Building a vertically integrated genomic learning health system: The biobank at the Colorado Center for Personalized Medicine.

Precision medicine initiatives across the globe have led to a revolution of repositories linking large-scale genomic data with electronic health records, enabling genomic analyses across the entire phenome. Many of these initiatives focus solely on research insights, leading to limited direct benefit to patients. We describe the biobank at the Colorado Center for Personalized Medicine (CCPM Biobank) that was jointly developed by the University of Colorado Anschutz Medical Campus and UCHealth to serve as a unique, dual-purpose research and clinical resource accelerating personalized medicine. This living resource currently has more than 200,000 participants with ongoing recruitment. We highlight the clinical, laboratory, regulatory, and HIPAA-compliant informatics infrastructure along with our stakeholder engagement, consent, recontact, and participant engagement strategies. We characterize aspects of genetic and geographic diversity unique to the Rocky Mountain region, the primary catchment area for CCPM Biobank participants. We leverage linked health and demographic information of the CCPM Biobank participant population to demonstrate the utility of the CCPM Biobank to replicate complex trait associations in the first 33,674 genotyped individuals across multiple disease domains. Finally, we describe our current efforts toward return of clinical genetic test results, including high-impact pathogenic variants and pharmacogenetic information, and our broader goals as the CCPM Biobank continues to grow. Bringing clinical and research interests together fosters unique clinical and translational questions that can be addressed from the large EHR-linked CCPM Biobank resource within a HIPAA- and CLIA-certified environment.

Real-world evaluation of early remdesivir in high-risk COVID-19 outpatients during Omicron including BQ.1/BQ.1.1/XBB.1.5.

BACKGROUND: A trial performed among unvaccinated, high-risk outpatients with COVID-19 during the delta period showed remdesivir reduced hospitalization. We used our real-world data platform to determine the effectiveness of remdesivir on reducing 28-day hospitalization among outpatients with mild-moderate COVID-19 during an Omicron period including BQ.1/BQ.1.1/XBB.1.5. METHODS: We did a propensity-matched, retrospective cohort study of non-hospitalized adults with SARS-CoV-2 infection between April 7, 2022, and February 7, 2023. Electronic healthcare record data from a large health system in Colorado were linked to statewide vaccination and mortality data. We included patients with a positive SARS-CoV-2 test or outpatient remdesivir administration. Exclusion criteria were other SARS-CoV-2 treatments or positive SARS-CoV-2 test more than seven days before remdesivir. The primary outcome was all-cause hospitalization up to day 28. Secondary outcomes included 28-day COVID-related hospitalization and 28-day all-cause mortality. RESULTS: Among 29,270 patients with SARS-CoV-2 infection, 1,252 remdesivir-treated patients were matched to 2,499 untreated patients. Remdesivir was associated with lower 28-day all-cause hospitalization (1.3% vs. 3.3%, adjusted hazard ratio (aHR) 0.39 [95% CI 0.23-0.67], p < 0.001) than no treatment. All-cause mortality at 28 days was numerically lower among remdesivir-treated patients (0.1% vs. 0.4%; aOR 0.32 [95% CI 0.03-1.40]). Similar benefit of RDV treatment on 28-day all-cause hospitalization was observed across Omicron periods, aOR (95% CI): BA.2/BA2.12.1 (0.77[0.19-2.41]), BA.4/5 (0.50[95% CI 0.50-1.01]), BQ.1/BQ.1.1/XBB.1.5 (0.21[95% CI 0.08-0.57]. CONCLUSION: Among outpatients with SARS-CoV-2 during recent Omicron surges, remdesivir was associated with lower hospitalization than no treatment, supporting current National Institutes of Health Guidelines.

Broiler farming practices using new or re-used bedding, inclusive of free-range, have no impact on Campylobacter levels, species diversity, Campylobacter community profiles and Campylobacter bacteriophages.

A multi-stage option to address food-safety can be produced by a clearer understanding of Campylobacter's persistence through the broiler production chain, its environmental niche and its interaction with bacteriophages. This study addressed Campylobacter levels, species, genotype, bacteriophage composition/ levels in caeca, litter, soil and carcasses across commercial broiler farming practices to inform on-farm management, including interventions. Broilers were sequentially collected as per company slaughter schedules over two-years from 17 farms, which represented four commercially adopted farming practices, prior to the final bird removal (days 39-53). The practices were conventional full clean-out, conventional litter re-use, free-range-full cleanout and free-range-litter re-use. Caeca, litter and soil collected on-farm, and representative carcases collected at the processing plant, were tested for Campylobacter levels, species dominance and Campylobacter bacteriophages. General community profiling via denaturing gradient gel electrophoresis of the flaA gene was used to establish the population relationships between various farming practices on representative Campylobacter isolates. The farming practice choices did not influence the high caeca Campylobacter levels (log 7.5 to log 8.5 CFU/g), the carcass levels (log 2.5 to log 3.2 CFU/carcass), the C. jejuni/C. coli dominance and the on-farm bacteriophage presence/levels. A principal coordinate analysis of the flaA distribution for farm and litter practices showed strong separation but no obvious farming practice related grouping of Campylobacter. Bacteriophages originated from select farms, were not practice-dependent, and were detected in the environment (litter) only if present in the birds (caeca). This multifaceted study showed no influence of farming practices on on-farm Campylobacter dynamics. The significance of this study means that a unified on-farm risk-management could be adopted irrespective of commercial practice choices to collectively address caeca Campylobacter levels, as well as the potential to include Campylobacter bacteriophage biocontrol. The impact of this study means that there are no constraints in re-using bedding or adopting free-range farming, thus contributing to environmentally sustainable (re-use) and emerging (free-range) broiler farming choices.

Effectiveness of subcutaneous monoclonal antibody treatment in emergency department outpatients with COVID-19.

Objectives: To evaluate whether subcutaneous neutralizing monoclonal antibody (mAb) treatment given in the emergency department (ED) setting was associated with reduced hospitalizations, mortality, and severity of disease when compared to nontreatment among mAb-eligible patients with coronavirus disease 2019 (COVID-19). Methods: This retrospective observational cohort study of ED patients utilized a propensity score-matched analysis to compare patients who received subcutaneous casirivimab and imdevimab mAb to nontreated COVID-19 control patients in November-December 2021. The primary outcome was all-cause hospitalization within 28 days, and secondary outcomes were 90-day hospitalization, 28- and 90-day mortality, and ED length of stay (LOS). Results: Of 1340 patients included in the analysis, 490 received subcutaneous casirivimab and imdevimab, and 850 did not received them. There was no difference observed for 28-day hospitalization (8.4% vs. 10.6%; adjusted odds ratio [aOR] 0.79, 95% confidence intervals [CI] 0.53-1.17) or 90-day hospitalization (11.6% vs. 12.5%; aOR 0.93, 95% CI 0.65-1.31). However, mortality at both the 28-day and 90-day timepoints was substantially lower in the treated group (28-day 0.6% vs. 3.1%; aOR 0.18, 95% CI 0.08-0.41; 90-day 0.6% vs. 3.9%; aOR 0.14, 95% CI 0.06-0.36). Among hospitalized patients, treated patients had shorter hospital LOS (5.7 vs. 11.4 days; adjusted rate ratio [aRR] 0.47, 95% CI 0.33-0.69), shorter intensive care unit LOS (3.8 vs. 10.2 days; aRR 0.22, 95% CI 0.14-0.35), and the severity of hospitalization was lower (aOR 0.45, 95% CI 0.21-0.97) compared to untreated. Conclusions: Among ED patients who presented for symptomatic COVID-19 during the Delta variant phase, ED subcutaneous casirivimab/imdevimab treatment was not associated with a decrease in hospitalizations. However, treatment was associated with lower mortality at 28 and 90 days, hospital LOS, and overall severity of illness.

Real-world use of nirmatrelvir-ritonavir in COVID-19 outpatients during BQ.1, BQ.1.1., and XBB.1.5 predominant omicron variants in three U.S. health systems: a retrospective cohort study.

Background: Ritonavir-boosted Nirmatrelvir (NMV-r), a protease inhibitor with in vitro activity against SARS-CoV-2, can reduce risk of progression to severe COVID-19 among high-risk individuals infected with earlier variants, but less is known about its effectiveness against omicron variants BQ.1/BQ.1.1/XBB.1.5. We sought to evaluate effectiveness of NMV-r in BQ.1/BQ.1.1/XBB.1.5 omicron variants by comparing hospitalisation rates to NMV-r treated patients during a previous omicron phase and to contemporaneous untreated patients. Methods: We conducted a retrospective observational cohort study of non-hospitalised adult patients with SARS-CoV-2 infection using real-world data from three health systems in Colorado and Utah, and compared hospitalisation rates in NMV-r-treated patients in a BA.2/BA.2.12.1/BA.4/BA.5 variant-predominant (first) phase (April 3, 2022-November 12, 2022), with a BQ.1/BQ.1.1/XBB.1.5 variant-predominant (second) phase (November 13, 2022-March 7, 2023). In the primary analysis, we used Firth logistic regression with a two-segment (phase) linear time model, and pre-specified non-inferiority bounds for the mean change between segments. In a pre-specified secondary analysis, we inferred NMV-r effectiveness in a cohort of treated and untreated patients infected during the second phase. For both analyses, the primary outcome was 28-day all-cause hospitalisation. Subgroup analyses assessed treatment effect heterogeneity. Findings: In the primary analysis, 28-day all-cause hospitalisation rates in NMV-r treated patients in the second phase (n = 12,061) were non-inferior compared to the first phase (n = 25,075) (198 [1.6%] vs. 345 [1.4%], adjusted odds ratio (aOR): 0.76 [95% CI 0.54-1.06]), with consistent results among secondary endpoints and key subgroups. Secondary cohort analyses revealed additional evidence for NMV-r effectiveness, with reduced 28-day hospitalisation rates among treated patients compared to untreated patients during a BQ.1/BQ.1.1/XBB.1.5 predominant phase (198/12,061 [1.6%] vs. 376/10,031 [3.7%], aOR 0.34 [95% CI 0.30-0.38), findings robust to additional sensitivity analyses. Interpretation: Real-world evidence from major US healthcare systems suggests ongoing NMV-r effectiveness in preventing hospitalisation during a BQ.1/BQ.1.1/XBB.1.5-predominant phase in the U.S, supporting its continued use in similar patient populations. Funding: U.S. National Institutes of Health.