BMC Medicine最新文献

Background: Despite robust evidence that genetic factors substantially influence both osteoporosis development and fracture risk, current screening guidelines fail to incorporate genetic factors into risk-assessment protocols. This study aims to determine personalized screening ages for osteoporosis based on polygenic risk score (PRS).

Methods: This prospective cohort study utilized data from 223,818 women in the UK Biobank, and only participants who were osteoporosis-free at baseline were included in the study. Participants were categorized into three subgroups (low, medium, and high groups) based on their PRS. Ten-year cumulative risk of osteoporosis, risk-adapted starting age of osteoporosis screening, and risk advancement periods (RAP) of women across different stratifications based on PRS were calculated as the main outcomes.

Results: In the general female population at age 65 (current US Preventive Services Task Force recommended screening age), the 10-year cumulative osteoporosis risk was 5.95%. Women reached this risk threshold depending on their PRS, which was 60 years for high-risk women and 69 years for low-risk women. Compared to medium-risk participants, high-risk participants developed osteoporosis 4.99 years earlier (RAP, 4.99; 95% CI, 4.94, 6.28), whereas low-risk participants developed it 4.89 years later (RAP, - 4.89; 95% CI, - 6.54, - 4.69).

Conclusions: The integration of PRS could revolutionize osteoporosis prevention by enabling early detection in genetically high-risk women, potentially years before the current screening guidelines. Our findings advance the field of precision prevention for osteoporosis and may significantly reduce the population burden of osteoporotic fractures.

Background: Our previous study demonstrated that continuous theta burst stimulation (cTBS) may enhance motor recovery but did not significantly improve pushing behavior in patients with poststroke lateropulsion, necessitating a novel repetitive transcranial magnetic stimulation (rTMS) protocol. Furthermore, the cortical hemodynamic mechanisms underlying postural recovery remain unexplored, limiting insight into how rTMS modulates posture-related neuroplasticity in this population.

Methods: A randomized, three-arm, patient- and assessor-blinded sham-controlled trial was conducted. Forty-two eligible participants with poststroke lateropulsion were randomly assigned to receive either cTBS or high-frequency rTMS or sham rTMS for 3 weeks. Primary outcomes were Burke lateropulsion scale and scale for contraversive pushing. Secondary outcomes included short falls efficacy scale international, modified Rivermead mobility index, Fugl-Meyer assessment scale-motor domain, and stroke-specific quality of life scale. Cortical hemodynamics were monitored via functional near-infrared spectroscopy over ten posture-related cortices.

Results: A significant main effect of time was observed on Burke lateropulsion scale (BLS) (F = 21.8, P < 0.001), scale for contraversive pushing (F = 16.5, P < 0.001), short falls efficacy scale international (F = 16.3, P < 0.001), modified Rivermead mobility index (F = 26.2, P < 0.001), and Fugl-Meyer assessment scale-motor domain (F = 13.6, P < 0.001). In the subgroup analysis, a significant difference on BLS was observed at T3 between the cTBS and Sham rTMS groups in patients with mild-moderate lateropulsion [- 2.4 (- 4.6, - 0.3), P = 0.026]. Regarding posture-related cortical hemodynamics, a significant three-way interaction was observed in the left dorsolateral prefrontal cortex for the mean difference in oxygenated hemoglobin between sitting task and baseline rest (F = 3.9, P = 0.012). However, no significant main effects of time or intervention were detected in this cortex. Multiple linear regression analyses revealed no significant linear relationship between mean difference in oxygenated hemoglobin from sitting task to baseline rest (T3-T0) across ten cortices and either BLS (T3-T0) (R² = 0.189, P = 0.699) or SCP (T3-T0) (R² = 0.272, P = 0.355).

Conclusions: cTBS significantly improved the pushing behavior in patients with mild-moderate lateropulsion. These findings support the efficacy of rTMS in improving poststroke lateropulsion and provide a foundation for future studies aimed at optimizing rTMS protocol targeting this condition.

Trial registration: URL: http://www.chictr.org.cn. ; Unique identifier: ChiCTR2300068243.

Background: Immune responses after SARS-CoV-2 infection remain poorly characterized in African populations, despite widespread viral transmission and proportionally lower COVID-19 severity and mortality than in other regions. We aimed to define the determinants and durability of humoral and cellular immunity in sub-Saharan Africa and to identify immune correlates of protection against reinfection.

Methods: We conducted a 12-month longitudinal immunological study involving 513 adults with asymptomatic or mild-to-moderate COVID-19 enrolled across four sub-Saharan African countries (Ghana, Democratic Republic of Congo, Ethiopia, and Mozambique) during four pandemic waves (2020-2022). We profiled levels of IgA, IgG, and IgM against eight SARS-CoV-2 antigens and neutralizing antibody activity against ancestral and variant strains by Luminex, and antigen-specific T- and B-cell responses by flow cytometry. Immune kinetics, decay, immune escape, and reinfection risk were evaluated alongside the impact of clinical and demographic variables, including prior exposure, epidemic wave, geographic site, treatment allocation, and host factors. Statistical analyses included non-parametric tests (Kruskal-Wallis with Benjamini-Hochberg adjustment), Spearman correlations, logistic regression for reinfection, and mixed-effects models for longitudinal determinants.

Results: Humoral and cellular immune responses were robust and sustained across participants. Estimated antibody half-lives during the early decay phase exceeded 50 days for IgA and IgG. Higher IgA, IgG, and neutralizing levels were significantly associated with lower odds of reinfection during follow-up. Repurposed COVID-19 treatments showed no measurable impact on immune responses. Prior infection and vaccination were the main determinants of antibody magnitude and persistence, greatly surpassing the effects of age, sex, symptoms, and comorbidities. Antibody levels also varied significantly by epidemic wave and site, higher in later waves and, across sites, generally higher in Ethiopia and lower in DRC. Comorbidities were primarily associated with increased SARS-CoV-2-specific T-cell activation. Strong correlations were observed between binding and neutralizing antibodies, and variant-specific immune escape was confirmed for Beta, Gamma, and Omicron.

Conclusions: This multi-country study provides a comprehensive characterization of SARS-CoV-2 humoral and cellular immune responses in African cohorts and identifies prior exposure and local epidemiological context as the main determinants of immune magnitude, durability, and protection, outweighing other host factors.

Background: Pathogenic mutations in the POLE gene disrupt its proofreading function during DNA replication, causing an accumulation of erroneous nucleotide incorporations. This defect leads to a significantly elevated tumor mutation burden (TMB) and increased generation of tumor neoantigens. These molecular characteristics suggest a potential association between POLE-mutant tumors and distinct prognostic outcomes in colorectal cancer (CRC); however, clinical evidence supporting this correlation remains limited.

Methods: We retrospectively collected a cohort of CRC patients harboring pathogenic POLE mutations. Comparative analyses were performed between POLE-mutant and POLE wild-type CRCs regarding their clinical characteristics, prognostic outcomes, and genomic profiles. Additionally, we evaluated the response to immunotherapy in metastatic POLE-mutant CRC cases.

Results: Among 35,108 CRC patients, pathogenic POLE mutations were identified in 261 individuals, accounting for 0.74% of the cohort. The median age at diagnosis for POLE-mutant patients was 48 years, with a male predominance (74.4%) and a substantial proportion (50.4%) of tumors localized in the right-sided colon. All patients with pathogenic POLE mutations exhibited hypermutated phenotypes, characterized by a median TMB of 235.26 mutations per megabase (range: 71.20-719.00 mutations/Mb). In stage II CRC, POLE mutations were significantly associated with a reduced risk of recurrence (hazard ratio [HR] 0.344, 95% confidence interval [CI] 0.157-0.754, p = 0.008) when compared to POLE wild-type, microsatellite stable CRC patients. However, this association was not evident in stage III patients (HR 1.004, 95% CI 0.490-2.057, p = 0.992). Importantly, the incorporation of immune checkpoint inhibitors in first-line treatment regimens significantly improved progression-free survival (HR = 0.247, 95% CI 0.117-0.552, p = 0.0002) and overall survival (HR = 0.317, 95% CI 0.103-1.143, p = 0.0832) in metastatic CRC patients with pathogenic POLE mutations.

Conclusions: Pathogenic POLE-mutant CRC constitutes a relatively rare, yet clinically important, subtype. These cancers exhibit distinct clinicopathological and genomic features. Our results indicate that mutations in the POLE gene may serve as a valuable prognostic marker and a potential indicator of benefit to immunotherapy in CRC, offering promising avenues for personalized treatment strategies.

Background: Enhanced cough sensitivity is proposed as a potential cause for refractory chronic cough (RCC), and modulation of sensory nerve hyperresponsiveness is suggested as an effective treatment. However, the treatment of RCC has considerable potential for enhancement, particularly in terms of the targets and side effects. We aimed to investigate the efficacy and safety of duloxetine, a selective 5-HT and norepinephrine reuptake inhibitor, in patients with RCC.

Methods: This is a prospective, randomized, double-blind trial. RCC patients without mood disorders in the Tongji Hospital of Tongji University outpatient clinic were invited to participate in this study. Patients were randomly assigned to the duloxetine group or placebo group, with both patients and investigators being masked. The co-primary endpoint was the change in Leicester cough questionnaire (LCQ) score and cough frequency.

Results: Between Oct 2020 and May 2024, 98 patients were randomly assigned to duloxetine (n = 49) and placebo (n = 49) groups. After an 8-week treatment phase and a 3-week follow-up period, the mean number of coughs per hour in the duloxetine group was reduced from 83.96 ± 28.95 to 33.12 ± 22.99, showing a significant decrease than that of the placebo group (87.67 ± 31.75 to 80.36 ± 31.75) (p < 0.001). In addition, duloxetine significantly improved scores on the LCQ (12.75 ± 2.44 to 14.88 ± 2.45), whereas no significant reduction was observed in the placebo group (12.17 ± 2.64 to 12.81 ± 2.32) (P < 0.001 between groups). However, adverse events such as nausea 5 (11.36%), dizziness 7 (15.91%), and somnolence 4 (9.09%) occurred more frequently in the duloxetine group (all P < 0.05).

Conclusions: Duloxetine reduced cough frequency and sensitivity, which appears to be a novel therapeutic approach for RCC.

Trial registration: The study was approved by the Ethics Committee of Shanghai Tongji Hospital (2020-KYSB-160, 2021-086) and registered in the Chinese Clinical Trial Registry (ChiCTR2000037429).

Background: Pain-anxiety comorbidity represents a prevalent clinical concern. This study aims to investigate the molecular mechanisms underlying the comorbidities via focusing on the activity of dorsal raphe nucleus (DRN) glutamatergic neurons and the functional role of their 5-hydroxytryptamine 2C (5-HT2C) receptors in relation to gut microbiota.

Methods: We established a Complete Freund's Adjuvant (CFA)-induced pain-anxiety comorbidity model in mice and systematically investigated the role of the brain-gut axis in the comorbidity using behavioral phenotyping, molecular biology, pharmacological/chemogenetic modulation, and gut microbiota profiling.

Results: Heightened activity in the glutamatergic neurons of the DRN was found in mice with comorbidity. Chemogenetic activation of DRN glutamatergic neurons replicated the comorbid phenotype in naïve mice, while the selective inhibition of DRN glutamatergic neurons effectively reversed the behavioral and physiological impairments induced by CFA. Notably, a significant upregulation in the protein levels of 5-HT2C receptors in the DRN was detected in the comorbid state. Bidirectional manipulation of 5-HT2C receptors in the DRN glutamatergic neurons bidirectionally regulates neuronal excitability and comorbid phenotypes: agonism or overexpression exacerbates comorbidity, while antagonism or knockdown attenuates CFA-induced deficits.

Conclusions: These findings uncover the role of 5-HT2C receptors in DRN glutamatergic neurons in pain-anxiety comorbidity, thereby presenting novel targets for potential therapeutic interventions.

Background: Helicobacter pylori (H. pylori) infection is associated with enhanced efficacy of immunotherapy in gastric cancer (GC). However, the mechanisms underlying this enhancement are not fully understood.

Methods: We recruited 218 GC patients, 134 esophageal squamous cell carcinoma (ESCC) patients, and 86 dMMR/MSI-H colorectal cancer (CC) patients and collected their stool and tumor samples to analyze the gut and intratumoral microbiome. We assessed microbial diversity and composition and correlated these findings with clinical outcomes to evaluate the relationship between H. pylori status, microbiome alterations, and immunotherapy efficacy.

Results: H. pylori-positive patients showed higher alpha diversity and unique microbial signatures, which were associated with increased immune-related progression-free survival (irPFS) and overall survival (irOS). In addition, we found that the abundance of 45 gut microbiome species was significantly different between the two groups. The gut microbiome of the H. pylori-positive GC group was enriched with species such as Clostridium leptum, Oscillibacter sp. ER4, and Ruminococcus bromii, which were associated with improved treatment response. However, they predicted poor prognosis in patients with esophageal squamous cell carcinoma and colorectal cancer patients with dMMR/MSI-H. Microbial co-occurrence network revealed significantly distinct interaction patterns among the groups. In addition, we found enhanced L-arginine biosynthesis in the gut microbiome of H. pylori-positive GC. In terms of intratumoral bacteria, we identified two genera, Streptococcus and Granulicatella, that were mutually exclusive with H. pylori infection in GC. Enhanced L-lysine fermentation to acetate and butanoate was observed among intratumoral bacteria, suggesting potential metabolic shifts in the tumor microenvironment. Incorporating H. pylori infection status into the microbiome-based prediction model further improved the accuracy of predicting immunotherapy outcomes in GC.

Conclusion: These findings suggest that H. pylori had significant effects on the structure and functional activity of gut and intratumoral microbiome, some of which may affect the efficacy of immunotherapy. The clinical value of H. pylori infection status should be considered when establishing a prediction model for immunotherapy efficacy based on gut microbiome.

Background: Current evidence is limited concerning the temporal impact of atrial fibrillation (AF) ablation timings on post-ablation outcomes.

Methods: Patients who experienced ablation in the CABANA trial were enrolled in our analysis. Diagnosis to ablation time (DAT) was calculated from the date when the initial AF episode was documented. The primary endpoint was a composite of death, disabling stroke, serious bleeding or cardiac arrest. Secondary end points included AF recurrence, all-cause mortality, and all-cause mortality or cardiovascular hospitalisation. Associations between DAT and post-ablation outcomes were evaluated by restricted cubic spline (RCS) curves based on Cox models.

Results: Out of 1145 patients (median age 67.0 years, interquartile range (IQR) 61.0-72.0; 36.7% female) included, 538 (47.0%) underwent early ablation (DAT ≤ 1 year), including 242 (45.0%) who received very early ablation (DAT ≤ 90 days). The overall median DAT was 423 days (IQR 118-1473). The L-shaped association was observed between DAT and the primary outcome (P for non-linear = 0.034). The lowest point was located at a DAT of approximately 1 to 3 years. For AF recurrences, the RCS curve rose progressively with increasing DAT (P for non-linear = 0.062), showing a reduced risk when DAT was less than 1 year. Effects of early ablation on the primary outcome favoured patients with initial AAD use (HR 0.86, 95% confidence interval (CI) 0.43-1.73 vs. HR 2.20, 95% CI p-interaction = 0.045).

Conclusions: The benefits of earlier ablation in reducing AF recurrence might not equate to improvements in post-ablation cardiovascular prognosis. Timely treatment combining AADs and ablation may provide additional cardiovascular benefits.

Trial registration: ClinicalTrials.gov Identifier: NCT00911508.

Background: Sodium-glucose cotransporter-2 (SGLT-2) inhibitors with pleiotropic effects beyond glycemic control potentially improve clinical outcomes in cirrhosis; however, large-scale human evidence remains limited. We aimed to compare liver outcomes and mortality risk in adults with type 2 diabetes and compensated cirrhosis, who initiated either SGLT-2 inhibitors or dipeptidyl peptidase-4 (DPP-4) inhibitors.

Methods: Using the TriNetX Global Collaborative Network and a target trial emulation framework, we identified adults with compensated cirrhosis and type 2 diabetes initiating an SGLT-2- or DPP-4 inhibitor between 2016 and 2024. Baseline demographics, laboratory information, comorbidities and concomitant medications were matched by propensity scores. The primary outcome was a composite of incident hepatic decompensation, hepatocellular carcinoma and all-cause mortality. We used Cox proportional hazards models to estimate the hazard ratios (HR) with 95% confidence intervals (CI).

Results: We included 5,398 patients (mean [SD] age: 63.9 [10.3] years), receiving SGLT-2 inhibitors, matched to 5,398 DPP-4 inhibitor users, with an overall mean follow-up of 49.8 months. Compared to DPP-4 inhibitors, SGLT-2 inhibitors were associated with a lower risk of the primary composite outcome (HR: 0.85, 95% CI: 0.79-0.91), with similar results for all-cause mortality (HR: 0.77, 95% CI: 0.69-0.85) and incident hepatic decompensation (HR: 0.89, 95% CI: 0.82-0.96), but not for hepatocellular carcinoma (HR: 0.96, 95% CI: 0.82-1.14).

Conclusions: Among adults with compensated cirrhosis and type 2 diabetes, SGLT-2 inhibitors were associated with lower risk of all-cause mortality and incident hepatic decompensation, compared to DPP-4 inhibitors. Future clinical trials are warranted to confirm this observation.

Background: Embryo implantation failure and early pregnancy loss remain significant challenges in assisted reproductive technology (ART). Lipid peroxidation is known to be involved in reproductive physiology. However, its role during the implantation window and its effects on post-embryo transfer outcomes remain incompletely understood.

Methods: This translational study combined clinical and animal model research. Clinically, serum samples (n = 2040) and uterine fluid samples (n = 487) from patients undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles were analyzed using propensity score matching (PSM), univariate and multivariate logistic regression analysis, restricted cubic spline (RCS) analysis, and subgroup analysis. A murine model of lipid peroxidation was established by administering erastin during the implantation window to investigate its effects on endometrial receptivity and decidualization.

Results: Elevated serum levels of malondialdehyde (MDA) and non-heme iron were independently associated with recurrent implantation failure (RIF). Among patients without RIF, elevated pre-transfer serum levels of MDA, non-heme iron, 12-hydroxyeicosatetraenoic acid (12-HETE), and 15-HETE were associated with implantation failure and early pregnancy loss. Consistent with this, intrauterine MDA levels were significantly higher in patients with these pregnancy failures compared to those with ongoing pregnancy. Complementary murine studies supported these clinical observations, showing that elevated lipid peroxidation during the maternal implantation window was associated with impaired endometrial receptivity and decidualization.

Conclusions: Elevated maternal lipid peroxidation is independently associated with RIF. In patients without RIF, it is similarly associated with implantation failure and early pregnancy loss. The endometrium appears particularly sensitive to this peroxidation, which may impair receptivity and decidualization. These support further investigation of redox-modulating strategies in ART.