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Cooperation is prevalent across bacteria, but risks being exploited by non-cooperative cheats. Horizontal gene transfer, particularly via plasmids, has been suggested as a mechanism to stabilize cooperation. A key prediction of this hypothesis is that genes which are more likely to be transferred, such as those on plasmids, should be more likely to code for cooperative traits. Testing this prediction requires identifying all genes for cooperation in bacterial genomes. However, previous studies used a method which likely misses some of these genes for cooperation. To solve this, we used a new genomics tool, SOCfinder, which uses three distinct modules to identify all kinds of genes for cooperation. We compared where these genes were located across 4648 genomes from 146 bacterial species. In contrast to the prediction of the hypothesis, we found no evidence that plasmid genes are more likely to code for cooperative traits. Instead, we found the opposite-that genes for cooperation were more likely to be carried on chromosomes. Overall, the vast majority of genes for cooperation are not located on plasmids, suggesting that the more general mechanism of kin selection is sufficient to explain the prevalence of cooperation across bacteria.

Aim: Marine biodiversity faces unprecedented threats from anthropogenic climate change. Ecosystem responses to climate change have exhibited substantial variability in the direction and magnitude of redistribution, posing challenges for developing effective climate-adaptive marine management strategies. Location: The California Current Ecosystem (CCE), USA. Methods: We project suitable habitat for 10 highly migratory species in the California Current System using an ensemble of three high-resolution (~10 km) downscaled ocean projections under the Representative Concentration Pathway 8.5 (RCP8.5). Spanning the period from 1980 to 2100, our analysis focuses on assessing the direction and distance of distributional shifts, as well as changes in core habitat area for each species. Results: Our findings reveal a divergent response among species to climate impacts. Specifically, four species were projected to undergo significant poleward shifts exceeding 100 km, and gain habitat (~7%–60%) in response to climate change. Conversely, six species were projected to shift towards the coast, resulting in a loss of habitat ranging from 10% to 66% by the end of the century. These divergent responses could typically be characterized by the mode of thermoregulation (i.e. ectotherm vs. endotherm) and species' affiliations with cool and productive upwelled waters that are characteristic of the region. Furthermore, our study highlights an increase in niche overlap between protected species and those targeted by fisheries, which may lead to increased human interaction events under climate change. Main Conclusions: By providing valuable species distribution projections, our research contributes to the understanding of climate change effects on marine biodiversity and offers critical insight and support for developing climate-ready management of protected and fished species.

2022 marked the third consecutive La Niña and extended the longest consecutive stretch of negative Oceanic Niño Index since 1998-2001. While physical and biological conditions in winter and spring largely adhered to prior La Niña conditions, summer and fall were very different. Similar to past La Niña events, in winter and spring coastal upwelling was either average or above average, temperature average or below average, salinity generally above average. In summer and fall, however, upwelling and temperature were generally average or slightly below average, salinity was close to average and chlorophyll a was close to average. Again, as during prior La Niña events, biomass of northern/southern copepods was above/below average off Oregon in winter, and body size of North Pacific krill in northern California was above average in winter. By contrast, later in the year the abundance of northern krill dropped off Oregon while southern copepods increased and body sizes of North Pacific krill fell in northern California. Off Oregon and Washington abundances of market squid and Pacific pompano (indicators of warm, non-typical La Niña conditions) were high. In the 20th century, Northern anchovy recruitment tended to be high during cold conditions, but despite mostly warm conditions from 2015-2021 anchovy populations boomed and remained high in 2022. Resident seabird reproductive success, which tended in the past to increase during productive La Niña conditions was highly variable throughout the system as common murre and pelagic cormorant, experienced complete reproductive failure at Yaquina Head, Oregon while Brandt’s cormorant reproduction was average. At three sampling locations off central California, however, common murre reproduction was close to or above average while both pelagic and Brandt’s cormorant were above average. California sealion reproduction has been above average each year since 2016, and pup weight was also above average in 2022, likely in response not to La Niña or El Niño but continuous high abundance of anchovy. The highly variable and often unpredictable physical and biological conditions in 2022 highlight a growing recognition of disconnects between basin-scale indices and local conditions in the CCE. “July-December 2022 is the biggest outlier from individual “strong” La Niña (events) ever going back to the 50s.” – Nate Mantua

BackgroundDespite evidence associating inflammatory biomarkers with worse outcomes in hospitalized adults with COVID-19, trials of immunomodulatory therapies have met with mixed results, likely due in part to biological heterogeneity of participants. Latent class analysis (LCA) of clinical and protein biomarker data has identified two subtypes of non-COVID acute respiratory distress syndrome (ARDS) with different clinical outcomes and treatment responses. We studied biological heterogeneity and clinical outcomes in a multi-institutional platform randomized controlled trial of adults with severe COVID-19 hypoxemic respiratory failure (I-SPY COVID).MethodsClinical and plasma protein biomarker data were analyzed from 400 trial participants enrolled from September 2020 until October 2021 with severe COVID-19 requiring ≥ 6 L/min supplemental oxygen. Seventeen hypothesis-directed protein biomarkers were measured at enrollment using multiplex Luminex panels or single analyte enzyme linked immunoassay methods (ELISA). Biomarkers and clinical variables were used to test for latent subtypes and longitudinal biomarker changes by subtype were explored. A validated parsimonious model using interleukin-8, bicarbonate, and protein C was used for comparison with non-COVID hyper- and hypo-inflammatory ARDS subtypes.ResultsAverage participant age was 60 ± 14 years; 67% were male, and 28-day mortality was 25%. At trial enrollment, 85% of participants required high flow oxygen or non-invasive ventilation, and 97% were receiving dexamethasone. Several biomarkers of inflammation (IL-6, IL-8, IL-10, sTNFR-1, TREM-1), epithelial injury (sRAGE), and endothelial injury (Ang-1, thrombomodulin) were associated with 28- and 60-day mortality. Two latent subtypes were identified. Subtype 2 (27% of participants) was characterized by persistent derangements in biomarkers of inflammation, endothelial and epithelial injury, and disordered coagulation and had twice the mortality rate compared with Subtype 1. Only one person was classified as hyper-inflammatory using the previously validated non-COVID ARDS model.ConclusionsWe discovered evidence of two novel biological subtypes of severe COVID-19 with significantly different clinical outcomes. These subtypes differed from previously established hyper- and hypo-inflammatory non-COVID subtypes of ARDS. Biological heterogeneity may explain inconsistent findings from trials of hospitalized patients with COVID-19 and guide treatment approaches.

Abstract Thermophily is a trait scattered across the fungal tree of life, with its highest prevalence within three fungal families (Chaetomiaceae, Thermoascaceae, and Trichocomaceae), as well as some members of the phylum Mucoromycota. We examined 37 thermophilic and thermotolerant species and 42 mesophilic species for this study and identified thermophily as the ancestral state of all three prominent families of thermophilic fungi. Thermophilic fungal genomes were found to encode various thermostable enzymes, including carbohydrate-active enzymes such as endoxylanases, which are useful for many industrial applications. At the same time, the overall gene counts, especially in gene families responsible for microbial defense such as secondary metabolism, are reduced in thermophiles compared to mesophiles. We also found a reduction in the core genome size of thermophiles in both the Chaetomiaceae family and the Eurotiomycetes class. The Gene Ontology terms lost in thermophilic fungi include primary metabolism, transporters, UV response, and O-methyltransferases. Comparative genomics analysis also revealed higher GC content in the third base of codons (GC3) and a lower effective number of codons in fungal thermophiles than in both thermotolerant and mesophilic fungi. Furthermore, using the Support Vector Machine classifier, we identified several Pfam domains capable of discriminating between genomes of thermophiles and mesophiles with 94% accuracy. Using AlphaFold2 to predict protein structures of endoxylanases (GH10), we built a similarity network based on the structures. We found that the number of disulfide bonds appears important for protein structure, and the network clusters based on protein structures correlate with the optimal activity temperature. Thus, comparative genomics offers new insights into the biology, adaptation, and evolutionary history of thermophilic fungi while providing a parts list for bioengineering applications.

This single-participant idiographic study examines the implications of a student's identity crisis in the climate classroom through the lens of existential phenomenology. The study analyses the ontological sense-making process of a mixed-race, bisexual female student reckoning with the racial dimensions of climate change during an environmental course in a liberal arts college in the Netherlands. By delving into the ontological implications of the participant's experience of the course, the analysis shows that environmental education can meaningfully impact the mind-body relationship and self-identification of students with marginalized identities. The findings challenge some of the assumptions of popular frameworks for understanding marginalization in environmental education, like intersectionality, and post-humanist perspectives. The authors conclude that attending to human sense-making in environmental education can benefit students with marginalized identities by grounding environmental education in practices that make space for these identities.

Large predators frequent the open ocean where subsurface light drives visually based trophic interactions. However, we lack knowledge on how predators achieve energy balance in the unproductive open ocean where prey biomass is minimal in well-lit surface waters but high in dim midwaters in the form of scattering layers. We use an interdisciplinary approach to assess how the bioenergetics of scattering layer forays by a model predator vary across biomes. We show that the mean metabolic cost rate of daytime deep foraging dives to scattering layers decreases as much as 26% from coastal to pelagic biomes. The more favorable energetics offshore are enabled by the addition of a shallow scattering layer that, if not present, would otherwise necessitate costlier dives to deeper layers. The unprecedented importance of this shallow scattering layer challenges assumptions that the globally ubiquitous primary deep scattering layer constitutes the only mesopelagic resource regularly targeted by apex predators.

Juvenile North Pacific Albacore tuna (Thunnus alalunga) support commercial and recreational fisheries in the California Current Large Marine Ecosystem (CCLME), where they forage during summer and fall. The distributions of the commercial and recreational fisheries and estimates of forage availability have varied substantially over the past century. Time-series quantifying Albacore diet can help link forage composition to variability in Albacore abundance and distribution and, consequently, their availability to fishers. Previous diet studies in the CCLME are of relatively short duration, and long-term variability in Albacore diet remains poorly understood. We describe the diets of juvenile Albacore from three regions in the CCLME from 2007 to 2019 and use classification and regression tree analysis to explore environmental drivers of variability. Important prey include Northern Anchovy (Engraulis mordax), rockfishes (Sebastes spp.), Boreal Clubhook Squid (Onychoteuthis borealijaponica), euphausiids (Order: Euphausiidae), and amphipods (Order: Amphipoda), each contributing >5% mean proportional abundance. Most prey items were short lived species or young-of-the-year smaller than 10 cm. Diet variability was related to environmental conditions over the first 6 months of the year (PDO, sea surface temperature, and NPGO) and conditions concurrent with Albacore capture (region and surface nitrate flux). We describe foraging flexibility over regional and annual scales associated with these environmental influences. Continuous, long-term studies offer the opportunity to identify flexibility in Albacore foraging behavior and begin to make a predictive link between environmental conditions early in the year and Albacore foraging during summer and fall.

The Far-INfrarEd Spectrometer for Surface Emissivity (FINESSE) instrument combines a commercial Bruker EM27 spectrometer with a front-end viewing and calibration rig developed at Imperial College London. FINESSE is specifically designed to enable accurate measurements of surface emissivity, covering the range 400–1600 cm−1, and, as part of this remit, can obtain views over the full 360° angular range. In this part, Part 1, we describe the system configuration, outlining the instrument spectral characteristics, our data acquisition methodology, and the calibration strategy. As part of the process, we evaluate the stability of the system, including the impact of knowledge of blackbody (BB) target emissivity and temperature. We also establish a numerical description of the instrument line shape (ILS), which shows strong frequency-dependent asymmetry. We demonstrate why it is important to account for these effects by assessing their impact on the overall uncertainty budget on the level 1 radiance products from FINESSE. Initial comparisons of observed spectra with simulations show encouraging performance given the uncertainty budget.

Studies have demonstrated that at least 20% of individuals infected with SARS-CoV-2 remain asymptomatic1-4. Although most global efforts have focused on severe illness in COVID-19, examining asymptomatic infection provides a unique opportunity to consider early immunological features that promote rapid viral clearance. Here, postulating that variation in the human leukocyte antigen (HLA) loci may underly processes mediating asymptomatic infection, we enrolled 29,947 individuals, for whom high-resolution HLA genotyping data were available, in a smartphone-based study designed to track COVID-19 symptoms and outcomes. Our discovery cohort (n = 1,428) comprised unvaccinated individuals who reported a positive test result for SARS-CoV-2. We tested for association of five HLA loci with disease course and identified a strong association between HLA-B*15:01 and asymptomatic infection, observed in two independent cohorts. Suggesting that this genetic association is due to pre-existing T cell immunity, we show that T cells from pre-pandemic samples from individuals carrying HLA-B*15:01 were reactive to the immunodominant SARS-CoV-2 S-derived peptide NQKLIANQF. The majority of the reactive T cells displayed a memory phenotype, were highly polyfunctional and were cross-reactive to a peptide derived from seasonal coronaviruses. The crystal structure of HLA-B*15:01-peptide complexes demonstrates that the peptides NQKLIANQF and NQKLIANAF (from OC43-CoV and HKU1-CoV) share a similar ability to be stabilized and presented by HLA-B*15:01. Finally, we show that the structural similarity of the peptides underpins T cell cross-reactivity of high-affinity public T cell receptors, providing the molecular basis for HLA-B*15:01-mediated pre-existing immunity.

It has been hypothesized that horizontal gene transfer on plasmids can facilitate the evolution of cooperation, by allowing genes to jump between bacteria, and hence increase genetic relatedness at the cooperative loci. However, we show theoretically that horizontal gene transfer only appreciably increases relatedness when plasmids are rare, where there are many plasmid-free cells available to infect (many opportunities for horizontal gene transfer). In contrast, when plasmids are common, there are few opportunities for horizontal gene transfer, meaning relatedness is not appreciably increased, and so cooperation is not favored. Plasmids, therefore, evolve to be rare and cooperative, or common and noncooperative, meaning plasmid frequency and cooperativeness are never simultaneously high. The overall level of plasmid-mediated cooperation, given by the product of plasmid frequency and cooperativeness, is therefore consistently negligible or low.

Abstract The Gulf Stream's (GS) impact on the marine boundary layer (MBL) is well established, yet the mechanisms and timescales through which it affects the upper‐troposphere and contributes to precipitation are debatable. Using a high‐resolution regional atmospheric model, we shed light on the impact of ocean intrinsic variability (OIV) along GS on midlatitude‐atmosphere. Taking advantage of a 24‐member ensemble of ocean model integrations, we devised a novel experimental setup where the same weather system feels different realizations of GS sea surface temperature (SST). We introduce the “Eddy Recharge‐Frontal Lift” (ERFL) mechanism, highlighting the joint importance of synoptic variability and boundary layer processes. ERFL mechanism proposes that OIV recharges/discharges MBL with moisture and heat, while convergence associated with passing atmospheric‐fronts uplifts these MBL‐trapped anomalies to upper‐troposphere and imprints on precipitation in surprisingly short periods (a month). The impact of OIV on precipitation depends on the background mean SST.

We present a case report of a 55-year-old woman who had a femoral vein intravascular papillary endothelial hyperplasia that required excision of the mass and subsequent repair of the right femoral vein using her right anterior accessory saphenous vein. She first presented with findings of a non-occlusive deep vein thrombus. However, after 6 months of persistent and enlarging mass with subsequent intravascular component on a follow-up duplex scan, a decision was made to bring her to the operating room for exploration and excision.

BackgroundLimited data are available describing the effects of SARS-CoV-2 breakthrough infections on the plasma proteome.MethodsPCR-positive SARS-CoV-2 patients, enrolled in a natural history study, underwent analysis of the plasma proteome. A prospective cohort of 66 unvaccinated and 24 vaccinated persons with different degrees of infection severity were evaluated acutely (within 40 days of symptom onset), and at three and ten months. Comparisons based on vaccination status alone and unsupervised hierarchical clustering were performed. A second cohort of vaccinated Omicron patients were evaluated acutely and at ten months.ResultsAcutely, unvaccinated patients manifested overexpression of proteins involved in immune and inflammatory responses, while vaccinated patients exhibited adaptive immune responses without significant inflammation. At three and ten months, only unvaccinated patients had diminished but sustained inflammatory (C3b, CCL15, IL17RE) and immune responses (DEFA5,TREM1). Both groups had underexpression of pathways essential for cellular function, signaling, and angiogenesis (AKT1, MAPK14, HSPB1) across phases. Unsupervised clustering, based on protein expression, identified four groups of patients with variable vaccination rates demonstrating that additional clinical factors influence the plasma proteome. The proteome of vaccinated Omicron patients did not differ from vaccinated pre-Omicron patients.ConclusionsVaccination attenuates the inflammatory response to SARS-CoV-2 infection across phases. However, at ten months after symptom onset, changes in the plasma proteome persist in both vaccinated and unvaccinated individuals, which may be relevant to post-acute sequelae of SARS-CoV-2 and other viral infections associated with post-acute infection syndromes.

BACKGROUND: The first epidemic wave of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in Scotland resulted in high case numbers and mortality in care homes. In Lothian, over one-third of care homes reported an outbreak, while there was limited testing of hospital patients discharged to care homes. AIM: To investigate patients discharged from hospitals as a source of SARS-CoV-2 introduction into care homes during the first epidemic wave. METHODS: A clinical review was performed for all patients discharges from hospitals to care homes from 1st March 2020 to 31st May 2020. Episodes were ruled out based on coronavirus disease 2019 (COVID-19) test history, clinical assessment at discharge, whole-genome sequencing (WGS) data and an infectious period of 14 days. Clinical samples were processed for WGS, and consensus genomes generated were used for analysis using Cluster Investigation and Virus Epidemiological Tool software. Patient timelines were obtained using electronic hospital records. FINDINGS: In total, 787 patients discharged from hospitals to care homes were identified. Of these, 776 (99%) were ruled out for subsequent introduction of SARS-CoV-2 into care homes. However, for 10 episodes, the results were inconclusive as there was low genomic diversity in consensus genomes or no sequencing data were available. Only one discharge episode had a genomic, time and location link to positive cases during hospital admission, leading to 10 positive cases in their care home. CONCLUSION: The majority of patients discharged from hospitals were ruled out for introduction of SARS-CoV-2 into care homes, highlighting the importance of screening all new admissions when faced with a novel emerging virus and no available vaccine.

Abstract Background The National Health Service in England aims to implement tobacco dependency treatment services in all hospitals by 2024. We aimed to assess the uptake of a new service, adapted from the Ottawa Model of Smoking Cessation, and its impact on 6-month quit rates and readmission or death at 1-year follow-up. Methods We conducted a pragmatic service evaluation of a tobacco dependency service implemented among 2067 patients who smoked who were admitted to 2 acute hospitals in London, England, over a 12-month period from July 2020. The intervention consisted of the systematic identification of smoking status, automatic referral to tobacco dependence specialists, provision of pharmacotherapy and behavioural support throughout the hospital stay, and telephone support for 6 months after discharge. The outcomes were (i) patient acceptance of the intervention during admission, (ii) quit success at 6 months after discharge, (iii) death, or (iv) readmission up to 1 year following discharge. Multivariable logistic regression was used to estimate the impact of a range of clinical and demographic variables on these outcomes. Results The majority (79.4%) of patients accepted support at the first assessment. Six months after discharge, 35.1% of successfully contacted patients reported having quit smoking. After adjustment, odds of accepting support were 51–61% higher among patients of all non-White ethnicity groups, relative to White patients, but patients of Mixed, Asian, or Other ethnicities had decreased odds of quit success (adjusted odds ratio (AOR) = 0.32, 95%CI = 0.15–0.66). Decreased odds of accepting support were associated with a diagnosis of cardiovascular disease or diabetes; however, diabetes was associated with increased odds of quit success (AOR = 1.88, 95%CI = 1.17–3.04). Intention to make a quit attempt was associated with a threefold increase in odds of quit success, and 60% lower odds of death, compared to patients who did not intend to quit. A mental health diagnosis was associated with an 84% increase in the odds of dying within 12 months. Conclusions The overall quit rates were similar to results from Ottawa models implemented elsewhere, although outcomes varied by site. Outcomes also varied according to patient demographics and diagnoses, suggesting personalised and culturally tailored interventions may be needed to optimise quit success.

SoTL has been embraced as a viable approach to professional development for higher education faculty. Workshops and programs of various types and lengths have offered guidance and provided mentorship for SoTL novices. Many books, manuals, and websites describe how to undertake a SoTL investigation, but far fewer sources of advice exist for those assisting faculty beginning in SoTL. In this article, two Carnegie scholars reflect on their experiences and lessons learned helping others join the SoTL community. They discuss common characteristics of the new scholars they encountered and the types of assistance, both intellectual and institutional, that the scholars needed. They offer advice and suggest resources for working with new SoTL scholars and describe some of the benefits that accrue from this work.

The challenges of conducting hyperacute stroke research and obtaining informed consent have been increasingly recognized within the stroke research community in recent years. Deferral of consent, in which a patient is enrolled in a trial and then provides consent at some point thereafter, is increasingly used to enroll patients into hyperacute stroke trials in Canada and Europe, although it is not permitted in the United States. Deferral of consent offers several potential advantages-quicker door-to-randomization, increased enrolment, decreased selection bias-but these must be balanced against the risk of enrolling patients against their wishes. We seek to minimize the attendant risks of deferral of consent by offering practical guidance regarding how to conduct acute stroke trials using deferral of consent. Building on existing guidelines and recent experiences with deferral of consent in acute stroke trials, we have developed a protocol for the use of deferral of consent that aims to maximize patient involvement while minimizing ethical and scientific risks.

Background Cerebral small vessel disease is associated with higher ratios of soluble-epoxide hydrolase derived linoleic acid diols (12,13-dihydroxyoctadecenoic acid [DiHOME] and 9,10-DiHOME) to their parent epoxides (12(13)-epoxyoctadecenoic acid [EpOME] and 9(10)-EpOME); however, the relationship has not yet been examined in stroke. Methods and Results Participants with mild to moderate small vessel stroke or large vessel stroke were selected based on clinical and imaging criteria. Metabolites were quantified by ultra-high-performance liquid chromatography-mass spectrometry. Volumes of stroke, lacunes, white matter hyperintensities, magnetic resonance imaging visible perivascular spaces, and free water diffusion were quantified from structural and diffusion magnetic resonance imaging (3 Tesla). Adjusted linear regression models were used for analysis. Compared with participants with large vessel stroke (n=30), participants with small vessel stroke (n=50) had a higher 12,13-DiHOME/12(13)-EpOME ratio (β=0.251, P=0.023). The 12,13-DiHOME/12(13)-EpOME ratio was associated with more lacunes (β=0.266, P=0.028) but not with large vessel stroke volumes. Ratios of 12,13-DiHOME/12(13)-EpOME and 9,10-DiHOME/9(10)-EpOME were associated with greater volumes of white matter hyperintensities (β=0.364, P

Introduction: Understanding how abundance, productivity and distribution of individual species may respond to climate change is a critical first step towards anticipating alterations in marine ecosystem structure and function, as well as developing strategies to adapt to the full range of potential changes. Methods: This study applies the NOAA (National Oceanic and Atmospheric Administration) Fisheries Climate Vulnerability Assessment method to 64 federally-managed species in the California Current Large Marine Ecosystem to assess their vulnerability to climate change, where vulnerability is a function of a species’ exposure to environmental change and its biological sensitivity to a set of environmental conditions, which includes components of its resiliency and adaptive capacity to respond to these new conditions. Results: Overall, two-thirds of the species were judged to have Moderate or greater vulnerability to climate change, and only one species was anticipated to have a positive response. Species classified as Highly or Very Highly vulnerable share one or more characteristics including: 1) having complex life histories that utilize a wide range of freshwater and marine habitats; 2) having habitat specialization, particularly for areas that are likely to experience increased hypoxia; 3) having long lifespans and low population growth rates; and/or 4) being of high commercial value combined with impacts from non-climate stressors such as anthropogenic habitat degradation. Species with Low or Moderate vulnerability are either habitat generalists, occupy deep-water habitats or are highly mobile and likely to shift their ranges. Discussion: As climate-related changes intensify, this work provides key information for both scientists and managers as they address the long-term sustainability of fisheries in the region. This information can inform near-term advice for prioritizing species-level data collection and research on climate impacts, help managers to determine when and where a precautionary approach might be warranted, in harvest or other management decisions, and help identify habitats or life history stages that might be especially effective to protect or restore.

IntroductionEquipoise, generally defined as uncertainty about the relative effects of the treatments being compared in a trial, is frequently referenced as an ethical standard for the conduct of randomized clinical trials. However, it seems to be defined in several different ways and may be used differently by different individuals. We explored how clinical researchers, chairs of research ethics boards, and philosophers of science define and reason with this term.MethodsWe completed semi-structured interviews about clinical trial ethics with 15 clinical researchers, 15 research ethics board chairs, and 15 philosophers of science/bioethicists. Each participant was asked a standardized set of 10 questions, 4 of which were specifically about equipoise. All interviews were conducted telephonically and transcribed. Responses were grouped and analysed via a modified grounded theory method.ResultsForty-three respondents defined equipoise in 7 logically distinct ways, and 2 respondents could not explicitly define it. The most common definition, offered by 14 respondents (31%), defined "equipoise" as a disagreement at the level of a community of physicians. There was significant variability in definitions offered between and within groups. When asked how they would "operationalize" equipoise - i.e. check or test for its presence - respondents provided 7 alternatives, the most common being in relation to a literature review (15/45, 33%). The vast majority of respondents (35/45, 78%) felt the concept was helpful, though many acknowledged that the lack of a clear definition or operationalization was problematic.ConclusionThere is significant variation in definitions of equipoise offered by respondents, suggesting that parties within groups and between groups may be referring to different concepts when they reference "equipoise". This non-uniformity may impact fairness and transparency and opens the door to potential ethical problems in the evaluation of clinical trials - for instance, a patient may understand equipoise very differently than the researchers enrolling her in a trial, which could cause her agreement to participate to be based upon false premises.

Objectives This study aims to show whether correlation exists between pediatric residency applicants’ quantitative scores on the United States Medical Licensing Exam Step 2 Clinical Knowledge examination and their subsequent performance in residency training based on the Accreditation Council for Graduate Medical Education Milestones, which are competency-based assessments that aim to determine residents’ ability to work unsupervised after postgraduate training. No previous literature has correlated Step 2 Clinical Knowledge scores with pediatric residency performance assessed by Milestones. Methods In this retrospective cohort study, the United States Medical Licensing Exam Step 2 Clinical Knowledge Scores and Milestones data were collected from all 188 residents enrolled in a single categorical pediatric residency program from 2012 - 2017. Pearson correlation coefficients were calculated amongst available test and milestone data points to determine correlation between test scores and clinical performance. Results Using Pearson correlation coefficients, no significant correlation was found between quantitative scores on the Step 2 Clinical Knowledge exam and average Milestones ratings (r = -0.1 for post-graduate year 1 residents and r = 0.25 for post-graduate year 3 residents). Conclusions These results demonstrate that Step 2 scores have no correlation to success in residency training as measured by progression along competency-based Milestones. This information should limit the importance residency programs place on quantitative Step 2 scores in their ranking of residency applicants. Future studies should include multiple residency programs across multiple specialties to help make these findings more generalizable.

Background The long-term outcomes of COVID-19 hospitalisation in individuals with pre-existing airway diseases are unknown. Methods Adult participants hospitalised for confirmed or clinically suspected COVID-19 and discharged between 5 March 2020 and 31 March 2021 were recruited to the Post-hospitalisation COVID-19 (PHOSP-COVID) study. Participants attended research visits at 5 months and 1 year post discharge. Clinical characteristics, perceived recovery, burden of symptoms and health-related quality of life (HRQoL) of individuals with pre-existing airway disease (i.e., asthma, COPD or bronchiectasis) were compared to the non-airways group. Results A total of 615 out of 2697 (22.8%) participants had a history of pre-existing airway diseases (72.0% diagnosed with asthma, 22.9% COPD and 5.1% bronchiectasis). At 1 year, the airways group participants were less likely to feel fully recovered (20.4% versus 33.2%, p

Objective: To describe the health characteristics, condition-specific measures, chronic disease risk factors, and healthcare and medication use over time of individuals with musculoskeletal conditions awaiting orthopaedic surgical consultation. Study importance: Musculoskeletal conditions are highly prevalent in the general population and often coexist with chronic diseases. However, little is documented about the overall health of this group. This study describes the health of these individuals, with particular emphasis on modifiable risk factors of chronic disease. Study type: A repeated measures longitudinal cohort study of individuals referred for orthopaedic consultation across three time points (2014, 2015 and 2016). Methods: This study was undertaken in the orthopaedic outpatient service of a public tertiary referral hospital in New South Wales, Australia. Participants were aged 18 years and older and were referred for and awaiting orthopaedic surgical consultation for a musculoskeletal condition (back, neck, hand or wrist pain, or hip or knee osteoarthritis). Measures included patient demographics, condition-specific indicators (e.g. pain, disability, quality of life [QoL]) and chronic disease risk factors (e.g., excess weight, smoking). Results: The mean age of participants was 57.7 years, and 7.3% identified as Aboriginal and/or Torres Strait Islander. Back (43.1%) and knee (35.0%) pain were the most prevalent conditions. At baseline (N = 1052), participants reported moderate pain (mean numerical pain rating scale score of 6.4, standard deviation [SD] 2.4) and QoL (Physical Component Score of 32.7, SD 10.7; Mental Component Score of 46.6, SD 13.3). Chronic disease risk factors were highly prevalent, with 74.6% of participants having three or more. For most measures, there were only small changes over time. Conclusion: Individuals with musculoskeletal conditions who are awaiting orthopaedic surgical consultation have a complex clinical picture and numerous chronic disease risk factors. Given the modifiable nature of many of these risk factors, identifying and addressing them before or while awaiting consultation may improve the health of these individuals.

Background: This study evaluates the impact of Real-Time Prescription Benefits (RTPB), a tool integrated into electronic health records (EHRs), on patient out-of-pocket costs in an academic institution. RTPB provides prescribers with alternative, less expensive medications based on insurance plans. The primary measure was cost-savings, defined as the difference between the out-of-pocket cost of the prescribed medication and its alternative. Methods: A retrospective analysis of prescriptions from outpatient clinics in a university-based health system was conducted between May 2020 and July 2021. Prescriptions were analyzed at the 2nd level of the Anatomical Therapeutic Chemical (ATC) classification system. Costs were standardized to a 30-day supply. Standardized cost and total cost per prescription, and overall savings for the top 20 medication classes at the 2nd ATC level were calculated. The overall impact of RTPB was estimated based on selecting the least expensive alternative suggested by RTPB. Results: The study found that RTPB information was provided for 22% of prescriptions, with suggested alternatives for 1.26%. Among prescriptions with an alternative selected, the standardized average cost saving was $38.83. The study realized $15,416 in patient total cost savings. If the least expensive RTPB-suggested alternative were chosen for all prescriptions, an estimated $276,386 could have been saved. Psychoanaleptic and psycholeptic medications were the most prescribed with an alternative, with most savings in specialty drugs like anthelmintic and immunostimulant medications. Conclusion: The study highlights the importance of RTPB in reducing patient costs. It reports patient cost-savings with RTPB in prescribing decisions. Future research could explore the impact of RTPB on medication adherence using pharmacy claims data.

BackgroundLevels of plasma SARS-CoV-2 nucleocapsid (N) antigen may be an important biomarker in patients with COVID-19 and enhance our understanding of the pathogenesis of COVID-19.ObjectiveTo evaluate whether levels of plasma antigen can predict short-term clinical outcomes and identify clinical and viral factors associated with plasma antigen levels in hospitalized patients with SARS-CoV-2.DesignCross-sectional study of baseline plasma antigen level from 2540 participants enrolled in the TICO (Therapeutics for Inpatients With COVID-19) platform trial from August 2020 to November 2021, with additional data on day 5 outcome and time to discharge.Setting114 centers in 10 countries.ParticipantsAdults hospitalized for acute SARS-CoV-2 infection with 12 days or less of symptoms.MeasurementsBaseline plasma viral N antigen level was measured at a central laboratory. Delta variant status was determined from baseline nasal swabs using reverse transcriptase polymerase chain reaction. Associations between baseline patient characteristics and viral factors and baseline plasma antigen levels were assessed using both unadjusted and multivariable modeling. Association between elevated baseline antigen level of 1000 ng/L or greater and outcomes, including worsening of ordinal pulmonary scale at day 5 and time to hospital discharge, were evaluated using logistic regression and Fine-Gray regression models, respectively.ResultsPlasma antigen was below the level of quantification in 5% of participants at enrollment, and 1000 ng/L or greater in 57%. Baseline pulmonary severity of illness was strongly associated with plasma antigen level, with mean plasma antigen level 3.10-fold higher among those requiring noninvasive ventilation or high-flow nasal cannula compared with room air (95% CI, 2.22 to 4.34). Plasma antigen level was higher in those who lacked antispike antibodies (6.42 fold; CI, 5.37 to 7.66) and in those with the Delta variant (1.73 fold; CI, 1.41 to 2.13). Additional factors associated with higher baseline antigen level included male sex, shorter time since hospital admission, decreased days of remdesivir, and renal impairment. In contrast, race, ethnicity, body mass index, and immunocompromising conditions were not associated with plasma antigen levels. Plasma antigen level of 1000 ng/L or greater was associated with a markedly higher odds of worsened pulmonary status at day 5 (odds ratio, 5.06 [CI, 3.41 to 7.50]) and longer time to hospital discharge (median, 7 vs. 4 days; subhazard ratio, 0.51 [CI, 0.45 to 0.57]), with subhazard ratios similar across all levels of baseline pulmonary severity.LimitationsPlasma samples were drawn at enrollment, not hospital presentation. No point-of-care test to measure plasma antigen is currently available.ConclusionElevated plasma antigen is highly associated with both severity of pulmonary illness and clinically important patient outcomes. Multiple clinical and viral factors are associated with plasma antigen level at presentation. These data support a potential role of ongoing viral replication in the pathogenesis of SARS-CoV-2 in hospitalized patients.Primary funding sourceU.S. government Operation Warp Speed and National Institute of Allergy and Infectious Diseases.