Genome-wide analysis in over 1 million individuals of European ancestry yields improved polygenic risk scores for blood pressure traits.

Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (P < 5 × 10-8) from the largest single-stage blood pressure (BP) genome-wide association study to date (n = 1,028,980 European individuals). These associations explain more than 60% of single nucleotide polymorphism-based BP heritability. Comparing top versus bottom deciles of polygenic risk scores (PRSs) reveals clinically meaningful differences in BP (16.9 mmHg systolic BP, 95% CI, 15.5-18.2 mmHg, P = 2.22 × 10-126) and more than a sevenfold higher odds of hypertension risk (odds ratio, 7.33; 95% CI, 5.54-9.70; P = 4.13 × 10-44) in an independent dataset. Adding PRS into hypertension-prediction models increased the area under the receiver operating characteristic curve (AUROC) from 0.791 (95% CI, 0.781-0.801) to 0.826 (95% CI, 0.817-0.836, ∆AUROC, 0.035, P = 1.98 × 10-34). We compare the 2,103 loci results in non-European ancestries and show significant PRS associations in a large African-American sample. Secondary analyses implicate 500 genes previously unreported for BP. Our study highlights the role of increasingly large genomic studies for precision health research.

Circulating 25-hydroxyvitamin D and survival outcomes of colorectal cancer: evidence from population-based prospective cohorts and Mendelian randomisation.

BACKGROUND: To investigate the association between circulating 25-hydroxyvitamin D (25-OHD) and colorectal cancer (CRC) survival outcomes. METHODS: We conducted analyses among the Study of Colorectal Cancer in Scotland (SOCCS) and the UK Biobank (UKBB). Both cancer-specific survival (CSS) and overall survival (OS) outcomes were examined. The 25-OHD levels were categorised into three groups, and multi-variable Cox-proportional hazard models were applied to estimate hazard ratios (HRs). We performed individual-level Mendelian randomisation (MR) through the generated polygenic risk scores (PRS) of 25-OHD and summary-level MR using the inverse-variance weighted (IVW) method. RESULTS: We observed significantly poorer CSS (HR = 0.65,95%CI = 0.55-0.76,P = 1.03 × 10-7) and OS (HR = 0.66,95%CI = 0.58-0.75,P = 8.15 × 10-11) in patients with the lowest compared to those with the highest 25-OHD after adjusting for covariates. These associations remained across patients with varied tumour sites and stages. However, we found no significant association between 25-OHD PRS and either CSS (HR = 0.98,95%CI = 0.80-1.19,P = 0.83) or OS (HR = 1.07,95%CI = 0.91-1.25,P = 0.42). Furthermore, we found no evidence for causal effects by conducting summary-level MR analysis for either CSS (IVW:HR = 1.04,95%CI = 0.85-1.28,P = 0.70) or OS (IVW:HR = 1.10,95%CI = 0.93-1.31,P = 0.25). CONCLUSION: This study supports the observed association between lower circulating 25-OHD and poorer survival outcomes for CRC patients. Whilst the genotype-specific association between better outcomes and higher 25-OHD is intriguing, we found no support for causality using MR approaches.

Setting research priorities for global pandemic preparedness: An international consensus and comparison with ChatGPT's output.

Background: In this priority-setting exercise, we sought to identify leading research priorities needed for strengthening future pandemic preparedness and response across countries. Methods: The International Society of Global Health (ISoGH) used the Child Health and Nutrition Research Initiative (CHNRI) method to identify research priorities for future pandemic preparedness. Eighty experts in global health, translational and clinical research identified 163 research ideas, of which 42 experts then scored based on five pre-defined criteria. We calculated intermediate criterion-specific scores and overall research priority scores from the mean of individual scores for each research idea. We used a bootstrap (n = 1000) to compute the 95% confidence intervals. Results: Key priorities included strengthening health systems, rapid vaccine and treatment production, improving international cooperation, and enhancing surveillance efficiency. Other priorities included learning from the coronavirus disease 2019 (COVID-19) pandemic, managing supply chains, identifying planning gaps, and promoting equitable interventions. We compared this CHNRI-based outcome with the 14 research priorities generated and ranked by ChatGPT, encountering both striking similarities and clear differences. Conclusions: Priority setting processes based on human crowdsourcing - such as the CHNRI method - and the output provided by ChatGPT are both valuable, as they complement and strengthen each other. The priorities identified by ChatGPT were more grounded in theory, while those identified by CHNRI were guided by recent practical experiences. Addressing these priorities, along with improvements in health planning, equitable community-based interventions, and the capacity of primary health care, is vital for better pandemic preparedness and response in many settings.

X-chromosome and kidney function: evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements.

X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.

The landscape of the methodology in drug repurposing using human genomic data: a systematic review.

The process of drug development is expensive and time-consuming. In contrast, drug repurposing can be introduced to clinical practice more quickly and at a reduced cost. Over the last decade, there has been a significant expansion of large biobanks that link genomic data to electronic health record data, public availability of various databases containing biological and clinical information and rapid development of novel methodologies and algorithms in integrating different sources of data. This review aims to provide a thorough summary of different strategies that utilize genomic data to seek drug-repositioning opportunities. We searched MEDLINE and EMBASE databases to identify eligible studies up until 1 May 2023, with a total of 102 studies finally included after two-step parallel screening. We summarized commonly used strategies for drug repurposing, including Mendelian randomization, multi-omic-based and network-based studies and illustrated each strategy with examples, as well as the data sources implemented. By leveraging existing knowledge and infrastructure to expedite the drug discovery process and reduce costs, drug repurposing potentially identifies new therapeutic uses for approved drugs in a more efficient and targeted manner. However, technical challenges when integrating different types of data and biased or incomplete understanding of drug interactions are important hindrances that cannot be disregarded in the pursuit of identifying novel therapeutic applications. This review offers an overview of drug repurposing methodologies, providing valuable insights and guiding future directions for advancing drug repurposing studies.

The metabolic overdrive hypothesis: hyperglycolysis and glutaminolysis in bipolar mania.

Evidence from diverse areas of research including chronobiology, metabolomics and magnetic resonance spectroscopy indicate that energy dysregulation is a central feature of bipolar disorder pathophysiology. In this paper, we propose that mania represents a condition of heightened cerebral energy metabolism facilitated by hyperglycolysis and glutaminolysis. When oxidative glucose metabolism becomes impaired in the brain, neurons can utilize glutamate as an alternative substrate to generate energy through oxidative phosphorylation. Glycolysis in astrocytes fuels the formation of denovo glutamate, which can be used as a mitochondrial fuel source in neurons via transamination to alpha-ketoglutarate and subsequent reductive carboxylation to replenish tricarboxylic acid cycle intermediates. Upregulation of glycolysis and glutaminolysis in this manner causes the brain to enter a state of heightened metabolism and excitatory activity which we propose to underlie the subjective experience of mania. Under normal conditions, this mechanism serves an adaptive function to transiently upregulate brain metabolism in response to acute energy demand. However, when recruited in the long term to counteract impaired oxidative metabolism it may become a pathological process. In this article, we develop these ideas in detail, present supporting evidence and propose this as a novel avenue of investigation to understand the biological basis for mania.

Respiratory Syncytial Virus-Associated Hospital Admissions by Deprivation Levels Among Children and Adults in Scotland.

BACKGROUND: Socioeconomic deprivation may predispose individuals to respiratory tract infections. We estimated RSV-associated hospitalizations by socioeconomic deprivation in Scotland. METHODS: Using national routine health care records and virological surveillance from 2010 to 2016, we used a time-series linear regression model and a direct measurement based on ICD-10 coded diagnoses to estimate RSV-associated hospitalizations by Scottish Index of Multiple Deprivation (SIMD) quintile and age in comparison to influenza-associated hospitalizations. RESULTS: We estimated an annual average rate per 1000 people of 0.76 (95% CI: 0.43-0.90) in the least deprived group to 1.51 (1.03-1.79) for the most deprived group using model-based approach. The rate ratio (RR) was 1.96 (1.23-3.25), 1.60 (1.0-2.66), 1.35 (0.85-2.25), and 1.12 (0.7-1.85) in the 1st to 4th quintile versus the least deprived group. The pattern of RSV-associated hospitalization rates variation with SIMD was most pronounced in children 0-2y. The ICD-10 approach provided much lower rates than the model-based approach but yielded similar RR estimates between SIMD. Influenza-associated hospitalization rate generally increased with higher deprivation levels among individuals 1y+. CONCLUSIONS: Higher RSV and influenza hospitalization rates are related to higher deprivation levels. Differences between deprivation levels are most pronounced in infants and young children for RSV, and are more apparent among individuals 1y+ for influenza.

Respiratory Syncytial Virus-Associated Hospitalization in Adults With Comorbidities in 2 European Countries: A Modeling Study.

BACKGROUND: Individuals with comorbidities are at increased risk of severe respiratory syncytial virus (RSV) infection. We estimated RSV-associated respiratory hospitalization among adults aged ≥45 years with comorbidities in Denmark and Scotland. METHODS: By analyzing national hospital and virologic data, we estimated annual RSV-associated hospitalizations by 7 selected comorbidities and ages between 2010 and 2018. We estimated rate ratios of RSV-associated hospitalization for adults with comorbidity than the overall population. RESULTS: In Denmark, annual RSV-associated hospitalization rates per 1000 adults ranged from 3.1 for asthma to 19.4 for chronic kidney disease (CKD). In Scotland, rates ranged from 2.4 for chronic liver disease to 9.0 for chronic obstructive pulmonary disease (COPD). In both countries, we found a 2- to 4-fold increased risk of RSV hospitalization for adults with COPD, ischemic heart disease, stroke, and diabetes; a 1.5- to 3-fold increased risk for asthma; and a 3- to 7-fold increased risk for CKD. RSV hospitalization rates among adults aged 45 to 64 years with COPD, asthma, ischemic heart disease, or CKD were higher than the overall population. CONCLUSIONS: This study provides important evidence for identifying risk groups and assisting health authorities in RSV vaccination policy making.

Global health economics: The Equitable Impact Sensitive Tool (EQUIST) - development, validation, implementation and evaluation of impact (2011 to 2022).

Background: The Equitable Impact Sensitive Tool (EQUIST) was developed to address the limitations of the traditional cost-effectiveness analysis (CEA) in global health, which often overlooked equity considerations. Its primary aim was to create more effective and efficient health systems by explicitly incorporating equity as a key driver in health policy decisions. This was done in response to the recognition that, while CEA helped reduce mortality rates through interventions like childhood vaccinations, it was insufficient in addressing growing inequalities in health, especially in low-and-middle-income countries (LMICs). Methods: The development of EQUIST involved a multi-stage process which began in 2011 with the recognition of the need for a more nuanced approach than CEA alone. This led to a proposal for creating a tool that balanced cost-effectiveness with equity. The conceptual framework, developed between March and May 2012, included assessments of intervention efficiency by equity strata, effectiveness, impact, and cost-effectiveness. Key to EQUIST's development was its integration with other data science platforms, notably the Lives Saved Tool and the Marginal Budgeting for Bottlenecks tool, allowing EQUIST to draw on comprehensive data sets and thus enabling a more detailed analysis of health interventions' impacts across different socio-economic strata. Results: EQUIST was validated in 2012 through applications in five representative countries, demonstrating its ability to identify more equitable and cost-effective health interventions which targeted vulnerable populations, leading to more lives saved compared to traditional methods. It was then used to develop investment cases for the Global Financing Facility, resulting in significant funding being made available for maternal and child health programmes. Consequently, EQUIST directly influenced the development of national health policies and resource allocations in over 26 African countries. Conclusions: EQUIST has proven to be a valuable tool in developing health policies that are both cost-effective and equitable. In the future, it will be further integrated with other tools and expanded in scope to address broader health issues, including adolescent health and human immunodeficiency virus/acquired immunodeficiency syndrome programme planning. Overall, EQUIST represents a paradigm shift in global health economics, emphasising the importance of equity alongside cost-effectiveness in health policy decisions. Its development and implementation have had a tangible impact on health outcomes, particularly in LMICs, where it has been instrumental in reducing maternal and child mortality while addressing health inequities.

Evaluation of feasibility phase of adaptive version of locally made bubble continuous positive airway pressure oxygen therapy for the treatment of COVID-19 positive and negative adults with severe pneumonia and hypoxaemia.

Background: Bubble continuous positive airway pressure (bCPAP) oxygen therapy has been shown to be safe and effective in treating children with severe pneumonia and hypoxaemia in Bangladesh. Due to lack of adequate non-invasive ventilatory support during coronavirus disease 2019 (COVID-19) crisis, we aimed to evaluate whether bCPAP was safe and feasible when adapted for use in adults with similar indications. Methods: Adults (18-64 years) with severe pneumonia and moderate hypoxaemia (80 to <90% oxygen saturation (SpO2) in room air) were provided bCPAP via nasal cannula at a flow rate of 10 litres per minute (l/min) oxygen at 10 centimetres (cm) H2O pressure, in two tertiary hospitals in Dhaka, Bangladesh. Qualitative interviews and focus group discussions, using a descriptive phenomenological approach, were performed with patients and staff (n = 39) prior to and after the introduction (n = 12 and n = 27 respectively) to understand the operational challenges to the introduction of bCPAP. Results: We enrolled 30 adults (median age 52, interquartile range (IQR) 40-60 years) with severe pneumonia and hypoxaemia and/or acute respiratory distress syndrome (ARDS) irrespective of coronavirus disease 2019 (COVID-19) test results to receive bCPAP. At baseline mean SpO2 on room air was 87% (±2) which increased to 98% (±2), after initiation of bCPAP. The mean duration of bCPAP oxygen therapy was 14.4 ± 24.8 hours. There were no adverse events of note, and no treatment failure or deaths. Operational challenges to the clinical introduction of bCPAP were lack of functioning pulse oximeters, difficult nasal interface fixation among those wearing nose pin, occasional auto bubbling or lack of bubbling in water-filled plastic bottle, lack of holder for water-filled plastic bottle, rapid turnover of trained clinicians at the hospitals, and limited routine care of patients by hospital clinicians particularly after official hours. Discussion: If the tertiary hospitals in Bangladesh are supplied with well-functioning good quality pulse oximeters and enhanced training of the doctors and nurses on proper use of adapted version of bCPAP, in treating adults with severe pneumonia and hypoxaemia with or without ARDS, the bCPAP was found to be safe, well tolerated and not associated with treatment failure across all study participants. These observations increase the confidence level of the investigators to consider a future efficacy trial of adaptive bCPAP oxygen therapy compared to WHO standard low flow oxygen therapy in such patients. Conclusion: s Although bCPAP oxygen therapy was found to be safe and feasible in this pilot study, several challenges were identified that need to be taken into account when planning a definitive clinical trial.

Pilot study of a ketogenic diet in bipolar disorder.

BACKGROUND: Recent evidence from case reports suggests that a ketogenic diet may be effective for bipolar disorder. However, no clinical trials have been conducted to date. AIMS: To assess the recruitment and feasibility of a ketogenic diet intervention in bipolar disorder. METHOD: Euthymic individuals with bipolar disorder were recruited to a 6-8 week trial of a modified ketogenic diet, and a range of clinical, economic and functional outcome measures were assessed. Study registration number: ISRCTN61613198. RESULTS: Of 27 recruited participants, 26 commenced and 20 completed the modified ketogenic diet for 6-8 weeks. The outcomes data-set was 95% complete for daily ketone measures, 95% complete for daily glucose measures and 95% complete for daily ecological momentary assessment of symptoms during the intervention period. Mean daily blood ketone readings were 1.3 mmol/L (s.d. = 0.77, median = 1.1) during the intervention period, and 91% of all readings indicated ketosis, suggesting a high degree of adherence to the diet. Over 91% of daily blood glucose readings were within normal range, with 9% indicating mild hypoglycaemia. Eleven minor adverse events were recorded, including fatigue, constipation, drowsiness and hunger. One serious adverse event was reported (euglycemic ketoacidosis in a participant taking SGLT2-inhibitor medication). CONCLUSIONS: The recruitment and retention of euthymic individuals with bipolar disorder to a 6-8 week ketogenic diet intervention was feasible, with high completion rates for outcome measures. The majority of participants reached and maintained ketosis, and adverse events were generally mild and modifiable. A future randomised controlled trial is now warranted.

Burden of Respiratory Syncytial Virus in the European Union: estimation of RSV-associated hospitalizations in children under 5 years.

BACKGROUND: No overall estimate of respiratory syncytial virus (RSV)-associated hospitalizations in children aged under 5 years has been published for the European Union (EU). We aimed to estimate the RSV hospitalization burden in children aged under 5 years in EU countries and Norway, by age group. METHODS: We collated national RSV-associated hospitalization estimates calculated using linear regression models via the RESCEU project for Denmark, England, Finland, Norway, the Netherlands, and Scotland, 2006-2018. Additional estimates were obtained from a systematic review. Using multiple imputation and nearest neighbor matching methods, we estimated overall RSV-associated hospitalizations and rates in the EU. RESULTS: Additional estimates for 2 countries (France and Spain) were found in the literature. In the EU, an average of 245 244 (95% confidence interval [CI], 224 688-265 799) yearly hospital admissions with a respiratory infection per year were associated with RSV in children aged under 5 years, with most cases occurring among children aged under 1 year (75%). Infants aged under 2 months represented the most affected group (71.6 per 1000 children; 95% CI, 66.6-76.6). CONCLUSIONS: Our findings will help support decisions regarding prevention efforts and represent an important benchmark to understand changes in the RSV burden following the introduction of RSV immunization programs in Europe.

Estimation of the Number of Respiratory Syncytial Virus-Associated Hospitalizations in Adults in the European Union.

BACKGROUND: Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in adults that can result in hospitalizations. Estimating RSV-associated hospitalization is critical for planning RSV-related healthcare across Europe. METHODS: We gathered RSV-associated hospitalization estimates from the RSV Consortium in Europe (RESCEU) for adults in Denmark, England, Finland, Norway, Netherlands, and Scotland from 2006 to 2017. We extrapolated these estimates to 28 European Union (EU) countries using nearest-neighbor matching, multiple imputations, and 2 sets of 10 indicators. RESULTS: On average, 158 229 (95% confidence interval [CI], 140 865-175 592) RSV-associated hospitalizations occur annually among adults in the EU (≥18 years); 92% of these hospitalizations occur in adults ≥65 years. Among 75-84 years, the annual average is estimated at 74 519 (95% CI, 69 923-79 115) at a rate of 2.24 (95% CI, 2.10-2.38) per 1000. Among ≥85 years, the annual average is estimated at 37 904 (95% CI, 32 444-43 363) at a rate of 2.99 (95% CI, 2.56-3.42). CONCLUSIONS: Our estimates of RSV-associated hospitalizations in adults are the first analysis integrating available data to provide the disease burden across the EU. Importantly, for a condition considered in the past to be primarily a disease of young children, the average annual hospitalization estimate in adults was lower but of a similar magnitude to the estimate in young children (0-4 years): 158 229 (95% CI, 140 865-175 592) versus 245 244 (95% CI, 224 688-265 799).

Feasibility and acceptability of bubble continuous positive airway pressure oxygen therapy for the treatment of childhood severe pneumonia and hypoxaemia in Bangladeshi children.

Background: Effective management of hypoxaemia is key to reducing pneumonia deaths in children. In an intensive care setting within a tertiary hospital in Bangladesh, bubble continuous positive airway pressure (bCPAP) oxygen therapy was beneficial in reducing deaths in this population. To inform a future trial, we investigated the feasibility of introducing bCPAP in this population in non-tertiary/district hospitals in Bangladesh. Methods: We conducted a qualitative assessment using a descriptive phenomenological approach to understand the structural and functional capacity of the non-tertiary hospitals (Institute of Child and Mother Health and Kushtia General Hospital) for the clinical use of bCPAP. We conducted interviews and focus group discussions (23 nurses, seven physicians, 14 parents). We retrospectively (12 months) and prospectively (three months) measured the prevalence of severe pneumonia and hypoxaemia in children attending the two study sites. For the feasibility phase, we enrolled 20 patients with severe pneumonia (age two to 24 months) to receive bCPAP, putting in place safeguards to identify risk. Results: Retrospectively, while 747 of 3012 (24.8%) children had a diagnosis of severe pneumonia, no pulse oxygen saturation information was available. Of 3008 children prospectively assessed with pulse oximetry when attending the two sites, 81 (3.7%) had severe pneumonia and hypoxaemia. The main structural challenges to implementation were the inadequate number of pulse oximeters, lack of power generator backup, high patient load with an inadequate number of hospital staff, and inadequate and non-functioning oxygen flow meters. Functional challenges were the rapid turnover of trained clinicians in the hospitals, limited post-admission routine care for in-patients by hospital clinicians due to their extreme workload (particularly after official hours). The study implemented a minimum of four hourly clinical reviews and provided oxygen concentrators (with backup oxygen cylinders), and automatic power generator backup. Twenty children with a mean age of 6.7 (standard deviation (SD) = 5.0)) months with severe pneumonia and hypoxaemia (median (md) SpO2 = 87% in room air, interquartile range (IQR) = 85-88)) with cough (100%) and severe respiratory difficulties (100%) received bCPAP oxygen therapy for a median of 16 hours (IQR = 6-16). There were no treatment failures or deaths. Conclusions: Implementation of low-cost bCPAP oxygen therapy is feasible in non-tertiary/district hospitals when additional training and resources are allocated.

Cross-cancer pleiotropic analysis identifies three novel genetic risk loci for colorectal cancer.

BACKGROUND: To understand the shared genetic basis between colorectal cancer (CRC) and other cancers and identify potential pleiotropic loci for compensating the missing genetic heritability of CRC. METHODS: We conducted a systematic genome-wide pleiotropy scan to appraise associations between cancer-related genetic variants and CRC risk among European populations. Single nucleotide polymorphism (SNP)-set analysis was performed using data from the UK Biobank and the Study of Colorectal Cancer in Scotland (10 039 CRC cases and 30 277 controls) to evaluate the overlapped genetic regions for susceptibility of CRC and other cancers. The variant-level pleiotropic associations between CRC and other cancers were examined by CRC genome-wide association study meta-analysis and the pleiotropic analysis under composite null hypothesis (PLACO) pleiotropy test. Gene-based, co-expression and pathway enrichment analyses were performed to explore potential shared biological pathways. The interaction between novel genetic variants and common environmental factors was further examined for their effects on CRC. RESULTS: Genome-wide pleiotropic analysis identified three novel SNPs (rs2230469, rs9277378 and rs143190905) and three mapped genes (PIP4K2A, HLA-DPB1 and RTEL1) to be associated with CRC. These genetic variants were significant expressions quantitative trait loci in colon tissue, influencing the expression of their mapped genes. Significant interactions of PIP4K2A and HLA-DPB1 with environmental factors, including smoking and alcohol drinking, were observed. All mapped genes and their co-expressed genes were significantly enriched in pathways involved in carcinogenesis. CONCLUSION: Our findings provide an important insight into the shared genetic basis between CRC and other cancers. We revealed several novel CRC susceptibility loci to help understand the genetic architecture of CRC.

Results from the second WHO external quality assessment for the molecular detection of respiratory syncytial virus, 2019-2020.

Background: External quality assessments (EQAs) for the molecular detection of human respiratory syncytial virus (RSV) are necessary to ensure the standardisation of reliable results. The Phase II, 2019-2020 World Health Organization (WHO) RSV EQA included 28 laboratories in 26 countries. The EQA panel evaluated performance in the molecular detection and subtyping of RSV-A and RSV-B. This manuscript describes the preparation, distribution, and analysis of the 2019-2020 WHO RSV EQA. Methods: Panel isolates underwent whole genome sequencing and in silico primer matching. The final panel included nine contemporary, one historical virus and two negative controls. The EQA panel was manufactured and distributed by the UK National External Quality Assessment Service (UK NEQAS). National laboratories used WHO reference assays developed by the United States Centers for Disease Control and Prevention, an RSV subtyping assay developed by the Victorian Infectious Diseases Reference Laboratory (Australia), or other in-house or commercial assays already in use at their laboratories. Results: An in silico analysis of isolates showed a good match to assay primer/probes. The panel was distributed to 28 laboratories. Isolates were correctly identified in 98% of samples for detection and 99.6% for subtyping. Conclusions: The WHO RSV EQA 2019-2020 showed that laboratories performed at high standards. Updating the composition of RSV molecular EQAs with contemporary strains to ensure representation of circulating strains, and ensuring primer matching with EQA panel viruses, is advantageous in assessing diagnostic competencies of laboratories. Ongoing EQAs are recommended because of continued evolution of mismatches between current circulating strains and existing primer sets.

The ability of non-physician health workers to identify chest indrawing to detect pneumonia in children below five years of age in low- and middle-income countries: A systematic review and meta-analysis.

Background: Non-physician health workers play a vital role in diagnosing and treating pneumonia in children in low- and middle-income countries (LMICs). Chest indrawing is a key indicator for pneumonia diagnosis, signifying the severity of the disease. We conducted this systematic review to summarize the evidence on non-physician health workers' ability to identify chest indrawing to detect pneumonia in children below five years of age in LMICs. Methods: We comprehensively searched four electronic databases, including MEDLINE, Embase, Web of Science, and Scopus, and reference lists from the identified studies, from January 1, 1990, to January 20, 2022, with no language restrictions. Studies evaluating the performance of non-physician health workers in identifying chest indrawing compared to a reference standard were included. We used the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool to assess the methodological quality of the selected studies and conducted a meta-analysis following a bivariate random effects model to estimate the pooled sensitivity and specificity. Results: We identified nine studies covering 4468 children that reported the accuracy of a non-physician health worker in identifying chest indrawing. Most studies were conducted in the 1990s, based at health facility settings, with children aged 2-59 months, and with pediatricians/physicians as the reference standard. Using the QUADAS-2, we evaluated most studies as having a low risk of bias and a low concern regarding applicability in all domains. The median sensitivity, specificity, positive predictive value, and negative predictive value were 44%, 97%, 55%, and 95%, respectively. We selected five studies for the meta-analysis. The pooled sensitivity was 46% (95% confidence interval (CI) = 37-56), and the pooled specificity was 95% (95% CI = 91-97). Conclusions: We found the ability of non-physician health workers in LMICs in identifying chest indrawing pneumonia is relatively poor. Appropriate measures, such as targeted identification and training, supportive supervision, regular performance assessment, and feedback for those who have a poor ability to recognize chest indrawing, should be taken to improve the diagnosis of pneumonia in children. New studies are needed to assess the new generation of health workers. Registration: PROSPERO (CRD42022306954).

Phenome-wide association study of genetically predicted B vitamins and homocysteine biomarkers with multiple health and disease outcomes: analysis of the UK Biobank.

BACKGROUND: Although a number of health outcomes such as CVDs, metabolic-related outcomes, neurological disorders, pregnancy outcomes, and cancers have been identified in relation to B vitamins, evidence is of uneven quality and volume, and there is uncertainty about putative causal relationships. OBJECTIVES: To explore the effects of B vitamins and homocysteine on a wide range of health outcomes based on a large biorepository linking biological samples and electronic medical records. METHODS: First, we performed a phenome-wide association study (PheWAS) to investigate the associations of genetically predicted plasma concentrations (genetic component of the circulating concentrations) of folate, vitamin B6, vitamin B12, and their metabolite homocysteine with a wide range of disease outcomes (including both prevalent and incident events) among 385,917 individuals in the UK Biobank. Second, 2-sample Mendelian randomization (MR) analysis was used to replicate any observed associations and detect causality. We considered MR P <0.05 as significant for replication. Third, dose-response, mediation, and bioinformatics analyses were carried out to examine any nonlinear trends and to disentangle the underlying mediating biological mechanisms for the identified associations. RESULTS: In total, 1117 phenotypes were tested in each PheWAS analysis. After multiple corrections, 32 phenotypic associations of B vitamins and homocysteine were identified. Two-sample MR analysis supported that 3 of them were causal, including associations of higher plasma vitamin B6 with lower risk of calculus of kidney (OR: 0.64; 95% CI: 0.42, 0.97; P = 0.033), higher homocysteine concentration with higher risk of hypercholesterolemia (OR: 1.28, 95% CI: 1.04, 1.56; P = 0.018), and chronic kidney disease (OR: 1.32, 95% CI: 1.06, 1.63; P = 0.012). Significant nonlinear dose-response relationships were observed for the associations of folate with anemia, vitamin B12 with vitamin B-complex deficiencies, anemia and cholelithiasis, and homocysteine with cerebrovascular disease. CONCLUSIONS: This study provides strong evidence for the associations of B vitamins and homocysteine with endocrine/metabolic and genitourinary disorders.