BackgroundSupporting workers with post-COVID condition in returning to work is critical. Qualitative evidence may provide insight into the complex factors shaping this process and inform intervention and policy development.ObjectiveTo identify and synthesize qualitative evidence on barriers and facilitators influencing return to work following post-COVID condition.MethodsWe conducted a scoping review using the Arksey and O'Malley framework, refined by Levac et al. MEDLINE, EMBASE, CINAHL, and Scopus were searched from inception to July 2025. Eligible qualitative and mixed-methods studies examined barriers and facilitators to returning to work among working-age adults with post-COVID condition or healthcare professionals involved in their care. Data were synthesized using critical interpretive synthesis, informed by the International Classification of Functioning, Disability and Health framework.ResultsTwenty-nine qualitative or mixed-methods studies (n=1902 participants) were included. Barriers and facilitators operated across domains within broader organizational and systemic contexts. Fluctuating, unpredictable symptoms were major barriers, while gradual rehabilitation and energy management facilitated return to work. Mismatches between work capacity and job demands limited work participation. Environmental barriers included stigma, inflexible policies, limited accommodations, and financial or compensation pressures, while facilitators included flexible work arrangements, supportive leadership, and collaborative planning. Guilt and fear of underperformance were personal barriers, while acceptance and motivation facilitated return to work. Specialists identified fragmented services and limitations of current care models as systemic concerns.ConclusionsPost-COVID condition necessitates flexible, multidisciplinary return-to-work models that accommodate symptom variability and address psychosocial needs. Improved coordination across healthcare, workplace, and social systems is essential for sustainable workforce participation.RegistrationThe review protocol was publicly registered on the Open Science Framework prior to screening and was approved by all team members (https://osf.io/nrbu5/).

Childhood immunization is essential to public health; however, vaccination coverage among First Nations communities in Canada remains suboptimal. We conducted our rapid review as the initial phase of a broader project to improve childhood immunization in Canadian First Nations communities using a rigorous, systematic approach often lacking in traditional literature review. We systematically synthesized existing evidence, identified key barriers and enablers, and highlighted critical research gaps, providing a foundation for community-driven research and culturally safe interventions. Following Cochrane Rapid Reviews Methods Group guidelines, we searched Web of Science, PubMed, and Scopus for peer-reviewed studies published between 2003 and 2023. Eligible studies were limited to those published in English and focused on Canadian First Nations populations, reporting on factors influencing childhood immunization. We synthesized findings thematically, identifying patterns in barriers and enabling conditions. We synthesized findings thematically, identifying patterns in barriers and enabling conditions. Four studies met the inclusion criteria. The data revealed three overarching domains: caregiver-related, provider-related, and system-level factors. Barriers at the caregiver level included fear of needle pain, misinformation, safety concerns, difficulty scheduling, transportation issues, and child illness. Provider-related barriers involved communication challenges, limited availability, and perceived disrespect. At the system level, rigid appointment systems, long wait times, and fragmented immunization records were identified as key obstacles. Conversely, enablers of childhood immunization included strong relationships with healthcare providers, culturally respectful care, awareness of disease threats, on-reserve service availability, flexible delivery models, improved data-sharing infrastructure, and community involvement. Addressing these issues requires comprehensive community-based public health strategies that consider cultural, logistical, and systemic dimensions. These interventions should prioritize enhancing cultural safety, engaging communities, improving provider communication, and ensuring accessible, flexible immunization services, supported by robust information-sharing systems.

Introduction:This article shares insights from the Learning Health Systems Symposium, "Charting the Future of Saskatchewan Healthcare: Generating Value within our Health Systems." Methods:Patient Partners and over 100 professionals in the fields of research, healthcare, and policy joined the Saskatchewan Centre for Patient-Oriented Research (SCPOR) in Regina, Saskatchewan Canada, for a day filled with knowledge about learning health systems (LHSs). Attendees provided key insights on how to build provincial capacity in LHSs and thereby improve the health of people in Saskatchewan. Results:Key insights from the symposium included strengthening meaningful partnerships with patients and the community; establishing a shared vision for LHSs; harmonizing conflicting priorities; removing silos; recognizing the natural tensions between academia and the healthcare system; and building on and aligning infrastructure to support LHSs development. Conclusion:The LHSs symposium provided a way for health system leaders, Patient Partners, researchers, clinicians, and students to develop a common understanding of LHSs and envision a future for LHSs in Saskatchewan, Canada. Key next steps were to strengthen patient and community engagement, work collaboratively to establish a shared vision of LHSs, better understand existing assets to support LHSs, and identify opportunities to build future LHSs infrastructure.

Introduction:The Canadian Métis population experiences higher cancer rates, leading to reduced life expectancy. Culture is vital to Indigenous health, offering belonging and improving well-being. This community-based study aimed to create a framework for cancer prevention based on Métis Cultural Continuity that can be adapted for use in other Métis communities. Methods:Participants were recruited from seven Métis Nation-Saskatchewan (MN-S) cultural events held between June 2022 and March 2023, during which researchers engaged in Métis cultural activities (eg, beading, hide tanning). Semistructured telephone interviews with 24 MN-S citizens (12 men, 12 women) were analysed using the Collective Consensual Data Analytic Procedure, enabling the diverse Research Advisory Committee members to identify main categories. Results:Key themes included colonisation and its impacts, community, cultural revitalisation, strength and pride. Participants highlighted the profound effects of colonisation on their lives and communities while celebrating the resilience and solidarity that define the Métis community. These themes were used to develop a Métis Cultural Revitalisation Framework for Cancer Prevention, rooted in the symbolism of the Red River Cart, which is a significant cultural emblem for the Métis people. Each theme was conceptualised as a spoke of the cartwheel, playing a vital role in ensuring both stability and progress for the cart and the Métis community. Conclusions:For the Métis community, strong cultural connections are essential for fostering a sense of belonging, reducing risk behaviours and promoting both mental and physical well-being. These factors are vital for achieving a healthy lifestyle and can contribute to health promotion.

Telomerase reverse transcriptase (hTERT) overexpression, a hallmark of most cancers, drives tumorigenesis by enabling limitless replicative potential. Direct targeting of hTERT is challenging, necessitating alternative strategies. Through genome-wide synthetic dosage lethality (SDL) screening in cancer models, including patient-derived organoids, we identify FTSJ3, an RNA 2'-O-methyltransferase, as a critical vulnerability in hTERT-overexpressing cells. FTSJ3 methylates telomeric repeat-containing RNA (TERRA), a modification essential for recruiting SUV39H1 to telomeric ends to mediate H3K9 trimethylation and establish stable heterochromatin. Loss of FTSJ3 disrupts this cascade, impairing H3K9 trimethylation, HP1-alpha recruitment, and telomeric heterochromatin maintenance. Notably, this reveals an unexpected dependency on TERRA methylation for telomeric heterochromatin stability in hTERT-driven cancers. Non-malignant cells, lacking telomerase activity and de novo telomere repeat synthesis, are unaffected by FTSJ3 suppression. Our findings establish the FTSJ3/TERRA/SUV39H1 axis as a critical mechanism supporting telomeric heterochromatin stability in hTERT-driven cancers. This telomere-directed epigenetic strategy provides a robust framework for translational therapeutic innovation. ### Competing Interest Statement S.M. is cofounder, director, shareholder, and chair of the clinical and scientific advisory committee of Telo Genomics Corp. K.B. is the founder and CEO of Thoth Biosimulations.

PURPOSE:Breast cancer is uncommon in adolescent and young adult (AYA) women, accounting for approximately 1.8% of all breast cancers. There is a risk of delayed diagnosis of breast cancer among AYA women, especially among those residing in rural areas. The aim of this study was to assess the outcomes of AYA women for breast cancer in relation to rural residence. METHODS:This cohort study evaluated all women aged 35 years and younger with histologically confirmed breast cancer diagnosed between 2000 and 2019 in a Canadian province. A multivariate Cox proportional hazards model was used to assess the prognostic significance of rural residence and other variables for overall survival (OS) across all stages and disease-free survival in early-stage breast cancer. RESULTS:A total of 248 eligible AYA women with a median age of 32 years were identified, of whom 24% were younger than 30 years. Of all patients, 51% had node-positive disease, and 11% had stage IV disease at diagnosis. Among those with invasive breast cancer, 45% had hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative disease; 30% had HER2-positive disease; and 25% had triple-negative breast cancer (TNBC). There were 53% rural and 47% urban residents. In multivariate analysis for OS for stage 0 to IV disease, rural residence (hazard ratio [HR], 1.75 [95% CI, 1.08 to 2.81]), TNBC (HR, 2.25 [95% CI, 1.34 to 3.80]), and stage IV disease (HR, 8.1 [95% CI, 4.72 to 13.94]) were associated with inferior OS. CONCLUSION:AYA women with breast cancer have a high incidence of node-positive disease and aggressive subtypes. This study found a significant association between rural residence and OS. These findings emphasize the need for enhanced early detection and personalized treatment strategies, particularly for rural patients and those with TNBC.

OBJECTIVES:To develop survey items for a national patient registry on Long COVID using a modified Delphi process. DESIGN:This study was based on a modified Delphi process involving three rounds of anonymous, online surveys to develop consensus on and prioritise survey elements to be included in a minimum dataset for use in a national patient registry in Canada. Initial Long COVID items were identified through an environmental scan of the literature. SETTING:This study focused on healthcare systems in Canada and was conducted online. PARTICIPANTS:A panel of 52 experts (patients, caregivers, clinicians and researchers) participated in all three rounds of the online survey. These participants were recruited through the Long COVID Web network and word of mouth. RESULTS:In total, 243 survey elements related to care, quality of life and symptoms were included in round 1 of the survey. 200 reached consensus and moved to round 2 with two additional elements being developed based on open-ended responses. In round 2, participants ranked these survey elements and 34 advanced. In round 3, 33 survey elements met the threshold of consensus with one added a priori. The 33 survey elements were then used to develop a Long COVID minimum dataset, which consists of 48 items. CONCLUSIONS:The findings affirm broad consensus for collecting data related to fatigue, post-exertional malaise, cardiovascular issues, respiratory problems and cognitive issues. This highlighted the desire for quality-of-life indicators and information related to care utilisation, quality and access.

Background: The imperative to conduct relevant and responsive research to improve healthcare for patients, families, and communities, means researchers must develop best practices to work in concert with the health system research needs. Audience: This workshop will interest researchers, patient partners, and policy makers who work alongside each other for health system transformation. The session will explore challenges that arise during health system research and potential solutions to these challenges. Participants are encouraged to bring their own examples of what has worked well, what has not, and why (or why not). Approach:Introduction (0 minutes)Designed to foster discussion and generate solutions to challenges commonly faced by research teams when engaging in health system research, this session will encourage researchers, patient partners, and policy makers to share their own research experiences. This workshop, co-led by patient partners and researchers from Saskatchewan, Canada, will outline the provincial context for health services research. This will include a description of the relationships among patient partners, researchers, and Saskatchewan Health Authority (SHA) policy makers. Case Studies (5 minutes)The case studies will be briefly introduced by the principal investigators and patient partners, who will provide an outline of how, why, and for whom, what worked, and/or what did not work. These patient-oriented research (POR) case studies demonstrate a spectrum of successful engagement with health system transformation. The first case study addresses the multiple challenges presented when the researcher had limited access to control over the resources. The second case study highlights the opportunities for the research to be more responsive to changes in the direction of the project when the researcher was an embedded member of a health system working group. The final case study illustrates a situation where the researcher was an embedded co-lead of the health system initiative. Each case will also include a description of the challenges patient partners faced when collaborating across the two complex systems. After presenting the lessons learned from the case studies, participants will be provided with questions to engage them in small group discussions of their own experiences with the challenges and successes of POR health system research. Small Group Discussion (25 minutes)Participants will be invited to discuss their perspectives regarding POR in health systems. Each group of 4-6 participants will be facilitated by a patient partner and a designated group member will record and report on the group discussion. For the first ten minutes, participants will be asked to discuss: What are the similarities and differences between your own experiences and the case studies that were presented? Next, participants will be asked: what are your perspectives on best practices to overcome challenges engaging in research with multi-stakeholder teams of patient partners, researchers, and policy-makers? By the end of the discussion, each group will have identified one take-home message about best practices for health system transformation research. Group Feedback and Reporting (0 minutes)The designated group member will report their conclusions to the larger group. The goal will be to identify commonalities across the groups. Key commonalities will be recorded by workshop co-leads on PowerPoint slides. Summary and Closing (5 minutes)The key takeaways from the session will be summarized by the workshop facilitator, who is an expert in knowledge mobilization. The content of the slides will be disseminated to interested workshop participants following the session for future reference.

Background Narrative operative reports (NORs) often lack key information that can guide postoperative management of thyroid disease. We aimed to develop and validate a nationally standardized synoptic operative report (SOR) for thyroid surgery. Materials and Methods Surgeons were surveyed for their opinions of current operative reporting practices. Reportable elements from thyroidectomy NORs were ranked by thyroid disease specialists and reviewed by a national advisory committee to develop a standardized SOR using the Modified Delphi Method. Six thyroid surgeons piloted the SOR. Completeness and reporting frequencies of SOR elements were compared with pre-pilot NORs using Wilcoxon rank sum, chi-squared, and Fisher's exact analyses. A post-pilot survey assessed provider satisfaction. Results Among 42 Canadian thyroid surgeons from 9 provinces, 31% expressed dissatisfaction with current reporting practices and 100% expressed interest in a SOR. In total, 109 reportable thyroidectomy elements were collected from 142 NORs and ranked by 46 thyroid disease specialists. Consensus agreed upon a 21-element SOR by a national advisory committee. Among 172 NORs and 170 piloted SORs, SORs had higher median overall completeness (100% [100-100%]) than NORs (65% [47-70%], p < 0.001). SORs improved reporting of cancer-specific elements, including the presence of gross extrathyroidal cancer extension (SOR: 100%, NOR: 43%, p < 0.001) and residual gross disease (SOR: 100%, NOR: 16%, p < 0.001). More than half of users and readers reported improved reporting completeness and impact on patient care with SORs. Conclusions Implementation of a nationally developed thyroid surgery SOR enhanced completeness, delivery of cancer-specific information, and provider satisfaction, which can improve quality of patient care.

Afghan refugees in Iran, estimated at over 5 million, represent a large vulnerable population whose attitudes towards COVID-19 vaccination are crucial to understand. This cross-sectional study was conducted in Shiraz, Iran, in 2023. Adult Afghan refugees with children aged 5–17 were recruited using a snowball sampling method. A previously validated survey tool was adapted for the Afghan population in this study to assess underlying sociodemographic and psychosocial factors influencing the COVID-19 vaccine acceptance. Among 400 participants, 79

BACKGROUND:Clinical pathways (CPWs) are structured multidisciplinary care plans. They aim to translate evidence into practice and optimize clinical outcomes. This is the first update of the previous systematic review. OBJECTIVES:To investigate the effect of CPWs on patient outcomes, length of stay, costs and charges, adherence to recommended practice, and to measure the impact of different approaches to implementation of CPWs. SEARCH METHODS:For this update, CENTRAL, MEDLINE, and Embase were searched on 25 July 2024. Two trial registries were searched on 26 July 2024, along with reference checking, citation searching and contacting authors to identify additional studies. SELECTION CRITERIA:We considered two groups of participants: health professionals involved in CPW utilization, including (but not limited to) physicians, nurses, physiotherapists, pharmacists, occupational therapists and social workers; and patients managed using a CPW. We included randomized trials, non-randomized trials, controlled before-after (CBA) studies, and interrupted time-series (ITS) studies comparing (1) stand-alone clinical pathways with usual care, and (2) clinical pathways as part of a multifaceted intervention with usual care. DATA COLLECTION AND ANALYSIS:Two authors independently screened all titles, abstracts and full-text manuscripts to assess eligibility and the methodological quality of included studies using the Cochrane Effective Practice and Organization of Care 'Risk of Bias' tool. Certainty of evidence was assessed by two authors independently. Interventions were scored as 'high', 'moderate' or 'low' for the evidence-based implementation process. MAIN RESULTS:The update provided 31 additional studies for a total of 58 included studies (24,841 patients and 2027 healthcare professionals). Forty-one (71%) were randomized trials, four (7%) non-randomized trials, four (7%) CBA studies and nine (16%) ITS studies. Forty-nine studies compared stand-alone CPWs to usual care and nine compared multifaceted interventions including a CPW to usual care. Collectively, the risk of bias was high due to potential contamination by healthcare professionals, lack of blinding of patients and personnel, lack of allocation concealment and selective reporting in ITS studies. Stand-alone clinical pathway interventions It is uncertain whether stand-alone CPWs reduce inhospital mortality (13% v 16%: OR 0.79, 95% CI 0.53 to 1.20; P = 0.27; I² = 65%; 7 randomized trials; n = 4603; low-certainty evidence due to serious imprecision and inconsistency) or mortality (up to 6 months) (4% v 3%: OR 1.37, 95% CI 0.72 to 2.60; P = 0.34; I² = 20%; 3 randomized trials, n = 805; low-certainty evidence due to serious risk of bias and imprecision). Stand-alone CPWs likely reduce inhospital complications (10% v 17%: OR 0.57, 95% CI 0.41 to 0.80; P = 0.001; I² = 52%; 11 randomized trials, n = 3668; moderate-certainty evidence due to serious risk of bias). It is very uncertain whether stand-alone CPWs reduce hospital readmissions (up to 6 months) (9% v 13%: OR 0.67, 95% CI 0.44 to 1.03; P = 0.07; I² = 11%; 9 randomized trials, n = 1578; very low-certainty evidence due to serious risk of bias and very serious imprecision). Stand-alone CPWs likely reduce the length of hospital stay compared to usual care (MD -1.12 days, 95% CI -1.60 to -0.65; P < 0.00001; I² = 64%; 21 studies; n = 5201; moderate-certainty evidence due to serious inconsistency). Costs and charges were generally lower in CPWs as indicated by negative MDs in nine studies (10 studies, n = 2113, data not pooled; very low-certainty evidence due to serious indirectness and very serious inconsistency). Stand-alone CPWs may slightly increase adherence to recommended practice compared with usual care (3 randomized studies, n = 573; data not pooled; low-certainty evidence due to serious risk of bias and serious inconsistency). Multifaceted clinical pathway interventions It is uncertain whether multifaceted CPWs reduce inhospital mortality (2 randomized studies, n = 6304, data not pooled; low-certainty evidence due to very serious inconsistency). Multifaceted CPWs may make little or no difference to mortality (up to 6 months) (9% v 8%: OR 1.05, 95% CI 0.88 to 1.25; P = 0.61; I² = 0%; 3 randomized studies; n = 6531; low-certainty evidence due to serious imprecision and serious risk of bias). It is uncertain whether multifaceted CPWs reduce inhospital complications (9% v 23%: OR 0.32, 95% CI 0.12 to 0.87; 1 study, n = 140; low-certainty evidence due to very serious imprecision). It is uncertain whether multifaceted CPWs reduce hospital readmission (up to 6 months) (2 randomized studies, n =1569, data not pooled; low-certainty evidence due to very serious inconsistency), or length of stay (4 randomized studies, n = 1936, data not pooled; low-certainty evidence due to very serious inconsistency), or hospital costs and charges (4 randomized studies, n = 2015, data not pooled; very low-certainty evidence due to very serious imprecision and serious indirectness in outcome measures). It is uncertain whether multifaceted CPWs increase adherence to recommended practice (2 randomized studies, n = 6304, data not pooled, low-certainty evidence due to very serious inconsistency). Key study characteristics The highest proportion of included studies were from the USA (36%), followed by Australia (10%), China (10%), Japan (5%), the UK (5%), Canada (5%), Italy (5%), and Germany (5%). More than half of the included studies tested CPW in general acute wards (53%), followed by emergency departments (17%), intensive care (14%), and extended-stay facilities (10%). The most common clinical conditions were asthma (16%), stroke (10%), mechanical ventilation (9%) and myocardial infarction (7%). AUTHORS' CONCLUSIONS:Stand-alone CPWs are likely to reduce inhospital complications and length of hospital stay and may slightly increase adherence to recommended practice. There was little conclusive evidence for multifaceted CPWs due to mixed results from a limited number of included studies. It is uncertain whether stand-alone CPWs or CPWs, as part of a multifaceted approach, reduce inhospital mortality, mortality (up to 6 months), hospital readmission (up to 6 months) or costs and charges.

Background: A team of patient partners, researchers, and health system collaborators evaluated the pilot implementation of patient reported metrics in primary care health networks in Saskatchewan, Canada with the intent to recommend best practices for provincial scale-up. Approach: The Saskatchewan Health Authority (SHA) is responsible for health services in Saskatchewan, Canada, including the delivery of primary care services across 38 health networks. Health networks are intended to connect teams of healthcare professionals and community partners to meet the needs of the people they serve. To ensure that the health system delivers care that matters to patients, the People Centred Measurement (PCM) working group, an SHA, patient, and health system partner collaboration, was established in 2020. In November 2022, the PCM working group launched an initiative called Integrating Patient Reported Data into Health Networks in Saskatchewan For this pilot project, an online survey was developed and implemented in 4 of 38 health networks to gather patient reports of their primary care experiences. University of Saskatchewan (USask) researchers and three patient partners who were embedded in the PCM working group engaged in a developmental evaluation of the pilot initiative to recommend policy options to scale up the implementation of patient reported data across Saskatchewan health networks. Working alongside the principal knowledge user who was the PCM working group director and a collaborator who led the development and implementation of the survey, one USask researcher attended all health network meetings and offered evaluative feedback in real time. Early in the evaluation, the researchers and patient partners produced an initial report suggesting the need to increase patient partner engagement and the limitations of a survey approach to the collection of patient reported experiences. Given the PCM imperative to implement patient reported measurement using the survey, the research team was encouraged to engage in a new data collection strategy. The research team pivoted to directly gather perspectives of the pilot project participants using semi-structured virtual interviews. Results: Based on 5 interviews with participants, patient partners and researchers presented the following recommendations at an end of project policy forum: a) Ensure resources for onboarding and support of patients and community members to contribute to ongoing People-Centred Measurement, b) Build processes that engage Indigenous communities, newcomers, hard-to-reach and under-served populations in a meaningful way that directly impacts their experience of care c) Foster relationships and collaboration across SHA portfolios to leverage expertise in People-Centred Measurement design and implementation d) Recognize the difference in capacity between remote, rural, and urban healthcare centres and co-design People-Centred Measurement strategies accordingly, and e) Continuously evaluate People-Centred Measurement implementation and adapt to changing social, economic, and environmental contexts. Implications: With the growing need to incorporate PCM into healthcare systems to deliver on the promise of patient-centred care, Saskatchewan is gradually improving its collection, analysis, and dissemination. Driven by patient partner engagement, findings from our evaluation will inform what is required for the successful collection of patient-reported experience and outcome measures to inform policies that will improve the health of SK people.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies, with limited benefit from current cytotoxic regimens and poor predictive value of genomics alone. Patient-derived organoids (PDOs) represent a promising platform for functional precision oncology, yet systematic pharmacotyping of genomically annotated PDAC PDOs remains sparse. We established a clinically annotated panel of ten treatment-naïve PDAC PDOs spanning well-, moderately-, and poorly differentiated tumors. PDOs were evaluated for morphologic and genomic fidelity and screened against 1,813 clinically relevant small molecules in a high-throughput 384-well format. Drug sensitivities were quantified at the compound and drug-family levels and integrated with histologic grade, pathway-level mutational profiles, and available clinical treatment information. PDOs preserved hallmark tumor features, including glandular organization and subclonal mutational architecture. Pharmacotyping revealed both shared and subtype-specific vulnerabilities. Classical (well/moderately differentiated) PDOs showed enriched mutations in DNA repair, mitotic spindle, and chromatin-regulatory pathways and were preferentially sensitive to topoisomerase inhibitors, microtubule poisons, and HDAC inhibitors. In contrast, basal (poorly differentiated) PDOs displayed coordinated defects in mitochondrial function, vesicle trafficking, and ubiquitin-mediated proteostasis, at the pathway level, that conferred a previously unrecognized vulnerability to cardiac glycosides. Sensitivities to standard PDAC agents were heterogeneous across models, underscoring the limited predictive value of genotype alone and the need for functional drug testing. This integrated genomic and pharmacologic analysis demonstrates that PDO pharmacotyping identifies biologically grounded, actionable vulnerabilities in PDAC, including novel therapeutic opportunities in basal, chemo-resistant tumors. These findings support PDO-guided functional profiling as a clinically relevant platform for refining drug selection and expanding treatment options for patients with PDAC. PDAC is dominated by chemoresistance and lacks reliable genomic predictors of therapy response. By integrating high-throughput drug screening with mutation-informed pathway analysis in patient-derived organoids, we identify differentiation-linked therapeutic liabilities, including a previously unrecognized vulnerability to cardiac glycosides in basal PDAC. These results highlight PDO pharmacotyping as a powerful functional complement to genomics for guiding treatment selection in pancreatic cancer.

Childhood vaccination is vital for disease prevention intervention, yet some Northern Saskatchewan First Nations communities have immunization coverage below the 95% target. We aimed to explore community perspectives on the barriers and facilitators of childhood immunization uptake in First Nations communities in Northern Saskatchewan. We used a qualitative design informed by Indigenous methodologies and community-based participatory approaches to engage three First Nations communities and conducted sharing circles to gather rich, culturally grounded perspectives on childhood immunization. We purposefully recruited parents, caregivers, an Elder, and a community leader. We audio-recorded and transcribed one sharing circle (5 participants) discussion, then analyzed data thematically with Indigenous research principles, ensuring community collaboration and ethical stewardship throughout the study. The results were validated through a community feedback session. Participants described several structural and social factors that limited access to immunization, including transportation barriers, limited clinic hours, geographic isolation, and reduced services during the COVID-19 pandemic. Caregiver mental health issues, substance use, and unstable home environments were identified as barriers to immunization uptake. Language barriers, lack of health literacy, and historical trauma also shaped vaccine hesitancy. Key enablers identified included establishining trusting relationships with local healthcare providers, use of  mobile clinics, peer support, tailored communication strategies, community events that incorporated immunization programs rooted in cultural practices, and involvement of Elders and local leadership in planning and delivery. Our findings show that vaccine uptake in Northern Saskatchewan First Nations communities reflects a complex set of contextual factors, shaped by structural conditions and historical experiences. We recommend policy and practice approaches that support culturally safe, community-led immunization programming. Strengthening trust, expanding flexible service models, and integrating First Nations knowledge systems into public health planning can help improve childhood vaccination coverage and contribute to health equity in northern and remote settings. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Yes ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: We conducted this study in accordance with established ethical guidelines for research involving human participants and Indigenous communities. We respected Indigenous cultural protocols at each stage of engagement. The leadership of the Northern Inter-Tribal Health Authority approved the project, enabling us to engage in initiatives that will significantly benefit the communities. Our research project followed the principles of the Tri-Council Policy Statement (TCPS-2), “Chapter 9: Research Involving the First Nations, Inuit, and Metis Peoples of Canada” (28) and the First Nations principles of Ownership, Control, Access, and Power (OCAP) (20) to ensure that the research was used to derive positive impacts for communities while preserving traditional ways of knowing and governance. We obtained written consent form all participants. The University of Saskatchewan’s Behavioural Research Ethics Board approved the study (ID# Beh-REB4894). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All relevant data are within the manuscript and its Supporting Information files.

Culture is a determinant of health for Indigenous peoples, providing a sense of belonging, strengthening resilience, and promoting wellness. Consequently, there is growing interest in exploring the relationship between Métis (distinct Indigenous people, rooted in both First Nations and European ancestry, Canada), culture, and health. A search of scholarly databases and gray literature resulted in 14 records that met inclusion criteria. Articles revealed seven frameworks and three models that applied Métis knowledge to health. Reiterative readings were used to analyze models and frameworks. Results indicated that one or multiple approaches to health were incorporated: (1) Métis symbolism and concepts; (2) social determinants of health and the life course perspective; (3) engagement with Métis government, organizations, and community; and (4) research methods and knowledge translation. These findings can foster the development of culturally appropriate models, frameworks, and strategies that favor Métis culture in health research to more effectively promote Métis health.

To develop a national atlas of (1) Canadian cohorts studying or with the potential to study adults living with long COVID (LC) and (2) harmonize provincial and territorial administrative datasets to facilitate the creation of validated case-ascertainment algorithms and foster national collaboration on LC research. We conducted a multifaceted environmental scan that included a comprehensive literature search and a survey of members of Canada’s national LC research network between August 21, 2023, and November 10, 2023. We identified provincial and territorial cohorts, including those that were linkable to administrative data and common data elements among administrative datasets. We included 19 Canadian cohorts from five provinces (Alberta, British Columbia, Manitoba, Ontario, and Québec) containing data on over 580,000 adults. The majority of the cohorts measured sociodemographic data (e.g., age, sex) and measures of healthcare use, whereas equity-related measures such as gender, ethnicity, and race were limited. There was wide variability in the definitions of LC used across all cohorts. Comparable population-level administrative data are currently available in Alberta, British Columbia, Manitoba, Ontario, Québec, New Brunswick, Newfoundland and Labrador, Nova Scotia, and Saskatchewan. Canada has a rich repository of LC datasets that are limited by variable definitions of LC and inadequate equity-related measures such as gender, ethnicity, and race. Standardization and diversification of these measures will facilitate efforts to study healthcare use and develop health policy to improve the care of Canadian adults living with LC at a population level.

Melanoma is one of the deadliest forms of skin cancer. Irreversible electroporation (IRE) is an innovative, non-thermal ablation technology for treating irresectable solid cancers. However, most IRE treatments are incapable of cancer eradication and only temporarily prolong patient survival. In this study, we developed a novel IRE + Combo treatment regimen that combines IRE-ablation with Combo-adjuvant [CpG, anti-PD-L1 antibody (PD-L1-Ab) and CD40-agonist] and investigated its anti-tumor immunity in a mouse BL6-10OVA (BLOVA) melanoma model. We demonstrated that inclusion of the CD40-agonist in the IRE + Combo treatment regimen promoted a more robust CD8+ T cell response (6.89

Irreversible electroporation (IRE) is a relatively new, non-thermal ablation technology for cancer treatment that requires further investigation to optimize its therapeutic efficacy. To improve IRE-ablation, we developed an IRE+Combo-treatment regimen that included the Combo adjuvants poly-I:C (pIC)/CpG, anti-PD-L1 antibody (PD-L1-Ab) and the 41BB-agonist, and investigated its anti-tumor immunity in a 3LLOVA lung cancer model. We demonstrated that inclusion of the 41BB-agonist in the IRE+Combo-ablation stimulated a more efficient CD8+ T cell response (5.3%) than that observed in the absence of 41BB-agonist (3.0%) or upon IRE ablation alone (0.4%), leading to eradication of subcutaneous 3LLOVA cancer in 75% of 3LLOVA-bearing mice. We further showed that the IRE+Combo-treatment regimen resulted in the eradication of both 3LLOVA cancer and lung tumor metastases. Interestingly, our flow cytometry analyses argued that addition of the 41BB-agonist to the IRE+Combo-ablation stimulated a higher frequency of novel CD8+CD103+ conventional type-1 dendritic cells (cDC1) (14.4%) in tumor-drainage lymph-nodes (TDLNs) relative to control IRE+CpG/pIC/PD-L1-Ab- (7.5%) and IRE- (4.0%) treatment groups. This novel cDC1 subpopulation exhibited the most robust expression of DC maturation markers and costimulatory 41BBL and 41BB of all cDC1 subsets. The 41BB-agonist also stimulated a higher frequency of 41BB+CD103+TCF-1+ tissue-resident memory T (TRM) cells (14.5%) in TDLNs when compared with the two control (2.6% and 0.3%) treatment groups. Importantly, the IRE+Combo-treatment regimen was more efficient than the two control groups at converting the immunosuppressive tumor microenvironment (TME), an effect that was mitigated by reducing the frequency of inhibitory myeloid-derived suppressive cells while increasing that of immunogenic cDC1 and CD8+ T cells and rescuing T cell exhaustion. Taken together, our data establish that the 41BB-agonist potentiates the efficacy of IRE+Combo-therapy for lung cancer treatment by promoting unexpected cDC1 and TRM cell responses, and emphasize the importance of targeting this promising molecular signal to improve current cancer IRE-ablation protocols.