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With the continued rise of the global incidence of COVID-19 infection and emergent second wave, the need to understand characteristics that impact susceptibility to infection, clinical severity, and outcomes remains vital. The objective of this study was to assess modifying effects of demographic factors on COVID-19 testing status and outcomes in a large, diverse single health system cohort. The Mount Sinai Health System de-identified COVID-19 database contained records of 39,539 patients entering the health system from 02/28/2020 to 06/08/2020 with 7,032 laboratory-confirmed cases. The prevalence of qRT-PCR nasopharyngeal swabs (χ 2 = 665.7, p<0.0001) and case rates (χ 2 = 445.3, p<0.0001) are highest in Hispanics and Black or African Americans. The likelihood of admission and/or presentation to an intensive care unit (ICU) versus non-ICU inpatient unit, emergency department, and outpatient services, which reflects the severity of the clinical course, was also modified by race and ethnicity. Females were less likely to be tested [Relative Risk(RR) = 1.121, p<0.0001], and males had a higher case prevalence (RR = 1.224, p<0.001). Compared to other major ethnic groups, Whites experienced a higher prevalence of mortality (p<0.05). Males experienced a higher risk of mortality (RR = 1.180, p = 0.0012) at relatively younger ages (70.58±11.75) compared to females (73.02±11.46) (p = 0.0004). There was an increased severity of disease in older patient populations of both sexes. Although Hispanic and Black or African American race was associated with higher testing prevalence and positive testing rates, the only disparity with respect to mortality was a higher prevalence in Whites.

With the continuing rise of SARS-CoV2 infection globally and the emergence of various waves in different countries, understanding characteristics of susceptibility to infection, clinical severity, and outcomes remain vital. In this retrospective study, data was extracted for 39,539 patients from the de-identified Mount Sinai Health System COVID-19 database. We assessed the risk of mortality based on the presence of comorbidities and organ-specific sequelae in 7,032 CoV2 positive (+) patients. Prevalence of cardiovascular and metabolic comorbidities was high among SARS-CoV2+ individuals. Diabetes, obesity, coronary artery disease, hypertension, atrial fibrillation, and heart failure all increased overall mortality risk, while asthma did not. Ethnicity modified the risk of mortality associated with these comorbidities. With regards to secondary complications in the setting of infection, individuals with acute kidney injury and acute myocardial injury showed an increase in mortality risk. Cerebral infarcts and acute venous thromboembolic events were not associated with increased risk of mortality. Biomarkers for cardiovascular injury, coagulation, and inflammation were compared between deceased and survived individuals. We found that cardiac and coagulation biomarkers were elevated and fell beyond normal range more often in deceased patients. Several, but not all, inflammatory markers evaluated were increased in deceased patients. In summary, we identified comorbidities and sequelae along with peripheral blood biomarkers that were associated with elevated clinical severity and poor outcomes in COVID-19 patients. Overall, these findings detail the granularity of previously reported factors which may impact susceptibility, clinical severity, and mortality during the course of COVID-19 disease.

The Western diet (WD) has been linked to various structural and functional alterations in the left ventricle (LV), but the molecular response of the right ventricle (RV) remains largely unknown. Given the RV’s distinct anatomical and functional characteristics, it is crucial to understand how long-term WD exposure affects RV gene expression, especially in a sex-specific context. Our objective was to perform gene expression profiling of the RV late responses to WD in wild-type mice. Male and female C57BL/6J mice were fed a WD for 125 days from 300 to 425 days of age, and RV tissues were collected at 530 and 640/750 (female/male) days. mRNA sequencing was performed on RV tissues to identify differentially expressed genes (DEGs) between WD-fed and normal diet (ND)-fed groups. Data processing and analysis were conducted using the STAR aligner and DESeq2. WD-induced RV transcriptomic changes were characterized by differential expression of genes associated with cardiac remodeling and transcriptional regulation in both sexes. In females, additional genes showing altered expression were associated with immune response, whereas in males, changes were more limited, primarily involving genes related to circadian rhythm and cardiac remodeling. Echocardiography revealed modest, sex-specific differences: WD-fed females showed a decrease in right-ventricular internal diameter in diastole and a trend toward increased pulmonary trunk diameter, whereas males showed no notable changes. These exploratory results suggest that WD is associated with modest transcriptomic changes in the RV in both sexes, with only minor structural differences observed in females, indicating subtle sex-specific effects after a switch to normal chow.

Space irradiation (IR) is an important health risk for deep-space missions. We reported heart failure with preserved ejection fraction like cardiac phenotype 660-days following exposure to a single-dose of a simplified galactic cosmic ray simulation (simGCRsim) only in males with functional and structural impairment in left ventricular (LV) function. This sex-based dichotomy prompted us to investigate sex-specific changes in the LV transcriptome in three-month-old male and female mice exposed to 137 Cs-γ- or simGCRsim-IR. Non-IR male and female (10 each) mice served as controls. LVs were collected at 440/660- and 440/550-days post-IR, male and female, respectively. RNA sequencing, differential gene expression, and functional annotation were performed on tissues from 5 mice/group. Sex and post-IR time points had the greatest influence on gene expression, surpassing the IR-type effects. SimGCRsim-IR showed more persistent transcriptome changes than γ-IR. We suggest that the single IR effects can persist up to 550–660 days, with overwhelmingly sex-biased responses at individual gene expression level.

Background Long-term consumption of Western Diet (WD) is a well-established risk factor for the development of cardiovascular disease (CVD); however, there is a paucity of studies on the long-term effects of WD on the pathophysiology of CVD and sex-specific responses. Methods Our study aimed to investigate the sex-specific pathophysiological changes in left ventricular (LV) function using transthoracic echocardiography (ECHO) and LV tissue transcriptomics in WD-fed C57BL/6 J mice for 125 days, starting at the age of 300 through 425 days. Results In female mice, consumption of the WD diet showed long-term effects on LV structure and possible development of HFpEF-like phenotype with compensatory cardiac structural changes later in life. In male mice, ECHO revealed the development of an HFrEF-like phenotype later in life without detectable structural alterations. The transcriptomic profile revealed a sex-associated dichotomy in LV structure and function. Specifically, at 530-day, WD-fed male mice exhibited differentially expressed genes (DEGs), which were overrepresented in pathways associated with endocrine function, signal transduction, and cardiomyopathies. At 750 days, WD-fed male mice exhibited dysregulation of several genes involved in various lipid, glucagon, and glutathione metabolic pathways. At 530 days, WD-fed female mice exhibited the most distinctive set of DEGs with an abundance of genes related to circadian rhythms. At 640 days, altered DEGs in WD-fed female mice were associated with cardiac energy metabolism and remodeling. Conclusions Our study demonstrated distinct sex-specific and age-associated differences in cardiac structure, function, and transcriptome signature between WD-fed male and female mice. Graphical Abstract

With planned deep space and commercial spaceflights, gaps remain to address health risks in astronauts. Multiple studies have shown associations between clonal expansion of hematopoietic cells with hematopoietic malignancies and cardiometabolic disease. This expansion of clones in the absence of overt hematopoietic disorders is termed clonal hematopoiesis (CH) of indeterminate potential (CHIP). Using deep, error-corrected, targeted DNA sequencing we assayed for somatic mutations in CH-driver genes in peripheral blood mononuclear cells isolated from de-identified blood samples collected from 14 astronauts who flew Shuttle missions between 1998–2001. We identified 34 nonsynonymous mutations of relatively low variant allele fraction in 17 CH-driver genes, with the most prevalent mutations in TP53 and DNMT3A . The presence of these small clones in the blood of relatively young astronaut cohort warrants further retrospective and prospective investigation of their clinical relevance and potential application in monitoring astronaut’s health. Deep targeted DNA sequencing of peripheral blood mononuclear cells isolated from blood samples from 14 astronauts who flew Shuttle missions between 1998–2001 identifies 34 non-silent mutations, predominantly in TP53 and DNMT3A.

Deep space represents a challenging environment for human exploration and can be accompanied by harmful health-related risks. We aimed to assess the effect of simplified galactic cosmic ray simulated (simGCRsim) and gamma (γ) ionizing radiation (IR) on transcriptome changes in right ventricular (RV) tissue after a single low dose (0.5 Gy, 500 MeV/nucleon) full body exposure in C57BL/6J male and female mice. In females, no differentially expressed genes (DEGs) and only 2 upregulated genes in males exposed to γ-IR were revealed. In contrast, exposure to simGCRsim-IR resulted in 4 DEGs in females and 371 DEGs in males, suggesting longer-lasting and sex-biased DEGs after simGCRsim-IR. Overrepresentation analysis of DEGs in simGCRsim-IR males revealed significant enrichment in pathways related to muscle contraction, hypertrophic cardiomyopathy, oxytocin release, the regulation of cytoskeleton, and genes associated with Alzheimer’s, Huntington’s, and Parkinson’s diseases. Our results suggested the RV transcriptome exhibits distinct responses after exposure based on both the IR and sex.

Compared to low doses of gamma irradiation (γ-IR), high-charge-and-energy (HZE) particle IR may have different biological response thresholds in cardiac tissue at lower doses, and these effects may be IR type and dose dependent. Three- to four-month-old female CB6F1/Hsd mice were exposed once to one of four different doses of the following types of radiation: γ-IR 137Cs (40-160 cGy, 0.662 MeV), 14Si-IR (4-32 cGy, 260 MeV/n), or 22Ti-IR (3-26 cGy, 1 GeV/n). At 16 months post-exposure, animals were sacrificed and hearts were harvested and archived as part of the NASA Space Radiation Tissue Sharing Forum. These heart tissue samples were used in our study for RNA isolation and microarray hybridization. Functional annotation of twofold up/down differentially expressed genes (DEGs) and bioinformatics analyses revealed the following: (i) there were no clear lower IR thresholds for HZE- or γ-IR; (ii) there were 12 common DEGs across all 3 IR types; (iii) these 12 overlapping genes predicted various degrees of cardiovascular, pulmonary, and metabolic diseases, cancer, and aging; and (iv) these 12 genes revealed an exclusive non-linear DEG pattern in 14Si- and 22Ti-IR-exposed hearts, whereas two-thirds of γ-IR-exposed hearts revealed a linear pattern of DEGs. Thus, our study may provide experimental evidence of excess relative risk (ERR) quantification of low/very low doses of full-body space-type IR-associated degenerative disease development.

Of note, sRNAseq was performed using RNA isolated from sEVs of 14 astronauts, while qPCR analysis could only be performed on seven astronauts due to the exceptionally rare sample availability. [...]out of an abundance of caution, we narrowed our focus to hsa-miR-4732-3p, which displayed significant regulation at R+3 compared to L-10 by qPCR. [...]we extended our analysis to determine potential diseases that hsa-miR-4732-3p may be involved. [...]our data suggest that short LEO spaceflight induced significant changes in plasma-derived sEV miRNA content and identified hsa-miR-4732-3p to be significantly upregulated post-flight.