Military Medical Research最新文献

Background: In 2022, China experienced an unprecedented heatwave event, raising concerns about the health impacts of heatwaves. This study aims to understand the devastating health risk of the exceptional heatwave in 2022 by comparing heatwave-related mortality burden in 2022 with that during 2000-2021.

Methods: We collected daily mortality and daily maximum temperature (DMT) during 2006-2017 in 364 locations (counties/districts) of China. Heatwave was defined as an event with 2 or more consecutive days of DMT exceeding the 92.5th percentile. We employed a distributed lag nonlinear model (DLNM) and a meta-analysis to examine the heatwave-mortality association based on the data from 364 counties/districts, and then this association was used to assess the mortality burden attributable to heatwaves during 2000-2022 in 368 cities in China. A percentage change (%) indicator, comparing the 2022 mortality burden to the average value from 2000 to 2021, was further calculated to highlight the severity of heatwaves in 2022.

Results: In the past 2 decades, the frequency and intensity of heatwaves in China significantly increased, with the cumulative excessive degree-day increasing to 31,626 in 2022 compared with the annual average value of 13,772 during 2000-2021 across China. In 2022, we observed 62,961 [95% confidence internal (CI) 54,945-70,413] heatwave-related deaths in China, which was much higher than the annual average [35,987 (95% CI 31,252-40,471)] attributable to heatwaves during 2000-2021. The vulnerability groups of heatwave-related mortality in 2022 primarily included patients with cardiovascular diseases [40,567 (95% CI 35,313-45,404)], females [35,876 (95% CI 31,035-41,005)], and people aged over 65 years [56,208 (95% CI 49,023-62,864)]; and greater heatwave-related mortality was found in eastern-central China. The attributable fraction (AF) of heatwave-related deaths increased from an annual average of 11.01‰ (95% CI 9.56-12.38) during 2000-2021 to 18.11‰ (95% CI 15.80-20.25) in 2022 with 64.43% increment (95% CI 38.10-93.78), and the increase rates were greater in Xizang Autonomous Region (159.77%, 95% CI 12.84-477.87) and Sichuan Province (133.64%, 95% CI 3.84-416.61).

Conclusions: This study indicated that the frequency and intensity of heatwaves significantly increased in the past 2 decades in China, and the 2022 heatwaves were linked to a substantial mortality burden in China, with significant population and regional heterogeneity. Our findings underscore the need for developing comprehensive heat adaptation plans in the context of rapid aging and ongoing global warming.

Background: Anemia is a major global health problem. There were 89% of all anemia-related disabilities in developing countries. We aim to analyze the burden of anemia and its underlying causes in China from 1990 to 2023.

Methods: Utilizing the data of the 2023 Global Burden of Disease (GBD 2023) study, this study analyzed the burden of anemia in China between 1990 and 2023. Then we analyzed the number and rate of anemia attributed to 16 underlying causes for all genders and ages. Drivers of change in prevalence and years lived with disability (YLD) numbers due to anemia were explored by decomposition analysis. And locally weighted regression was used to estimate the relationship between socio-demographic index (SDI) and age-standardized prevalence rate (ASPR) and age-standardized YLD rate due to anemia.

Results: From 1990 to 2023, the ASPR and age-standardized YLD rate showed a downward trend among all anemia types (P < 0.05), and the ASPR and age-standardized YLD rate of anemia in females were higher than those in males. The highest number and rate of prevalence were found in mild anemia, and the highest number and rate of YLD were found in moderate anemia. As age increased, the prevalence and YLD rate of anemia increased, with a significant increase in females aged 20-54, in particular of moderate anemia. In 2023, the highest ASPR and age-standardized YLD rate among all anemia types were in the Northwestern regions. Compared to 1990, 31 provinces, Hong Kong, and Macao exhibited declines in both the ASPR and the age-standardized YLD rate for anemia. In China, most of the prevalent cases and YLD were attributable to dietary iron deficiency in 2023. The total prevalence of anemia decreased by 46.14% [95% uncertainty interval (UI) 27.54-61.02], of which age-specific rate, population growth, and population aging accounted for -77.32%, 21.33%, and 9.84%, respectively. A negative association between SDI and the ASPR and age-standardized YLD rate of anemia was shown in China.

Conclusions: From 1990 to 2023, the burden of anemia in China has decreased but remained heavy among women of childbearing age, the elderly, and in the Northwestern region. Tailored prevention and control strategies should be strengthened to reduce the burden of anemia in high-risk areas.

Background: Physiological, pharmacological, and pathological alterations of consciousness provide critical windows into its neural substrates. Given the inherent complexity and multidimensionality of consciousness, defining quantitative, dynamic signatures of neural activity, and translating them into clinically applicable tools remains challenge. This study aimed to build an electroencephalography (EEG)-based methodological guideline for clinical consciousness assessment.

Methods: EEG signals were systematically categorized across periodic and aperiodic activity, connectivity and network topology, spatiotemporal dynamics, self-organized criticality, and transcranial magnetic stimulation (TMS)-evoked responses. These biomarkers were mapped onto a conceptual framework of consciousness, comprising wakefulness and internal/external awareness, based on their validation across clinical conditions. The discriminative efficacy of various biomarkers was then evaluated across 4 independent datasets.

Results: Integrated EEG features each captured distinct yet complementary dimensions of consciousness, supporting a unified neurophysiological architecture underlying diverse alterations of consciousness. Spectral power and peak frequency tracked the loss of consciousness during propofol anesthesia and sleep. Steeper aperiodic slopes, loss of frontoparietal connectivity, disrupted small-world organization, and reduced effective dimensionality were particularly effective in distinguishing minimally conscious state (MCS) from unresponsive wakefulness syndrome (UWS). Additionally, spatiotemporal patterns exhibited consciousness-specific alterations, with both pharmacological and pathological alterations influencing specific microstate dynamics.

Conclusions: Synthesizing integrated neural dynamics and multidimensional consciousness, this guideline establishes both methodological and theoretical foundations for translating neurophysiological biomarkers into clinical applications. While this work advances both conceptual clarity and practical methodology, large-scale validation across expanded clinical cohorts, experimental models, and multimodal platforms is essential to fully establish causal linkages and translational utility.

Background: Type 2 diabetes (T2D) is a global epidemic that reduces life expectancy. Evidence is limited on the benefits of achieving multiple guideline-recommended targets and cross-country differences. This study aimed to quantify the associations of risk factor control with mortality and life expectancy among individuals with T2D using nationwide cohorts from China, the USA, and the UK.

Methods: We included 46,351 adults with T2D at baseline from China Chronic Disease and Risk Factors Surveillance (CCDRFS; 2013, follow-up until 2021), USA National Health and Nutrition Examination Survey (USA NHANES; 1999-2018, follow-up until 2019), and UK Biobank (2006-2010, follow-up until 2022). Patients with T2D were matched to controls without T2D using propensity score matching based on key demographic factors. Cox regression estimated mortality associated with lifestyle and metabolic factors outside target ranges [physical inactivity, smoking, unhealthy diet, elevated hemoglobin A1c (HbA1c), dyslipidemia, high blood pressure].

Results: Only a small proportion of participants achieved ≥ 5 combined targets: 16.0% in CCDRFS, 9.9% in USA NHANES, and 6.8% in UK Biobank. During 470,369 person-years of follow-up, 7650 deaths (16.5%) occurred among individuals with T2D, and 9349 deaths (10.2%) occurred among controls over 965,249 person-years. At age 50, individuals with ≤ 1 risk factor outside the target lived 6-9 years longer than those with ≥ 5, and their life expectancy was comparable to that of controls without T2D. The association was independent of genetic predisposition to shorter lifespan in the UK Biobank. Additionally, individuals with T2D who failed to achieve optimal metabolic control but maintained a healthy lifestyle had a longer life expectancy compared with those who achieved optimal metabolic control but had an unhealthy lifestyle across all cohorts, with life expectancy gains ranging from 1.5 to 3.4 years depending on sex and cohort. Among individuals with T2D, healthy lifestyle behaviors (physical activity, non-smoking, a healthy diet) and HbA1c control contributed most to gains in life expectancy. Variations in multiple risk factor control and their associations with all-cause mortality were observed across different population subgroups.

Conclusions: Achievement of guideline targets for multiple risk factors was low among individuals with T2D in China, the USA, and the UK. Comprehensive management of multiple risk factors, particularly lifestyle factors, was associated with a substantial reduction in the life expectancy gap between those with and without T2D, underscoring the importance of guideline-based care and individualized management.

Disruptions in lipid metabolism cause numerous metabolic diseases, including obesity, diabetes, cardiovascular diseases, and liver disorders. Consequently, lipid metabolism serves as a potential therapeutic target, influencing the progression of various non-metabolic diseases such as kidney diseases, cancer, neurodegenerative disorders, aging, and bone-related diseases. The metabolic pathways involved in lipid metabolism are complex and highly interconnected. Although the abundance of metabolic targets presents opportunities for lipid metabolism regulation, the limited precision and safety of traditional therapeutic approaches remain significant challenges. These limitations have catalyzed the development of multifunctional nano-delivery platforms aimed at targeted intervention in lipid metabolic processes, further enhancing the flexibility of lipid metabolism regulation. This review outlines the latest advancements and representative applications of these multifunctional nano-delivery platforms. Notably, extensive research has been conducted on nanoparticles and liposomes, with these technologies being relatively mature. Furthermore, numerous novel biomaterials, including engineered adipocytes, exosome vesicles secreted by natural cells, smart-responsive nanomicelles, composite hydrogels, and engineered lipid droplets, are being increasingly explored. Finally, the review discusses the advantages of drug delivery strategies based on the targeted intervention of lipid metabolic processes, the limitations of current technologies, promising future research directions, and treatment challenges.

Sepsis is a dysregulated host response to infection that frequently results in fatal multiple organ dysfunction. Despite advances in clinical identification and management, both its incidence and mortality have remained persistently high. Emerging evidence indicates that cell-free DNA (cfDNA), as a novel biomarker and molecular therapeutic target, holds promise for improving the clinical management of sepsis. cfDNA refers to DNA fragments present in body fluids, including naked DNA, membrane-coated DNA, nucleosomes, and neutrophil extracellular traps (NETs). cfDNA is released from host cells or pathogens into body fluids through pathways, such as NETosis, mitochondrial damage, cell necrosis, apoptosis, pyroptosis, and erythroblast enucleation. The released cfDNA triggers a strong inflammatory response by activating Toll-like receptor (TLR) 9, the absent in melanoma 2 (AIM2) inflammasome, and the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway. At the same time, cfDNA activates the coagulation cascade and inhibits anticoagulant and fibrinolytic systems through multiple mechanisms, resulting in microcirculatory disorders. These pathological effects are closely associated with sepsis-related organ dysfunction and poor prognosis. Elucidation of the release and pathological mechanisms of cfDNA provides a foundation for the development of targeted treatment strategies. Currently, molecular therapeutic approaches targeting cfDNA, including peptidylarginine deiminase (PAD) 4 inhibitors, pore-forming inhibitors, antioxidants, cfDNA scavengers, and deoxyribonucleases (DNases), have shown certain efficacy in treating sepsis and systemic inflammation. In terms of sepsis monitoring, compared with traditional markers, cfDNA exhibits extremely high timeliness and dynamic monitoring capability. cfDNA can simultaneously indicate the complex interplay among infection, host response, and organ damage, making it suitable for early diagnosis, prognosis assessment, treatment monitoring, organ function evaluation, and pathogen detection. Given its broad application prospects in the diagnosis and treatment of sepsis, this paper systematically elaborates on the mechanisms of cfDNA release and pathological effects in sepsis, reviews progress in cfDNA-targeted monitoring and therapeutic strategies, discusses technical challenges, and outlines potential future directions.

Background: Peritoneal fibrosis represents a major clinical challenge for end-stage renal disease (ESRD) patients when they are undergoing peritoneal dialysis (PD). Single-cell RNA sequencing identified that peritoneal mesothelial cells undergo a senescence fate transition in long-term PD patients. Whereas the existence of mesothelial cell senescence and the underlying mechanisms should be thoroughly explored.

Methods: To further investigate mesothelial cell senescence, we utilized a clinical cohort comprising dialysate effluents from PD patients and peritoneal biopsy specimens, peritoneal dialysis fluid (PDF)-induced mouse models, and cultured primary mesothelial cells. Single-cell RNA sequencing, transcriptome sequencing, immunofluorescence, Western blotting, and other analyses were administered. To validate the critical role of β-catenin in mesothelial cell senescence, β-catenin knockout mice were employed. Additionally, the senolytic drugs dasatinib plus quercetin were administered to PDF mice to assess the key role of mesothelial cell senescence in peritoneal fibrosis.

Results: Single-cell RNA sequencing demonstrated that mesothelial cells derived from long-term PD patients are major trend to senescence fate. Moreover, β-catenin signaling was significantly upregulated, as well as transforming growth factor-β (TGF-β) pathways. We observed that senescent mesothelial cells were highly increased in both dialysate effluent and peritoneal biopsies of long-term PD patients. In dialysate effluent, matrix metalloproteinase-7 (MMP-7), an indicator of downstream targets of β-catenin, was positively correlated with TGF-β1. Both biomarkers were also positively associated with PD duration. Mechanistically, we found that β-catenin promotes dynamin-related protein 1 (Drp1) expression, a key mediator of mitochondrial fission, thereby inducing mesothelial cell senescence. Then, TGF-β1 was secreted to activate the Smad signaling pathway in fibroblasts, leading to myofibroblast activation and subsequent peritoneal fibrosis. Notably, administration of senolytic drugs, dasatinib plus quercetin, significantly alleviated peritoneal fibrosis regardless of treatment timing.

Conclusion: Targeting β-catenin signaling and mesothelial cell senescence may represent potential therapeutic interventions for preventing peritoneal fibrosis.

Background: Targeted alpha therapy (TAT) has emerged as a promising strategy for cancer treatment by selectively delivering high linear energy transfer (LET) alpha-emitters to tumor cells while minimizing off-target toxicity. However, the clinical translation of alpha-emitters, particularly radium-223 (²²³Ra), remains challenging due to inefficient targeted delivery and uncontrolled release of recoil daughter products, leading to systemic toxicity.

Methods: Herein, a dual-locked pretargeted strategy was developed integrating platinum^IV (Pt^IV)-loaded hydrogel nanoparticles (HNPs) (HAQ@HNPs) and ²²³Ra-loaded HNPs (²²³Ra@HNPs) into an inverse electron demand Diels-Alder (IEDDA)-activated drug delivery system. In vitro cytotoxicity, ROS, and apoptosis, together with in vivo biodistribution, imaging, and therapeutic studies, were performed to evaluate the therapeutic efficacy and immune activation.

Results: This caged dual-locked approach enables precise pretargeted accumulation at the tumor site, followed by rapid dissociation and controlled release of ²²³Ra and Pt^IV upon IEDDA-triggered activation, thereby ensuring high tumor specificity while minimizing systemic exposure. The synergistic combination of TAT and chemotherapy effectively disrupts redox homeostasis, induces immunogenic cell death (ICD), and elicits a robust antitumor immune response. Furthermore, when combined with programmed death-ligand 1 (PD-L1) blockade, this strategy significantly enhances systemic antitumor immunity, leading to robust inhibition of tumor growth and metastasis.

Conclusions: These findings underscore the potential of dual-locked pretargeted strategies to advance TAT by improving therapeutic efficacy and addressing the critical challenge of radionuclide leakage, paving the way for next-generation precision-targeted radiopharmaceuticals.