OBJECTIVES/GOALS: Understanding how SARS-CoV-2 is evolving as well as spreading within and between communities is vital for the design of rational, evidence-based control measures. Continuous genomic surveillance is imperative to identify and track variants and can be paired with clinical data, to identify associations with severity or vaccine breakthroughs. METHODS/STUDY POPULATION: In June of 2021, we established UNM as a CDC-funded hub for genomic surveillance of SARS-CoV-2 for New Mexico and 3 other Rocky Mountain region states (Wyoming, Idaho, Montana). Through our Rocky Mountain COVID Consortium (RMCC), we have sequenced over 6,000 genomes of SARS-CoV-2 from RMCC partners. For New Mexico we integrate county and zip code data to provide more granular insights into how SARS-CoV-2, and particular variants, are transmitting within the state. We also pair this data with vaccine breakthrough cases identified by the NMDOH, as well as with clinical outcome data. RESULTS/ANTICIPATED RESULTS: We sequenced over 6,000 SARS-CoV-2 genomes from New Mexico (n=3091), Idaho (n=1538), Arkansas (n=1101), Wyoming (n=251), and Montana (n=33). We used this data to infer the transmission dynamics, identify variants, and map the spread of the virus. We identified a novel local variant that spread across New Mexico in early 2021, but was quickly replaced by the Alpha variant. In all RMCC states, the Delta variant overtook Alpha and has become nearly the only variant currently circulating in these states. We identified sequenced isolates from vaccine breakthrough cases in NM and demonstrate their role in onward transmission. We can identify shifts at a county or zip-code level in circulating lineages which may correspond to clinical outcomes or fluctuating case counts. DISCUSSION/SIGNIFICANCE: This integrated genomic data can be used by policy and decision makers within the New Mexico Department of Health and our RMCC partners to guide their public health response to the COVID-19 pandemic.

We offer a preliminary examination of whether national and organizational level contexts amplify or reduce the effects of de-globalization on the performance of MNCs. Theoretically, we borrow ideas from both event system theory and institutional fit to propose a model explicating key dimensions of the relationship between de-globalization, national and organizational context, and MNC performance. We then test our ideas using data assembled from 283 MNCs in 20 countries. We find that while de-globalization has a negative effect on MNC performance, national and organizational level contextual endowments do moderate this relationship. We discuss some implications of our findings and highlight attendant limitations.

ABSTRACT IMPACT: It is our hope that a better understanding of the relationship between genetic variants that influence heart failure precursor traits will not only inform clinical care, but enable better assessment of inherited risk and will identify new biological targets for drug development. OBJECTIVES/GOALS: In this project, using a large-scale human genomic dataset with extensive phenotype data available, we intend to interrogate the known MTSS1 variants that have been associated with heart failure (HF) in previous GWAS studies in order to understand the directionality and mechanisms of their effects. METHODS/STUDY POPULATION: Data was obtained from the UK Biobank, a large prospective cohort of ˜500,000 patients across the United Kingdom with extensive phenotype data, including ˜50,000 patients with cardiac MRI and ˜200,000 with whole exome sequencing. We test for associations between genetic variants at the MTSS1 locus and HF precursor traits using logistic regression or linear regression, adjusting for age, gender, and principal components (PCs) of ancestry. For rare variant analyses we ‘bin’ rare variants (MAF < 0.01) using the software tool BioBin to aggregate low frequency genetic variants into single genetic units. RESULTS/ANTICIPATED RESULTS: Preliminary data have shown that variants in the known MTSS1 enhancer region which reduce MTSS1 expression are associated with smaller, more contractile hearts. We anticipate that common variants known to reduce enhancer activity will attenuate heart failure precursor traits, will be associated with a reduced risk clinical heart failure, and will favorably impact clinical outcomes once HF is established. We also anticipate that rare exonic variants predicted to impair MTSS1 function will attenuate heart failure precursor traits. DISCUSSION/SIGNIFICANCE OF FINDINGS: Through this work, we intend to take advantage of multiple novel approaches to better understand a complex disease process, identify a new potential therapeutic target (namely one that targets cardiac function), and to determine which patient subgroups will benefit from this our therapeutic interventions and why.

Background: Central neuropathic pain syndromes are a result of central nervous system injury, most commonly related to stroke, traumatic spinal cord injury, or multiple sclerosis. These syndromes are distinctly less common than peripheral neuropathic pain, and less is known regarding the underlying pathophysiology, appropriate pharmacotherapy, and long-term outcomes. The objective of this study was to determine the long-term clinical effectiveness of the management of central neuropathic pain relative to peripheral neuropathic pain at tertiary pain centers. Methods: Patients diagnosed with central (n=79) and peripheral (n=710) neuropathic pain were identified for analysis from a prospective observational cohort study of patients with chronic neuropathic pain recruited from seven Canadian tertiary pain centers. Data regarding patient characteristics, analgesic use, and patient-reported outcomes were collected at baseline and 12-month follow-up. The primary outcome measure was the composite of a reduction in average pain intensity and pain interference. Secondary outcome measures included assessments of function, mood, quality of life, catastrophizing, and patient satisfaction. Results: At 12-month follow-up, 13.5% (95% confidence interval [CI], 5.6-25.8) of patients with central neuropathic pain and complete data sets (n=52) achieved a ≥30% reduction in pain, whereas 38.5% (95% CI, 25.3-53.0) achieved a reduction of at least 1 point on the Pain Interference Scale. The proportion of patients with central neuropathic pain achieving both these measures, and thus the primary outcome, was 9.6% (95% CI, 3.2-21.0). Patients with peripheral neuropathic pain and complete data sets (n=463) were more likely to achieve this primary outcome at 12 months (25.3% of patients; 95% CI, 21.4-29.5) (p=0.012). Conclusion: Patients with central neuropathic pain syndromes managed in tertiary care centers were less likely to achieve a meaningful improvement in pain and function compared with patients with peripheral neuropathic pain at 12-month follow-up.

Background: Considerable evidence from twin and adoption studies indicates that genetic and shared environmental factors play a role in the initiation of smoking behavior. Although twin and adoption designs are powerful to detect genetic and environmental influences, they do not provide information on the processes of assortative mating and parent–offspring transmission and their contribution to the variability explained by genetic and/or environmental factors. Methods: We examined the role of genetic and environmental factors in individual differences for smoking initiation (SI) using an extended kinship design. This design allows the simultaneous testing of additive and non-additive genetic, shared and individual-specific environmental factors, as well as sex differences in the expression of genes and environment in the presence of assortative mating and combined genetic and cultural transmission, while also estimating the regression of the prevalence of SI on age. A dichotomous lifetime ‘ever’ smoking measure was obtained from twins and relatives in the ‘Virginia 30,000’ sample and the ‘Australian 25,000’. Results: Results demonstrate that both genetic and environmental factors play a significant role in the liability to SI. Major influences on individual differences appeared to be additive genetic and unique environmental effects, with smaller contributions from assortative mating, shared sibling environment, twin environment, cultural transmission, and resulting genotype-environment covariance. Age regression of the prevalence of SI was significant. The finding of negative cultural transmission without dominance led us to investigate more closely two possible mechanisms for the lower parent–offspring correlations compared to the sibling and DZ twin correlations in subsets of the data: (1) age × gene interaction, and (2) social homogamy. Neither of the mechanism provided a significantly better explanation of the data. Conclusions: This study showed significant heritability, partly due to assortment, and significant effects of primarily non-parental shared environment on liability to SI.