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Background: The Diuretic Comparison Project (DCP) was a multi-center, embedded pragmatic trial conducted within the VA healthcare system comparing chlorthalidone and hydrochlorothiazide in preventing major adverse cardiovascular events and non-cancer deaths in hypertensive patients. Study procedures were decentralized, and facility leadership first had to agree and accept study procedures before staff approached participants. Recent evidence suggests facilities that choose and choose not to participate in trials may differ and this study considered such differences within DCP., Methods: A cross-sectional comparison of facilities participating in DCP was conducted with data from the study start (June 2016) including: 2016 American Community Survey, 2016 Strategic Analytics for Improvement and Learning reports, star ratings, and 2014 hospital complexity. Characteristics of participating and non-participating centers were compared using logistic regression, including county-level socio-economic features and hospital-level performance., Results: Of 144 VA medical centers, leadership at 75 centers (52 %) initiated participation. Facilities in highly-urban and higher median income counties were more likely to participate, as were higher-complexity facilities. Facilities with research experience were 2.18 times as likely to participate. No other hospital performance metrics or county-level demographics were associated with participation., Conclusions: Overall, this study suggests research exposure and quality care metrics may impact a facility's decision to participate. These results highlight key considerations for recruitment to multi-site, and particularly pragmatic, clinical trials. Consideration of supporting facilities that have not historically participated in research may be fruitful for recruitment. These results emphasize the importance of education about pragmatic study design and its integration with clinical care., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Objectives: To evaluate the feasibility of the Bali Yoga Programme for Residents (PYB-R), an 8-week virtual yoga-based intervention and determine its impact on the mental health of resident physicians., Design: Single-group repeated measures study., Setting: Associations from the four postgraduate medical education programmes in Québec, Canada., Participants: Overall, 55 resident physicians were recruited to participate of which 53 (96.4%) completed the assessment pre-PYB-R. The postintervention assessment was completed by 43 residents (78.2%) and 39 (70.9%) completed all phases (including 3-month follow-up). Most were in their first year (43.4%) or second year (32.1%) of residency. The majority were female (81.1%) with a mean age of 28±3.6 years., Primary and Secondary Outcome Measures: The primary outcome measure was feasibility as measured by participation in the PYB-R. Secondary outcome measures were psychological variables (anxiety, depression, burn-out, emotional exhaustion, compassion fatigue and compassion satisfaction) and satisfaction with the PYB-R. Residents were further subgrouped based on the quality of work life and a number of PYB-R sessions attended., Results: The attrition rate for programme completion was 19%. Of the 43 residents who completed the PYB-R, 90.6% attended between 6 and 8 sessions. Repeated-measures analysis of variances (ANOVAs) at three time points (baseline, PYB-R completion and 3-month follow-up) confirmed a decrease in scores for depression and anxiety, and an increase in scores for compassion satisfaction. No changes were observed in the other psychological variables evaluated. ANOVAs also confirmed that a better quality of life at work helps develop compassion satisfaction, a protective factor to compassion fatigue. Most participants (92.9%) indicated they were satisfied or very satisfied with the quality of the programme., Conclusions: A virtual yoga-based programme is feasible and has lasting positive effects for up to 3 months on the mental health of resident physicians. Further research is warranted to validate these findings using a larger sample of residents with a control group., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To determine the impact of comorbid depression on readmission after vestibular schwannoma resection., Study Design: Retrospective database analysis., Setting: National database of readmitted patients., Patients: The Nationwide Readmission Database (NRD) was retrospectively reviewed for patients with history of vestibular schwannoma, identified by International Classification of Disease, Ninth Revision (ICD-9) code 225.1 and ICD-10 code D33.3, who underwent surgical resection (ICD-9 04.01, ICD-10-PCS 00BN0ZZ) in 2020., Interventions: Therapeutic., Main Outcome Measures: Need for rehabilitation, need for procedures, length of stay, cost of readmission, and insurance status., Results: A total of 1997 patients were readmitted after resection of vestibular schwannoma in 2020. Of these patients, 290 had history of a comorbid depressive disorder.A significantly higher proportion of patients with history of comorbid depression were transferred to a rehabilitation facility after readmission (11.30% versus 4.30%, p < 0.001). Length of stay (p = 0.227) and total readmission cost (p = 0.723) did not differ significantly, but a significantly lower proportion had private insurance (55.40% versus 64.40%, p = 0.027)., Conclusion: Depression is associated with higher utilization of postoperative rehabilitation services and higher rates of medical comorbidities, and should be considered during preoperative evaluation., Competing Interests: The authors disclose no conflicts of interest., (Copyright © 2024, Otology & Neurotology, Inc.)

Context: The changes in host membrane phospholipids are crucial in airway infection pathogenesis. Phospholipase A2 hydrolyzes host cell membranes, producing lyso-phospholipids and free fatty acids, including arachidonic acid (AA), which contributes significantly to lung inflammation., Aim: Follow these changes and their evolution from day 1, day 3 to day 7 in airway aspirates of 89 patients with COVID-19-associated acute respiratory distress syndrome and examine whether they correlate with the severity of the disease. The patients were recruited in three French intensive care units. The analysis was conducted from admission to the intensive care unit until the end of the first week of mechanical ventilation., Results: In the airway aspirates, we found significant increases in the levels of host cell phospholipids, including phosphatidyl-serine and phosphatidyl-ethanolamine, and their corresponding lyso-phospholipids. This was accompanied by increased levels of AA and its inflammatory metabolite prostaglandin E2 (PGE2). Additionally, enhanced levels of ceramides, sphingomyelin, and free cholesterol were observed in these aspirates. These lipids are known to be involved in cell death and/or apoptosis, whereas free cholesterol plays a role in virus entry and replication in host cells. However, there were no significant changes in the levels of dipalmitoyl-phosphatidylcholine, the major surfactant phospholipid. A correlation analysis revealed an association between mortality risk and levels of AA and PGE2, as well as host cell phospholipids., Conclusion: Our findings indicate a correlation between heightened cellular phospholipid modifications and variations in AA and PGE2 with the severity of the disease in patients. Nevertheless, there is no indication of surfactant alteration in the initial phases of the illness., Competing Interests: Declaration of competing interest There is no conflict of interest., (Copyright © 2024 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.)

For many, including military veterans and their families, support between individuals with shared lived experiences, or peer support, has long been utilized as a way to support each other through many different challenges. Building on other reviews and guided by the seven domains of well-being in the Canadian veteran well-being framework, the objective of this paper is to describe and catalogue the nature of peer support activities and related outcomes in the veteran, serving member, and family member populations. A scoping review following the five stages outlined by Arksey and O'Malley was conducted; it was guided by the question: What is currently known about peer support activities for veterans, serving members, and their families that has been evaluated in the literature? In total, 101 publications from 6 different countries were included in this review and catalogued based on publication characteristics, participant information, peer support activity information, and peer information. Peer support activities have the potential to positively influence the well-being of veterans, serving members, and their families on a holistic level across multiple domains. This scoping review highlights the existing gaps in the literature and provides an important foundation for future research on peer support for these populations, specifically in the Canadian context.

Background: Unravelling the mystery of Alzheimer's disease (AD) requires urgent resolution given the worldwide increase of the aging population. There is a growing concern that the current leading AD hypothesis, the amyloid cascade hypothesis, does not stand up to validation with respect to emerging new data. Indeed, several paradoxes are being discussed in the literature, for instance, both the deposition of the amyloid-β peptide (Aβ) and the intracellular neurofibrillary tangles could occur within the brain without any cognitive pathology. Thus, these paradoxes suggest that something more fundamental is at play in the onset of the disease and other key and related pathomechanisms must be investigated., Objective: The present study follows our previous investigations on the infectious hypothesis, which posits that some pathogens are linked to late onset AD. Our studies also build upon the finding that Aβ is a powerful antimicrobial agent, produced by neurons in response to viral infection, capable of inhibiting pathogens as observed in in vitro experiments. Herein, we ask what are the molecular mechanisms in play when Aβ neutralizes infectious pathogens?, Methods: To answer this question, we probed at nanoscale lengths with FRET (Förster Resonance Energy Transfer), the interaction between Aβ peptides and glycoprotein B (responsible of virus-cell binding) within the HSV-1 virion., Results: The experiments show an energy transfer between Aβ peptides and glycoprotein B when membrane is intact. No energy transfer occurs after membrane disruption or treatment with blocking antibody., Conclusion: We concluded that Aβ insert into viral membrane, close to glycoprotein B, and participate in virus neutralization., Competing Interests: The authors declare no conflicts of interest., (© 2022 – The authors. Published by IOS Press.)

Cationic antimicrobial peptides (CAMPs) are important actors in host innate immunity and represent a promising alternative to combat antibiotic resistance. Here, the bactericidal activity of two CAMPs (LL-37 and CAMA) was evaluated against Pseudomonas aeruginosa (PA) in the presence of IB3-1 cells, a cell line derived from patients with cystic fibrosis. The two CAMPs exerted different effects on PA survival depending on the timing of their administration. We observed a greater bactericidal effect when IB3-1 cells were pretreated with sub-minimum bactericidal concentrations (Sub-MBCs) of the CAMPs prior to infection. These findings suggest that CAMPs induce the production of factors by IB3-1 cells that improve their bactericidal action. However, we observed no bactericidal effect when supra-minimum bactericidal concentrations (Supra-MBCs) of the CAMPs were added to IB3-1 cells at the same time or after infection. Western-blot analysis showed a large decrease in LL-37 levels in supernatants of infected IB3-1 cells and an increase in LL-37 binding to these cells after LL-37 administration. LL-37 induced a weak inflammatory response in the cells without being toxic. In conclusion, our findings suggest a potential prophylactic action of CAMPs. The bactericidal effects were low when the CAMPs were added after cell infection, likely due to degradation of CAMPs by bacterial or epithelial cell proteases and/or due to adherence of CAMPs to cells becoming less available for direct bacterial killing., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Objectives: Stress influences metabolic activity and increases risk for cardiovascular disease (CVD). We sought to a) examine feasibility and acceptability of mindfulness-based stress reduction (MBSR) in older adults at risk for CVD, and b) obtain preliminary data on its metabolic impact., Methods: A pilot RCT was conducted using a pre-post, 2-month follow-up design. Eighty-one individuals with metabolic syndrome and non-normative responses to stress in a previous investigation were invited. Participants were randomized (by sex and stress response) to a 9-week MBSR or a wait-list control group. Feasibility and acceptability were assessed and blood assayed. Between-subjects (MBSR vs waitlist control) ANOVAs on metabolic parameter change scores, and one-way repeated measures ANOVAs (pre-, post-, follow-up) were performed., Results: Thirty-three individuals (41%) responded to invitations, 26 were interested, of whom 19 were randomized (M age  = 67 years, SD  = 7.70). Completion rate of MBSR was 72% and overall attendance was 96%. Reported benefits included increased relaxation, greater interpersonal connection, and increased body awareness. MBSR led to a decrease of 15% in LDL cholesterol and 10% in total cholesterol versus 4.5% and 1%, respectively, in the waitlist. Within group analyses showed notable decreases in LDL, triglycerides, and waist circumference post-MBSR and 2 months later., Conclusions: A RCT was largely feasible and MBSR acceptable to participants. MBSR may lead to sustained decreases in cholesterol levels, warranting development of large-scale research on this topic., Clinical Implications: Given the role of stress in CVD, addition of stress management interventions may serve as a useful complement to risk management among older individuals.

Background: The impacts of the COVID-19 pandemic have disproportionally affected different population groups. Veterans are more likely to have pre-existing mental health conditions compared to the general Canadian population, experience compounded stressors resulting from disruptions to familial, social, and occupational domains, and were faced with changes in health-care delivery (e.g. telehealth). The objectives of this study are to assess (a) the mental health impact of COVID-19 and related life changes on the well-being of Veterans and (b) perceptions of and satisfaction with changes in health-care treatments and delivery during the pandemic., Methods: A total of 1136 Canadian Veterans participated in an online survey. Participants completed questions pertaining to their mental health and well-being, lifestyle changes, and concerns relating to the COVID-19 pandemic, as well as experiences and satisfaction with health-care treatments during the pandemic., Results: Results showed that 55.9% of respondents reported worse mental health functioning compared to before the pandemic. The frequency of probable posttraumatic stress disorder, major depressive disorder, generalized anxiety disorder, alcohol use disorder, and suicidal ideation were 34.2%, 35.3%, 26.8%, 13.0%, and 22.0%, respectively. Between 38.6% and 53.1% of respondents attributed their symptoms as either directly related to or exacerbated by the pandemic. Approximately 18% of respondents reported using telehealth for mental health services during the pandemic, and among those, 72.8% indicated a choice to use telehealth even after the pandemic., Conclusions: This study found that Veterans experienced worsening mental health as a result of the COVID-19 pandemic. The use of telehealth services was widely endorsed by mental health treatment-seeking Veterans who transitioned to virtual care during the pandemic. Our findings have important clinical and programmeadministrator implications, emphasizing the need to reach out to support veterans, especially those with pre-existing mental health conditions and to enhance and maintain virtual care even post-pandemic., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Background: The COVID-19 pandemic has resulted in significant changes to everyday life, including social distancing mandates, changes to health care, and a heightened risk of infection. Previous research has shown that Canadian Armed Forces (CAF) veterans are at higher risk of developing mental and physical health conditions. Veterans and their families may face unique social challenges that can compound with pandemic-related disruptions to negatively impact well-being., Objective: This study aims to longitudinally characterize the mental health of CAF veterans and spouses of CAF veterans throughout the pandemic and to understand the dynamic influences of pandemic-related stressors on psychological health over time., Methods: We employed a prospective longitudinal panel design using an online data collection platform. Study participation was open to all CAF veterans and spouses of CAF veterans residing in Canada. Participants were asked to complete a comprehensive battery of assessments representing psychological well-being, chronic pain, health care access patterns, physical environment, employment, social integration, and adjustment to pandemic-related lifestyle changes. Follow-up assessments were conducted every 3 months over an 18-month period. This study was approved by the Western University Health Sciences and Lawson Health Research Institute Research Ethics Boards., Results: Baseline data were collected between July 2020 and February 2021. There were 3 population segments that participated in the study: 1047 veterans, 366 spouses of veterans, and 125 veterans who are also spouses of veterans completed baseline data collection. As of November 2021, data collection is ongoing, with participants completing the 9- or 12-month follow-up surveys depending on their date of self-enrollment. Data collection across all time points will be complete in September 2022., Conclusions: This longitudinal survey is unique in its comprehensive assessment of domains relevant to veterans and spouses of veterans during the COVID-19 pandemic, ranging from occupational, demographic, social, mental, and physical domains, to perceptions and experiences with health care treatments and access. The results of this study will be used to inform policy for veteran and veteran family support, and to best prepare for similar emergencies should they occur in the future., International Registered Report Identifier (irrid): DERR1-10.2196/34984., (©Callista A Forchuk, Anthony Nazarov, Rachel A Plouffe, Jenny J W Liu, Erisa Deda, Tri Le, Dominic Gargala, Vanessa Soares, Jesse Bourret-Gheysen, Kate St Cyr, Maede S Nouri, Fardous Hosseiny, Patrick Smith, Gabrielle Dupuis, Maya Roth, Michelle Marlborough, Rakesh Jetly, Alexandra Heber, Ruth Lanius, J Don Richardson. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 11.01.2022.)

Background: Research is urgently needed to understand health care workers' (HCWs') experiences of moral-ethical dilemmas encountered throughout the COVID-19 pandemic, and their associations with organizational perceptions and personal well-being. This research is important to prevent long-term moral and psychological distress and to ensure that workers can optimally provide health services., Objective: Evaluate associations between workplace experiences during COVID-19, moral distress, and the psychological well-being of Canadian HCWs., Method: A total of 1362 French- and English-speaking Canadian HCWs employed during the COVID-19 pandemic were recruited to participate in an online survey. Participants completed measures reflecting moral distress, perceptions of organizational response to the pandemic, burnout, and symptoms of psychological disorders, including depression, anxiety, and posttraumatic stress disorder (PTSD)., Results: Structural equation modelling showed that when organizational predictors were considered together, resource adequacy, positive work life impact, and ethical work environment negatively predicted severity of moral distress, whereas COVID-19 risk perception positively predicted severity of moral distress. Moral distress also significantly and positively predicted symptoms of depression, anxiety, PTSD, and burnout., Conclusions: Our findings highlight an urgent need for HCW organizations to implement strategies designed to prevent long-term moral and psychological distress within the workplace. Ensuring availability of adequate resources, reducing HCW risk of contracting COVID-19, providing organizational support regarding individual priorities, and upholding ethical considerations are crucial to reducing severity of moral distress in HCWs., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Background: Over 85% of active members of the Canadian Armed Forces have been exposed to potentially traumatic events linked to the development of posttraumatic stress disorder (PTSD). At the time of transition to civilian life, as high as 1 in 8 veterans may be diagnosed with PTSD. Given the high prevalence of PTSD in military and veteran populations, the provision of effective treatment considering their unique challenges and experiences is critical for mental health support and the well-being of these populations., Objective: This paper presents the protocol for a meta-analysis and systematic review that will examine the effectiveness of treatment approaches for military-related PTSD., Methods: This PROSPERO-preregistered meta-analysis is being conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and Cochrane guidelines. A comprehensive search of the literature was conducted using the databases PsycInfo, Medline, Embase, CINAHL, and ProQuest Dissertation & Theses. Effect sizes will be computed based on changes in PTSD symptom scores over time across studies using validated PTSD scales. A multilevel meta-analysis will examine the overall effects, between-study effects, and within-study effects of available evidence for PTSD treatments in military populations. Effect sizes will be compared between pharmacotherapeutic, psychotherapeutic, and alternative/emerging treatment interventions. Finally, meta-regression and subgroup analyses will explore the moderating roles of clinical characteristics (eg, PTSD symptom clusters), treatment approaches (eg, therapeutic orientations in psychotherapy and alternative therapies and classifications of drugs in pharmacotherapy), as well as treatment characteristics (eg, length of intervention) on treatment outcomes., Results: The literature search was completed on April 14, 2021. After the removal of duplicates, a total of 12,002 studies were screened for inclusion. As of July 2021, title and abstract screening has been completed, with 1469 out of 12,002 (12.23%) studies included for full-text review. Full review is expected to be completed in the summer of 2021, with initial results expected for publication by early winter of 2021., Conclusions: This meta-analysis will provide information on the current state of evidence on the efficacy and effectiveness of various treatment approaches for military-related PTSD and identify factors that may influence treatment outcomes. The results will inform clinical decision-making for service providers and service users. Finally, the findings will provide insights into future treatment development and practice recommendations to better support the well-being of military and veteran populations., Trial Registration: PROSPERO CRD42021245754; https://tinyurl.com/y9u57c59., International Registered Report Identifier (irrid): DERR1-10.2196/33151., (©Jenny J W Liu, Anthony Nazarov, Bethany Easterbrook, Rachel A Plouffe, Tri Le, Callista Forchuk, Alec Brandwood, Kate St Cyr, Edouard Auger, Ken Balderson, Mathieu Bilodeau, Amer M Burhan, Murray W Enns, Patrick Smith, Fardous Hosseiny, Gabrielle Dupuis, Maya Roth, Natalie Mota, Vicky Lavoie, J Don Richardson. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 25.10.2021.)

Background: Health care workers (HCWs) have experienced several stressors associated with the COVID-19 pandemic. Structural stressors, including extended work hours, redeployment, and changes in organizational mandates, often intersect with interpersonal and personal stressors, such as caring for those with COVID-19 infections; worrying about infection of self, family, and loved ones; working despite shortages of personal protective equipment; and encountering various difficult moral-ethical dilemmas., Objective: The paper describes the protocol for a longitudinal study seeking to capture the unique experiences, challenges, and changes faced by HCWs during the COVID-19 pandemic. The study seeks to explore the impact of COVID-19 on the mental well-being of HCWs with a particular focus on moral distress, perceptions of and satisfaction with delivery of care, and how changes in work structure are tolerated among HCWs providing clinical services., Methods: A prospective longitudinal design is employed to assess HCWs' experiences across domains of mental health (depression, anxiety, posttraumatic stress, and well-being), moral distress and moral reasoning, work-related changes and telehealth, organizational responses to COVID-19 concerns, and experiences with COVID-19 infections to self and to others. We recruited HCWs from across Canada through convenience snowball sampling to participate in either a short-form or long-form web-based survey at baseline. Respondents to the baseline survey are invited to complete a follow-up survey every 3 months, for a total of 18 months., Results: A total of 1926 participants completed baseline surveys between June 26 and December 31, 2020, and 1859 participants provided their emails to contact them to participate in follow-up surveys. As of July 2021, data collection is ongoing, with participants nearing the 6- or 9-month follow-up periods depending on their initial time of self-enrollment., Conclusions: This protocol describes a study that will provide unique insights into the immediate and longitudinal impact of the COVID-19 pandemic on the dimensions of mental health, moral distress, health care delivery, and workplace environment of HCWs. The feasibility and acceptability of implementing a short-form and long-form survey on participant engagement and data retention will also be discussed., International Registered Report Identifier (irrid): DERR1-10.2196/32663., (©Jenny J W Liu, Anthony Nazarov, Rachel A Plouffe, Callista A Forchuk, Erisa Deda, Dominic Gargala, Tri Le, Jesse Bourret-Gheysen, Vanessa Soares, Maede S Nouri, Fardous Hosseiny, Patrick Smith, Maya Roth, Arlene G MacDougall, Michelle Marlborough, Rakesh Jetly, Alexandra Heber, Joy Albuquerque, Ruth Lanius, Ken Balderson, Gabrielle Dupuis, Viraj Mehta, J Don Richardson. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 27.09.2021.)

Background: Shorter telomere length (TL) may indicate premature cellular aging and increased risk for disease. While there is substantial evidence for shorter TL in individuals suffering from psychiatric disorders, data is scarce on maladaptive personality traits related to coronary artery disease (CAD). The purpose of this study was to evaluate the association of TL with hostility and defensiveness in individuals with CAD or other non-cardiovascular illnesses and whether associations were moderated by CAD status and sex., Methods: One thousand thirty-six individuals (M age = 65.40 ± 6.73 years) with and without CAD completed the Marlowe-Crowne Social Desirability Scale and the Cook-Medley Hostility Scale. Relative TL was measured via quantitative polymerase chain reaction of total genomic DNA samples. Analyses involved hierarchical regressions on TL, performed separately for hostility and defensiveness, controlling for pertinent sociodemographic, behavioural, and medical risk factors. Separate analyses were performed on 25 healthy participants., Results: A hostility by sex interaction emerged (β = - .08, p = .006) in the patient groups, where greater hostility was associated with shorter TL in women only (p < .01). A Defensiveness by CAD status interaction (β = - .06, p = .049) revealed longer TL in more defensive CAD patients only (p = .06). In healthy men, shorter TL was observed in those with greater defensiveness (β = .52, p = .006) but lower hostility (β = - .43, p = .049)., Conclusion: Hostility and defensiveness are differentially associated with TL as a function of sex and health status. The implication of these results for health remains to be determined, but propose an additional pathway through which the effect of maladaptive personality traits may contribute to CV and other disease.

Tolerogenic dendritic cells (toDCs) are crucial to controlling the development of autoreactive T cell responses and the prevention of autoimmunity. We have reported that NOD.CD11c Stat5b-CA transgenic mice expressing a constitutively active (CA) form of Stat5b under the control of a CD11c promoter are protected from diabetes and that Stat5b-CA-expressing DCs are tolerogenic and halt ongoing diabetes in NOD mice. However, the molecular mechanisms by which Stat5b-CA modulates DC tolerogenic function are not fully understood. Here, we used bone marrow-derived DCs (BMDCs) from NOD.CD11c Stat5b-CA transgenic mice (Stat5b-CA.BMDCs) and found that Stat5b-CA.BMDCs displayed high levels of MHC class II, CD80, CD86, PD-L1, and PD-L2 and produced elevated amounts of TGFβ but low amounts of TNFα and IL-23. Stat5b-CA.BMDCs upregulated Irf4 and downregulated Irf8 genes and protein expression and promoted CD11c + CD11b + DC2 subset differentiation. Interestingly, we found that the histone methyltransferase Ezh2 and Stat5b-CA bound gamma-interferon activated site (GAS) sequences in the Irf8 enhancer IRF8 transcription, whereas Stat5b but not Ezh2 bound GAS sequences in the Irf4 promoter to enhance IRF4 transcription. Injection of Stat5b-CA.BMDCs into prediabetic NOD mice halted progression of islet inflammation and protected against diabetes. Importantly, inhibition of Ezh2 in tolerogenic Stat5b-CA.BMDCs reduced their ability to prevent diabetes development in NOD recipient mice. Taken together, our data suggest that the active form of Stat5b induces tolerogenic DC function by modulating IRF4 and IRF8 expression through recruitment of Ezh2 and highlight the fundamental role of Ezh2 in Stat5b-mediated induction of tolerogenic DC function.

We demonstrate subwavelength axial sectioning on biological samples with a stimulated emission depletion (STED) microscope combined with supercritical angle fluorescence (SAF) detection. SAF imaging is a powerful technique for imaging the membrane of the cell based on the direct exploitation of the fluorophore emission properties. Indeed, only when fluorophores are close to the interface can their evanescent near-field emission become propagative and be detected beyond the critical angle. Therefore, filtering out the SAF emission from the undercritical angle fluorescence (UAF) emission in the back focal plane of a high-NA objective lens permits nanometer axial sectioning of fluorescent emitters close to the coverslip. When combined with STED microscopy, a straightforward gain in axial resolution can be reached without any alteration of the STED beam path. Indeed, STED-SAF implementation only requires a modification in the detection path of the STED microscope and thus could be widely implemented., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Doxylamine (Donormyl®, Lidene®, Generics) is commonly proposed by pharmacists as a sleeping pill which does not require a prescription. In France, today it is only prescribed for occasional insomnia in adults. In light of knowledge about the role of the histamine H1 inverse agonist drugs in the treatment of insomnia, and specifically the low dose doxepin (3 mg and 6 mg) marketed in the US and Canada (Silenor®), we suggest that the use of doxylamine may be appropriate for treating insomnia in the last third of the night. Better information to the pharmacist on the prescription of this anti-H1 hypnotic would be beneficial to the patient., (Copyright © 2019 L'Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.)

Background: Emergency departments (EDs) in rural and remote areas face challenges in delivering accessible, high quality and efficient services. The objective of this pilot study was to test the feasibility and relevance of the selected approach and to explore challenges and solutions to improve delivery of care in selected EDs., Methods: We conducted an exploratory multiple case study in two rural EDs in Québec, Canada. A survey filled out by the head nurse for each ED provided a descriptive statistical portrait. Semi-structured interviews were conducted with ED health professionals, decision-makers and citizens (n = 68) and analyzed inductively and thematically., Results: The two EDs differed with regards to number of annual visits, inter-facility transfers and wait time. Stakeholders stressed the influence of context on ED challenges and solutions, related to: 1) governance and management (e.g. lack of representation, poor efficiency, ill-adapted standards); 2) health services organization (e.g. limited access to primary healthcare and long-term care, challenges with transfers); 3) resources (e.g. lack of infrastructure, limited access to specialists, difficult staff recruitment/retention); 4) and professional practice (e.g. isolation, large scope, maintaining competencies with low case volumes, need for continuing education, teamwork and protocols). There was a general agreement between stakeholder groups., Conclusions: Our findings show the feasibility and relevance of mobilizing stakeholders to identify context-specific challenges and solutions. It confirms the importance of undertaking a larger study to improve the delivery of care in rural EDs.

High molar masses homopolymers of both acrylamide (AM) and 2-acrylamido-2-methylpropanesulfonate (AMPS) as well as poly(AM- stat -AMPS) exhibiting a large range copolymer composition has been obtained via the optimization of a purely adiabatic gel process. Monomer concentrations ranging from 2.0 to 3.47 M have been successfully tested while keeping the control of the molar masses up to 5 × 10 6 g mol -1 . The products have been characterized in terms of molecular mass and viscosimetric properties., Competing Interests: The authors declare no competing financial interest.

Objectives: As Canada's second largest province, the geography of Quebec poses unique challenges for trauma management. Our primary objective was to compare mortality rates between trauma patients treated at rural emergency departments (EDs) and urban trauma centres in Quebec. As a secondary objective, we compared the availability of trauma care resources and services between these two settings., Design: Retrospective cohort study., Setting: 26 rural EDs and 33 level 1 and 2 urban trauma centres in Quebec, Canada., Participants: 79 957 trauma cases collected from Quebec's trauma registry., Primary and Secondary Outcome Measures: Our primary outcome measure was mortality (prehospital, ED, in-hospital). Secondary outcome measures were the availability of trauma-related services and staff specialties at rural and urban facilities. Multivariable generalised linear mixed models were used to determine the relationship between the primary facility and mortality., Results: Overall, 7215 (9.0%) trauma patients were treated in a rural ED and 72 742 (91.0%) received treatment at an urban centre. Mortality rates were higher in rural EDs compared with urban trauma centres (13.3% vs 7.9%, p<0.001). After controlling for available potential confounders, the odds of prehospital or ED mortality were over three times greater for patients treated in a rural ED (OR 3.44, 95% CI 1.88 to 6.28). Trauma care setting (rural vs urban) was not associated with in-hospital mortality. Nearly all of the specialised services evaluated were more present at urban trauma centres., Conclusions: Trauma patients treated in rural EDs had a higher mortality rate and were more likely to die prehospital or in the ED compared with patients treated at an urban trauma centre. Our results were limited by a lack of accurate prehospital times in the trauma registry., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Here, we present a 3D localization-based super-resolution technique providing a slowly varying localization precision over a 1 μm range with precisions down to 15 nm. The axial localization is performed through a combination of point spread function (PSF) shaping and supercritical angle fluorescence (SAF), which yields absolute axial information. Using a dual-view scheme, the axial detection is decoupled from the lateral detection and optimized independently to provide a weakly anisotropic 3D resolution over the imaging range. This method can be readily implemented on most homemade PSF shaping setups and provides drift-free, tilt-insensitive and achromatic results. Its insensitivity to these unavoidable experimental biases is especially adapted for multicolor 3D super-resolution microscopy, as we demonstrate by imaging cell cytoskeleton, living bacteria membranes and axon periodic submembrane scaffolds. We further illustrate the interest of the technique for biological multicolor imaging over a several-μm range by direct merging of multiple acquisitions at different depths.

Objective: The objective of this article is to describe the elements involved with transporting extremely low birth weight (ELBW) infants from referring centers to our center's neonatal intensive care unit (NICU) and then from the NICU to the catheterization lab for transcatheter closure of patent ductus arteriosus (PDA)., Setting: Several referring centers are over 300 miles away. ELBW infants are transferred in to our NICU safely for the procedure and transferred back following the procedure. A multidisciplinary team approach is necessary in order to achieve a safe transport of these fragile patients., Patients: To date, we have over 12 centers referring patients that weigh <1000 g for transcatheter PDA closure (TCPC). Three of these centers are over 300 miles away. Five other centers are between 100 and 300 miles from the hospital in which we perform TCPC., Interventions: Fixed-wing aircrafts are necessary for long-distance transfers. Various modes of mechanical ventilators including transport oscillators are built into temperature- and humidity-controlled incubators in which these infants are transported. Ambulances are used to take the patient between the airport and the hospital. Shorter distance transports are accomplished via helicopters or ambulances. Transfer from the NICU to the catheterization lab to perform TCPC is a relatively easier endeavor., Outcome Measures: Patients' body temperature, fluid balance, and hemodynamics have to be maintained throughout the transport and the procedure for best outcomes., Results: There has been 100% procedural success of performing TCPC in ELBW infants with no hemodynamic compromise during transport., Conclusions: TCPC has shown promise in improving overall patient outcomes that the potential hazards associated with complex transport measures are worth it. Successful transfer to and from referring centers and to and from the catheterization lab can be accomplished safely with increasing institutional experience., (© 2019 Wiley Periodicals, Inc.)

Competing Interests: Les auteurs déclarent n’avoir aucun lien d’intérêts.

Objectives: The Quebec Emergency Department Management Guide (QEDMG) is a unique document with 78 recommendations designed to improve the organization of emergency departments (EDs) in the province of Quebec. However, no study has examined how this guide is perceived or used by rural health care management., Methods: We invited all directors of professional services (DPS), directors of nursing services (DNS), head nurses (HN), and emergency department directors (EDD) working in Quebec's rural hospitals to complete an online survey (144 questions). Simple frequency analyses (percentage [%] and 95% confidence interval) were conducted to establish general familiarity and use of the QEDMG, as well as perceived usefulness and implementation of its recommendations., Results: Seventy-three percent (19/26) of Quebec's rural EDs participated in the study. A total of 82% (62/76) of the targeted stakeholders participated. Sixty-one percent of respondents reported being "moderately or a lot" familiar with the QEDMG, whereas 77% reported "almost never or sometimes" refer to this guide. Physician management (DPS, EDD) were more likely than nursing management (DNS and especially HN) to report "not at all" or "little" familiarity on use of the guide. Finally, 98% of the QEDMG recommendations were considered useful., Conclusions: Although the QEDMG is considered a useful guide for rural EDs, it is not optimally known or used in rural EDs, especially by physician management. Stakeholders should consider these findings before implementing the revised versions of the QEDMG.

Dendritic cells (DCs) play a major role in innate and adaptive immunity and self-immune tolerance. Immunogenic versus tolerogenic DC functions are dictated by their levels of costimulatory molecules and their cytokine expression profile. The transcription factor C/EBPβ regulates the expression of several inflammatory genes in many cell types including macrophages. However, little is known regarding the role of C/EBPβ in tolerogenic versus immunogenic DCs functions. We have previously reported that bone marrow-derived DCs generated with GM-CSF (GM/DCs) acquire the signature of semi-mature tolerogenic IL-10-producing DCs as opposed to immunogenic DCs generated with GM-CSF and IL-4 (IL-4/DCs). Here, we show that tolerogenic GM/DCs exhibit higher levels of phosphorylation and enhanced DNA binding activity of C/EBPβ and CREB than immunogenic IL-4/DCs. We also show that the p38 MAPK/CREB axis and GSK3 play an important role in regulating C/EBPβ phosphorylation and DNA binding activity. Inhibition of p38 MAPK in GM/DCs resulted in a drastic decrease of C/EBPβ and CREB DNA binding activities, a reduction of their IL-10 production and an increase of their IL-12p70 production, a characteristic of immunogenic IL-4/DCs. We also present evidence that GSK3 inhibition in GM/DCs reduced C/EBPβ DNA binding activity and increased expression of costimulatory molecules in GM/DCs and their production of IL-10. Analysis of GM/DCs of C/EBPβ -/- mice showed that C/EBPβ was essential to maintain the semimature phenotype and the production of IL-10 as well as low CD4⁺ T cell proliferation. Our results highlight the importance of the p38MAPK-C/EBPβ pathway in regulating phenotype and function of tolerogenic GM/DCs., Competing Interests: The authors declare no conflict of interest.

Congenital Zika virus syndrome consists of a large spectrum of neurologic abnormalities seen in infants infected with Zika virus in utero. However, little is known about the effects of Zika virus intrauterine infection on the neurocognitive development of children born without birth defects. Using a case-control study design, we investigated the temporal association of a cluster of congenital defects with Zika virus infection. In a nested study, we also assessed the early childhood development of children recruited in the initial study as controls who were born without known birth defects,. We found evidence for an association of congenital defects with both maternal Zika virus seropositivity (time of infection unknown) and symptomatic Zika virus infection during pregnancy. Although the early childhood development assessment found no excess burden of developmental delay associated with maternal Zika virus infection, larger, longer-term studies are needed.

Background: Adolescent depression may increase risk for poor mental health outcomes in adulthood. The objective of this study was to systematically review the literature on the association between adolescent depression and adult anxiety and depressive disorders as well as suicidality., Methods: EMBASE, MEDLINE, and PSYCinfo databases were searched and longitudinal cohort studies in which depression was measured in adolescence (age 10-19) and outcomes of depressive disorders, anxiety disorders, or suicidality were measured in adulthood (age 21+), were selected. Meta-analysis using inverse variance and random effects modeling, along with sensitivity analyses, were used to synthesize article estimates., Results: Twenty articles were identified, representing 15 unique cohorts. Seventeen of 18 articles showed adolescent depression increased risk for adult depression; eleven pooled cohorts estimated that adolescents with depression had 2.78 (1.97, 3.93) times increased odds of depression in adulthood. Seven of eight articles that investigated the association between adolescent depression and any adult anxiety found a significant association. Three of five articles showed a significant association between adolescent depression and adult suicidality., Conclusion: This review shows that adolescent depression increases the risk for subsequent depression later in life. Articles consistently found that adolescent depression increases the risk for anxiety disorders in adulthood, but evidence was mixed on whether or not a significant association existed between adolescent depression and suicidality in adulthood. Early intervention in adolescent depression may reduce long-term burden of disease., (© 2018 Wiley Periodicals, Inc.)

Alzheimer's disease (AD) is the most frequent type of dementia. The pathological hallmarks of the disease are extracellular senile plaques composed of beta-amyloid peptide (Aβ) and intracellular neurofibrillary tangles composed of pTau. These findings led to the "beta-amyloid hypothesis" that proposes that Aβ is the major cause of AD. Clinical trials targeting Aβ in the brain have mostly failed, whether they attempted to decrease Aβ production by BACE inhibitors or by antibodies. These failures suggest a need to find new hypotheses to explain AD pathogenesis and generate new targets for intervention to prevent and treat the disease. Many years ago, the "infection hypothesis" was proposed, but received little attention. However, the recent discovery that Aβ is an antimicrobial peptide (AMP) acting against bacteria, fungi, and viruses gives increased credence to an infection hypothesis in the etiology of AD. We and others have shown that microbial infection increases the synthesis of this AMP. Here, we propose that the production of Aβ as an AMP will be beneficial on first microbial challenge but will become progressively detrimental as the infection becomes chronic and reactivates from time to time. Furthermore, we propose that host measures to remove excess Aβ decrease over time due to microglial senescence and microbial biofilm formation. We propose that this biofilm aggregates with Aβ to form the plaques in the brain of AD patients. In this review, we will develop this connection between Infection - Aβ - AD and discuss future possible treatments based on this paradigm.

Alzheimer's disease is one of the most devastating neurodegenerative diseases. The exact cause of the disease is still not known although many scientists believe in the beta amyloid hypothesis which states that the accumulation of the amyloid peptide beta (Aβ) in brain is the initial cause which consequently leads to pathological neuroinflammation. However, it was recently shown that Aβ may have an important role in defending the brain against infections. Thus, the balance between positive and negative impact of Aβ may determine disease progression. Microglia in the brain are innate immune cells, and brain-initiated inflammatory responses reflected in the periphery suggests that Alzheimer's disease is to some extent also a systemic inflammatory disease. Greater permeability of the blood brain barrier facilitates the transport of peripheral immune cells to the brain and vice versa so that a vicious circle originating on the periphery may contribute to the development of overt clinical AD. Persistent inflammatory challenges by pathogens in the periphery, increasing with age, may also contribute to the central propagation of the pathological changes seen clinically. Therefore, the activation status of peripheral innate immune cells may represent an early biomarker of the upcoming impact on the brain. The modulation of these cells may thus become a useful mechanism for modifying disease progression., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Daptomycin is a last-resort membrane-targeting lipopeptide approved for the treatment of drug-resistant staphylococcal infections, such as bacteremia and implant-related infections. Although cases of resistance to this antibiotic are rare, increasing numbers of clinical, in vitro , and animal studies report treatment failure, notably against Staphylococcus aureus The aim of this study was to identify the features of daptomycin and its target bacteria that lead to daptomycin treatment failure. We show that daptomycin bactericidal activity against S. aureus varies significantly with the growth state and strain, according to the membrane fatty acid composition. Daptomycin efficacy as an antibiotic relies on its ability to oligomerize within membranes and form pores that subsequently lead to cell death. Our findings ascertain that daptomycin interacts with tolerant bacteria and reaches its membrane target, regardless of its bactericidal activity. However, the final step of pore formation does not occur in cells that are daptomycin tolerant, strongly suggesting that it is incapable of oligomerization. Importantly, membrane fatty acid contents correlated with poor daptomycin bactericidal activity, which could be manipulated by fatty acid addition. In conclusion, daptomycin failure to treat S. aureus is not due to a lack of antibiotic-target interaction, but is driven by its capacity to form pores, which depends on membrane composition. Manipulation of membrane fluidity to restore S. aureus daptomycin bactericidal activity in vivo could open the way to novel antibiotic treatment strategies., (Copyright © 2018 American Society for Microbiology.)

The innate and adaptive branches of the immune system display changes with aging, a fact referred to as immunosenescence. Furthermore, it has been established that adaptive immunity is more susceptible to age-related changes than innate immunity. The most prominent phenotypic changes that reflect the specific differentiation and role of each T cell subpopulation are two-fold. They are a decreased number of naïve T cells that parallels an increase in memory T cells, mainly in the cytotoxic CD8 + T cell population, which can be subdivided into naïve, central, effector memory and TEMRA cells. The two main T cell properties that are the most affected with aging are the altered clonal expansion and decreased cytokine production, especially IL-2. These T cell functions have been shown to be affected in the early events of signaling. The aim of the present study was to investigate the influence of age on TCR- and CD28-dependent activation of the downstream signaling effectors Lck, SHP-1, Akt, PI3K p85α and mTOR in differentiated subpopulations of CD4 + and CD8 + T cells. Results showed that lymphocytes of elderly subjects were already in an activated state that could not be upregulated by external stimulation. Results also showed that the age-related signal transduction changes were more important than phenotype in the CD4 + and CD8 + T subpopulations. These observations suggested that age-related molecular and biochemical changes have a more significant influence on T cell functions than T cell phenotype., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: Stroke is one of the leading causes of death in Canada. While stroke care has improved dramatically over the last decade, outcomes following stroke among patients treated in rural hospitals have not yet been reported in Canada., Objectives: To describe variation in 30-day post-stroke in-hospital mortality rates between rural and urban academic hospitals in Canada. We also examined 24/7 in-hospital access to CT scanners and selected services in rural hospitals., Materials and Methods: We included Canadian Institute for Health Information (CIHI) data on adjusted 30-day in-hospital mortality following stroke from 2007 to 2011 for all acute care hospitals in Canada excluding Quebec and the Territories. We categorized rural hospitals as those located in rural small towns providing 24/7 emergency physician coverage with inpatient beds. Urban hospitals were academic centres designated as Level 1 or 2 trauma centres. We computed descriptive data on local access to a CT scanner and other services and compared mean 30-day adjusted post-stroke mortality rates for rural and urban hospitals to the overall Canadian rate., Results: A total of 286 rural hospitals (3.4 million emergency department (ED) visits/year) and 24 urban hospitals (1.5 million ED visits/year) met inclusion criteria. From 2007 to 2011, 30-day in-hospital mortality rates following stroke were significantly higher in rural than in urban hospitals and higher than the Canadian average for every year except 2008 (rural average range = 18.26 to 21.04 and urban average range = 14.11 to 16.78). Only 11% of rural hospitals had a CT-scanner, 1% had MRI, 21% had in-hospital ICU, 94% had laboratory and 92% had basic x-ray facilities., Conclusion: Rural hospitals in Canada had higher 30-day in-hospital mortality rates following stroke than urban academic hospitals and the Canadian average. Rural hospitals also have very limited local access to CT scanners and ICUs. These rural/urban discrepancies are cause for concern in the context of Canada's universal health care system.

We propose a straightforward sample-based technique to calibrate the axial detection in 3D single-molecule localization microscopy. Using microspheres coated with fluorescent molecules, the calibration curves of point spread function-shaping or intensity-based measurements can be obtained over the imaging depth range. This experimental method takes into account the effect of the spherical aberration without requiring computational correction. We demonstrate its efficiency for astigmatic imaging in a 1.2 μm range above the coverslip.

The immune system is the most important protective physiological system of the organism. It has many connections with other systems and is, in fact, often considered as part of the larger neuro-endocrine-immune axis. Most experimental data on immune changes with aging show a decline in many immune parameters when compared to young healthy subjects. The bulk of these changes is termed immunosenescence. Immunosenescence has been considered for some time as detrimental because it often leads to subclinical accumulation of pro-inflammatory factors and inflamm-aging. Together, immunosenescence and inflamm-aging are suggested to stand at the origin of most of the diseases of the elderly, such as infections, cancer, autoimmune disorders, and chronic inflammatory diseases. However, an increasing number of immune-gerontologists have challenged this negative interpretation of immunosenescence with respect to its significance in aging-related alterations of the immune system. If one considers these changes from an evolutionary perspective, they can be viewed preferably as adaptive or remodeling rather than solely detrimental. Whereas it is conceivable that global immune changes may lead to various diseases, it is also obvious that these changes may be needed for extended survival/longevity. Recent cumulative data suggest that, without the existence of the immunosenescence/inflamm-aging duo (representing two sides of the same phenomenon), human longevity would be greatly shortened. This review summarizes recent data on the dynamic reassessment of immune changes with aging. Accordingly, attempts to intervene on the aging immune system by targeting its rejuvenation, it may be more suitable to aim to maintain general homeostasis and function by appropriately improving immune-inflammatory-functions.

Background: Long-term effects of psychosocial interventions to reduce emotional distress, sleep difficulties, and fatigue of breast cancer patients are rarely examined. We aim to assess the effectiveness of three group interventions, based on cognitive behavioural therapy (CBT), yoga, and self-hypnosis, in comparison to a control group at a 9-month follow-up., Methods: A total of 123 patients chose to participate in one of the interventions. A control group was set up for those who agreed not to participate. Emotional distress, fatigue, and sleep quality were assessed before (T0) and after interventions (T1), and at 3-month (T2) and 9-month follow-ups (T3)., Results: Nine months after interventions, there was a decrease of anxiety (P=0.000), depression (P=0.000), and fatigue (P=0.002) in the hypnosis group, and a decrease of anxiety (P=0.024) in the yoga group. There were no significant improvements for all the investigated variables in the CBT and control groups., Conclusions: Our results showed that mind-body interventions seem to be an interesting psychological approach to improve the well-being of breast cancer patients. Further research is needed to improve the understanding of the mechanisms of action of such interventions and their long-term effects on quality of life.

Complementary and alternative medicine has been shown to be beneficial in reducing chemotherapy-induced nausea and vomiting. However, conclusive results are lacking in order to confirm its usefulness. The purpose of this study was to determine whether a standardized yoga intervention could reduce these adverse symptoms. This was a partially randomized and blinded controlled trial comparing a standardized yoga intervention with standard care. Eligible patients were adults diagnosed with stages I to III breast cancer receiving chemotherapy. Patients randomized to the experimental group participated in an 8-week yoga program. There was no significant difference between the experimental and control groups on chemotherapy-induced nausea and vomiting after 8 weeks. Results suggest the yoga program is not beneficial in managing these adverse symptoms. However, considering preliminary evidence suggesting yoga's beneficial impact in cancer symptom management, methodological limitations should be explored and additional studies should be conducted.

Introduction: Emergency departments (EDs) are an important safety net for rural populations. Results of our earlier studies suggest that rural Canadian hospitals have limited access to advanced imaging services and intensive care units and that patients are transferred over large distances. They also revealed significant geographical variations in rural services. In the absence of national standards, our studies raise questions about inequities in rural access to emergency services and the risks for citizens. Our goal is to build recommendations for improving services by mobilising stakeholders interested in rural emergency care. With help and full engagement of stakeholders, we will (1) identify solutions for improving quality and performance in rural EDs; (2) formulate and prioritise recommendations; (3) transfer knowledge of the recommendations to rural EDs and support operationalisation and (4) assess knowledge transfer and explore further impacts of this participatory action research project., Methodology: We will use a participatory action research approach. We will plan for a governance structure that includes all stakeholders’ representatives, so throughout this project, stakeholders are fully engaged at every step. Our sample will be 26 EDs in rural Quebec. We will conduct semistructured individual and focus group interviews with relevant and representative participants, including patients and citizens (estimated n=200). Interviews will be thematically analysed to extract potential solutions and other qualitative information.An expert panel (±15) will use an analysis grid to develop consensus recommendations from solutions suggested and will evaluate feasibility, impacts, costs, conditions for implementation and establish monitoring indicators. Recommendations will be transferred to stakeholders using tailored knowledge translation strategies (web platform, meetings and so on)., Discussion and Expected Results: This study will result in a comprehensive consensus list of feasible and high-priority recommendations enabling decision-makers in emergency care to implement improvements in rural emergency care in Quebec., Ethics and Dissemination: This protocol has been approved by the CSSS Alphonse-Desjardins research ethics committee (Project number: MP 2017-009). The qualitative material will be kept confidential and the data will be presented in a way that respects confidentiality. The dissemination plan for the study includes publications in scientific and professional journals. We will also use social media to disseminate our findings and activities such as communications in public conferences., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Alzheimer disease (AD) is the most prevalent form of dementia although the underlying cause(s) remains unknown at this time. However, neuroinflammation is believed to play an important role and suspected contributing immune parameters can be revealed in studies comparing patients at the stage of amnestic mild cognitive impairment (aMCI) to healthy age-matched individuals. A network of immune regulatory cells including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) maintains immune homeostasis but there are very few data on the role of these cells in AD. Here, we investigated the presence of these cells in the blood of subjects with aMCI and mild AD (mAD) in comparison with healthy age-matched controls. We also quantitated several pro- and anti-inflammatory cytokines in sera which can influence the development and activation of these cells. We found significantly higher levels of MDSCs and Tregs in aMCI but not in mAD patients, as well as higher serum IL-1β levels. Stratifying the subjects based on CMV serostatus that is known to influence multiple immune parameters showed an absence of differences between aMCI subjects compared to mAD patients and healthy controls. We suggest that the increase in MDSCs and Tregs number in aMCI subjects may have a beneficial role in modulating inflammatory processes. However, this protective mechanism may have failed in mAD patients, allowing progression of the disease. This working hypothesis obviously requires testing in future studies.

Determining how cells generate and transduce mechanical forces at the nanoscale is a major technical challenge for the understanding of numerous physiological and pathological processes. Podosomes are submicrometer cell structures with a columnar F-actin core surrounded by a ring of adhesion proteins, which possess the singular ability to protrude into and probe the extracellular matrix. Using protrusion force microscopy, we have previously shown that single podosomes produce local nanoscale protrusions on the extracellular environment. However, how cellular forces are distributed to allow this protruding mechanism is still unknown. To investigate the molecular machinery of protrusion force generation, we performed mechanical simulations and developed quantitative image analyses of nanoscale architectural and mechanical measurements. First, in silico modeling showed that the deformations of the substrate made by podosomes require protrusion forces to be balanced by local traction forces at the immediate core periphery where the adhesion ring is located. Second, we showed that three-ring proteins are required for actin polymerization and protrusion force generation. Third, using DONALD, a 3D nanoscopy technique that provides 20 nm isotropic localization precision, we related force generation to the molecular extension of talin within the podosome ring, which requires vinculin and paxillin, indicating that the ring sustains mechanical tension. Our work demonstrates that the ring is a site of tension, balancing protrusion at the core. This local coupling of opposing forces forms the basis of protrusion and reveals the podosome as a nanoscale autonomous force generator.

The authors asked breast cancer (BC) patients to participate in 1 of 3 mind-body interventions (cognitive-behavioral therapy (CBT), yoga, or self-hypnosis) to explore their feasibility, ease of compliance, and impact on the participants' distress, quality of life (QoL), sleep, and mental adjustment. Ninety-nine patients completed an intervention (CBT: n = 10; yoga: n = 21; and self-hypnosis: n = 68). Results showed high feasibility and high compliance. After the interventions, there was no significant effect in the CBT group but significant positive effects on distress in the yoga and self-hypnosis groups, and, also, on QoL, sleep, and mental adjustment in the self-hypnosis group. In conclusion, mind-body interventions can decrease distress in BC patients, but RCTs are needed to confirm these findings.

The mechanisms of neurodegeneration in Alzheimer's disease (AD) remain under investigation. Alterations in the blood-brain barrier facilitate exchange of inflammatory mediators and immune cells between the brain and the periphery in AD. Here, we report analysis of phenotype and functions of polymorphonuclear neutrophils (PMN) in peripheral blood from patients with amnestic mild cognitive impairment (aMCI, n = 13), patients with mild AD (mAD, n = 15), and healthy elderly controls (n = 13). Results showed an increased expression of CD177 in mAD but not in healthy or aMCI patients. IL-8 stimulated increased expression of the CD11b integrin in PMN of healthy subjects in vitro but PMN of aMCI and mAD patients failed to respond. CD14 and CD16 expression was lower in PMN of mAD but not in aMCI individuals relative to controls. Only PMN of aMCI subjects expressed lower levels of CD88. Phagocytosis toward opsonized E. coli was differentially impaired in PMN of aMCI and mAD subjects whereas the capacity to ingest Dextran particles was absent only in mAD subjects. Killing activity was severely impaired in aMCI and mAD subjects whereas free radical production was only impaired in mAD patients. Inflammatory cytokine (TNFα, IL-6, IL-1β, IL-12p70) and chemokine (MIP-1α, MIP-1β, IL-8) production in response to LPS stimulation was very low in aMCI and nearly absent in mAD subjects. TLR2 expression was low only in aMCI. Our data showed a differentially altered capacity of PMN of aMCI and mAD subjects to respond to pathological aggression that may impact impaired responses associated with AD development.

Defects in dendritic cells (DCs) development and function lead to autoimmune disorders. Autoimmune diabetes in humans and NOD mice results from a breakdown of self-tolerance, ending in T cell-mediated β-cell destruction. DCs dysfunction in NOD mice results in part from a defect in the JAK-STAT5 signaling pathway associated with the idd4 susceptibility locus. The involvement of Stat5b in DCs tolerogenic functions remains unknown. We have generated transgenic mice (NOD.CD11c Stat5b-CA ) expressing a constitutively active form of the Stat5b gene (Stat5b-CA) under control of CD11c promoter. All NOD.CD11c Stat5b-CA mice were protected against diabetes. Protection was associated with an increased in the pool and suppressive function of Tregs, a promotion of Th2 and Tc2 immune response and a decreased percentage of CD8 + T cells. Splenic DCs of NOD.CD11c Stat5b-CA mice acquired a mature phenotype, promoted and induced better conversion of CD4 + CD25 - Foxp3 - T cells into Tregs (CD4 + CD25 + Foxp3 + T cells) than DCs of NOD mice. Stat5b-CA.DC-educated CD4 + CD25 - T cells delayed diabetes onset whereas Stat5b-CA.DC-educated Tregs blocked ongoing diabetes in 8-10 weeks old NOD recipient mice. Importantly, injection of Stat5b.CA.DC to 8-10-week old NOD mice halted diabetes progression and educated their splenocytes to loose their diabetogenic potential when transferred to NOD.SCID mice. Our work is the first to report that an active form of Stat5b restored DCs tolerogenic functions that re-educated Tregs to re-establish and to sustain long-term protective immune response against diabetes in NOD mice., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Aging is a complex biological process that leads to several physiological changes. Among these changes, the most striking are those involving the innate and adaptive parts of the immune system. Furthermore, these changes are associated with a low-grade inflammation called inflamm-aging, which is the result of several lifelong antigenic stimulations, including chronic viral infections such as cytomegalovirus. Immunosenescence, concomitantly with inflamm-aging, is considered as the leading cause of age-related diseases including cardiovascular, neurodegenerative and metabolic diseases, and cancer. HIV infection, once considered a unique deadly infectious disease, has now become a chronic disease with efficacious highly active antiretroviral therapy. This signifies that the treatment transforms HIV infection from a chronic infection to a chronic inflammatory disease. Most people with HIV infection become aged, and older adults have been contracting HIV infection. Thus, there is a great interest to study HIV infection in relation to immunosenescence and inflamm-aging to determine whether immunosenescence contributes to HIV infection, or if HIV is causing immunosenescence and, as such, represents a premature immunosenescence and accelerated aging. Although there are many similarities in the immune and inflammatory changes and the occurrence of age-related chronic diseases between normal aging and HIV infection, the interaction between these processes is not well understood, and consequently the concept that HIV infection is an accelerated aging model is questioned. Future studies are needed to effectively answer this question for the better care of HIV-infected elderly patients., (© 2017 S. Karger AG, Basel.)

Background Several cognitive behavioral interventions have been reported to reduce psychological symptoms in breast cancer (BC) patients. The goal of this study was to evaluate the effects of a yoga intervention in reducing depression and anxiety symptoms in BC patients. Methods This study was a randomized, partially blinded, controlled trial comparing a standardized yoga intervention to standard care. It was conducted at three medical centers in Montreal, Canada. Eligible patients were women diagnosed with stage I-III BC receiving chemotherapy. Participants were randomly assigned to receive yoga intervention immediately (experimental group, n=58) or after a waiting period (n=43 control group). The Bali Yoga Program for Breast Cancer Patients (BYP-BC) consisted of 23 gentle Hatha asanas (poses), 2 prayanamas (breathing techniques), shavasanas (relaxation corpse poses) and psychoeducational themes. Participants attended eight weekly sessions lasting 90 min each and received a DVD for home practice with 20- and 40-min sessions. Participants in the wait list control group received standard care during the 8-week waiting period. Results A total of 101 participants took part in the final intention-to-treat analyses. The repeated measures analyses demonstrated that depression symptoms increased in the control group (p=0.007), while no change was reported in the BYP-BC group (p=0.29). Also, depression symptoms decreased in the WL control group after receiving the BYP-BC intervention (p=0.03). Finally, there was no statistical significance in terms of anxiety symptoms (p=0.10). Conclusions Results support the BYP-BC intervention as a beneficial means of reducing and preventing the worsening of depression symptoms during chemotherapy treatment.

Amyloid-β (Aβ) peptides generated by the amyloidogenic pathway of amyloid-β protein precursor processing contribute significantly to neurodegeneration characteristic of Alzheimer's disease (AD). The involvement of Aβ peptides in the etiology of AD remains a subject of debate. Data published in the last 6 years by three different groups have added a new twist by revealing that Aβ peptides could act as antimicrobial peptides (AMP) in in vitro assays against some common and clinically relevant microorganisms, inhibit replication of seasonal and pandemic strains of influenza A and HSV-1 virus. These observations are of significance with respect to the notion that pathogens may be important contributors to the development of AD, particularly in the case of herpes simplex virus (HSV) infection, which often resides in the same cerebral sites where AD arises. Here, we review the data that support the interpretation that Aβ peptides behave as AMP, with an emphasis on studies concerning HSV-1 and a putative molecular mechanism that suggests that interactions between Aβ peptides and the HSV-1 fusogenic protein gB lead to impairment of HSV-1 infectivity by preventing the virus from fusing with the plasma membrane. A number of avenues for future research are suggested.

The aim was to see whether qualitative analysis improved quantitative measurement of illness perception after heart transplant. Two methods of evaluating illness representations were compared: one quantitative (administration of the Illness Perception Questionnaire-Revised) and one qualitative (phenomenological reduction). The qualitative analysis provided greater insight into the idiosyncratic and dynamic nature of the concept of illness representations. Adjustments to the Illness Perception Questionnaire-Revised are suggested to improve the evaluation of illness perception in terms of dispersion of scores, emotional impact, coping strategies and treatment, and social support, and ultimately to enhance interventions designed to promote treatment compliance., (© The Author(s) 2015.)

Background: Evidence-based indicators of quality of care have been developed to improve care and performance in Canadian emergency departments. The feasibility of measuring these indicators has been assessed mainly in urban and academic emergency departments. We sought to assess the feasibility of measuring quality-of-care indicators in rural emergency departments in Quebec., Methods: We previously identified rural emergency departments in Quebec that offered medical coverage with hospital beds 24 hours a day, 7 days a week and were located in rural areas or small towns as defined by Statistics Canada. A standardized protocol was sent to each emergency department to collect data on 27 validated quality-of-care indicators in 8 categories: duration of stay, patient safety, pain management, pediatrics, cardiology, respiratory care, stroke and sepsis/infection. Data were collected by local professional medical archivists between June and December 2013., Results: Fifteen (58%) of the 26 emergency departments invited to participate completed data collection. The ability to measure the 27 quality-of-care indicators with the use of databases varied across departments. Centres 2, 5, 6 and 13 used databases for at least 21 of the indicators (78%-92%), whereas centres 3, 8, 9, 11, 12 and 15 used databases for 5 (18%) or fewer of the indicators. On average, the centres were able to measure only 41% of the indicators using heterogeneous databases and manual extraction. The 15 centres collected data from 15 different databases or combinations of databases. The average data collection time for each quality-of-care indicator varied from 5 to 88.5 minutes. The median data collection time was 15 minutes or less for most indicators., Interpretation: Quality-of-care indicators were not easily captured with the use of existing databases in rural emergency departments in Quebec. Further work is warranted to improve standardized measurement of these indicators in rural emergency departments in the province and to generalize the information gathered in this study to other health care environments., Competing Interests: Conflicts of Interest: None declared.This article has been peer reviewed.

Background: Over the past 20 years, many researchers have worked in developing various methods for measuring quality of life (QoL) of people with dementia. The aim of this review is to develop the conceptual frameworks of the dementia-specific QoL instruments, to identify their evolution over time and to provide elements of reflection on the QoL concept in dementia and its evaluation., Methods: An electronic search was conducted on PsycINFO and MEDLINE databases, from January 1985 to June 2015 using a combination of key words that include QoL, dementia, and review., Results: The analysis of the conceptual frameworks of the 18 selected dementia-specific QoL tools shows a great diversity in: (1) the QoL definitions (e.g. health-related QoL definitions, QoL definitions based on Lawton's work, or similar to this latter); (2) the theoretical QoL models (e.g. Lawton' work and modified Lawton, adaptation, personhood); (3) the domains and dimensions; (4) the way to construct the instrument (e.g. development based on literature, opinion of the experts), and (5) the items' formulation (e.g. use of criterion of intensity or frequency)., Conclusions: There are different conceptual frameworks in the dementia-specific QoL measures with improvements over time (e.g. inclusion of interesting concepts such as adaptation, taking into account the views of patients themselves). Each of the conceptual parameters (definitions, models, domains, and dimensions) is discussed to identify the scales that are conceptually the strongest. Through their review, recommendations for future instrument refinement and development are discussed and a new QoL definition is proposed.

Integration of e-Health technologies for purposes of both assessment and intervention has recently become an interest area in pediatric psychology. The purpose of this study is to present psychometric characteristics of a technology-based (i.e., tablet administration) approach for measuring quality of life (QOL) in children. Eighty children (8-12 years) completed the Quality of Life Systemic Inventory for Children (QLSI-C) twice over a 2-week delay, in a crossover design that used paper and tablet-based modes of administration. Equivalence of scores across methods was examined using intraclass correlation coefficients (ICC), augmented by paired t test and Pearson's correlations. Test-retest reliability was assessed using paired t test and Pearson's correlations while internal consistency was assessed using Cronbach's coefficient. Results showed a good concordance across methods of administration (ICCs = .72 to .91; r = .56 to .83). Paired t test showed no significant differences between the tablet and paper version of the QLSI-C. Internal consistency reliability yielded acceptable Cronbach's alphas for all QLSI-C scores, with all α > .70. Test-retest reliability for the tablet-administered QLSI-C was good (r = .66 to .90). Paired t test showed no significant difference between Time 1 and 2 for the QLSI-C scores, except for the state score. Findings established the reliability of the tablet-administered QLSI-C scores. This technology approach to assessment is more attractive for children, decreases time for administration, and enhances the ease of scoring. These advantages might encourage both clinicians and researchers to consider using e-Health developments in assessment in pediatric psychology. (PsycINFO Database Record, ((c) 2016 APA, all rights reserved).)

Introduction: Trauma remains the primary cause of death in individuals under 40 years of age in Canada. In Quebec, the Trauma Care Continuum (TCC) has been demonstrated to be effective in decreasing the mortality rate among trauma victims. Although rural citizens are at greater risk for trauma and trauma death, no empirical data concerning the effectiveness of the TCC for the rural population in Quebec are available. The emergency departments (EDs) are important safety nets for rural citizens. However, our data indicate that access to diagnostic support services, such as intensive care units and CT is limited in rural areas. The objectives are to (1) draw a portrait of trauma services in rural EDs; (2) explore geographical variations in trauma care in Quebec; (3) identify adaptable factors that could reduce variation; and (4) establish consensus solutions for improving the quality of care., Methods and Analysis: The study will take place from November 2015 to November 2018. A mixed methodology (qualitative and quantitative) will be used. We will include data (2009-2013) from all trauma victims treated in the 26 rural EDs and tertiary/secondary care centres in Quebec. To meet objectives 1 and 2, data will be gathered from the Ministry's Database of the Quebec Trauma Registry Information System. For objectives 3 and 4, the project will use the Delphi method to develop consensus solutions for improving the quality of trauma care in rural areas. Data will be analysed using a Poisson regression to compare mortality rate during hospital stay or death on ED arrival (objectives 1 and 2). Average scores and 95% CI will be calculated for the Delphi questionnaire (objectives 3 and 4)., Ethics and Dissemination: This protocol has been approved by CSSS Alphonse-Desjardins research ethics committee (Project MP-HDL-2016-003). The results will be published in peer-reviewed journals., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)