Clinical Validation of a Multitarget Fecal Immunochemical Test for Colorectal Cancer Screening: A Diagnostic Test Accuracy Study: Annals of Internal Medicine: Vol 174, No 9

Background: The fecal immunochemical test (FIT) is used in colorectal cancer (CRC) screening, yet it leaves room for improvement. Objective: To develop a multitarget FIT (mtFIT) with better diagnostic performance than FIT. Design: Diagnostic test accuracy study. Setting: Colonoscopy-controlled series. Participants: Persons (n = 1284) from a screening (n = 1038) and referral (n = 246) population were classified by their most advanced lesion (CRC [n = 47], advanced adenoma [n = 135], advanced serrated polyp [n = 30], nonadvanced adenoma [n = 250], and nonadvanced serrated polyp [n = 53]), along with control participants (n = 769). Measurements: Antibody-based assays were developed and applied to leftover FIT material. Classification and regression tree (CART) analysis was applied to biomarker concentrations to identify the optimal combination for detecting advanced neoplasia. Performance of this combination, the mtFIT, was cross-validated using a leave-one-out approach and compared with FIT at equal specificity. Results: The CART analysis showed a combination of hemoglobin, calprotectin, and serpin family F member 2—the mtFIT—to have a cross-validated sensitivity for advanced neoplasia of 42.9% (95% CI, 36.2% to 49.9%) versus 37.3% (CI, 30.7% to 44.2%) for FIT (P = 0.025), with equal specificity of 96.6%. In particular, cross-validated sensitivity for advanced adenomas increased from 28.1% (CI, 20.8% to 36.5%) to 37.8% (CI, 29.6% to 46.5%) (P = 0.006). On the basis of these results, early health technology assessment indicated that mtFIT-based screening could be cost-effective compared with FIT. Limitation: Study population is enriched with persons from a referral population. Conclusion: Compared with FIT, the mtFIT showed better diagnostic accuracy in detecting advanced neoplasia because of an increased detection of advanced adenomas. Moreover, early health technology assessment indicated that these results provide a sound basis to pursue further development of mtFIT as a future test for population-based CRC screening. A prospective screening trial is in preparation. Primary Funding Source: Stand Up to Cancer/Dutch Cancer Society, Dutch Digestive Foundation, and HealthHolland.

Major Update: Remdesivir for Adults With COVID-19: A Living Systematic Review and Meta-analysis for the American College of Physicians Practice Points: Annals of Internal Medicine: Vol 174, No 5

An updated version of this article was published on 1 March 2022. Background: Remdesivir is being studied and used for treatment of coronavirus disease 2019 (COVID-19). Purpose: To update a previous review of remdesivir for adults with COVID-19, including new meta-analyses of patients with COVID-19 of any severity compared with control. Data Sources: Several sources from 1 January 2020 through 7 December 2020. Study Selection: English-language, randomized controlled trials (RCTs) of remdesivir for COVID-19. New evidence is incorporated by using living review methods. Data Extraction: 1 reviewer abstracted data; a second reviewer verified the data. The Cochrane Risk of Bias Tool and GRADE (Grading of Recommendations Assessment, Development and Evaluation) method were used. Data Synthesis: The update includes 5 RCTs, incorporating data from a new large RCT and the final results of a previous RCT. Compared with control, a 10-day course of remdesivir probably results in little to no reduction in mortality (risk ratio [RR], 0.93 [95% CI, 0.82 to 1.06]; 4 RCTs) but may result in a small reduction in the proportion of patients receiving mechanical ventilation (RR, 0.71 [CI, 0.56 to 0.90]; 3 RCTs). Remdesivir probably results in a moderate increase in the percentage of patients who recovered and a moderate decrease in serious adverse events and may result in a large reduction in time to recovery. Effect on hospital length of stay or percentage remaining hospitalized is mixed. Compared with a 10-day course for those not requiring ventilation at baseline, a 5-day course may reduce mortality, the need for ventilation, and serious adverse events while increasing the percentage of patients who recovered or clinically improved. Limitation: Summarizing findings was challenging because of varying disease severity definitions and outcomes. Conclusion: In hospitalized adults with COVID-19, remdesivir probably results in little to no mortality difference but probably improves the percentage recovered and reduces serious harms and may result in a small reduction in the proportion receiving ventilation. For patients not receiving ventilation, a 5-day course may provide greater benefits and fewer harms with lower drug costs than a 10-day course. Primary Funding Source: U.S. Department of Veterans Affairs.

Diabetes Screening by Race and Ethnicity in the United States: Equivalent Body Mass Index and Age Thresholds

Background: Racial/ethnic minority populations in the United States have increased rates of diabetes compared with White populations. The 2021 guidelines from the U.S. Preventive Services Task Force recommend diabetes screening for adults aged 35 to 70 years with a body mass index (BMI) of 25 kg/m2 or greater. Objective: To determine the BMI threshold for diabetes screening in major racial/ethnic minority populations with benefits and harms equivalent to those of the current diabetes screening threshold in White adults. Design: Cross-sectional study. Setting: NHANES (National Health and Nutrition Examination Survey), 2011 to 2018. Participants: Nonpregnant U.S. adults aged 18 to 70 years (n = 19 335). Measurements: A logistic regression model was used to estimate diabetes prevalence at various BMIs for White, Asian, Black, and Hispanic Americans. For each racial/ethnic minority group, the equivalent BMI threshold was defined as the BMI at which the prevalence of diabetes in 35-year-old persons in that group is equal to that in 35-year-old White adults at a BMI of 25 kg/m2. Ranges were estimated to account for the uncertainty in prevalence estimates for White and racial/ethnic minority populations. Results: Among adults aged 35 years with a BMI of 25 kg/m2, the prevalence of diabetes in Asian Americans (3.8% [95% CI, 2.8% to 5.1%]), Black Americans (3.5% [CI, 2.7% to 4.7%]), and Hispanic Americans (3.0% [CI, 2.1% to 4.2%]) was significantly higher than that in White Americans (1.4% [CI, 1.0% to 2.0%]). Compared with a BMI threshold of 25 kg/m2 in White Americans, the equivalent BMI thresholds for diabetes prevalence were 20 kg/m2 (range, <18.5 to 23 kg/m2) for Asian Americans, less than 18.5 kg/m2 (range, <18.5 to 23 kg/m2) for Black Americans, and 18.5 kg/m2 (range, <18.5 to 24 kg/m2) for Hispanic Americans. Limitation: Sample size limitations precluded assessment of heterogeneity within racial/ethnic groups. Conclusion: Among U.S. adults aged 35 years or older, offering diabetes screening to Black Americans and Hispanic Americans with a BMI of 18.5 kg/m2 or greater and Asian Americans with a BMI of 20 kg/m2 or greater would be equivalent to screening White adults with a BMI of 25 kg/m2 or greater. Using screening thresholds specific to race/ethnicity has the potential to reduce disparities in diabetes diagnosis. Primary Funding Source: Richard A. and Susan F. Smith Center for Outcomes Research in Cardiology.

A Public Health COVID-19 Vaccination Strategy to Maximize the Health Gains for Every Single Vaccine Dose

Donor HLA Class 1 Evolutionary Divergence Is a Major Predictor of Liver Allograft Rejection: A Retrospective Cohort Study: Annals of Internal Medicine: Vol 174, No 10

Background: The HLA evolutionary divergence (HED), a continuous metric quantifying the peptidic differences between 2 homologous HLA alleles, reflects the breadth of the immunopeptidome presented to T lymphocytes. Objective: To assess the potential effect of donor or recipient HED on liver transplant rejection. Design: Retrospective cohort study. Setting: Liver transplant units. Patients: 1154 adults and 113 children who had a liver transplant between 2004 and 2018. Measurements: Liver biopsies were done 1, 2, 5, and 10 years after the transplant and in case of liver dysfunction. Donor-specific anti-HLA antibodies (DSAs) were measured in children at the time of biopsy. The HED was calculated using the physicochemical Grantham distance for class I (HLA-A or HLA-B) and class II (HLA-DRB1 or HLA-DQB1) alleles. The influence of HED on the incidence of liver lesions was analyzed through the inverse probability weighting approach based on covariate balancing, generalized propensity scores. Results: In adults, class I HED of the donor was associated with acute rejection (hazard ratio [HR], 1.09 [95% CI, 1.03 to 1.16]), chronic rejection (HR, 1.20 [CI, 1.10 to 1.31]), and ductopenia of 50% or more (HR, 1.33 [CI, 1.09 to 1.62]) but not with other histologic lesions. In children, class I HED of the donor was also associated with acute rejection (HR, 1.16 [CI, 1.03 to 1.30]) independent of the presence of DSAs. There was no effect of either donor class II HED or recipient class I or class II HED on the incidence of liver lesions in adults and children. Limitation: The DSAs were measured only in children. Conclusion: Class I HED of the donor predicts acute or chronic rejection of liver transplant. This novel and accessible prognostic marker could orientate donor selection and guide immunosuppression. Primary Funding Source: Institut National de la Santé et de la Recherche Médicale.

Annual Tuberculosis Preventive Therapy for Persons With HIV Infection: A Randomized Trial: Annals of Internal Medicine: Vol 174, No 10

Background: Tuberculosis preventive therapy for persons with HIV infection is effective, but its durability is uncertain. Objective: To compare treatment completion rates of weekly isoniazid–rifapentine for 3 months versus daily isoniazid for 6 months as well as the effectiveness of the 3-month rifapentine–isoniazid regimen given annually for 2 years versus once. Design: Randomized trial. (ClinicalTrials.gov: NCT02980016) Setting: South Africa, Ethiopia, and Mozambique. Participants: Persons with HIV infection who were receiving antiretroviral therapy, were aged 2 years or older, and did not have active tuberculosis. Intervention: Participants were randomly assigned to receive weekly rifapentine–isoniazid for 3 months, given either annually for 2 years or once, or daily isoniazid for 6 months. Participants were screened for tuberculosis symptoms at months 0 to 3 and 12 of each study year and at months 12 and 24 using chest radiography and sputum culture. Measurements: Treatment completion was assessed using pill counts. Tuberculosis incidence was measured over 24 months. Results: Between November 2016 and November 2017, 4027 participants were enrolled; 4014 were included in the analyses (median age, 41 years; 69.5% women; all using antiretroviral therapy). Treatment completion in the first year for the combined rifapentine–isoniazid groups (n = 3610) was 90.4% versus 50.5% for the isoniazid group (n = 404) (risk ratio, 1.78 [95% CI, 1.61 to 1.95]). Tuberculosis incidence among participants receiving the rifapentine–isoniazid regimen twice (n = 1808) or once (n = 1802) was similar (hazard ratio, 0.96 [CI, 0.61 to 1.50]). Limitation: If rifapentine–isoniazid is effective in curing subclinical tuberculosis, then the intensive tuberculosis screening at month 12 may have reduced its effectiveness. Conclusion: Treatment completion was higher with rifapentine–isoniazid for 3 months compared with isoniazid for 6 months. In settings with high tuberculosis transmission, a second round of preventive therapy did not provide additional benefit to persons receiving antiretroviral therapy. Primary Funding Source: The U.S. Agency for International Development through the CHALLENGE TB grant to the KNCV Tuberculosis Foundation.

Impact of Population Growth and Aging on Estimates of Excess U.S. Deaths During the COVID-19 Pandemic, March to August 2020

Background: Excess death estimates quantify the full impact of the coronavirus disease 2019 (COVID-19) pandemic. Widely reported U.S. excess death estimates have not accounted for recent population changes, especially increases in the population older than 65 years. Objective: To estimate excess deaths in the United States in 2020, after accounting for population changes. Design: Surveillance study. Setting: United States, March to August 2020. Participants: All decedents. Measurements: Age-specific excess deaths in the United States from 1 March to 31 August 2020 compared with 2015 to 2019 were estimated, after changes in population size and age were taken into account, by using Centers for Disease Control and Prevention provisional death data and U.S. Census Bureau population estimates. Cause-specific excess deaths were estimated by month and age. Results: From March through August 2020, 1 671 400 deaths were registered in the United States, including 173 300 COVID-19 deaths. An average of 1 370 000 deaths were reported over the same months during 2015 to 2019, for a crude excess of 301 400 deaths (128 100 non–COVID-19 deaths). However, the 2020 U.S. population includes 5.04 million more persons aged 65 years and older than the average population in 2015 to 2019 (a 10% increase). After population changes were taken into account, an estimated 217 900 excess deaths occurred from March through August 2020 (173 300 COVID-19 and 44 600 non–COVID-19 deaths). Most excess non–COVID-19 deaths occurred in April, July, and August, and 34 900 (78%) were in persons aged 25 to 64 years. Diabetes, Alzheimer disease, and heart disease caused the most non–COVID-19 excess deaths. Limitation: Provisional death data are underestimated because of reporting delays. Conclusion: The COVID-19 pandemic resulted in an estimated 218 000 excess deaths in the United States between March and August 2020, and 80% of those deaths had COVID-19 as the underlying cause. Accounting for population changes substantially reduced the excess non–COVID-19 death estimates, providing important information for guiding future clinical and public health interventions. Primary Funding Source: National Cancer Institute.

Estimated Effect on Life Expectancy of Alleviating Primary Care Shortages in the United States

Background: Prior studies have reported that greater numbers of primary care physicians (PCPs) per population are associated with reduced population mortality, but the effect of increasing PCP density in areas of low density is poorly understood. Objective: To estimate how alleviating PCP shortages might change life expectancy and mortality. Design: Generalized additive models, mixed-effects models, and generalized estimating equations. Setting: 3104 U.S. counties from 2010 to 2017. Participants: Children and adults. Measurements: Age-adjusted life expectancy; all-cause mortality; and mortality due to cardiovascular disease, cancer, infectious disease, respiratory disease, and substance use or injury. Results: Persons living in counties with less than 1 physician per 3500 persons in 2017 had a mean life expectancy that was 310.9 days shorter than for persons living in counties above that threshold. In the low-density counties (n = 1218), increasing the density of PCPs above the 1:3500 threshold would be expected to increase mean life expectancy by 22.4 days (median, 19.4 days [95% CI, 0.9 to 45.6 days]), and all such counties would require 17 651 more physicians, or about 14.5 more physicians per shortage county. If counties with less than 1 physician per 1500 persons (n = 2636) were to reach the 1:1500 threshold, life expectancy would be expected to increase by 56.3 days (median, 55.6 days [CI, 4.2 to 105.6 days]), and all such counties would require 95 754 more physicians, or about 36.3 more physicians per shortage county. Limitation: Some projections are based on extrapolations of the actual data. Conclusion: In counties with fewer PCPs per population, increases in PCP density would be expected to substantially improve life expectancy. Primary Funding Source: None.

Quantification of Occupational and Community Risk Factors for SARS-CoV-2 Seropositivity Among Health Care Workers in a Large U.S. Health Care System

Background: Identifying occupational risk factors for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among health care workers (HCWs) can improve HCW and patient safety. Objective: To quantify demographic, occupational, and community risk factors for SARS-CoV-2 seropositivity among HCWs in a large health care system. Design: A logistic regression model was fitted to data from a cross-sectional survey conducted in April to June 2020, linking risk factors for occupational and community exposure to coronavirus disease 2019 (COVID-19) with SARS-CoV-2 seropositivity. Setting: A large academic health care system in the Atlanta, Georgia, metropolitan area. Participants: Employees and medical staff members elected to participate in SARS-CoV-2 serology testing offered to all HCWs as part of a quality initiative and completed a survey on exposure to COVID-19 and use of personal protective equipment. Measurements: Demographic risk factors for COVID-19, residential ZIP code incidence of COVID-19, occupational exposure to HCWs or patients who tested positive on polymerase chain reaction test, and use of personal protective equipment as potential risk factors for infection. The outcome was SARS-CoV-2 seropositivity. Results: Adjusted SARS-CoV-2 seropositivity was estimated to be 3.8% (95% CI, 3.4% to 4.3%) (positive, n = 582) among the 10 275 HCWs (35% of the Emory Healthcare workforce) who participated in the survey. Community contact with a person known or suspected to have COVID-19 (adjusted odds ratio [aOR], 1.9 [CI, 1.4 to 2.6]; 77 positive persons [10.3%]) and community COVID-19 incidence (aOR, 1.5 [CI, 1.0 to 2.2]) increased the odds of infection. Black individuals were at high risk (aOR, 2.1 [CI, 1.7 to 2.6]; 238 positive persons [8.3%]). Limitations: Participation rates were modest and key workplace exposures, including job and infection prevention practices, changed rapidly in the early phases of the pandemic. Conclusion: Demographic and community risk factors, including contact with a COVID-19–positive person and Black race, are more strongly associated with SARS-CoV-2 seropositivity among HCWs than is exposure in the workplace. Primary Funding Source: Emory COVID-19 Response Collaborative.

The Evidence Behind Robot-Assisted Abdominopelvic Surgery: A Systematic Review: Annals of Internal Medicine: Vol 174, No 8

Background: Use of robot-assisted surgery has increased dramatically since its advent in the 1980s, and nearly all surgical subspecialties have adopted it. However, whether it has advantages compared with laparoscopy or open surgery is unknown. Purpose: To assess the quality of evidence and outcomes of robot-assisted surgery compared with laparoscopy and open surgery in adults. Data Sources: PubMed, EMBASE, Scopus, and the Cochrane Central Register of Controlled Trials were searched from inception to April 2021. Study Selection: Randomized controlled trials that compared robot-assisted abdominopelvic surgery with laparoscopy, open surgery, or both. Data Extraction: Two reviewers independently extracted study data and risk of bias. Data Synthesis: A total of 50 studies with 4898 patients were included. Of the 39 studies that reported incidence of Clavien–Dindo complications, 4 (10%) showed fewer complications with robot-assisted surgery. The majority of studies showed no difference in intraoperative complications, conversion rates, and long-term outcomes. Overall, robot-assisted surgery had longer operative duration than laparoscopy, but no obvious difference was seen versus open surgery. Limitations: Heterogeneity was present among and within the included surgical subspecialties, which precluded meta-analysis. Several trials may not have been powered to assess relevant differences in outcomes. Conclusion: There is currently no clear advantage with existing robotic platforms, which are costly and increase operative duration. With refinement, competition, and cost reduction, future versions have the potential to improve clinical outcomes without the existing disadvantages. Primary Funding Source: None. (PROSPERO: CRD42020182027)