Phosphate, oxidative stress, and nuclear factor-κB activation in vascular calcification

Phosphate-induced vascular calcification, characterized by induction of osteogenic programs, mineral vesicle release, and apoptosis, is prevalent in patients with kidney disease. Zhao et al. provide a mechanistic link between phosphate-induced calcification and increased mitochondrial membrane potential, increased mitochondrial reactive oxygen species, activation of the nuclear factor-κB pathway, and subsequent expression of osteogenic genes and vascular mineralization. This link clarifies the intracellular mechanism of vascular calcification and may allow exploration of antioxidants as therapeutic agents for vascular calcification

Air pollution and acute kidney injury in the U.S. Medicare population: A longitudinal cohort study

BACKGROUND: Recent studies have reported the association between air pollution exposure and reduced kidney function. However, it is unclear whether air pollution is associated with an increased risk of acute kidney injury (AKI). OBJECTIVES: To address this gap in knowledge, we investigated the effect estimates of long-term exposures to fine particulate matter [PM METHODS: This nationwide population-based longitudinal cohort study included 61,300,754 beneficiaries enrolled in Medicare Part A fee-for-service (FFS) who were RESULTS: Exposure to DISCUSSION: This study found an association between exposures to air pollution and the risk of the first hospital admission with AKI, and this association persisted even at low concentrations of air pollution. Our findings provide beneficial implications for public health policies and air pollution guidelines to alleviate health care expenditures and the disease burden attributable to AKI. https://doi.org/10.1289/EHP10729

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

Long-term gastrointestinal outcomes of COVID-19

A comprehensive evaluation of the risks and 1-year burdens of gastrointestinal disorders in the post-acute phase of COVID-19 is needed but is not yet available. Here we use the US Department of Veterans Affairs national health care databases to build a cohort of 154,068 people with COVID-19, 5,638,795 contemporary controls, and 5,859,621 historical controls to estimate the risks and 1-year burdens of a set of pre-specified incident gastrointestinal outcomes. We show that beyond the first 30 days of infection, people with COVID-19 exhibited increased risks and 1-year burdens of incident gastrointestinal disorders spanning several disease categories including motility disorders, acid related disorders (dyspepsia, gastroesophageal reflux disease, peptic ulcer disease), functional intestinal disorders, acute pancreatitis, hepatic and biliary disease. The risks were evident in people who were not hospitalized during the acute phase of COVID-19 and increased in a graded fashion across the severity spectrum of the acute phase of COVID-19 (non-hospitalized, hospitalized, and admitted to intensive care). The risks were consistent in comparisons including the COVID-19 vs the contemporary control group and COVID-19 vs the historical control group as the referent category. Altogether, our results show that people with SARS-CoV-2 infection are at increased risk of gastrointestinal disorders in the post-acute phase of COVID-19. Post-covid care should involve attention to gastrointestinal health and disease

Long-term neurologic outcomes of COVID-19

The neurologic manifestations of acute COVID-19 are well characterized, but a comprehensive evaluation of postacute neurologic sequelae at 1 year has not been undertaken. Here we use the national healthcare databases of the US Department of Veterans Affairs to build a cohort of 154,068 individuals with COVID-19, 5,638,795 contemporary controls and 5,859,621 historical controls; we use inverse probability weighting to balance the cohorts, and estimate risks and burdens of incident neurologic disorders at 12 months following acute SARS-CoV-2 infection. Our results show that in the postacute phase of COVID-19, there was increased risk of an array of incident neurologic sequelae including ischemic and hemorrhagic stroke, cognition and memory disorders, peripheral nervous system disorders, episodic disorders (for example, migraine and seizures), extrapyramidal and movement disorders, mental health disorders, musculoskeletal disorders, sensory disorders, Guillain-Barré syndrome, and encephalitis or encephalopathy. We estimated that the hazard ratio of any neurologic sequela was 1.42 (95% confidence intervals 1.38, 1.47) and burden 70.69 (95% confidence intervals 63.54, 78.01) per 1,000 persons at 12 months. The risks and burdens were elevated even in people who did not require hospitalization during acute COVID-19. Limitations include a cohort comprising mostly White males. Taken together, our results provide evidence of increased risk of long-term neurologic disorders in people who had COVID-19

Risks of mental health outcomes in people with covid-19: Cohort study

OBJECTIVE: To estimate the risks of incident mental health disorders in survivors of the acute phase of covid-19. DESIGN: Cohort study. SETTING: US Department of Veterans Affairs. PARTICIPANTS: Cohort comprising 153 848 people who survived the first 30 days of SARS-CoV-2 infection, and two control groups: a contemporary group (n=5 637 840) with no evidence of SARS-CoV-2, and a historical control group (n=5 859 251) that predated the covid-19 pandemic. MAIN OUTCOMES MEASURES: Risks of prespecified incident mental health outcomes, calculated as hazard ratio and absolute risk difference per 1000 people at one year, with corresponding 95% confidence intervals. Predefined covariates and algorithmically selected high dimensional covariates were used to balance the covid-19 and control groups through inverse weighting. RESULTS: The covid-19 group showed an increased risk of incident anxiety disorders (hazard ratio 1.35 (95% confidence interval 1.30 to 1.39); risk difference 11.06 (95% confidence interval 9.64 to 12.53) per 1000 people at one year), depressive disorders (1.39 (1.34 to 1.43); 15.12 (13.38 to 16.91) per 1000 people at one year), stress and adjustment disorders (1.38 (1.34 to 1.43); 13.29 (11.71 to 14.92) per 1000 people at one year), and use of antidepressants (1.55 (1.50 to 1.60); 21.59 (19.63 to 23.60) per 1000 people at one year) and benzodiazepines (1.65 (1.58 to 1.72); 10.46 (9.37 to 11.61) per 1000 people at one year). The risk of incident opioid prescriptions also increased (1.76 (1.71 to 1.81); 35.90 (33.61 to 38.25) per 1000 people at one year), opioid use disorders (1.34 (1.21 to 1.48); 0.96 (0.59 to 1.37) per 1000 people at one year), and other (non-opioid) substance use disorders (1.20 (1.15 to 1.26); 4.34 (3.22 to 5.51) per 1000 people at one year). The covid-19 group also showed an increased risk of incident neurocognitive decline (1.80 (1.72 to 1.89); 10.75 (9.65 to 11.91) per 1000 people at one year) and sleep disorders (1.41 (1.38 to 1.45); 23.80 (21.65 to 26.00) per 1000 people at one year). The risk of any incident mental health diagnosis or prescription was increased (1.60 (1.55 to 1.66); 64.38 (58.90 to 70.01) per 1000 people at one year). The risks of examined outcomes were increased even among people who were not admitted to hospital and were highest among those who were admitted to hospital during the acute phase of covid-19. Results were consistent with those in the historical control group. The risk of incident mental health disorders was consistently higher in the covid-19 group in comparisons of people with covid-19 not admitted to hospital versus those not admitted to hospital for seasonal influenza, admitted to hospital with covid-19 versus admitted to hospital with seasonal influenza, and admitted to hospital with covid-19 versus admitted to hospital for any other cause. CONCLUSIONS: The findings suggest that people who survive the acute phase of covid-19 are at increased risk of an array of incident mental health disorders. Tackling mental health disorders among survivors of covid-19 should be a priority

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

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\u27 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

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

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