Publications by authors named "James Brian Byrd"

48 Publications

Urinary extracellular vesicles: A position paper by the Urine Task Force of the International Society for Extracellular Vesicles.

J Extracell Vesicles 2021 May 21;10(7):e12093. Epub 2021 May 21.

Department of Cell and Molecular Biology QIMR Berghofer Medical Research Institute Brisbane Australia.

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 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 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.
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http://dx.doi.org/10.1002/jev2.12093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138533PMC
May 2021

Separation, characterization, and standardization of extracellular vesicles for drug delivery applications.

Adv Drug Deliv Rev 2021 Jul 5;174:348-368. Epub 2021 May 5.

Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.

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.
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http://dx.doi.org/10.1016/j.addr.2021.04.027DOI Listing
July 2021

Challenges in defining Long COVID: Striking differences across literature, Electronic Health Records, and patient-reported information.

medRxiv 2021 Mar 26. Epub 2021 Mar 26.

Since late 2019, the novel coronavirus SARS-CoV-2 has introduced a wide array of health challenges globally. In addition to a complex acute presentation that can affect multiple organ systems, increasing evidence points to long-term sequelae being common and impactful. The worldwide scientific community is forging ahead to characterize a wide range of outcomes associated with SARS-CoV-2 infection; however the underlying assumptions in these studies have varied so widely that the resulting data are difficult to compareFormal definitions are needed in order to design robust and consistent studies of Long COVID that consistently capture variation in long-term outcomes. Even the condition itself goes by three terms, most widely "Long COVID", but also "COVID-19 syndrome (PACS)" or, "post-acute sequelae of SARS-CoV-2 infection (PASC)". In the present study, we investigate the definitions used in the literature published to date and compare them against data available from electronic health records and patient-reported information collected via surveys. Long COVID holds the potential to produce a second public health crisis on the heels of the pandemic itself. Proactive efforts to identify the characteristics of this heterogeneous condition are imperative for a rigorous scientific effort to investigate and mitigate this threat.
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http://dx.doi.org/10.1101/2021.03.20.21253896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010765PMC
March 2021

Identification and Development of Therapeutics for COVID-19.

ArXiv 2021 Mar 3. Epub 2021 Mar 3.

After emerging in China in late 2019, the novel Severe acute respiratory syndrome-like coronavirus 2 (SARS-CoV-2) spread worldwide and as of early 2021, continues to significantly impact most countries. Only a small number of coronaviruses are known to infect humans, and only two are associated with the severe outcomes associated with SARS-CoV-2: Severe acute respiratory syndrome-related coronavirus, a closely related species of SARS-CoV-2 that emerged in 2002, and Middle East respiratory syndrome-related coronavirus, which emerged in 2012. Both of these previous epidemics were controlled fairly rapidly through public health measures, and no vaccines or robust therapeutic interventions were identified. However, previous insights into the immune response to coronaviruses gained during the outbreaks of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) have proved beneficial to identifying approaches to the treatment and prophylaxis of novel coronavirus disease 2019 (COVID-19). A number of potential therapeutics against SARS-CoV-2 and the resultant COVID-19 illness were rapidly identified, leading to a large number of clinical trials investigating a variety of possible therapeutic approaches being initiated early on in the pandemic. As a result, a small number of therapeutics have already been authorized by regulatory agencies such as the Food and Drug Administration (FDA) in the United States, and many other therapeutics remain under investigation. Here, we describe a range of approaches for the treatment of COVID-19, along with their proposed mechanisms of action and the current status of clinical investigation into each candidate. The status of these investigations will continue to evolve, and this review will be updated as progress is made.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941644PMC
March 2021

ST-segment elevation in patients presenting with COVID-19: case series.

Eur Heart J Case Rep 2021 Feb 8;5(2):ytaa553. Epub 2021 Feb 8.

BHF Centre for Cardiovascular Science, University of Edinburgh, Chancellors Building, Royal Infirmary of Edinburgh, Edinburgh EH16 4SA, UK.

Background : The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for the now pandemic disease, coronavirus disease (COVID-19). A number of reports have emerged suggesting these patients may present with signs and symptoms consistent with ST-segment elevation myocardial infarction without coronary artery occlusion.

Case Summary : We report an international case series of patients with confirmed COVID-19 infection who presented with suspected ST-segment elevation myocardial infarction. Three patients with confirmed COVID-19 presented with electrocardiogram criteria for ST-segment elevation myocardial infarction. No patient had obstructive coronary disease at coronary angiography. Post-mortem histology in one case demonstrated myocardial ischaemia in the absence of coronary atherothrombosis or myocarditis.

Discussion : Patients with COVID-19 may present with features consistent with ST-segment elevation myocardial infarction and patent coronary arteries. The prevalence and clinical outcomes of this condition require systematic investigation in consecutive unselected patients.
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http://dx.doi.org/10.1093/ehjcr/ytaa553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898565PMC
February 2021

Pathogenesis, Symptomatology, and Transmission of SARS-CoV-2 through analysis of Viral Genomics and Structure.

ArXiv 2021 Feb 1. Epub 2021 Feb 1.

The novel coronavirus SARS-CoV-2, which emerged in late 2019, has since spread around the world infecting tens of millions of people with coronavirus disease 2019 (COVID-19). While this viral species was unknown prior to January 2020, its similarity to other coronaviruses that infect humans has allowed for rapid insight into the mechanisms that it uses to infect human hosts, as well as the ways in which the human immune system can respond. Here, we contextualize SARS-CoV-2 among other coronaviruses and identify what is known and what can be inferred about its behavior once inside a human host. Because the genomic content of coronaviruses, which specifies the virus's structure, is highly conserved, early genomic analysis provided a significant head start in predicting viral pathogenesis. The pathogenesis of the virus offers insights into symptomatology, transmission, and individual susceptibility. Additionally, prior research into interactions between the human immune system and coronaviruses has identified how these viruses can evade the immune system's protective mechanisms. We also explore systems-level research into the regulatory and proteomic effects of SARS-CoV-2 infection and the immune response. Understanding the structure and behavior of the virus serves to contextualize the many facets of the COVID-19 pandemic and can influence efforts to control the virus and treat the disease.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885912PMC
February 2021

The National COVID Cohort Collaborative: Clinical Characterization and Early Severity Prediction.

medRxiv 2021 Jan 13. Epub 2021 Jan 13.

Background: The majority of U.S. reports of COVID-19 clinical characteristics, disease course, and treatments are from single health systems or focused on one domain. Here we report the creation of the National COVID Cohort Collaborative (N3C), a centralized, harmonized, high-granularity electronic health record repository that is the largest, most representative U.S. cohort of COVID-19 cases and controls to date. This multi-center dataset supports robust evidence-based development of predictive and diagnostic tools and informs critical care and policy.

Methods And Findings: In a retrospective cohort study of 1,926,526 patients from 34 medical centers nationwide, we stratified patients using a World Health Organization COVID-19 severity scale and demographics; we then evaluated differences between groups over time using multivariable logistic regression. We established vital signs and laboratory values among COVID-19 patients with different severities, providing the foundation for predictive analytics. The cohort included 174,568 adults with severe acute respiratory syndrome associated with SARS-CoV-2 (PCR >99% or antigen <1%) as well as 1,133,848 adult patients that served as lab-negative controls. Among 32,472 hospitalized patients, mortality was 11.6% overall and decreased from 16.4% in March/April 2020 to 8.6% in September/October 2020 (p = 0.002 monthly trend). In a multivariable logistic regression model, age, male sex, liver disease, dementia, African-American and Asian race, and obesity were independently associated with higher clinical severity. To demonstrate the utility of the N3C cohort for analytics, we used machine learning (ML) to predict clinical severity and risk factors over time. Using 64 inputs available on the first hospital day, we predicted a severe clinical course (death, discharge to hospice, invasive ventilation, or extracorporeal membrane oxygenation) using random forest and XGBoost models (AUROC 0.86 and 0.87 respectively) that were stable over time. The most powerful predictors in these models are patient age and widely available vital sign and laboratory values. The established expected trajectories for many vital signs and laboratory values among patients with different clinical severities validates observations from smaller studies, and provides comprehensive insight into COVID-19 characterization in U.S. patients.

Conclusions: This is the first description of an ongoing longitudinal observational study of patients seen in diverse clinical settings and geographical regions and is the largest COVID-19 cohort in the United States. Such data are the foundation for ML models that can be the basis for generalizable clinical decision support tools. The N3C Data Enclave is unique in providing transparent, reproducible, easily shared, versioned, and fully auditable data and analytic provenance for national-scale patient-level EHR data. The N3C is built for intensive ML analyses by academic, industry, and citizen scientists internationally. Many observational correlations can inform trial designs and care guidelines for this new disease.
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http://dx.doi.org/10.1101/2021.01.12.21249511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814838PMC
January 2021

Testing for Primary Aldosteronism and Mineralocorticoid Receptor Antagonist Use Among U.S. Veterans : A Retrospective Cohort Study.

Ann Intern Med 2021 03 29;174(3):289-297. Epub 2020 Dec 29.

Stanford University School of Medicine, Stanford, California (V.B.).

Background: Primary aldosteronism is a common cause of treatment-resistant hypertension. However, evidence from local health systems suggests low rates of testing for primary aldosteronism.

Objective: To evaluate testing rates for primary aldosteronism and evidence-based hypertension management in patients with treatment-resistant hypertension.

Design: Retrospective cohort study.

Setting: U.S. Veterans Health Administration.

Participants: Veterans with apparent treatment-resistant hypertension ( = 269 010) from 2000 to 2017, defined as either 2 blood pressures (BPs) of at least 140 mm Hg (systolic) or 90 mm Hg (diastolic) at least 1 month apart during use of 3 antihypertensive agents (including a diuretic), or hypertension requiring 4 antihypertensive classes.

Measurements: Rates of primary aldosteronism testing (plasma aldosterone-renin) and the association of testing with evidence-based treatment using a mineralocorticoid receptor antagonist (MRA) and with longitudinal systolic BP.

Results: 4277 (1.6%) patients who were tested for primary aldosteronism were identified. An index visit with a nephrologist (hazard ratio [HR], 2.05 [95% CI, 1.66 to 2.52]) or an endocrinologist (HR, 2.48 [CI, 1.69 to 3.63]) was associated with a higher likelihood of testing compared with primary care. Testing was associated with a 4-fold higher likelihood of initiating MRA therapy (HR, 4.10 [CI, 3.68 to 4.55]) and with better BP control over time.

Limitations: Predominantly male cohort, retrospective design, susceptibility of office BPs to misclassification, and lack of confirmatory testing for primary aldosteronism.

Conclusion: In a nationally distributed cohort of veterans with apparent treatment-resistant hypertension, testing for primary aldosteronism was rare and was associated with higher rates of evidence-based treatment with MRAs and better longitudinal BP control. The findings reinforce prior observations of low adherence to guideline-recommended practices in smaller health systems and underscore the urgent need for improved management of patients with treatment-resistant hypertension.

Primary Funding Source: National Institutes of Health.
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http://dx.doi.org/10.7326/M20-4873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7965294PMC
March 2021

Detection of patients at risk of developing heart failure responsive to mineralocorticoid receptor antagonists (MRAs): new insights and opportunities.

Eur Heart J 2021 02;42(6):697-699

University of Michigan School of Medicine, Department of Medicine, Division of Cardiovascular Medicine, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA.

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http://dx.doi.org/10.1093/eurheartj/ehaa765DOI Listing
February 2021

Primary Aldosteronism: New Insights Into its Detection and Cardiac Involvement.

JACC Cardiovasc Imaging 2020 10 16;13(10):2160-2161. Epub 2020 Sep 16.

Department of Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan.

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http://dx.doi.org/10.1016/j.jcmg.2020.06.025DOI Listing
October 2020

Randomized elimination and prolongation of ACE inhibitors and ARBs in coronavirus 2019 (REPLACE COVID) Trial Protocol.

J Clin Hypertens (Greenwich) 2020 10 16;22(10):1780-1788. Epub 2020 Sep 16.

Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), is associated with high incidence of multiorgan dysfunction and death. Angiotensin-converting enzyme 2 (ACE2), which facilitates SARS-CoV-2 host cell entry, may be impacted by angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), two commonly used antihypertensive classes. In a multicenter, international randomized controlled trial that began enrollment on March 31, 2020, participants are randomized to continuation vs withdrawal of their long-term outpatient ACEI or ARB upon hospitalization with COVID-19. The primary outcome is a hierarchical global rank score incorporating time to death, duration of mechanical ventilation, duration of renal replacement or vasopressor therapy, and multiorgan dysfunction severity. Approval for the study has been obtained from the Institutional Review Board of each participating institution, and all participants will provide informed consent. A data safety monitoring board has been assembled to provide independent oversight of the project.
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http://dx.doi.org/10.1111/jch.14011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722152PMC
October 2020

Extracellular Vesicles in Essential Hypertension: Hidden Messengers.

Curr Hypertens Rep 2020 09 3;22(10):76. Epub 2020 Sep 3.

Department of Internal Medicine, Division of Nephrology, University of Virginia Health System, 1300 Jefferson Park Avenue, Charlottesville, VA, 22908-0133, USA.

Purpose Of Review: Hypertension affects about half of all Americans, yet in the vast majority of cases, the factors causing the hypertension cannot be clearly delineated. Developing a more precise understanding of the molecular pathogenesis of HTN and its various phenotypes is therefore a pressing priority. Circulating and urinary extracellular vesicles (EVs) are potential novel candidates as biomarkers and bioactivators in HTN. EVs are a heterogeneous population of small membrane fragments shed from various cell types into various body fluids. As EVs carry protein, RNA, and lipids, they also play a role as effectors and novel cell-to-cell communicators. In this review, we discuss the diagnostic, functional, and regenerative role of EVs in essential HTN and focus on EV protein and RNA cargo as the most extensively studied EV cargo.

Recent Findings: The field of EVs in HTN is still a young one and earlier studies have not used the novel EV detection tools currently available. More rigor and transparency in EV research are needed. Current data suggest that EVs represent potential novel biomarkers in HTN. EVs correlate with HTN severity and possibly end-organ damage. However, it has yet to be discerned which specific subtype(s) of EV reflects best HTN pathophysiology. Evolving studies are also showing that EVs might be novel regulators in vascular and renal tubular function and also be therapeutic. RNA in EVs has been studied in the context of hypertension, largely in the form of studies of miRNA, which are reviewed herein. Beyond miRNAs, mRNA in urinary EVs changed in response to sodium loading in humans. EVs represent promising novel biomarkers and bioactivators in essential HTN. Novel tools are being developed to apply more rigor in EV research including more in vivo models and translation to humans.
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http://dx.doi.org/10.1007/s11906-020-01084-8DOI Listing
September 2020

Responsible, practical genomic data sharing that accelerates research.

Nat Rev Genet 2020 10 21;21(10):615-629. Epub 2020 Jul 21.

Childhood Cancer Data Lab, Alex's Lemonade Stand Foundation, Philadelphia, PA, USA.

Data sharing anchors reproducible science, but expectations and best practices are often nebulous. Communities of funders, researchers and publishers continue to grapple with what should be required or encouraged. To illuminate the rationales for sharing data, the technical challenges and the social and cultural challenges, we consider the stakeholders in the scientific enterprise. In biomedical research, participants are key among those stakeholders. Ethical sharing requires considering both the value of research efforts and the privacy costs for participants. We discuss current best practices for various types of genomic data, as well as opportunities to promote ethical data sharing that accelerates science by aligning incentives.
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http://dx.doi.org/10.1038/s41576-020-0257-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7974070PMC
October 2020

Managing hypertension during the COVID-19 pandemic.

J Hum Hypertens 2020 06 14;34(6):415-417. Epub 2020 May 14.

Department of Internal Medicine, University of Michigan Medical Schooll, Ann Arbor, MI, USA.

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http://dx.doi.org/10.1038/s41371-020-0356-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7224587PMC
June 2020

Rigor before speculation in COVID-19 therapy.

Am J Physiol Lung Cell Mol Physiol 2020 05;318(5):L1027-L1028

Department of Medicine, Duke University School of Medicine, and Durham Veterans Affairs Medical Centers, Durham, North Carolina.

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http://dx.doi.org/10.1152/ajplung.00152.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203572PMC
May 2020

Pandemic Pandemonium: Pausing Clinical Research During the COVID-19 Outbreak.

Circulation 2020 06 22;141(25):2045-2047. Epub 2020 Apr 22.

Center for Translational Bioethics and Health Care Policy, Geisinger Health System, Danville, PA (M.N.M.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.047347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302083PMC
June 2020

Angiotensin Receptor Blockers and the Risk of Cancer: Insights from Clinical Trials and Recent Drug Recalls.

Curr Hypertens Rep 2020 02 29;22(3):20. Epub 2020 Feb 29.

Department of Internal Medicine, Division of Cardiovascular Medicine, Medical School, University of Michigan, 5570C MSRB II, 1150 W. Medical Center Dr., Ann Arbor, MI, 48109, USA.

Purpose Of Review: The purpose of this review is to familiarize readers with issues surrounding angiotensin receptor blockers (ARBs) and the risk of cancer, both from the perspective of clinical trial data and the more recent concerns about impurities in certain ARB products.

Recent Findings: Approximately 45.6% of adults in the USA have hypertension. ARB-containing medications are widely used in the USA, with tens of millions of prescriptions written yearly. Whether exposure to certain ARB drug products contributes to the development of cancer has been the topic of a series of publications. Nonetheless, ARBs' link to cancer, if any, remains inconclusive. Any mechanistic link between ARBs and cancer is poorly understood, with a variety of basic science studies suggesting that ARBs should exert a protective effect. Due to the presence of potentially carcinogenic nitrosamine impurities in certain ARB products, a series of large recalls in the USA and in countries around the world has occurred since 2018. These recalls have occurred in the context of two recent trends affecting antihypertensive drugs: nearly ubiquitous reliance on generic drugs and increased use of manufacturing facilities in China and India to supply the USA. Despite substantial efforts directed toward understanding whether ARBs have the potential to cause cancer, the available studies do not provide a consistent answer, and a causal link remains speculative. The principal conclusion must be that there is not a definitive signal for cancer associated with ARB exposure, although the possibility has not been fully excluded. The problem of nitrosamine impurities in certain ARB products (and some other drug products) is in need of further investigation, so that the risks can be mitigated by eliminating these impurities from the drug supply chain.
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http://dx.doi.org/10.1007/s11906-020-1021-0DOI Listing
February 2020

Medicare reimbursement policy for ambulatory blood pressure monitoring: A qualitative analysis of public comments to the Centers for Medicare and Medicaid Services.

J Clin Hypertens (Greenwich) 2019 12 23;21(12):1803-1809. Epub 2019 Oct 23.

Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.

Ambulatory blood pressure monitoring (ABPM) is considered the best means of diagnosing hypertension. However, it is rarely used and is reimbursed only under narrow conditions. We sought to gain insight into the perceived value of ABPM among stakeholders who responded to the Centers for Medicare and Medicaid Services' (CMS) request for comments to inform the first revision of ABPM reimbursement policy in over 15 years. We found that most comments were classifiable in two main themes, current coverage and future coverage. Individuals and institutions representing multiple disciplines and specialties were highly supportive of expanding the current CMS coverage of ABPM, including for a wide range of clinical indications and populations. It is clear from the comments reviewed that there is wide support for expanding CMS coverage for ABPM. Broad support for a change in ABPM reimbursement policy may lead to changes in the way this technology is used in the United States.
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http://dx.doi.org/10.1111/jch.13719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7018518PMC
December 2019

Current Status of Angiotensin Receptor Blocker Recalls.

Hypertension 2019 12 21;74(6):1275-1278. Epub 2019 Oct 21.

From the Division of Cardiovascular Medicine, Department of Internal Medicine (P.M.G., J.B.B.), University of Michigan, Ann Arbor.

Losartan was the ninth most prescribed drug in the United States in 2016, and several other angiotensin-II receptor blockers (ARBs) are widely prescribed. Since July 2018, >2 dozen specific ARB products have been recalled owing to the presence of potentially carcinogenic nitrosamine impurities in selected lots. As is the case with all U.S. drug recalls, the ARB recalls have been voluntary on the part of the companies involved. In April 2019, the Food and Drug Administration categorized marketed ARB products with respect to nitrosamine impurities: (1) not present, (2) to be determined with no prior lots removed from the market (TBD), or (3) to be determined in the context of prior lots having been removed from the market (TBD*). The data were structured as hundreds of rows of products. Owing to the complexity of these data, more than a year into the recalls, it remains difficult for clinicians to understand which ARB products are free of impurities.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.13955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021211PMC
December 2019

For what factors should we normalize urinary extracellular mRNA biomarkers?

Biomol Detect Quantif 2019 Mar 23;17:100090. Epub 2019 Apr 23.

Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.

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.
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http://dx.doi.org/10.1016/j.bdq.2019.100090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591792PMC
March 2019

Privacy-Preserving Generative Deep Neural Networks Support Clinical Data Sharing.

Circ Cardiovasc Qual Outcomes 2019 07 9;12(7):e005122. Epub 2019 Jul 9.

Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia. (C.W., C.S.G.).

Background: Data sharing accelerates scientific progress but sharing individual-level data while preserving patient privacy presents a barrier.

Methods And Results: Using pairs of deep neural networks, we generated simulated, synthetic participants that closely resemble participants of the SPRINT trial (Systolic Blood Pressure Trial). We showed that such paired networks can be trained with differential privacy, a formal privacy framework that limits the likelihood that queries of the synthetic participants' data could identify a real a participant in the trial. Machine learning predictors built on the synthetic population generalize to the original data set. This finding suggests that the synthetic data can be shared with others, enabling them to perform hypothesis-generating analyses as though they had the original trial data.

Conclusions: Deep neural networks that generate synthetic participants facilitate secondary analyses and reproducible investigation of clinical data sets by enhancing data sharing while preserving participant privacy.
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http://dx.doi.org/10.1161/CIRCOUTCOMES.118.005122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041894PMC
July 2019

Clinical research using extracellular vesicles: insights from the International Society for Extracellular Vesicles 2018 Annual Meeting.

J Extracell Vesicles 2018 26;7(1):1535744. Epub 2018 Oct 26.

Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.

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.
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http://dx.doi.org/10.1080/20013078.2018.1535744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6211232PMC
October 2018

Hypertension.

Ann Intern Med 2019 05;170(9):ITC65-ITC80

University of Michigan, Ann Arbor, Michigan (J.B.B., R.D.B.).

Recent guidelines on diagnosis and management of high blood pressure (BP) include substantial changes and several new concepts compared with previous guidelines. These are reviewed and their clinical implications are discussed in this article. The goal is to provide a practical reference to assist clinicians with up-to-date management of patients with high BP. Important issues include new diagnostic thresholds, out-of-office BP monitoring, intensified treatment goals, and a different approach to resistant hypertension. Finally, differences among guidelines, the persistent controversies that have led to them, and their implications for clinical practice are discussed.
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http://dx.doi.org/10.7326/AITC201905070DOI Listing
May 2019

Score one for the clinical trial data sharing experiment.

Authors:
James Brian Byrd

Eur J Prev Cardiol 2019 04 6;26(6):567-568. Epub 2019 Jan 6.

Department of Internal Medicine, University of Michigan Medical School, USA.

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http://dx.doi.org/10.1177/2047487318821770DOI Listing
April 2019

Strengthening a societal tie and other new initiatives for 2019.

J Hum Hypertens 2019 03 7;33(3):173. Epub 2019 Mar 7.

Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.

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http://dx.doi.org/10.1038/s41371-019-0172-4DOI Listing
March 2019

Personalized Medicine and the Treatment of Hypertension.

Curr Hypertens Rep 2019 02 12;21(2):13. Epub 2019 Feb 12.

Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical School, 5570C MSRB II, 1150 West Medical Center Drive, SPC 5678, Ann Arbor, MI, 48109-5678, USA.

Purpose Of Review: The purpose of this review is to discuss the implications of personalized medicine for the treatment of hypertension, including resistant hypertension.

Recent Findings: We suggest a framework for the personalized treatment of hypertension based on the concept of a trade-off between simplicity and personalization. This framework is based on treatment strategies classified as low, medium, or high information burden personalization approaches. The extent to which a higher information burden is justified depends on the clinical scenario, particularly the ease with which the blood pressure can be controlled. A one-size-fits-many treatment strategy for hypertension is efficacious for most people; however, a more personalized approach could be useful in patients with subtypes of hypertension that do not respond as expected to treatment. Clinicians seeing patients with unusual hypertension phenotypes should be familiar with emerging trends in personalized treatment of hypertension.
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http://dx.doi.org/10.1007/s11906-019-0921-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594382PMC
February 2019

Out-of-Office Blood Pressure Monitoring in 2018.

JAMA 2018 Nov;320(17):1805-1806

Department of Medicine, University of Michigan Medical School, Ann Arbor.

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http://dx.doi.org/10.1001/jama.2018.14865DOI Listing
November 2018

Primary Aldosteronism: Practical Approach to Diagnosis and Management.

Circulation 2018 08;138(8):823-835

Division of Metabolism, Endocrinology, and Diabetes (A.F.T., R.J.A.).

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.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.033597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205759PMC
August 2018