Disparities in Tuberculosis Incidence by Race and Ethnicity Among the U.S.-Born Population in the United States, 2011 to 2021: An Analysis of National Disease Registry Data: Annals of Internal Medicine: Vol 177, No 4

Background: Elevated tuberculosis (TB) incidence rates have recently been reported for racial/ethnic minority populations in the United States. Tracking such disparities is important for assessing progress toward national health equity goals and implementing change. Objective: To quantify trends in racial/ethnic disparities in TB incidence among U.S.-born persons. Design: Time-series analysis of national TB registry data for 2011 to 2021. Setting: United States. Participants: U.S.-born persons stratified by race/ethnicity. Measurements: TB incidence rates, incidence rate differences, and incidence rate ratios compared with non-Hispanic White persons; excess TB cases (calculated from incidence rate differences); and the index of disparity. Analyses were stratified by sex and by attribution of TB disease to recent transmission and were adjusted for age, year, and state of residence. Results: In analyses of TB incidence rates for each racial/ethnic population compared with non-Hispanic White persons, incidence rate ratios were as high as 14.2 (95% CI, 13.0 to 15.5) among American Indian or Alaska Native (AI/AN) females. Relative disparities were greater for females, younger persons, and TB attributed to recent transmission. Absolute disparities were greater for males. Excess TB cases in 2011 to 2021 represented 69% (CI, 66% to 71%) and 62% (CI, 60% to 64%) of total cases for females and males, respectively. No evidence was found to indicate that incidence rate ratios decreased over time, and most relative disparity measures showed small, statistically nonsignificant increases. Limitation: Analyses assumed complete TB case diagnosis and self-report of race/ethnicity and were not adjusted for medical comorbidities or social determinants of health. Conclusion: There are persistent disparities in TB incidence by race/ethnicity. Relative disparities were greater for AI/AN persons, females, and younger persons, and absolute disparities were greater for males. Eliminating these disparities could reduce overall TB incidence by more than 60% among the U.S.-born population. Primary Funding Source: Centers for Disease Control and Prevention.

The New Proposed U.S. Preventive Services Task Force Recommendation on Breast Cancer Screening for Women in Their 40s: Should the Message Change?

School Mask Mandates and COVID-19: The Challenge of Using Difference-in-Differences Analysis of Observational Data to Estimate the Effectiveness of a Public Health Intervention

Background: There are considerable challenges when using difference-in-differences (DiD) analysis of ecological data to estimate the effectiveness of public health interventions in rapidly changing situations. Objective: To discuss the shortcomings of DiD methodology for the estimation of the effects of public health interventions using ecological data. Design: As an example, the authors consider an analysis that used DiD methodology and reported a causal reduction in COVID-19 cases due to the maintenance of school mask mandates. They did alternate analyses using various control groups to assess the robustness of the prior analysis. Setting: School districts in the greater Boston area and Massachusetts during the 2021-to-2022 academic year. Participants: Students and school staff. Measurements: Changes in COVID-19 case rates in districts that did and did not lift mask mandates. Results: Important potential confounders rendered DiD methodology inappropriate for causal inference, including prior immunity, temporal variation in rates of infection, and changes in testing practices. The racial composition and income of intervention and control groups also differed substantially. Compared with maintaining the mask requirement, dropping the requirement was associated with anywhere from an increase of 5.64 cases (95% CI, 3.00 to 8.29 cases) per 1000 persons to a decrease of 2.74 cases (CI, 0.63 to 4.85 cases) per 1000 persons, depending on choice of control group and whether students or staff were examined. Limitation: Ecological data were used; detailed data on all potential confounders were unavailable. Conclusion: Alternate analyses yielded estimates consistent with a wide range of both negative and positive associations in COVID-19 case rates after removal of mask mandates. The findings highlight the challenges of using DiD analysis of ecological data to estimate the effectiveness of interventions in divergent intervention and control groups during rapidly changing circumstances. Primary Funding Source: None.

Association Between Autoimmune Diseases and Monoclonal Gammopathy of Undetermined Significance: An Analysis From a Population-Based Screening Study: Annals of Internal Medicine: Vol 177, No 6

Background: Monoclonal gammopathy of undetermined significance (MGUS) is a precursor of multiple myeloma (MM) and related conditions. In previous registry-based, retrospective studies, autoimmune diseases have been associated with MGUS. However, these studies were not based on a screened population and are therefore prone to ascertainment bias. Objective: To examine whether MGUS is associated with autoimmune diseases. Design: A cross-sectional study within iStopMM (Iceland Screens, Treats, or Prevents MM), a prospective, population-based screening study of MGUS. Setting: Icelandic population of adults aged 40 years or older. Patients: 75 422 persons screened for MGUS. Measurements: Poisson regression for prevalence ratios (PRs) of MGUS among persons with or without an autoimmune disease, adjusted for age and sex. Results: A total of 10 818 participants had an autoimmune disorder, of whom 599 had MGUS (61 with a prior clinical diagnosis and 538 diagnosed at study screening or evaluation). A diagnosis of an autoimmune disease was not associated with MGUS (PR, 1.05 [95% CI, 0.97 to 1.15]). However, autoimmune disease diagnoses were associated with a prior clinical diagnosis of MGUS (PR, 2.11 [CI, 1.64 to 2.70]). Limitation: Registry data were used to gather information on autoimmune diseases, and the homogeneity of the Icelandic population may limit the generalizability of these results. Conclusion: The study did not find an association between autoimmune disease and MGUS in a systematically screened population. Previous studies not done in systematically screened populations have likely been subject to ascertainment bias. The findings indicate that recommendations to routinely screen patients with autoimmune disease for MGUS may not be warranted. Primary Funding Source: The International Myeloma Foundation and the European Research Council.

Computer-Aided Diagnosis for Leaving Colorectal Polyps In Situ: A Systematic Review and Meta-analysis: Annals of Internal Medicine: Vol 177, No 7

Background: Computer-aided diagnosis (CADx) allows prediction of polyp histology during colonoscopy, which may reduce unnecessary removal of nonneoplastic polyps. However, the potential benefits and harms of CADx are still unclear. Purpose: To quantify the benefit and harm of using CADx in colonoscopy for the optical diagnosis of small (≤5-mm) rectosigmoid polyps. Data Sources: Medline, Embase, and Scopus were searched for articles published before 22 December 2023. Study Selection: Histologically verified diagnostic accuracy studies that evaluated the real-time performance of physicians in predicting neoplastic change of small rectosigmoid polyps without or with CADx assistance during colonoscopy. Data Extraction: The clinical benefit and harm were estimated on the basis of accuracy values of the endoscopist before and after CADx assistance. The certainty of evidence was assessed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) framework. The outcome measure for benefit was the proportion of polyps predicted to be nonneoplastic that would avoid removal with the use of CADx. The outcome measure for harm was the proportion of neoplastic polyps that would be not resected and left in situ due to an incorrect diagnosis with the use of CADx. Histology served as the reference standard for both outcomes. Data Synthesis: Ten studies, including 3620 patients with 4103 small rectosigmoid polyps, were analyzed. The studies that assessed the performance of CADx alone (9 studies; 3237 polyps) showed a sensitivity of 87.3% (95% CI, 79.2% to 92.5%) and specificity of 88.9% (CI, 81.7% to 93.5%) in predicting neoplastic change. In the studies that compared histology prediction performance before versus after CADx assistance (4 studies; 2503 polyps), there was no difference in the proportion of polyps predicted to be nonneoplastic that would avoid removal (55.4% vs. 58.4%; risk ratio [RR], 1.06 [CI, 0.96 to 1.17]; moderate-certainty evidence) or in the proportion of neoplastic polyps that would be erroneously left in situ (8.2% vs. 7.5%; RR, 0.95 [CI, 0.69 to 1.33]; moderate-certainty evidence). Limitation: The application of optical diagnosis was only simulated, potentially altering the decision-making process of the operator. Conclusion: Computer-aided diagnosis provided no incremental benefit or harm in the management of small rectosigmoid polyps during colonoscopy. Primary Funding Source: European Commission. (PROSPERO: CRD42023402197)

Association of Albuminuria With Chronic Kidney Disease Progression in Persons With Chronic Kidney Disease and Normoalbuminuria: A Cohort Study: Annals of Internal Medicine: Vol 177, No 4

Background: Albuminuria is a major risk factor for chronic kidney disease (CKD) progression, especially when categorized as moderate (30 to 300 mg/g) or severe (>300 mg/g). However, there are limited data on the prognostic value of albuminuria within the normoalbuminuric range (<30 mg/g) in persons with CKD. Objective: To estimate the increase in the cumulative incidence of CKD progression with greater baseline levels of albuminuria among persons with CKD who had normoalbuminuria (<30 mg/g). Design: Multicenter prospective cohort study. Setting: 7 U.S. clinical centers. Participants: 1629 participants meeting criteria from the CRIC (Chronic Renal Insufficiency Cohort) study with CKD (estimated glomerular filtration rate [eGFR], 20 to 70 mL/min/1.73 m2) and urine albumin–creatinine ratio (UACR) less than 30 mg/g. Measurements: Baseline spot urine albumin divided by spot urine creatinine to calculate UACR as the exposure variable. The 10-year adjusted cumulative incidences of CKD progression (composite of 50% eGFR decline or kidney failure [dialysis or kidney transplantation]) from confounder adjusted survival curves using the G-formula. Results: Over a median follow-up of 9.8 years, 182 of 1629 participants experienced CKD progression. The 10-year adjusted cumulative incidences of CKD progression were 8.7% (95% CI, 5.9% to 11.6%), 11.5% (CI, 8.8% to 14.3%), and 19.5% (CI, 15.4% to 23.5%) for UACR levels of 0 to less than 5 mg/g, 5 to less than 15 mg/g, and 15 mg/g or more, respectively. Comparing persons with UACR 15 mg/g or more to those with UACR 5 to less than 15 mg/g and 0 to less than 5 mg/g, the absolute risk differences were 7.9% (CI, 3.0% to 12.7%) and 10.7% (CI, 5.8% to 15.6%), respectively. The 10-year adjusted cumulative incidence increased linearly based on baseline UACR levels. Limitation: UACR was measured once. Conclusion: Persons with CKD and normoalbuminuria (<30 mg/g) had excess risk for CKD progression, which increased in a linear fashion with higher levels of albuminuria. Primary Funding Source: None.

Clinical Outcomes With Electronic Nudges to Increase Influenza Vaccination: A Prespecified Analysis of a Nationwide, Pragmatic, Registry-Based, Randomized Implementation Trial: Annals of Internal Medicine: Vol 177, No 4

Background: In the NUDGE-FLU (Nationwide Utilization of Danish Government Electronic letter system for increasing inFLUenza vaccine uptake) trial, electronic letters incorporating cardiovascular (CV) gain-framing and repeated messaging increased influenza vaccination by approximately 1 percentage point. Objective: To evaluate the effects of the successful nudging interventions on downstream clinical outcomes. Design: Prespecified exploratory analysis of a nationwide randomized implementation trial. (ClinicalTrials.gov: NCT05542004) Setting: The 2022 to 2023 influenza season. Participants: 964 870 Danish citizens aged 65 years or older. Intervention: Usual care or 9 different electronically delivered behavioral nudging letters. Measurements: Cardiovascular, respiratory, and other clinical end points during follow-up from intervention delivery (16 September 2022) through 31 May 2023. Results: The analysis set included 691 820 participants. Hospitalization for pneumonia or influenza occurred in 3354 of 346 327 (1.0%) participants in the usual care group, 396 of 38 586 (1.0%) in the CV gain-framing group (hazard ratio [HR], 1.06 [95% CI, 0.95 to 1.18]; versus usual care), and 403 of 38 231 (1.1%) in the repeated letter group (HR, 1.09 [CI, 0.98 to 1.21]; versus usual care). In the usual care group, 44 682 (12.9%) participants were hospitalized for any cause, compared with 5002 (13.0%) in the CV gain-framing group (HR, 1.00 [CI, 0.97 to 1.03]; versus usual care) and 4965 (13.0%) in the repeated letter group (HR, 1.01 [CI, 0.98 to 1.04]; versus usual care). A total of 6341 (1.8%) participants died in the usual care group, compared with 721 (1.9%) in the CV gain-framing group (HR, 1.02 [CI, 0.94 to 1.10]; versus usual care) and 646 (1.7%) in the repeated letter group (HR, 0.92 [CI, 0.85 to 1.00]; versus usual care). Limitation: Prespecified but exploratory analysis, potential misclassification of events in routinely collected registry data, and results may not be generalizable to other health systems or countries with other racial compositions and/or cultural or societal norms. Conclusion: In a prespecified exploratory analysis, modest increases in influenza vaccination rates seen with electronic nudges did not translate into observable improvements in clinical outcomes. Seasonal influenza vaccination should remain strongly recommended. Primary Funding Source: Sanofi.

Long-Term Effect of Randomization to Calcium and Vitamin D Supplementation on Health in Older Women: Postintervention Follow-up of a Randomized Clinical Trial: Annals of Internal Medicine: Vol 177, No 4

Background: Although calcium and vitamin D (CaD) supplementation may affect chronic disease in older women, evidence of long-term effects on health outcomes is limited. Objective: To evaluate long-term health outcomes among postmenopausal women in the Women’s Health Initiative CaD trial. Design: Post hoc analysis of long-term postintervention follow-up of the 7-year randomized intervention trial of CaD. (ClinicalTrials.gov: NCT00000611) Setting: A multicenter (n = 40) trial across the United States. Participants: 36 282 postmenopausal women with no history of breast or colorectal cancer. Intervention: Random 1:1 assignment to 1000 mg of elemental calcium as calcium carbonate with 400 IU of vitamin D3 daily or placebo. Measurements: Incidence of colorectal, invasive breast, and total cancer; disease-specific and all-cause mortality; total cardiovascular disease (CVD); and hip fracture by randomization assignment (through December 2020). Analyses were stratified on personal supplement use. Results: For women randomly assigned to CaD versus placebo, a 7% reduction in cancer mortality was observed after a median cumulative follow-up of 22.3 years (1817 vs. 1943 deaths; hazard ratio [HR], 0.93 [95% CI, 0.87 to 0.99]), along with a 6% increase in CVD mortality (2621 vs. 2420 deaths; HR, 1.06 [CI, 1.01 to 1.12]). There was no overall effect on other measures, including all-cause mortality (7834 vs. 7748 deaths; HR, 1.00 [CI, 0.97 to 1.03]). Estimates for cancer incidence varied widely when stratified by whether participants reported supplement use before randomization, whereas estimates on mortality did not vary, except for CVD mortality. Limitation: Hip fracture and CVD outcomes were available on only a subset of participants, and effects of calcium versus vitamin D versus joint supplementation could not be disentangled. Conclusion: Calcium and vitamin D supplements seemed to reduce cancer mortality and increase CVD mortality after more than 20 years of follow-up among postmenopausal women, with no effect on all-cause mortality. Primary Funding Source: National Heart, Lung, and Blood Institute of the National Institutes of Health.

A Risk Profile Using Simple Hematologic Parameters to Assess Benefits From Baricitinib in Patients Hospitalized With COVID-19: A Post Hoc Analysis of the Adaptive COVID-19 Treatment Trial-2

Background: The ACTT risk profile, which was developed from ACTT-1 (Adaptive COVID-19 Treatment Trial-1), demonstrated that hospitalized patients with COVID-19 in the high-risk quartile (characterized by low absolute lymphocyte count [ALC], high absolute neutrophil count [ANC], and low platelet count at baseline) benefited most from treatment with the antiviral remdesivir. It is unknown which patient characteristics are associated with benefit from treatment with the immunomodulator baricitinib. Objective: To apply the ACTT risk profile to the ACTT-2 cohort to investigate potential baricitinib-related treatment effects by risk quartile. Design: Post hoc analysis of ACTT-2, a randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT04401579) Setting: Sixty-seven trial sites in 8 countries. Participants: Adults hospitalized with COVID-19 (n = 999; 85% U.S. participants). Intervention: Baricitinib+remdesivir versus placebo+remdesivir. Measurements: Mortality, progression to invasive mechanical ventilation (IMV) or death, and recovery, all within 28 days; ALC, ANC, and platelet count trajectories. Results: In the high-risk quartile, baricitinib+remdesivir was associated with reduced risk for death (hazard ratio [HR], 0.38 [95% CI, 0.16 to 0.86]; P = 0.020), decreased progression to IMV or death (HR, 0.57 [CI, 0.35 to 0.93]; P = 0.024), and improved recovery rate (HR, 1.53 [CI, 1.16 to 2.02]; P = 0.002) compared with placebo+remdesivir. After 5 days, participants receiving baricitinib+remdesivir had significantly larger increases in ALC and significantly larger decreases in ANC compared with control participants, with the largest effects observed in the high-risk quartile. Limitation: Secondary analysis of data collected before circulation of current SARS-CoV-2 variants. Conclusion: The ACTT risk profile identifies a subgroup of hospitalized patients who benefit most from baricitinib treatment and captures a patient phenotype of treatment response to an immunomodulator and an antiviral. Changes in ALC and ANC trajectory suggest a mechanism whereby an immunomodulator limits severe COVID-19. Primary Funding Source: National Institute of Allergy and Infectious Diseases.

Development of a Multivariable Model to Predict the Need for Bone Marrow Sampling in Persons With Monoclonal Gammopathy of Undetermined Significance: A Cohort Study Nested in a Clinical Trial: Annals of Internal Medicine: Vol 177, No 4

Background: Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic precursor conditions to multiple myeloma and related disorders. Smoldering multiple myeloma is distinguished from MGUS by 10% or greater bone marrow plasma cells (BMPC) on sampling, has a higher risk for progression, and requires specialist management. Objective: To develop a multivariable prediction model that predicts the probability that a person with presumed MGUS has 10% or greater BMPC (SMM or worse by bone marrow criteria) to inform the decision to obtain a bone marrow sample and compare its performance to the Mayo Clinic risk stratification model. Design: iStopMM (Iceland Screens, Treats or Prevents Multiple Myeloma), a prospective population-based screening study of MGUS. (ClinicalTrials.gov: NCT03327597) Setting: Icelandic population of adults aged 40 years or older. Patients: 1043 persons with IgG, IgA, light-chain, and biclonal MGUS detected by screening and an interpretable bone marrow sample. Measurements: Monoclonal gammopathy of undetermined significance isotype; monoclonal protein concentration; free light-chain ratio; and total IgG, IgM, and IgA concentrations were used as predictors. Bone marrow plasma cells were categorized as 0% to 4%, 5% to 9%, 10% to 14%, or 15% or greater. Results: The c-statistic for SMM or worse was 0.85 (95% CI, 0.82 to 0.88), and calibration was excellent (intercept, −0.07; slope, 0.95). At a threshold of 10% predicted risk for SMM or worse, sensitivity was 86%, specificity was 67%, positive predictive value was 32%, and negative predictive value was 96%. Compared with the Mayo Clinic model, the net benefit for the decision to refer for sampling was between 0.13 and 0.30 higher over a range of plausible low-risk thresholds. Limitation: The prediction model will require external validation. Conclusion: This accurate prediction model for SMM or worse was developed in a population-based cohort of persons with presumed MGUS and may be used to defer bone marrow sampling and referral to hematology. Primary Funding Source: International Myeloma Foundation and the European Research Council.