Cooperation Between Platelet ß1 and ß3 Integrins in the Arrest of Bleeding Under Inflammatory Conditions in Mice.

BACKGROUND: Platelets prevent bleeding in a variety of inflammatory settings, the adhesion receptors and activation pathways involved being highly context-dependent and functionally redundant. In some situations, platelets recruited to inflammatory sites act independently of aggregation. The mechanisms underlying stable platelet adhesion in inflamed microvessels remain incompletely understood, in particular, whether and if so, how ß1 and ß3 integrins are involved. METHODS: The impact of isolated or combined platelet deficiency in ß1 and ß3 integrins on inflammation-associated hemostasis was investigated in 3 models of acute inflammation: immune complex-based cutaneous reverse passive Arthus reaction, intranasal lipopolysaccharide-induced lung inflammation, and cerebral ischemia-reperfusion following transient (2-hour) occlusion of the transient middle cerebral artery. RESULTS: Mice with platelet-directed inactivation of Itgb1 (PF4Cre-ß1-/-) displayed no bleeding in any of the inflammation models, while mice defective in platelet Itgb3 (PF4Cre-ß3-/-) exhibited bleeding in all 3 models. Remarkably, the bleeding phenotype of PF4Cre-ß3-/- mice was exacerbated in the reverse passive Arthus model by the concomitant deletion of ß1 integrins, PF4Cre-ß1-/-/ß3-/- animals presenting increased bleeding. Intravital microscopy in reverse passive Arthus experiments highlighted a major defect in the adhesion of PF4Cre-ß1-/-/ß3-/- platelets to inflamed microvessels. Unlike PF4Cre-ß1-/- and PF4Cre-ß3-/- mice, PF4Cre-ß1-/-/ß3-/- animals developed early hemorrhagic transformation 6 hours after transient middle cerebral artery occlusion. PF4Cre-ß1-/-/ß3-/- mice displayed no more bleeding in lipopolysaccharide-induced lung inflammation than PF4Cre-ß3-/- animals. CONCLUSIONS: Altogether, these results show that the requirement for and degree of functional redundancy between platelet ß1 and ß3 integrins in inflammation-associated hemostasis vary with the inflammatory situation.

3-Dimensional Virtual Reality Versus 2-Dimensional Video for Distraction During the Induction of Anesthesia in Children to Reduce Anxiety: A Randomized Controlled Trial.

BACKGROUND: Preoperative anxiety is common in children. It can contribute to negative experiences with anesthetic induction and may cause adverse physiological and psychological effects. Virtual reality (VR) and electronic tablet devices are 2 audiovisual distraction tools that may help to reduce anxiety and enhance the preoperative experience. This study aimed to compare the use of an immersive 3-dimensional (3D) VR to 2-dimensional (2D) video on anxiety in children during induction of general anesthesia. METHODS: Two hundred children (4-13 years) undergoing elective or emergency surgery under general anesthesia were enrolled in this randomized, controlled trial. Participants were randomized to use either the 3D VR goggles (intervention) or 2D video tablet (control) during anesthetic induction. Anxiety, the primary outcome, was measured using the modified Yale Preoperative Anxiety Scale Short Form (mYPAS-SF) at 2 time points: in the preoperative holding area before randomization (T1) and during induction of general anesthesia (T2). The primary outcome was analyzed using a linear regression model, including demographic and other covariates, to investigate any differences in anxiety scores. Secondary outcomes included evaluating compliance during the anesthetic induction (Induction Compliance Checklist), emergence of delirium (Cornell Assessment of Pediatric Delirium), perceived usefulness of the device, and child satisfaction. RESULTS: Participant characteristics were similar between the 3D VR (n = 98) and 2D video (n = 90) groups, with a mean (±standard deviation) age 8. 8 ± 2.8 years. The median (lower quartile, upper quartile) mYPAS-SF scores for the 3D VR group at the preoperative holding area were 22.9 (22.9, 35.4), then 29.2 (24.0, 41.7) during induction. For the 2D Video group, the scores were 27.1 (22.9, 35.4) and then 30.2 (22.9, 41.1). No significant difference was observed in the increase in mYPAS-SF scores between groups (P = .672). Children in the 3D VR group were less likely to be rated as having a perfect induction (P = .039). There was no evidence of a difference between the groups in emergence delirium. Both devices were rated highly for usefulness and patient satisfaction. Children preferred VR, while anesthesiologists and parents felt the 2D was more useful. CONCLUSIONS: This randomized controlled trial demonstrated that preoperative anxiety was equally low and induction compliance high with both 3D VR and 2D video distraction in children with parental presence during anesthetic induction.

Patient and Staff Insights on Digital Care Pathways for Patients With Low Back Pain in the Emergency Department: A Qualitative Study.

BACKGROUND: Back pain is a huge global problem. For some people, the pain is so severe that they feel the need to present to an emergency department (ED). Our aim was to explore patient and staff perspectives for the development of a digital care pathway (DCP) for people with back pain who have presented to ED, including acceptability, barriers and facilitators. METHODS: We used a descriptive phenomenology approach using semi-structured interviews with patient and staff participants at a tertiary hospital. Interviews were transcribed and data codes were developed using inductive thematic analysis. Themes were discussed between researchers until consensus was achieved. RESULTS: A total of 16 interviews were carried out, half of which involved patient participants. We identified three major themes: (i) expectations and experiences of staff and patients with low back pain in ED; (ii) a digital care pathway can empower patients and support clinicians in providing care; and (iii) acceptability, barriers, facilitators and recommendations of engaging with a DCP to track the trajectory of back pain. Each theme was further categorised into subthemes. CONCLUSION: Introducing a DCP was perceived as acceptable and beneficial by patients and staff. Both groups were aware of the potential participant burden if surveys were too long. Introducing a DCP could be a valuable adjunct to current management care models, providing a standardised source of education with the potential for individualised tracking and monitoring. The design and development of a DCP will need to consider reported facilitators and address perceived barriers for engagement. PATIENT OR PUBLIC CONTRIBUTION: This project sought insights from patients and staff about a digital care pathway. This forms the first step of patient and consumer consultation before implementing a digital care pathway. All consumers were offered the opportunity to review their responses and our interpretation.

BackTrAC: A Digital Care Pathway for People Presenting to Emergency with Lower Back Pain. A Development and Feasibility Study Protocol.

OBJECTIVES: Back pain is a prevalent condition that affects 1 in 6 Australians at any time, with high associated health care costs. To date, there is limited information relating to symptom severity and recovery trajectory in people with back pain who present to the emergency department for care. A digital care pathway (DCP) can track patient outcomes following presentation with back pain. The primary aim of this protocol is to outline the co-development, implementation, and evaluation of a DCP for back pain patients who present to the emergency department. METHODS: The primary aim will be addressed in 3 overlapping phases: Phase 1 (co-design) will include interviews with back pain patients and health care professionals from the Northern Hospital Emergency Department. Interview findings will inform education resources featured on the DCP and establish questionnaire content and frequency acceptability. Phase 2 (implementation) will include the rollout of the DCP and tracking of patient-reported outcome measures, which will be collected over 12 weeks. Phase 3 (evaluation) will include interviews with a subset of back pain patients who have participated in Phase 2 to evaluate the acceptability of the DCP and the barriers and facilitators of using the DCP. ETHICS AND DISSEMINATION: This project has been approved via the National Health and Medical Research Council of Australia's National Mutual Acceptance Scheme by St Vincent's Hospital Human Ethics Committee (2022/PID06476), La Trobe University Research Governance (HEC#206/22), and Northern Health Research Governance (NH-2023-372687). We plan to publish the findings in a peer-reviewed journal and present them at conferences.

Race, geography, and risk of breast cancer treatment delays: A population-based study 2004-2015.

BACKGROUND: Treatment delays affect breast cancer survival and constitute poor-quality care. Black patients experience more treatment delay, but the relationship of geography to these disparities is poorly understood. METHODS: We studied a population-based, retrospective, observational cohort of patients with breast cancer in North Carolina between 2004 and 2017 from the Cancer Information and Population Health Resource, which links cancer registry and sociodemographic data to multipayer insurance claims. We included patients >18 years with Stage I-III breast cancer who received surgery or chemotherapy as their first treatment. Delay was defined as >60 days from diagnosis to first treatment. Counties were aggregated into nine Area Health Education Center regions. Race was dichotomized as Black versus non-Black. RESULTS: Among 32,626 patients, 6190 (19.0%) were Black. Black patients were more likely to experience treatment delay >60 days (15.0% of Black vs. 8.0% of non-Black). Using race-stratified modified Poisson regression, age-adjusted relative risk of delay in the highest risk region was approximately twice that in the lowest risk region among Black (relative risk, 2.1; 95% CI, 1.6-2.6) and non-Black patients (relative risk, 1.9; 95% CI, 1.5-2.3). Adjustment for clinical and sociodemographic features only slightly attenuated interregion differences. The magnitude of the racial gap in treatment delay varied by region, from 0.0% to 9.4%. CONCLUSIONS: Geographic region was significantly associated with risk of treatment delays for both Black and non-Black patients. The magnitude of racial disparities in treatment delay varied markedly between regions. Future studies should consider both high-risk geographic regions and high-risk patient groups for intervention to prevent delays.

The relative importance of platelet integrins in hemostasis, thrombosis and beyond.

Integrins are heterodimeric transmembrane receptors composed of α and ß chains, with an N-terminal extracellular domain forming a globular head corresponding to the ligand binding site. Integrins regulate various cellular functions including adhesion, migration, proliferation, spreading and apoptosis. On platelets, integrins play a central role in adhesion and aggregation on subendothelial matrix proteins of the vascular wall, thereby ensuring hemostasis. Platelet integrins belong either to the ß1 family (α2ß1, α5ß1 and α6ß1) or to the ß3 family (αIIbß3 and αvß3). On resting platelets, integrins can engage their ligands when the latter are immobilized but not in their soluble form. The effects of various agonists promote an inside-out signal in platelets, increasing the affinity of integrins for their ligands and conveying a modest signal reinforcing platelet activation, called outside-in signaling. This outside-in signal ensures platelet adhesion, shape change, granule secretion and aggregation. In this review, we examine the role of each platelet integrin in hemostatic plug formation, hemostasis and arterial thrombosis and also beyond these classical functions, notably in tumor metastasis and sepsis.

Consumer research priorities for pediatric anesthesia and perioperative medicine.

BACKGROUND: Consumer-driven research is increasingly being prioritized. AIM: Our aim was to partner with consumers to identify the top 10 research priorities for pediatric anesthesia and perioperative medicine. The ACORN (Anesthesia Consumer Research Network) was formed to collaborate with children and families across Australia. METHODS: A prospective online survey was developed to generate research ideas from consumers. The survey was developed in Qualtrics, a survey research platform. Consumers were invited to participate through poster advertising, social media posts, via consumer networks at participating hospitals and in addition 35 national consumer/patient representative organizations were approached. We also conducted a similar idea generating survey for clinicians through email invitation and via Twitter. A second round of surveys was conducted to prioritize the long list of research questions and a shortlist of priorities developed. A single consensus meeting was held, and a final consensus list of top 10 priorities emerged. RESULTS: A total of 281 research ideas were submitted between 356 consumers in the idea generating survey and from four consumer/patient representative groups. Seventy-five clinicians responded to the clinician idea generation survey. This was consolidated into 20 research ideas/themes for the second survey for each group. 566 responses were received to the consumer prioritization top 10 survey and 525 responses to the clinician survey. The consensus meeting produced the final 10 consumer research priorities. CONCLUSION: This study has given Australian consumers the opportunity to shape the anesthesia and perioperative medicine research agenda for pediatric patients both nationally and internationally.

Myosin IIA suppresses glioblastoma development in a mechanically sensitive manner.

The ability of glioblastoma to disperse through the brain contributes to its lethality, and blocking this behavior has been an appealing therapeutic approach. Although a number of proinvasive signaling pathways are active in glioblastoma, many are redundant, so targeting one can be overcome by activating another. However, these pathways converge on nonredundant components of the cytoskeleton, and we have shown that inhibiting one of these-the myosin II family of cytoskeletal motors-blocks glioblastoma invasion even with simultaneous activation of multiple upstream promigratory pathways. Myosin IIA and IIB are the most prevalent isoforms of myosin II in glioblastoma, and we now show that codeleting these myosins markedly impairs tumorigenesis and significantly prolongs survival in a rodent model of this disease. However, while targeting just myosin IIA also impairs tumor invasion, it surprisingly increases tumor proliferation in a manner that depends on environmental mechanics. On soft surfaces myosin IIA deletion enhances ERK1/2 activity, while on stiff surfaces it enhances the activity of NFκB, not only in glioblastoma but in triple-negative breast carcinoma and normal keratinocytes as well. We conclude myosin IIA suppresses tumorigenesis in at least two ways that are modulated by the mechanics of the tumor and its stroma. Our results also suggest that inhibiting tumor invasion can enhance tumor proliferation and that effective therapy requires targeting cellular components that drive both proliferation and invasion simultaneously.

Evaluation of Cisplatin-Induced Pathology in the Larval Zebrafish Lateral Line.

Cisplatin is an effective anticancer agent, but also causes permanent hearing loss by damaging hair cells-the sensory receptors essential for hearing. There is an urgent clinical need to protect cochlear hair cells in patients undergoing cisplatin chemotherapy. The zebrafish lateral line organ contains hair cells and has been frequently used in studies to screen for otoprotective compounds. However, these studies have employed a wide range of cisplatin dosages and exposure times. We therefore performed a comprehensive evaluation of cisplatin ototoxicity in the zebrafish lateral line with the goal of producing a standardized, clinically relevant protocol for future studies. To define the dose- and time-response patterns of cisplatin-induced hair-cell death, we treated 6-day-old larvae for 2 h in 50 µM-1 mM cisplatin and allowed them to recover. We observed delayed hair cell death, which peaked at 4-8 h post-exposure. Cisplatin also activated a robust inflammatory response, as determined by macrophage recruitment and phagocytosis of hair cells. However, selective depletion of macrophages did not affect hair cell loss. We also examined the effect of cisplatin treatment on fish behavior and found that cisplatin-induced lateral line injury measurably impaired rheotaxis. Finally, we examined the function of remaining hair cells that appeared resistant to cisplatin treatment. We observed significantly reduced uptake of the cationic dye FM1-43 in these cells relative to untreated controls, indicating that surviving hair cells may be functionally impaired. Cumulatively, these results indicate that relatively brief exposures to cisplatin can produce hair cell damage and delayed hair cell death. Our observations provide guidance on standardizing methods for the use of the zebrafish model in studies of cisplatin ototoxicity.

Intervention Strategies and Lessons Learned From a Student-Led Initiative to Support Lactating Women in the University Setting.

The benefits of breastfeeding for mother and baby are strongly supported by research. However, lactating parents who return to school or work soon after delivery face many barriers to continued breastfeeding. This article presents a student-led initiative to support lactation at a large public university that emerged from advocacy efforts of student mothers of color. The socioecological model was used as a framework to understand and address the multifaceted influences on breastfeeding practices. Project activities included providing breastfeeding education to lactating parents and their partners, measuring availability and accessibility of lactation spaces, improving lactation spaces, connecting university stakeholders, and strengthening university lactation policies. The project achieved the following outcomes: formation of a stakeholder group with members across campus departments, improvement in accessibility and appropriateness of lactation spaces, provision of breastfeeding services through workshops and one-on-one appointments with lactation educators, and creation and dissemination of an online toolkit outlining parents' lactation rights and support available on campus. Comprehensive lactation support at universities is essential to enhance educational and professional equity for women and to promote postpartum and infant health. Throughout the project implementation, the team learned many lessons that can help guide similar university initiatives.

Pharmacological Blockade of Glycoprotein VI Promotes Thrombus Disaggregation in the Absence of Thrombin.

OBJECTIVE: Atherothrombosis occurs upon rupture of an atherosclerotic plaque and leads to the formation of a mural thrombus. Computational fluid dynamics and numerical models indicated that the mechanical stress applied to a thrombus increases dramatically as a thrombus grows, and that strong inter-platelet interactions are essential to maintain its stability. We investigated whether GPVI (glycoprotein VI)-mediated platelet activation helps to maintain thrombus stability by using real-time video-microscopy. Approach and Results: We showed that GPVI blockade with 2 distinct Fab fragments promoted efficient disaggregation of human thrombi preformed on collagen or on human atherosclerotic plaque material in the absence of thrombin. ACT017-induced disaggregation was achieved under arterial blood flow conditions, and its effect increased with wall shear rate. GPVI regulated platelet activation within a growing thrombus as evidenced by the loss in thrombus contraction when GPVI was blocked, and the absence of the disaggregating effect of an anti-GPVI agent when the thrombi were fully activated with soluble agonists. The GPVI-dependent thrombus stabilizing effect was further supported by the fact that inhibition of any of the 4 key immunoreceptor tyrosine-based motif signalling molecules, src-kinases, Syk, PI3Kß, or phospholipase C, resulted in kinetics of thrombus disaggregation similar to ACT017. The absence of ACT017-induced disaggregation of thrombi from 2 afibrinogenemic patients suggests that the role of GPVI requires interaction with fibrinogen. Finally, platelet disaggregation of fibrin-rich thrombi was also promoted by ACT017 in combination with r-tPA (recombinant tissue plasminogen activator). CONCLUSIONS: This work identifies an unrecognized role for GPVI in maintaining thrombus stability and suggests that targeting GPVI could dissolve platelet aggregates with a poor fibrin content.

Cost Utility of cognition-enhancing interventions for individuals with first-episode psychosis: a naturalistic evaluation.

BACKGROUND: Although effective treatments are available to address the cognitive deficits experienced by individuals with first-episode psychosis, provision of such treatments within Coordinated Specialty Care (CSC) programs is rare. One factor that may contribute to this is uncertainty about the cost implications of providing cognitive-enhancing treatments within the American mental healthcare system. The aim of this study is to complete a naturalistic evaluation of the cost utility of incorporating two different cognitive-enhancing interventions within an American CSC program. METHODS: Participants included 66, predominately white (75.38%), individuals with first-episode psychosis (19 women and 47 men) with a mean age of 22.71 years. Quality adjusted life years (QALYs) and cost of care were tracked among these individuals during their participation in a CSC program. These data were compared among three groups of participants during their first six months of care: (i) individuals who participated in metacognitive remediation therapy (MCR), (ii) individuals who participated in computerized cognitive remediation (CCR), and (iii) individuals who participated in no cognitive-enhancing intervention. RESULTS: Participation in MCR, but not CCR, was associated with larger gains in QALYs than participation in no cognitive-enhancing intervention within a CSC program. Moreover, data support the cost utility of MCR as compared to CCR or no-cognitive enhancing intervention within a CSC program. Conversely, CCR did not appear to be a cost-effective addition to CSC services. CONCLUSIONS: Our results highlight the potential cost utility of incorporating MCR within CSC programs for individuals with first-episode psychosis. However, given study limitations, these results should be interpreted cautiously until replicated by large, randomized controlled trials. Trial Registration ClinicalTrials.gov Identifier NCT01570972, registered April 4, 2012, Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT01570972?term=breitborde&draw=2&rank=6 .

Diagnostic prediction model development using data from dried blood spot proteomics and a digital mental health assessment to identify major depressive disorder among individuals presenting with low mood.

With less than half of patients with major depressive disorder (MDD) correctly diagnosed within the primary care setting, there is a clinical need to develop an objective and readily accessible test to enable earlier and more accurate diagnosis. The aim of this study was to develop diagnostic prediction models to identify MDD patients among individuals presenting with subclinical low mood, based on data from dried blood spot (DBS) proteomics (194 peptides representing 115 proteins) and a novel digital mental health assessment (102 sociodemographic, clinical and personality characteristics). To this end, we investigated 130 low mood controls, 53 currently depressed individuals with an existing MDD diagnosis (established current MDD), 40 currently depressed individuals with a new MDD diagnosis (new current MDD), and 72 currently not depressed individuals with an existing MDD diagnosis (established non-current MDD). A repeated nested cross-validation approach was used to evaluate variation in model selection and ensure model reproducibility. Prediction models that were trained to differentiate between established current MDD patients and low mood controls (AUC = 0.94 ± 0.01) demonstrated a good predictive performance when extrapolated to differentiate between new current MDD patients and low mood controls (AUC = 0.80 ± 0.01), as well as between established non-current MDD patients and low mood controls (AUC = 0.79 ± 0.01). Importantly, we identified DBS proteins A1AG1, A2GL, AL1A1, APOE and CFAH as important predictors of MDD, indicative of immune system dysregulation; as well as poor self-rated mental health, BMI, reduced daily experiences of positive emotions, and tender-mindedness. Despite the need for further validation, our preliminary findings demonstrate the potential of such prediction models to be used as a diagnostic aid for detecting MDD in clinical practice.

High indirect fitness benefits for helpers across the nesting cycle in the tropical paper wasp Polistes canadensis.

Explaining the evolution of helping behaviour in the eusocial insects where nonreproductive ("worker") individuals help raise the offspring of other individuals ("queens") remains one of the most perplexing phenomena in the natural world. Polistes paper wasps are popular study models, as workers retain the ability to reproduce: such totipotency is likely representative of the early stages of social evolution. Polistes is thought to have originated in the tropics, where seasonal constraints on reproductive options are weak and social groups are effectively perennial. Yet, most Polistes research has focused on nontropical species, where seasonality causes family groups to disperse; cofoundresses forming new nests the following spring are often unrelated, leading to the suggestion that direct fitness through nest inheritance is key in the evolution of helping behaviour. Here, we present the first comprehensive genetic study of social structure across the perennial nesting cycle of a tropical Polistes-Polistes canadensis. Using both microsatellites and newly developed single nucleotide polymorphism markers, we show that adult cofoundresses are highly related and that brood production is monopolized by a single female across the nesting cycle. Nonreproductive cofoundresses in tropical Polistes therefore have the potential to gain high indirect fitness benefits as helpers from the outset of group formation, and these benefits persist through the nesting cycle. Direct fitness may have been less important in the origin of Polistes sociality than previously suggested. These findings stress the importance of studying a range of species with diverse life history and ecologies when considering the evolution of reproductive strategies.

WASPnest: a worldwide assessment of social Polistine nesting behavior.

Cooperative breeding decreases the direct reproductive output of subordinate individuals, but cooperation can be evolutionarily favored when there are challenges or constraints to breeding independently. Environmental factors, including temperature, precipitation, latitude, high seasonality, and environmental harshness have been hypothesized to correlate with the presence of cooperative breeding. However, to test the relationship between cooperation and ecological constraints requires comparative data on the frequency and variation of cooperative breeding across differing environments, ideally replicated across multiple species. Paper wasps are primitively social species, forming colonies composed of reproductively active dominants and foraging subordinates. Adult female wasps, referred to as foundresses, initiate new colonies. Nests can be formed by a single solitary foundress (noncooperative) or by multiple foundress associations (cooperative). Cooperative behavior varies within and among species, making paper wasps species well suited to disentangling ecological correlates of variation in cooperative behavior. This data set reports the frequency and extent of cooperative nest founding for 87 paper wasp species. Data were assembled from more than 170 published sources, previously unpublished field observations, and photographs contributed by citizen scientists to online natural history repositories. The data set includes 25,872 nest observations and reports the cooperative behavioral decisions for 45,297 foundresses. Species names were updated to reflect modern taxonomic revisions. The type of substrate on which the nest was built is also included, when available. A smaller population-level version of this data set found that the presence or absence of cooperative nesting in paper wasps was correlated with temperature stability and environmental harshness, but these variables did not predict the extent of cooperation within species. This expanded data set contains details about individual nests and further increases the power to address the relationship between the environment and the presence and extent of cooperative breeding. Beyond the ecological drivers of cooperation, these high-resolution data will be useful for future studies examining the evolutionary consequences of variation in social behavior. This data set may be used for research or educational purposes provided that this data paper is cited.

Glucocerebrosidase mutations and neuropsychiatric phenotypes in Parkinson's disease and Lewy body dementias: Review and meta-analyses.

Heterozygous mutations in glucocerebrosidase gene (GBA) are a major genetic risk factor for Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Recently, there has been a considerable focus on the relationship between GBA mutations and emergence of cognitive impairment and neuropsychiatric symptoms in these diseases. Here, we review the literature in this area, with a particular focus, including meta-analysis, on the key neuropsychiatric symptoms of cognitive impairment, psychosis, and depression in Parkinson's disease. Our meta-analysis demonstrated that GBA mutations are associated with a 2.4-fold increased risk of cognitive impairment. In addition, our novel meta-analyses of psychosis and depression showed a 1.8- and 2.2-fold increased risk respectively associated with GBA mutations, although due to possible bias and heterogeneity the depression findings should be interpreted with caution. While the precise mechanisms which increase susceptibility to neurodegeneration in GBA carriers are not known, evidence of greater cortical Lewy body pathology, reduced patterns of cortical activation, and hippocampal pathology in animal models are all consistent with a direct effect of GBA mutations on these symptoms. Extension of this work in DLB and individuals without neurodegeneration will be important in further characterizing how GBA mutations increase risk for PD and DLB and influence disease course.

The 'ouR-HOPE' approach for ethics and communication about neonatal neurological injury.

Predicting neurological outcomes of neonates with acute brain injury is an essential component of shared decision-making, in order to guide the development of treatment goals and appropriate care plans. It can aid parents in imagining the child's future, and guide timely and ongoing treatment decisions, including shifting treatment goals and focusing on comfort care. However, numerous challenges have been reported with respect to evidence-based practices for prognostication such as biases about prognosis among clinicians. Additionally, the evaluation or appreciation of living with disability can differ, including the well-known disability paradox where patients self-report a good quality of life in spite of severe disability. Herein, we put forward a set of five practice principles captured in the "ouR-HOPE" approach (Reflection, Humility, Open-mindedness, Partnership, and Engagement) and related questions to encourage clinicians to self-assess their practice and engage with others in responding to these challenges. We hope that this proposal paves the way to greater discussion and attention to ethical aspects of communicating prognosis in the context of neonatal brain injury.

Examining chronic care patient preferences for involvement in health-care decision making: the case of Parkinson's disease patients in a patient-centred clinic.

BACKGROUND: Patient-centred care is a recommended model of care for Parkinson's disease (PD). It aims to provide care that is respectful and responsive to patient preferences, values and perspectives. Provision of patient-centred care should entail considering how patients want to be involved in their care. OBJECTIVE: To understand the participation preferences of patients with PD from a patient-centred care clinic in health-care decision-making processes. DESIGN, SETTING AND PARTICIPANTS: Mixed-methods study with early-stage Parkinson's disease patients from a patient-centred care clinic. Study involved a modified Autonomy Preference Index survey (N=65) and qualitative, semi-structured in-depth interviews, analysed using thematic qualitative content analysis (N=20, purposefully selected from survey participants). Interviews examined (i) the patient preferences for involvement in health-care decision making; (ii) patient perspectives on the patient-physician relationship; and (iii) patient preferences for communication of information relevant to decision making. RESULTS: Preferences for participation in decision making varied between individuals and also within individuals depending on decision type, relational and contextual factors. Patients had high preferences for communication of information, but with acknowledged limits. The importance of communication in the patient-physician relationship was emphasized. DISCUSSION: Patient preferences for involvement in decision making are dynamic and support shared decision making. Relational autonomy corresponds to how patients envision their participation in decision making. Clinicians may need to assess patient preferences on an on-going basis. CONCLUSION: Our results highlight the complexities of decision-making processes. Improved understanding of individual preferences could enhance respect for persons and make for patient-centred care that is truly respectful of individual patients' wants, needs and values.

The concept of 'vulnerability' in research ethics: an in-depth analysis of policies and guidelines.

BACKGROUND: The concept of vulnerability has held a central place in research ethics guidance since its introduction in the United States Belmont Report in 1979. It signals mindfulness for researchers and research ethics boards to the possibility that some participants may be at higher risk of harm or wrong. Despite its important intended purpose and widespread use, there is considerable disagreement in the scholarly literature about the meaning and delineation of vulnerability, stemming from a perceived lack of guidance within research ethics standards. The aim of this study was to assess the concept of vulnerability as it is employed in major national and international research ethics policies and guidelines. METHODS: We conducted an in-depth analysis of 11 (five national and six international) research ethics policies and guidelines, exploring their discussions of the definition, application, normative justification and implications of vulnerability. RESULTS: Few policies and guidelines explicitly defined vulnerability, instead relying on implicit assumptions and the delineation of vulnerable groups and sources of vulnerability. On the whole, we found considerable richness in the content on vulnerability across policies, but note that this relies heavily on the structure imposed on the data through our analysis. CONCLUSIONS: Our results underscore a need for policymakers to revisit the guidance on vulnerability in research ethics, and we propose that a process of stakeholder engagement would well-support this effort.