BMC Medicine最新文献

Background: We aim to evaluate the impact of statin prescription on stroke risk in patients with hypercholesterolaemia and to assess disparities in statin prescribing.

Methods: We analysed electronic health records from patients with hypercholesterolaemia, registered in 41 general practices in south London between 2005 and 2021. The cause-specific hazard ratio of statin prescription on stroke, adjusted for patients' sociodemographic characteristics and stroke risk factors (smoking ever, hypertension, and diabetes), was estimated using a time-varying exposure Cox proportional hazards model stratified by history of heart diseases. The association between statin prescription and patients' sociodemographic characteristics was evaluated using a logistic regression.

Results: Of the 849,968 registered patients, 166,124 (19.5%) had records of hypercholesterolaemia. Among them, 33.5% were prescribed statins, 2.6% had a record of stroke, and 50.6% were female, 31.7%, 16.2% and 8.9% had records of hypertension, diabetes and history of heart diseases, respectively. In a Cox model stratified by history of heart diseases, statin prescription was associated with a reduced hazard of stroke (cause-specific hazard ratio: 0.74; 95% confidence interval (CI): 0.68-0.80, p < 0.001), with follow-up administratively censored at 79 years (n = 161,527; 97.2%). Statins were less likely prescribed to female patients and patients of Black ethnicity (odds ratio: 0.70, 95% CI: 0.68-0.72, p < 0.001 and odds ratio: 0.82, 95% CI: 0.79-0.85, p < 0.001, respectively).

Conclusions: Statin therapy prescription is associated with reduced stroke risk in patients with hypercholesterolaemia, yet it was under-prescribed to women and patients of Black ethnicity, highlighting avoidable disparities in preventive care.

Background: Circulating tumor DNA (ctDNA) profiling offers a noninvasive approach to monitor minimal residual disease (MRD) and clonal evolution in diffuse large B-cell lymphoma (DLBCL).

Methods: In this study, we analyzed 164 newly diagnosed DLBCL patients from the First Affiliated Hospital of Nanjing Medical University undergoing R-CHOP-like therapy. Tissue and serial plasma samples were sequenced using a 475-gene lymphoma-specific panel.

Results: We defined end-of-treatment MRD (EOT-MRD) positivity based on detectable tissue-informed variants or published driver mutations, which identified 37.2% (61/164) of patients as EOT-MRD( +). EOT-MRD status significantly predicted progression-free and overall survival, complementing both International Prognostic Index (IPI) and positron emission tomography-computed tomography response assessment. Integration of EOT-MRD with IPI into a composite "IPI-M" model improved risk stratification. CtDNA dynamics revealed that 77.1% (37/48) of patients acquired new gene alterations (GAs) at progression, of which most were enriched in cell cycle regulation, p53 pathway, PI3K/AKT signaling pathway, and epigenetic regulation. In addition, primary refractory patients exhibited a higher proportion of shared mutations from baseline to progression, while relapsed patients gained more emergent mutations at progression. Different genetic subtypes manifest divergent progression and distinct evolutionary patterns. TP53-disrupted subtype drove primary refractoriness via persistence of TP53 mutation, MCD subtype was prone to relapse despite high remission rate with frequent baseline mutation clearance and propensity for branched evolution, and BN2 showed mixed refractoriness and relapse with predominance of shared alterations.

Conclusions: Our findings underscore the dual utility of ctDNA in enhancing prognostic stratification and elucidating subtype-specific evolutionary dynamics, supporting personalized treatment strategies in DLBCL.

Background: Cardiovascular-kidney-metabolic (CKM) disease and chronic obstructive pulmonary disease (COPD) are associated with major adverse cardiovascular events (MACE). Whether COPD further increases MACE risk within CKM populations, and whether this potential risk is modifiable through inhaled corticosteroids (ICS), is unknown. Within CKM populations, we investigated the relationship between (1) COPD and subsequent MACE, and (2) amongst concurrent CKM-COPD populations, we investigated the relationship between ICS and subsequent MACE.

Methods: We used Clinical Practice Research Datalink (CPRD) Aurum, Hospital Episode Statistics and Office of National Statistics data, between January 1st, 2010, and March 29th, 2021. We created five discrete cohorts: chronic kidney disease (CKD), type-II diabetes mellitus (T2DM), obesity, MACE history, and older adults (aged ≥ 65 years old ["Age65 + "]). CKD, T2DM, obesity, and Age65 + cohorts were MACE-naïve at the time of inclusion. Aim (1) exposures were (a) COPD, (b) incident COPD, and (c) being at risk of COPD without diagnosis (defined as age ≥ 40 years old, smoking history, no evidence of asthma, and frequent respiratory infections requiring antibiotics). Aim (2) exposure was ICS prescription (control group: long-acting bronchodilators). The outcome was MACE (acute coronary syndrome, arrhythmia, heart failure, ischaemic stroke, or cardiovascular-specific mortality). We implemented Cox proportional hazards models.

Results: COPD was associated with MACE amongst all cohorts, but was comparatively weak in the MACE history cohort (cohort total; adjusted hazard ratio [95% confidence interval]): CKD (N = 573,626; 1.29 [1.26, 1.32]), T2DM (N = 649,506; 1.30 [1.26, 1.35], obesity (N = 225,273; 1.41 [1.34, 1.48]), MACE history (N = 507,889; 1.04 [1.02, 1.06]), and Age65 + (N = 592,123, 1.59 [1.52, 1.66]). Incident COPD was associated with subsequent MACE in CKD only (1.28 [1.13, 1.45]). Being at risk of COPD was associated with subsequent MACE in CKD (1.18 [1.07, 1.30]), MACE history (1.16 [1.08, 1.25]), and Age65 + (1.28 [1.13, 1.46]). ICS prescription was not associated with subsequent MACE in any concurrent CKM-COPD cohort.

Conclusions: COPD was an independent risk factor for MACE in CKM populations. ICS did not attenuate MACE amongst CKM-COPD groups. Incident COPD was associated with MACE in CKD, and being at risk of COPD was associated with MACE in CKD, MACE history, and Age65 + cohorts.

Background: Metabolic dysfunction-associated fatty liver disease (MAFLD) is an emerging cardiovascular risk factor; evidence-based blood pressure (BP) management strategies for this population remain limited. We aimed to evaluate the efficacy and safety of a multifaceted intervention anchored by intensive BP control (< 130/80 mmHg) in patients with MAFLD using data from the China Rural Hypertension Control Project (CRHCP) trial.

Methods: This study is a post hoc analysis of the CRHCP trial, an open-label, cluster-randomized controlled trial conducted from 2018 to 2023 across 326 villages in China. Adults aged ≥ 40 years with hypertension were eligible. Participants were randomized in a 1:1 ratio to receive either intensive BP control (target < 130/80 mmHg) or usual care. MAFLD was diagnosed using the hepatic steatosis index (HSI ≥ 36) combined with metabolic criteria. The primary outcome was a composite of stroke, myocardial infarction, heart failure, or cardiovascular death; secondary outcomes included individual components of the primary outcome and all-cause death. The CRHCP trial is registered with ClinicalTrials.gov NCT03527719.

Results: A total of 29,624 participants (12,912 with MAFLD) were included in this analysis. The mean (SD) age was 63.2 (9.2) years, and 18,348 (61.9%) were female. During 48-month follow-up, risk reductions for composite CVD with intensive BP control were similar in patients with MAFLD (adjusted HR, 0.69; 95% CI, 0.61-0.78; P < 0.001) and those without MAFLD (HR, 0.70; 95% CI, 0.63-0.77; P < 0.001), with comparable reductions in stroke and cardiovascular death (adjusted HR for patients with MAFLD, 0.72; 95% CI, 0.55-0.95; P = 0.019; adjusted HR for patients without MAFLD, 0.63; 95% CI, 0.53-0.76; P < 0.001). All-cause mortality declined in patients without MAFLD (adjusted HR, 0.84; 95% CI, 0.76-0.93; P < 0.001) but not significantly in those with MAFLD (adjusted HR, 0.93; 95% CI, 0.79-1.09; P = 0.366), though the interaction was not significant (P for interaction = 0.601). There was an increased risk of hypotension in patients with or without MAFLD. Subgroup analyses confirmed consistent benefits.

Conclusions: This study demonstrates that multifaceted intensive BP control at < 130/80 mmHg significantly reduces the risk of cardiovascular disease in patients with MAFLD. These findings provide preliminary evidence for BP management in patients with MAFLD and require confirmation in future prospective clinical trials.

Background: The non-breast non-ovarian cancers associated with BRCA1 and BRCA2 pathogenic variants (PVs) are controversial. We aimed to examine this using a prospective cohort design.

Methods: This study included 1260 BRCA1 and 1058 BRCA2 PV carriers (91% were females) from two consortia: the Breast Cancer Family Registry (BCFR) and the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer Follow-Up Study (kConFab-FUS). The carriers were free of cancer other than breast or ovarian cancer at baseline and had a median baseline age of 45.5 years. For 16 types of non-breast, non-ovarian cancers, standardized incidence ratios (SIRs) relative to population incidence, the probabilities of relative risk effect size > 2 (i.e., moderate risk) and cumulative risks to age 80 years were estimated.

Results: During a median follow-up time of 11.4 years, 161 non-breast, non-ovarian cancers were observed. For BRCA1 PV carriers, little evidence of increased risk was observed. The prostate, pancreatic, and all non-pancreatic cancer SIRs were 1.7 (95% CI 0.7-4.2), 1.1 (95% CI 0.3-4.6) and 0.85 (95% CI 0.68-1.06), respectively; the probabilities of relative risk > 2 were 0 and 67% for prostate and pancreatic cancers, respectively. For BRCA2 PV carriers, increased risks of pancreatic (SIR = 6.6, 95% CI 3.8-11.6), prostate (SIR = 3.6, 95% CI 1.9-6.8) and stomach (SIR = 3.1, 95% CI 1.01-9.8) cancer were observed, with a cumulative risk to age 80 years of 8.3, 82.0, and 1.6%, respectively. For all the other non-breast, non-ovarian cancers combined, the SIR was 0.85 (95% CI 0.66-1.10).

Conclusions: Apart from pancreatic, prostate, and possibly stomach cancers for BRCA2 PV carriers, and possibly pancreatic cancer for BRCA1 PV carriers, there is no evidence that BRCA1 and BRCA2 PV carriers have substantially increased risks of other non-breast, non-ovarian cancers. Our prospective risk estimates are informative for cancer risk assessment for people with BRCA1 and BRCA2 PVs.

Background: Bulbar palsy typically causes severe dysphagia. Based on rehabilitation interventions, stellate ganglion block (SGB) might improve swallowing function by regulating sympathoexcitation and cerebral perfusion. This study explored the short- and long-term effects of SGB on swallowing function, anxiety, and cerebral blood flow in patients with bulbar palsy after ischemic stroke.

Methods: This randomized double-blind placebo-controlled trial included 124 participants in rehabilitation departments from March 2024 to July 2025 in China. The participants were randomized 1:1 to SGB or placebo groups, and all received routine treatment for 10 consecutive days. The SGB group received SGB with lidocaine hydrochloride, whereas the placebo group received block with normal saline. The primary outcome was the clinical severity of dysphagia. The secondary outcomes were airway protection, forward and upward movement distances of the hyoid bone, accumulation of secretions, pharyngeal residue, anxiety, and mean blood flow velocity (V_m) and internal diameter of the vertebral artery. The V_m and internal diameter were additionally assessed one hour after the first SGB. Repeated measures ANOVA and generalized estimating equations were used to explore time, group, and their interaction effects.

Results: There were no significant baseline inter-group differences. After treatment, significant (P < 0.001) interaction effects were observed for dysphagia severity (η² > 0.06), movement distances of the hyoid bone (η² > 0.19), airway protection (β = - 0.774), pharyngeal residue (β < - 0.54), accumulation of secretions (β = - 0.371), and anxiety (η² = 0.462). These effects remained significant at follow-up. After the first SGB, the V_m and internal diameter of the vertebral artery on the SGB side significantly increased (P < 0.001) in the SGB group, but the inter-group differences were non-significant after the intervention period.

Conclusions: In patients with bulbar palsy after ischemic stroke who receive routine treatment, SGB is safe and can effectively improve swallowing function, airway protection, and anxiety. The effects of SGB on vertebral artery blood flow are temporary, but the functional impacts are long-term.

Trial registration: ClinicalTrials.gov. (Unique identifier: NCT06319534, 20/03/2024).

Background: Alterations in lipid metabolism are manifestations of amyotrophic lateral sclerosis (ALS) that contribute to the risk and rate of progression. Blood levels of triglycerides and cholesterol are altered in ALS patients and pre-symptomatic gene carriers, but mechanistic insights into these changes are lacking.

Methods: Serum samples from sporadic ALS patients (n = 118), mutated SOD1 and FUS/TARDBP (n = 20, 40, 17, respectively) with age and gender-matched controls (n = 96) were analysed for alterations in the angiopoietin-like protein (ANGPTL) system using enzyme-linked immunosorbent assays. SOD1^G93A murine model was studied at pre-symptomatic (P50), early symptomatic (P90), and fully symptomatic (P110) stages, along with their wild-type (WT) littermates for ANGPTLs. Untargeted lipidomics on serum was performed using high-resolution liquid chromatography-mass spectrometry. Further, the involvement of the hypothalamus was studied using hypothalamic volumetry in patients and an antibody array spanning 308 proteins in mice.

Results: We show that mutation-specific patterns of systemic lipid abnormalities appear in ALS and that they correlate with reduced levels of angiopoietin-like proteins 3 and 4. ANGPTL-3/4, in turn, correlates with hypothalamic atrophy but not with corticospinal involvement, as determined by MRI volumetry and diffusion tensor imaging. Lipid phenotype and decreased ANGPTL in humans are recapitulated in two SOD1 murine ALS models, in which ANGPTL-3, -4, and -8 expression patterns are consistent with the repartitioning of lipid utilisation from muscles to the brown adipose tissue; systemic levels of ANGPTL-3 correlate with hypothalamic neuroinflammation and vascular permeability and with hypothalamic levels of agouti-related protein and neuropeptide Y.

Conclusions: These data provide a molecular mechanism linking peripheral lipid metabolism to the dysfunction of a specific hypothalamic circuit through the mediation of systemic ANGPTL-3 and -4. This finding constitutes a molecularly defined entry point to manipulate lipid metabolism in ALS.

Background: Compared to conventional chemotherapy, metronomic chemotherapy (MCT), with lower drug dosage which may cause less damage to the immune system, has shown potential for synergy in combination with PD-1-based immunotherapy. However, this synergistic immunotherapy efficacy in neoadjuvant setting for advanced esophageal squamous cell carcinoma (ESCC) requires further clinical validation.

Methods: This pilot phase 2, single-center, randomized clinical trial enrolled 30 untreated patients with resectable stage II or III ESCC. Participants were randomly assigned to either the MCT group (paclitaxel, cisplatin, and 5-fluorouracil) or the IO + MCT group (same regimen plus camrelizumab). Primary outcomes included the pCR rate after neoadjuvant therapy, and the safety of each regimen assessed by adverse events. Digital spatial profiling (DSP-WTA), multiplex immunofluorescent staining (mIF), and bulk RNA sequencing were performed to explore the possible therapeutic mechanisms.

Results: Twenty-four patients (13 in MCT, 11 in IO + MCT) underwent R0 resection. The pCR rates were 15.4% in the MCT group and 54.5% in the IO + MCT group. Both treatments were well tolerated, with manageable side effects. DSP-WTA and mIF revealed that IO + MCT effectively decreased the number of tumor-infiltrating T cells with the positive expression of terminal exhaustion marker CD39 and increased the number of primary and secondary follicle-like tertiary lymphoid structures (TLSs), particularly in pCR patients.

Conclusions: Neoadjuvant MCT combined with camrelizumab led to an increased pCR rate (54.5 vs. 16.7%) in ESCC patients compared to MCT alone. This combination therapy may offer a promising approach for enhancing cancer treatment outcomes.

Trial registration: ClinicalTrials.gov identifier: ChiCTR2000039638.

Background: The critical age window during which early-life adiposity impacts liver health remains unclear. This study aimed to identify the timing of adiposity gain associated with elevated alanine aminotransferase (ALT) levels in 8-year-old children.

Methods: This prospective cohort study included 1322 children (665 boys; mean age 96.2 ± 3.4 months) from a subset of the Japan Environment and Children's Study. Anthropometric data were collected at birth and at 1, 2, 3, 4, 5, 6, and 8 years. Adiposity gain was assessed using conditional weight, a residual-based metric adjusted for prior weight and current height. Excess adiposity was defined as conditional weight above the 90th percentile. ALT was measured at age 8, with elevation defined as > 26 IU/L in boys and > 22 IU/L in girls. Multivariable regression models were adjusted for maternal, perinatal, and early-life factors.

Results: ALT elevation was observed in 3.3% of the children. Adiposity gain was significantly associated with higher ALT concentrations, beginning at age 3 in girls (adjusted coefficient: 0.11, p < 0.01) and at age 4 in boys (adjusted coefficient: 0.10, p < 0.05). The 4-5-year interval marked the earliest period of notable risk, with adjusted risk ratios (95% CI) of 4.18 (1.77-9.87) in boys and 3.29 (1.04-10.40) in girls. Birth weight and adiposity during infancy were not consistently associated with ALT concentrations.

Conclusions: Early childhood-particularly between ages 3 and 5 years-may represent a period during which associations between excess adiposity gain and later liver health become detectable. Because liver enzymes were assessed at a single time point, the temporal onset of these associations cannot be established. These findings should be interpreted cautiously and warrant confirmation using longitudinal assessments of liver health.

Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has improved outcomes in patients with acute myeloid leukemia (AML) harboring FLT3-internal tandem duplication (FLT3-ITD) mutations. However, relapse still occurs in 15-35% of these patients after transplantation. Therefore, early and highly sensitive detection methods are required to identify patients at risk of relapse and enable timely post-transplant intervention.

Methods: In this NICHE cohort study, a total of 136 patients were included, then we evaluated whether high-sensitivity polymerase chain reaction (PCR)-next-generation sequencing (NGS) for FLT3-ITD (limit of detection: 5 × 10^-6) on day + 30 post-HSCT could identify patients at a high risk of relapse and inform decisions regarding maintenance therapy.

Results: Among the 136 patients, 37 patients (27.2%) had detectable FLT3-ITD clones on day + 30. These patients exhibited a significantly higher cumulative incidence of post-HSCT multiparameter flow cytometry (MFC)-measurable residual disease (MRD) relapse (40.3% vs. 18.8%, p = 0.001). Notably, FLT3-ITD-positive patients who received FLT3 inhibitor maintenance therapy had no relapses, while 6 out of the 13 patients who did not receive maintenance therapy relapsed. Conversely, FLT3-ITD-negative patients without high-risk factors (2022 European LeukemiaNet adverse-risk group, relapsed/refractory AML, MFC-MRD positivity pre-HSCT) showed limited benefit from maintenance therapy (MFC-MRD-free survival: hazard ratio (HR) = 0.25 (0.03-2.11), p = 0.204; OS: HR = 0.20 (0.02-1.70), p = 0.142).

Conclusions: This is the first study to demonstrate that detection of minimal FLT3-ITD clones at the fixed time point of day + 30 post-HSCT can reliably stratify relapse risk in AML patients and provide a rationale for individualized post-transplant maintenance therapy.