Comparative Effectiveness of BNT162b2 and mRNA-1273 Vaccines in U.S. Veterans.

BACKGROUND: The messenger RNA (mRNA)-based vaccines BNT162b2 and mRNA-1273 are more than 90% effective against coronavirus disease 2019 (Covid-19). However, their comparative effectiveness for a range of outcomes across diverse populations is unknown. METHODS: We emulated a target trial using the electronic health records of U.S. veterans who received a first dose of the BNT162b2 or mRNA-1273 vaccine between January 4 and May 14, 2021, during a period marked by predominance of the SARS-CoV-2 B.1.1.7 (alpha) variant. We matched recipients of each vaccine in a 1:1 ratio according to their risk factors. Outcomes included documented severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, symptomatic Covid-19, hospitalization for Covid-19, admission to an intensive care unit (ICU) for Covid-19, and death from Covid-19. We estimated risks using the Kaplan-Meier estimator. To assess the influence of the B.1.617.2 (delta) variant, we emulated a second target trial that involved veterans vaccinated between July 1 and September 20, 2021. RESULTS: Each vaccine group included 219,842 persons. Over 24 weeks of follow-up in a period marked by alpha-variant predominance, the estimated risk of documented infection was 5.75 events per 1000 persons (95% confidence interval [CI], 5.39 to 6.23) in the BNT162b2 group and 4.52 events per 1000 persons (95% CI, 4.17 to 4.84) in the mRNA-1273 group. The excess number of events per 1000 persons for BNT162b2 as compared with mRNA-1273 was 1.23 (95% CI, 0.72 to 1.81) for documented infection, 0.44 (95% CI, 0.25 to 0.70) for symptomatic Covid-19, 0.55 (95% CI, 0.36 to 0.83) for hospitalization for Covid-19, 0.10 (95% CI, 0.00 to 0.26) for ICU admission for Covid-19, and 0.02 (95% CI, -0.06 to 0.12) for death from Covid-19. The corresponding excess risk (BNT162b2 vs. mRNA-1273) of documented infection over 12 weeks of follow-up in a period marked by delta-variant predominance was 6.54 events per 1000 persons (95% CI, -2.58 to 11.82). CONCLUSIONS: The 24-week risk of Covid-19 outcomes was low after vaccination with mRNA-1273 or BNT162b2, although risks were lower with mRNA-1273 than with BNT162b2. This pattern was consistent across periods marked by alpha- and delta-variant predominance. (Funded by the Department of Veterans Affairs and others.).

Estimating the effect of bariatric surgery on cardiovascular events using observational data?

BACKGROUND: Observational studies have estimated strongly protective effects of bariatric surgery on cardiovascular disease, but with oversimplified definitions of the intervention, eligibility criteria, and follow-up, which deviate from those in a randomized trial. We describe studying the effect of bariatric surgery on cardiovascular disease without introducing these sources of bias, which may not be entirely possible with existing observational data. METHODS: We propose target trials among persons with diabetes: (1) bariatric operation (vs. no operation) among individuals who have undergone pre-operative preparation (lifestyle modifications, screening) and (2) pre-operative preparation and bariatric surgery (vs. neither pre-operative nor operative component). RESULTS: We emulated both target trials using observational data of U.S. veterans. Comparing bariatric surgery with no surgery (target trial #1; 8,087 individuals), the 7-year cardiovascular risk was 18.0% (95% CI, 6.9 to 32.7) in the surgery group and 18.9% (95% CI, 17.7 to 20.1) in the no surgery group (risk difference -0.9, 95% CI -12.0 to 14.0). Comparing pre-operative components plus surgery vs. neither (target trial #2; 10,065 individuals), the 7-year cardiovascular risk was 17.4% (95% CI, 13.6 to 22.0) in the surgery group and 18.8% (95% CI, 17.8 to 19.9) in the no surgery group (risk difference -1.4, 95% CI -5.1 to 3.2). Body mass index and hemoglobin A1c were reduced with bariatric interventions in both emulations. CONCLUSIONS: Within limitations of available observational data, our estimates do not provide evidence that bariatric surgery reduces cardiovascular disease and support equipoise for a randomized trial of bariatric surgery for cardiovascular disease prevention.

Comparison of the Test-negative Design and Cohort Design With Explicit Target Trial Emulation for Evaluating COVID-19 Vaccine Effectiveness.

BACKGROUND: Observational studies are used for estimating vaccine effectiveness under real-world conditions. The practical performance of two common approaches-cohort and test-negative designs-need to be compared for COVID-19 vaccines. METHODS: We compared the cohort and test-negative designs to estimate the effectiveness of the BNT162b2 vaccine against COVID-19 outcomes using nationwide data from the United States Department of Veterans Affairs. Specifically, we (1) explicitly emulated a target trial using follow-up data and evaluated the potential for confounding using negative controls and benchmarking to a randomized trial, (2) performed case-control sampling of the cohort to confirm empirically that the same estimate is obtained, (3) further restricted the sampling to person-days with a test, and (4) implemented additional features of a test-negative design. We also compared their performance in limited datasets. RESULTS: Estimated BNT162b2 vaccine effectiveness was similar under all four designs. Empirical results suggested limited residual confounding by healthcare-seeking behavior. Analyses in limited datasets showed evidence of residual confounding, with estimates biased downward in the cohort design and upward in the test-negative design. CONCLUSION: Vaccine effectiveness estimates under a cohort design with explicit target trial emulation and a test-negative design were similar when using rich information from the VA healthcare system, but diverged in opposite directions when using a limited dataset. In settings like ours with sufficient information on confounders and other key variables, the cohort design with explicit target trial emulation may be preferable as a principled approach that allows estimation of absolute risks and facilitates interpretation of effect estimates.

Impact of Coronavirus Disease 2019 (COVID-19) Severity on Long-term Events in United States Veterans Using the Veterans Affairs Severity Index for COVID-19 (VASIC).

In this retrospective cohort study of 94 595 severe acute respiratory syndrome coronavirus 2-positive cases, we developed and validated an algorithm to assess the association between coronavirus disease 2019 (COVID-19) severity and long-term complications (stroke, myocardial infarction, pulmonary embolism/deep vein thrombosis, heart failure, and mortality). COVID-19 severity was associated with a greater risk of experiencing a long-term complication 31-120 days postinfection. Most incident events occurred 31-60 days postinfection and diminished after day 91, except heart failure for severe patients and death for moderate patients, which peaked on days 91-120. Understanding the differential impact of COVID-19 severity on long-term events provides insight into possible intervention modalities and critical prevention strategies.

The oral microbiome in relation to pancreatic cancer risk in African Americans.

BACKGROUND: African Americans have the highest pancreatic cancer incidence of any racial/ethnic group in the United States. The oral microbiome was associated with pancreatic cancer risk in a recent study, but no such studies have been conducted in African Americans. Poor oral health, which can be a cause or effect of microbial populations, was associated with an increased risk of pancreatic cancer in a single study of African Americans. METHODS: We prospectively investigated the oral microbiome in relation to pancreatic cancer risk among 122 African-American pancreatic cancer cases and 354 controls. DNA was extracted from oral wash samples for metagenomic shotgun sequencing. Alpha and beta diversity of the microbial profiles were calculated. Multivariable conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between microbes and pancreatic cancer risk. RESULTS: No associations were observed with alpha or beta diversity, and no individual microbial taxa were differentially abundant between cases and control, after accounting for multiple comparisons. Among never smokers, there were elevated ORs for known oral pathogens: Porphyromonas gingivalis (OR = 1.69, 95% CI: 0.80-3.56), Prevotella intermedia (OR = 1.40, 95% CI: 0.69-2.85), and Tannerella forsythia (OR = 1.36, 95% CI: 0.66-2.77). CONCLUSIONS: Previously reported associations between oral taxa and pancreatic cancer were not present in this African-American population overall.

Changes in Pain Self-Efficacy, Coping Skills, and Fear-Avoidance Beliefs in a Randomized Controlled Trial of Yoga, Physical Therapy, and Education for Chronic Low Back Pain.

OBJECTIVE: We evaluated exercise interventions for cognitive appraisal of chronic low back pain (cLBP) in an underserved population. METHODS: We conducted a secondary analysis of the Back to Health Trial, showing yoga to be noninferior to physical therapy (PT) for pain and function outcomes among adults with cLBP (n = 320) recruited from primary care clinics with predominantly low-income patients. Participants were randomized to 12 weeks of yoga, PT, or education. Cognitive appraisal was assessed with the Pain Self-Efficacy Questionnaire (PSEQ), Coping Strategies Questionnaire (CSQ), and Fear-Avoidance Beliefs Questionnaire (FABQ). Using multiple imputation and linear regression, we estimated within- and between-group changes in cognitive appraisal at 12 and 52 weeks, with baseline and the education group as references. RESULTS: Participants (mean age = 46 years) were majority female (64%) and majority Black (57%), and 54% had an annual household income <$30,000. All three groups showed improvements in PSEQ (range 0-60) at 12 weeks (yoga, mean difference [MD] = 7.0, 95% confidence interval [CI]: 4.9, 9.0; PT, MD = 6.9, 95% CI: 4.7 to 9.1; and education, MD = 3.4, 95% CI: 0.54 to 6.3), with yoga and PT improvements being clinically meaningful. At 12 weeks, improvements in catastrophizing (CSQ, range 0-36) were largest in the yoga and PT groups (MD = -3.0, 95% CI: -4.4 to -1.6; MD = -2.7, 95% CI: -4.2 to -1.2, respectively). Changes in FABQ were small. No statistically significant between-group differences were observed on PSEQ, CSQ, or FABQ at either time point. Many of the changes observed at 12 weeks were sustained at 52 weeks. CONCLUSION: All three interventions were associated with improvements in self-efficacy and catastrophizing among low-income, racially diverse adults with cLBP. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01343927.

Early Convalescent Plasma Therapy and Mortality Among US Veterans Hospitalized With Nonsevere COVID-19: An Observational Analysis Emulating a Target Trial.

BACKGROUND: Early convalescent plasma transfusion may reduce mortality in patients with nonsevere coronavirus disease 2019 (COVID-19). METHODS: This study emulates a (hypothetical) target trial using observational data from a cohort of US veterans admitted to a Department of Veterans Affairs (VA) facility between 1 May and 17 November 2020 with nonsevere COVID-19. The intervention was convalescent plasma initiated within 2 days of eligibility. Thirty-day mortality was compared using cumulative incidence curves, risk differences, and hazard ratios estimated from pooled logistic models with inverse probability weighting to adjust for confounding. RESULTS: Of 11 269 eligible person-trials contributed by 4755 patients, 402 trials were assigned to the convalescent plasma group. Forty and 671 deaths occurred within the plasma and nonplasma groups, respectively. The estimated 30-day mortality risk was 6.5% (95% confidence interval [CI], 4.0%-9.7%) in the plasma group and 6.2% (95% CI, 5.6%-7.0%) in the nonplasma group. The associated risk difference was 0.30% (95% CI, -2.30% to 3.60%) and the hazard ratio was 1.04 (95% CI, .64-1.62). CONCLUSIONS: Our target trial emulation estimated no meaningful differences in 30-day mortality between nonsevere COVID-19 patients treated and untreated with convalescent plasma. Clinical Trials Registration. NCT04545047.

Pharmacoepidemiology, Machine Learning, and COVID-19: An Intent-to-Treat Analysis of Hydroxychloroquine, With or Without Azithromycin, and COVID-19 Outcomes Among Hospitalized US Veterans.

Hydroxychloroquine (HCQ) was proposed as an early therapy for coronavirus disease 2019 (COVID-19) after in vitro studies indicated possible benefit. Previous in vivo observational studies have presented conflicting results, though recent randomized clinical trials have reported no benefit from HCQ among patients hospitalized with COVID-19. We examined the effects of HCQ alone and in combination with azithromycin in a hospitalized population of US veterans with COVID-19, using a propensity score-adjusted survival analysis with imputation of missing data. According to electronic health record data from the US Department of Veterans Affairs health care system, 64,055 US Veterans were tested for the virus that causes COVID-19 between March 1, 2020 and April 30, 2020. Of the 7,193 veterans who tested positive, 2,809 were hospitalized, and 657 individuals were prescribed HCQ within the first 48-hours of hospitalization for the treatment of COVID-19. There was no apparent benefit associated with HCQ receipt, alone or in combination with azithromycin, and there was an increased risk of intubation when HCQ was used in combination with azithromycin (hazard ratio = 1.55; 95% confidence interval: 1.07, 2.24). In conclusion, we assessed the effectiveness of HCQ with or without azithromycin in treatment of patients hospitalized with COVID-19, using a national sample of the US veteran population. Using rigorous study design and analytic methods to reduce confounding and bias, we found no evidence of a survival benefit from the administration of HCQ.

Which Chronic Low Back Pain Patients Respond Favorably to Yoga, Physical Therapy, and a Self-care Book? Responder Analyses from a Randomized Controlled Trial.

PURPOSE: To identify baseline characteristics of adults with chronic low back pain (cLBP) that predict response (i.e., a clinically important improvement) and/or modify treatment effect across three nonpharmacologic interventions. DESIGN: Secondary analysis of a randomized controlled trial. SETTING: Academic safety net hospital and seven federally qualified community health centers. SUBJECTS: Adults with cLBP (N = 299). METHODS: We report patient characteristics that were predictors of response and/or modified treatment effect across three 12-week treatments: yoga, physical therapy [PT], and a self-care book. Using preselected characteristics, we used logistic regression to identify predictors of "response," defined as a ≥30% improvement in the Roland Morris Disability Questionnaire. Then, using "response" as our outcome, we identified baseline characteristics that were treatment effect modifiers by testing for statistical interaction (P < 0.05) across two comparisons: 1) yoga-or-PT vs self-care and 2) yoga vs PT. RESULTS: Overall, 39% (116/299) of participants were responders, with more responders in the yoga-or-PT group (42%) than the self-care (23%) group. There was no difference in proportion responding to yoga (48%) vs PT (37%, odds ratio [OR] = 1.5, 95% confidence interval = 0.88 - 2.6). Predictors of response included having more than a high school education, a higher income, employment, few depressive symptoms, lower perceived stress, few work-related fear avoidance beliefs, high pain self-efficacy, and being a nonsmoker. Effect modifiers included use of pain medication and fear avoidance beliefs related to physical activity (both P = 0.02 for interaction). When comparing yoga or PT with self-care, a greater proportion were responders among those using pain meds (OR = 5.3), which differed from those not taking pain meds (OR = 0.94) at baseline. We also found greater treatment response among those with lower (OR = 7.0), but not high (OR = 1.3), fear avoidance beliefs around physical activity. CONCLUSIONS: Our findings revealed important subgroups for whom referral to yoga or PT may improve cLBP outcomes.

Aspirin use and risk of breast cancer in African American women.

BACKGROUND: Use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been hypothesized to be associated with reduced risk of breast cancer; however, results of epidemiological studies have been mixed. Few studies have investigated these associations among African American women. METHODS: To assess the relation of aspirin use to risk of breast cancer in African American women, we conducted a prospective analysis within the Black Women's Health Study, an ongoing nationwide cohort study of 59,000 African American women. On baseline and follow-up questionnaires, women reported regular use of aspirin (defined as use at least 3 days per week) and years of use. During follow-up from 1995 through 2017, 1919 invasive breast cancers occurred, including 1112 ER+, 569 ER-, and 284 triple-negative (TN) tumors. We used age-stratified Cox proportional hazards regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations of aspirin use with risk of ER+, ER-, and TN breast cancer, adjusted for established breast cancer risk factors. RESULTS: Overall, the HR for current regular use of aspirin relative to non-use was 0.92 (95% CI 0.81, 1.04). For ER+, ER-, and TN breast cancer, corresponding HRs were 0.98 (0.84, 1.15), 0.81 (0.64, 1.04), and 0.70 (0.49, 0.99), respectively. CONCLUSIONS: Our findings with regard to ER- and TN breast cancer are consistent with hypothesized inflammatory mechanisms of ER- and TN breast cancer, rather than hormone-dependent pathways. Aspirin may represent a potential opportunity for chemoprevention of ER- and TN breast cancer.

Yoga, Physical Therapy, and Back Pain Education for Sleep Quality in Low-Income Racially Diverse Adults with Chronic Low Back Pain: a Secondary Analysis of a Randomized Controlled Trial.

BACKGROUND: Poor sleep is common among adults with chronic low back pain (cLBP), but the influence of cLBP treatments, such as yoga and physical therapy (PT), on sleep quality is under studied. OBJECTIVE: Evaluate the effectiveness of yoga and PT for improving sleep quality in adults with cLBP. DESIGN: Secondary analysis of a randomized controlled trial. SETTING: Academic safety-net hospital and 7 affiliated community health centers. PARTICIPANTS: A total of 320 adults with cLBP. INTERVENTION: Twelve weekly yoga classes, 1-on-1 PT sessions, or an educational book. MAIN MEASURES: Sleep quality was measured using the Pittsburgh Sleep Quality Index (PSQI) global score (0-21) at baseline, 12 weeks, and 52 weeks. Additionally, we also evaluated how the proportion of participants who achieved a clinically meaningful improvement in sleep quality (> 3-point reduction in PSQI) at 12 weeks varied by changes in pain and physical function at 6 weeks. KEY RESULTS: Among participants (mean age = 46.0, 64% female, 82% non-white), nearly all (92%) reported poor sleep quality (PSQI > 5) at baseline. At 12 weeks, modest improvements in sleep quality were observed among the yoga (PSQI mean difference [MD] = - 1.19, 95% confidence interval [CI] - 1.82, - 0.55) and PT (PSQI MD = - 0.91, 95% CI - 1.61, - 0.20) groups. Participants who reported a ≥ 30% improvement in pain or physical function at 6 weeks, compared with those who improved < 10%, were more likely to be a sleep quality responder at 12 weeks (odds ratio [OR] = 3.51, 95% CI 1.73, 7.11 and OR = 2.16, 95% CI 1.18, 3.95, respectively). Results were similar at 52 weeks. CONCLUSION: In a sample of adults with cLBP, virtually all with poor sleep quality prior to intervention, modest but statistically significant improvements in sleep quality were observed with both yoga and PT. Irrespective of treatment, clinically important sleep improvements at the end of the intervention were associated with mid-intervention pain and physical function improvements. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01343927.

Association of Degree of European Genetic Ancestry With Serum Vitamin D Levels in African Americans.

Circulating levels of vitamin D are generally lower in African Americans than in US whites, and 1 prior analysis carried out in a small number of African Americans suggested that, within this population, vitamin D levels may be related to the degree of genetic admixture. We assessed the association between percentage of European ancestry and serum vitamin D level (assessed in 2013-2015) among 2,183 African-American women from the Black Women's Health Study whose DNA had been genotyped for ancestry-informative markers. ADMIXMAP software was used to estimate the percentage of European ancestry versus African ancestry in each individual. In linear regression analyses with adjustment for genotype batch, age, body mass index, supplemental vitamin D use, ultraviolet B radiation flux in the participant's state of residence, and season of blood draw, each 10% increase in European ancestry was associated with a 0.67-ng/mL increase in serum vitamin D concentration (95% confidence interval: 0.17, 1.17). The association was statistically significant only among women who were not taking vitamin D supplements (for each 10% increase in European ancestry, ß = 0.86, 95% confidence interval: 0.14, 1.57). Among African Americans, use of vitamin D supplements may help to reduce vitamin D deficiency associated with genetic ancestry.

Amerindian ancestry and extended longevity in Nicoya, Costa Rica.

OBJECTIVES: The aim of this study was to address the hypothesis that Amerindian ancestry is associated with extended longevity in the admixed population of Nicoya, Costa Rica. The Nicoya Peninsula of Costa Rica has been considered a "longevity island," particularly for males. METHODS: We estimated Amerindian ancestry using 464 ancestral informative markers in 20 old Nicoyans aged ≥99 years, and 20 younger Nicoyans (60-65 years). We used logistic regression to estimate odds ratio (OR) and 95% confidence interval (CI) of the association of Amerindian ancestry and longevity. RESULTS: Older Nicoyans had higher Amerindian ancestry compared to younger Nicoyans (43.3% vs 36.0%, P = .04). Each 10% increase of Amerindian ancestry was associated with more than twice the odds of being long-lived (OR = 2.32, 95% CI = 1.03-5.25). CONCLUSIONS AND IMPLICATIONS: To our knowledge, this is the first time that ancestry is implicated as a likely determinant of extended longevity. Amerindian-specific alleles may protect against early mortality. The identification of these protective alleles should be the focus of future studies.

Pubertal growth and adult height in relation to breast cancer risk in African American women.

Adult height has been positively associated with breast cancer risk. The timing of pubertal growth-as measured by age at menarche and age at attained height-may also influence risk. We evaluated associations of adult height, age at attained height, and age at menarche with incidence of invasive breast cancer in 55,687 African American women in the prospective Black Women's Health Study. Over 20 years, 1,826 invasive breast cancers [1,015 estrogen receptor (ER) positive; 542 ER negative] accrued. We used multivariable Cox proportional hazards regression to estimate hazards ratios (HRs) and 95% confidence intervals (CIs) for associations with breast cancer overall and by ER status, mutually adjusted for the three factors of interest. Adult height was associated with increased risk of ER+ breast cancer (HR for ≥70 inches vs ≤63 inches: 1.44; 95% CI: 1.09, 1.89) but not ER- (corresponding HR: 1.16; 95% CI: 0.78, 1.71) (p heterogeneity = 0.34). HRs for attained height before age 13 versus age >17 were 1.30 (95% CI: 0.96, 1.76) for ER+ and 1.25 (95% CI: 0.80, 1.96) for ER- breast cancer. Results for age at menarche (≤11 vs ≥14 years) were similar for ER+ and ER- breast cancer (HR for breast cancer overall: 1.30; 95% CI: 1.12, 1.50). We confirmed height as a strong risk factor for ER+ breast cancer in African American women and identified early age at attained height as a risk factor for both ER+ and ER- breast cancer, albeit without statistical significance of the latter associations. While adult height and timing of pubertal growth are inter-related, our findings suggest that they may be independent risk factors for breast cancer.

Predicted 25-hydroxyvitamin D in relation to incidence of breast cancer in a large cohort of African American women.

BACKGROUND: Vitamin D deficiency, which has been linked to an increased risk of colorectal cancer, is particularly common among African Americans. Previous studies of vitamin D status and breast cancer risk, mostly conducted in white women, have had conflicting results. We examined the relationship between predicted vitamin D status and incidence of breast cancer in a cohort of 59,000 African American women. METHODS: Participants in the Black Women's Health Study have been followed by biennial mail questionnaires since 1995, with self-reported diagnoses of cancer confirmed by hospital and cancer registry records. Repeated five-fold cross-validation with linear regression was used to derive the best 25-hydroxyvitamin D (25(OH)D) prediction model based on measured 25(OH)D in plasma specimens obtained from 2856 participants in 2013-2015 and questionnaire-based variables from the same time frame. In the full cohort, including 1454 cases of incident invasive breast cancer, Cox proportional hazards models were used to compute the incidence rate ratio (IRR) for each quartile of predicted vitamin D score relative to the highest quartile. Predicted vitamin D score for each two-year exposure period was a cumulative average of predicted scores from all exposure periods up to that time. RESULTS: Twenty-two percent of women with measured 25(OH)D were categorized as "deficient" (<20 ng/mL) and another 25 % as "insufficient" (20-29 ng/mL). The prediction model explained 25 % of variation in measured 25(OH)D and the correlation coefficient for predicted versus observed 25(OH)D averaged across all cross-validation runs was 0.49 (SD 0.026). Breast cancer risk increased with decreasing quartile of predicted 25(OH)D, p for trend 0.015; the IRR for the lowest versus highest quartile was 1.23 (95 % confidence interval 1.04, 1.46). CONCLUSIONS: In prospective data, African American women in the lowest quartile of cumulative predicted 25(OH)D were estimated to have a 23 % increased risk of breast cancer relative to those with relatively high levels. Preventing vitamin D deficiency may be an effective means of reducing breast cancer incidence in African American women.

Night-shift work and incident diabetes among African-American women.

AIMS/HYPOTHESIS: The aim of this study was to assess shift work in relation to incident type 2 diabetes in African-American women. METHODS: In the Black Women's Health Study (BWHS), an ongoing prospective cohort study, we followed 28,041 participants for incident diabetes during 2005-2013. They answered questions in 2005 about having worked a night shift. We estimated HR and 95% CIs for incident diabetes using Cox proportional hazards models. The basic multivariable model included age, time period, family history of diabetes, education and neighbourhood socioeconomic status. In further models, we controlled for lifestyle factors and BMI. RESULTS: Over the 8 years of follow-up, there were 1,786 incident diabetes cases. Relative to never having worked the night shift, HRs (95% CI) for diabetes were 1.17 (1.04, 1.31) for 1-2 years of night-shift work, 1.23 (1.06, 1.41) for 3-9 years and 1.42 (1.19, 1.70) for ≥ 10 years (p-trend < 0.0001). The monotonic positive association between night-shift work and type 2 diabetes remained after multivariable adjustment (p-trend = 0.02). The association did not vary by obesity status, but was stronger in women aged <50 years. CONCLUSIONS/INTERPRETATION: Long duration of shift work was associated with an increased risk of type 2 diabetes. The association was only partially explained by lifestyle factors and BMI. A better understanding of the mechanisms by which shift work may affect the risk of diabetes is needed in view of the high prevalence of shift work among workers in the USA.

Comparative effectiveness of third doses of mRNA-based COVID-19 vaccines in US veterans.

Vaccination against SARS-CoV-2 has been effective in reducing the burden of severe disease and death from COVID-19. Third doses of mRNA-based vaccines have provided a way to address waning immunity and broaden protection against emerging SARS-CoV-2 variants. However, their comparative effectiveness for a range of COVID-19 outcomes across diverse populations is unknown. We emulated a target trial using electronic health records of US veterans who received a third dose of either BNT162b2 or mRNA-1273 vaccines between 20 October 2021 and 8 February 2022, during a period that included Delta- and Omicron-variant waves. Eligible veterans had previously completed an mRNA vaccine primary series. We matched recipients of each vaccine in a 1:1 ratio according to recorded risk factors. Each vaccine group included 65,196 persons. The excess number of events over 16 weeks per 10,000 persons for BNT162b2 compared with mRNA-1273 was 45.4 (95% CI: 19.4, 84.7) for documented infection, 3.7 (2.2, 14.1) for symptomatic COVID-19, 10.6 (5.1, 19.7) for COVID-19 hospitalization, 2.0 (-3.1, 6.3) for COVID-19 intensive care unit admission and 0.2 (-2.2, 4.0) for COVID-19 death. After emulating a second target trial of veterans who received a third dose between 1 January and 1 March 2022, during a period restricted to Omicron-variant predominance, the excess number of events over 9 weeks per 10,000 persons for BNT162b2 compared with mRNA-1273 was 63.2 (95% CI: 15.2, 100.7) for documented infection. The 16-week risks of COVID-19 outcomes were low after a third dose of mRNA-1273 or BNT162b2, although risks were lower with mRNA-1273 than with BNT162b2, particularly for documented infection.

Statins, Mortality, and Major Adverse Cardiovascular Events Among US Veterans With Chronic Kidney Disease.

Importance: There are limited data for the utility of statins for primary prevention of atherosclerotic cardiovascular disease (ASCVD) and death in adults with chronic kidney disease (CKD). Objective: To evaluate the association of statin use with all-cause mortality and major adverse cardiovascular events (MACE) among US veterans older than 65 years with CKD stages 3 to 4. Design, Setting, and Participants: This cohort study used a target trial emulation design for statin initiation among veterans with moderate CKD (stages 3 or 4) using nested trials with a propensity weighting approach. Linked Veterans Affairs (VA) Healthcare System, Medicare, and Medicaid data were used. This study considered veterans newly diagnosed with moderate CKD between 2005 and 2015 in the VA, with follow-up through December 31, 2017. Veterans were older than 65 years, within 5 years of CKD diagnosis, had no prior ASCVD or statin use, and had at least 1 clinical visit in the year prior to trial baseline. Eligibility criteria were assessed for each nested trial, and Cox proportional hazards models with bootstrapping were run. Analysis was conducted from July 2021 to October 2023. Exposure: Statin initiation vs none. Main Outcomes and Measures: Primary outcome was all-cause mortality; secondary outcome was time to first MACE (myocardial infarction, transient ischemic attack, stroke, revascularization, or mortality). Results: Included in the analysis were 14 828 veterans. Mean (SD) age at CKD diagnosis was 76.9 (8.2) years, 14 616 (99%) were men, 10 539 (72%) White, and 2568 (17%) Black. After expanding to person-trials and assessing eligibility at each baseline, there were 151 243 person-trials (14 685 individuals) of nonstatin initiators and 2924 person-trials (2924 individuals) of statin initiators included. Propensity score adjustment via overlap weighting with nonparametric bootstrapping resulted in covariate balance, with mean (SD) follow-up of 3.6 (2.7) years. The hazard ratio for all-cause mortality was 0.91 (95% CI, 0.85-0.97) comparing statin initiators to noninitiators. The hazard ratio for MACE was 0.96 (95% CI, 0.91-1.02). Results remained consistent in prespecified subgroup analyses. Conclusions and Relevance: In this target trial emulation of statin initiation in US veterans older than 65 years with CKD stages 3 to 4 and no prior ASCVD, statin initiation was significantly associated with a lower risk of all-cause mortality but not MACE. Results should be confirmed in a randomized clinical trial.

Impact of obesity and knee osteoarthritis on morbidity and mortality in older Americans.

BACKGROUND: Obesity and knee osteoarthritis are among the most frequent chronic conditions affecting Americans aged 50 to 84 years. OBJECTIVE: To estimate quality-adjusted life-years lost due to obesity and knee osteoarthritis and health benefits of reducing obesity prevalence to levels observed a decade ago. DESIGN: The U.S. Census and obesity data from national data sources were combined with estimated prevalence of symptomatic knee osteoarthritis to assign persons aged 50 to 84 years to 4 subpopulations: nonobese without knee osteoarthritis (reference group), nonobese with knee osteoarthritis, obese without knee osteoarthritis, and obese with knee osteoarthritis. The Osteoarthritis Policy Model, a computer simulation model of knee osteoarthritis and obesity, was used to estimate quality-adjusted life-year losses due to knee osteoarthritis and obesity in comparison with the reference group. SETTING: United States. PARTICIPANTS: U.S. population aged 50 to 84 years. MEASUREMENTS: Quality-adjusted life-years lost owing to knee osteoarthritis and obesity. RESULTS: Estimated total losses of per-person quality-adjusted life-years ranged from 1.857 in nonobese persons with knee osteoarthritis to 3.501 for persons affected by both conditions, resulting in a total of 86.0 million quality-adjusted life-years lost due to obesity, knee osteoarthritis, or both. Quality-adjusted life-years lost due to knee osteoarthritis and/or obesity represent 10% to 25% of the remaining quality-adjusted survival of persons aged 50 to 84 years. Hispanic and black women had disproportionately high losses. Model findings suggested that reversing obesity prevalence to levels seen 10 years ago would avert 178,071 cases of coronary heart disease, 889,872 cases of diabetes, and 111,206 total knee replacements. Such a reduction in obesity would increase the quantity of life by 6,318,030 years and improve life expectancy by 7,812,120 quality-adjusted years in U.S. adults aged 50 to 84 years. LIMITATIONS: Comorbidity incidences were derived from prevalence estimates on the basis of life expectancy of the general population, potentially resulting in conservative underestimates. Calibration analyses were conducted to ensure comparability of model-based projections and data from external sources. CONCLUSION: The number of quality-adjusted life-years lost owing to knee osteoarthritis and obesity seems to be substantial, with black and Hispanic women experiencing disproportionate losses. Reducing mean body mass index to the levels observed a decade ago in this population would yield substantial health benefits. PRIMARY FUNDING SOURCE: The National Institutes of Health and the Arthritis Foundation.

30-day mortality following COVID-19 and influenza hospitalization among US veterans aged 65 and older.

BACKGROUND: COVID-19 and influenza are important sources of morbidity and mortality among older adults. Understanding how outcomes differ for older adults hospitalized with either infection is important for improving care. We compared outcomes from infection with COVID-19 and influenza among hospitalized older adults. METHODS: We conducted a retrospective study of 30-day mortality among veterans aged 65+ hospitalized with COVID-19 from March 1, 2020-December 31, 2020 or with influenza A/B from September 1, 2017 to August 31, 2019 in Veterans Affairs Health Care System (VAHCS). COVID-19 infection was determined by a positive PCR test and influenza by tests used in the VA system. Frailty was defined by the claims-based Veterans Affairs Frailty Index (VA-FI). Logistic regressions of mortality on frailty, age, and infection were adjusted for multiple confounders. RESULTS: A total of 15,474 veterans were admitted with COVID-19 and 7867 with influenza. Mean (SD) ages were 76.1 (7.8) and 75.8 (8.3) years, 97.7% and 97.4% were male, and 66.9% and 76.4% were white in the COVID-19 and influenza cohorts respectively. Crude 30-day mortality (95% CI) was 18.9% (18.3%-19.5%) for COVID-19 and 4.3% (3.8%-4.7%) for influenza. Combining cohorts, the odds ratio for 30-day mortality from COVID-19 (versus influenza) was 6.61 (5.74-7.65). There was a statistically significant interaction between infection with COVID-19 and frailty, but there was no significant interaction between COVID-19 and age. Separating cohorts, greater 30-day mortality was significantly associated with older age (p: COVID-19: <0.001, Influenza: <0.001) and for frail compared with robust individuals (p for trend: COVID-19: <0.001, Influenza: <0.001). CONCLUSION: Mortality from COVID-19 exceeded that from influenza among hospitalized older adults. However, odds of mortality were higher at every level of frailty among those admitted with influenza compared to COVID-19. Prevention will remain key to reducing mortality from viral illnesses among older adults.