The Impact of Advance Care Planning on Healthcare Professionals' Well-being: A Systematic Review.

CONTEXT: Advance care planning (ACP) improves care for patients with chronic illnesses and reduces family stress. However, the impact of ACP interventions on healthcare professionals' well-being remains unknown. OBJECTIVE: To systematically review the literature evaluating the impact of ACP interventions on healthcare professionals' well-being. METHODS: We followed the Joanna Briggs Institute methodology for systematic reviews and registered the protocol in PROSPERO (CRD42022346354). We included primary studies in all languages that assessed the well-being of healthcare professionals in ACP interventions. We excluded any studies on ACP in psychiatric care and in palliative care that did not address goals of care. Searches were conducted on April 4, 2022, and March 6, 2023 in Embase, CINAHL, Web of Science, and PubMed. We used the Mixed Methods Appraisal Tool for quality analysis. We present results as a narrative synthesis because of their heterogeneity. RESULTS: We included 21 articles published in English between 1997 and 2021 with 17 published after 2019. All were conducted in high-income countries, and they involved a total of 1278 participants. Three reported an interprofessional intervention and two included patient partners. Studies had significant methodological flaws but most reported that ACP had a possible positive impact on healthcare professionals' well-being. CONCLUSION: This review is the first to explore the impact of ACP interventions on healthcare professionals' well-being. ACP interventions appear to have a positive impact, but high-quality studies are scarce. Further research is needed, particularly using more rigorous and systematic methods to implement interventions and report results.

Spontaneous Scaling of a Primary Care Innovation in Real-Life Conditions: Protocol for a Case Study.

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.

Engagement of Older Adults Receiving Home Care Services and Their Caregivers in Health Decisions in Partnership With Clinical Teams: Protocol for a Multimethod Study to Prioritize and Culturally Adapt Decision Aids for Home Care.

BACKGROUND: Older adults (people aged 65 years and older) face many difficult decisions. Patient decision aids (PtDAs) can help them and their families make informed value-congruent decisions. Some PtDAs have been developed for the home care context, but little is known about scaling them for use with older adults in a different culture. OBJECTIVE: This study aims to (1) assess the scalability of existing PtDAs for older adults in the home care context; (2) prioritize those that best match the decisional needs of older adults in home care; and (3) culturally adapt the prioritized PtDAs so they can be scaled successfully to the Quebec health care system. METHODS: This multimethod study includes 3 phases. All phases will be overseen by a steering committee of older adults, caregivers, health professionals, decision makers, community organization representatives, and researchers with the needed expertise. In phase 1, we will use the Innovation Scalability Self-administered Questionnaire, a validated scalability self-assessment tool, to assess the scalability of 33 PtDAs previously identified in a systematic review. Based on their scalability, their quality (based on the International Patient Decision Aids Standards), and the importance of the decision point, we will retain approximately a third of these. In phase 2, we will conduct a 2-round web-based Delphi to prioritize the PtDAs selected in phase 1. Using a snowball recruitment strategy, we aim to recruit 60 Delphi participants in the province of Quebec, including older adults, caregivers, health professionals, decision makers involved in home care services, and PtDA experts. In the first round, we will ask participants to rate the importance of several PtDA decision points according to various criteria such as prevalence and difficulty on a 5-point Likert scale (1=not important to 5=very important). Approximately 6 of the highest-rated PtDAs will be retained for presentation in the second round, and we will select up to 3 PtDAs judged as having the highest priority for cultural adaptation. In phase 3, using the Chenel framework and user-centered design methods, we will update and adapt the PtDAs to the Quebec health care system and integrate these PtDAs into an interprofessional shared decision-making training program for home care teams. The adapted PtDAs will respect the International Patient Decision Aids Standards criteria. RESULTS: This study was funded in March 2022 by the Canadian Institutes of Health Research. Data collection for the web-based Delphi began in October 2023. Results are expected to be published in May 2024. CONCLUSIONS: This project will provide relevant and culturally appropriate decision support tools for older adults making difficult decisions and their home care teams that will be ready for scaling across the province of Quebec. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/53150.

Development and Evaluation of Serious Illness Conversation Training for Interprofessional Primary Care Teams.

Background: Early advance care planning (ACP) conversations are essential to deliver patient-centered care. While primary care is an ideal setting to initiate ACP, such as Serious Illness Conversations (SICs), many barriers exist to implement such conversations in routine practice. An interprofessional team approach holds promises to address barriers. Objective: To develop and evaluate SIC training for interprofessional primary care teams (IP-SIC). Design: An existing SIC training was adapted for IP-SIC and then implemented and evaluated for acceptability and effectiveness. Setting/Context: Interprofessional teams in 15 primary care clinics in five US states. Measures: Acceptability of the IP-SIC training and participants' self-reported likelihood to engage in ACP after the training. Results: The 156 participants were a mix of physicians and advanced practice providers (APPs) (44%), nurses and social workers (31%), and others (25%). More than 90% of all participants rated the IP-SIC training positively. While nurse/social worker and other groups were less likely than physician and APP group to engage in ACP before training (4.4, 3.7, and 6.4 on a 1-10 scale, respectively), all groups showed significant increase in likelihood to engage in ACP after the IP-SIC training (8.5, 7.7, and 9.2, respectively). Both physician/APP and nurse/social worker groups showed significant increase in likelihood to use the SIC Guide after the IP-SIC training, whereas an increase in likelihood to use SIC Guide among other groups was not statistically significant. Conclusion: The new IP-SIC training was well accepted by interprofessional team members and effective to improve their likelihood to engage in ACP. Further research exploring how to facilitate collaboration among interprofessional team members to maximize opportunities for more and better ACP is warranted. ClinicalTrials.gov ID: NCT03577002.

Effectiveness of Shared Decision-making Training Programs for Health Care Professionals Using Reflexivity Strategies: Secondary Analysis of a Systematic Review.

BACKGROUND: Shared decision-making (SDM) leads to better health care processes through collaboration between health care professionals and patients. Training is recognized as a promising intervention to foster SDM by health care professionals. However, the most effective training type is still unclear. Reflexivity is an exercise that leads health care professionals to question their own values to better consider patient values and support patients while least influencing their decisions. Training that uses reflexivity strategies could motivate them to engage in SDM and be more open to diversity. OBJECTIVE: In this secondary analysis of a 2018 Cochrane review of interventions for improving SDM by health care professionals, we aimed to identify SDM training programs that included reflexivity strategies and were assessed as effective. In addition, we aimed to explore whether further factors can be associated with or enhance their effectiveness. METHODS: From the Cochrane review, we first extracted training programs targeting health care professionals. Second, we developed a grid to help identify training programs that used reflexivity strategies. Third, those identified were further categorized according to the type of strategy used. At each step, we identified the proportion of programs that were classified as effective by the Cochrane review (2018) so that we could compare their effectiveness. In addition, we wanted to see whether effectiveness was similar between programs using peer-to-peer group learning and those with an interprofessional orientation. Finally, the Cochrane review selected programs that were evaluated using patient-reported or observer-reported outcome measurements. We examined which of these measurements was most often used in effective training programs. RESULTS: Of the 31 training programs extracted, 24 (77%) were interactive, among which 10 (42%) were considered effective. Of these 31 programs, 7 (23%) were unidirectional, among which 1 (14%) was considered effective. Of the 24 interactive programs, 7 (29%) included reflexivity strategies. Of the 7 training programs with reflexivity strategies, 5 (71%) used a peer-to-peer group learning strategy, among which 3 (60%) were effective; the other 2 (29%) used a self-appraisal individual learning strategy, neither of which was effective. Of the 31 training programs extracted, 5 (16%) programs had an interprofessional orientation, among which 3 (60%) were effective; the remaining 26 (84%) of the 31 programs were without interprofessional orientation, among which 8 (31%) were effective. Finally, 12 (39%) of 31 programs used observer-based measurements, among which more than half (7/12, 58%) were effective. CONCLUSIONS: Our study is the first to evaluate the effectiveness of SDM training programs that include reflexivity strategies. Its conclusions open avenues for enriching future SDM training programs with reflexivity strategies. The grid developed to identify training programs that used reflexivity strategies, when further tested and validated, can guide future assessments of reflexivity components in SDM training.

Integration of sex and gender in a continuing professional development course on diabetes and depression: a mixed methods feasibility study.

OBJECTIVES: Assess the feasibility and impact of a continuous professional development (CPD) course on type 2 diabetes and depression on health professionals' intention to include sex and gender considerations in patient care. DESIGN AND SETTING: In collaboration with CPD organisations and patient-partners, we conducted a mixed-methods feasibility controlled trial with postintervention measures in three Canadian provinces. PARTICIPANTS: Of 178 eligible health professionals, 127 completed questionnaires and 67 participated in semistructured group discussions. INTERVENTION AND COMPARATOR: An interactive 1 hour CPD course, codesigned with patient-partners, on diabetes and depression that included sex and gender considerations (innovation) was compared with a similar course that did not include them (comparator). OUTCOMES: Feasibility of recruitment and retention of CPD organisations and patient-partners throughout the study; adherence to planned activities; health professionals' intention to include sex and gender considerations in patient care as measured by the CPD-Reaction questionnaire; and barriers and facilitators using the Theoretical Domains Framework. RESULTS: All recruited CPD organisations and patient-partners remained engaged throughout the study. All planned CPD courses occurred. Overall, 71% of eligible health professionals participated (63% under 44 years old; 79.5% women; 67.7% practising in French; 66.9% practising in Quebec; 78.8% in urban practice). After training, mean intention scores for the innovation (n=49) and control groups (n=78) were 5.65±0.19 and 5.19±0.15, respectively. Mean difference was -0.47 (CI -0.95 to 0.01; p=0.06). Adjusted for age, gender and practice settings, mean difference was -0.57 (CI -1.09 to -0.05; p=0.03). We identified eight theoretical domains related to barriers and six related to facilitators for providing sex-adapted and gender-adapted diabetes and depression care. CONCLUSIONS: CPD training on diabetes and depression that includes sex and gender considerations is feasible and, compared with CPD training that does not, may prompt health professionals to modify their care. Addressing identified barriers and facilitators could increase intention. TRIAL REGISTRATION NUMBER: NCT03928132 with ClinicalTrials.gov; Post-results.

Use of the CPD-REACTION Questionnaire to Evaluate Continuing Professional Development Activities for Health Professionals: Systematic Review.

BACKGROUND: Continuing professional development (CPD) is essential for physicians to maintain and enhance their knowledge, competence, skills, and performance. Web-based CPD plays an essential role. However, validated theory-informed measures of their impact are lacking. The CPD-REACTION questionnaire is a validated theory-informed tool that evaluates the impact of CPD activities on clinicians' behavioral intentions. OBJECTIVE: We aimed to review the use of the CPD-REACTION questionnaire, which measures the impact of CPD activities on health professionals' intentions to change clinical behavior. We examined CPD activity characteristics, ranges of intention, mean scores, score distributions, and psychometric properties. METHODS: We conducted a systematic review informed by the Cochrane review methodology. We searched 8 databases from January 1, 2014, to April 20, 2021. Gray literature was identified using Google Scholar and Research Gate. Eligibility criteria included all health care professionals, any study design, and participants' completion of the CPD-REACTION questionnaire either before, after, or before and after a CPD activity. Study selection, data extraction, and study quality evaluation were independently performed by 2 reviewers. We extracted data on characteristics of studies, the CPD activity (eg, targeted clinical behavior and format), and CPD-REACTION use. We used the Mixed Methods Appraisal Tool to evaluate the methodological quality of the studies. Data extracted were analyzed using descriptive statistics and the Student t test (2-tailed) for bivariate analysis. The results are presented as a narrative synthesis reported according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. RESULTS: Overall, 65 citations were eligible and referred to 52 primary studies. The number of primary studies reporting the use of CPD-REACTION has increased continuously since 2014 from 1 to 16 publications per year (2021). It is available in English, French, Spanish, and Dutch. Most of the studies were conducted in Canada (30/52, 58%). Furthermore, 40 different clinical behaviors were identified. The most common CPD format was e-learning (34/52, 65%). The original version of the CPD-REACTION questionnaire was used in 31 of 52 studies, and an adapted version in 18 of 52 studies. In addition, 31% (16/52) of the studies measured both the pre- and postintervention scores. In 22 studies, CPD providers were university-based. Most studies targeted interprofessional groups of health professionals (31/52, 60%). CONCLUSIONS: The use of CPD-REACTION has increased rapidly and across a wide range of clinical behaviors and formats, including a web-based format. Further research should investigate the most effective way to adapt the CPD-REACTION questionnaire to a variety of clinical behaviors and contexts. TRIAL REGISTRATION: PROSPERO CRD42018116492; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=116492.

Web-Based Training for Nurses on Using a Decision Aid to Support Shared Decision-making About Prenatal Screening: Parallel Controlled Trial.

BACKGROUND: Nurses play an important role in supporting pregnant women making decisions about prenatal screening for Down syndrome. We developed a web-based shared decision-making (SDM) training program for health professionals focusing on Down syndrome screening decisions. OBJECTIVE: In this study, we aim to assess the impact of an SDM training program on nurses' intention to use a decision aid with pregnant women deciding on prenatal screening for Down syndrome. METHODS: In this 2-arm, parallel controlled trial, French-speaking nurses working with pregnant women in the province of Quebec were recruited by a private survey firm. They were allocated by convenience either to the intervention group (web-based SDM course that included prenatal screening) or to the control group (web-based course focusing on prenatal screening alone, with no SDM content). The primary outcome was the intention to use a decision aid. Secondary outcomes were psychosocial variables of intention, knowledge, satisfaction, acceptability, perceived usefulness, and reaction to the pedagogical approach. All outcomes were self-assessed through web-based questionnaires, including the space for written comments. We used 2-tailed Student t test and Fisher exact test to compare continuous and categorical variables between groups, respectively. RESULTS: Of the 57 participants assessed for eligibility, 40 (70%) were allocated to the intervention (n=20) or control group (n=20) and 36 (n=18 in each) completed the courses. The mean age of the participants was 41 (SD 9) years. Most were women (39/40, 98%), White (38/40, 95%), clinical nurses (28/40, 70%), and had completed at least a bachelor's degree (30/40, 75%). After the intervention, the mean score of intention was 6.3 (SD 0.8; 95% CI 5.9-6.7) for the intervention group and 6.0 (SD 1.2; 95% CI 5.42-6.64) for the control group (scale 1-7). The differences in intention and other psychosocial variable scores between the groups were not statistically significant. Knowledge scores for SDM were significantly higher in the intervention group (79%, 95% CI 70-89 vs 64%, 95% CI 57-71; P=.009). The intervention was significantly more acceptable in the intervention group (4.6, 95% CI 4.4-4.8 vs 4.3, 95% CI 4.1-4.5; P=.02), and reaction to the pedagogical approach was also significantly more positive in the intervention group (4.7, 95% CI 4.5-4.8 vs 4.4, 95% CI 4.2-4.5; P=.02). There was no significant difference in overall satisfaction (or in perceived usefulness). Furthermore, 17 participants (9 in the intervention group and 8 in the control group) provided written comments on the intervention. CONCLUSIONS: This study focuses on web-based nursing education and its potential to support pregnant women's decision-making needs. It shows that nurses' intention to use a decision aid to enhance SDM in prenatal care is high, with or without training, but that their knowledge about SDM can be improved with web-based training. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/17878.

Strategies for involving patients and the public in scaling-up initiatives in health and social services: protocol for a scoping review and Delphi survey.

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/ ).

"They heard our voice!" patient engagement councils in community-based primary care practices: a participatory action research pilot study.

BACKGROUND: Patient engagement could improve the quality of primary care practices. However, we know little about effective patient engagement strategies. We aimed to assess the acceptability and feasibility of embedding advisory councils of clinicians, managers, patients and caregivers to conduct patient-oriented quality improvement projects in primary care practices. METHODS: Using a participatory action research approach, we conducted our study in two non-academic primary care practices in Quebec City (Canada). Patient-experts (patients trained in research) were involved in study design, council recruitment and meeting facilitation. Advisory councils were each to include patients and/or caregivers, clinicians and managers. Over six meetings, councils would identify quality improvement priorities and plan projects accordingly. We assessed acceptability and feasibility of the councils using non-participant observations, audio-recordings and self-administered questionnaires. We used descriptive analyses, triangulated qualitative data and performed inductive thematic analysis. RESULTS: Between December 2017 and June 2018, two advisory councils were formed, each with 11 patients (36% male, mean age 53.8 years), a nurse and a manager practising as a family physician (25% male, mean age 45 years). The six meetings per practice occurred within the study period with a mean of eight patients per meeting. Councils worked on two projects each: the first council on a new information leaflet about clinic organization and operation, and on communications about local public health programs; the second on methods to further engage patients in the practice, and on improving the appointment scheduling system. Median patient satisfaction was 8/10, and 66.7% perceived councils had an impact on practice operations. They considered involvement of a manager, facilitation by patient-experts, and the fostering of mutual respect as key to this impact. Clinicians and managers liked having patients as facilitators and the respect among members. Limiting factors were difficulty focusing on a single feasible project and time constraints. Managers in both practices were committed to pursuing the councils post-study. CONCLUSION: Our results indicated that embedding advisory councils of clinicians, managers, patients and caregivers to conduct patient-oriented quality improvement projects in primary care practices is both acceptable and feasible. Future research should assess its transferability to other clinical contexts.

How to engage patients in research and quality improvement in community-based primary care settings: protocol for a participatory action research pilot study.

PLAIN ENGLISH SUMMARY: Making primary care clinics more patient-centered is key to improving patients' experience of care. If patients themselves were engaged in helping define priorities and suggesting quality improvements in the clinic, care would respond better to their needs. However, patient engagement is a new phenomenon, particularly in community based primary care clinics. How to engage patients in quality improvement in these clinics, or what effect this might have, is not well known. The involvement of patients needs to be adapted to the way these clinics function. The aim of this study is to create and evaluate a new model of patient engagement for quality improvement in community based primary care clinics. Patients, primary care professionals and researchers will create advisory councils in two primary care clinics in Quebec City (Canada). In each clinic, the advisory council will include 12 patients or caregivers registered at the clinic, a clinician and a clinic manager. The advisory council will meet every 6 weeks for a total of six meetings. Two patient-experts will facilitate meetings. During meetings, members of the council will list their needs in order of importance. Then they will suggest improvements in line with these needs. We will study if our advisory council model is well adapted to community based primary care settings and meets participants' expectations. At the end of the study we will be able to offer guidance about engaging patients with health professionals in quality improvement in primary care clinics. ABSTRACT: Background Involvement of end-users, including patients, managers and clinicians, in identifying quality improvement and research priorities might improve the relevance of projects and increase their impact. Few patient engagement initiatives have taken place in community based primary care practices (CBPCPs) and best practices for engaging patients in such settings are not well defined. The aim of this pilot study is to develop and assess the feasibility of a new collaborative model of advisory council involving clinicians, managers, patients and caregivers in CBPCP to strengthen their capacity to conduct quality improvement and patient-oriented research projects. Methods We will conduct a participatory action research project in two non-academic CBPCPs in Quebec City (Canada). In each CBPCP, the advisory council will include 12 patients or caregivers, a clinician and a clinic manager. Patients or their caregivers will be identified by clinicians and contacted by patient-experts. They will be eligible if they are registered at the practice, motivated, and available to attend meetings. The council will meet every 6 weeks for a total of six meetings. Two patient-experts will guide council members to identify quality improvement priorities and patient-oriented research questions based on their experience in the clinic. They will then be supported to plan actions to target these priorities. Analysis of meetings will be based on feasibility criteria, notes by non-participant observers in log books, audio-recording of the meetings and questionnaires to evaluate council members' perceptions and the likelihood they would engage in such councils. Discussion The results of this study will  be a model of patient engagement and a discussion of factors to improve the model to fit the needs of primary care patients and professionals. This will lay the foundation for a sustainable structure for long-term patient engagement and contribute to the development of a patient-centered and quality-improvement culture in CBPCPs.

Environmental factors associated with familial or non-familial forms of Paget's disease of bone.

OBJECTIVES: The most frequent mutation linked to Paget's disease of bone (PDB), p.Pro392Leu within SQSTM1 gene, leads to phenotypic characteristics of PDB, but this mutation is seemingly insufficient to result in complete pagetic osteoclast phenotype, suggesting that possible environmental factors play a role in PDB pathogenesis. We performed an exploratory study to identify environmental factors potentially associated with familial or non-familial form of PDB in the French-Canadian population. METHODS: We investigated environmental factors through a questionnaire in 176 pagetic patients, including 86 patients with a familial form, and 147 healthy controls. All participants lived in the same geographic area, within a 120km radius of Quebec City. Associations between environmental factors and familial and non-familial forms of PDB were searched. RESULTS: In the multivariate model adjusted for intra-familial correlation, PDB was associated with wood fired heating in childhood and/or adolescence (OR=2.10; 95% CI 1.13-3.90, P=0.02). In the multivariate model without considering correlation for family relatedness, familial form of PDB was associated with residency near a mine (OR=11.70; 95% CI 2.92-46.80, P<0.01) and hunting (OR=2.92; 95% CI 1.14-7.47, P=0.03). Wood fired heating during childhood and/or adolescence (P=0.02) was associated with both familial and non-familial forms. CONCLUSIONS: In conclusion, PDB was significantly associated with wood fired heating in childhood and/or adolescence, regardless of the form of PDB, familial or not.

Development of a molecular test of Paget's disease of bone.

Depending on populations, 15 to 40% of patients have a familial form of Paget's disease of bone (PDB), which is transmitted in an autosomal-dominant mode of inheritance with incomplete penetrance. To date, only SQSTM1 gene mutations have been linked to the disease. Several single nucleotide polymorphisms (SNPs) have been associated with PDB in patient non-carriers of SQSTM1 mutations, but they have minor size effects. The current clinical practice guidelines still recommend to measure total serum alkaline phosphatase (sALP) for PDB screening. However, genetic or bone biomarkers alone may lack sensitivity to detect PDB. Thus, the objective of this study was to develop a molecular test of PDB, combining genetic and bone biomarkers, in order to detect PDB, which is frequently asymptomatic. We genotyped 35 SNPs previously associated with PDB in 305 patients, and 292 healthy controls. In addition, serum levels of 14 bone biomarkers were assayed in 51 patients and 151 healthy controls. Bivariate and multivariate logistic regression models with adjustment for age and sex were fitted to search for a combination of SNPs and/or bone biomarkers that could best detect PDB in patient non-carriers of SQSTM1 mutations. First, a combination of five genetic markers gave rise to the highest area under the ROC curve (AUC) with 95% confidence interval [95% CI] of 0.731 [0.688; 0.773], which allowed us to detect 81.5% of patients with PDB. Second, a combination of two bone biomarkers had an AUC of 0.822 [0.726; 0.918], and was present in 81.5% of patients with PDB. Then, the combination of the five genetic markers and the two bone biomarkers increased the AUC up to 0.892 [0.833; 0.951], and detected 88.5% of patients with PDB. These results suggested that an algorithm integrating first a screen for SQSTM1 gene mutations, followed by either a genetic markers combination or a combined genetic and biochemical markers test in patients non-carrier of any SQSTM1 mutation, may detect the PDB phenotype better than biomarkers already available in the clinical practice.

Detection of SQSTM1/P392L post-zygotic mutations in Paget's disease of bone.

Paget's disease of bone (PDB) is transmitted, in one-third of cases, in an autosomal dominant mode of inheritance with incomplete penetrance. The SQSTM1/P392L germinal mutation is the most common mutation associated with PDB. Given the focal nature of PDB, one team of investigators showed that SQSTM1/P392L somatic mutations could occur in pagetic bone lesions in the absence of germinal mutations detectable in the peripheral blood. The objectives of this study were to develop a reliable method to detect SQSTM1/P392L post-zygotic mutations, by optimizing a polymerase chain reaction (PCR)-clamping method reported to be effective in detecting post-zygotic mutations in peripheral blood from patients with fibrous dysplasia; and to evaluate the frequency of this post-zygotic mutation in PDB patients. We used a locked nucleic acid (LNA) specifically designed for the SQSTM1/P392L mutation, which blocks the wild-type allele amplification during the PCR. DNA from 376 pagetic patients and 297 controls, all without any SQSTM1/P392L germinal mutation, was analyzed. We found that 4.8 % of PDB patients and 1.4 % of controls were carriers of this post-zygotic mutation [p = 0.013, OR 3.68 (1.23; 11.00)]. PDB patient carriers of a post-zygotic mutation had a lower number of affected bones and Renier's index than patients carrying a germinal mutation, suggesting a lower disease extension. We also demonstrated that this post-zygotic mutation was restricted to the monocytic lineage. These results confirmed that LNA PCR clamping is effective for the detection of SQSTM1/P392L post-zygotic mutations, which may occur in patients with PDB.

Identification of rare genetic variants in novel loci associated with Paget's disease of bone.

In genome-wide association studies, single nucleotide polymorphisms located in five novel loci were associated with PDB. We aimed at identifying rare genetic variants of candidate genes located in these loci and search for genetic association with PDB in the French-Canadian population. Exons, promoter and exon-intron junctions from patients with familial PDB and healthy individuals were sequenced in candidate genes, located within novel loci associated with PDB in our population. Rare variant was defined by a minor allele frequency <0.05 or absent from dbSNP (NCBI). We sequenced seven genes in 1p13 locus, three genes in 7q33, three genes in 8q22, and five genes in 15q24 locus. We identified 126 rare variants in at least one patient with PDB of whom 55 were located in 1p13 locus, 32 in 7q33, 10 in 8q22 and 29 in 15q24 locus. We located 71 of these 126 rare variants in an intron, 30 in an exon and 9 in an untranslated region. 60 % of these variants were located in functionally relevant gene regions. Among the 12 missense rare variants in PDB, two (rs62620995 in TM7SF4; rs62641691 in CD276) were predicted to be damaging by in silico analysis tools. Rs62620995, which altered a conserved amino acid (p.Leu397Phe) in the TM7SF4 gene, encoding the DC-STAMP protein involved in osteoclastogenesis through RANK signaling pathway, was found to have a marginal association with PDB (p = 0.09). Rs35500845, located in the CTHRC1 gene, which encodes a regulator of collagen matrix deposition, was also associated with PDB in the French-Canadian population (p = 0.046).

Genetic association study of Dickkopf-1 and sclerostin genes with paget disease of bone.

Increased expression of DKK1 gene was reported in pagetic osteoblasts and stromal cells, and increased serum levels of DKK1 and SOST proteins were reported in patients with Paget disease of bone (PDB). This study aimed at identifying rare genetic variants of the DKK1 and SOST genes and at testing for genetic association with PDB in the French-Canadian population. Exons, promoters, and exon-intron junctions of these genes were sequenced in patients with PDB and healthy controls. An association study of Tag SNPs of both genes was also performed in 239 pagetic patients and 297 healthy individuals. Three rare variants were identified in this study, all located in the DKK1 gene: one variant in the second exon leading to alteration in a highly conserved amino acid (p.R120L), one in the 5'-untranslated region (-50 C/A), and one in a splice site of intron 1 (IVS1 184 T/C), although none of these rare variants were associated with PDB. A genetic association of a Tag SNP of the DKK1 gene was found: the G allele of rs1569198 was significantly decreased in patients in comparison to controls (42 vs. 49 %, uncorrected P = 0.03, OR = 0.77, 95 % CI 0.61-0.98). In conclusion, this study identified three rare genetic variants in DKK1 in the French-Canadian population. In addition, a weak genetic association of a common variant of DKK1, rs1569198, which is located on a predicted new acceptor site for splicing of this gene, was observed in PDB, whereas no rare variant or genetic association was found in the SOST gene.