Postacute sequelae of COVID-19 at 2 years.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to postacute sequelae in multiple organ systems, but evidence is mostly limited to the first year postinfection. We built a cohort of 138,818 individuals with SARS-CoV-2 infection and 5,985,227 noninfected control group from the US Department of Veterans Affairs and followed them for 2 years to estimate the risks of death and 80 prespecified postacute sequelae of COVID-19 (PASC) according to care setting during the acute phase of infection. The increased risk of death was not significant beyond 6 months after infection among nonhospitalized but remained significantly elevated through the 2 years in hospitalized individuals. Within the 80 prespecified sequelae, 69% and 35% of them became not significant at 2 years after infection among nonhospitalized and hospitalized individuals, respectively. Cumulatively at 2 years, PASC contributed 80.4 (95% confidence interval (CI): 71.6-89.6) and 642.8 (95% CI: 596.9-689.3) disability-adjusted life years (DALYs) per 1,000 persons among nonhospitalized and hospitalized individuals; 25.3% (18.9-31.0%) and 21.3% (18.2-24.5%) of the cumulative 2-year DALYs in nonhospitalized and hospitalized were from the second year. In sum, while risks of many sequelae declined 2 years after infection, the substantial cumulative burden of health loss due to PASC calls for attention to the care needs of people with long-term health effects due to SARS-CoV-2 infection.

Comparative effectiveness of SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, and sulfonylureas on risk of major adverse cardiovascular events: emulation of a randomised target trial using electronic health records.

BACKGROUND: Randomised clinical trials showed that compared with placebo, SGLT2 inhibitors and GLP-1 receptor agonists reduced risk of adverse cardiovascular events. The evidence base for the older antihyperglycaemic drug classes (DPP-4 inhibitors and sulfonylureas) is generally less well developed. Because most randomised trials evaluated one antihyperglycaemic medication versus placebo, a head-to-head comparative effectiveness analysis of the newer drug classes (SGLT2 inhibitors vs GLP-1 receptor agonists) or newer (SGLT2 inhibitors or GLP-1 receptor agonists) versus older (DPP-4 inhibitors or sulfonylureas) drug classes on risk of major adverse cardiovascular events (MACE) is not available. In this study, we aimed to evaluate the comparative effectiveness of incident use of SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, or sulfonylureas on risk of MACE. METHODS: We first specified the protocol of a four-arm randomised pragmatic clinical trial and then emulated it using the health-care databases of the US Department of Veterans Affairs. We built a cohort of metformin users with incident use of SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, or sulfonylureas between Oct 1, 2016 and Sept 30, 2021, and followed up until Dec 31, 2022. We used the overlap weighting approach to balance the treatment groups using a battery of predefined variables and a set of algorithmically selected variables from high-dimensional data domains. Both intention-to-treat and per-protocol analyses (the latter estimated the effect of maintained use of the antihyperglycaemic throughout follow-up) were conducted to estimate risk of MACE-defined as a composite endpoint of stroke, myocardial infarction, and all-cause mortality. FINDINGS: The final cohort consisted of 283 998 new users of SGLT2 inhibitors (n=46 516), GLP-1 receptor agonists (n=26 038), DPP-4 inhibitors (n=55 310), or sulfonylureas (n=156 134). In intention-to-treat analyses, compared with sulfonylureas, SGLT2 inhibitors, GLP-1 receptor agonists, and DPP-4 inhibitors were associated with lower risk of MACE (hazard ratio [HR] 0·77 [95% CI 0·74-0.80], 0·78 [0·74-0·81), and 0·90 [0·86-0.93], respectively). Both SGLT2 inhibitors and GLP-1 receptor agonists were associated with a lower risk of MACE when compared with DPP-4 inhibitors (HR 0·86 [0·82-0·89] and 0·86 [0·82-0·90], respectively). The risk of MACE between SGLT2 inhibitors and GLP-1 receptor agonists yielded an HR of 0·99 (0·94-1·04). In per-protocol analyses, compared with sulfonylureas, SGLT2 inhibitors, GLP1 receptor agonists, and DPP-4 inhibitors were associated with reduced risk of MACE (HR 0·77 [95% CI 0·73-0·82], 0·77 [0·72-0·82], and 0·88 [0·83-0·93], respectively). Both SGLT2 inhibitors and GLP-1 receptor agonists were associated with a lower risk of MACE when compared with DPP-4 inhibitors (HR 0·88 [0·83-0·93] and 0·88 [0·82-0·93], respectively). The risk of MACE between SGLT2 inhibitors and GLP-1 receptor agonists yielded an HR of 1·01 (0·94-1·07). INTERPRETATION: Both SGLT2 inhibitors and GLP-1 receptor agonists were associated with reduced risk of MACE compared with DPP-4 inhibitors or sulfonylureas. DPP-4 inhibitors were associated with reduced risk of MACE compared with sulfonylureas. There was no statistically significant difference in risk of MACE between SGLT2 inhibitors and GLP-1 receptor agonists. The results provide evidence of the real-world comparative effectiveness of the four most commonly used second-line antihyperglycaemics and could guide choice of antihyperglycaemic therapy. FUNDING: US Department of Veterans Affairs and the American Society of Nephrology.

Nirmatrelvir and risk of hospital admission or death in adults with covid-19: emulation of a randomized target trial using electronic health records.

OBJECTIVE: To estimate the effectiveness of nirmatrelvir, compared with no treatment, in reducing admission to hospital or death at 30 days in people infected with the SARS-CoV-2 virus and at risk of developing severe disease, according to vaccination status and history of previous SARS-CoV-2 infection. DESIGN: Emulation of a randomized target trial with electronic health records. SETTING: Healthcare databases of the US Department of Veterans Affairs PARTICIPANTS: 256 288 participants with a SARS-CoV-2 positive test result and at least one risk factor for developing severe covid-19 disease, between 3 January and 30 November 2022. 31 524 were treated with nirmatrelvir within five days of testing positive for SARS-CoV-2 and 224 764 received no treatment. MAIN OUTCOME MEASURES: The effectiveness of starting nirmatrelvir within five days of a positive SARS-CoV-2 test result versus no treatment in reducing the risk of admission to hospital or death at 30 days was estimated in those who were not vaccinated, in those who received one or two doses of vaccine, and those who received a vaccine booster and, separately, in participants with a primary SARS-CoV-2 infection or reinfection. The inverse probability weighting method was used to balance personal and health characteristics between the groups. Relative risk and absolute risk reduction were computed from cumulative incidence at 30 days, estimated by weighted Kaplan-Meier estimator. RESULTS: Among people who were not vaccinated (n=76 763; 5338 nirmatrelvir and 71 425 no treatment), compared with no treatment, the relative risk of nirmatrelvir in reducing admission to hospital or death at 30 days was 0.60 (95% confidence interval 0.50 to 0.71); the absolute risk reduction was 1.83% (95% confidence interval 1.29% to 2.49%). The relative risk and absolute risk reduction, compared with no treatment, were 0.65 (0.57 to 0.74) and 1.27% (0.90% to 1.61%), respectively, in people who received one or two doses of vaccine (n=84 620; 7989 nirmatrelvir and 76 631 no treatment); 0.64 (0.58 to 0.71) and 1.05% (0.85% to 1.27%) in individuals who received a booster dose of vaccine (n=94 905; 18 197 nirmatrelvir and 76 708 no treatment); 0.61 (0.57 to 0.65) and 1.36% (1.19% to 1.53%) in participants with a primary SARS-CoV-2 infection (n=228 081; 26 350 nirmatrelvir and 201 731 no treatment); and 0.74 (0.63 to 0.87) and 0.79% (0.36% to 1.18%) in participants who were reinfected with the SARS-CoV-2 virus (n=28 207; 5174 nirmatrelvir and 23 033 no treatment). Nirmatrelvir was associated with a reduced risk of admission to hospital or death in those aged ≤65 years and > 65 years; in men and women; in black and white participants; in those with 1-2, 3-4, and ≥5 risk factors for progression to severe covid-19 illness; and in those infected during the omicron BA.1 or BA.2 predominant era, and the BA.5 predominant era. CONCLUSIONS: In people with SARS-CoV-2 infection who were at risk of developing severe disease, compared with no treatment, nirmatrelvir was associated with a reduced risk of admission to hospital or death at 30 days in people who were not vaccinated, vaccinated, and had received a booster vaccine, and in those with a primary SARS-CoV-2 infection and reinfection.

Molnupiravir and risk of hospital admission or death in adults with covid-19: emulation of a randomized target trial using electronic health records.

OBJECTIVE: To emulate a randomized target trial to estimate the association between the antiviral drug molnupiravir and hospital admission or death in adults with SARS-CoV-2 infection in the community during the omicron predominant era who were at high risk of progression to severe covid-19. DESIGN: Emulation of a randomized target trial using electronic health records. SETTING: US Department of Veterans Affairs. PARTICIPANTS: 85 998 adults with SARS-CoV-2 infection between 5 January and 30 September 2022 and at least one risk factor for progression to severe covid-19: 7818 participants were eligible for and treated with molnupiravir and 78 180 received no treatment. MAIN OUTCOMES MEASURE: The primary outcome was a composite of hospital admission or death at 30 days. The clone method with inverse probability of censoring weighting was used to adjust for informative censoring and balance baseline characteristics between the groups. The cumulative incidence function was used to estimate the relative risk and the absolute risk reduction at 30 days. RESULTS: Molnupiravir was associated with a reduction in hospital admissions or death at 30 days (relative risk 0.72 (95% confidence interval 0.64 to 0.79)) compared with no treatment; the event rates for hospital admission or death at 30 days were 2.7% (95% confidence interval 2.5% to 3.0%) for molnupiravir and 3.8% (3.7% to 3.9%) for no treatment; the absolute risk reduction was 1.1% (95% confidence interval 0.8% to 1.4%). Molnupiravir appeared to be effective in those who had not been vaccinated against covid-19 (relative risk 0.83 (0.70 to 0.97) and absolute risk reduction 0.9% (0.2% to 1.9%)), had received one or two vaccine doses (0.69 (0.56 to 0.83) and 1.3% (0.7% to 1.9%)), and had received a booster dose (0.71 (0.58 to 0.83) and 1.0% (0.5% to 1.4%)); in those infected during the era when the omicron subvariant BA.1 or BA.2 was predominant (0.72 (0.62 to 0.83) and 1.2% (0.7% to 1.6%)) and when BA.5 was predominant (0.75 (0.66 to 0.86) and 0.9% (0.5% to 1.3%)); and in those with no history of SARS-CoV-2 infection (0.72 (0.64 to 0.81) and 1.1% (0.8% to 1.4%)) and with a history of SARS-CoV-2 infection (0.75 (0.58 to 0.97) and 1.1% (0.1% to 1.8%)). CONCLUSIONS: The findings of this emulation of a randomized target trial suggest that molnupiravir might have reduced hospital admission or death at 30 days in adults with SARS-CoV-2 infection in the community during the recent omicron predominant era who were at high risk of progression to severe covid-19 and eligible for treatment with molnupiravir.

Acute Pancreatitis Recurrences Augment Long-Term Pancreatic Cancer Risk.

INTRODUCTION: In animal models, inflammation caused by experimental acute pancreatitis (AP) promotes pancreatic carcinogenesis that is preventable by suppressing inflammation. Recent studies noted higher long-term risk of pancreatic ductal adenocarcinoma (PDAC) after AP. In this study, we evaluated whether the long-term PDAC risk after AP was influenced by the etiology of AP, number of recurrences, and if it was because of progression to chronic pancreatitis (CP). METHODS: This retrospective study used nationwide Veterans Administration database spanning 1999-2015. A 2-year washout period was applied to exclude patients with preexisting AP and PDAC. PDAC risk was estimated in patients with AP without (AP group) and with underlying CP (APCP group) and those with CP alone (CP group) and compared with PDAC risk in patients in a control group, respectively, using cause-specific hazards model. RESULTS: The final cohort comprised 7,147,859 subjects (AP-35,550 and PDAC-16,475). The cumulative PDAC risk 3-10 years after AP was higher than in controls (0.61% vs 0.18%), adjusted hazard ratio (1.7 [1.4-2.0], P < 0.001). Adjusted hazard ratio was 1.5 in AP group, 2.4 in the CP group, and 3.3 in APCP group. PDAC risk increased with the number of AP episodes. Elevated PDAC risk after AP was not influenced by the etiology of AP (gallstones, smoking, or alcohol). DISCUSSION: There is a higher PDAC risk 3-10 years after AP irrespective of the etiology of AP, increases with the number of episodes of AP and is additive to higher PDAC risk because of CP.

Acute and postacute sequelae associated with SARS-CoV-2 reinfection.

First infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with increased risk of acute and postacute death and sequelae in various organ systems. Whether reinfection adds to risks incurred after first infection is unclear. Here we used the US Department of Veterans Affairs' national healthcare database to build a cohort of individuals with one SARS-CoV-2 infection (n = 443,588), reinfection (two or more infections, n = 40,947) and a noninfected control (n = 5,334,729). We used inverse probability-weighted survival models to estimate risks and 6-month burdens of death, hospitalization and incident sequelae. Compared to no reinfection, reinfection contributed additional risks of death (hazard ratio (HR) = 2.17, 95% confidence intervals (CI) 1.93-2.45), hospitalization (HR = 3.32, 95% CI 3.13-3.51) and sequelae including pulmonary, cardiovascular, hematological, diabetes, gastrointestinal, kidney, mental health, musculoskeletal and neurological disorders. The risks were evident regardless of vaccination status. The risks were most pronounced in the acute phase but persisted in the postacute phase at 6 months. Compared to noninfected controls, cumulative risks and burdens of repeat infection increased according to the number of infections. Limitations included a cohort of mostly white males. The evidence shows that reinfection further increases risks of death, hospitalization and sequelae in multiple organ systems in the acute and postacute phase. Reducing overall burden of death and disease due to SARS-CoV-2 will require strategies for reinfection prevention.

Long COVID after breakthrough SARS-CoV-2 infection.

The post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-also referred to as Long COVID-have been described, but whether breakthrough SARS-CoV-2 infection (BTI) in vaccinated people results in post-acute sequelae is not clear. In this study, we used the US Department of Veterans Affairs national healthcare databases to build a cohort of 33,940 individuals with BTI and several controls of people without evidence of SARS-CoV-2 infection, including contemporary (n = 4,983,491), historical (n = 5,785,273) and vaccinated (n = 2,566,369) controls. At 6 months after infection, we show that, beyond the first 30 days of illness, compared to contemporary controls, people with BTI exhibited a higher risk of death (hazard ratio (HR) = 1.75, 95% confidence interval (CI): 1.59, 1.93) and incident post-acute sequelae (HR = 1.50, 95% CI: 1.46, 1.54), including cardiovascular, coagulation and hematologic, gastrointestinal, kidney, mental health, metabolic, musculoskeletal and neurologic disorders. The results were consistent in comparisons versus the historical and vaccinated controls. Compared to people with SARS-CoV-2 infection who were not previously vaccinated (n = 113,474), people with BTI exhibited lower risks of death (HR = 0.66, 95% CI: 0.58, 0.74) and incident post-acute sequelae (HR = 0.85, 95% CI: 0.82, 0.89). Altogether, the findings suggest that vaccination before infection confers only partial protection in the post-acute phase of the disease; hence, reliance on it as a sole mitigation strategy may not optimally reduce long-term health consequences of SARS-CoV-2 infection. The findings emphasize the need for continued optimization of strategies for primary prevention of BTI and will guide development of post-acute care pathways for people with BTI.

Long-term cardiovascular outcomes of COVID-19.

The cardiovascular complications of acute coronavirus disease 2019 (COVID-19) are well described, but the post-acute cardiovascular manifestations of COVID-19 have not yet been comprehensively characterized. Here we used national healthcare databases from the US Department of Veterans Affairs to build a cohort of 153,760 individuals with COVID-19, as well as two sets of control cohorts with 5,637,647 (contemporary controls) and 5,859,411 (historical controls) individuals, to estimate risks and 1-year burdens of a set of pre-specified incident cardiovascular outcomes. We show that, beyond the first 30 d after infection, individuals with COVID-19 are at increased risk of incident cardiovascular disease spanning several categories, including cerebrovascular disorders, dysrhythmias, ischemic and non-ischemic heart disease, pericarditis, myocarditis, heart failure and thromboembolic disease. These risks and burdens were evident even among individuals who were not hospitalized during the acute phase of the infection and increased in a graded fashion according to the care setting during the acute phase (non-hospitalized, hospitalized and admitted to intensive care). Our results provide evidence that the risk and 1-year burden of cardiovascular disease in survivors of acute COVID-19 are substantial. Care pathways of those surviving the acute episode of COVID-19 should include attention to cardiovascular health and disease.

A Deep Learning Approach for the Estimation of Glomerular Filtration Rate.

An accurate estimation of glomerular filtration rate (GFR) is clinically crucial for kidney disease diagnosis and predicting the prognosis of chronic kidney disease (CKD). Machine learning methodologies such as deep neural networks provide a potential avenue for increasing accuracy in GFR estimation. We developed a novel deep learning architecture, a deep and shallow neural network, to estimate GFR (dlGFR for short) and examined its comparative performance with estimated GFR from Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations. The dlGFR model jointly trains a shallow learning model and a deep neural network to enable both linear transformation from input features to a log GFR target, and non-linear feature embedding for stage of kidney function classification. We validate the proposed methods on the data from multiple studies obtained from the NIDDK Central Database Repository. The deep learning model predicted values of GFR within 30% of measured GFR with 88.3% accuracy, compared to the 87.1% and 84.7% of the accuracy achieved by CKD-EPI and MDRD equations (p = 0.051 and p < 0.001, respectively). Our results suggest that deep learning methods are superior to equations resulting from traditional statistical methods in estimating glomerular filtration rate. Based on these results, an end-to-end predication system has been deployed to facilitate use of the proposed dlGFR algorithm.

Burdens of post-acute sequelae of COVID-19 by severity of acute infection, demographics and health status.

The Post-Acute Sequelae of SARS-CoV-2 infection (PASC) have been characterized; however, the burden of PASC remains unknown. Here we used the healthcare databases of the US Department of Veterans Affairs to build a cohort of 181,384 people with COVID-19 and 4,397,509 non-infected controls and estimated that burden of PASC-defined as the presence of at least one sequela in excess of non-infected controls-was 73.43 (72.10, 74.72) per 1000 persons at 6 months. Burdens of individual sequelae varied by demographic groups (age, race, and sex) but were consistently higher in people with poorer baseline health and in those with more severe acute infection. In sum, the burden of PASC is substantial; PASC is non-monolithic with sequelae that are differentially expressed in various population groups. Collectively, our results may be useful in informing health systems capacity planning and care strategies of people with PASC.

Association of Ambient Fine Particulate Matter Air Pollution With Kidney Transplant Outcomes.

Importance: Increased levels of ambient fine particulate matter (PM2.5) air pollution are associated with increased risks for detrimental health outcomes, but risks for patients with kidney transplants (KTs) remain unknown. Objective: To investigate the association of PM2.5 exposure with KT outcomes. Design, Setting, and Participants: This retrospective cohort study was conducted using data on patients who received KTs from 2004 to 2016 who were identified in the national US transplant registry and followed up through March 2021. Multiple databases were linked to obtain data on PM2.5 concentration, KT outcomes, and patient clinical, transplant, and contextual factors. Data were analyzed from April 2020 through July 2021. Exposures: Exposures included post-KT time-dependent annual mean PM2.5 level (in 10 µg/m3) and mean PM2.5 level in the year before KT (ie, baseline levels) in quartiles, as well as baseline annual mean PM2.5 level (in 10 µg/m3). Main Outcomes and Measures: Acute kidney rejection (ie, rejection within 1 year after KT), time to death-censored graft failure, and time to all-cause death. Multivariable logistic regression for kidney rejection and Cox analyses with nonlinear assessment of exposure-response for death-censored graft failure and all-cause death were performed. The national burden of graft failure associated with PM2.5 levels greater than the Environmental Protection Agency recommended level of 12 µg/m3 was estimated. Results: Among 112 098 patients with KTs, 70 522 individuals (62.9%) were older than age 50 years at the time of KT, 68 117 (60.8%) were men, and the median (IQR) follow-up was 6.0 (3.9-8.9) years. There were 37 265 Black patients (33.2%), 17 047 Hispanic patients (15.2%), 48 581 White patients [43.3%]), and 9205 patients (8.2%) of other race or ethnicity. The median (IQR) baseline PM2.5 level was 9.8 (8.3-11.9) µg/m3. Increased baseline PM2.5 level, compared with quartile 1 baseline PM2.5 level, was not associated with higher odds of acute kidney rejection for quartile 2 (adjusted odds ratio [aOR], 0.99; 95% CI, 0.92-1.06) but was associated with increased odds for quartile 3 (aOR, 1.11; 95% CI, 1.04-1.20) and quartile 4 (aOR, 1.13; 95% CI, 1.05-1.23). Nonlinear assessment of exposure-response for graft failure and death showed no evidence for nonlinearity. Increased PM2.5 levels were associated with increased risk of death-censored graft failure (adjusted hazard ratio [aHR] per 10 µg/m3 increase, 1.17; 95% CI, 1.09-1.25) and all-cause death (aHR per 10 µg/m3 increase, 1.21; 95% CI, 1.14-1.28). The national burden of death-censored graft failure associated with PM2.5 above 12 µg/m3 was 57 failures (95% uncertainty interval, 48-67 failures) per year among patients with KTs. Conclusions and Relevance: This cohort study found that PM2.5 level was an independent risk factor associated with acute rejection, graft failure, and death among patients with KTs. These findings suggest that efforts toward decreasing levels of PM2.5 concentration may be associated with improved outcomes after KT.

Kidney Outcomes in Long COVID.

BACKGROUND: COVID-19 is associated with increased risk of post-acute sequelae involving pulmonary and extrapulmonary organ systems-referred to as long COVID. However, a detailed assessment of kidney outcomes in long COVID is not yet available. METHODS: We built a cohort of 1,726,683 US Veterans identified from March 1, 2020 to March 15, 2021, including 89,216 patients who were 30-day survivors of COVID-19 and 1,637,467 non-infected controls. We examined risks of AKI, eGFR decline, ESKD, and major adverse kidney events (MAKE). MAKE was defined as eGFR decline ≥50%, ESKD, or all-cause mortality. We used inverse probability-weighted survival regression, adjusting for predefined demographic and health characteristics, and algorithmically selected high-dimensional covariates, including diagnoses, medications, and laboratory tests. Linear mixed models characterized intra-individual eGFR trajectory. RESULTS: Beyond the acute illness, 30-day survivors of COVID-19 exhibited a higher risk of AKI (aHR, 1.94; 95% CI, 1.86 to 2.04), eGFR decline ≥30% (aHR, 1.25; 95% CI, 1.14 to 1.37), eGFR decline ≥40% (aHR, 1.44; 95% CI, 1.37 to 1.51), eGFR decline ≥50% (aHR, 1.62; 95% CI, 1.51 to 1.74), ESKD (aHR, 2.96; 95% CI, 2.49 to 3.51), and MAKE (aHR, 1.66; 95% CI, 1.58 to 1.74). Increase in risks of post-acute kidney outcomes was graded according to the severity of the acute infection (whether patients were non-hospitalized, hospitalized, or admitted to intensive care). Compared with non-infected controls, 30-day survivors of COVID-19 exhibited excess eGFR decline (95% CI) of -3.26 (-3.58 to -2.94), -5.20 (-6.24 to -4.16), and -7.69 (-8.27 to -7.12) ml/min per 1.73 m2 per year, respectively, in non-hospitalized, hospitalized, and those admitted to intensive care during the acute phase of COVID-19 infection. CONCLUSIONS: Patients who survived COVID-19 exhibited increased risk of kidney outcomes in the post-acute phase of the disease. Post-acute COVID-19 care should include attention to kidney disease.

Temporal trends of COVID-19 mortality and hospitalisation rates: an observational cohort study from the US Department of Veterans Affairs.

OBJECTIVES: To investigate the temporal trends of 30-day mortality and hospitalisation in US Veterans with COVID-19 and 30-day mortality in hospitalised veterans with COVID-19 and to decompose the contribution of changes in the underlying characteristics of affected populations to these temporal changes. DESIGN: Observational cohort study. SETTING: US Department of Veterans Affairs. PARTICIPANTS: 49 238 US veterans with a positive COVID-19 test between 20 March 2020 and 19 September 2020; and 9428 US veterans hospitalised with a positive COVID-19 test during the same period. OUTCOME MEASURES: 30-day mortality rate and hospitalisation rate. RESULTS: Between 20 March 2020 and 19 September 2020 and in COVID-19 positive individuals, 30-day mortality rate dropped by 9.2% from 13.6% to 4.4%; hospitalisation rate dropped by 16.8% from 33.8% to 17.0%. In hospitalised COVID-19 individuals, 30-day mortality rate dropped by 12.7% from 23.5% to 10.8%. Among COVID-19 positive individuals, decomposition analyses suggested that changes in demographic, health and contextual characteristics, COVID-19 testing capacity, and hospital occupancy rates accounted for 40.2% and 33.3% of the decline in 30-day mortality and hospitalisation, respectively. Changes in the underlying characteristics of hospitalised COVID-19 individuals accounted for 29.9% of the decline in 30-day mortality. CONCLUSION: Between March and September 2020, changes in demographic and health characteristics of people infected with COVID-19 contributed measurably to the substantial decline in 30-day mortality and hospitalisation.

Comparative Effectiveness of Sodium-Glucose Cotransporter 2 Inhibitors vs Sulfonylureas in Patients With Type 2 Diabetes.

Importance: In the treatment of type 2 diabetes, evidence of the comparative effectiveness of sodium-glucose cotransporter 2 (SGLT2) inhibitors vs sulfonylureas-the second most widely used antihyperglycemic class after metformin-is lacking. Objective: To evaluate the comparative effectiveness of SGLT2 inhibitors and sulfonylureas associated with the risk of all-cause mortality among patients with type 2 diabetes using metformin. Design, Setting, and Participants: A cohort study used data from the US Department of Veterans Affairs compared the use of SGLT2 inhibitors vs sulfonylureas in individuals receiving metformin for treatment of type 2 diabetes. A total of 23 870 individuals with new use of SGLT2 inhibitors and 104 423 individuals with new use of sulfonylureas were enrolled between October 1, 2016, and February 29, 2020, and followed up until January 31, 2021. Exposures: New use of SGLT2 inhibitors or sulfonylureas. Main Outcomes and Measures: This study examined the outcome of all-cause mortality. Predefined variables and covariates identified by a high-dimensional variable selection algorithm were used to build propensity scores. The overlap weighting method based on the propensity scores was used to estimate the intention-to-treat effect sizes of SGLT2 inhibitor compared with sulfonylurea therapy. The inverse probability of the treatment adherence weighting method was used to estimate the per-protocol effect sizes. Results: Among the 128 293 participants (mean [SD] age, 64.60 [9.84] years; 122 096 [95.17%] men), 23 870 received an SGLT2 inhibitor and 104 423 received a sulfonylurea. Compared with sulfonylureas, SGLT2 inhibitors were associated with reduced risk of all-cause mortality (hazard ratio [HR], 0.81; 95% CI, 0.75-0.87), yielding an event rate difference of -5.15 (95% CI, -7.16 to -3.02) deaths per 1000 person-years. Compared with sulfonylureas, SGLT2 inhibitors were associated with a reduced risk of death, regardless of cardiovascular disease status, in several categories of estimated glomerular filtration rate (including rates from >90 to ≤30 mL/min/1.73 m2) and in participants with no albuminuria (albumin to creatinine ratio [ACR] ≤30 mg/g), microalbuminuria (ACR >30 to ≤300 mg/g), and macroalbuminuria (ACR >300 mg/g). In per-protocol analyses, continued use of SGLT2 inhibitors was associated with a reduced risk of death compared with continued use of sulfonylureas (HR, 0.66; 95% CI, 0.60-0.74; event rate difference, -10.10; 95% CI, -12.97 to -7.24 deaths per 1000 person-years). In additional per-protocol analyses, continued use of SGLT2 inhibitors with metformin was associated with a reduced risk of death compared with SGLT2 inhibitor treatment without metformin (HR, 0.70; 95% CI, 0.50-0.97; event rate difference, -7.62; 95% CI, -17.12 to -0.48 deaths per 1000 person-years). Conclusions and Relevance: In this comparative effectiveness study analyzing data from the US Department of Veterans Affairs, among patients with type 2 diabetes receiving metformin therapy, SGLT2 inhibitor treatment was associated with a reduced risk of all-cause mortality compared with sulfonylureas. The results provide data from a real-world setting that might help guide the choice of antihyperglycemic therapy.

Ambient fine particulate matter air pollution and the risk of hospitalization among COVID-19 positive individuals: Cohort study.

BACKGROUND: Ecologic analyses suggest that living in areas with higher levels of ambient fine particulate matter air pollution (PM2.5) is associated with higher risk of adverse COVID-19 outcomes. Studies accounting for individual-level health characteristics are lacking. METHODS: We leveraged the breadth and depth of the US Department of Veterans Affairs national healthcare databases and built a national cohort of 169,102 COVID-19 positive United States Veterans, enrolled between March 2, 2020 and January 31, 2021, and followed them through February 15, 2021. Annual average 2018 PM2.5 exposure, at an approximately 1 km2 resolution, was linked with residential street address at the year prior to COVID-19 positive test. COVID-19 hospitalization was defined as first hospital admission between 7 days prior to, and 15 days after, the first COVID-19 positive date. Adjusted Poisson regression assessed the association of PM2.5 with risk of hospitalization. RESULTS: There were 25,422 (15.0%) hospitalizations; 5,448 (11.9%), 5,056 (13.0%), 7,159 (16.1%), and 7,759 (19.4%) were in the lowest to highest PM2.5 quartile, respectively. In models adjusted for State, demographic and behavioral factors, contextual characteristics, and characteristics of the pandemic a one interquartile range increase in PM2.5 (1.9 µg/m3) was associated with a 10% (95% CI: 8%-12%) increase in risk of hospitalization. The association of PM2.5 and risk of hospitalization among COVID-19 individuals was present in each wave of the pandemic. Models of non-linear exposure-response suggested increased risk at PM2.5 concentrations below the national standard 12 µg/m3. Formal effect modification analyses suggested higher risk of hospitalization associated with PM2.5 in Black people compared to White people (p = 0.045), and in those living in socioeconomically disadvantaged neighborhoods (p < 0.001). CONCLUSIONS: Exposure to higher levels of PM2.5 was associated with increased risk of hospitalization among COVID-19 infected individuals. The risk was evident at PM2.5 levels below the regulatory standards. The analysis identified those of Black race and those living in disadvantaged neighborhoods as population groups that may be more susceptible to the untoward effect of PM2.5 on risk of hospitalization in the setting of COVID-19.

Clinical Implications of Estimated Glomerular Filtration Rate Dip Following Sodium-Glucose Cotransporter-2 Inhibitor Initiation on Cardiovascular and Kidney Outcomes.

Background The frequency of the initial short-term decline in estimated glomerular filtration rate (eGFR), eGFR dip, following initiation of sodium-glucose cotransporter-2 inhibitors (SGLT2i) and its clinical implications in real-world practice are not clear. Methods and Results We built a cohort of 36 638 new users of SGLT2i and 209 025 new users of other antihyperglycemics. Inverse probability weighting was used to estimate the excess rate of eGFR dip, risk of the composite cardiovascular outcome of nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, or all-cause mortality, and risk of the composite kidney outcome of eGFR decline >50%, end-stage kidney disease, or all-cause mortality. In the first 6 months of therapy, compared with other antihyperglycemics, excess rates of eGFR dip >10% and eGFR dip >30% were 9.86 (95% CI: 8.83-11.00) and 1.15 (0.70-1.62) per 100 SGLT2i users, respectively. In mediation analyses that accounted for eGFR dipping, SGLT2i use was associated with reduced risk of cardiovascular and kidney outcomes (hazard ratio, 0.92 [0.84-0.99] and 0.78 [0.71-0.87], respectively); the magnitude of the association reduced by eGFR dipping was small for both outcomes. SGLT2i was associated with reduced risk of both outcomes in those with higher than average probability of eGFR dip >10% or 30%. Compared with discontinuation, continued use of SGLT2i at 6 months was associated with reduced risk of cardiovascular and kidney outcomes in those with no eGFR dip or eGFR dip ≤10%, in those with eGFR dip >10%, and in those with eGFR dip >30%. Conclusions The salutary association of SGLT2i with cardiovascular and kidney outcomes was maintained regardless of eGFR dipping; concerns about eGFR dipping should not preclude use, and occurrence of eGFR dip after SGLT2i initiation may not warrant discontinuation.

High-dimensional characterization of post-acute sequelae of COVID-19.

The acute clinical manifestations of COVID-19 have been well characterized1,2, but the post-acute sequelae of this disease have not been comprehensively described. Here we use the national healthcare databases of the US Department of Veterans Affairs to systematically and comprehensively identify 6-month incident sequelae-including diagnoses, medication use and laboratory abnormalities-in patients with COVID-19 who survived for at least 30 days after diagnosis. We show that beyond the first 30 days of illness, people with COVID-19 exhibit a higher risk of death and use of health resources. Our high-dimensional approach identifies incident sequelae in the respiratory system, as well as several other sequelae that include nervous system and neurocognitive disorders, mental health disorders, metabolic disorders, cardiovascular disorders, gastrointestinal disorders, malaise, fatigue, musculoskeletal pain and anaemia. We show increased incident use of several therapeutic agents-including pain medications (opioids and non-opioids) as well as antidepressant, anxiolytic, antihypertensive and oral hypoglycaemic agents-as well as evidence of laboratory abnormalities in several organ systems. Our analysis of an array of prespecified outcomes reveals a risk gradient that increases according to the severity of the acute COVID-19 infection (that is, whether patients were not hospitalized, hospitalized or admitted to intensive care). Our findings show that a substantial burden of health loss that spans pulmonary and several extrapulmonary organ systems is experienced by patients who survive after the acute phase of COVID-19. These results will help to inform health system planning and the development of multidisciplinary care strategies to reduce chronic health loss among individuals with COVID-19.

Ambient Fine Particulate Matter Air Pollution and Risk of Weight Gain and Obesity in United States Veterans: An Observational Cohort Study.

BACKGROUND: Experimental evidence and studies of children and adolescents suggest that ambient fine particulate matter [particulate matter ≤2.5µm in aerodynamic diameter (PM2.5)] air pollution may be obesogenic, but the relationship between PM2.5 and the risk of body weight gain and obesity in adults is uncertain. OBJECTIVES: Our goal was to characterize the association between PM2.5 and the risks of weight gain and obesity. METHODS: We followed 3,902,440 U.S. Veterans from 2010 to 2018 (median 8.1 y, interquartile range: 7.3-8.4) and assigned time-updated PM2.5 exposures by linking geocoded residential street addresses with satellite-based estimates of surface-level PM2.5 mass (at ∼1-km2 resolution). Associations with PM2.5 were estimated using Cox proportional hazards models for incident obesity [body mass index (BMI)≥30 kg/m2] and a 10-lb increase in weight relative to baseline and linear mixed models for associations with intra-individual changes in BMI and weight. RESULTS: A 10-µg/m3 higher average annual PM2.5 concentration was associated with risk of incident obesity [n=2,325,769; hazard ratio (HR)=1.08 (95% CI: 1.06, 1.11)] and the risk of a 10-lb (4.54 kg) increase in weight [HR=1.07 (95% CI: 1.06, 1.08)] and with higher intra-individual changes in BMI [0.140 kg/m2 per year (95% CI: 0.139, 0.142)] and weight [0.968 lb/y (95% CI: 0.955, 0.981)]. Nonlinear exposure-response models indicated associations at PM2.5 concentrations below the national standard of 12 µg/m3. As expected, a negative exposure control (ambient air sodium) was not associated with obesity or weight gain. Associations were consistent in direction and magnitude across sensitivity analyses that included alternative outcomes and exposures assigned at different spatial resolutions. DISCUSSION: PM2.5 air pollution was associated with the risk of obesity and weight gain in a large predominantly male cohort of U.S. Veterans. Discussions about health effects of PM2.5 should include its association with obesity, and deliberations about the epidemiology of obesity should consider its association with PM2.5. Investigation in other cohorts will deepen our understanding of the relationship between PM2.5 and weight gain and obesity. https://doi.org/10.1289/EHP7944.

Temporal Trends in Incidence Rates of Lower Extremity Amputation and Associated Risk Factors Among Patients Using Veterans Health Administration Services From 2008 to 2018.

Importance: Lower extremity amputation (LEA) is associated with significant morbidity and mortality. However, national temporal trends of LEA incidence rates among US veterans and associated factors have not been well characterized. Objective: To describe the temporal trends of LEA, characterize associated risk factors, and decompose the associations of these risk factors with changes in temporal trends of LEA among US veterans using Department of Veteran Affairs (VA) services between 2008 and 2018. Design, Setting, and Participants: This cohort study used VA data from 2008 to 2018 to estimate incidence rates of LEA among veterans using VA services. Cox regression models were used to identify risk factors associated with LEA. Decomposition analyses estimated the associations of changes in prevalence of risk factors with changes in LEA rates. Data were analyzed from October 1, 2007, to September 30, 2018. Main Outcomes and Measures: Toe, transmetatarsal, below-knee, or above-knee LEA. Results: A total of 6 493 141 veterans were included (median [interquartile range] age, 64 [54-76] years; 6 060 390 [93.4%] men). Veterans were studied for a median (interquartile range) of 10.9 (5.6-11.0) years. Between 2008 and 2018, rates of LEA increased from 12.89 (95% CI, 12.53-13.25) LEA per 10 000 persons to 18.12 (95% CI, 17.70-18.54) LEA per 10 000 persons, representing a net increase of 5.23 (95% CI, 4.68-5.78) LEA per 10 000 persons. Between 2008 and 2018, toe amputation rates increased by 3.24 (2.89-3.59) amputations per 10 000 persons, accounting for 62.0% of the total increase in LEA rates. Transmetatarsal amputations increased by 1.54 (95% CI, 1.27-1.81) amputations per 10 000 persons; below-knee amputation rates increased by 0.81 (95% CI, 0.56-1.05) amputations per 10 000 persons; and above-knee amputation rates decreased by 0.37 (95% CI, 0.14-0.59) amputations per 10 000 persons. Compared with men, women had decreased risk of any LEA (hazard ratio [HR], 0.34 [95% CI, 0.31-0.37]). Factors associated with increased risk of any LEA included Black race (HR, 1.25 [95% CI, 1.21-1.28]) or another non-White race (ie, Asian, Latino, or other; HR, 2.36 [95% CI, 2.30-2.42]), obesity (HR, 1.59 [95% CI, 1.55-1.63]), diabetes (HR, 6.38 [95% CI, 6.22-6.54]), chronic kidney disease (CKD; eg, CKD stage 5: HR, 3.94 [95% CI, 3.22-4.83]), and smoking status (eg, current smoking: HR, 1.97 [95% CI, 1.92-2.03]). Decomposition analyses suggested that while changes in demographic composition, primarily driven by increased proportion of women veterans, associated with a decrease of 0.18 (95% CI, 0.14-0.22) LEA per 10 000 persons, and decreases in smoking rates, associated with a decrease of 0.88 (95% CI, 0.79-0.97) LEA per 10 000 persons. However, these were overwhelmed by increased rates of diabetes, associated with an increase of 1.86 (95% CI, 1.72-1.99) LEA per 10 000 persons; peripheral arterial disease, associated with an increase of 1.53 (95% CI, 1.41-1.65) LEA per 10 000 persons; CKD, associated with an increase of 1.45 (95% CI, 1.33-1.57) LEA per 10 000 persons; and other clinical factors, including body mass index, cancer, cardiovascular disease, cerebrovascular disease, chronic lung disease, dementia, and hypertension, associated with an increase of 1.45 (95% CI, 1.33-1.57) LEA per 10 000 persons. Conclusions and Relevance: This cohort study found that incidence rates of LEA among veterans using VA services increased between 2008 and 2018. Efforts aimed at reducing burden of LEA should target the reduction of diabetes, peripheral arterial disease, and CKD at the individual and population levels.