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.

Respiratory syncytial virus (RSV) vaccine effectiveness against RSV-associated hospitalisations and emergency department encounters among adults aged 60 years and older in the USA, October, 2023, to March, 2024: a test-negative design analysis.

BACKGROUND: Respiratory syncytial virus vaccines first recommended for use during 2023 were efficacious against lower respiratory tract disease in clinical trials. Limited real-world data regarding respiratory syncytial virus vaccine effectiveness are available. To inform vaccine policy and address gaps in evidence from the clinical trials, we aimed to assess the effectiveness against respiratory syncytial virus-associated hospitalisations and emergency department encounters among adults aged at least 60 years. METHODS: We conducted a test-negative design analysis in an electronic health records-based network in eight states in the USA, including hospitalisations and emergency department encounters with respiratory syncytial virus-like illness among adults aged at least 60 years who underwent respiratory syncytial virus testing from Oct 1, 2023, to March 31, 2024. Respiratory syncytial virus vaccination status at the time of the encounter was derived from electronic health record documentation, state and city immunisation registries, and, for some sites, medical claims. Vaccine effectiveness was estimated by immunocompromise status, comparing the odds of vaccination among respiratory syncytial virus-positive case patients and respiratory syncytial virus-negative control patients, and adjusting for age, race and ethnicity, sex, calendar day, social vulnerability index, number of underlying non-respiratory medical conditions, presence of respiratory underlying medical conditions, and geographical region. FINDINGS: Among 28 271 hospitalisations for respiratory syncytial virus-like illness among adults aged at least 60 years without immunocompromising conditions, vaccine effectiveness was 80% (95% CI 71-85) against respiratory syncytial virus-associated hospitalisations, and vaccine effectiveness was 81% (52-92) against respiratory syncytial virus-associated critical illness (ICU admission or death, or both). Among 8435 hospitalisations for respiratory syncytial virus-like illness among adults with immunocompromising conditions, vaccine effectiveness was 73% (48-85) against associated hospitalisation. Among 36 521 emergency department encounters for respiratory syncytial virus-like illness among adults aged at least 60 years without an immunocompromising condition, vaccine effectiveness was 77% (70-83) against respiratory syncytial virus-associated emergency department encounters. Vaccine effectiveness estimates were similar by age group and product type. INTERPRETATION: Respiratory syncytial virus vaccination was effective in preventing respiratory syncytial virus-associated hospitalisations and emergency department encounters among adults aged at least 60 years in the USA during the 2023-24 respiratory syncytial virus season, which was the first season after respiratory syncytial virus vaccine was approved. FUNDING: The Centers for Disease Control and Prevention.

Identification and epidemiological analysis of a putative novel hantavirus in Australian flying foxes.

In July 2017, an investigation into the cause of neurological signs in a black flying fox (Pteropus alecto, family Pteropodidae) identified a putative novel hantavirus (Robina virus, ROBV, order Bunyavirales, family Hantaviridae, genus Mobatvirus) in its brain. Analysis of the evolutionary relationship between other hantaviruses using maximum-likelihood, a systematic Bayesian clustering approach, and a minimum spanning tree, all suggest that ROBV is most closely related to another Mobatvirus, Quezon virus, previously identified in the lung of a Philippine frugivorous bat (Rousettus amplexicaudatus, also family Pteropodidae). Subsequently, between March 2018 and October 2023, a total of 495 bats were opportunistically screened for ROBV with an experimental qRT-PCR. The total prevalence of ROBV RNA detected in Pteropus spp. was 4.2% (95% CI 2.8-6.4%). Binomial modelling identified that there was substantial evidence supporting an increase (P = 0.033) in the detection of ROBV RNA in bats in 2019 and 2020 suggesting of a possible transient epidemic. There was also moderate evidence to support the effect of season (P = 0.064), with peak detection in the cooler seasons, autumn, and winter, possibly driven by physiological and ecological factors similar to those already identified for other bat-borne viruses. This is Australia's first reported putative hantavirus and its identification could expand the southern known range of hantaviruses in Australasia.

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.

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.

Effect of temperature and humidity on insect DNA integrity evaluated by real-time PCR.

Insects collected in dry traps can degrade rapidly, especially in warm, humid environments where many biodiversity and biosecurity surveillance activities are undertaken. Degradation can severely impact diagnostics, as trap catches can become difficult to identify to species level using morphological characters or, of increasing importance, molecular approaches. This is especially problematic for biosecurity surveillance of exotic tephritid fruit flies, where diagnostics are heavily reliant on morphological characters. We tested the effects of differing temperature and humidity conditions on mock samples of tephritid fruit flies in a controlled environment and compared our results to field trap catches. DNA degradation was quantified using real-time PCR assays, including one assay newly developed and tested here. We observed a correlation between increasing DNA degradation and increasing temperature and humidity. The greatest DNA degradation occurred under combined high humidity (90% relative humidity) and constant high temperature (35 °C). Unexpectedly, fluctuating temperature did not have a significant impact on DNA. Other factors, such as trap design, time in the field, and rainfall, did not significantly correlate with DNA quality across the field samples tested. When plotted against mock samples, field samples clustered together, with no clear pattern or predictability regarding the quantity of DNA preserved, indicating other untested environmental variables may be at play. Predictably, increased exposure time was found to have a detrimental effect on DNA quality for all treatments. These findings will improve the delivery of surveillance activities through the implementation of shorter trap clearance timeframes and improved trap designs and procedures.

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.

The impact of successful chronic total occlusion percutaneous coronary intervention on clinical outcomes: a tertiary single-center analysis.

Background: The benefit of chronic total occlusion (CTO)-percutaneous coronary intervention (PCI) is controversial because of a lack of high-quality evidence. We aim to evaluate the impact of CTO-PCI on symptoms, quality of life and mortality. Methods: We conducted a retrospective single center study of patients with CTO-PCI in a tertiary center in Austria. The study outcomes were Canadian Cardiovascular Society (CCS) angina score, quality of life measured by Seattle Angina Questionnaire (SAQ), and death at median follow up for patients with successful vs. failed CTO-PCI. Results: A total of 300 patients underwent CTO-PCI for coronary artery disease, of which 252 (84%) were technically successful with median follow up of 3.4 years. There were no significant differences in in-hospital or all-cause mortality, major adverse cardiovascular event, or stent-related complications between the groups of failed and successful CTO-PCI. Among patients with successful CTO-PCI there was a significant improvement in CCS score, which was not found for the group with failed CTO-PCI. Successful reopening was associated with significant benefits of the SAQ domains of angina with stressful activity [3.7 ± 0.9 vs. 3.1 ± 0.5, p = 0.004, use of nitrates (4.7 ± 0.5 vs. 3.0 ± 1.0) p = 0.005] and satisfaction from angina relief (4.4 ± 1.1 vs. 3.6 ± 1.4 p < 0.001). Conclusion: While there was no significant difference in mortality, successful CTO-PCI was associated with greater reduction in angina and the use of nitrates compared to unsuccessful CTO-PCI.

A Machine Learning Method for Allocating Scarce COVID-19 Monoclonal Antibodies.

Importance: During the COVID-19 pandemic, the effective distribution of limited treatments became a crucial policy goal. Yet, limited research exists using electronic health record data and machine learning techniques, such as policy learning trees (PLTs), to optimize the distribution of scarce therapeutics. Objective: To evaluate whether a machine learning PLT-based method of scarce resource allocation optimizes the treatment benefit of COVID-19 neutralizing monoclonal antibodies (mAbs) during periods of resource constraint. Design, Setting, and Participants: This retrospective cohort study used electronic health record data from October 1, 2021, to December 11, 2021, for the training cohort and data from June 1, 2021, to October 1, 2021, for the testing cohort. The cohorts included patients who had positive test results for SARS-CoV-2 and qualified for COVID-19 mAb therapy based on the US Food and Drug Administration's emergency use authorization criteria, ascertained from the patient electronic health record. Only some of the qualifying candidates received treatment with mAbs. Data were analyzed between from January 2023 to May 2024. Main Outcomes and Measures: The primary outcome was overall expected hospitalization, assessed as the potential reduction in overall expected hospitalization if the PLT-based allocation system was used. This was compared to observed allocation using risk differences. Results: Among 9542 eligible patients in the training cohort (5418 female [56.8%]; age distribution: 18-44 years, 4151 [43.5%]; 45-64 years, 3146 [33.0%]; and ≥65 years, 2245 [23.5%]), a total of 3862 (40.5%) received mAbs. Among 6248 eligible patients in the testing cohort (3416 female [54.7%]; age distribution: 18-44 years, 2827 [45.2%]; 45-64 years, 1927 [30.8%]; and ≥65 years, 1494 [23.9%]), a total of 1329 (21.3%) received mAbs. Treatment allocation using the trained PLT model led to an estimated 1.6% reduction (95% CI, -2.0% to -1.2%) in overall expected hospitalization compared to observed treatment allocation in the testing cohort. The visual assessment showed that the PLT-based point system had a larger reduction in 28-day hospitalization compared with the Monoclonal Antibody Screening Score (maximum overall hospitalization difference, -1.0% [95% CI, -1.3% to -0.7%]) in the testing cohort. Conclusions and Relevance: This retrospective cohort study proposes and tests a PLT method, which can be linked to a electronic health record data platform to improve real-time allocation of scarce treatments. Use of this PLT-based allocation method would have likely resulted in fewer hospitalizations across a population than were observed in usual care, with greater expected reductions than a commonly used point system.

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.