Viral and Host Factors Are Associated With Mortality in Hospitalized Patients With COVID-19.

BACKGROUND: Persistent mortality in adults hospitalized due to acute COVID-19 justifies pursuit of disease mechanisms and potential therapies. The aim was to evaluate which virus and host response factors were associated with mortality risk among participants in Therapeutics for Inpatients with COVID-19 (TICO/ACTIV-3) trials. METHODS: A secondary analysis of 2625 adults hospitalized for acute SARS-CoV-2 infection randomized to 1 of 5 antiviral products or matched placebo in 114 centers on 4 continents. Uniform, site-level collection of participant baseline clinical variables was performed. Research laboratories assayed baseline upper respiratory swabs for SARS-CoV-2 viral RNA and plasma for anti-SARS-CoV-2 antibodies, SARS-CoV-2 nucleocapsid antigen (viral Ag), and interleukin-6 (IL-6). Associations between factors and time to mortality by 90 days were assessed using univariate and multivariable Cox proportional hazards models. RESULTS: Viral Ag ≥4500 ng/L (vs <200 ng/L; adjusted hazard ratio [aHR], 2.07; 1.29-3.34), viral RNA (<35 000 copies/mL [aHR, 2.42; 1.09-5.34], ≥35 000 copies/mL [aHR, 2.84; 1.29-6.28], vs below detection), respiratory support (<4 L O2 [aHR, 1.84; 1.06-3.22]; ≥4 L O2 [aHR, 4.41; 2.63-7.39], or noninvasive ventilation/high-flow nasal cannula [aHR, 11.30; 6.46-19.75] vs no oxygen), renal impairment (aHR, 1.77; 1.29-2.42), and IL-6 >5.8 ng/L (aHR, 2.54 [1.74-3.70] vs ≤5.8 ng/L) were significantly associated with mortality risk in final adjusted analyses. Viral Ag, viral RNA, and IL-6 were not measured in real-time. CONCLUSIONS: Baseline virus-specific, clinical, and biological variables are strongly associated with mortality risk within 90 days, revealing potential pathogen and host-response therapeutic targets for acute COVID-19 disease.

Effect of Neutralizing Monoclonal Antibody Treatment on Early Trajectories of Virologic and Immunologic Biomarkers in Patients Hospitalized With COVID-19.

BACKGROUND: Neutralizing monoclonal antibodies (nmAbs) failed to show clear benefit for hospitalized patients with coronavirus disease 2019 (COVID-19). Dynamics of virologic and immunologic biomarkers remain poorly understood. METHODS: Participants enrolled in the Therapeutics for Inpatients with COVID-19 trials were randomized to nmAb versus placebo. Longitudinal differences between treatment and placebo groups in levels of plasma nucleocapsid antigen (N-Ag), anti-nucleocapsid antibody, C-reactive protein, interleukin-6, and D-dimer at enrollment, day 1, 3, and 5 were estimated using linear mixed models. A 7-point pulmonary ordinal scale assessed at day 5 was compared using proportional odds models. RESULTS: Analysis included 2149 participants enrolled between August 2020 and September 2021. Treatment resulted in 20% lower levels of plasma N-Ag compared with placebo (95% confidence interval, 12%-27%; P < .001), and a steeper rate of decline through the first 5 days (P < .001). The treatment difference did not vary between subgroups, and no difference was observed in trajectories of other biomarkers or the day 5 pulmonary ordinal scale. CONCLUSIONS: Our study suggests that nmAb has an antiviral effect assessed by plasma N-Ag among hospitalized patients with COVID-19, with no blunting of the endogenous anti-nucleocapsid antibody response. No effect on systemic inflammation or day 5 clinical status was observed. CLINICAL TRIALS REGISTRATION: NCT04501978.

Epidemiology of the 2022 Mpox Outbreak in the US Veterans Health Administration.

BACKGROUND: In May 2022, mpox cases were reported in nonendemic countries, including the United States. We examined mpox infections in the Veterans Health Administration (VHA). METHODS: Mpox diagnostic and whole genome sequencing (WGS) results, demographics, risk factors, hospitalizations, exposures, deaths, and pharmacy and immunization data were obtained from VHA data sources (23 May 2022-31 May 2023). RESULTS: Of 1144 Veterans tested, 251 (21.9%) were presumptive positive for nonvariola orthopoxvirus (NVO) or confirmed positive for NVO and Monkeypox virus (MPXV). Incidence rate was 7.5 per 100 000 Veterans in care, with the highest rate observed in Veterans aged 25-34 years (13.83 cases per 100 000). Higher odds of NVO or NVO/MPXV positivity was associated with male sex; non-Hispanic Black race/ethnicity; syphilis or human immunodeficiency virus (HIV) positivity; or genital/rectal sample site, whereas older age and vaccination with JYNNEOS or vaccinia (smallpox) had lower odds. Among 209 with confirmatory testing, 90.4% reported intimate contact and/or an epidemiological link, 84.5% were men who have sex with men (MSM), 24.2% received tecovirimat, and 8.1% were hospitalized with 1 death. Eighty-six sequenced samples had evaluable WGS results. All were clade IIb, representing 10 different lineages from 20 states and the District of Columbia. CONCLUSIONS: Mpox affected younger, MSM, non-Hispanic Black, and HIV/syphilis-positive men among US Veterans. Viral diversity was noted across geographic regions. At-risk Veterans would benefit from vaccination and risk reduction strategies for mpox and other sexually transmitted infections.

Risk of Hospitalization and Mortality Following Medically Attended Norovirus Infection-Veterans Health Administration, 2010-2018.

Background: While prior studies have suggested a role for norovirus gastroenteritis in contributing to severe morbidity and mortality, the importance of norovirus as a causal pathogen for hospitalization and mortality remains poorly understood. We estimated the effect of laboratory-confirmed norovirus infection on hospitalization and mortality among a national cohort of veterans who sought care within the Veterans Affairs health care system. Methods: We analyzed electronic health record data from a cohort study of adults who were tested for norovirus within the Veterans Affairs system between 1 January 2010 and 31 December 2018. Adjusted risk ratios (aRRs) for hospitalization and mortality were estimated using log-binomial regression models, adjusting for age, Clostridioides difficile, underlying medical conditions, and nursing home residence. Results: In total, 23 196 veterans had 25 668 stool samples tested for norovirus; 2156 samples (8.4%) tested positive. Testing positive for norovirus infection, compared with testing negative, was associated with a slight increased risk of hospitalization (aRR, 1.13 [95% confidence interval, 1.06-1.21]) and a significant increased risk of mortality within 3 days after the norovirus test (2.14 [1.10-4.14]). The mortality aRR within 1 week and 1 month were reduced to 1.40 (95% confidence interval, .84-2.34) and 0.97 (.70-1.35), respectively. Conclusions: Older veterans with multiple comorbid conditions were at a slight increased risk of hospitalization and significant increased risk of mortality in the 3 days after a norovirus-positive test, compared with those testing negative. Clinicians should be aware of these risks and can use these data to inform clinical management for veterans with norovirus.

Integrative analyses highlight functional regulatory variants associated with neuropsychiatric diseases.

Noncoding variants of presumed regulatory function contribute to the heritability of neuropsychiatric disease. A total of 2,221 noncoding variants connected to risk for ten neuropsychiatric disorders, including autism spectrum disorder, attention deficit hyperactivity disorder, bipolar disorder, borderline personality disorder, major depression, generalized anxiety disorder, panic disorder, post-traumatic stress disorder, obsessive-compulsive disorder and schizophrenia, were studied in developing human neural cells. Integrating epigenomic and transcriptomic data with massively parallel reporter assays identified differentially-active single-nucleotide variants (daSNVs) in specific neural cell types. Expression-gene mapping, network analyses and chromatin looping nominated candidate disease-relevant target genes modulated by these daSNVs. Follow-up integration of daSNV gene editing with clinical cohort analyses suggested that magnesium transport dysfunction may increase neuropsychiatric disease risk and indicated that common genetic pathomechanisms may mediate specific symptoms that are shared across multiple neuropsychiatric diseases.

Epidemiology of Coccidioidomycosis in the Veterans Health Administration, 2013-2022.

We describe the epidemiology of coccidioidomycosis among a national cohort of Veterans. Using electronic health record data from adults tested for coccidioidomycosis between 1 January 2013 and 31 December 2022, we analyzed differences in baseline demographics (age, sex, race/ethnicity, birth country, comorbidities, residence, and Charlson Comorbidity Index score) between 4204 coccidioidomycosis-test-positive and 63,322 test-negative Veterans. Log-binomial regression models with adjusted risk ratios (aRRs) were used to evaluate risk factors associated with coccidioidomycosis including dissemination, hospitalization, and mortality. Case counts and incidence rates were highest in select counties in Arizona and California where Coccidioides is endemic. Coccidioidomycosis-positive Veterans were younger, more likely to be male, and Philippine-born. The risk factors most highly associated with being coccidioidomycosis-positive included Native Hawaiian/Pacific Islander (aRR 1.068 [95%CI: 1.039-1.098]), Asian (aRR 1.060 [95%CI: 1.037-1.083]), Black (aRR 1.029 [95%CI: 1.022-1.036]), American Indian/Alaska Native (aRR 1.026 [95%CI: 1.004-1.048]) race, and Hispanic/Latino ethnicity (aRR 1.021 [95%CI: 1.013-1.028]). Black race (aRR: 1.058 [95%CI: 1.037-1.081]) and Hispanic/Latino ethnicity (aRR 1.018 [95%CI: 1.0003-1.036]) were also associated with disseminated coccidioidomycosis, strengthening the evidence for the association of coccidioidomycosis, including severe infections, with specific racial and ethnic groups. There were no statistically significant differences in hospitalization within 45 days of testing or 30-day all-cause mortality. Improving our understanding of coccidioidomycosis risk factors is important for targeted prevention strategies and to reduce delays in diagnosis and ineffective treatment.

Early Outcomes of SARS-CoV-2 Infection in a Multisite Prospective Cohort of Inpatient Veterans.

Background: Over 870 000 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections have occurred among Veterans Health Administration users, and 24 000 have resulted in death. We examined early outcomes of SARS-CoV-2 infection in hospitalized veterans. Methods: In an ongoing, prospective cohort study, we enrolled veterans age ≥18 tested for SARS-CoV-2 and hospitalized at 15 Department of Veterans Affairs medical centers between February 2021 and June 2022. We estimated adjusted odds ratios (aORs), adjusted incidence rate ratios (aIRRs), and adjusted hazard ratios (aHRs) for maximum illness severity within 30 days of study entry (defined using the 4-category VA Severity Index for coronavirus disease 2019 [COVID-19]), as well as length of hospitalization and rehospitalization within 60 days, in relationship with demographic characteristics, Charlson comorbidity index (CCI), COVID-19 vaccination, and calendar period of enrollment. Results: The 542 participants included 329 (61%) who completed a primary vaccine series (with or without booster; "vaccinated"), 292 (54%) enrolled as SARS-CoV-2-positive, and 503 (93%) men, with a mean age of 64.4 years. High CCI scores (≥5) occurred in 61 (44%) vaccinated and 29 (19%) unvaccinated SARS-CoV-2-positive participants. Severe illness or death occurred in 29 (21%; 6% died) vaccinated and 31 (20%; 2% died) unvaccinated SARS-CoV-2-positive participants. SARS-CoV-2-positive inpatients per unit increase in CCI had greater multivariable-adjusted odds of severe illness (aOR, 1.21; 95% CI, 1.01-1.45), more hospitalization days (aIRR, 1.06; 95% CI, 1.03-1.10), and rehospitalization (aHR, 1.07; 95% CI, 1.01-1.12). Conclusions: In a cohort of hospitalized US veterans with SARS-CoV-2 infection, those with a higher CCI had more severe COVID-19 illness, more hospital days, and rehospitalization, after adjusting for vaccination status, age, sex, and calendar period.

Trends in Follow-up Testing Among Patients Positive for Chlamydia and Gonorrhea in the Veterans Health Administration, 2013 to 2019.

BACKGROUND: The Centers for Disease Control and Prevention (CDC) recommends testing patients with chlamydia (CT)/gonorrhea (GC) for other sexually transmitted infections (STIs) and repeating CT/GC testing 3 to 12 months later. We assessed repeat CT/GC testing and testing for HIV/syphilis in accordance with CDC guidelines in the US Veterans Health Administration. METHODS: Molecular laboratory testing for CT/GC during January 1, 2013-December 31, 2020 was retrieved from Veterans Health Administration data sources. Patients were evaluated for syphilis, HIV, and repeat CT/GC testing within 1 year after a positive CT/GC test result. Differences of CT/GC-positive patients associated with receiving recommended testing were assessed using χ2 /Fisher exact tests. RESULTS: A total of 41,630 of 1,005,761 CT (4.1%) and 17,649 of 1,013,198 GC (1.7%) results were positive. Median ages of positive CT/GC patients were 29 and 36 years, respectively. Repeat testing rates for CT/GC within 90 to 119 days were 3.9% and 2.9%, and rates within 90 to 365 days were 32.8% and 34.7%, with 8.6% and 15% being positive again, respectively. Guideline-compatible repeat testing in known HIV-positive patients nearly doubled (75.7% for CT and 67.8% for GC). The CDC-recommended HIV testing was performed for 72.4% and 65.5% CT and GC first positives, respectively, whereas syphilis testing was completed for 66.5% and 60.5% CT and GC, respectively. Compared with 25- to 34-year-old patients with CT or GC, those younger than 25 years had higher odds of guideline-discordant repeat testing but had lower odds of not receiving HIV/syphilis testing. CONCLUSIONS: Nearly two-thirds of patients did not receive recommended repeat testing, and nearly one-third were not tested for HIV/syphilis. Veterans Health Administration providers may benefit from additional education on CDC-recommended sexually transmitted infection guidelines and testing recommendations.

Nationwide Genomic Surveillance and Response to COVID-19: The VA SeqFORCE and SeqCURE Consortiums.

Background: The US Department of Veterans Affairs (VA) has dedicated significant resources toward countering the COVID-19 pandemic. Sequencing for Research Clinical and Epidemiology (SeqFORCE) and Sequencing Collaborations United for Research and Epidemiology (SeqCURE) were developed as clinical and research consortiums, respectively, focused on the genetic COVID-19 surveillance. Observations: Through genetic sequencing, VA SeqFORCE and SeqCURE collaborations contributed to the COVID-19 pandemic response and scientific understanding. Future directions for each program include the assessment of the unique impact of COVID-19 on the veteran population, as well as the adaptation of these programs to future infectious disease threats. We foresee the use of these established platforms beyond infectious diseases. Conclusions: VA SeqFORCE and SeqCURE were established as clinical and research programs dedicated to sequencing COVID-19 as part of ongoing clinical and surveillance efforts. In the future, we anticipate that having these programs embedded within the largest integrated health care system in the US will enable the study of pathogens and pandemics beyond COVID-19 and at an unprecedented scale. The investment in these programs will form an integral part of our nation's response to emerging infectious diseases, with future applications to precision medicine and beyond.

Exposure Sources Among Veterans With Elevated Blood Lead Levels, United States, 2015‒2021.

Objectives. To determine characteristics and sources of exposure in veterans with elevated blood lead levels (BLLs). Methods. We included users of US Veterans Health Administration care aged 18 years or older tested for BLL from October 2015 to September 2021. Prevalence of BLL 10 micrograms per deciliter (µg/dL) or higher and 25 µg/dL or higher was determined within demographic groups. Logistic regression analysis measured association of International Classification of Diseases, Tenth Revision, Clinical Modification‒coded conditions with elevated BLL. Electronic notes were reviewed for exposure sources. Results. Among 1007 unique veterans with BLL 10 µg/dL or higher, prevalence of BLL 10 µg/dL or higher and 25 µg/dL or higher peaked at 4.9 and 1.3 per 100 000 veterans, respectively (fiscal year 2019), and was highest in non-Hispanic White men and those aged 25 to 34 years. Conditions predicted by elevated BLL were attention-deficit/hyperactivity disorder (ADHD) and nausea or vomiting. Firearms represented 70.1% of occupational and 85.9% of nonoccupational exposures. Toxicology consults occurred in 17 of 298 (6%) with BLL 25 µg/dL or higher. Conclusions. Firearms were the largest exposure source among veterans with elevated BLL. Clinicians should be alert for potential conditions (including ADHD and nausea or vomiting in our study) associated with lead exposure. Standardization of care regarding toxicology referral practices is warranted. (Am J Public Health. 2022;112(S7):S670-S678. https://doi.org/10.2105/AJPH.2022.306936).

Risk Factors for Acute Gastroenteritis Among Patients Hospitalized in 5 Veterans Affairs Medical Centers, 2016-2019.

Background: In the United States, ∼179 million acute gastroenteritis (AGE) episodes occur annually. We aimed to identify risk factors for all-cause AGE, norovirus-associated vs non-norovirus AGE, and severe vs mild/moderate AGE among hospitalized adults. Methods: We enrolled 1029 AGE cases and 624 non-AGE controls from December 1, 2016, to November 30, 2019, at 5 Veterans Affairs Medical Centers. Patient interviews and medical chart abstractions were conducted, and participant stool samples were tested using the BioFire Gastrointestinal Panel. Severe AGE was defined as a modified Vesikari score of ≥11. Multivariate logistic regression was performed to assess associations between potential risk factors and outcomes; univariate analysis was conducted for norovirus-associated AGE due to limited sample size. Results: Among 1029 AGE cases, 551 (54%) had severe AGE and 44 (4%) were norovirus positive. Risk factors for all-cause AGE included immunosuppressive therapy (adjusted odds ratio [aOR], 5.6; 95% CI, 2.7-11.7), HIV infection (aOR, 3.9; 95% CI, 1.8-8.5), severe renal disease (aOR, 3.1; 95% CI, 1.8-5.2), and household contact with a person with AGE (aOR, 2.9; 95% CI, 1.3-6.7). Household (OR, 4.4; 95% CI, 1.6-12.0) and non-household contact (OR, 5.0; 95% CI, 2.2-11.5) with AGE was associated with norovirus-associated AGE. Norovirus positivity (aOR, 3.4; 95% CI, 1.3-8.8) was significantly associated with severe AGE. Conclusions: Patients with immunosuppressive therapy, HIV, and severe renal disease should be monitored for AGE and may benefit from targeted public health messaging regarding AGE prevention. These results may also direct future public health interventions, such as norovirus vaccines, to specific high-risk populations.

Evaluation of independent self-collected blood specimens for COVID-19 antibody detection among the US veteran population.

Feasibility of home blood sample collection methods for the presence of SARS-CoV-2 antibodies from VA Million Veteran Program (MVP) participants was tested to determine COVID-19 infection or vaccination status. Participants (n = 312) were randomly assigned to self-collect blood specimens using the Neoteryx Mitra Clamshell (n = 136) or Tasso-SST (n = 176) and asked to rate their experience. Mitra tip blood was eluted and Tasso tubes were centrifuged. All samples were stored at -80 °C until tested with InBios SCoV-2 Detect™ IgG ELISA, BioRad Platelia SARS-CoV-2 Total Ab Assay, Abbott SARS-CoV-2 IgG and AdviseDx SARS-CoV-2 IgG II assays. Participants rated both devices equally. The Abbott assay had the highest sensitivity (87% Mitra, 98% Tasso-SST) for detecting known COVID infection and/or vaccination. The InBios assay with Tasso-SST had the best sensitivity (97%) and specificity (80%) for detecting known COVID-19 infection and/or vaccination. Veterans successfully collected their own specimens with no strong preference for either device.

Effectiveness of mRNA COVID-19 vaccines against Omicron and Delta variants in a matched test-negative case-control study among US veterans.

OBJECTIVE: To estimate the effectiveness of messenger RNA (mRNA) booster doses during the period of Delta and Omicron variant dominance. DESIGN: We conducted a matched test-negative case-control study to estimate the vaccine effectiveness (VE) of three and two doses of mRNA vaccines against infection (regardless of symptoms) and against COVID-19-related hospitalisation and death. SETTING: Veterans Health Administration. PARTICIPANTS: We used electronic health record data from 114 640 veterans who had a SARS-CoV-2 test during November 2021-January 2022. Patients were largely 65 years or older (52%), male (88%) and non-Hispanic white (59%). MAIN OUTCOME MEASURES: First positive result for a SARS-CoV-2 PCR or antigen test. RESULTS: Against infection, booster doses had higher estimated VE (64%, 95% CI 63 to 65) than two-dose vaccination (12%, 95% CI 10 to 15) during the Omicron period. For the Delta period, the VE against infection was 90% (95% CI 88 to 92) among boosted vaccinees, higher than the VE among two-dose vaccinees (54%, 95% CI 50 to 57). Against hospitalisation, booster dose VE was 89% (95% CI 88 to 91) during Omicron and 94% (95% CI 90 to 96) during Delta; two-dose VE was 63% (95% CI 58 to 67) during Omicron and 75% (95% CI 69 to 80) during Delta. Against death, the VE with a booster dose was 94% (95% CI 90 to 96) during Omicron and 96% (95% CI 87 to 99) during Delta. CONCLUSIONS: Among an older, mostly male, population with comorbidities, we found that an mRNA vaccine booster was highly effective against infection, hospitalisation and death. Although the effectiveness of booster vaccination against infection was moderately higher against Delta than against the Omicron SARS-CoV-2 variant, effectiveness against severe disease and death was similarly high against both variants.

Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised, double-blind, double placebo-controlled trial.

BACKGROUND: Baricitinib and dexamethasone have randomised trials supporting their use for the treatment of patients with COVID-19. We assessed the combination of baricitinib plus remdesivir versus dexamethasone plus remdesivir in preventing progression to mechanical ventilation or death in hospitalised patients with COVID-19. METHODS: In this randomised, double-blind, double placebo-controlled trial, patients were enrolled at 67 trial sites in the USA (60 sites), South Korea (two sites), Mexico (two sites), Singapore (two sites), and Japan (one site). Hospitalised adults (≥18 years) with COVID-19 who required supplemental oxygen administered by low-flow (≤15 L/min), high-flow (>15 L/min), or non-invasive mechanical ventilation modalities who met the study eligibility criteria (male or non-pregnant female adults ≥18 years old with laboratory-confirmed SARS-CoV-2 infection) were enrolled in the study. Patients were randomly assigned (1:1) to receive either baricitinib, remdesivir, and placebo, or dexamethasone, remdesivir, and placebo using a permuted block design. Randomisation was stratified by study site and baseline ordinal score at enrolment. All patients received remdesivir (≤10 days) and either baricitinib (or matching oral placebo) for a maximum of 14 days or dexamethasone (or matching intravenous placebo) for a maximum of 10 days. The primary outcome was the difference in mechanical ventilation-free survival by day 29 between the two treatment groups in the modified intention-to-treat population. Safety analyses were done in the as-treated population, comprising all participants who received one dose of the study drug. The trial is registered with ClinicalTrials.gov, NCT04640168. FINDINGS: Between Dec 1, 2020, and April 13, 2021, 1047 patients were assessed for eligibility. 1010 patients were enrolled and randomly assigned, 516 (51%) to baricitinib plus remdesivir plus placebo and 494 (49%) to dexamethasone plus remdesivir plus placebo. The mean age of the patients was 58·3 years (SD 14·0) and 590 (58%) of 1010 patients were male. 588 (58%) of 1010 patients were White, 188 (19%) were Black, 70 (7%) were Asian, and 18 (2%) were American Indian or Alaska Native. 347 (34%) of 1010 patients were Hispanic or Latino. Mechanical ventilation-free survival by day 29 was similar between the study groups (Kaplan-Meier estimates of 87·0% [95% CI 83·7 to 89·6] in the baricitinib plus remdesivir plus placebo group and 87·6% [84·2 to 90·3] in the dexamethasone plus remdesivir plus placebo group; risk difference 0·6 [95% CI -3·6 to 4·8]; p=0·91). The odds ratio for improved status in the dexamethasone plus remdesivir plus placebo group compared with the baricitinib plus remdesivir plus placebo group was 1·01 (95% CI 0·80 to 1·27). At least one adverse event occurred in 149 (30%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 179 (37%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·5% [1·6 to 13·3]; p=0·014). 21 (4%) of 503 patients in the baricitinib plus remdesivir plus placebo group had at least one treatment-related adverse event versus 49 (10%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 6·0% [2·8 to 9·3]; p=0·00041). Severe or life-threatening grade 3 or 4 adverse events occurred in 143 (28%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 174 (36%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·7% [1·8 to 13·4]; p=0·012). INTERPRETATION: In hospitalised patients with COVID-19 requiring supplemental oxygen by low-flow, high-flow, or non-invasive ventilation, baricitinib plus remdesivir and dexamethasone plus remdesivir resulted in similar mechanical ventilation-free survival by day 29, but dexamethasone was associated with significantly more adverse events, treatment-related adverse events, and severe or life-threatening adverse events. A more individually tailored choice of immunomodulation now appears possible, where side-effect profile, ease of administration, cost, and patient comorbidities can all be considered. FUNDING: National Institute of Allergy and Infectious Diseases.

Association of Secretor Status and Recent Norovirus Infection With Gut Microbiome Diversity Metrics in a Veterans Affairs Population.

Norovirus infection causing acute gastroenteritis could lead to adverse effects on the gut microbiome. We assessed the association of microbiome diversity with norovirus infection and secretor status in patients from Veterans Affairs medical centers. Alpha diversity metrics were lower among patients with acute gastroenteritis but were similar for other comparisons.

Effectiveness of Messenger RNA-based Vaccines During the Emergence of the Severe Acute Respiratory Syndrome Coronavirus 2 Omicron Variant.

BACKGROUND: We evaluated the effectiveness of mRNA-based vaccines following emergence of SARS-CoV-2 Omicron variant. METHODS: Recipients of a third dose of BNT162b2 or mRNA-1273 ≥180 days after the primary series were matched to primary-series recipients and unvaccinated persons. Participants were followed from 1 December 2021 to 12 March 2022. Outcomes were documented SARS-CoV-2 infection, COVID-19 hospitalization, and COVID-19 death. Effectiveness was calculated from 100-day risks estimated with the Kaplan-Meier estimator. RESULTS: BNT162b2 and mRNA-1273 groups included 221 267 and 187 507 third-dose recipients, respectively, matched to equal numbers of primary-series recipients and unvaccinated persons. Compared with no vaccination, effectiveness of a third dose of BNT162b2 was 47.8% (95% confidence interval [CI], 45.2-50.3), 81.8% (95% CI, 79.2-84.2), and 89.6% (95% CI, 85.0-93.6) against infection, hospitalization, and death, respectively. Effectiveness of a third dose of BNT162b2 compared with the primary series was 30.1% (95% CI, 26.2-33.7), 61.4% (95% CI, 55.0-67.1), and 78.8% (95% CI, 67.9-87.5) against infection, hospitalization, and death, respectively. Effectiveness of a third dose of mRNA-1273 compared with no vaccination was 61.9% (95% CI, 59.4-64.4), 87.9% (95% CI, 85.3-90.2), and 91.4% (95% CI, 86.4-95.6) against infection, hospitalization, and death, respectively. Effectiveness of a third dose of mRNA-1273 compared with the primary series was 37.1% (95% CI, 32.2-41.7), 63.5% (95% CI, 53.7-71.6), and 75.0% (95% CI, 55.4-88.0) against infection, hospitalization, and death, respectively. CONCLUSIONS: BNT162b2 and mRNA-1273 were effective against COVID-19 following emergence of Omicron variant. A third dose provided additional protection over the primary series.

Public health surveillance in the U.S. Department of Veterans Affairs: evaluation of the Praedico surveillance system.

BACKGROUND: Early threat detection and situational awareness are vital to achieving a comprehensive and accurate view of health-related events for federal, state, and local health agencies. Key to this are public health and syndromic surveillance systems that can analyze large data sets to discover patterns, trends, and correlations of public health significance. In 2020, Department of Veterans Affairs (VA) evaluated its public health surveillance system and identified areas for improvement. METHODS: Using the Centers for Disease Control and Prevention (CDC) Guidelines for Evaluating Public Health Surveillance Systems, we assessed the ability of the Praedico Surveillance System to perform public health surveillance for a variety of health issues and evaluated its performance compared to an enterprise data solution (VA Corporate Data Warehouse), legacy surveillance system (VA ESSENCE) and a national, collaborative syndromic surveillance platform (CDC NSSP BioSense). RESULTS: Review of system attributes found that the system was simple, flexible, and stable. Representativeness, timeliness, sensitivity, and Predictive Value Positive were acceptable but could be further improved. Data quality issues and acceptability present challenges that potentially affect the overall usefulness of the system. CONCLUSIONS: Praedico is a customizable surveillance and data analytics platform built on big data technologies. Functionality is straightforward, with rapid query generation and runtimes. Data can be graphed, mapped, analyzed, and shared with key decision makers and stakeholders. Evaluation findings suggest that future development and system enhancements should focus on addressing Praedico data quality issues and improving user acceptability. Because Praedico is designed to handle big data queries and work with data from a variety of sources, it could be enlisted as a tool for interdepartmental and interagency collaboration and public health data sharing. We suggest that future system evaluations include measurements of value and effectiveness along with additional organizations and functional assessments.

Implementation of large-scale laboratory-based detection of COVID-19 in the Veterans Health Administration, March 2020 - February 2021.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presented numerous operational challenges to healthcare delivery networks responsible for implementing large scale detection of Coronavirus Disease 2019 (COVID-19), the infection caused by SARS-CoV-2. We describe testing performance, review data quality metrics, and summarize experiences during the scale up of laboratory-based detection of COVID-19 in the Veterans Health Administration, the largest healthcare system in the United States. During March 2020 to February 2021, we observed rapid increase in testing volume, decreases in test turnaround time, improvements in testing of hospitalized persons, changes in test positivity, and varying utilization of different tests. Though performance metrics improved over time, surges challenged testing capacity and data quality remained suboptimal. Future planning efforts should focus on fortifying supply chains for consumables and equipment repair, optimizing distribution of testing workload across laboratories, and improving informatics to accurately monitor operations and intent for testing during a public health emergency.

The US Department of Veterans Affairs Science and Health Initiative to Combat Infectious and Emerging Life-Threatening Diseases (VA SHIELD): A Biorepository Addressing National Health Threats.

Background: The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has demonstrated the need to share data and biospecimens broadly to optimize clinical outcomes for US military Veterans. Methods: In response, the Veterans Health Administration established VA SHIELD (Science and Health Initiative to Combat Infectious and Emerging Life-threatening Diseases), a comprehensive biorepository of specimens and clinical data from affected Veterans to advance research and public health surveillance and to improve diagnostic and therapeutic capabilities. Results: VA SHIELD now comprises 12 sites collecting de-identified biospecimens from US Veterans affected by SARS-CoV-2. In addition, 2 biorepository sites, a data processing center, and a coordinating center have been established under the direction of the Veterans Affairs Office of Research and Development. Phase 1 of VA SHIELD comprises 34 157 samples. Of these, 83.8% had positive tests for SARS-CoV-2, with the remainder serving as contemporaneous controls. The samples include nasopharyngeal swabs (57.9%), plasma (27.9%), and sera (12.5%). The associated clinical and demographic information available permits the evaluation of biological data in the context of patient demographics, clinical experience and management, vaccinations, and comorbidities. Conclusions: VA SHIELD is representative of US national diversity with a significant potential to impact national healthcare. VA SHIELD will support future projects designed to better understand SARS-CoV-2 and other emergent healthcare crises. To the extent possible, VA SHIELD will facilitate the discovery of diagnostics and therapeutics intended to diminish COVID-19 morbidity and mortality and to reduce the impact of new emerging threats to the health of US Veterans and populations worldwide.