IMPORTANCE: Influenza vaccine effectiveness (VE) is commonly assessed against prevention of illness that requires medical attention. Few studies have evaluated VE against secondary influenza infections. OBJECTIVE: To determine the estimated effectiveness of influenza vaccines in preventing secondary infections after influenza was introduced into households. DESIGN, SETTINGS, AND PARTICIPANTS: During 3 consecutive influenza seasons (2017-2020), primary cases (the first household members with laboratory-confirmed influenza) and their household contacts in Tennessee and Wisconsin were enrolled into a prospective case-ascertained household transmission cohort study. Participants collected daily symptom diaries and nasal swabs for up to 7 days. Data were analyzed from September 2022 to February 2024. EXPOSURES: Vaccination history, self-reported and verified through review of medical and registry records. MAIN OUTCOMES AND MEASURES: Specimens were tested using reverse transcription-polymerase chain reaction to determine influenza infection. Longitudinal chain binomial models were used to estimate secondary infection risk and the effectiveness of influenza vaccines in preventing infection among household contacts overall and by virus type and subtype and/or lineage. RESULTS: The analysis included 699 primary cases and 1581 household contacts. The median (IQR) age of the primary cases was 13 (7-38) years, 381 (54.5%) were female, 60 (8.6%) were Hispanic, 46 (6.6%) were non-Hispanic Black, 553 (79.1%) were Non-Hispanic White, and 343 (49.1%) were vaccinated. Among household contacts, the median age was 31 (10-41) years, 833 (52.7%) were female, 116 (7.3%) were Hispanic, 78 (4.9%) were non-Hispanic Black, 1283 (81.2%) were non-Hispanic White, 792 (50.1%) were vaccinated, and 356 (22.5%) had laboratory-confirmed influenza during follow-up. The overall secondary infection risk of influenza among household contacts was 18.8% (95% CI, 15.9% to 22.0%). The risk was highest among children and was 20.3% (95% CI, 16.4% to 24.9%) for influenza A and 15.9% (95% CI, 11.8% to 21.0%) for influenza B. The overall estimated VE for preventing secondary infections among unvaccinated household contacts was 21.0% (95% CI, 1.4% to 36.7%) and varied by type; estimated VE against influenza A was 5.0% (95% CI, -22.3% to 26.3%) and 56.4% (95% CI, 30.1% to 72.8%) against influenza B. CONCLUSIONS AND RELEVANCE: After influenza was introduced into households, the risk of secondary influenza among unvaccinated household contacts was approximately 15% to 20%, and highest among children. Estimated VE varied by influenza type, with demonstrated protection against influenza B virus infection.

BACKGROUND: Implications of relabeling grade group (GG) 1 prostate cancer as non-cancer will depend on the recommended active surveillance (AS) strategy. Whether relabeling should prompt de-intensifying, PSA-based active monitoring approaches is unclear. We investigated outcomes of biopsy-based AS strategies vs PSA-based active monitoring for GG1 diagnoses under different patient adherence rates. METHODS: We analyzed longitudinal PSA levels and time to GG ≥ 2 reclassification among 850 patients diagnosed with GG1 disease from the Canary Prostate Active Surveillance Study (2008-2013). We then simulated 20,000 patients over 12 years, comparing GG ≥ 2 detection under biennial biopsy against three PSA-based strategies:(1) PSA: biopsy for PSA change ≥20%/year, (2) PSA+MRI: MRI for PSA change ≥20%/year and biopsy for PI-RADS ≥3, and (3) Predicted risk: biopsy for predicted upgrading risk ≥10%. RESULTS: Under biennial biopsies and 20% dropout to active treatment, 17% of patients had a > 2-year delay in GG ≥ 2 detection. The PSA strategy reduced biopsies by 39% but delayed detection in 32% of patients. The PSA+MRI strategy cut biopsies by 52%, with a 34% delay. The predicted risk strategy reduced biopsies by 31%, with only an 8% delay. These findings are robust to biopsy sensitivity and confirmatory biopsy. CONCLUSIONS: PSA-based active monitoring could substantially reduce biopsy frequency; however, a precision strategy based on an individual upgrading risk is most likely to minimize delays in disease progression detection. This strategy may be preferred if AS is deintensified under relabeling, provided patient adherence remains unaffected.

We investigated a suspected norovirus outbreak associated with a wedding reception in Wisconsin in May 2015. Fifty-six of 106 (53%) wedding attendees were interviewed and 23 (41%) reported symptoms consistent with norovirus infection. A retrospective cohort study identified fruit salad as the likely vehicle of infection (risk ratio 3.2, 95% confidence interval 1.1- 8.3). Norovirus was detected by real-time reverse transcription polymerase chain reaction (RT-qPCR) in stool specimens collected from four attendees and one food handler and in 12 leftover fruit salad samples from both an opened and a sealed container. Norovirus-positive clinical samples (n=4) were genotyped as GII.4 Sydney and norovirus-positive fruit salad samples (n=2) confirmed the presence of GII.4 norovirus by Sanger sequencing with 98% nucleotide (n=236) similarity in 5' end of ORF2 between fruit salad and clinical specimens. In conclusion, this comprehensive norovirus outbreak investigation combined epidemiologic, virologic, and environmental findings to traceback the contaminated food as the source of the outbreak.

Pregnancy is associated with increased risk for severe illness and complications associated with influenza infection. Insufficient knowledge about the risk for influenza among pregnant women and their health care providers in China is an important barrier to increasing influenza vaccination coverage and treating influenza and its complications among pregnant women. Improved influenza incidence estimates might promote wider vaccine acceptance and higher vaccination coverage. In Suzhou, active population-based surveillance during October 2018-September 2023 estimated that the annual rate of hospitalization for acute respiratory or febrile illness (ARFI) among women who were pregnant or <2 weeks postpartum was 11.1 per 1,000 live births; the annual rate of laboratory-confirmed influenza-associated ARFI (influenza ARFI) hospitalization in this group was 2.1 per 1,000 live births. A majority of hospitalized pregnant or early postpartum patients with ARFI (82.6%; 2,588 of 3,133) or influenza ARFI (85.5%; 423 of 495) were admitted to obstetrics wards rather than respiratory medicine wards. Only one (0.03%) pregnant or postpartum ARFI patient had received influenza vaccination, and 31.3% of pregnant or postpartum women hospitalized for influenza ARFI received antiviral treatment; the lowest percentage of hospitalized women with influenza ARFI who received antiviral treatment was among women admitted to obstetrics and gynecology wards (29.6% and 23.1%, respectively), compared with 54.1% of those admitted to a respiratory medicine ward. These findings highlight the risk for influenza and its associated complications among pregnant and postpartum women, the low rates of influenza vaccination among pregnant women, and of antiviral treatment of women with ARFI admitted to obstetrics and gynecology wards. Increasing awareness of the prevalence of influenza ARFI among pregnant women, the use of empiric antiviral treatment for ARFI, and the infection control in obstetrics wards during influenza seasons might help reduce influenza-associated morbidity among pregnant and postpartum women.

BACKGROUND: Evidence from toxicological studies indicate organophosphate esters (OPEs) are neurotoxic, but few epidemiological studies investigated associations between gestational OPEs and executive function. OBJECTIVE: To examine the associations between gestational concentrations of OPE urinary metabolites and executive function at 12 years METHODS: We used data from 223 mother-adolescent dyads from the Health Outcomes of Measures of the Environment (HOME) Study. Women provided spot urine samples at 16 weeks gestation, 26 weeks gestation, and at delivery for quantification of bis(1,3-dichloro-2-propyl) phosphate, bis-2-chloroethyl phosphate (BCEP), diphenyl phosphate (DPHP), and di-n-butyl phosphate (DNBP). Executive function was assessed at age 12 years using the parent- and self-report Behavior Rating Inventory of Executive Function (BRIEF2). Covariate-adjusted associations between specific gravity-corrected OPEs and BRIEF2 scores were estimated using multiple informant models. Bayesian Kernel Machine Regression (BKMR) was used to assess the impact of all OPEs simultaneously. RESULTS: Parent- and self-report BRIEF2 indices and composite scores were weakly to moderately correlated (r(s)=0.32-0.41). A natural-log unit increase in BCEP at 26 weeks was associated with approximately a 1-point increase on the self-report Cognitive Regulation Index [CRI] (95% CI 0.4, 2.3), the Emotion Regulation Index [ERI] (95% CI 0.3, 2.2), and the Global Executive Composite [GEC] (95% CI 0.4, 2.2), indicating poorer performance. Higher DPHP at 16 weeks was associated with lower parent-report GEC score (β=-1.1, 95% CI -2.3, -0.003). BKMR identified BCEP and DNBP at 26 weeks as important contributors to CRI and ERI, respectively. CONCLUSION: OPE metabolites during gestational development, particularly BCEP, may influence adolescent executive function. However, since the FDR p-values failed to reach statistical significance, additional studies would benefit from using larger cohorts.

OBJECTIVE: To characterize presentation and care pathways of patients with systemic lupus erythematosus (SLE), and delays in access to SLE-specialized care. METHODS: We included patients with incident SLE from the Lupus Midwest Network registry. Time from the first medical encounter for SLE clinical manifestation to access to SLE-specialized care, physician diagnosis, and treatment was estimated. Delays were defined as ≥6 months to access specialized care. We compared SLE manifestations, disease activity (SLEDAI-2k), and SLICC/ACR damage indexes (SDI) between patients with and without delays. Logistic regression models assessed associations with delays. RESULTS: The study included 373 patients with SLE. The median time to access SLE-specialized care was 1.1 months (95% confidence interval [CI] 0.9-1.5); time to diagnosis 30.6 months (95% CI 18.9-48.1), and time to treatment initiation 4.7 months (95% CI 3.9-8.4). Approximately 25% (93/373) of patients experienced delays accessing specialized care, which were associated with fewer SLE manifestations at first SLE-related encounter (<2 SLE domains; 92% vs 72%, P < 0.001). Patients with mucocutaneous or musculoskeletal manifestations were less likely to experience delays, while hematologic (odds ratio [OR] 1.71, 95% CI 1.03-2.84) or antiphospholipid antibodies domains (OR 6.05, 95% CI 2.46-14.88) were associated with delays. Delays were associated with damage at first access to SLE-specialized care (SDI ≥1; 30% vs 7%, P < 0.001). CONCLUSIONS: Patients follow a heterogeneous pathway to receive care. One-fourth of patients experienced delays accessing SLE-specialized care, which was associated with damage. Fewer manifestations, hematologic, or antiphospholipid antibodies were associated with delays.

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) can be triggered by infectious agents including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the impact of the coronavirus disease 2019 (COVID-19) pandemic on ME/CFS prevalence is not well characterized. METHODS: In this population-based cross-sectional study, we enrolled a stratified random sample of 9,825 adult participants in the Kaiser Permanente Northern California (KPNC) integrated health system from July to October 2022 to assess overall ME/CFS-like illness prevalence and the proportion that were identified following COVID-19 illness. We used medical record and survey data to estimate the prevalence of ME/CFS-like illness based on self-reported symptoms congruent with the 2015 Institute of Medicine ME/CFS criteria. History of COVID-19 was based on a positive SARS-CoV-2 nucleic acid amplification test or ICD-10 diagnosis code in the medical record, or self-report of prior COVID-19 on a survey. RESULTS: Of 2,745,374 adults in the eligible population, an estimated 45,892 (95% confidence interval [CI]: 32,869, 58,914) or 1.67% (CI 1.20%, 2.15%) had ME/CFS-like illness. Among those with ME/CFS-like illness, an estimated 14.12% (CI 3.64%, 24.6%) developed the illness after COVID-19. Among persons who had COVID-19, those with ME/CFS-like illness after COVID-19 were more likely to be unvaccinated and to have had COVID-19 before June 1, 2021. All persons with ME/CFS-like illness had significant impairment in physical, mental, emotional, social, and occupational functioning compared to persons without ME/CFS-like illness. CONCLUSIONS: In a large, integrated health system, 1.67% of adults had ME/CFS-like illness and 14.12% of all persons with ME/CFS-like illness developed it after COVID-19. Though COVID-19 did not substantially increase ME/CFS-like illness in the KPNC population during the study time period, ME/CFS-like illness nevertheless affects a notable portion of this population and is consistent with estimates of ME/CFS prevalence in other populations. Additional attention is needed to improve awareness, diagnosis, and treatment of ME/CFS.

BACKGROUND: During COVID-19 pandemic, the general public used any face-worn products they could get to overcome the shortage of N95 respirators and surgical masks. These products, often not meeting any standards, raised concerns about their effectiveness in reducing the spread of respiratory viruses. METHODS: This study quantified total outward leakage (TOL) of units from nine face-worn product categories used by members of the general public. A benchtop system was devised to test two units from each category on two different-sized headforms with silicone elastomer skin. Each unit was donned five times per headform. RESULTS: Both face-worn product category and headform size significantly affected TOL (P-Value <0.05). The TOL of tested face-worn products varied from 10% to 58% depending on both model and headform size. Face-worn products donned on the medium headform had a higher mean TOL compared to those donned on the larger headform. CONCLUSIONS: Overall, single-layer cloth masks are the least effective measure for source control due to their highest TOL among the tested face-worn products. Three-layer disposable face masks may be a favorable option for source control among the public. A standard should be developed for face-worn product design and manufacturing to accommodate different facial sizes.

Following the detection of highly pathogenic avian influenza (HPAI) virus in countries bordering Kenya to the west, we conducted surveillance among domestic and wild birds along the shores of Lake Victoria. In addition, between 2018 and 2020, we conducted surveillance among poultry and poultry workers in live bird markets and among wild migratory birds in various lakes that are resting sites during migration to assess introduction and circulation of avian influenza viruses in these populations. We tested 7464 specimens (oropharyngeal (OP) and cloacal specimens) from poultry and 6531 fresh fecal specimens from wild birds for influenza A viruses by real-time RT-PCR. Influenza was detected in 3.9% (n = 292) of specimens collected from poultry and 0.2% (n = 10) of fecal specimens from wild birds. On hemagglutinin subtyping, most of the influenza A positives from poultry (274/292, 93.8%) were H9. Of 34 H9 specimens randomly selected for further subtyping, all were H9N2. On phylogenetic analysis, these viruses were genetically similar to other H9 viruses detected in East Africa. Only two of the ten influenza A-positive specimens from the wild bird fecal specimens were successfully subtyped; sequencing analysis of one specimen collected in 2018 was identified as a low-pathogenicity avian influenza H5N2 virus of the Eurasian lineage, and the second specimen, collected in 2020, was subtyped as H11. A total of 18 OP and nasal specimens from poultry workers with acute respiratory illness (12%) were collected; none were positive for influenza A virus. We observed significant circulation of H9N2 influenza viruses in poultry in live bird markets in Kenya. During the same period, low-pathogenic H5N2 virus was detected in a fecal specimen collected in a site hosting a variety of migratory and resident birds. Although HPAI H5N8 was not detected in this survey, these results highlight the potential for the introduction and establishment of highly pathogenic avian influenza viruses in poultry populations and the associated risk of spillover to human populations.

Background: Inequities in stroke outcomes have existed for decades, and the COVID-19 pandemic amplified these inequities. Objectives: This study examined the association between social vulnerability and all-cause mortality among Medicare beneficiaries hospitalized with acute ischemic stroke (AIS) during COVID-19 pandemic periods. Methods: We analyzed data on Medicare fee-for-service beneficiaries aged ≥65 years hospitalized with AIS between April 1, 2020, and December 31, 2021 (followed until December 31, 2023) merged with county-level data from the 2020 Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry's Social Vulnerability Index (SVI). We used a Cox proportional hazard model to examine the association between SVI quartile and all-cause mortality. Results: Among 176,123 Medicare fee-for-service beneficiaries with AIS, 29.9% resided in the most vulnerable counties (SVI quartile 4), while 14.9% resided in counties with least social vulnerability (SVI quartile 1). AIS Medicare beneficiaries living in the most vulnerable counties had the highest proportions of adults aged 65 to 74 years, non-Hispanic Black or Hispanic, severe stroke at admission, a history of COVID-19, and more prevalent comorbidities. Compared to those living in least vulnerable counties, AIS Medicare beneficiaries living in most vulnerable counties had significantly higher all-cause mortality (adjusted HR: 1.11, 95% CI: 1.08-1.14). The pattern of association was largely consistent in subgroup analyses by age group, sex, and race and ethnicity. Conclusions: Higher social vulnerability levels were associated with increased all-cause mortality among AIS Medicare beneficiaries. To improve outcomes and address disparities, it may be important to focus efforts toward addressing social vulnerability. © 2024

INTRODUCTION: This study examined the association between American Heart Association's (AHA) cardiovascular health (CVH) metrics -Life's Essential 8 (LE8)- and predicted heart age among U.S. adults. METHODS: The sample comprised 7,075 participants aged 30-74 years without CVD and/or stroke from the National Health and Nutrition Examination Survey (NHANES) 2015-March 2020. LE8 was measured according to AHA's metrics (overall score ranging from 0 to 100 points), and nonlaboratory-based Framingham Risk Score was used to estimate predicted heart age. Analyses were completed in June 2024. RESULTS: Median LE8 scores were 62.8 for men and 66.0 for women. Over 80% of participants had less than optimal CVH scores, affecting 141.5 million people and 1-in-6 participants had a low CVH score, impacting 30.0 million people. Mean predicted heart age and excess heart age (EHA, difference between actual and predicted heart age) were 56.6 (95% CI 56.1-57.1) and 8.6 (8.1-9.1) years for men and 54.0 (53.4-54.7) and 5.9 (5.2-6.5) years for women. Participants in the low CVH group (scores<50), had an EHA that was 20.7 years higher than those in the high CVH group (score 80-100). Compared to the high CVH group, participants in low CVH group had 15 times (for men) and 44 times (for women) higher risk of having EHA ≥10 years. The pattern of differences in predicted heart age, EHA, and prevalence of EHA ≥10 years by LE8 groups remained largely consistent across subpopulations. CONCLUSIONS: These findings highlight the importance of maintaining a healthy lifestyle to improve cardiovascular health and reduce excess heart age.

BACKGROUND: The 2022-2023 United States influenza season had unusually early influenza activity with high hospitalization rates. Vaccine-matched A(H3N2) viruses predominated, with lower levels of A(H1N1)pdm09 activity also observed. METHODS: Using the test-negative design, we evaluated influenza vaccine effectiveness (VE) during the 2022-2023 season against influenza A-associated emergency department/urgent care (ED/UC) visits and hospitalizations from October 2022 to March 2023 among adults (aged ≥18 years) with acute respiratory illness (ARI). VE was estimated by comparing odds of seasonal influenza vaccination among case-patients (influenza A test positive by molecular assay) and controls (influenza test negative), applying inverse-propensity-to-be-vaccinated weights. RESULTS: The analysis included 85 389 ED/UC ARI encounters (17.0% influenza A positive; 37.8% vaccinated overall) and 19 751 hospitalizations (9.5% influenza A positive; 52.8% vaccinated overall). VE against influenza A-associated ED/UC encounters was 44% (95% confidence interval [CI], 40%-47%) overall and 45% and 41% among adults aged 18-64 and ≥65 years, respectively. VE against influenza A-associated hospitalizations was 35% (95% CI, 27%-43%) overall and 23% and 41% among adults aged 18-64 and ≥65 years, respectively. CONCLUSIONS: VE was moderate during the 2022-2023 influenza season, a season characterized with increased burden of influenza and co-circulation with other respiratory viruses. Vaccination is likely to substantially reduce morbidity, mortality, and strain on healthcare resources.

About 80% of persons with chronic hepatitis B virus (HBV) infection in the United States are non-US-born. Despite improvements in infant hepatitis B vaccination globally since 2000, work remains to attain the World Health Organization's (WHO) global 2030 goal of 90% vaccination. We explore the impacts on the United States of global progress in hepatitis B vaccination since 2000 and of achieving WHO hepatitis B vaccination goals. We simulated immigrants with HBV infection arriving to the United States from 2000 to 2070 using models of the 10 countries from which the largest numbers of individuals with HBV infection were born. We estimated costs in the United States among these cohorts using a disease simulation model. We simulated three scenarios: a scenario with no progress in infant vaccination for hepatitis B since 2000 (baseline), current (2020) progress and achieving WHO 2030 goals for hepatitis B vaccination. We estimate current hepatitis B vaccination progress since the 2000 baseline in these 10 countries will lead to 468,686 fewer HBV infections, avoid 35,582 hepatitis B-related deaths and save $4.2 billion in the United States through 2070. Achieving the WHO 2030 90% hepatitis B infant vaccination targets could lead to an additional 16,762 fewer HBV infections, 989 fewer hepatitis B-related deaths and save $143 million through 2070. Global hepatitis B vaccination since 2000 reduced prevalence of HBV infection in the United States. Achieving the WHO 2030 infant vaccination goals globally could lead to over one hundred million dollars in additional savings.

Maternal morbidity and mortality remain significant challenges in the United States, with substantial burden during the postpartum period. The Centers for Disease Control and Prevention, in partnership with the National Association of Community Health Centers, began an initiative to build capacity in Federally Qualified Health Centers to (1) improve the infrastructure for perinatal care measures and (2) use perinatal care measures to identify and address gaps in postpartum care. Two partner health center-controlled networks implemented strategies to integrate evidence-based recommendations into the clinic workflow and used data-driven health information technology (HIT) systems to improve data standardization for quality improvement of postpartum care services. Ten measures were created to capture recommended care and services. To support measure capture, a data cleaning algorithm was created to prioritize defining pregnancy episodes and delivery dates and address data inconsistencies. Quality improvement activities targeted postpartum care delivery tailored to patients and care teams. Data limitations, including inconsistencies in electronic health record documentation and data extraction practices, underscored the complexity of integrating HIT solutions into postpartum care workflows. Despite challenges, the project demonstrated continuous quality improvement to support data quality for perinatal care measures. Future solutions emphasize the need for standardized data elements, collaborative care team engagement, and iterative HIT implementation strategies to enhance perinatal care quality. Our findings highlight the potential of HIT-driven interventions to improve postpartum care within health centers, with a focus on the importance of addressing data interoperability and documentation challenges to optimize and monitor initiatives to improve postpartum health outcomes.

BACKGROUND: Nirmatrelvir/ritonavir (N/R) reduces severe outcomes from coronavirus disease 2019 (COVID-19); however, rebound after treatment has been reported. We compared symptom and viral dynamics in individuals with COVID-19 who completed N/R treatment and similar untreated individuals. METHODS: We identified symptomatic participants who tested severe acute respiratory syndrome coronavirus 2-positive and were N/R eligible from a COVID-19 household transmission study. Index cases from ambulatory settings and their households contacts were enrolled. We collected daily symptoms, medication use, and respiratory specimens for quantitative polymerase chain reaction for 10 days during March 2022-May 2023. Participants who completed N/R treatment (treated) were propensity score matched to untreated participants. We compared symptom rebound, viral load (VL) rebound, average daily symptoms, and average daily VL by treatment status measured after N/R treatment completion or 7 days after symptom onset if untreated. RESULTS: Treated (n = 130) and untreated participants (n = 241) had similar baseline characteristics. After treatment completion, treated participants had greater occurrence of symptom rebound (32% vs 20%; P = .009) and VL rebound (27% vs 7%; P < .001). Average daily symptoms were lower among treated participants without symptom rebound (1.0 vs 1.6; P < .01) but not statistically lower with symptom rebound (3.0 vs 3.4; P = .5). Treated participants had lower average daily VLs without VL rebound (0.9 vs 2.6; P < .01) but not statistically lower with VL rebound (4.8 vs 5.1; P = .7). CONCLUSIONS: Individuals who completed N/R treatment experienced fewer symptoms and lower VL but rebound occured more often compared with untreated individuals. Providers should prescribe N/R, when indicated, and communicate rebound risk to patients.

Ribonucleoside monophosphates (rNMPs) are abundantly found within genomic DNA of cells. The embedded rNMPs alter DNA properties and impact genome stability. Mutations in ribonuclease (RNase) H2, a key enzyme for rNMP removal, are associated with the Aicardi-Goutières syndrome (AGS), a severe neurological disorder. Here, we engineered orthologs of the human RNASEH2A-G37S and RNASEH2C-R69W AGS mutations in yeast Saccharomyces cerevisiae: rnh201-G42S and rnh203-K46W. Using the ribose-seq technique and the Ribose-Map bioinformatics toolkit, we unveiled rNMP abundance, composition, hotspots, and sequence context in these AGS-ortholog mutants. We found a high rNMP presence in the nuclear genome of rnh201-G42S-mutant cells, and an elevated rCMP content in both mutants, reflecting preferential cleavage of RNase H2 at rGMP. We discovered unique rNMP patterns in each mutant, showing differential activity of the AGS mutants on the leading or lagging replication strands. This study guides future research on rNMP characteristics in human genomes with AGS mutations. © 2024 The Authors

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved into numerous lineages with unique spike mutations and caused multiple epidemics domestically and globally. Although COVID-19 vaccines are available, new variants with the capacity for immune evasion continue to emerge. To understand and characterize the evolution of circulating SARS-CoV-2 variants in the U.S., the Centers for Disease Control and Prevention (CDC) initiated the National SARS-CoV-2 Strain Surveillance (NS3) program and has received thousands of SARS-CoV-2 clinical specimens from across the nation as part of a genotype to phenotype characterization process. Focus reduction neutralization with various antisera was used to antigenically characterize 143 SARS-CoV-2 Delta, Mu and Omicron subvariants from selected clinical specimens received between May 2021 and February 2023, representing a total of 59 unique spike protein sequences. BA.4/5 subvariants BU.1, BQ.1.1, CR.1.1, CQ.2 and BA.4/5 + D420N + K444T; BA.2.75 subvariants BM.4.1.1, BA.2.75.2, CV.1; and recombinant Omicron variants XBF, XBB.1, XBB.1.5 showed the greatest escape from neutralizing antibodies when analyzed against post third-dose original monovalent vaccinee sera. Post fourth-dose bivalent vaccinee sera provided better protection against those subvariants, but substantial reductions in neutralization titers were still observed, especially among BA.4/5 subvariants with both an N-terminal domain (NTD) deletion and receptor binding domain (RBD) substitutions K444M + N460K and recombinant Omicron variants. This analysis demonstrated a framework for long-term systematic genotype to antigenic characterization of circulating and emerging SARS-CoV-2 variants in the U.S., which is critical to assessing their potential impact on the effectiveness of current vaccines and antigen recommendations for future updates.

BACKGROUND: SARS-CoV2, the virus that causes coronavirus disease 2019 (COVID-19), can affect multiple human organs structurally and functionally, including the cardiovascular system and brain. Many studies focused on the acute effects of COVID-19 on risk of cardiovascular disease (CVD) and stroke especially among hospitalized patients with limited follow-up time. This study examined long-term mortality, hospitalization, CVD and stroke outcomes after non-hospitalized COVID-19 among Medicare fee-for-service (FFS) beneficiaries in the United States. METHODS: This retrospective matched cohort study included 944,371 FFS beneficiaries aged ≥66 years diagnosed with non-hospitalized COVID-19 from April 1, 2020, to April 30, 2021, and followed-up to May 31, 2022, and 944,371 propensity score matched FFS beneficiaries without COVID-19. Primary outcomes were all-cause mortality, hospitalization, and incidence of 15 CVD and stroke. Because most outcomes violated the proportional hazards assumption, we used restricted cubic splines to model non-proportional hazards in Cox models and presented time-varying hazard ratios (HRs) and Bonferroni corrected 95% confidence intervals (CI). RESULTS: The mean age was 75.3 years; 58.0% women and 82.6% non-Hispanic White. The median follow-up was 18.5 months (interquartile range 16.5 to 20.5). COVID-19 showed initial stronger effects on all-cause mortality, hospitalization and 12 incident CVD outcomes with adjusted HRs in 0-3 months ranging from 1.05 (95% CI 1.01-1.09) for mortality to 2.55 (2.26-2.87) for pulmonary embolism. The effects of COVID-19 on outcomes reduced significantly after 3-month follow-up. Risk of mortality, acute myocardial infarction, cardiomyopathy, deep vein thrombosis, and pulmonary embolism returned to baseline after 6-month follow-up. Patterns of initial stronger effects of COVID-19 were largely consistent across age groups, sex, and race/ethnicity. CONCLUSIONS: Our results showed a consistent time-varying effects of COVID-19 on mortality, hospitalization, and incident CVD among non-hospitalized COVID-19 survivors.

OBJECTIVE: To characterize high type 1 diabetes (T1D) genetic risk in a population where type 2 diabetes (T2D) predominates. RESEARCH DESIGN AND METHODS: Characteristics typically associated with T1D were assessed in 109,594 Million Veteran Program participants with adult-onset diabetes, 2011-2021, who had T1D genetic risk scores (GRS) defined as low (0 to <45%), medium (45 to <90%), high (90 to <95%), or highest (≥95%). RESULTS: T1D characteristics increased progressively with higher genetic risk (P < 0.001 for trend). A GRS ≥ 90% was more common with diabetes diagnoses before age 40 years, but 95% of those participants were diagnosed at age ≥40 years, and they resembled T2D in mean age (64.3 years) and BMI (32.3 kg/m2). Compared with the low risk group, the highest-risk group was more likely to have diabetic ketoacidosis (low 0.9% vs. highest GRS 3.7%), hypoglycemia prompting emergency visits (3.7% vs. 5.8%), outpatient plasma glucose <50 mg/dL (7.5% vs. 13.4%), a shorter median time to start insulin (3.5 vs. 1.4 years), use of a T1D diagnostic code (16.3% vs. 28.1%), low C-peptide levels if tested (1.8% vs. 32.4%), and glutamic acid decarboxylase antibodies (6.9% vs. 45.2%), all P < 0.001. CONCLUSIONS: Characteristics associated with T1D were increased with higher genetic risk, and especially with the top 10% of risk. However, the age and BMI of those participants resemble people with T2D, and a substantial proportion did not have diagnostic testing or use of T1D diagnostic codes. T1D genetic screening could be used to aid identification of adult-onset T1D in settings in which T2D predominates.

BACKGROUND: Widespread outbreaks of person-to-person transmitted hepatitis A virus (HAV), particularly among people who inject drugs (PWID), continue across the United States and globally. However, the herd immunity threshold and vaccination coverage required to prevent outbreaks are unknown. We used surveillance data and dynamic modeling to estimate herd immunity thresholds among PWID in 16 US states. METHODS: We used a previously published dynamic model of HAV transmission calibrated to surveillance data from outbreaks involving PWID in 16 states. Using state-level calibrated models, we estimated the basic reproduction number (R0) and herd immunity threshold for PWID in each state. We performed a meta-analysis of herd immunity thresholds to determine the critical vaccination coverage required to prevent most HAV outbreaks among PWID. RESULTS: Estimates of R0 for HAV infection ranged from 2.2 (95% confidence interval [CI], 1.9-2.5) for North Carolina to 5.0 (95% CI, 4.5-5.6) for West Virginia. Corresponding herd immunity thresholds ranged from 55% (95% CI, 47%-61%) for North Carolina to 80% (95% CI, 78%-82%) for West Virginia. Based on the meta-analysis, we estimated a pooled herd immunity threshold of 64% (95% CI, 61%-68%; 90% prediction interval, 52%-76%) among PWID. Using the prediction interval upper bound (76%) and assuming 95% vaccine efficacy, we estimated that vaccination coverage of 80% could prevent most HAV outbreaks. CONCLUSIONS: Hepatitis A vaccination programs in the United States may need to achieve vaccination coverage of at least 80% among PWID in order to prevent most HAV outbreaks among this population.

BACKGROUND: Oral pre-exposure prophylaxis (PrEP) with emtricitabine/tenofovir disoproxil fumarate (F/TDF) has high efficacy against HIV-1 acquisition. Seventy-two prospective studies of daily oral F/TDF PrEP were conducted to evaluate HIV-1 incidence, drug resistance, adherence, and bone and renal safety in diverse settings. METHODS: HIV-1 incidence was calculated from incident HIV-1 diagnoses after PrEP initiation and within 60 days of discontinuation. Tenofovir concentration in dried blood spots (DBS), drug resistance, and bone/renal safety indicators were evaluated in a subset of studies. RESULTS: Among 17,274 participants, there were 101 cases with new HIV-1 diagnosis (0.77 per 100 person-years; 95% CI 0.63-0.94). In 78 cases with resistance data, 18 (23%) had M184I or V, one (1.3%) had K65R, and three (3.8%) had both mutations. In 54 cases with tenofovir concentration data from DBS, 45 (83.3%), 2 (3.7%), 6 (11.1%), and 1 (1.9%) had average adherence of <2, 2-3, 4-6, and ≥7 doses/week, respectively, and the corresponding incidence was 3.9 (95% CI 2.9-5.3), 0.24 (0.060-0.95), 0.27 (0.12-0.60), and 0.054 (0.008-0.38) per 100 person-years. Adherence was low in younger participants, Hispanic/Latinx and Black participants, cisgender women, and transgender women. Bone and renal adverse event incidence rates were 0.69 and 11.8 per 100 person-years, respectively, consistent with previous reports. CONCLUSIONS: Leveraging the largest pooled analysis of global PrEP studies to date, we demonstrate that F/TDF is safe and highly effective, even with less than daily dosing, in diverse clinical settings, geographies, populations, and routes of HIV-1 exposure.

BACKGROUND: Although psychiatric disorders have been associated with reduced immune responses to other vaccines, it remains unknown whether they influence COVID-19 vaccine effectiveness (VE). This study evaluated risk of COVID-19 hospitalization and estimated mRNA VE stratified by psychiatric disorder status. METHODS: In a retrospective cohort analysis of the VISION Network in four US states, the rate of laboratory-confirmed COVID-19-associated hospitalization between December 2021 and August 2022 was compared across psychiatric diagnoses and by monovalent mRNA COVID-19 vaccination status using Cox proportional hazards regression. RESULTS: Among 2,436,999 adults, 22.1% had ≥1 psychiatric disorder. The incidence of COVID-19-associated hospitalization was higher among patients with any versus no psychiatric disorder (394 vs. 156 per 100,000 person-years, p < 0.001). Any psychiatric disorder (adjusted hazard ratio [aHR], 1.27; 95% CI, 1.18-1.37) and mood (aHR, 1.25; 95% CI, 1.15-1.36), anxiety (aHR, 1.33, 95% CI, 1.22-1.45), and psychotic (aHR, 1.41; 95% CI, 1.14-1.74) disorders were each significant independent predictors of hospitalization. Among patients with any psychiatric disorder, aHRs for the association between vaccination and hospitalization were 0.35 (95% CI, 0.25-0.49) after a recent second dose, 0.08 (95% CI, 0.06-0.11) after a recent third dose, and 0.33 (95% CI, 0.17-0.66) after a recent fourth dose, compared to unvaccinated patients. Corresponding VE estimates were 65%, 92%, and 67%, respectively, and were similar among patients with no psychiatric disorder (68%, 92%, and 79%). CONCLUSION: Psychiatric disorders were associated with increased risk of COVID-19-associated hospitalization. However, mRNA vaccination provided similar protection regardless of psychiatric disorder status, highlighting its benefit for individuals with psychiatric disorders.

OBJECTIVE: To evaluate the association between workplace psychosocial, organization, and physical risk factors with low back pain (LBP) among U.S. workers. METHODS: 2015 National Health Interview Survey data was analyzed to calculate prevalences and prevalence ratios for LBP across levels of workplace psychosocial and organizational risk factors among 17,464 U.S. adult workers who worked ≥20 hours/week. Results were also stratified by workplace physical exertion. RESULTS: The adjusted prevalences of LBP were significantly elevated for workers reporting high job demand, low job control, work-family imbalance, bullying, job insecurity, working alternate shifts, and physical exertion. Job control and nonstandard shifts were significantly associated with LBP only among those who reported low/no physical exertion. CONCLUSIONS: LBP prevalence was associated with select workplace psychosocial and organization risk factors. Stratification by physical exertion modified multiple associations.

IMPORTANCE: Emtricitabine and tenofovir disoproxil fumarate (F/TDF) for HIV preexposure prophylaxis (PrEP) is highly effective in cisgender men who have sex with men (MSM) when adherence is high (>4 doses/week). Real-world effectiveness and adherence with F/TDF for PrEP in cisgender women is less well characterized. OBJECTIVE: To characterize the effectiveness of F/TDF for PrEP and its relationship with adherence in cisgender women. DESIGN, SETTING, AND PARTICIPANTS: Data were pooled from 11 F/TDF PrEP postapproval studies conducted in 6 countries that included 6296 cisgender women aged 15 to 69 years conducted from 2012 to 2020. HIV incidence was evaluated according to adherence level measured objectively (tenofovir diphosphate concentration in dried blood spots or tenofovir concentration in plasma; n = 288) and subjectively (electronic pill cap monitoring, pill counts, self-report, and study-reported adherence scale; n = 2954) using group-based trajectory modeling. EXPOSURES: F/TDF prescribed orally once a day. HIV incidence was analyzed in subgroups based on adherence trajectory. MAIN OUTCOMES AND MEASURES: HIV incidence. RESULTS: Of the 6296 participants, 46% were from Kenya, 28% were from South Africa, 21% were from India, 2.9% were from Uganda, 1.6% were from Botswana, and 0.8% were from the US. The mean (SD) age at PrEP initiation across all studies was 25 (7) years, with 61% of participants being younger than 25 years. The overall HIV incidence was 0.72 per 100 person-years (95% CI, 0.51-1.01; 32 incident HIV diagnoses among 6296 participants). Four distinct groups of adherence trajectories were identified: consistently daily (7 doses/week), consistently high (4-6 doses/week), high but declining (from a mean of 4-6 doses/week and then declining), and consistently low (less than 2 doses/week). None of the 498 women with consistently daily adherence acquired HIV. Only 1 of the 658 women with consistently high adherence acquired HIV (incidence rate, 0.13/100 person-years [95% CI, 0.02-0.92]). The incidence rate was 0.49 per 100 person-years (95% CI, 0.22-1.08) in the high but declining adherence group (n = 1166) and 1.27 per 100 person-years (95% CI, 0.53-3.04) in the consistently low adherence group (n = 632). CONCLUSIONS AND RELEVANCE: In a pooled analysis of 11 postapproval studies of F/TDF for PrEP among cisgender women, overall HIV incidence was 0.72 per 100 person-years; individuals with consistently daily or consistently high adherence (4-6 doses/week) to PrEP experienced very low HIV incidence.

In the United States, annual influenza vaccination is recommended for all persons aged ≥6 months. Using data from four vaccine effectiveness (VE) networks during the 2023-24 influenza season, interim influenza VE was estimated among patients aged ≥6 months with acute respiratory illness-associated medical encounters using a test-negative case-control study design. Among children and adolescents aged 6 months-17 years, VE against influenza-associated outpatient visits ranged from 59% to 67% and against influenza-associated hospitalization ranged from 52% to 61%. Among adults aged ≥18 years, VE against influenza-associated outpatient visits ranged from 33% to 49% and against hospitalization from 41% to 44%. VE against influenza A ranged from 46% to 59% for children and adolescents and from 27% to 46% for adults across settings. VE against influenza B ranged from 64% to 89% for pediatric patients in outpatient settings and from 60% to 78% for all adults across settings. These findings demonstrate that the 2023-24 seasonal influenza vaccine is effective at reducing the risk for medically attended influenza virus infection. CDC recommends that all persons aged ≥6 months who have not yet been vaccinated this season get vaccinated while influenza circulates locally.

Hexavalent chromium [Cr(VI)] is a common environmental pollutant and chronic exposure to Cr(VI) causes lung cancer in humans, however, the mechanism of Cr(VI) carcinogenesis has not been well understood. Lung cancer is the leading cause of cancer-related death, although the mechanisms of how lung cancer develops and progresses have been poorly understood. While long non-coding RNAs (lncRNAs) are found abnormally expressed in cancer, how dysregulated lncRNAs contribute to carcinogenesis remains largely unknown. The goal of this study is to investigate the mechanism of Cr(VI)-induced lung carcinogenesis focusing on the role of the lncRNA ABHD11 antisense RNA 1 (tail to tail) (ABHD11-AS1). It was found that the lncRNA ABHD11-AS1 expression levels are up-regulated in chronic Cr(VI) exposure-transformed human bronchial epithelial cells, chronically Cr(VI)-exposed mouse lung tissues, and human lung cancer cells as well. Bioinformatics analysis revealed that ABHD11-AS1 levels are up-regulated in lung adenocarcinomas (LUADs) tissues and associated with worse overall survival of LUAD patients but not in lung squamous cell carcinomas. It was further determined that up-regulation of ABHD11-AS1 expression plays an important role in chronic Cr(VI) exposure-induced cell malignant transformation and tumorigenesis, and the stemness of human lung cancer cells. Mechanistically, it was found that ABHD11-AS1 directly binds SART3 (spliceosome associated factor 3, U4/U6 recycling protein). The interaction of ABHD11-AS1 with SART3 promotes USP15 (ubiquitin specific peptidase 15) nuclear localization. Nuclear localized USP15 interacts with pre-mRNA processing factor 19 (PRPF19) to increase CD44 RNA alternative splicing activating β-catenin and enhancing cancer stemness. Together, these findings indicate that lncRNA ABHD11-AS1 interacts with SART3 and regulates CD44 RNA alternative splicing to promote cell malignant transformation and lung carcinogenesis.

The σ54-σS sigma factor cascade plays a central role in regulating differential gene expression during the enzootic cycle of Borreliella burgdorferi, the Lyme disease pathogen. In this pathway, the primary transcription of rpoS (which encodes σS) is under the control of σ54 which is activated by a bacterial enhancer-binding protein (EBP), Rrp2. The σ54-dependent activation in B. burgdorferi has long been thought to be unique, requiring an additional factor, BosR, a homologue of classical Fur/PerR repressor/activator. However, how BosR is involved in this σ54-dependent activation remains unclear and perplexing. In this study, we demonstrate that BosR does not function as a regulator for rpoS transcriptional activation. Instead, it functions as a novel RNA-binding protein that governs the turnover rate of rpoS mRNA. We further show that BosR directly binds to the 5' untranslated region (UTR) of rpoS mRNA, and the binding region overlaps with a region required for rpoS mRNA degradation. Mutations within this 5'UTR region result in BosR-independent RpoS production. Collectively, these results uncover a novel role of Fur/PerR family regulators as RNA-binding proteins and redefine the paradigm of the σ54-σS pathway in B. burgdorferi.

BACKGROUND: Tuberculosis (TB) infection prevention and control (IPC) in healthcare facilities is key to reducing transmission risk. A framework for systematically improving TB IPC through training and mentorship was implemented in 9 healthcare facilities in China from 2017 to 2019. METHODS: Facilities conducted standardized TB IPC assessments at baseline and quarterly thereafter for 18 months. Facility-based performance was assessed using quantifiable indicators for IPC core components and administrative, environmental, and respiratory protection controls, and as a composite of all control types We calculated the percentage changes in scores over time and differences by IPC control type and facility characteristics. RESULTS: Scores for IPC core components increased by 72% during follow-up when averaged across facilities. The percentage changes for administrative, environmental, and respiratory protection controls were 39%, 46%, and 30%, respectively. Composite scores were 45% higher after the intervention. Overall, scores increased most during the first 6 months. There was no association between IPC implementation and provincial economic development or volume of TB services. CONCLUSIONS: TB IPC policies and practices showed most improvement early during implementation and did not differ consistently by facility characteristics. The training component of the project helped increase the capacity of healthcare professionals to manage TB transmission risks. Lessons learned here will inform national TB IPC guidance.

Whatman 903 filter paper is the only filter paper that has been used for HIV drug resistance (HIVDR) genotyping in resource-limited settings. In this study, we evaluated another dried blood specimen collection device, termed SampleTanker(®) (ST), for HIVDR genotyping. Blood specimens from 123 antiretroviral therapy (ART)-experienced patients were used to prepare ST whole blood and ST plasma specimens; they were then stored at ambient temperature for 2 or 4 weeks. The remaining plasma specimens were stored at -80°C and used as frozen plasma controls. Frozen plasma viral load (VL) was determined using the Roche Amplicor HIV-1 Monitor test, v.1.5 and 50 specimens with VL ≥3.00 log10 copies/ml were genotyped using the broadly sensitive genotyping assay. The medium VL for the 50 frozen plasma specimens with VL ≥3.00 log10 was 3.58 log10 copies/ml (IQR: 3.32-4.11) and 96.0% (48/50) of them were genotyped. Comparing to frozen plasma specimens, significantly lower genotyping rates were obtained from ST whole blood (48.98% and 42.85%) and ST plasma specimens (36.0% and 36.0%) stored at ambient temperature for 2 and 4 weeks, respectively (p<0.001). Nucleotide sequence identity and resistance profile analyses between the matched frozen plasma and ST whole blood or ST plasma specimens revealed high nucleotide sequence identities and concordant resistance profiles (98.1% and 99.0%, and 96.6% and 98.9%, respectively). Our results indicate that with the current design, the ST may not be the ideal dried blood specimen collection device for HIVDR monitoring for ART patients in resource-limited settings.

In areas without newborn screening for severe combined immunodeficiency (SCID), disease-defining infections may lead to diagnosis, and in some cases, may not be identified prior to the first year of life. We describe a female infant who presented with disseminated vaccine-acquired varicella (VZV) and vaccine-acquired rubella infections at 13 months of age. Immunological evaluations demonstrated neutropenia, isolated CD4 lymphocytopenia, the presence of CD8(+) T cells, poor lymphocyte proliferation, hypergammaglobulinaemia and poor specific antibody production to VZV infection and routine immunizations. A combination of whole exome sequencing and custom-designed chromosomal microarray with exon coverage of primary immunodeficiency genes detected compound heterozygous mutations (one single nucleotide variant and one intragenic copy number variant involving one exon) within the IL7R gene. Mosaicism for wild-type allele (20-30%) was detected in pretransplant blood and buccal DNA and maternal engraftment (5-10%) demonstrated in pretransplant blood DNA. This may be responsible for the patient's unusual immunological phenotype compared to classical interleukin (IL)-7Rα deficiency. Disseminated VZV was controlled with anti-viral and immune-based therapy, and umbilical cord blood stem cell transplantation was successful. Retrospectively performed T cell receptor excision circle (TREC) analyses completed on neonatal Guthrie cards identified absent TREC. This case emphasizes the danger of live viral vaccination in severe combined immunodeficiency (SCID) patients and the importance of newborn screening to identify patients prior to high-risk exposures. It also illustrates the value of aggressive pathogen identification and treatment, the influence newborn screening can have on morbidity and mortality and the significant impact of newer genomic diagnostic tools in identifying the underlying genetic aetiology for SCID patients.