Nature Metabolism

Multimorbidity is highly prevalent in ageing populations, yet its shared molecular basis remains poorly defined, limiting the development of therapies that target multiple conditions. We systematically integrated measurements of 1,954 circulating proteins from 54,219 individuals in discovery and 35,559 in replication, focusing on ten common age-related diseases: coronary artery disease, chronic kidney disease, chronic obstructive pulmonary disease, dementia, heart failure, major depressive disorder, osteoarthritis, Parkinson's disease, stroke, and type 2 diabetes. Coronary artery disease emerged as a central condition in the multimorbidity network, sharing circulating protein signatures with seven other diseases. Through genetic causal-inference analyses, we identified 40 circulating proteins with cross-disease relevance, of which four were further supported by colocalization of genetic variant associations. Among these, complement C1r, encoded by C1R, emerged as a key link between coronary artery disease and dementia, supported by independent colocalization evidence (PP.H4 = 0.86). Phenome-wide association analyses of C1R variants suggested that this signal was not driven by widespread unrelated genetic effects, but instead may reflect a more specific contribution to coronary artery disease-dementia pathogenesis. In vitro experiments further suggested that fibroblast-derived C1R promotes endothelial inflammation and neuronal apoptosis, providing mechanistic plausibility. Together, these findings position C1R as a biologically plausible and therapeutically relevant molecular link between coronary artery disease and dementia.

Insulin signalling contributes to neurodevelopment and brain function, and insulin resistance (IR)-related traits are associated with cognitive performance. However, the genetic architecture shared across specific cognitive domains and IR-related phenotypes remains insufficiently defined. We analysed large-scale genome-wide association study summary statistics for 11 IR-related traits (N=53,334-933,970) and 10 cognitive measures (N=28,156-436,853) to quantify global and local genetic correlations, fine-map shared association signals, and annotate implicated genes and drug-gene interactions. Pairwise global and local genetic correlations were estimated, and shared high-confidence variants were prioritised using the multivariate Sum of Single Effects model. Positional and expression quantitative trait locus mapping was performed, and implicated genes were examined through functional annotation, tissue enrichment, and drug-gene interaction analyses. Low-to-moderate genetic correlations were observed between six IR-related traits and seven cognitive measures (|rg|=0.08-0.34), with predominantly opposite directions, except for correlations involving visual declarative short-term memory. Local genetic correlations showed mixed effect directions across most trait pairs, and multivariate fine-mapping prioritised 696 shared likely causal variants with high posterior support. Gene annotation indicated enrichment in several pathways, including immune-related, signal transduction, neurogenesis, neurotransmitter metabolism, receptor regulation, and lipid and cholesterol metabolism regulation. Implicated genes were expressed across various brain regions and showed prior associations with neuropsychiatric and cardiometabolic conditions. Several drug-gene interactions were identified, involving immunomodulatory and anti-inflammatory compounds. These findings indicate widespread heterogeneous genetic overlap between IR-related traits, particularly body mass index and waist-to-hip ratio, and cognitive measures of general intelligence, processing speed, and short-term visual declarative memory. The findings prioritise apolipoprotein-related lipid transport and inflammatory and oxidative stress pathways as candidate mechanisms linking cognitive, cardiometabolic, and neuropsychiatric phenotypes.

While extensive cellular heterogeneity in renal cell carcinomas (RCC) is linked to diverse clinical outcomes, our understanding of this diversity is limited to those driven by clonal patterns or activity of canonical pathways. Here, we present a compendium of over 85,000 single-cell gene expression profiles from primary and metastatic tumors as well as patient-derived models across four RCC subtypes, including the rare clear cell papillary renal cell tumors, which we show are often misclassified and for which we identify CASP14 as a highly sensitive and specific biomarker. We dissect malignant cell variation within and across tumors using a generative modeling framework that accounts for clonal and copy number-driven expression shifts, defining 59 gene expression programs that deconstruct canonical pathways into functional submodules with divergent activity patterns, distinct regulators, and differential association with clinical outcomes. Despite the canonical view that VHL-deficient clear cell RCC exists in a constitutive pseudohypoxic state, we show strong intra-tumor variability of a hypoxia inducible factor 2 (HIF2)-driven program linked to poor outcome. We also identify early, spatially organized activation of a complete epithelial-to-mesenchymal transition (EMT) program, loss of epithelial identity, and upregulation of protein translation programs as key characteristics of metastatic progression. Finally, a metastatic signature capturing cellular de-differentiation and translational activity identifies primary tumors associated with adverse clinical outcomes. Together, this resource establishes a framework for dissecting malignant cell heterogeneity, refines RCC subtype classification, and defines transcriptional programs underlying metastasis progression.

This review evaluates the biological pathways linking soft drink consumption with the risk of several cancers within the framework of the Global Cancer Update Programme (CUP Global). Soft drink consumption has been associated with increased risk of multiple cancers, and glucose or insulin dysregulation has been proposed as a potential underlying mechanism. We applied a three-stage framework. In the first stage, we identified insulin sensitivity as the key biological process potentially linking soft drink consumption (sugar-sweetened or artificially sweetened) to cancer risk, with glucose-related and insulin-related biomarkers as potential intermediate phenotypes, using a combination of expert knowledge and a web-based text mining tool. In the second stage, we conducted targeted PubMed searches to identify studies examining associations between consumption of soft drinks and these intermediate phenotypes (IPs) and between these IPs and the risk of several cancers in adult humans. In the third stage, the evidence was evaluated by the Expert Committee on Cancer Mechanisms (MEC), who assessed the strength of the evidence for these associations. The MEC concluded that there was weak evidence supporting a role of glucose or insulin-related processes as a potential mechanistic pathway linking the consumption of sugar-sweetened or artificially sweetened beverages to the risk of various cancers evaluated.

Somatic copy-number amplification is pervasive in cancer, and the genes it carries are candidate drug targets - but only those whose amplification is transmitted to accessible surface protein can be reached by an antibody-drug conjugate (ADC). We build an integrated map of copy-number-to-protein transmission across six tumour types and ask, for every amplified gene, whether its dosage reaches the surface. Copy number transmits to mRNA (median per-gene r = 0.21) but is attenuated at the protein level in 85% of genes, and the mRNA ranking is largely preserved to protein (rho = 0.70); the ranking is set principally at the chromatin/transcription step - among directly measured regulatory inputs, promoter DNA methylation and tumour chromatin accessibility each explain about an order of magnitude more of the transmission variance than gene structure, and do so complementarily. Critically, transmissibility is a stable, gene-intrinsic property: it is predictable from gene properties alone, with no proteomic input, at a leave-gene-out rank correlation of 0.52 (R2 = 0.29); it is not positional (holding out whole chromosome arms changes accuracy by 0.001); and it transfers across lineages (Kendall W = 0.97 across leave-one-lineage-out refits). This licenses a predictor that nominates surface targets in cancer types that lack a tissue-referenced proteome, combining direct protein measurement where it is available with prediction where it is not. Requiring co-elevation on a recurrent amplicon with measured transmissibility and an accessible extracellular ectodomain nominates 22 surface antigens on 18 distinct recurrent amplicons across four cancer types (renal, endometrial and both lung subtypes) - for example ITGB8+TSPAN13+TTYH3 on lung 7p, NCSTN+HSD17B7+MPZL1 on 1q (recurrent in several types), the transferrin receptor TFRC on squamous 3q, and FZD1 on clear-cell renal 7q; 21 of the 22 are non-driver passengers and 10 are confirmed on the experimental Cell Surface Protein Atlas. In single malignant cells, against a null that controls for per-cell sequencing depth, the co-detected constructs sit at a modest 1.05-1.45x above independence (p < 0.001, donor-block bootstrap intervals clear of 1.0), and at binding-relevant thresholds the normal-tissue co-expression collapses - so an avidity AND-gate that binds stably only where the antigens co-occur would spare normal cells that carry only one. Observed transmissibility itself transfers strongly between the two lung subtypes ({rho} = 0.88) and remains positive across distant lineages, consistent with the shared cell-of-origin regulation the map implies. Single-cell co-detection is demonstrated wherever a malignant single-cell atlas exists (both lung subtypes and glioblastoma - the latter entirely from prediction, using no GBM surface-abundance measurement); the remaining cohorts are nominated on the same genetic and topological evidence. The result is a pan-cancer, confidence-tiered catalogue of multi-antigen ADC co-target sets with a concrete plan to test them.

Dementia is a progressive condition that impairs cognitive processes such as memory, decision making, and the ability to manage daily activities. Recent estimates suggest that more than half of all dementia cases could be preventable by addressing their risk factors, including disease comorbidities such as diabetes and vision loss. Yet, we lack a comprehensive molecular map of dementia comorbidities. In this work, we analyzed Austrian nationwide hospital claims data, comprising 13 million hospital stays from 2015 to 2019, to systematically assess dementia-related risk across disease comorbidity patterns, covering both their molecular relationships and their epidemiological overrepresentation. We identified disease trajectories occurring before and at the time of dementia diagnosis, revealing both sex-specific and shared comorbidity patterns. Overall, we identified 51 potential risk factors, with a prominent contribution from endocrine and metabolic disorders. While Parkinson's disease emerged as a strong molecularly related driver of dementia, we also identified emerging and previously under chracterized risk factors, including vitamin D deficiency. This integrative framework provides a comprehensive view of dementia associated disease networks and identifies novel, potentially modifiable risk factors. These results offer new opportunities for targeted prevention strategies and advance our understanding of the complex interplay between comorbidities and dementia development.

Background: Childhood obesity is a prevalent public health concern, particularly among children from marginalized backgrounds. Epigenomic mechanisms, including DNA methylation (DNAm), offer insight into the biological embedding of metabolic risk, yet protective family-level factors remain understudied. This study examined whether participation in a positive parenting intervention was associated with reduced epigenetic cardiometabolic risk among preschool-aged children. Methods: Participants were 74 children (n = 35 intervention; n = 39 services-as-usual; mean age = 36 months). Using a secondary analysis of a randomized controlled trial, DNAm-derived body mass index (BMI) and anthropometric BMI were assessed at baseline and 12-month follow-up, and parenting practices were observed post-treatment. Results: Children in the intervention group demonstrated significantly lower DNAm BMI at 12 months relative to controls, adjusting for child sex, race and/or ethnicity, and anthropometric BMI. No treatment effect was observed for anthropometric BMI, and DNAm BMI was not associated with anthropometric BMI at 12 months. Although parenting practices improved, they did not mediate intervention effects on DNAm-derived BMI. Conclusions: Parenting interventions may influence biological pathways related to cardiometabolic risk, even before changes in anthropometric outcomes, underscoring the potential of family-centered approaches to promote early metabolic health.

Insulin resistance, an often-untreated precursor of type 2 diabetes mellitus (T2DM), is implicated in cognitive decline in adults, yet its impact on the developing brain in youth with obesity remains poorly understood. We investigate whether insulin resistance moderates the relation between hippocampal volume and unhealthy food-seeking in overweight and depressed youth ages 9-17 who completed an oral glucose tolerance test and a cognitive task assessing unhealthy food-seeking motivation at baseline, 6-, and 24-months follow-up, and structural MRI at baseline and 6-months follow-up. Insulin sensitivity moderated this relation: smaller baseline hippocampal subfield volumes predicted increased unhealthy food-seeking over 24 months (ps<0.05). Categorical grouping revealed subfield CA2/3 and 4 volumes predicted this relation among insulin-resistant (ps<0.05), but not insulin-sensitive (ps>0.10), youth, suggesting that threshold criteria for insulin resistance are physiologically meaningful. These findings identify a neuro-metabolic risk phenotype that precedes T2DM and may accelerate unhealthy food-seeking severity in youth with obesity.

CRISPR-Cas12a nucleases are classically activated through CRISPR RNA (crRNA) guided and PAM-dependent target recognition, which together establish a canonical heteroduplex associated with nuclease activation. Here we identify a crRNA- and PAM-independent activation pathway for Cas12a that reveals previously unrecognized conformational plasticity within its nucleic acid recognition interface. We show that short RNAs can directly occupy the canonical crRNA-binding channel and trigger a catalytically competent trans cleavage state in the absence of PAM recognition or canonical R-loop formation. Biochemical assays indicate that short RNAs bind the crRNA-binding channel and are competitively displaced by cognate crRNA, consistent with binding at a conserved nucleic acid-binding interface. Cryo-electron microscopy (cryo-EM) further reveals that Cas12a maintains its global catalytic architecture while exhibiting loss of canonical PAM-dependent stabilization and increased flexibility of the RuvC lid, alongside accommodation of a noncanonical RNA-DNA hybrid with inverted polarity relative to the crRNA-target duplex. This crRNA-independent activation pathway enables programmable, amplification-free detection of DNA and RNA targets independent of canonical guide-mediated recognition. Together, these findings define an alternative activation geometry for Cas12a and expand models of Class 2 CRISPR-Cas effector activation beyond crRNA- and PAM-directed recognition.

Objectives: We tested how multi-level socioeconomic disadvantage relates to biological aging and systemic inflammation in women and men from the population-based Canadian Longitudinal Study on Aging (CLSA). Methods: We examined cross-sectional data from 8,516 CLSA participants with baseline measures on systemic inflammatory biomarkers (C-reactive protein, interleukin-6, and tumoral necrosis factor-) and biological aging (metabolomic and six DNA methylation [DNAm] age estimates). Plasma samples underwent metabolomic profiling by Metabolon, Inc. Metabolomic age was estimated separately in males and females using sex-stratified models based on age-correlated metabolite levels. DNAm data generated using the Illumina Infinium MethylationEPIC v1.0 array were used to estimate DNAm age across six established models, including Horvath, Hannum, PhenoAge, GrimAge, GrimAge2, and DunedinPACE. We used log-transformed metabolite levels to calculate metabolomic age by sex. We linked education, income, material and social deprivation to biomarkers of systemic inflammation and biological aging stratified by sex using generalized linear models. Multivariable models were adjusted by age, major behavioral risk factors, and chronic conditions. Results: Participants were aged on average of 62.6 years of age, and approximately 50% were females. In multivariable linear adjusted models, we found that in comparison to those earning [&ge;]$100K a year, women earning less <$20K were on average 1.14 (95%CI: 0.46, 1.82) year older with respect to metabolomic age; those earning [&ge;]$20K & <$50K were on average 0.90 (95%CI: 0.26, 1.53) years older; and those earning [&ge;]$50K & <$100K were on average 0.70 (95%CI: 0.05, 1.34) years older. We did not observe this dose response among men. A similar dose-response association was observed for interleukin-6 in both men and women. Discussion: These findings suggest that socioeconomic adversity influences not only inflammatory pathways but also distinct biological aging processes, including metabolomic aging.

The insulin-like growth factor (IGF)/IGF-binding protein (IGFBP) axis has been implicated in diabetes mellitus and the associated burden of cardiovascular complications. Higher circulating levels of IGFBP-1 and IGFBP-2 have been established as markers of protection from incident type 2 diabetes, yet their associations with cardiovascular disease remain unclear. Utilising the UK Biobank (UKB) resource to integrate disease outcomes, plasma proteomics and MRI data, we examined associations of IGFBP-1 and IGFBP-2 with incident diabetes and cardiovascular disease. Approximately 50,000 UKB participants with plasma proteomic measurements for IGFBP-1 and IGFBP-2 were included. Multivariate Cox regression models revealed that participants in the highest quartiles of IGFBP-1 and IGFBP-2 had a substantially lower risk of incident diabetes (hazard ratio (HR) = 0.31 and 0.32 respectively), but, paradoxically, had increased risks of incident macrovascular disease, all-cause and cardiovascular-related mortality (HR = 1.81 and 2.39). Both proteins were negatively associated with HbA1c levels, triglyceride/HDL ratio and abdominal adiposity, yet positively associated with NT-proBNP, troponin I, cardiac chamber size and aortic dimensions. In summary, negative associations of IGFBP-1 and IGFBP-2 with incident diabetes mellitus did not translate to a reduced cardiovascular risk, suggesting potentially complex actions of IGFBP-1 and IGFBP-2 in the pathophysiology of cardiometabolic disease.

Prenatal alcohol exposure (PAE) is a major cause of neurodevelopmental disorders, yet most children are diagnosed late or misdiagnosed. Neuroplacentology suggest that placental factors released into maternal and/or umbilical cord blood contribute to fetal brain development. Consistently, a preclinical inter-organ transcriptomic database revealed that PAE disrupts the expression ratio of angiogenic and inflammatory factors suggesting an angio-inflammatory response. This study aimed i) to assay, by multiplex immunoassay, angiogenic and inflammatory factors in maternal and umbilical cord blood from alcohol-consuming women and ii) to perform a maternofetal analysis according to neonatal sex. Afterwards, dysregulated factors from mothers who gave birth to females or males were submitted to STRING and ShinyGO analyses. Results showed that PAE differently altered the distribution profiles of dysregulated angiogenic and inflammatory factors in maternal and umbilical cord blood. Moreover, sex-specific differences were observed, with 36% of dysregulated proteins specific to males, 48% to females, and 16% common to both. STRING analysis revealed robust functional protein-protein interactions linking together inflammatory and angiogenic clusters while the ShinyGO analysis identified enriched pathways related to vascular shear stress. These findings provide the first maternofetal analysis of combined angiogenic and inflammatory factors from alcohol-consuming mothers.

Background The 2022-2023 global mpox outbreak highlighted the critical need for robust genomic surveillance capabilities to track mpox virus (MPXV) evolution and transmission dynamics. Methods Building upon our established SARS-CoV-2 sequencing infrastructure, we implemented a Molecular Loop probe-based long-read sequencing approach using Pacific Biosciences Sequel II technology for comprehensive MPXV genomic surveillance across the United States (US). From August 2024 to June 2025, we generated 326 high-quality whole genome sequences from residual mpox-positive clinical specimens collected by Labcorp across all 10 US Department of Health and Human Services regions. Results Our analysis identified two samples containing clade Ib MPXV in January and June 2025 and captured shifting trends in clade IIb diversity, with 13 distinct lineages observed. We also identified multiple instances of large (~1.6-17.6kb) deletions proximal to the inverted terminal repeats in clade IIb genomes. APOBEC3 mutation analysis indicated substantial evidence of human-to-human transmission among both clades. Further, we observed significantly higher APOBEC3-associated SNPs per kilobase (P<0.001) in clade IIb genomic variable regions relative to their central conserved region. Our assay exhibited strong reproducibility across biological replicates from individual patients and accuracy was confirmed via parallel sequencing of select specimens by US Centers for Disease Control and Prevention (CDC) using metagenomic sequencing. We also demonstrated via custom simulation that our assay discriminates all known MPXV clades and lineages, including those we have not observed in the US. Conclusions Our integrated nationwide surveillance system facilitates real-time genomic tracking of outbreak evolution, with demonstrated capacity across SARS-CoV-2 and MPXV, positioning this platform for rapid deployment during future pathogen emergence.

Estimating dengue force of infection (FOI) is essential for understanding transmission dynamics and targeting intervention programmes, yet surveillance data in endemic settings required for estimations are often incomplete, with varying formats. We developed a Bayesian hierarchical catalytic model that jointly fits age-stratified case data, aggregate case data, and seroprevalence surveys within a single framework, incorporating external covariates to improve parameter identifiability. Synthetic validation showed that covariates alone recovered accurate FOI point estimates even when most districts contributed only aggregate data, but did so with poorly calibrated uncertainty; anchoring the model with a single seroprevalence survey was necessary to bring credible interval coverage close to nominal. Applied to 128 districts across Java and Bali, Indonesia (2016-2024), the model revealed substantial spatial heterogeneity in FOI and reporting rates. Many districts in Java exceeded the WHO-suggested seroprevalence threshold for vaccine introduction, yet were classified as low-priority when using reported incidence as prioritisation criterion, particularly in areas with weak surveillance. Model-based seroprevalence estimation, integrating multiple data sources, offers a more consistent basis for identifying high-priority districts for vaccine introduction, and is less susceptible to surveillance bias than reported incidence.

Background: Monoclonal antibodies have emerged as a prophylactic strategy to prevent symptomatic SARS-CoV-2 infection in immunocompromised individuals. However, the evolutionary and clinical implications of breakthrough infections under this regime remain unclear. Methods: A male in their 80s with a haematological/oncological diagnosis received a 2000 mg intravenous infusion of sotrovimab in March 2023 and was diagnosed with COVID-19 by RT-qPCR from a nasopharyngeal swab in August 2023. Weekly samples (n=24) were collected through February 2024 (171 days). All samples underwent whole-genome sequencing, with select mutations subjected to functional assessment. Findings: Sequencing identified the GE.1 lineage at all timepoints. An intra-host recombination event in ORF1ab (positions 8942-12458) was detected prior to 23 weeks post-detection, followed by a 14-fold increase in viral load (7.42e+06 to 1.00e+08 RNA copies/mL) and a marked shift in the viral population. E340D, a sotrovimab resistance mutation, was detected at low abundance (46%) within the first week post-infection, fluctuated over time, and was nearly fixed by week 15 (107 days) post-detection. We assessed five spike mutations - V36M, S98F, and V213G in the N-terminal domain, Y505P in the receptor-binding domain, and P681Q near the S1/S2 cleavage site - and additionally evaluated the impact of E340D. V36M conferred the highest infectivity across all cell lines, with the most significant effect in low-TMPRSS2 cells. While all mutations showed enhanced infectivity with the addition of E340D, the effect was most pronounced in mutations with lower baseline infectivity. The addition of E340D significantly decreased relative neutralizing titres for V36M, S98F, and V213G, enabling escape from neutralizing antibodies in XBB-responsive individuals, illustrating an enhanced phenotypic advantage. Patient neutralizing activity was absent pre-sotrovimab, and sotrovimab-induced neutralization was further compromised by selection of E340D. Interpretation: Sotrovimab pre-exposure prophylaxis in an immunocompromised patient did not prevent SARS-CoV-2 infection, and selected for resistant mutation E340D, with unexpected fitness consequences across non-receptor binding domain spike regions.

Background: Opioid use disorder (OUD) is heritable, yet most genome-wide association studies (GWAS) have focused on European populations, leaving the genetic architecture of OUD in non-European populations underexplored. Methods: We conducted GWAS of OUD across three ancestries using electronic health records and genomic data from 52,357 All of Us Research Program participants (8,912 cases; 43,445 matched opioid-exposed controls; 48.5% female). Participants were stratified into European (EUR), African (AFR), and Admixed American (AMR) ancestry groups for logistic regression GWAS, with independent replication in the Million Veteran Program. We then applied the deep-learning model AlphaGenome to predict the tissue-specific transcriptomic and splicing consequences of top risk variants across 13 reward-pathway brain regions. Results: We identified and replicated a novel DDX6 risk locus, alongside established OPRM1 and FURIN signals. AlphaGenome predicted the DDX6 regulatory allele downregulates the stress-resistance gene FOXR1 in the nucleus accumbens, while the protective OPRM1 variant (rs1799971) upregulates OPRM1 expression across reward networks. Other signals of interest included IL6R and SHISA9 (EUR); GHR (AFR); and ASTN2 (AMR). Conclusions: This study identifies DDX6 as a novel OUD risk locus, replicates associations with OPRM1 and FURIN, and highlights biologically plausible ancestry-specific signals in AFR and AMR populations. We also replicated top variants in an independent population. Finally, integrating GWAS with deep-learning annotations provides specific, localized biological hypotheses to guide future experimental validation and targeted therapeutics.

Stochastic epidemic models are a cornerstone of infectious disease epidemiology and are often used to study intervention scenarios. However, large run-to-run variability can make intervention effects difficult to estimate precisely. We revisit the epidemic Sellke construction, which assigns each individual an infection threshold for the cumulative infection hazard such that, conditional on the thresholds, the epidemic trajectory becomes deterministic. This enables coupling of simulations with and without an intervention, yielding low-variance effect estimates even when outcomes such as final size or peak incidence vary widely between runs. We develop an exact, event-driven implementation that maintains infection and recovery events in priority queues. Cumulative infection-hazard updates require O(log N) time per event, yielding overall complexity O(Elog N) for E events in a population of size N. The implementation achieves computational performance comparable to the classical Gillespie algorithm while naturally accommodating non-Markovian infectious periods and complex infectiousness profiles. We illustrate the approach using distance-dependent spread of avian influenza between poultry farms in the Netherlands and a multilayer population with households, schools, and workplaces. In both examples, coupling enables efficient within-run comparisons of intervention scenarios across stochastic realisations.

Objective: There is a bidirectional relationship between emotional distress and pain. However, this relationship is understudied in people with HIV in low-resource settings. This study sought to describe the temporal relationship between emotional distress and pain in people with HIV. Design: Longitudinal observational study. Methods: Participants with virally suppressed HIV, reporting either no pain or persistent pain at baseline, provided weekly remote ratings of distress, worst pain, and average pain using 0-10 visual analogue scales. Within-individual fluctuations in distress and pain were visualised over time. Group-level correlations were determined using Spearman's correlation tests. Cumulative link mixed models assessed whether distress and pain each predicted the other in the following week. Results: 72 participants provided responses over 49 weeks. The participants had a median (IQR) age of 43 (37-51) years, 63% (n=45) were unemployed and most were females (n=51;71%). Distress and pain fluctuated concurrently within individuals: distress was positively correlated with worst pain ({rho}=0.66, 95% CI= 0.60-0.72, p<0.001) and average pain ({rho}=0.70, 95% CI=0.64-0.75, p<0.001) intensity within the same week. Worst pain (OR=1.42, 95% CI=1.17-1.71, p<0.001) and average pain (OR=1.43, 95% CI=1.20-1.71, p<0.001) intensity both predicted distress in the next week. Distress predicted worst pain intensity (OR=1.25, 95% CI=1.07-1.46, p=0.023) but not average pain intensity (OR=1.19, 95% CI=1.01-1.40, p=0.152) in the next week. Conclusions: The temporal relationship between distress and worst pain intensity was bidirectional, whereas distress did not temporally predict average pain intensity. Both pain and emotional distress should receive attention from HIV research and clinical care in low-resource settings.

Background: Children born prematurely (before 37 weeks) or admitted to the neonatal unit (NNU) are at increased risk of adverse long-term physical health outcomes. It is also recognised that there is an association with later academic performance and special educational needs, however it is not clear whether these broad risk factors could be used as stand-alone heuristics to identify children who may benefit from additional support in educational settings. We aimed to examine the associations between neonatal unit (NNU) admission and educational attainment in mid-childhood. Methods and Findings: Pregnancy data from a prospective birth cohort (Pregnancy Outcome Prediction Study, Cambridge, United Kingdom, 2008-2012) were linked to national educational outcomes (Department for Education, United Kingdom). Multivariable regression models adjusted for maternal, child, and socioeconomic factors were used to evaluate associations between (i) all NNU admissions, (ii) at term NNU admissions >48 hours, (iii) preterm birth without ongoing physical health needs, and educational outcomes at ages 5-11 years. Children who required any NNU care were more likely not to meet expected educational standards across multiple ages and domains in early and mid-childhood: age 5 early year foundation (aOR 1.64, 95% CI 1.19-2.27, p=0.003), phonics at age 6 (aOR 2.43, 95% CI 1.72-3.57, p<0.001), and at age 7 (here assessments were divided into multiple domains): reading (aOR 1.67, 95% CI 1.18-2.38, p=0.004), writing (aOR 1.72, 95% CI 1.25-2.38, p<0.001), mathematics (aOR 1.56, 95% CI 1.09-2.22, p=0.020), and science (aOR 1.85, 95% CI 1.22-2.78, p=0.003). Similar patterns were observed among both at term-born infants who stayed >48hrs in NNU (phonics assessment at age 6 aOR 2.26, 95% CI 1.51-3.36, p<0.001) and in children born preterm without long-term physical health sequelae (phonics assessment at age 6 aOR 3.07, 95% CI 1.96-4.81, p<0.001). These associations were robust to adjustment for demographic, perinatal, and socio-economic factors. By age 11, differences in academic attainment were attenuated and no longer clearly distinguishable across all exposure groups. However, there was an increased likelihood of special educational needs (SEN) at age 11 associated with any NNU admission (aOR 1.78, 95% CI 1.15-2.73, p=0.009), at term NNU admission for >48hrs (aOR 1.88, 95% CI 1.19-3.00, p=0.007), and children born preterm without long-term physical health sequelae (aOR 1.50, 95% CI 1.00-2.25, p=0.049). Predictive performance of any NNU admission for SEN at age 11 was moderate (AUC 0.70, 95% CI: 1.14-2.65, p=0.010), with balanced sensitivity and specificity and high negative predictive value. Conclusions: NNU admission, for both term and preterm infants, is associated with poorer educational outcomes and an increased likelihood of special educational needs in mid-childhood.

Background Post-infection conditions (PICs), such as Long Covid, are associated with heterogeneous, fluctuating symptoms that profoundly affect daily functioning. Despite moderate-certainty evidence from the NIHR-funded LISTEN trial (COV-LT2-0009) that personalised self management support improves outcomes and may reduce societal and economic impacts of Long Covid, many people living with PICs still receive condition-specific services, generic advice, or stand-alone digital tools that do not address their complex needs. Aim To map care approaches in general practice and synthesise UK evidence for PIC management. Design and setting Scoping review and online survey. Method A two-phase study was conducted: (1) a scoping review of UK evidence on PIC management in general practice; and (2) a supplementary online survey of practitioners working in UK general practice to provide contextual insights. Results The scoping review identified 32 studies focused on Long Covid. One study included a comparator group (ME/CFS). Study populations were predominantly white ethnicity and female. Evidence for non-Covid PICs in UK general practice was largely absent. The supplementary survey (n=46) provided preliminary practice-level insights. Healthcare practitioners reported varied PIC presentations, diagnostic uncertainty, limited referral pathways, inequitable access, and low confidence in managing PICs. Conclusion Evidence informing PIC management in UK general practice remains predominantly Long Covid-focused and may not reflect the range of PICs encountered in practice. While survey findings are preliminary and require confirmation in larger samples, they highlight uncertainty around PIC management. Further research is needed to evaluate whether existing Long Covid pathways should be expanded or complemented by broader PIC models. Keywords general practice; Long Covid; self-management; post-viral syndromes