Development and Validation of a Protein Risk Score for Mortality in Heart Failure: A Community Cohort Study: Annals of Internal Medicine: Vol 177, No 1

Background: Heart failure (HF) is a complex clinical syndrome with high mortality. Current risk stratification approaches lack precision. High-throughput proteomics could improve risk prediction. Its use in clinical practice to guide the management of patients with HF depends on validation and evidence of clinical benefit. Objective: To develop and validate a protein risk score for mortality in patients with HF. Design: Community-based cohort. Setting: Southeast Minnesota. Participants: Patients with HF enrolled between 2003 and 2012 and followed through 2021. Measurements: A total of 7289 plasma proteins in 1351 patients with HF were measured using the SomaScan Assay (SomaLogic). A protein risk score was derived using least absolute shrinkage and selection operator regression and temporal validation in patients enrolled between 2003 and 2007 (development cohort) and 2008 and 2012 (validation cohort). Multivariable Cox regression was used to examine the association between the protein risk score and mortality. The performance of the protein risk score to predict 5-year mortality risk was assessed using calibration plots, decision curves, and relative utility analyses and compared with a clinical model, including the Meta‐Analysis Global Group in Chronic Heart Failure mortality risk score and N-terminal pro–B-type natriuretic peptide. Results: The development (n = 855; median age, 78 years; 50% women; 29% with ejection fraction <40%) and validation cohorts (n = 496; median age, 76 years; 45% women; 33% with ejection fraction <40%) were mostly similar. In the development cohort, 38 unique proteins were selected for the protein risk score. Independent of ejection fraction, the protein risk score demonstrated good calibration, reclassified mortality risk particularly at the extremes of the risk distribution, and showed greater clinical utility compared with the clinical model. Limitation: Participants were predominantly of European ancestry, potentially limiting the generalizability of the findings to different patient populations. Conclusion: Validation of the protein risk score demonstrated good calibration and evidence of predicted benefits to stratify the risk for death in HF superior to that of clinical methods. Further studies are needed to prospectively evaluate the score’s performance in diverse populations and determine risk thresholds for interventions. Primary Funding Source: Division of Intramural Research at the National Heart, Lung, and Blood Institute of the National Institutes of Health.

Assessing Clinician Utilization of Next-Generation Antibiotics Against Resistant Gram-Negative Infections in U.S. Hospitals: A Retrospective Cohort Study: Annals of Internal Medicine: Vol 177, No 5

Background: The U.S. antibiotic market failure has threatened future innovation and supply. Understanding when and why clinicians underutilize recently approved gram-negative antibiotics might help prioritize the patient in future antibiotic development and potential market entry rewards. Objective: To determine use patterns of recently U.S. Food and Drug Administration (FDA)-approved gram-negative antibiotics (ceftazidime–avibactam, ceftolozane–tazobactam, meropenem–vaborbactam, plazomicin, eravacycline, imipenem–relebactam–cilastatin, and cefiderocol) and identify factors associated with their preferential use (over traditional generic agents) in patients with gram-negative infections due to pathogens displaying difficult-to-treat resistance (DTR; that is, resistance to all first-line antibiotics). Design: Retrospective cohort. Setting: 619 U.S. hospitals. Participants: Adult inpatients. Measurements: Quarterly percentage change in antibiotic use was calculated using weighted linear regression. Machine learning selected candidate variables, and mixed models identified factors associated with new (vs. traditional) antibiotic use in DTR infections. Results: Between quarter 1 of 2016 and quarter 2 of 2021, ceftolozane–tazobactam (approved 2014) and ceftazidime–avibactam (2015) predominated new antibiotic usage whereas subsequently approved gram-negative antibiotics saw relatively sluggish uptake. Among gram-negative infection hospitalizations, 0.7% (2551 [2631 episodes] of 362 142) displayed DTR pathogens. Patients were treated exclusively using traditional agents in 1091 of 2631 DTR episodes (41.5%), including “reserve” antibiotics such as polymyxins, aminoglycosides, and tigecycline in 865 of 1091 episodes (79.3%). Patients with bacteremia and chronic diseases had greater adjusted probabilities and those with do-not-resuscitate status, acute liver failure, and Acinetobacter baumannii complex and other nonpseudomonal nonfermenter pathogens had lower adjusted probabilities of receiving newer (vs. traditional) antibiotics for DTR infections, respectively. Availability of susceptibility testing for new antibiotics increased probability of usage. Limitation: Residual confounding. Conclusion: Despite FDA approval of 7 next-generation gram-negative antibiotics between 2014 and 2019, clinicians still frequently treat resistant gram-negative infections with older, generic antibiotics with suboptimal safety–efficacy profiles. Future antibiotics with innovative mechanisms targeting untapped pathogen niches, widely available susceptibility testing, and evidence demonstrating improved outcomes in resistant infections might enhance utilization. Primary Funding Source: U.S. Food and Drug Administration; NIH Intramural Research Program.

Food Insecurity Among Low-Income U.S. Adults During the COVID-19 Pandemic

Reducing Care Overuse in Older Patients Using Professional Norms and Accountability: A Cluster Randomized Controlled Trial: Annals of Internal Medicine: Vol 177, No 3

Background: Effective strategies are needed to curtail overuse that may lead to harm. Objective: To evaluate the effects of clinician decision support redirecting attention to harms and engaging social and reputational concerns on overuse in older primary care patients. Design: 18-month, single-blind, pragmatic, cluster randomized trial, constrained randomization. (ClinicalTrials.gov: NCT04289753) Setting: 60 primary care internal medicine, family medicine and geriatrics practices within a health system from 1 September 2020 to 28 February 2022. Participants: 371 primary care clinicians and their older adult patients from participating practices. Intervention: Behavioral science–informed, point-of-care, clinical decision support tools plus brief case-based education addressing the 3 primary clinical outcomes (187 clinicians from 30 clinics) were compared with brief case-based education alone (187 clinicians from 30 clinics). Decision support was designed to increase salience of potential harms, convey social norms, and promote accountability. Measurements: Prostate-specific antigen (PSA) testing in men aged 76 years and older without previous prostate cancer, urine testing for nonspecific reasons in women aged 65 years and older, and overtreatment of diabetes with hypoglycemic agents in patients aged 75 years and older and hemoglobin A1c (HbA1c) less than 7%. Results: At randomization, mean clinic annual PSA testing, unspecified urine testing, and diabetes overtreatment rates were 24.9, 23.9, and 16.8 per 100 patients, respectively. After 18 months of intervention, the intervention group had lower adjusted difference-in-differences in annual rates of PSA testing (−8.7 [95% CI, −10.2 to −7.1]), unspecified urine testing (−5.5 [CI, −7.0 to −3.6]), and diabetes overtreatment (−1.4 [CI, −2.9 to −0.03]) compared with education only. Safety measures did not show increased emergency care related to urinary tract infections or hyperglycemia. An HbA1c greater than 9.0% was more common with the intervention among previously overtreated diabetes patients (adjusted difference-in-differences, 0.47 per 100 patients [95% CI, 0.04 to 1.20]). Limitation: A single health system limits generalizability; electronic health data limit ability to differentiate between overtesting and underdocumentation. Conclusion: Decision support designed to increase clinicians’ attention to possible harms, social norms, and reputational concerns reduced unspecified testing compared with offering traditional case-based education alone. Small decreases in diabetes overtreatment may also result in higher rates of uncontrolled diabetes. Primary Funding Source: National Institute on Aging.

Cardiovascular Health of Middle-Aged U.S. Adults by Income Level, 1999 to March 2020: A Serial Cross-Sectional Study: Annals of Internal Medicine: Vol 176, No 12

Background: Although cardiovascular mortality has increased among middle-aged U.S. adults since 2011, how the burden of cardiovascular risk factors has changed for this population by income level over the past 2 decades is unknown. Objective: To evaluate trends in the prevalence, treatment, and control of cardiovascular risk factors among low-income and higher-income middle-aged adults and how social determinants contribute to recent associations between income and cardiovascular health. Design: Serial cross-sectional study. Setting: NHANES (National Health and Nutrition Examination Survey), 1999 to March 2020. Participants: Middle-aged adults (aged 40 to 64 years). Measurements: Age-standardized prevalence of hypertension, diabetes, hyperlipidemia, obesity, and cigarette use; treatment rates for hypertension, diabetes, and hyperlipidemia; and rates of blood pressure, glycemic, and cholesterol control. Results: The study population included 20 761 middle-aged adults. The prevalence of hypertension, diabetes, and cigarette use was consistently higher among low-income adults between 1999 and March 2020. Low-income adults had an increase in hypertension over the study period (37.2% [95% CI, 33.5% to 40.9%] to 44.7% [CI, 39.8% to 49.5%]) but no changes in diabetes or obesity. In contrast, higher-income adults did not have a change in hypertension but had increases in diabetes (7.8% [CI, 5.0% to 10.6%] to 14.9% [CI, 12.4% to 17.3%]) and obesity (33.0% [CI, 26.7% to 39.4%] to 44.0% [CI, 40.2% to 47.7%]). Cigarette use was high and stagnant among low-income adults (33.2% [CI, 28.4% to 38.0%] to 33.9% [CI, 29.6% to 38.3%]) but decreased among their higher-income counterparts (18.6% [CI, 13.5% to 23.7%] to 11.5% [CI, 8.7% to 14.3%]). Treatment and control rates for hypertension were unchanged in both groups (>80%), whereas diabetes treatment rates improved only among the higher-income group (58.4% [CI, 44.4% to 72.5%] to 77.4% [CI, 67.6% to 87.1%]). Income-based disparities in hypertension, diabetes, and cigarette use persisted in more recent years even after adjustment for insurance coverage, health care access, and food insecurity. Limitation: Sample size limitations could preclude detection of small changes in treatment and control rates. Conclusion: Over 2 decades in the United States, hypertension increased in low-income middle-aged adults, whereas diabetes and obesity increased in their higher-income counterparts. Income-based disparities in hypertension, diabetes, and smoking persisted even after adjustment for other social determinants of health. Primary Funding Source: National Institutes of Health.

Asthma Disparities in the United States Narrowed During the COVID-19 Pandemic: Findings From a National Survey, 2019 to 2022

HIV Testing and Preexposure Prophylaxis Prescriptions Among U.S. Commercially Insured Transgender Men and Women, 2014 to 2021

Background: Transgender persons are disproportionately affected by HIV, but preexposure prophylaxis (PrEP) use has been low in this population. Clinical encounters for gender-affirming hormone therapy (GAHT) provide opportunities for HIV prevention. Objective: To estimate the number of commercially insured transgender women (TGW) and transgender men (TGM) in the United States and their use of HIV prevention services. Design: Retrospective analysis of secondary data. Setting: Merative MarketScan commercial databases from 2014 to 2021. Participants: TGW and TGM, defined as those with transgender-related diagnoses and prescriptions for feminizing or masculinizing GAHT. Measurements: HIV testing and PrEP use. Results: A substantially increasing trend was observed in the prevalence of transgender-related diagnosis codes from 2014 to 2021 and in the proportion of persons who used GAHT. The increases were driven by persons aged 18 to 34 years. In 2021, among 10 613 TGW with a test for or a diagnosis of a sexually transmitted infection (STI) in the previous 12 months, 61.1% had an HIV test; among those, 20.2% were prescribed PrEP. Among 4184 TGM with STI risk, 48.3% had an HIV test; among those, 10.2% were prescribed PrEP. The prevalence of TGW and TGM who had a test for or a diagnosis of an STI, had an HIV test, and were prescribed PrEP increased substantially from 2014 to 2021. Limitation: The findings represent only persons with commercial health insurance who sought health care services for GAHT. Conclusion: It is important to identify transgender persons to monitor their receipt of HIV prevention services. Encounters for GAHT provide opportunities to offer HIV prevention and other prevention services. Many HIV prevention opportunities were likely missed at clinical encounters for GAHT. Primary Funding Source: None.

Effectiveness of Recombinant Zoster Vaccine Against Herpes Zoster in a Real-World Setting

Background: A 2-dose series of recombinant zoster vaccine (RZV) was 97% effective against herpes zoster (HZ) in a pivotal clinical trial. Objective: To evaluate real-world effectiveness of RZV against HZ. Design: Prospective cohort study. Setting: Four health care systems in the Vaccine Safety Datalink. Participants: Persons aged 50 years or older. Measurements: The outcome was incident HZ defined by a diagnosis with an antiviral prescription. Cox regression was used to estimate the hazard of HZ in vaccinated persons compared with unvaccinated persons, with adjustment for covariates. Vaccine effectiveness (VE) was calculated as 1 minus the adjusted hazard ratio and was estimated by time since the last RZV dose and by corticosteroid use. Results: The study included nearly 2.0 million persons who contributed 7.6 million person-years of follow-up. After adjustment, VE of 1 dose was 64% and VE of 2 doses was 76%. After 1 dose only, VE was 70% during the first year, 45% during the second year, 48% during the third year, and 52% after the third year. After 2 doses, VE was 79% during the first year, 75% during the second year, and 73% during the third and fourth years. Vaccine effectiveness was 65% in persons who received corticosteroids before vaccination and 77% in those who did not. Limitation: Herpes zoster could not be identified as accurately in these observational data as in the previous clinical trials. Conclusion: Two doses of RZV were highly effective, although less effective than in the previous clinical trials. Two-dose effectiveness waned very little during the 4 years of follow-up. However, 1-dose effectiveness waned substantially after 1 year, underscoring the importance of the second dose. Primary Funding Source: Centers for Disease Control and Prevention.

Accurate Measurements of Gastric Emptying and Gastrointestinal Symptoms in the Evaluation of Glucagon-like Peptide-1 Receptor Agonists

Prevalence of Pharmacologic and Nonpharmacologic Pain Management Therapies Among Adults With Chronic Pain—United States, 2020