"I feel more confident": a mixed methods evaluation of the influence of Good Life with osteoarthritis Denmark (GLA:D®) on physical activity participation, capability, barriers, and facilitators in people with knee osteoarthritis.

BACKGROUND: A mixed methods study which aimed to evaluate the influence of Good Life with osteoArthritis Denmark (GLA:D®) on physical activity participation, including perceived capability, barriers, and facilitators in people with knee osteoarthritis. OBJECTIVE: Quantify changes in physical activity participation at 3- and 12-months for people with knee osteoarthritis who participated in an education and exercise-therapy program (GLA:D®). METHODS: A mixed-methods study involving 44 participants with knee osteoarthritis who completed GLA:D®. Guided by the Theoretical Domains Framework, 19 were interviewed, with transcripts analysed using reflexive thematic analysis. University of California Los Angeles physical activity scores were dichotomised as 'more' (≥7) or 'less' active (≤6), and compared between baseline and 3- and 12-months using McNemar's test. Motivation and confidence to exercise (0-10 scale); fear of knee joint damage with exercise (yes/no); and Knee Osteoarthritis Outcome Scores (KOOS) were evaluated. RESULTS: Four overarching themes were identified: prior to GLA:D® 1) fear of knee joint damage, and scarcity of exercise and physical activity information prior to GLA:D®; and following GLA:D® 2) varied exercise-therapy and physical activity participation; 3) facilitators including reduced fear of knee damage, increased confidence, routine, strategies, and support; and 4) ongoing barriers including persistent knee pain, comorbidities, cost, and lack of opportunity and motivation. There was no difference in the proportion of 'more' active participants between baseline (41%) and at 3-months (37%, p = 0.774) or 12-months (35%, p = 0.375). The proportion with fear of damage reduced from baseline (50%) to 3-months (5%) and 12-months (21%). Self-reported motivation (9.1/10) and confidence (9.1/10) to exercise at 3-months were high, and all KOOS subscales improved from baseline to 3-months (effect sizes = 0.41-0.58) and 12-months (effect sizes = 0.29-0.66). CONCLUSION: Varied and often inadequate physical activity participation following GLA:D® indicates more targeted interventions to address ongoing barriers may be required.

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.

What are participant beliefs regarding physical therapy led treatment? A qualitative study of people living with femoroacetabular impingement syndrome.

BACKGROUND: Physical therapist-led treatment programs are recommended for patients with femoroacetabular impingement (FAI) syndrome. Views of people with FAI syndrome regarding such interventions are currently unknown, including perceptions of potential barriers and facilitators to participation and adherence to exercise programs. OBJECTIVES: To explore participant perceptions of physical therapist-led programs for FAI syndrome, including barriers and facilitators for accessing physical therapy, and adhering to a rehabilitation program. METHODS: Our qualitative study used semi-structured interviews to explore the perceptions of patients with FAI syndrome undertaking physical therapy-led treatment, where treatment was ceased due to Coronavirus Disease 2019 (COVID-19). The interview topic guide was informed by the Theoretical Domain Framework. Interviews were transcribed verbatim and data categories were developed using inductive thematic analysis. Themes were discussed between researchers until consensus was reached. RESULTS: Fourteen participants (mean age: 30 years) with a range of physical activity backgrounds undertook interviews. We identified four key themes, 1) Patients believed their hip pain was caused by structural damage worsened through exercise; 2) Barriers and facilitators on the feasibility of physical therapist-led programs; 3) Participants held beliefs regarding the importance of adjunct treatments to exercise; and 4) Impact of FAI syndrome on physical activity participation. CONCLUSION: People with FAI syndrome believe they have structural damage which leads to their hip pain and are often afraid to exercise due to fear of causing more damage to their hip. Our findings suggest that people with FAI syndrome want clear education about exercise, imaging, and expectations of cost and duration of treatment.

Facilitation of motor evoked potentials after tetanic peripheral nerve stimulation.

OBJECTIVE: Tetanic stimulation of a peripheral nerve prior to transcranial electrical stimulation (TES) may enhance motor evoked potential (MEP) amplitudes. The purpose of this study was to investigate the post-tetanic MEP (p-MEP) technique in improving MEP amplitudes. METHODS: Conventional TES MEPs (c-MEP) and p-MEPs with left upper limb stimulation (p-MEPUL) or left lower limb stimulation (p-MEPLL) were performed in 26 patients. Bilateral hand and foot MEP amplitudes obtained with each protocol were compared. Subgroup comparisons were performed for myelopathy and peripheral neuropathy patients. Within-subject amplitude differences between c-MEP and each p-MEP technique were compared using a Wilcoxon test. RESULTS: The mean age of the patients was 52.7 years (range, 12-79 years). Overall, p-MEPUL resulted in MEP improvement in 25 of 26 (96%) patients, and p-MEPLL improved MEPs in 19 of 26 (73%) patients. The increase in MEP amplitudes were statistically significant in all muscle groups except left foot. Similar improvements were seen in the myelopathy group; in the neuropathy group, p-MEPUL produced similar results, but p-MEPLL did not. CONCLUSIONS: The p-MEP technique can improve MEP amplitudes, including in patients with myelopathy. In patients with peripheral neuropathy, the results were mixed. SIGNIFICANCE: Tetanic stimulation can enhance intraoperative MEP amplitudes.

Metabolomic Biomarker Signatures for Bipolar and Unipolar Depression.

Importance: Bipolar disorder (BD) is frequently misdiagnosed as major depressive disorder (MDD) because of overlapping symptoms and the lack of objective diagnostic tools. Objective: To identify a reproducible metabolomic biomarker signature in patient dried blood spots (DBSs) that differentiates BD from MDD during depressive episodes and assess its added value when combined with self-reported patient information. Design, Setting, and Participants: This diagnostic analysis used samples and data from the Delta study, conducted in the UK between April 27, 2018, and February 6, 2020. The primary objective was to identify BD in patients with a recent (within the past 5 years) diagnosis of MDD and current depressive symptoms (Patient Health Questionnaire-9 score of 5 or more). Participants were recruited online through voluntary response sampling. The analysis was carried out between February 2022 and July 2023. Main Outcomes and Measures: Patient data were collected using a purpose-built online questionnaire (n = 635 questions). DBS metabolites (n = 630) were analyzed using a targeted mass spectrometry-based platform. Mood disorder diagnoses were established using the Composite International Diagnostic Interview. Results: Of 241 patients in the discovery cohort, 170 (70.5%) were female; 67 (27.8%) were subsequently diagnosed with BD and 174 (72.2%) were confirmed as having MDD; and the mean (SD) age was 28.1 (7.1) years. Of 30 participants in the validation cohort, 16 (53%) were female; 9 (30%) were diagnosed with BD and 21 (70%) with MDD; and the mean (SD) age was 25.4 (6.3) years. DBS metabolite levels were assessed in 241 patients with depressive symptoms with a recent diagnosis of MDD, of whom 67 were subsequently diagnosed with BD by the Composite International Diagnostic Interview and 174 were confirmed as having MDD. The identified 17-biomarker panel provided a mean (SD) cross-validated area under the receiver operating characteristic curve (AUROC) of 0.71 (SD, 0.12; P < .001), with ceramide d18:0/24:1 emerging as the strongest biomarker. Combining biomarker data with patient-reported information significantly enhanced diagnostic performance of models based on extensive demographic data, PHQ-9 scores, and the outcomes from the Mood Disorder Questionnaire. The identified biomarkers were correlated primarily with lifetime manic symptoms and were validated in a separate group of patients who received a new clinical diagnosis of MDD (n = 21) or BD (n = 9) during the study's 1-year follow-up period, with a mean (SD) AUROC of 0.73 (0.06; P < .001). Conclusions and Relevance: This study provides a proof of concept for developing an accessible biomarker test to facilitate the differential diagnosis of BD and MDD and highlights the potential involvement of ceramides in the pathophysiological mechanisms of mood disorders.

Using SUpported Motivational InTerviewing (SUMIT) to increase physical activity for people with knee osteoarthritis: a pilot, feasibility randomised controlled trial.

OBJECTIVE: The objective of this study was to determine the feasibility and effectiveness of using SUpported Motivational InTerviewing (SUMIT) to increase physical activity in people with knee osteoarthritis (KOA). DESIGN: Randomised controlled trial. SETTING: We recruited people who had completed Good Life with osteoArthritis Denmark (GLA:D) from private, public and community settings in Victoria, Australia. INTERVENTIONS: Participants were randomised participants to receive SUMIT or usual care. SUMIT comprised five motivational interviewing sessions targeting physical activity over 10 weeks, and access to a multimedia web-based platform. PARTICIPANTS: Thirty-two participants were recruited (17 SUMIT, 15 control) including 22 females (69%). OUTCOME MEASURES: Feasibility outcomes included recruitment rate, adherence to motivational interviewing, ActivPAL wear and drop-out rate. Effect sizes (ESs) were calculated for daily steps, stepping time, time with cadence >100 steps per minute, time in bouts >1 min; 6 min walk distance, Knee Osteoarthritis Outcome Score (KOOS) subscales (pain, symptoms, function, sport and recreation, and quality of life (QoL)), Euroqual, systolic blood pressure, body mass index, waist circumference, 30 s chair stand test and walking speed during 40 m walk test. RESULTS: All feasibility criteria were achieved, with 32/63 eligible participants recruited over seven months; with all participants adhering to all motivational interviewing calls and achieving sufficient ActivPAL wear time, and only two drop-outs (6%).12/15 outcome measures showed at least a small effect (ES>0.2) favouring the SUMIT group, including daily time with cadence >100 steps per minute (ES=0.43). Two outcomes, walking speed (ES= 0.97) and KOOS QoL (ES=0.81), showed a large effect (ES>0.8). CONCLUSION: SUMIT is feasible in people with knee osteoarthritis. Potential benefits included more time spent walking at moderate intensity, faster walking speeds and better QoL. TRIAL REGISTRATION NUMBER: ACTRN12621000267853.

Association of baseline physical activity participation with participant characteristics and outcomes following education and exercise-therapy in people with knee osteoarthritis: A GLA:D® Australia prospective cohort study.

OBJECTIVES: To investigate whether participants with knee osteoarthritis classified as 'more' or 'less' physically active at baseline differ in characteristics and/or outcomes at baseline and at 3 and 12 months following the commencement of an education and exercise-therapy program. METHODS: Prospective cohort study using the GLA:D® Australia registry. The University of California, Los Angeles Physical Activity Scale (UCLA) participant data dichotomised as 'more' (≥7) or 'less' active (≤6). Groups were compared using chi-square (obesity [baseline only], comorbidity prevalence, medication consumption, fear of damage from physical activity); and linear mixed model regression (12-item Injury Osteoarthritis Outcome Score [KOOS-12], pain [visual analogue scale], health-related quality of life [QoL] [EQ-5D-5L]) statistics, adjusted for age, sex and baseline physical activity at 3 and 12 months. RESULTS: We included 1059 participants (70% female). At baseline, 267 (25%) were classified as 'more' active, increasing to 29% and 30% at 3 and 12 months, respectively. At baseline, compared to the 'less' active group, the 'more' active group had a lower proportion of participants who were obese ('more' = 21% vs. 'less' = 44%), had comorbidities (58% vs. 74%) and consumed medications (71% vs. 85%); lower pain intensity (37 vs. 47); and higher KOOS-12 (59 vs. 50), and health-related QoL (0.738 vs. 0.665) scores. When accounting for age, sex and baseline physical activity, improvements seen in knee-related burden and health-related QoL were not different between groups at 3 or 12 months. Compared to the 'less' active group, the proportion of participants not consuming medication remained higher in the 'more' active group at 3 ('more' 45% vs. 'less' 28%) and 12 months (43% vs. 32%). CONCLUSION: 'More' active people with knee osteoarthritis were less likely to be obese, had fewer comorbidities, lower medication consumption, knee-related burden and pain intensity, and higher health-related QoL than 'less' active participants at all timepoints.

Use of a mixed-methods approach to develop a guidebook with messaging to encourage colorectal cancer screening among Black individuals 45 and older.

INTRODUCTION: Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States and disproportionately impacts Black individuals. Here, we describe the mixed-methods approach used to develop a tailored message guidebook to promote CRC screening among Black individuals in the setting of recently updated screening guidelines. METHODS: This mixed-methods study included 10 in-depth qualitative interviews and 490 surveys in a nationally representative sample of unscreened Black individuals age ≥ 45. Messages were developed based on American Cancer Society (ACS) and National Colorectal Cancer Roundtable (NCCRT) research findings, tested among Black individuals using MaxDiff analytic methods, and reviewed by a multi-sector expert advisory committee of NCCRT members. RESULTS: The most frequently reported screening barrier in all age groups was self-reported procrastination (40.0% in age 45-49, 42.8% for age 50-54, 34.2% for age ≥ 55). Reasons for procrastination varied by age and included financial concerns, COVID-19 concerns, and fear of the test and bowel preparation. Additional screening barriers included lack of symptoms, provider recommendation, and family history of CRC. Most individuals age 45-49 preferred to receive screening information from a healthcare provider (57.5%); however, only 20% reported that a provider had initiated a screening conversation. CONCLUSIONS: We identified age-specific barriers to CRC screening and tailored messaging to motivate participation among unscreened Black people age ≥ 45. Findings informed the development of the NCCRT and ACS guidebook for organizations and institutions aiming to increase CRC screening participation in Black individuals.

Nonpoint source pollution measures in the Clean Water Act have no detectable impact on decadal trends in nutrient concentrations in U.S. inland waters.

The Clean Water Act (CWA) of 1972 regulates water quality in U.S. inland waters under a system of cooperative federalism in which states are delegated implementation and enforcement authority of CWA provisions by the U.S. Environmental Protection Agency. We leveraged heterogeneity in state implementation of the CWA to evaluate the efficacy of its nonpoint source provisions in reducing nutrient pollution, the leading cause of water quality impairment in U.S. inland waters. We used national survey data to estimate changes in nutrient concentrations over a decade and evaluated the effect of state-level policy implementation. We found no evidence to support an effect of (i) grant spending on nonpoint source pollution remediation, (ii) nutrient criteria development, or (iii) water quality monitoring intensity on 10-year trends in nutrient concentrations. These results suggest that the current federal policy paradigm for improving water quality is not creating desired outcomes.

Social complexity, life-history and lineage influence the molecular basis of castes in vespid wasps.

A key mechanistic hypothesis for the evolution of division of labour in social insects is that a shared set of genes co-opted from a common solitary ancestral ground plan (a genetic toolkit for sociality) regulates caste differentiation across levels of social complexity. Using brain transcriptome data from nine species of vespid wasps, we test for overlap in differentially expressed caste genes and use machine learning models to predict castes using different gene sets. We find evidence of a shared genetic toolkit across species representing different levels of social complexity. We also find evidence of additional fine-scale differences in predictive gene sets, functional enrichment and rates of gene evolution that are related to level of social complexity, lineage and of colony founding. These results suggest that the concept of a shared genetic toolkit for sociality may be too simplistic to fully describe the process of the major transition to sociality.

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.

Airborne Lidar Measurements of XCO2 in Synoptically Active Environment and Associated Comparisons With Numerical Simulations.

Frontal boundaries have been shown to cause large changes in CO2 mole-fractions, but clouds and the complex vertical structure of fronts make these gradients difficult to observe. It remains unclear how the column average CO2 dry air mole-fraction (XCO2) changes spatially across fronts, and how well airborne lidar observations, data assimilation systems, and numerical models without assimilation capture XCO2 frontal contrasts (ΔXCO2, i.e., warm minus cold sector average of XCO2). We demonstrated the potential of airborne Multifunctional Fiber Laser Lidar (MFLL) measurements in heterogeneous weather conditions (i.e., frontal environment) to investigate the ΔXCO2 during four seasonal field campaigns of the Atmospheric Carbon and Transport-America (ACT-America) mission. Most frontal cases in summer (winter) reveal higher (lower) XCO2 in the warm (cold) sector than in the cold (warm) sector. During the transitional seasons (spring and fall), no clear signal in ΔXCO2 was observed. Intercomparison among the MFLL, assimilated fields from NASA's Global Modeling and Assimilation Office (GMAO), and simulations from the Weather Research and Forecasting--Chemistry (WRF-Chem) showed that (a) all products had a similar sign of ΔXCO2 though with different levels of agreement in ΔXCO2 magnitudes among seasons; (b) ΔXCO2 in summer decreases with altitude; and (c) significant challenges remain in observing and simulating XCO2 frontal contrasts. A linear regression analyses between ΔXCO2 for MFLL versus GMAO, and MFLL versus WRF-Chem for summer-2016 cases yielded a correlation coefficient of 0.95 and 0.88, respectively. The reported ΔXCO2 variability among four seasons provide guidance to the spatial structures of XCO2 transport errors in models and satellite measurements of XCO2 in synoptically-active weather systems.

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.

Endosomal LC3C-pathway selectively targets plasma membrane cargo for autophagic degradation.

Autophagy selectively targets cargo for degradation, yet mechanistic understanding remains incomplete. The ATG8-family plays key roles in autophagic cargo recruitment. Here by mapping the proximal interactome of ATG8-paralogs, LC3B and LC3C, we uncover a LC3C-Endocytic-Associated-Pathway (LEAP) that selectively recruits plasma-membrane (PM) cargo to autophagosomes. We show that LC3C localizes to peripheral endosomes and engages proteins that traffic between PM, endosomes and autophagosomes, including the SNARE-VAMP3 and ATG9, a transmembrane protein essential for autophagy. We establish that endocytic LC3C binds cargo internalized from the PM, including the Met receptor tyrosine kinase and transferrin receptor, and is necessary for their recruitment into ATG9 vesicles targeted to sites of autophagosome initiation. Structure-function analysis identified that LC3C-endocytic localization and engagement with PM-cargo requires the extended carboxy-tail unique to LC3C, the TBK1 kinase, and TBK1-phosphosites on LC3C. These findings identify LEAP as an unexpected LC3C-dependent pathway, providing new understanding of selective coupling of PM signalling with autophagic degradation.

Low lamin A levels enhance confined cell migration and metastatic capacity in breast cancer.

Aberrations in nuclear size and shape are commonly used to identify cancerous tissue. However, it remains unclear whether the disturbed nuclear structure directly contributes to the cancer pathology or is merely a consequence of other events occurring during tumorigenesis. Here, we show that highly invasive and proliferative breast cancer cells frequently exhibit Akt-driven lower expression of the nuclear envelope proteins lamin A/C, leading to increased nuclear deformability that permits enhanced cell migration through confined environments that mimic interstitial spaces encountered during metastasis. Importantly, increasing lamin A/C expression in highly invasive breast cancer cells reflected gene expression changes characteristic of human breast tumors with higher LMNA expression, and specifically affected pathways related to cell-ECM interactions, cell metabolism, and PI3K/Akt signaling. Further supporting an important role of lamins in breast cancer metastasis, analysis of lamin levels in human breast tumors revealed a significant association between lower lamin A levels, Akt signaling, and decreased disease-free survival. These findings suggest that downregulation of lamin A/C in breast cancer cells may influence both cellular physical properties and biochemical signaling to promote metastatic progression.