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Adherence to healthy diet principles and to cardiopreventive medication, both key behaviors in cardiovascular disease (CVD) prevention, is known to differ between women and men. Whether these adherence behaviors are differentially related among women and men has never been thoroughly assessed. The objective was to assess gender differences in the association between adherence to healthy diet principles and to cardiopreventive medication in adults free of CVD. This cross-sectional study included 268 women and 204 men from the CARTaGENE cohort (Québec, Canada) who were using antihypertensive and/or cholesterol-lowering medication. Adherence to healthy diet principles was assessed using the Alternate Healthy Eating Index (AHEI, %), calculated from a validated food frequency questionnaire (FFQ) assessing diet in the 12-month preceding its completion. Medication adherence was assessed using the daily pharmacotherapy possession rate (DPPR, %), calculated from prescription claim data over the same 12-month period. In multivariable-adjusted analyses, an inverse association between AHEI and DPPR was observed among men (β AHEI for 10% increment in DPPR=-0.65%; 95% CI: -1.28%, -0.03%; P =0.04), while it tended to be positive among women (β=0.44%; 95% CI: -0.11%, 1.00%; P =0.12; P gender*DPPR =0.01). The negative association between AHEI and DPPR was stronger among men who never smoked or used cholesterol-lowering medication only. Among women, the positive association was stronger and statistically significant among those with obesity or using ≥3 medications simultaneously. Association between adherence to healthy diet principles and to cardiopreventive medication differs between women and men, with men potentially facing greater challenges in achieving optimal complementarity between these two behaviors.

Background: Artificial intelligence (AI) predictive models in primary health care have the potential to enhance population health by rapidly and accurately identifying individuals who should receive care and health services. However, these models also carry the risk of perpetuating or amplifying existing biases toward diverse groups. We identified a gap in the current understanding of strategies used to assess and mitigate bias in primary health care algorithms related to individuals' personal or protected attributes., Objective: This study aimed to describe the attempts, strategies, and methods used to mitigate bias in AI models within primary health care, to identify the diverse groups or protected attributes considered, and to evaluate the results of these approaches on both bias reduction and AI model performance., Methods: We conducted a scoping review following Joanna Briggs Institute (JBI) guidelines, searching Medline (Ovid), CINAHL (EBSCO), PsycINFO (Ovid), and Web of Science databases for studies published between January 1, 2017, and November 15, 2022. Pairs of reviewers independently screened titles and abstracts, applied selection criteria, and performed full-text screening. Discrepancies regarding study inclusion were resolved by consensus. Following reporting standards for AI in health care, we extracted data on study objectives, model features, targeted diverse groups, mitigation strategies used, and results. Using the mixed methods appraisal tool, we appraised the quality of the studies., Results: After removing 585 duplicates, we screened 1018 titles and abstracts. From the remaining 189 full-text articles, we included 17 studies. The most frequently investigated protected attributes were race (or ethnicity), examined in 12 of the 17 studies, and sex (often identified as gender), typically classified as "male versus female" in 10 of the studies. We categorized bias mitigation approaches into four clusters: (1) modifying existing AI models or datasets, (2) sourcing data from electronic health records, (3) developing tools with a "human-in-the-loop" approach, and (4) identifying ethical principles for informed decision-making. Algorithmic preprocessing methods, such as relabeling and reweighing data, along with natural language processing techniques that extract data from unstructured notes, showed the greatest potential for bias mitigation. Other methods aimed at enhancing model fairness included group recalibration and the application of the equalized odds metric. However, these approaches sometimes exacerbated prediction errors across groups or led to overall model miscalibrations., Conclusions: The results suggest that biases toward diverse groups are more easily mitigated when data are open-sourced, multiple stakeholders are engaged, and during the algorithm's preprocessing stage. Further empirical studies that include a broader range of groups, such as Indigenous peoples in Canada, are needed to validate and expand upon these findings., Trial Registration: OSF Registry osf.io/9ngz5/; https://osf.io/9ngz5/., International Registered Report Identifier (irrid): RR2-10.2196/46684., (©Maxime Sasseville, Steven Ouellet, Caroline Rhéaume, Malek Sahlia, Vincent Couture, Philippe Després, Jean-Sébastien Paquette, David Darmon, Frédéric Bergeron, Marie-Pierre Gagnon. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 07.01.2025.)

Background: Shared decision-making is an imperative in chronic pain care. However, we know little about the decision-making process, especially in primary care where most chronic pain care is provided. We sought to understand decisional needs of people living with chronic pain in Canada., Methods: We conducted a population-based cross-sectional online survey of random samples of adults living in Canada with chronic noncancer pain and registered with the Leger Marketing panel. We followed the International Association for Study of Pain definition of chronic pain (i.e., persistent or recurrent pain lasting longer than three months). We used a stratified proportional random sampling based on the population and chronic pain prevalence of each province to achieve representativeness. Based on the Ottawa Decision Support Framework, we collected data on difficult decisions (i.e., decision with more than one option and no clear best option) related to their chronic pain condition, the level of decisional conflict associated with the most difficult decisions (i.e., Decisional Conflict Scale), the assumed and preferred role during the decision-making process (i.e., Control Preferences Scale), and respondents' characteristics. We used descriptive quantitative analyses of survey responses., Results: Of the 31,545 invited panellists, 2,666 met the eligibility criteria, and 1,649 respondents from the 10 Canadian provinces completed the survey. Respondents had diverse socio-demographic profiles. Mean age was 51.8 years (SD = 16.3). Half were men (51.4%), most lived in urban areas (87.8%), mean pain duration was 8.5 years (SD = 9.6), and respondents reported an average number of painful body regions of 2.3 (SD = 1.5). We observed that 96.7% of respondents faced at least one difficult decision across their care pathways. These difficult decisions were related to numerous issues from the medical consultation, diagnosis, treatment, and daily life. Almost half of respondents made their most difficult decision with a primary care physician. One third of respondents experienced a high level of clinically significant decisional conflict (Decisional Conflict Scale score ≥ 37.5). Two-thirds of respondents self-reported having a collaborative role during their decision while three-quarters wanted this role., Conclusions: People living with chronic pain in Canada have unmet decisional needs and need support to make optimal decisions to manage their chronic pain. Our findings will guide future development of interventions to implement shared decision-making, especially to support primary care where discussions about difficult decisions often occur., Competing Interests: Declarations. Ethics approval and consent to participate: We obtained the ethics approval from the Research Ethics Board of the Research Centre at the Centre Hospitalier Universitaire de Sherbrooke (project #2022–4645). We conducted the survey following the Canadian Personal Information Protection and Electronic Documents Act and the Marketing Research and Intelligence Association’s Charter of Respondent Rights. Respondents consented to participate in the study. All respondents had to give their consent before their participation and could request to be removed from the study at any time. Respondents also had to consent to Leger Marketing’s terms of use and privacy policy. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: People with chronic diseases can benefit from wearable devices in managing their health and encouraging healthy lifestyle habits. Wearables such as activity trackers or blood glucose monitoring devices can lead to positive health impacts, including improved physical activity adherence or better management of type 2 diabetes. Few literature reviews have focused on the intersection of various chronic diseases, the wearable devices used, and the outcomes evaluated in intervention studies, particularly in the context of primary health care., Objective: This study aims to identify and describe (1) the chronic diseases represented in intervention studies, (2) the types or combinations of wearables used, and (3) the health or health care outcomes assessed and measured., Methods: We conducted a scoping review following the Joanna Briggs Institute guidelines, searching the MEDLINE and Web of Science databases for studies published between 2012 and 2022. Pairs of reviewers independently screened titles and abstracts, applied the selection criteria, and performed full-text screening. We included interventions using wearables that automatically collected and transmitted data to adult populations with at least one chronic disease. We excluded studies with participants with only a predisposition to develop a chronic disease, hospitalized patients, patients with acute diseases, patients with active cancer, and cancer survivors. We included randomized controlled trials and cohort, pretest-posttest, observational, mixed methods, and qualitative studies., Results: After the removal of 1987 duplicates, we screened 4540 titles and abstracts. Of the remaining 304 articles after exclusions, we excluded 215 (70.7%) full texts and included 89 (29.3%). Of these 89 texts, 10 (11%) were related to the same interventions as those in the included studies, resulting in 79 studies being included. We structured the results according to chronic disease clusters: (1) diabetes, (2) heart failure, (3) other cardiovascular conditions, (4) hypertension, (5) multimorbidity and other combinations of chronic conditions, (6) chronic obstructive pulmonary disease, (7) chronic pain, (8) musculoskeletal conditions, and (9) asthma. Diabetes was the most frequent health condition (18/79, 23% of the studies), and wearable activity trackers were the most used (42/79, 53% of the studies). In the 79 included studies, 74 clinical, 73 behavioral, 36 patient technology experience, 28 health care system, and 25 holistic or biopsychosocial outcomes were reported., Conclusions: This scoping review provides an overview of the wearable devices used in chronic disease self-management intervention studies, revealing disparities in both the range of chronic diseases studied and the variety of wearable devices used. These findings offer researchers valuable insights to further explore health care outcomes, validate the impact of concomitant device use, and expand their use to other chronic diseases., Trial Registration: Open Science Framework Registries (OSF) s4wfm; https://osf.io/s4wfm., (©Marie-Pierre Gagnon, Steven Ouellet, Eugène Attisso, Wilfried Supper, Samira Amil, Caroline Rhéaume, Jean-Sébastien Paquette, Christian Chabot, Marie-Claude Laferrière, Maxime Sasseville. Originally published in the Interactive Journal of Medical Research (https://www.i-jmr.org/), 09.12.2024.)

We aimed to measure the sustainability of health professionals' intention to have serious illness conversations with patients using the Serious Illness Conversation Guide (SICG) after individual-focused training versus team-based training. In a cluster randomised trial, we trained healthcare professionals in 40 primary care clinics and measured their intention to hold serious illness conversations immediately (T1), after 1 year (T2) and after 2 years (T3). Primary care clinics ( n  = 40) were randomly assigned to individual-focused training (comparator) or team-based training (intervention). Average age of the 373 participants was 35-44 years, 79% were women. On a scale of 1 to 7, at T1, the mean intention was 5.33 (SD 0.20) in the individual-focused group and 5.36 (SD 0.18) in the team-based group; at T2, these scores were 4.94 (SD 0.23) and 4.87 (SD 0.21) and at T3, 5.14 (SD 0.24) and 4.59 (SD 0.21), respectively. At T3, the difference in mean intention between study groups had a significant p-value of 0.01. Intention to have serious illness conversations was lower at T2 and T3 after team-based training than after individual-focused training, with a significant difference at 2 years in favour of individual-focused training. Health professionals reported not enough time during consultations for serious illness conversations as a major barrier., Registration Number: ClinicalTrials.gov (ID NCT03577002) for the parent clinical trial., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Symptoms of the Post-COVID-19 Condition are often non-specific making it a challenge to distinguish them from symptoms due to other medical conditions. In this study, we compare the proportion of emergency department patients who developed symptoms consistent with the World Health Organization's Post-COVID-19 Condition clinical case definition between those who tested positive for Severe Acute Respiratory Syndrome Coronavirus-2 infection and time-matched patients who tested negative. Our results show that over one-third of emergency department patients with a proven acute infection meet Post-COVID-19 Condition criteria 3 months post-index visit. However, one in five test-negative patients who claim never having been infected also report symptoms consistent with Post-COVID-19 Condition highlighting the lack of specificity of the clinical case definition. Testing for SARS-CoV-2 during the acute phase of a suspected infection should continue until specific biomarkers of Post-COVID-19 Condition become available for diagnosis and treatment., (© 2024. The Author(s).)

Risk-stratified breast screening has been proposed as a strategy to overcome the limitations of age-based screening. A prospective cohort study was undertaken within the PERSPECTIVE I&I project, which will generate the first Canadian evidence on multifactorial breast cancer risk assessment in the population setting to inform the implementation of risk-stratified screening. Recruited females aged 40-69 unaffected by breast cancer, with a previous mammogram, underwent multifactorial breast cancer risk assessment. The adoption of multifactorial risk assessment, the effectiveness of methods for collecting risk factor information and the costs of risk assessment were examined. Associations between participant characteristics and study sites, as well as data collection methods, were assessed using logistic regression; all p -values are two-sided. Of the 4246 participants recruited, 88.4% completed a risk assessment, with 79.8%, 15.7% and 4.4% estimated at average, higher than average and high risk, respectively. The total per-participant cost for risk assessment was CAD 315. Participants who chose to provide risk factor information on paper/telephone (27.2%) vs. online were more likely to be older ( p = 0.021), not born in Canada ( p = 0.043), visible minorities ( p = 0.01) and have a lower attained education ( p < 0.0001) and perceived fair/poor health ( p < 0.001). The 34.4% of participants requiring risk factor verification for missing/unusual values were more likely to be visible minorities ( p = 0.009) and have a lower attained education ( p ≤ 0.006). This study demonstrates the feasibility of risk assessment for risk-stratified screening at the population level. Implementation should incorporate an equity lens to ensure cancer-screening disparities are not widened.

Background: Scaling effective primary care innovations to benefit more people is of interest to decision makers. However, we know little about how promising innovations are being scaled "spontaneously," that is, without deliberate guidance., Objective: We aim to observe, document, and analyze how, in real-life conditions, 1 primary care innovation spontaneously scales up across Quebec, Canada., Methods: We will conduct a participative study using a descriptive single-case study. It will be guided by the McLean and Gargani principles for scaling and reported according to the COREQ (Consolidated Criteria for Reporting Qualitative Research) guidelines. Informed by an integrated knowledge translation approach, our steering committee will include patient users throughout the project. Inspired by the Quebec College of Family Physician's "Dragons' Den" primary care program, we will identify a promising primary care innovation that is being or will be scaled spontaneously. We will interview the innovation team about their scaling experiences every month for 1 year. We will conduct interviews and focus groups with decision makers, health care providers, and end users in the innovation team and the target site about their experience of both scaling and receiving the scaled innovation and document meetings as nonparticipant observers. Interview transcripts and documentary data will be analyzed to (1) compare the spontaneous scaling plan and implementation with the McLean and Gargani principles for scaling and (2) determine how it was consistent with or diverged from the 4 McLean and Gargani guiding principles: justification, optimal scale, coordination, and dynamic evaluation., Results: This study was funded in March 2020 by the Canadian Institutes of Health Research. Recruitment began in November 2023 and data collection began in December 2023. Results are expected to be published in the first quarter of 2024., Conclusions: Our study will advance the science of scaling by providing practical evidence-based material about scaling health and social care innovations in real-world settings using the 4 guiding principles of McLean and Gargani., International Registered Report Identifier (irrid): PRR1-10.2196/54855., (©France Légaré, Diogo G V Mochcovitch, Roberta de Carvalho Corôa, Amédé Gogovor, Ali Ben Charif, Cynthia Cameron, Annie Plamondon, Marie Cimon, Sabrina Guay-Bélanger, Geneviève Roch, Maxine Dumas Pilon, Jean-Sébastien Paquette, Robert K D McLean, Andrew Milat. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 28.12.2023.)

Aging is not a disease; it is a natural evolution of human physiology. Medical advances have extended our life expectancy, but chronic diseases and geriatric syndrome continue to affect the increasingly aging population. Yet modern medicine perpetuates an approach based on treatment rather than prevention and education. In order to help solve this ever-growing problem, a new discipline has emerged: lifestyle medicine. Nutrition, physical activity, stress management, restorative sleep, social connection, and avoidance of risky substances are the pillars on which lifestyle medicine is founded. The aim of this discipline is to increase healthspan and reduce the duration of morbidity by making changes to our lifestyle. In this review, we propose the use of klotho protein as a novel biomarker for lifestyle medicine in order to quantify and monitor the health status of individuals, as no integrative tool currently exists.

Background: Management of high blood pressure (BP), a key feature of the metabolic syndrome (MetS), relies on diet and medication. Whether these modalities are used as complements has never been evaluated in real-world settings. This study assessed the relationship between diet quality and antihypertensive medication intensity among adults with MetS-associated high BP., Methods: This cross-sectional study included 915 adults with MetS-associated high BP from the CARTaGENE cohort (Québec, Canada), of whom 677 reported using BP-lowering medication. Antihypertensive medication intensity was graded per the number of BP-lowering classes used simultaneously. Diet quality was assessed using the D ietary A pproach to S top H ypertension (DASH) score., Results: No evidence of a relationship between antihypertensive medication intensity and diet quality was found (β for each additional antihypertensive = -0.05; 95% CI, -0.35; 0.26 DASH score points). However, among men aged < 50 years and women aged < 60 years, the DASH score was inversely associated with medication intensity (β = -0.72; 95% CI, -1.24, -0.19), whereas this relationship tended to be positive among older participants (β = 0.32; 95% CI, -0.05, 0.69). Among participants with low Framingham risk score, the DASH score was inversely associated with medication intensity (β = -0.70; 95% CI, -1.31, -0.09), but no evidence of an association was found among individuals at moderate (β = 0.00; 95% CI, -0.45, 0.45) or high (β = 0.30, 95% CI, -0.24, 0.84) risk., Conclusions: In this cohort of adults with MetS-associated high BP, there was an overall lack of complementarity between diet quality and BP-lowering medication, especially among younger individuals and those with a lower risk for cardiovascular disease for whom diet quality was inversely associated with intensity of medication., (© 2023 The Authors.)

Background: Health measurement guides policies and health care decisions are necessary to describe and attain the quintuple aim of improving patient experience, population health, care team well-being, health care costs, and equity. In the primary care setting, patient-reported outcome measurement allows outcome comparisons within and across settings and helps improve the clinical management of patients. However, these digital patient-reported outcome measures (PROMs) are still not adapted to the clinical context of primary health care, which is an indication of the complexity of integrating these tools in this context. We must then gather evidence of their impact on chronic disease management in primary health care and understand the characteristics of effective implementation., Objective: We will conduct a systematic review to identify and assess the impact of electronic PROMs (ePROMs) implementation in primary health care for chronic disease management. Our specific objectives are to (1) determine the impact of ePROMs in primary health care for chronic disease management and (2) compare and contrast characteristics of effective ePROMs' implementation strategies., Methods: We will conduct a systematic review of the literature in accordance with the guidelines of the Cochrane Methods Group and in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for its reporting. A specific search strategy was developed for relevant databases to identify studies. Two reviewers will independently apply the inclusion criteria using full texts and will extract the data. We will use a 2-phase sequential mixed methods synthesis design by conducting a qualitative synthesis first, and use its results to perform a quantitative synthesis., Results: This study was initiated in June 2022 by assembling the research team and the knowledge transfer committee. The preliminary search strategy will be developed and completed in September 2022. The main search strategy, data collection, study selection, and application of inclusion criteria were completed between October and December 2022., Conclusions: Results from this review will help support implementation efforts to accelerate innovations and digital adoption for primary health care and will be relevant for improving clinical management of chronic diseases and health care services and policies., Trial Registration: PROSPERO International Prospective Register of Systematic Reviews CRD42022333513; https://www.crd.york.ac.uk/prospero/display&#95;record.php?RecordID=333513., International Registered Report Identifier (irrid): DERR1-10.2196/48155., (©Maxime Sasseville, Wilfried Supper, Jean-Baptiste Gartner, Géraldine Layani, Samira Amil, Peter Sheffield, Marie-Pierre Gagnon, Catherine Hudon, Sylvie Lambert, Eugène Attisso, Victoria Bureau Lagarde, Mylaine Breton, Marie-Eve Poitras, Pierre Pluye, Pierre-Henri Roux-Levy, James Plaisimond, Frédéric Bergeron, Rachelle Ashcroft, Sabrina Wong, Antoine Groulx, Nicolas Beaudet, Jean-Sébastien Paquette, Natasha D'Anjou, Sylviane Langlois, Annie LeBlanc. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 18.08.2023.)

Background: Primary care and other health services have been disrupted during the COVID-19 pandemic, yet the consequences of these service disruptions on patients' care experiences remain largely unstudied. People with mental-physical multimorbidity are vulnerable to the effects of the pandemic, and to sudden service disruptions. It is thus essential to better understand how their care experiences have been impacted by the current pandemic. This study aims to improve understanding of the care experiences of people with mental-physical multimorbidity during the pandemic and identify strategies to enhance these experiences., Methods: We will conduct a mixed-methods study with multi-phase approach involving four distinct phases. Phase 1 will be a qualitative descriptive study in which we interview individuals with mental-physical multimorbidity and health professionals in order to explore the impacts of the pandemic on care experiences, as well as their perspectives on how care can be improved. The results of this phase will inform the design of study phases 2 and 3. Phase 2 will involve journey mapping exercises with a sub-group of participants with mental-physical multimorbidity to visually map out their care interactions and experiences over time and the critical moments that shaped their experiences. Phase 3 will involve an online, cross-sectional survey of care experiences administered to a larger group of people with mental disorders and/or chronic physical conditions. In phase 4, deliberative dialogues will be held with key partners to discuss and plan strategies for improving the delivery of care to people with mental-physical multimorbidity. Pre-dialogue workshops will enable us to synthesize an prepare the results from the previous three study phases., Discussion: Our study results will generate much needed evidence of the positive and negative impacts of the COVID-19 pandemic on the care experiences of people with mental-physical multimorbidity and shed light on strategies that could improve care quality and experiences., (© 2023. The Author(s).)

Background: The current literature identifies several potential benefits of artificial intelligence models for populations' health and health care systems' efficiency. However, there is a lack of understanding on how the risk of bias is considered in the development of primary health care and community health service artificial intelligence algorithms and to what extent they perpetuate or introduce potential biases toward groups that could be considered vulnerable in terms of their characteristics. To the best of our knowledge, no reviews are currently available to identify relevant methods to assess the risk of bias in these algorithms. The primary research question of this review is which strategies can assess the risk of bias in primary health care algorithms toward vulnerable or diverse groups?, Objective: This review aims to identify relevant methods to assess the risk of bias toward vulnerable or diverse groups in the development or deployment of algorithms in community-based primary health care and mitigation interventions deployed to promote and increase equity, diversity, and inclusion. This review looks at what attempts to mitigate bias have been documented and which vulnerable or diverse groups have been considered., Methods: A rapid systematic review of the scientific literature will be conducted. In November 2022, an information specialist developed a specific search strategy based on the main concepts of our primary review question in 4 relevant databases in the last 5 years. We completed the search strategy in December 2022, and 1022 sources were identified. Since February 2023, two reviewers independently screened the titles and abstracts on the Covidence systematic review software. Conflicts are solved through consensus and discussion with a senior researcher. We include all studies on methods developed or tested to assess the risk of bias in algorithms that are relevant in community-based primary health care., Results: In early May 2023, almost 47% (479/1022) of the titles and abstracts have been screened. We completed this first stage in May 2023. In June and July 2023, two reviewers will independently apply the same criteria to full texts, and all exclusion motives will be recorded. Data from selected studies will be extracted using a validated grid in August and analyzed in September 2023. Results will be presented using structured qualitative narrative summaries and submitted for publication by the end of 2023., Conclusions: The approach to identifying methods and target populations of this review is primarily qualitative. However, we will consider a meta-analysis if quantitative data and results are sufficient. This review will develop structured qualitative summaries of strategies to mitigate bias toward vulnerable populations and diverse groups in artificial intelligence models. This could be useful to researchers and other stakeholders to identify potential sources of bias in algorithms and try to reduce or eliminate them., Trial Registration: OSF Registries qbph8; https://osf.io/qbph8., International Registered Report Identifier (irrid): DERR1-10.2196/46684., (©Maxime Sasseville, Steven Ouellet, Caroline Rhéaume, Vincent Couture, Philippe Després, Jean-Sébastien Paquette, Karine Gentelet, David Darmon, Frédéric Bergeron, Marie-Pierre Gagnon. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 26.06.2023.)

Introduction: The 2021 Action Plan for Pain from the Canadian Pain Task Force advocates for patient-centred pain care at all levels of healthcare across provinces. Shared decision-making is the crux of patient-centred care. Implementing the action plan will require innovative shared decision-making interventions, specifically following the disruption of chronic pain care during the COVID-19 pandemic. The first step in this endeavour is to assess current decisional needs (ie, decisions most important to them) of Canadians with chronic pain across their care pathways., Methods and Analysis: Design Grounded in patient-oriented research approaches, we will perform an online population-based survey across the ten Canadian provinces. We will report methods and data following the CROSS reporting guidelines. Sampling The Léger Marketing company will administer the online population-based survey to its representative panel of 500 000 Canadians to recruit 1646 adults (age ≥18 years old) with chronic pain according to the definition by the International Association for the Study of Pain (eg, pain ≥12 weeks). Content Based on the Ottawa Decision Support Framework, the self-administered survey has been codesigned with patients and contain six core domains: (1) healthcare services, consultation and postpandemic needs, (2) difficult decisions experienced, (3) decisional conflict, (4) decisional regret, (5) decisional needs and (6) sociodemographic characteristics. We will use several strategies such as random sampling to improve survey quality. Analysis We will perform descriptive statistical analysis. We will identify factors associated with clinically significant decisional conflict and decision regret using multivariate analyses., Ethics and Dissemination: Ethics was approved by the Research Ethics Board at the Research Centre of the Centre Hospitalier Universitaire de Sherbrooke (project #2022-4645). We will codesign knowledge mobilisation products with research patient partners (eg, graphical summaries and videos). Results will be disseminated via peer-reviewed journals and national and international conferences to inform the development of innovative shared decision-making interventions for Canadians with chronic pain., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: To reduce the transmission of SARS-CoV-2 and the associated spread of COVID-19, many jurisdictions around the world imposed mandatory or recommended social or physical distancing. As a result, at the beginning of the pandemic, various communication materials appeared online to promote distancing. Explanations of the science underlying these mandates or recommendations were either highly technical or highly simplified., Objective: This study aimed to understand the effects of a dynamic visualization on distancing. Our overall aim was to help people understand the dynamics of the spread of COVID-19 in their community and the implications of their own behavior for themselves, those around them, the health care system, and society., Methods: Using Scrum, which is an agile framework; JavaScript (Vue.js framework); and code already developed for risk communication in another context of infectious disease transmission, we rapidly developed a new personalized web application. In our application, people make avatars that represent themselves and the people around them. These avatars are integrated into a 3-minute animation illustrating an epidemiological model for COVID-19 transmission, showing the differences in transmission with and without distancing. During the animation, the narration explains the science of how distancing reduces the transmission of COVID-19 in plain language in English or French. The application offers full captions to complement the narration and a descriptive transcript for people using screen readers. We used Google Analytics to collect standard usage statistics. A brief, anonymous, optional survey also collected self-reported distancing behaviors and intentions in the previous and coming weeks, respectively. We launched and disseminated the application on Twitter and Facebook on April 8, 2020, and April 9, 2020., Results: After 26 days, the application received 3588 unique hits from 82 countries. The optional survey at the end of the application collected 182 responses. Among this small subsample of users, survey respondents were nearly (170/177, 96%) already practicing distancing and indicated that they intended to practice distancing in the coming week (172/177, 97.2%). Among the small minority of people (n=7) who indicated that they had not been previously practicing distancing, 2 (29%) reported that they would practice distancing in the week to come., Conclusions: We developed a web application to help people understand the relationship between individual-level behavior and population-level effects in the context of an infectious disease spread. This study also demonstrates how agile development can be used to quickly create personalized risk messages for public health issues like a pandemic. The nonrandomized design of this rapid study prevents us from concluding the application's effectiveness; however, results thus far suggest that avatar-based visualizations may help people understand their role in infectious disease transmission., (©Doriane Etienne, Patrick Archambault, Donovan Aziaka, Selma Chipenda-Dansokho, Eve Dubé, Catherine S Fallon, Hina Hakim, Jason Kindrachuk, Dan Krecoum, Shannon E MacDonald, Ruth Ndjaboue, Magniol Noubi, Jean-Sébastien Paquette, Elizabeth Parent, Holly O Witteman. Originally published in JMIR Formative Research (https://formative.jmir.org), 25.04.2023.)

Introduction: Approximately 33% of people who contracted COVID-19 still experience symptoms 12 weeks after infection onset. This persistence of symptoms is now considered a syndrome itself called 'long COVID'. Evidence regarding long COVID and its cognitive and physical impacts is growing, but the literature is currently lacking objectively measured data to guide towards adapted healthcare trajectories. The objectives are to describe the physical and cognitive impairments experienced by individuals living with long COVID using self-reported and clinical objective measures, and to compare the evolution over time of the physical and cognitive state between adults living with long COVID (at least one physical or cognitive COVID-19 symptom for more than 12 weeks following infection; long COVID group), people who developed COVID-19 but did not experience persistent symptoms (short COVID group) and people who did not develop COVID-19 (control group)., Methods and Analysis: In this longitudinal cohort study, 120 participants will be recruited in each group. Variables will be collected through three evaluation sessions over 6 months (baseline, 3 months, 6 months). Variables include self-administered questionnaires on health-related quality of life, comorbidity, sleep, pain, anxiety, depressive symptoms, fatigue and cognitive function, as well as objective measures of cognitive (attention, memory, executive functioning) and physical (grip strength, balance, gait speed, gait endurance, VO2, frailty) functions. Activity, heart rate and sleep will be monitored with a fitness tracker watch for 7 days following evaluation sessions. Maximum-likelihood analyses of variance (ANOVAs) will be used to compare data at baseline between groups. Repeated measures ANOVAs will be used to compare the longitudinal performance variations across groups of the self-reported and clinical variables., Ethics and Dissemination: Ethics committees of the CIUSSS de la Capitale-Nationale and CIUSSS de l'Est-de-l'Île-de-Montréal approved the project. Results will be disseminated through clinical and community platforms as well as through peer-reviewed manuscripts and international conferences., Trial Registration Number: NCT05216536., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Little is known about engaging patients and stakeholders in the process of scaling up effective knowledge translation interventions targeting the public., Objective: Using an integrated knowledge translation approach, we aimed to scale up and evaluate an effective pilot program to disseminate research results in public libraries., Methods: We conducted a scaling-up study targeting the public. On the basis of our successful pilot project, we codeveloped and implemented a large-scale program of free citizen workshops in public libraries, in a close research partnership with stakeholders and patient representatives. Citizen workshops, each facilitated by 1 participating physician and 1 science communicator, consisted of a 45-minute computer-assisted presentation and a 45-minute open exchange. The intervention outcome was knowledge gained. The scale-up outcomes were satisfaction, appropriateness, coverage, and costs. An evaluation questionnaire was used to collect data of interest. Both quantitative and qualitative analyses were performed., Results: The workshop theme chosen by the patient and stakeholder representatives was the high prevalence of medication overuse among people aged ≥65 years. From April to May 2019, 26 workshops were conducted in 25 public libraries reaching 362 people. The mean age of participants was 64.8 (SD 12.5) years. In total, 18 participating physicians and 6 science communicators facilitated the workshops. Participants reported significant knowledge gain (mean difference 2.1, 95% CI 2.0-2.2; P<.001). The median score for overall public satisfaction was 9 out of 10 (IQR 8-10). The public participants globally rated the workshops as having a high level of appropriateness. Coverage was 92% (25/27) of the total number of public libraries targeted. Costs were CAD $6051.84 (US $4519.69) for workshop design and CAD $22,935.41 (US $17,128.85) for scaling them up., Conclusions: This project successfully established a large-scale and successful implementation science or knowledge translation bridge among researchers, clinicians, and citizens via public libraries. This study provides a model for a dissemination practice that benefits the public by both engaging them in the dissemination process and targeting them directly., (©José Massougbodji, Hervé Tchala Vignon Zomahoun, Evehouenou Lionel Adisso, Jasmine Sawadogo, Valérie Borde, Cynthia Cameron, Hélène Moisan, Jean-Sébastien Paquette, Zamzam Akbaraly, Lëa-Kim Châteauneuf, Geneviève David, Bibliothèques2 Group, France Légaré. Originally published in JMIR Aging (https://aging.jmir.org), 19.08.2022.)

Background: The use of electronic health records (EHR) has revolutionized medical practice by improving the quality of care. Childhood obesity (CO) increases the risk of developing other chronic diseases and has a serious psychosocial impact on children. Using EHR may improve this clinical condition since early diagnosis is a crucial means of preventing its negative impacts., Objectives: The aim of the study was to assess the diagnosis and management of CO in a Canadian academic family medicine group unit (FMG-U) that uses EHR with an integrated CO diagnosis tool., Methods: This is a retrospective study conducted in an FMG-U in the province of Quebec. The clinical practice guidelines established by the World Health Organization (WHO) were used to assess diagnosis and management of CO. EHR of every patient from 5 to 12 years old who had a medical appointment at the FMG-U in 2017 ( n  = 618) were analyzed. EHR use by clinicians was assessed by a closed-ended online survey sent to clinicians who provided pediatric care at that clinic in 2017., Results: We identified 69 patients as obese according to the WHO, of whom 40 had been diagnosed by health professionals at the clinic. Of these, 33 received nutritional counseling; 33 received physical activity counseling; 13 received parent involvement counseling; 19 were referred to another health professional; and 12 were followed up within 6 months. Ten out of 15 clinicians responded to the survey. They all used the EHR integrated CO diagnosis tool but only 20% were truly familiar with it., Conclusions: This study shows that CO is still underdiagnosed in primary care, notwithstanding the use of EHR with integrated tools. This affects the quality of care. Moreover, even if CO were correctly diagnosed, its management remains incomplete. Knowledge translation by medical organizations plays an important role in addressing this problem., Competing Interests: The authors declare no conflicts of interest., (© 2022 The Authors. Health Science Reports published by Wiley Periodicals LLC.)

Background: Older adults (≥65 years) with diabetes and multiple chronic conditions (MCC) (> 2 chronic conditions) experience reduced function and quality of life, increased health service use, and high mortality. Many community-based self-management interventions have been developed for this group, however the evidence for their effectiveness is limited. This paper presents the protocol for a randomized controlled trial (RCT) comparing the effectiveness and implementation of the Aging, Community and Health Research Unit-Community Partnership Program (ACHRU-CPP) to usual care in older adults with diabetes and MCC and their caregivers., Methods: We will conduct a cross-jurisdictional, multi-site implementation-effectiveness type II hybrid RCT. Eligibility criteria are: ≥65 years, diabetes diagnosis (Type 1 or 2) and at least one other chronic condition, and enrolled in a primary care or diabetes education program. Participants will be randomly assigned to the intervention (ACHRU-CPP) or control arm (1:1 ratio). The intervention arm consists of home/telephone visits, monthly group wellness sessions, multidisciplinary case conferences, and system navigation support. It will be delivered by registered nurses and registered dietitians/nutritionists from participating primary care or diabetes education programs and program coordinators from community-based organizations. The control arm consists of usual care provided by the primary care setting or diabetes education program. The primary outcome is the change from baseline to 6 months in mental functioning. Secondary outcomes will include, for example, the change from baseline to 6 months in physical functioning, diabetes self-management, depressive symptoms, and cost of use of healthcare services. Analysis of covariance (ANCOVA) models will be used to analyze all outcomes, with intention-to-treat analysis using multiple imputation to address missing data. Descriptive and qualitative data from older adults, caregivers and intervention teams will be used to examine intervention implementation, site-specific adaptations, and scalability potential., Discussion: An interprofessional intervention supporting self-management may be effective in improving health outcomes and client/caregiver experience and reducing service use and costs in this complex population. This pragmatic trial includes a scalability assessment which considers a range of effectiveness and implementation criteria to inform the future scale-up of the ACHRU-CPP., Trial Registration: Clinical Trials.gov Identifier NCT03664583 . Registration date: September 10, 2018., (© 2022. The Author(s).)

Objective: This study documents the adoption of telehealth by various types of primary healthcare (PHC) providers working in teaching PHC clinics in Quebec during the COVID-19 pandemic. It also identifies the perceived advantages and disadvantages of telehealth., Method: A cross-sectional study was conducted between May and August 2020. The e-survey was completed by 48/50 teaching primary care clinics representing 603/1,357 (44%) PHC providers., Results: Telephone use increased the most, becoming the principal virtual modality of consultation, during the pandemic. Video consultations increased, with variations by type of PHC provider: between 2% and 16% reported using it "sometimes." The main perceived advantages of telehealth were minimizing the patient's need to travel, improved efficiency and reduction in infection transmission risk. The main disadvantages were the lack of physical exam and difficulties connecting with some patients., Conclusion: The variation in telehealth adoption by type of PHC provider may inform strategies to maximize the potential of telehealth and help create guidelines for its use in more normal times., (Copyright © 2021 Longwoods Publishing.)

The success of risk-stratified approaches in improving population-based breast cancer screening programs depends in no small part on women's buy-in. Fear of genetic discrimination (GD) could be a potential barrier to genetic testing uptake as part of risk assessment. Thus, the objective of this study was twofold. First, to evaluate Canadian women's knowledge of the legislative context governing GD. Second, to assess their concerns about the possible use of breast cancer risk levels by insurance companies or employers. We use a cross-sectional survey of 4293 (age: 30-69) women, conducted in four Canadian provinces (Alberta, British Colombia, Ontario and Québec). Canadian women's knowledge of the regulatory framework for GD is relatively limited, with some gaps and misconceptions noted. About a third (34.7%) of the participants had a lot of concerns about the use of their health information by employers or insurers; another third had some concerns (31.9%), while 20% had no concerns. There is a need to further educate and inform the Canadian public about GD and the legal protections that exist to prevent it. Enhanced knowledge could facilitate the implementation and uptake of risk prediction informed by genetic factors, such as the risk-stratified approach to breast cancer screening that includes risk levels.

Early detection of breast cancer through screening reduces breast cancer mortality. The benefits of screening must also be considered within the context of potential harms (e.g., false positives, overdiagnosis). Furthermore, while breast cancer risk is highly variable within the population, most screening programs use age to determine eligibility. A risk-based approach is expected to improve the benefit-harm ratio of breast cancer screening programs. The PERSPECTIVE I&I (Personalized Risk Assessment for Prevention and Early Detection of Breast Cancer: Integration and Implementation) project seeks to improve personalized risk assessment to allow for a cost-effective, population-based approach to risk-based screening and determine best practices for implementation in Canada. This commentary describes the four inter-related activities that comprise the PERSPECTIVE I&I project. 1: Identification and validation of novel moderate to high-risk susceptibility genes. 2: Improvement, validation, and adaptation of a risk prediction web-tool for the Canadian context. 3: Development and piloting of a socio-ethical framework to support implementation of risk-based breast cancer screening. 4: Economic analysis to optimize the implementation of risk-based screening. Risk-based screening and prevention is expected to benefit all women, empowering them to work with their healthcare provider to make informed decisions about screening and prevention.

In recent years, cultural safety has been proposed as a transformative approach to health care allowing improved consideration of Indigenous patient needs, expectations, rights and identities. This community-based participatory study aimed to identify potential barriers and enablers to cultural safety in health care provided to Atikamekw living with diabetes in Québec, Canada. Based on a qualitative descriptive design, the study uses talking circles as a data collection strategy. Three talking circles were conducted with Atikamekw living with diabetes and caregivers, as well as with health professionals of the family medicine teaching clinic providing services to the community. Two team members performed deductive thematic analysis based on key dimensions of cultural safety. Results highlight four categories of barriers and enablers to cultural safety for Atikamekw living with diabetes, related to social determinants of health (including colonialism), health services organization, language and communication, as well as Atikamekw traditional practices and cultural perspectives of health. This study is one of the few that provides concrete suggestions to address key aspects of diabetes care in a culturally respectful way. Our findings indicate that potential enablers of cultural safety reside at different (from individual to structural) levels of change. Solutions in this matter will require strong political will and policy support to ensure intervention sustainability. PATIENT OR PUBLIC CONTRIBUTION: Partners and patients have been involved in identifying the need for this study, framing the research question, developing the data collection tools, recruiting participants and interpreting results., (© 2020 The Authors. Health Expectations published by John Wiley & Sons Ltd.)

Background: In Canada, 30%-60% of patients presenting to emergency departments are ambulatory. This category has been labeled as a source of emergency department overuse. Acting on the presumption that primary care practices and walk-in clinics offer equivalent care at a lower cost, governments have invested massively in improving access to these alternative settings in the hope that patients would present there instead when possible, thereby reducing the load on emergency departments. Data in support of this approach remain scarce and equivocal., Objective: The aim of this study is to compare the value of care received in emergency departments, walk-in clinics, and primary care practices by ambulatory patients with upper respiratory tract infection, sinusitis, otitis media, tonsillitis, pharyngitis, bronchitis, influenza-like illness, pneumonia, acute asthma, or acute exacerbation of chronic obstructive pulmonary disease., Methods: A multicenter prospective cohort study will be performed in Ontario and Québec. In phase 1, a time-driven activity-based costing method will be applied at each of the 15 study sites. This method uses time as a cost driver to allocate direct costs (eg, medication), consumable expenditures (eg, needles), overhead costs (eg, building maintenance), and physician charges to patient care. Thus, the cost of a care episode will be proportional to the time spent receiving the care. At the end of this phase, a list of care process costs will be generated and used to calculate the cost of each consultation during phase 2, in which a prospective cohort of patients will be monitored to compare the care received in each setting. Patients aged 18 years and older, ambulatory throughout the care episode, and discharged to home with one of the aforementioned targeted diagnoses will be considered. The estimated sample size is 1485 patients. The 3 types of care settings will be compared on the basis of primary outcomes in terms of the proportion of return visits to any site 3 and 7 days after the initial visit and the mean cost of care. The secondary outcomes measured will include scores on patient-reported outcome and experience measures and mean costs borne wholly by patients. We will use multilevel generalized linear models to compare the care settings and an overlap weights approach to adjust for confounding factors related to age, sex, gender, ethnicity, comorbidities, registration with a family physician, socioeconomic status, and severity of illness., Results: Phase 1 will begin in 2021 and phase 2, in 2023. The results will be available in 2025., Conclusions: The end point of our program will be for deciders, patients, and care providers to be able to determine the most appropriate care setting for the management of ambulatory emergency respiratory conditions, based on the quality and cost of care associated with each alternative., International Registered Report Identifier (irrid): PRR1-10.2196/25619., (©Simon Berthelot, Mylaine Breton, Jason Robert Guertin, Patrick Michel Archambault, Elyse Berger Pelletier, Danielle Blouin, Bjug Borgundvaag, Arnaud Duhoux, Laurie Harvey Labbé, Maude Laberge, Philippe Lachapelle, Lauren Lapointe-Shaw, Géraldine Layani, Gabrielle Lefebvre, Myriam Mallet, Deborah Matthews, Kerry McBrien, Shelley McLeod, Eric Mercier, Alexandre Messier, Lynne Moore, Judy Morris, Kathleen Morris, Howard Ovens, Paul Pageau, Jean-Sébastien Paquette, Jeffrey Perry, Michael Schull, Mathieu Simon, David Simonyan, Henry Thomas Stelfox, Denis Talbot, Samuel Vaillancourt. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 22.02.2021.)

Background: The scale-up of evidence-based innovations is required to reduce waste and inequities in health and social services (HSS). However, it often tends to be a top-down process initiated by policy makers, and the values of the intended beneficiaries are forgotten. Involving multiple stakeholders including patients and the public in the scaling-up process is thus essential but highly complex. We propose to identify relevant strategies for meaningfully and equitably involving patients and the public in the science and practice of scaling up in HSS., Methods: We will adapt our overall method from the RAND/UCLA Appropriateness Method. Following this, we will perform a two-prong study design (knowledge synthesis and Delphi study) grounded in an integrated knowledge translation approach. This approach involves extensive participation of a network of stakeholders interested in patient and public involvement (PPI) in scaling up and a multidisciplinary steering committee. We will conduct a systematic scoping review following the methodology recommended in the Joanna Briggs Institute Reviewers Manual. We will use the following eligibility criteria: (1) participants-any stakeholder involved in creating or testing a strategy for PPI; (2) intervention-any PPI strategy proposed for scaling-up initiatives; (3) comparator-no restriction; (4) outcomes: any process or outcome metrics related to PPI; and (5) setting-HSS. We will search electronic databases (e.g., Medline, Web of Science, Sociological Abstract) from inception onwards, hand search relevant websites, screen the reference lists of included records, and consult experts in the field. Two reviewers will independently select and extract eligible studies. We will summarize data quantitatively and qualitatively and report results using the PRISMA extension for Scoping Reviews (PRISMA-ScR) checklist. We will conduct an online Delphi survey to achieve consensus on the relevant strategies for PPI in scaling-up initiatives in HSS. Participants will include stakeholders from low-, middle-, and high-income countries. We anticipate that three rounds will allow an acceptable degree of agreement on research priorities., Discussion: Our findings will advance understanding of how to meaningfully and equitably involve patients and the public in scaling-up initiatives for sustainable HSS., Systematic Review Registration: We registered this protocol with the Open Science Framework on August 19, 2020 ( https://osf.io/zqpx7/ ).

Risk-stratified screening for breast cancer (BC) is increasingly considered as a promising approach. However, its implementation is challenging and needs to be acceptable to women. We examined Canadian women's attitudes towards, comfort level about, and willingness to take part in BC risk-stratified screening. We conducted an online survey in women aged 30 to 69 years in four Canadian provinces. In total, 4293 women completed the questionnaire (response rate of 63%). The majority of women (63.5% to 72.8%) expressed favorable attitudes towards BC risk-stratified screening. Most women reported that they would be comfortable providing personal and genetic information for BC risk assessment (61.5% to 67.4%) and showed a willingness to have their BC risk assessed if offered (74.8%). Most women (85.9%) would also accept an increase in screening frequency if they were at higher risk, but fewer (49.3%) would accept a reduction in screening frequency if they were at lower risk. There were few differences by province; however, outcomes varied by age, education level, marital status, income, perceived risk, history of BC, prior mammography, and history of genetic test for BC (all p ≤ 0.01). Risk-based BC screening using multifactorial risk assessment appears to be acceptable to most women. This suggests that the implementation of this approach is likely to be well-supported by Canadian women.

Background: Herd immunity or community immunity refers to the reduced risk of infection among susceptible individuals in a population through the presence and proximity of immune individuals. Recent studies suggest that improving the understanding of community immunity may increase intentions to get vaccinated., Objective: This study aims to design a web application about community immunity and optimize it based on users' cognitive and emotional responses., Methods: Our multidisciplinary team developed a web application about community immunity to communicate epidemiological evidence in a personalized way. In our application, people build their own community by creating an avatar representing themselves and 8 other avatars representing people around them, for example, their family or coworkers. The application integrates these avatars in a 2-min visualization showing how different parameters (eg, vaccine coverage, and contact within communities) influence community immunity. We predefined communication goals, created prototype visualizations, and tested four iterative versions of our visualization in a university-based human-computer interaction laboratory and community-based settings (a cafeteria, two shopping malls, and a public library). Data included psychophysiological measures (eye tracking, galvanic skin response, facial emotion recognition, and electroencephalogram) to assess participants' cognitive and affective responses to the visualization and verbal feedback to assess their interpretations of the visualization's content and messaging., Results: Among 110 participants across all four cycles, 68 (61.8%) were women and 38 (34.5%) were men (4/110, 3.6%; not reported), with a mean age of 38 (SD 17) years. More than half (65/110, 59.0%) of participants reported having a university-level education. Iterative changes across the cycles included adding the ability for users to create their own avatars, specific signals about who was represented by the different avatars, using color and movement to indicate protection or lack of protection from infectious disease, and changes to terminology to ensure clarity for people with varying educational backgrounds. Overall, we observed 3 generalizable findings. First, visualization does indeed appear to be a promising medium for conveying what community immunity is and how it works. Second, by involving multiple users in an iterative design process, it is possible to create a short and simple visualization that clearly conveys a complex topic. Finally, evaluating users' emotional responses during the design process, in addition to their cognitive responses, offers insights that help inform the final design of an intervention., Conclusions: Visualization with personalized avatars may help people understand their individual roles in population health. Our app showed promise as a method of communicating the relationship between individual behavior and community health. The next steps will include assessing the effects of the application on risk perception, knowledge, and vaccination intentions in a randomized controlled trial. This study offers a potential road map for designing health communication materials for complex topics such as community immunity., (©Hina Hakim, Julie A Bettinger, Christine T Chambers, S Michelle Driedger, Eve Dubé, Teresa Gavaruzzi, Anik M C Giguere, Éric Kavanagh, Julie Leask, Shannon E MacDonald, Rita Orji, Elizabeth Parent, Jean-Sébastien Paquette, Jacynthe Roberge, Beate Sander, Aaron M Scherer, Martin Tremblay-Breault, Kumanan Wilson, Daniel Reinharz, Holly O Witteman. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 30.10.2020.)

Human immunodeficiency virus type 1 (HIV-1) carries virus-encoded and host-derived proteins. Recent advances in the functional characterization of host molecules inserted into mature virus particles have revealed that HIV-1 biology is influenced by the acquisition of host cell membrane components. The CD28/B7 receptor/ligand system is considered one of the fundamental elements of the normal immune response. Two major cell types that harbor HIV-1 in vivo, i.e., monocytes/macrophages and CD4+ T cells, express the costimulatory molecules CD80 (B7.1) and CD86 (B7.2). We investigated whether CD80 and CD86 are efficiently acquired by HIV-1, and if so, whether these host-encoded molecules can contribute to the virus life cycle. Here we provide the first evidence that the insertion of CD80 and CD86 into HIV-1 increases virus infectivity by facilitating the attachment and entry process due to interactions with their two natural ligands, CD28 and CTLA-4. Moreover, we demonstrate that NF-kappaB is induced by CD80- and CD86-bearing virions when they are combined with the engagement of the T-cell receptor/CD3 complex, an event that is inhibited upon surface expression of CTLA-4. Finally, both CD80 and CD86 were found to be efficiently incorporated into R5- and X4-tropic field strains of HIV-1 expanded in cytokine-treated macrophages. Thus, besides direct interactions between the virus envelope glycoproteins and cell surface constituents, such as CD4 and some specific chemokine coreceptors, HIV-1 may attach to target cells via interactions between cell-derived molecules incorporated into virions and their natural ligands. These findings support the theory that HIV-1-associated host proteins alter virus-host dynamics.

The isolation of human bronchial epithelial (HBEC) and fibroblastic cells (HBFC) from biopsies of asthmatic and non-asthmatic volunteers provided unique cellular materials to be used for the production of bioengineered bronchial equivalents (BE) in vitro. The HBEC are grown on a mesenchymal layer seeded with HBFC and the BE can be maintained for at least 15 days in culture. Under the BE culture conditions established previously, HBEC undergo differentiation into ciliated and goblet cells, within a pseudostratified organization comparable to human bronchi. We published previously the results from histologic and functional analyses of such BE produced exclusively using non-asthmatic HBEC and HBFC. We report here the comparative analyses of BE produced with non-asthmatic and asthmatic living HBEC and HBFC (naBE and aBE, respectively). Our data indicated that all asthmatic HBEC populations grown on a mesenchymal layer, containing non-asthmatic HBFC, slowly reached a confluent state but then detached from the matrix upon culture time. These BE appear to be very good models to study the mechanisms involved in asthma in vitro.

We have reported morphological and functional features of cells isolated from human bronchial biopsies. Both epithelial and fibroblastic cells were isolated from the same biopsies using collagenase. A few models have been established to study normal bronchial response to various agents and to understand the mechanisms responsible for some disorders, such as asthma. We produced three-dimensional bronchial equivalents in culture, using human epithelial and fibroblastic cells. We previously showed that peripheral anchorage can prevent the dramatic collagen contraction in gels seeded with fibroblasts when properly adapted to the size and type of cultured tissues. Our bilayered bronchial constructs were anchored and cultured under submerged conditions and at the air-liquid interface. Three culture media were compared. Serum-free medium supplemented with retinoic acid (5 x 10(-8) M) was found to be the best for maintenance of bronchial cell properties in the reconstructed bronchial tissue. Immunohistological and ultrastructural analyses showed that these equivalents present good structural organization, allowing ciliogenesis to occur in culture. Moreover, human bronchial goblet cells could differentiate and secrete mucus with culture time. Laminin, a major constituent of the basement membrane and basal cells, was also detected at the mesenchymoepithelial interface. Such models will be useful for studying human bronchial properties in vitro.

The immunosuppressive macrolide rapamycin is used in humans to prevent graft rejection. This drug acts by selectively repressing the translation of proteins that are encoded by an mRNA bearing a 5'-polypyrimidine tract (e.g., ribosomal proteins, elongation factors). The human immunodeficiency virus type 1 (HIV-1) carries a polypyrimidine motif that is located within the tat exon 2. Treatment of human T lymphoid cells with rapamycin resulted in a marked diminution of HIV-1 transcription when infection was performed with luciferase reporter T-tropic and macrophage-tropic viruses. Replication of fully infectious HIV-1 particles was abolished by rapamycin treatment. The rapamycin-mediated inhibitory effect on HIV-1 production was reversed by FK506. The anti-HIV-1 effect of rapamycin was also seen in primary human cells (i.e., peripheral blood lymphocytes) from different healthy donors. Rapamycin was shown to diminish basal HIV-1 long terminal repeat gene expression, and the observed effect of rapamycin on HIV-1 replication seems to be independent of the virus-specific transactivating Tat protein. A constitutive beta-actin promoter-based reporter gene vector was unaffected by rapamycin treatment. Kinetic virus infection studies and exposure to reporter viruses pseudotyped with heterologous envelope proteins (i.e., amphotropic murine leukemia virus and vesicular stomatitis virus G) suggested that rapamycin is primarily affecting the life cycle of HIV-1 at a transcriptional level. Northern blot analysis confirmed that this compound is selectively targeting HIV-1 mRNA synthesis.

Using virions harvested from 293T cells stably expressing either low or high levels of surface ICAM-1, we determined that the number of virus-embedded host ICAM-1 proteins is positively influenced by the expression level of ICAM-1 on virus producer cells. Moreover, the increase in virion-bound host cell membrane ICAM-1 led to a concomitant enhancement of virus infectivity when a T-cell-tropic strain of human immunodeficiency virus type 1 (HIV-1) was used. The phenomenon was also seen when primary human cells were infected with virions pseudotyped with the envelope protein from a macrophage-tropic HIV-1 isolate, thus ruling out any envelope-specific effect. We also observed that target cells treated with NKI-L16, an anti-LFA-1 antibody known to increase the affinity of LFA-1 for ICAM-1, were markedly more susceptible to infection with HIV-1 particles bearing on their surfaces large numbers of host-derived ICAM-1 proteins. Given that cellular activation of leukocytes is known to modify the conformational state of LFA-1 and induce ICAM-1 surface expression, it is tempting to speculate that activation of virus-infected cells will lead to the production of HIV-1 particles bearing more host ICAM-1 on their surfaces and that such progeny virions will preferentially infect and replicate more efficiently in activated cells which are prevalent in lymphoid organs.