BMC Medicine最新文献

Background: Musculoskeletal injuries comprise a growing source of disability worldwide, and the recovery of muscle strength following injury is a critical determinant of patient reported outcomes. Females experience exacerbated muscle atrophy, poorer outcomes, and higher re-injury rates, necessitating a comprehensive interrogation of sex-specific skeletal muscle differences. Our purpose in the current study was to perform an unbiased transcriptomic profiling of muscle samples to identify putative sex-specific molecular targets to enhance recovery in patients who underwent anterior cruciate ligament reconstruction (ACLR).

Methods: We performed cellular phenotyping, bulk and single nucleus RNA-sequencing on muscle biopsy samples obtained from thirty-six participants (18 M, 18F). Muscle samples were obtained from the ACLR and contralateral limb with follow-up tissue collection of the injured limb also occurring at seven days and four months post-ACLR. Transcriptomic analyses illuminated putative molecular mechanisms through which sex influences muscle recovery following acute injury.

Results: Females exhibited greater muscle atrophy relative to males at 4 months post-ACLR compared to the uninjured limb. Bulk and single nucleus paired-limb transcriptomic analyses revealed the emergence of sex-specific myonuclear signaling cascades that demonstrate impaired reactive oxygen species scavenging in females. Females exhibited attenuated SOD2 expression that was associated with increased indices of oxidative stress and protein damage. Within females, angiogenesis signaling was also impaired and associated with capillary rarefaction after reconstructive surgery.

Conclusions: These findings reveal inherent sex-based differences in muscle pathology that likely necessitate unique clinical treatments following musculoskeletal injury.

Background: The malaria vaccine R21/Matrix-M is recommended for young children in malaria-endemic regions. However, the small vaccine-eligible population and waning vaccine efficacy mean that routine vaccination is unlikely to prevent severe cases in older children who experience significant malaria burden. As R21/Matrix-M vaccination expands, targeting older age groups may be warranted, depending on funding.

Methods: Using a stochastic, individual-based Plasmodium falciparum malaria transmission model, we estimate the impact of (1) one-off catch-up campaigns with R21/Matrix-M to previously unvaccinated age groups between age 6 months and 14 years, and/or (2) extra boosters at 2, 5, and/or 10 years after the primary series in low, moderate, and high transmission settings. We assume that vaccine immunogenicity in older children is equivalent to that of the standard target age group, though clinical trials have shown lower immunogenicity in older children.

Results: Catch-up campaigns in moderate-to-high transmission settings targeting younger children averted the most uncomplicated cases per 1000 additional doses (358 (95% credible interval (CI) 113-570) in children aged 6 months-2 years at 45% PfPR_2-10), compared with targeting older children. In low transmission settings, the impact was similar across age groups, with a slightly higher impact when targeting school-aged children (373 (95% CrI 240-518) in children aged 5-9 years at 5% PfPR_2-10). Across extra booster strategies, an extra booster 10 years post- primary series averted the most severe cases per 1000 additional doses at low transmission (12 (95% CrI 6-18) at 5% PfPR_2-10), but the least at high transmission (- 4 (95% CrI - 11-3) at 45% PfPR_2-10). Expanding the vaccine-eligible population in areas of moderate-to-high transmission often had higher incremental efficiency than routine age-based vaccination at low transmission. For example, an extra booster 5 years post-primary series averted 835 (95% CrI 605-1274) clinical cases per 1000 additional doses in a 45% PfPR_2-10 perennial setting versus 247 (95% CrI 177-345) clinical cases per 1000 doses with routine vaccination in a 5% PfPR_2-10 perennial setting. Sensitivity analyses assuming lower immunogenicity in older children modestly reduced the per-dose impact, but overall conclusions remained unchanged.

Conclusions: Catch-up campaigns or extra booster doses of R21/Matrix-M can provide benefits beyond routine administration, with the per-additional-dose value approaching that of routine vaccination, but this varies by transmission and seasonality setting. Further empirical studies, particularly on vaccine efficacy in older children, are warranted to inform policy guidance for malaria vaccination implementation.

Background: Chronic diseases can impact physical function, yet little is known about how specific disease combinations relate to long-term physical performance trajectories and whether these associations vary across different performance measures. This population-based study explored the association between multimorbidity patterns and 15-year changes in physical performance among older adults.

Methods: We analyzed 15-year longitudinal data on 3112 dementia-free individuals aged 60 and older participating in the Swedish National study on Aging and Care in Kungsholmen. Physical performance was assessed through walking speed and chair-stand tests, further combined into a z-standardized overall measure. Latent class analysis was used to identify groups of individuals with similar patterns of diseases. Linear mixed models were used to evaluate the association between multimorbidity patterns and changes in physical performance scores over time. Inverse probability weighting was used to account for attrition over the follow-up.

Results: Four multimorbidity patterns were identified: 1) psychiatric, respiratory, & musculoskeletal, 2) anemia & sensory impairment, 3) cardiometabolic & inflammatory, and 4) unspecific. Compared to individuals without multimorbidity (≤ 1 disease), all patterns were associated with faster annual declines in physical performance, with the steepest decline observed for the cardiometabolic & inflammatory pattern (β*time = -0.066, 95%CI: -0.111, -0.021), followed by the anemia & sensory impairment pattern (β*time = -0.043, 95%CI: -0.063, -0.023). Results remained consistent after adjustment for the number of chronic diseases.

Conclusions: Multimorbidity patterns are differentially associated with the rate of decline in physical performance, with the cardiometabolic & inflammatory pattern being associated with the fastest decrease. Classifying individuals according to multimorbidity patterns may help guide targeted strategies to preserve physical function in later life.

Background: This study aims to characterize the epidemiological and clinical features of pulmonary tuberculosis with diabetes mellitus (PTB-DM), identify risk factors for unsuccessful treatment outcomes, and develop predictive models to aid in outcome assessment for these patients.

Methods: Clinical data from 3886 pulmonary tuberculosis (PTB) cases treated at Liuzhou People's Hospital Affiliated to Guangxi Medical University between July 2017 and December 2023 were analyzed. A case-control study was conducted to investigate the epidemiological and clinical profiles of PTB-DM. A retrospective cohort study and the LASSO-Logistic regression model were employed to identify independent risk factors for unsuccessful treatment outcomes, and a risk nomogram prediction model was developed to assess the predictive performance of the model.

Results: From 2017 to 2023, the rates of diabetes mellitus among pulmonary tuberculosis patients were 7.14%, 9.44%, 13.96%, 12.37%, 11.78%, 14.45%, and 19.63%, respectively. The proportion of pulmonary tuberculosis with diabetes mellitus showed a significant upward trend (P < 0.001). Various parameters including bacteriological positivity rate, sputum smear positivity rate at baseline, secondary pulmonary tuberculosis,and clinical symptoms like hemoptysis and chest pain, as well as imaging findings such as pulmonary cavity and pleural effusion, and unsuccessful treatment outcomes were all notably higher in PTB-DM patients compared to non PTB-DM patients (P < 0.05). Risk factors for unsuccessful outcomes in PTB-DM patients included being aged 65 or older (OR = 7.334, 95% CI: 2.654-23.136), hemoptysis (OR = 9.245, 95% CI: 3.411-27.464), positive sputum smear at baseline (OR = 3.774, 95% CI: 1.451-10.388), pulmonary cavity (OR = 3.850, 95% CI: 1.426-10.721), elevated CKMB levels (OR = 1.074, 95% CI: 1.014-1.136), elevated ESR (OR = 1.049, 95% CI: 1.025-1.077), and elevated HbAlc (OR = 1.352, 95% CI: 1.105-1.678), while higher ALB levels (OR = 0.874, 95% CI: 0.778-0.977) was a protective factor. A nomogram model incorporating these variables demonstrated high discriminative ability (AUC = 0.959, 95% CI: 0.931-0.987), with good calibration as assessed by the Hosmer-Lemeshow goodness-of-fit test (P = 0.474).

Conclusions: Pulmonary tuberculosis patients with diabetes mellitus exhibit more severe clinical manifestations and a higher risk of unsuccessful treatment outcomes compared to those without diabetes. The nomogram model developed based on selected predictors demonstrates excellent predictive performance and can assist clinicians in early risk stratification and individualized management of PTB-DM patients.

Background: It remains unclear whether digital health-based multidomain management is associated with long-term cardiometabolic health control in real-world scenarios.

Methods: We conducted a retrospective analysis of a real-world health management program involving 40,216 adults from 2018 to 2024 across 30 provinces in China. The program combined digital health platforms (including mobile health apps and smartwatches) with offline wellness centers to provide personalized lifestyle management. Participants' demographics, physiological (blood pressure, blood glucose, body composition, heart rate, grip strength, and cholesterol), psychological, and lifestyles (sleep and physical activity) data were longitudinally collected. Program engagement was measured by mobile health app usage frequency, device wear time, and wellness center participation. The population-level trajectory of cardiometabolic health changes was fitted over a 12-month follow-up using the linear mixed-effects models. Associations between participants' engagement and cardiometabolic health (blood pressure, blood glucose, and body fat percentage) improvement were further examined.

Results: The median (IQR) age of 40,216 participants was 71 (64-75). During the 5-year management period, participants contributed a total of 9,749,898 physical activity, 8,623,004 heart rate, 8,323,161 sleep, 2,925,903 body composition, 2,619,725 blood pressure, and 291,240 blood glucose data. Over the 5 years, participants used mobile health app to upload their health data for an average of 5.7 days per week, and wore smartwatches 5.8 days per week, with 95.5% wearing them for ≥ 8 h per valid day. Older age, female sex, and higher education level were associated with higher weekly frequency of mobile health app usage. Among participants with elevated blood pressure, elevated blood glucose, or obesity, those with high engagement were associated with greater reductions in systolic blood pressure (- 3.85 [-5.2 to -2.49] mmHg), blood glucose (- 1.20 [ -2.06 to -0.34] mmol/L), and body fat percentage (- 1.24% [-1.59% to -0.88%]). Explorative mediation analyses suggested that reductions in body fat percentage partially mediated these associations.

Conclusions: Findings of this study suggest that a digital health-based multidomain program may support daily cardiometabolic health monitoring and management. Such frameworks can be feasible and scalable to help facilitate proactive prevention strategies.

Background: This study aims to evaluate the clinical effectiveness and feasibility of a novel bilateral sequential accelerated theta-burst stimulation (BS-aTBS) protocol in treatment-resistant depression (TRD) patients, compared to a standard intermittent TBS (a-iTBS) protocol.

Methods: In this randomized controlled clinical trial, 94 TRD patients were randomly assigned to receive either BS-aTBS (n = 46) or a-iTBS (n = 48). Both groups delivered 10 daily TBS sessions (1800 pulses/session) for 5 consecutive days. The primary outcome was score on the 24-item Hamilton Depression Rating Scale (HDRS-24) after treatment, normalized to baseline (week 0).

Results: Both BS-aTBS and a-iTBS protocols significantly reduced HDRS-24 scores by week 1 (65.52% vs. 54.32%, p = 0.008) and week 5 (77.10% vs. 67.77%, p = 0.006), and the BS-aTBS group showed significantly greater symptom improvement at both time points. Compared to a-iTBS, the BS-aTBS yielded higher response rates at week 1 (78.26% vs. 58.33%, p = 0.038) and week 5 (93.48% vs. 77.08%, p = 0.026), and elicited greater alleviation for anxiety and suicidal ideation at week 5. Moreover, clinical improvement on sleep quality and cognitive abilities was larger in the BS-aTBS group, and the effects on anhedonia and alexithymia were comparable between the two protocols. No serious adverse events were observed.

Conclusions: The BS-aTBS protocol provided rapid and well-tolerated antidepressant effects in TRD patients lasting for 1 month, with additional benefits for anxiety and suicidal ideation. Considering its clinical advantages and shortened treatment time, the BS-aTBS may serve as a promising treatment protocol for TRD patients with high feasibility and efficiency.

Trial registration: This trial was registered at Chinese Clinical Trial Registry (ChiCTR2400091459).

Background: Biallelic SPG7 mutations cause one of the most common forms of hereditary spastic paraplegia (HSP). Several reports have suggested that heterozygous SPG7 variants may also play a role in HSP, but also in amyotrophic lateral sclerosis (ALS). However, it remains controversial whether heterozygous SPG7 mutations are pathogenic on their own, or if other mechanisms are at play. We recently provided evidence for non-Mendelian inheritance in spastic paraplegia 7 (SPG7), as heterozygous carriers of SPG7 mutations often also carried mutations in other disease-related genes, including AFG3L2, more frequently than expected by chance. Given that SPG7 and AFG3L2 encode interacting subunits of the mitochondrial m-AAA protease complex, we hypothesized that combined heterozygous mutations in these genes may act synergistically to disrupt mitochondrial function and contribute to disease. In this study, we aimed to examine whether digenic heterozygous mutations in SPG7 and AFG3L2 can lead to a spectrum of neurodegenerative disorders.

Methods: We first analyzed genome and exome sequencing data of 6644 unrelated individuals including 4817 motor neuron disorder (MND) and ataxia patients and 1827 controls. We next analyzed an additional 18,748 exome data from rare disease cohorts to further examine the occurrence of variants in SPG7 and AFG3L2.

Results: Among the first 4817 MND and ataxia patients, we identified a total of 6 patients, 4 of whom were unrelated, who carried potentially pathogenic variants in both SPG7 and AFG3L2, in contrast to none in 1827 unrelated controls. Further analysis of the 18,748 additional patients with rare disease, as well as a comprehensive literature review, identified 6 more patients, 5 of whom were unrelated, who had digenic mutations in SPG7 and AFG3L2. In the two families we identified, digenic mutations in SPG7 and AFG3L2 perfectly segregated with the disease. The 12 patients reported here exhibited predominant signs of motor neuron and cerebellar involvement.

Conclusions: Our findings demonstrate that digenic inheritance of concurrent heterozygous mutations in SPG7 and AFG3L2 may cause motor neuron and cerebellar disorders. Screening of the entire SPG7 and AFG3L2 genes in genetically undiagnosed cases of MND and spastic ataxia may help to increase the diagnostic yield.

Background: Type 2 diabetes worsens functional outcome after stroke, severely affecting the rehabilitation processes, with no therapy available for this medical problem.

Main text: Weight loss is an effective strategy for managing type 2 diabetes, with some studies also showing that it can reduce cardiovascular and stroke risk in this population. Recent animal studies suggest that weight loss induced by a diet change or pharmacologically (via the activation of the glucagon-like peptide 1 receptor) also improves functional outcome after stroke. Today, however, no clinical study has yet addressed this question. This issue is important to address since type 2 diabetes is one of the strongest risk factors for stroke and the growing prevalence of diabetes is leading to an increasing number of stroke patients with type 2 diabetes who will require effective therapies. Here, we discuss recent findings showing the positive effects of weight loss in type 2 diabetes and its cardiovascular complications, underlining the need to perform new clinical studies specifically focused on understanding the potential therapeutic role of weight loss to improve functional outcomes after stroke.

Conclusions: In summary, this debate underscores a critical clinical gap in current post-stroke care strategies and highlights the potential for weight loss as a novel treatment paradigm to improve functional stroke outcomes in type 2 diabetes. If validated in clinical studies, this approach will significantly improve the quality of life of many stroke patients with type 2 diabetes.

Background: Chronic conditions often cluster together, forming distinct multimorbidity patterns. We aimed to explore how such patterns are associated with the risk of albuminuria.

Methods: We utilized the Stockholm Creatinine Measurements (SCREAM) project, comprising 675,570 adults undergoing outpatient albuminuria testing in Stockholm, Sweden. Disease patterns were derived in adults without albuminuria at baseline, stratified by age (18-64, 65-74, ≥ 75 years). Associations with incident albuminuria (albumin-creatinine ratio > 30 mg/g) and macroalbuminuria (> 300 mg/g) were examined using Cox and Fine-Gray competing risk models.

Results: We identified four multimorbidity patterns in younger participants (18-64), six in the 65-74 group, and seven among those aged ≥ 75. Across all age groups, most patterns-including cardiovascular, mental health, and eye patterns-were consistently associated with elevated albuminuria risk compared to those without multimorbidity. In the 65-74 stratum, the cardiovascular pattern had the highest risk compared to those without multimorbidity (HR 3.09: 95% CI: 2.85-3.34). Among those aged ≥ 75, almost all identified patterns showed higher risk, with those in the vascular pattern being at highest risk (HR: 2.41, 95% CI: 2.08-2.80). The dementia pattern showed no significant association. High-burden patterns in older participants with numerous chronic conditions (e.g., multisystem and cardiovascular patterns) were at increased risk, but this was attenuated after accounting for the competing risk of death. The 5- to 6-year cumulative incidence of albuminuria exceeded 10-14% in the highest-risk patterns, 5-9% higher than for those without multimorbidity. In interaction analyses, reduced estimated glomerular filtration rate amplified risk among younger individuals. Females generally had lower risk, except with mental health patterns in younger ages or cardiovascular multimorbidity in those 65 to 74.

Conclusions: Multimorbidity patterns, including those characterized by non-traditional CKD risk factors, can help identify individuals at elevated albuminuria risk. Targeted screening of these groups may enable preventive strategies to slow or prevent kidney damage.