IMPORTANCE: The test-negative design (TND) has been widely used to assess postmarketing COVID-19 vaccine effectiveness but requires further evaluation for this application. OBJECTIVE: To determine whether the TND reliably evaluates vaccine effectiveness against symptomatic COVID-19 using placebo-controlled vaccine efficacy randomized clinical trials (RCTs). DESIGN, SETTING, AND PARTICIPANTS: This secondary cross-protocol analysis constructed TND study datasets from study sites in 16 countries across 5 continents using the blinded phase cohorts of 5 harmonized phase 3 COVID-19 Prevention Network RCTs: COVE (Coronavirus Vaccine Efficacy and Safety), AZD1222, ENSEMBLE, PREVENT-19 (Prefusion Protein Subunit Vaccine Efficacy Novavax Trial COVID-19), and VAT00008. Participants included adults who received the intended number of doses, experienced COVID-19-like symptoms, and obtained SARS-CoV-2 testing. Start dates ranged from July 27, 2020, to October 19, 2021; data cutoff dates ranged from March 26, 2021, to March 15, 2022. Statistical analysis was performed from May 11, 2023, to February 25, 2025. INTERVENTIONS: Participants received vaccines consisting of messenger RNA-1273 (COVE; 2 doses 28 days apart), ChAdOx1 nCoV-19 (AZD1222; 2 doses 28 days apart), Ad26.COV2.S (ENSEMBLE; 1 dose), NVX-CoV2373 (PREVENT-19; 2 doses 21 days apart), CoV2 preS dTM-AS03 (VAT00008; D614) (2 doses 21 days apart), or CoV2 preS dTM-AS03 (D614 plus B.1.351) (VAT00008; 2 doses 21 days apart) or placebo. MAIN OUTCOMES AND MEASURES: Main outcomes were symptomatic COVID-19 according to each trial's primary efficacy definition and the Centers for Disease Control and Prevention definition. Vaccine effectiveness was estimated using targeted maximum likelihood estimation under a semiparametric logistic regression model and ordinary logistic regression. Noncase exchangeability, a core TND assumption for unbiased estimation, was also assessed by estimating vaccine efficacy against non-COVID-19 illness. RESULTS: Among the 12 157 participants included in the analysis, mean (SD) age was 45 (15) years, 6414 were female (53%), 5858 were vaccinated (48%), 2835 experienced primary COVID-19 (23%), and 2992 experienced Centers for Disease Control and Prevention-defined COVID-19 (25%). TND vaccine effectiveness estimates were concordant with RCT vaccine efficacy estimates (concordance correlation coefficient, 0.86 [95% CI, 0.58-0.96] for both outcomes). The semiparametric method had 48% smaller variance estimates than ordinary logistic regression. Noncase exchangeability was generally supported with a median vaccine efficacy against non-COVID-19 illness of 7.7% (IQR, 2.7%-16.8%) across trial cohorts and most 95% CIs including 0. CONCLUSIONS AND RELEVANCE: In this cross-protocol analysis, the TND provided reliable inferences on COVID-19 vaccine effectiveness in health care-seeking populations for multiple vaccines and symptom definitions when confounding and selection bias were absent. A machine-learning approach for robust confounding control in postmarketing TND studies was also introduced.

OBJECTIVE: The Diabetes in Children, Adolescents, and Young Adults (DiCAYA) network seeks to create a nationwide electronic health record (EHR)-based diabetes surveillance system. This study aimed to develop a DiCAYA-wide EHR-based computable phenotype (CP) to identify prevalent cases of diabetes. RESEARCH DESIGN AND METHODS: We conducted network-wide chart reviews of 2,134 youth (aged <18 years) and 2,466 young adults (aged 18 to <45 years) among people with possible diabetes. Within this population, we compared the performance of three alternative CPs, using diabetes diagnoses determined by chart review as the gold standard. CPs were evaluated based on their accuracy in identifying diabetes and its subtype. RESULTS: The final DiCAYA CP requires at least one diabetes diagnosis code from clinical encounters. Subsequently, diabetes type classification was based on the ratio of type 1 diabetes (T1D) or type 2 diabetes (T2D) diagnosis codes in the EHR. For both youth and young adults, the sensitivity, specificity, and positive and negative predictive values (PPV and NPV, respectively) in finding diabetes cases were >90%, except for the specificity and NPV in young adults, which were slightly lower at 83.8% and 80.6%, respectively. The final DiCAYA CP achieved >90% sensitivity, specificity, PPV, and NPV in classifying T1D, and demonstrated lower but robust performance in identifying T2D, consistently maintaining >80% across metrics. CONCLUSIONS: The DiCAYA CP effectively identifies overall diabetes and T1D in youth and young adults, though T2D misclassification in youth highlights areas for refinement. The simplicity of the DiCAYA CP enables broad deployment across diverse EHR systems for diabetes surveillance.

BACKGROUND: TB preventive treatment (TPT) prevents the development of TB disease in individuals at risk of progression from infection to disease. However, implementation of TPT for children is poor in most high-burden settings. The long duration and pill burden of the 6-month once-daily isoniazid regimen (6H) pose significant barriers to completion. We aimed to understand children's, caregivers', and healthcare providers' experiences of the 12-week once-weekly rifapentine and isoniazid (3HP) regimen using a dispersible tablet formulation in South Africa. METHODS: Serial, in-depth qualitative interviews with 20 child-caregiver dyads, including 5 children living with HIV (CLWH) and 9 healthcare providers across two study sites implementing a pharmacokinetic and safety trial of 3HP, were analysed deductively. RESULTS: Of those with experience using both 3HP and 6H, caregivers and healthcare providers preferred 3HP, and study participants reported that the 3HP formulation was more palatable and easier to prepare and administer. Caregivers and healthcare providers were concerned about optimally integrating 3HP into routine care, primarily due to its once-weekly administration. Children with HIV preferred the once-daily 6H regimen for its ease of use with their daily antiretroviral therapy. CONCLUSIONS: 3HP reduced the administration burden for children and their caregivers. Once weekly, 3HP dosing will require education and adherence support to ensure completion.

OBJECTIVES: Trivalent inactivated influenza vaccine effectiveness was low in a prospective cohort of healthcare personnel (HCP) in Israel from 2016 to 2019. We conducted a randomised immunogenicity trial of quadrivalent recombinant influenza vaccine (RIV4) and standard-dose inactivated influenza vaccine (IIV4) among frequently and infrequently vaccinated previous cohort participants. METHODS: From October 2019 to January 2020, we enrolled and randomly allocated HCP from two Israeli hospitals to receive IIV4 or RIV4. Hemagglutination inhibition (HAI) antibody titres against 2019-2020 vaccine reference influenza viruses were compared between vaccine groups using geometric mean titre (GMT) ratios from sera collected one-month post-vaccination and by frequency of vaccination in the past 5 years (>2 vs ≤2). RESULTS: Among 415 HCP, the GMT ratio comparing RIV4 to IIV4 was 2.0 (95% confidence interval [CI] 1.7-2.7) for A(H1N1)pdm09, 1.6 (95% CI: 1.3-1.9) for A(H3N2), 1.8 (95% CI: 1.4-2.2) for B(Yamagata), and 1.1 (95% CI: 0.9-1.4) for B(Victoria). Similarly, RIV4 elicited higher HAI titres than IIV4 against all 2019-2020 vaccine reference viruses except B(Victoria) among infrequently and frequently vaccinated HCP (lower bound of GMT ratio 95% CIs ≥1.0). CONCLUSION: RIV4 had improved immunogenicity for influenza vaccine strains among both infrequent and frequent vaccinees compared to standard-dose IIV4. CLINICAL TRIALS REGISTRATION: NCT04523324.

BackgroundHealthcare personnel (HCP) are at high risk for respiratory infections through occupational exposure to respiratory viruses.AimWe used data from a prospective influenza vaccine effectiveness study in HCP to quantify the incidence of acute respiratory infections (ARI) and their associated presenteeism and absenteeism.MethodsAt the start and end of each season, HCP at two Israeli hospitals provided serum to screen for antibodies to influenza virus using the haemagglutination inhibition assay. During the season, active monitoring for the development of ARI symptoms was conducted twice a week by RT-PCR testing of nasal swabs for influenza and respiratory syncytial virus (RSV). Workplace presenteeism and absenteeism were documented. We calculated incidences of influenza- and RSV-associated ARI and applied sampling weights to make estimates representative of the source population.ResultsThe median age of 2,505 participating HCP was 41 years, and 70% were female. Incidence was 9.1 per 100 person-seasons (95% CI: 5.8-14.2) for RT-PCR-confirmed influenza and 2.5 per 100 person-seasons (95% CI: 0.9-7.1) for RSV illness. Each season, 18-23% of unvaccinated and influenza-negative HCP seroconverted. The incidence of seroconversion or RT-PCR-confirmed influenza was 27.5 per 100 person-seasons (95% CI: 17.8-42.5). Work during illness occurred in 92% (95% CI: 91-93) of ARI episodes, absence from work in 38% (95% CI: 36-40).ConclusionInfluenza virus and RSV infections and associated presenteeism and absenteeism were common among HCP. Improving vaccination uptake among HCP, infection control, and encouraging sick HCP to stay home are important strategies to reduce ARI incidence and decrease the risk of in-hospital transmission.

INTRODUCTION: Despite a longstanding Israel Ministry of Health recommendation that all healthcare personnel (HCP) receive a seasonal influenza vaccine, vaccine uptake among HCP remains below the country's target of 60% coverage. To understand factors related to vaccine hesitancy, we used data from a prospective three-year (2016-2019) influenza vaccine effectiveness study among Israeli HCP to examine knowledge, attitudes, and practices (KAP) about influenza vaccination and their association with vaccine uptake. METHODS: At the start of each influenza season, all participating HCP completed a questionnaire that included questions about socio-demographic and occupational characteristics, health status, and KAP related to seasonal influenza vaccination. We extracted vaccination history from electronic medical records and employee vaccination registries. We used logistic regression models to identify demographic and occupational factors, and KAP about influenza vaccination, associated with receipt of vaccination. RESULT: A total of 2,126 HCP were enrolled and had available data on vaccination history. Their median age was 42 years [IQR 35-52], and 73 % self-identified as female. Influenza vaccine uptake in 2016, 2017 and 2018 was 46 %, 48 % and 47 %, respectively. Overall, 36 % of HCP had received an influenza vaccine in ≥ 4 of the eight years prior. HCP aged 35-49 years were less likely to receive influenza vaccine compared to HCP aged ≥ 50 years (OR: 0.81 [95 % CI: 0.67-0.98]). Nurses and allied personnel were less likely to receive influenza vaccine compared to physicians (OR: 0.63 [95 % CI: 0.50-0.78] and OR: 0.53 [95 % CI: 0.40-0.70], respectively). The emotional benefit of vaccination (e.g., anticipating regret if not vaccinated) and the perception of vaccine safety were factors associated with vaccine uptake (OR: 7.60 [95 % CI: 6.27-9.22] and OR: 3.43 [95 % CI:2.91-4.03], respectively). CONCLUSION: Among HCP at two hospitals in Israel, less than half received an annual influenza vaccine. Older HCP, physicians, and those who reported the emotional benefit of vaccination or agreed that influenza vaccines are safe were more likely to be vaccinated. Future influenza vaccination campaigns could focus on these demographic groups and tailor messages emphasizing the emotional benefits of vaccination and vaccine safety to increase seasonal influenza vaccine uptake among HCP in Israel.

BACKGROUND: Tuberculosis (TB) preventive treatment (TPT) is recommended by the World Health Organization (WHO) for persons living with HIV, including pregnant and breastfeeding women. Given the President's Emergency Plan for AIDS Relief (PEPFAR)'s investment in TPT services for persons living with HIV as a strategy to prevent TB as well as uncertainty in guidelines and policy regarding use of TPT during pregnancy and the postpartum period, we conducted a review of current relevant national guidelines among PEPFAR-supported countries. METHODS: Our review included 44/49 PEPFAR-supported countries to determine if TB screening and TPT are recommended specifically for pregnant and breastfeeding women living with HIV (WLHIV). National guidelines reviewed and abstracted included TB, HIV, prevention of vertical HIV transmission, TPT, and any other relevant guidelines. We abstracted information regarding TB screening, including screening tools and frequency; and TPT, including timing, regimen, frequency, and laboratory monitoring. RESULTS: Of 44 PEPFAR-supported countries for which guidelines were reviewed, 66% were high TB incidence countries; 41% were classified by WHO as high TB burden countries, and 43% as high HIV-associated TB burden countries. We found that 64% (n = 28) of countries included TB screening recommendations for pregnant WLHIV in their national guidelines, and most (n = 35, 80%) countries recommend TPT for pregnant WLHIV. Fewer countries included recommendations for breastfeeding as compared to pregnant WLHIV, with only 32% (n = 14) mentioning TB screening and 45% (n = 20) specifically recommending TPT for this population; most of these recommend isoniazid-based TPT regimens for pregnant and breastfeeding WLHIV. However, several countries also recommend isoniazid combined with rifampicin (3RH) or rifapentine (3HP). CONCLUSIONS: Despite progress in the number of PEPFAR-supported countries that specifically include TB screening and TPT recommendations for pregnant and breastfeeding WLHIV in their national guidelines, many PEPFAR-supported countries still do not include specific screening and TPT recommendations for pregnant and breastfeeding WLHIV.

INTRODUCTION: Traditional survey-based surveillance is costly, limited in its ability to distinguish diabetes types and time-consuming, resulting in reporting delays. The Diabetes in Children, Adolescents and Young Adults (DiCAYA) Network seeks to advance diabetes surveillance efforts in youth and young adults through the use of large-volume electronic health record (EHR) data. The network has two primary aims, namely: (1) to refine and validate EHR-based computable phenotype algorithms for accurate identification of type 1 and type 2 diabetes among youth and young adults and (2) to estimate the incidence and prevalence of type 1 and type 2 diabetes among youth and young adults and trends therein. The network aims to augment diabetes surveillance capacity in the USA and assess performance of EHR-based surveillance. This paper describes the DiCAYA Network and how these aims will be achieved. METHODS AND ANALYSIS: The DiCAYA Network is spread across eight geographically diverse US-based centres and a coordinating centre. Three centres conduct diabetes surveillance in youth aged 0-17 years only (component A), three centres conduct surveillance in young adults aged 18-44 years only (component B) and two centres conduct surveillance in components A and B. The network will assess the validity of computable phenotype definitions to determine diabetes status and type based on sensitivity, specificity, positive predictive value and negative predictive value of the phenotypes against the gold standard of manually abstracted medical charts. Prevalence and incidence rates will be presented as unadjusted estimates and as race/ethnicity, sex and age-adjusted estimates using Poisson regression. ETHICS AND DISSEMINATION: The DiCAYA Network is well positioned to advance diabetes surveillance methods. The network will disseminate EHR-based surveillance methodology that can be broadly adopted and will report diabetes prevalence and incidence for key demographic subgroups of youth and young adults in a large set of regions across the USA.

Today's ambulatory care providers face numerous challenges as they try to practice efficient, patient-centered medicine. This article explains how community health workers (CHWs) can be engaged to address many patient- and system-related barriers currently experienced in ambulatory care practices. Community health workers are frontline public health workers who serve as a trusted bridge between community members and health care providers. Among their varied roles, CHWs can educate and support patients in managing their risk factors and diseases and link these patients to needed resources. As shown in this overview (CHW 101), including CHWs as members of multidisciplinary care teams has the potential to strengthen both current and emerging models of health care delivery.

INTRODUCTION: Inequitable access to leisure-time physical activity (LTPA) resources may explain geographic disparities in type 2 diabetes (T2D). We evaluated whether the neighborhood socioeconomic environment (NSEE) affects T2D through the LTPA environment. RESEARCH DESIGN AND METHODS: We conducted analyses in three study samples: the national Veterans Administration Diabetes Risk (VADR) cohort comprising electronic health records (EHR) of 4.1 million T2D-free veterans, the national prospective cohort REasons for Geographic and Racial Differences in Stroke (REGARDS) (11 208 T2D free), and a case-control study of Geisinger EHR in Pennsylvania (15 888 T2D cases). New-onset T2D was defined using diagnoses, laboratory and medication data. We harmonized neighborhood-level variables, including exposure, confounders, and effect modifiers. We measured NSEE with a summary index of six census tract indicators. The LTPA environment was measured by physical activity (PA) facility (gyms and other commercial facilities) density within street network buffers and population-weighted distance to parks. We estimated natural direct and indirect effects for each mediator stratified by community type. RESULTS: The magnitudes of the indirect effects were generally small, and the direction of the indirect effects differed by community type and study sample. The most consistent findings were for mediation via PA facility density in rural communities, where we observed positive indirect effects (differences in T2D incidence rates (95% CI) comparing the highest versus lowest quartiles of NSEE, multiplied by 100) of 1.53 (0.25, 3.05) in REGARDS and 0.0066 (0.0038, 0.0099) in VADR. No mediation was evident in Geisinger. CONCLUSIONS: PA facility density and distance to parks did not substantially mediate the relation between NSEE and T2D. Our heterogeneous results suggest that approaches to reduce T2D through changes to the LTPA environment require local tailoring.

Recent investments in built environment infrastructure to create healthy communities have highlighted the need for equity and environmental justice. Although the benefits of healthy community design (e.g., connecting transportation systems and land use changes) are well established, some reports suggest that these changes may increase property values. These increases can raise the risk of displacement for people with low incomes and/or who are from racial and ethnic minority groups, who would then miss out on benefits from changes in community design. This review scanned the literature for displacement mitigation and prevention measures, with the goal of providing a compilation of available strategies for a wide range of audiences including public health practitioners. A CDC librarian searched the Medline, EbscoHost, Scopus, and ProQuest Central databases, and we identified grey literature using Google and Google Scholar searches. The indexed literature search identified 6 articles, and the grey literature scan added 18 articles. From these 24 total articles, we identified 141 mitigation and prevention strategies for displacement and thematically characterized each by domain using an adapted existing typology. This work provides a well-categorized inventory for practitioners and sets the stage for future evaluation research on the implementation of strategies and practices to reduce displacement.

Evaluation of geographic disparities in type 2 diabetes (T2D) onset requires multidimensional approaches at a relevant spatial scale to characterize community types and features that could influence this health outcome. Using Geisinger electronic health records (2008-2016), we conducted a nested case-control study of new onset T2D in a 37-county area of Pennsylvania. The study included 15,888 incident T2D cases and 79,435 controls without diabetes, frequency-matched 1:5 on age, sex, and year of diagnosis or encounter. We characterized patients' residential census tracts by four dimensions of social determinants of health (SDOH) and into a 7-category SDOH census tract typology previously generated for the entire United States by dimension reduction techniques. Finally, because the SDOH census tract typology classified 83% of the study region's census tracts into two heterogeneous categories, termed rural affordable-like and suburban affluent-like, to further delineate geographies relevant to T2D, we subdivided these two typology categories by administrative community types (U.S. Census Bureau minor civil divisions of township, borough, city). We used generalized estimating equations to examine associations of 1) four SDOH indexes, 2) SDOH census tract typology, and 3) modified typology, with odds of new onset T2D, controlling for individual-level confounding variables. Two SDOH dimensions, higher socioeconomic advantage and higher mobility (tracts with fewer seniors and disabled adults) were independently associated with lower odds of T2D. Compared to rural affordable-like as the reference group, residence in tracts categorized as extreme poverty (odds ratio [95% confidence interval] = 1.11 [1.02, 1.21]) or multilingual working (1.07 [1.03, 1.23]) were associated with higher odds of new onset T2D. Suburban affluent-like was associated with lower odds of T2D (0.92 [0.87, 0.97]). With the modified typology, the strongest association (1.37 [1.15, 1.63]) was observed in cities in the suburban affluent-like category (vs. rural affordable-like-township), followed by cities in the rural affordable-like category (1.20 [1.05, 1.36]). We conclude that in evaluating geographic disparities in T2D onset, it is beneficial to conduct simultaneous evaluation of SDOH in multiple dimensions. Associations with the modified typology showed the importance of incorporating governmentally, behaviorally, and experientially relevant community definitions when evaluating geographic health disparities.

INTRODUCTION: Community fears of gentrification have created concerns about building active living infrastructure in neighborhoods with low-income populations. However, little empirical research exists related to these concerns. This work describes characteristics of residents who reported 1) concerns about increased cost of living caused by neighborhood development and 2) support for infrastructural improvements even if the changes lead to a higher cost of living. METHODS: Data on concerns about or support for transportation-related and land use-related improvements and sociodemographic characteristics were obtained from the 2018 SummerStyles survey, an online panel survey conducted on a nationwide sample of US adults (n = 3,782). Descriptive statistics characterized the sample, and χ(2) tests examined associations among variables. RESULTS: Overall, 19.1% of study respondents agreed that development had caused concerns about higher cost of living. Approximately half (50.7%) supported neighborhood changes for active living opportunities even if they lead to higher costs of living. Prevalences of both concern and support were higher among respondents who were younger and who had higher levels of education than their counterparts. Support did not differ between racial or ethnic groups, but concern was reported more often by Hispanic/Latino (28.9%) and other non-Hispanic (including multiracial) respondents (25.5%) than by non-Hispanic White respondents (15.6%). Respondents who reported concerns were more likely to express support (65.3%) than respondents who did not report concerns (47.3%). CONCLUSION: The study showed that that low-income, racial, or ethnic minority populations support environmental changes to improve active living despite cost of living concerns associated with community revitalization.

OBJECTIVE: We examined whether relative availability of fast-food restaurants and supermarkets mediates the association between worse neighborhood socioeconomic conditions and risk of developing type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: As part of the Diabetes Location, Environmental Attributes, and Disparities Network, three academic institutions used harmonized environmental data sources and analytic methods in three distinct study samples: (1) the Veterans Administration Diabetes Risk (VADR) cohort, a national administrative cohort of 4.1 million diabetes-free veterans developed using electronic health records (EHRs); (2) Reasons for Geographic and Racial Differences in Stroke (REGARDS), a longitudinal, epidemiologic cohort with Stroke Belt region oversampling (N = 11,208); and (3) Geisinger/Johns Hopkins University (G/JHU), an EHR-based, nested case-control study of 15,888 patients with new-onset T2D and of matched control participants in Pennsylvania. A census tract-level measure of neighborhood socioeconomic environment (NSEE) was developed as a community type-specific z-score sum. Baseline food-environment mediators included percentages of (1) fast-food restaurants and (2) food retail establishments that are supermarkets. Natural direct and indirect mediating effects were modeled; results were stratified across four community types: higher-density urban, lower-density urban, suburban/small town, and rural. RESULTS: Across studies, worse NSEE was associated with higher T2D risk. In VADR, relative availability of fast-food restaurants and supermarkets was positively and negatively associated with T2D, respectively, whereas associations in REGARDS and G/JHU geographies were mixed. Mediation results suggested that little to none of the NSEE-diabetes associations were mediated through food-environment pathways. CONCLUSIONS: Worse neighborhood socioeconomic conditions were associated with higher T2D risk, yet associations are likely not mediated through food-environment pathways.

BACKGROUND: There are limited data on influenza vaccine effectiveness (IVE) in preventing laboratory-confirmed influenza illness among healthcare personnel (HCP). METHODS: HCP with direct patient contact working full-time in hospitals were followed during three influenza seasons in Israel (2016-2017 to 2018-2019) and Peru (2016 to 2018). Trivalent influenza vaccines were available at all sites, except during 2018-2019 when Israel used quadrivalent vaccines; vaccination was documented by electronic medical records, vaccine registries, and/or self-report (for vaccinations outside the hospital). Twice-weekly active surveillance identified acute respiratory symptoms or febrile illness (ARFI); self-collected respiratory specimens were tested by real-time reverse transcription polymerase chain reaction (PCR) assay. IVE was 100 × 1-hazard ratio (adjusted for sex, age, occupation, and hospital). RESULTS: Among 5,489 HCP who contributed 10,041 person-seasons, influenza vaccination coverage was 47% in Israel and 32% in Peru. Of 3,056 ARFIs in Israel and 3,538 in Peru, A or B influenza virus infections were identified in 205 (7%) in Israel and 87 (2.5%) in Peru. IVE against all viruses across seasons was 1% (95% confidence interval [CI] = -30%, 25%) in Israel and 12% (95% CI = -61%, 52%) in Peru. CONCLUSION: Estimates of IVE were null using person-time models during six study seasons in Israel and Peru.

Background: While there are known individual-level risk factors for kidney disease at time of type 2 diabetes diagnosis, little is known regarding the role of community context. We evaluated the association of community socioeconomic deprivation (CSD) and community type with estimated glomerular filtration rate (eGFR) when type 2 diabetes is diagnosed. Method(s): This was a retrospective cohort study of 13,144 adults with newly diagnosed type 2 diabetes in Pennsylvania. The outcome was the closest eGFR measurement within one year prior to and two weeks after type 2 diabetes diagnosis, calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) equation. We used adjusted multinomial regression models to estimate associations of CSD (quartile 1, least deprivation) and community type (township, borough, city) with eGFR and used adjusted generalized estimating equation models to evaluate whether community features were associated with the absence of diabetes screening in the years prior to type 2 diabetes diagnosis. Result(s): Of the participants, 1279 (9.7%) had hyperfiltration and 1377 (10.5%) had reduced eGFR. Women were less likely to have hyperfiltration and more likely to have reduced eGFR. Black (versus White) race was positively associated with hyperfiltration when the eGFR calculation was corrected for race but inversely associated without the correction. Medical Assistance (ever versus never) was positively associated with reduced eGFR. Higher CSD and living in a city were each positively associated (odds ratio [95% confidence interval]) with reduced eGFR (CSD quartiles 3 and 4 versus quartile 1, 1.23 [1.04, 1.46], 1.32 [1.11, 1.58], respectively; city versus township, 1.38 [1.15, 1.65]). These features were also positively associated with the absence of a type 2 diabetes screening measure. Conclusion(s): In a population-based sample, more than twenty percent had hyperfiltration or reduced eGFR at time of type 2 diabetes diagnosis. Individual- and community-level factors were associated with these outcomes. Copyright © 2021 The Authors

Infection with human and simian immunodeficiency viruses (HIV/SIV) requires binding of the viral envelope glycoprotein (Env) to the host protein CD4 on the surface of immune cells. Although invariant in humans, the Env binding domain of the chimpanzee CD4 is highly polymorphic, with nine coding variants circulating in wild populations. Here, we show that within-species CD4 diversity is not unique to chimpanzees but found in many African primate species. Characterizing the outermost (D1) domain of the CD4 protein in over 500 monkeys and apes, we found polymorphic residues in 24 of 29 primate species, with as many as 11 different coding variants identified within a single species. D1 domain amino acid replacements affected SIV Env-mediated cell entry in a single-round infection assay, restricting infection in a strain- and allele-specific fashion. Several identical CD4 polymorphisms, including the addition of N-linked glycosylation sites, were found in primate species from different genera, providing striking examples of parallel evolution. Moreover, seven different guenons (Cercopithecus spp.) shared multiple distinct D1 domain variants, pointing to long-term trans-specific polymorphism. These data indicate that the HIV/SIV Env binding region of the primate CD4 protein is highly variable, both within and between species, and suggest that this diversity has been maintained by balancing selection for millions of years, at least in part to confer protection against primate lentiviruses. Although long-term SIV-infected species have evolved specific mechanisms to avoid disease progression, primate lentiviruses are intrinsically pathogenic and have left their mark on the host genome.

Salutogenic effects of living near aquatic areas (blue space) remain underexplored, particularly in non-coastal and non-urban areas. We evaluated associations of residential proximity to inland freshwater blue space with new onset type 2 diabetes (T2D) in central and northeast Pennsylvania, USA, using medical records to conduct a nested case-control study. T2D cases (n = 15,888) were identified from diabetes diagnoses, medication orders, and laboratory test results and frequency-matched on age, sex, and encounter year to diabetes-free controls (n = 79,435). We calculated distance from individual residences to the nearest lake, river, tributary, or large stream, and residence within the 100-year floodplain. Logistic regression models adjusted for community socioeconomic deprivation and other confounding variables and stratified by community type (townships [rural/suburban], boroughs [small towns], city census tracts). Compared to individuals living ≥ 1.25 miles from blue space, those within 0.25 miles had 8% and 17% higher odds of T2D onset in townships and boroughs, respectively. Among city residents, T2D odds were 38–39% higher for those living 0.25 to < 0.75 miles from blue space. Residing within the floodplain was associated with 16% and 14% higher T2D odds in townships and boroughs. A post-hoc analysis demonstrated patterns of lower residential property values with nearer distance to the region's predominant waterbody, suggesting unmeasured confounding by socioeconomic disadvantage. This may explain our unexpected findings of higher T2D odds with closer proximity to blue space. Our findings highlight the importance of historic and economic context and interrelated factors such as flood risk and lack of waterfront development in blue space research.

Greenness may impact blood pressure (BP), though evidence is limited among individuals with type 2 diabetes (T2D), for whom BP management is critical. We evaluated associations of residential greenness with BP among individuals with T2D in geographically diverse communities in Pennsylvania. To address variation in greenness type, we evaluated modification of associations by percent forest. We obtained systolic (SBP) and diastolic (DBP) BP measurements from medical records of 9593 individuals following diabetes diagnosis. Proximate greenness was estimated within 1250-m buffers surrounding individuals' residences using the normalized difference vegetation index (NDVI) prior to blood pressure measurement. Percent forest was calculated using the U.S. National Land Cover Database. Linear mixed models with robust standard errors accounted for spatial clustering; models were stratified by community type (townships/boroughs/cities). In townships, the greenest communities, an interquartile range increase in NDVI was associated with reductions in SBP of 0.87 mmHg (95% CI: -1.43, -0.30) and in DBP of 0.41 mmHg (95% CI: -0.78, -0.05). No significant associations were observed in boroughs or cities. Evidence for modification by percent forest was weak. Findings suggest a threshold effect whereby high greenness may be necessary to influence BP in this population and support a slight beneficial impact of greenness on cardiovascular disease risk.

OBJECTIVES: To evaluate associations of community types and features with new onset type 2 diabetes in diverse communities. Understanding the location and scale of geographic disparities can lead to community-level interventions. DESIGN: Nested case-control study within the open dynamic cohort of health system patients. SETTING: Large, integrated health system in 37 counties in central and northeastern Pennsylvania, USA. PARTICIPANTS AND ANALYSIS: We used electronic health records to identify persons with new-onset type 2 diabetes from 2008 to 2016 (n=15 888). Persons with diabetes were age, sex and year matched (1:5) to persons without diabetes (n=79 435). We used generalised estimating equations to control for individual-level confounding variables, accounting for clustering of persons within communities. Communities were defined as (1) townships, boroughs and city census tracts; (2) urbanised area (large metro), urban cluster (small cities and towns) and rural; (3) combination of the first two; and (4) county. Community socioeconomic deprivation and greenness were evaluated alone and in models stratified by community types. RESULTS: Borough and city census tract residence (vs townships) were associated (OR (95% CI)) with higher odds of type 2 diabetes (1.10 (1.04 to 1.16) and 1.34 (1.25 to 1.44), respectively). Urbanised areas (vs rural) also had increased odds of type 2 diabetes (1.14 (1.08 to 1.21)). In the combined definition, the strongest associations (vs townships in rural areas) were city census tracts in urban clusters (1.41 (1.22 to 1.62)) and city census tracts in urbanised areas (1.33 (1.22 to 1.45)). Higher community socioeconomic deprivation and lower greenness were each associated with increased odds. CONCLUSIONS: Urban residence was associated with higher odds of type 2 diabetes than for other areas. Higher community socioeconomic deprivation in city census tracts and lower greenness in all community types were also associated with type 2 diabetes.

BACKGROUND: Diabetes prevalence and incidence vary by neighborhood socioeconomic environment (NSEE) and geographic region in the United States. Identifying modifiable community factors driving type 2 diabetes disparities is essential to inform policy interventions that reduce the risk of type 2 diabetes. OBJECTIVE: This paper aims to describe the Diabetes Location, Environmental Attributes, and Disparities (LEAD) Network, a group funded by the Centers for Disease Control and Prevention to apply harmonized epidemiologic approaches across unique and geographically expansive data to identify community factors that contribute to type 2 diabetes risk. METHODS: The Diabetes LEAD Network is a collaboration of 3 study sites and a data coordinating center (Drexel University). The Geisinger and Johns Hopkins University study population includes 578,485 individuals receiving primary care at Geisinger, a health system serving a population representative of 37 counties in Pennsylvania. The New York University School of Medicine study population is a baseline cohort of 6,082,146 veterans who do not have diabetes and are receiving primary care through Veterans Affairs from every US county. The University of Alabama at Birmingham study population includes 11,199 participants who did not have diabetes at baseline from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a cohort study with oversampling of participants from the Stroke Belt region. RESULTS: The Network has established a shared set of aims: evaluate mediation of the association of the NSEE with type 2 diabetes onset, evaluate effect modification of the association of NSEE with type 2 diabetes onset, assess the differential item functioning of community measures by geographic region and community type, and evaluate the impact of the spatial scale used to measure community factors. The Network has developed standardized approaches for measurement. CONCLUSIONS: The Network will provide insight into the community factors driving geographical disparities in type 2 diabetes risk and disseminate findings to stakeholders, providing guidance on policies to ameliorate geographic disparities in type 2 diabetes in the United States. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/21377.

BACKGROUND: We examined cytokine immune response profiles among contacts to tuberculosis patients to identify immunologic and epidemiologic correlates of tuberculosis. METHODS: We prospectively enrolled 1272 contacts of culture-confirmed pulmonary tuberculosis patients at 9 United States and Canadian sites. Epidemiologic characteristics were recorded. Blood was collected and stimulated with Mycobacterium tuberculosis culture filtrate protein, and tumor necrosis factor (TNF-α), interferon gamma (IFN-γ), and interleukin 10 (IL-10) concentrations were determined using immunoassays. RESULTS: Of 1272 contacts, 41 (3.2%) were diagnosed with tuberculosis before or < 30 days after blood collection (co-prevalent tuberculosis) and 19 (1.5%) during subsequent four-year follow-up (incident tuberculosis). Compared with contacts without tuberculosis, those with co-prevalent tuberculosis had higher median baseline TNF-α and IFN-γ concentrations (in pg/mL, TNF-α 129 versus 71, P < .01; IFN-γ 231 versus 27, P < .001), and those who subsequently developed incident tuberculosis had higher median baseline TNF-α concentrations (in pg/mL, 257 vs. 71, P < .05). In multivariate analysis, contact age < 15 years, US/Canadian birth, and IFN or TNF concentrations > the median were associated with co-prevalent tuberculosis (P < .01 for each); female sex (P = .03) and smoking (P < .01) were associated with incident tuberculosis. In algorithms combining young age, positive skin test results, and elevated CFPS TNF-α, IFN-γ, and IL-10 responses, the positive predictive values for co-prevalent and incident tuberculosis were 40 and 25%, respectively. CONCLUSIONS: Cytokine concentrations and epidemiologic factors at the time of contact investigation may predict co-prevalent and incident tuberculosis.

BACKGROUND: The Estudio Vacuna de Influenza Peru (VIP) cohort aims to describe the frequency of influenza virus infection, identify predictors of vaccine acceptance, examine the effects of repeated influenza vaccination on immunogenicity, and evaluate influenza vaccine effectiveness among HCP. METHODS: The VIP cohort prospectively followed HCP in Lima, Peru, during the 2016-2018 influenza seasons; a fourth year is ongoing. Participants contribute blood samples before and after the influenza season and after influenza vaccination (for vaccinees). Weekly surveillance is conducted to identify acute respiratory or febrile illnesses (ARFI). When an ARFI is identified, participants self-collect nasal swabs that are tested for influenza viruses by real-time reverse transcriptase-polymerase chain reaction. Influenza vaccination status and 5-year vaccination history are ascertained. We analyzed recruitment and enrollment results for 2016-2018 and surveillance participation for 2016-2017. RESULTS: In the first 3 years of the cohort, VIP successfully contacted 92% of potential participants, enrolled 76% of eligible HCP, and retained >90% of participants across years. About half of participants are medical assistants (54%), and most provide "hands-on" medical care (76%). Sixty-nine percent and 52% of participants completed surveillance for >70% of weeks in years 1 and 2, respectively. Fewer weeks of completed surveillance was associated with older age (>/=50 years), being a medical assistant, self-rated health of fair or poor, and not receiving the influenza vaccine during the current season (P-values < .05). CONCLUSIONS: The VIP cohort provides an opportunity to address knowledge gaps about influenza virus infection, vaccination uptake, effectiveness and immunogenicity among HCP.

BACKGROUND: The Study of Healthcare Personnel with Influenza and other Respiratory Viruses in Israel (SHIRI) prospectively follows a cohort of healthcare personnel (HCP) in two hospitals in Israel. SHIRI will describe the frequency of influenza virus infections among HCP, identify predictors of vaccine acceptance, examine how repeated influenza vaccination may modify immunogenicity, and evaluate influenza vaccine effectiveness in preventing influenza illness and missed work. METHODS: Cohort enrollment began in October, 2016; a second year of the study and a second wave of cohort enrollment began in June 2017. The study will run for at least 3 years and will follow approximately 2000 HCP (who are both employees and members of Clalit Health Services [CHS]) with routine direct patient contact. Eligible HCP are recruited using a stratified sampling strategy. After informed consent, participants complete a brief enrollment survey with questions about occupational responsibilities and knowledge, attitudes, and practices about influenza vaccines. Blood samples are collected at enrollment and at the end of influenza season; HCP who choose to be vaccinated contribute additional blood one month after vaccination. During the influenza season, participants receive twice-weekly short message service (SMS) messages asking them if they have acute respiratory illness or febrile illness (ARFI) symptoms. Ill participants receive follow-up SMS messages to confirm illness symptoms and duration and are asked to self-collect a nasal swab. Information on socio-economic characteristics, current and past medical conditions, medical care utilization and vaccination history is extracted from the CHS database. Information about missed work due to illness is obtained by self-report and from employee records. Respiratory specimens from self-collected nasal swabs are tested for influenza A and B viruses, respiratory syncytial virus, human metapneumovirus, and coronaviruses using validated multiplex quantitative real-time reverse transcription polymerase chain reaction assays. The hemagglutination inhibition assay will be used to detect the presence of neutralizing influenza antibodies in serum. DISCUSSION: SHIRI will expand our knowledge of the burden of respiratory viral infections among HCP and the effectiveness of current and repeated annual influenza vaccination in preventing influenza illness, medical utilization, and missed workdays among HCP who are in direct contact with patients. TRIAL REGISTRATION: NCT03331991 . Registered on November 6, 2017.

OBJECTIVES: To describe concussion rates in high school athletes and involvement of healthcare professionals in concussion diagnosis, management and compliance with return to play (RTP) guidelines. METHODS: Data were analysed from injury reports in the National High School Sports-Related Injury Surveillance System between 2009/2010 and 2012/2013 to identify student athletes with concussion and determine compliance with RTP guidelines. Compliance with RTP guidelines was examined using logistic regression, adjusting for sport and injury-related variables. RESULTS: There were 5611 concussions recorded during 15 712 475 athlete exposures (AEs), a rate of 3.6 concussions per 10 000 AEs. Rates were higher during competition and among girls compared to boys in gender equitable sports. Healthcare professionals were less likely to be present at the time of concussion for girls' sports, lower competition levels and practices. Compliance with RTP guidelines was higher for athletes with recurrent concussions, those sustained in collision sports, for athletes reporting more symptoms and when a physician made the RTP decision. CONCLUSIONS: Presence of healthcare professionals and compliance with RTP guidelines varied by sport, gender, level of play and exposure type. High school athletes with concussion are best served by assessment teams with athletic trainers and physicians working together to manage concussions and contribute to RTP decisions.

BACKGROUND: Carbon monoxide (CO) is an insidious gas responsible for approximately 21,000 emergency department visits, 2300 hospitalizations, and 500 deaths in the United States annually. We analyzed 10 combined years of data from two Agency for Toxic Substances and Disease Registry acute hazardous substance release surveillance programs to evaluate CO incident-related injuries. METHODS: Seventeen states participated in these programs during 2005-2014. RESULTS: In those 10years, the states identified 1795 CO incidents. Our analysis focused on 897 CO incidents having injured persons. Of the 3414 CO injured people, 61.0% were classified as general public, 27.7% were employees, 7.6% were students, and 2.2% were first responders. More than 78% of CO injured people required hospital or pre-hospital treatment and 4.3% died. The location for most injured people (39.9%) were homes or apartments, followed by educational facilities (10.0%). Educational services had a high number of people injured per incident (16.3%). The three most common sources of CO were heating, ventilation, and air conditioning systems; generators; and motor vehicles. Equipment failure was the primary contributing factor for most CO incidents. CONCLUSIONS: States have used the data to evaluate trends in CO poisoning and develop targeted public health outreach. Surveillance data are useful for setting new policies or supporting existing policy such as making CO poisoning a reportable condition at the state level and requiring CO alarms in all schools and housing. Public health needs to remain vigilant to the sources and causes of CO to help reduce this injury and death.

RATIONALE: More information on risk factors for death from tuberculosis in the United States could help reduce the tuberculosis mortality rate, which has remained steady for over a decade. Objective(s) To identify risk factors for tuberculosis-related death in adults. METHODS: We performed a retrospective study of 1,304 adults with tuberculosis who died before treatment completion and 1,039 frequency-matched controls who completed tuberculosis treatment in 2005-2006 in thirteen states reporting 65% of U.S. tuberculosis cases. We used in-depth record abstractions and a standard algorithm to classify deaths in persons with tuberculosis as tuberculosis-related or not. We then compared these classifications to causes of death as coded in death certificates. We used multivariable logistic regression to calculate adjusted odds ratios (aOR) for predictors of tuberculosis-related death among adults compared with those who completed tuberculosis treatment. RESULTS: Of 1,304 adult deaths, 942 (72%) were tuberculosis-related, 272 (21%) were not, and 90 (7%) couldn't be classified. Of 847 tuberculosis-related deaths with death certificates available, 378 (45%) did not list tuberculosis as a cause of death. Adjusting for known risks, we identified new risks for tuberculosis-related death during treatment: absence of pyrazinamide in the initial regimen (aOR=3.4, 95% CI=1.9-6.0); immunosuppressive medications (aOR=2.5, 95% CI=1.1-5.6); incomplete TB diagnostic evaluation (aOR=2.2, 95% CI=1.5-3.3), and an alternative non-TB diagnosis prior to TB diagnosis (aOR=1.6, 95% CI=1.2-2.2). Conclusions Most persons who died with tuberculosis had a tuberculosis-related death. Intensive record review revealed tuberculosis as a cause of death more often than did death certificate diagnoses. New tools, such as a TB mortality risk score based on our study findings, may identify TB patients for in-hospital interventions to prevent death.

Objectives: To evaluate the effectiveness of practices used to support appropriate clinical laboratory test utilization. Methods: This review followed the Centers for Disease Control and Prevention (CDC) Laboratory Medicine Best Practices A6 cycle method. Eligible studies assessed one of the following practices for effect on outcomes relating to over- or underutilization: computerized provider order entry (CPOE), clinical decision support systems/tools (CDSS/CDST), education, feedback, test review, reflex testing, laboratory test utilization (LTU) teams, and any combination of these practices. Eligible outcomes included intermediate, systems outcomes (eg, number of tests ordered/performed and cost of tests), as well as patient-related outcomes (eg, length of hospital stay, readmission rates, morbidity, and mortality). Results: Eighty-three studies met inclusion criteria. Fifty-one of these studies could be meta-analyzed. Strength of evidence ratings for each practice ranged from high to insufficient. Conclusion: Practice recommendations are made for CPOE (specifically, modifications to existing CPOE), reflex testing, and combined practices. No recommendation for or against could be made for CDSS/CDST, education, feedback, test review, and LTU. Findings from this review serve to inform guidance for future studies.

Background: Nondaily dosing of oral preexposure prophylaxis (PrEP) may provide equivalent coverage of sex events compared with daily dosing. Methods: At-risk men and transgender women who have sex with men were randomly assigned to 1 of 3 dosing regimens: 1 tablet daily, 1 tablet twice weekly with a postsex dose (time-driven), or 1 tablet before and after sex (event-driven), and were followed for coverage of sex events with pre- and postsex dosing measured by weekly self-report, drug concentrations, and electronic drug monitoring. Results: From July 2012 to May 2014, 357 participants were randomized. In Bangkok, the coverage of sex events was 85% for the daily arm compared with 84% for the time-driven arm (P = .79) and 74% for the event-driven arm (P = .02). In Harlem, coverage was 66%, 47% (P = .01), and 52% (P = .01) for these groups. In Bangkok, PrEP medication concentrations in blood were consistent with use of >/=2 tablets per week in >95% of visits when sex was reported in the prior week, while in Harlem, such medication concentrations occurred in 48.5% in the daily arm, 30.9% in the time-driven arm, and 16.7% in the event-driven arm (P < .0001). Creatinine elevations were more common in the daily arm (P = .050), although they were not dose limiting. Conclusions: Daily dosing recommendations increased coverage and protective drug concentrations in the Harlem cohort, while daily and nondaily regimens led to comparably favorable outcomes in Bangkok, where participants had higher levels of education and employment. Clinical Trials Registration: NCT01327651.

AIMS: We compared cystatin C in youth with versus without diabetes and determined factors associated with cystatin C in youth with type 1 diabetes (T1D) and type 2 diabetes (T2D). METHODS: Youth (ages 12-19years) without diabetes (N=544) were ascertained from the NHANES Study 2000-2002 and those with T1D (N=977) and T2D (N=168) from the SEARCH for Diabetes in Youth Study. Adjusted means of cystatin C concentrations were compared amongst the 3 groups. Next, we performed multivariable analyses within the T1D and T2D SEARCH samples to determine the association between cystatin C and race, sex, age, diabetes duration, HbA1c, fasting glucose, and BMI. RESULTS: Adjusted cystatin C concentrations were statistically higher in NHANES (0.85mg/L) than in either the T1D (0.75mg/L) or T2D (0.70mg/L) SEARCH groups (P<0.0001). Fasting glucose was inversely related to cystatin C only in T1D (P<0.001) and BMI positively associated only in T2D (P<0.01) while HbA1c was inversely associated in both groups. CONCLUSIONS: Cystatin C concentrations are statistically higher in youth without diabetes compared to T1D or T2D, however the clinical relevance of this difference is quite small, especially in T1D. In youth with diabetes, cystatin C varies with BMI and acute and chronic glycemic control, however their effects may be different according to diabetes type.