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Abstract Background Existing frameworks of older persons’ experiences in health and social care systems are usually based on single stakeholder perspectives and focused on limited aspects that are independent from one another. This study aimed to describe such experiences from the perspective of diverse stakeholders and develop a comprehensive experience-based framework for actionable priorities to enhance Canada’s health and social care system. Methods We adapted a nominal group technique with a qualitative approach. We formed four groups of stakeholders (4 older persons, 7 clinicians, 5 managers, 4 decision-makers) in the province of Quebec. First, participants individually completed a questionnaire to rank the six domains of an international set of metrics of quality of care for older persons in terms of their importance. Then, we conducted a remote discussion with each stakeholder group, obtained consensus on the priority domains, and explored personal/professional experiences explaining prioritization processes and what changes are needed. An inductive-deductive thematic analysis was conducted to develop a framework for actionable health and social care priorities. Results The framework included six key categories revolving around a core category of ‘health equity’. (1) ‘Access to services and care’ focused on improved accessibility of healthcare navigators, primary and home care services, and end-of life care. (2) ‘Respect for older persons’ involved individuality and uniqueness, daily needs, advocacy in defence of vulnerability, and decision-making valuing care preferences. (3) ‘Involvement of family and friends’ encompassed formal recognition, responsibilities, and trajectories associated with caregiving. (4) ‘Communication and education’ consisted of adaptive communication between older persons, caregivers, and professionals and societal-level education and awareness-raising. (5) ‘Coordination and integration of care’ comprised health and social services organization, cross-sectoral approaches, and interdisciplinary collaboration. (6) ‘Responsiveness to evolving needs’ of older persons involved timely response to health transitions and promoting holistic approaches. Conclusions This study illustrates the complex challenges of caring for older persons. The framework suggests several areas for improvement in care practices and policies for older persons and caregivers. Proposed intervention targets include public healthcare system navigators, standardized goals of care practices respecting persons’ wishes, formal recognition of caregiver contributions, society-level education, cross-sectoral initiatives, and holistic approaches.

Abstract The RhoH protein is a member of the Ras superfamily of guanosine triphosphate-binding proteins. RhoH is an atypical Rho family member that is always GTP-bound and thus always activated. It is restrictively expressed in normal hematopoietic cells, where it is a negative regulator of cell growth and survival. We previously analyzed the RHOH gene structure and demonstrated that this gene is composed of 7 exons, one single encoding exon located at the 3ʹ extremity of the gene, preceded by 6 noncoding exons. To further understand the transcription events associated with this gene, we performed full-length RNA-Seq on 12 B-cell lines. We identified new exons, new splice events and new splice sites, leading to the discovery of 38 RHOH mRNA molecules, 27 of which have never been described before. Here, we also describe new fusion transcripts. Moreover, our method allowed quantitative measurements of the different mRNA species relative to each other in relation to B-cell differentiation.

Sporadic outbreaks of influenza A virus (IAV) infections have been reported in pinnipeds in the United States and Europe, most commonly in harbor (Phoca vitulina) and gray (Halichoerus grypus) seals [...]

Abstract Background and Objective Acute myelogenous leukemia (AML) is a common blood cancer marked by heterogeneity in disease and diverse genetic abnormalities. Additional therapies are needed as the 5-year survival remains below 30%. Trametinib is a mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor that is widely used in solid tumors and also in tumors with activating RAS mutations. A subset of patients with AML carry activating RAS mutations; however, a small-scale clinical trial with trametinib showed little efficacy. Here, we sought to identify transcriptomic determinants of trametinib sensitivity in AML. Methods We tested the activity of trametinib against a panel of tumor cells from patients with AML ex vivo and compared this with RNA sequencing (RNA-Seq) data from untreated blasts from the same patient samples. We then used a correlation analysis between gene expression and trametinib sensitivity to identify potential biomarkers predictive of drug response. Results We found that a subset of AML tumor cells were sensitive to trametinib ex vivo, only a fraction of which (3/10) carried RAS mutations. On the basis of our RNA-Seq analysis we found that markers of trametinib sensitivity are associated with a myeloid differentiation profile that includes high expression of CD14 and CLEC7A (Dectin-1), similar to the gene expression profile of monocytes. Further characterization confirmed that trametinib-sensitive samples display features of monocytic differentiation with high CD14 surface expression and were enriched for the M4 subtypes of the FAB classification. Conclusions Our study identifies additional molecular markers that can be used with molecular features including RAS status to identify patients with AML that may benefit from trametinib treatment.

Abstract Background Tumour dormancy, a resistance mechanism employed by cancer cells, is a significant challenge in cancer treatment, contributing to minimal residual disease (MRD) and potential relapse. Despite its clinical importance, the mechanisms underlying tumour dormancy and MRD remain unclear. In this study, we employed two syngeneic murine models of myeloid leukemia and melanoma to investigate the genetic, epigenetic, transcriptomic and protein signatures associated with tumour dormancy. We used a multiomics approach to elucidate the molecular mechanisms driving MRD and identify potential therapeutic targets. Results We conducted an in-depth omics analysis encompassing whole-exome sequencing (WES), copy number variation (CNV) analysis, chromatin immunoprecipitation followed by sequencing (ChIP-seq), transcriptome and proteome investigations. WES analysis revealed a modest overlap of gene mutations between melanoma and leukemia dormancy models, with a significant number of mutated genes found exclusively in dormant cells. These exclusive genetic signatures suggest selective pressure during MRD, potentially conferring resistance to the microenvironment or therapies. CNV, histone marks and transcriptomic gene expression signatures combined with Gene Ontology (GO) enrichment analysis highlighted the potential functional roles of the mutated genes, providing insights into the pathways associated with MRD. In addition, we compared “murine MRD genes” profiles to the corresponding human disease through public datasets and highlighted common features according to disease progression. Proteomic analysis combined with multi-omics genetic investigations, revealed a dysregulated proteins signature in dormant cells with minimal genetic mechanism involvement. Pathway enrichment analysis revealed the metabolic, differentiation and cytoskeletal remodeling processes involved in MRD. Finally, we identified 11 common proteins differentially expressed in dormant cells from both pathologies. Conclusions Our study underscores the complexity of tumour dormancy, implicating both genetic and nongenetic factors. By comparing genomic, transcriptomic, proteomic, and epigenomic datasets, our study provides a comprehensive understanding of the molecular landscape of minimal residual disease. These results provide a robust foundation for forthcoming investigations and offer potential avenues for the advancement of targeted MRD therapies in leukemia and melanoma patients, emphasizing the importance of considering both genetic and nongenetic factors in treatment strategies. Graphical Abstract

Abstract Introduction Patients on veno-arterial extracorporeal membrane oxygenation (V-A ECMO) support are at a high risk of hemorrhagic complications, including upper gastrointestinal bleeding (UGIB). The objective of this study was to evaluate the incidence and impact of this complication in V-A ECMO patients. Materials and methods A retrospective single-center study (2013–2017) was conducted on V-A ECMO patients, excluding those who died within 24 h. All patients with suspected UGIB underwent esophagogastroduodenoscopy (EGD) and were analyzed and compared to the remainder of the cohort, from the initiation of ECMO until 5 days after explantation. Results A total of 150 V-A ECMO cases (65 after cardiac surgery and 85 due to medical etiology) were included. 90% of the patients received prophylactic proton pump inhibitor therapy and enteral nutrition. Thirty-one patients underwent EGD for suspected UGIB, with 16 confirmed cases of UGIB. The incidence was 10.7%, with a median occurrence at 10 [7–17] days. There were no significant differences in clinical or biological characteristics on the day of EGD. However, patients with UGIB had significant increases in packed red blood cells and fresh frozen plasma needs, mechanical ventilation duration and V-A ECMO duration, as well as in length of intensive care unit and hospital stays. There was no significant difference in mortality. The only independent risk factor of UGIB was a history of peptic ulcer (OR = 7.32; 95% CI [1.07–50.01], p = 0.042). Conclusion UGIB occurred in at least 1 out of 10 cases of V-A ECMO patients, with significant consequences on healthcare resources. Enteral nutrition and proton pump inhibitor prophylaxis did not appear to protect V-A ECMO patients. Further studies should assess their real benefits in these patients with high risk of hemorrhage.

OBJECTIVE: This study aims to investigate patterns of cochlear ossification (CO) in cadaveric temporal bones of patients who underwent vestibular schwannoma (VS) surgery via the translabyrinthine (TL), middle cranial fossa (MF), or retrosigmoid (RS) approaches. STUDY DESIGN: Histopathologic analysis of cadaveric temporal bones. SETTING: Multi-institutional national temporal bone repository. METHODS: The National Institute of Deafness and Communication Disorders and House Temporal Bone Laboratory at the University of California, Los Angeles and the Massachusetts Eye and Ear Otopathology Laboratory were searched for cadaveric temporal bones with a history of VS for which microsurgery was performed. Exclusion criteria included non-VS and perioperative death within 30 days of surgery. Temporal bones were analyzed histologically for CO of the basal, middle, and apical turns. RESULTS: Of 92 temporal bones with a history of schwannoma from both databases, 12 of these cases met the inclusion criteria. The approaches for tumor excision included 2 MF, 4 RS, and 6 TL approaches. CO was observed in all temporal bones that had undergone TL surgery. Among temporal bones that had undergone MF or RS surgeries, 5/6 had no CO, and 1/6 had partial ossification. This single case was noted to have intraoperative vestibular violation after RS surgery upon histopathologic and chart review. CONCLUSION: In this temporal bone series, all temporal bones that had undergone TL demonstrated varying degrees of CO on histological analysis. MF and RS cases did not exhibit CO except in the case of vestibular violation. When cochlear implantation is planned or possible after VS surgery, surgeons may consider using a surgical approach that does not violate the labyrinth.

Student ratings of instruction (SRI) are commonly used to evaluate courses and teaching in higher education. Much debate about their validity in evaluating teaching exists, which is due to concerns of bias by factors unrelated to teaching quality (Spooren et al., 2013). Our objective was to identify peer-reviewed original research published in English from January 1, 2012, to March 10, 2021, on potential sources of bias in SRIs. Our systematic review of 63 articles demonstrated strong support for the continued existence of gender bias, favoring male instructors and bias against faculty with minority ethnic and cultural backgrounds. These and other biases must be considered when implementing SRIs and reviewing results. Critical practices for reducing bias when using SRIs include implementing bias awareness training and avoiding use of SRIs as a singular measure of teaching quality when making decisions for teaching development or hiring and promotion.

Forests across the Western U.S. face unprecedented risk due to historic fire exclusion, environmental degradation, and climate change. Forest management activities like ecological thinning, prescribed burning, and meadow restoration can improve landscape resilience. Resilient forests are at a lower risk of high-intensity wildfires, drought, insects, and other disturbances and provide a wide range of benefits to ecosystems and communities. However, insufficient funding limits implementation of critically needed management. To address this challenge, we propose a multi-benefit framework that leverages the diverse benefits of forest management to engage a suite of stakeholders in sharing project costs. We take a three-pronged approach to develop our conceptual model: examining existing frameworks for environmental project implementation, conducting a literature review of forest management benefits, and evaluating case studies. Through our framework, we describe the steps to engage partners, starting by identifying benefits that could accrue to potential public and private beneficiaries, and moving through an iterative and collaborative process of valuing benefits, which can accrue over different spatial and temporal scales, in close consultation with potential beneficiaries themselves. The aim of this approach is to stack funding streams associated with each valued benefit to fully fund a given forest management project. The multi-benefit framework has the potential to unlock new sources of funding to meet the exceptional challenges of climate and wildfire disturbances. We apply the framework to dry forests of the Western U.S., but opportunities exist for expanding and modifying this approach to any geography or ecosystem where management provides multiple benefits.

Abstract Background Scholars recommend providing migrants living with HIV (MLWH) with free treatment, rapidly, once linked to care to optimize their HIV-related experiences and health outcomes. Quantitative evaluations of patient-reported measures for MLWH in such models are necessary to explore the viability of these recommendations. Methods Within a 96-week prospective cohort study at a multidisciplinary HIV clinic, participants received bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) for free and rapidly following care linkage. Eight patient-reported measures were administered at weeks 4, 24, and 48: (1) mMOS-SS to measure perceived social support; (2) IA-RSS to measure internalized stigma; (3) K6 to measure psychological distress; (4) PROMIS to measure self-efficacy with treatment taking; (5) G-MISS to measure perceived compliance with clinicians’ treatment plans; (6) HIVTSQ to measure treatment satisfaction; (7) CARE to measure perceived provider empathy; and (8) PRPCC to measure perceived clinician cultural competence. Linear mixed modelling with bootstrapping was conducted to identify significant differences by sociodemographics and time. Results Across weeks 4, 24, and 48, results suggest that MLWH enrolled in this study experienced moderate levels of social support; elevated levels of HIV-related stigma; moderate levels of distress; high self-efficacy with daily medication self-management; great compliance with clinicians’ treatment plans; high treatment satisfaction; high perceived empathy; and high perceived cultural competence. Experience of social support (i.e., mMOS-SS scores) differed significantly by birth region. Experience of HIV-related stigma (i.e., IA-RSS scores) differed significantly by birth region, age, and language. Experience of distress (i.e., K6 scores) differed significantly by sexual orientation. Experience of treatment satisfaction (i.e., HIVTSQ scores) differed significantly by birth region and age. No significant differences were identified by time for any measure. Conclusion Overall, participants expressed positive experiences around treatment and care, alongside comparably lower perceptions of social support, internalized stigma, and distress, potentially underscoring a need to embed targeted, well-funded, and accessible mental health support within HIV care models.

We describe an unusual mortality event caused by a highly pathogenic avian influenza (HPAI) A(H5N1) virus clade 2.3.4.4b involving harbor (Phoca vitulina) and gray (Halichoerus grypus) seals in the St. Lawrence Estuary, Quebec, Canada, in 2022. Fifteen (56%) of the seals submitted for necropsy were considered to be fatally infected by HPAI H5N1 containing fully Eurasian or Eurasian/North American genome constellations. Concurrently, presence of large numbers of bird carcasses infected with HPAI H5N1 at seal haul-out sites most likely contributed to the spillover of infection to the seals. Histologic changes included meningoencephalitis (100%), fibrinosuppurative alveolitis, and multiorgan acute necrotizing inflammation. This report of fatal HPAI H5N1 infection in pinnipeds in Canada raises concerns about the expanding host of this virus, the potential for the establishment of a marine mammal reservoir, and the public health risks associated with spillover to mammals. Nous décrivons un événement de mortalité inhabituelle causé par un virus de l’influenza aviaire hautement pathogène A(H5N1) clade 2.3.4.4b chez des phoques communs (Phoca vitulina) et gris (Halichoerus grypus) dans l’estuaire du Saint-Laurent au Québec, Canada, en 2022. Quinze (56%) des phoques soumis pour nécropsie ont été considérés comme étant fatalement infectés par le virus H5N1 de lignées eurasiennes ou de réassortiment eurasiennes/nord-américaines. Un grand nombre simultané de carcasses d’oiseaux infectés par le H5N1 sur les sites d’échouement a probablement contribué à la contamination de ces phoques. Les changements histologiques associés à cette infection incluaient : méningo-encéphalite (100%), alvéolite fibrinosuppurée et inflammation nécrosante aiguë multi-organique. Cette documentation soulève des préoccupations quant à l’émergence de virus mortels, à la possibilité d’établissement de réservoirs chez les mammifères marins, et aux risques pour la santé publique associés aux propagations du virus chez les mammifères.

BackgroundHuman pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) show tremendous promise for cardiac regeneration following myocardial infarction (MI), but their transplantation gives rise to transient ventricular tachycardia (VT) in large-animal MI models, representing a major hurdle to translation. Our group previously reported that these arrhythmias arise from a focal mechanism whereby graft tissue functions as an ectopic pacemaker; therefore, we hypothesized that hPSC-CMs engineered with a dominant negative form of the pacemaker ion channel HCN4 (dnHCN4) would exhibit reduced automaticity and arrhythmogenic risk following transplantation.MethodsWe used CRISPR/Cas9-mediated gene-editing to create transgenic dnHCN4 hPSC-CMs, and their electrophysiological behavior was evaluated in vitro by patch-clamp recordings and optical mapping. Next, we transplanted WT and homozygous dnHCN4 hPSC-CMs in a pig MI model and compared post-transplantation outcomes including the incidence of spontaneous arrhythmias and graft structure by immunohistochemistry.ResultsIn vitro dnHCN4 hPSC-CMs exhibited significantly reduced automaticity and pacemaker funny current (If) density relative to wildtype (WT) cardiomyocytes. Following transplantation with either dnHCN4 or WT hPSC-CMs, all recipient hearts showed transmural infarct scar that was partially remuscularized by scattered islands of human myocardium. However, in contrast to our hypothesis, both dnHCN4 and WT hPSC-CM recipients exhibited frequent episodes of ventricular tachycardia (VT).ConclusionsWhile genetic silencing of the pacemaker ion channel HCN4 suppresses the automaticity of hPSC-CMs in vitro, this intervention is insufficient to reduce VT risk post-transplantation in the pig MI model, implying more complex mechanism(s) are operational in vivo.

Cochlear implants provide effective auditory rehabilitation for patients with severe to profound sensorineural hearing loss. Recent advances in cochlear implant technology and surgical approaches have enabled a greater number of patients to benefit from this technology, including those with significant residual low frequency acoustic hearing. Nearly all cochleae implanted with a cochlear implant electrode array develop an inflammatory and fibrotic response. This tissue reaction can have deleterious consequences for implant function, residual acoustic hearing, and the development of the next generation of cochlear prosthetics. This article reviews the current understanding of the inflammatory/foreign body response (FBR) after cochlear implant surgery, its impact on clinical outcome, and therapeutic strategies to mitigate this response. Findings from both in human subjects and animal models across a variety of species are highlighted. Electrode array design, surgical techniques, implant materials, and the degree and type of electrical stimulation are some critical factors that affect the FBR and inflammation. Modification of these factors and various anti-inflammatory pharmacological interventions have been shown to mitigate the inflammatory/FBR response. Ongoing and future approaches that seek to limit surgical trauma and curb the FBR to the implanted biomaterials of the electrode array are discussed. A better understanding of the anatomical, cellular and molecular basis of the inflammatory/FBR response after cochlear implantation has the potential to improve the outcome of current cochlear implants and also facilitate the development of the next generation of neural prostheses.

The sudden move from traditional face-to-face teaching and learning to unfamiliar virtual spaces during the early weeks and months of the COVID-19 pandemic demanded many members of educational communities around the world to be flexible and teach and learn outside of their comfort zones. The abruptness of this transition contributed to instructors' concerns about academic cheating as they could no longer assess learning and monitor student progress using their usual strategies and methods. Students also experienced disruptions to their usual ways of learning, which may have contributed to poor decision-making, including engagement in academic misconduct. The present study examined students' beliefs about increased engagement in academic misconduct by their peers during the rapid obligatory transition to remote instruction due to the COVID-19 pandemic in March 2020. In January 2021, a retrospective online survey was distributed to students in undergraduate courses. We focused our analyses of the responses from students at a single university in Canada. We found that beliefs of increased cheating depended upon student gender (men vs women), status (domestic vs international), year of study (Years 1/2 vs Years 3 +), and discipline (Science, Technology, Engineering, and Mathematics vs Social Sciences and Humanities). These are important findings as they provide insight into the nature of the culture of academic integrity during a stressful and confusing period in postsecondary students' lives.

En este artículo se presenta el resultado de un análisis comparativo de la literatura en torno a la compleja relación entre creatividad, tecnología y juego en la era digital. Con la finalidad de explorar los retos y oportunidades en esta relación, se analiza cómo el software, a pesar de ser una herramienta útil, puede ejercer una influencia sutil pero limitante en los procesos creativos. Se identifica el juego, particularmente el juego inestructurado o paida, como un elemento esencial para nutrir la creatividad y la libertad de expresión. Asimismo, se propone entender la metapoiesis, un concepto que busca trascender los límites de la producción creativa tradicional, simultáneamente como meta paralela a la emancipación creativa y como proceso esencial para informar los esfuerzos pedagógicos en torno a la rehumanización de nuestra relación con la tecnología. Se discuten las implicaciones para la praxis en espacios de aprendizaje y en espacios de trabajo. Finalmente, se realiza una propuesta de profundización para futuras investigaciones.

Housework is a significant part of our daily lives. In this visualization, the authors consider how time spent on housework varies across gender and age throughout the day. Using the nationally representative 2015 Canadian General Social Survey with detailed time diary information, the authors present how women’s and men’s time allocation patterns on housework vary across age groups. The visualization shows that women and older Canadians engaged more in housework. A clear pattern reveals higher engagement during mealtimes, while participation becomes more evenly distributed throughout the day among older adults compared with younger women and men.

Abstract The mainstay of acute myeloid leukemia (AML) treatment still relies on traditional chemotherapy, with a survival rate of approximately 30% for patients under 65 years of age and as low as 5% for those beyond. This unfavorable prognosis primarily stems from frequent relapses, resistance to chemotherapy, and limited approved targeted therapies for specific AML subtypes. Around 70% of all AML cases show overexpression of the transcription factor HOXA9, which is associated with a poor prognosis, increased chemoresistance, and higher relapse rates. However, direct targeting of HOXA9 in a clinical setting has not been achieved yet. The dysregulation caused by the leukemic HOXA9 transcription factor primarily results from its binding activity to DNA, leading to differentiation blockade. Our previous investigations have identified two HOXA9/DNA binding competitors, namely DB1055 and DB818. We assessed their antileukemic effects in comparison to HOXA9 knockdown or cytarabine treatment. Using human AML cell models, DB1055 and DB818 induced in vitro cell growth reduction, death, differentiation, and common transcriptomic deregulation but did not impact human CD34+ bone marrow cells. Furthermore, DB1055 and DB818 exhibited potent antileukemic activities in a human THP‐1 AML in vivo model, leading to the differentiation of monocytes into macrophages. In vitro assays also demonstrated the efficacy of DB1055 and DB818 against AML blasts from patients, with DB1055 successfully reducing leukemia burden in patient‐derived xenografts in NSG immunodeficient mice. Our findings indicate that inhibiting HOXA9/DNA interaction using DNA ligands may offer a novel differentiation therapy for the future treatment of AML patients dependent on HOXA9.

Summary: Multiple myeloma (MM) is an incurable hematological malignancy in which MYC alterations contribute to the malignant phenotype. Nevertheless, MYC lacks therapeutic druggability. Here, we leveraged large-scale loss-of-function screens and conducted a small molecule screen to identify genes and pathways with enhanced essentiality correlated with MYC expression. We reported a specific gene dependency in glutaminase (GLS1), essential for the viability and proliferation of MYC overexpressing cells. Conversely, the analysis of isogenic models, as well as cell lines dataset (CCLE) and patient datasets, revealed GLS1 as a non-oncogenic dependency in MYC-driven cells. We functionally delineated the differential modulation of glutamine to maintain mitochondrial function and cellular biosynthesis in MYC overexpressing cells. Furthermore, we observed that pharmaceutical inhibition of NAMPT selectively affects MYC upregulated cells. We demonstrate the effectiveness of combining GLS1 and NAMPT inhibitors, suggesting that targeting glutaminolysis and NAD synthesis may be a promising strategy to target MYC-driven MM.

Abstract Background Work-related stressors and work-family conflict are important social determinants of mental health. While the impact of these stressors on parents’ mental health is well documented, we know comparatively less about their impact on children’s mental health. Furthermore, though the COVID-19 pandemic has significantly altered these stressors, particularly with the increase in teleworking, major knowledge gaps persist regarding the association between parents’ stressors and perceived parental concern for their children’s mental health during the COVID-19 pandemic. Based on the stress contagion perspective, this study tests (1) the mediating role of parents’ depressive symptoms with parental concern for their children’s mental health, and (2) whether these associations vary depending on whether parents had the opportunity to engage in telework. Methods A path analysis was performed from a cross-sectional analytic sample of 780 employed parents in the province of Quebec (Canada). The same model was then stratified by teleworking opportunity. The model’s indirect associations were obtained by the bootstrap bias-corrected method with 1,000 replications. Results The results show that the stressors of work-to-family conflict, increased difficulties in work-family balance since the COVID-19 pandemic, irregular schedules, low esteem derived from work, and job insecurity were all indirectly associated with an increase in parental concern for their children’s mental health through increased parents’ depressive symptoms. However, some associations differ depending on teleworking status. The indirect associations involving increased difficulties in work-family balance since the COVID-19 pandemic as well as irregular work schedules were observed only in the teleworking group. Conclusions This study fills a gap in research on the association between the work-family interface and parental concern for their children’s mental health during the COVID-19 pandemic. It highlights the importance of concerted and cohesive action between child health policies and those regarding work and work-family balance to prevent work-related psychosocial risks, particularly considering the post pandemic expanded and persistent reliance on teleworking.

Abstract Background ATRX is an ATP-dependent chromatin remodeling protein with essential roles in safeguarding genome integrity and modulating gene expression. Deficiencies in this protein cause ATR-X syndrome, a condition characterized by intellectual disability and an array of developmental abnormalities, including features of autism. Previous studies demonstrated that deleting ATRX in mouse forebrain excitatory neurons postnatally resulted in male-specific memory deficits, but no apparent autistic-like behaviours. Methods We generated mice with an earlier embryonic deletion of ATRX in forebrain excitatory neurons and characterized their behaviour using a series of memory and autistic-related paradigms. Results We found that mutant mice displayed a broader spectrum of impairments, including fear memory, decreased anxiety-like behaviour, hyperactivity, as well as self-injurious and repetitive grooming. Sex-specific alterations were also observed, including male-specific aggression, sensory gating impairments, and decreased social memory. Conclusions Collectively, the findings indicate that early developmental abnormalities arising from ATRX deficiency in forebrain excitatory neurons contribute to the presentation of fear memory deficits as well as autistic-like behaviours.

Abstract Background The Laval-ROSA Transilab is a living lab that aims to support the Laval Integrated Health and Social Services Centres (Quebec, Canada) in consolidating the Quebec Alzheimer Plan. It aims to improve care transitions between different settings (Family Medicine Groups, home care, and community services) and as such improve the care of people living with dementia and their care partners. Four transition-oriented innovations are targeted. Two are already underway and will be co-evaluated: A) training of primary care professionals on dementia and interprofessional collaboration; B) early referral process to community services. Two will be co-developed and co-evaluated: C) developing a structured communication strategy around the dementia diagnosis disclosure; D) designation of a care navigator from the time of dementia diagnosis. The objectives are to: 1) co-develop a dashboard for monitoring transitions; 2) co-develop and 3) co-evaluate the four targeted innovations on transitions. In addition, we will 4) co-evaluate the impact and implementation process of the entire Laval-ROSA Transilab transformation, 5) support its sustainability, and 6) transfer it to other health organizations. Methods Multi-methods living lab approach based on the principles of a learning health system. Living labs are open innovation systems that integrate research co-creation and knowledge exchange in real-life settings. Learning health systems centers care improvement on developing the organization's capacity to learn from their practices. We will conduct two learning cycles (data to knowledge, knowledge to practice, and practice to data) and involve various partners. We will use multiple data sources, including health administrative databases, electronic health records data, surveys, semi-structured interviews, focus groups, and observations. Discussion Through its structuring actions, the Laval-ROSA Transilab will benefit people living with dementia, their care partners, and healthcare professionals. Its strategies will support sustainability and will thus allow for improvements throughout the care continuum so that people can receive the right services, at the right time, in the right place, and from the right staff.

Splicing factor mutations are common in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but how they alter cellular functions is unclear. We show that the pathogenic [SRSF2.sup.P95H/+] mutation disrupts the splicing of mitochondrial mRNAs, impairs mitochondrial complex I function, and robustly increases mitophagy. We also identified a mitochondrial surveillance mechanism by which mitochondrial dysfunction modifies splicing of the mitophagy activator PINK1 to remove a poison intron, increasing the stability and abundance of PINK1 mRNA and protein. [SRSF2.sup.P95H]-induced mitochondrial dysfunction increased PINK1 expression through this mechanism, which is essential for survival of [SRSF2.sup.P95H/+] cells. Inhibition of splicing with a glycogen synthase kinase 3 inhibitor promoted retention of the poison intron, impairing mitophagy and activating apoptosis in [SRSF2.sup.P95H/+] cells. These data reveal a homeostatic mechanism for sensing mitochondrial stress through PINK1 splicing and identify increased mitophagy as a disease marker and a therapeutic vulnerability in [SRSF2.sup.P95H] mutant MDS and AML., Introduction Myelodysplastic syndrome (MDS) is a clonal hematopoietic disorder characterized by hyperproliferative bone marrow, dysplastic hematopoietic cells, peripheral cytopenias, and high risk of progression to acute myeloid leukemia (AML). Recurrent [...]