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 Evidence of the Neutralizing Monoclonal Antibody Sotrovimab for Preventing Hospitalization and Mortality in COVID-19 Outpatients.

BACKGROUND: It is not known whether sotrovimab, a neutralizing monoclonal antibody (mAb) treatment authorized for early symptomatic coronavirus disease 2019 (COVID-19) patients, is also effective in preventing the progression of severe disease and mortality following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta variant infection. METHODS: In an observational cohort study of nonhospitalized adult patients with SARS-CoV-2 infection, 1 October 2021-11 December 2021, using electronic health records from a statewide health system plus state-level vaccine and mortality data, we used propensity matching to select 3 patients not receiving mAbs for each patient who received outpatient sotrovimab treatment. The primary outcome was 28-day hospitalization; secondary outcomes included mortality and severity of hospitalization. RESULTS: Of 10 036 patients with SARS-CoV-2 infection, 522 receiving sotrovimab were matched to 1563 not receiving mAbs. Compared to mAb-untreated patients, sotrovimab treatment was associated with a 63% decrease in the odds of all-cause hospitalization (raw rate 2.1% vs 5.7%; adjusted odds ratio [aOR], 0.37; 95% confidence interval [CI], .19-.66) and an 89% decrease in the odds of all-cause 28-day mortality (raw rate 0% vs 1.0%; aOR, 0.11; 95% CI, .0-.79), and may reduce respiratory disease severity among those hospitalized. CONCLUSIONS: Real-world evidence demonstrated sotrovimab effectiveness in reducing hospitalization and all-cause 28-day mortality among COVID-19 outpatients during the Delta variant phase.

Association between treatment failure and hospitalization after receipt of neutralizing monoclonal antibody treatment for COVID-19 outpatients.

BACKGROUND: Neutralizing monoclonal antibodies (mAbs) are highly effective in reducing hospitalization and mortality among early symptomatic COVID-19 patients in clinical trials and real-world data. While resistance to some mAbs has since emerged among new variants, characteristics associated with treatment failure of mAbs remain unknown. METHODS: This multicenter, observational cohort study included patients with COVID-19 who received mAb treatment between November 20, 2020, and December 9, 2021. We utilized electronic health records from a statewide health system plus state-level vaccine and mortality data. The primary outcome was mAb treatment failure, defined as hospitalization or death within 28 days of a positive SARS-CoV-2 test. RESULTS: COVID-19 mAb was administered to 7406 patients. Hospitalization within 28 days of positive SARS-CoV-2 test occurred in 258 (3.5%) of all patients who received mAb treatment. Ten patients (0.1%) died within 28 days, and all but one were hospitalized prior to death. Characteristics associated with treatment failure included having two or more comorbidities excluding obesity and immunocompromised status (adjusted odds ratio [OR] 3.71, 95% confidence interval [CI] 2.52-5.56), lack of SARS-CoV-2 vaccination (OR 2.73, 95% CI 2.01-3.77), non-Hispanic black race/ethnicity (OR 2.21, 95% CI 1.20-3.82), obesity (OR 1.79, 95% CI 1.36-2.34), one comorbidity (OR 1.68, 95% CI 1.11-2.57), age ≥ 65 years (OR 1.62, 95% CI 1.13-2.35), and male sex (OR 1.56, 95% CI 1.21-2.02). Immunocompromised status (none, mild, or moderate/severe), pandemic phase, and type of mAb received were not associated with treatment failure (all p > 0.05). CONCLUSIONS: Comorbidities, lack of prior SARS-CoV-2 vaccination, non-Hispanic black race/ethnicity, obesity, age ≥ 65 years, and male sex are associated with treatment failure of mAbs.

Multicenter Study Evaluating Nitrous Oxide Use for Labor Analgesia at High- and Low-Altitude Institutions.

BACKGROUND: Nitrous oxide (N2O) has been used nationally as an analgesic in many clinical settings. While neuraxial analgesia is still the most commonly used labor analgesic in the United States, there is increasing use of N2O in labor. Given the reduction in the partial pressure of gases at a higher altitude, N2O has been reported to have reduced analgesic properties. However, there is no study to date evaluating the impact of altitude on labor analgesia and N2O. METHODS: We conducted a multicenter retrospective data analysis of a N2O registry collected from 4 institutions over a 3-year period. We compared the impact of altitude on 50% N2O administration for labor analgesia, conversion rates to another analgesic modality, as well as collected side effect frequencies and conversion predictors. Multivariable regression models were used to compare clinical characteristics and outcomes between parturients at high and low altitudes, while adjusting for race, ethnicity, education, and age (logistic and linear regressions for categorical and quantitative outcomes, respectively). RESULTS: A total of 1856 laboring parturients (age 18-50) were included in the analysis. The odds of converting from 50% N2O to another analgesic modality had no statistically significant difference between high- versus low-altitude institutions (adjusted odds ratio [aOR], 1.13; 95% confidence interval [CI], 0.90-1.42; P = .3). Yet, when parturients at low altitude converted from N2O, they were more likely (aOR, 3.03; 95% CI, 1.59-5.88) to choose neuraxial analgesia instead of another analgesic modality when compared to high-altitude parturients. This is possibly due to higher epidural rates at the low-altitude institutions. When parturients at high altitude did convert into another modality, they were more likely (aOR, 2.19; 95% CI, 1.14-4.21) to convert due to inadequate pain relief compared to low-altitude parturients; however, missing data may have affected this finding. Laboring individuals at low altitude were significantly more likely to experience side effects (aOR, 2.13; 95% CI, 1.45-3.12). Those requiring labor augmentation, assisted vaginal, or cesarean delivery converted to neuraxial analgesia significantly more often than those that delivered via spontaneous vaginal delivery (P < .05) in both high- and low-altitude groups. CONCLUSIONS: This is the first study evaluating 50% N2O as a labor analgesic at high altitude. As expected, we found lower side effects at high altitude, likely due to the lower partial pressure of N2O. However, there was not a statistically significant increase in conversion from N2O to another analgesic modality at high altitude and no clinically significant differences in neonatal outcomes.

Introducing Benzene-1,3,5-tri(dithiocarboxylate) as a Multidentate Linker in Coordination Chemistry.

Benzene-1,3,5-tri(dithiocarboxylate) (BTDTC3-), the sulfur-donor analogue of trimesate (BTC3-, benzene-1,3,5-tricarboxylate), is introduced, and its potential as a multidentate, electronically bridging ligand in coordination chemistry is evaluated. For this, the sodium salt Na3BTDTC has been synthesized, characterized, and compared with the sodium salt of the related ditopic benzene-1,4-di(dithiocarboxylate) (Na2BDDTC). Single-crystal X-ray diffraction of the respective tetrahydrofuran (THF) solvates reveals that such multitopic aromatic dithiocarboxylate linkers can form both discrete metal complexes (Na3BTDTC·9THF) and (two-dimensional) coordination polymers (Na2BDDTC·4THF). Additionally, the versatile coordination behavior of the novel BTDTC3- ligand is demonstrated by successful synthesis and characterization of trinuclear Cu(I) and hexanuclear Mo(II)2 paddlewheel complexes. The electronic structure and molecular orbitals of both dithiocarboxylate ligands as well as their carboxylate counterparts are investigated by density functional theory computational methods. Electrochemical investigations suggest that BTDTC3- enables electronic communication between the coordinated metal ions, rendering it a promising tritopic linker for functional coordination polymers.

Investigation of Solvatomorphism and Its Photophysical Implications for Archetypal Trinuclear Au3(1-Methylimidazolate)3.

A new solvatomorph of [Au3(1-Methylimidazolate)3] (Au3(MeIm)3)-the simplest congener of imidazolate-based Au(I) cyclic trinuclear complexes (CTCs)-has been identified and structurally characterized. Single-crystal X-ray diffraction revealed a dichloromethane solvate exhibiting remarkably short intermolecular Au⋯Au distances (3.2190(7) Å). This goes along with a dimer formation in the solid state, which is not observed in a previously reported solvent-free crystal structure. Hirshfeld analysis, in combination with density functional theory (DFT) calculations, indicates that the dimerization is generally driven by attractive aurophilic interactions, which are commonly associated with the luminescence properties of CTCs. Since Au3(MeIm)3 has previously been reported to be emissive in the solid-state, we conducted a thorough photophysical study combined with phase analysis by means of powder X-ray diffraction (PXRD), to correctly attribute the photophysically active phase of the bulk material. Interestingly, all investigated powder samples accessed via different preparation methods can be assigned to the pristine solvent-free crystal structure, showing no aurophilic interactions. Finally, the observed strong thermochromism of the solid-state material was investigated by means of variable-temperature PXRD, ruling out a significant phase transition being responsible for the drastic change of the emission properties (hypsochromic shift from 710 nm to 510 nm) when lowering the temperature down to 77 K.

Controlling Multiphoton Absorption Efficiency by Chromophore Packing in Metal-Organic Frameworks.

Coordination polymers show great potential for the tailored design of advanced photonic applications by employing crystal chemistry concepts. One challenge for achieving a rational design of nonlinear optically active MOF materials is deriving fundamental structure-property relations of the interplay between the photonic properties and the spatial arrangements of optically active chromophores within the network. We here investigate two-photon-absorption (TPA)-induced photoluminescence of two new MOFs based on a donor-acceptor tetraphenylphenylenediamine (tPPD) chromophore linker (H4TPBD) and Zn(II) and Cd(II) as metal centers. The TPA efficiencies are controlled by the network topologies, degree of interpenetration, packing densities, and the specific spatial arrangement of the chromophores. The effects can be rationalized within the framework of established excited-state theories of molecular crystals. The results presented here demonstrate the key effect of chromophore orientation on the nonlinear optical properties of crystalline network compounds and allow for establishing quantitative design principles for efficient TPA materials.

Non-Innocent Methylene Linker in Bridged Lewis Pair Initiators.

Deprotonation usually occurs as an unwanted side reaction in the Lewis pair polymerization of Michael acceptors, for which the conjugated addition of the Lewis base to the acid-activated monomer is the commonly accepted initiation mechanism. This has also been reported for B-P-based bridged Lewis pairs (BLPs) that form macrocyclic addition products. We now show that the formerly unwanted deprotonation is the likely initiation pathway in the case of Al-P-based BLPs. In a detailed study of a series of Al-P-based BLPs, using a combination of single-crystal diffraction experiments (X-ray and neutron) and mechanistic investigations (experimental and computational), an active role of the methylene bridge was revealed, acting as a base towards the α-acidic monomers. Additionally, the polymerization studies proved a living behavior combined with significantly high activities, narrow molecular mass distributions, and the possibility of copolymerization.

Nonlinear optical properties, upconversion and lasing in metal-organic frameworks.

The building block modular approach that lies behind coordination polymers (CPs) and metal-organic frameworks (MOFs) results not only in a plethora of materials that can be obtained but also in a vast array of material properties that could be aimed at. Optical properties appear to be particularly predetermined by the character of individual structural units and by the intricate interplay between them. Indeed, the "design principles" shaping the optical properties of these materials seem to be well explored for luminescence and second-harmonic generation (SHG) phenomena; these have been covered in numerous previous reviews. Herein, we shine light on CPs and MOFs as optical media for state-of-the-art photonic phenomena such as multi-photon absorption, triplet-triplet annihilation (TTA) and stimulated emission. In the first part of this review we focus on the nonlinear optical (NLO) properties of CPs and MOFs, with a closer look at the two-photon absorption property. We discuss the scope of applicability of most commonly used measurement techniques (Z-scan and two-photon excited fluorescence (TPEF)) that can be applied for proper determination of the NLO properties of these materials; in particular, we suggest recommendations for their use, along with a discussion of the best reporting practices of NLO parameters. We also outline design principles, employing both intramolecular and intermolecular strategies, that are necessary for maximizing the NLO response. A review of recent literature on two-, three- and multi-photon absorption in CPs and MOFs is further supplemented with application-oriented processes such as two-photon 3D patterning and data storage. Additionally, we provide an overview of the latest achievements in the field of frequency doubling (SHG) and tripling (third-harmonic generation, THG) in these materials. Apart from nonlinear processes, in the next sections we also target the photonic properties of MOFs that benefit from their porosity, and resulting from this their ability to serve as containers for optically-active molecules. Thus, we survey dye@MOF composites as novel media in which efficient upconversion via triplet energy migration (TEM) occurs as well as materials for stimulated emission and multi-photon pumped lasing. Prospects for producing lasing as an intrinsic property of MOFs has also been discussed. Overall, further development of the optical processes highlighted herein should allow for realization of various photonic, data storage, biomedical and optoelectronic applications.

HEMATOLOGY, PLASMA BIOCHEMISTRY, AND URINALYSIS OF FREE-RANGING GREY-HEADED FLYING FOXES ( PTEROPUS POLIOCEPHALUS) IN AUSTRALIA.

The grey-headed flying fox ( Pteropus poliocephalus) is a species endemic to coastal eastern Australia. This study presents a comprehensive set of biochemistry, hematology, and urinalysis biomarkers from which reference values were derived. Blood samples collected from free-ranging P. poliocephalus were submitted for hematology ( n = 140) and plasma biochemistry ( n = 161) and urine for urinalysis ( n = 95). The values for P. poliocephalus were broadly consistent with those values published for other Australian Pteropus species. Statistically significant within-species age and sex effects were observed: adult P. poliocephalus had higher mean corpuscular volume, mean corpuscular hemoglobin, urea, creatinine, bilirubin, alanine transferase (ALT), protein, globulin, urinary specific gravity, and urinary ketones, whereas subadults had higher mean red blood cell, white blood cell (WBC), lymphocyte, and monocyte counts, and juveniles had higher mean neutrophil count and alkaline phosphatase; male P. poliocephalus had higher mean reticulocyte count, alanine transferase, glucose, and urinary ketones, whereas females had higher mean WBC, lymphocyte, and monocyte counts. The findings inform both clinical and research scenarios for P. poliocephalus in captivity or rehabilitation and for health assessments of free-living populations.

Repeat liver resection for recurrent colorectal metastases: a single-centre, 13-year experience.

OBJECTIVES: Isolated intrahepatic recurrence is noted in up to 40% of patients following curative liver resection for colorectal liver metastases (CLM). The aims of this study were to analyse the outcomes of repeat hepatectomy for recurrent CLM and to identify factors predicting survival. METHODS: Data for all liver resections for CLM carried out at one centre between 1998 and 2011 were analysed. RESULTS: A total of 1027 liver resections were performed for CLM. Of these, 58 were repeat liver resections performed in 53 patients. Median time intervals were 10.5 months between the primary resection and first hepatectomy, and 15.4 months between the first and repeat hepatectomies. The median tumour size was 3.0 cm and the median number of tumours was one. Six patients had a positive margin (R1) resection following first hepatectomy. There were no perioperative deaths. Significant complications included transient liver dysfunction in one and bile leak in two patients. Rates of 1-, 3- and 5-year overall survival following repeat liver resection were 85%, 61% and 52%, respectively, at a median follow-up of 23 months. R1 resection at first hepatectomy (P = 0.002), a shorter time interval between the first and second hepatectomies (P = 0.02) and the presence of extrahepatic disease (P = 0.02) were associated with significantly worse overall survival. CONCLUSIONS: Repeat resection of CLM is safe and can achieve longterm survival in carefully selected patients. A preoperative knowledge of poor prognostic factors helps to facilitate better patient selection.

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.

Improved statistical methods for estimating infestation rates in quarantine research when hosts are naturally infested.

Trading partners often require phytosanitary or quarantine treatments for fresh horticultural produce to ensure no economically important pest species are moved with the imported product. When developing such treatments, it is essential that the level of treatment efficacy can be determined. This is often based on the mortality of the total number of target pests exposed to treatment, but in naturally infested products this number is not always known. In such cases, the infestation rate and subsequently an estimate of the number of pests are obtained directly from a set of untreated control samples of the host product. The International Plant Protection Convention (IPPC) Secretariat has provided 2 formulas for these situations that place an interval around the point estimate obtained from the control samples to obtain an estimate of the infestation rate. However, these formulas do not allow a confidence level to be assigned to the estimate, and there are concerns with the assumptions regarding the distribution and the measure of variability used in the formulas. In this article, we propose 2 alternative formulas. We propose that the lower one-sided confidence limit should be applied to all infestation datasets that are approximately normally distributed. As infestation data are sometimes skewed, it is proposed the lower one-sided modified Cox confidence limit is applied to data approximately log-normal distributed. These well-recognized formulas are compared to the formulas recommended by the IPPC and applied to 3 datasets involving natural infestation.

Real-world use of nirmatrelvir-ritonavir in outpatients with COVID-19 during the era of omicron variants including BA.4 and BA.5 in Colorado, USA: a retrospective cohort study.

BACKGROUND: Nirmatrelvir is a protease inhibitor with in-vitro activity against SARS-CoV-2, and ritonavir-boosted nirmatrelvir can reduce the risk of progression to severe COVID-19 among individuals at high risk infected with delta and early omicron variants. However, less is known about the effectiveness of nirmatrelvir-ritonavir during more recent BA.2, BA2.12.1, BA.4, and BA.5 omicron variant surges. We used our real-world data platform to evaluate the effect of nirmatrelvir-ritonavir treatment on 28-day hospitalisation, mortality, and emergency department visits among outpatients with early symptomatic COVID-19 during a SARS-CoV-2 omicron (BA.2, BA2.12.1, BA.4, and BA.5) predominant period in Colorado, USA. METHODS: We did a propensity-matched, retrospective, observational cohort study of non-hospitalised adult patients infected with SARS-CoV-2 between March 26 and Aug 25, 2022, using records from a statewide health system in Colorado. We obtained data from the electronic health records of University of Colorado Health, the largest health system in Colorado, with 13 hospitals and 141 000 annual hospital admissions, and with numerous ambulatory sites and affiliated pharmacies around the state. Included patients had a positive SARS-CoV-2 test or nirmatrelvir-ritonavir medication order. Exclusion criteria were an order for or administration of other SARS-CoV-2 treatments within 10 days of a positive SARS-CoV-2 test, hospitalisation at the time of positive SARS-CoV-2 test, and positive SARS-CoV-2 test more than 10 days before a nirmatrelvir-ritonavir order. We propensity score matched patients treated with nirmatrelvir-ritonavir with untreated patients. The primary outcome was 28-day all-cause hospitalisation. FINDINGS: Among 28 167 patients infected with SARS-CoV-2 between March 26 and Aug 25, 2022, 21 493 met the study inclusion criteria. 9881 patients received treatment with nirmatrelvir-ritonavir and 11 612 were untreated. Nirmatrelvir-ritonavir treatment was associated with reduced 28-day all-cause hospitalisation compared with no antiviral treatment (61 [0·9%] of 7168 patients vs 135 [1·4%] of 9361 patients, adjusted odds ratio (OR) 0·45 [95% CI 0·33-0·62]; p<0·0001). Nirmatrelvir-ritonavir treatment was also associated with reduced 28-day all-cause mortality (two [<0·1%] of 7168 patients vs 15 [0·2%] of 9361 patients; adjusted OR 0·15 [95% CI 0·03-0·50]; p=0·0010). Using subsequent emergency department visits as a surrogate for clinically significant relapse, we observed a decrease after nirmatrelvir-ritonavir treatment (283 [3·9%] of 7168 patients vs 437 [4·7%] of 9361 patients; adjusted OR 0·74 [95% CI 0·63-0·87]; p=0·0002). INTERPRETATION: Real-world evidence reported during a BA.2, BA2.12.1, BA.4, and BA.5 omicron surge showed an association between nirmatrelvir-ritonavir treatment and reduced 28-day all-cause hospitalisation, all-cause mortality, and visits to the emergency department. With results that are among the first to suggest effectiveness of nirmatrelvir-ritonavir for non-hospitalised patients during an omicron period inclusive of BA.4 and BA.5 subvariants, these data support nirmatrelvir-ritonavir as an ongoing first-line treatment for adults acutely infected with SARS-CoV-2. FUNDING: US National Institutes of Health.

COVID-19 Mortality in the Colorado Center for Personalized Medicine Biobank.

Over 6.37 million people have died from COVID-19 worldwide, but factors influencing COVID-19-related mortality remain understudied. We aimed to describe and identify risk factors for COVID-19 mortality in the Colorado Center for Personalized Medicine (CCPM) Biobank using integrated data sources, including Electronic Health Records (EHRs). We calculated cause-specific mortality and case-fatality rates for COVID-19 and common pre-existing health conditions defined by diagnostic phecodes and encounters in EHRs. We performed multivariable logistic regression analyses of the association between each pre-existing condition and COVID-19 mortality. Of the 155,859 Biobank participants enrolled as of July 2022, 20,797 had been diagnosed with COVID-19. Of 5334 Biobank participants who had died, 190 were attributed to COVID-19. The case-fatality rate was 0.91% and the COVID-19 mortality rate was 122 per 100,000 persons. The odds of dying from COVID-19 were significantly increased among older men, and those with 14 of the 61 pre-existing conditions tested, including hypertensive chronic kidney disease (OR: 10.14, 95% CI: 5.48, 19.16) and type 2 diabetes with renal manifestations (OR: 5.59, 95% CI: 3.42, 8.97). Male patients who are older and have pre-existing kidney diseases may be at higher risk for death from COVID-19 and may require special care.

Change in effectiveness of sotrovimab for preventing hospitalization and mortality for at-risk COVID-19 outpatients during an Omicron BA.1 and BA.1.1-predominant phase.

OBJECTIVES: Sotrovimab effectively prevented progression to severe disease and mortality following infection with pre-Omicron SARS-CoV-2 variants. We sought to determine whether sotrovimab is similarly effective against SARS-CoV-2 Omicron variant infection. METHODS: Observational cohort study of non-hospitalized adult patients with SARS-CoV-2 infection from December 26, 2021, to March 10, 2022, using electronic health records from a statewide health system. We propensity-matched patients not receiving authorized treatment for each patient treated with sotrovimab. The primary outcome was 28-day hospitalization; secondary outcomes included mortality. We also propensity-matched sotrovimab-treated patients from the Omicron and Delta phases. Logistic regression was used to determine sotrovimab effectiveness during Omicron and between variant phases. RESULTS: Of 30,247 SARS-CoV-2 Omicron variant infected outpatients, we matched 1542 receiving sotrovimab to 3663 not receiving treatment. Sotrovimab treatment was not associated with reduced odds of 28-day hospitalization (2.5% vs 3.2%; adjusted odds ratio [OR] 0.82, 95% CI 0.55, 1.19) or mortality (0.1% vs 0.2%; adjusted OR 0.62, 95% CI 0.07, 2.78). Between phases, the observed treatment OR was higher during Omicron than during Delta (OR 0.85 vs 0.39, respectively; interaction P-value = 0.053). CONCLUSION: Real-world evidence demonstrated that sotrovimab was not associated with reduced 28-day hospitalization or mortality among COVID-19 outpatients during the Omicron BA.1 phase.

Real-world evaluation of bebtelovimab effectiveness during the period of COVID-19 Omicron variants, including BA.4/BA.5.

OBJECTIVES: Bebtelovimab is an anti-SARS-CoV-2 monoclonal antibody active against Omicron lineage variants authorized to treat high-risk outpatients with COVID-19. We sought to determine the real-world effectiveness of bebtelovimab during the Omicron phases BA.2/BA2.12.1/BA4/BA5. METHODS: We conducted a retrospective cohort study of adults with SARS-CoV-2 infection between April 6 and October 11, 2022, using health records linked to vaccine and mortality data. We used propensity scores to match of bebtelovimab-treated with untreated outpatients. The primary outcome was 28-day all-cause hospitalization. The secondary outcomes were 28-day COVID-19-related hospitalization, 28-day all-cause mortality, 28-day emergency department visits, maximum respiratory support level, intensive care unit admission, and in-hospital mortality among hospitalized patients. We used logistic regression to determine bebtelovimab treatment effectiveness. RESULTS: Among 22,720 patients with SARS-COV-2 infection, 3739 bebtelovimab-treated patients were matched to 5423 untreated patients. Compared with no treatment, bebtelovimab was associated with lower odds of 28-day all-cause hospitalization (1.3% vs 2.1%, adjusted odds ratio: 0.53; 95% confidence interval: 0.37-0.74, P <0.001), as well as COVID-19-related hospitalization (1.0% vs 2.0%, adjusted odds ratio: 0.44 [95% confidence interval: 0.30-0.64], P <0.001). Bebtelovimab appeared to be more beneficial in lowering the odds of hospitalization among patients with two or more comorbidities (interaction P = 0.03). CONCLUSION: During the Omicron BA.2/BA.2.12.1/BA.4/BA.5 variant phase, bebtelovimab was associated with lower hospitalization.

Real-World Evidence of Neutralizing Monoclonal Antibodies for Preventing Hospitalization and Mortality in COVID-19 Outpatients.

BACKGROUND: Neutralizing monoclonal antibodies (mAbs) were authorized for the treatment of COVID-19 outpatients based on clinical trials completed early in the pandemic, which were underpowered for mortality and subgroup analyses. Real-world data studies are promising for further assessing rapidly deployed therapeutics. RESEARCH QUESTION: Did mAb treatment prevent progression to severe disease and death across pandemic phases and based on risk factors, including prior vaccination status? STUDY DESIGN AND METHODS: This observational cohort study included nonhospitalized adult patients with SARS-CoV-2 infection from November 2020 to October 2021 using electronic health records from a statewide health system plus state-level vaccine and mortality data. Using propensity matching, we selected approximately 2.5 patients not receiving mAbs for each patient who received mAb treatment under emergency use authorization. The primary outcome was 28-day hospitalization; secondary outcomes included mortality and hospitalization severity. RESULTS: Of 36,077 patients with SARS-CoV-2 infection, 2,675 receiving mAbs were matched to 6,677 patients not receiving mAbs. Compared with mAb-untreated patients, mAb-treated patients had lower all-cause hospitalization (4.0% vs 7.7%; adjusted OR, 0.48; 95% CI, 0.38-0.60) and all-cause mortality (0.1% vs 0.9%; adjusted OR, 0.11; 95% CI, 0.03-0.29) to day 28; differences persisted to day 90. Among hospitalized patients, mAb-treated patients had shorter hospital length of stay (5.8 vs 8.5 days) and lower risk of mechanical ventilation (4.6% vs 16.6%). Results were similar for preventing hospitalizations during the Delta variant phase (adjusted OR, 0.35; 95% CI, 0.25-0.50) and across subgroups. Number-needed-to-treat (NNT) to prevent hospitalization was lower for subgroups with higher baseline risk of hospitalization; for example, multiple comorbidities (NNT = 17) and not fully vaccinated (NNT = 24) vs no comorbidities (NNT = 88) and fully vaccinated (NNT = 81). INTERPRETATION: Real-world data revealed a strong association between receipt of mAbs and reduced hospitalization and deaths among COVID-19 outpatients across pandemic phases. Real-world data studies should be used to guide practice and policy decisions, including allocation of scarce resources.