Background Extracellular microRNAs (miRNAs) embedded in circulating exosomes may serves as prognostic biomarkers in cancer. Objective To identify and evaluate plasma exosomal miRNAs for prognosis in castration-resistant prostate cancer (CRPC). Design, setting, and participants RNA sequencing was performed to identify candidate exosomal miRNAs associated with overall survival in a screening cohort of 23 CRPC patients. Candidate miRNAs were further evaluated for prognosis using quantitative real-time polymerase chain reaction in a follow-up cohort of 100 CRPC patients. Outcome measurements and statistical analysis Cox regression and Kaplan-Meier survival analyses were used to evaluate survival association using candidate miRNAs along with clinical prognostic factors. Results and limitations RNA sequencing in screening cohort generated approximately 6.80 million mappable reads per patient. Of those with normalized read counts ≥5, 43% were mapped to miRNAs for a total of 375 known and 57 novel miRNAs. Cox regression analysis identified an association of miR-1290, -1246, and -375 with overall survival (false discover rate <0.05). Of those, higher levels of miR-1290 and -375 were significantly associated with poor overall survival (p < 0.004) in the follow-up cohort. Incorporation of miR-1290/-375 into putative clinical prognostic factors-based models in CRPC stage significantly improved predictive performance with a time-dependent area under the curve increase from 0.66 to 0.73 (p = 6.57 × 10−6). Conclusions Plasma exosomal miR-1290 and miR-375 are promising prognostic biomarkers for CRPC patients. Prospective validation is needed for further development of these candidate miRNAs. Patient summary In this study, we evaluated whether small RNAs circulating in blood could be used to predict clinical outcomes in late-stage prostate cancer patients. We identified two blood-based small RNAs whose levels showed significant association with survival. Our results warrant further investigation because the noninvasive blood-based test has great potential in the management of late-stage prostate cancer.

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Peripheral artery disease is an atherosclerotic disease of the lower extremities associated with high cardiovascular mortality. Management of this condition may include lifestyle modifications, medical management, endovascular repair, or surgery. The medical approach to peripheral artery disease is multifaceted and includes cholesterol reduction, antiplatelet therapy, anticoagulation, peripheral vasodilators, blood pressure management, exercise therapy, and smoking cessation. Adherence to this regimen can reduce limb-related complications like critical limb ischemia and amputation, as well as systemic complications of atherosclerosis like stroke and myocardial infarction. Relative to coronary artery disease, peripheral artery disease is an undertreated condition. In this article, we explore the evidence behind medical therapies for the management of peripheral artery disease.

Symptomatic severe aortic stenosis is associated with high mortality rates, up to 50% at 1 year, 1 and the prevalence will likely increase as the population ages. 2 Until recently, surgical valve replacement was the only durable therapeutic option; however, many older patients with aortic stenosis have prohibitive surgical risk. Transcatheter aortic valve replacement (TAVR) has emerged as an option for these patients and, more recently, for patients with high and moderate surgical risk. We identified trends in mortality due to aortic stenosis, considering these recent therapeutic advances.

Summary Particulate matter ≤2.5μm (PM 2.5 ) air pollution is a leading environmental risk factor contributing disproportionately to the global burden of non-communicable disease. We compared impact of chronic exposure to PM 2.5 alone, or with light at night exposure (LL) on metabolism. PM 2.5 induced peripheral insulin resistance, circadian rhythm (CR) dysfunction, and metabolic and brown adipose tissue (BAT) dysfunction, akin to LL (with no additive interaction between PM 2.5 and LL). Transcriptomic analysis of liver and BAT revealed widespread but unique alterations in CR genes, with evidence for differentially accessible promoters and enhancers of CR genes in response to PM 2.5 by ATAC-seq. The histone deacetylases 2, 3, and 4 were downregulated with PM 2.5 exposure, with increased promoter occupancy by the histone acetyltransferase p300 as evidenced by ChIP-seq. These findings suggest a previously unrecognized role of PM 2.5 in promoting CR disruption and metabolic dysfunction through epigenetic regulation of circadian targets.

Ambient air pollution due to particulate matter ≤2.5 μ is the leading environmental risk factor contributing to global mortality, with a preponderant majority of these deaths attributable to atherosclerotic cardiovascular disease (ASCVD) causes such as stroke and myocardial infarction. Epidemiological studies in humans have provided refined estimates of exposure risk, with evidence suggesting that risk association with particulate matter ≤2.5 levels and ASCVD continues at levels well below air quality guidelines in North America and Europe. Mechanistic studies in animals and humans have provided a framework of understanding of the duration and pathways by which air pollution exposure may predispose to atherosclerosis. Although acute exposure to particulate matter ≤2.5 is associated with oxidative stress and inflammation, system transmission of signals from the lungs to extrapulmonary sites may involve direct translocation of components, biologic intermediates, and autonomic nervous system activation. End-organ effector pathways such as endothelial barrier disruption/dysfunction, thrombosis, vasoconstriction/increased blood pressure, and plaque instability, may contribute to ASCVD. The strength of the association of air pollution with ASCVD offers an opportunity to mitigate its consequences. Although elimination of anthropogenic sources of air pollution with a switch to clean energy provides the ultimate solution, this may not be possible in the interim and may require personal protection efforts and an integrated approach to managing risk posed by air pollution for ASCVD.

We believe that this was accomplished: two random strains of E coli would probably not show the degree of identity found in our tests. E coli adheres to uroepithelium by pili, which are protein filaments on its surface. They are of two types, depending on whether adhesion is inhibited by mannose (mannose-sensitive) or not (mannoseresistant). The E coli strains produced only mannose-resistant pili, and such strains are found in only 26% ofunselected cases of significant E coli bacteriuria (Abraham et al, in preparation). Symptomatic urinary tract infection correlates highly with isolation of such strains. 2 We assumed that our patient had unwittingly ingested E coli SP88, that her intestinal tract had thus become colonised, and that her urinary tract infection had come about by the accepted ascending route.3 We were unable to find E coli with the required characteristics in her faecal flora. We cannot exclude that she had transferred the infecting strain to the introitus from her fingers. Nevertheless our observations suggest that E coli SP88 is highly virulent for the urinary tract and that mannose-resistant pili may be a long-sought colonisation and virulence factor of E coli in the urinary tract.