BMC Medicine最新文献

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, appearing to be associated with accelerated brain aging. Although increased brain age has been associated with mortality risk in older adults, it remains unclear how the brain aging process is accelerated in ALS and how this acceleration relates to patient prognosis.

Methods: One hundred seventy sporadic ALS patients and 84 age- and sex-matched HCs were recruited and underwent neuropsychological tests and T1-weighted magnetic resonance imaging (MRI) scans. A brain-age prediction model was developed using a 3D-Conformer deep learning framework trained on 4310 healthy T1-weighted MRI data from public datasets. Brain age was predicted in HCs and ALS patients, and then the predicted-age difference (PAD = brain age-chronological age) was calculated. In the ALS cohort, the neuroanatomical association of PAD was examined, and cell-specific gene expression of PAD-related volume loss was analyzed using transcriptomic data from the Allen Human Brain Atlas. Associations between PAD, neuropsychological performance, clinical characteristics, and survival outcomes were further evaluated in ALS patients.

Results: The brain aging process was accelerated in ALS by an average PAD of 1.77 years, which was predominantly associated with a widespread loss of gray matter volume. Cell-specific gene expression analyses showed microglia, inhibitory neurons, endothelial cells, and pericytes as significant contributors to the accelerated brain aging in ALS, with endothelial cells and pericytes being essential for constructing the blood-brain barrier (BBB) and microglia being involved in neuroinflammation. The acceleration in brain aging was more prominent in older patients and was associated with cognitive impairments. Notably, older brain age at initial diagnosis was an independent risk factor for death (hazard ratio, 1.026; 95% CI [1.008, 1.045]) and was associated with shorter survival and more rapid disease progression.

Conclusions: Accelerated brain aging is common in ALS; this could be hypothesized to be associated with the interplay between BBB breakdown and neuroinflammation, leading to gray matter degeneration. Furthermore, older brain age at initial diagnosis is associated with worse clinical outcomes. These findings suggest that therapeutic strategies targeting neuroinflammation and BBB integrity may help attenuate accelerated brain aging and improve prognosis.

Background: Maternal infections during pregnancy may increase the risk of childhood cancer (CC) in offspring by affecting foetal immunity and genetics. Existing evidence seems inconclusive, necessitating a comprehensive review to understand this association. We aimed to evaluate the risk of various CC outcomes following prenatal exposure to different types of maternal infections.

Methods: We searched Medline, Web of Science, Embase, Cochrane Library, and bibliographies for relevant studies from inception to October 2025. The study protocol was registered in PROSPERO (ID:CRD42023483706). We included original human epidemiological studies that examined the association between maternal infections during pregnancy and CC with appropriate reference groups and no language restrictions. We excluded studies if they were reviews or reports, if they did not assess individual-level infection or if they used therapies for infections (e.g., antibiotics) as markers of infection exposure. Two independent reviewers extracted data and assessed methodological quality following PRISMA guidelines. Pooled estimates (ES) and 95% confidence intervals (95%CIs) were calculated using random-effect models. Heterogeneity was examined in subgroup analyses. Publication bias was evaluated using Egger's tests and Funnel plots.

Results: From 9284 studies identified by the search, 46 studies (39 case-control,7 cohort) with over nine million participants were included, covering 33 analyses of 12 types of infection and five CC sites. Overall, maternal infection during pregnancy was associated with increased risk of CC (ES = 1.36;95%CI,1.17-1.59). Sexually transmitted infections (STIs) were associated with increased overall CC risk (ES = 2.86;95%CI,1.88-4.33). Viral infections were also associated with increased risk of overall CC (ES = 1.43;1.18,1.74), with cytomegalovirus and rubella virus infections showing positive associations upon stratification by pathogen-type. Genitourinary tract infections (GUTIs) were associated with increased risk of leukaemia (ES = 1.49;95%CI,1.05-2.12) and solid tumours (ES = 1.60, 95%CI;1.06-2.42) and viral infections with the risk of acute lymphoblastic leukaemia (ES = 1.58;95%CI,1.15-2.18).

Conclusions: Maternal STIs, GUTIs, and viral infections during pregnancy are associated with increased risk of CC, with GUTIs and viral infections specifically associated with increased risk of leukaemia. Targeted prevention strategies towards specific infections during pregnancy may protect against CC. Large-scale prospective studies with precise infection assessment and stratification by pathogen-type, and mechanistic considerations are needed to deepen knowledge in this area.

Background: Observational studies link high blood pressure in pregnancy to numerous adverse pregnancy and perinatal outcomes; however, findings may be affected by residual confounding or reverse causation. This study aimed to assess the causal effect of blood pressure during pregnancy on a range of pregnancy and perinatal outcomes.

Methods: We performed two-sample Mendelian randomization (MR) to assess the effect of systolic and diastolic blood pressure (SBP/DBP) during pregnancy on 16 primary and eight secondary adverse pregnancy and perinatal outcomes. We obtained genetic association data from large-scale meta-analyses of genome-wide association studies involving predominantly European ancestry individuals for SBP/DBP (N = 1,028,980), and pregnancy and perinatal outcomes (N = 74,368-714,899). We used inverse-variance weighted (IVW) MR for main analyses and MR-Egger, weighted median, weighted mode, multivariable MR, and IVW adjusted for fetal genetic effects for sensitivity analyses.

Results: A 10 mmHg higher genetically predicted maternal SBP increased the odds of gestational diabetes, induction of labour, low birth weight (LBW), small-for-gestational age (SGA), preterm birth (PTB), and neonatal intensive care unit (NICU) admission (OR ranging from 1.11 [95% CI 1.02 to 1.20] for NICU admission to 1.33 [1.26 to 1.41] for LBW); while decreasing the odds of high birth weight (HBW), large-for-gestational age (LGA), and post-term birth [OR ranging from 0.76 (0.69 to 0.83) for HBW to 0.94 (0.90 to 0.99) for post-term birth]. We did not find evidence that genetically predicted higher maternal SBP was related to miscarriage or stillbirth. The results for maternal DBP were similar to the results for SBP. Overall, the main results were consistent across sensitivity analyses accounting for pleiotropic instruments and fetal genetic effects.

Conclusions: Higher maternal blood pressure reduces gestation duration and fetal growth and increases the risks of induction of labour, gestational diabetes, and neonatal intensive care unit admission. This and other emerging evidence highlight the value of interventions aimed at controlling blood pressure in the population to reduce the burden of adverse pregnancy outcomes.

Background: Molecular tumor boards (MTBs) are essential for selecting therapies for patients with rare and advanced cancers. We hypothesized that integrating biomarkers beyond targeted DNA/RNA next-generation sequencing (NGS) could increase actionable findings. Human epidermal growth factor receptor 2 (HER2)-low status has emerged as a critical biomarker in breast cancer, with potential relevance across other tumor types. Homologous recombination deficiency (HRD) is pivotal for the application of Poly(ADP-Ribose)-Polymerase (PARP) inhibitors in ovarian and breast cancer, although its role in other malignancies remains unclear. Antibody-drug conjugates (ADCs) are expanding precision oncology, with promising biomarkers like Trop-2, Nectin-4, and folate receptor alpha (FRα) showing potential across multiple tumor entities.

Methods: Tumors were analyzed using the TSO500® panel, enabling tumor mutational burden (TMB) readout. HER2 status was assessed via immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), alongside antibody-drug conjugate (ADC) IHC, microsatellite instability (MSI) polymerase chain reaction (PCR), mismatch repair (MMR) IHC, programmed death-ligand 1 (PD-L1) IHC, and HRD analysis. Cases were discussed weekly, and outcomes were systematically tracked. Data analysis evaluated the benefit of additional biomarker assessments.

Results: Among 658 patients, 329 received therapy recommendations, 182 based on supplementary biomarker analyses. One hundred recommendations were implemented, with 37% attributed to supplementary diagnostics. Among 64 response-evaluable patients, the clinical benefit rate (complete response + partial response + stable disease) was 45.3%. HER2-low status notably expanded targeted therapy options across tumor types, with similar implementation rates for HER2-low and HER2-amplified tumors. HRD analysis refined stratification in tumors with mutations in homologous recombination repair (HRR) genes beyond BRCA1/2, including PALB2, ATM, and CHEK2. ADC IHC supported 20 recommendations and two therapy implementations.

Conclusions: The integration of additional biomarker assessments into MTB workflows enhances precision oncology by expanding the pool of patients eligible for targeted therapies.

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.