Background: Endothelial dysfunction plays a critical role in the development of sepsis-related organ failure; however, the mechanisms that govern its development are not fully understood. Endothelial progenitor cells (EPCs) reduce vascular leak and organ failure in experimental sepsis while modulating plasma expression of microRNA (miRNA). MicroRNAs are small, noncoding segments of RNA that regulate gene expression and are known to modulate endothelial cell function and inflammatory signaling pathways. We hypothesized that miRNA may play an etiologic role in the endothelial dysfunction of sepsis and that their extracellular expression levels would be altered in those with shock. Methods: Thirteen miRNAs were identified by literature search and analysis of the contents of human EPC-derived exosomes using real-time PCR. Plasma samples were obtained from patients within 24 hours of their admission to ICUs with severe sepsis (n = 62) and from healthy controls (n = 32) and real-time PCR was used to measure the expression of the candidate miRNAs. The Wilcoxon rank sum test was used to compare expression levels of the 13 candidate miRNAs in septic patients with (n = 29) and without (n = 33) shock while logistic regression was used to determine the area under the curve for associations between miRNA expression and shock. Bioinformatic analyses using miRNA databases were performed to identify pathways and gene targets of differentially expressed miRNA with potential relevance to sepsis-related shock. Results: MiRNA-34a expression was significantly increased in the group who developed shock (p = 0.03) while miR-15a and miR-27a expressions were significantly decreased in this group (p = 0.006 and 0.03, respectively). The combined expression of these three miRNAs predicted shock with an area under the curve of 0.78 (95 % CI 0.66–0.90). In silico analyses predict that these three miRNAs regulate genes involved in endothelial cell cycle, apoptosis, VEGF signaling, LPS-stimulated MAPK signaling, and nuclear factor kappa B signaling. Conclusions: The plasma levels of miRNA are altered in patients with severe sepsis complicated by shock and may offer prognostic value as well as insights into the mechanisms of endothelial dysfunction in sepsis.

Amyloid plaques and neurofibrillary tangles, the molecular lesions that characterize Alzheimer’s disease (AD) and other forms of dementia, are emerging as determinants of proteinopathies ‘beyond the brain’. This study aims to establish tau’s putative pathophysiological mechanistic roles and potential future therapeutic targeting of tau in heart failure (HF). A mouse model of tauopathy and human myocardial and brain tissue from patients with HF, AD, and controls was employed in this study. Tau protein expression was examined together with its distribution, and in vitro tau-related pathophysiological mechanisms were identified using a variety of biochemical, imaging, and functional approaches. A novel tau-targeting immunotherapy was tested to explore tau-targeted therapeutic potential in HF. Tau is expressed in normal and diseased human hearts, in contradistinction to the current oft-cited observation that tau is expressed specifically in the brain. Notably, the main cardiac isoform is high-molecular-weight (HMW) tau (also known as big tau), and hyperphosphorylated tau segregates in aggregates in HF and AD hearts. As previously described for amyloid-beta, the tauopathy phenotype in human myocardium is of diastolic dysfunction. Perturbation in the tubulin code, specifically a loss of tyrosinated microtubules, emerged as a potential mechanism of myocardial tauopathy. Monoclonal anti-tau antibody therapy improved myocardial function and clearance of toxic aggregates in mice, supporting tau as a potential target for novel HF immunotherapy. The study presents new mechanistic evidence and potential treatment for the brain–heart tauopathy axis in myocardial and brain degenerative diseases and ageing. Tangle-like aggregates of hyperphosphorylated tau are present in the heart of patients with dilated cardiomyopathy or Alzheimer’s disease. A mouse model of tauopathy recapitulates the pathological findings of the human disease. Disruption of microtubule de/tyrosination causes myocardial diastolic dysfunction observed in the mouse model, and it can be targeted with immunotherapy. Abbreviations: iDCM, idiopathic dilated cardiomyopathy; PAO, pre-amyloid oligomers; TOMA, tau oligomer monoclonal antibody.

Dichotomization of continuous variables to discriminate a dichotomous outcome is often useful in statistical applications. If a true threshold for a continuous variable exists, the challenge is identifying it. This paper examines common methods for dichotomization to identify which ones recover a true threshold. We provide mathematical and numeric proofs demonstrating that maximizing the odds ratio, Youden’s statistic, Gini Index, chi-square statistic, relative risk and kappa statistic all theoretically recover a true threshold. A simulation study evaluating the ability of these statistics to recover a threshold when sampling from a population indicates that maximizing the chi-square statistic and Gini Index have the smallest bias and variability when the probability of being larger than the threshold is small while maximizing Kappa or Youden’s statistics is best when this probability is larger. Maximizing odds ratio is the most variable and biased of the methods.

Importance: The association between degree of neighborhood deprivation and primary hypertension diagnosis in youth remains understudied.Objective: To assess the association between neighborhood measures of deprivation and primary hypertension diagnosis in youth.Design, Setting, and Participants: This cross-sectional study included 65 452 Delaware Medicaid-insured youths aged 8 to 18 years between January 1, 2014, and December 31, 2019. Residence was geocoded by national area deprivation index (ADI).Exposures: Higher area deprivation.Main Outcomes and Measures: The main outcome was primary hypertension diagnosis based on International Classification of Diseases, Ninth Revision and Tenth Revision codes. Data were analyzed between September 1, 2021, and December 31, 2022.Results: A total of 65 452 youths were included in the analysis, including 64 307 (98.3%) without a hypertension diagnosis (30 491 [47%] female and 33 813 [53%] male; mean [SD] age, 12.5 (3.1) years; 12 500 [19%] Hispanic, 25 473 [40%] non-Hispanic Black, 24 565 [38%] non-Hispanic White, and 1769 [3%] other race or ethnicity; 13 029 [20%] with obesity; and 31 548 [49%] with an ADI ≥50) and 1145 (1.7%) with a diagnosis of primary hypertension (mean [SD] age, 13.3 [2.8] years; 464 [41%] female and 681 [59%] male; 271 [24%] Hispanic, 460 [40%] non-Hispanic Black, 396 [35%] non-Hispanic White, and 18 [2%] of other race or ethnicity; 705 [62%] with obesity; and 614 [54%] with an ADI ≥50). The mean (SD) duration of full Medicaid benefit coverage was 61 (16) months for those with a diagnosis of primary hypertension and 46.0 (24.3) months for those without. By multivariable logistic regression, residence within communities with ADI greater than or equal to 50 was associated with 60% greater odds of a hypertension diagnosis (odds ratio [OR], 1.61; 95% CI 1.04-2.51). Older age (OR per year, 1.16; 95%, CI, 1.14-1.18), an obesity diagnosis (OR, 5.16; 95% CI, 4.54-5.85), and longer duration of full Medicaid benefit coverage (OR, 1.03; 95% CI, 1.03-1.04) were associated with greater odds of primary hypertension diagnosis, whereas female sex was associated with lower odds (OR, 0.68; 95%, 0.61-0.77). Model fit including a Medicaid-by-ADI interaction term was significant for the interaction and revealed slightly greater odds of hypertension diagnosis for youths with ADI less than 50 (OR, 1.03; 95% CI, 1.03-1.04) vs ADI ≥50 (OR, 1.02; 95% CI, 1.02-1.03). Race and ethnicity were not associated with primary hypertension diagnosis.Conclusions and Relevance: In this cross-sectional study, higher childhood neighborhood ADI, obesity, age, sex, and duration of Medicaid benefit coverage were associated with a primary hypertension diagnosis in youth. Screening algorithms and national guidelines may consider the importance of ADI when assessing for the presence and prevalence of primary hypertension in youth.