Human blood metabolites and risk of sepsis: A Mendelian randomization investigation.

BACKGROUND: Evidence supports the observational correlations between human blood metabolites and sepsis. However, whether these associations represent a causal relationship is unknown. In this study, we applied two-sample Mendelian randomization (MR) analyses to examine causality between genetically proxied 486 blood metabolites and sepsis risk. METHODS: We used summary data from genome-wide association studies (GWAS) on 486 metabolites involving 7824 individuals as exposure and a sepsis GWAS including 11,643 cases and 474,841 controls as the outcome. The inverse-variance weighted (IVW) was the primary method to estimate the causal relationship between exposure and outcome, with MR-Egger and weighted median serving as supplements. Sensitivity analyses were implemented with Cochrane's Q test, MR-Egger intercept, MR-PRESSO and leave-one-out analysis. In addition, we performed replication MR, meta-analysis, Steiger test, linkage disequilibrium score (LDSC) regression and multivariable MR (MVMR) to thoroughly verify the causation. RESULTS: We identified that genetically determined high levels of 1-oleoylglycerophosphoethanolamine (odds ratio (OR) = .52, 95% confidence interval (CI): .31-.87, p = .0122), alpha-glutamyltyrosine (OR = .75, 95% CI: .60-.93, p = .0102), heptanoate (7:0) (OR = .51, 95% CI: .33-.81, p = .0041) and saccharin (OR = .84, 95% CI: .74-.94, p = .0036) were causally associated with a lower risk of sepsis. MVMR analysis demonstrated the independent causal effect of these metabolites on sepsis. CONCLUSIONS: These findings indicated that four blood metabolites have a protective impact on sepsis, thus providing novel perspectives into the metabolite-mediated development mechanism of sepsis by combining genomics and metabolomics.

Association of gut microbiota with COVID-19 susceptibility and severity: A two-sample Mendelian randomization study.

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.

Human blood metabolites and risk of severe COVID-19: A Mendelian randomization study.

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.

Association of autoimmune diseases with the occurrence and 28-day mortality of sepsis: an observational and Mendelian randomization study.

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.

Correlation between home systolic blood pressure variability and cognitive impairment in maintenance hemodialysis patients.

INTRODUCTION: To investigate the correlation between home blood pressure variability and cognitive function in maintenance hemodialysis (MHD) patients. METHODS: Patients who received MHD were included. Their home blood pressure on nondialysis days within 1 week was collected. All patients were assessed with the Montreal Cognitive Assessment scale, according to which the patients were divided into cognitive impairment (CI) group and non-CI group, and the differences between two groups were compared. RESULTS: A total of 224 patients were included in the study, of which 168 had CI (75%). Compared with non-CI group, patients in CI group had larger variability of systolic blood pressure (SBPV) (8.4 [6.7, 10.6]% vs. 6.9 [4.9, 8.8]%, P < 0.001). The smooth fitting curve (OR = 1.2, 95% CI [1.1-1.4], P < 0.001) and trend test (P for trend = 0.004) showed that the risk of CI raised with the increase of SBPV. The patients were further divided into tertiles according to the SBPV. We also found a gradual increase in the proportion of incident CI in the three tertiles. Multiple logistic regression analysis showed that age, shorter years of education, less frequency of hemodialysis, and greater SBPV were the dependent risk of CI. CONCLUSION: In conclusion, greater SBPV indicates higher risk of cognitive impairment in MHD patients.

The value of clinical parameters in predicting the severity of COVID-19.

To study the relationship between clinical indexes and the severity of coronavirus disease 2019 (COVID-19), and to explore its role in predicting the severity of COVID-19. Clinical data of 443 patients with COVID-19 admitted to our hospital were retrospectively analyzed, which were divided into nonsevere group (n = 304) and severe group (n = 139) according to their condition. Clinical indicators were compared between different groups. The differences in sex, age, the proportion of patients with combined heart disease, leukocyte, neutrophil-to-lymphocyte ratio (NLR), neutrophil, lymphocyte, platelet, D-dimer, C-reactive protein (CRP), procalcitonin, lactate dehydrogenase, and albumin on admission between the two groups were statistically significant (P < .05). Multivariate logistic regression analysis showed NLR and CRP were independent risk factors for severe COVID-19. Platelets were independent protective factors for severe COVID-19. The receiver operating characteristic (ROC) curve analysis demonstrated area under the curve of NLR, platelet, CRP, and combination was 0.737, 0.634, 0.734, and 0.774, respectively. NLR, CRP, and platelets can effectively assess the severity of COVID-19, among which NLR is the best predictor of severe COVID-19, and the combination of three clinical indicators can further predict severe COVID-19.

The Predictive Value of Urinary Kidney Injury Molecular 1 for the Diagnosis of Contrast-Induced Acute Kidney Injury after Cardiac Catheterization: A Meta-Analysis.

BACKGROUND: Urinary kidney injury molecule 1 (uKIM-1) is a proximal tubular injury biomarker for predicting acute kidney injury (AKI); its prognostic value varies depending on the clinical and population characteristics. However, the predictive value of uKIM-1 for diagnosis of contrast-induced acute kidney injury (CI-AKI) remains unclear. METHOD: Medline, Embase, ClinicalTrials.gov, Cochrane Library database, and the China National Knowledge Infrastructure (CNKI) were used to identify relevant studies from their inception to November 31, 2019. Studies that met the inclusion criteria were included. Relevant data were extracted to obtain pooled sensitivity (SEN) and specificity (SPE), summary receiver operating characteristic curve (ROC), and area under the ROC (AUC or AUROC). A bivariate mixed-effects regression model was used for data analysis. RESULTS: A total of 946 patients from 8 eligible studies were included. Across all the studies, the diagnostic odds ratio (DOR) for uKIM-1 level to predict CI-AKI was 19 (95% CI 10-39), with SEN and SPE of 0.84 and 0.78, respectively. The AUROC for uKIM-1 in predicting CI-AKI was 0.88 (95% CI 0.85-0.90). There was a substantial heterogeneity across the studies (I 2 was 37.73% for the summary sensitivity and 69.31% for the summary specificity). CONCLUSION: Urinary KIM-1 has a high predictive value for diagnosis of CI-AKI in patients who have undergone cardiac catheterization.

Contrast-induced acute kidney injury and adverse clinical outcomes risk in acute coronary syndrome patients undergoing percutaneous coronary intervention: a meta-analysis.

BACKGROUND: Recent studies have shown associations between contrast-induced acute kidney injury (CI-AKI) and increased risk of adverse clinical outcomes in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI); however, the estimates are inconsistent and vary widely. Therefore, this meta-analysis aimed to evaluate the precise associations between CI-AKI and adverse clinical consequences in patients undergoing PCI for ACS. METHODS: EMBASE, PubMed, Web of Science™ and Cochrane Library databases were systematically searched from inception to December 16, 2016 for cohort studies assessing the association between CI-AKI and any adverse clinical outcomes in ACS patients treated with PCI. The results were demonstrated as pooled risk ratios (RRs) with 95% confidence intervals (CI). Heterogeneity was explored by subgroup analyses. RESULTS: We identified 1857 articles in electronic search, of which 22 (n = 32,781) were included. Our meta-analysis revealed that in ACS patients undergoing PCI, CI-AKI significantly increased the risk of adverse clinical outcomes including all-cause mortality (18 studies; n = 28,367; RR = 3.16, 95% CI 2.52-3.97; I2 = 56.9%), short-term all-cause mortality (9 studies; n = 13,895; RR = 5.55, 95% CI 3.53-8.73; I2 = 60.1%), major adverse cardiac events (7 studies; n = 19,841; RR = 1.49, 95% CI: 1.34-1.65; I2 = 0), major adverse cardiovascular and cerebrovascular events (3 studies; n = 2768; RR = 1.86, 95% CI: 1.42-2.43; I2 = 0) and stent restenosis (3 studies; n = 130,678; RR = 1.50, 95% CI: 1.24-1.81; I2 = 0), respectively. Subgroup analyses revealed that the studies with prospective cohort design, larger sample size and lower prevalence of CI-AKI might have higher short-term all-cause mortality risk. CONCLUSIONS: CI-AKI may be a prognostic marker of adverse outcomes in ACS patients undergoing PCI. More attention should be paid to the diagnosis and management of CI-AKI.

Nephrolithiasis and risk of hypertension: a meta-analysis of observational studies.

BACKGROUND: Observational studies have demonstrated an association between nephrolithiasis and hypertension. The aim of this meta-analysis was to summarize all available evidence. METHODS: PubMed, EMBASE, the Cochrane Central Register of Controlled Trials databases, and the reference lists of relevant articles were searched to identify observational studies that reported study-specific risk estimates comparing the risk of hypertension in patients with nephrolithiasis. We used a random-effect model to pool the study-specific risk estimates. We also assessed the potential heterogeneity by subgroup analyses, meta-regression analyses, and sensitivity analyses. RESULTS: A total of 7 articles including 9 studies (n = 313,222 participants) were eventually identified in this meta-analysis. In comparison with the patients who did not have nephrolithiasis, nephrolithiasis significantly increased the risk of hypertension (OR, 1.43; 95% CI, 1.30-1.56), with significant heterogeneity between these studies (I 2 = 83.5%, P <0.001). The heterogeneity reduced in subgroups of cohort studies, USA, large sample size trials, men, and adjustment for confounding factors ≥ 5. Sensitivity analysis further demonstrated the results to be robust. CONCLUSIONS: Nephrolithiasis is associated with increased risk of hypertension. Future randomized, high-quality clinical trials are encouraged to definitively clarify the relationship between nephrolithiasis and hypertension, which may influence clinical management and primary prevention of hypertension in nephrolithiasis patients.

The N-terminal Domain of Escherichia coli Assimilatory NADPH-Sulfite Reductase Hemoprotein Is an Oligomerization Domain That Mediates Holoenzyme Assembly.

Assimilatory NADPH-sulfite reductase (SiR) from Escherichia coli is a structurally complex oxidoreductase that catalyzes the six-electron reduction of sulfite to sulfide. Two subunits, one a flavin-binding flavoprotein (SiRFP, the α subunit) and the other an iron-containing hemoprotein (SiRHP, the ß subunit), assemble to make a holoenzyme of about 800 kDa. How the two subunits assemble is not known. The iron-rich cofactors in SiRHP are unique because they are a covalent arrangement of a Fe4S4 cluster attached through a cysteine ligand to an iron-containing porphyrinoid called siroheme. The link between cofactor biogenesis and SiR stability is also ill-defined. By use of hydrogen/deuterium exchange and biochemical analysis, we show that the α8ß4 SiR holoenzyme assembles through the N terminus of SiRHP and the NADPH binding domain of SiRFP. By use of small angle x-ray scattering, we explore the structure of the SiRHP N-terminal oligomerization domain. We also report a novel form of the hemoprotein that occurs in the absence of its cofactors. Apo-SiRHP forms a homotetramer, also dependent on its N terminus, that is unable to assemble with SiRFP. From these results, we propose that homotetramerization of apo-SiRHP serves as a quality control mechanism to prevent formation of inactive holoenzyme in the case of limiting cellular siroheme.

Association of peripheral arterial disease with all-cause and cardiovascular mortality in hemodialysis patients: a meta-analysis.

BACKGROUND: Recent studies have shown an association between peripheral arterial disease (PAD) and increased risk of mortality in hemodialysis (HD) patients; however, the estimates vary widely and are inconsistent. It is necessary to elucidate the degree of mortality risk for PAD patients in HD population. METHODS: PubMed, EMBASE, Web of Science and Cochrane Library (from inception to September 4th, 2016) were systematically searched for cohort studies assessing the association between PAD and mortality in HD patients. We calculated the pooled risk ratios (RRs) with 95% confidence intervals (CI) of all-cause and cardiovascular (CV) mortality using random effects models. Subgroup analyses were conducted to explore the source of heterogeneity. RESULTS: The search identified 2,973 potentially eligible records and 10 studies (n = 32,864) were included. Our meta-analysis revealed that PAD significantly increased the risk of all-cause mortality (RR 2.15, 95 % CI 1.67-2.77, n = 32,864) and CV mortality (RR 2.99, 95 % CI 1.66-5.38, n = 31,794) in HD patients after multivariate adjustment. Subgroup analyses showed the study design and follow-up time might be two sources of heterogeneity. CONCLUSION: PAD may be a prognostic marker of all-cause and CV mortality in HD patients. More attention should be paid to diagnosis and management of PAD in HD patients.

The histone chaperones Vps75 and Nap1 form ring-like, tetrameric structures in solution.

NAP-1 fold histone chaperones play an important role in escorting histones to and from sites of nucleosome assembly and disassembly. The two NAP-1 fold histone chaperones in budding yeast, Vps75 and Nap1, have previously been crystalized in a characteristic homodimeric conformation. In this study, a combination of small angle X-ray scattering, multi angle light scattering and pulsed electron-electron double resonance approaches were used to show that both Vps75 and Nap1 adopt ring-shaped tetrameric conformations in solution. This suggests that the formation of homotetramers is a common feature of NAP-1 fold histone chaperones. The tetramerisation of NAP-1 fold histone chaperones may act to shield acidic surfaces in the absence of histone cargo thus providing a 'self-chaperoning' type mechanism.

Analysis of 4931 renal biopsy data in central China from 1994 to 2014.

The purpose of this study is to investigate the changing spectrum and clinicopathologic correlation of biopsy-proven renal diseases in central China. We retrospectively analyzed data of 4931 patients who underwent renal biopsy in ten hospitals between September 1994 and December 2014. Among them, 81.55% were primary glomerular diseases (GD), and 13.02% were secondary GD. IgA nephropathy (IgAN) was the most common primary GD (43.45%), followed by focal glomerulonephritis (16.79%), mesangial proliferative glomerulonephritis (MsPGN, 14.35%), and membranous nephropathy (MN, 13.28%). IgAN was leading primary GD in patients under 60 years old, while MN was the leading one over 60 years old. The most frequent secondary GD was lupus nephritis (LN) (47.35%). The prevalence of IgAN, MN and minimal change disease was found to increase significantly (p < 0.001, p < 0.001, and p < 0.01, respectively), while that of MsPGN, membranoproliferative glomerulonephritis and LN decreased significantly (p < 0.001, p < 0.001, and p < 0.05, respectively). The main indication for renal biopsy was proteinuria and hematuria (49.03%), followed by nephrotic syndrome (NS, 20.36%). IgAN was the most common cause in patients with proteinuria and hematuria, chronic-progressive kidney injury, hematuria and acute kidney injury; and MN was the leading cause of NS. Primary GD remained the predominant renal disease in central China. IgAN and LN were the most prevalent histopathologic lesions of primary and secondary GD, respectively. The spectrum of biopsy-proven renal disease had a great change in the past two decades. Proteinuria and hematuria was the main indication for renal biopsy.

Structural flexibility of RNA as molecular basis for Hfq chaperone function.

In enteric bacteria, many small regulatory RNAs (sRNAs) associate with the RNA chaperone host factor Q (Hfq) and often require the protein for regulation of target mRNAs. Previous studies suggested that the hexameric Escherichia coli Hfq (Hfq(Ec)) binds sRNAs on the proximal site, whereas the distal site has been implicated in Hfq-mRNA interactions. Employing a combination of small angle X-ray scattering, nuclear magnetic resonance and biochemical approaches, we report the structural analysis of a 1:1 complex of Hfq(Ec) with a 34-nt-long subsequence of a natural substrate sRNA, DsrA (DsrA(34)). This sRNA is involved in post-transcriptional regulation of the E. coli rpoS mRNA encoding the stationary phase sigma factor RpoS. The molecular envelopes of Hfq(Ec) in complex with DsrA(34) revealed an overall asymmetric shape of the complex in solution with the protein maintaining its doughnut-like structure, whereas the extended DsrA(34) is flexible and displays an ensemble of different spatial arrangements. These results are discussed in terms of a model, wherein the structural flexibility of RNA ligands bound to Hfq stochastically facilitates base pairing and provides the foundation for the RNA chaperone function inherent to Hfq.

Gut microbiota and sepsis and sepsis-related death: a Mendelian randomization investigation.

Background: It 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. Methods: This 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. Results: For 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. Conclusion: This 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.

Thymopentin plays a key role in restoring the function of macrophages to alleviate the sepsis process.

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.

Nonstructural proteins 7 and 8 of feline coronavirus form a 2:1 heterotrimer that exhibits primer-independent RNA polymerase activity.

Nonstructural proteins 7 and 8 of severe acute respiratory syndrome coronavirus (SARS-CoV) have previously been shown by X-ray crystallography to form an 8:8 hexadecamer. In addition, it has been demonstrated that N-terminally His(6)-tagged SARS-CoV Nsp8 is a primase able to synthesize RNA oligonucleotides with a length of up to 6 nucleotides. We present here the 2.6-Å crystal structure of the feline coronavirus (FCoV) Nsp7:Nsp8 complex, which is a 2:1 heterotrimer containing two copies of the α-helical Nsp7 with conformational differences between them, and one copy of Nsp8 that consists of an α/ß domain and a long-α-helix domain. The same stoichiometry is found for the Nsp7:Nsp8 complex in solution, as demonstrated by chemical cross-linking, size exclusion chromatography, and small-angle X-ray scattering. Furthermore, we show that FCoV Nsp8, like its SARS-CoV counterpart, is able to synthesize short oligoribonucleotides of up to 6 nucleotides in length when carrying an N-terminal His(6) tag. Remarkably, the same protein harboring the sequence GPLG instead of the His(6) tag at its N terminus exhibits a substantially increased, primer-independent RNA polymerase activity. Upon addition of Nsp7, the RNA polymerase activity is further enhanced so that RNA up to template length (67 nucleotides) can be synthesized. Further, we show that the unprocessed intermediate polyprotein Nsp7-10 of human coronavirus (HCoV) 229E is also capable of synthesizing oligoribonucleotides up to a chain length of six. These results indicate that in case of FCoV as well as of HCoV 229E, the formation of a hexadecameric Nsp7:Nsp8 complex is not necessary for RNA polymerase activity. Further, the FCoV Nsp7:Nsp8 complex functions as a noncanonical RNA polymerase capable of synthesizing RNA of up to template length.

Thymosin alpha1 use in adult COVID-19 patients: A systematic review and meta-analysis on clinical outcomes.

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 = 1152, control = 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 = 0.92, I2 = 90 %]. Subgroup analyses demonstrated that the beneficial effect in mortality was associated with mean age＞60 years in the Tα1 group [RR 0.68 (0.58, 0.78), p < 0.0000.1, I2 = 0 %], the proportion of female ≤ 40 % in the Tα1 group [RR 0.67 (0.58, 0.77), p < 0.0000.1, I2 = 0 %], and severe/critical COVID-19 patients [RR 0.66 (0.57, 0.76), p < 0.0000.1, I2 = 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.

The number of valvular insufficiency is a strong predictor of cardiovascular and all-cause mortality in hemodialysis patients.

OBJECTIVES: To investigate the relationship between the number of valvular insufficiency (VI) and emergency hospitalization or mortality in maintenance hemodialysis (HD) patients. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Association between Mean Arterial Pressure during the First 24 Hours and Clinical Outcome in Critically Ill Stroke Patients: An Analysis of the MIMIC-III Database.

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.