Comparison of SARS-CoV-2 Reverse Transcriptase Polymerase Chain Reaction and BinaxNOW Rapid Antigen Tests at a Community Site During an Omicron Surge: A Cross-Sectional Study: Annals of Internal Medicine: Vol 175, No 5

Background: SARS-CoV-2 rapid antigen tests are an important public health tool. Objective: To evaluate field performance of the BinaxNOW rapid antigen test (Abbott) compared with reverse transcriptase polymerase chain reaction (RT-PCR) for detecting infection with the Omicron variant of SARS-CoV-2. Design: Cross-sectional surveillance study. Setting: Free, walk-up, outdoor, urban community testing and vaccine site led by Unidos en Salud, serving a predominantly Latinx community highly impacted by COVID-19. Participants: Persons seeking COVID-19 testing in January 2022. Measurements: Simultaneous BinaxNOW and RT-PCR from nasal, cheek, and throat swabs, including cycle threshold (Ct) measures; a lower Ct value is a surrogate for higher amounts of virus. Results: Among 731 persons tested with nasal swabs, there were 296 (40.5%) positive results on RT-PCR; 98.9% were the Omicron variant. BinaxNOW detected 95.2% (95% CI, 91% to 98%) of persons who tested positive on RT-PCR with a Ct value below 30, 82.1% (CI, 77% to 87%) of those who tested positive on RT-PCR with a Ct value below 35, and 65.2% (CI, 60% to 71%) of all who were positive on RT-PCR. Among 75 persons with simultaneous nasal and cheek swabs, BinaxNOW using a cheek swab failed to detect 91% (20 of 22) of specimens that were positive on BinaxNOW with a nasal swab. Among persons with simultaneous nasal and throat swabs who were positive on RT-PCR with a Ct value below 30, 42 of 49 (85.7%) were detected by nasal BinaxNOW, 23 of 49 (46.9%) by throat BinaxNOW, and 44 of 49 (89.8%) by either. Limitation: Participants were a cross-sectional sample from a community-based sentinel surveillance site, precluding study of viral or symptom dynamics. Conclusion: BinaxNOW detected persons with high SARS-CoV-2 levels during the Omicron surge, enabling rapid responses to positive test results. Cheek or throat swabs should not replace nasal swabs. As currently recommended, high-risk persons with an initial negative BinaxNOW result should have repeated testing. Primary Funding Source: University of California, San Francisco.

Preventing Obesity in Midlife Women: A Systematic Review for the Women's Preventive Services Initiative

Background: Despite high prevalence rates of obesity in the United States, no clinical guidelines exist for obesity prevention in midlife women who commonly experience weight gain. Purpose: To evaluate evidence on the effectiveness and harms of behavioral interventions to reduce weight gain and improve health outcomes for women aged 40 to 60 years without obesity. Data Sources: English-language searches of Ovid MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews (inception to 26 October 2021); ClinicalTrials.gov (October 2021); and reference lists of studies and reviews. Study Selection: Randomized controlled trials (RCTs) enrolling predominantly midlife women comparing behavioral interventions to prevent weight gain with control groups and reporting health outcomes and potential harms. Data Extraction: Dual extraction and quality assessment of individual studies. Data Synthesis: Seven RCTs in 12 publications (n = 51 638) were included. Four RCTs showed statistically significant favorable differences in weight change for counseling interventions versus control groups (mean difference of weight change, −0.87 to −2.5 kg), whereas 1 trial of counseling and 2 trials of exercise showed no differences; 1 of 2 RCTs reported improved quality-of-life measures. Interventions did not increase measures of depression or stress in 1 trial; self-reported falls (37% vs. 29%; P < 0.001) and injuries (19% vs. 14%; P = 0.03) were higher with exercise counseling in 1 trial. Limitation: Trials were generally small, heterogeneous, and lacked data on harms, long-term health outcomes, and specific patient populations. Conclusion: Counseling interventions to prevent weight gain in women during midlife may result in modest differences in weight change without causing important harms. More research is needed to determine optimal content, frequency, length, and number of sessions required and should include additional patient populations. Primary Funding Source: Health Resources and Services Administration.

Characteristics of High-Need, High-Cost Patients: A “Best-Fit” Framework Synthesis: Annals of Internal Medicine: Vol 175, No 12

Background: Accurately identifying high-need, high-cost (HNHC) patients to reduce their preventable or modifiable health care use for their chronic conditions is a priority and a challenge for U.S. policymakers, health care delivery systems, and payers. Purpose: To identify characteristics and criteria to distinguish HNHC patients. Data Sources: Searches of multiple databases and gray literature from 1 January 2000 to 22 January 2022. Study Selection: English-language studies of characteristics and criteria to identify HNHC adult patients, defined as those with high use (emergency department, inpatient, or total services) or high cost. Data Extraction: Independent, dual-review extraction and quality assessment. Data Synthesis: The review included 64 studies comprising multivariate exposure studies (n = 47), cluster analyses (n = 11), and qualitative studies (n = 6). A National Academy of Medicine (NAM) taxonomy was an initial “best-fit” framework for organizing the synthesis of the findings. Patient characteristics associated with being HNHC included number and severity of comorbid conditions and having chronic clinical conditions, particularly heart disease, chronic kidney disease, chronic lung disease, diabetes, cancer, and hypertension. Patients' risk for being HNHC was often amplified by behavioral health conditions and social risk factors. The reviewers revised the NAM taxonomy to create a final framework, adding chronic pain and prior patterns of high health care use as characteristics associated with an increased risk for being HNHC. Limitation: Little evidence distinguished potentially preventable or modifiable health care use from overall use. Conclusion: A combination of characteristics can be useful for identifying HNHC patients. Because of the complexity of their conditions and circumstances, improving their quality of care will likely also require an individualized assessment of care needs and availability of support services. Primary Funding Source: Agency for Healthcare Research and Quality. (PROSPERO: CRD42020161179)

Mortality and Morbidity in Mild Primary Hyperparathyroidism: Results From a 10-Year Prospective Randomized Controlled Trial of Parathyroidectomy Versus Observation

Background: Primary hyperparathyroidism (PHPT) is a common endocrine disorder associated with increased risk for fractures, cardiovascular disease, kidney disease, and cancer and increased mortality. In mild PHPT with modest hypercalcemia and without known morbidities, parathyroidectomy (PTX) is debated because no long-term randomized trials have been performed. Objective: To examine the effect of PTX on mild PHPT with regard to mortality (primary end point) and key morbidities (secondary end point). Design: Prospective randomized controlled trial. (ClinicalTrials.gov: NCT00522028) Setting: Eight Scandinavian referral centers. Patients: From 1998 to 2005, 191 patients with mild PHPT were included. Intervention: Ninety-five patients were randomly assigned to PTX, and 96 were assigned to observation without intervention (OBS). Measurements: Date and causes of death were obtained from the Swedish and Norwegian Cause of Death Registries 10 years after randomization and after an extended observation period lasting until 2018. Morbidity events were prospectively registered annually. Results: After 10 years, 15 patients had died (8 in the PTX group and 7 in the OBS group). Within the extended observation period, 44 deaths occurred, which were evenly distributed between groups (24 in the PTX group and 20 in the OBS group). A total of 101 morbidity events (cardiovascular events, cerebrovascular events, cancer, peripheral fractures, and renal stones) were also similarly distributed between groups (52 in the PTX group and 49 in the OBS group). During the study, a total of 16 vertebral fractures occurred in 14 patients (7 in each group). Limitation: During the study period, 23 patients in the PTX group and 27 in the OBS group withdrew. Conclusion: Parathyroidectomy does not appear to reduce morbidity or mortality in mild PHPT. Thus, no evidence of adverse effects of observation was seen for at least a decade with respect to mortality, fractures, cancer, cardiovascular and cerebrovascular events, or renal morbidities. Primary Funding Source: Swedish government, Norwegian Research Council, and South-Eastern Norway Regional Health Authority.

Preconception Antidiabetic Drugs in Men and Birth Defects in Offspring: A Nationwide Cohort Study: Annals of Internal Medicine: Vol 175, No 5

Background: Diabetes reduces semen quality and increasingly occurs during reproductive years. Diabetes medications, such as metformin, have glucose-independent effects on the male reproductive system. Associations with birth defects in offspring are unknown. Objective: To evaluate whether the risk for birth defects in offspring varies with preconceptional pharmacologic treatment of fathers with diabetes. Design: Nationwide prospective registry-based cohort study. Setting: Denmark from 1997 to 2016. Participants: All liveborn singletons from mothers without histories of diabetes or essential hypertension. Measurements: Offspring were considered exposed if their father filled 1 or more prescriptions for a diabetes drug during the development of fertilizing sperm. Sex and frequencies of major birth defects were compared across drugs, times of exposure, and siblings. Results: Of 1 116 779 offspring included, 3.3% had 1 or more major birth defects (reference). Insulin-exposed offspring (n = 5298) had the reference birth defect frequency (adjusted odds ratio [aOR], 0.98 [95% CI, 0.85 to 1.14]). Metformin-exposed offspring (n = 1451) had an elevated birth defect frequency (aOR, 1.40 [CI, 1.08 to 1.82]). For sulfonylurea-exposed offspring (n = 647), the aOR was 1.34 (CI, 0.94 to 1.92). Offspring whose fathers filled a metformin prescription in the year before (n = 1751) or after (n = 2484) sperm development had reference birth defect frequencies (aORs, 0.88 [CI, 0.59 to 1.31] and 0.92 [CI, 0.68 to 1.26], respectively), as did unexposed siblings of exposed offspring (3.2%; exposed vs. unexposed OR, 1.54 [CI, 0.94 to 2.53]). Among metformin-exposed offspring, genital birth defects, all in boys, were more common (aOR, 3.39 [CI, 1.82 to 6.30]), while the proportion of male offspring was lower (49.4% vs. 51.4%, P = 0.073). Limitation: Information on underlying disease status was limited. Conclusion: Preconception paternal metformin treatment is associated with major birth defects, particularly genital birth defects in boys. Further research should replicate these findings and clarify the causation. Primary Funding Source: National Institutes of Health.

Time for a Change: Optimizing Drug Data and Informed Choice in Pregnancy

Challenges in Estimating the Effectiveness of COVID-19 Vaccination Using Observational Data

The COVID-19 vaccines were developed and rigorously evaluated in randomized trials during 2020. However, important questions, such as the magnitude and duration of protection, their effectiveness against new virus variants, and the effectiveness of booster vaccination, could not be answered by randomized trials and have therefore been addressed in observational studies. Analyses of observational data can be biased because of confounding and because of inadequate design that does not consider the evolution of the pandemic over time and the rapid uptake of vaccination. Emulating a hypothetical “target trial” using observational data assembled during vaccine rollouts can help manage such potential sources of bias. This article describes 2 approaches to target trial emulation. In the sequential approach, on each day, eligible persons who have not yet been vaccinated are matched to a vaccinated person. The single-trial approach sets a single baseline at the start of the rollout and considers vaccination as a time-varying variable. The nature of the confounding depends on the analysis strategy: Estimating “per-protocol” effects (accounting for vaccination of initially unvaccinated persons after baseline) may require adjustment for both baseline and “time-varying” confounders. These issues are illustrated by using observational data from 2 780 931 persons in the United Kingdom aged 70 years or older to estimate the effect of a first dose of a COVID-19 vaccine. Addressing the issues discussed in this article should help authors of observational studies provide robust evidence to guide clinical and policy decisions.

Development and Validation of the Summary Elixhauser Comorbidity Score for Use With ICD-10-CM–Coded Data Among Older Adults

Background: Older adults have many comorbidities contributing to mortality. Objective: To develop a summary Elixhauser (S-Elixhauser) comorbidity score to predict 30-day, in-hospital, and 1-year mortality in older adults using the 38 comorbidities operationalized by the Agency for Healthcare Research and Quality (AHRQ). Design: Retrospective cohort study. Setting: Medicare beneficiaries from 2017 to 2019. Patients: Persons hospitalized in 2018 (n = 899 844) and 3 disease-specific hospitalized cohorts. Measurements: Weights were derived for 38 comorbidities to predict 30-day, in-hospital, and 1-year mortality. The S-Elixhauser score was internally validated and calibrated. Individual Elixhauser comorbidity indicators (38 comorbidities), the modified application of the AHRQ-derived Elixhauser summary score, the Charlson comorbidity indicators (17 comorbidities), and the Charlson summary score were externally validated. The c-statistic was used to evaluate discrimination of a comorbidity score model. Results: The S-Elixhauser score was well calibrated and internally validated, with a c-statistic of 0.705 (95% CI, 0.703 to 0.707) in predicting 30-day mortality, 0.654 (CI, 0.651 to 0.657) for in-hospital mortality, and 0.743 (CI, 0.741 to 0.744) for 1-year mortality. In external validation of other comorbidity indices for 30-day mortality, the c-statistic was 0.711 (CI, 0.709 to 0.713) for the individual Elixhauser comorbidity indicators, 0.688 (CI, 0.686 to 0.690) for the AHRQ Elixhauser score, 0.696 (CI, 0.694 to 0.698) for the Charlson comorbidity indicators, and 0.690 (CI, 0.688 to 0.693) for the Charlson summary score. In 3 disease-specific populations, the discrimination of the S-Elixhauser score in predicting 30-day mortality ranged from 0.657 to 0.732. Limitation: Validation of the S-Elixhauser comorbidity score and head-to-head comparison with other comorbidity scores in an external population are needed to evaluate comparative performance. Conclusion: The S-Elixhauser comorbidity score is well calibrated and internally validated but its advantage over the AHRQ Elixhauser and Charlson summary scores is unclear. Primary Funding Source: National Institute on Aging.

SARS-CoV-2 Vaccine Antibody Response and Breakthrough Infection in Patients Receiving Dialysis

Background: Whether breakthrough SARS-CoV-2 infections after vaccination are related to the level of postvaccine circulating antibody is unclear. Objective: To determine longitudinal antibody-based response and risk for breakthrough infection after SARS-CoV-2 vaccination. Design: Prospective study. Setting: Nationwide sample from dialysis facilities. Patients: 4791 patients receiving dialysis. Measurements: Remainder plasma from a laboratory processing routine monthly tests was used to measure qualitative and semiquantitative antibodies to the receptor-binding domain (RBD) of SARS-CoV-2. To evaluate whether peak or prebreakthrough RBD values were associated with breakthrough infection, a nested case–control analysis matched each breakthrough case patient to 5 control patients by age, sex, and vaccination month and adjusted for diabetes status and region of residence. Results: Of the 4791 patients followed with monthly RBD assays, 2563 were vaccinated as of 14 September 2021. Among the vaccinated patients, the estimated proportion with an undetectable RBD response increased from 6.6% (95% CI, 5.5% to 7.8%) 14 to 30 days after vaccination to 20.2% (CI, 17.0% to 23.3%) 5 to 6 months after vaccination. Estimated median index values decreased from 91.9 (CI, 78.6 to 105.2) 14 to 30 days after vaccination to 8.4 (CI, 7.6 to 9.3) 5 to 6 months after vaccination. Breakthrough infections occurred in 56 patients, with samples collected a median of 21 days before breakthrough infection. Compared with prebreakthrough index RBD values of 23 or higher (equivalent to ≥506 binding antibody units per milliliter), prebreakthrough RBD values less than 10 and values from 10 to less than 23 were associated with higher odds for breakthrough infection (rate ratios, 11.6 [CI, 3.4 to 39.5] and 6.0 [CI, 1.5 to 23.6], respectively). Limitations: Single measure of vaccine response; ascertainment of COVID-19 diagnosis from electronic health records. Conclusion: The antibody response to SARS-CoV-2 vaccination wanes rapidly in persons receiving dialysis. In this population, the circulating antibody response is associated with risk for breakthrough infection. Primary Funding Source: Ascend Clinical Laboratory.

Reinfection and Risk Behaviors After Treatment of Hepatitis C Virus Infection in Persons Receiving Opioid Agonist Therapy: A Cohort Study: Annals of Internal Medicine: Vol 175, No 9

Background: Hepatitis C virus (HCV) reinfection after successful treatment may reduce the benefits of cure among people who inject drugs. Objective: To evaluate the rate of HCV reinfection for 3 years after successful treatment among people receiving opioid agonist therapy (OAT). Design: A 3-year, long-term, extension study of persons enrolled in the CO-STAR (Hepatitis C Patients on Opioid Substitution Therapy Antiviral Response) study (ClinicalTrials.gov: NCT02105688). Setting: 55 clinical trial sites in 13 countries. Patients: Aged 18 years and older with chronic HCV infection with genotypes 1, 4, or 6 receiving stable OAT. Intervention: No treatments were administered. Measurements: Serum samples were assessed for HCV reinfection. Urine drug screening was performed. Results: Among 296 participants who received treatment, 286 were evaluable for reinfection and 199 were enrolled in the long-term extension study. The rate of HCV reinfection was 1.7 [95% CI, 0.8 to 3.0] per 100 person-years; 604 person-years of follow-up). A higher rate of reinfection was seen among people with recent injecting drug use (1.9 [95% CI, 0.5 to 4.8] per 100 person-years; 212 person-years). Ongoing drug use and injecting drug use were reported by 59% and 21% of participants, respectively, at the 6-month follow-up visit and remained stable during 3 years of follow-up. Limitations: Participants were required to be 80% adherent to OAT at baseline and may represent a population with higher stability and lower risk for HCV reinfection. Rate of reinfection may be underestimated because all participants did not continue in the long-term extension study; whether participants who discontinued were at higher risk for reinfection is unknown. Conclusion: Reinfection with HCV was low but was highest in the first 24 weeks after treatment completion and among people with ongoing injecting drug use and needle–syringe sharing. Primary Funding Source: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.