An investment case analysis for the prevention and treatment of adolescent mental disorders and suicide in England

BackgroundAdolescent mental health (AMH) needs in England have increased dramatically and needs exceed treatment availability. This study undertook a comparative assessment of the health and economic return on investment (ROI) of interventions to prevent and treat mental disorders among adolescents (10–19 years) and examined intervention affordability and readiness.MethodsInterventions were identified following a review of published and grey literature. A Markov model followed a simulated adolescent cohort to estimate implementation costs and health, education, and economic benefits. Intervention affordability was assessed, comparing annual cost per adolescent with NHS England per capita spending, and an expert panel assessed intervention readiness using a validated framework.ResultsOver 10- and 80-year horizons, interventions to treat mild anxiety and mild depression were most cost-effective, with the highest individual lifetime ROI (GBP 5822 GBP 1 and GBP 257: GBP 1). Preventing anxiety and depression was most affordable and ‘implementation ready’ and offered the highest health and economic benefits. A priority package (anxiety and depression prevention; mild anxiety and mild depression treatment) would avert 5 million disability-adjusted life-years (DALYS) and achieve an ROI of GBP 15: GBP 1 over 10 years or 11.5 million DALYs (ROI of GBP 55: GBP 1) over 80 years.ConclusionThe economic benefits from preventing and treating common adolescent mental disorders equivalent to 25% of NHS England’s annual spending in 2021 over 10 years and 91% over 80 years. Preventing and early treatment for anxiety and depression had the highest ROIs and strong implementation readiness.<br/

Biomedical knowledge graph-enhanced prompt generation for large language models

Large Language Models (LLMs) have been driving progress in AI at an unprecedented rate, yet still face challenges in knowledge-intensive domains like biomedicine. Solutions such as pre-training and domain-specific fine-tuning add substantial computational overhead, and the latter require domain-expertise. External knowledge infusion is task-specific and requires model training. Here, we introduce a task-agnostic Knowledge Graph-based Retrieval Augmented Generation (KG-RAG) framework by leveraging the massive biomedical KG SPOKE with LLMs such as Llama-2-13b, GPT-3.5-Turbo and GPT-4, to generate meaningful biomedical text rooted in established knowledge. KG-RAG consistently enhanced the performance of LLMs across various prompt types, including one-hop and two-hop prompts, drug repurposing queries, biomedical true/false questions, and multiple-choice questions (MCQ). Notably, KG-RAG provides a remarkable 71% boost in the performance of the Llama-2 model on the challenging MCQ dataset, demonstrating the framework's capacity to empower open-source models with fewer parameters for domain-specific questions. Furthermore, KG-RAG enhanced the performance of proprietary GPT models, such as GPT-3.5 which exhibited improvement over GPT-4 in context utilization on MCQ data. Our approach was also able to address drug repurposing questions, returning meaningful repurposing suggestions. In summary, the proposed framework combines explicit and implicit knowledge of KG and LLM, respectively, in an optimized fashion, thus enhancing the adaptability of general-purpose LLMs to tackle domain-specific questions in a unified framework.Comment: 28 pages, 5 figures, 2 tables, 1 supplementary fil

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Global inequities and emissions in Western European textiles and clothing consumption

YesRising demand for cheaper textiles and clothing in Western Europe is well documented, as are changes in the Textiles and Clothing industry's globalised production structure. We apply a sub-systems global multi-regional input–output accounting framework to examine the sustainability implications of meeting Western European demand for textiles and clothing goods between 1995 and 2009. Our framework estimates environmental and socio-economic impacts of consumption in a consistent manner and shows where these occur both geographically and in the value chain. The results demonstrate that Western European textiles and clothing consumption remains dependent on low-cost labour from Brazil, Russia, India and China (BRIC), principally in the Textiles and Clothing and Agricultural sectors. Conversely, we show that the wage rate for BRIC workers in the global value chains serving Western European textiles and clothing consumption has risen over time but remains low relative to the wage rate paid to Western European workers. Likewise, we find that profits are increasingly generated within BRIC and that they are now at comparable levels to those generated in Western Europe. We find a slight overall decrease in the amount of carbon emitted in the production of textiles and clothing goods for Western Europe between 1995 and 2009. However, the trend is not linear and the importance of different underlying drivers varies over the timeseries. We conclude by discussing the implications of these results for a more sustainable future for Western European textiles and clothing consumption

Genome-Wide Association Study and Functional Characterization Identifies Candidate Genes for Insulin-Stimulated Glucose Uptake

Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in \u3e55,000 participants from three ancestry groups. We identified ten new loci (P \u3c 5 × 10-8) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits

COVID-19 trajectories among 57 million adults in England: a cohort study using electronic health records

BACKGROUND: Updatable estimates of COVID-19 onset, progression, and trajectories underpin pandemic mitigation efforts. To identify and characterise disease trajectories, we aimed to define and validate ten COVID-19 phenotypes from nationwide linked electronic health records (EHR) using an extensible framework. METHODS: In this cohort study, we used eight linked National Health Service (NHS) datasets for people in England alive on Jan 23, 2020. Data on COVID-19 testing, vaccination, primary and secondary care records, and death registrations were collected until Nov 30, 2021. We defined ten COVID-19 phenotypes reflecting clinically relevant stages of disease severity and encompassing five categories: positive SARS-CoV-2 test, primary care diagnosis, hospital admission, ventilation modality (four phenotypes), and death (three phenotypes). We constructed patient trajectories illustrating transition frequency and duration between phenotypes. Analyses were stratified by pandemic waves and vaccination status. FINDINGS: Among 57 032 174 individuals included in the cohort, 13 990 423 COVID-19 events were identified in 7 244 925 individuals, equating to an infection rate of 12·7% during the study period. Of 7 244 925 individuals, 460 737 (6·4%) were admitted to hospital and 158 020 (2·2%) died. Of 460 737 individuals who were admitted to hospital, 48 847 (10·6%) were admitted to the intensive care unit (ICU), 69 090 (15·0%) received non-invasive ventilation, and 25 928 (5·6%) received invasive ventilation. Among 384 135 patients who were admitted to hospital but did not require ventilation, mortality was higher in wave 1 (23 485 [30·4%] of 77 202 patients) than wave 2 (44 220 [23·1%] of 191 528 patients), but remained unchanged for patients admitted to the ICU. Mortality was highest among patients who received ventilatory support outside of the ICU in wave 1 (2569 [50·7%] of 5063 patients). 15 486 (9·8%) of 158 020 COVID-19-related deaths occurred within 28 days of the first COVID-19 event without a COVID-19 diagnoses on the death certificate. 10 884 (6·9%) of 158 020 deaths were identified exclusively from mortality data with no previous COVID-19 phenotype recorded. We observed longer patient trajectories in wave 2 than wave 1. INTERPRETATION: Our analyses illustrate the wide spectrum of disease trajectories as shown by differences in incidence, survival, and clinical pathways. We have provided a modular analytical framework that can be used to monitor the impact of the pandemic and generate evidence of clinical and policy relevance using multiple EHR sources. FUNDING: British Heart Foundation Data Science Centre, led by Health Data Research UK

Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension

High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to ~192,000 individuals, and used ~155,063 samples for independent replication. We identified 31 novel blood pressure or hypertension associated genetic regions in the general population, including three rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5mmHg/allele) than common variants. Multiple rare, nonsense and missense variant associations were found in A2ML1 and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment