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Background After the coronavirus disease 2019 (COVID-19) pandemic, no studies on bacterial and atypical pathogens were conducted in primary care. We aimed to describe the etiological composition of acute respiratory tract infections (ARTIs) presenting to primary care with limited resources after the pandemic. Methods 1958 adult patients with ARTIs from 17 primary care clinics were recruited prospectively from January 2024 to March 2024. 17 and 62 pathogens in throat swab samples were tested using polymerase chain reaction (PCR) and targeted next-generation sequencing (tNGS), respectively. We analyzed the pathogen spectrum and co-infectious pattern of viral, bacterial or atypical pathogens. Then, the associations between clinical characteristics and pathogens were investigated. Results In PCR test, the positive rate of any pathogens was 80.3%, consisting of 60.2% for viruses, 41.8% for bacteria and 21.7% for viral-bacterial co-infection. In tNGS test, the positive rate was 89.1%, consisting of 64.7% for viruses, 55.2% for bacteria and 30.9% for viral-bacterial co-infection. Influenza virus B (18.2%), influenza virus A (16.8%) and severe acute respiratory syndrome coronavirus 2 (14.1%) were the three leading viral pathogens, and H. influenzae (36.1%), S. anginosus (15.7%) and S. pneumoniae (8.4%) were the three leading bacterial pathogens. Few M. pneumoniae (1.6%) were detected. The mixed bacterial or mixed viral-bacterial co-infections were the most common co-infectious patterns. The mixed bacterial or mixed viral-bacterial co-infections were the most common co-infectious patterns. Overall, patients with viral infection or viral-bacterial co-infection had more clinical symptoms, and patients with bacterial infection had higher inflammatory indicators. Conclusions After the COVID-19 pandemic, the main viral pathogens of ARTIs were unevenly distributed, and less bacterial and atypical pathogens were detected in primary care. The microbiological evidences can optimize the precision diagnosis and treatment of ARTIs in primary care with limited resources.

Risk aggregation and capital allocation are of paramount importance in business, as they play critical roles in pricing, risk management, project financing, performance management, regulatory supervision, etc. The state-of-the-art practice often includes two steps: (i) determine standalone capital requirements for individual business lines and aggregate them at a corporate level; and (ii) allocate the total capital back to individual lines of business or at more granular levels. There are three pitfalls with such a practice, namely, lack of consistency, negligence of cost of capital, and disentanglement of allocated capitals from standalone capitals. In this paper, we introduce a holistic approach that aims to strike a balance of optimality by taking into account competing interests of various stakeholders and conflicting priorities in a corporate hierarchy. While unconventional in its objective, the new approach results in an allocation of diversification benefit, which conforms to the diversification strategy of many risk management frameworks including regulatory capital and economic capital. The holistic capital setting and allocation principle provides a remedy to aforementioned problems with the existing two-step industry practice.

BackgroundMost patients with biliary tract cancer (BTC) do not derive durable clinical benefit (DCB) from immune checkpoint inhibitors (ICIs), underscoring the urgent need for predictive biomarkers. While urinary proteomics represents a non-invasive approach for biomarker discovery and mechanism exploration, its utility in ICI-treated patients with cancer remains unexplored.ObjectiveWe aimed to establish urinary proteomics as a predictive tool for ICI responsiveness and to elucidate its relationship with tumour dynamics and tumour microenvironment (TME) remodelling in BTC.DesignWe performed a staged mass spectrometry (MS)-based discovery-validation proteomics workflow in 211 urine samples from 97 treatment-naïve patients with BTC undergoing ICI-based therapy. A machine learning model was developed based on baseline proteomic features for ICI response prediction. Single-cell transcriptomics of 11 pretreatment tumour biopsies and spatial transcriptomics were integrated to explore the link between urinary proteomics and TME.ResultsPatients achieving DCB exhibited enrichment of immune activation and systemic inflammatory pathways, whereas non-durable benefit was correlated with protumourigenic processes. Longitudinal urinary proteomic dynamics could mirror TME remodelling and tumour evolution. A machine learning-derived 4-urinary protein panel (protein tyrosine phosphatase non-receptor 13 (PTPN13), SUB1, MICAL-L1, VARS1) robustly predicted DCB and early responses. Subsequent external validation in an independent cohort (n=24) using parallel reaction monitoring-MS further confirms its generalisability. PTPN13+ malignant cells were identified as key regulators of proapoptotic TME states, contributing to sustained ICI responsiveness.ConclusionsThis study pioneers the application of urinary proteomics in immuno-oncology, providing a non-invasive approach to predict and monitor ICI responsiveness, while offering mechanistic insights into TME dynamics in BTC.

Backgrounds Most significant findings from the Global Tuberculosis (TB) Report 2023 indicate that India, Indonesia, China, the Philippines, Pakistan, Nigeria, Bangladesh, and the Democratic Republic of the Congo (DRC) collectively contribute to approximately two-thirds of global TB cases. This study aims to provide crucial data-driven insights and references to improve TB control measures through a comprehensive analysis of these eight high-burden countries. Methods The eight high-burden TB countries analyzed in this study include India, Indonesia, China, the Philippines, Pakistan, Nigeria, Bangladesh, and the DRC. Age-standardized incidence rates (ASIR) of TB were derived from the Global Burden of Diseases Study 2021 data. Temporal trends were analyzed using Joinpoint regression. An age-period-cohort model was applied to examine the risk ratios (RR) of TB across diverse age groups, periods, and birth cohorts. A Bayesian age-period-cohort framework was employed to predict the ASIR of TB by 2030. Results The study found that the Philippines (average annual percentage change = 3.1%, P  < 0.001) exhibited an upward trend from 1990 to 2021. In India, the Philippines, Pakistan, and Bangladesh, the RR of TB incidence exceeded 1 after individuals reached 25 years old. Notably, the RR has shown a consistent upward trend since 2001, peaking during the period of 2017–2021 with an estimated RR of 1.5 ( P  < 0.001) in the Philippines. Similarly, the highest RR was observed during the period of 2017–2021 reaching 1.1 ( P  < 0.001) in the DRC. In the Philippines, the markedly increasing RR values for TB have been observed among individuals born after 1997–2001. Projections suggest that the ASIR of TB is expected to follow a continued upward trajectory, with an estimated rate of 392.9 per 100,000 by 2030 in the Philippines; India and Indonesia are projected to achieve less than 20.0% of the target set by the World Health Organization (WHO). Conclusions Among the eight high-burden countries, the Philippines, India and Indonesia are diverging from the goals set by the WHO, and the risk of TB in the Philippines and the DRC shows a trend toward affecting younger populations, which suggests that the management strategies for TB patients need to be further strengthened. Graphical Abstract

Cervical cancer is one of the most aggressive human cancers with poor prognosis due to constant chemoresistance and repeated relapse. Tubeimoside I (TBM) has been identified as a potent antitumor agent that inhibits cancer cell proliferation by triggering apoptosis and inducing cell cycle arrest. Nevertheless, the detailed mechanism remains unclear and needs to be further elucidated, especially in cervical cancer. In this study, we found that TBM could induce proliferation inhibition and cell death in cervical cancer cells both in vitro and in vivo. Further results demonstrated that treatment with TBM could induce autophagosome accumulation, which was important to TBM against cervical cancer cells. Mechanism studies showed that TBM increased autophagosome by two pathways: First, TBM could initiate autophagy by activating AMPK that would lead to stabilization of the Beclin1-Vps34 complex via dissociating Bcl-2 from Beclin1; Second, TBM could impair lysosomal cathepsin activity and block autophagic flux, leading to accumulation of impaired autophagolysosomes. In line with this, inhibition of autophagy initiation attenuated TBM-induced cell death, whereas autophagic flux inhibition could exacerbated the cytotoxic activity of TBM in cervical cancer cells. Strikingly, as a novel lethal impaired autophagolysosome inducer, TBM might enhance the therapeutic effects of chemotherapeutic drugs towards cervical cancer, such as cisplatin and paclitaxel. Together, our study provides new insights into the molecular mechanisms of TBM in the antitumor therapy, and establishes potential applications of TBM for cervical cancer treatment in clinic.

Diabetic retinopathy (DR) substantially threatens ocular health, necessitating the accurate and prompt assessment of its onset and progression. Optical coherence tomography angiography (OCTA) is a valuable tool for evaluating periocular microvascular indicators, offering insights crucial for diagnosing and treating DR. This meta-analysis aims to evaluate the progression of diabetic retinopathy (DR) by examining periocular microvascular indicators using optical coherence tomography angiography (OCTA). The objective is to provide substantive evidence for the future diagnosis and treatment of DR. We analyzed the relevant research retrieved from PubMed and Web of Science until January 2023. The inclusion and exclusion criteria were carefully applied to select eligible studies. Quality assessment was performed using the Newcastle-Ottawa Scale, with studies scoring 4 or less excluded. Meta-analysis was conducted using Revman 5.3 software and focused on key indicators, including peripapillary vascular length density (pVLD) and peripapillary vascular density (pVD). Heterogeneity was assessed using I2 and P values, with effect sizes determined via fixed-effect or random-effects models based on heterogeneity levels. Six studies involving 839 DR-afflicted eyes and 3209 non-DR eyes were included after screening. All selected articles exhibited high reference value, with quality scores ranging from 5 to 8 points. The meta-analysis demonstrated that DR patients displayed significantly lower pVD and pVLD in the superficial (SCP) and deep capillary plexus (DCP) compared to non-DR patients (P < .05). These findings remained consistent across different effect models, reaffirming their validity. Patients with DR exhibit reduced levels of pVD and pVLD in the SCP and DCP compared to non-DR individuals. OCTA examination of periocular microvascular indicators emerges as an effective tool for assessing the onset and progression of DR.

Background Hand, Foot, and Mouth Disease (HFMD) remains an important public health issue in China with numerous studies showing significant association between temperature and the disease. Amid growing concerns of the impact of climate change on disease, we specifically explore the relationship between temperature and HFMD in mainland China to investigate and estimate key epidemiological parameters and potential heterogeneity. Methods We developed an integrated modeling approach that combined HFMD incidence data from 68 cities across 28 Chinese provinces and municipalities from 2013 to 2019 and temperature data with the Susceptible–Exposed–Infectious–Recovered (SEIR) transmission model and Iterated Filtering (IF2) data assimilation. The approach estimated key epidemiological parameters and quantified the impact of temperature on HFMD transmission in different regions. Results HFMD transmission characteristics varied considerably by regions. The basic reproduction number ( ) declined spatially from the southeastern coast to the northwestern inland areas, with a maximum of 3.11 in South China, and minimum of 1.49 in Northeast China. The optimal temperature range for HFMD transmission was between 13.61 °C and 29.48 °C, with statistically significant regional differences in these ranges. Conclusion The SEIR-IF2 model accurately fit the observed outbreak patterns and estimated key epidemiological parameters. Furthermore, it identified the optimal temperature range and revealed spatial heterogeneity in HFMD transmission in mainland China, providing a scientific basis for developing targeted prevention and control strategies.

Microscopical nonuniformity of mechanical properties caused by phase transformation is one of the main reasons for the failure of the materials in engineering applications. Accurate measurement of the mechanical properties of each phase is of virtual importance, in which the traditional approach like Vickers hardness cannot accomplish, due to the large testing range. In this study, nanoindentation is firstly used to analyze the mechanical properties of each phase and demonstrate the phase transformation in thermal barrier coatings during high-temperature aging. The distribution of T-prime metastable tetragonal phase, cubic and tetragonal phase is determined by mapping mode of nanoindentation and confirmed with X-ray diffraction and scanning electron microscope observation. The results show that during 1300 °C aging, the phase transition of metastable Yttria-Stabilized Zirconia induces the quick decrease of T′ phase content and an increase of T and C phases accordingly. It is found that there are some fluctuations in the mechanical properties of individual phase during annealing. The hardness and Young’s modulus of T′ increase at first 9 h, due to the precipitation of Y3+ lean T phase and then decrease to a constant value accompanied by the precipitation of Y3+ rich C phase. The relevant property of C phases also increases a little firstly and then decreases to a constant, due to the homogenization of Y3+ content, while the hardness and Young’s modulus of T phase remain unchanged. After aging of 24h the hardness of T′, C and T phases are 20.5 GPa, 21.3 GPa and 19.1 GPa, respectively. The Young’s modulus of T′, C and T phases are 274 GPa, 275 GPa and 265 GPa, respectively. Present work reveals the availability of nanoindentation method to demonstrate the phase transformation and measure mechanical properties of composites. It also provides an efficient application for single phase identification of ceramics.

Background Host–microbiome interactions play essential roles in the development of Alzheimer’s disease (AD), yet the host genetic impacts on gut microbial alterations in AD remain poorly understood. Results Here, we simultaneously profiled host genotype and gut microbiome in 252 Chinese individuals with varying degrees of cognitive disability. Using the latent Dirichlet allocation topic model, we identified the Anaerostipes -enriched enterosignature (ES-Ana) at the microbial subgroup level as significantly negatively associated with cognitive disability, which could be recapitulated in external cohorts. With the whole-genome sequencing data, we performed microbiome genome-wide association studies for the ES-Ana relative abundance. We prioritized 41 lead genetic variants and confirmed that the high ES-Ana relative abundance showed a negative correlation with the polygenic risk score of AD, indicating its protective effect against AD. Furthermore, we identified 174 ES-Ana-associated genes, which are enriched in AD-related biological functions and phenotypes, and exhibite pervasive underexpression in glial cells during brain aging. Conclusions In summary, our study reveals the complex genetic effects on the gut microbiota in AD, and provides novel evidence for the roles of the gut–brain axis in AD. 19Mdqa4SQc5WgL3ys2ad99 Video Abstract

Stroke is the second leading cause of death among adults worldwide. (−)-Epigallocatechin-3-gallate (EGCG) has been demonstrated to exhibit neuroprotective functions in cerebral ischemia/reperfusion injury. However, the underlying mechanisms in this process and its contribution to the protection function remain unknown. The current study examined the neuroprotective effects of EGCG after transient middle cerebral artery occlusion (tMCAO) in rats. tMCAO for 120 min was induced in male Sprague-Dawley rats treated with EGCG (50 mg/kg, i.p.) or Vehicle immediately after reperfusion. Neurological score, infarct ratio and inflammation-related molecules (assessed by 2,3,5-triphenyltetrazolium chloride, enzyme-linked immunosorbent assays, quantitative real-time PCR or western blotting) were estimated at 24 h after operation. EGCG prevented the impairment of neurological function and decreased the infarct volume, compared with the Vehicle group. The inflammation-related molecules TNF-α, IL-1β, IL-6 levels usually caused by ischemia/reperfusion were significantly ameliorated by EGCG. EGCG also inhibited the upregulation of nuclear factor-kappa B/p65 (NF-κB/p65), and induction of cyclooxygenase 2 and inducible nitric oxide synthase. The present study indicates that EGCG may be a promising therapeutic agent for cerebral ischemia/reperfusion injury through attenuation of inflammation.