BMC Medicine[JOURNAL]
Sun
200 papers
Survey to inform personalised prescribing in a British South Asian community: pharmacogenomics and traditional medicine use.
Magavern EF, Marengo G, Kanoni S … +7 more , Patel MG, Spreckley M, Raza M, Khan T, Genes & Health Research Team, Collier D, Caulfield MJ
BMC Med · 2026 May · PMID 42141473 · Full text
BACKGROUND: Pharmacogenomics (PGx) uses genetic information to personalize medication, reducing adverse reactions and improving efficacy. Despite its promise, low public awareness and disparities in PGx acceptability amo...
BACKGROUND: Pharmacogenomics (PGx) uses genetic information to personalize medication, reducing adverse reactions and improving efficacy. Despite its promise, low public awareness and disparities in PGx acceptability among under-represented groups may exacerbate health inequalities. The objective of this study was to elucidate a British South Asian community's attitudes toward personalised prescribing. METHODS: Adults of Bangladeshi or Pakistani ancestry from the Genes & Health (G&H) study completed a survey. Community feedback guided theme prioritization. Multivariable logistic regression analyses (controlling for age and gender) explored relationships among survey variables, and case-control Genome Wide Association Studies (GWAS) and candidate variant enrichment analysis examined the genetic architecture underlying herbal remedy use. RESULTS: Out of 553 respondents (57% female, mostly aged 25-54), 72% reported medication inefficacy, and 54% experienced side effects. Herbal remedies were widely used (66%), notably Black seed (39%), Turmeric (37%), and Ginger (36%). Participants who reported not using traditional or herbal medicines had higher medication adherence MARS-5 scores (Odds Ratio (OR) 1.10, 95% Confidence Interval (CI) 1.05-1.16, p < 0.0002). All three commonly used herbal remedies inhibit the pharmacogenomically variable CYP2C9 enzyme responsible for metabolising commonly used medications. 58% of respondents were willing to provide DNA samples for PGx testing, yet 70% agreed that they would be more likely to take medication as instructed if PGx results suggested the medicine would suit them. Concerns about PGx testing were common (27%), especially among non-English speakers. Most (69%) were concerned about misuse of PGx data, particularly by pharmaceutical companies (82%). Importantly, 87% demanded stronger PGx data protections compared to other health data. CONCLUSIONS: Compared to a national UK population, the surveyed subpopulation reported higher rates of adverse drug reactions (ADRs) and perceived medication inefficacy, yet fewer respondents indicated willingness to undergo PGx testing. This highlights the need for tailored implementation strategies and underscores the importance of engaging underrepresented populations in policy development. The inverse relationship between medication adherence and herbal remedy use indicates an association between cultural health practices and medication behaviours that merits further investigation. Increased awareness of the common use of these CYP2C9 inhibitors and further research into the genetic architecture underlying herbal remedy use are warranted.
Maintenance and disruption of the physiological dimer structure of TDP-43 in amyotrophic lateral sclerosis and frontotemporal lobar degeneration.
Tamaki Y, Kaneko S, Urushitani M
BMC Med · 2026 May · PMID 42135750 · Full text
BACKGROUND: Transactive response DNA-binding protein of 43 kDa (TDP-43) is an essential regulator of RNA metabolism, playing a pivotal role in splicing, transport, and stability. While its cytoplasmic aggregation is the...
BACKGROUND: Transactive response DNA-binding protein of 43 kDa (TDP-43) is an essential regulator of RNA metabolism, playing a pivotal role in splicing, transport, and stability. While its cytoplasmic aggregation is the pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), recent evidence suggests that the earliest pathogenic event is the disruption of its physiological homodimeric structure. Under healthy conditions, TDP-43 forms dimers via its N-terminal domain, a configuration that is crucial for its nuclear solubility and cooperative RNA binding. In this review, we propose the "Molecular Zipper" hypothesis to describe the maintenance of TDP-43 structural homeostasis. In this framework, the N-terminal domain acts as a stabilizing "NTD-mediated anchor" that keeps the protein in a functional, "zipped" dimeric state, effectively sequestering its aggregation-prone C-terminal regions. Pathogenic triggers-including genetic mutations, aberrant post-translational modifications such as phosphorylation and acetylation, and environmental stressors-can "unzip" this structure, leading to the formation of pathogenic monomers. These pathogenic monomers show increased propensity for cytoplasmic mislocalization and recruit wild-type protein into aggregates through a prion-like seeded aggregation mechanism, culminating in nuclear functional loss and cytoplasmic gain-of-toxicity. We further evaluate the emerging diagnostic landscape, focusing on methods to monitor the dimer-to-monomer ratio. SHORT CONCLUSION: Integrating prior biochemical data on TDP-43 dimerization with structural modeling enables a more coherent account of the transition from the physiological dimer to pathological conformers. The Molecular Zipper framework offers a conceptual foundation for reconciling existing experimental findings and for guiding future studies on early structural changes in TDP-43 proteinopathy.
Beyond data and technology: the need for new thinking to enable the era of precision prevention.
Tsakiroglou M, Harish P, Hemingway H … +9 more , Blagden SP, Gardner S, O'Connor D, Rentsch CT, Ford G, Saoulidis A, Maclean RH, Denniston AK, Pirmohamed M
BMC Med · 2026 May · PMID 42135719 · Full text
BACKGROUND: Global flagship initiatives increasingly advocate for proactive health maintenance to alleviate the growing burden on reactive, disease-focused healthcare systems. Precision prevention is conceived as the tar...
BACKGROUND: Global flagship initiatives increasingly advocate for proactive health maintenance to alleviate the growing burden on reactive, disease-focused healthcare systems. Precision prevention is conceived as the targeted modulation of causal pathways across the disease continuum, from latent risk and pre-disease states to clinical manifestation, surpassing conventional public health prevention strategies that prioritise managing population-level risk factors. Traditional discovery and implementation models, however, remain poorly aligned with the pace and breadth of scientific and technological advances. This review outlines key barriers to scaling precision prevention and argues for the integration of conceptual, methodological, and policy perspectives into a single implementation‑oriented framework. MAIN: Individualised risk stratification lies at the core of precision prevention. Genomics serves as a stable substrate for lifetime susceptibility assessment, while meaningful prediction in multifactorial chronic disease requires additional risk monitoring using dynamic intermediate molecular markers and high-resolution exposomic data. Machine learning and other artificial intelligence (AI) methods are increasingly helpful tools for integrating large, heterogeneous and temporally structured real-world data to generate personalised predictions of health trajectories. Trustworthy AI-enabled risk prediction or decision-support systems are expected to provide transparency about model logic, assumptions and performance. In discovery, existing diagnostic classifications and conventional case-control designs can obscure mechanistic heterogeneity. Shifting toward precision phenotyping and biologically grounded disease redefinition could reveal a new layer of molecular understanding. Evidence generation strategies that reflect the temporal change of disease, including high‑risk enrichment, surrogate endpoints, and adaptive, trajectory-based monitoring, are particularly important for common conditions with prolonged latency periods (e.g., cancer, cardiovascular disease). Features often dismissed as "noise", such as stochastic molecular variation and minimal exposures, may in fact encode meaningful individual-level signals and thus merit investigation. CONCLUSION: To shift healthcare from reactive treatment toward proactive health maintenance requires coordinated action from stakeholders to reshape the pillars of discovery, reform outcome assessments and modernise implementation strategies.
Associations of centrally acting analgesic use with total joint arthroplasty compared to selective serotonin reuptake inhibitor among osteoarthritis patients in a large prospective cohort.
Wang Z, Westerland M, Peloquin C … +6 more , LaValley M, Petrow E, Clancy M, Hu W, Ding C, Neogi T
BMC Med · 2026 May · PMID 42129763 · Full text
BACKGROUND: Centrally acting analgesics (CAAs) are first-line therapy for neuropathic pain, while selective serotonin reuptake inhibitors (SSRIs) are first-line agents for managing depression, but their effects on osteoa...
BACKGROUND: Centrally acting analgesics (CAAs) are first-line therapy for neuropathic pain, while selective serotonin reuptake inhibitors (SSRIs) are first-line agents for managing depression, but their effects on osteoarthritis (OA) are unclear. We aimed to evaluate the relation of CAA versus SSRI use to risk of total joint arthroplasty (TJA) among people with OA in a population-based cohort. METHODS: We conducted a propensity score-matched, new-user design, active comparator, population-based cohort study using data from IQVIA Medical Record Database (IMRD), limited to people with OA aged between 40 and 89. We identified incident CAA and SSRI users and propensity-score matched them 1:1 using one-year cohort accrual blocks. We compared the risk of TJA among CAA initiators to SSRI initiators using Cox proportional hazards regression. We conducted subgroup analyses limited to those with both OA and depression. We repeated analyses accounting for the competing risk of death using a Fine-Gray model. RESULTS: CAA initiators (n = 11,734) had a higher risk of knee/hip arthroplasty compared with SSRI initiators (n = 11,734), with the propensity score-matched hazard ratio (HR) of 1.81 (95% CI 1.59, 2.07). When additionally adjusted for confounders and when accounting for competing risk of death and drug discontinuation, the effect estimate was slightly reduced (HR 1.48; 95% CI 1.22, 1.80). Subgroup analysis limited to those with both OA and depression demonstrated a positive but non-significant effect estimate. CONCLUSIONS: CAA initiation was associated with higher risk of TJA compared with SSRI initiation. These results may suggest that agents that predominantly impact depression may also have beneficial effects on knee OA progression.
Sodium-glucose cotransporter 2 inhibitors and the risk of kidney cancer among patients with type 2 diabetes: a population-based cohort study.
Lee M, Lee H, Kim EJ … +4 more , Son D, Lee HH, Kim HC, Kang ES
BMC Med · 2026 May · PMID 42121200 · Full text
BACKGROUND: There is an important need to develop clinical strategies to reduce the risk of incident kidney cancer, especially in patients with type 2 diabetes (T2D) often accompanied by chronic kidney disease. Here, we...
BACKGROUND: There is an important need to develop clinical strategies to reduce the risk of incident kidney cancer, especially in patients with type 2 diabetes (T2D) often accompanied by chronic kidney disease. Here, we investigated whether sodium-glucose cotransporter 2 (SGLT2) inhibitor use is associated with reduced kidney cancer risk compared to dipeptidyl peptidase-4 (DPP-4) inhibitor use in patients with T2D, using a nationwide cohort of the Korean national health insurance claims and health examination database. METHODS: After 1:1 propensity score matching, 57,103 SGLT2 inhibitor new users and 57,103 DPP-4 inhibitor new users were selected from 581,702 kidney cancer-free participants, aged 20 to 79 years, who started oral glucose-lowering drugs for T2D from 2014 to 2018. RESULTS: During 408,481 person-years of follow-up, 102 (25.0 per 100,000 person-years) new kidney cancer events occurred. SGLT2 inhibitor use was associated with a 40% reduced risk of kidney cancer compared with DPP-4 inhibitor use (18.9 vs. 30.8 per 100,000 person-years; hazard ratio [HR] 0.60, 95% CI 0.40 to 0.89). The reduced kidney cancer risk associated with SGLT2 inhibitor use versus DPP-4 inhibitor use was consistent even after additional adjustment for all variables composing the propensity scores (HR 0.60, 95% CI 0.40 to 0.90) and regardless of age, sex, body mass index, current smoking, hypertension, medication use, or diabetic complications including nephropathy (all p > 0.05 for interaction). When comparing SGLT2 inhibitor users with 1:1 propensity score-matched non-users, SGLT2 inhibitor use was associated with a 34% reduced risk of kidney cancer compared to non-use (HR 0.66, 95% CI 0.49 to 0.89). CONCLUSIONS: Our findings suggest a potential association between SGLT2 inhibitor use and a lower risk of kidney cancer, which needs to be further validated.
Disentangling the relationship between intrauterine exposures and offspring growth in mid-childhood.
Nguyen KM, Karimi R, Vaudel M … +4 more , Havdahl A, Johansson S, Evans DM, Warrington NM
BMC Med · 2026 May · PMID 42116159 · Full text
BACKGROUND: Conventional epidemiological studies have suggested that lower birthweight and adverse pregnancy events are associated with later life obesity and cardiometabolic disorders, suggesting that intrauterine facto...
BACKGROUND: Conventional epidemiological studies have suggested that lower birthweight and adverse pregnancy events are associated with later life obesity and cardiometabolic disorders, suggesting that intrauterine factors may play an important role in the offspring's later life health. Nevertheless, it remains unclear whether the link between intrauterine factors and childhood anthropometry is causal or driven by confounding or genetic factors. METHODS: We performed two-sample Mendelian randomization (MR) to assess whether adverse pregnancy-related conditions (gestational diabetes, gestational hypertension and pre-eclampsia) and birth outcomes (birthweight, gestational duration and placental weight) have a causal effect on mid-childhood (age 8-10) body mass index (BMI) and height. We selected independent genetic variants from the largest publicly available genome-wide association studies that were associated (P < 5 × 10) with each of the exposures. We partitioned the genetic effect on mid-childhood BMI and height into maternal- and offspring-specific components using 26,301 genotyped mother-offspring pairs from three birth cohorts to account for the correlation between maternal and offspring genotype. The analyses were replicated in 3,885 mother-offspring pairs from the UK Biobank. RESULTS: We found evidence for a causal effect of birthweight on mid-childhood height (β = 0.45 standard deviation (SD) per SD change in birthweight, 95% CI = 0.33-0.57), which can partially be explained by birth length and maternal height, rather than strong mediation through intrauterine factors. Meanwhile, the relationship between birthweight and mid-childhood BMI (β = 0.30 SD per SD change in birthweight, 95% CI = 0.21-0.40) was predominantly driven by genetic pleiotropy. Neither pregnancy-related conditions nor maternal intrauterine effect through gestational duration and placental weight showed no strong evidence of having a causal effect on offspring BMI or height in mid-childhood. CONCLUSIONS: Our study suggests that intrauterine exposures acting through gestational diabetes, gestational hypertension, preeclampsia, birthweight, gestational duration and placental weight are unlikely to be key drivers of offspring mid-childhood BMI or height. The causal relationship identified between birthweight and mid-childhood height but not with mid-childhood BMI suggests that the intrauterine environmental and genetic factors impacting birthweight may be predominantly related to skeletal growth.
The therapeutic effect of novel endoscopic submucosal dissection with lymph node dissection surgery on T1 ESCC: A single center, prospective, and nested case-control study.
Mei Y, Zhou J, Jiang W … +8 more , Pang S, Huang Q, Mei P, Huang Y, Li K, Dong Y, Liao Y, Lin R
BMC Med · 2026 May · PMID 42106806 · Full text
BACKGROUND: Endoscopic submucosal dissection is effective for treating T1 early esophageal squamous cell carcinoma. However, there is a risk of lymph node metastasis . Standard radical surgery may be overtreatment for T1...
BACKGROUND: Endoscopic submucosal dissection is effective for treating T1 early esophageal squamous cell carcinoma. However, there is a risk of lymph node metastasis . Standard radical surgery may be overtreatment for T1 ESCC. This trial was designed to clarify the efficacy of novel dual-scopy combined surgery in the treatment of T1 ESCC. METHODS: Between December 2021 and May 2025, 21 patients underwent dual-scopy combined surgery, 197 underwent ESD, and 213 underwent radical surgery for early (T1 stage) ESCC. This study included 63 patients who underwent ESD, dual-scopy combined surgery, and standard radical surgery (1:1:1) in the efficacy analysis. The patients' overall survival, recurrence-free survival, disease-specific survival, complications, and clinical outcomes were evaluated. RESULTS: There was no significant difference among the three groups in OS, RFS, and DSS. Complication rates were similar between the ESD and dual-scopy groups, both lower than in the radical surgery group. Compared to the radical surgery group, the ESD and dual-scopy groups demonstrated significantly shorter hospital stays and lower costs. Postoperative quality of life and nutritional levels were better in both the ESD and dual-scopy groups compared to radical surgery. CONCLUSIONS: For T1-stage ESCC patients without clear metastasis, the novel dual-scopy combined surgery may achieve lesion resection and lymph node dissection without affecting patient survival. Moreover, it may reduce postoperative complications, hospitalization time, and costs, and potentially improve quality of life and nutritional status compared to standard radical surgery. TRIAL REGISTRATION: This study was registered as a clinical trial with the China Clinical Trial Registration Center (ChiCTR2100053603).
A multi-modal parcellation of human globus pallidus and its implications for symptom prediction and stratification in Parkinson's disease.
Yan T, Wang K, Han Z … +5 more , Ma Y, Wang X, Zhang K, Yang G, Liu T
BMC Med · 2026 May · PMID 42106795 · Full text
BACKGROUND: The globus pallidus (GP) is a critical basal ganglia nucleus for motor and cognitive control. However, traditional single-modality parcellations provide an incomplete understanding of its internal organizatio...
BACKGROUND: The globus pallidus (GP) is a critical basal ganglia nucleus for motor and cognitive control. However, traditional single-modality parcellations provide an incomplete understanding of its internal organization, thereby increasing the risk of imprecision and side effects during therapeutic targeting of its subregions. METHODS: In this study, we developed a multi-modal approach that combines structural and functional connectivity, termed hybrid pallidum parcellation (HPP), to parcellate the GP into anterior (aGP), middle (mGP), and posterior (pGP) subregions. This approach was rigorously evaluated for reproducibility and homogeneity in healthy individuals and behavioral prediction accuracy in healthy individuals and patients with Parkinson's disease (PD). Connectivity and behavioral prediction analyses were further used to explore the structural and functional differences in the GP subregions. RESULTS: Compared with unimodal (structural or functional connectivity-based) and two public parcellations, HPP demonstrated superior reproducibility and homogeneity. In addition, the HPP-based subregions revealed a posterior-to-anterior structural and functional connectivity gradient in GP, reflecting a transition from primary to higher-order networks. Specifically, the pGP dominated in sensorimotor function prediction and the aGP in emotional processing, while the mGP exhibited a more flexible pattern in cognition and higher-order motor control. Furthermore, the HPP parcellation demonstrated generalizability and superiority in better predicting behavioral measures than other parcellations in both healthy individuals and patients with PD. CONCLUSIONS: Overall, HPP provides new insights into the GP's hierarchical functional organization and its subregional roles in PD motor and non-motor symptoms, offering potential to improve patient stratification for PD and related disorders.
Association between air pollution exposure and increased chronic kidney disease risk: the modifying effects of genetic susceptibility, transcriptomic, and proteomic signatures.
Lu J, Sun S, Shang X … +4 more , Deng Z, Wang S, Jiang S, Li W
BMC Med · 2026 May · PMID 42106700 · Full text
BACKGROUND: Air pollution exposure is increasingly recognized as a risk factor for chronic kidney disease (CKD), but the underlying mechanisms, especially the complex gene-environment interactions as reflected in genetic...
BACKGROUND: Air pollution exposure is increasingly recognized as a risk factor for chronic kidney disease (CKD), but the underlying mechanisms, especially the complex gene-environment interactions as reflected in genetic susceptibility, transcriptomic, and proteomic signatures, remain to be elucidated. METHODS: We conducted a large-scale prospective cohort study including 330,002 UK Biobank participants with an average follow-up of 13.0 years. Annual average concentrations of PM, PM, PM, NO, and NO were assessed. Cox proportional hazards models were applied to estimate CKD risk associated with long-term air pollution exposure. We further evaluated non-linear relationships using restricted cubic splines (RCS), potential mediators via mediation analyses, and CKD susceptibility through additive interaction analyses with baseline comorbidities and polygenic risk scores (PRS). Additionally, transcriptome-wide association study (TWAS) and proteome-wide two-step Mendelian randomization (MR) were integrated to explore potential molecular pathways. RESULTS: Higher exposures to PM (HR: 1.36, 95% CI: 1.22-1.51, per 5 µg/m³), PM (HR: 1.25, 95% CI: 1.07-1.46, per 5 µg/m³), PM (HR: 1.20, 95% CI: 1.06-1.36, per 10 µg/m³), and NO (HR: 1.04, 95% CI: 1.02-1.07, per 20 µg/m³) were significantly associated with increased CKD risk, whereas NO showed no significant association (HR: 0.98, 95% CI: 0.95-1.00, per 10 µg/m³). RCS revealed non-linear relationships for PM and PM. Mediation analyses indicated that incident hypertension and type 2 diabetes mellitus (T2DM) acted as potential mediators in these associations. Crucially, additive interaction analyses revealed that participants with pre-existing hypertension or type 1 diabetes mellitus (T1DM) were significantly more vulnerable to specific pollution-driven CKD. Compared to individuals with low genetic risk and low air pollution exposure, those with both high genetic risk and high exposure exhibited the highest CKD risk, demonstrating a clear gradient effect across categories. TWAS identified shared genes potentially linking air pollutants with CKD, including upregulated transcripts (STX2, PHOSPHO2, NECAB3) and downregulated transcripts (CDK3, MEIOB, NDUFAF1, CRIPAK). Furthermore, proteome-wide MR analyses identified ALDH3A1, F12, and SNCG as potential risk proteins, and GNLY and MEGF10 as protective proteins. CONCLUSIONS: This study provides comprehensive evidence that long-term air pollution exposure is associated with increased CKD risk and offers exploratory insights into the potential molecular pathways underlying this association, advocating the incorporation of renal health considerations into air quality control policies.
Structural connectome architecture and biological vulnerability shape cortical atrophy in cocaine use disorder.
Han Z, Liu T, Wang K … +2 more , Yang G, Yan T
BMC Med · 2026 May · PMID 42106690 · Full text
BACKGROUND: Cocaine use disorder (CUD) is highly prevalent and characterized by widespread gray matter atrophy across the cerebral cortex. Yet, it remains unclear whether and how connectome-based circuits and biological...
BACKGROUND: Cocaine use disorder (CUD) is highly prevalent and characterized by widespread gray matter atrophy across the cerebral cortex. Yet, it remains unclear whether and how connectome-based circuits and biological features shape these structural abnormalities. METHODS: We mapped cortical atrophy patterns in CUD (discovery cohort: N = 53; replication cohort: N = 74; controls: N = 364) onto the brain's structural connectome, functional connectivity, transcriptomic similarity and receptor similarity architecture. Using a multimodal and multiscale connectivity-based framework, we identified CUD epicenters and evaluated their spatial correspondence with therapeutic brain stimulation targets and individual variations in clinical symptoms. RESULTS: We found that CUD-related regional atrophy is constrained by the white matter (WM) structural connectome. Along these WM pathways, regions that share similar haemodynamic activity and molecular features are more likely to exhibit convergent atrophy profiles. By integrating the structural connectome with multiple connectivity blueprints, we subsequently identified CUD epicenters and revealed that the prefrontal and visual cortices serve as core systems. Furthermore, we linked these epicenters to cortical transcriptomic patterns and receptor architectures, identifying synaptic and neural homeostasis-related gene enrichment and the strongest spatial correspondence with serotonergic (5-HT/5-HT) and dopaminergic (D) receptors. Finally, we demonstrated that the spatial distribution of these epicenters correlates with cocaine craving-response maps derived from repeated transcranial magnetic stimulation and can track individual variations in clinical behavioural representations, suggesting their potential as targets for therapeutic intervention. CONCLUSIONS: Altogether, our findings establish a structurally constrained framework for the spread of pathology underlying cortical atrophy in CUD, where initial perturbations propagate via structural connectome pathways to vulnerable regions shaped by neural activity and molecular landscapes.
Combined targeting of VISTA and sorafenib activates T cell-mediated anti-tumor immunity via the NF-κB/TNF axis in hepatocellular carcinoma.
Wang J, Zeng X, Liu W … +13 more , Ou Z, Wu W, Tian S, Li S, Tan X, Zhai X, Li L, Wang M, Hua W, Long J, Wang Y, Chen L, Zhang W
BMC Med · 2026 May · PMID 42106688 · Full text
BACKGROUND: Hepatocellular carcinoma (HCC) is a highly aggressive malignancy, with most patients diagnosed at advanced stages. Sorafenib, a multi-targeted tyrosine kinase inhibitor, remains a first-line therapy but has l...
BACKGROUND: Hepatocellular carcinoma (HCC) is a highly aggressive malignancy, with most patients diagnosed at advanced stages. Sorafenib, a multi-targeted tyrosine kinase inhibitor, remains a first-line therapy but has limited efficacy as monotherapy. Combining sorafenib with immune checkpoint inhibitors has become a leading strategy for unresectable advanced HCC. However, intrinsic and acquired resistance, together with immune-related adverse events, limit clinical benefit to a subset of patients, highlighting the need for new immunotherapeutic targets. V-domain Ig suppressor of T cell activation (VISTA), an emerging immune checkpoint molecule, is overexpressed in multiple cancers and associated with prognosis, suggesting its therapeutic potential in HCC. METHODS: VISTA expression and its association with T-cell infiltration were evaluated in human HCC tissues. An in vitro co-culture system and an orthotopic HCC model in C57BL/6 mice were used to assess the antitumor efficacy of anti-VISTA antibody and sorafenib, alone or in combination. Sequential and concurrent regimens were further compared. The efficacy of combination therapy relative to monotherapy was validated in a patient-derived xenograft (PDX) model in NCG mice with adoptive T cell transfer. Transcriptomic sequencing and functional rescue experiments were performed to investigate the underlying mechanisms. RESULTS: VISTA was significantly overexpressed in HCC tissues and positively correlated with T cell infiltration. In the C57BL/6 orthotopic model, only the combination regimen significantly inhibited tumor growth compared with control treatment, whereas neither monotherapy reached statistical significance. Combination therapy enhanced T cell infiltration and cytotoxic function compared with monotherapy. Notably, only concurrent administration significantly suppressed tumor growth, whereas both sequential regimens showed nonsignificant inhibitory trends. In the NCG mouse PDX model, monotherapies produced moderate antitumor effects; the combination group showed significantly greater antitumor activity than anti-VISTA monotherapy and a numerical, but nonsignificant, advantage over sorafenib monotherapy. Transcriptomic profiling and functional rescue experiments implicated the NF-κB/TNF signaling pathway in this synergistic effect. CONCLUSIONS: Concurrent VISTA blockade plus sorafenib exerts synergistic antitumor effects in HCC, associated with enhanced T cell function and NF‑κB/TNF pathway modulation. Concurrent treatment showed stronger antitumor trends than sequential regimens. These findings support further exploration of VISTA‑targeted combination immunotherapy and provide insights into optimal regimen sequencing.
Placental insulin-mTOR and stress-inflammatory signaling patterns are associated with childhood adiposity.
Francis EC, Boyle KE, Gyllenhammer LE … +3 more , Dabelea D, Jansson T, Perng W
BMC Med · 2026 May · PMID 42104380 · Full text
BACKGROUND: Placental signaling pathways regulate nutrient transport and fetal growth, with potential long-term consequences for offspring metabolic health. Most prior human studies have focused on individual placental m...
BACKGROUND: Placental signaling pathways regulate nutrient transport and fetal growth, with potential long-term consequences for offspring metabolic health. Most prior human studies have focused on individual placental markers, limiting insight into the role of coordinated activity across multiple pathways in relation to offspring outcomes. Our objective was to identify patterns across placental nutrient signaling pathways and assess whether the latent placental signaling patterns were associated with early childhood adiposity, and secondarily, explore associations of adiposity-associated patterns with metabolic biomarkers. METHODS: Among 108 mother-child pairs from the Healthy Start cohort, we quantified 33 placental signaling proteins and their phosphorylated-to-total protein ratios involved in nutrient sensing, insulin/growth factor signaling, stress/inflammation, and mitochondrial biogenesis using Simple Western assays of term placental villus tissue. We applied unsupervised methods to identify latent patterns and LASSO regression was used to select patterns associated with %fat mass at age 4. Multivariable linear regression was used to estimate associations adjusting for offspring age, sex, and maternal pre-pregnancy BMI. These same models were used in exploratory analysis of fasting levels of adiponectin, leptin, insulin, glucose, and lipids at age 4. RESULTS: We identified two placental signaling patterns associated with %fat mass. The insulin-mTOR-energy sensing pattern was associated with lower childhood %fat mass (β = -2.46, 95% CI - 4.84, - 0.09) and adiponectin, and the stress-inflammatory MAPK pattern was associated with higher %fat mass (β = 1.28, 95% CI 0.05, 2.51), leptin, and triglycerides; however, the FDR p-values ranged from 0.06 to 0.13. CONCLUSION: Two placental signaling patterns were associated with childhood %fat mass and metabolic markers. These findings indicate that capturing placental activity across several signaling pathways may yield insights into early origins of adiposity and metabolic health.
Genetic predisposition for depression, psychosocial and behavioural factors and premenstrual symptoms: a cross-sectional study among young women in China.
Zhao Y, Pan Q, Chen M … +7 more , Zhang Y, Ho GWK, Lin Y, Song H, Huang J, Li Y, Lu D
BMC Med · 2026 May · PMID 42104340 · Full text
BACKGROUND: Premenstrual disorders (PMDs) affect approximately one in three women of reproductive age and have a substantial impact on daily functioning and mental health. Given the challenges observed in diagnosis and c...
BACKGROUND: Premenstrual disorders (PMDs) affect approximately one in three women of reproductive age and have a substantial impact on daily functioning and mental health. Given the challenges observed in diagnosis and clinical management, understanding whether genetic predisposition and readily assessable factors jointly mark greater symptom burden may help inform future risk-stratified monitoring and assessment. METHODS: After excluding 424 participants with missing data, we conducted a cross-sectional study of 1528 female college students from the Care of Premenstrual Emotion (COPE) cohort in China. Premenstrual symptoms and probable PMD cases were assessed with the Calendar of Premenstrual Experiences. Four psychosocial and behavioural factors, including alcohol consumption, psychological resilience, adverse childhood experiences (ACEs), and body mass index (BMI), were recorded through electronic questionnaires. The polygenic risk score (PRS) of depression was derived from trans-ancestry genome-wide association study (GWAS) summary statistics. The associations and interactions of the PRS for depression and psychosocial and behavioural factors with premenstrual symptoms and probable PMD cases were examined. RESULTS: The average age of the participants was 20.1 ± 1.59 years. Positive associations were observed between the depression PRS, alcohol consumption, low psychological resilience, ACEs, and premenstrual symptoms; additionally, positive associations between low psychological resilience, ACEs, and probable PMDs were observed. The psychosocial and behavioural factor score was associated with more severe premenstrual symptoms (β = 0.49, 95% CI: 0.35-0.62, P < 0.001) and higher odds of probable PMDs (OR = 1.97, 95% CI: 1.42-2.73, P < 0.001). Specifically, compared with participants with low depression PRS and no adverse psychosocial-behavioural factors, participants with high depression PRS and alcohol consumption (β = 0.32, 95% CI: 0.14-0.51, P = 0.001), low psychological resilience (β = 0.54, 95% CI: 0.33-0.75, P < 0.001) or ACEs (β = 0.26, 95% CI: 0.08-0.43, P = 0.003) exhibited more severe premenstrual symptoms; moreover, participants with high depression PRS and ≥ 2 psychosocial-behavioural factor scores demonstrated the greatest burden of premenstrual symptoms (β = 0.59, 95% CI: 0.37-0.81, P < 0.001) and higher odds of probable PMDs (OR = 1.79, 95% CI: 1.05-3.11, P = 0.035). CONCLUSIONS: If confirmed in prospective studies, a combined profile of genetic predisposition and psychosocial and behavioural factors may help identify young women who warrant closer evaluation for PMDs, and may inform future prevention-oriented studies focused on actionable exposures.
Waist circumference and grip strength and their joint relations to type 2 diabetes incidence in UK Biobank.
Wirler J, Stein MJ, Baurecht H … +5 more , Bohmann P, Freisling H, Lendt C, Sedlmeier AM, Leitzmann MF
BMC Med · 2026 May · PMID 42098747 · Full text
BACKGROUND: Waist circumference and grip strength are each associated with type 2 diabetes (T2D) risk, but their joint associations have been less well studied. METHODS: We examined the separate and joint associations of...
BACKGROUND: Waist circumference and grip strength are each associated with type 2 diabetes (T2D) risk, but their joint associations have been less well studied. METHODS: We examined the separate and joint associations of waist circumference and grip strength with incident T2D among 483,578 adults aged 40-69 years (55% women) without T2D at baseline (2006-2010) from UK Biobank. Waist circumference was measured by trained staff and categorized using World Health Organization thresholds. Grip strength was assessed using a hydraulic dynamometer and categorized into age- and sex-specific tertiles. Incident T2D was ascertained through linkage to hospital inpatient records until 2022. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression, adjusting for sociodemographic, lifestyle, and clinical covariates. RESULTS: During 13.0 years of follow-up (6.3 million person-years), 30,240 participants (6.3%) developed T2D. Compared to individuals with low waist circumference (men: ≤ 94 cm, women: ≤ 80 cm), HRs were 2.11 (95% CI 2.03-2.19) for those with intermediate (men: 95-102 cm, women: 81-88 cm) and 5.48 (95% CI 5.30-5.66) for those with high waist circumference (men: > 102 cm, women: > 88 cm). Compared to individuals with high grip strength, HRs were 1.08 (95% CI 1.05-1.11) for those with intermediate and 1.35 (95% CI 1.32-1.39) for those with low grip strength. Joint analyses showed the highest risk among participants with the combination of high waist circumference and low grip strength (HR 7.68, 95% CI 7.22-8.17) compared to individuals with the combination of low waist circumference and high grip strength. Associations between waist circumference and T2D were stronger in women, whereas associations with grip strength were stronger in men. Both patterns were more pronounced among younger adults. CONCLUSIONS: Waist circumference and grip strength were separately and jointly associated with T2D risk. The combination of high waist circumference and low grip strength conferred the greatest risk. Joint assessment of waist circumference and grip strength identifies individuals at particularly elevated risk and may inform preventive strategies, though formal evaluation of incremental predictive utility is needed.
Smartphone-based lightweight AI system for real-time multiple anterior segment disease screening: development and real-world validation.
Liu Y, Xu C, Wu S … +15 more , Wang Y, Guan W, Wang S, Lin X, Zhang Q, Liu Z, Liu Q, Fan J, Wu H, Li Y, Zhang H, Zou W, Hu J, Luo Z, Liu Z
BMC Med · 2026 May · PMID 42098713 · Full text
BACKGROUND: Anterior segment diseases are a major global cause of preventable blindness, especially in regions with limited access to specialized ophthalmic care. Diagnosis typically requires slit-lamp biomicroscopy, cre...
BACKGROUND: Anterior segment diseases are a major global cause of preventable blindness, especially in regions with limited access to specialized ophthalmic care. Diagnosis typically requires slit-lamp biomicroscopy, creating a significant access bottleneck in primary care and rural settings. Existing AI solutions often lack the efficiency and generalizability necessary for widespread mobile deployment and primarily focus on individual conditions, failing to meet the demand for scalable, multi-disease screening platforms. METHODS: We developed the Intelligent Detection System (IDS), a smartphone-compatible AI platform for real-time, automated, multi-disease screening of anterior segment diseases. The core model, Eye-YOLO, is a novel, lightweight deep learning model optimized for standard smartphone images. IDS integrates image quality assessment and urgency classification. The model was rigorously trained on a large, heterogeneous multi-center dataset of 24,671 images (comprising 17,853 slit-lamp and 6,818 smartphone images) collected from three tertiary hospitals in China. IDS was prospectively deployed and validated via a widely accessible WeChat Mini Program for community screening. RESULTS: Eye-YOLO achieved a mean average precision of 0.816 with an exceptionally compact architecture (2.77 million parameters and 7.3G FLOPs), enabling real-time inference at 131 FPS on mobile devices. In controlled testing, IDS demonstrated high diagnostic performance (93.50% accuracy; AUC = 0.9837) with consistent performance across multiple smartphone brands (AUC > 0.95). Crucially, with AI assistance, junior ophthalmologists achieved an accuracy of 93.79% (AUC 0.8984), compared with 95.79% for senior experts. In real-world external validation via the WeChat Mini Program, IDS achieved 98.25% accuracy. CONCLUSIONS: IDS provides a highly efficient, robust, and globally scalable framework for multi-disease anterior segment screening using ubiquitous smartphone technology. Its deployment through a widely accessible mobile platform offers a promising public health solution that facilitates early detection and triage, with the potential to improve access to ophthalmic care between specialized centers and primary care settings. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR2200060808.
Obesity-derived metabolites modulate anti-tumor immunity in the tumor microenvironment: from mechanisms to clinical applications.
Cai Y, Jin J, Wang Y … +6 more , Han D, Yu X, Jin F, Li M, Li Y, Li X
BMC Med · 2026 May · PMID 42092892 · Full text
The tumor microenvironment (TME) is increasingly understood as a metabolically dynamic ecosystem in which local metabolite availability, composition, and trafficking shape immune cell fitness and therapeutic responsivene...
The tumor microenvironment (TME) is increasingly understood as a metabolically dynamic ecosystem in which local metabolite availability, composition, and trafficking shape immune cell fitness and therapeutic responsiveness. Against the backdrop of the global obesity epidemic, obesity-associated systemic metabolic dysregulation has been implicated in tumor initiation and progression and may also influence the immune contexture and treatment responsiveness of tumors. This Review examines how obesity-derived systemic metabolites may modulate anti-tumor immunity and influence cancer immunotherapy, with particular emphasis on pathways involved in metabolic reprogramming and TME remodeling. We further discuss intervention strategies spanning (i) upstream metabolite generation, (ii) systemic-to-local trafficking into the TME, and (iii) direct functional antagonism within the TME. However, the available evidence remains heterogeneous across metabolite classes, tumor types, and experimental contexts, and this heterogeneity is likely to contribute to divergent immunotherapeutic phenotypes, including obesity-associated heterogeneity in immune checkpoint blockade (ICB) responsiveness. By integrating these layers into a source-to-sink framework, we highlight translationally relevant directions for understanding how systemic metabolites may reshape the metabolic niche of the TME and for informing more precise, context-aware, and safety-conscious metabolite-directed strategies in cancer immunotherapy.
Maternal B-vitamin status modifies the risk of congenital heart disease in offspring associated with prenatal persistent organic pollutants exposure.
Li S, Lin H, Wang C … +8 more , Yang C, Cheng Q, Liu J, Zhang Y, Jin L, Li Z, Ren A, Wang L
BMC Med · 2026 May · PMID 42083004 · Full text
BACKGROUND: No epidemiological studies have systematically evaluated the associations between prenatal exposure to organophosphate esters and polychlorinated biphenyls and the risk of congenital heart disease (CHD) in of...
BACKGROUND: No epidemiological studies have systematically evaluated the associations between prenatal exposure to organophosphate esters and polychlorinated biphenyls and the risk of congenital heart disease (CHD) in offspring. Moreover, the potential modifying role of maternal B-vitamin status in persistent organic pollutants (POPs)-CHD associations has not been examined. We therefore investigated the cardiotoxic effects of prenatal POPs exposure and evaluated effect modification by maternal B-vitamin levels. METHODS: A multicenter case-control study was conducted in China from 2016 to 2021, including 425 participants. Thirty POPs and seven plasma B vitamins were quantified using high-resolution mass spectrometry. Single-exposure associations were examined by logistic regression, while multipollutant effects were assessed through Bayesian kernel machine regression (BKMR) and Weighted Quantile Sum (WQS) models. Potential effect modification by B vitamins was systematically evaluated. RESULTS: Prenatal exposure to p-cresyl diphenyl phosphate was associated with an increased risk of CHD (odds ratio [OR] = 1.36, 95% confidence interval [CI]: 1.08, 1.71). Mixture analyses consistently showed an increasing trend in CHD risk with higher exposure to the POPs mixture, with the WQS model yielding a statistically significant association (OR = 1.20, 95% CI: 1.03, 1.40). Higher concentrations of pyridoxamine, pyridoxal, and vitamin B12 were inversely associated with CHD risk, and mixture analyses using both BKMR and WQS regression further demonstrated a significant negative association between the overall B-vitamin mixture and CHD risk. In the interaction analysis, B vitamins significantly modified the association between prenatal POPs exposure and CHD risk (OR = 0.14, 95% CI: 0.04, 0.52). CONCLUSIONS: This study provides the first population evidence that prenatal POPs exposure is associated with increased CHD risk and adequate maternal B-vitamin levels may attenuate the developmental cardiotoxicity of emerging flame retardants, highlighting the importance of maternal nutritional status in modifying environmental risk factors for CHD.
Nourishing future generations: the critical role of healthy school lunches and strategic food procurement.
Perez-Cornago A, Piernas C
BMC Med · 2026 May · PMID 42082955 · Full text
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Impact of a real-time automatic quality control system for magnetically controlled capsule gastroscopy: a multicenter randomized controlled trial.
Wang X, Shen D, Zhao Y … +15 more , Xing J, Liu J, Zhou R, Yang C, Liu C, Ma X, Ge J, Zhang H, Yuan W, Zhang H, Ma Y, Hu P, Zuo X, Li Y, Li Z
BMC Med · 2026 May · PMID 42069608 · Full text
BACKGROUND: Quality control can reduce variations in operators' performance conducting magnetically controlled capsule gastroscopy (MCCG). However, an optimal method for quality control in routine MCCG procedures is stil...
BACKGROUND: Quality control can reduce variations in operators' performance conducting magnetically controlled capsule gastroscopy (MCCG). However, an optimal method for quality control in routine MCCG procedures is still lacking. This study aimed to develop an automatic quality control system (AQCS) and assess its effectiveness in a clinical trial. METHODS: We developed the AQCS using convolutional neural network (CNN) models to monitor inspection completeness, evaluate gastric cleanliness, and identify suspicious lesions. Then, patients were prospectively randomized to undergo routine MCCG with or without AQCS assistance. The primary outcome was the blind spot rate in the AQCS and control groups. RESULTS: The CNN model demonstrated specificity of 98.27-99.30% and sensitivity of 76.33-96.35% in gastric site identification. Between August 27, 2021, and July 28, 2022, a total of 200 patients were randomized, with 98 and 96 patients analyzed in the AQCS and control groups, respectively. Compared to the control group, the AQCS group achieved lower blind spot rates (median: 0.00% vs. 16.67%, P < 0.01), higher lesion detection rates (75.51% vs. 60.42%, P = 0.02), and comparable gastric examination time (28.63 min vs. 27.58 min, P = 0.48). Additionally, AQCS showed high consistency with expert evaluations in cleanliness assessment (Kappa = 0.95, P < 0.01). No serious adverse events occurred in either group. CONCLUSIONS: AQCS significantly reduced the blind spot rate during MCCG procedures. It could be a powerful assistant tool to mitigate operator skill variability and enhance the overall quality of routine MCCG examinations. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT04954677.
Medicine price and affordability in China and selected ASEAN countries: a cross-country comparison with forward-looking implications for regional pooled procurement.
Li Z, Zhang S, Xu Q … +1 more , Liu B
BMC Med · 2026 May · PMID 42069603 · Full text
BACKGROUND: The China-ASEAN regional medical procurement platform was launched in early 2025. However, the scope and operational mechanisms of the platform remain unclear. This study aims to assess medicine prices and af...
BACKGROUND: The China-ASEAN regional medical procurement platform was launched in early 2025. However, the scope and operational mechanisms of the platform remain unclear. This study aims to assess medicine prices and affordability in China and ASEAN countries, explore potential implementation challenges of the platform, provide policy suggestions. METHODS: We selected commonly used medicines from four ATC categories (alimentary tract and metabolism, cardiovascular system, anti-infective for systemic use, nervous system). Prices were standardized to WHO defined-daily-dose (DDD) prices and converted into median price ratio (MPR) using Management Sciences for Health (MSH) international reference prices (IRP). All prices data were collected from official public sources and converted to US dollars using the official 2024 annual average exchange rate. Affordability was estimated the number of days' statutory gross daily minimum wages required to purchase one DDD, with wage data obtained from the International Labor Organization (ILO). Descriptive statistics were performed. RESULTS: A total of 68 medicines were included, with 68, 68, 60, and 59 available in China, Thailand, Indonesia, and the Philippines, respectively. Median MPRs were 0.88 (IQR:0.46-3.49), 0.97 (IQR:0.50-2.20), 1.69 (IQR:0.77-3.16), 1.86(IQR:0.72-5.03), respectively, and 45.6%, 45.6%, 61.7%, and 67.8% of medicines were priced above the IRPs. Prices varied widely across and within countries. For cardiovascular medicines, median MPRs exceeded the IRPs in China 1.72(IQR:0.53-6.30), Indonesia 1.79(IQR:0.78-2.80), the Philippines 2.85(IQR:1.31-6.43), while Thailand achieved a lower price of 0.78(IQR:0.31-1.37). The overall affordability was higher in China, Indonesia and Thailand, where one DDD of medicine required less than 6% of a day's wage, with median values of 4.8% (IQR:2.5%-19.3%), 5.1% (IQR:2.3%-9.6%), and 3.6% (IQR:1.8%-8.1%), respectively, compared with 14.0% (IQR:5.4%-37.7%) in the Philippines. Sensitivity analysis excluding extreme affordability values yielded similar results. CONCLUSIONS: Our findings suggest that understanding cross-country disparities in medicine prices and affordability may help inform the design of future regional purchasing strategies. Realizing the benefits of such joint procurement will require strong political commitment to establish a legal framework, enhance price transparency, harmonize regulations, and strengthen supply chains to ensure the platform's effectiveness and sustainability.
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