Cardiovascular Dynamics in HIV: The Influence of Adrenal Function and Nutritional Status.

This interdisciplinary review explores the intricate nexus between HIV infection, nutrition, adrenal gland function, and cardiovascular health, highlighting a critical aspect of HIV management often overlooked in current literature. With the advent of antiretroviral therapy, the life expectancy of people living with HIV has dramatically improved, transforming HIV into a manageable chronic condition. However, this success brings forth new challenges, notably an increased risk of cardiovascular diseases among people living with HIV. We examine the normal physiology of the adrenal gland, including its role in mineral metabolism, a crucial facet of nutrition. We discuss the evolution of knowledge tying adrenal pathology to cardiovascular disease. We explore the impact of HIV on adrenal gland findings from a gross pathology perspective, as well as the clinical impact of adrenal insufficiency in HIV. The review further elucidates the role of nutrition in this context, considering the double burden of undernutrition and obesity prevalent in regions heavily affected by HIV. By aggregating findings from longitudinal studies and recent clinical trials, the review presents compelling evidence of increased cardiovascular disease among people living with HIV compared with people without HIV. It highlights the critical role of the adrenal glands in regulating nutrient metabolism and its implications for cardiovascular health, drawing attention to the potential for dietary interventions and targeted therapies to mitigate these risks. This review urges a paradigm shift in the management of HIV, advocating for a holistic approach that incorporates nutritional assessment and interventions into routine HIV care to address the complex interplay between HIV, adrenal function, and cardiovascular health. Through this lens, we offer insights into novel therapeutic strategies aimed at reducing cardiovascular risk in people living with HIV, contributing to the ongoing efforts to enhance the quality of life and longevity in this population.

Responsible, practical genomic data sharing that accelerates research.

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.

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

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 (n = 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.

Stepped Exercise Program for Patients With Knee Osteoarthritis : A Randomized Controlled Trial.

BACKGROUND: Evidence-based models are needed to deliver exercise-related services for knee osteoarthritis efficiently and according to patient needs. OBJECTIVE: To examine a stepped exercise program for patients with knee osteoarthritis (STEP-KOA). DESIGN: Randomized controlled trial. (ClinicalTrials.gov: NCT02653768). SETTING: 2 U.S. Department of Veterans Affairs sites. PARTICIPANTS: 345 patients (mean age, 60 years; 15% female; 67% people of color) with symptomatic knee osteoarthritis. INTERVENTION: Participants were randomly assigned in a 2:1 ratio to STEP-KOA or an arthritis education (AE) control group, respectively. The STEP-KOA intervention began with 3 months of an internet-based exercise program (step 1). Participants who did not meet response criteria for improvement in pain and function after step 1 progressed to step 2, which involved 3 months of biweekly physical activity coaching calls. Participants who did not meet response criteria after step 2 went on to in-person physical therapy visits (step 3). The AE group received educational materials via mail every 2 weeks. MEASUREMENTS: Primary outcome was Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score. Scores for the STEP-KOA and AE groups at 9 months were compared by using linear mixed models. RESULTS: In the STEP-KOA group, 65% of participants (150 of 230) progressed to step 2 and 35% (81 of 230) to step 3. The estimated baseline WOMAC score for the full sample was 47.5 (95% CI, 45.7 to 49.2). At 9-month follow-up, the estimated mean WOMAC score was 6.8 points (CI, -10.5 to -3.2 points) lower in the STEP-KOA than the AE group, indicating greater improvement. LIMITATION: Participants were mostly male veterans, and follow-up was limited. CONCLUSION: Veterans in STEP-KOA reported modest improvements in knee osteoarthritis symptoms compared with the control group. The STEP-KOA strategy may be efficient for delivering exercise therapies for knee osteoarthritis. PRIMARY FUNDING SOURCE: Department of Veterans Affairs, Health Services Research and Development Service.

The Role of Organizational Slack in Buffering Financially Distressed Hospitals from Market Exits.

EXECUTIVE SUMMARY: Financial distress is a persistent problem in U.S. hospitals, leading them to close at an alarming rate over the past two decades. Given the potential adverse effects of hospital closures on healthcare access and public health, interest is growing in understanding more about the financial health of U.S. hospitals. In this study, we set out to explore the extent to which relevant organizational and environmental factors potentially buffer financially distressed hospitals from closure, and even at the brink of closure, enable some to merge with other hospitals. We tested our hypotheses by first examining how factors such as slack resources, environmental munificence, and environmental complexity affect the likelihood of survival versus closing or merging with other organizations. We then tested how the same factors affect the likelihood of merging relative to closing for financially distressed hospitals that undergo one of these two events. We found that different types of slack resources and environmental forces impact different outcomes. In this article, we discuss the implications of our findings for hospital stakeholders.

EV-TRACK: transparent reporting and centralizing knowledge in extracellular vesicle research.

We argue that the field of extracellular vesicle (EV) biology needs more transparent reporting to facilitate interpretation and replication of experiments. To achieve this, we describe EV-TRACK, a crowdsourcing knowledgebase (http://evtrack.org) that centralizes EV biology and methodology with the goal of stimulating authors, reviewers, editors and funders to put experimental guidelines into practice.

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

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.

Extracellular Vesicles in Essential Hypertension: Hidden Messengers.

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.

Hypertension.

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.

Primary Aldosteronism: Practical Approach to Diagnosis and Management.

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.

Personalized Medicine and the Treatment of Hypertension.

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.

Blood pressure, heart rate, and mortality in chronic obstructive pulmonary disease: the SUMMIT trial.

Aims: To characterize the relationship between blood pressure (BP) or heart rate and mortality and morbidity in chronic obstructive pulmonary disease (COPD). Methods and results: We performed post hoc analysis of baseline BP or heart rate and all-cause mortality and cardiovascular events in the SUMMIT trial. SUMMIT was a randomized double-blind outcome trial of 16 485 participants (65 ± 8 years, 75% male, and 47% active smokers) enrolled at 1368 sites in 43 countries. Participants with moderate COPD with or at risk for cardiovascular disease (CVD) were randomized to placebo, long-acting beta agonist, inhaled corticosteroid, or their combination. All-cause mortality increased in relation to high systolic [≥140 mmHg; hazard ratio (HR) 1.27, 95% confidence interval (CI) 1.12-1.45] or diastolic (≥90 mmHg; HR 1.35, 95% CI 1.14-1.59) BP and low systolic (<120 mmHg; HR 1.36, 95% CI 1.13-1.63) or diastolic (<80 mmHg; HR 1.15, 95% CI 1.00-1.32) BP. Higher heart rates (≥80 per minute; HR 1.39, 95% CI 1.21-1.60) and pulse pressures (≥80 mmHg; HR 1.39, 95% CI 1.07-1.80) were more linearly related to increases in all-cause mortality. The risks of cardiovascular events followed similar patterns to all-cause mortality. Similar findings were observed in subgroups of patients without established CVD. Conclusion: A 'U-shaped' relationship between BP and all-cause mortality and cardiovascular events exists in patients with COPD and heightened cardiovascular risk. A linear relationship exists between heart rate and all-cause mortality and cardiovascular events in this population. These findings extend the prognostic importance of BP to this growing group of patients and raise concerns that both high and low BP may pose health risks.

Effect of bradykinin receptor antagonism on ACE inhibitor-associated angioedema.

BACKGROUND: The B2 receptor antagonist icatibant is approved for treatment of attacks of hereditary angioedema. Icatibant has been reported to decrease time-to-resolution of angiotensin-converting enzyme (ACE) inhibitor-associated angioedema in 1 study of European patients. OBJECTIVE: We sought to test the hypothesis that a bradykinin B2 receptor antagonist would shorten time-to-resolution from ACE inhibitor-associated angioedema. METHODS: Patients with ACE inhibitor-associated angioedema (defined as swelling of lips, tongue, pharynx, or face during ACE inhibitor use and no swelling in the absence of ACE inhibitor use) were enrolled at Vanderbilt University Medical Center from October 2007 through September 2015 and at Massachusetts General Hospital in 2012. C1 inhibitor deficiency and patients with bowel edema only were excluded. Patients were randomized within 6 hours of presentation to subcutaneous icatibant 30 mg or placebo at 0 and 6 hours later. Patients assessed severity of swelling using a visual analog scale serially following study drug administration or until discharge. RESULTS: Thirty-three patients were randomized and 31 received treatment, with 13 receiving icatibant and 18 receiving placebo. One patient randomized to icatibant did not complete the visual analog scale and was excluded from analyses. Two-thirds of patients were black and two-thirds were women. Time-to-resolution of symptoms was similar in placebo and icatibant treatment groups (P = .19 for the primary symptom and P > .16 for individual symptoms of face, lip, tongue, or eyelid swelling). Frequency of administration of H1 and H2 blockers, corticosteroids, and epinephrine was similar in the 2 treatment groups. Time-to-resolution of symptoms was similar in black and white patients. CONCLUSIONS: This study does not support clinical efficacy of a bradykinin B2 receptor antagonist in ACE inhibitor-associated angioedema.

Reach Out Churches: A Community-Based Participatory Research Pilot Trial to Assess the Feasibility of a Mobile Health Technology Intervention to Reduce Blood Pressure Among African Americans.

Innovative strategies are needed to reduce the hypertension epidemic among African Americans. Reach Out was a faith-collaborative, mobile health, randomized, pilot intervention trial of four mobile health components to reduce high blood pressure (BP) compared to usual care. It was designed and tested within a community-based participatory research framework among African Americans recruited and randomized from churches in Flint, Michigan. The purpose of this pilot study was to assess the feasibility of the Reach Out processes. Feasibility was assessed by willingness to consent (acceptance of randomization), proportion of weeks participants texted their BP readings (intervention use), number lost to follow-up (retention), and responses to postintervention surveys and focus groups (acceptance of intervention). Of the 425 church members who underwent BP screening, 94 enrolled in the study and 73 (78%) completed the 6-month outcome assessment. Median age was 58 years, and 79% were women. Participants responded with their BPs on an average of 13.7 (SD = 10.7) weeks out of 26 weeks that the BP prompts were sent. All participants reported satisfaction with the intervention. Reach Out, a faith-collaborative, mobile health intervention was feasible. Further study of the efficacy of the intervention and additional mobile health strategies should be considered.

Discordance between imaging and immunohistochemistry in unilateral primary aldosteronism.

OBJECTIVE: Correct subtyping of primary aldosteronism (PA) is essential for good surgical outcomes. Adrenal vein sampling (AVS) and/or computed tomography (CT) are used for PA subclassification. Clinical and/or biochemical improvement after surgery, however, is not always achieved in patients with presumed unilateral PA. We aimed to identify the pitfalls in PA subclassification leading to surgical treatment failures. PATIENTS AND DESIGN: We retrospectively studied 208 patients who underwent adrenal vein sampling (AVS) for PA subclassification in a tertiary referral centre, between January 2009 and August 2016. Simultaneous bilateral AVS was performed before and after cosyntropin administration. We implemented immunohistochemistry for aldosterone synthase (CYP11B2) and 17α-hydroxylase/17,20 lyase (CYP17A1) in adrenal glands resected from patients without improvement of PA after surgical treatment and from those with limitations in AVS interpretation. RESULTS: Of 55 patients who underwent adrenalectomy, three (5.5%) had no improvement of PA. All three patients underwent partial adrenalectomy to remove a CT-detected nodule present on the same side with AVS lateralization. Immunohistochemistry revealed a CYP11B2-negative nodule in both cases available. All patients who underwent total adrenalectomy based on AVS lateralization benefitted from surgery, including three patients with unilateral unsuccessful AVS and aldosterone suppression in the catheterized side vs inferior vena cava. CONCLUSIONS: Radiographically identified adrenal nodules are not always a source of PA, even when ipsilateral with AVS lateralization. These data caution against reliance on imaging findings, either alone or in conjunction with AVS, to guide surgery for PA.

Low expression of galectin-3 is associated with poor survival in node-positive breast cancers and mesenchymal phenotype in breast cancer stem cells.

BACKGROUND: Galectin-3 (Gal3) plays diverse roles in cancer initiation, progression, and drug resistance depending on tumor type characteristics that are also associated with cancer stem cells (CSCs). Recurrence of breast carcinomas may be attributed to the presence of breast CSCs (BCSCs). BCSCs exist in mesenchymal-like or epithelial-like states and the transition between these states endows BCSCs with the capacity for tumor progression. The discovery of a feedback loop with galectins during epithelial-to-mesenchymal transition (EMT) prompted us to investigate its role in breast cancer stemness. METHOD: To elucidate the role of Gal3 in BCSCs, we performed various in vitro and in vivo studies such as sphere-formation assays, Western blotting, flow cytometric apoptosis assays, and limited dilution xenotransplant models. Histological staining for Gal3 in tissue microarrays of breast cancer patients was performed to analyze the relationship of clinical outcome and Gal3 expression. RESULTS: Here, we show in a cohort of 87 node-positive breast cancer patients treated with doxorubicin-based chemotherapy that low Gal3 was associated with increased lymphovascular invasion and reduced overall survival. Analysis of in vitro BCSC models demonstrated that Gal3 knockdown by small hairpin RNA (shRNA) interference in epithelial-like mammary spheres leads to EMT, increased sphere-formation ability, drug-resistance, and heightened aldefluor activity. Furthermore, Gal3negative BCSCs were associated with enhanced tumorigenicity in orthotopic mouse models. CONCLUSIONS: Thus, in at least some breast cancers, loss of Gal3 might be associated with EMT and cancer stemness-associated traits, predicts poor response to chemotherapy, and poor prognosis.

Robot-Assisted Neck Dissection Through a Modified Facelift Incision.

OBJECTIVES: The aim of this study is to describe the feasibility as well as oncologic outcomes of robot-assisted neck dissection (RAND) through a modified facelift incision in an American population. STUDY DESIGN: Retrospective case series. SETTING: University tertiary care hospital. METHODS: All patients who underwent RAND between November 2012 and December 2014 were included. Medical records were reviewed for demographics, medical histories, staging, operative information, postoperative hospital course and complications, and oncologic outcomes. RESULTS: There were 11 RANDs identified among 10 patients. Five patients had known nodal metastasis at the time of surgery. Two patients had been previously irradiated. The average time of surgery was 284.4 ± 72.3 minutes, including other associated procedures. The average lymph node yield was 28.5 ± 9.3 nodes. There were no major complications. Average follow-up was 19.4 months. There was 1 supraclavicular recurrence in a previously irradiated patient. All patients are currently alive and without evidence of disease. CONCLUSIONS: Robot-assisted neck dissection is a safe and feasible procedure that can be performed by surgeons with familiarity with neck dissection and robot-assisted surgery and who have been trained in RAND. Appropriate oncologic outcomes can be obtained in a patient wishing to avoid a noticeable scar.