Precision Prediction for Dengue Fever in Singapore: A Machine Learning Approach Incorporating Meteorological Data.

OBJECTIVE: This study aimed to improve dengue fever predictions in Singapore using a machine learning model that incorporates meteorological data, addressing the current methodological limitations by examining the intricate relationships between weather changes and dengue transmission. METHOD: Using weekly dengue case and meteorological data from 2012 to 2022, the data was preprocessed and analyzed using various machine learning algorithms, including General Linear Model (GLM), Support Vector Machine (SVM), Gradient Boosting Machine (GBM), Decision Tree (DT), Random Forest (RF), and eXtreme Gradient Boosting (XGBoost) algorithms. Performance metrics such as Mean Absolute Error (MAE), Root Mean Square Error (RMSE), and R-squared (R2) were employed. RESULTS: From 2012 to 2022, there was a total of 164,333 cases of dengue fever. Singapore witnessed a fluctuating number of dengue cases, peaking notably in 2020 and revealing a strong seasonality between March and July. An analysis of meteorological data points highlighted connections between certain climate variables and dengue fever outbreaks. The correlation analyses suggested significant associations between dengue cases and specific weather factors such as solar radiation, solar energy, and UV index. For disease predictions, the XGBoost model showed the best performance with an MAE = 89.12, RMSE = 156.07, and R2 = 0.83, identifying time as the primary factor, while 19 key predictors showed non-linear associations with dengue transmission. This underscores the significant role of environmental conditions, including cloud cover and rainfall, in dengue propagation. CONCLUSION: In the last decade, meteorological factors have significantly influenced dengue transmission in Singapore. This research, using the XGBoost model, highlights the key predictors like time and cloud cover in understanding dengue's complex dynamics. By employing advanced algorithms, our study offers insights into dengue predictive models and the importance of careful model selection. These results can inform public health strategies, aiming to improve dengue control in Singapore and comparable regions.

Natural variables separate the endemic areas of Clonorchis sinensis and Opisthorchis viverrini along a continuous, straight zone in Southeast Asia.

BACKGROUND: Clonorchiasis and opisthorchiasis, caused by the liver flukes Clonorchis sinensis and Opisthorchis viverrini respectively, represent significant neglected tropical diseases (NTDs) in Asia. The co-existence of these pathogens in overlapping regions complicates effective disease control strategies. This study aimed to clarify the distribution and interaction of these diseases within Southeast Asia. METHODS: We systematically collated occurrence records of human clonorchiasis (n = 1809) and opisthorchiasis (n = 731) across the Southeast Asia countries. Utilizing species distribution models incorporating environmental and climatic data, coupled machine learning algorithms with boosted regression trees, we predicted and distinguished endemic areas for each fluke species. Machine learning techniques, including geospatial analysis, were employed to delineate the boundaries between these flukes. RESULTS: Our analysis revealed that the endemic range of C. sinensis and O. viverrini in Southeast Asia primarily spans across part of China, Vietnam, Thailand, Laos, and Cambodia. During the period from 2000 to 2018, we identified C. sinensis infections in 84 distinct locations, predominantly in southern China (Guangxi Zhuang Autonomous Region) and northern Vietnam. In a stark contrast, O. viverrini was more widely distributed, with infections documented in 721 locations across Thailand, Laos, Cambodia, and Vietnam. Critical environmental determinants were quantitatively analyzed, revealing annual mean temperatures ranging between 14 and 20 °C in clonorchiasis-endemic areas and 24-30 °C in opisthorchiasis regions (P < 0.05). The machine learning model effectively mapped a distinct demarcation zone, demonstrating a clear separation between the endemic areas of these two liver flukes with AUC from 0.9 to1. The study in Vietnam delineates the coexistence and geographical boundaries of C. sinensis and O. viverrini, revealing distinct endemic zones and a transitional area where both liver fluke species overlap. CONCLUSIONS: Our findings highlight the critical role of specific climatic and environmental factors in influencing the geographical distribution of C. sinensis and O. viverrini. This spatial delineation offers valuable insights for integrated surveillance and control strategies, particularly in regions with sympatric transmission. The results underscore the need for tailored interventions, considering regional epidemiological variations. Future collaborations integrating eco-epidemiology, molecular epidemiology, and parasitology are essential to further elucidate the complex interplay of liver fluke distributions in Asia.

Impact of varied immunosuppressive agents and post-transplant diabetes mellitus on prognosis among diverse transplant recipients (experimental studies).

The success of solid organ transplantation (SOT) and the use of immunosuppressive agents offer hope to patients with end-stage diseases. However, the impact of post-transplant diabetes mellitus (PTDM) on SOT patients has become increasingly evident. In our study, we utilized the Scientific Registry of Transplant Recipients (SRTR) database to investigate the association between PTDM and patient survival in various types of organ transplantations, including liver, kidney, intestinal, heart, lung, and combined heart-lung transplantations (all P <0.001). Our findings revealed a negative effect of PTDM on the survival of these patients. Furthermore, we examined the effects of both generic and innovator immunosuppressive agents on the development of PTDM and the overall survival of different SOT populations. Interestingly, the results were inconsistent, indicating that the impact of these agents may vary depending on the specific type of transplantation and patient population. Overall, our study provides a comprehensive and systematic assessment of the effects of different immunosuppressive agents on prognosis, as well as the impact of PTDM on the survival of patients undergoing various types of SOT. These findings emphasize the need for further research and highlight the importance of optimizing immunosuppressive regimens and managing PTDM in SOT patients to improve their long-term outcomes.

AMXT-1501 targets membrane phospholipids against Gram-positive and -negative multidrug-resistant bacteria.

The rapid proliferation of multidrug-resistant (MDR) bacterial pathogens poses a serious threat to healthcare worldwide. Carbapenem-resistant (CR) Enterobacteriaceae, which have near-universal resistance to available antimicrobials, represent a particularly concerning issue. Herein, we report the identification of AMXT-1501, a polyamine transport system inhibitor with antibacterial activity against Gram-positive and -negative MDR bacteria. We observed minimum inhibitory concentration (MIC)50/MIC90 values for AMXT-1501 in the range of 3.13-12.5 µM (2.24-8.93 µg /mL), including for methicillin-resistant Staphylococcus aureus (MRSA), CR Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. AMXT-1501 was more effective against MRSA and CR E. coli than vancomycin and tigecycline, respectively. Subinhibitory concentrations of AMXT-1501 reduced the biofilm formation of S. aureus and Enterococcus faecalis. Mechanistically, AMXT-1501 exposure damaged microbial membranes and increased membrane permeability and membrane potential by binding to cardiolipin (CL) and phosphatidylglycerol (PG). Importantly, AMXT-1501 pressure did not induce resistance readily in the tested pathogens.

Interpretable machine learning for predicting chronic kidney disease progression risk.

Objective: Chronic kidney disease (CKD) poses a major global health burden. Early CKD risk prediction enables timely interventions, but conventional models have limited accuracy. Machine learning (ML) enhances prediction, but interpretability is needed to support clinical usage with both in diagnostic and decision-making. Methods: A cohort of 491 patients with clinical data was collected for this study. The dataset was randomly split into an 80% training set and a 20% testing set. To achieve the first objective, we developed four ML algorithms (logistic regression, random forests, neural networks, and eXtreme Gradient Boosting (XGBoost)) to classify patients into two classes-those who progressed to CKD stages 3-5 during follow-up (positive class) and those who did not (negative class). For the classification task, the area under the receiver operating characteristic curve (AUC-ROC) was used to evaluate model performance in discriminating between the two classes. For survival analysis, Cox proportional hazards regression (COX) and random survival forests (RSFs) were employed to predict CKD progression, and the concordance index (C-index) and integrated Brier score were used for model evaluation. Furthermore, variable importance, partial dependence plots, and restrict cubic splines were used to interpret the models' results. Results: XGBOOST demonstrated the best predictive performance for CKD progression in the classification task, with an AUC-ROC of 0.867 (95% confidence interval (CI): 0.728-0.100), outperforming the other ML algorithms. In survival analysis, RSF showed slightly better discrimination and calibration on the test set compared to COX, indicating better generalization to new data. Variable importance analysis identified estimated glomerular filtration rate, age, and creatinine as the most important predictors for CKD survival analysis. Further analysis revealed non-linear associations between age and CKD progression, suggesting higher risks in patients aged 52-55 and 65-66 years. The association between cholesterol levels and CKD progression was also non-linear, with lower risks observed when cholesterol levels were in the range of 5.8-6.4 mmol/L. Conclusions: Our study demonstrated the effectiveness of interpretable ML models for predicting CKD progression. The comparison between COX and RSF highlighted the advantages of ML in survival analysis, particularly in handling non-linearity and high-dimensional data. By leveraging interpretable ML for unraveling risk factor relationships, contrasting predictive techniques, and exposing non-linear associations, this study significantly advances CKD risk prediction to enable enhanced clinical decision-making.

The burden of depression, anxiety and schizophrenia among the older population in ageing and aged countries: an analysis of the Global Burden of Disease Study 2019.

Background: Depression, anxiety and schizophrenia among older persons have become global public health challenges. However, the burden of these disorders in ageing and aged countries has not been analysed. Aims: To investigate the burden of depression, anxiety and schizophrenia among older adults in ageing and aged countries. Methods: Using data from the Global Burden of Disease Study 2019, we calculated the estimated annual percentage change (EAPC) in the age-standardised incidence rates (ASIR) and age-standardised disability-adjusted life years (DALYs) rates (ASDR) for depression, anxiety and schizophrenia of older people in ageing countries (China, India, Indonesia) and aged countries (Japan, Italy, Portugal) between 1990 and 2019. Trends in incidence and DALYs were analysed by gender and age. Results: In 2019, the highest incidence of depression, anxiety and schizophrenia in the older population in aged countries was in Japan (927 271.3 (752 552.3-1 125 796.5), 51 498.2 (37 625.7-70 487.3) and 126.0 (61.0-223.2), respectively), while the highest incidence in ageing countries was in China (5 797 556.9 (4 599 403.4-7 133 006.5), 330 256.1 (246 448.9-445 987.4) and 1067.7 (556.2-1775.9), respectively). DALYs for these disorders were similar, with the highest in Japan and China. From 1990 to 2019, the ASIR for depressive disorders decreased in aged countries but increased in ageing countries; the ASIR for anxiety disorders and schizophrenia declined in both ageing and aged countries. The ASDR for depressive disorders was consistent with the ASIR but not for anxiety disorders and schizophrenia. The ASIR for depressive disorders was higher in older women, while the opposite was observed in anxiety disorders and schizophrenia. Notably, the conditions of burden of depressive disorders, anxiety disorders and schizophrenia in the 65-70-year-old age group were the most burdensome. Conclusions: The incidence and DALYs of these three mental disorders increased while exhibiting differences between ageing and aged countries. Raising awareness about formulating health policies for preventing and treating mental disorders in the older population is necessary to reduce the future burden posed by the ageing challenge.

Dual-Fuel Propelled Nanomotors with Two-Stage Permeation for Deep Bacterial Infection in the Treatment of Pulpitis.

Bacterial infection-induced inflammatory response could cause irreversible death of pulp tissue in the absence of timely and effective therapy. Given that, the narrow structure of root canal limits the therapeutic effects of passive diffusion-drugs, considerable attention has been drawn to the development of nanomotors, which have high tissue penetration abilities but generally face the problem of insufficient fuel concentration. To address this drawback, dual-fuel propelled nanomotors (DPNMs) by encapsulating L-arginine (L-Arg), calcium peroxide (CaO2 ) in metal-organic framework is developed. Under pathological environment, L-Arg could release nitric oxide (NO) by reacting with reactive oxygen species (ROS) to provide the driving force for movement. Remarkably, the depleted ROS could be supplemented through the reaction between CaO2 with acids abundant in the inflammatory microenvironment. Owing to high diffusivity, NO achieves further tissue penetration based on the first-stage propulsion of nanomotors, thereby removing deep-seated bacterial infection. Results indicate that the nanomotors effectively eliminate bacterial infection based on antibacterial activity of NO, thereby blocking inflammatory response and oxidative damage, forming reparative dentine layer to avoid further exposure and infection. Thus, this work provides a propagable strategy to overcome fuel shortage and facilitates the therapy of deep lesions.

Association of TNF-α, IGF-1, and IGFBP-1 levels with the severity of osteopenia in mice with nonalcoholic fatty liver disease.

BACKGROUNDS: Nonalcoholic fatty liver disease (NAFLD) exhibits a close association with osteoporosis. This work aims to assess the potential effects of NAFLD on the progression of osteopenia in animal models. METHODS: Forty-eight C57BL/6 female mice were randomly divided to wild-type (WT) group and high-fat diet (HFD) group. The corresponding detections were performed after sacrifice at 16, 24 and 32 weeks, respectively. RESULTS: At 16 weeks, an remarkable increase in body weight and lipid aggregation in the hepatocytes of HFD group was observed compared to the WT group, while the bone structure parameters showed no significant difference. At 24 weeks, the levels of TNF-α and IL-6 in NAFLD mice were significantly increased, while the level of osteoprotegerin mRNA in bone tissue was decreased, and the level of receptor activator of nuclear factor Kappa-B ligand mRNA was increased. Meanwhile, the function of osteoclasts was increased, and the bone microstructure parameters showed significant changes. At 32 weeks, in the HFD mice, the mRNA levels of insulin-like growth factor-1 (IGF-1), runt-related transcription factor 2, and osterix mRNA were reduced, while the insulin-like growth factor binding protein-1 (IGFBP-1) level was increased. Simultaneously, the osteoblast function was decreased, and the differences of bone structure parameters were more significant, showing obvious osteoporosis. CONCLUSIONS: The bone loss in HFD mice is pronounced as NAFLD progresses, and the changes of the TNF-α, IL-6, IGF-1, and IGFBP-1 levels may play critical roles at the different stages of NAFLD in HFD.

Ubiquitination-mediated Golgi-to-endosome sorting determines the toxin-antidote duality of fission yeast wtf meiotic drivers.

Killer meiotic drivers (KMDs) skew allele transmission in their favor by killing meiotic progeny not inheriting the driver allele. Despite their widespread presence in eukaryotes, the molecular mechanisms behind their selfish behavior are poorly understood. In several fission yeast species, single-gene KMDs belonging to the wtf gene family exert selfish killing by expressing a toxin and an antidote through alternative transcription initiation. Here we investigate how the toxin and antidote products of a wtf-family KMD gene can act antagonistically. Both the toxin and the antidote are multi-transmembrane proteins, differing only in their N-terminal cytosolic tails. We find that the antidote employs PY motifs (Leu/Pro-Pro-X-Tyr) in its N-terminal cytosolic tail to bind Rsp5/NEDD4 family ubiquitin ligases, which ubiquitinate the antidote. Mutating PY motifs or attaching a deubiquitinating enzyme transforms the antidote into a toxic protein. Ubiquitination promotes the transport of the antidote from the trans-Golgi network to the endosome, thereby preventing it from causing toxicity. A physical interaction between the antidote and the toxin enables the ubiquitinated antidote to translocate the toxin to the endosome and neutralize its toxicity. We propose that post-translational modification-mediated protein localization and/or activity changes may be a common mechanism governing the antagonistic duality of single-gene KMDs.

Assessing the association between the circulating levels of inflammatory cytokines and the risk of tuberculosis: A bidirectional two-sample mendelian randomization study.

BACKGROUND: Numerous observational studies have previously reported an association between inflammatory cytokines and tuberculosis (TB). However, the causal relationship between these factors remains unclear. Consequently, we conducted two-sample Mendelian randomization (MR) analyses to ascertain the causal link between levels of inflammatory cytokines and the risk of TB. METHODS: Single nucleotide polymorphisms (SNPs) robustly associated with the cytokines, located in or close to their coding gene. SNP was obtained from genome-wide association studies (GWAS) of 8293 individuals of Finnish. TB data was obtained from the UK Biobank, which included 46,293 individuals of European ancestry (comprising 2277 TB cases and 46,056 controls). Two-sample, bi-directional MR analyses using inverse-variance weighted (IVW) method as the primary analysis. Followed by comprehensive sensitivity analyses to validate the robustness of results. RESULT: The study showed that the causal relationship between circulating levels of interleukin (IL)-7 and risk of TB (odds ratio [OR] = 1.001, 95% confidence intervals [CIs]: 1.000, 1.003. p = 0.047). No causal associations were observed between other influencing factors and the occurrence of TB. Furthermore, the analysis revealed that TB infection exhibited negative causal associations with macrophage inflammatory protein 1 alpha ([MIP-1α], OR = 0.007, 95% CI: 0.000, 0.192. p = 0.004), IL-2 (OR = 0.014, 95% CI: 0.010, 0.427. p = 0.014), interleukin-2 receptor alpha chain([IL-2rα], OR = 0.019, 95% CI: 0.001, 0.525. p = 0.019) and basic fibroblast growth factor ([bFGF], OR = 0.066, 95% CI: 0.006, 0.700. p = 0.024). CONCLUSION: The study has illuminated the causal link between inflammatory cytokines and TB, thereby enhancing our comprehension of the potential mechanisms underlying TB pathogenesis. This discovery offers promising avenues for the identification of novel therapeutic targets in TB treatment. These insights may ultimately pave the way for more effective treatment approaches, thereby improving patient outcomes.

Optimized strategy for schistosomiasis elimination: results from marginal benefit modeling.

BACKGROUND: Poverty contributes to the transmission of schistosomiasis via multiple pathways, with the insufficiency of appropriate interventions being a crucial factor. The aim of this article is to provide more economical and feasible intervention measures for endemic areas with varying levels of poverty. METHODS: We collected and analyzed the prevalence patterns along with the cost of control measures in 11 counties over the last 20 years in China. Seven machine learning models, including XGBoost, support vector machine, generalized linear model, regression tree, random forest, gradient boosting machine and neural network, were used for developing model and calculate marginal benefits. RESULTS: The XGBoost model had the highest prediction accuracy with an R2 of 0.7308. Results showed that risk surveillance, snail control with molluscicides and treatment were the most effective interventions in controlling schistosomiasis prevalence. The best combination of interventions was interlacing seven interventions, including risk surveillance, treatment, toilet construction, health education, snail control with molluscicides, cattle slaughter and animal chemotherapy. The marginal benefit of risk surveillance is the most effective intervention among nine interventions, which was influenced by the prevalence of schistosomiasis and cost. CONCLUSIONS: In the elimination phase of the national schistosomiasis program, emphasizing risk surveillance holds significant importance in terms of cost-saving.

Synergistic Effects of Rotavirus and Co-Infecting Viral Enteric Pathogens on Diarrheal Disease - Guangzhou City, Guangdong Province, China, 2019.

What is already known about this topic?: Diarrhea represents a substantial public health issue, contributing globally to a high number of pediatric medical consultations, hospital admissions, and mortality rates. What is added by this report?: An increase in diarrheal frequency serves as a critical benchmark for evaluating severity. The predominant pathogens associated with pediatric diarrhea are rotavirus and norovirus, with co-infections exerting a notable compounding effect that leads to more severe diarrhea. What are the implications for public health practice?: Implementing sensitive diagnostic techniques and comprehensive monitoring is paramount in identifying co-infections. Such strategies can provide physicians with critical insights into disease progression, thus considerably reducing the burden of diarrhea.

Impact factors of Blastocystis hominis infection in persons living with human immunodeficiency virus: a large-scale, multi-center observational study from China.

BACKGROUND: Blastocystis hominis (Bh) is zoonotic parasitic pathogen with a high prevalent globally, causing opportunistic infections and diarrhea disease. Human immunodeficiency virus (HIV) infection disrupts the immune system by depleting CD4+ T lymphocyte (CD4+ T) cell counts, thereby increasing Bh infection risk among persons living with HIV (PLWH). However, the precise association between Bh infection risk and HIV-related biological markers and treatment processes remains poorly understood. Hence, the purpose of the study was to explore the association between Bh infection risk and CD4+ T cell counts, HIV viral load (VL), and duration of interruption in antiviral therapy among PLWH. METHODS: A large-scale multi-center cross-sectional study was conducted in China from June 2020 to December 2022. The genetic presence of Bh in fecal samples was detected by real-time fluorescence quantitative polymerase chain reaction, the CD4+ T cell counts in venous blood was measured using flowcytometry, and the HIV VL in serum was quantified using fluorescence-based instruments. Restricted cubic spline (RCS) was applied to assess the non-linear association between Bh infection risk and CD4+ T cell counts, HIV VL, and duration of interruption in highly active antiretroviral therapy (HARRT). RESULTS: A total of 1245 PLWH were enrolled in the study, the average age of PLWH was 43 years [interquartile range (IQR): 33, 52], with 452 (36.3%) being female, 50.4% (n = 628) had no immunosuppression (CD4+ T cell counts > 500 cells/µl), and 78.1% (n = 972) achieved full virological suppression (HIV VL < 50 copies/ml). Approximately 10.5% (n = 131) of PLWH had interruption. The prevalence of Bh was found to be 4.9% [95% confidence interval (CI): 3.8-6.4%] among PLWH. Significant nonlinear associations were observed between the Bh infection risk and CD4+ T cell counts (Pfor nonlinearity < 0.001, L-shaped), HIV VL (Pfor nonlinearity < 0.001, inverted U-shaped), and duration of interruption in HARRT (Pfor nonlinearity < 0.001, inverted U-shaped). CONCLUSIONS: The study revealed that VL was a better predictor of Bh infection than CD4+ T cell counts. It is crucial to consider the simultaneous surveillance of HIV VL and CD4+ T cell counts in PLWH in the regions with high level of socioeconomic development. The integrated approach can offer more comprehensive and accurate understanding in the aspects of Bh infection and other opportunistic infections, the efficacy of therapeutic drugs, and the assessment of preventive and control strategies.

Genetically predicted circulating levels of cytokines and the risk of depression: a bidirectional Mendelian-randomization study.

Objective: Inflammatory cytokines disturbance is the main result of immune dysregulation, which is widely described in major depressive disorder (MDD). However, the potential causal relationship between these two factors has not been discovered. Therefore, the purpose of this study was to investigate the causal relationship between inflammatory cytokines and MDD risk by using the two-sample Mendelian randomization (MR) analysis. Method: Two genetic instruments obtained from publicly available gene profile data were utilized for the analysis. We obtained the genetic variation data of 41 inflammatory cytokines from genome-wide association studies (GWAS) meta-analysis of 8293 individuals of Finnish descent. The MDD data, including 135,458 MDD cases and 344,901 controls, were obtained from the Psychiatric Genomics Consortium Database. For the Mendelian randomization (MR) estimation, several methods were employed, namely, MR-Egger regression, inverse-variance weighted (IVW), weighted median, and MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO) methods. Result: A causal relationship was identified between the genetically proxied levels of Interleukin (IL) -18, IL-1ß, and Regulated upon activation normal T cell expressed and secreted (RANTES) and the risk of MDD (OR = 0.968, 95%CI = 0.938, 0.998, p = 0.036; OR = 0.875, 95%CI = 0.787, 0.971, p = 0.012; OR = 0.947, 95%CI = 0.902, 0.995, p = 0.03; respectively). However, our Mendelian randomization (MR) estimates provided no causality of MDD on inflammatory cytokines. Conclusion: Our study elucidates the connection between inflammatory cytokines and MDD by using MR analysis, thereby enhancing our comprehension of the potential mechanisms. By identifying these associations, our findings hold substantial implications for the development of more effective treatments aimed at improving patient outcomes. However, further investigation is required to fully comprehend the exact biological mechanisms involved.

Soil-transmitted helminthiasis in mainland China from 2016 to 2020: a population-based study.

Background: Soil-transmitted helminthiasis is epidemic in China and many other countries of the world, and has caused substantial burdens to human health. We conducted successive national monitoring in China from 2016 to 2020 to analyze the prevalence, changing trends, and factors influencing soil-transmitted helminthiasis, which provided a reference for future control strategies. Methods: Soil-transmitted helminth monitoring was carried out in 31 provinces (autonomous regions or municipalities, herein after referred to as "provinces") throughout China. Each province determined the number and location of monitoring sites (counties), and a unified sampling method was employed. At least 1,000 subjects were investigated in each monitoring county. Stool samples were collected and the modified Kato-Katz thick smear method was employed for stool examination. Infection data and the details of factors influencing soil-transmitted helminthiasis from 2016 to 2020 were collected from national monitoring sites. Additional influencing factors such as environment, climate and human activities were obtained from authoritative websites. Prevalence of soil-transmitted helminths was presented by species, province, sex, and age group. ArcGIS software was used to conduct spatial autocorrelation and hotspot analysis on the infection data. A Poisson distribution model and SaTScan software were used to analyze the infection data with retrospective spatiotemporal scan statistics. A database was built by matching village-level infection rate data with influencing factors. Subsequently, machine learning methods, including a Linear Regression (LR), a Random Forest (RF), a Gradient Boosted Machine (GBM), and an Extreme gradient boosting (XGBOOST) model was applied to construct a model to analyze the main influencing factors of soil-transmitted helminthiasis. Findings: The infection rates of soil-transmitted helminths at national monitoring sites from 2016 to 2020 were 2.46% (6,456/262,380), 1.78% (5,293/297,078), 1.29% (4,200/326,207), 1.40% (5,959/424,766), and 0.84% (3,485/415,672), respectively. The infection rate of soil-transmitted helminths in 2020 decreased by 65.85% compared to that in 2016. From 2016 to 2020, the infection rate of soil-transmitted helminthiasis was relatively high in southern and southwestern China, including Hainan, Yunnan, Sichuan, Guizhou, and Chongqing. In general, the infection rate was higher in females than in males, with the highest rate in the population aged 60 years and above, and the lowest in children aged 0-6 years. Global autocorrelation and hotspot analyses revealed spatial aggregation in both the national and local distribution of soil-transmitted helminthiasis in China from 2016 to 2020. The hotspots were concentrated in southwestern China. The spatiotemporal scanning analysis revealed aggregation years from 2016 to 2017 located in southwestern China, including Yunnan, Sichuan, Chongqing, Guizhou and Guangxi. The RF model was the best fit model for the infection rate of soil-transmitted helminths in China. The top six influencing factors of this disease in the model were landform, barefoot farming, isothermality, temperature seasonality, year, and the coverage of sanitary toilets. Interpretation: The overall infection rate of soil-transmitted helminths in China showed a decreasing trend from 2016-2020 due to the implementation of control measures and the economic boom in China. However, there are still areas with high infection rates and the distribution of such areas exhibit spatiotemporal aggregation. As a strategic next step, control measures should be adjusted to local conditions based on the main influencing factors and the prevalence of different sites to aid in the control and elimination of soil-transmitted helminthiasis. Funding: This research was funded by the National Key Research and Development Program of China (Grant Nos. 2021YFC2300800 and 2021YFC2300804) and the National Natural Science Foundation of China (Grant No. 32161143036).

Global and Regional Estimate of HIV-Associated Stroke Burden: A Meta-Analysis and Population Attributable Modeling Study.

BACKGROUND: This study aimed to determine the correlation between human-immunodeficiency-virus (HIV) infection and stroke, as well as to estimate the global, regional, and national burden of HIV-associated stroke. METHODS: A registered meta-analysis was performed by searching PubMed, Embase, and Web of Science for relevant literature up to October 31, 2022. The pooled relative risk of stroke in HIV-infected people was calculated using a random-effects model. HIV prevalence and disability-adjusted life years (DALYs) datasets were obtained from the Joint United Nations Program on HIV and AIDS, and the Global Health Data Exchange, respectively. The population attributable fraction was estimated and delivered to calculate the HIV-associated DALYs of stroke from 1990 to 2019, at the global, regional, and national levels. Pearson correlation analysis were conducted to assess the correlation between the age-standardized rate or estimated annual percentage changes and the sociodemographic index. RESULTS: Out of 10 080 identified studies, 11 were included in this meta-analysis. Compared with individuals without HIV-infection, the pooled relative risk of stroke in HIV-infected individuals was 1.40 (95% CI, 1.18-1.65). From 1990 to 2019, the global population attributable fraction of HIV-associated stroke increased almost 3-fold, while the HIV-associated DALYs increased from 18 595 (95% CI, 7485-31 196) in 1990 to 60 684 (95% CI, 24 281-101 894) in 2019. Meanwhile, HIV-associated DALYs varied by region, with Eastern and Southern Africa having the highest value of 126 160 in 2019. Moreover, countries with middle social development index were shouldering the highest increase trend of the HIV-associated DALYs age-standardized rates. CONCLUSIONS: HIV-infected individuals face a significantly higher risk of stroke, and the global burden of HIV-associated stroke has increased over the past 3 decades, showing regional variations. Eastern and Southern Africa bear the highest burden, while Eastern Europe and Central Asia have seen significant growth. Health care providers, researchers, and decision-makers should give increased attention to stroke prevention and management in HIV-endemic areas. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: CRD42022367450.

Analyzing the Activity of Micafungin Combined with Tobramycin Against Pseudomonas Aeruginosa Biofilm.

BACKGROUND: This study assessed the potential effect of combining micafungin and tobramycin in vitro against biofilms of clinical Pseudomonas aeruginosa isolates. METHODS: Nine biofilm-positive clinical isolates of P. aeruginosa were used in this study. The minimum inhibitory concentrations (MICs) of micafungin and tobramycin for planktonic bacteria were determined using the agar dilution method. The planktonic bacterial growth curve was plotted for micafungin treatment. Biofilms of these nine strains were treated with different concentrations of micafungin and combined with tobramycin in microtiter plates. Biofilm biomass was detected by crystal violet staining and spectrophotometry. Phenotypic reduction in biofilm formation and the eradication of mature biofilm were significant based on average optical density (p < 0.05). The kinetics of micafungin combined with tobramycin to eradicate mature biofilms was investigated in vitro using the time-kill method. RESULTS: Micafungin exhibited no antibacterial effect on P. aeruginosa, and tobramycin minimum inhibitory concentrations (MICs) did not change in the presence of micafungin. Micafungin alone inhibited biofilm formation and eradicated established biofilms of all isolates in a dose-dependent manner, but the required minimum concentration varied. An increase in micafungin concentration resulted in an observed inhibition rate of 64.9% - 72.3% and achieved an eradication rate of 59.2% - 64.5%. Its combination with tobramycin exhibited synergistic effects, including inhibiting the biofilm formation of PA02, PA05, PA23, PA24, and PA52 isolates above 1/4 × MIC or 1/2 × MIC and eradicating mature biofilms of PA02, PA04, PA23, PA24, and PA52 above 32 × MIC, 2 × MIC, 16 × MIC, 32 × MIC, and 1 × MIC, respectively. Micafungin addition could eradicate biofilm-embedded bacterial cells more rapidly; at 32 mg/L, the biofilm eradication time lowered from 24 hours to 12 hours for the inoculum groups with 106 CFU/mL, and from 12 hours to 8 hours for 105 CFU/mL. Whereas at 128 mg/L, the time was lowered from 12 hours to 8 hours for the inoculum groups with 106 CFU/mL, and from 8 hours to 4 hours for 105 CFU/mL. CONCLUSIONS: Micafungin showed good anti-biofilm activity at low concentrations. The combination of micafungin with tobramycin displayed a synergistic effect in controlling P. aeruginosa biofilm.

Mechanisms of Rapid Bactericidal and Anti-Biofilm Alpha-Mangostin In Vitro Activity against Staphylococcus aureus.

Alpha-mangostin (α-mangostin) was discovered as a potent natural product against Gram-positive bacteria, whereas the underlying molecular mechanisms are still unclear. This study indicated that α-mangostin (at 4 × MIC) rapidly killed Staphylococcus aureus planktonic cells more effectively (at least 2-log10 CFU/ml) than daptomycin, vancomycin and linezolid at 1 and 3 h in the time-killing test. Interestingly, this study also found that a high concentration of α-mangostin (≥4×MIC) significantly reduced established biofilms of S. aureus. There were 58 single nucleotide polymorphisms (SNPs) in α-mangostin nonsensitive S. aureus isolates by whole-genome sequencing, of which 35 SNPs were located on both sides of the sarT gene and 10 SNPs in the sarT gene. A total of 147 proteins with a different abundance were determined by proteomics analysis, of which 91 proteins increased, whereas 56 proteins decreased. The abundance of regulatory proteins SarX and SarZ increased. In contrast, the abundance of SarT and IcaB was significantly reduced (they belonged to SarA family and ica system, associated with the biofilm formation of S. aureus). The abundance of cell membrane proteins VraF and DltC was augmented, but the abundance of cell membrane protein UgtP remarkably decreased. Propidium iodide and DiBaC4(3) staining assay revealed that the fluorescence intensities of DNA and the cell membrane were elevated in the α-mangostin treated S. aureus isolates. In conclusion, this study reveals that α-mangostin was effective against S. aureus planktonic cells by targeting cell membranes. The anti-biofilm effect of α-mangostin may be through inhibiting the function of SarT and IcaB.

Neobavaisoflavone Inhibits Biofilm Formation and α-Toxin Activity of Staphylococcus aureus.

Neobavaisoflavone had antimicrobial activities against Gram-positive multidrug-resistant (MDR) bacteria, but the effect of neobavaisoflavone on the virulence and biofilm formation of S. aureus has not been explored. The present study aimed to investigate the possible inhibitory effect of neobavaisoflavone on the biofilm formation and α-toxin activity of S. aureus. Neobavaisoflavone presented strong inhibitory effect on the biofilm formation and α-toxin activity of both methicillin-sensitive S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) strains at 25 µM, but did not affect the growth of S. aureus planktonic cells. Genetic mutations were identified in four coding genes, including cell wall metabolism sensor histidine kinase walK, RNA polymerase sigma factor rpoD, tetR family transcriptional regulator, and a hypothetical protein. The mutation of WalK (K570E) protein was identified and verified in all the neobavaisoflavone-induced mutant S. aureus isolates. The ASN501, LYS504, ILE544 and GLY565 of WalK protein act as hydrogen acceptors to form four hydrogen bonds with neobavaisoflavone by molecular docking analysis, and TRY505 of WalK protein contact with neobavaisoflavone to form a pi-H bond. In conclusion, neobavaisoflavone had excellent inhibitory effect on the biofilm formation and α-toxin activity of S. aureus. The WalK protein might be a potential target of neobavaisoflavone against S. aureus.

Global burden of myocarditis and cardiomyopathy in children and prediction for 2035 based on the global burden of disease study 2019.

Background: Myocarditis and cardiomyopathy are commonly occurring cardiovascular diseases that seriously threaten children's health. It was urgent to update the global incidence and mortality of childhood myocarditis and cardiomyopathy, and to predict the incidence rate of 2035 by the Global Burden of Disease database. Methods: The Global Burden of Disease study data from 1990 to 2019 in 204 countries and territories were used to determine: global incidence and mortality rates of childhood myocarditis and cardiomyopathy from 0 to 19 by five age groups; relationship between sociodemographic index (SDI) and incidence and mortality rates by age group; and, based on an age-period-cohort model, the projected incidence of childhood myocarditis and cardiomyopathy for 2035. Results: From 1990 to 2019, global age-standardized incidence rate decreased by 0.1% (95% UI 0.0-0.1) to 7.7% (95% UI 5.1-11.1). Boys had higher age-standardized incidence of childhood myocarditis and cardiomyopathy than girls [9.12, (95% UI 6.05-13.07) vs. 6.18, (95% UI 4.06-8.92)]. Childhood myocarditis and cardiomyopathy affected 121,259 (95% UI 80,467-173,790) boys and 77,216 (95% UI 50,684-111,535) girls in 2019. At the regional level, SDI changes in most areas showed no meaningful difference. In East Asia and high-income Asia Pacific, increased SDI was associated with decreased and increased incidence rate, respectively. In 2019, 11,755 (95% UI 9,611-14,509) children died from myocarditis and cardiomyopathy worldwide. Age-standardized mortality rate decreased significantly by 0.4% (95% UI 0.2-0.6)-0.5% (95% UI 0.4-0.6). Number of deaths from childhood myocarditis and cardiomyopathy in 2019 was highest in the <5-year-old group [7,442 (95% UI 5,834-9,699)]. Myocarditis and cardiomyopathy incidence in 10-14- and 15-19-year-olds is projected to increase by 2035. Conclusion: Global data on childhood myocarditis and cardiomyopathy from 1990 to 2019 showed a decreasing trend in incidence and mortality, and an increasing trend in older children, especially in high SDI regions.