Efficacy of JAK1/2 inhibition in murine immune bone marrow failure.

Immune aplastic anemia (AA) is a severe blood disease characterized by T-lymphocyte- mediated stem cell destruction. Hematopoietic stem cell transplantation and immunosuppression are effective, but they entail costs and risks, and are not always successful. The Janus kinase (JAK) 1/2 inhibitor ruxolitinib (RUX) suppresses cytotoxic T-cell activation and inhibits cytokine production in models of graft-versus-host disease. We tested RUX in murine immune AA for potential therapeutic benefit. After infusion of lymph node (LN) cells mismatched at the major histocompatibility complex [C67BL/6 (B6)⇒CByB6F1], RUX, administered as a food additive (Rux-chow), attenuated bone marrow hypoplasia, ameliorated peripheral blood pancytopenia, preserved hematopoietic progenitors, and prevented mortality, when used either prophylactically or therapeutically. RUX suppressed the infiltration, proliferation, and activation of effector T cells in the bone marrow and mitigated Fas-mediated apoptotic destruction of target hematopoietic cells. Similar effects were obtained when Rux-chow was fed to C.B10 mice in a minor histocompatibility antigen mismatched (B6⇒C.B10) AA model. RUX only modestly suppressed lymphoid and erythroid hematopoiesis in normal and irradiated CByB6F1 mice. Our data support clinical trials of JAK/STAT inhibitors in human AA and other immune bone marrow failure syndromes.

A polygenic risk score improves risk stratification of coronary artery disease: a large-scale prospective Chinese cohort study.

AIMS: To construct a polygenic risk score (PRS) for coronary artery disease (CAD) and comprehensively evaluate its potential in clinical utility for primary prevention in Chinese populations. METHODS AND RESULTS: Using meta-analytic approach and large genome-wide association results for CAD and CAD-related traits in East Asians, a PRS comprising 540 genetic variants was developed in a training set of 2800 patients with CAD and 2055 controls, and was further assessed for risk stratification for CAD integrating with the guideline-recommended clinical risk score in large prospective cohorts comprising 41 271 individuals. During a mean follow-up of 13.0 years, 1303 incident CAD cases were identified. Individuals with high PRS (the highest 20%) had about three-fold higher risk of CAD than the lowest 20% (hazard ratio 2.91, 95% confidence interval 2.43-3.49), with the lifetime risk of 15.9 and 5.8%, respectively. The addition of PRS to the clinical risk score yielded a modest yet significant improvement in C-statistic (1%) and net reclassification improvement (3.5%). We observed significant gradients in both 10-year and lifetime risk of CAD according to the PRS within each clinical risk strata. Particularly, when integrating high PRS, intermediate clinical risk individuals with uncertain clinical decision for intervention would reach the risk levels (10-year of 4.6 vs. 4.8%, lifetime of 17.9 vs. 16.6%) of high clinical risk individuals with intermediate (20-80%) PRS. CONCLUSION: The PRS could stratify individuals into different trajectories of CAD risk, and further refine risk stratification for CAD within each clinical risk strata, demonstrating a great potential to identify high-risk individuals for targeted intervention in clinical utility.

Immunosuppressive Activity of Exosomes from Granulocytic Myeloid-Derived Suppressor Cells in a Murine Model of Immune Bone Marrow Failure.

We previously reported that granulocytic myeloid-derived suppressor cells (G-MDSCs) suppressed T-cell activation and attenuated bone marrow failure (BMF) in a minor histocompatibility (minor-H) antigen mismatched murine aplastic anemia (AA) model. In the current study, we tested the hypothesis that exosomes, a subset of extracellular vesicles, are responsible at least partially for G-MDSCs' therapeutic efficacy. Indeed, exosomes isolated from GMDSCs (G-MDSC-exos) suppressed CD4+ and CD8+ T-cell proliferation in vitro and mildly attenuated immune BMF in the minor-H mismatched AA model. G-MDSC-exos treatment significantly increased red blood cells, hemoglobin, and total bone marrow (BM) cells, and moderately reduced BM CD8+ T cells. G-MDSC-exos' effects were associated with upregulations in an array of lymphocyte-suppression-related miRNAs such as hsa-miR-142-5p, miR-19a-3p, and miR-19b-3p in both BM CD4+ and CD8+ T cells. We concluded that G-MDSC-exos attenuate immune BMF via modulating the delivery of immunosuppressive miRNAs into activated T lymphocytes.

Sirolimus augments hematopoietic stem and progenitor cell regeneration following hematopoietic insults.

The role of mammalian target of rapamycin and its suppressor sirolimus in the regulation of hematopoietic stem and progenitor cells (HSPCs) is controversial. We show here that sirolimus enhanced regeneration of HSPCs in mice exposed to sublethal total body irradiation (TBI) and other regenerative stressors. Sorted Lin- CD150+ bone marrow cells from sirolimus-treated TBI mice had increased expression of c-Kit and other hematopoietic genes. HSPCs from sirolimus-treated TBI mice were functionally competent when tested by competitive engraftment in vivo. Postradiation regeneration of HSPCs in mice treated with sirolimus was accompanied by decreased γ-H2AX levels detected by flow cytometry and increased expression of DNA repair genes by quantitative polymerase chain reaction. Reduction of cell death and DNA damage post-radiation by sirolimus was associated with enhanced clearance of cellular reactive oxygen species (ROS) in HSPCs. Increased HSPC recovery with sirolimus was also observed in mice injected with hematoxic agents, busulfan and 5-fluorouracil. In contrast, sirolimus showed no effect on HSPCs in normal mice at steady state, but stimulated HSPC expansion in mice carrying the Wv mutation at the c-Kit locus. In human to mouse xenotransplantation, sirolimus enhanced engraftment of irradiated human CD34+ cells. In summary, our results are consistent with sirolimus' acceleration of HSPC recovery in response to hematopoietic stress, associated with reduced DNA damage and ROS. Sirolimus might have clinical application for the treatment and prevention of hematopoietic injury.

Microglia and immunotherapy in Alzheimer's disease.

Microglia are a type of glial cells that play a key role in the repair of damage to the central nervous system (CNS). In the pathological condition of Alzheimer's disease (AD), ß-amyloid peptide and a variety of pro-inflammatory factors can activate microglia, resulting in the secretion of a variety of inflammatory factors and neurotoxins. This leads to neuronal damage and even apoptosis, thus triggering AD. In contrast, microglia can protect the CNS by phagocytizing Aß to slow down AD development. In this review, the roles of microglia in AD neuroinflammation and the scope of immunotherapy for AD are summarized to provide a theoretical basis for AD prevention and treatment.

Metabolomics study of blood pressure salt-sensitivity and hypertension.

BACKGROUND AND AIMS: Identify novel metabolite associations with blood pressure (BP) salt-sensitivity and hypertension. METHODS AND RESULTS: The Genetic Epidemiology Network of Salt Sensitivity (GenSalt) Replication study includes 698 Chinese participants who underwent a 3-day baseline examination followed by a 7-day low-sodium feeding and 7-day high-sodium feeding. Latent mixture models identified three trajectories of blood pressure (BP) responses to the sodium interventions. We selected 50 most highly salt-sensitive and 50 most salt-resistant participants for untargeted metabolomics profiling. Multivariable adjusted mixed logistic regression models tested the associations of baseline metabolites with BP salt-sensitivity. Multivariable adjusted mixed linear regression models tested the associations of BP salt-sensitivity with metabolite changes during the sodium interventions. Identified metabolites were tested for associations with hypertension among 1249 Bogalusa Heart Study (BHS) participants using multiple logistic regression. Fifteen salt-sensitivity metabolites were associated with hypertension in the BHS. Baseline values of serine, 2-methylbutyrylcarnitine and isoleucine directly associated with high salt-sensitivity. Among them, serine indirectly associated with hypertension while 2-methylbutyrylcarnitine and isoleucine directly associated with hypertension. Baseline salt-sensitivity status predicted changes in 14 metabolites when switching to low-sodium or high-sodium interventions. Among them, glutamate, 1-carboxyethylvaline, 2-methylbutyrylcarnitine, 3-methoxytyramine sulfate, glucose, alpha-ketoglutarate, hexanoylcarnitine, gamma-glutamylisoleucine, gamma-glutamylleucine, and gamma-glutamylphenylalanine directly associated with hypertension. Conversely, serine, histidine, threonate and 5-methyluridine indirectly associated with hypertension. Together, these metabolites explained an additional 7% of hypertension susceptibility when added to a model including traditional risk factors. CONCLUSIONS: Our findings contribute to the molecular characterization of BP response to sodium and provide novel biological insights into salt-sensitive hypertension.

A Pooled Analysis of the PCR for the Detection of Candida Auris.

BACKGROUND: Candida auris is an opportunistic pathogen with multiple drug resistance. Therefore, researchers conducted a meta-analysis to review PCR's ability to diagnose Candida auris to promote the development of accurate Candida auris diagnosis. METHODS: Researchers systematically retrieved relevant articles from PubMed, Cochrane Library, Embase, and Web of Science. Then, researchers extracted the key data required for the study from the selected articles. Meta-DiSc 1.4 was used for the statistical analysis. RevMan 5.3 was employed to assess the quality of the included literature. A funnel plot can appraise whether the included articles have publication bias. RESULTS: Five articles were included in the study. The results suggest that the pooled sensitivity and pooled specificity were 0.94 (95% CI: 0.92 - 0.95) and 0.99 (95% CI: 0.99 - 0.99), respectively. The positive and negative likelyhood ratios were 100.94 (95% CI: 47.51 - 214.47) and 0.07 (95% CI: 0.05 - 0.10), respectively. The diagnostic odds ratio was 1,814.70 (95% CI: 717.30 - 4,591.04), and the area under the SROC curve was 0.9935. Deek's funnel plot indicated that there was no publication bias. CONCLUSIONS: The results of the analysis indicate that PCR can become a valuable technique for the clinical diagnosis of Candida auris due to its excellent performance.

Accuracy of Xpert MTB/RIF assay for the diagnosis of tuberculous pleural effusion.

BACKGROUND: Tuberculosis poses a severe threat to human health. At present, compared with the traditional diagnostic methods for tuberculosis pleural effusion, such as Löwenstein-Jensen culture, pleural biopsy, and Ziehl-Neelsen smear microscopy, Xpert MTB/RIF was regarded as an emerging technology for its efficiency. The Xpert MTB/RIF accuracy for tuberculous pleural effusion diagnosis was evaluated in this systematic study. MATERIALS AND METHODS: We searched the relevant literature published before January 2021 in PubMed, Cochrane, EMBASE, and Web of Science databases. Utilizing Review Manager 5.3 software, the quality of the included literature was evaluated based on the Quality Assessment of Diagnostic Accuracy Studies criteria. Sensitivity, specificity, and the summary receiver operating characteristic curves were plotted and analyzed with Metadisc 1.40 software. We used Stata 12.0 software to evaluate the publication bias of this study. RESULTS: Eighteen articles were identified in total. The sensitivity of Xpert MTB/RIF in the pleural effusion was 0.24, and specificity was 1.00, respectively. The area under the summary receiver operating characteristic curve was 0.9737, which indicated that the overall accuracy of the Xpert MTB/RIF was high. In addition, based on the Deeks funnel plot, no publication bias of the study was found. CONCLUSION: Xpert MTB/RIF is a rapid method with high specificity but relatively low sensitivity for detecting Mycobacterium tuberculosis in pleural effusion. Its less sensitivity made it difficult to be used clinically, but the high specificity suggests that it can be used as a specific diagnostic method for tuberculous pleural effusion.

Identification of Key Pathways and Genes in SARS-CoV-2 Infecting Human Intestines by Bioinformatics Analysis.

COVID-19 is a serious infectious disease that has recently swept the world, and research on its causative virus, SARS-CoV-2, remains insufficient. Therefore, this study uses bioinformatics analysis techniques to explore the human digestive tract diseases that may be caused by SARS-CoV-2 infection. The gene expression profile data set, numbered GSE149312, is from the Gene Expression Omnibus (GEO) database and is divided into a 24-h group and a 60-h group. R software is used to analyze and screen out differentially expressed genes (DEGs) and then gene ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses are performed. In KEGG, the pathway of non-alcoholic fatty liver disease exists in both the 24-h group and 60-h group. STRING is used to establish a protein-protein interaction (PPI) network, and Cytoscape is then used to visualize the PPI and define the top 12 genes of the node as the hub genes. Through verification, nine statistically significant hub genes are identified: AKT1, TIMP1, NOTCH, CCNA2, RRM2, TTK, BUB1B, KIF20A, and PLK1. In conclusion, the results of this study can provide a certain direction and basis for follow-up studies of SARS-CoV-2 infection of the human digestive tract and provide new insights for the prevention and treatment of diseases caused by SARS-CoV-2.

Investigation of hub gene associated with the infection of Staphylococcus aureus via weighted gene co-expression network analysis.

INTRODUCTION: Staphylococcus aureus is a gram-positive bacterium that causes serious infection. With the increasing resistance of bacteria to current antibiotics, it is necessary to learn more about the molecular mechanism and cellular pathways involved in the Staphylococcus aureus infection. METHODS: We downloaded the GSE33341 dataset from the GEO database and applied the weighted gene co-expression network analysis (WGCNA), from which we obtained some critical modules. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) were applied to illustrate the biological functions of genes in these modules. We constructed the protein-protein interaction (PPI) network by Cytoscape and selected five candidate hub genes. Five potential hub genes were validated in GSE30119 by GraphPad Prism 8.0. The diagnostic values of these genes were calculated and present in the ROC curve based on the GSE13670 dataset. Their gene functions were analyzed by Gene Set Enrichment Analysis (GSEA). RESULTS: A co-expression network was built with 5000 genes divided into 11 modules. The genes in green and turquoise modules demonstrated a high correlation. According to the KEGG and GO analyses, genes in the green module were closely related to ubiquitination and autophagy. Subsequently, we picked out the top five hub genes in the green module. And UBB was determined as the hub gene in the GSE30119 dataset. The expression level of UBB, ASB, and MKRN1 could significantly differentiate between Staphylococcus aureus infection and healthy controls based on the ROC curve. The GSEA analysis indicated that lower expression levels of UBB were associated with the P53 signal pathway. CONCLUSIONS: We identified some hub genes and significant signal enrichment pathways in Staphylococcus aureus infection via bioinformatics analysis, which may facilitate the development of potential clinical therapeutic strategies.

Long-term impacts of ambient fine particulate matter exposure on overweight or obesity in Chinese adults: The China-PAR project.

Although emerging researches have linked ambient fine particulate matter (PM2.5) to obesity, evidence from high-polluted regions is still lacking. We thus assessed the long-term impacts of PM2.5 on body mass index (BMI) and the risk of the prevalence of overweight/obesity (BMI≥25 kg/m2), by incorporating the well-established Prediction for Atherosclerotic Cardiovascular Disease Risk in China (China-PAR) project comprising 77,609 participants with satellite-based PM2.5 estimates at 1-km spatial resolution. The average of long-term PM2.5 level was 70.4 µg/m3, with the range of 32.1-94.2 µg/m3. Each 10 µg/m3 increment of PM2.5 was associated with 0.421 kg/m2 (95% confidence interval [CI]: 0.402, 0.439) and 13.5% (95% CI: 12.8%, 14.3%) increased BMI and overweight/obesity risk, respectively. Moreover, compared with the lowest quartile of PM2.5 (≤57.5 µg/m3), the relative risk of the prevalence of overweight/obesity from the highest quartile (>85.9 µg/m3) was 1.611 (95% CI: 1.566, 1.657). The exposure-response curve suggested a non-linear relationship between PM2.5 exposure and overweight/obesity. Besides, the association was modified by age, diabetes mellitus, hypertension and dyslipidemia status. Our study provides the evidence for the adverse impacts of long-term PM2.5 on BMI and overweight/obesity in China, and the findings are important for policy development on air quality, especially in severely polluted areas.

Chronic Effects of High Fine Particulate Matter Exposure on Lung Cancer in China.

Rationale: Limited cohort studies have evaluated chronic effects of high fine particulate matter (particulate matter with an aerodynamic diameter ≤2.5 µm [PM2.5]) exposure on lung cancer.Objectives: To investigate the response pattern of lung cancer associated with high PM2.5 exposure.Methods: A Chinese cohort of 118,551 participants was followed up from 1992 to 2015. By incorporating PM2.5 exposure at 1 km spatial resolution generated using the satellite-based model during 2000-2015, we estimated the association between lung cancer and time-weighted average PM2.5 concentration using Cox proportional hazard models.Measurements and Main Results: A total of 844 incident lung cancer cases were identified during 915,053 person-years of follow-up. Among them, 701 lung cancer deaths occurred later. The exposure-response curves for lung cancer associated with PM2.5 exposure were nonlinear, with steeper slopes at the higher concentrations. Adjusted for age, sex, geographical region, urbanization, education level, smoking status, alcohol consumption, work-related physical activity, and body mass index, participants exposed to the second-fifth quintiles of PM2.5 had higher risk for lung cancer incidence than those exposed to the first quintile, with hazard ratios of 1.44 (95% confidence interval [CI], 1.10-1.88), 1.49 (95% CI, 1.12-1.99), 2.08 (95% CI, 1.42-3.04), and 2.45 (95% CI, 1.83-3.29), respectively. The corresponding hazard ratios for lung cancer mortality were 1.83 (95% CI, 1.33-2.50), 1.80 (95% CI, 1.29-2.53), 2.50 (95% CI, 1.62-3.86), and 2.95 (95% CI, 2.09-4.17), respectively.Conclusions: We provide strong evidence that high PM2.5 exposure leads to an elevated risk of lung cancer incidence and mortality, highlighting that remarkable public health benefits could be obtained from the improvement of air quality in highly polluted regions.

Benefits of active commuting on cardiovascular health modified by ambient fine particulate matter in China: A prospective cohort study.

BACKGROUND: Active commuting as a contributor to daily physical activity is beneficial for cardiovascular health, but leads to more chances of exposure to ambient air pollution. This study aimed to investigate associations between active commuting to work with cardiovascular disease (CVD), mortality and life expectancy among general Chinese adults, and to further evaluate the modification effect of fine particulate matter (PM2.5) exposure on these associations. METHODS: We included 76,176 Chinese adults without CVD from three large cohorts of the Prediction for Atherosclerotic Cardiovascular Disease Risk in China project. Information about commuting mode and physical activity were collected by unified questionnaire. Satellite-based PM2.5 concentrations at 1-km spatial resolution was used for estimating PM2.5 exposure of participants. Hazard ratios (HRs) and 95% confidence intervals (CIs) for CVD incidence, mortality and all-cause mortality were estimated using Cox proportional hazards regression models. Multiplicative interaction term of commuting mode and PM2.5 level was tested to investigate potential effect modification. RESULTS: During 448,499 person-years of follow-up, 2230 CVD events and 2777 all-cause deaths were recorded. Compared with the non-active commuters, the multivariable-adjusted HRs (95% CIs) of CVD incidence and all-cause mortality were 0.95(0.85-1.05) and 0.79(0.72-0.87) for walking commuters, respectively. Corresponding HRs (95% CIs) for cycling commuters were 0.71(0.62-0.82) and 0.67(0.59-0.76). Active commuters over 45 years old were estimated to have more CVD-free years and life expectancy than non-active commuters under lower PM2.5 concentration. However, these beneficial effects of active commuting were alleviated or counteracted by long-term exposure to high PM2.5 concentration. Significant multiplicative interaction of commuting mode and PM2.5 level was showed in all-cause mortality, with the lowest risk observed in cycling participants exposed to lower level of PM2.5. CONCLUSIONS: Active commuting was associated with lower risk of CVD, all-cause mortality, and longer life expectancy among Chinese adults under ambient settings with lower PM2.5 level. It will be valuable to encourage active commuting among adults and develop stringent strategies on ambient PM2.5 pollution control for prevention of CVD and prolongation of life expectancy.

Attenuation of immune-mediated bone marrow damage in conventionally housed mice.

In humans, bone marrow (BM) failure syndromes, both constitutional and acquired, predispose to myeloid malignancies. We have modeled acquired immune aplastic anemia, the paradigmatic disease of these syndromes, in the mouse by infusing lymph node cells from specific pathogen-free (SPF) CD45.1 congenic C57BL/6 (B6) donors into hybrid CByB6F1 recipients housed either in conventional (CVB) or SPF facilities. The severity of BM damage was reduced in CVB recipients; they also had reduced levels of CD44+ CD62L- effector memory T cells, reduced numbers of donor-type CD44+ T cells, and reduced expansion of donor-type CD8 T cells carrying T-cell receptor ß-variable regions 07, 11, and 17. Analyses of fecal samples through 16S ribosomal RNA amplicon sequencing revealed greater gut microbial alpha diversity in CVB mice relative to that of SPF mice. Thus, the presence of a broader spectrum of gut microorganisms in CVB-housed CByB6F1 could have primed recipient animal's immune system leading to suppression of allogeneic donor T-cell activation and expansion and attenuation of host BM destruction. These results suggest the potential benefit of diverse gut microbiota in patients receiving BM transplants.

Macrophage TNF-α licenses donor T cells in murine bone marrow failure and can be implicated in human aplastic anemia.

Interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) have been implicated historically in the immune pathophysiology of aplastic anemia (AA) and other bone marrow (BM) failure syndromes. We recently defined the essential roles of IFN-γ produced by donor T cells and the IFN-γ receptor in the host in murine immune-mediated BM failure models. TNF-α has been assumed to function similarly to IFN-γ. We used our murine models and mice genetically deficient in TNF-α or TNF-α receptors (TNF-αRs) to establish an analogous mechanism. Unexpectedly, infusion of TNF-α-/- donor lymph node (LN) cells into CByB6F1 recipients or injection of FVB LN cells into TNF-αR-/- recipients both induced BM failure, with concurrent marked increases in plasma IFN-γ and TNF-α levels. Surprisingly, in TNF-α-/- recipients, BM damage was attenuated, suggesting that TNF-α of host origin was essential for immune destruction of hematopoiesis. Depletion of host macrophages before LN injection reduced T-cell IFN-γ levels and reduced BM damage, whereas injection of recombinant TNF-α into FVB-LN cell-infused TNF-α-/- recipients increased T-cell IFN-γ expression and accelerated BM damage. Furthermore, infusion of TNF-αR-/- donor LN cells into CByB6F1 recipients reduced BM T-cell infiltration, suppressed T-cell IFN-γ production, and alleviated BM destruction. Thus, TNF-α from host macrophages and TNF-αR expressed on donor effector T cells were critical in the pathogenesis of murine immune-mediated BM failure, acting by modulation of IFN-γ secretion. In AA patients, TNF-α-producing macrophages in the BM were more frequent than in healthy controls, suggesting the involvement of this cytokine and these cells in human disease.

Long-Term Effects of High Exposure to Ambient Fine Particulate Matter on Coronary Heart Disease Incidence: A Population-Based Chinese Cohort Study.

Evidence of long-term effects of high exposure to ambient fine particulate matter (PM2.5) on coronary heart disease (CHD) remains limited. We incorporated the high-resolution satellite-based PM2.5 estimates with a large-scale, population-based Chinese cohort comprising 118 229 individuals, to assess the CHD risk of long-term exposure to high PM2.5. During the follow-up of 908 376 person-years, 1586 incident CHD cases were identified. The long-term average PM2.5 concentration for study population was 64.96 µg/m3, ranging from 31.17 to 96.96 µg/m3. For an increment of 10 µg/m3 in PM2.5, the multivariate-adjusted hazard ratios (HRs) were 1.43 (95% confidence interval [CI]: 1.35-1.51) for total CHD, 1.45 (95% CI: 1.36-1.56) for nonfatal CHD, and 1.38 (95% CI: 1.25-1.53) for fatal CHD, respectively. The effects were different across specific CHD outcomes, with greater effects for unstable angina (HR, 1.71 [95% CI, 1.56-1.88]), and weaker effects for acute myocardial infarction (HR, 1.28 [95% CI, 1.19-1.39]) and other CHD (HR, 1.27 [95% CI, 1.10-1.48]). The exposure-response curve suggested that HRs increased with elevated PM2.5 concentration over the entire exposure range. Elderly and hypertensive individuals were more susceptible to PM2.5-induced CHD. Our findings demonstrate the adverse health effects of severe air pollution and highlight the potential health benefits of air quality improvement.

Sex-Specific Association of Blood Pressure Categories With All-Cause Mortality: The Rural Chinese Cohort Study.

INTRODUCTION: The relationship between blood pressure categories and all-cause mortality has not been fully addressed in cohort studies, especially in the general Chinese population. Our study aimed to assess the sex-specific association of systolic blood pressure (SBP), diastolic blood pressure (DBP), and 2017 United States hypertension guidelines with all-cause mortality in China. METHODS: We conducted a prospective study of 13,760 rural Chinese adults aged 18 or older (41.1% men). Mean age overall was 49.4, 51.0 for men, and 48.3 for women. We analyzed the blood pressure-mortality relationship by using restricted cubic splines and Cox proportional-hazards regression analysis, estimating hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: During a mean follow-up of 5.95 years, 710 people died (60.3% men) from any cause. We found a U-shaped SBP-mortality or DBP-mortality relationship for both sexes. Mortality risk was increased for men with SBP 120-139 mm Hg (adjusted HR [aHR], 1.42; 95% CI, 1.10-1.82) or ≥140 mm Hg (aHR, 2.05; 95% CI, 1.54-2.72), and for DBP ≥90 mm Hg (aHR, 1.53; 95% CI, 1.10-2.13) as compared with SBP 100-119 mm Hg or DBP 70-79 mm Hg. Mortality risk also was increased for men with blood pressure status defined according to 2017 US hypertension guidelines as elevated, SBP 120-129 and DBP >80 mm Hg (aHR 1.48; 95% CI,1.11-1.98); stage 1 hypertension, SBP/DBP 130-139/80-89 mm Hg (aHR 1.53; CI, 1.19-1.97); and stage 2 hypertension, SBP/DBP ≥140/90 mm Hg (aHR 1.83; CI, 1.33-2.51). No significant relationship was observed for women. CONCLUSION: Elevated blood pressure and stages 1 and 2 hypertension were positively associated with all-cause mortality for men but not women in rural China.

Conventional Co-Housing Modulates Murine Gut Microbiota and Hematopoietic Gene Expression.

Specific-pathogen-free (SPF) mice have improved hematopoietic characteristics relative to germ-free mice, however, it is not clear whether improvements in hematopoietic traits will continue when the level of microorganism exposure is further increased. We co-housed SPF C57BL/6 mice in a conventional facility (CVT) and found a significant increase in gut microbiota diversity along with increased levels of myeloid cells and T cells, especially effector memory T cells. Through single cell RNA sequencing of sorted KL (c-Kit+Lin-) cells, we imputed a decline in long-term hematopoietic stem cells and an increase in granulocyte-monocyte progenitors in CVT mice with up-regulation of genes associated with cell survival. Bone marrow transplantation through competitive repopulation revealed a significant increase in KSL (c-Kit+Sca-1+Lin-) cell reconstitution in recipients of CVT donor cells which occurred when donors were co-housed for both one and twelve months. However, there was minimal to no gain in mature blood cell engraftment in recipients of CVT donor cells relative to those receiving SPF donor cells. We conclude that co-housing SPF mice with mice born in a conventional facility increased gut microbiota diversity, augmented myeloid cell production and T cell activation, stimulated KSL cell reconstitution, and altered hematopoietic gene expression.

Association of Lipids With Ischemic and Hemorrhagic Stroke: A Prospective Cohort Study Among 267 500 Chinese.

Background and Purpose- Previous results on the association between lipids and stroke were controversial. We investigated the association of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C ), high-density lipoprotein cholesterol (HDL-C), and triglyceride with stroke. Methods- Six cohort studies in China with 267 500 participants were included. Cox proportional hazards regression models and restricted cubic spline analyses were used to estimate hazard ratios and 95% CIs and explore linear and nonlinear relationships of lipids and stroke, respectively. Results- The median follow-up duration ranged from 6 to 19 years. During 2 295 881 person-years, 8072 people developed stroke. Multivariable adjusted hazard ratios (95% CIs) per 1 mmol/L increase in TC, LDL-C, triglyceride were 1.08 (1.05-1.11), 1.08 (1.04-1.11), 1.07 (1.05-1.09) for ischemic stroke, respectively. Compared with participants with TC 160-199.9 mg/dL, hazard ratios (95% CIs) were 1.43 (1.11-1.85) for hemorrhagic stroke in those with TC <120 mg/dL. Compared with participants with HDL-C 50 to 59.9 mg/dL, hazard ratios (95% CIs) were 1.23 (1.12-1.35), 1.13 (1.04-1.22) for ischemic stroke, and 1.28 (1.10-1.49), 1.17 (1.03-1.33) for hemorrhagic stroke in those with HDL-C <40 and 40 to 49.9 mg/dL, respectively. Restricted cubic spline analyses showed linear relationships of TC and LDL-C, and nonlinear relationships of HDL-C and triglyceride with ischemic stroke (all P<0.001). Hemorrhagic stroke showed linear relationships with TC and HDL-C (P=0.029 and <0.001 respectively), but no relationship with LDL-C and triglyceride (all P>0.05). Conclusions- TC, LDL-C, and triglyceride showed positive associations with ischemic stroke. The risk of hemorrhagic stroke was higher when TC was lower than 120 mg/dL. LDL-C and triglyceride showed no association with hemorrhagic stroke. The risks of ischemic and hemorrhagic stroke might be higher when HDL-C was lower than 50 mg/dL.

Predicting 10-Year and Lifetime Stroke Risk in Chinese Population.

Background and Purpose- Risk assessment is essential for the primary prevention of stroke. However, the current available tools derived from Chinese populations are insufficient for individualized 10-year and lifetime stroke risk prediction. Our study aims to develop and validate personalized 10-year and lifetime stroke risk equations incorporating 4 large Chinese cohorts. Methods- We used 2 prospective cohorts of 21 320 participants with similar survey protocols as the derivation cohort to develop sex-specific 10-year and lifetime stroke risk equations. Two other independent cohorts with 14 123 and 70 838 participants were used for external validation. In addition, the performance of the 10-year stroke risk equations among participants aged ≥55 years was compared with the new Framingham Stroke Risk Profile. Results- The sex-specific equations for predicting 10-year stroke risk had C statistics being 0.810 for men and 0.810 for women, with calibration χ2 being 15.0 (P=0.092) and 7.8 (P=0.550), respectively. The lifetime stroke risk equations also showed C statistics around 0.800 and calibration χ2 below 20 for both sexes. In the validation cohorts, we found good agreement between the observed and predicted stroke probabilities for both the 10-year and lifetime stroke risk equations. Further compared with the new Framingham Stroke Risk Profile, our 10-year stroke risk equations displayed better prediction capability. In addition, based on lifetime stroke risk assessment, 5.7% of study participants aged 35 to 49 years old were further reclassified as high risk, who were initially categorized as low 10-year risk. Conclusions- We developed a well-performed tool for predicting personalized 10-year and lifetime stroke risk among the Chinese adults, which will facilitate the further identification of high-risk individuals and community-based stroke prevention in China.