Primary aldosteronism (PA) is the most common form of secondary hypertension. In many cases, somatic mutations in ion channels and pumps within adrenal cells initiate the pathogenesis of PA, and this ...mechanism might explain why PA is so common and suggests that milder and evolving forms of PA must exist. Compared with primary hypertension, PA causes more end-organ damage and is associated with excess cardiovascular morbidity, including heart failure, stroke, nonfatal myocardial infarction, and atrial fibrillation. Screening is simple and readily available, and targeted therapy improves blood pressure control and mitigates cardiovascular morbidity. Despite these imperatives, screening rates for PA are low, and mineralocorticoid-receptor antagonists are underused for hypertension treatment. After the evidence for the prevalence of PA and its associated cardiovascular morbidity is summarized, a practical approach to PA screening, referral, and management is described. All physicians who treat hypertension should routinely screen appropriate patients for PA.
Urine is commonly used for clinical diagnosis and biomedical research. The discovery of extracellular vesicles (EV) in urine opened a new fast‐growing scientific field. In the last decade urinary ...extracellular vesicles (uEVs) were shown to mirror molecular processes as well as physiological and pathological conditions in kidney, urothelial and prostate tissue. Therefore, several methods to isolate and characterize uEVs have been developed. However, methodological aspects of EV separation and analysis, including normalization of results, need further optimization and standardization to foster scientific advances in uEV research and a subsequent successful translation into clinical practice. This position paper is written by the Urine Task Force of the Rigor and Standardization Subcommittee of ISEV consisting of nephrologists, urologists, cardiologists and biologists with active experience in uEV research. Our aim is to present the state of the art and identify challenges and gaps in current uEV‐based analyses for clinical applications. Finally, recommendations for improved rigor, reproducibility and interoperability in uEV research are provided in order to facilitate advances in the field.
Numerous publications describe the clinical manifestations of post-acute sequelae of SARS-CoV-2 (PASC or “long COVID”), but they are difficult to integrate because of heterogeneous methods and the ...lack of a standard for denoting the many phenotypic manifestations. Patient-led studies are of particular importance for understanding the natural history of COVID-19, but integration is hampered because they often use different terms to describe the same symptom or condition. This significant disparity in patient versus clinical characterization motivated the proposed ontological approach to specifying manifestations, which will improve capture and integration of future long COVID studies.
The Human Phenotype Ontology (HPO) is a widely used standard for exchange and analysis of phenotypic abnormalities in human disease but has not yet been applied to the analysis of COVID-19.
We identified 303 articles published before April 29, 2021, curated 59 relevant manuscripts that described clinical manifestations in 81 cohorts three weeks or more following acute COVID-19, and mapped 287 unique clinical findings to HPO terms. We present layperson synonyms and definitions that can be used to link patient self-report questionnaires to standard medical terminology. Long COVID clinical manifestations are not assessed consistently across studies, and most manifestations have been reported with a wide range of synonyms by different authors. Across at least 10 cohorts, authors reported 31 unique clinical features corresponding to HPO terms; the most commonly reported feature was Fatigue (median 45.1%) and the least commonly reported was Nausea (median 3.9%), but the reported percentages varied widely between studies.
Translating long COVID manifestations into computable HPO terms will improve analysis, data capture, and classification of long COVID patients. If researchers, clinicians, and patients share a common language, then studies can be compared/pooled more effectively. Furthermore, mapping lay terminology to HPO will help patients assist clinicians and researchers in creating phenotypic characterizations that are computationally accessible, thereby improving the stratification, diagnosis, and treatment of long COVID.
U24TR002306; UL1TR001439; P30AG024832; GBMF4552; R01HG010067; UL1TR002535; K23HL128909; UL1TR002389; K99GM145411.
mRNA is a critical biomolecule involved in the manifestation of the genetic code into functional protein molecules. Its critical role in the central dogma has made it a key target in many studies to ...determine biomarkers and drug targets for numerous diseases. Currently, there is a growing body of evidence to suggest that RNA molecules around the size of full-length mRNA transcripts can be assayed in the supernatant of human urine and urinary extracellular mRNA could provide information about transcription in cells of urogenital tissues. However, the optimal means of normalizing these signals is unclear. In this paper, we describe relevant first principles as well as research findings from our lab and other labs toward normalization of urinary extracellular mRNA.
Multiple methodologies have been developed to identify and predict adverse events (AEs); however, many of these methods do not consider how patient population characteristics, such as diseases, age, ...and gender, affect AEs seen. In this study, we evaluated the utility of collecting and analyzing AE data related to hydroxychloroquine (HCQ) and chloroquine (CQ) from US Prescribing Information (USPIs, also called drug product labels or package inserts), the FDA Adverse Event Reporting System (FAERS), and peer-reviewed literature from PubMed/EMBASE, followed by AE classification and modeling using the Ontology of Adverse Events (OAE). Our USPI analysis showed that CQ and HCQ AE profiles were similar, although HCQ was reported to be associated with fewer types of cardiovascular, nervous system, and musculoskeletal AEs. According to EMBASE literature mining, CQ and HCQ were associated with QT prolongation (primarily when treating COVID-19), heart arrhythmias, development of Torsade des Pointes, and retinopathy (primarily when treating lupus). The FAERS data was analyzed by proportional ratio reporting, Chi-square test, and minimal case number filtering, followed by OAE classification. HCQ was associated with 63 significant AEs (including 21 cardiovascular AEs) for COVID-19 patients and 120 significant AEs (including 12 cardiovascular AEs) for lupus patients, supporting the hypothesis that the disease being treated affects the type and number of certain CQ/HCQ AEs that are manifested. Using an HCQ AE patient example reported in the literature, we also ontologically modeled how an AE occurs and what factors (e.g., age, biological sex, and medical history) are involved in the AE formation. The methodology developed in this study can be used for other drugs and indications to better identify patient populations that are particularly vulnerable to AEs.
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Extracellular vesicles (EVs) are membranous nanovesicles secreted from living cells, shuttling macromolecules in intercellular communication and potentially possessing intrinsic ...therapeutic activity. Due to their stability, low immunogenicity, and inherent interaction with recipient cells, EVs also hold great promise as drug delivery vehicles. Indeed, they have been used to deliver nucleic acids, proteins, and small molecules in preclinical investigations. Furthermore, EV-based drugs have entered early clinical trials for cancer or neurodegenerative diseases. Despite their appeal as delivery vectors, however, EV-based drug delivery progress has been hampered by heterogeneity of sample types and methods as well as a persistent lack of standardization, validation, and comprehensive reporting. This review highlights specific requirements for EVs in drug delivery and describes the most pertinent approaches for separation and characterization. Despite residual uncertainties related to pharmacodynamics, pharmacokinetics, and potential off-target effects, clinical-grade, high-potency EV drugs might be achievable through GMP-compliant workflows in a highly standardized environment.
The abstracts presented at the 2018 International Society for Extracellular Vesicles Annual Meeting offer unique insight into the newest discoveries related to the biology and applied use of ...extracellular vesicles (EVs). As an extension of a recent "Clinical-Wrap Up" discussion at the International Society for Extracellular Vesicles 2018 Annual Meeting, a systematic review of each abstract was performed to determine which abstracts could be considered clinical research. Once the clinical research abstracts were identified, systematic data extraction included: the major focus of each clinical research abstract; the countries in which the work was done; and the sample size, if provided in the abstract. Each abstract was reviewed by two independent authors, with a third author resolving discrepancies in cases of disagreement. 174 out of 656 (27%) unique abstracts were determined to be clinical research. Oncology was a principal research focus (51 of the 174 clinical research abstracts, 29%). Many other clinical research abstracts presented at the International Society for Extracellular Vesicles 2018 Annual Meeting focused on the use of human samples for development of methods for potential application in the clinic. Beyond oncology and methods development, a wide range of topics was represented, including cardiovascular disease, neurodegenerative disease, genetics, and many others. Current research involving EVs highlights the common, but false dichotomy of science into curiosity-driven basic science or application-driven clinical research, when in fact both quest for understanding and intent to apply the findings appeared to drive much of the work at the International Society for Extracellular Vesicles 2018 Annual Meeting. Using Pasteur's Quadrant as a framework, we discuss where the field of EV research is heading and how we may gain insight into the biological function of EVs in tandem with how they may benefit individual health.
Angioedema is a potentially life-threatening adverse effect of angiotensin-converting enzyme inhibitors. Bradykinin and substance P, substrates of angiotensin-converting enzyme, increase vascular ...permeability and cause tissue edema in animals. Studies indicate that amino-terminal degradation of these peptides, by aminopeptidase P and dipeptidyl peptidase IV, may be impaired in individuals with angiotensin-converting enzyme inhibitor-associated angioedema. This case-control study tested the hypothesis that dipeptidyl peptidase IV activity and antigen are decreased in sera of patients with a history of angiotensin-converting enzyme inhibitor-associated angioedema. Fifty subjects with a history of angiotensin-converting enzyme inhibitor-associated angioedema and 176 angiotensin-converting enzyme inhibitor-exposed control subjects were ascertained. Sera were assayed for angiotensin-converting enzyme activity, aminopeptidase P activity, aminopeptidase N activity, dipeptidyl peptidase IV activity, and antigen and the ex vivo degradation half-lives of bradykinin, des-Arg(9)-bradykinin, and substance P in a subset. The prevalence of smoking was increased and of diabetes decreased in case versus control subjects. Overall, dipeptidyl peptidase IV activity (26.6+/-7.8 versus 29.6+/-7.3 nmol/mL per minute; P=0.026) and antigen (465.8+/-260.8 versus 563.1+/-208.6 ng/mL; P=0.017) were decreased in sera from individuals with angiotensin-converting enzyme inhibitor-associated angioedema compared with angiotensin-converting enzyme inhibitor-exposed control subjects without angioedema. Dipeptidyl peptidase IV activity (21.5+/-4.9 versus 29.8+/-6.7 nmol/mL per minute; P=0.001) and antigen (354.4+/-124.7 versus 559.8+/-163.2 ng/mL; P=0.003) were decreased in sera from cases collected during angiotensin-converting enzyme inhibition but not in the absence of angiotensin-converting enzyme inhibition. The degradation half-life of substance P correlated inversely with dipeptidyl peptidase IV antigen during angiotensin-converting enzyme inhibition. Environmental or genetic factors that reduce dipeptidyl peptidase IV activity may predispose individuals to angioedema.
Background Electronic health records (EHRs) have been identified as a key tool for quality improvement (QI) in health care. However, EHR data must be of sufficient quality to support QI efforts. In ...2005, the Department of Veterans Affairs (VA) began using a novel EHR tool—the CART Program—to support QI in cardiac catheterization laboratories. We evaluated whether data collected by the CART Program were of sufficient quality to support QI. Methods We evaluated the data validity, completeness, and timeliness of CART Program data using a random sample of 200 coronary procedures performed in 10 geographically diverse VA medical centers. Results Of 1690 observations in the CART Program data repository, 1664 (98.5%) were valid, as compared to the VA medical record. The CART Program reports were more complete than cardiac catheterization laboratory reports generated prior to CART Program implementation (79% vs. 63.1%, P < .001). Finally, there was a trend toward earlier availability of completed procedure reports to treating providers after CART Program implementation, with 75% of CART Program reports available within 1 day compared to 4 days for reports generated prior to CART Program implementation ( P = .06). Conclusions Cardiac catheterization reports generated by the VA's CART Program demonstrate excellent data validity, superior completeness, and a trend toward more timely availability to referring providers relative to cardiac catheterization laboratory reports generated prior to CART Program implementation. This demonstration of data quality is a key step in realizing CART Program's aim of supporting QI efforts in VA catheter laboratories.
Background
Optimal management of androgen excess in 21-hydroxylase deficiency (21OHD) remains challenging. 11-oxygenated-C
19
steroids (11-oxyandrogens) have emerged as promising biomarkers of ...disease control, but data regarding their response to treatment are lacking.
Objective
To compare the dynamic response of a broad set of steroids to both conventional oral glucocorticoids (OG) and circadian cortisol replacement
via
continuous subcutaneous hydrocortisone infusion (CSHI) in patients with 21OHD based on 24-hour serial sampling.
Participants and Methods
We studied 8 adults (5 women), ages 19-43 years, with poorly controlled classic 21OHD who participated in a single-center open-label phase I–II study comparing OG with CSHI. We used mass spectrometry to measure 15 steroids (including 11-oxyandrogens and Δ
5
steroid sulfates) in serum samples obtained every 2 h for 24 h after 3 months of stable OG, and 6 months into ongoing CSHI.
Results
In response to OG therapy, androstenedione, testosterone (T), and their four 11-oxyandrogen metabolites:11β-hydroxyandrostenedione, 11-ketoandrostenedione, 11β-hydroxytestosterone and 11-ketotestosterone (11KT) demonstrated a delayed decline in serum concentrations, and they achieved a nadir between 0100-0300. Unlike DHEAS, which had little diurnal variation, pregnenolone sulfate (PregS) and 17-hydoxypregnenolone sulfate peaked in early morning and declined progressively throughout the day. CSHI dampened the early ACTH and androgen rise, allowing the ACTH-driven adrenal steroids to return closer to baseline before mid-day. 11KT concentrations displayed the most consistent difference between OG and CSHI across all time segments. While T was lowered by CSHI as compared with OG in women, T increased in men, suggesting an improvement of the testicular function in parallel with 21OHD control in men.
Conclusion
11-oxyandrogens and PregS could serve as biomarkers of disease control in 21OHD. The development of normative data for these promising novel biomarkers must consider their diurnal variability.
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