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Abstract Background Physical activity and emotional self-management has the potential to enhance health-related quality of life (HRQoL), but few people with chronic kidney disease (CKD) have access to resources and support. The Kidney BEAM trial aims to evaluate whether an evidence-based physical activity and emotional wellbeing self-management programme (Kidney BEAM) leads to improvements in HRQoL in people with CKD. Methods This was a prospective, multicentre, randomised waitlist-controlled trial, with health economic analysis and nested qualitative studies. In total, three hundred and four adults with established CKD were recruited from 11 UK kidney units. Participants were randomly assigned to the intervention (Kidney BEAM) or a wait list control group (1:1). The primary outcome was the between-group difference in Kidney Disease Quality of Life (KDQoL) mental component summary score (MCS) at 12 weeks. Secondary outcomes included the KDQoL physical component summary score, kidney-specific scores, fatigue, life participation, depression and anxiety, physical function, clinical chemistry, healthcare utilisation and harms. All outcomes were measured at baseline and 12 weeks, with long-term HRQoL and adherence also collected at six months follow-up. A nested qualitative study explored experience and impact of using Kidney BEAM. Results 340 participants were randomised to Kidney BEAM (n = 173) and waiting list (n = 167) groups. There were 96 (55%) and 89 (53%) males in the intervention and waiting list groups respectively, and the mean (SD) age was 53 (14) years in both groups. Ethnicity, body mass, CKD stage, and history of diabetes and hypertension were comparable across groups. The mean (SD) of the MCS was similar in both groups, 44.7 (10.8) and 45.9 (10.6) in the intervention and waiting list groups respectively. Conclusion Results from this trial will establish whether the Kidney BEAM self management programme is a cost-effective method of enhancing mental and physical wellbeing of people with CKD. Trial Registration NCT04872933. Registered 5th May 2021.

Abstract Identifying genetic drivers of chronic diseases is necessary for drug discovery. Here, we develop a machine learning-assisted genetic priority score, which we call ML-GPS, that incorporates genetic associations with predicted disease phenotypes to enhance target discovery. First, we construct gradient boosting models to predict 112 chronic disease phecodes in the UK Biobank and analyze associations of predicted and observed phenotypes with common, rare, and ultra-rare variants to model the allelic series. We integrate these associations with existing evidence using gradient boosting with continuous feature encoding to construct ML-GPS, training it to predict drug indications in Open Targets and externally testing it in SIDER. We then generate ML-GPS predictions for 2,362,636 gene-phecode pairs. We find that the use of predicted phenotypes, which identify substantially more genetic associations than observed phenotypes across the allele frequency spectrum, significantly improves the performance of ML-GPS. ML-GPS increases coverage of drug targets, with the top 1% of all scores providing support for 15,077 gene-phecode pairs that previously had no support. ML-GPS can also identify well-known target-disease relationships, promising targets without indicated drugs, and targets for several drugs in clinical trials, including LRRK2 inhibitors for Parkinson’s disease and olpasiran for cardiovascular disease.

The purpose of this manuscript is to examine the implications of the current ideological underpinnings of sport education programs (SEPs) in the United States (U.S.) and present a new equity-minded and anti-ism sport education (EASE) framework that reflects a paradigm shift towards equity-mindedness, anti-ism, cultural responsiveness, inclusive excellence, and transformational leadership. The sport industry has transformed from modest recreational activities for leisure entertainment at the local levels into a multi-billion-dollar global corporatized industry with far-reaching economic, political and sociocultural impacts. Despite the growth in popularity of SEPs, a major area of concern is the lack of critical reflection on their sociopolitical and cultural origins of the curriculum and corresponding metrics of success. Thus, we argue current SEPs (e.g. sport management, sport administration, sport leadership, sport business, parks and recreation, and sport entertainment, hospitality, and tourism) perpetuate colorblind racism, sexism, and classism based on their philosophical foundations. In an effort to reflect a responsiveness to an increasingly global and multicultural sport industry, we present a new EASE framework for preparing professionals to ignite transformational change in and through sport in the twenty-first century.

Abstract Respiratory viral infections cause morbidity and mortality worldwide. Despite the success of vaccines, vaccination efficacy is weakened by the rapid emergence of viral variants with immunoevasive properties. The development of an off-the-shelf, effective, and safe therapy against respiratory viral infections is thus desirable. Here, we develop NanoSTING, a nanoparticle formulation of the endogenous STING agonist, 2′−3′ cGAMP, to function as an immune activator and demonstrate its safety in mice and rats. A single intranasal dose of NanoSTING protects against pathogenic strains of SARS-CoV-2 (alpha and delta VOC) in hamsters. In transmission experiments, NanoSTING reduces the transmission of SARS-CoV-2 Omicron VOC to naïve hamsters. NanoSTING also protects against oseltamivir-sensitive and oseltamivir-resistant strains of influenza in mice. Mechanistically, NanoSTING upregulates locoregional interferon-dependent and interferon-independent pathways in mice, hamsters, as well as non-human primates. Our results thus implicate NanoSTING as a broad-spectrum immune activator for controlling respiratory virus infection.

Abstract Immunization programs against SARS-CoV-2 with commercial intramuscular vaccines prevent disease but are less efficient in preventing infections. Mucosal vaccines can provide improved protection against transmission, ideally for different variants of concern (VOCs) and related sarbecoviruses. Here, we report a multi-antigen, intranasal vaccine, NanoSTING-SN (NanoSTING-Spike-Nucleocapsid), eliminates virus replication in both the lungs and the nostrils upon challenge with the pathogenic SARS-CoV-2 Delta VOC. We further demonstrate that NanoSTING-SN prevents transmission of the SARS-CoV-2 Omicron VOC (BA.5) to vaccine-naïve hamsters. To evaluate protection against other sarbecoviruses, we immunized mice with NanoSTING-SN. We showed that immunization affords protection against SARS-CoV, leading to protection from weight loss and 100% survival in mice. In non-human primates, animals immunized with NanoSTING-SN show durable serum IgG responses (6 months) and nasal wash IgA responses cross-reactive to SARS-CoV-2 (XBB1.5), SARS-CoV and MERS-CoV antigens. These observations have two implications: (1) mucosal multi-antigen vaccines present a pathway to reducing transmission of respiratory viruses, and (2) eliciting immunity against multiple antigens can be advantageous in engineering pan-sarbecovirus vaccines.

Abstract Background Inflammatory bowel disease (IBD) and Parkinson’s disease (PD) are chronic disorders that have been suggested to share common pathophysiological processes. LRRK2 has been implicated as playing a role in both diseases. Exploring the genetic basis of the IBD-PD comorbidity through studying high-impact rare genetic variants can facilitate the identification of the novel shared genetic factors underlying this comorbidity. Methods We analyzed whole exomes from the BioMe BioBank and UK Biobank, and whole genomes from a cohort of 67 European patients diagnosed with both IBD and PD to examine the effects of LRRK2 missense variants on IBD, PD and their co-occurrence (IBD-PD). We performed optimized sequence kernel association test (SKAT-O) and network-based heterogeneity clustering (NHC) analyses using high-impact rare variants in the IBD-PD cohort to identify novel candidate genes, which we further prioritized by biological relatedness approaches. We conducted phenome-wide association studies (PheWAS) employing BioMe BioBank and UK Biobank whole exomes to estimate the genetic relevance of the 14 prioritized genes to IBD-PD. Results The analysis of LRRK2 missense variants revealed significant associations of the G2019S and N2081D variants with IBD-PD in addition to several other variants as potential contributors to increased or decreased IBD-PD risk. SKAT-O identified two significant genes, LRRK2 and IL10RA, and NHC identified 6 significant gene clusters that are biologically relevant to IBD-PD. We observed prominent overlaps between the enriched pathways in the known IBD, PD, and candidate IBD-PD gene sets. Additionally, we detected significantly enriched pathways unique to the IBD-PD, including MAPK signaling, LPS/IL-1 mediated inhibition of RXR function, and NAD signaling. Fourteen final candidate IBD-PD genes were prioritized by biological relatedness methods. The biological importance scores estimated by protein–protein interaction networks and pathway and ontology enrichment analyses indicated the involvement of genes related to immunity, inflammation, and autophagy in IBD-PD. Additionally, PheWAS provided support for the associations of candidate genes with IBD and PD. Conclusions Our study confirms and uncovers new LRRK2 associations in IBD-PD. The identification of novel inflammation and autophagy-related genes supports and expands previous findings related to IBD-PD pathogenesis, and underscores the significance of therapeutic interventions for reducing systemic inflammation.

Abstract Chronic pancreatitis (CP) is a complex disease with genetic and environmental factors at play. Through trio exome sequencing, a de novo SEC16A frameshift variant in a Chinese teenage CP patient is identified. Subsequent targeted next‐generation sequencing of the SEC16A gene in 1,061 Chinese CP patients and 1,196 controls reveals a higher allele frequency of rare nonsynonymous SEC16A variants in patients (4.90% vs 2.93%; odds ratio [OR], 1.71; 95% confidence interval [CI], 1.26–2.33). Similar enrichments are noted in a French cohort (OR, 2.74; 95% CI, 1.67–4.50) and in a biobank meta‐analysis (OR, 1.16; 95% CI, 1.04–1.31). Notably, Chinese CP patients with SEC16A variants exhibit a median onset age 5 years earlier than those without (40.0 vs 45.0; p = 0.012). Functional studies using three CRISPR/Cas9‐edited HEK293T cell lines show that loss‐of‐function SEC16A variants disrupt coat protein complex II (COPII) formation, impede secretory protein vesicles trafficking, and induce endoplasmic reticulum (ER) stress due to protein overload. Sec16a+/− mice, which demonstrate impaired zymogen secretion and exacerbated ER stress compared to Sec16a+/+, are further generated. In cerulein‐stimulated pancreatitis models, Sec16a+/− mice display heightened pancreatic inflammation and fibrosis compared to wild‐type mice. These findings implicate a novel pathogenic mechanism predisposing to CP.

Summary: Background: Genome-wide association studies (GWAS) have revealed many brain disorder-associated SNPs residing in the noncoding genome, rendering it a challenge to decipher the underlying pathogenic mechanisms. Methods: Here, we present an unsupervised Bayesian framework to identify disease-associated genes by integrating risk SNPs with long-range chromatin interactions (iGOAT), including SNP-SNP interactions extracted from ∼500,000 patients and controls from the UK Biobank, and enhancer–promoter interactions derived from multiple brain cell types at different developmental stages. Findings: The application of iGOAT to three psychiatric disorders and three neurodegenerative/neurological diseases predicted sets of high-risk (HRGs) and low-risk (LRGs) genes for each disorder. The HRGs were enriched in drug targets, and exhibited higher expression during prenatal brain developmental stages than postnatal stages, indicating their potential to affect brain development at an early stage. The HRGs associated with Alzheimer's disease were found to share genetic architecture with schizophrenia, bipolar disorder and major depressive disorder according to gene co-expression module analysis and rare variants analysis. Comparisons of this method to the eQTL-based method, the TWAS-based method, and the gene-level GWAS method indicated that the genes identified by our method are more enriched in known brain disorder-related genes, and exhibited higher precision. Finally, the method predicted 205 risk genes not previously reported to be associated with any brain disorder, of which one top-risk gene, MLH1, was experimentally validated as being schizophrenia-associated. Interpretation: iGOAT can successfully leverage epigenomic data, phenotype–genotype associations, and protein–protein interactions to advance our understanding of brain disorders, thereby facilitating the development of new therapeutic approaches. Funding: The work was funded by the National Key Research and Development Program of China (2024YFF1204902), the Natural Science Foundation of China (82371482), Guangzhou Science and Technology Research Plan (2023A03J0659) and Natural Science Foundation of Guangdong (2024A1515011363).

Summary: Mir483 is a conserved and highly expressed microRNA in placental mammals, embedded within the Igf2 gene. Its expression is dysregulated in a number of human diseases, including metabolic disorders and certain cancers. Here, we investigate the developmental regulation and function of Mir483 in vivo. We find that Mir483 expression is dependent on Igf2 transcription and the regulation of the Igf2/H19 imprinting control region. Transgenic Mir483 overexpression in utero causes fetal, but not placental, growth restriction through insulin-like growth factor 1 (IGF1) and IGF2 and also causes cardiovascular defects leading to fetal death. Overexpression of Mir483 post-natally results in growth stunting through IGF1 repression, increased hepatic lipid production, and excessive adiposity. IGF1 infusion rescues the post-natal growth restriction. Our findings provide insights into the function of Mir483 as a growth suppressor and metabolic regulator and suggest that it evolved within the INS-IGF2-H19 transcriptional region to limit excessive tissue growth through repression of IGF signaling.

Abstract Long-read sequencing data, particularly those derived from the Oxford Nanopore sequencing platform, tend to exhibit high error rates. Here, we present NextDenovo, an efficient error correction and assembly tool for noisy long reads, which achieves a high level of accuracy in genome assembly. We apply NextDenovo to assemble 35 diverse human genomes from around the world using Nanopore long-read data. These genomes allow us to identify the landscape of segmental duplication and gene copy number variation in modern human populations. The use of NextDenovo should pave the way for population-scale long-read assembly using Nanopore long-read data.

Abstract Background De novo mutations (DNMs) are variants that occur anew in the offspring of noncarrier parents. They are not inherited from either parent but rather result from endogenous mutational processes involving errors of DNA repair/replication. These spontaneous errors play a significant role in the causation of genetic disorders, and their importance in the context of molecular diagnostic medicine has become steadily more apparent as more DNMs have been reported in the literature. In this study, we examined 46,489 disease-associated DNMs annotated by the Human Gene Mutation Database (HGMD) to ascertain their distribution across gene and disease categories. Results Most disease-associated DNMs reported to date are found to be associated with developmental and psychiatric disorders, a reflection of the focus of sequencing efforts over the last decade. Of the 13,277 human genes in which DNMs have so far been found, the top-10 genes with the highest proportions of DNM relative to gene size were H3-3 A, DDX3X, CSNK2B, PURA, ZC4H2, STXBP1, SCN1A, SATB2, H3-3B and TUBA1A. The distribution of CADD and REVEL scores for both disease-associated DNMs and those mutations not reported to be de novo revealed a trend towards higher deleteriousness for DNMs, consistent with the likely lower selection pressure impacting them. This contrasts with the non-DNMs, which are presumed to have been subject to continuous negative selection over multiple generations. Conclusion This meta-analysis provides important information on the occurrence and distribution of disease-associated DNMs in association with heritable disease and should make a significant contribution to our understanding of this major type of mutation.

Background: Obesity [defined as a body mass index (BMI) ≥ 30 kg/m2] represents a considerable public health problem and is associated with a significant range of comorbidities and an increased mortality risk. The primary aim of the management of obesity is to achieve weight reduction in the interests of health. For obese patients who cannot achieve or maintain a healthy weight by non-pharmacological means, drug therapy is recommended in combination with non-pharmacological interventions such as dietary modifications and exercise. Objective: To evaluate the clinical effectiveness and cost-effectiveness of three pharmacological interventions in obese patients. Data sources: Clinical effectiveness data used in the meta-analysis were sourced from articles identified in a systematic review of the literature. Data used to inform transitions to obesity-related comorbidities were derived from the General Practice Research Database (GPRD). The results of the meta-analysis and GPRD analyses informed the economic model supplemented by data from the Health Survey for England and other UK-specific data sourced from the literature. Review methods: A systematic literature review was conducted of the clinical effectiveness and cost-effectiveness of orlistat, sibutramine and rimonabant within their licensed indications for the treatment of obese patients. Electronic bibliographic databases including MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, The Cochrane Library databases and Cumulative Index to Nursing and Allied Health Literature (CINAHL) were searched in January 2009, and the reference lists of relevant articles were checked. Studies were included if they compared orlistat, sibutramine or rimonabant with lifestyle and/or exercise advice (standard care), placebo or metformin. Results: Overall, 94 studies involving 24,808 individuals were included in the clinical meta-analysis. Eighty-three trials included data on weight change, 41 included data on BMI change and 45 and 36 studies reported on 5% and 10% body weight loss, respectively. Overall, the results show that the active drug interventions are all effective at reducing weight and BMI compared with placebo. In the case of sibutramine, the higher dose (15 mg) resulted in a greater reduction than the lower dose (10 mg). Generally, the data quality of the trials included was low with poor reporting of standard errors and standard deviations. Results from the BMI risk models derived from the GPRD showed consistent increases in risk with increasing BMI. Adjustments for key confounders, such as age, sex and smoking status, were found to be statistically significant at the 5% level, in all risk models. Applying linear models to estimate BMI trajectories, for the diabetic cohort, an average increase in BMI of 0.040 per year for both men and women was observed. The non-diabetic cohort model showed an increase in BMI of 0.175 per year for women and 0.145 per year for men. The results of the cost-effectiveness analyses suggest that sibutramine 15 mg dominates the other three active interventions and the net benefit analyses show that sibutramine 15 mg is the most cost-effective alternative for thresholds > £2000 per quality-adjusted life-year (QALY). However, both sibutramine and rimonabant have been withdrawn because of safety concerns relating to potential treatment-induced fatal adverse events. If the proportion of patients who experienced a fatal adverse event was > 1.8% (1.5%, 1.0%) for sibutramine 15 mg (sibutramine 10 mg, rimonabant) the treatment would not be considered cost-effective when using a threshold of £20,000 per QALY. Limitations: The clinical review did not include all possible lifestyle comparators, with the inclusion limited to only those trials included one of the active drug interventions. We also excluded all studies not reported in English. Although the clinical review included data from 94 studies, the quality of data was generally low, particularly in terms of the reporting of standard deviation. There was also inconsistency between the results of the mixed-treatment comparison (MTC) and the pair-wise analyses. Conclusion: The MTC of anti-obesity treatments shows that all the active treatments are effective at reducing weight and BMI. The economic results show that, compared with placebo, the treatments are all cost-effective when using a threshold of £20,000 per QALY, and, within the limitations of the data available, sibutramine 15 mg dominates the other three interventions. This work has highlighted many areas of methodological research that could be explored, including assessing inconsistencies within a network to determine differences between the results of pair-wise and MTC analyses; the use of meta-regression methods to look for effect modifiers; exploring the effect of local publication bias; and the use of joint models to analyse the repeated measures of BMI and the time-to-event processes simultaneously. Funding: The National Institute for Health Research Health Technology Assessment programme.

Background: Etanercept, infliximab and adalimumab are licensed in the UK for the treatment of active and progressive psoriatic arthritis (PsA) in adults who have an inadequate response to standard treatment. Objective: To determine the clinical effectiveness, safety and cost-effectiveness of these biologic agents in the treatment of active and progressive PsA. Data sources: Systematic reviews were performed, with data sought from 10 electronic databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Science Citation Index, Conference Proceedings Citation Index – Science, ClinicalTrials.gov, metaRegister of Current Controlled Trials, NHS Economic Evaluation Database, Health Economic Evaluations Database and EconLit) up to June 2009. Review methods: Full paper manuscripts of titles/abstracts considered relevant were obtained and assessed for inclusion by two reviewers according to criteria on study design, interventions, participants and outcomes. Data on study and participant characteristics, efficacy outcomes, adverse effects, costs to the health service and cost-effectiveness were extracted, along with baseline data where reported. The primary efficacy outcomes were measures of anti-inflammatory response, skin lesion response and functional status, and the safety outcome was the incidence of serious adverse events. The primary measure of cost-effectiveness was incremental cost per additional quality-adjusted life-year (QALY). Standard meta-analytic techniques were applied to efficacy data. Published cost-effectiveness studies and the economic analyses submitted to the National Institute for Health and Clinical Excellence (NICE) by the biologic manufacturers were reviewed. An economic model was developed by updating the model produced by the York Assessment Group for the previous NICE appraisal of biologics in PsA. Results: Pooled estimates of effect demonstrated a significant improvement in patients with PsA for all joint disease and functional status outcomes at 12–14 weeks’ follow-up. The biologic treatment significantly reduced joint symptoms for etanercept [relative risk (RR) 2.60, 95% confidence interval (CI) 1.96 to 3.45], infliximab (RR 3.44, 95% CI 2.53 to 4.69) and adalimumab (RR 2.24, 95% CI 1.74 to 2.88), with 24-week data demonstrating maintained treatment effects. Trial data demonstrated a significant effect of all three biologics on skin disease at 12 or 24 weeks. Evidence synthesis found that infliximab appeared to be most effective across all outcomes of joint and skin disease. The response in joint disease was greater with etanercept than with adalimumab, whereas the response in skin disease was greater with adalimumab than with etanercept, although these differences are not statistically significant. Under base-case assumptions, etanercept was the most likely cost-effective strategy for patients with PsA and mild-to-moderate psoriasis if the threshold for cost-effectiveness was £20,000 or £30,000 per QALY. All biologics had a similar probability of being cost-effective for patients with PsA and moderate-to-severe psoriasis at a threshold of £20,000 per QALY. Limitations: Limited available efficacy data and difficulty in assessing PsA activity and its response to biologic therapy. Conclusions: The data indicated that etanercept, infliximab and adalimumab were efficacious in the treatment of PsA compared with placebo, with beneficial effects on joint symptoms, functional status and skin. Short-term data suggested that these biologic agents can delay joint disease progression and evidence to support their use in the treatment of PsA is convincing. Future research would benefit from long-term observational studies with large sample sizes of patients with PsA to demonstrate that beneficial effects are maintained, along with further monitoring of the safety profiles of the biologic agents. Funding: The National Institute for Health Research Health Technology Assessment programme.

Objectives: To evaluate the clinical effectiveness (including adverse events) and cost-effectiveness of antivirals for the treatment of naturally acquired influenza for ‘at-risk’ and otherwise healthy populations. Data sources: Eleven electronic databases (MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature, Pascal, Science Citation Index, BIOSIS, Latin American and Caribbean Health Sciences, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effects, and Health Technology Assessment Database) were searched from October 2001 to November 2007. A supplementary search was undertaken in June 2008 for information relating to drug resistance during the 2007–8 influenza season. Review methods: Systematic reviews of the evidence on the clinical effectiveness and cost-effectiveness of antivirals for the treatment of influenza were undertaken. Twenty-nine randomised controlled trials comparing antivirals with each other, placebo, or best symptomatic care were included in the evaluation of clinical effectiveness in patients presenting with an influenza-like illness (ILI). Primary outcomes were measures of symptom duration (median time to alleviation of symptoms and median time to return to normal activity). Incidence of complications, mortality, hospitalisations, antibiotic use (as a surrogate for complications) and adverse events was also assessed. In addition, an independent decision model was developed to evaluate the cost-effectiveness of antiviral treatment from the perspective of the UK NHS. Results: Amantadine was excluded at an early stage, owing to a lack of any new trials that met the inclusion criteria and the limitations of the existing evidence. The review therefore focused on the neuraminidase inhibitors (NIs) oseltamivir and zanamivir, both of which were found to be effective in reducing symptom duration (zanamavir by 0.5–1.0 days and oseltamivir by 0.5–1.5 days). However, the effect sizes were often small and unlikely to be clinically significant in many cases, particularly in healthy adults. For the at-risk subgroups, effect sizes for differences in symptom duration were generally larger, and potentially more clinically significant, than those seen in healthy adults (median duration of symptoms reduced by 1–2 days with zanamivir and 0.50–0.75 days with oseltamivir). However, there was greater uncertainty around these results, with estimates often failing to reach statistical significance. The most consistent data and strongest evidence related to antibiotic use, with both zanamivir and oseltamivir resulting in statistically significant reductions in antibiotic use. In general, the estimates from the cost-effectiveness model were more favourable in at-risk populations (including adults and children with comorbid conditions and the elderly) compared with otherwise healthy populations. Zanamivir was the optimal NI treatment in each of the at-risk populations considered, and oseltamivir was optimal for healthy populations (both adults and children). Conclusions: The clinical effectiveness data for population subgroups used to inform the multiparameter evidence synthesis and cost-effectiveness modelling were, in places, limited and this should be borne in mind when interpreting the findings of this review. Trials were often not designed to determine clinical effectiveness in population subgroups and hence, although the direction of effect was clear, estimates of differences in symptom duration tended to be subject to greater uncertainty in subgroups. Despite some concerns, the use of NIs in at-risk populations appeared to be a cost-effective approach for the treatment of influenza. Well-designed observational studies might also be considered to evaluate the clinical course of influenza in terms of complications, hospitalisation, mortality and quality of life, as well as the impact of NIs.

Abstract Gain-of-function (GOF) variants give rise to increased/novel protein functions whereas loss-of-function (LOF) variants lead to diminished protein function. Experimental approaches for identifying GOF and LOF are generally slow and costly, whilst available computational methods have not been optimized to discriminate between GOF and LOF variants. We have developed LoGoFunc, a machine learning method for predicting pathogenic GOF, pathogenic LOF, and neutral genetic variants, trained on a broad range of gene-, protein-, and variant-level features describing diverse biological characteristics. LoGoFunc outperforms other tools trained solely to predict pathogenicity for identifying pathogenic GOF and LOF variants and is available at https://itanlab.shinyapps.io/goflof/ .

Abstract Background Lipoprotein lipase (LPL) is the rate-limiting enzyme for triglyceride hydrolysis. Homozygous or compound heterozygous LPL variants cause autosomal recessive familial chylomicronemia syndrome (FCS), whereas simple heterozygous LPL variants are associated with hypertriglyceridemia (HTG) and HTG-related disorders. LPL frameshift coding sequence variants usually cause complete functional loss of the affected allele, thereby allowing exploration of the impact of different levels of LPL function in human disease. Methods All exons and flanking intronic regions of LPL were Sanger sequenced in patients with HTG-related acute pancreatitis (HTG-AP) or HTG-AP in pregnancy. Previously reported LPL frameshift coding sequence variants were collated from the Human Gene Mutation Database and through PubMed keyword searching. Original reports were manually evaluated for the following information: zygosity status of the variant, plasma LPL activity of the variant carrier, disease referred for genetic analysis, patient’s age at genetic analysis, and patient’s disease history. SpliceAI was employed to predict the potential impact of collated variants on splicing. Results Two novel rare variants were identified, and 53 known LPL frameshift coding sequence variants were collated. Of the 51 variants informative for zygosity, 30 were simple heterozygotes, 12 were homozygotes, and 9 were compound heterozygotes. Careful evaluation of the 55 variants with respect to their clinical and genetic data generated several interesting findings. First, we conclude that 6–7% residual LPL function could significantly delay the age of onset of FCS and reduce the prevalence of FCS-associated syndromes. Second, whereas a large majority of LPL frameshift coding sequence variants completely disrupt gene function through their "frameshift" nature, a small fraction of these variants may act wholly or partly as "in-frame" variants, leading to the generation of protein products with some residual LPL function. Third, we identified two candidate LPL frameshift coding sequence variants that may retain residual function based on genotype–phenotype correlation or SpliceAI-predicted data. Conclusions This study reported two novel LPL variants and yielded new insights into the genotype–phenotype relationship as it pertains to LPL frameshift coding sequence variants.

Abstract Background Lipoprotein lipase (LPL) is the key enzyme responsible for the hydrolysis of triglycerides. Loss-of-function variants in the LPL gene are associated with hypertriglyceridemia (HTG) and HTG-related diseases. Unlike nonsense, frameshift and canonical GT-AG splice site variants, a pathogenic role for clinically identified LPL missense variants should generally be confirmed by functional analysis. Herein, we describe the clinical and functional analysis of a rare LPL missense variant. Methods Chinese patients with HTG-associated acute pancreatitis (HTG-AP) were screened for rare nonsense, frameshift, missense or canonical GT-AG splice site variants in LPL and four other lipid metabolism-related genes (APOC2, APOA5, GPIHBP1 and LMF1) by Sanger sequencing. The functional consequences of the LPL missense variant of interest were characterized by in vitro expression in HEK-293T and COS-7 cells followed by Western blot and LPL activity assays. Results Five unrelated HTG-AP patients were found to be heterozygous for a rare East Asian-specific LPL missense variant, c.862G > A (p.Ala288Thr). All five patients were adult males, and all were overweight and had a long history of alcohol consumption. Transfection of LPL wild-type and c.862G > A expression vectors into two cell lines followed by Western blot analysis served to exclude the possibility that the p.Ala288Thr missense variant either impaired protein synthesis or increased protein degradation. Contrary to a previous functional study that claimed that p.Ala288Thr had a severe impact on LPL function (reportedly having 36% normal activity), our experiments consistently demonstrated that the variant had a comparatively mild effect on LPL functional activity, which was mediated through its impact upon LPL protein secretion (~ 20% reduced secretion compared to wild-type). Conclusions In this study, we identified the East Asian-specific LPL c.862G > A (p.Ala288Thr) missense variant in five unrelated HTG-AP patients. We demonstrated that this variant exerted only a relatively mild effect on LPL function in two cell lines. Heterozygosity for this LPL variant may have combined with alcohol consumption to trigger HTG-AP in these patients.

IntroductionGroup A streptococcus (GAS) infections, such as pharyngitis and impetigo, can lead to rheumatic fever and rheumatic heart disease (RHD). Australian Aboriginal and Torres Strait Islander populations experience high rates of RHD and GAS skin infection, yet rates of GAS pharyngitis are unclear. Anecdotally, clinical presentations of pharyngitis, including tonsillar hypertrophy and sore throat, are uncommon. This study aimed to develop a standardised set of tonsil photographs and determine tonsil size distribution from an urban paediatric population.MethodsA prospective cohort of children aged 3–15 years were recruited at the public events “Discover Day” and “Telethon Weekend” (October 2017) in Perth, Western Australia, Australia. Tonsil photographs, symptomatology, and GAS rapid antigen detection tests (RADT) were collected. Tonsil size was graded from the photographs using the Brodsky Grading Scale of tonsillar hypertrophy (Brodsky) by two independent clinicians, and inter-rater reliability calculated. Pharyngitis symptoms and GAS RADT were correlated, and immediate results provided.ResultsFour hundred and twenty-six healthy children participated in the study over three days. The median age was seven years [interquartile range (IQR) 5.9–9.7 years]. Tonsil photographs were collected for 92% of participants, of which 62% were rated as good-quality photographs and 79% were deemed of adequate quality for assessment by both clinicians. When scored by two independent clinicians, 57% received the same grade. Average Brodsky grades (between clinicians) were 11%, 35%, 28%, 22% and 5% of grades 0,1,2,3 and 4, respectively. There was moderate agreement in grading using photographs, and minimal to weak agreement for signs of infection. Of 394 participants, 8% reported a sore throat. Of 334 GAS RADT performed,

Abstract Analysis of circulating tumor DNA (ctDNA) to monitor cancer dynamics and detect minimal residual disease has been an area of increasing interest. Multiple methods have been proposed but few studies have compared the performance of different approaches. Here, we compare detection of ctDNA in serial plasma samples from patients with breast cancer using different tumor‐informed and tumor‐naïve assays designed to detect structural variants (SVs), single nucleotide variants (SNVs), and/or somatic copy‐number aberrations, by multiplex PCR, hybrid capture, and different depths of whole‐genome sequencing. Our results demonstrate that the ctDNA dynamics and allele fractions (AFs) were highly concordant when analyzing the same patient samples using different assays. Tumor‐informed assays showed the highest sensitivity for detection of ctDNA at low concentrations. Hybrid capture sequencing targeting between 1,347 and 7,491 tumor‐identified mutations at high depth was the most sensitive assay, detecting ctDNA down to an AF of 0.00024% (2.4 parts per million, ppm). Multiplex PCR targeting 21–47 tumor‐identified SVs per patient detected ctDNA down to 0.00047% AF (4.7 ppm) and has potential as a clinical assay.

Analyzing data from a national deidentified electronic health record-based data set using a matched case–control study design, we found that antibiotic use and severity of illness were independent risk factors for healthcare-associated candidemia in adult patients hospitalized with SARS-CoV-2 infection. Interleukin-6 inhibitor and corticosteroid use were not independent risk factors.

Abstract Objective: Social media’s arrival eased the sharing of mis- and disinformation. False information proved challenging throughout the coronavirus disease 2019 (COVID-19) pandemic with many clinicians and researchers analyzing the “infodemic.” We systemically reviewed and synthesized COVID-19 mis- and disinformation literature, identifying the prevalence and content of false information and exploring mitigation and prevention strategies. Design: We identified and analyzed publications on COVID-19-related mis- and disinformation published from March 1, 2020, to December 31, 2022, in PubMed. We performed a manual topic review of the abstracts along with automated topic modeling to organize and compare the different themes. We also conducted sentiment (ranked −3 to +3) and emotion analysis (rated as predominately happy, sad, angry, surprised, or fearful) of the abstracts. Results: We reviewed 868 peer-reviewed scientific publications of which 639 (74%) had abstracts available for automatic topic modeling and sentiment analysis. More than a third of publications described mitigation and prevention-related issues. The mean sentiment score for the publications was 0.685, and 56% of studies had a negative sentiment (fear and sadness as the most common emotions). Conclusions: Our comprehensive analysis reveals a significant proliferation of dis- and misinformation research during the COVID-19 pandemic. Our study illustrates the pivotal role of social media in amplifying false information. Research into the infodemic was characterized by negative sentiments. Combining manual and automated topic modeling provided a nuanced understanding of the complexities of COVID-19-related misinformation, highlighting themes such as the source and effect of misinformation, and strategies for mitigation and prevention.

Abstract Background: The interplay between SARS-CoV-2 and contemporaneous bacterial or fungal culture growth may have crucial implications for clinical outcomes of hospitalized patients. This study aimed to quantify the effect of microbiological culture positivity on mortality among hospitalized patients with SARS-CoV-2. Methods: In this retrospective cohort study, we included adult hospitalized patients from OPTUM COVID-19 specific data set, who tested positive for SARS-CoV-2 within 14 days of hospitalization between 01/20/2020 and 01/20/2022. We examined outcomes of individuals with organisms growing on cultures from the bloodstream infections (BSIs), urinary tract, and respiratory tract, and a composite of the three sites. We used propensity score matching on covariates included demographics, comorbidities, and hospitalization clinical parameters. In a sensitivity analysis, we included same covariates but excluded critical care variables such as length of stay, intensive care unit stays, mechanical ventilation, and extracorporeal membrane oxygenation. Results: The cohort included 104,560 SARS-CoV-2 positive adult hospitalized patients across the United States. The unadjusted mortality odds increased significantly with BSIs (98.7%) and with growth on respiratory cultures (RC) (176.6%), but not with growth on urinary cultures (UC). Adjusted analyses showed that BSIs and positive RC independently contribute to mortality, even after accounting for critical care variables. Conclusions: In SARS-CoV-2-positive hospitalized patients, positive bacterial and fungal microbiological cultures, especially BSIs and RC, are associated with an increased risk of mortality even after accounting for critical care variables associated with disease severity. These findings underscore the importance of stringent infection control and the effective management of secondary infections to improve patient outcomes.

Complementary feeding induces dramatic ecological shifts in the infant gut microbiota toward more diverse compositions and functional metabolic capacities, with potential implications for immune and metabolic health. The aim of this study was to examine whether the age at which solid foods are introduced differentially affects the microbiota in predominantly breastfed infants compared with predominantly formula-fed infants. We performed whole-genome shotgun metagenomic sequencing of infant stool samples from a cohort of six-month-old Australian infants enrolled in a nested study within the ORIGINS Project longitudinal birth cohort. Infants born preterm or those who had been administered antibiotics since birth were excluded. The taxonomic composition was highly variable among individuals at this age. Predominantly formula-fed infants exhibited a higher microbiome diversity than predominantly breastfed infants. Among the predominantly breastfed infants, the introduction of solid foods prior to five months of age was associated with higher alpha diversity than solid food introduction after six months of age, primarily due to the loss of Bifidobacterium infantis. In contrast, the age at which solid food was introduced was not associated with the overall change in diversity among predominantly formula-fed infants but was associated with compositional changes in Escherichia abundance. Examining the functional capacity of the microbiota in relation to these changes, we found that the introduction of solid foods after six months of age was associated with elevated one-carbon compound metabolic pathways in both breastfed and formula-fed infants, although the specific metabolic sub-pathways differed, likely reflecting different taxonomic compositions. Our findings suggest that the age of commencement of solid foods influences the gut microbiota composition differently in predominantly breastfed infants than in predominantly formula-fed infants.

A transparent corrections process is essential to assist in the maintenance of public confidence in scientific and medical research. In the era of preprints, fast-paced peer review, and early-access publication, errors and oversights from both authors and editors might be more common. The swift and open correction of the public record requires the participation of authors, journal editors, and publishers, and in this Viewpoint we share The Lancet group’s best practices around errors and corrections.

Abstract Background Acute pancreatitis in pregnancy (APIP) is a life‐threatening disease for both mother and fetus. To date, only three patients with recurrent hypertriglyceridemia‐induced APIP (HTG‐APIP) have been reported to carry rare variants in the lipoprotein lipase (LPL) gene, which encodes the key enzyme responsible for triglyceride (TG) metabolism. Coincidently, all three patients harbored LPL variants on both alleles and presented with complete or severe LPL deficiency. Methods The entire coding regions and splice junctions of LPL and four other TG metabolism genes (APOC2, APOA5, GPIHBP1, and LMF1) were analyzed by Sanger sequencing in a Han Chinese patient who had experienced two episodes of HTG‐APIP. The impact of a novel LPL missense variant on LPL protein expression and activity was analyzed by transient expression in HEK293T cells. Results A novel heterozygous LPL missense variant, p.His210Leu (c.629A > T), was identified in our patient. This variant did not affect protein synthesis but significantly impaired LPL secretion and completely abolished the enzymatic activity of the mutant protein. Conclusion This report describes the first identification and functional characterization of a heterozygous variant in the LPL that predisposed to recurrent HTG‐APIP. Our findings confirm a major genetic contribution to the etiology of individual predisposition to HTG‐APIP.