BMC Medicine[JOURNAL]
Sun
200 papers
Effects of ambient PM2.5 and its components on the prognosis of colorectal cancer survivors: disease progression and potential mediation pathways.
Qin Q, Wu W, Yin C … +12 more , Li Z, Yu X, Cai H, Xu X, Lin X, Wu X, Li S, Yuan Z, Hu Q, Wang Y, Xia L, Zhang W
BMC Med · 2026 May · PMID 42174596 · Full text
BACKGROUND: Evidence continues to support the role of air pollution as a contributor to adverse outcomes in colorectal cancer (CRC); however, its effects on the mortality and disease progression transitions in CRC surviv...
BACKGROUND: Evidence continues to support the role of air pollution as a contributor to adverse outcomes in colorectal cancer (CRC); however, its effects on the mortality and disease progression transitions in CRC survivors, and the mediation pathways, remain uncertain. METHODS: This retrospective cohort study enrolled 3,357 patients diagnosed with non-metastatic colorectal cancer who underwent curative surgery at Sun Yat-sen University Cancer Center between 2012 and 2017. The annual average concentrations of PM and its components were derived from the ChinaHighAirPollutants (CHAP) dataset and matched to participants based on their residential addresses. The associations between PM and its components with CRC mortality were assessed using Cox proportional hazards models. To delineate risks at different disease progression transitions, we employed multi-state models. Mediation analysis was conducted to elucidate the role of systemic inflammation and oxidative stress biomarkers in the exposure-outcome pathway. RESULTS: An increase in PM exposure per IQR was linked to a 35% elevated risk of CRC mortality (HR = 1.35, 95% CI: 1.18-1.54). Among the specific components analyzed, ammonium (NH₄⁺; HR = 1.51, 95% CI: 1.13-2.01) and sulfate (SO₄²⁻; HR = 1.68, 95% CI: 1.20-2.34) demonstrated significant positive associations. Stratified analyses suggested stronger associations among older patients, males, smokers, those with later-stage disease, and patients with a family history of malignancy. In multi-state models, PM exposure was consistently related to all three disease progression transitions, with HRs of 1.14 (95% CI: 1.04-1.26) for diagnosis → DFS event, 1.99 (95% CI: 1.71-2.32) for DFS event → CRC death, and 1.58 (95% CI: 1.30-1.92) for diagnosis → CRC death. Mediation analysis identified multiple inflammatory and oxidative stress biomarkers with significant indirect effects, with proportions mediated ranging from 1.7% to 8.9%. The strongest mediators were MLR (8.9%), HDL (6.6%), and PLR (3.0%). CONCLUSIONS: Long-term exposure to PM was associated with poorer CRC prognosis and more rapid disease progression, partly via systemic inflammation and oxidative stress. These findings support precise air quality policies and integrated survivorship strategies targeting pollution-related mortality in cancer survivors.
Quantitative assessment of efficacy and evaluation of feasibility of exercise training protocols in adult and pediatric primary mitochondrial disease.
Martin I, Flickinger J, Rahaman I … +8 more , Sarna T, Ballance EB, Ginelli N, Peterson JT, Uryash A, Adams JA, Xiao R, Zolkipli-Cunningham Z
BMC Med · 2026 May · PMID 42174583 · Full text
BACKGROUND: Exercise has been demonstrated to be effective in the general population and in a small number of Primary Mitochondrial Disease (PMD) human studies, raising the potential of exercise as standard of care in PM...
BACKGROUND: Exercise has been demonstrated to be effective in the general population and in a small number of Primary Mitochondrial Disease (PMD) human studies, raising the potential of exercise as standard of care in PMD. However, standardized exercise prescriptions have not been established in this heterogeneous patient population. This study aimed to identify effective and feasible exercise training protocols, to inform the design of rigorous exercise studies in adults and/or children with PMD. This was achieved through integration of a structured feasibility evaluation preceded by a quantitative review of published PMD studies, with specific focus on subgroup analyses by exercise type (aerobic, resistance, interval, and combination exercise). METHODS: A systematic literature review was conducted to identify published exercise studies in PMD cohorts. Due to the limited number of PMD exercise studies, the search was expanded to include disorders with secondary mitochondrial dysfunction (SMD), with similar symptoms of muscle weakness, muscle fatigue and exercise intolerance, as occurs in PMD. In total, 77 studies comprising 109 exercise training protocols were identified. Of those, a quantitative analysis was performed on 37 PMD and SMD studies reporting key outcome measures to assess the effects of aerobic, resistance, combination or interval exercise training. All 109 exercise training protocols were then systematically evaluated for feasibility, as defined by the likelihood of successful implementation in future exercise studies of PMD, using a standardized scoring system. RESULTS: Results of our quantitative analysis demonstrate the significant effect of distinct exercise types including aerobic exercise training on relative peak oxygen consumption (VO), peak work, and Short-Form 36 (SF-36) physical summary score; and combination (interval/resistance/inspiratory muscle training) exercise training on relative peak VO and SF-36 across PMD studies. Feasibility evaluation across PMD and SMD studies involving expert group consensus review identified high-intensity circuit training (HICT), low-intensity steady-state (LISS) aerobic exercise, low-intensity resistance training, and blood flow restriction resistance training (BFR-RT) as being potentially feasible and effective in PMD. CONCLUSIONS: Results of this study highlight specific exercise training protocols that merit assessment in future rigorously designed exercise studies to determine their feasibility and therapeutic efficacy in adults and/or children with PMD.
Autoimmune diseases and risk of adverse pregnancy outcomes: a population-based cohort study of five million pregnancies in the UK.
Singh M, Subramanian A, Wambua S … +9 more , Cockburn N, Hanley SJ, Lee SI, Gonzalez-Izquierdo A, Black M, Reynolds JA, Crowe FL, Nirantharakumar K, MuM-PreDiCT
BMC Med · 2026 May · PMID 42169116 · Full text
BACKGROUND: With an increasing trend in the prevalence of maternal autoimmune diseases in pregnancy, there is need for evidence on the association between autoimmune diseases and pregnancy outcomes. METHODS: This populat...
BACKGROUND: With an increasing trend in the prevalence of maternal autoimmune diseases in pregnancy, there is need for evidence on the association between autoimmune diseases and pregnancy outcomes. METHODS: This population-based cohort study used data on pregnancies from primary care practices that contributed to the UK Clinical Practice Research Datalink (CPRD) database (Gold and Aurum) between 2000 and 2022, linked to Hospital Episode Statistics (HES). Modified Poisson regression with robust standard errors estimated adjusted relative risks (aRR) and 95% confidence intervals (95% CI) assessing the association between 17 autoimmune diseases and 12 pregnancy outcomes, selected following literature review and expert consultation. Models were adjusted for demographic and comorbidity variables. Findings were evaluated using the Benjamini-Yekutieli procedure to control for multiple testing across autoimmune disease-outcome associations. RESULTS: A total of 5,239,383 pregnancies from the CPRD pregnancy register and 2,485,366 births recorded in HES maternity data met the eligibility criteria. Women with autoimmune diseases had an increased risk across all pregnancy outcomes examined. Among antenatal outcomes, markedly elevated risks were observed for hyperemesis gravidarum in Addison's disease (aRR 3.72, 95% CI 2.48-5.59), miscarriage in Sjögren's syndrome (1.66, 1.02-2.70), gestational hypertension in type 1 diabetes mellitus (T1DM; 2.95, 2.77-3.15), pre-eclampsia/eclampsia in T1DM (3.56, 3.32-3.82), and gestational diabetes mellitus in Graves' disease (1.37, 1.21-1.54). For obstetric outcomes, increased risks were observed for caesarean birth in inflammatory bowel disease (IBD; 1.27, 1.22-1.31), small for gestational age in systemic lupus erythematosus (SLE; 2.45, 1.65-3.62), preterm birth in rheumatoid arthritis (1.53, 1.33-1.76), and stillbirth in SLE (1.82, 1.12-1.84). Perinatal mental health outcomes were more common across several autoimmune diseases, with particularly high risks in myasthenia gravis (anxiety 3.05, 1.89-4.92; depression 1.77, 1.37-2.28), SLE (anxiety 2.11, 1.67-2.67; depression 1.36, 1.22-1.53), and multiple sclerosis (anxiety 1.76, 1.38-2.23; depression 1.94, 1.77-2.12). Inverse associations were observed for hyperemesis gravidarum in systemic sclerosis, SLE, and myasthenia gravis, and for hypertensive disorders of pregnancy in multiple sclerosis. After Benjamini-Yekutieli correction for multiple testing, the number of statistically significant associations was reduced, with a core set of robust associations persisting across selected autoimmune diseases particularly, T1DM, SLE, Graves' disease, IBD and key pregnancy outcomes. CONCLUSIONS: Autoimmune diseases were associated with increased risks across a wide range of adverse pregnancy outcomes, with marked heterogeneity between individual conditions. This study provides adjusted relative risks across multiple domains of pregnancy outcomes including antenatal (e.g. miscarriage, hyperemesis gravidarum, gestational hypertension, pre-eclampsia, gestational diabetes), obstetric (e.g. preterm birth, caesarean birth, small for gestational age, stillbirth), and perinatal mental health outcomes (anxiety and depression), for both common and less frequently studied autoimmune diseases. The findings highlight the importance of disease-specific evaluation of pregnancy risks.
Phase 1 randomized trial of HS-10353, a novel GABA(A) positive allosteric modulator for treatment of major depressive disorder.
Wang Z, Li M, Xu X … +7 more , Zhang R, Lin H, Yang F, Qi J, Zhang H, Tao Y, Shen Q
BMC Med · 2026 May · PMID 42169103 · Full text
BACKGROUND: HS-10353 is a novel positive allosteric modulator of γ-aminobutyric acid A receptors that is under development for the treatment of major depressive disorder (MDD). METHODS: This is a double-blind, randomized...
BACKGROUND: HS-10353 is a novel positive allosteric modulator of γ-aminobutyric acid A receptors that is under development for the treatment of major depressive disorder (MDD). METHODS: This is a double-blind, randomized, placebo-controlled, phase 1 trial comprising single ascending dose (SAD) and multiple ascending dose (MAD) parts. In SAD, 8 healthy volunteers of each cohort were randomized (6:2) to receive HS-10353 (2-55 mg) or placebo in a fasted state. In MAD, 12 MDD patients of each cohort were randomized (9:3) to receive HS-10353 (15-65 mg/day given for up to 7 days) or placebo. The primary objective was to assess the safety and tolerability of HS-10353. The efficacy endpoint in the MAD part included the change in the total score of the 17-item Hamilton Rating Scale for Depression (HAM-D17) at day 8. Pharmacokinetic (PK) analysis was performed as a secondary objective. RESULTS: Forty-eight healthy participants and forty-eight MDD participants completed the study. The most frequently observed treatment emergent adverse events (TEAEs) in the HS-10353 dose groups (occurring in ≥ 3 cases) included white blood cells urine positive and alanine aminotransferase increased in the SAD part, white blood cell count decreased and somnolence in the MAD part. All adverse events (AEs) were mild to moderate, and there were no serious adverse events or AEs that led to withdrawal from the trial. Treatment with 50 mg of HS-10353 for only 7 days showed therapeutic effects, with a difference of -4.7 (95% CI: -8.9 to -0.5) in change from baseline of HAM-D17 score on day 8 compared to placebo. HS-10353 exhibited a terminal half-life of 14 to 22 h with minimal accumulation upon repeat dosing (approximately 1.3- to 2.5-fold), supporting once-daily dosing; while absorption saturation was observed at fasting dose levels greater than 45 mg. CONCLUSIONS: Single and multiple oral doses of HS-10353 were safe and well tolerated with a favorable PK profile. The findings in this small, short duration study suggest an early signal in patients with MDD that should be further investigated. TRIAL REGISTRATION: The trial is registered at China Drug Trials (CTR20210105, 2021-01-21) and ClinicalTrials.gov (NCT05195203, 2022-01-13).
γH2AX and p53 Immunohistochemistry predict the incidence risk of esophageal squamous precancerous lesions.
Cheng X, Liu Y, Chen H … +16 more , Pan Y, Hu Z, Liu Z, Liu F, Yang W, Guo C, Zhang L, Zhang L, Li F, Li J, Liu X, Yang H, Cai M, Liu M, He Z, Ke Y
BMC Med · 2026 May · PMID 42169100 · Full text
BACKGROUND: Current screening practices for esophageal squamous cell carcinoma (ESCC) subject to both over- and under-surveillance of precancerous lesions. This study aims to evaluate potential immunohistochemical (IHC)...
BACKGROUND: Current screening practices for esophageal squamous cell carcinoma (ESCC) subject to both over- and under-surveillance of precancerous lesions. This study aims to evaluate potential immunohistochemical (IHC) markers associated with the incidence of ESCC and to establish an IHC-based panel for surveillance. METHODS: Tissue microarrays were constructed using 946 formalin-fixed, paraffin-embedded (FFPE) samples from 883 participants with baseline Lugol-unstained lesions (LULs) enrolled in a population-based screening trial. Candidate IHC markers were identified from literature and our previous findings. IHC results (H-scores) were quantified via HALO software, and optimal cut-offs were set by X-tile. Incident esophageal malignancy identified during a median follow-up of 11.76 years served as the outcome. Cox regression models were applied to identify predictive markers. RESULTS: Eight candidate markers were evaluated. After multivariable adjustment and backward elimination, γH2AX and p53 were identified as significant predictors [HR (95% CI) =2.91 (1.94-4.34), HR (95% CI) =3.57 (2.40-5.30)]. The IHC score, combining the expression of γH2AX and p53, demonstrated strong predictive accuracy (C-index = 0.705) with AUCs of 0.894 (3-year), 0.909 (5-year), and 0.733 (10-year). Compared with the current surveillance strategy, 5.06% of the previous low-risk group with non-dysplastic LULs changed to the high-risk group (both γH2AX and p53 positive) with a cumulative incidence of HGIN and above (HGINA) of 44.7% (17/38). while 29.17% of individuals in the previous high-risk group with low-grade intraepithelial neoplasia > 1 cm changed to the low-risk group (neither γH2AX nor p53 positive) with no incident of HGINA (0/7). CONCLUSIONS: γH2AX, a novel incidence-warning IHC marker for esophageal squamous precancerous lesions, combined with p53, showed robust and durable predictive performance for incident malignancy after one-time screening. Integrating IHC testing could help refine risk stratification and mitigate over- and under-surveillance within current ESCC screening protocol.
Frozen melanoma tissues yield extracellular vesicles with preserved diagnostic and immunogenic properties.
D Arrigo D, Park KS, Lässer C … +7 more , Sigalas GP, Symonds E, Urzí O, Locatelli C, Olofsson Bagge R, Lötvall J, Crescitelli R
BMC Med · 2026 May · PMID 42169004 · Full text
BACKGROUND: Extracellular vesicles (EVs) isolated from tumor tissues carry disease-associated proteins and surface antigens, making them promising candidates for cancer diagnostics and immunotherapy. For EV-based approac...
BACKGROUND: Extracellular vesicles (EVs) isolated from tumor tissues carry disease-associated proteins and surface antigens, making them promising candidates for cancer diagnostics and immunotherapy. For EV-based approaches to reach clinical application, it is essential that functional EVs can be obtained from clinically accessible materials, including cryopreserved tumor tissues stored in biobanks. Whether cryopreservation alters EV integrity and function remains unclear. This study evaluates whether EVs derived from cryopreserved tumor tissues retain key molecular and biological properties required for diagnostic and therapeutic use. METHODS: EVs were isolated from human metastatic melanoma tissues processed immediately after surgical resection (fresh) or after storage at - 80 °C (frozen), using a protocol consistent with standard biobank procedures. EV isolation was performed through ultracentrifugation followed by an iodixanol density cushion. The resulting EVs were characterized by transmission electron microscopy, nanoparticle tracking analysis, and mass spectrometry to assess EV morphology, purity, and molecular composition. The diagnostic potential was evaluated by examining the presence of previously identified cancer-associated membrane proteins. Furthermore, therapeutic potential was assessed in vivo by co-administering EVs from fresh or frozen melanoma tissues with synthetic bacterial vesicles and evaluating their effects on tumor growth in melanoma-bearing mice. RESULTS: EVs from fresh and frozen tissues showed similar morphology, size distribution, yield, and purity. Moreover, the protein composition, including cancer-associated markers such as MT-CO2, COX6c, SLC24A22, HLA-DR, and Erlin2, was highly consistent between EVs derived from fresh and frozen tissues, with no relevant enrichment of intracellular or mitochondrial contaminants in frozen-derived EVs. Functionally, EVs from cryopreserved tissues combined with synthetic bacterial vesicles significantly inhibited tumor progression in vivo, demonstrating antitumor effects comparable to those of EVs from fresh tissues. CONCLUSIONS: Our results validate cryopreserved tissues as a reliable source of functional EVs, comparable to fresh tissues. This supports the potential use of existing biobanks for retrospective EV-based biomarker discovery and functional research.
Global immunisation planning and economic development potential: a panel data analysis for the macroeconomic impact of hepatitis B vaccination from 2000 to 2018.
Quan L, Fang Y, Zhang L
BMC Med · 2026 May · PMID 42168979 · Full text
BACKGROUND: The Immunisation Agenda 2030, led by the World Health Organisation (WHO), outlines a ten-year strategy to ensure universal access to vaccines worldwide to improve health and well-being. The hepatitis B virus...
BACKGROUND: The Immunisation Agenda 2030, led by the World Health Organisation (WHO), outlines a ten-year strategy to ensure universal access to vaccines worldwide to improve health and well-being. The hepatitis B virus (HBV) vaccine, included in the Global Alliance for Vaccines and Immunisation (Gavi) pentavalent vaccine, has been successfully introduced in many low-income countries since 2000. Despite its recognised cost-effectiveness in enhancing health capital, the economic pathways through which vaccination rate affects development remain underexplored. This study aims to examine the effect of vaccination rate on gross domestic product (GDP) growth and its underlying mechanisms after the launch of Gavi. METHODS: Data were mainly obtained from WHO, World Development Indicators (WDI), Penn World Table 10.0 (PWT 10.0), WHO and UNICEF Estimates for National Immunisation Coverage (WUENIC). A conditional convergence model was used to evaluate the association between the three-dose vaccine of HBV (HBV3) vaccination rate and GDP growth from 2000 to 2018 across countries. Guided by Grossman's health capital theory, the study further explored mediation pathways via the under-5 mortality rate and the number of persons engaged. Income-group-based heterogeneity analyses were also conducted. RESULTS: HBV3 vaccination rates rose globally during the study period, with the rate gap across income groups narrowing from over 20% to around 10%. A 1% increase in HBV3 vaccination rate was associated with a 1.17% GDP per capita convergence rate per year (p < 0.01). Vaccination rate was negatively associated with the under-5 mortality rate (β=-0.104, p < 0.01) and positively with the number of persons engaged (β = 6.935, p < 0.01), though mediation was only partial. Heterogeneity analyses by income group revealed that the economic impact of vaccination rate was significantly concentrated (β = 0.0164, p < 0.01) in lower-middle-income countries (LMICs). CONCLUSIONS: These findings suggest that improved HBV3 vaccination rate promotes GDP growth through enhanced health capital, especially in LMICs. Therefore, sustained investments in routine immunisation are crucial for maximising economic and health returns and addressing vaccine inequities. However, the limitations of the analytical framework and data accessibility hinder solid conclusions regarding the long-term economic impacts driven by delayed health benefits.
Disability free life expectancy: a simulation study of scenarios to extend healthy years and reduce inequalities.
Sinclair DR, Davies LE, Hanratty B … +3 more , Todd C, Matthews FE, Kingston A
BMC Med · 2026 May · PMID 42168976 · Full text
BACKGROUND: The gap in Disability-Free Life Expectancy between affluent and deprived areas of England is stark, at over 15 years. Successive governments have recognised the need to narrow this and extend the years of lif...
BACKGROUND: The gap in Disability-Free Life Expectancy between affluent and deprived areas of England is stark, at over 15 years. Successive governments have recognised the need to narrow this and extend the years of life spent without disability, but there is little evidence outlining how large an intervention must be to achieve meaningful gains. This study examines intervention scenarios to (i) extend Disability-Free Life Expectancy and (ii) reduce socioeconomic inequalities in Disability-Free Life Expectancy, among older people in England. METHODS: We applied multistate modelling to longitudinal data on 16 899 individuals, aged 50 + in England, incorporating disability data from three cohort studies: the English Longitudinal Study of Ageing, the Cognitive Function and Ageing Study II, and the Newcastle 85 + Study. Simulations assessed how reducing the risk of disability associated with age and area-based socioeconomic deprivation could extend Disability-Free Life Expectancy. In these simulations, deprivation-targeted interventions reduced the excess disability risk and differential recovery observed in people living in the 20% most deprived areas. Age-targeted interventions reduced the age-related increase in disability risk and the corresponding decline in recovery. RESULTS: Interventions targeted solely at the most deprived quintile yielded modest Disability-Free Life Expectancy gains (up to 2.8 years for women and 2.3 years for men, in deprived areas only). Interventions targeting age-related disability risk alone were associated with increases in Disability-Free Life Expectancy of 6.3 to 8.7 years under a 40% reduction in age-related disability risk, but exacerbated the gap between the most and least deprived populations. Interventions addressing both age- and deprivation-associated risks demonstrated the greatest potential. A 30% decrease in the age-based probability of disability, and commensurate increases in recovery from disability, alongside removal of deprivation-associated inequalities, increased Disability-Free Life Expectancy by 4.8 to 8.6 years for men and women aged 50, with women living in deprived areas benefiting most. CONCLUSIONS: Extending Disability-Free Life Expectancy while reducing socioeconomic inequality is difficult, but possible by tackling both age- and deprivation-related risks. Taken on their own, age-based interventions risk increasing inequalities, as they disproportionately benefit people living in less deprived areas.
Development and validation of an MRI-based deep learning system for triple-class ER expression classification in breast cancer: a large-scale multicenter study.
Dai Y, Wong C, Du S … +15 more , Xu Z, Wei Z, Liang Y, Han C, Lian C, Aishanjiang D, Chen M, Huang R, Qu J, Zhang L, Cheng G, Zhang X, Wang Y, Liu Z, Shi Z
BMC Med · 2026 May · PMID 42163319 · Full text
BACKGROUND: Estrogen receptor (ER) expression is a key prognostic and predictive marker in breast cancer. The 2020 ASCO/CAP guidelines classify tumors with ≥ 1% ER-positive nuclei as ER-positive, yet ER-low positive (1%-...
BACKGROUND: Estrogen receptor (ER) expression is a key prognostic and predictive marker in breast cancer. The 2020 ASCO/CAP guidelines classify tumors with ≥ 1% ER-positive nuclei as ER-positive, yet ER-low positive (1%-10%) breast cancer remains biologically distinct with an unclear response to endocrine therapy (ET). Given the limitations of invasive ER assessment, we developed and validated an MRI-based deep learning system (BERC) for non-invasive classification of ER negative, ER-low positive, and ER-high positive breast cancer using multicenter data. METHODS: This diagnostic study retrospectively analyzed pretreatment DCE-MRI data from 3500 breast cancer patients across six institutions (February 2016-August 2023). Patients were categorized into ER negative, ER-low positive, and ER-high positive groups based on pathology. Tumor segmentation on DCE T1-weighted images was performed using an automated deep learning algorithm. A DCE-MRI-based model was developed and evaluated for classification performance using the area under the receiver operating characteristic curve (AUC), along with sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) with 95% confidence intervals. Model interpretability was evaluated through t-SNE and UMAP for feature visualization, along with SHAP analysis for interpreting key predictive features. RESULTS: The training dataset included 1862 patients (median age 49 years, interquartile range [IQR] 21-88), while 1638 patients from four external centers formed the test dataset (median ages ranging from 47 to 51 years across centers). The model achieved Micro-/Macro-average AUCs of 0.918/0.882 in training and 0.923/0.900 in internal validation. In external testing, Micro-average AUCs ranged from 0.828 to 0.923 and Macro-average AUCs from 0.825 to 0.905 across four independent centers. Visualization techniques revealed clear, biologically plausible clustering patterns across the ER expression categories. CONCLUSIONS: BERC shows potential for non-invasive, preoperative ER status prediction in breast cancer, with implications for personalized therapy.
Cardiorespiratory fitness, genetic susceptibility, and the risk of chronic obstructive pulmonary disease: findings from observational and two-sample bidirectional Mendelian randomisation analyses.
Chen Z, Collings PJ, Shi Q … +6 more , Yeung SLA, Luo S, Li C, Gonzales T, Brage S, Kim Y
BMC Med · 2026 May · PMID 42163317 · Full text
BACKGROUND: Cardiorespiratory fitness (CRF) is a common risk factor for cardiometabolic diseases, but the causal relation of CRF with chronic obstructive pulmonary disease (COPD) and its interplay with genetic risk remai...
BACKGROUND: Cardiorespiratory fitness (CRF) is a common risk factor for cardiometabolic diseases, but the causal relation of CRF with chronic obstructive pulmonary disease (COPD) and its interplay with genetic risk remain unknown. We integrated genetic susceptibility and causal inference methods to evaluate the protective roles of CRF in COPD development. METHODS: We included 68,288 White British individuals from the UK Biobank (aged 40-79 years) without prevalent COPD at the baseline (2006-13). CRF was assessed using heart rate responses to submaximal bike tests. Genetic risk for COPD was quantified using a polygenic risk score constructed from 71 uncorrelated single nucleotide polymorphisms. Cox regression was used to estimate the hazard of COPD. Causal inference was evaluated via two-sample Mendelian randomisation (MR). Potential reverse causation was assessed using a bidirectional MR. RESULTS: Within an MR framework, we found that higher genetically predicted CRF is causally associated with lower risk of COPD. Observational analysis found: (1) compared with low CRF (bottom tertile), hazard ratios (95% CI) of COPD were 0.80 (0.72-0.89) and 0.71 (0.64-0.80) for medium and high CRF, respectively; (2) compared to the high CRF-low genetic risk group, COPD hazards were higher for individuals who had medium or high genetic risk combined with low or medium CRF but not for those who had medium genetic risk but high CRF; (3) low CRF combined with any levels of genetic risk showed consistently higher COPD hazards relative to high CRF and low genetic risk combination. CONCLUSIONS: Being more aerobically fit may prevent or delay the onset of COPD. Improving CRF has the potential to attenuate the increased risk of COPD associated with elevated genetic risk. Public health initiatives should prioritise making measurable improvements in cardiorespiratory fitness (beyond merely being active or exercising more) as a promising intervention target for reducing the risk of COPD.
Cost-effectiveness of prehabilitation for elderly (pre-)frail patients prior to elective surgery compared to standard care - an economic evaluation from a societal perspective.
Rombey T, Eckhardt H, Quentin W … +10 more , Weber Z, Buchka S, Kiselev J, Loidl V, Mansmann U, Schaller SJ, Schmidt K, Spies C, Busse R, Schöner L
BMC Med · 2026 May · PMID 42163295 · Full text
BACKGROUND: Frailty syndrome is highly prevalent among elderly surgical patients, increasing their risk of experiencing perioperative complications and developing long-term disability. Prehabilitation may reduce these ri...
BACKGROUND: Frailty syndrome is highly prevalent among elderly surgical patients, increasing their risk of experiencing perioperative complications and developing long-term disability. Prehabilitation may reduce these risks by optimising patients' physiological reserves prior to surgery. The PRAEP-GO trial, a multicentre randomised controlled outcome assessor-blinded trial conducted in Germany, evaluated the (cost-)effectiveness of prehabilitation for older (pre-)frail patients undergoing elective surgery compared to standard care. METHODS: The economic evaluation comprised (i) a cost-utility analysis with the quality-adjusted life year (QALY) as the outcome and (ii) a cost-effectiveness analysis. The latter used the change in level of care dependency from baseline to 12 months postoperatively (deterioration versus no deterioration) as the primary effect measure and the WHO Disability Assessment Schedule (WHODAS 2.0) at 12 months as secondary effect measure. We calculated incremental cost-effectiveness ratios (ICERs) and determined the probability of cost-effectiveness at arbitrary willingness-to-pay thresholds. The main analysis was an intention-to-treat analysis. Additionally, we performed complete case, per-protocol and sensitivity analyses as well as subgroup analyses. RESULTS: The cost-utility analysis yielded an ICER of 45,547 EUR per QALY gained, indicating a 52% probability of cost-effectiveness at a willingness-to-pay of 50,000 EUR. The cost-effectiveness analysis yielded an ICER of 27,197 EUR per patient with a deterioration in care dependency level prevented, with a 69% probability of being cost-effective at 50,000 EUR. Regarding the QALY, the probabilities were higher in the per-protocol analyses, which included patients who received at least 15 sessions of prehabilitation and those who additionally underwent the planned surgery. The cost-effectiveness analysis based on the WHODAS 2.0 yielded an ICER of 1,241 EUR per point gained. Subgroup analyses revealed that the intervention is cost-effective for patients who received prehabilitation in an outpatient setting compared to a propensity-score matched control. CONCLUSIONS: The intervention was found to be more effective, but also more costly than standard preoperative care. Cost-utility was higher when the intervention was completed as intended. It may be cost-effective in patients who received prehabilitation in an outpatient setting. Future efforts should therefore prioritise optimising adherence and ensuring effective outpatient delivery. TRIAL REGISTRATION: Economic evaluation: OSF Registries (osf.io/ecm74), PRAEP-GO trial: ClinicalTrials.gov (NCT04418271).
Application of age- and sex-specific reference intervals for thyroid-stimulating hormone and free thyroxine in evaluating incidence and trends of thyroid dysfunctions: A population-based cohort study.
Lu J, Tang CM, Ge GM … +7 more , Cheng KK, Lee KC, Tan KC, Lam SK, Cheung EY, Cheung CL, Li GH
BMC Med · 2026 May · PMID 42163258 · Full text
BACKGROUND: Diagnosis of thyroid dysfunctions heavily relies on the biochemical tests for thyroid-stimulating hormone (TSH) and free thyroxine (FT4). Conventional laboratory-specific reference intervals (RIs) for TSH and...
BACKGROUND: Diagnosis of thyroid dysfunctions heavily relies on the biochemical tests for thyroid-stimulating hormone (TSH) and free thyroxine (FT4). Conventional laboratory-specific reference intervals (RIs) for TSH and FT4 are uniform across adults and ignore age-, sex-, and time-related variations, which may lead to misdiagnosis of thyroid dysfunction. This study aimed to establish the age- and sex-specific RIs for TSH and FT4, and to evaluate their implications on the incidence and secular trends of thyroid dysfunctions. METHODS: Using a population-based electronic health record database in Hong Kong, we identified individuals without thyroid-related disorders who had valid TSH (N = 2,111,661) and FT4 (N = 825,522) measurements from 2006 to 2019. After harmonizing data across multiple institutions, we derived age- and sex-specific lower and upper reference limits (LRLs and URLs) for TSH and FT4 using the 2.5th and 97.5th percentiles of the biomarker distribution in seven age groups for both females and males. In comparison with the laboratory-specific RIs, we reclassified the thyroid status of the cohort individuals. We also compared the standardized incidence rates and secular trends in thyroid dysfunctions defined by the age- and sex-specific RIs and the conventional RIs. RESULTS: TSH and FT4 distributions varied by age, sex, and calendar year. Age- and sex-specific RIs for TSH and FT4 were significantly wider among elderly individuals (≥ 70 years) compared to the youngest adults (18-29 years). Among those with both TSH and FT4 measurements, 30.78% were classified as having thyroid dysfunctions using laboratory-specific RIs, whereas applying age- and sex-specific RIs reduced this proportion to 18.57%. The use of age- and sex-specific RIs was associated with lower observed incidence rates and revealed estimates of incidence and secular trends that are likely closer to the underlying disease burden. CONCLUSIONS: Age- and sex-specific RIs could mitigate misdiagnosis of thyroid dysfunctions, thereby improving diagnostic accuracy and enabling more precise monitoring of secular trends. The secular trends and joinpoints identified for the age- and sex-specific URLs and LRLs of TSH and FT4 from 2006 to 2019 indicate that regular RI review is needed to ensure their continued clinical relevance. Future validation in geographically and ethnically diverse populations is warranted.
The tissue-specific effects of glucose-lowering drug targets on aging mediated through DNA methylation: a multi-omics genetic study.
Sun Y, Zheng H, Huang L … +8 more , Ma M, Gu R, Wang M, Fang S, Sun Y, Yang Q, Bi Y, Zheng J
BMC Med · 2026 May · PMID 42163256 · Full text
BACKGROUND: DNA methylation plays a key role in mediating the anti-aging effects of glucose-lowering drugs. This study aims to systematically explore the potential anti-aging effects of target genes of FDA-approved gluco...
BACKGROUND: DNA methylation plays a key role in mediating the anti-aging effects of glucose-lowering drugs. This study aims to systematically explore the potential anti-aging effects of target genes of FDA-approved glucose-lowering drugs and the underlying epigenetic mediators. METHODS: We conducted a two-sample Mendelian randomization (MR) study to investigate the putative causal relationships between the gene expression levels of glucose-lowering drug targets and 10 aging-related phenotypes, followed by a two-step MR to estimate the mediation effect of DNA methylation. Drug candidates were selected according to the latest review of clinical drug use for type 2 diabetes, and their target genes were obtained from the DGIdb. Tissue-specific cis-expression quantitative trait loci (eQTLs) from GTEx Consortium were selected as genetic instruments to proxy the expression level of drug-target genes. Glycemic phenotypes were used as positive controls to validate the instruments. The cis- and trans-methylation QTLs of Cytosine-phosphate-Guanine sites near the drug target genes were obtained from GoDMC Consortium. Additionally, we performed enrichment analyses focused on tissue specificity and aging pathways to further corroborate our findings. RESULTS: We obtained 194 target genes interacting with 36 FDA-approved anti-diabetic drugs, of which the tissue-specific eQTLs were used to proxy the drug target effects. MR showed strong evidence that nine interacting genes of six glucose-lowering drugs showed anti-aging potential on one or more aging-related phenotypes mediated by DNA methylation: EHMT2, HSPA4, IGF2BP2, IRS1, LPL, NDUFAF1, NDUFS3, SLC22A3, and TCF7L2. These genes were distributed in 17 tissues, especially in the central nervous system, suggesting a potential neural component in their anti-aging effects. For instance, expression of EHMT2 in several brain basal ganglia regions, where the gene interacted with Tolazamide, showed a protective effect on frailty (odds ratio (OR) in caudate = 1.02, 95%CI = 1.01-1.04, FDR adjusted P = 1.69 × 10; OR in putamen = 1.02, 95% CI = 1.01-1.03, P = 3.37 × 10, OR in nucleus accumbens = 1.02, 95% CI = 1.01-1.04, P = 3.37 × 10). These associations were externally validated by searching literature evidence in existing EWAS and TWAS studies, as well as evidence from enrichment analyses. CONCLUSIONS: This study prioritizes nine glucose-lowering genes as anti-aging drug targets in specific tissues and prioritizes their epigenetic regulation through DNA methylation for future drug development.
Bowel cancer care in individuals with an intellectual disability: a population-based cohort study of symptoms, diagnostic pathways, treatment and survival.
Kennedy OJ, Chauhan U, Gorman L … +6 more , Lorigan P, Merriel SWD, Perumal A, Van Staa T, Wright A, Ashcroft DM
BMC Med · 2026 May · PMID 42157251 · Full text
BACKGROUND: People with an intellectual disability (ID) are at increased risk of bowel cancer. However, evidence on their presenting symptoms, diagnostic pathways, treatments and survival remains limited. METHODS: A matc...
BACKGROUND: People with an intellectual disability (ID) are at increased risk of bowel cancer. However, evidence on their presenting symptoms, diagnostic pathways, treatments and survival remains limited. METHODS: A matched cohort study was conducted using linked primary care (Clinical Practice Research Datalink), hospital, cancer, and mortality records. Outcomes included symptoms associated with bowel cancer, faecal immunochemical or faecal occult blood (FIT/FOB) testing, urgent suspected cancer (USC) referral, endoscopy, surgery, systemic anticancer therapy (SACT), and bowel cancer-specific mortality. Adjusted incidence rate ratios (aIRRs), risk ratios (aRRs), and hazard ratios (aHRs) were estimated using Poisson, modified Poisson and Cox regression. RESULTS: A total of 111,034 individuals with an ID were matched to 1,964,420 comparators. ID was associated with increased risk of bowel cancer (aHR 1.30, 1.18-1.44), particularly before age 50 years (aRR 2.19, 1.68-2.85). People with an ID presented more frequently with symptoms associated with bowel cancer (aIRR 2.59, 2.53-2.65) but, following such symptoms, were less likely to undergo FIT/FOB testing (aRR 0.74, 0.67-0.83), USC referral (aRR 0.57, 0.52-0.62), endoscopy (aRR 0.45, 0.42-0.49), or receive a diagnosis within 56 days (aRR 0.52, 0.41-0.67). They were also less likely to be diagnosed via screening (aRR 0.27, 0.14-0.50) or USC referral (aRR 0.62, 0.50-0.76), and more likely to be diagnosed via emergency presentation (aRR 1.76, 1.52-2.02), on the date of death (aRR 5.08, 2.92-8.84), or with stage IV disease (aRR 1.25, 1.01-1.56). ID was associated with similar proportions receiving curative surgery for stage I-III disease (aRR 0.98, 0.79-1.19), but markedly lower proportions receiving SACT for stage IV (aRR 0.15, 0.05-0.46), and higher bowel cancer-specific mortality across all stages (aHR 2.00, 1.71-2.33). CONCLUSIONS: People with an ID experience worse outcomes across nearly all stages of the bowel cancer care pathway, including referral, investigation, treatment and survival. Earlier screening may be justified given the elevated risk in those under age 50 years.
Design considerations for hypertension chronotherapy trials: insights from experience and modelling.
Walch O, Rogers A, Huang YP … +7 more , Ruben MD, Dyar KA, Flynn RWV, Mackenzie IS, Manfredini R, Cappuccio FP, Pigazzani F
BMC Med · 2026 May · PMID 42157233 · Full text
Chronotherapy aims to maximise treatment efficacy while minimising side effects by scheduling treatment according to personal biological rhythms. In recent years, randomised clinical trials (RCTs) have been conducted to...
Chronotherapy aims to maximise treatment efficacy while minimising side effects by scheduling treatment according to personal biological rhythms. In recent years, randomised clinical trials (RCTs) have been conducted to evaluate whether scheduled blood pressure interventions can improve patient outcomes. However, reports of time-of-day effects have attracted rebuttals and engendered methodological debate. A perfectly controlled chronotherapy trial (i.e., a trial that assesses the effect of assigning time of intervention) will never be feasible in the real world; yet some factors may be more critical to consider and control for than others. To advance the conversation about how best to evaluate the effects of antihypertensive chronotherapeutic interventions in RCTs, we discuss critical considerations for clinical trials of chronotherapy for hypertension and apply mathematical modelling to provide quantitative insights into the extent to which such factors may influence the detected effect size.
Understanding experiences of psychedelic treatments for eating disorders: a meta-synthesis of qualitative studies.
Morris R, Gundogan A, Lawrence V … +3 more , Himmerich H, Treasure J, Keeler JL
BMC Med · 2026 May · PMID 42157199 · Full text
BACKGROUND: Eating disorders (EDs) have complex presentations with high rates of comorbidities and low recovery rates. Current treatment options often lack sufficiency in improving ED symptoms. Psychedelic-assisted thera...
BACKGROUND: Eating disorders (EDs) have complex presentations with high rates of comorbidities and low recovery rates. Current treatment options often lack sufficiency in improving ED symptoms. Psychedelic-assisted therapies represent a novel treatment approach for the treatment of EDs, with research documenting preliminary positive evidence. However, psychedelics have their own challenges and risks which need to be considered within an ED population to inform study design and future clinical application. The primary aim of this meta-synthesis was to integrate existing qualitative data on the experience of using psychedelics in ED treatment from the perspectives of both individuals with EDs and providers (e.g. clinicians, ceremony leaders), using meta-ethnography to generate new interpretative insights. METHODS: The methods followed the seven steps of a meta ethnographic approach. An electronic search of three databases (PubMed, Medline, and PsycINFO) was conducted. Papers were included if they were qualitative studies exploring the use of typical or atypical psychedelics, from the perspective of either a provider or individual experiencing an ED. RESULTS: A total of eight studies were included. From the data we identified five meta-themes that together depict how psychedelic experiences may act as catalysts for transformation. Our interpretive narrative posits that core transformative processes (Mind-Body-Spirit, Emotional Processing), unfold within specific contextual conditions (Navigating Challenges and Risks, Enabling Safe and Supportive Experiences), and lead to meaningful outcomes (Therapeutic Improvements). Meta- and sub-themes reflect ED-specific elements, highlighting that psychedelics may improve emotion processing and enhance perception of and connection with the body and the self, which is pertinent to ED recovery. Themes also indicate the increased risk for adverse side effects with low weight and other physical vulnerabilities associated with EDs. CONCLUSIONS: The themes and interpretive narratives identified in this meta-synthesis suggest that to achieve therapeutic outcomes, ED-specific contextual conditions are required to facilitate internal processes during psychedelic therapy for EDs. This includes minimising the uncertainty that typifies EDs through exploration of expectations and autonomy in selection of setting elements (e.g. lighting, music, eye-mask) or collaboratively agreeing strategies for if anxiety spikes. Further, facilitators should require dual competency in psychedelic treatment and ED psychopathology and treatment.
Mpox severity and mortality in Africa: a systematic review and meta-analysis.
Cheuyem FZL, Zefack JT, Achangwa C … +2 more , Tchamani R, Asahngwa CT
BMC Med · 2026 May · PMID 42152055 · Full text
BACKGROUND: Mpox presents a significant public health threat with variable severity driven by viral clades and host factors. After over 50 years of outbreaks, this study aimed at providing a comprehensive continent-wide...
BACKGROUND: Mpox presents a significant public health threat with variable severity driven by viral clades and host factors. After over 50 years of outbreaks, this study aimed at providing a comprehensive continent-wide assessment of its severity and mortality for evidence-based public health planning and clinical management. METHODS: This systematic review and meta-analysis, conducted per PRISMA guidelines and registered with PROSPERO (CRD420251133745), aggregated data from studies on mpox severity and mortality in Africa from 1970 to 2025. A systematic search of multiple databases was performed. The primary outcomes were the mpox severity rate (proportion of severe cases among confirmed cases) and the case fatality rate (CFR). Random-effects models were used due to high heterogeneity. RESULTS: The pooled severity rate among confirmed mpox cases in Africa was 43.8% (95% CI: 36.3-51.6; n = 5,417; 37 reports). The pooled CFR was 3.8% (95% CI: 1.9-7.6; n = 6,877; 43 reports) for confirmed cases and 2.5% (95% CI: 1.3-4.6; n = 3,815; 47 reports) for suspected cases. A significant temporal decline was observed; after the 2022 global outbreak, the CFR for confirmed cases dropped to 1.04% from 6.50% beforehand. Substantial geographical disparities existed, with the Central African region bearing the highest burden (severity: 45.51%; CFR: 5.44%), compared to West Africa (severity: 25.43%; CFR: 0.97%). Infections with Clades Ia and Ib were associated with higher severity, whereas Clade II was linked to milder disease. Key risk factors for severe outcomes and death included young age (< 10 years), HIV coinfection, lack of prior smallpox vaccination, and pregnancy. Community-based studies reported higher CFRs than hospital-based studies. No significant publication bias was detected, and sensitivity analyses confirmed the robustness of the pooled estimates. CONCLUSIONS: This study confirms a high but declining burden of severe and fatal mpox in Africa, characterized by significant temporal, geographic, and clade-specific variations. While a global shift towards milder disease is evident, Central Africa remains disproportionately at risk due to the persistent circulation of more virulent clades and underlying health inequities. Sustained investment in surveillance, vaccination, and strengthened healthcare capacity in endemic regions is crucial to reduce future morbidity and mortality.
Generative AI for spatial tumor growth on MRI: a proof-of-principle study in pediatric diffuse midline glioma.
Laslo D, Wolleb J, Monzon M … +21 more , Kottke R, Sirin S, Müller T, Suhami D, Vogt F, Bhatia A, Gandhi DB, Kazerooni AF, Familiar AM, Nguyen T, Jiang Z, Parida A, Gerber NU, Stücklin AG, Nabavizadeh A, Nazarian J, Linguraru MG, Rauschecker AM, Müller S, Jutzeler C, Brüningk S
BMC Med · 2026 May · PMID 42151998 · Full text
BACKGROUND: Magnetic resonance imaging (MRI) is a cornerstone of non-invasive diagnosis and response monitoring in neuro-oncology, and predictions of spatial tumor progression conditioned on the patients' anatomy are inc...
BACKGROUND: Magnetic resonance imaging (MRI) is a cornerstone of non-invasive diagnosis and response monitoring in neuro-oncology, and predictions of spatial tumor progression conditioned on the patients' anatomy are increasingly important. We present a proof-of-principle of personalized spatial tumor progression on MRI through generative AI, focusing on pediatric Diffuse Midline Glioma (DMG). METHODS: We employed guided Denoising Diffusion Implicit Models (DDIM) to model anatomical tumor growth in pediatric DMGs on MRI. Multiparametric scans from adult (n = 1,251) and pediatric (n = 144) patients from the BraTS23 challenge were used to train a slice-based framework, conditioned on baseline scans and a target tumor size. Repeated image generations produce probabilistic tumor growth maps highlighting likely regions of progression. The realism of the generated MRIs was evaluated quantitatively and qualitatively through expert assessment. Spatial growth predictions were validated against an independent dataset of longitudinal MRI scans from a multi-institutional pre-radiotherapy DMG dataset (n = 178 paired slices). RESULTS: We generated anatomically coherent, patient-specific T2-FLAIR (fluid-attenuated inversion recovery) MRI axial slices. Quantitative measures and expert evaluations confirmed the high quality of the generated images, which trained radiologists were unable to reliably distinguish from real scans (accuracy 0.53 ± 0.03). While radiomic features analyses showed good agreement (83% non-significant features) between synthetic and real images, a classifier detected subtle pixel-wise differences (accuracy of 0.69). Tumor growth probability maps aligned well with true tumor growth observed in follow-up imaging, obtaining a mean continuous DICE score of 0.79 ± 0.13. CONCLUSIONS: We present guided DDIMs as a predictive tool for spatial tumor growth, illustrated for the progression of DMGs, that demonstrates potential for its integration in personalized radiotherapy planning. Our comprehensive image quality analysis highlights the importance of carefully evaluating synthetic data and its integration in research and clinical workflows.
The impacts of introducing online postal self-sampling for sexually transmitted infections on the sustainability and equity of sexual health systems: lessons learned from a multi-method UK-wide realist evaluation.
Sheringham J, Wong G, Spence T … +17 more , Stirrup O, Tostevin A, Howarth A, Copas A, Crundwell D, Jackson L, Mercer CH, Mohammed H, Apea V, Day S, Ross JDC, Sullivan A, Tittle V, Winter A, Dewsnap C, Gibbs J, Burns F
BMC Med · 2026 May · PMID 42151930 · Full text
BACKGROUND: Online postal self-sampling (OPSS) for sexually transmitted infections and blood borne viruses (STI/BBVs) has been introduced in several countries, because it may lower costs, and increase access for service...
BACKGROUND: Online postal self-sampling (OPSS) for sexually transmitted infections and blood borne viruses (STI/BBVs) has been introduced in several countries, because it may lower costs, and increase access for service users. There are gaps in the evidence on the equitable delivery to underserved populations beyond men who have sex with men, the implementation and maintenance of programmes and its impact on wider health systems. This study synthesised evidence from the ASSIST research programme, which evaluated the implementation, equity, impacts and economic consequences of OPSS in England (2015-2022), with a focus on understanding how and why unintended consequences may emerge in other contexts. METHODS: A synthesis using a realist logic of analysis was undertaken across multiple sources of evidence from ASSIST workstreams. Context-mechanism-outcome configurations were developed from a systems perspective. They were iterated through comparisons with initial programme theory and through feedback obtained from sexual health providers, funders, researchers and service users. RESULTS: In England, OPSS appears convenient and achieved higher testing uptake for lower costs per diagnosis. However, there were unintended consequences, principally: (1) difficulties in containing demand for OPSS could result in higher total costs than planned; (2) the introduction of OPSS affected wider sexual health system sustainability, particularly when the context changed; (3) inequalities in sexual health may widen after the introduction of OPSS in part due to missed presentation opportunities. These challenges prompted adaptive responses in health systems, leading to a rebalancing between OPSS and clinic-based services. CONCLUSIONS: While the introduction of OPSS in the context of reducing sexual health budgets offers some clear advantages to entirely clinic-based sexual health services, excessive demand and difficulties in access and use risk destabilising sexual health systems and worsening inequalities. Strategic rebalancing of OPSS and clinic-based provision is essential to mitigate unintended effects and ensure equitable, resilient service delivery. PROTOCOL: https://doi.org/10.1136/bmjopen-2022-067170.
Clustering of multimorbidity in stroke and transient ischaemic attack survivors: a population-based study.
Massou E, Edwards D, Zhu Y … +2 more , Yang Z, Mant J
BMC Med · 2026 May · PMID 42151925 · Full text
BACKGROUND: Stroke and transient ischaemic attack (TIA) survivors frequently experience multiple long-term conditions (multimorbidity) placing substantial demands on healthcare systems. Moving away from a single-disease...
BACKGROUND: Stroke and transient ischaemic attack (TIA) survivors frequently experience multiple long-term conditions (multimorbidity) placing substantial demands on healthcare systems. Moving away from a single-disease approach could lead to more efficient and effective care for stroke survivors with multimorbidity. However, it is unclear how to categorise the stroke population to achieve this. To inform care, this population-based study identified and described clusters of stroke survivors with multimorbidity. METHODS: Using the Clinical Practice Research Datalink GOLD database, we identified 69,372 adult stroke/TIA survivors who were currently registered with a general practice on the 1st July 2017. We defined multimorbidity as the co-occurrence of ≥ 2 of 36 long-term conditions (including stroke/TIA) and divided patients into four age strata (< 45, 45-64, 65-84, ≥ 85). Within each stratum, Latent Class Analysis identified classes of co-morbid stroke survivors based on statistical diagnostics, clustering interpretation and clinical input. We investigated the validity of our findings, using a training and a test set. We described clusters according to prevalence of long-term conditions, demographic factors (age, gender, ethnicity, smoking, BMI) and health outcomes (mortality, hospital admissions, primary care consultations, prescriptions). RESULTS: In the UK, 94·7% of adult stroke/TIA survivors live with at least one additional long-term condition, with a median of five conditions per patient. We identified 12 clusters. Among 45-64-year-olds, the "alcohol and substance misuse" (6%) and the "established cardiovascular disease" (5%) clusters, have the highest mortality, while the "lower morbidity, better outcomes" cluster included 49% of patients. In ages 65-84, the "poor mental health" cluster (25%) exhibits the highest mortality. Among patients [Formula: see text]85, the "dementia-dominant" cluster had the highest rates of mortality, whereas the "established cardiovascular disease" cluster had the most hospital admissions. In each age strata, a cluster with increased mental health needs, and another with lower rates of multimorbidity and the best health outcomes could be identified. CONCLUSIONS: Internally validated clusters of stroke survivors can be identified with distinct patterns of multimorbidity, healthcare utilisation, and mortality. By understanding these clusters, more targeted, efficient, and integrated models of post-stroke care can be designed to better address the overall healthcare needs of stroke survivors.
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