Faculty Bibliography

Context:Increased renal sodium reabsorption contributes to hypertension in Cushing syndrome (CS). Renal sodium transporters can be analyzed noninvasively in urinary extracellular vesicles (uEVs). Objective:To analyze renal sodium transporters in uEVs of patients with CS and hypertension. Design:Observational study. Setting:University hospital. Participants:The uEVs were isolated by ultracentrifugation and analyzed by immunoblotting in 10 patients with CS and 7 age-matched healthy participants. In 7 patients with CS, uEVs were analyzed before and after treatment. Main Outcome Measure:Abundance of protein in uEVs. Results:The 10 patients with CS were divided in those with suppressed and nonsuppressed renin-angiotensin-aldosterone system (RAAS; n = 5 per group). Patients with CS with suppressed RAAS had similar blood pressure but significantly lower serum potassium than patients with CS with nonsuppressed RAAS. Compared with healthy participants, only patients with suppressed RAAS had higher phosphorylated Na+-K+-Cl- cotransporter type 2 (pNKCC2) and higher total and phosphorylated Na+-Cl- cotransporter (pNCC) in uEVs. Serum potassium but not urinary free cortisol correlated with pNKCC2, pNCC, and Na+-Cl- cotransporter (NCC) in uEVs. Treatment of CS reversed the increases in pNKCC2, NCC, and pNCC. Conclusions:CS increases renal sodium transporter abundance in uEVs in patients with hypertension and suppressed RAAS. Potassium has recently been identified as an important driver of NCC activity, and low serum potassium may also contribute to increased renal sodium reabsorption and hypertension in CS. These results may also be relevant for hypertension induced by exogenous glucocorticoids.

In-hospital continuous electrocardiographic monitoring, commonly referred to as telemetry, has allowed for rapid recognition of life-threatening conditions, including complex arrhythmias and myocardial ischemia. However, inappropriate use can lead to unnecessary downstream testing from "false alarms," which in turn affects clinician efficiency and increases health care costs without benefiting patients. For these reasons, the Society of Hospital Medicine's Choosing Wisely campaign recommended use of a protocol-driven discontinuation of telemetry. The American Heart Association (AHA) developed a set of Practice Standards for the appropriate use of telemetry monitoring in 2004, which they updated in 2017. Unfortunately, the AHA Practice Standards have not been widely adopted-with as many as 43% of monitored patients lacking a recommended indication for monitoring. Thus, we created an overview discussing the safety and efficacy of incorporating the AHA Practice Standards and a review of studies highlighting their successful incorporation within patient care workflow. We conclude by outlining an "implementation blueprint" for health system professionals and administrators seeking to change their institution's culture of telemetry use. As the health care landscape continues to shift, enacting high-value initiatives that improve patient safety and efficiency of care will be critical.

Obstructive sleep apnea (OSA) is common, and many cross-sectional and longitudinal studies have established OSA as an independent risk factor for the development of a variety of adverse metabolic disease states, including hypertension, insulin resistance, type 2 diabetes, nonalcoholic fatty liver disease, dyslipidemia, and atherosclerosis. Nasal continuous positive airway pressure (CPAP) has long been the mainstay of therapy for OSA, but definitive studies demonstrating the efficacy of CPAP in improving metabolic outcomes, or in reducing incident disease burden, are lacking; moreover, CPAP has variable rates of adherence. Therefore, the future of OSA management, particularly with respect to limiting OSA-related metabolic dysfunction, likely lies in a coming wave of alternative approaches to endophenotyping OSA patients, personalized care, and defining and targeting mechanisms of OSA-induced adverse health outcomes.

BACKGROUND:Hepatocellular carcinoma (HCC) is a complication of chronic hepatitis B and C virus (HBV and HCV) infection. New York City (NYC) has a high prevalence of HBV and HCV, and infected persons likely face increased mortality from HCC and other causes. We describe the mortality profile of NYC residents with HBV or HCV, emphasizing the contributions of HCC and HIV coinfection. METHODS: Two existing data sets were combined to examine all individuals diagnosed with HBV or HCV in NYC first reported to the Health Department during 2001-2012 and their HCC, HIV, and vital status. Logistic regression was used to calculate the odds of HCC diagnosis by viral hepatitis status, whereas Cox proportional hazard regression was used to estimate the hazard of death by HCC/HIV status. RESULTS:In total, 120 952 and 127 933 individuals were diagnosed with HBV or HCV, respectively. HCV-infected individuals had 17% higher odds of HCC diagnosis than HBV-infected individuals and 3.2 times higher odds of HIV coinfection. Those with HCV were twice as likely to die during the study period (adjusted hazard ratio, 2.04; 95% confidence interval, 1.96-2.12). The risk of death increased for those with HIV or HCC and was highest for those with both conditions. CONCLUSIONS:HCC and HIV represent substantial risks to survival for both HBV- and HCV-infected individuals. Individuals with HBV need close monitoring and treatment, when indicated, and routine HCC screening. Those with HCV need increased, timely access to curative medications before developing liver disease.

OBJECTIVES/OBJECTIVE:The National Patient-Centered Clinical Research Network (PCORnet) supports observational and clinical research using healthcare data. The PCORnet Antibiotics and Childhood Growth Study is one of PCORnet's inaugural observational studies. The objectives of this manuscript are to describe (1) the processes used to integrate and analyze data from children across 36 participating institutions and (2) the cohort characteristics and prevalence of antibiotic use. METHODS:percentile. RESULTS:681,739 children met the cohort inclusion criteria and were racially/ethnically diverse (24.9% black, 17.5% Hispanic). Before 24 months, 55.2% of children received at least one antibiotic prescription; 21.3% received a single antibiotic prescription, 14.3% received four or more, and 33.3% received a broad spectrum antibiotic. Overweight and obesity prevalence was 27.6% at 4 to <6 years of age (n=362,044) and 36.2% at 9 to <11 years (n=58,344). CONCLUSION/CONCLUSIONS:The PCORnet Antibiotics study is a large, national longitudinal observational study in a diverse population that will examine the relationship between early antibiotic use and subsequent growth patterns in children.

Polymyxin B and fosfomycin are two 'old' antibiotics that consistently maintain activity against Klebsiella pneumoniae carbapenemase (KPC)-producing organisms based on in vitro susceptibility testing. However, each antibiotic's use in monotherapy has been associated with high rates of treatment failure. Therefore, our objective was to investigate the combinatorial pharmacodynamics of polymyxin B and fosfomycin against KPC-producing K. pneumoniae. Polymyxin B front-loading (3.33 mg/kg for 1 dose followed by 1.43 mg/kg q12h starting 12h later) and burst (5.53 mg/kg for 1 dose followed by no subsequent doses) simulated dosing regimens were explored in combination with fosfomycin (4g q8h) against KPC-2-producing K. pneumoniae ST258 in a hollow fibre infection model over 120h. Population analysis profiles were used to track the temporal polymyxin B and fosfomycin resistance profiles. Against isolate KPC-Kp 9A (polymyxin B MIC: 0.5mg/L, fosfomycin MIC: ≤8mg/L), monotherapies resulted in >3 log₁₀CFU/mL killing within 3h, but regrowth and proliferation of resistant subpopulations within 48h. Polymyxin B combinations with fosfomycin demonstrated rapid bacterial killing (>6 log₁₀CFU/mL reductions) while preventing propagation of polymyxin and fosfomycin resistance. Against isolate KPC-Kp 24A with a higher fosfomycin MIC (polymyxin B MIC: 0.5mg/L, fosfomycin MIC: 32g/L), a polymyxin B burst and fosfomycin combination caused a >6 log₁₀CFU/mL reduction within 1 hour, although bacterial regrowth occurred with the amplification of fosfomycin-resistant subpopulations. Polymyxin B in combination with fosfomycin may provide a practicable treatment strategy against KPC-producing K. pneumoniae and warrants further investigation.

INTRODUCTION:Treatment of type 2 diabetes (T2D) in children and adolescents is particularly challenging. Metformin monotherapy is the standard initial treatment for youth with T2D, once metabolic control is restored with insulin in patients who present with ketosis and/or marked hyperglycemia. Insulin, the only other drug approved for use in youth with T2D, is also used as add-on therapy when patients fail metformin mono-therapy. Areas covered: In this paper, we will summarize the current use of both metformin and insulin in the treatment of pediatric type 2 diabetes, as well as comment on their limitations. Given the rapid progression of T2D in youth, there is also considerable interest in treating youth with new oral and injectable agents that have been approved for use in adults with T2D. The potential for improving clinical outcomes of each of the main classes of new drugs for the treatment of pediatric T2D will be summerized. Expert commentary: We will conclude by reviewing why phase 3 randomized clinical trials examining the safety and efficacy of these medications in the pediatric population have been difficult to complete and discuss a potential pathway to overcome these obstacles to regulatory approval for these drugs for adolescents with T2D.