BACKGROUND:Sepsis is a global health challenge associated with high morbidity and mortality rates. Early diagnosis and treatment are challenging because of the limited understanding of its underlying mechanisms. This study aimed to identify effective biomarkers for diagnosing and treating sepsis through an integrated multi-method approach. METHODS:Publicly available single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq datasets were analyzed for naive CD4 + T cell-specific genes. Based on these hub genes, Mendelian randomization (MR) analysis, followed by the MR-Bayesian model averaging (MR-BMA) algorithm, was implemented to explore the causality between these genes and sepsis. In addition, single-cell-type expression analysis, cell-cell communication detection, metabonomic evaluation, clinical samples, and both in vivo and in vitro studies were conducted to unveil the underlying mechanisms of potential therapeutic targets. RESULTS:scRNA-seq revealed significant depletion of naive CD4 + T cells in sepsis, identifying 33 key genes. Both MR and MR-BMA analyses confirmed that elevated proportion of naive CD4 + T cell in total CD4 + T cells were related to sepsis occurrence (odds ratio [OR] = 0.90, 95% confidence interval [CI], 0.83-0.97, P = 0.007) and 28-day mortality associated with sepsis (OR = 0.75, 95% CI, 0.64-0.88, P <0.001). Notably, among the 33 hub genes, PC-esterase domain containing 1B ( PCED1B ) exhibited a strong causal association with 28-day mortality in patients with sepsis (OR = 0.64, 95% CI, 0.51-0.81, P <0.001), which was further validated by bulk RNA-seq analysis. PCED1B mediated the impact of proportion of naive CD4 + T cell in CD4 + T cell on sepsis-related mortality. In addition, clinical samples and both in vivo and in vitro experiments validated the elevated expression of PCED1B in naive CD4 + T cells derived from sepsis patients and mice. Mechanistic investigations revealed PCED1B+ CD4 + T cells may interact with monocytes/dendritic cells through the macrophage migration inhibitory factor (MIF)-(CD74 + CD44) axis, concurrently engaging with B cells/plasmablasts through the MIF-(CD74 + CXCR4) axis, thereby regulating multiple metabolic alterations in sepsis. CONCLUSION:The interplay between PCED1B and naive CD4 + T cells, as revealed by this study, is instrumental in developing immunotherapeutic strategies for sepsis.

Objectives To evaluate the efficacy and safety of Ilaprazole in preventing stress ulcer-associated upper gastrointestinal bleeding in critically ill patients. Design A Randomized, Double-Blind, non-inferiority Phase 3 Trial. Setting 70 hospitals across China from July 16, 2021, to April 28, 2022. Patients 441 Patients (mean age 59 years; 150 female) at high risk for stress ulcer bleeding requiring invasive mechanical ventilation were enrolled. Interventions Patients were randomly assigned to receive either Ilaprazole (10 mg once daily, first dose doubled; 220 patients) or esomeprazole (40 mg twice daily; 221 patients). Measurements and main results 441 patients (mean age 59 years; 150 female) were enrolled: 220 received Ilaprazole and 221 received esomeprazole. In FAS set, the primary endpoint occurred in 213 (96.80%) patients in the Ilaprazole and 215 (97.30%) in esomeprazole arms (Absolute Risk Difference: -0.47, 95% CI: -4.02, 3.03, p = 0.772). Secondary outcomes showed comparable incidences of clinically insignificant UGI bleeding, any gastrointestinal bleeding, 28-day mortality, ICU mortality, and pneumonitis. Adverse events were similar between groups, but Ilaprazole had a significantly lower incidence of hepatobiliary disorders (0.9% vs. 5%, p = 0.012). Conclusions Ilaprazole demonstrated non-inferiority to esomeprazole in preventing UGI bleeding in critically ill patients at high risk of stress ulcer.

[This corrects the article DOI: 10.1016/j.jointm.2025.08.011.].

Background::Previous studies have highlighted the importance of intensive care units (ICUs) in providing specialized care for critically ill patients. However, little is known about the current distribution of ICU resources, medical personnel, and available technologies across hospitals of different levels in Chinese mainland. In response, this study evaluated the distribution of ICU resources, personnel, major diseases, medical techniques, and the relationship between ICU bed availability and economic development to provide an overview of the current state of ICU services in Chinese mainland.Methods::A comprehensive questionnaire was distributed to intensivists at all levels of hospitals in Chinese mainland via the Questionnaire Starmini-program, a commonly used web-based survey platform in China. The questionnaire covered a wide range of items, including the demographic characteristics of intensivists, ICU type and capacity, composition of medical teams, disease classification, and available medical techniques.Results::Data were analyzed from 3637 intensivists working in 2005 hospitals throughout Chinese mainland, representing approximately half of all hospitals with ICU settings nationwide. The median number of hospital beds was 1000 (interquartile range [IQR], 547-1800), and the median number of ICU beds was 17 (IQR: 11-25). Overall, 600 (IQR: 300-1091) patients were admitted to the ICU annually at each hospital. The mean number of ICU beds per 100,000 people was 5.31 in 2022. The majority of the surveyed medical groups (ranging from 97.7% to 98.8%) led by chief physicians have experience in treating the eight most common conditions managed in the ICU, including severe pneumonia, cardiogenic shock, hypovolemic shock, sepsis, septic shock, cardiopulmonary resuscitation, acute respiratory distress syndrome, and acute renal injury. Regarding essential medical techniques in the ICU, 98.2%, 86.5%, 71.2%, and 24.1% of surveyed hospitals have implemented invasive mechanical ventilation, continuous blood purification, bedside ultrasound, and extracorporeal membrane oxygenation, respectively.Conclusions::This survey indicates that, although ICUs in Chinese mainland have advanced significantly to some extent, there are still challenges to address, such as regional disparities and hospital grade differences.

Ethnopharmacological relevance Yi-Shen-Hua-Shi granules (YSHSG) have been shown to improve kidney function in various renal disorders, which are characterized by the sudden decline and impairment of kidney function. Aim of the study : To investigate the precise mechanisms and targets of YSHSG in combating sepsis-induced AKI. Materials and methods Through network pharmacology, the active ingredients, main target proteins, and related signaling pathways of YSHSG in the treatment of sepsis-induced AKI were predicted. The AKI model was induced by sepsis using the cecal ligation and puncture (CLP) technique. Prior to the operation, YSHSG was administered intragastrically once daily for 1 week. Blood and kidney tissues were collected 48 h post-CLP to verify the network pharmacology analysis. Results The core target proteins of YSHSG in the treatment of sepsis-induced AKI include AKT1, JUN, IL6, PTGS2, NFKBIA, MAPK3, Caspase-3 and MMP9, which were further confirmed by molecular docking. Pathway analyses such as Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) show that YSHSG plays a role in protecting the kidneys from sepsis-induced AKI through the PI3K/AKT, TNF, and IL17 signaling pathways. These findings were validated using qPCR and western blotting. In vivo experiments demonstrated that YSHSG inhibits the activation of TNF and IL17 signaling pathways while protecting against deactivation of the PI3K/AKT signaling pathway in sepsis-induced AKI. YSHSG also exhibits an effect on attenuating inflammation response and pyroptosis processes associated with the PI3K/AKT, TNF, and IL17 signaling pathways. Conclusion YSHSG mitigated sepsis-induced AKI by influencing the PI3K/AKT, TNF, and IL17 signaling pathways associated with inflammation and pyroptosis.

Background:As the global population ages, pancreatitis in older adults has become a public health issue. Nonetheless, detailed information on its global impact and changing patterns is limited. We sought to explore the epidemiological trends of pancreatitis among older adults (aged ≥65 years) from 1992 to 2021. Methods:Data for pancreatitis incidence and mortality across seven age brackets (65-69, 70-74, 75-79, 80-84, 85-89, 90-94, and ≥95 years) were sourced from the 2021 Global Burden of Diseases, Injuries, and Risk Factors Study. The age-standardized incidence and mortality rates for pancreatitis in older adults were calculated using the direct method of age standardization. Joinpoint regression analysis was used to examine the evolution of age-standardized incidence and mortality rates from 1992 to 2021. Age-period-cohort analysis was conducted to determine the distinct impacts of age, period, and birth cohorts. In addition, Nordpred analysis was applied to forecast global epidemiological trends through 2044. Results:In 2021, the estimated global age-standardized incidence and mortality rates of pancreatitis among older adults were 85.20% (95% confidence interval [CI]: 59.10 to 118.00) per 100,000 population and 7.97% (95% CI: 6.84 to 9.41) per 100,000 population, respectively. The disease burden of incidence and mortality was greatest in Eastern Europe. From 1992 to 2021, both the estimated global age-standardized incidence and mortality rates of pancreatitis among older adults demonstrated significant declining trends. The evolution of trends varied significantly across different regions and 204 countries, with an increased trend of age-standardized incidence rates in the Sociodemographic Index (SDI) regions. The age-period-cohort analysis results showed that the relative risk of incidence and mortality generally exhibited unfavorable trends over time in low-middle and low SDI regions. In addition, the age-standardized incidence and mortality rates were predicted to decrease annually, whereas case numbers of these metrics were predicted to keep increasing until 2044. Conclusions:There are strong heterogeneities in the incidence and mortality trends of older pancreatitis across the world, including both growing case numbers and distributive disparities, which may be instructive for future explorations in the prevention and treatment of this disease.

Clostridium paraputrificum infection in humans is extremely rare, and its pathogenesis and evolutionary mechanisms remain poorly understood. We sequenced the genome of strain CP_SH01 isolated from the blood culture of an ICU patient with acute abdominal injury and bloodstream infection. The genome harbored an intact prophage and ten insertion-sequence elements. Genome-wide metabolic reconstruction uncovered 42 fully complete modules linked to the utilization of different sugars and fermentation. Phylogenomic analysis of 42 global strains revealed two clades with substantial genetic diversity. A comparative genomic analysis was carried out to decode the pangenomic structure of C. paraputrificum, and functional differences between 2,434 core genes and 5,939 accessory genes. Meanwhile, 52 genes linked to 16 virulence factors and 15 antimicrobial resistance genes were identified. The majority of these clinically relevant genes, especially drug-resistant genes, were accessory and likely acquired via possible horizontal transfer. Additionally, genes under positive Darwinian selection were identified, potentially crucial for bacterial adaptation and immune interaction. This study presents the first blood-derived C. paraputrificum genome, revealing the global distribution of virulence and resistance genes. The accessory genome serves as a reservoir for clinically relevant traits, and positively selected genes provide insights into adaptive evolution and pathogenicity. Pangenomic and Phylogenomic analyses of global Clostridium paraputrificum strains offer novel insights into population diversity, patterns of clinically relevant genes, and adaptive evolution.

The treatment of sepsis is challenging due to unclear mechanisms. Propionate is increasingly seen as critical to sepsis pathophysiology by bridging gut microbiota and immunity, but the mechanisms remain unclear. Our study analysed differences in propionate metabolism in peripheral blood mononuclear cells from septic patients and healthy controls using single-cell RNA-seq (scRNA-seq) data. Differentially expressed genes (DEGs) analysis, pathway enrichment, transcription factor (TF) prediction, intercellular communication, and trajectory inference were used to explore the role of propionate metabolism in sepsis. We constructed a sepsis diagnostic model using LASSO and machine learning (XGBoost, CatBoost, NGBoost) with bulk RNA-seq data. scRNA-seq analysis revealed that propionate metabolism was highest in plasma cells (PCs), which can be classified into high and low metabolism groups, identifying 9,155 DEGs. High propionate metabolism was associated with metabolism such as short-chain fatty acids, while low metabolism was related to negative regulation of wound healing. The DoRothEA regulator algorithm showed TFs such as IRF4, ARID3A, FOXO4, and ATF2 were activated in high propionate metabolism subgroups, whereas NR5A1, BCL6, and CDX2 were activated in low subgroups. Cell-cell communication revealed that both groups interacted primarily with B cells and neutrophils, with the high propionate metabolism PCs showing more significant interactions. The receptor-ligand pairs primarily involved were VEGFA-FLT1 and VEGFB-FLT1, and the high propionate metabolism PCs and B cells might interact through BMP8B-BMPR2. Trajectory analysis indicated differentiation from B cells, first to low, then high propionate metabolism PCs. Finally, the LASSO algorithm identified 13 key genes, with the CatBoost model achieving perfect diagnostic performance (AUC = 1.000). These 13 key genes were validated through in vitro experiments. Collectively, these findings suggest that propionic acid metabolism may be a potential target for diagnosing and treating sepsis, offering new insights into its pathophysiology.

Immune dysfunction is one of the leading causes of death of sepsis. How to regulate host immune functions to improve prognoses of septic patients has always been a clinical focus. Here we elaborate on the efficacy and potential mechanism of a classical drug, thymopentin (TP5). TP5 could decrease peritoneal bacterial load, and reduce inflammatory cytokine levels both in the peritoneal lavage fluid (PLF) and serum, alleviate pathological injuries in tissue and organ, coaxed by cecal ligation and perforation (CLP) in mice, ultimately improve the prognosis of septic mice. Regarding the mechanism, using RNA-seq and flow cytometry, we found that TP5 induced peptidoglycan recognition protein 1 (PGLYRP1) expression, increased phagocytosis and restored TNF-α expression of small peritoneal macrophage (SPM) in the septic mice. This may be increased SPM's ability to clear peritoneal bacteria, thereby attenuates the inflammatory response both in the peritoneal cavity and the serum. It was shown that TP5 plays a key role in restoring the function of peritoneal macrophages to alleviate the sepsis process. We reckon that this is closely relevant to SPM phagocytosis, which might involve increased PGLYRP1 expression and restored TNF-α secretion.

BackgroundIt is unclear what the causal relationship is between the gut microbiota and sepsis. Therefore, we employed Mendelian randomization (MR) to determine whether a causal link exists between the two.MethodsThis study used publicly available genome-wide association studies (GWAS) summary data of gut microbiota, sepsis, sepsis (critical care), and sepsis (28-day death in critical care) to perform a two-sample MR analysis. To ensure the robustness of the results, we also conducted a sensitivity analysis.ResultsFor sepsis susceptibility, inverse variance weighted (IVW) estimates revealed that Victivallales (OR = 0.86, 95% CI, 0.78–0.94, p = 0.0017) was protective against sepsis, while Lentisphaerae (OR = 0.89, 95% CI, 0.80–0.99), Gammaproteobacteria (OR = 1.37, 95% CI, 1.08–1.73), Clostridiaceae1 (OR = 1.21, 95% CI, 1.04–1.40), RuminococcaceaeUCG011 (OR = 1.10, 95% CI, 1.01–1.20), Dialister (OR = 0.85, 95% CI, 0.74–0.97), and Coprococcus2 (OR = 0.81, 95% CI, 0.69–0.94) presented a suggestive association with the development of sepsis (all p < 0.05). For sepsis (critical care), IVW estimates indicated that Lentisphaerae (OR = 0.70, 95% CI, 0.53–0.93), Victivallales (OR = 0.67, 95% CI, 0.50–0.91), Anaerostipes (OR = 0.49, 95% CI, 0.31–0.76), LachnospiraceaeUCG004 (OR = 0.51, 95% CI, 0.34–0.77), and Coprococcus1 (OR = 0.66, 95% CI, 0.44–0.99) showed a suggestive negative correlation with sepsis (critical care) (all p < 0.05). For sepsis (28-day death in critical care), IVW estimates suggested that four bacterial taxa had a normally significant negative correlation with the risk of sepsis-related death, including Victivallales (OR = 0.54, 95% CI, 0.30–0.95), Coprococcus2 (OR = 0.34, 95% CI, 0.14–0.83), Ruminiclostridium6 (OR = 0.43, 95% CI, 0.22–0.83), and Coprococcus1 (OR = 0.45, 95% CI, 0.21–0.97), while two bacterial taxa were normally significantly positively linked to the risk of sepsis-related death, namely, Mollicutes (OR = 2.03, 95% CI, 1.01–4.08) and Bacteroidales (OR = 2.65, 95% CI, 1.18–5.96) (all p < 0.05). The robustness of the above correlations was verified by additional sensitivity analyses.ConclusionThis MR research found that several gut microbiota taxa were causally linked to the risk of sepsis, sepsis in critical care, and sepsis-related 28-day mortality in critical care.

BackgroundMaternal sepsis and other maternal infections (MSMIs) are major public health concerns worldwide. However, comprehensive data on their global burden and evolving trends remain sparse. This study aims to explore the epidemiological trends of MSMIs in women of childbearing age (WCBA) from 1990 to 2019, investigate the relationship between disease burden and age, period, and birth cohorts, and then provide a prediction of MSMIs incidence and deaths.MethodsThe estimates and 95% uncertainty intervals (UIs) for the incidence and death number of MSMIs in seven age groups (15–19, 20–24, 25–29, 30–34, 35–39, 40–44, 45–49 years) were obtained from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019. The age-standardized incidence and mortality rates of MSMIs in WCBA were estimated utilizing the age standardization by direct method. Joinpoint regression analysis was employed to investigate the changing trends of age-standardized incidence and mortality rates from 1990 to 2019. Age-period-cohort analysis was utilized to estimate the independent effects of age, period, and birth cohorts. Furthermore, a Nordpred age-period-cohort analysis was implemented to predict the global epidemiological trends through 2044.ResultsIn 2019, the estimated global age-standardized incidence and mortality rates of MSMIs in WCBA were 1072.90 (95% UI: 725.93 to 1483.46) and 0.86 (95% UI: 0.69 to 1.05), respectively. The highest disease burden existed in the African Region. From 1990 to 2019, the estimated global age-standardized incidence and mortality rates of MSMIs (AAPC: -1.32, 95% CI: −1.34 to −1.30; AAPC: -3.39, 95% CI: −4.28 to −2.48) in WCBA both demonstrated significant declining trends. The changing trends varied significantly across 6 regions and 204 countries. The effects of age, period, and cohort on incidence and mortality rates differed. From 2020 to 2044, the global age-standardized incidence rate of MSMIs in WCBA was predicted to decrease whereas the case number increases slowly.ConclusionThe global trends in MSMIs incidence and mortality generally showed a decline with considerable heterogeneity, indicating both the effectiveness and unevenness of global management of MSMIs. Moreover, the predicted increased case number highlights prominent challenges in the control of MSMIs.

目的 梳理脓毒症和肠道菌群研究领域的热点和前沿趋势,为后续研究提供思路和参考.方法 在 Web of Science数据库检索截至 2022 年 12 月 31 日有关肠道菌群和脓毒症的所有文献,通过 VOSviewer 1.6.18 软件和 R包"bibliometrix"进行统计分析.结果 共纳入 1 105 篇文献,结果显示该领域发文量逐年递增;美国、中国和英国是发文量最多国家;美国芝加哥大学是发文量最多机构;该领域初步形成了核心期刊群,但尚未形成核心作者群;Singer M,2016,JA-参考文献;高频关键词主要包括益生菌、炎症反应、菌群失调、菌群移位、粪菌移植、代谢组学、短链脂肪酸等.结论 这是第一个全面总结脓毒症和肠道菌群研究领域的文献计量学分析.该领域的研究热点集中在疾病状态下的肠道菌群组成、菌群改变的机制、肠道菌群在脓毒症发生发展中的作用及机制和以微生物为靶点的治疗四个方面.

Abnormal blood pressure is common in critically ill stroke patients. However, the association between mean arterial pressure (MAP) and mortality of critically ill stroke patients remains unclear. We extracted eligible acute stroke patients from the MIMIC-III database. The patients were divided into three groups: a low MAP group (MAP ≤ 70 mmHg), a normal MAP group (70 mmHg < MAP ≤ 90 mmHg), and a high MAP group (MAP > 90 mmHg). The Cox proportional hazards model and restricted cubic splines were used to assess the association between MAP and mortality. Sensitivity analyses were conducted to investigate whether MAP had different effects on mortality in different subpopulations. A total of 2885 stroke patients were included in this study. The crude 7-day and 28-day mortality was significantly higher in the low MAP group than that in the normal MAP group. By contrast, patients in the high MAP group did not have higher crude 7-day and 28-day mortality than those in the normal MAP group. After multiple adjustments using the Cox regression model, patients with low MAP were consistently associated with higher 7-day and 28-day mortality than those with normal MAP in the following subgroups: age > 60 years, male, those with or without hypertension, those without diabetes, and those without CHD (p < 0.05), but patients with high MAP were not necessarily associated with higher 7-day and 28-day mortality after adjustments (most p > 0.05). Using the restricted cubic splines, an approximately L-shaped relationship was established between MAP and the 7-day and 28-day mortality in acute stroke patients. The findings were robust to multiple sensitivity analyses in stroke patients. In critically ill stroke patients, a low MAP significantly increased the 7-day and 28-day mortality, while a high MAP did not, suggesting that a low MAP is more harmful than a high MAP in critically ill stroke patients.

Objective: Thymosin alpha1 (Ta1) is widely used to treat patients with coronavirus disease 2019 (COVID-19), however, its effect remains unclear. This systematic review and meta-analysis aimed to evaluate the effect of Ta1 as a COVID-19 therapy.Methods: PubMed, EMBASE, the Cochrane library, Web of Science, and the reference lists of relevant articles were searched to identify eligible studies. Assessment of heterogeneity was done using the I-squared (I2) test and random/fixed effect analysis was done to determine the risk ratio (RR). We polled the data related to mortality mainly by using Review Manager 5.4. Predefined subgroup analyses and sensitivity analyses were also performed.Results: A total of 9 studies were included, on a total of 5352 (Ta1 symbolscript 1152, control symbolscript 4200) patient outcomes. Meta-analysis results indicated that Ta1 therapy had no statistically significant effect on mortality [RR 1.03 (0.60, 1.75), p symbolscript 0.92, I2 symbolscript 90 %]. Subgroup analyses demonstrated that the beneficial effect in mortality was associated with mean age>60 years in the T alpha 1 group [RR 0.68 (0.58, 0.78), p < 0.0000.1, I2 symbolscript 0 %], the proportion of female symbolscript 40 % in the T alpha 1 group [RR 0.67 (0.58, 0.77), p < 0.0000.1, I2 symbolscript 0 %], and severe/critical COVID-19 patients [RR 0.66 (0.57, 0.76), p < 0.0000.1, I2 symbolscript 0 %]. Sensitivity analysis further demonstrated the results to be robust.Conclusions: The results of this meta-analysis do not support the use of Ta1 in hospitalized adult COVID-19 patients.

Background Observational studies have indicated a potential association between autoimmune diseases and the occurrence of sepsis, with an increased risk of mortality among affected patients. However, whether a causal relationship exists between the two remains unknown. Methods In the Mendelian randomization (MR) study, we accessed exposure Genome-wide association study (GWAS) data from both the MRC Integrative Epidemiology Unit (MRC-IEU) and the FinnGen consortium. GWAS data for sepsis and its 28-day mortality were obtained from MRC-IEU. We employed univariable, multivariable, and reverse MR analyses to explore potential associations between autoimmune disorders and sepsis and its 28-day mortality. Additionally, a two-step mediation MR analysis was performed to investigate indirect factors possibly influencing the relationship between autoimmune disorders and sepsis. Afterward, we conducted an observational analysis to further explore the relationship between autoimmune disease and occurrence as well as 28-day mortality of sepsis using a real-world database (the MIMIC-IV database). A cohort of 2537 patients diagnosed with autoimmune disease were extracted from the database for analysis. Multivariable logistic regression models were used to confirm the association between autoimmune diseases and the occurrence of sepsis, as well as the 28-day mortality associated with sepsis. Results In univariable MR analysis, there appeared to be causal relationships between genetically predicted type 1 diabetes (OR = 1.036, 95% CI = 1.023–1.048, p = 9.130E-09), rheumatoid arthritis (OR = 1.077, 95% CI = 1.058–1.097, p = 1.00E-15) and sepsis, while a potential causal link was observed between celiac disease and sepsis (OR = 1.013, 95% CI = 1.002–1.024, p = 0.026). In a subsequent multivariable MR analysis, only rheumatoid arthritis was found to be independently associated with the risk of sepsis (OR = 1.138, 95% CI = 1.044–1.240, p = 3.36E-03). Furthermore, there was no causal link between autoimmune disorders and 28-day mortality from sepsis. In reverse MR analysis, sepsis was suggested to potentially trigger the onset of psoriasis (OR = 1.084, 95% CI = 1.040–1.131, p = 1.488E-04). In the real-world observational study, adjusting for multiple confounders, rheumatoid arthritis (OR = 1.34, 95% CI = 1.11–1.64, p = 0.003) and multiple sclerosis (OR = 1.31, 95% CI = 1.03–1.68, p = 0.02) were associated with a higher risk of sepsis. In addition, we did not find that autoimmune diseases were associated with 28-day mortality from sepsis. Conclusion Both in observational and MR analysis, only rheumatoid arthritis is highly correlated with occurrence of sepsis. However, autoimmune disease was not associated with an increased 28-day mortality in patient with sepsis. Sepsis may increase the risk of developing psoriasis.

Evidence supports the observational associations of gut microbiota with the risk of COVID-19; however, it is unclear whether these associations reflect a causal relationship. This study investigated the association of gut microbiota with COVID-19 susceptibility and severity. Data were obtained from a large-scale gut microbiota data set (n = 18 340) and the COVID-19 Host Genetics Initiative (n = 2 942 817). Causal effects were estimated with inverse variance weighted (IVW), MR-Egger, and weighted median, and sensitivity analyses were implemented with Cochran's Q test, MR-Egger intercept test, MR-PRESSO, leave-one-out analysis, and funnel plots. For COVID-19 susceptibility, IVW estimates suggested that Gammaproteobacteria (odds ratio [OR] = 0.94, 95% confidence interval [CI], 0.89-0.99, p = 0.0295] and Streptococcaceae (OR = 0.95, 95% CI, 0.92-1.00, p = 0.0287) had a reduced risk, while Negativicutes (OR = 1.05, 95% CI, 1.01-1.10, p = 0.0302), Selenomonadales (OR = 1.05, 95% CI, 1.01-1.10, p = 0.0302), Bacteroides (OR = 1.06, 95% CI, 1.01-1.12, p = 0.0283), and Bacteroidaceae (OR = 1.06, 95% CI, 1.01-1.12, p = 0.0283) were associated with an increased risk (all p < 0.05, nominally significant). For COVID-19 severity, Subdoligranulum (OR = 0.80, 95% CI, 0.69-0.92, p = 0.0018), Cyanobacteria (OR = 0.85, 95% CI, 0.76-0.96, p = 0.0062), Lactobacillales (OR = 0.87, 95% CI, 0.76-0.98, p = 0.0260), Christensenellaceae (OR = 0.87, 95% CI, 0.77-0.99, p = 0.0384), Tyzzerella3 (OR = 0.89, 95% CI, 0.81-0.97, p = 0.0070), and RuminococcaceaeUCG011 (OR = 0.91, 95% CI, 0.83-0.99, p = 0.0247) exhibited negative correlations, while RikenellaceaeRC9 (OR = 1.09, 95% CI, 1.01-1.17, p = 0.0277), LachnospiraceaeUCG008 (OR = 1.12, 95% CI, 1.00-1.26, p = 0.0432), and MollicutesRF9 (OR = 1.14, 95% CI, 1.01-1.29, p = 0.0354) exhibited positive correlations (all p < 0.05, nominally significant). Sensitivity analyses validated the robustness of the above associations. These findings suggest that gut microbiota might influence the susceptibility and severity of COVID-19 in a causal way, thus providing novel insights into the gut microbiota-mediated development mechanism of COVID-19.

To investigate the relationship between the number of valvular insufficiency (VI) and emergency hospitalization or mortality in maintenance hemodialysis (HD) patients. The maintenance HD patients with cardiac ultrasonography were included. According to the number of VI ≥ 2 or not, the patients were divided into two groups. The difference of emergency hospitalized for acute heart failure, arrhythmia, acute coronary syndrome (ACS) or stroke, cardiovascular mortality, and all-cause mortality between the two groups were compared. Among 217 maintenance HD patients, 81.57% had VI. 121 (55.76%) patients had two or more VI, and 96 (44.24%) with one VI or not. The study subjects were followed up for a median of 47 (3–107) months. At the end of the follow up, 95 patients died (43.78%), of whom 47 (21.66%) patients died because of cardiovascular disease. Age (HR 1.033, 95% CI 1.007–1.061, P = 0.013), number of VI ≥ 2 (HR 2.035, 95% CI 1.083–3.821, P = 0.027) and albumin (HR 0.935, 95% CI 0.881–0.992, P = 0.027) were independent risk factors for cardiovascular mortality. The three parameters were also independent risk factors for all-cause mortality. The patients with number of VI ≥ 2 were more likely to be emergency hospitalized for acute heart failure (56 [46.28%] vs 11 [11.46%], P = 0.001). On the contrary, the number of VI was not associated with emergency hospitalized for arrhythmia, ACS or stroke. Survival analysis results showed that probability of survival was statistically different in the two groups (P < 0.05), no matter based on cardiovascular mortality or all-cause mortality. Based on age, number of VI ≥ 2 and albumin, nomogram models for 5-year cardiovascular and all-cause mortality were built. In maintenance HD patients, the prevalence of VI is prominently high. The number of VI ≥ 2 is associated with emergency hospitalized for acute heart failure, cardiovascular and all-cause mortality. Combining age, number of VI ≥ 2, and albumin can predict cardiovascular and all-cause mortality.

BACKGROUND:Evidence supports the observational associations of human blood metabolites with the risk of severe COVID-19. However, little is known about the potential pathological mechanisms and the analysis of blood metabolites may offer a better understanding of the underlying biological processes. METHODS:We applied a two-sample Mendelian randomization (MR) analysis to evaluate relationships between 486 blood metabolites and the risk of severe COVID-19. The inverse-variance weighted (IVW) model was used as the primary two-sample MR analysis method to estimate the causal relationship of the exposure on the outcome. Sensitivity analyses were implemented with Cochran's Q test, MR-Egger intercept test, MR-PRESSO, leave-one-out analysis and the funnel plot. RESULTS:Four hunderd and eighty six metabolites were included for MR analysis following rigorous genetic variants selection. After MR analyses and sensitivity analysis filtration, we found weak evidence of an association between 3-hydroxybutyrate (odds ratio [OR] = 1.21, 95% CI, 1.07-1.38, p = .0036) and the risk of severe COVID-19. A series of sensitivity analyses have been carried out to confirm the rigidity of the above results. CONCLUSION:This study suggested a causal relationship between 3-hydroxybutyrate and the severity of COVID-19, thus providing novel insights into biomarkers and pathways for COVID-19 prevention and clinical interventions.