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BackgroundThe Critical Assessment of Genome Interpretation (CAGI) aims to advance the state-of-the-art for computational prediction of genetic variant impact, particularly where relevant to disease. The five complete editions of the CAGI community experiment comprised 50 challenges, in which participants made blind predictions of phenotypes from genetic data, and these were evaluated by independent assessors.ResultsPerformance was particularly strong for clinical pathogenic variants, including some difficult-to-diagnose cases, and extends to interpretation of cancer-related variants. Missense variant interpretation methods were able to estimate biochemical effects with increasing accuracy. Assessment of methods for regulatory variants and complex trait disease risk was less definitive and indicates performance potentially suitable for auxiliary use in the clinic.ConclusionsResults show that while current methods are imperfect, they have major utility for research and clinical applications. Emerging methods and increasingly large, robust datasets for training and assessment promise further progress ahead.

Abstract Background Endothelial glycocalyx (EG) degradation occurs in septic humans and EG products can be used as biomarkers of endothelial injury. Information about EG biomarkers and their association with disease severity is lacking in hospitalized foals. Objectives Measure serum syndecan‐1 (SDC‐1), heparan sulfate (HS), angiopoietin‐2 (ANG‐2), aldosterone (ALD), and plasma atrial natriuretic peptide (ANP) concentrations and to determine their association with disease severity and death in hospitalized foals. Animals Ninety foals ≤3 days old. Methods Prospective, multicenter, longitudinal study. Foals were categorized into hospitalized (n = 74; 55 septic; 19 sick nonseptic) and 16 healthy foals. Serum ([SDC‐1], [HS], [ANG‐2], [ALD]) and plasma (ANP) were measured over 72 hours using immunoassays. Results Serum ([SDC‐1], [HS], [ANG‐2], [ALD]) and plasma (ANP) were significantly higher in hospitalized and septic than healthy foals (P 58.7 ng/mL had higher odds of nonsurvival (odds ratio [OR] = 6.1; 95% confidence interval [CI] = 1.02‐36.7). Plasma (ANP) >11.5 pg/mL was associated with the likelihood of nonsurvival in hospitalized foals (OR = 7.2; 95% CI = 1.4‐37.4; P 1018 pg/mL on admission had higher odds of nonsurvival (OR = 6.5; 95% CI =1.2‐36.6; P

Abstract Background Improving palliative care for inpatients is urgently needed. Data from patient-reported experience measures (PREM) can assist in identifying areas for focused improvement. This study aimed to describe patient reported experience of care in inpatients with palliative care needs, to inform a baseline understanding of care experience and identify key areas for improvement. Methods Cross-sectional study design where inpatients with palliative care needs were invited to complete ‘consideRATE,’ a patient reported experience measure of care, over six months in 2022. Inpatients with palliative care needs receiving care on an oncology, general medicine/renal and general medicine/respiratory ward (n = 3) at an Australian metropolitan hospital were screened for eligibility. Carers could provide proxy responses where inpatients were unable to participate. Descriptive statistics were used to analyse quantitative ratings, whilst free text responses were analysed using integrated thematic analysis. Results One-hundred and twenty participants (108 patients and 12 carers) completed consideRATE. The questions with the highest number of ‘very good’ responses were attention to symptoms, attention to feelings and attention to what matters most; the questions with the lowest number of ‘very good’ responses was attention to patients’ affairs, what to expect, and the environment of care. Almost half (n = 57, 48%) indicated that attention to patients’ affairs ‘did not apply’ to their inpatient stay. Analysis of 532 free text responses across 8 questions highlighted the importance of feeling supported, feeling informed, feeling heard and navigating the clinical environment. Conclusion Enabling inpatients with palliative care needs to provide feedback about their experience of care is one method of ensuring improvements matter to patients. Supporting clinical teams to understand and use these data to make tailored improvements is the next step in this multi-phase research.

Mitigation practices for nitrogen leaching losses from livestock agriculture are needed to protect freshwater quality and increase the efficiency of agricultural production. Within New Zealand, the most common pasture type is a two-species mix of perennial ryegrass (Lolium perenne) and white clover (Trifolium repens). Ecological theory suggests that increasing species and functional diversity improves ecosystem function, including nitrogen (N) retention. Use of more diverse pasture types, including a mix of pasture grasses, legumes and other forbs, particularly plantain (Plantago lanceolata), with functional traits, including winter activity, deep-rooting, N fixation, and biological inhibition of nitrification in the soil, is a potential mitigation practice that requires further verification with long-term field measurements. Here we utilize a network of large lysimeters to make field-based measurements of N leaching from 5–8 species diverse pasture, including plantain, under a range of soil, climate and management conditions, for comparison with losses from traditional ryegrass-clover pasture. Over 3 years of measurements, leaching from fully established diverse pasture was 2–80 kg N ha−1 y−1. No differences were observed in dry matter production or N leaching of diverse pasture compared to ryegrass-clover lysimeters. Large losses, up to 120 kg N ha−1, were observed during periods when pasture was not fully established, including cultivation and sowing of new pasture, depending on season. Timing of management activities could be optimized to minimize these losses. These data provide critical assessment of diverse pasture as a mitigation approach for reducing N losses. Further work on diverse pastures should include higher diversity mixes as well as consideration of animal mediated effects of diverse pasture diets on N inputs.

Significant efforts have been made to characterize the biophysical properties of proteins. Small proteins have received less attention because their annotation has historically been less reliable. However, recent improvements in sequencing, proteomics, and bioinformatics techniques have led to the high-confidence annotation of small open reading frames (smORFs) that encode for functional proteins, producing smORF-encoded proteins (SEPs). SEPs have been found to perform critical functions in several species, including humans. While significant efforts have been made to annotate SEPs, less attention has been given to the biophysical properties of these proteins. We characterized the distributions of predicted and curated biophysical properties, including sequence composition, structure, localization, function, and disease association of a conservative list of previously identified human SEPs. We found significant differences between SEPs and both larger proteins and control sets. In addition, we provide an example of how our characterization of biophysical properties can contribute to distinguishing protein-coding smORFs from noncoding ones in otherwise ambiguous cases.

Understanding how genetic variants impact molecular phenotypes is a key goal of functional genomics, currently hindered by reliance on a single haploid reference genome. Here, we present the EN-TEx resource of 1,635 open-access datasets from four donors (∼30 tissues × ∼15 assays). The datasets are mapped to matched, diploid genomes with long-read phasing and structural variants, instantiating a catalog of >1 million allele-specific loci. These loci exhibit coordinated activity along haplotypes and are less conserved than corresponding, non-allele-specific ones. Surprisingly, a deep-learning transformer model can predict the allele-specific activity based only on local nucleotide-sequence context, highlighting the importance of transcription-factor-binding motifs particularly sensitive to variants. Furthermore, combining EN-TEx with existing genome annotations reveals strong associations between allele-specific and GWAS loci. It also enables models for transferring known eQTLs to difficult-to-profile tissues (e.g., from skin to heart). Overall, EN-TEx provides rich data and generalizable models for more accurate personal functional genomics.

Abstract Cobalamin, vitamin B12, is an important micronutrient that has been investigated for decades in the marine context because it is required for phytoplankton growth. The biologically active forms (Me‐B12, Ado‐B12) and the synthetic form (CN‐B12) quickly convert to OH‐B12 after light exposure in various aqueous solutions, but puzzlingly have been frequently reported to dominate dissolved cobalamin pools in the sunlit ocean. Here, we document photodegradation timescales for these cobalamin forms in natural seawater using targeted mass spectrometry, providing quantitative evidence that OH‐B12 is expected to be the dominant dissolved form in irradiated seawater. Then, through high‐resolution mass spectrometry, we identify four photodegradation products of OH‐B12 which represent potential building blocks microbes could salvage and remodel to satisfy cellular cobalamin requirements. Taken together, these results clarify the impact of light on marine cobalamin dynamics, laying a foundation for a more quantitative understanding of the role of cobalamin in microbial communities and biogeochemical cycles.

Abstract Background Tunnelled cuffed haemodialysis catheters are at increased risk of incarceration or becoming ‘stuck’ via fibrotic adhesion to the central veins when left in situ for prolonged periods of time. Stuck catheters cannot be removed using standard techniques such as bedside dissection of the cuff. Whilst there are several strategies published for the removal of these incarcerated lines, there is no consensus on the best approach. Here we present a challenging case of a stuck haemodialysis catheter in the acute post transplantation period. Case Presentation A 66-year-old female on haemodialysis presented for kidney transplantation with a tunnelled-cuffed haemodialysis catheter in situ for five years. Following transplantation, removal of the line was unsuccessful despite dissection of the cuff, with traction causing a choking sensation with tracheal movement. Eventually, the line was removed without complications utilising sequential balloon dilatation by interventional radiology and the patient was discharged without complications. Conclusions This case serves as a timely reminder of the risks of long-term tunnelled haemodialysis catheters and as a caution towards proceeding with kidney transplantation in those with long-term haemodialysis catheters in situ. Greater nephrologist awareness of interventional radiology techniques for this challenging situation will help to avoid more invasive strategies. The risks of a stuck catheter should be included in the discussions about the optimal vascular access and transplantation suitability for a given patient.

Objectives This scoping review aimed to identify and critically appraise resources for health professionals to identify, diagnose, refer, and support individuals with fetal alcohol spectrum disorder (FASD)—including the extent to which the resources are appropriate for use in communities with First Nations Peoples.Method Seven peer-reviewed databases (April 2022) and 14 grey literature websites (August 2022) were searched. The reference lists of all sources that underwent full-text review were handsearched, and FASD experts were consulted for additional sources. Resources were assessed using the Appraisal of Guidelines for REsearch and Evaluation II instrument and an adapted version of the National Health and Medical Research Council FORM Framework and iCAHE Guideline Quality Checklist.Results A total of 41 resources underwent data extraction and critical appraisal, as screening and/or diagnosis guidelines were excluded because they are covered in other reviews. Most were recently published or updated (n=24), developed in the USA (n=15, 36.6%) or Australia (n=12, 29.3%) and assisted with FASD patient referral or support (n=40). Most management guidelines scored 76%–100% on overall quality assessment (n=5/9) and were recommended for use in the Australian context with modifications (n=7/9). Most of the guides (n=15/22) and factsheets (n=7/10) received a ‘good’ overall score. Few (n=3/41) resources were explicitly designed for or with input from First Nations Australians.Conclusion High-quality resources are available to support health professionals providing referrals and support to individuals with FASD, including language guides. Resources should be codesigned with people living with FASD to capture and integrate their knowledge and preferences.

Octopus fisheries face heightened demand driven by depleted fish stocks and escalating economic value, leading to overextraction of octopus populations and magnifying threats to coastal ecosystems and the livelihoods of fishers who depend on them. Implementation of management strategies such as periodic fishing closures can offer sanctuary for octopus, providing the necessary space and time for the growth and reproduction of this rapidly proliferating species. Despite evidence of positive management outcomes, the role of periodic closures in the long-term sustainability of octopus populations remains uncertain. Here, we examine trends in octopus landings over time and the effects of periodic closures along the Mozambique Channel from Comoros to Madagascar (12°-25°S). Long-term trends in octopus landings varied across three regions: generally stable over a 6-year period in Comoros, increasing over a 4-year period in the Barren Isles and declining over a 17-year period in Atsimo Andrefana, Madagascar. We observed a significant increase in mean catch per unit effort (CPUE, kilograms/fisher-day), and mean total catch (kilograms/day) following periodic closures across villages extracting octopus from closure areas. When evaluating each region independently, we observed this positive effect across Comoros and Atsimo Andrefana, Madagascar while trends in the Barren Isles showed no effect of octopus closures. We applied generalized linear mixed models to examine the influence of 10 covariates on mean daily total catch and CPUE within 7 days and 30 days post-closure. Baseline conditions (quantified by the pre-closure CPUE and daily total catch), closure duration and start month of closure had positive, statistically significant correlations with post-closure CPUE and daily total catch. Additionally, closure duration from 13 to 16 weeks and closure size of approximately 70 hectares were qualitatively associated with net gains in CPUE. Although periodic closures yield positive outcomes for octopus fisheries, the effects may be short-lived, as observed in Atsimo Andrefana, Madagascar, where catch declined over the long-term despite temporary improvements. Our findings underscore a need for a diverse portfolio of management strategies to restore and sustain populations over the long-term.

AbstractCuban bulrush (Oxycaryum cubense [Poepp. & Kunth] Lye) is an invasive floating aquatic plant that causes negative ecological and economic impacts in the southeastern United States. Temperatures in the United States have increased over recent decades which can result in geographic expansion of invasive plants in North America. Accumulated degree-days (ADD) were utilized to develop predictive models (state and regional models) for Cuban bulrush growth from harvested biomass collected over one year in Mississippi, Louisiana, and Florida. Peak emergent biomass occurred from early to mid-fall (September-October) with growth continuing into winter. Accumulated degree days needed for Cuban bulrush to reach peak emergent biomass ranged from 6,469 (Mississippi), 7111 (regional), 7,643 (Florida), and 7,903 (Louisiana). Calendar days needed for Cuban bulrush to reach peak emergent biomass ranged from 292 (Mississippi) to 334 (Florida). Base temperature thresholds for Cuban bulrush were −6 C, −3 C, −3 C, and −2 C for Mississippi, Louisiana, regional, and Florida models respectively. The models suggest Cuban bulrush has a tolerance to lower air temperatures that could allow for survival in moderate winter conditions. Overall, model predictability was less accurate for populations further south (Florida) due to warmer winter temperatures, year-round growth, and difficulty defining when peak emergent biomass occurred. Results from this study indicate that Cuban bulrush growth is greater in warmer temperatures, though low base temperature thresholds suggest this species may be capable of expanding its invaded range to cooler climates beyond the southeastern United States.

Abstract Background The Promoting Action on Research Implementation in Health Services (PARIHS) and integrated-PARIHS (i-PARIHS) frameworks position facilitation as an overarching strategy to enable implementation. In the revised i-PARIHS framework, facilitation is operationalised through a multi-level model with novice, experienced and expert facilitators working together in a network structure to build facilitation knowledge and skills along a continuum. To date, there has been limited evaluation of this facilitation model in practice, which is the aim of the study reported here. Methods A descriptive, qualitative longitudinal study was undertaken to track a team of four novice and two experienced facilitators involved in facilitating the implementation of an intervention known as ‘Eat Walk Engage’ to improve multidisciplinary team delivery of age-friendly care principles in hospital. Over an 18-month period, repeat interviews were conducted to explore the learning, development, and evolving roles of novice facilitators and the roles of the experienced facilitators in providing support and mentoring. Interview data were analysed using a descriptive qualitative approach and findings were interpreted in collaboration with the participating facilitators. Results The findings demonstrated experiential learning in both the novice and experienced facilitator groups as they enacted their roles in practice. The novice facilitators progressively transitioned to becoming more experienced facilitators and the experienced facilitators became increasingly expert, in line with the i-PARIHS concept of a facilitation journey from novice to expert. Strategies to support this development included a staggered approach to learning, regular meetings between the experienced and novice facilitators, reflective writing and informal peer support and networking. However, the roles were not without challenge and these challenges changed over time, from a more specific focus on the demands of the facilitator role to concerns about embedding and sustaining improvements in practice. Conclusions Within a network of peers and a mentored relationship with more experienced facilitators, individuals who are new to an implementation facilitator role can transition along a continuum to become experienced facilitators. Building implementation facilitation capability in this way takes time and requires tailored support and mentorship using a mix of structured and flexible approaches incorporating opportunities for reflection to support individual and group learning.

Historians typically explain the Marshall Plan (1948–52) as an effect of a bipartisan embrace of liberal internationalism, which became the dominant ideology of US foreign policy. However, predominant accounts downplay interpretive contention, historical contingencies, and counterfactual possibilities that are very much in evidence. There was no bipartisan liberal internationalist consensus immediately after World War II; indeed, there were no “liberal internationalists” until 1947. The present analysis identifies two interconnected processes behind the Plan: the emergence of a new kind of political actor, the credibly anti-Communist New Deal liberal, and the coalescence of an unlikely coalition of Trumanites, New Dealers, and congressional conservatives. Together, these processes enabled the passage of a large-scale, Keynesian-style spending initiative that excluded Russia, despite the electoral weakness of New Dealers, and the consolidation of liberal internationalist ideology in American foreign policy—with significance for today's era of renewed great power competition.

Abstract Anthropogenic climate change is intensifying natural disturbance regimes, which negatively affects some species, while benefiting others. This could alter the trait composition of ecological communities and influence resilience to disturbance. We investigated how the frequency and intensification of the regional storm regime (and likely other disturbances) is altering coral species composition and in turn resistance and recovery. We developed regional databases of coral cover and composition (3144 reef locations from 1970 to 2017) and of the path and strength of cyclonic storms in the region (including 10,058 unique storm-reef intersections). We found that total living coral cover declined steadily through 2017 (the median annual loss rate was ~ 0.25% per year). Our results also indicate that despite the observed increase in the intensity of Atlantic cyclonic storms, their effect on coral cover has decreased markedly. This could be due in part to selection for disturbance-resistant taxa in response to the intensifying disturbance regime. We found that storms accelerated the loss of threatened acroporid corals but had no measurable effect on the cover of more resilient “weedy” corals, thereby increasing their relative cover. Although resistance to disturbance has increased, recovery rates have slowed due to the dominance of small, slow-growing species. This feedback loop is locking coral communities into a low-functioning state dominated by weedy species with limited ecological or societal value.

Abstract Background Older inpatients are at high risk of hospital-associated complications, particularly delirium and functional decline. These can be mitigated by consistent attention to age-friendly care practices such as early mobility, adequate nutrition and hydration, and meaningful cognitive and social activities. Eat Walk Engage is a ward-based improvement programme theoretically informed by the i-PARIHS framework which significantly reduced delirium in a four-hospital cluster trial. The objective of this process evaluation was to understand how Eat Walk Engage worked across trial sites. Methods Prospective multi-method implementation evaluation on medical and surgical wards in four hospitals implementing Eat Walk Engage January 2016-May 2017. Using UK Medical Research Council guidance, this process evaluation assessed context, implementation (core components, implementation strategies and improvements) and mechanisms of impact (practice changes measured through older person interviews, structured mealtime observations and activity mapping) at each site. Results The four wards had varied contextual barriers which altered dynamically with time. One ward with complex outer organisational barriers showed poorer implementation and fewer practice changes. Two experienced facilitators supported four novice site facilitators through interactive training and structured reflection as well as data management, networking and organisational influence. Novice site facilitators used many implementation strategies to facilitate 45 discrete improvements at individual, team and system level. Patient interviews (42 before and 38 after implementation) showed better communication about program goals in three sites. Observations of 283 meals before and 297 after implementation showed improvements in mealtime positioning and assistance in all sites. Activity mapping in 85 patients before and 111 patients after implementation showed improvements in cognitive and social engagement in three sites, but inconsistent changes in mobility. The improvements in mealtime care and cognitive and social engagement are plausible mediators of reduced delirium observed in the trial. The lack of consistent mobility improvements may explain why the trial did not show reduction in functional decline. Conclusions A multi-level enabling facilitation approach supported adaptive implementation to varied contexts to support mechanisms of impact which partly achieved the programme goals. Contexts changed over time, suggesting the need for adequate time and continued facilitation to embed, enhance and sustain age-friendly practices on acute care wards and optimise outcomes. Trial registration The CHERISH trial was prospectively registered with the ANZCTR ( http://www.anzctr.org.au ): ACTRN12615000879561.