We investigate the performance of three strategies to detect loci in maternal and fetal genome-wide association studies (GWASs) of the same quantitative trait: (i) the traditional strategy of analysing maternal and fetal GWASs separately; (ii) a two-degree-of-freedom test which combines information from maternal and fetal GWASs; and (iii) a one-degree-of-freedom test where signals from maternal and fetal GWASs are meta-analysed together conditional on estimated sample overlap. We demonstrate that the optimal strategy depends on the extent of sample overlap, correlation between phenotypes, whether loci exhibit fetal and/or maternal effects, and whether these effects are directionally concordant.

DNA Methylation in Alzheimer's Disease.

To date, DNA methylation is the best characterized epigenetic modification in Alzheimer's disease. Involving the addition of a methyl group to the fifth carbon of the cytosine pyrimidine base, DNA methylation is generally thought to be associated with the silencing of gene expression. It has been hypothesized that epigenetics may mediate the interaction between genes and the environment in the manifestation of Alzheimer's disease, and therefore studies investigating DNA methylation could elucidate novel disease mechanisms.

Navigating the light and shadow of scientific publishing faced with machine learning and generative AI.

Background: The public release of ChatGPT in November 2022 sparked a boom and public interest in generative artificial intelligence (AI) that has led to journals and journal families hastily releasing generative AI policies, ranging from asking authors for acknowledgement or declaration to the outright banning of use.

Results: Here, we briefly discuss the basics of machine learning, generative AI, and how it will affect scientific publishing. We focus especially on potential risks and benefits to the scientific community as a whole and journals specifically.

Phenotypic spectrum of dual diagnoses in developmental disorders.

As more patients receive genome-wide sequencing, the number of individuals diagnosed with multiple monogenic conditions is increasing. We sought to investigate the relative phenotypic contribution of dual diagnoses using both manual curation and computational approaches. First, we computed 1,003,236 semantic similarity scores for all possible pairs of 1,417 genes in the Developmental Disorder Gene2Phenotype (DDG2P) database using Human Phenotype Ontology terms.

Rare disease genomic testing in the UK and Ireland: promoting timely and equitable access.

Purpose And Scope: The aim of this position statement is to provide recommendations regarding the delivery of genomic testing to patients with rare disease in the UK and Ireland. The statement has been developed to facilitate timely and equitable access to genomic testing with reporting of results within commissioned turnaround times.

Methods Of Statement Development: A 1-day workshop was convened by the UK Association for Clinical Genomic Science and attended by key stakeholders within the NHS Genomic Medicine Service, including clinical scientists, clinical geneticists and patient support group representatives.