AI News Archive: August 14, 2026 — Part 13
Sourced from 500+ daily AI sources, scored by relevance.
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- AI4Loop: an Artificial Intelligence Framework Reveals Increased 3D Chromatin Interactions and Therapeutic Vulnerabilities across 12,000 Cancer Samples
Three-dimensional chromatin interactions shape gene regulation, but their large-scale analysis remains limited by the cost and complexity of experimental assays. Here we present AI4Loop, a deep learning framework that infers genome-wide gene-centered chromatin interaction networks directly from RNA-seq data. Across multiple cell types, AI4Loop recovered interaction patterns consistent with clinical samples and orthogonal chromatin conformation datasets. Applied to 12,347 transcriptomes from 32 cancer types, AI4Loop revealed pervasive increases in gene-centered chromatin interactions in tumors, particularly at oncogene-associated loci. These inferred interaction networks outperformed gene expression alone in cancer classification. Integration with more than 50,000 drug-treated transcriptomes identified compounds predicted to reverse cancer-associated interaction gains. Hi-C experiments confirmed that the oxazolidinone antibiotics eperezolid and radezolid reduce breast cancer-gain chromatin interactions. Together, these results identify increased gene-centered chromatin interactions as a pan-cancer feature and provide a scalable strategy for linking 3D genome dysregulation to therapeutic vulnerabilities.
- SpatialMOC: Accurate reconstruction of spatial multi-omics landscapes through cross-modality prediction
Spatial multi-omics technologies provide unprecedented opportunities to characterize tissue organization by measuring complementary molecular layers within their native spatial context. However, simultaneous profiling of multiple molecular modalities remains technically challenging, limiting the widespread application of spatial multi-omics and leaving most studies reliant on single-modality measurements. Here, we present SpatialMOC, a computational framework that reconstructs missing spatial molecular modalities by integrating spatial context with cross-modality representation learning. Across multiple tissues, molecular modalities, developmental stages, sequencing platforms, and degraded datasets, SpatialMOC consistently outperformed existing computational approaches in bidirectional molecular prediction. Beyond accurate prediction, SpatialMOC faithfully reconstructed tissue architecture, preserved dynamic molecular and regulatory heterogeneity, and recovered biologically meaningful spatial landscapes from technically compromised measurements. Together, these results establish SpatialMOC as a general framework for spatial multi-omics reconstruction, extending the analytical value of existing spatial omics datasets and facilitating comprehensive investigations of tissue organization, development, and disease.
- A leakage-controlled benchmark shows apparent codon-language-model advantages in synonymous-variant prediction are evaluation artifacts
Synonymous codon choices shape mRNA stability, translation, and folding, and codon language models (cLMs) are increasingly reported to read this biology from sequence. However, when a true signal is thin relative to a confounding one, standard evaluation protocols can manufacture the reported gain rather than measure it, and we show this is what has happened for cLMs on synonymous-variant prediction. Under random splits, the codon advantage is large: tokenization gaps of +2.3~14.3 percentage points (pp) and pretrained codon leads of +8.0 pp over the strongest protein model (ESM-1b) and up to +10.0 pp over ESM-2. We find these numbers are properties of the measurement, not the models. A memorization baseline outscores every neural model; the advantage collapses under gene-held-out evaluation; the sole surviving residual dissolves into six defensible probe defaults; and the synonym-randomization drop that appeared to confirm true signal is itself variance under pooled analysis (0.3 pp, p = 0.49). No advantage survives leakage-controlled evaluation with pooled statistics. We release CodonBench, a leakage-controlled benchmark with an emergent audit cascade, and characterize how artifacts accumulate at every pipeline step. A thin signal (I({sigma};Y|A) {approx} 0.04 bits) may exist but is not reliably detectable at current sample sizes; we specify what detecting it would require.
- Topographic-prognostic gradients of cortical hypometabolism in temporal lobe epilepsy
Abstract Anterior temporal lobectomy (ATL) remains the standard surgical treatment for pharmacoresistant temporal lobe epilepsy (TLE), yet long-term seizure freedom remains suboptimal. Neuroimaging studies show neocortical metabolic abnormalities beyond the mesiotemporal epicentre, but how such patterns inform resection extent remains unclear. We hypothesized that neocortical hypometabolism in TLE follows a quantifiable spatial gradient that can be translated into personalized surgical strategies. Our multicentre study included 358 participants across discovery, validation, and sensitivity analyses. Multimodal MRI and FDG-PET data were processed to derive vertex-wise structural, intensity, and metabolic features. Individual metabolic abnormalities were quantified using a normative asymmetry modelling approach. In the discovery cohort (227 patients undergoing ATL and 37 healthy controls), we characterized the topography of neocortical hypometabolism, and evaluated its correspondence to cytoarchitectural profiles, multimodal MRI features, and hippocampal measures. Three gradient-informed surgical metrics were evaluated in relation to seizure outcomes, with replication in an independent prospective validation cohort of 38 patients undergoing ATL. An additional sensitivity cohort comprising 56 surgical candidates, whose procedure spared the temporal neocortex was included to assess the robustness. Neocortical hypometabolism in TLE followed a spatially organized gradient, with the most severe hypometabolism at the hippocampal-neocortical interface that diminished with increasing geodesic distance (r = 0.955, Pperm < 0.001). Regions closer to the interface exhibited lower cytoarchitectonic differentiation and stronger FLAIR-related alterations. Hippocampal abnormalities also showed distance-dependent coupling with neocortical metabolism (r = 0.871, Pperm < 0.001). Among surgical metrics, greater resection of severe hypometabolism was associated with seizure freedom (OR = 1.448, P = 0.022). The association was replicated in the validation cohort. The present study identified a hypometabolic gradient in TLE, which covaries with cytoarchitectonic organization, microstructural changes, and hippocampal-neocortical interactions. The gradient provides a biologically grounded framework for precise surgical planning, emphasizing that targeting severe hypometabolism may optimize prognosis.
- NeuroMorph: A Unified Morphological Reference Space for Cross-Disease Brain Profiling
Structural MRI is routinely acquired in clinical practice, yet quantitative morphometry has had limited impact on clinical decision-making. Overlapping symptoms, trajectories and comorbidities remain difficult to interpret within disease-specific frameworks, leaving it unclear how individual patients relate to the broader organization of brain disease. Here, we construct a cross-disease morphological reference space from 110,591 T1w MRI scans of 78,794 participants, spanning four disease families, 19 diagnoses, and seven subtypes. To construct this space, we developed NeuroMorph, an AI framework deriving thirteen interpretable morphological descriptors and individual normative deviation profiles. The reference space reveals shared and distinct morphological signatures that distinguish conditions within a hierarchy of disease families, diagnoses, subtypes and individual profiles. It identifies overlapping and comorbid morphological profiles and captures longitudinal deviations that precede clinical diagnosis and track progression. Together, these findings establish a unified framework for mapping brain disease organization and positioning individual patients within its morphological landscape.
- Dual-phase vessel wall MRI deep learning for identifying composite unstable intracranial aneurysm phenotypes: a multicenter study
Objectives: To develop and externally validate a wall-focused deep learning framework for identifying composite unstable intracranial aneurysm phenotypes on dual-phase high-resolution vessel wall imaging (HR-VWI), and to visualize model attention on the aneurysm wall surface. Methods: This retrospective multicenter study included patients with intracranial aneurysms who underwent both non-contrast and contrast-enhanced HR-VWI. Center 1 was used for model development and patient-level five-fold out-of-fold assessment, whereas Centers 2 and 3 served as independent external validation cohorts. For each aneurysm, dual-phase local wall patches and larger spatial context patches were generated. The Wall-Constrained Encoding Network (WCE-Net) extracted mask-constrained local wall features, and a transfer-learning U-Net with Nested Transformers (UNesT) branch extracted spatial context information. Branch outputs were fused by logit-level stacking. Model performance was evaluated using discrimination, calibration, and decision curve analysis. Three-dimensional gradient-weighted class activation mapping (Grad-CAM) responses were projected onto the reconstructed aneurysm wall surface and compared with HR-VWI surface signal intensity. Results: A total of 629 patients with 773 aneurysms were included. The final fusion model achieved areas under the receiver operating characteristic curves (AUCs) of 0.908, 0.857, and 0.855 in Center 1, external Center 2, and external Center 3, respectively. Corresponding Brier scores were 0.119, 0.153, and 0.150. Surface Grad-CAM showed partial spatial overlap between model-attention hotspots and high-signal HR-VWI regions. Conclusions: Dual-phase wall-focused local-context fusion showed feasibility for identifying composite unstable intracranial aneurysm phenotypes across centers. Surface Grad-CAM provided anatomically referenced visualization of model attention.
- Modifiable Contributors to Socioeconomic Inequality in Brain Aging
Importance Socioeconomic disadvantage is associated with accelerated brain aging. However, the modifiable factors accounting for this association, and whether they differ across socioeconomic indicators, remains unclear. Objective To determine whether modifiable risk factors account for socioeconomic differences in the brain age gap, and whether the contributions of these risk factors differ between individual-level and area-level socioeconomic indicators. Design, Setting, and Participants This cohort study used data from participants in the UK Biobank, a population-based cohort recruited at ages 40 to 70 years from 2006 to 2010. Participants with T1-weighted and T2-FLAIR brain magnetic resonance imaging at first imaging visit were eligible; 7700 participants used for model development in previous work were excluded, yielding 36 878. Data were analyzed from April to July 2026. Exposures Household income, highest educational attainment, and area-level deprivation (Townsend Deprivation Index). Main Outcomes and Measures Brain Age Gap (predicted minus chronological age, years) from T1-weighted (primary) and T2-FLAIR (secondary) magnetic resonance imaging, derived with a deep learning model. Eleven risk factors and the Life's Essential 8 composite cardiovascular health score were modeled as mediators; indirect effects were estimated in single-mediator and parallel mediation models with 95% confidence intervals from 5000 bootstrap resamples. Results Among 36 878 participants (mean [SD] age, 65.1 [7.7] years; 20 360 [55.2%] female), lower income and greater area deprivation were associated with a larger brain age gap: lowest vs highest income group, 0.35 years (95% CI, 0.22-0.47); most vs least deprived quartile, 0.33 years (95% CI, 0.23-0.43). Education showed weaker associations that differed in direction between imaging contrasts. Life's Essential 8 score mediated 36% of the income (indirect effect, 0.031 [95% CI, 0.025-0.036]) and 17.9% of the area-deprivation (0.024 [95% CI, 0.019-0.029]) associations. In parallel models, where all risk factors were entered simultaneously, smoking was the largest mediator for both income (0.022 [95% CI, 0.016-0.028]) and area-deprivation (0.030 [95% CI, 0.023-0.037]). Higher income was associated with higher alcohol intake, offsetting part of the income association. Conclusions and Relevance Socioeconomic differences in brain age gap were partly accounted for by modifiable cardiovascular and lifestyle risk factors, with smoking being the single largest contributor. These findings identify modifiable cardiovascular risk factors as a substantial component of socioeconomic inequalities in brain aging.
- Avacopan for the Treatment of ANCA-Associated Vasculitis: The Primary Endpoints Readjudication
Background The phase 3 ADVOCATE trial evaluated the efficacy and safety of avacopan in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). Concerns raised regarding the 2019 primary endpoint adjudication process prompted a blinded, independent readjudication of all participants' primary outcomes, the results of which are described here. Methods Patients with GPA or MPA were randomized 1:1 to receive oral avacopan 30 mg twice daily or oral prednisone on a scheduled taper, each in combination with rituximab- or cyclophosphamide-based standard of care. In 2026, the Duke Clinical Research Institute Clinical Events Classification group conducted an independent, blinded committee re-adjudicated the Birmingham Vasculitis Activity Score (BVAS), relapse, and remission from weeks 26 through 52 using procedures aligned with the original adjudication charter. The primary endpoints were remission at week 26 and sustained remission at week 52. As per the original analysis plan, noninferiority and superiority were declared if the lower bounds of the 95% confidence interval (CI) for the difference in the primary outcome rates between avacopan and a prednisone taper were greater than -20.0 and 0.0 percentage points, respectively. Results Among 330 participants in the intent-to-treat population, remission at week 26 was achieved by 68.1% (113/166) and 67.1% (110/164) of participants in the avacopan and prednisone taper groups, respectively, in the 2026 readjudication (adjusted difference: 2.2%; 95% CI, -7.5, 11.9), compared with 72.3% (120/166) and 70.1% (115/164) in the 2019 primary outcome adjudication (adjusted difference: 3.4%; 95% CI, -6.0, 12.8). Sustained remission at week 52 was achieved by 61.4% (102/166) and 52.4% (86/164) of participants, respectively, in the 2026 readjudication (adjusted difference: 9.8%; 95% CI, -0.3, 19.9), compared with 65.7% (109/166) and 54.9% (90/164) in the 2019 readjudication (adjusted difference: 12.5%; 95% CI, 2.6, 22.3). Concordance between the 2019 and 2026 adjudications was 95.2% for remission and 93.6% for sustained remission. Conclusion The re-analysis of ADVOCATE based on the 2026 readjudication further supports the efficacy of avacopan for GPA/MPA. Non-inferiority of avacopan versus a prednisone taper was confirmed at weeks 26 and 52 despite a median 81% reduction in glucocorticoid exposure observed in the avacopan versus prednisone taper groups. While a consistent numerical difference favoring avacopan at week 52 was observed in the 2019 and 2026 analyses, this difference did not reach statistical superiority.
- GCH1 genetic variation as a prognostic factor in Parkinson disease across populations
Background: Pathogenic variants in GCH1 have been associated with Parkinson's disease (PD), but the clinical phenotype and longitudinal disease course of GCH1-associated PD remain incompletely characterized. Objectives: To characterize the genetic spectrum, clinical phenotype, and longitudinal progression of GCH1-associated PD across multiple populations. Methods: Whole-genome sequencing (WGS) and clinical exome sequencing (CES) data from the Global Parkinson Genetics Program (GP2) were analyzed together with unpublished and published GCH1-associated PD patients. Variant pathogenicity was classified according to ACMG criteria. Demographic, clinical, and longitudinal features were compared between GCH1 P/LP variant carriers and non-carrier PD patients; individuals with known pathogenic variants in PD-associated genes were excluded from both groups. Results: In the GP2 cohort (PD, n=22,825; controls, n=4,453), 16 pathogenic or likely pathogenic (P/LP) GCH1 variants were identified in 58 individuals, including 54 PD patients, one control, and three individuals with other neurodegenerative phenotypes (two with progressive supranuclear palsy and one with dementia with Lewy bodies). In the pooled-ancestry WGS analysis, GCH1 P/LP variants were enriched in PD patients versus controls (0.267% vs 0.023%; OR=11.854; 95% CI=1.620-86.699; p=0.0006). Variant frequencies in PD patients ranged from 0.121% to 0.714% across ancestries. In the CES cohort, P/LP variants were identified in 0.201% of PD patients. After integrating GP2 with additional unpublished and published datasets, 119 GCH1-associated PD patients were analyzed. Compared with noncarriers, carriers of P/LP GCH1 variants had an earlier age at onset (mean [SD], 53.7 [14.8] vs 59.2 [11.7] years; P < .001), lower levodopa equivalent daily dose requirements (mean [SD , 467.5 [331.7] vs 680.3 [466.4] mg/d; P < .001), and a higher frequency of a family history of Parkinson disease (47.6% vs 19.9%; P < .001). Adjusted Cox models showed significant delayed progression to motor fluctuations (HR=0.32, 95% CI=0.16-0.62) and levodopa-induced dyskinesias (HR=0.51, 95% CI=0.30-0.87). Conclusion: GCH1 pathogenic variants were associated with a clinically distinct phenotype characterized by earlier disease onset and slower progression of motor complications. These findings suggest that GCH1 genetic variants may serve as genetic biomarkers for patient stratification and prognosis in PD.
- Use of nicotine replacement therapy to reduce children's exposure to second-hand smoke in the home: Findings of a pilot randomised controlled trial conducted in Scotland
Introduction: Childrens exposure to second hand tobacco smoke is a preventable global public health issue, yet there is no consensus on how best to support families to create a smoke free home. This pilot randomised controlled trial tested the feasibility of use of free nicotine replacement therapy combined with telephone delivered support to reduce childrens exposure to second hand smoke in the home, and inform a future full scale trial. Methods: Parents and carers aged 18 and over, who smoke in the home and care for one or more children aged 0 to 16 years were recruited through existing initiatives and social media. Participants were randomised to either the intervention or control arm. Group A received free posted to home nicotine replacement therapy, alongside fortnightly telephone calls to support smoking abstinence in the home. Group B were signposted to the Scottish Government Take it Right Outside website which provides interactive advice on creating a smoke free home. To measure second-hand smoke levels, participants installed an air quality monitor in their living room for 7 days to measure fine particulate matter at baseline and 12 week follow-up. Results: Approximately one-quarter (27 of 100) of the intended sample size was recruited. Median fine particulate matter concentrations reduced in both the intervention (by 36mg per cubic metre) and control (by 16mg per cubic metre) groups. Retention rates and adherence rates to nicotine replacement therapy were 70 percent and above, with no risks and or safety concerns reported, suggesting this approach is feasible and acceptable to participants. The estimated cost of delivering this 12 week intervention was two hundred and forty four pounds per individual. Conclusions: Although recruitment rates were insufficient to recommend progression to a larger trial to test effectiveness of this approach in Scotland, this study could inform trial development in other countries where smoking in the home is commonplace. Insights regarding the alignment of smoke free home interventions with broader smoking cessation initiatives could inform future policy and public health approaches.
- The implementation of a falls observational tool and its clinical effectiveness of reducing falls in a palliative care setting: a mixed methods study
Background Falls are a major safety concern in healthcare. In palliative care, patients are particularly vulnerable due to complex symptom burdens and rapid physical decline. However, standard falls risk assessment tools, primarily designed for acute clinical environments, rely on static risk scores and lack efficacy in hospice settings. The Falls Early Warning Score (FEWS) is a observational tool developed to address the specific contributing factors and complex needs of palliative patients. Aims To explore and understand staff views regarding the implementation, utility, and benefits of the FEWS tool to identify people at risk of falling in a specialist palliative care inpatient unit. Methods A mixed-methods study was conducted at a UK hospice. Healthcare professionals with clinical experience using the FEWS chart completed an electronic questionnaire assessing their confidence, practice, and perceived barriers. Questionnaire outcomes informed subsequent face-to-face, semi-structured interviews. Qualitative data were evaluated using reflexive thematic analysis. Results Eleven staff completed the questionnaire, and five participated in interviews. Three major themes were identified: (1) Education, highlighting staff preferences for 1:1 training and the necessity of dedicated user guides; (2) Location and format of the FEWS tool, contrasting the data collection benefits of electronic formats against the bedside accessibility of paper charts; and (3) Recognised benefits of the FEWS tool, including its ability to prompt safe staffing levels, highlight variable patient presentation, and mitigate the emotional and physical impact of falls. Conclusions It is feasible and highly acceptable to integrate bespoke falls risk assessment tools into palliative care. By addressing the unique complexities of hospice patients, customised tools like FEWS can empower staff and support dynamic clinical decision-making. Further research is required to evaluate their clinical efficacy in reducing falls.
- Circulating Immune Cell Phenotypes are Associated with Socioeconomic Status and Severity of Environmental Enteropathy Among Zambian Adults
Environmental enteropathy (EE) is a chronic, subclinical disorder of the small intestine common in low- and middle-income countries (LMICs), where access to sanitation and exposure to enteric pathogens vary greatly by socioeconomic status (SES). Systemic immune cell activation by enteric microbial exposure is a suspected but poorly characterized driver of EE severity. We hypothesised that adults from Low-SES communities would have more severe EE than adults from High-SES communities and that this would be associated with distinct circulating immune cell phenotypes. We enrolled clinically healthy adults from High- (n=26) and Low-SES (n=76) communities in Lusaka, Zambia. Duodenal biopsies from these adults were used for microscopic morphometry assessments, while plasma and stool biomarkers of epithelial damage, intestinal inflammation, microbial translocation, and systemic inflammation were measured by ELISA. Circulating monocyte, neutrophil and T cell phenotypes were characterised in buffy coat cells by flow cytometry. Compared with the High-SES group, adults from Low-SES communities had higher duodenal villus width and crypt depth and lower epithelial surface area, indicative of more severe EE pathology, and higher levels of plasma biomarkers associated with microbial translocation and systemic inflammation. The Low-SES group also had higher expression of activation markers (CD86 and TLR4) and lower expression of HLA-DR on circulating classical monocytes and neutrophils, higher percentages of gut-homing (4{beta}7+) and activated/exhausted (PD-1+) T cells, including gut-homing (4{beta}7+) regulatory T cells. Principal Component Analysis identified key patterns of immune cell phenotypes across SES groups. Confounder-adjusted linear regression models showed that Principal Component 1 (monocyte/neutrophil activation) was inversely associated with duodenal villus height and epithelial surface area across SES groups. These findings indicate that EE severity varies by SES within LMIC and suggest that monocyte and neutrophil activation is linked to greater duodenal remodelling in adults with EE.
- Efficacy-adjusted use: modelling a refined metric of insecticide treated net coverage across Africa
Insecticide-treated net (ITN) use - defined as the proportion of a population that use ITNs - is a measure of ITN uptake that is used in the estimation of malaria burden and evaluation of intervention programs. However, binary classification of individuals as users or non-users does not account for variations in ITN-related protection attributed to deleterious factors such as chemical and physical degradation, and increased insecticide resistance in vector populations. In this paper, we present a parsimonious model for malaria dynamics in mosquito-human populations in the presence of varying ITN use conditions. Using this model, we propose a new standardised measure of ITN coverage termed the "efficacy-adjusted use" defined as the equivalent level of use, assuming fully efficacious nets, that would be required to achieve the same level of theoretical EIR reduction. This more nuanced measure is used as a proxy for studying ITN-attributed protection across 44 African countries. We find that estimated protection levels in current ITN paradigms is significantly lower than indicated by crude ITN use metrics, with insecticide resistance having the largest deleterious effect. Furthermore, recent adoption of next-generation nets is estimated to have mitigated a 13% reduction in protection compared to a counterfactual pyrethroid only scenario.
- Within-mouth spillover of dental restorations on periodontal status
Abstract Aim: To test whether neighbouring-tooth restorations affect a focal tooths periodontal status (within-mouth spillover), and whether accounting for them alters the established association at the restored surface. Materials and methods: Prospective tooth-surface data from the Study of Health in Pomerania (SHIP): SHIP-START (N=2,715/1,982/1,397, follow-ups 1-3) and SHIP-TREND (N=2,123). Own and neighbouring-tooth restoration were defined at baseline; probing depth (PD), clinical attachment level (CAL), bleeding on probing (BOP) and deep pockets (PD >=4 mm) at follow-up. A neighbourhood-exposure mixed model with generalized propensity-score adjustment estimated both effects, with two corroborating estimators. Results: Own restoration was associated with worse periodontal status at that surface (crown PD exp(beta) up to 1.10). Neighbouring-tooth restorations raised focal-tooth PD (spillover exp(beta) 1.03-1.05) and deep-pocket risk (risk ratio up to 1.25); CAL and BOP showed none consistently. It attenuated with tooth-lag, nearing the null by two to three teeth in most estimators. Ignoring interference modestly inflated the direct effect; an opposing-tooth negative control showed none; untreated caries reproduced it. Conclusions: Dental restorations exert a within-mouth spillover on neighbouring-tooth PD: their periodontal footprint extends beyond the restored tooth. The direct association persists, modestly attenuated, after accounting for the neighbourhood.
- Diagnostic accuracy of point-of-care urine tenofovir test, and associations between metrics of tenofovir use and treatment outcomes in a community ART programme
Background Urine tenofovir (uTFV) and dried blood spot (DBS) tenofovir diphosphate (TFV-DP) concentrations respectively estimate short- and medium-term adherence to tenofovir disoproxil fumarate (TDF)-based antiretroviral therapy (ART). We evaluated the accuracy of a point-of-care uTFV assay, and associations between uTFV/TFV-DP, and viral load (VL) and retention outcomes within a South African community ART programme. Methods We measured uTFV and DBS TFV-DP concentrations using liquid chromatography-tandem mass spectrometry (LC-MS/MS). We calculated sensitivity and specificity of the point-of-care uTFV assay at the manufacturer-recommended threshold of [≥]1,500 ng/mL compared to LC-MS/MS. We assessed associations of the point-of-care uTFV assay, and DBS TFV-DP concentrations with concurrent viraemia, and with retention-in-care by 16 weeks post-enrolment. Results Of 196 adults median age was 44 years, 127 (64.8%) were female, and 191 (97.4%) were receiving TDF. 185 (94.4%) had detectable point-of-care uTFV, which had high sensitivity (99.5%, 95% CI 96.5-100%) and moderate specificity (76.9%, 95% CI 46.0-93.8%) for detecting uTFV [≥]1,500 ng/mL. Two participants had concurrent viraemia [≥]1,000 copies/mL; of these 50.0% (95% CI 9.4-90.5) had undetectable point-of-care uTFV, and 100% (95% CI 19.7-100) had low TFV-DP <483 fmol/punch. Among participants without viraemia 97.4% (95% CI 93.6-99.0) had detectable uTFV, and 98.1% (95.3-99.6) had high TFV-DP [≥]483 fmol/punch. Point-of-care uTFV and DBS TFV-DP were not associated with retention-in-care. Conclusions The point-of-care uTFV assay demonstrated high sensitivity and moderate specificity to detect uTFV. Over 95% of people without viraemia had detectable point-of-care uTFV or high DBS TFV-DP levels respectively, but these were not associated with 16-week retention-in-care.
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- The impact of quality of primary care on secondary healthcare utilisation for patients with multiple long-term conditions
Objectives To assess the concurrent and lagged associations between quality of primary care and planned and unplanned secondary care use for patients with multimorbidity, examining the modifying role of frailty. Design A retrospective cohort study Setting This population-level analysis included 468,172 patients with multimorbidity in England from the Discover research platform (April 2022-March 2024). Participants Patients with multimorbidity Main outcome measures We used principal component analysis to combine a set of quality indicators (QIs) and assessed the impacts of QIs on both planned and unplanned care. Results Generally, patients with higher QI attainment also had higher likelihood of planned (outpatient visits) and unplanned care (emergency admissions and ED visits) utilisation. There was a lower lagged odds of elective hospital admissions in the following 12 months among those with higher attainment of multimorbidity-specific QIs (OR=0.94, 95%CI 0.93-0.95). In the complex multimorbidity cohort ([≥]3 conditions), multimorbidity-specific QIs were longitudinally associated with lower odds of elective admissions (OR=0.94, 95%CI 0.92-0.95) and outpatient visits (OR=0.96, 95%CI 0.95-0.98), while generic QIs were related to lower odds of outpatient non-attendance (OR=0.95, 95%CI 0.91-0.99). In non-frail patients with multimorbidity, multimorbidity-specific QIs were longitudinally associated with reduced odds of outpatient visits (OR=0.98, 95%CI 0.97-0.99), elective admissions (OR=0.92, 95%CI 0.90-0.94) and prolonged elective hospital stay (IRR=0.94, 95%CI 0.89-0.99). Conclusions Attainment of generic and multimorbidity QIs was generally associated with slightly increased planned and unplanned care. However, patients for whom we identified higher attainment of multimorbidity-specific QIs had lower odds of elective admissions and outpatient visits, especially for those with complex multimorbidity. Our research suggests that the quality of primary care may influence patients' use of secondary care, with the potential to improve care for people with multimorbidity and warrant further investigation into management strategies.
- Perceived Hearing Symptoms Organize the Ear-Disease Comorbidity Network but Are Not a Causal Lever for Brain Health: A Triangulated Analysis
Background: Hearing loss is a potentially modifiable risk factor for brain health, but whether it acts as a causal lever remains unclear. Methods: We constructed an ear-disease comorbidity network from NHANES 2011-2020 (N=18,939, 16 nodes, 62 edges), performed bidirectional Mendelian randomization (MR) across 24 exposure-outcome pairs, and triangulated evidence with longitudinal data from CHARLS (N=17,101). Results: Subjective hearing symptoms (prevalence 6.1%) occupied hub positions in the comorbidity network, whereas objective hearing impairment (8.0%) was sparsely connected. All forward MR estimates were null after multiple-testing correction (IVW P>.05 for 9 of 9 pairs). Reverse MR showed one nominally significant association (cognition to objective hearing beta=-0.15, P=.013) that did not survive correction. Longitudinal analysis yielded HR=1.57 (P=.00004) for subjective hearing symptoms predicting incident depression. Conclusions: Perceived hearing symptoms organize the ear-disease comorbidity network but are not a causal lever for brain health. These findings support a "flag, not lever" framework: subjective hearing symptoms warrant clinical attention as markers of systemic multimorbidity rather than intervention targets for dementia prevention.
- Scalable context-dependent single-cell eQTL mapping reveals disease-relevant regulatory variation beyond static models
Many disease-associated variants are thought to act through gene regulation, yet conventional eQTL mapping explains only a fraction of GWAS loci, potentially because regulatory effects vary across cellular states and environments. We present CASTIE, a scalable Poisson mixed-model framework that directly models sparse single-cell read counts and enables genome-wide testing of genotype-by-context interactions without pre-screening for static effects. Applying CASTIE to 1.2 million peripheral blood mononuclear cells from 982 OneK1K donors identified 3,155 context-dependent eQTL associations, including 2,022 eGenes without detectable static effects. These associations yielded 374 colocalizations across 94 traits, representing 270 unique loci, of which 197 were not recovered using the corresponding static eQTLs. The colocalizations linked trait associations to specific cellular contexts and genes including GCHFR, RNASET2 and ATP1A3. In adipose-derived mesenchymal stem cells exposed to metabolic stimulations, CASTIE increased eGene discovery by 36-92% across cell populations and identified stimulation-dependent regulatory effects at metabolic trait loci. Thus, modeling cellular context reveals disease-relevant regulatory variation beyond static eQTL mapping.
- Improved visualization and segmentation of the choroid plexus using double inversion recovery MRI
Background: Choroid plexus (CP) volume is an emerging magnetic resonance imaging (MRI) biomarker in various disorders of the central nervous system (CNS). However, clinical translation is hindered by methodological heterogeneity and inconsistent anatomical coverage. Double inversion recovery (DIR) - a sequence providing dual-tissue suppression - is a promising candidate to improve CP segmentation. Methods: The dataset included 93 scans across healthy subjects and individuals with multiple sclerosis (MS), divided into a training set (n = 63), an internal test set (n = 20), and an external test set (n = 10). First, relative CP signal intensity and tissue contrast ratios on DIR were compared against fluid-attenuated inversion recovery (FLAIR) and T1-weighted (T1w) sequences (pre- and post-contrast). Reproducibility of manual CP segmentations was assessed via intraclass correlation coefficients (ICCs). Subsequently, we developed a 3D nnU-Net model for CP segmentation based on manually labeled DIR masks. Model performance was evaluated against manual segmentation using spatial overlap and volumetric error metrics. Finally, we compared our DIR-based model against three publicly available T1w- or FLAIR-based tools by assessing slice-wise volume distributions and voxel-wise density maps. Results: DIR demonstrated the highest CP signal intensity and most consistent tissue contrast among evaluated MRI sequences (p < 0.001). Intra- and inter-rater agreement for manual CP segmentations was robust (ICC = 0.92 and 0.83, respectively). The trained nnU-Net achieved high internal accuracy (Dice = 0.82) independent of scanner, diagnosis, or absolute CP volume, and generalized well to the external test set (Dice = 0.75). Compared to public T1w- and FLAIR-based models, DIR-based approaches (nnU-Net and manual) yielded significantly larger CP volumes (p < 0.01). Axial volume distribution analysis attributed this difference to a distinct bimodal profile in DIR segmentations, more fully capturing the CP inside the temporal horn of the lateral ventricle (p < 0.001 against T1w- and FLAIR-based models). Conclusions: By leveraging the superior tissue contrast of DIR, our nnU-Net model achieves highly accurate CP segmentation that generalizes across scanners and captures the inferior extent of the C-shaped structure often missed by conventional models. This may improve standardization of CP volumetry and allow for more reliable studies in CNS disorders.
- A Digital-Ready Framework for Ongoing Performance Evaluation of India's Integrated Disease Surveillance Program (IDSP) using Weekly Outbreak Reports: A Study from Bihar, 2016-2018
Background: Evaluation of public health surveillance systems is a programmatic obligation but has largely been conducted as a periodic, externally commissioned activity requiring dedicated resources and additional data collection. India's Integrated Disease Surveillance Program (IDSP) generates continuous outbreak data through weekly reports but lacks a routine, embedded performance evaluation mechanism. This study assessed the quality of IDSP outbreak detection and response across multiple surveillance attributes and developed a weighted composite performance scoring framework using only routine program data. Methods: A cross-sectional evaluation study was conducted across 38 districts of Bihar using secondary data from IDSP Central Surveillance Unit weekly outbreak reports for 2016 - 2018 (n=559 outbreaks). Six surveillance quality attributes were assessed - timeliness, completeness, representativeness, relative sensitivity, acceptability and flexibility. A weighted composite performance scoring scale was developed using expert opinion-derived attribute weightages (n=25 experts). District-level scores were computed and scaled to 100. Results: Timeliness was the poorest-performing attribute, with fewer than 15% of outbreaks notified within 48 hours across all three years. Private sector participation was entirely absent - the acceptability score was 0 across all 38 districts for all three years. Completeness was the strongest attribute, exceeding 95% in all years. The mean composite score remained consistently low (23 - 27 out of 100) with widening inter-district disparity over time. Four districts (10.5%) scored 0 in all three years. Conclusions: This study presents a dynamic, routine-data-based composite performance evaluation framework for IDSP outbreak detection and response. The modular, configurable framework functions at any administrative level (from block to national) and is compatible with digital health information platforms, enabling continuous, embedded performance monitoring without additional data collection. The framework has been registered as an Intellectual Property with the Government of India. Keywords: Disease surveillance; IDSP; IDSR; performance evaluation; composite score; outbreak detection; timeliness; completeness; relative sensitivity; digital health
- Association of age at menopause and risk of depression during the perimenopause and postmenopause
Importance The menopausal transition has been associated with an increased risk of depression, although findings are inconsistent. While most research has focused on menopausal stage, some studies suggest that later age at menopause may be associated with lower depression risk. Objective To examine the association between age at menopause and depression risk during perimenopause and early postmenopause using multivariable regression and genetic approaches. Design Prospective cohort study using data from the mothers of the Avon Longitudinal Study of Parents and Children (ALSPAC), a UK birth cohort that recruited pregnant women in 1991-1992. Setting UK community-based cohort study. Participants Up to 3,307 women with repeated measures of depressive symptoms across the perimenopausal and postmenopausal periods and data on observed or genetically predicted age at menopause. Exposure Observed age at menopause, a polygenic risk score (PRS) for age at menopause, and genetically predicted age at menopause. Main Outcome(s) and Measure(s) Depressive symptoms during the perimenopausal and early postmenopausal periods were assessed using the Edinburgh Postnatal Depression Scale (EPDS), with depression defined as a score >= 13. Results Effect estimates across multivariable regression and genetic analyses were small and directionally consistent with lower odds of depression with older age at menopause, although most confidence intervals included the null. In analyses using observed age at menopause, there was little evidence of an association with depression during perimenopause (Odds ratio (OR) per year increase in age at menopause 0.98, 95%CI 0.89-1.08) or postmenopause (OR 1.00, 95%CI 0.89-1.13). Results were similar when using a PRS as a genetic proxy for age at menopause during perimenopause (OR per standard deviation (SD) increase in PRS 0.98, 95%CI 0.89-1.09) but suggested lower odds of depression during postmenopause (OR 0.92, 95%CI 0.86-0.99). Mendelian randomization analyses did not support a causal effect (OR per year increase 1.00, 95%CI 0.89-1.13 for perimenopause, and OR 0.97, 95%CI 0.86-1.09 for postmenopause). Conclusions and Relevance Age at menopause is unlikely to be a major driver of midlife depression risk. However, consistent effect directions across approaches suggest a small association may exist, but further research in larger samples is needed to confirm this.
- Age norms for DunedinPACE: An epigenetic pace of aging biomarker
Epigenetic clocks have transformed the study of biological aging in epidemiology and clinical trials. However, the utility of these measures in clinical settings is limited by a lack of population-based norms that clinicians, patients, and researchers can use to understand and communicate how fast an individual is aging relative to same-aged peers. Here, we developed age norms for DunedinPACE, an epigenetic Pace of Aging measure derived from DNA methylation. To do so, we meta-analyzed data from 11 cohorts (N = 37,855 individuals, ages 17-99 years) to characterize the association between chronological age and DunedinPACE. We investigated sex differences and nonlinearity, confirmed results using longitudinal data, verified that age-normed DunedinPACE scores predict clinical outcomes, and illustrated how norms support the needs of clinical aging research. The age norms reported here will help integrate biomarkers of aging, such as DunedinPACE, into precision public health and medicine.
- Pharmaco-nutritional strategies to increase nitric oxide signaling in Raynaud phenomenon (Nivose): a series of N-of-1 trials
Background Treatment of Raynaud phenomenon(RP) with oral vasodilators(calcium channel block-ers and phosphodiesterase type 5 inhibitors) has shown moderate efficacy, may not benefit to all patients, and adverse effects often compromise long-term treatment. In addition, a large placebo effect may jeopardize the assessment of treatment benefits. Pharmaconutritional strategies aiming at increasing nitric oxide bioavailability (beet-root juice and L-citrulline) may be promising alternatives, and we further hypothesized that patient preference for a treatment could be a driver of the response. Methods This study consisted of a series of randomized, double-blind, N-of-1 trials conducted in outpa-tients with primary or secondary RP. Each patient underwent a multiple crossover design with repeated blocks of randomized treatments periods: 2 weeks of placebo, 2 weeks of active treat-ments, and 1 week of washout. Outcomes included the Raynaud Condition Score(RCS), fre-quency and daily duration of attacks. Each patient prespecified its preferred primary outcome, efficacy threshold and preferred treatment, which was used for stratified randomization. Gener-alized linear mixed-effects models were used to determine individual and aggregated efficacy. Results Twenty-one patients completed 2 to 8 treatment blocks. Seventeen patients tested L-citrulline, 17 beetroot juice and 13 both treatments. Ten patients selected RCS as a primary outcome, 6 patients the number of attacks and 5 the duration of attacks. Me-dian threshold for considering treatment efficacy chosen by patients was 50% (min-max 20% to 75%) reduction of symptoms. Using individual criteria to define efficacy neither L-citrulline nor beetroot juice showed significant efficacy compared to baseline. Based on the aggregated data, our results show no significant difference between L-citrulline and the L-citrulline-based placebo, nor between beetroot juice and nitrate-depleted beetroot juice, with the exception of the daily duration of RP attacks with beetroot juice (p=0.002). Finally, there was a marked placebo response, notably when patients received their preferred treatment. Conclusions: Our study did not show significant beetroot juice or L-citrulline efficacy in RP. However, we found that individual preference for one treatment over another maximizes responses to both placebo and active treatments, particularly with regard to the frequency and duration of RP attacks, thus suggesting that a real and modifiable placebo effect exists in RP.
- A Simulation Study Comparing Multiple Imputation and Complete Case Analysis for Handling Missing Preschool Body Mass Index
Background and Objective. Missing data frequently occurs in health databases and can bias analyses if not correctly dealt with. Using real-world data, we compared complete-case and multiple-imputation methods for recovering true parameters of a multivariable logistic regression model for the association between maternal glucose levels during pregnancy and child excess weight at preschool age, where missing values were present in as much as 30% of our sample. Methods. This study utilized a cohort of 130,424 children with complete preschool-age body mass index (BMI) measurements from the Calgary and Edmonton health regions of Alberta, Canada. In the complete BMI data, we introduced missingness through deletion following three distinct mechanisms: missing completely at random (MCAR), at random (MAR), and not at random (MNAR). To handle the missing data created, we employed complete-case and multiple-imputation methods. Maternal glucose levels during pregnancy were categorized into five groups and its association with child excess weight at pre-school age was determined based on a logistic regression model using the full observed data (yielding true values), observed data that was not deleted (complete-case estimates), and imputed data (multiple-imputation estimates). The accuracy of complete-case and multiple-imputation estimates were evaluated against the true values. Finally, we conducted a sensitivity analysis for the MNAR mechanism using pattern-mixture models with an additive shift. Results. Under MCAR and MAR, multiple-imputation generally outperformed complete-case, yielding smaller absolute and relative bias. Both methods achieved high significance ([≥] 0.96) for most effects. Mean squared errors for multiple-imputation and complete-case were similar missing completely at random, missing at random, and coverage was consistently high ([≥] 0.99). Under MNAR, both complete-case and multiple-imputation showed poor performance regarding bias and statistical significance. Sensitivity analysis using pattern-mixture models indicated performance varied by specific effect. Conclusions. Under MCAR and MAR, multiple-imputation introduced higher bias but demonstrated superior overall performance based on mean squared error and restored statistical power. Conversely, both methods failed under MNAR, where pattern-mixture modeling sensitivity analyses revealed highly variable, effect-specific performance due to unverifiable shift assumptions. When faced with missing data, researchers should assess missingness mechanisms, report both complete-case and multiple-imputation estimates under MCAR/MAR while accounting for power-versus-bias tradeoffs, and employ pattern-mixture sensitivity analyses to test robustness when MNAR is plausible.
- Prevalence of Non-alcoholic fatty liver disease (NAFLD) among Children and Adolescents (<18 years) in India: A Systematic Review and Meta-Analysis
Background Non-alcoholic fatty liver disease (NAFLD) has become a common metabolic disorder in paediatric age groups and is a major contributor to the burden of health economics. However, there is a lack of comprehensive data on the prevalence of this condition among children. Methods English language literature published from inception until April 2025 was searched from the electronic databases, i.e., PubMed/Medline, Scopus, Embase, and CINAHL. Original data published in any form that reported NAFLD prevalence among children and/or adolescents in India were included. The subgroup analysis of prevalence was done based on the risk category, i.e., average risk group and high risk group (obesity or overweight, metabolic syndrome, etc.). The prevalence estimates were pooled using the random-effects model. Results A total of 11 studies (six in high-risk populations and 5 in the average-risk general population) comprising data from 3512 individuals were found eligible and were included. The overall pooled estimate of NAFLD prevalence among the children and adolescents was 35.4% (95% CI: 19.7% to 52.9%) with very high heterogeneity(I2=99.0%). The pooled prevalence of NAFLD among average/low risk children and adolescents was 10.7% (95%CI: 5.2% to 20.5%) with high heterogeneity across the studies (I2= 96.6%, p=0.001) whereas the pooled prevalence of NAFLD in high risk overweight/obese children and adolescents was found to be 59.7% (95% CI:55.2% to 64.1%) with moderate heterogeneity across the studies (I2=50.90%; H2=2.04; Q (5) = 10.03; p=0.07) Conclusion This systematic review demonstrates that non-alcoholic fatty liver disease (NAFLD) poses a growing health concern among Indian children and adolescents, as 1 out of 3 children/adolescents is suffering from it, with a disproportionately high burden observed in those who are overweight or obese.
- Cardiovascular and autonomic responses to transcutaneous spinal cord stimulation combined with activity-based therapy after chronic spinal cord injury: An exploratory study from the MACHINE trial
Objective: To describe cardiovascular and autonomic responses to body weight-supported treadmill training (BWSTT) combined with active or sham transcutaneous spinal cord stimulation (TSCS) in individuals with chronic, motor-complete spinal cord injury (SCI). Design and setting: Exploratory case series from randomized, sham-controlled clinical trial in a tertiary Rehabilitation Centre in Vancouver, Canada. Participants: Eight adults with chronic ([≥]1 year post-injury) traumatic, motor-complete (American Spinal Injury Association Impairment Scale A-B) SCI at or above T6 Interventions: Participants were randomized to 12 weeks of BWSTT plus lumbosacral TSCS or BWSTT plus sham stimulation, delivered 3 sessions/week. TSCS was delivered at T11-L1 using 30 Hz stimulation with a 10 kHz carrier frequency. Five participants completed the intervention, and four completed full cardiovascular testing (TSCS n=2; sham n=2). Outcome measures: Ambulatory blood pressure (BP) monitoring, participant-reported symptoms of AD and OH (via ADFSCI questionnaire), BP variability, orthostatic hemodynamics, echocardiography, electrocardiography (ECG)- and heart rate variability (HRV)-derived indices, and baroreflex function. Results: Among complete cases, several cardiovascular indices changed over time, including reduced daytime hypotensive burden in TSCS participants, preserved nocturnal dipping, and small changes in stroke volume and ECG-derived variability indices; however, responses were heterogeneous and overlapped with Sham. Both TSCS and Sham participants showed reduced autonomic symptom scores, while low-frequency blood pressure variability responses during orthostatic stress were heterogeneous and did not indicate a pattern that was specific to a cohort. Conclusion: Although preliminary, this exploratory complete-case analysis suggests that cardiovascular responses to BWSTT with active or sham TSCS are measurable but highly individualized after chronic motor-complete SCI. Given the small sample and overlapping Sham responses, findings are exploratory and larger trials are needed to determine whether TSCS augments cardiovascular autonomic adaptations to locomotor training.