Background: Since 2009, the CDC has invested in nationwide outbreak response capacity through Healthcare-associated Infections and Antimicrobial Resistance (HAI/AR) Programs in public health departments. The unpredictable nature of outbreaks requires public health programs to be able to scale operations and adapt strategies to effectively respond to emerging challenges, as demonstrated by the COVID-19 pandemic. This analysis characterizes HAI/AR Programs response capacity in scalability, adaptability, and technical expertise. Method: We reviewed data from HAI/AR Programs in 50 state, 6 local, and 2 territorial health departments (August 2019–December 2022). HAI/AR responses were defined as specific public health actions to assess an acute risk and prevent further harm in the context of a confirmed or possible healthcare outbreak; responses were categorized as involving novel or targeted multi-drug resistant organisms (nMDROs), COVID-19, and HAIs or infection control breaches. Descriptive statistics were used to analyze reported responses in three domains: scalability (number of responses per year), adaptability (number of pathogens and healthcare facility types involved in responses), and technical expertise (number of responses involving onsite or remote infection control assessments). The annual number of responses conducted in 2019 was estimated based on five months of data (Aug–Dec); all other results were calculated directly. Results: From August 2019 to December 2022, 58 HAI/AR Programs reported 141,445 responses (87% COVID-19, 11% nMDROs, 2% other HAIs or infection control breaches). Annually, programs conducted an estimated 5,546 responses in 2019, and this figure rose to 42,359 in 2020, 49,124 in 2021, and 47,651 in 2022. Outbreak responses involved 110 different pathogens, including emerging infectious diseases (e.g., SARS-CoV-2, mpox), nMDRO (e.g., carbapenemase-producing organisms, Candida auris), and other pathogens (e.g., hepatitis viruses, Mycobacterium abscessus) across >20 setting types (e.g., acute care hospitals, skilled nursing facilities, ambulatory surgery centers, assisted living facilities). Additionally, programs responded to infection control breaches in the absence of identified patient infections, including drug diversion, medical device reprocessing, and injection safety breaches. Programs conducted 50,245 infection control assessments during reported responses. Conclusion: From 2019–2022, as the COVID-19 pandemic took hold, HAI/AR Programs effectively utilized CDC funding to scale their response operations with an 8-fold increase in annual response activity, including a 24% increase for non-COVID-19 responses. Programs adapted responses to various pathogens, including emerging infectious diseases, across various setting types. Health department staff utilized technical expertise to conduct infection control assessments. This analysis provides valuable insights into the resilience and impact of HAI/AR Programs nationwide.

Background: Medicare claims are frequently used to study Clostridioides difficile infection (CDI) epidemiology. Categorizing CDI based on location of onset and potential exposure is critical in understanding transmission patterns and prevention strategies. While claims data are well-suited for identifying prior healthcare utilization exposures, they lack specimen collection and diagnosis dates to assign likely location of onset. Algorithms to classify CDI onset and healthcare association using claims data have been published, but the degree of misclassification is unknown. Methods: We linked patients with laboratory-confirmed CDI reported to four Emerging Infections Program (EIP) sites from 2016-2020 to Medicare beneficiaries using residence, birth date, sex, and hospitalization and/or healthcare exposure dates. Uniquely linked patients with fee-for-service Medicare A/B coverage and complete EIP case report forms were included. Patients with a claims CDI diagnosis code within ±28 days of a positive CDI test reported to EIP were categorized as hospital-onset (HO), long-term care facility onset (LTCFO), or community-onset (CO, either healthcare facility-associated [COHCFA] or community-associated [CA]) using a previously published algorithm based on claim type, ICD-10-CM code position, and duration of hospitalization (if applicable). EIP classifies CDI into these categories using positive specimen collection date and other information from chart review (e.g. admit/discharge dates). We assessed concordance of EIP and claims case classifications using Cohen’s kappa. Results: Of 10,002 eligible EIP-identified CDI cases, 7,064 were linked to a unique beneficiary; 3,451 met Medicare A/B fee-for-service coverage inclusion criteria. Of these, 650 (19%) did not have a claims diagnosis code ±28 days of the EIP specimen collection date (Table); 48% (313/650) of those without a claims diagnosis code were categorized by EIP as CA CDI. Among those with a CDI diagnosis code, concurrence of claims-based and EIP CDI classification was 68% (κ=0.56). Concurrence was highest for HO and lowest for COHCFA CDI. A substantial number of EIP-classified CO CDIs (30%, Figure) were misclassified as HO using the claims-based algorithm; half of these had a primary ICD-10 diagnosis code of sepsis (226/454; 50%). Conclusions: Evidence of CDI in claims data was found for 81% of EIP-reported CDI cases. Medicare classification algorithms concurred with the EIP classification in 68% of cases. Discordance was most common for community-onset CDI patients, many of whom were hospitalized with a primary diagnosis of sepsis. Misclassification of CO-CDI as HO may bias findings of claims-based CDI studies.

Background: Multiplex molecular tests for infectious diseases can provide highly sensitive results rapidly; however, these tests may more readily detect asymptomatic colonization. There are reports of non-FDA approved laboratory-developed multiplex tests for the diagnosis of urinary tract infections (UTI). Differentiating UTI from asymptomatic bacteriuria is challenging, especially in older adults. The increased sensitivity of multiplex tests may exacerbate this challenge. We sought to describe the use of multiplex testing for UTIs in Medicare claims. Methods: Multiplex testing was identified using carrier claims submitted by non-institutional providers using the Chronic Conditions Warehouse for 2016 – 2022. Because there are no CPT-4 codes specifying UTI multiplex testing, we included claims as described in Figure 1 and categorized claims based on the primary ICD-10-CM diagnosis. The payment amounts for line items related to testing for infectious agents were summed. Laboratories were counted using CLIA numbers listed on corresponding claims. Beneficiaries residing in a nursing home at the time of their claim were identified using stay information derived from the Minimum Dataset 3.0. For comparison, similar characteristics among carrier claims with a CPT-4 code indicating urine culture were also described. Results: Claims for unspecified multiplex molecular tests overall have increased, driven by increases in claims with a primary UTI diagnosis (from 8,521 in 2016 to 386,943 in 2022), while urine cultures have not (Figure 1). In 2022, 65% of all unspecified multiplex tests were linked to a diagnosis of UTI; UTI multiplex claims were associated with 647 laboratories. For UTI claims, the median cost per claim for line items related to multiplex testing was $589 compared to $13 for urine culture-related line items. Overall, 8% of UTI multiplex claims were for beneficiaries residing in a nursing home. Conclusions: Claims for non-FDA approved unspecified multiplex tests associated with a primary diagnosis of UTI have increased >45-times between 2016-2021 and have >45-times higher median costs than urine cultures. The use of this testing in the Medicare population, including nursing home residents, is of potential concern given that inappropriate treatment of asymptomatic bacteriuria has been described to be common in older adults. Research is needed to outline use cases where UTI multiplex testing may be beneficial. Appropriate use of diagnostic testing is important to minimize diagnostic errors and avoid unnecessary antibiotic use.

Prenatal stress has a significant, but small, negative effect on children’s executive function (EF) in middle and high socioeconomic status (SES) households. Importantly, rates and severity of prenatal stress are higher and protective factors are reduced in lower SES households, suggesting prenatal stress may be particularly detrimental for children’s EF in this population. This study examined whether prenatal stress was linked to 5-year-old’s EF in a predominantly low SES sample and child sex moderated this association, as males may be more vulnerable to adverse prenatal experiences. Participants were 132 mother-child dyads drawn from a prospective prenatal cohort. Mothers reported on their depression symptoms, trait anxiety, perceived stress, everyday discrimination, and sleep quality at enrollment and once each trimester, to form a composite prenatal stress measure. Children’s EF was assessed at age 5 years using the parent-report Behavior Rating Inventory of Executive Function - Preschool (BRIEF-P) Global Executive Composite subscale and neuropsychological tasks completed by the children. Mixed models revealed higher prenatal stress was associated with lower BRIEF-P scores, indicating better EF, for females only. Higher prenatal stress was associated with lower performance on neuropsychological EF measures for both males and females. Results add to the limited evidence about prenatal stress effects on children’s EF in low SES households.

Persons with mental illnesses may experience stigma from their immediate family members in addition to other forms of stigma. Using semi-structured interviews, we investigated experiences of familial mental illness stigma among 15 people diagnosed with mental illnesses in a mid-sized city in Canada. We identified five themes that speak to participants’ experiences of familial mental illness stigma and ways to reduce it. The themes include the following: diagnosis as a ‘double-edged sword,’ potential familial isolation, familial stigma as societal stigma localized, stories of acceptance, and confronting potential familial mental illness stigma. Participants’ narratives indicate that familial mental illness stigma is rooted in the broader social or public stigma, which sees its way into familial relations as well. This stigma takes various forms, including relationship bias or unfair treatment, breakdown in romantic relationships, loss of status, verbal and emotional abuse, exclusion from decision-making, and alienation within their immediate and extended families. Familial mental illness stigma experiences negatively impact participant’s psychological well-being and personal empowerment. However, participants also shared ways that family members create supportive environments or actively confront or prevent stigma. Overall, this study has contributed to knowledge on mental illness stigma, particularly familial mental illness stigma from the perspective of participants living with a mental illness in a high-income country. Suggestions for future research include a focus on strategies to prevent ongoing familial mental illness stigma and large-scale studies to explore familial mental illness stigma to understand why families might perpetrate stigma.

Empowering the Participant Voice (EPV) is an NCATS-funded six-CTSA collaboration to develop, demonstrate, and disseminate a low-cost infrastructure for collecting timely feedback from research participants, fostering trust, and providing data for improving clinical translational research. EPV leverages the validated Research Participant Perception Survey (RPPS) and the popular REDCap electronic data-capture platform. This report describes the development of infrastructure designed to overcome identified institutional barriers to routinely collecting participant feedback using RPPS and demonstration use cases. Sites engaged local stakeholders iteratively, incorporating feedback about anticipated value and potential concerns into project design. The team defined common standards and operations, developed software, and produced a detailed planning and implementation Guide. By May 2023, 2,575 participants diverse in age, race, ethnicity, and sex had responded to approximately 13,850 survey invitations (18.6%); 29% of responses included free-text comments. EPV infrastructure enabled sites to routinely access local and multi-site research participant experience data on an interactive analytics dashboard. The EPV learning collaborative continues to test initiatives to improve survey reach and optimize infrastructure and process. Broad uptake of EPV will expand the evidence base, enable hypothesis generation, and drive research-on-research locally and nationally to enhance the clinical research enterprise.

We recently reported on the radio-frequency attenuation length of cold polar ice at Summit Station, Greenland, based on bi-static radar measurements of radio-frequency bedrock echo strengths taken during the summer of 2021. Those data also allow studies of (a) the relative contributions of coherent (such as discrete internal conducting layers with sub-centimeter transverse scale) vs incoherent (e.g. bulk volumetric) scattering, (b) the magnitude of internal layer reflection coefficients, (c) limits on signal propagation velocity asymmetries (‘birefringence’) and (d) limits on signal dispersion in-ice over a bandwidth of ~100 MHz. We find that (1) attenuation lengths approach 1 km in our band, (2) after averaging 10 000 echo triggers, reflected signals observable over the thermal floor (to depths of ~1500 m) are consistent with being entirely coherent, (3) internal layer reflectivities are ≈–60$\to$–70 dB, (4) birefringent effects for vertically propagating signals are smaller by an order of magnitude relative to South Pole and (5) within our experimental limits, glacial ice is non-dispersive over the frequency band relevant for neutrino detection experiments.

OBJECTIVES/GOALS: Glioblastomas (GBMs) are heterogeneous, treatment-resistant tumors that are driven by populations of cancer stem cells (CSCs). In this study, we perform an epigenetic-focused functional genomics screen in GBM organoids and identify WDR5 as an essential epigenetic regulator in the SOX2-enriched, therapy resistant cancer stem cell niche. METHODS/STUDY POPULATION: Despite their importance for tumor growth, few molecular mechanisms critical for CSC population maintenance have been exploited for therapeutic development. We developed a spatially resolved loss-of-function screen in GBM patient-derived organoids to identify essential epigenetic regulators in the SOX2-enriched, therapy resistant niche. Our niche-specific screens identified WDR5, an H3K4 histone methyltransferase responsible for activating specific gene expression, as indispensable for GBM CSC growth and survival. RESULTS/ANTICIPATED RESULTS: In GBM CSC models, WDR5 inhibitors blocked WRAD complex assembly and reduced H3K4 trimethylation and expression of genes involved in CSC-relevant oncogenic pathways. H3K4me3 peaks lost with WDR5 inhibitor treatment occurred disproportionally on POU transcription factor motifs, required for stem cell maintenance and including the POU5F1(OCT4)::SOX2 motif. We incorporated a SOX2/OCT4 motif driven GFP reporter system into our CSC cell models and found that WDR5 inhibitor treatment resulted in dose-dependent silencing of stem cell reporter activity. Further, WDR5 inhibitor treatment altered the stem cell state, disrupting CSC in vitro growth and self-renewal as well as in vivo tumor growth. DISCUSSION/SIGNIFICANCE: Our results unveiled the role of WDR5 in maintaining the CSC state in GBM and provide a rationale for therapeutic development of WDR5 inhibitors for GBM and other advanced cancers. This conceptual and experimental framework can be applied to many cancers, and can unmask unique microenvironmental biology and rationally designed combination therapies.

OBJECTIVES/GOALS: As hospitals across the nation respond to the need to address community violence, there is a dearth of Hospital-based Violence Intervention Programs (HVIPs) in the South despite having disproportionate rates. This research aims to identify key factors and strategies for implementation of an HVIP among rural patient populations in a southern state. METHODS/STUDY POPULATION: Semi-structured interviews will be conducted with medical providers, social service organizations, and patients transferred from four high-risk rural areas in Arkansas. Data will be analyzed using Framework Analysis, a rapid analysis approach involving framework development, code application, impactful statement identification, and content analysis. Evidence- Based Quality Improvement (EBQI), a group consensus making process, will be conducted to identify key implementation strategies and factors to adapt based interview findings. Priority areas for adaptation will be identified via systematic rating. The EBQI team, including researchers and key rural stakeholders will engage in a series of discussion, vote on final strategies, and develop a guide for future HVIP implementation and pilot testing. RESULTS/ANTICIPATED RESULTS: Findings from this study will result in a prioritized list of barriers and facilitators across sample groups. Factors will be rated by level of importance. Cluster maps will display the relationships among factors. Go and no-go zones will be identified based on importance and feasibility. Implementation strategies will be mapped to barriers and facilitators. DISCUSSION/SIGNIFICANCE: The findings will result in a culturally and geographically relevant HVIP model and package of implementation strategies to test in future hybrid trials (feasibility pilot & multi-site RCT); and shape the future of violence prevention efforts in healthcare settings across the rural South.

Pre-diagnostic deficits in social motivation are hypothesized to contribute to autism spectrum disorder (ASD), a heritable neurodevelopmental condition. We evaluated psychometric properties of a social motivation index (SMI) using parent-report item-level data from 597 participants in a prospective cohort of infant siblings at high and low familial risk for ASD. We tested whether lower SMI scores at 6, 12, and 24 months were associated with a 24-month ASD diagnosis and whether social motivation’s course differed relative to familial ASD liability. The SMI displayed good internal consistency and temporal stability. Children diagnosed with ASD displayed lower mean SMI T-scores at all ages and a decrease in mean T-scores across age. Lower group-level 6-month scores corresponded with higher familial ASD liability. Among high-risk infants, strong decline in SMI T-scores was associated with 10-fold odds of diagnosis. Infant social motivation is quantifiable by parental report, differentiates children with versus without later ASD by age 6 months, and tracks with familial ASD liability, consistent with a diagnostic and susceptibility marker of ASD. Early decrements and decline in social motivation indicate increased likelihood of ASD, highlighting social motivation’s importance to risk assessment and clarification of the ontogeny of ASD.

From 2014 to 2020, we compiled radiocarbon ages from the lower 48 states, creating a database of more than 100,000 archaeological, geological, and paleontological ages that will be freely available to researchers through the Canadian Archaeological Radiocarbon Database. Here, we discuss the process used to compile ages, general characteristics of the database, and lessons learned from this exercise in “big data” compilation.

Micronutrients are important for normal cardiovascular function. They may play a role in the increased risk of cardiovascular disease observed in people with type 2 diabetes (T2D) and T2D-related heart failure. The aims of this study were to (1) examine micronutrient status in people with T2D v. healthy controls; (2) assess any changes following a nutritionally complete meal replacement plan (MRP) compared with routine care; (3) determine if any changes were associated with changes in cardiovascular structure/function. This was a secondary analysis of data from a prospective, randomised, open-label, blinded end-point trial of people with T2D, with a nested case–control [NCT02590822]. Anthropometrics, cardiac resonance imaging and fasting blood samples (to quantify vitamins B1, B6, B12, D and C; and iron and ferritin) were collected at baseline and 12 weeks following the MRP or routine care. Comparative data in healthy controls were collected at baseline. A total of eighty-three people with T2D and thirty-six healthy controls were compared at baseline; all had micronutrient status within reference ranges. Vitamin B1 was higher (148⋅9 v. 131⋅7; P 0⋅01) and B6 lower (37⋅3 v. 52⋅9; P 0⋅01) in T2D v. controls. All thirty participants randomised to routine care and twenty-four to the MRP completed the study. There was an increase in vitamins B1, B6, D and C following the MRP, which were not associated with changes in cardiovascular structure/function. In conclusion, changes in micronutrient status following the MRP were not independently associated with improvements in cardiovascular structure/function in people with T2D.

Patients with single-ventricle CHD undergo a series of palliative surgeries that culminate in the Fontan procedure. While the Fontan procedure allows most patients to survive to adulthood, the Fontan circulation can eventually lead to multiple cardiac complications and multi-organ dysfunction. Care for adolescents and adults with a Fontan circulation has begun to transition from a primarily cardiac-focused model to care models, which are designed to monitor multiple organ systems, and using clues from this screening, identify patients who are at risk for adverse outcomes. The complexity of care required for these patients led our centre to develop a multidisciplinary Fontan Management Programme with the primary goals of earlier detection and treatment of complications through the development of a cohesive network of diverse medical subspecialists with Fontan expertise.

Availability of trained professionals to assist researchers navigating regulatory pathways for new drug and device development is limited within academic institutions. We created ReGARDD (Regulatory Guidance for Academic Research of Drugs and Devices), a regional forum initially involving regulatory professionals from four Clinical and Translational Science Award (CTSA)-funded institutions, to build and capitalize on local expertise and to develop a regulatory guidance website geared toward academic researchers. Since 2015, members organized 15 forums covering topics such as FDA premarket submissions, gene therapy, and intellectual property for devices and therapeutics. Through user feedback, targeted surveys, and ongoing iterative processes, we refined and maintained a shared regulatory website, which reached 6000+ users in 2019. Website updates improved navigation to drug versus device topic areas, provided new educational content and videos to address commonly asked questions, and created a portal for posting upcoming training opportunities. Survey respondents rated the website favorably and endorsed expanding ReGARDD as a centralized resource. ReGARDD strengthened the regional regulatory workforce, increased regulatory efficiency, and promulgated best organizational and operational practices. Broad-scale deployment of the ReGARDD model across the CTSA consortium may facilitate the creation of a network of regional forums and reduce gaps in access to regulatory support.