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Sandra L Carroll,1–3 Gayathri Embuldeniya,3 Jasprit Pannag,1 Krystina B Lewis,4 Jeff S Healey,2,3,5 Michael McGillion,1,2 Lehana Thabane,2,6,7 Dawn Stacey4,8 1School of Nursing, McMaster University, Hamilton, ON, Canada; 2Population Health Research Institute, Hamilton Health Sciences, Hamilton, ON, Canada; 3Hamilton Health Sciences, Hamilton, ON, Canada; 4School of Nursing, University of Ottawa, Ottawa, ON, Canada; 5Department of Medicine, McMaster University, Hamilton, ON, Canada; 6Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada; 7Biostatistics Unit, St. Joseph’s Healthcare, Hamilton, ON, Canada; 8Ottawa Hospital Research Institute, Ottawa, ON, Canada Purpose: Patients’ values are a key component of patient-centered care and shared decision making in health care organizations. There is limited understanding on how patients’ values guide their health related decision making or how patients understand the concept of values during these processes. This study investigated patients’ understanding of their values in the context of considering the risks/benefits of receiving an implantable cardioverter-defibrillator (ICD). Patients and methods: A qualitative substudy was conducted within a feasibility trial with first-time ICD candidates randomized to receive a patient decision aid or usual care prior to specialist consultation. Semi-structured interviews were conducted with participants post-implantation or post-specialist consultation. Results: Sixteen patients (ten male) aged 47–87 years participated. Of these, ten (62.5%) received the patient decision aid prior to specialist consultation. Findings revealed patients were confused by the word “values” and had difficulty expressing values related to risks/benefits during ICD decision making. When probed, values were conceptualized broadly capturing other factors such as desire to live, good quality of life, family’s views, ICD information, control over decision, and medical authority. Conclusion: This study revealed the difficulty patients considering an ICD had with articulating their values in the context of an ICD health decision and highlighted the challenge to effectively elicit patients’ values within health decisions overall. It is suggested that there should be a shift away from the use of the word “values” when speaking directly to patients toward language such as “what matters to you the most” or “what is most important to you”. Keywords: values, patient preferences, patient engagement, qualitative, health decision

Sandra L Carroll,1 Gayathri Embuldeniya,1 Julia Abelson,2 Michael McGillion,1 Alexandre Berkesse,3 Jeff S Healey4 1Faculty of Health Sciences, School of Nursing, McMaster University, Hamilton, ON, 2Faculty of Health Sciences, Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, 3Faculty of Medicine, University of Montreal, Montreal, QC, 4Faculty of Health Sciences, Department of Medicine, McMaster University, Hamilton, ON, Canada Background: Patient engagement in research is a dominant discourse in clinical research settings as it is seen as a move toward sustainable and equitable health care systems. In Canada, a key driver is the Strategy for Patient-Oriented Research of the Canadian Institutes of Health Research, which asserts that meaningful patient engagement can only be fostered when stakeholders understand its value. This study assessed researchers’ perceptions of the meaning and value of patient engagement in research within a Canadian cardiovascular research network. In doing so, the secondary aim was to inform the development of a structured patient engagement initiative by identifying potential challenges and related mitigation strategies.Methods: We employed a multi-method strategy involving electronic surveys and semi-structured telephone interviews with network research scientists across Canada. Interview data were analyzed using thematic and content analysis. Survey data were analyzed using descriptive statistics.Results: Thirty-eight electronic surveys (response rate =33%) and 16 interviews were completed with network members. Some participants were uncertain about the meaning and value of patient engagement. While voicing guarded support, four challenges relating to patient engagement were identified from the interviews: 1) identification of representative and appropriate patients, 2) uncertainty about the scope of patients’ roles given concerns about knowledge discrepancies, 3) a perceived lack of evidence of the impact of patient engagement, and 4) the need for education and culture change as a prerequisite for patient engagement. Research scientists were largely concerned that patients untrained in science and tasked with conveying an authentic patient experience and being a conduit for the voices of others might unsettle a traditional model of conducting research.Conclusion: Concerns about patient involvement in research were related to a lack of clarity about the meaning, process, and impact of involvement. This study highlights the need for education on the meaning of patient engagement, evidence of its impact, and guidance on practical aspects of implementation within this research community. Keywords: patient oriented research, health policy, medical culture, patient-centered care, stroke

BACKGROUND:: Implantable cardioverter defibrillators (ICDs) are increasingly offered to patients for primary prevention of sudden cardiac death. Candidates for ICD receive ICD-related patient education material when they make decisions to consent or decline a primary prevention ICD. Printed patient education material directed at ICD candidates has not been the focus of direct appraisal. OBJECTIVE:: We evaluated the readability and content of ICD-related print education materials made available to patients who were enrolled in a study involving patient decision making for ICD from 3 ICD sites in southern Ontario, Canada. METHODS:: All ICD print materials referred to during interviews and/or that were available in ICD site waiting rooms were collected for analysis. Readability testing was conducted using the 'simple measurement of gobbledygook' and Fry methods. The material was evaluated according to selected plain-language criteria, thematic content analysis, and rhetoric analysis. RESULTS:: Twenty-one print materials were identified and analyzed. Documents were authored by device manufacturers, tertiary care hospitals, and cardiac support organizations. Although many documents adhered to plain-language recommendations, text-reading levels were higher than recommended. Twelve major content themes were identified. Content focused heavily on the positive aspects of living with the device to the exclusion of other possible information that could be relevant to the decisions that patients made. CONCLUSIONS:: Print-based patient education materials for ICD candidates are geared to a highly literate population. The focus on positive information to the exclusion of potentially negative aspects of the ICD, or alternatives to accepting 1, could influence and/or confuse patients about the purpose and implications of this medical device. Development of print materials is indicated that includes information about possible problems and that would be relevant for the multicultural and debilitated population who may require ICDs. The findings are highly relevant for nurses who care for primary prevention ICD candidates. [ABSTRACT FROM AUTHOR]

BACKGROUND: Increasingly, patients are receiving implantable cardioverter defibrillators (ICDs) for prevention of sudden cardiac death. ICDs are implanted for primary prevention (patients at risk for ventricular arrhythmia [PP]) and secondary prevention (patients who have had/survived a sustained ventricular arrhythmia or cardiac arrest [SP]). Few prospective studies have examined psychosocial factors associated with these patients. OBJECTIVES: To determine if patients receiving their first ICD for PP versus SP differed in uncertainty, anxiety, and optimism, before, 1 week, and 1 month after implant. DESIGN: Prospective, descriptive, correlational pilot. PARTICIPANTS AND SETTING: Fifteen PP and 15 SP patients receiving their first ICD were enrolled. Mean ages (+/- SD) were 65.7+/-11.3 and 67.9+/-7.7 respectively. METHODS: Mishel's Uncertainty in Illness Scale (MUIS-C), State-Trait Anxiety Inventory (STAI) and the Life Orientation Test (LOT-R) were taken pre-implant, at the first post-implant visit, and at 1 month. Measures were compared using Student't-tests and ANOVA. RESULTS: Pre-implant, both groups had moderately high MUIS-C scores (mean+/-SD; PP=67.67+/-13.36; SP=70.27+/-6.80; t=0.67; t(df)=28; p=0.507). LOT-R scores were 15.67+/-3.8 for PP and 16.47+/-3.6 for SP; t=0.59; t(df)=28; p=0.557. Pre-implant state anxiety scores were (mean PP=37.40+/-10.0, SP=37.73+/-13.6; t=0.076; t(df)=28; p=0.940). At 1-month PP patients had significantly lower uncertainty scores than the SP group (mean 62.33+/-4.17 versus 67.87+/-4.61; t=3.45; t(df)=28; p=0.002). A main effect for time, between pre-implant and 1-month, was found for uncertainty (F(2,56)=3.26; p<0.05) and state anxiety (F(2,56)=3.61, p<0.05), where both groups showed lower scores. CONCLUSION: This study identified moderately high uncertainty in PP and SP patients prior to receiving their ICD. Though uncertainty was high, both groups reported an optimistic disposition and normal anxiety. At 1-month, SP patients had higher uncertainty scores than PP patients. This post-intervention uncertainty among patients who experienced an arrhythmic event warrants attention from nurses caring for ICD patients. Interventions to ameliorate uncertainty should be tailored to consider ICD indication. [ABSTRACT FROM AUTHOR]

What are the experiences of patients and partners regarding return to sexual activity after implantable cardioverter defibrillator (ICD) insertion?DESIGNA qualitative descriptive study.SETTINGWichita and Topeka, Kansas, USA.PARTICIPANTS12 patients (10 men and 2 women) (age range 20-83 y) with ICDs and 4 partners (1 man and 3 women) (age range 22-76 y). All but 1 patient reported being sexually active; this patient ceased all sexual activity after an episode of ICD discharge during sexual activity.METHODSData were collected using semistructured interviews, which were recorded, transcribed verbatim, and analysed using a qualitative descriptive approach.MAIN FINDINGS(1) Anxiety and apprehension regarding sexual activity. Most patients and partners expressed concerns about resuming sex after ICI) implantation. 9 of 12 patients expressed sexual concerns. They were apprehensive about what might set off the ICD and feared that the ICD would fire with each sexual encounter. Some patients described this as an initial concern, whereas for others, it was an ongoing concern. All 4 partner interviews reflected considerable worry and anxiety about the effect of the ICD on the patient. Partners reported being watchful of patients, particularly with respect to activities, the device itself, and medications. Concerns about ICD discharge during sexual activity also had an effect on the couple's usual activities. One partner stated, 'It's the fear that you have to not go as far as you used to. Because you don't know if it will go off...maybe we should just kind of wait.' Partner anxiety often resulted in overprotectiveness of the patient with an ICD. (2) Varying interest and patterns of sexual activity. Most patients described continued or increased interest in sexual activity. 10 of 12 patients reported strong sexual interest. 2 patients described an increase in sexual activity. Likewise, 3 partners reported strong sexual interest, although anxiety was evident. However, a few patients--particularly those who had the ICD discharge with sexual activity--reported decreased sexual interest during some time periods. Both patients and partners discussed sexual activities outside of sexual intercourse. Also, the frequency and usual patterns of sexual activity were affected by the ICD. Backing off and waiting to resume sex after ICD discharge was common. (3) Powerfulness of ICD discharge. Patients compared ICD discharge to having the 'top of your head blown off' or 'being shot up close with a 9 mm (gun).' Some patients also described the surprise, fear, and sensations that occurred when the ICD discharged with sexual activity. Sensations included seeing lights or flashing and 'ears popping.' Partners felt physical sensations such as 'bumping together really hard,' being kicked (by the patient) while asleep in the middle of the night, or a bolt of lightening. Furthermore, ICD discharge with sexual activity did not have a predictable pattern. (4) A need for information and sexual counselling. Some participants identified a cardiologist, family physician, nurse practitioner, or physician assistant as healthcare providers with whom they would prefer to discuss sexual concerns related to the ICD. However, 7 patients did not have a preference as long as the provider was knowledgeable and could provide the needed information. Although talking with healthcare providers was one approach for obtaining information, 6 patients believed that topics such as living with the ICD, including sexual issues, could be discussed with an ICD support group member. The ideal support group member was described as a sexually active patient who had had an ICD discharge. The lack of information on resuming sexual activity was also evident front participant reports. 7 patients and 1 partner discussed the need for more information and what to expect on resuming sexual activity. 6 participants specifically wanted information on the possibility of ICD discharge with sexual activity. Advice on what to tell other patients with an ICD included that patients with newly inserted ICDs should he given permission to resume sexual activity, reassurance that one could resume a normal sex life, and the importance of open communication between the patient and partner about the experience of living with the ICD. Overall, the ICD was viewed as a way to resume a normal lifestyle.CONCLUSIONPatients with an implantable cardioverter defibrillator approached sexual activity with anxiety, apprehension, varied interest and patterns of activity, and expressed a need for information and sexual counselling. [ABSTRACT FROM AUTHOR]

Conservation plans that explicitly account for the social landscape where people and wildlife co-occur can yield more effective and equitable conservation practices and outcomes. Yet, social data remain underutilized, often because social data are treated as aspatial or are analyzed with approaches that do not quantify uncertainty or address bias in self-reported data. We conducted a survey (questionnaires) of 177 households in a multiuse landscape in the Kenya-Tanzania borderlands. In a mixed-methods approach, we used Bayesian hierarchical models to quantify and map local attitudes toward African elephant (Loxodonta africana) conservation while accounting for response bias and then combined inference from attitude models with thematic analysis of open-ended responses and cointerpretation of results with local communities to gain deeper understanding of what explains attitudes of people living with wildlife. Model estimates showed that believing elephants have sociocultural value increased the probability of respondents holding positive attitudes toward elephant conservation in general (mean increase = 0.31 [95% credible interval, CrI, 0.02-0.67]), but experiencing negative impacts from any wildlife species lowered the probability of respondents holding a positive attitude toward local elephant conservation (mean decrease = -0.20 [95% CrI -0.42 to 0.03]). Qualitative data revealed that safety and well-being concerns related to the perceived threats that elephants pose to human lives and livelihoods, and limited incentives to support conservation on community and private lands lowered positive local attitude probabilities and contributed to negative perceptions of human-elephant coexistence. Our spatially explicit modeling approach revealed fine-scale variation in drivers of conservation attitudes that can inform targeted conservation planning. Our results suggest that approaches focused on sustaining existing sociocultural values and relationships with wildlife, investing in well-being, and implementing species-agnostic approaches to wildlife impact mitigation could improve conservation outcomes in shared landscapes., (© 2024 The Author(s). Conservation Biology published by Wiley Periodicals LLC on behalf of Society for Conservation Biology.)

Patients with the autosomal dominant tumor susceptibility syndrome neurofibromatosis type 1 (NF1) commonly develop plexiform neurofibromas (PNs) that subsequently transform into highly aggressive malignant peripheral nerve sheath tumors (MPNSTs). Understanding the process by which a PN transforms into an MPNST would be facilitated by the availability of genetically engineered mouse (GEM) models that accurately replicate the PN-MPNST progression seen in humans with NF1. Unfortunately, GEM models with Nf1 ablation do not fully recapitulate this process. This led us to develop P0-GGFβ3 mice, a GEM model in which overexpression of the Schwann cell mitogen neuregulin-1 (NRG1) in Schwann cells results in the development of PNs that progress to become MPNSTs with high frequency. However, to determine whether tumorigenesis and neoplastic progression in P0-GGFβ3 mice accurately model the processes seen in NF1 patients, we had to first prove that the pathology of P0-GGFβ3 peripheral nerve sheath tumors recapitulates the pathology of their human counterparts. Here, we describe the specialized methodologies used to accurately diagnose and grade peripheral nervous system neoplasms in GEM models, using P0-GGFβ3 and P0-GGFβ3;Trp53 +/- mice as an example. We describe the histologic, immunohistochemical, and histochemical methods used to diagnose PNs and MPNSTs, how to distinguish these neoplasms from other tumor types that mimic their pathology, and how to grade these neoplasms. We discuss the establishment of early-passage cultures from GEM MPNSTs, how to characterize these cultures using immunocytochemistry, and how to verify their tumorigenicity by establishing allografts. Collectively, these techniques characterize the pathology of PNs and MPNSTs that arise in GEM models and critically compare the pathology of these murine tumors to their human counterparts.

Aim: Patient reported outcomes (PROs) provide important insights into patients' acceptance of their medical devices. ATLAS, a randomized, multi-center, open-label clinical trial, recently reported fewer perioperative complications in S-ICD compared to TV-ICD patients. This study reports PROs, including device-specific and generic quality of life (QOL) from the ATLAS trial., Methods and Results: Device-specific QOL was the primary PRO using the Florida Patient Acceptance Survey (FPAS) at 1-and 6-months post-implantation. Secondary outcomes included generic QOL using the Medical Outcomes Survey (SF-36) pre-implant and 6-months post-implantation. FPAS and SF-36 were analyzed using ANCOVA. Pain measured using a Numeric Rating Scale, at 1-and 6-months, anesthetic, BMI and within/between differences were analyzed using descriptive statistics and mixed-effects linear models (MLM). Of the 503 patients randomized in ATLAS, 404 had complete FPAS data to include in this analysis. Participant characteristics were balanced. There were no significant differences between S-ICD and TV-ICD for FPAS or SF-36, across timepoints. Mean total FPAS scores increased from 73.73 (16.09) to 77.05 (16.13) and 74.43 (15.35) to 78.25 (15.88) for S-ICD and TV-ICD, respectively, (p <0.001). PROs suggested that both devices were associated with good QOL., Conclusion: Device-specific and generic QOL were similar between S-ICD and TV-ICD groups up to 6-months post-implantation indicating that regardless of device type, both groups reported good device specific QOL in ATLAS patients. S-ICD patients reported higher pain scores at implant, but pain decreased by 6 months. The findings offer evidence that can be included during shared decision-making. The inclusion of patient partners in ATLAS provided opportunity to measure PROs that were deemed important to patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Youth experiencing socioeconomic deprivation may be exposed to disadvantage in multiple contexts (e.g., neighborhood, family, and school). To date, however, we know little about the underlying structure of socioeconomic disadvantage, including whether the 'active ingredients' driving its robust effects are specific to one context (e.g., neighborhood) or whether the various contexts increment one another as predictors of youth outcomes., Methods: The present study addressed this gap by examining the underlying structure of socioeconomic disadvantage across neighborhoods, families, and schools, as well as whether the various forms of disadvantage jointly predicted youth psychopathology and cognitive performance. Participants were 1,030 school-aged twin pairs from a subsample of the Michigan State University Twin Registry enriched for neighborhood disadvantage., Results: Two correlated factors underlay the indicators of disadvantage. Proximal disadvantage comprised familial indicators, whereas contextual disadvantage represented deprivation in the broader school and neighborhood contexts. Results from exhaustive modeling analyses indicated that proximal and contextual disadvantage incremented one another as predictors of childhood externalizing problems, disordered eating, and reading difficulties, but not internalizing symptoms., Conclusions: Disadvantage within the family and disadvantage in the broader context, respectively, appear to represent distinct constructs with additive influence, carrying unique implications for multiple behavioral outcomes during middle childhood.

One of the most significant conceptual advances in immunology in recent history is the recognition that signals from the innate immune system are required for induction of adaptive immune responses. Two breakthroughs were critical in establishing this paradigm: the identification of dendritic cells (DCs) as the cellular link between innate and adaptive immunity and the discovery of pattern recognition receptors (PRRs) as a molecular link that controls innate immune activation as well as DC function. Here, we recount the key events leading to these discoveries and discuss our current understanding of how PRRs shape adaptive immune responses, both indirectly through control of DC function and directly through control of lymphocyte function. In this context, we provide a conceptual framework for how variation in the signals generated by PRR activation, in DCs or other cell types, can influence T cell differentiation and shape the ensuing adaptive immune response., Competing Interests: Declaration of interests G.M.B. is a member of the Scientific Advisory Boards of X-Biotix Therapeutics and Actym Therapeutics and has served as a consultant for Lycia Therapeutics., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To determine timing and risk factors associated with readmission within 30 days of discharge following noncardiac surgery., Background: Hospital readmission after noncardiac surgery is costly. Data on the drivers of readmission have largely been derived from single-center studies focused on a single surgical procedure with uncertainty regarding generalizability., Methods: We undertook an international (28 centers, 14 countries) prospective cohort study of a representative sample of adults ≥45 years of age who underwent noncardiac surgery. Risk factors for readmission were assessed using Cox regression (ClinicalTrials.gov, NCT00512109)., Results: Of 36,657 eligible participants, 2744 (7.5%; 95% confidence interval [CI], 7.2-7.8) were readmitted within 30 days of discharge. Rates of readmission were highest in the first 7 days after discharge and declined over the follow-up period. Multivariable analyses demonstrated that 9 baseline characteristics (eg, cancer treatment in past 6 months; adjusted hazard ratio [HR], 1.44; 95% CI, 1.30-1.59), 5 baseline laboratory and physical measures (eg, estimated glomerular filtration rate or on dialysis; HR, 1.47; 95% CI, 1.24-1.75), 7 surgery types (eg, general surgery; HR, 1.86; 95% CI, 1.61-2.16), 5 index hospitalization events (eg, stroke; HR, 2.21; 95% CI, 1.24-3.94), and 3 other factors (eg, discharge to nursing home; HR, 1.61; 95% CI, 1.33-1.95) were associated with readmission., Conclusions: Readmission following noncardiac surgery is common (1 in 13 patients). We identified perioperative risk factors associated with 30-day readmission that can help frontline clinicians identify which patients are at the highest risk of readmission and target them for preventive measures., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Individuals with Down syndrome (DS) have a partial or complete trisomy of chromosome 21, resulting in an increased risk for early-onset Alzheimer's disease (AD)-type dementia by early midlife. Despite ongoing clinical trials to treat late-onset AD, individuals with DS are often excluded. Furthermore, timely diagnosis or management is often not available. Of the genetic causes of AD, people with DS represent the largest cohort. Currently, there is a knowledge gap regarding the underlying neurobiological mechanisms of DS-related AD (DS-AD), partly due to limited access to well-characterized brain tissue and biomaterials for research. To address this challenge, we created an international consortium of brain banks focused on collecting and disseminating brain tissue from persons with DS throughout their lifespan, named the Down Syndrome Biobank Consortium (DSBC) consisting of 11 biobanking sites located in Europe, India, and the USA. This perspective describes the DSBC harmonized protocols and tissue dissemination goals., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Improved understanding of wildlife population connectivity among protected area networks can support effective planning for the persistence of wildlife populations in the face of land use and climate change. Common approaches to estimating connectivity often rely on small samples of individuals without considering the spatial structure of populations, leading to limited understanding of how individual movement links to demography and population connectivity. Recently developed spatial capture-recapture (SCR) models provide a framework to formally connect inference about individual movement, connectivity, and population density, but few studies have applied this approach to empirical data to support connectivity planning., Methods: We used mark-recapture data collected from 924 genetic detections of 598 American black bears (Ursus americanus) in 2004 with SCR ecological distance models to simultaneously estimate density, landscape resistance to movement, and population connectivity in Glacier National Park northwest Montana, USA. We estimated density and movement parameters separately for males and females and used model estimates to calculate predicted density-weighted connectivity surfaces., Results: Model results indicated that landscape structure influences black bear density and space use in Glacier. The mean density estimate was 16.08 bears/100 km 2 (95% CI 12.52-20.6) for females and 9.27 bears/100 km 2 (95% CI 7.70-11.14) for males. Density increased with forest cover for both sexes. For male black bears, density decreased at higher grizzly bear (Ursus arctos) densities. Drainages, valley bottoms, and riparian vegetation decreased estimates of landscape resistance to movement for male and female bears. For males, forest cover also decreased estimated resistance to movement, but a transportation corridor bisecting the study area strongly increased resistance to movement presenting a barrier to connectivity., Conclusions: Density-weighed connectivity surfaces highlighted areas important for population connectivity that were distinct from areas with high potential connectivity. For black bears in Glacier and surrounding landscapes, consideration of both vegetation and valley topography could inform the placement of underpasses along the transportation corridor in areas characterized by both high population density and potential connectivity. Our study demonstrates that the SCR ecological distance model can provide biologically realistic, spatially explicit predictions to support movement connectivity planning across large landscapes., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, currently untreatable Schwann cell-derived neoplasms with hyperactive mitogen-activated protein kinase and mammalian target of rapamycin signaling pathways. To identify potential therapeutic targets, previous studies used genome-scale shRNA screens that implicated the neuregulin-1 receptor erb-B2 receptor tyrosine kinase 3 (erbB3) in MPNST proliferation and/or survival. The current study shows that erbB3 is commonly expressed in MPNSTs and MPNST cell lines and that erbB3 knockdown inhibits MPNST proliferation and survival. Kinomic and microarray analyses of Schwann and MPNST cells implicate Src- and erbB3-mediated calmodulin-regulated signaling as key pathways. Consistent with this, inhibition of upstream (canertinib, sapitinib, saracatinib, and calmodulin) and parallel (AZD1208) signaling pathways involving mitogen-activated protein kinase and mammalian target of rapamycin reduced MPNST proliferation and survival. ErbB inhibitors (canertinib and sapitinib) or erbB3 knockdown in combination with Src (saracatinib), calmodulin [trifluoperazine (TFP)], or proviral integration site of Moloney murine leukemia kinase (AZD1208) inhibition even more effectively reduces proliferation and survival. Drug inhibition enhances an unstudied calmodulin-dependent protein kinase IIα phosphorylation site in an Src-dependent manner. The Src family kinase inhibitor saracatinib reduces both basal and TFP-induced erbB3 and calmodulin-dependent protein kinase IIα phosphorylation. Src inhibition (saracatinib), like erbB3 knockdown, prevents these phosphorylation events; and when combined with TFP, it even more effectively reduces proliferation and survival compared with monotherapy. These findings implicate erbB3, calmodulin, proviral integration site of Moloney murine leukemia kinases, and Src family members as important therapeutic targets in MPNSTs and demonstrate that combinatorial therapies targeting critical MPNST signaling pathways are more effective., (Copyright © 2023 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are derived from Schwann cells or their precursors. In patients with the tumor susceptibility syndrome neurofibromatosis type 1 (NF1), MPNSTs are the most common malignancy and the leading cause of death. These rare and aggressive soft-tissue sarcomas offer a stark future, with 5-year disease-free survival rates of 34-60%. Treatment options for individuals with MPNSTs are disappointingly limited, with disfiguring surgery being the foremost treatment option. Many once-promising therapies such as tipifarnib, an inhibitor of Ras signaling, have failed clinically. Likewise, phase II clinical trials with erlotinib, which targets the epidermal growth factor (EFGR), and sorafenib, which targets the vascular endothelial growth factor receptor (VEGF), platelet-derived growth factor receptor (PDGF), and Raf, in combination with standard chemotherapy, have also failed to produce a response in patients. In recent years, functional genomic screening methods combined with genetic profiling of cancer cell lines have proven useful for identifying essential cytoplasmic signaling pathways and the development of target-specific therapies. In the case of rare tumor types, a variation of this approach known as cross-species comparative oncogenomics is increasingly being used to identify novel therapeutic targets. In cross-species comparative oncogenomics, genetic profiling and functional genomics are performed in genetically engineered mouse (GEM) models and the results are then validated in the rare human specimens and cell lines that are available. This paper describes how to identify candidate driver gene mutations in human and mouse MPNST cells using whole exome sequencing (WES). We then describe how to perform genome-scale shRNA screens to identify and compare critical signaling pathways in mouse and human MPNST cells and identify druggable targets in these pathways. These methodologies provide an effective approach to identifying new therapeutic targets in a variety of human cancer types.

Behaviour-related issues are common in horses. Many 'undesirable behaviours' pose important safety concerns for the human handlers / riders / carers, as well as welfare concerns for the horse. Undesirable behaviours can also devalue a horse, or result in the horse being re-homed, relinquished, or euthanased. Undesirable behaviours occur for a range of reasons. These include physiological causes, poor management, and the use of inappropriate or poorly applied handling and training techniques. The potential contribution of each of these aspects must be considered when attempting to reduce or eliminate undesirable behaviours. Effectively modifying the existing behaviour includes investigation and treatment of potential physiological causes, assessing and adjusting existing handling, husbandry and management, and undertaking behaviour modifying training. Unlike in the treatment of dogs and cats, the use of psychotropic agents is uncommon in equine behaviour medicine but the benefits of using these agents in appropriate cases is gaining recognition. This review discusses potential causes for the development and maintenance of undesirable behaviours in horses and highlights the various considerations involved in determining the most appropriate course for reducing or eliminating these behaviours. There is also a brief discussion about the potential role of psychotropic agents as an additional component of an overall behaviour modification plan to reduce or eliminate undesirable behaviours in horses., Competing Interests: Declaration of Competing Interest None of the authors of this paper has a financial or personal relationship with other people or organisations that could inappropriately influence or bias the content of the paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: The role of multidisciplinary clinics for psychosocial care is increasingly recognized for those living with inherited cardiac conditions (ICC). In Canada, access to healthcare providers differ between clinics. Little is known about the relationship between access to specialty care and a patient's ability to cope with, and manage their condition., Methods: We leveraged the Hearts in Rhythm Organization (HiRO) to conduct a cross-sectional, community-based survey of individuals with ICC and their family members. We aimed to describe access to services, and explore the relationships between participants' characteristics, cardiac history and self-reported health status and self-efficacy (GSE: General Self-Efficacy Scale) and empowerment (GCOS-24: Genetic Counseling Outcome Scale)., Results: We collected 235 responses from Canadian participants in 10 provinces and territories. Overall, 63% of participants reported involvement of a genetic counsellor in their care. Access to genetic testing was associated with greater empowerment [mean GCOS-24: 121.14 (SD = 20.53) vs. 105.68 (SD = 21.69); p  = 0.004]. Uncertain genetic test results were associated with lower perceived self-efficacy (mean GSE: uncertain = 28.85 vs. positive = 33.16, negative = 34.13; p  = 0.01). Low global mental health scores correlated with both lower perceived self-efficacy and empowerment scores, with only 11% of affected participants reporting involvement of psychology services in their care., Conclusion: Differences in resource accessibility, clinical history and self-reported health status impact the perceived self-efficacy and empowerment of patients with ICC. Future research evaluating interventions to improve patient outcomes is recommended., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Davies, Allan, Carroll, Gibbs, Roberts, MacIntyre, Steinberg, Tadros, Dorian, Healey, Gardner, Laksman, Krahn, Fournier, Seifer and Lauck.)

Background: In 1942, Shaw and McKay reported that disadvantaged neighborhoods predict youth psychopathology (Shaw & McKay, ). In the decades since, dozens of papers have confirmed and extended these early results, convincingly demonstrating that disadvantaged neighborhood contexts predict elevated rates of both internalizing and externalizing disorders across childhood and adolescence. It is unclear, however, how neighborhood disadvantage increases psychopathology., Methods: Our study sought to fill this gap in the literature by examining the Area Deprivation Index (ADI), a composite measure of Census tract disadvantage, as an etiologic moderator of several common forms of psychopathology in two samples of school-aged twins from the Michigan State University Twin Registry ( N = 4815 and 1030 twin pairs, respectively), the latter of which was enriched for neighborhood disadvantage., Results: Across both samples, genetic influences on attention-deficit hyperactivity problems were accentuated in the presence of marked disadvantage, while nonshared environmental contributions to callous-unemotional traits increased with increasing disadvantage. However, neighborhood disadvantage had little moderating effect on the etiology of depression, anxiety, or somatic symptoms., Conclusions: Such findings suggest that, although neighborhood disadvantage does appear to serve as a general etiologic moderator of many (but not all) forms of psychopathology, this etiologic moderation is phenotype-specific.

Background: Trajectories of youth antisocial behavior (ASB) are characterized by continuity and change. Although numerous longitudinal studies have examined ASB, findings from person-centered and variable-centered research have not yet been integrated. The present paper integrates findings across statistical methods for a more comprehensive understanding of the development of ASB. Neighborhood disadvantage is considered as a core moderator., Methods: The study protocol was registered in the PROSPERO database of systematic reviews (registration number CRD42021255820). The PsycINFO and PubMed databases were examined (September 2022) to identify longitudinal studies of youth aggression and/or rule-breaking. Results from person-centered and variable-centered studies were integrated via narrative synthesis, and a systematic quality assessment was conducted., Results: Of 8227 studies identified, 136 met inclusion criteria. Our review indicated that rule-breaking trajectories were largely distinguished by differences in rate of change (i.e., slope), whereas aggression trajectories differed more by baseline level (i.e., intercept), particularly in childhood. For adolescents in disadvantaged neighborhoods, however, aggression trajectories differed by both intercept and slope., Conclusions: The respective importance of the intercept and slope differed across dimensions of ASB, developmental stage, and neighborhood residence. Neighborhood disadvantage was associated with trajectories of aggression, consistent with developmental theories emphasizing the role of person-environment interactions., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Schwann cell-derived neoplasms known as malignant peripheral nerve sheath tumors (MPNSTs) are the most common malignancy and the leading cause of death in individuals with neurofibromatosis Type 1. Using genome-scale shRNA screens, we have previously found evidence suggesting that lysophosphatidic acid receptors (LPARs) are essential for MPNST proliferation and/or survival. Here, we examine the expression and mutational status of all six LPA receptors in MPNSTs, assess the role that individual LPA receptors play in MPNST physiology and examine their ability to activate key neurofibromin-regulated signaling cascades. We found that human Schwann cells express LPAR1 and LPAR6, while MPNST cells express predominantly LPAR1 and LPAR3. Whole exome sequencing of 16 MPNST cell lines showed no evidence of mutations in any LPAR genes or ENPP2, a gene encoding a major LPA biosynthetic enzyme. Oleoyl-LPA, an LPA variant with an unsaturated side chain, promoted MPNST cell proliferation and migration. LPAR1 knockdown ablated the promigratory effect of LPA, while LPAR3 knockdown decreased proliferation. Inhibition of R-Ras signaling with a doxycycline-inducible dominant negative (DN) R-Ras mutant, which inhibits both R-Ras and R-Ras2, blocked LPA's promigratory effect. In contrast, DN R-Ras did not affect migration induced by neuregulin-1β (NRG1β), suggesting that LPA and NRG1β promote MPNST migration via distinct pathways. LPA-induced migration was also inhibited by Y27632, an inhibitor of the ROCK1/2 kinases that mediate R-Ras effects in MPNSTs. Thus, LPAR1 and aberrantly expressed LPAR3 mediate distinct effects in MPNSTs. These receptors and the signaling pathways that they regulate are potentially useful therapeutic targets in MPNSTs., (© 2022 Wiley Periodicals LLC.)

Socioeconomic disadvantage may be a significant risk factor for disordered eating, particularly for individuals with underlying genetic risk. However, little to nothing is known about the impact of disadvantage on disordered eating in boys during the critical developmental risk period. Crucially, risk models developed for girls may not necessarily apply to boys, as boys show different developmental patterns of disordered eating risk (i.e., earlier activation of genetic influences during adrenarche, an early stage of puberty). This is the first study to examine phenotypic and Genotype × Environment (G × E) effects of disadvantage in boys. Analyses examined 3,484 male twins ages 8-17 ( M age = 12.27, SD = 2.96) from the Michigan State University Twin Registry. Disordered eating (e.g., body dissatisfaction, binge eating) was measured using the parent-report Michigan Twins Project Eating Disorder Survey. Neighborhood disadvantage was measured using a census-tract level Area Deprivation Index, and family socioeconomic status was determined from parental income and education. Adrenarche status was determined using multiple indicators, including age and Pubertal Development Scale scores. G × E models suggested that genetic influences on disordered eating were activated earlier for boys experiencing familial or neighborhood disadvantage, with substantial genetic influences in early adrenarche, when genetic influences were low in more advantaged boys. Phenotypically, both neighborhood and familial disadvantage were associated with greater disordered eating for boys in late adrenarche, which could indicate a lasting impact of earlier activation of genetic influences on later risk. Results highlight disadvantage as a novel risk factor for disordered eating in boys, particularly those with genetic vulnerabilities. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Husbandry and veterinary procedures have the potential to generate fear and stress in animals. In horses, the associated responses can pose a significant safety risk to the human personnel involved in the procedure, as well as to the animal itself. Traditionally, physical restraint, punishment, and/or threat of an aversive, have been the most common strategies used to achieve compliance from the horse. However, from a welfare perspective, this is less than ideal. This approach also has the potential for creating a more dangerous response from the horse in future similar situations. When caring for companion animals, and captive animals within zoological facilities, there has been a steady transition away from this approach, and toward strategies aimed at reducing fear and stress during veterinary visits and when undertaking routine husbandry procedures. This review discusses the current approaches to horse care and training, the strategies being used in other animal sectors, and potential strategies for improving human safety, as well as the horse's experience, during husbandry and veterinary procedures., Competing Interests: The authors declare no conflicts of interest.

Objective: We explored understandings about dementia and lived experiences from carers among community-dwelling Aboriginal people in Western Australia (WA)., Methods: In partnership with Aboriginal medical services in WA, we conducted semi-structured interviews with Aboriginal people in Perth and Bunbury. All interviews were transcribed verbatim and coded thematically., Results: We conducted 39 interviews. Dementia was associated with 'losing your memory', a 'change in behaviour' and unhealthy lifestyles. Increasing awareness about dementia in the community was noted particularly to enable people to recognise the early signs, feel safe to ask for help and know how to best support families. Families were primarily responsible for caring for people with dementia and were finding it difficult to manage. They expressed negative experiences with currently available aged care facilities., Conclusions: Increased awareness of dementia in the community through public health messaging and by health professionals and culturally secure services focussing on dementia care is required., (© 2022 The Authors. Australasian Journal on Ageing published by John Wiley & Sons Australia, Ltd on behalf of AJA Inc’.)

Spatial capture-recapture (SCR) models are powerful analytical tools that have become the standard for estimating abundance and density of wild animal populations. When sampling populations to implement SCR, the number of unique individuals detected, total recaptures, and unique spatial relocations can be highly variable. These sample sizes influence the precision and accuracy of model parameter estimates. Testing the performance of SCR models with sparse empirical data sets typical of low-density, wide-ranging species can inform the threshold at which a more integrated modeling approach with additional data sources or additional years of monitoring may be required to achieve reliable, precise parameter estimates. Using a multi-site, multi-year Utah black bear (Ursus americanus) capture-recapture data set, we evaluated factors influencing the uncertainty of SCR structural parameter estimates, specifically density, detection, and the spatial scale parameter, sigma. We also provided some of the first SCR density estimates for Utah black bear populations, which ranged from 3.85 to 74.33 bears/100 km 2 . Increasing total detections decreased the uncertainty of density estimates, whereas an increasing number of total recaptures and individuals with recaptures decreased the uncertainty of detection and sigma estimates, respectively. In most cases, multiple years of data were required for precise density estimates (<0.2 coefficient of variation [CV]). Across study areas there was an average decline in CV of 0.07 with the addition of another year of data. One sampled population with very high estimated bear density had an atypically low number of spatial recaptures relative to total recaptures, apparently inflating density estimates. A complementary simulation study used to assess estimate bias suggested that when <30% of recaptured individuals were spatially recaptured, density estimates were unreliable and ranged widely, in some cases to >3 times the simulated density. Additional research could evaluate these requirements for other density scenarios. Large numbers of individuals detected, numbers of spatial recaptures, and precision alone may not be sufficient indicators of parameter estimate reliability. We provide an evaluation of simple summary statistics of capture-recapture data sets that can provide an early signal of the need to alter sampling design or collect auxiliary data before model implementation to improve estimate precision and accuracy., (© 2022 The Authors. Ecological Applications published by Wiley Periodicals LLC on behalf of The Ecological Society of America. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Neuregulins (NRGs) and their cognate neuronal receptor ERBB4, which is expressed in GABAergic and dopaminergic neurons, regulate numerous behaviors in rodents and have been identified as schizophrenia at-risk genes. ErbB4 transcripts are alternatively spliced to generate isoforms that either include (Cyt-1) or exclude (Cyt-2) exon 26, which encodes a cytoplasmic domain that imparts ErbB4 receptors the ability to signal via the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway. Although ErbB4 Cyt-1/2 isoforms have been studied in transfected cultured cells, their functions in vivo remain unknown. Here, we generated ErbB4-floxed (ErbB4-Cyt1 fl/fl ) mice to investigate the effects of germline (constitutive) and conditional (acute) deletions of the Cyt-1 exon. Overall receptor mRNA levels remain unchanged in germline ErbB4 Cyt-1 knockouts (Cyt-1 KOs), with all transcripts encoding Cyt-2 variants. In contrast to mice lacking all ErbB4 receptor function, GABAergic interneuron migration and number are unaltered in Cyt-1 KOs. However, basal extracellular dopamine (DA) levels in the medial prefrontal cortex are increased in Cyt-1 heterozygotes. Despite these neurochemical changes, Cyt-1 heterozygous and homozygous mice do not manifest behavioral abnormalities previously reported to be altered in ErbB4 null mice. To address the possibility that Cyt-2 variants compensate for the lack of Cyt-1 during development, we microinjected an adeno-associated virus expressing Cre-recombinase (AAV-Cre) into the DA-rich ventral tegmental area of adult ErbB4-Cyt1 fl/fl mice to acutely target exon 26. These conditional Cyt-1 KOs were found to exhibit behavioral abnormalities in the elevated plus maze and startle response, consistent with the idea that late exon 26 ablations may circumvent compensation by Cyt-2 variants. Taken together, our observations indicate that ErbB4 Cyt-1 function in vivo is important for DA balance and behaviors in adults., (© 2022 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Brain pericytes regulate cerebral blood flow, maintain the integrity of the blood-brain barrier (BBB), and facilitate the removal of amyloid β (Aβ), which is critical to healthy brain activity. Pericyte loss has been observed in brains from patients with Alzheimer's disease (AD) and animal models. Our previous data demonstrated that friend leukemia virus integration 1 (Fli-1), an erythroblast transformation-specific (ETS) transcription factor, governs pericyte viability in murine sepsis; however, the role of Fli-1 and its impact on pericyte loss in AD remain unknown. Here, we demonstrated that Fli-1 expression was up-regulated in postmortem brains from a cohort of human AD donors and in 5xFAD mice, which corresponded with a decreased pericyte number, elevated inflammatory mediators, and increased Aβ accumulation compared with cognitively normal individuals and wild-type (WT) mice. Antisense oligonucleotide Fli-1 Gapmer administered via intrahippocampal injection decelerated pericyte loss, decreased inflammatory response, ameliorated cognitive deficits, improved BBB dysfunction, and reduced Aβ deposition in 5xFAD mice. Fli-1 Gapmer-mediated inhibition of Fli-1 protected against Aβ accumulation-induced human brain pericyte apoptosis in vitro. Overall, these studies indicate that Fli-1 contributes to pericyte loss, inflammatory response, Aβ deposition, vascular dysfunction, and cognitive decline, and suggest that inhibition of Fli-1 may represent novel therapeutic strategies for AD., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

The pursuit of more efficient patient-friendly health systems and reductions in tertiary health services use has seen enormous growth in the application and study of remote patient monitoring systems for cardiovascular patient care. While there are many consumer-grade products available to monitor patient wellness, the regulation of these technologies varies considerably, with most products having little to no evaluation data. As the science and practice of virtual care continues to evolve, clinicians and researchers can benefit from an understanding of more comprehensive solutions capable of monitoring multiple biophysical parameters (eg, oxygen saturation, heart rate) continuously and simultaneously. These devices, herein referred to as continuous multiparameter remote automated monitoring (CM-RAM) devices, have the potential to revolutionise virtual patient care. Through seamless integration of multiple biophysical signals, CM-RAM technologies can allow for the acquisition of high-volume big data for the development of algorithms to facilitate early detection of negative changes in patient health status and timely clinician response. In this article, we review key principles, architecture, and components of CM-RAM technologies. Work to date in this field and related implications are also presented, including strategic priorities for advancing the science and practice of CM-RAM., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The RASopathies are a group of genetic diseases in which the Ras/MAPK signaling pathway is inappropriately activated as a result of mutations in genes encoding proteins within this pathway. As their causative mutations have been identified, this group of diseases has expanded to include neurofibromatosis type 1 (NF1), Legius syndrome, Noonan syndrome, CBL syndrome, Noonan syndrome-like disorder with loose anagen hair, Noonan syndrome with multiple lentigines, Costello syndrome, cardiofaciocutaneous syndrome, gingival fibromatosis and capillary malformation-arteriovenous malformation syndrome. Many of these genetic disorders share clinical features in common such as abnormal facies, short stature, varying degrees of cognitive impairment, cardiovascular abnormalities, skeletal abnormalities and a predisposition to develop benign and malignant neoplasms. Others are more dissimilar, even though their mutations are in the same gene that is mutated in a different RASopathy. Here, we describe the clinical features of each RASopathy and contrast them with the other RASopathies. We discuss the genetics of these disorders, including the causative mutations for each RASopathy, the impact that these mutations have on the function of an individual protein and how this dysregulates the Ras/MAPK signaling pathway. As several of these individual disorders are genetically heterogeneous, we also consider the different genes that can be mutated to produce disease with the same phenotype. We also discuss how our growing understanding of dysregulated Ras/MAPK signaling had led to the development of new therapeutic agents and what work will be critically important in the future to improve the lives of patients with RASopathies., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Adversity has consistently been found to predict poor mental health outcomes in youth. Perhaps the most omnipresent form of adversity in the past several decades has been the coronavirus pandemic of 2020, a global health crisis linked to elevated rates of numerous forms of youth psychopathology. The ongoing nature of the pandemic renders it critical to identify the mechanisms underlying its effects on mental health., Methods: The current study examines pandemic-related disruption across multiple domains (e.g., home life, finances) as an etiologic moderator of several common forms of youth psychopathology. Participants were 637 adolescent twin pairs from the Twin Study of Behavioral and Emotional Development in Children (TBED-C). Mothers reported on disruption experienced by the family, using the Epidemic-Pandemic Impacts Inventory., Results: A series of biometric genotype-by-environment interaction models revealed that disruption augmented the nonshared environmental contributions to emotional distress and conduct problems but had little effect on the etiology of attention-deficit hyperactivity problems., Conclusions: Our results indicate that identical and fraternal twin similarity in both emotional symptoms and conduct problems decreased with greater disruption, such that children in the same family became less alike, and did so regardless of their degree of genetic resemblance. Put differently, each twin sibling appeared to have their own idiosyncratic experience of pandemic-related disruptions, with downstream consequences for their mental health., (© 2021 The Authors.)

Emerging evidence suggests socioeconomic disadvantage may increase risk for eating disorders (EDs). However, there are very few studies on the association between disadvantage and EDs, and all have focused on individual-level risk factors (e.g., family income). Neighborhood disadvantage (i.e., elevated poverty and reduced resources in one's neighborhood) is associated with increased risk for anxiety/depression and poor physical health. To date, no studies have examined phenotypic associations between neighborhood disadvantage and disordered eating, or how any form of disadvantage may interact with genetic individual differences in risk for EDs. We examined phenotypic and etiologic associations between neighborhood disadvantage and disordered eating in 2,922 girls ages 8-17 from same-sex twin pairs recruited through the Michigan State University Twin Registry. Parents rated the twins on nine items assessing core disordered eating symptoms (e.g., weight preoccupation, binge eating), and neighborhood disadvantage was calculated from 17 indicators of contextual disadvantage (e.g., median home value, neighborhood unemployment). Puberty was measured using the Pubertal Development Scale to examine whether associations were consistent across development. At a phenotypic level, greater neighborhood disadvantage was associated with significantly greater disordered eating symptoms in girls at all stages of puberty (β = .07). Moreover, Genotype × Environment models showed that girls living in more disadvantaged neighborhoods exhibited stronger and earlier (i.e., during pre/early puberty) activation of genetic influences on disordered eating. Results highlight the critical importance of considering contextual disadvantage in research on etiology and risk for disordered eating, and the need for increased screening and treatment for EDs in disadvantaged youth. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

As a result of increasing CO 2 emissions and the prevalence of global climate change, ocean acidification (OA) is becoming more pervasive, affecting many trophic levels, particularly those that rely on succinctly balanced ocean chemistry. This ultimately threatens community structures, as well as the future sustainability of the fishing/aquaculture industry. Understanding the molecular stress response of key organisms will aid in predicting their future survivability under changing environmental conditions. This study sought to elucidate the molecular stress response of the South African abalone, Haliotis midae, an understudied organism with high economic value, utilising a high throughput iTRAQ-based proteomics methodology. Adult abalone were exposed to control (pH 7.9) and experimental (pH 7.5) conditions for 12, 72 and 168 h, following which protein was isolated from sampled haemocytes and subsequently processed. iTRAQ-labelled peptides were analysed using mass spectrometry, while an array of bioinformatics tools was utilised for analysing the proteomic data. COG analysis identified "Cytoskeleton", "Translation, ribosomal structure and biogenesis", "Post-translational modification, protein turnover, chaperones", and "Intracellular trafficking, secretion and vesicular transport" to be the most enriched functional classes, while statistical analysis identified a total of 33 up-regulated and 23 down-regulated effectors of OA stress in abalone. Several of the up-regulated proteins that were identified function in central metabolism (ENO1, PGK, DUOX1, GPD2), the stress/immune response (CAMKI, HSPA5/GRP78, MAPKI), and cytoskeleton, protein sorting and signal transduction (IQGAP1, MYO9B, TLN1, RDX, TCP-1/CCT, SNX6, CHMP1a, VPS13a). Protein-protein interactions were predicted using STRING DB, Cytoscape and Ingenuity Pathway Analysis, providing a model of the effects of OA on the H. midae haemocyte proteome. The data indicated that H. midae underwent a metabolic shift under OA conditions to utilize more energy-efficient mechanisms of ATP generation, while attempts at restoring haemocyte stabilisation and homeostasis were reflected by up-regulation of oxidative stress and cytoskeletal proteins. Our results support other molluscan studies that report a complex array of overlapping functions of both the stress and immune response systems. This interplay of the mounted stress and immune response is maintained and observed through the up-regulation of proteins involved in protein synthesis and turnover, as well as intracellular signalling and transport. The data presented in this study highlight the value of employing sensitive and robust -omics technologies for assessing the effects of changing environmental conditions on marine organisms., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Loss of the Ras GTPase-activating protein neurofibromin promotes nervous system tumor pathogenesis in patients with neurofibromatosis type 1 (NF1). Neurofibromin loss potentially hyperactivates classic Ras (H-Ras, N-Ras, K-Ras), M-Ras, and R-Ras (R-Ras, R-Ras2/TC21) subfamily proteins. We have shown that classic Ras proteins promote proliferation and survival, but not migration, in malignant peripheral nerve sheath tumor (MPNST) cells. However, it is unclear whether R-Ras, R-Ras2 and M-Ras are expressed and hyperactivated in MPNSTs and, if so, whether they contribute to MPNST pathogenesis. We assessed the expression and activation of these proteins in MPNST cells and inhibited them to determine the effect this had on proliferation, migration, invasion, survival and the phosphoproteome., Methods: NF1-associated (ST88-14, 90-8, NMS2, NMS-PC, S462, T265-2c) and sporadic (STS-26T, YST-1) MPNST lines were used. Cells were transfected with doxycycline-inducible vectors expressing either a pan-inhibitor of the R-Ras subfamily [dominant negative (DN) R-Ras] or enhanced green fluorescent protein (eGFP). Methodologies used included immunoblotting, immunocytochemistry, PCR, Transwell migration, 3 H-thymidine incorporation, calcein cleavage assays and shRNA knockdowns. Proteins in cells with or without DN R-Ras expression were differentially labeled with SILAC and mass spectrometry was used to identify phosphoproteins and determine their relative quantities in the presence and absence of DN R-Ras. Validation of R-Ras and R-Ras2 action and R-Ras regulated networks was performed using genetic and/or pharmacologic approaches., Results: R-Ras2 was uniformly expressed in MPNST cells, with R-Ras present in a major subset. Both proteins were activated in neurofibromin-null MPNST cells. Consistent with classical Ras inhibition, DN R-Ras and R-Ras2 knockdown inhibited proliferation. However, DN R-Ras inhibition impaired migration and invasion but not survival. Mass spectrometry-based phosphoproteomics identified thirteen protein networks distinctly regulated by DN R-Ras, including multiple networks regulating cellular movement and morphology. ROCK1 was a prominent mediator in these networks. DN R-Ras expression and RRAS and RRAS2 knockdown inhibited migration and ROCK1 phosphorylation; ROCK1 inhibition similarly impaired migration and invasion, altered cellular morphology and triggered the accumulation of large intracellular vesicles., Conclusions: R-Ras proteins function distinctly from classic Ras proteins by regulating distinct signaling pathways that promote MPNST tumorigenesis by mediating migration and invasion. Mutations of the NF1 gene potentially results in the activation of multiple Ras proteins, which are key regulators of many biologic effects. The protein encoded by the NF1 gene, neurofibromin, acts as an inhibitor of both classic Ras and R-Ras proteins; loss of neurofibromin could cause these Ras proteins to become persistently active, leading to the development of cancer. We have previously shown that three related Ras proteins (the classic Ras proteins) are highly activated in malignant peripheral nerve sheath tumor (MPNST) cells with neurofibromin loss and that they drive cancer cell proliferation and survival by activating multiple cellular signaling pathways. Here, we examined the expression, activation and action of R-Ras proteins in MPNST cells that have lost neurofibromin. Both R-Ras and R-Ras2 are expressed in MPNST cells and activated. Inhibition of R-Ras action inhibited proliferation, migration and invasion but not survival. We examined the activation of cytoplasmic signaling pathways in the presence and absence of R-Ras signaling and found that R-Ras proteins regulated 13 signaling pathways distinct from those regulated by classic Ras proteins. Closer study of an R-Ras regulated pathway containing the signaling protein ROCK1 showed that inhibition of either R-Ras, R-Ras2 or ROCK1 similarly impaired cellular migration and invasion and altered cellular morphology. Inhibition of R-Ras/R-Ras2 and ROCK1 signaling also triggered the accumulation of abnormal intracellular vesicles, indicating that these signaling molecules regulate the movement of proteins and other molecules in the cellular interior. Video Abstract., (© 2021. The Author(s).)

Background: Uncontrolled truncal hemorrhage remains the most common cause of potentially preventable death after injury. The notion of earlier hemorrhage control and blood product resuscitation is therefore attractive. Some systems have successfully implemented prehospital advanced resuscitative care (ARC) teams. Early identification of patients is key and is reliant on rapid decision making and communication. The purpose of this simulation study was to explore the feasibility of early identification of patients who might benefit from ARC in a typical US setting., Methods: We conducted a prospective observational/simulation study at a level I trauma center and two associated emergency medical service (EMS) agencies over a 9-month period. The participating EMS agencies were asked to identify actual patients who might benefit from the activation of a hypothetical trauma center-based ARC team. This decision was then communicated in real time to the study team., Results: Sixty-three patients were determined to require activation. The number of activations per month ranged from 2 to 15. The highest incidence of calls occurred between 4 pm to midnight. Of the 63 patients, 33 were transported to the trauma center. The most common presentation was with penetrating trauma. The median age was 27 years (interquartile range, 24-45 years), 75% were male, and the median Injury Severity Score was 11 (interquartile range, 7-20). Based on injury patterns, treatment received, and outcomes, it was determined that 6 (18%) of 33 patients might have benefited from ARC. Three of the patients died en-route to or soon after arrival at the trauma center., Conclusion: The prehospital identification of patients who might benefit from ARC is possible but faces challenges. Identifying strategies to adapt existing processes may allow better utilization of the existing infrastructure and should be a focus of future efforts., Level of Evidence: Prognostic/Epidemiologic, level III., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The contributions that the R-Ras subfamily [R-Ras, R-Ras2/teratocarcinoma 21 (TC21), and M-Ras] of small GTP-binding proteins make to normal and aberrant cellular functions have historically been poorly understood. However, this has begun to change with the realization that all three R-Ras subfamily members are occasionally mutated in Noonan syndrome (NS), a RASopathy characterized by the development of hematopoietic neoplasms and abnormalities affecting the immune, cardiovascular, and nervous systems. Consistent with the abnormalities seen in NS, a host of new studies have implicated R-Ras proteins in physiological and pathologic changes in cellular morphology, adhesion, and migration in the cardiovascular, immune, and nervous systems. These changes include regulating the migration and homing of mature and immature immune cells, vascular stabilization, clotting, and axonal and dendritic outgrowth during nervous system development. Dysregulated R-Ras signaling has also been linked to the pathogenesis of cardiovascular disease, intellectual disabilities, and human cancers. This review discusses the structure and regulation of R-Ras proteins and our current understanding of the signaling pathways that they regulate. It explores the phenotype of NS patients and their implications for the R-Ras subfamily functions. Next, it covers recent discoveries regarding physiological and pathologic R-Ras functions in key organ systems. Finally, it discusses how R-Ras signaling is dysregulated in cancers and mechanisms by which this may promote neoplasia., (Copyright © 2021 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Trajectories of youth antisocial behavior (ASB) are characterized by both continuity and change. Twin studies have further indicated that genetic factors underlie continuity, while environmental exposures unique to each child in a given family underlie change. However, most behavioral genetic studies have examined continuity and change during relatively brief windows of development (e.g., during childhood but not into adolescence). It is unclear whether these findings would persist when ASB trajectories are examined across multiple stages of early development (i.e., from early childhood into emerging adulthood). Our study sought to fill this gap by examining participants assessed up to five times between the ages of 3 and 22 years using an accelerated longitudinal design in the Michigan State University Twin Registry (MSUTR). We specifically examined the etiologies of stability and change via growth curve modeling and a series of univariate and bivariate twin analyses. While participants exhibited moderate-to-high rank-order stability, mean levels of ASB decreased linearly with age. Genetic and nonshared environmental influences that were present in early childhood also contributed to both stability and change across development, while shared environmental contributions were negligible. In addition, genetic and nonshared environmental influences that were not yet present at the initial assessment contributed to change over time. Although ASB tended to decrease in frequency with age, participants who engaged in high levels of ASB during childhood generally continued to do so throughout development. Moreover, the genetic and nonshared environmental contributions to ASB early in development also shaped the magnitude of the decrease with age., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The development of new drugs that precisely target key proteins in human cancers is fundamentally altering cancer therapeutics. However, before these drugs can be used, their target proteins must be validated as therapeutic targets in specific cancer types. This validation is often performed by knocking out the gene encoding the candidate therapeutic target in a genetically engineered mouse (GEM) model of cancer and determining what effect this has on tumor growth. Unfortunately, technical issues such as embryonic lethality in conventional knockouts and mosaicism in conditional knockouts often limit this approach. To overcome these limitations, an approach to ablating a floxed embryonic lethal gene of interest in short-term cultures of malignant peripheral nerve sheath tumors (MPNSTs) generated in a GEM model was developed. This paper describes how to establish a mouse model with the appropriate genotype, derive short-term tumor cultures from these animals, and then ablate the floxed embryonic lethal gene using an adenoviral vector that expresses Cre recombinase and enhanced green fluorescent protein (eGFP). Purification of cells transduced with adenovirus using fluorescence-activated cell sorting (FACS) and the quantification of the effects that gene ablation exerts on cellular proliferation, viability, the transcriptome, and orthotopic allograft growth is then detailed. These methodologies provide an effective and generalizable approach to identifying and validating therapeutic targets in vitro and in vivo. These approaches also provide a renewable source of low-passage tumor-derived cells with reduced in vitro growth artifacts. This allows the biological role of the targeted gene to be studied in diverse biologic processes such as migration, invasion, metastasis, and intercellular communication mediated by the secretome.

Aims: Implantable cardioverter-defibrillators (ICDs) deliver therapy for life-threatening arrhythmias. Evidence suggests that ICD candidates have misconceptions regarding ICD therapy and unmet information needs. We undertook a pilot feasibility trial comparing a nurse-led educational intervention plus standard care, vs. standard pre-ICD implantation care. Secondary aims included examination of anxiety, quality of life, and shock anxiety., Methods and Results: Implantable cardioverter-defibrillator candidates were consented and randomized to standard pre-ICD implantation care vs. standard care plus a nurse-led educational intervention. The primary feasibility outcomes included: recruitment rate, consent rate, randomization rate, proportion of participants able to complete all questionnaires, time to deliver intervention, and intervention topics completion. At baseline, demographic and Patient-Reported Outcomes Measurement Information System (PROMIS) anxiety scores were collected. Four weeks post-ICD implantation, participants completed the PROMIS, Florida Patient Acceptance Survey (FPAS), and Florida Shock Anxiety Scale (FSAS). Twenty patients consented (10 per group). Feasibility targets were achieved for all but two outcomes: consent rate was 87% vs. 95% target, and completion of data collection measures was 85% vs. 90% target. Consent rate was lower than expected as one patient declined, and two could not be approached. Completion rate was lower than expected as two patients were lost to follow-up, and one did not receive an ICD during the study period, leading to incomplete post-implantation survey collections., Conclusion: The results demonstrate the feasibility of conducting a trial comparing a nurse-led pre-implantation educational intervention to standard care in an outpatient setting. Further study to evaluate the effectiveness of this intervention on patient-reported outcomes is warranted., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Primary open-angle glaucoma (POAG) constitutes the most common type of glaucoma. Emerging evidence suggests that Endoplasmic Reticulum (ER) stress and the protein kinase RNA-like endoplasmic reticulum kinase (PERK)-mediated Unfolded Protein Response (UPR) signaling pathway play a key role in POAG pathogenesis. Thus, the main aim of the study was to evaluate the effectiveness of the PERK inhibitor LDN-0060609 in cellular model of glaucoma using primary human trabecular meshwork (HTM) cells. To evaluate the level of the ER stress marker proteins, Western blotting and TaqMan gene expression assay were used. The cytotoxicity was measured by XTT, LDH assays and Giemsa staining, whereas genotoxicity via comet assay. Changes in cell morphology were assessed by phase-contrast microscopy. Analysis of apoptosis was performed by caspase-3 assay and flow cytometry (FC), whereas cell cycle progression by FC. The results obtained have demonstrated that LDN-0060609 triggered a significant decrease of ER stress marker proteins within HTM cells with induced ER stress conditions. Moreover, LDN-0060609 effectively increased viability, reduced DNA damage, increased proliferation, restored normal morphology, reduced apoptosis and restored normal cell cycle distribution of HTM cells with induced ER stress conditions. Thereby, PERK inhibitors, such as LDN-0060609, may provide an innovative, ground-breaking treatment strategy against POAG.