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Abstract Culture-based microbial natural product discovery strategies fail to realize the extraordinary biosynthetic potential detected across earth’s microbiomes. Here we introduce Small Molecule In situ Resin Capture (SMIRC), a culture-independent method to obtain natural products directly from the environments in which they are produced. We use SMIRC to capture numerous compounds including two new carbon skeletons that were characterized using NMR and contain structural features that are, to the best of our knowledge, unprecedented among natural products. Applications across diverse marine habitats reveal biome-specific metabolomic signatures and levels of chemical diversity in concordance with sequence-based predictions. Expanded deployments, in situ cultivation, and metagenomics facilitate compound discovery, enhance yields, and link compounds to candidate producing organisms, although microbial community complexity creates challenges for the later. This compound-first approach to natural product discovery provides access to poorly explored chemical space and has implications for drug discovery and the detection of chemically mediated biotic interactions.

Abstract Background This study presents guidelines for implementation distilled from the findings of a realist evaluation. The setting was local health districts in New South Wales, Australia that implemented three clinical improvement initiatives as part of a state-wide program. We focussed on implementation strategies designed to develop health professionals’ capability to deliver value-based care initiatives for multisite programs. Capability, which increases implementers’ ability to cope with unexpected scenarios is key to managing change. Methods We used a mixed methods realist evaluation which tested and refined program theories elucidating the complex dynamic between context (C), mechanism (M) and outcome (O) to determine what works, for whom, under what circumstances. Data was drawn from program documents, a realist synthesis, informal discussions with implementation designers, and interviews with 10 key informants (out of 37 identified) from seven sites. Data analysis employed a retroductive approach to interrogate the causal factors identified as contributors to outcomes. Results CMO statements were refined for four initial program theories: Making it Relevant– where participation in activities was increased when targeted to the needs of the staff; Investment in Quality Improvement– where engagement in capability development was enhanced when it was valued by all levels of the organisation; Turnover and Capability Loss– where the effects of staff turnover were mitigated; and Community-Wide Priority– where there was a strategy of spanning sites. From these data five guiding principles for implementers were distilled: (1) Involve all levels of the health system to effectively implement large-scale capability development, (2) Design capability development activities in a way that supports a learning culture, (3) Plan capability development activities with staff turnover in mind, (4) Increased capability should be distributed across teams to avoid bottlenecks in workflows and the risk of losing key staff, (5) Foster cross-site collaboration to focus effort, reduce variation in practice and promote greater cohesion in patient care. Conclusions A key implementation strategy for interventions to standardise high quality practice is development of clinical capability. We illustrate how leadership support, attention to staff turnover patterns, and making activities relevant to current issues, can lead to an emergent learning culture.

Cells expressing features of senescence, including upregulation of p21 and p16, appear transiently following tissue injury, yet the properties of these cells or how they contrast with age-induced senescent cells remains unclear. Here, we used skeletal injury as a model and identified the rapid appearance following fracture of [p21.sup.+] cells expressing senescence markers, mainly as osteochondroprogenitors (OCHs) and neutrophils. Targeted genetic clearance of [p21.sup.+] cells suppressed senescence-associated signatures within the fracture callus and accelerated fracture healing. By contrast, [p21.sup.+] cell clearance did not alter bone loss due to aging; conversely, [p16.sup.+] cell clearance, known to alleviate skeletal aging, did not affect fracture healing. Following fracture, [p21.sup.+] neutrophils were enriched in signaling pathways known to induce paracrine stromal senescence, while [p21.sup.+] OCHs were highly enriched in senescence-associated secretory phenotype factors known to impair bone formation. Further analysis revealed an injury-specific stem cell-like OCH subset that was [p21.sup.+] and highly inflammatory, with a similar inflammatory mesenchymal population (fibro-adipogenic progenitors) evident following muscle injury. Thus, intercommunicating senescent-like neutrophils and mesenchymal progenitor cells were key regulators of tissue repair in bone and potentially across tissues. Moreover, our findings established contextual roles of [p21.sup.+] versus [p16.sup.+] senescent/ senescent-like cells that may be leveraged for therapeutic opportunities., Introduction At the cellular level, aging is characterized by several hallmarks, including cellular senescence (1), which is driven by an increase in the cyclin-dependent kinase inhibitors Cdknla (p21) and/or Cdknla [...]

Introduction Familial hypercholesterolaemia (FH) is an autosomal dominant inherited disorder of lipid metabolism and a preventable cause of premature cardiovascular disease. Current detection rates for this highly treatable condition are low. Early detection and management of FH can significantly reduce cardiac morbidity and mortality. This study aims to implement a primary-tertiary shared care model to improve detection rates for FH. The primary objective is to evaluate the implementation of a shared care model and support package for genetic testing of FH. This protocol describes the design and methods used to evaluate the implementation of the shared care model and support package to improve the detection of FH.Methods and analysis This mixed methods pre-post implementation study design will be used to evaluate increased detection rates for FH in the tertiary and primary care setting. The primary-tertiary shared care model will be implemented at NSW Health Pathology and Sydney Local Health District in NSW, Australia, over a 12-month period. Implementation of the shared care model will be evaluated using a modification of the implementation outcome taxonomy and will focus on the acceptability, evidence of delivery, appropriateness, feasibility, fidelity, implementation cost and timely initiation of the intervention. Quantitative pre-post and qualitative semistructured interview data will be collected. It is anticipated that data relating to at least 62 index patients will be collected over this period and a similar number obtained for the historical group for the quantitative data. We anticipate conducting approximately 20 interviews for the qualitative data.Ethics and dissemination Ethical approval has been granted by the ethics review committee (Royal Prince Alfred Hospital Zone) of the Sydney Local Health District (Protocol ID: X23-0239). Findings will be disseminated through peer-reviewed publications, conference presentations and an end-of-study research report to stakeholders.

Familial hypercholesterolaemia (FH), a common monogenic disorder, is a preventable cause of premature coronary artery disease and death. Up to 35 million people worldwide have FH, but most remain undetected and undertreated. Several clinical guidelines have addressed the gaps in care of FH, but little focus has been given to implementation science and practice. The International Atherosclerosis Society (IAS) has developed an evidence-informed guidance for the detection and management of patients with FH, supplemented with implementation strategies to optimize contextual models of care. The guidance is partitioned into detection, management and implementation sections. Detection deals with screening, diagnosis, genetic testing and counselling. Management includes risk stratification, treatment of adults and children with heterozygous and homozygous FH, management of FH during pregnancy, and use of lipoprotein apheresis. Specific and general implementation strategies, guided by processes specified by the Expert Recommendations for Implementing Change taxonomy, are provided. Core generic implementation strategies are given for improving care. Nation-specific cholesterol awareness campaigns should be utilized to promote better detection of FH. Integrated models of care should be underpinned by health policy and adapted to meet local, regional and national needs. Clinical centres of excellence are important for taking referrals from the community. General practitioners should work seamlessly with multidisciplinary teams. All health-care providers must receive training in essential skills for caring for patients and families with FH. Management should be supported by shared decision-making and service improvement driven by patient-reported outcomes. Improvements in services require sharing of existing resources that can support care. Advocacy should be utilized to ensure sustainable funding. Digital health technologies and clinical quality registries have special value. Finally, academic-service partnerships need to be developed to identify gaps in care and set priorities for research. This new IAS guidance on FH complements the recent World Heart Federation Cholesterol Roadmap.

A reduced kinetic method (RKM) with a first-principles collision operator is introduced in a 1D2V planar geometry and implemented in a computationally inexpensive code to investigate non-local ion heat transport in multi-species plasmas. The RKM successfully reproduces local results for multi-species ion systems and the important features expected to arise due to non-local effects on the heat flux are captured. In addition to this, novel features associated with multi-species, as opposed to single species, cases are found. Effects of non-locality on the heat flux are investigated in mass and charge symmetric and asymmetric ion mixtures with temperature, pressure, and concentration gradients. In particular, the enthalpy flux associated with diffusion is found to be insensitive to sharp pressure and concentration gradients, increasing its significance in comparison to the conductive heat flux driven by temperature gradients in non-local scenarios. The RKM code can be used for investigating other kinetic and non-local effects in a broader plasma physics context. Due to its relatively low computational cost it can also serve as a practical non-local ion heat flux closure in hydrodynamic simulations or as a training tool for machine learning surrogates. [ABSTRACT FROM AUTHOR]

Culture-based microbial natural product discovery strategies fail to realize the extraordinary biosynthetic potential detected across earth's microbiomes. Here we introduce Small Molecule In situ Resin Capture (SMIRC), a culture-independent method to obtain natural products directly from the environments in which they are produced. We use SMIRC to capture numerous compounds including two new carbon skeletons that were characterized using NMR and contain structural features that are, to the best of our knowledge, unprecedented among natural products. Applications across diverse marine habitats reveal biome-specific metabolomic signatures and levels of chemical diversity in concordance with sequence-based predictions. Expanded deployments, in situ cultivation, and metagenomics facilitate compound discovery, enhance yields, and link compounds to candidate producing organisms, although microbial community complexity creates challenges for the later. This compound-first approach to natural product discovery provides access to poorly explored chemical space and has implications for drug discovery and the detection of chemically mediated biotic interactions. Environmental analyses predict extensive, yet to be realized natural product diversity. Herein, the authors report an approach that directly captures natural products from the environment, circumventing previous challenges and yielding compounds with unusual structures and activities. [ABSTRACT FROM AUTHOR]

Our constitutional law of religious liberty is a riot of principles: principles of freedom of conscience, neutrality, separation of church and state, and others. To resolve concrete disputes, we must identify what those principles are and how they could ever jointly deliver singular answers to constitutional questions. Furthermore, to identify what the principles are, we must grasp what makes them so. This Article aims to meet these three needs. It clarifies what grounds our constitutional principles, sketches what our constitutional principles of religious liberty are today, and explains how the law could ever lie decisively on the side of one litigant or rule over another when individual principles point in opposite directions. It develops and tests its claims by analyzing two questions at the law’s frontiers: whether free exercise principles support a constitutional entitlement to exemption from antidiscrimination obligations beyond what free speech principles alone mandate, and whether publicly chartered religious schools are constitutionally permitted, required, or prohibited. This is an investigation into the constitutional law of religious liberty, of course. But two of the three essential tasks it tackles—explaining how our principles are what they are and how multiple principles could ever provide determinate legal answers to contested constitutional questions— are critical across all regions of constitutional law. Accordingly, this Article examines the constitutional law of religious liberty both for its own sake and as a window into the fundamental elements and mechanics of American constitutional law generally. Its central arguments are that principles are the building blocks of our constitutional law, that they change organically as legal practices and commitments change, and that they can yield singular constitutional facts or rules despite their plurality. [ABSTRACT FROM AUTHOR]

Background This study presents guidelines for implementation distilled from the findings of a realist evaluation. The setting was local health districts in New South Wales, Australia that implemented three clinical improvement initiatives as part of a state-wide program. We focussed on implementation strategies designed to develop health professionals’ capability to deliver value-based care initiatives for multisite programs. Capability, which increases implementers’ ability to cope with unexpected scenarios is key to managing change. Methods We used a mixed methods realist evaluation which tested and refined program theories elucidating the complex dynamic between context (C), mechanism (M) and outcome (O) to determine what works, for whom, under what circumstances. Data was drawn from program documents, a realist synthesis, informal discussions with implementation designers, and interviews with 10 key informants (out of 37 identified) from seven sites. Data analysis employed a retroductive approach to interrogate the causal factors identified as contributors to outcomes. Results CMO statements were refined for four initial program theories: Making it Relevant– where participation in activities was increased when targeted to the needs of the staff; Investment in Quality Improvement– where engagement in capability development was enhanced when it was valued by all levels of the organisation; Turnover and Capability Loss– where the effects of staff turnover were mitigated; and Community-Wide Priority– where there was a strategy of spanning sites. From these data five guiding principles for implementers were distilled: (1) Involve all levels of the health system to effectively implement large-scale capability development, (2) Design capability development activities in a way that supports a learning culture, (3) Plan capability development activities with staff turnover in mind, (4) Increased capability should be distributed across teams to avoid bottlenecks in workflows and the risk of losing key staff, (5) Foster cross-site collaboration to focus effort, reduce variation in practice and promote greater cohesion in patient care. Conclusions A key implementation strategy for interventions to standardise high quality practice is development of clinical capability. We illustrate how leadership support, attention to staff turnover patterns, and making activities relevant to current issues, can lead to an emergent learning culture. [ABSTRACT FROM AUTHOR]

Sea turtles are vulnerable to climate change since their reproductive output is influenced by incubating temperatures, with warmer temperatures causing lower hatching success and increased feminization of embryos. Their ability to cope with projected increases in ambient temperatures will depend on their capacity to adapt to shifts in climatic regimes. Here, we assessed the extent to which phenological shifts could mitigate impacts from increases in ambient temperatures (from 1.5 to 3°C in air temperatures and from 1.4 to 2.3°C in sea surface temperatures by 2100 at our sites) on four species of sea turtles, under a "middle of the road" scenario (SSP2‐4.5). Sand temperatures at sea turtle nesting sites are projected to increase from 0.58 to 4.17°C by 2100 and expected shifts in nesting of 26–43 days earlier will not be sufficient to maintain current incubation temperatures at 7 (29%) of our sites, hatching success rates at 10 (42%) of our sites, with current trends in hatchling sex ratio being able to be maintained at half of the sites. We also calculated the phenological shifts that would be required (both backward for an earlier shift in nesting and forward for a later shift) to keep up with present‐day incubation temperatures, hatching success rates, and sex ratios. The required shifts backward in nesting for incubation temperatures ranged from −20 to −191 days, whereas the required shifts forward ranged from +54 to +180 days. However, for half of the sites, no matter the shift the median incubation temperature will always be warmer than the 75th percentile of current ranges. Given that phenological shifts will not be able to ameliorate predicted changes in temperature, hatching success and sex ratio at most sites, turtles may need to use other adaptive responses and/or there is the need to enhance sea turtle resilience to climate warming. [ABSTRACT FROM AUTHOR]

Conservation reintroductions play a vital role in the recovery of threatened species, and clear goals and objectives are essential for evaluating their effectiveness. In this study, we assessed short‐term success (<18 months) of trial reintroductions of the Extinct in the Wild blue‐tailed skink (Cryptoblepharus egeriae) and Lister's gecko (Lepidodactylus listeri) on Christmas Island. Our evaluation criteria focused on body condition, reproduction, habitat suitability, survival and population growth. In 2018 and 2019, 170 C. egeriae and 160 L. listeri were translocated from a local captive breeding facility to a 2600 m2 outdoor fenced enclosure designed to exclude a predatory snake. Despite body condition declining immediately following release for both species, it had improved by 6 months post‐release. We also detected successful reproduction in both species. Apparent survival was high for C. egeriae but low for L. listeri, and population growth was only evident in C. egeriae. We were unable to determine whether low survival of L. listeri in the release site was due to high post‐release dispersal (beyond the exclosure) or mortality. Both species selected habitats that contained high rock and log cover and avoided areas with low ground cover. Appropriate assessment criteria, as utilized in this study, enable objective and timely evaluations of reintroduction success, thereby facilitating the improvement and refinement of reintroduction protocols. Our study showed that C. egeriae can establish (in the short‐ to medium‐term) in a site from which a principal threat has been excluded and undergo rapid population growth, whereas under current conditions L. listeri cannot. However, we also demonstrate that such medium‐term success may not lead to long‐term success, as the rapid increase in C. egeriae population was reversed between 29 and 31 months after release because the barrier used to exclude an invasive predator, the wolf snake (Lycodon capucinus), was breached. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effects of aging on phenylbutazone (PBZ) disposition in older horses (≥ 25 years old) compared to young adults (4 to 10 years old) by characterizing the pharmacokinetic profile of PBZ and its active metabolite, oxyphenbutazone (OPBZ), following a 2.2-mg/kg dose, IV. We hypothesized that the disposition of PBZ will be affected by age., Animals: 16 healthy horses (8 young adults aged 4 to 10 years and 8 geriatric horses ≥ 25 years old)., Methods: Horses were administered a single 2.2-mg/kg PBZ dose, IV. Plasma samples were collected at designated time points and frozen at -80 °C until assayed using liquid chromatography-tandem mass spectrometry. Pharmacokinetic analyses were performed using Phoenix WinNonlin, version 8.0 (Certara). Both clinical and pharmacokinetic data were compared between age groups using independent samples t tests, with P < .05 considered significant., Results: Baseline characteristics did not differ between groups, with the exception of age, weight, and plasma total solids. Plasma concentrations of PBZ were best described by a two-compartment model. The maximum plasma concentration of OPBZ was reached at 5 hours for both age groups, and the metabolite-to-parent-drug area-under-the-curve ratios were approximately 20% for both groups. None of the pharmacokinetic parameters of PBZ or its metabolite, OPBZ, differed significantly between age groups., Clinical Relevance: The hypothesis was rejected as there was no significant difference in PBZ disposition in young-adult horses compared to geriatric horses. Our data do not support the need for dose adjustments of PBZ in clinically healthy geriatric horses.

Morphogenesis is the process whereby the body of an organism develops its target shape. The morphogen BMP is known to play a conserved role across bilaterian organisms in determining the dorsoventral (DV) axis. Yet, how BMP governs the spatio-temporal dynamics of cytoskeletal proteins driving morphogenetic flow remains an open question. Here, we use machine learning to mine a morphodynamic atlas of Drosophila development, and construct a mathematical model capable of predicting the coupled dynamics of myosin, E-cadherin, and morphogenetic flow. Mutant analysis shows that BMP sets the initial condition of this dynamical system according to the following signaling cascade: BMP establishes DV pair-rule-gene patterns that set-up an E-cadherin gradient which in turn creates a myosin gradient in the opposite direction through mechanochemical feedbacks. Using neural tube organoids, we argue that BMP, and the signaling cascade it triggers, prime the conserved dynamics of neuroectoderm morphogenesis from fly to humans.

Introduction: Familial hypercholesterolaemia (FH) is an autosomal dominant inherited disorder of lipid metabolism and a preventable cause of premature cardiovascular disease. Current detection rates for this highly treatable condition are low. Early detection and management of FH can significantly reduce cardiac morbidity and mortality. This study aims to implement a primary-tertiary shared care model to improve detection rates for FH. The primary objective is to evaluate the implementation of a shared care model and support package for genetic testing of FH. This protocol describes the design and methods used to evaluate the implementation of the shared care model and support package to improve the detection of FH., Methods and Analysis: This mixed methods pre-post implementation study design will be used to evaluate increased detection rates for FH in the tertiary and primary care setting. The primary-tertiary shared care model will be implemented at NSW Health Pathology and Sydney Local Health District in NSW, Australia, over a 12-month period. Implementation of the shared care model will be evaluated using a modification of the implementation outcome taxonomy and will focus on the acceptability, evidence of delivery, appropriateness, feasibility, fidelity, implementation cost and timely initiation of the intervention. Quantitative pre-post and qualitative semistructured interview data will be collected. It is anticipated that data relating to at least 62 index patients will be collected over this period and a similar number obtained for the historical group for the quantitative data. We anticipate conducting approximately 20 interviews for the qualitative data., Ethics and Dissemination: Ethical approval has been granted by the ethics review committee (Royal Prince Alfred Hospital Zone) of the Sydney Local Health District (Protocol ID: X23-0239). Findings will be disseminated through peer-reviewed publications, conference presentations and an end-of-study research report to stakeholders., Competing Interests: Competing interests: DS has received grants from Regeneron, Amgen, Arrowhead, Ionis and Novartis via Sydney Local Health District; consulting fees and speaker fees from Amgen and Novartis; and drug samples for a treatment adherence programme from Sanofi. CMH has received Amgen, Sanofi and MRFF grants looking at FH identification in the general practice setting, and assisted in the Amgen-funded independent education design for the GP. MNS is supported by an NHMRC Investigator Grant and received honoraria related to consulting, research and/or speaker activities from Amgen., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Tapelifting is a common strategy to recover touch DNA deposits from porous exhibits in forensic DNA casework. However, it is known that only about 30 % of tapelifts submitted for DNA analysis in operational forensic laboratories yield profiles suitable for comparison or upload to a searchable database. A reliable means to identify and remove non-probative tapelifts from the workflow would reduce sample backlogs and provide significant cost savings. We investigated whether the amount of macroscopic or microscopic fluorescence on a tapelift following staining with Diamond Nucleic Acid Dye (DD), determined using a Polilight and Dino Lite microscope respectively, could predict the DNA yield and/or the DNA profiling outcome using controlled (saliva), semi-controlled (finger mark) and uncontrolled (clothing) samples. Both macroscopic and microscopic DD fluorescence could predict DNA yield and profiling outcome for all sample types, however the predictive power deteriorated as the samples became less controlled. For tapelifts of clothing, which are operationally relevant, Polilight fluorescence scores were significantly impacted by clothing fibres and other non-cellular debris and could not be used to identify non-probative samples. The presence of less than 500 cells on a clothing tapelift using microscopic counting of stained corneocytes was identified as a potential threshold for a non-probative DNA profiling outcome. A broader examination of the reliability of this threshold using a casework trial is recommended. Due to the labour intensiveness of microscopic cell counting, and the increased risk of inadvertent contamination, automation of this process using image software in conjunction with artificial neural networks (ANN) should be explored., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Globally, species are increasingly at risk from compounding threatening processes, an increasingly prominent driver of which is environmental disturbances. To facilitate effective conservation efforts following such events, methods that evaluate potential impacts across multiple species and provide landscape-scale information are needed to guide targeted responses. Often, the geographic overlap between a disturbance and species' distribution is calculated and then used as a proxy for potential impact. However, such methods do not account for the important influence of environmental heterogeneity throughout species' ranges. To address this shortcoming, we quantified the effects of environmental disturbances on species' environmental niche space. Using the Australian 2019 and 2020 Black Summer fires as a case study, we applied a niche-centric approach to examine the potential impacts of these fires on 387 vertebrate species. We examined the utility of established and novel niche metrics to assess the potential impacts of large-scale disturbance events on species by comparing the potential effects of the fires as determined by our various niche measures to those derived from geographic-based measures of impact. We examined the quality of environmental space affected by the disturbance by quantifying the position in niche space where the disturbance occurred (center or margin), the uniqueness of the environmental space that was burned, and the degree to which the remaining, unburned portion of the niche differed from a species' original prefire niche. There was limited congruence between the proportion of geographic and niche space affected, which showed that geographic-based approaches in isolation may have underestimated the impact of the fires for 56% of modeled species. For each species, when combined, these metrics provided a greater indication of postdisturbance recovery potential than geographic-based measures alone. Accordingly, the integration of niche-based analyses into conservation assessments following large-scale disturbance events will lead to a more nuanced understanding of potential impacts and guide more informed and effective conservation actions., (© 2024 The Authors. Conservation Biology published by Wiley Periodicals LLC on behalf of Society for Conservation Biology.)

Competing Interests: We all contributed to the Criminalized Care: How Louisiana's Abortion Bans Endanger Patients and Clinicians(7) report and MH and PKS contributed to In Clinicians' Own Words: How Abortion Bans Impede Emergency Medical Treatment for Pregnant Patients in Idaho(10) brief. We declare no other competing interests.

Background: Older patients with lower limb amputation, categorised as having "limited community mobility", are under-researched. Understanding their experience with a new prosthetic ankle-foot is important when designing clinical trials. The aim of this qualitative study was to explore the adjustments they made after amputation and the acceptability of a self-aligning ankle-foot (SA-AF) to older adults., Methods: Fourteen participants, who took part in the STEPFORWARD randomised controlled feasibility trial (ISRCTN15043643), were purposively recruited; nine were intervention participants and five were standard care participants. They were asked to reflect on their life prior to and consider the adjustments they made following their amputation. Participants in the intervention group were also asked about their views of the new SA-AF compared to their standard non-SA-AF. A thematic analysis was undertaken., Results: Three broad themes were identified: The impact of the amputation; Role of clinical support; and Experiences of the SA-AF. The findings tell a narrative of the long-term impact that amputation has on these individuals' lives. Participants randomised to receive the SA-AF were very positive about it, reporting less pain, greater mobility and being able to do more., Conclusion: Participants who used the SA-AF found it an acceptable intervention. These findings suggest that a full-scale RCT is warranted.

Background: There is limited evidence on the optimal surveillance approach in patients with low- and very low-risk gastrointestinal stromal tumors, resulting in inconsistent and arbitrary approaches to surveillance in this population. In this study, we reviewed our institutional approach to surveillance in patients with low- and very low-risk gastrointestinal stromal tumors and the costs associated with detecting recurrence., Methods: We retrospectively reviewed consecutive adult patients treated for low- and very low-risk gastrointestinal stromal tumors at our institution from 2010 to 2019. Data collected included patient and tumor characteristics, surgical management, and postoperative follow-up. Surveillance-related expenses were calculated using estimates of average costs obtained from our institution. A cost analysis was performed to evaluate estimated yearly costs based on the surveillance strategy used., Results: There were 60 patients included. The mean age at diagnosis was 63.9 (±12.5) years. The primary tumor was typically in the stomach (73%; n = 44). Computed tomography scan of the abdomen and pelvis with intravenous contrast was the most common surveillance modality (total = 226 scans). No recurrences were identified. Median follow-up duration was 49.0 (interquartile range = 19.5-61.5) months. The mean number of surveillance images per patient was 4 (±2.6). Surveillance imaging was obtained more frequently than just annually in 83% (n = 50) of patients, with an estimated yearly cost of $2,840.77 (interquartile range = $2,273.62-$3,895.92) and no detection of recurrence., Conclusion: In this study population, patients with low- and very low-risk gastrointestinal stromal tumors underwent frequent imaging studies for surveillance with little yield and at substantial cost. Further multi-institutional studies on practice patterns and outcomes of surveillance are warranted to better inform standardized surveillance recommendations., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: EDs are necessary for urgent health concerns; however, many physical ED visits could be better treated in alternate settings. The present study aimed to describe the feasibility, acceptability and effectiveness of a Virtual ED to reduce unnecessary physical ED presentations at a large tertiary health service in Australia., Methods: This observational study using the RE-AIM framework (Reach, Efficacy, Adoption, Implementation and Maintenance) evaluated the feasibility of a Virtual ED using routinely collected health service data and process-evaluation to assess intervention fidelity and adherence between April 2020 and 31 March 2022. The primary outcome for the present study was the feasibility of the Virtual ED model of care., Results: The Virtual ED received 2080 direct calls for patients with a mean age of 50.3 years, with 70.4% managed in the Virtual ED alone and 29.6% referred for physical ED presentation. Of the 2080 direct referrals, 95.8% were potentially avoidable ED presentations. Of those referred, 28.3% required an admission. Of calls managed entirely by Virtual ED, 18 (1.2%) unexpectedly required a hospital admission within 48 h. General practitioner respondents rated the Virtual ED service as helpful to very helpful. The service had an average of 212 referrals per month, with a 65.2% average growth rate. The Virtual ED service was considered helpful and clinically appropriate, with a high level of ED avoidance., Conclusion: The Virtual ED prevented 70% of community triaged patients from presenting to the physical ED, with good uptake from all referrers, supporting the use of virtual care pathways in emergency care management., (© 2023 The Authors. Emergency Medicine Australasia published by John Wiley & Sons Australia, Ltd on behalf of Australasian College for Emergency Medicine.)

Familial hypercholesterolaemia (FH), a common monogenic disorder, is a preventable cause of premature coronary artery disease and death. Up to 35 million people worldwide have FH, but most remain undetected and undertreated. Several clinical guidelines have addressed the gaps in care of FH, but little focus has been given to implementation science and practice. The International Atherosclerosis Society (IAS) has developed an evidence-informed guidance for the detection and management of patients with FH, supplemented with implementation strategies to optimize contextual models of care. The guidance is partitioned into detection, management and implementation sections. Detection deals with screening, diagnosis, genetic testing and counselling. Management includes risk stratification, treatment of adults and children with heterozygous and homozygous FH, management of FH during pregnancy, and use of lipoprotein apheresis. Specific and general implementation strategies, guided by processes specified by the Expert Recommendations for Implementing Change taxonomy, are provided. Core generic implementation strategies are given for improving care. Nation-specific cholesterol awareness campaigns should be utilized to promote better detection of FH. Integrated models of care should be underpinned by health policy and adapted to meet local, regional and national needs. Clinical centres of excellence are important for taking referrals from the community. General practitioners should work seamlessly with multidisciplinary teams. All health-care providers must receive training in essential skills for caring for patients and families with FH. Management should be supported by shared decision-making and service improvement driven by patient-reported outcomes. Improvements in services require sharing of existing resources that can support care. Advocacy should be utilized to ensure sustainable funding. Digital health technologies and clinical quality registries have special value. Finally, academic-service partnerships need to be developed to identify gaps in care and set priorities for research. This new IAS guidance on FH complements the recent World Heart Federation Cholesterol Roadmap., Competing Interests: G.F.W. has received honoraria related to consulting, research and/or speaker activities from Amgen, Arrowhead, AstraZeneca, CRISPR Therapeutics, Esperion, Novartis and Sanofi. L.K.J. is a consultant for Novartis. M.N.S. has received personal fees from Amgen. J.P. has received grants from the National Health and Medical Research Council (NHMRC, Australia), the Medical Research Future Fund (MRRF, Australia), the Department of Health of Western Australia and the Royal Perth Hospital Research Foundation. S.S.G. is a consultant for Esperion and on a scientific advisory panel for Silence Therapeutics. P.L. has received research funding from Novartis; is on the Board of Directors of XBiotech; has a financial interest in Soley Therapeutics, TenSixteen Bio and XBiotech; is an unpaid consultant to, or involved in clinical trials for, Amgen, AstraZeneca, Baim Institute, Beren Therapeutics, Esperion Therapeutics, Genentech, Kancera, Kowa Pharmaceuticals, Medimmune, Merck, Norvo Nordisk, Novartis, Pfizer and Sanofi-Regeneron; is a member of the scientific advisory board for Amgen, Caristo Diagnostics, Cartesian Therapeutics, CSL Behring, DalCor Pharmaceuticals, Dewpoint Therapeutics, Eulicid Bioimaging, Kancera, Kowa Pharmaceuticals, Olatec Therapeutics, Medimmune, Moderna, Novartis, PlaqueTec, Soley Thereapeutics, TenSixteen Bio and XBiotech. R.D.S. has received honoraria related to consulting, research and/or speaker activities from Abbott, Ache, Amgen, AstraZeneca, EMS, Esperion, GETZ Pharma, Kowa, Libbs, Novartis, Novo-Nordisk, Merck, MSD, Pfizer, PTC Therapeutics and Sanofi/Regeneron., (Copyright: © 2024 The Author(s).)

Background: The onset of disability in bathing is particularly important for older adults as it can be rapidly followed by disability in other daily activities; this may represent a judicious time point for intervention in order to improve health, well-being and associated quality of life. An important environmental and preventative intervention is housing adaptation, but there are often lengthy waiting times for statutory provision. In this randomised controlled trial (RCT), we aim to evaluate the effectiveness and cost-effectiveness of bathing adaptations compared to no adaptations and to explore the factors associated with routine and expedited implementation of bathing adaptations., Methods: BATH-OUT-2 is a multicentre, two-arm, parallel-group RCT. Adults aged 60 and over who are referred to their local authority for an accessible level access shower will be randomised, using pairwise randomisation, 1:1, to receive either an expedited provision of an accessible shower via the local authority or a usual care control waiting list. Participants will be followed up for a maximum of 12 months and will receive up to four follow-ups in this duration. The primary outcome will be the participant's physical well-being, assessed by the Physical Component Summary score of the Short Form-36 (SF-36), 4 weeks after the intervention group receives the accessible shower. The secondary outcomes include the Mental Component Summary score of the SF-36, self-reported falls, health and social care resource use, health-related quality of life (EQ-5D-5L), social care-related quality of life (Adult Social Care Outcomes Toolkit (ASCOT)), fear of falling (Short Falls Efficacy Scale), independence in bathing (Barthel Index bathing question), independence in daily activities (Barthel Index) and perceived difficulty in bathing (0-100 scale). A mixed-methods process evaluation will comprise interviews with stakeholders and a survey of local authorities with social care responsibilities in England., Discussion: The BATH-OUT-2 trial is designed so that the findings will inform future decisions regarding the provision of bathing adaptations for older adults. This trial has the potential to highlight, and then reduce, health inequalities associated with waiting times for bathing adaptations and to influence policies for older adults., Trial Registration: ISRCTN Registry ISRCTN48563324. Prospectively registered on 09/04/2021., (© 2024. The Author(s).)