Sowing "seeds of trust": How trust in normothermic regional perfusion is built in a continuum of care.

Normothermic regional perfusion (NRP) is a promising technology to improve organ transplantation outcomes by reversing ischemic injury caused by controlled donation after circulatory determination of death. However, it has not yet been implemented in Canada due to ethical questions. These issues must be resolved to preserve public trust in organ donation and transplantation. This qualitative, constructivist grounded theory study sought to understand how those most impacted by NRP perceived the ethical implications. We interviewed 29 participants across stakeholder groups of donor families, organ recipients, donation and transplantation system leaders, and care providers. The interview protocol included a short presentation about the purpose of NRP and procedures in abdomen versus chest and abdomen NRP, followed by questions probing potential violations of the dead donor rule and concerns regarding brain reperfusion. The results present a grounded theory placing NRP within a trust-building continuum of care for the donor, their family, and organ recipients. Stakeholders consistently described both forms of NRP as an ethical intervention, but their rationales were predicated on assumptions that neurologic criteria for death had been met following circulatory death determination. Empirical validation of these assumptions will help ground the implementation of NRP in a trust-preserving way.

Development and validation of a simple prostate cancer risk prediction model based on age, family history, and polygenic risk.

BACKGROUND: Accurate prostate cancer risk assessment will enable identification of men who are at increased risk of the disease. Using the UK Biobank population-based cohort, we developed and validated a simple model comprising age, family history, and a polygenic risk score (PRS) to predict 5-year risk of prostate cancer. METHODS: Eligible participants were unaffected Caucasian men aged 40-69 years at their baseline assessment who had genotyping data available and had completed 6 or more weeks of follow-up. Family history was the number of affected first-degree relatives: 0, 1, or 2+. We used 264 single-nucleotide polymorphisms (SNPs) of a previously developed 269-SNP PRS and population standardized the PRS to have a mean of 1. Age was categorized into 10-year groups: 40-49, 50-59, and 60-69. In a 70% training data set, we used Cox regression with age as the time axis to model family history, PRS, and age group. The model estimates were used with prostate cancer incidences to derive 5-year risks of prostate cancer. Using 5 years of follow-up in a 30% testing data set, the model was tested in terms of its association per quintile of risk, discrimination, and calibration. RESULTS: Of the 198 334 eligible participants, 8996 (4.5%) were diagnosed with incident prostate cancer during follow-up and had a mean age of 67.9 (SD = 5.8) years at diagnosis. The best-fitting model included the PRS, family history, 10-year age group, interactions between age and PRS, and age and family history. In the 30% testing data set with follow-up limited to 5 years, the hazard ratio per SD of 5-year risk was 3.058 (95% confidence interval [CI], 2.720-3.438) and the Harrell's C-index was 0.811 (95% CI, 0.800-0.821). Overall, there were 1088 observed and 1159.1 expected prostate cancers, a standardized incidence ratio of 0.939 (95% CI, 0.885-0.996). CONCLUSIONS: Men at increased risk of prostate cancer could benefit from informed discussions around the risks and benefits of available options for screening for prostate cancer. Although the model was developed in Caucasian men, it can be used with ethnicity-specific polygenic risk and incidence rates for other populations.

Whole-of-community invertebrate rewilding: Leaf litter transplants rapidly increase beetle diversity during restoration.

Restoration of degraded areas is now a central tool in humanity's response to continued species-loss. However, restoration projects often report exceedingly slow or failed recolonization of fauna, especially dispersal-constrained groups such as invertebrates. Active interventions via reintroducing or "rewilding" invertebrates may assist recolonization and speed up restoration of communities toward a desired target. However, invertebrate rewilding is rarely implemented during ecological restoration. Here, we studied the efficacy of invertebrate rewilding as a means of reintroducing dispersal-constrained species and improving diversity and compositional similarities to remnant communities during restoration. Rewilding was conducted by transplanting leaf litter and soil, including associated communities of invertebrates from species rich remnant sites into species poor, and geographically isolated, revegetated farmland sites. We sampled pre- and post-rewilding invertebrate communities in remnant, rewilded revegetation, and control revegetation sites. We analyzed morphospecies richness, abundance, community composition, and modeled morphospecies traits (dispersal method/trophic guild) using a Hierarchical Modelling of Species Communities approach to determine which biological properties facilitated establishment. Beetle (Coleoptera) morphospecies richness increased rapidly in rewilded sites and was indistinguishable from remnant communities as early as 7 months post-rewilding. Beetle community similarity in the rewilding sites significantly deviated from the control sites 27 months post-rewilding, however remnant communities remained distinct over the study timeframe. Establishment success varied as other taxa did not respond as consistently as beetles within the study timeframe. Furthermore, there were no discernible shifts in dispersal traits in rewilded sites. However, predatory morphospecies were more likely to establish post-rewilding than other trophic groups. Our results demonstrate that the relatively simple act of transplanting leaf litter can result in comparatively large increases in morphospecies richness during restoration in a short timeframe. We advocate methodologies such as ours should be adopted more frequently to address failed community restoration as they are cost-effective and can be easily applied by practitioners in various restoration settings. However, further efficacy tests (e.g., varying the number of rewilding events) and longer study timeframes are needed to ensure effectiveness for a broader range of invertebrate taxa and ecosystems.

Functional and structural brain network correlates of visual hallucinations in Lewy body dementia.

Visual hallucinations are a common feature of Lewy body dementia. Previous studies have shown that visual hallucinations are highly specific in differentiating Lewy body dementia from Alzheimer's disease dementia and Alzheimer-Lewy body mixed pathology cases. Computational models propose that impairment of visual and attentional networks is aetiologically key to the manifestation of visual hallucinations symptomatology. However, there is still a lack of experimental evidence on functional and structural brain network abnormalities associated with visual hallucinations in Lewy body dementia. We used EEG source localization and network based statistics to assess differential topographical patterns in Lewy body dementia between 25 participants with visual hallucinations and 17 participants without hallucinations. Diffusion tensor imaging was used to assess structural connectivity between thalamus, basal forebrain and cortical regions belonging to the functionally affected network component in the hallucinating group, as assessed with network based statistics. The number of white matter streamlines within the cortex and between subcortical and cortical regions was compared between hallucinating and not hallucinating groups and correlated with average EEG source connectivity of the affected subnetwork. Moreover, modular organization of the EEG source network was obtained, compared between groups and tested for correlation with structural connectivity. Network analysis showed that compared to non-hallucinating patients, those with hallucinations feature consistent weakened connectivity within the visual ventral network, and between this network and default mode and ventral attentional networks, but not between or within attentional networks. The occipital lobe was the most functionally disconnected region. Structural analysis yielded significantly affected white matter streamlines connecting the cortical regions to the nucleus basalis of Meynert and the thalamus in hallucinating compared to not hallucinating patients. The number of streamlines in the tract between the basal forebrain and the cortex correlated with cortical functional connectivity in non-hallucinating patients, while a correlation emerged for the white matter streamlines connecting the functionally affected cortical regions in the hallucinating group. This study proposes, for the first time, differential functional networks between hallucinating and not hallucinating Lewy body dementia patients, and provides empirical evidence for existing models of visual hallucinations. Specifically, the outcome of the present study shows that the hallucinating condition is associated with functional network segregation in Lewy body dementia and supports the involvement of the cholinergic system as proposed in the current literature.

Ethics of non-therapeutic research on imminently dying patients in the intensive care unit.

Non-therapeutic research with imminently dying patients in intensive care presents complex ethical issues. The vulnerabilities of the imminently dying, together with societal disquiet around death and dying, contribute to an intuition that such research is beyond the legitimate scope of scientific inquiry. Yet excluding imminently dying patients from research hinders the advancement of medical science to the detriment of future patients. Building on existing ethical guidelines for research, we propose a framework for the ethical design and conduct of research involving the imminently dying. To enable rapid translation to practice, we frame the approach in the form of eight ethical questions that researchers and research ethics committees ought to answer prior to conducting any research with this patient population. (1) Does the study hypothesis require the inclusion of imminently dying patients? (2) Are non-therapeutic risks and burdens minimised consistent with sound scientific design? (3) Are the risks of these procedures no more than minimal risk? (4) Are these non-therapeutic risks justified insofar as they are reasonable in relation to the anticipated benefits of the study? (5) Will valid informed consent be obtained from an authorised surrogate decision maker? (6) How will incidental findings be handled? (7) What additional steps are in place to protect families and significant others of research participants? (8) What additional steps are in place to protect clinical staff and researchers? Several ethical challenges hinder research with imminently dying patients. Nonetheless, provided adequate protections are in place, non-therapeutic research with imminently dying patients is ethically justifiable. Applying our framework to an ongoing study, we demonstrate how our question-driven approach is well suited to guiding investigators and research ethics committees.

Rationale for revisions to the definition of death and criteria for its determination in Canada.

Clarity regarding the biomedical definition of death and the criteria for its determination is critical to inform practices in clinical care, medical research, law, and organ donation. While best practices for death determination by neurologic criteria and circulatory criteria were previously outlined in Canadian medical guidelines, several issues have arisen to force their reappraisal. Ongoing scientific discovery, corresponding changes in medical practice, and legal and ethical challenges compel a comprehensive update. Accordingly, the A Brain-Based Definition of Death and Criteria for its Determination After Arrest of Neurologic or Circulatory Function in Canada project was undertaken to a develop a unified brain-based definition of death, and to establish criteria for its determination after devastating brain injury and/or circulatory arrest. Specifically, the project had three objectives: (1) to clarify that death is defined in terms of brain functions; (2) to clarify how a brain-based definition of death is articulated; and (3) to clarify the criteria for determining if the brain-based definition is met. The updated death determination guideline therefore defines death as the permanent cessation of brain function and describes corresponding circulatory and neurologic criteria to ascertain the permanent cessation of brain function. This article explores the challenges that prompted revisions to the biomedical definition of death and the criteria for its determination and outlines the rationales underpinning the project's three objectives. By clarifying that all death is defined in terms of brain function, the project seeks to align guidelines with contemporary medicolegal understandings of the biological basis of death.

RéSUMé: Il est essentiel que la définition biomédicale du décès et les critères de sa détermination soient précis afin d'éclairer les pratiques en matière de soins cliniques, de recherche médicale, de droit et de don d'organes. Alors que les meilleures pratiques pour la détermination du décès par des critères neurologiques et circulatoires ont déjà été décrites dans les lignes directrices médicales canadiennes, plusieurs problèmes ont été soulevés, lesquels ont motivé leur réévaluation. Les découvertes scientifiques en cours, les changements correspondants dans la pratique médicale et les défis juridiques et éthiques imposent une mise à jour complète. Par conséquent, le projet d'Élaboration d'une définition uniformisée de la mort cérébrale et de critères fondés sur des données probantes pour sa détermination au Canada a été entrepris dans le but d'élaborer une définition uniformisée de la mort cérébrale et d'établir des critères pour sa détermination après une lésion cérébrale dévastatrice et/ou un arrêt circulatoire. Plus précisément, le projet avait trois objectifs : (1) clarifier que le décès est défini en termes de fonctions cérébrales; (2) clarifier la façon dont une définition cérébrale du décès est articulée; et (3) clarifier les critères permettant de déterminer si la définition de mort cérébrale est respectée. Les lignes directrices mises à jour sur la détermination du décès définissent donc le décès comme l'arrêt permanent de la fonction cérébrale et décrivent les critères circulatoires et neurologiques correspondants pour établir l'arrêt permanent de la fonction cérébrale. Cet article explore les défis qui ont motivé la révision de la définition biomédicale du décès et des critères de sa détermination et décrit les raisons d'être qui sous-tendent les trois objectifs du projet. En précisant que tout décès est défini en termes de fonction cérébrale, le projet cherche à aligner les lignes directrices sur les compréhensions médicolégales contemporaines des fondements biologiques de la mort.

Navigating disagreement and conflict in the context of a brain-based definition of death.

In this paper, we discuss situations in which disagreement or conflict arises in the critical care setting in relation to the determination of death by neurologic criteria, including the removal of ventilation and other somatic support. Given the significance of declaring a person dead for all involved, an overarching goal is to resolve disagreement or conflict in ways that are respectful and, if possible, relationship preserving. We describe four different categories of reasons for these disagreements or conflicts: 1) grief, unexpected events, and needing time to process these events; 2) misunderstanding; 3) loss of trust; and 4) religious, spiritual, or philosophical differences. Relevant aspects of the critical care setting are also identified and discussed. We propose several strategies for navigating these situations, appreciating that these may be tailored for a given care context and that multiple strategies may be helpfully used. We recommend that health institutions develop policies that outline the process and steps involved in addressing situations where there is ongoing or escalating conflict. These policies should include input from a broad range of stakeholders, including patients and families, as part of their development and review.

RéSUMé: Dans cet article, nous discutons des situations dans lesquelles un désaccord ou un conflit survient dans le contexte des soins intensifs en ce qui concerne une détermination de décès selon des critères neurologiques, y compris le retrait de la ventilation et d'autres assistances somatiques. Compte tenu de l'importance pour toutes les personnes impliquées de déclarer une personne décédée, un objectif primordial est de résoudre les désaccords ou les conflits de manière respectueuse et, si possible, de préserver les relations. Nous décrivons quatre catégories différentes de raisons causant ces désaccords ou conflits : 1) le chagrin, des événements inattendus et le besoin de temps pour accepter ces événements; 2) les malentendus; 3) la perte de confiance; et 4) les différences religieuses, spirituelles ou philosophiques. Les aspects pertinents du milieu des soins intensifs sont également identifiés et discutés. Nous proposons plusieurs stratégies pour gérer ces situations, en étant conscients que celles-ci peuvent être adaptées à un contexte de soins donné et que plusieurs stratégies peuvent être utiles à appliquer. Nous recommandons que les établissements de santé élaborent des politiques qui décrivent le processus et les étapes nécessaires pour faire face aux situations où il y a un conflit en cours ou qui s'intensifie. Dans le cadre de leur élaboration et de leur examen, ces politiques devraient inclure les commentaires d'un large éventail d'intervenants, y compris les patients et les familles.

A brain-based definition of death and criteria for its determination after arrest of circulation or neurologic function in Canada: a 2023 clinical practice guideline.

This 2023 Clinical Practice Guideline provides the biomedical definition of death based on permanent cessation of brain function that applies to all persons, as well as recommendations for death determination by circulatory criteria for potential organ donors and death determination by neurologic criteria for all mechanically ventilated patients regardless of organ donation potential. This Guideline is endorsed by the Canadian Critical Care Society, the Canadian Medical Association, the Canadian Association of Critical Care Nurses, Canadian Anesthesiologists' Society, the Canadian Neurological Sciences Federation (representing the Canadian Neurological Society, Canadian Neurosurgical Society, Canadian Society of Clinical Neurophysiologists, Canadian Association of Child Neurology, Canadian Society of Neuroradiology, and Canadian Stroke Consortium), Canadian Blood Services, the Canadian Donation and Transplantation Research Program, the Canadian Association of Emergency Physicians, the Nurse Practitioners Association of Canada, and the Canadian Cardiovascular Critical Care Society.

RéSUMé: Ces Lignes directrices de pratique clinique 2023 Lignes directrices de pratique clinique dicale du décès basée sur l'arrêt permanent de la fonction cérébrale qui s'applique à toute personne, ainsi que des recommandations pour la détermination du décès par des critères circulatoires pour des donneurs d'organes potentiels et des recommandations pour la détermination du décès par des critères neurologiques pour tous les patients sous ventilation mécanique, indépendamment de leur potentiel de donneur d'organes. Les présentes Lignes directrices sont approuvées par la Société canadienne de soins intensifs, l'Association médicale canadienne, l'Association canadienne des infirmiers/infirmières en soins intensifs, la Société canadienne des anesthésiologistes, la Fédération des sciences neurologiques du Canada (représentant la Société canadienne de neurologie, la Société canadienne de neurochirurgie, la Société canadienne de neurophysiologie clinique, l'Association canadienne de neurologie pédiatrique, la Société canadienne de neuroradiologie et le Consortium neurovasculaire canadien), la Société canadienne du sang, le Programme de recherche en don et transplantation du Canada, l'Association canadienne des médecins d'urgence, l'Association des infirmières et infirmiers praticiens du Canada, et la Société canadienne de soins intensifs cardiovasculaires (CANCARE) et la Société canadienne de pédiatrie.

Development of an STR panel for a non-native population of an endangered species.

BACKGROUND: The establishment of non-native populations of threatened and legally protected species can have many implications for the areas where these species have been introduced. Non-native populations of threatened species have the potential to be exploited and therefore the subject of legal protection, while conversely, if they have become invasive in their introduced range, there is the likelihood that population control will be carried out to reduce abundance and negative impacts associated with introduced species. From both a legal and invasive species monitoring standpoint, it is important to know how many individuals are present. METHODS AND RESULTS: Short tandem repeats (STRs) were developed for the hog deer, an endangered species that was introduced following European settlement to Victoria, Australia using Illumina MiSeq sequencing technology. These markers were combined with previous STRs characterised for hog deer to create a 29-plex identification system. A total of 224 samples were genotyped across the population in Victoria, and further analyses of null allele frequencies, deviation from Hardy-Weinberg equilibrium, and the removal of monomorphic or low amplifying markers resulted in a final marker panel of 15 loci. Despite low values for number of alleles at each locus (2-4), probability of identity showed sufficient discrimination power, with an average probability of identity at 2.94 × 10-6, and a probability of sibling identity of 8.9 × 10-4 across all sites. CONCLUSIONS: It is feasible to create an informative DNA profiling system that can distinguish between individuals for applications in both wildlife forensic and population control research.

Research bystanders, justice, and the state: Reframing the debate on third-party protections in health research.

Research participants are afforded protections to ensure their rights and welfare are not unduly jeopardized by research activities. Yet people who do not meet the criteria for research participant status may likewise be impacted by research activities, and ethicists argue that protections should be afforded these "research bystanders." The standard rationale for extending protections to research bystanders contends that they are sufficiently like research participants that the ethical principles governing health research ought to extend to them. In this article we argue that this analogical reasoning is mistaken. Salient moral differences mean that research ethics frameworks are not fit for purpose. We defend the research bystander category by articulating a novel foundation for this new class of stakeholder. Focusing on bystanders directly impacted by publicly funded health research, we argue that bystanders are sometimes owed protections-but neither because of their similarity to research participants nor because research ethics principles should extend to them. Instead, we reframe the issue as a question of justice. Building on the work of Douglas MacKay, we argue that bystanders to publicly funded health research are owed protections as citizens of liberal states to whom the state owes duties of justice. The state has duties to protect the interests of citizens and to conduct health research. When the means by which the state fulfils the latter duty comes into conflict with the means by which it fulfils the former, the state must ensure that those impacted, including research bystanders, are afforded protections.

Effects of adding a diet intervention to exercise on hip osteoarthritis pain: protocol for the ECHO randomized controlled trial.

BACKGROUND: Hip osteoarthritis (OA) is a leading cause of musculoskeletal pain. Exercise is a core recommended treatment. Despite some clinical guidelines also recommending weight loss for hip OA, there is no evidence from randomised controlled trials (RCT) to substantiate these recommendations. This superiority, 2-group, parallel RCT will compare a combined diet and exercise program to an exercise only program, over 6 months. METHODS: One hundred people with symptomatic and radiographic hip OA will be recruited from the community. Following baseline assessment, participants will be randomly allocated to either, i) diet and exercise or; ii) exercise only. Participants in the diet and exercise group will have six consultations with a dietitian and five consultations with a physiotherapist via videoconferencing over 6 months. The exercise only group will have five consultations with a physiotherapist via videoconferencing over 6 months. The exercise program for both groups will include prescription of strengthening exercise and a physical activity plan, advice about OA management and additional educational resources. The diet intervention includes prescription of a ketogenic very low-calorie diet with meal replacements and educational resources to support weight loss and healthy eating. Primary outcome is self-reported hip pain via an 11-point numeric rating scale (0 = 'no pain' and 10 = 'worst pain possible') at 6 months. Secondary outcomes include self-reported body weight (at 0, 6 and 12 months) and body mass index (at 0, 6 and 12 months), visceral fat (measured using dual energy x-ray absorptiometry at 0 and 6 months), pain, physical function, quality of life (all measured using subscales of the Hip Osteoarthritis Outcome Scale at 0, 6 and 12 months), and change in pain and physical activity (measured using 7-point global rating of change Likert scale at 6 and 12 months). Additional measures include adherence, adverse events and cost-effectiveness. DISCUSSION: This study will determine whether a diet intervention in addition to exercise provides greater hip pain-relief, compared to exercise alone. Findings will assist clinicians in providing evidence-based advice regarding the effect of a dietary intervention on hip OA pain. TRIAL REGISTRATION: ClinicalTrials.gov . Identifier: NCT04825483 . Registered 31st March 2021.

Effects of adding aerobic physical activity to strengthening exercise on hip osteoarthritis symptoms: protocol for the PHOENIX randomised controlled trial.

BACKGROUND: Hip osteoarthritis (OA) is a leading cause of musculoskeletal pain. Exercise is a core recommended treatment. Most evidence is based on muscle-strengthening exercise, but aerobic physical activity has potential to enhance clinical benefits. The primary aim of this study is to test the hypothesis that adding aerobic physical activity to a muscle strengthening exercise leads to significantly greater reduction in hip pain and improvements in physical function, compared to a lower-limb muscle strengthening exercise program alone at 3 months. METHODS: This is a superiority, 2-group, parallel randomised controlled trial including 196 people with symptomatic hip OA from the community. Following baseline assessment, participants are randomly allocated to receive either i) aerobic physical activity and muscle strengthening exercise or; ii) muscle strengthening exercise only. Participants in both groups receive 9 consultations with a physiotherapist over 3 months. Both groups receive a progressive muscle strengthening exercise program in addition to advice about OA management. The aerobic physical activity plan includes a prescription of moderate intensity aerobic physical activity with a goal of attaining 150 min per week. Primary outcomes are self-reported hip pain assessed on an 11-point numeric rating scale (0 = 'no pain' and 10 = 'worst pain possible') and self-reported physical function (Western Ontario and McMaster Universities Osteoarthritis Index physical function subscale) at 3 months. Secondary outcomes include other measures of self-reported pain (assessed at 0, 3, 9 months), self-reported physical function (assessed at 0, 3, 9 months), performance-based physical function (assessed at 0, 3 months), joint stiffness (assessed at 0, 3, 9 months), quality of life (assessed at 0, 3, 9 months), muscle strength (assessed at 0, 3 months), and cardiorespiratory fitness (assessed at 0, 3 months). Other measures include adverse events, co-interventions, and adherence. Measures of body composition, serum inflammatory biomarkers, quantitative sensory measures, anxiety, depression, fear of movement and self-efficacy are included to explore causal mechanisms. DISCUSSION: Findings will assist to provide an evidence-based recommendation regarding the additional effect of aerobic physical activity to lower-limb muscle strengthening on hip OA pain and physical function. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry reference: ACTRN 12619001297112. Registered 20th September 2019.

Can a Hip Brace Improve Short-Term Hip-Related Quality of Life for People With Femoroacetabular Impingement and Acetabular Labral Tears: An Exploratory Randomized Trial.

OBJECTIVES: To examine whether a hip brace can improve hip health quality-of-life (QoL) and is well-tolerated in people with femoroacetabular impingement syndrome (FAIS) or symptomatic labral tears after 6 weeks of wear. DESIGN: Parallel, two-arm, exploratory randomized trial. SETTING: Hospital and private clinics of orthopaedic surgeons. PARTICIPANTS: Individuals >18 years with FAIS or labral tears. INTERVENTIONS: Usual conservative care versus usual conservative care plus a hip brace. MAIN OUTCOMES: Patient-reported outcomes were assessed with the International Hip Outcome Tool (iHOT-33), and Copenhagen Hip and Groin Outcome Scores (HAGOS). Brace acceptability was measured using the Quebec User Evaluation of Satisfaction with Assistive Technology survey. Independent t-tests assessed between-group differences. RESULTS: Thirty-eight participants were recruited, 19 each group, 60% women, mean age 39.3 ± 11.8 years, body mass index 25.3 ± 4.4 kg/m2, iHOT-33 36.6 ± 24.8. Three participants dropped out (one usual care, 2 braced). The mean between-group difference for iHOT-33 was 19.4 (95% confidence interval [CI] 1.68-37.06, P = 0.03) favoring the brace. There were improvements in most HAGOS subscale scores favoring the brace. Issues with brace tolerability for some participants were perceived comfort and effectiveness. Three brace-related adverse events were reported. CONCLUSION: Between-group differences favored the braced group for hip health QoL, pain, symptoms, and function. Although these were promising results, the CIs for the estimates were wide, the small sample size likely a contributing factor. Our results suggest that further investigation of the brace is warranted, we calculated sample sizes and made recommendations for the design of a future trial.

Global drivers of recent diversification in a marine species complex.

Investigating historical gene flow in species complexes can indicate how environmental and reproductive barriers shape genome divergence during speciation. The processes influencing species diversification under environmental change remain one of the central focal points of evolutionary biology, particularly for marine organisms with high dispersal potential. We investigated genome-wide divergence, introgression patterns and inferred demographic history between species pairs of all six extant rock lobster species (Jasus spp.), which have a long larval duration of up to two years and have populated continental shelf and seamount habitats around the globe at approximately 40o S. Genetic differentiation patterns reflected geographic isolation and the environment (i.e. habitat structure). Eastern Pacific species (J. caveorum and J. frontalis) were geographically more distant and genetically more differentiated from the remaining four species. Species associated with continental shelf habitats shared a common ancestry, but are geographically distant from one another. Similarly, species associated with island/seamount habitats in the Atlantic and Indian Oceans shared a common ancestry, but are also geographically distant. Benthic temperature was the environmental variable that explained most of the genetic differentiation (FST ), while controlling for the effects of geographic distance. Eastern Pacific species retained a signal of strict isolation following ancient migration, whereas species pairs from Australia and Africa, and seamounts in the Indian and Atlantic oceans, included events of introgression after secondary contact. Our results reveal important effects of habitat and demographic processes on the recent divergence of species within the genus Jasus, providing one of the first empirical studies of genome-wide drivers of diversification that incorporates all extant species in a marine genus with long pelagic larval duration.

Neurophysiological and clinical effects of the NMDA receptor antagonist lanicemine (BHV-5500) in PTSD: A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with hyperarousal and stress reactivity, features consistent with behavioral sensitization. In this Phase 1b, parallel-arm, randomized, double-blind, placebo-controlled trial, we tested whether the selective low-trapping N-methyl-D-aspartate receptor (NMDAR) antagonist [Lanicemine (BHV-5500)] blocks expression of behavioral sensitization. METHODS: Twenty-four participants with elevated anxiety potentiated startle (APS) and moderate-to-severe PTSD symptoms received three infusions of lanicemine 1.0 mg/ml (100 mg) or matching placebo (0.9% saline) (1:1 ratio), over a 5-day period. The primary outcome was change in APS from baseline to end of third infusion. We also examined changes in EEG gamma-band oscillatory activity as measures of NMDAR target engagement and explored Clinician-Administered PTSD Scale (CAPS-5) hyperarousal scores. RESULTS: Lanicemine was safe and well-tolerated with no serious adverse events. Using Bayesian statistical inference, the posterior probability that lanicemine outperformed placebo on APS T-score after three infusions was 38%. However, after the first infusion, there was a 90% chance that lanicemine outperformed placebo in attenuating APS T-score by a standardized effect size more than 0.4. CONCLUSION: We demonstrated successful occupancy of lanicemine on NMDAR using gamma-band EEG and effects on hyperarousal symptoms (Cohen's d = 0.75). While lanicemine strongly attenuated APS following a single infusion, differential changes from placebo after three infusions was likely obscured by habituation effects. To our knowledge, this is the first use of APS in the context of an experimental medicine trial of a NMDAR antagonist in PTSD. These findings support selective NMDAR antagonism as a viable pharmacological strategy for salient aspects of PTSD.

Development and validation of a clinical and genetic model for predicting risk of severe COVID-19.

Clinical and genetic risk factors for severe coronavirus disease 2019 (COVID-19) are often considered independently and without knowledge of the magnitudes of their effects on risk. Using severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) positive participants from the UK Biobank, we developed and validated a clinical and genetic model to predict risk of severe COVID-19. We used multivariable logistic regression on a 70% training dataset and used the remaining 30% for validation. We also validated a previously published prototype model. In the validation dataset, our new model was associated with severe COVID-19 (odds ratio per quintile of risk = 1.77, 95% confidence interval (CI) 1.64-1.90) and had acceptable discrimination (area under the receiver operating characteristic curve = 0.732, 95% CI 0.708-0.756). We assessed calibration using logistic regression of the log odds of the risk score, and the new model showed no evidence of over- or under-estimation of risk (α = -0.08; 95% CI -0.21-0.05) and no evidence or over-or under-dispersion of risk (ß = 0.90, 95% CI 0.80-1.00). Accurate prediction of individual risk is possible and will be important in regions where vaccines are not widely available or where people refuse or are disqualified from vaccination, especially given uncertainty about the extent of infection transmission among vaccinated people and the emergence of SARS-CoV-2 variants of concern.

Multi-centre randomised controlled trial comparing arthroscopic hip surgery to physiotherapist-led care for femoroacetabular impingement (FAI) syndrome on hip cartilage metabolism: the Australian FASHIoN trial.

BACKGROUND: Arthroscopic surgery for femoroacetabular impingement syndrome (FAI) is known to lead to self-reported symptom improvement. In the context of surgical interventions with known contextual effects and no true sham comparator trials, it is important to ascertain outcomes that are less susceptible to placebo effects. The primary aim of this trial was to determine if study participants with FAI who have hip arthroscopy demonstrate greater improvements in delayed gadolinium-enhanced magnetic resonance imaging (MRI) of cartilage (dGEMRIC) index between baseline and 12 months, compared to participants who undergo physiotherapist-led management. METHODS: Multi-centre, pragmatic, two-arm superiority randomised controlled trial comparing physiotherapist-led management to hip arthroscopy for FAI. FAI participants were recruited from participating orthopaedic surgeons clinics, and randomly allocated to receive either physiotherapist-led conservative care or surgery. The surgical intervention was arthroscopic FAI surgery. The physiotherapist-led conservative management was an individualised physiotherapy program, named Personalised Hip Therapy (PHT). The primary outcome measure was change in dGEMRIC score between baseline and 12 months. Secondary outcomes included a range of patient-reported outcomes and structural measures relevant to FAI pathoanatomy and hip osteoarthritis development. Interventions were compared by intention-to-treat analysis. RESULTS: Ninety-nine participants were recruited, of mean age 33 years and 58% male. Primary outcome data were available for 53 participants (27 in surgical group, 26 in PHT). The adjusted group difference in change at 12 months in dGEMRIC was -59 ms (95%CI - 137.9 to - 19.6) (p = 0.14) favouring PHT. Hip-related quality of life (iHOT-33) showed improvements in both groups with the adjusted between-group difference at 12 months showing a statistically and clinically important improvement in arthroscopy of 14 units (95% CI 5.6 to 23.9) (p = 0.003). CONCLUSION: The primary outcome of dGEMRIC showed no statistically significant difference between PHT and arthroscopic hip surgery at 12 months of follow-up. Patients treated with surgery reported greater benefits in symptoms at 12 months compared to PHT, but these benefits are not explained by better hip cartilage metabolism. TRIAL REGISTRATION DETAILS: Australia New Zealand Clinical Trials Registry reference: ACTRN12615001177549 . Trial registered 2/11/2015.

Temporal genetic patterns of diversity and structure evidence chaotic genetic patchiness in a spiny lobster.

Population structure of many marine organisms is spatially patchy and varies within and between years, a phenomenon defined as chaotic genetic patchiness. This results from the combination of planktonic larval dispersal and environmental stochasticity. Additionally, in species with bi-partite life, postsettlement selection can magnify these genetic differences. The high fecundity (up to 500,000 eggs annually) and protracted larval duration (12-24 months) and dispersal of the southern rock lobster, Jasus edwardsii, make it a good test species for chaotic genetic patchiness and selection during early benthic life. Here, we used double digest restriction site-associated DNA sequencing (ddRADseq) to investigate chaotic genetic patchiness and postsettlement selection in this species. We assessed differences in genetic structure and diversity of recently settled pueruli across four settlement years and between two sites in southeast Australia separated by approximately 1,000 km. Postsettlement selection was investigated by identifying loci under putative positive selection between recently settled pueruli and postpueruli and quantifying differences in the magnitude and strength of the selection at each year and site. Genetic differences within and among sites through time in neutral SNP markers indicated chaotic genetic patchiness. Recently settled puerulus at the southernmost site exhibited lower genetic diversity during years of low puerulus catches, further supporting this hypothesis. Finally, analyses of outlier SNPs detected fluctuations in the magnitude and strength of the markers putatively under positive selection over space and time. One locus under putative positive selection was consistent at both locations during the same years, suggesting the existence of weak postsettlement selection.

Fabricating PLGA microparticles with high loads of the small molecule antioxidant N-acetylcysteine that rescue oligodendrocyte progenitor cells from oxidative stress.

Reactive oxygen species (ROS), encompassing all oxygen radical or non-radical oxidizing agents, play key roles in disease progression. Controlled delivery of antioxidants is therapeutically relevant in such oxidant-stressed environments. Encapsulating small hydrophilic molecules into hydrophobic polymer microparticles via traditional emulsion methods has long been a challenge due to rapid mass transport of small molecules out of particle pores. We have developed a simple alteration to the existing water-in-oil-in-water (W/O/W) drug encapsulation method that dramatically improves loading efficiency: doping external water phases with drug to mitigate drug diffusion out of the particle during fabrication. PLGA microparticles with diameters ranging from 0.6 to 0.9 micrometers were fabricated, encapsulating high loads of 0.6-0.9 µm diameter PLGA microparticles were fabricated, encapsulating high loads of the antioxidant N-acetylcysteine (NAC), and released active, ROS-scavenging NAC for up to 5 weeks. Encapsulation efficiencies, normalized to the theoretical load of traditional encapsulation without doping, ranged from 96% to 400%, indicating that NAC-loaded external water phases not only prevented drug loss due to diffusion, but also doped the particles with additional drug. Antioxidant-doped particles positively affected the metabolism of oligodendrocyte progenitor cells (OPCs) under H2 O2 -mediated oxidative stress when administered both before (protection) or after (rescue) injury. Antioxidant doped particles improved outcomes of OPCs experiencing multiple doses of H2 O2 by increasing the intracellular glutathione content and preserving cellular viability relative to the injury control. Furthermore, antioxidant-doped particles preserve cell number, number of process extensions, cytoskeletal morphology, and nuclear size of H2 O2 -stressed OPCs relative to the injury control. These NAC-doped particles have the potential to provide temporally-controlled antioxidant therapy in neurodegenerative disorders such as multiple sclerosis (MS) that are characterized by continuous oxidative stress.