Cross-Sector Collaboration to Improve Access to Community Services for People Living With Diabetes: Contributions From Actor-Network Theory.

Diabetes is a global public health issue. The Public Health Agency of Canada published a Diabetes Framework 2022 which recommends collaborative work across sectors to mitigate the impact of diabetes on health and quality of life. Since 2020, the INMED-COMMUNITY pathway has been implemented in Laval, Québec developing collaboration between healthcare and community sectors through a participatory action research approach. The aim of this article is to gain a better understanding of the INMED-COMMUNITY pathway implementation process, based on the mobilization of network actor theory. Qualitative analysis of semi-structured interviews conducted from January to March 2023 with 12 participants from 3 different sectors (community, health system, research), were carried out using actor-network theory. The results explored the conditions for effective intersectoral collaboration in a participatory action research approach to implement the INMED-COMMUNITY pathway. These were: (1) contextualization of the project, (2) a consultation approach involving various stakeholders, (3) creation of new partnerships, (4) presence of a project coordinator, and (5) mobilization of stakeholders around a common definition of diabetes. Mediation supported by a project coordinator contributed to the implementation of an intersectoral collaborative health intervention, largely due to early identification of controversies.

Effects of miglustat therapy on neurological disorder and survival in early-infantile Niemann-Pick disease type C: a national French retrospective study.

BACKGROUND: Niemann-Pick disease type C (NP-C) is a rare neurovisceral lysosomal lipid storage disease characterized by progressive neurodegeneration and premature death. While miglustat can stabilize neurological manifestations in later onset forms of NP-C, its efficacy in the early-infantile neurological form has not been demonstrated. In this observational retrospective study, we compared long-term neurodevelopmental outcome and survival between an untreated and a treated group of early infantile NP-C patients. METHODS: Data available on all NP-C patients with early infantile neurological onset diagnosed in France between 1990 and 2013 were compiled. Patients with incomplete data or who had died from a systemic perinatal, rapidly fatal form were excluded. RESULTS: Ten patients were included in the treated group (year of birth: 2006-2012), and 16 patients in the untreated group [born 1987-2005 (n = 15), 2012 (n = 1)]. The median age at neurological onset was 9 months (5-18) in the treated group, and 12 months (3-18) in the untreated group (p = 0.22). Miglustat therapy was started at a median age of 24.5 months (9-29) and median duration was 30 months (11-56). Gastrointestinal adverse events were reported in 7/10 patients on miglustat. All patients developed loss of psychomotor acquisitions or additional neurological symptoms despite miglustat therapy. The ages of developmental milestones and neurological involvement did not significantly differ between the two groups. Four patients in the untreated group were lost to follow up. The 22 remaining patients had died by the end of the study and no patient survived beyond the age of 7.4 years. The median survival age was 4.42 years in the untreated group and 5.56 years in the treated group; the Kaplan-Meier survival curves were not significantly different (log-rank test: p = 0.11). CONCLUSIONS: Miglustat allowed no significant long-term neurodevelopmental improvement nor significant increase of survival in patients with early infantile NP-C.

Consensus clinical management guidelines for acid sphingomyelinase deficiency (Niemann-Pick disease types A, B and A/B).

BACKGROUND: Acid Sphingomyelinase Deficiency (ASMD) is a rare autosomal recessive disorder caused by mutations in the SMPD1 gene. This rarity contributes to misdiagnosis, delayed diagnosis and barriers to good care. There are no published national or international consensus guidelines for the diagnosis and management of patients with ASMD. For these reasons, we have developed clinical guidelines that defines standard of care for ASMD patients. METHODS: The information contained in these guidelines was obtained through a systematic literature review and the experiences of the authors in their care of patients with ASMD. We adopted the Appraisal of Guidelines for Research and Evaluation (AGREE II) system as method of choice for the guideline development process. RESULTS: The clinical spectrum of ASMD, although a continuum, varies substantially with subtypes ranging from a fatal infantile neurovisceral disorder to an adult-onset chronic visceral disease. We produced 39 conclusive statements and scored them according to level of evidence, strengths of recommendations and expert opinions. In addition, these guidelines have identified knowledge gaps that must be filled by future research. CONCLUSION: These guidelines can inform care providers, care funders, patients and their carers about best clinical practice and leads to a step change in the quality of care for patients with ASMD with or without enzyme replacement therapy (ERT).

Structuring and organizing interprofessional healthcare in partnership with patients with diabetes: the INterprofessional Management and Education in Diabetes care (INMED) pathway.

Type 2 diabetes is a complex chronic disease that requires ongoing monitoring by an interprofessional team to prevent complications. The INMED (INterprofessional Management and Education in Diabetes) care pathway was developed by our team to optimize primary care services for these patients and their families. The objective of this study is to describe the preliminary results of its adoption and implementation. The INMED care pathway is organized into four axes: (a) continuing professional education, (b) self-management support, (c) case management, and (d) ongoing evaluation of the quality of diabetes care and services. A multiple-case study is underway to document its effects on practice change using the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework. Preliminary results on the adoption and implementation revealed some strengths: (a) regular patient follow-up by the case manager, (b) scheduling of physician appointments when required, and (c) regular screening for risk factors. Barriers were also identified: (a) lack of clear understanding of the case manager role, (b) lack of referrals to team members, and (c) lack of use of the motivational interview approach. The INMED care pathway is being adopted by primary care teams but challenges need to be overcome to improve its reach and effectiveness.

A Retrospective Multicentric Study of 34 Patients with Niemann-Pick Type C Disease and Early Liver Involvement in France.

OBJECTIVE: To describe the clinical features and course of liver involvement in a cohort of patients with Niemann-Pick type C disease (NP-C), a severe lysosomal storage disorder. STUDY DESIGN: Patients with genetically confirmed NP-C (NPC1, n = 31; NPC2, n = 3) and liver involvement before age 6 months were retrospectively included. Clinical, laboratory test, and imaging data were collected until the last follow-up or death; available liver biopsy specimens were studied using anti-CD68 immunostaining. RESULTS: At initial evaluation (median age, 17 days of life), all patients had hepatomegaly, 33 had splenomegaly, and 30 had neonatal cholestasis. Portal hypertension and liver failure developed in 9 and 4 patients, respectively. Liver biopsy studies, performed in 16 patients, revealed significant fibrosis in all 16 and CD68+ storage cells in 15. Serum alpha-fetoprotein concentration measured in 21 patients was elevated in 17. Plasma oxysterol concentrations were increased in the 16 patients tested. Four patients died within 6 months of life, including 3 from liver involvement. In patients who survived beyond age 6 months (median follow-up, 6.1 years), cholestasis regressed in all, and portal hypertension regressed in all but 1; 25 patients developed neurologic involvement, which was fatal in 16 patients. CONCLUSIONS: Liver involvement in NP-C consisted of transient neonatal cholestasis with hepatosplenomegaly, was associated with liver fibrosis, and was responsible for death in 9% of patients. The combination of liver anti-CD68 immunostaining, serum alpha-fetoprotein measurement, and studies of plasma biomarkers should facilitate early identification of NP-C.

Implementation of targeted deprescribing of potentially inappropriate medications in patients on hemodialysis.

PURPOSE: Patients on hemodialysis have a high risk of medication-related problems. Studies using deprescribing algorithms to reduce the number of inappropriate medications in this population have been published, but none have used a patient-partnership approach. Our study evaluated the impact of a similar intervention with a patient-partnership approach. METHODS: The objective was to describe the implementation of a pharmacist-led intervention with a patient-partnership approach using deprescribing algorithms and its impact on the reduction of inappropriate medications in patients on hemodialysis. Eight algorithms were developed by pharmacists and nephrologists to assess the appropriateness of medications. Pharmacists identified patients taking targeted medications. Following patient enrollment, pharmacists assessed medications with patients and applied the algorithms. With patient consent, deprescription was suggested to nephrologists if applicable. Specific data on each targeted medication were collected at 4 and 16 weeks. Descriptive statistics were used to examine the effects of the deprescribing intervention. RESULTS: Of 270 patients, 256 were taking at least one targeted medication. Of the 122 patients taking at least one targeted medication who were approached to participate, 66 were included in the study. At enrollment, these patients were taking 252 targeted medications, of which 59 (23.4%) were determined to be inappropriate. Deprescription was initiated for 35 of these 59 medications (59.3%). At 4 weeks, 33 of the 59 medications (55.9%) were still deprescribed, while, at 16 weeks, 27 of the 59 medications (45.8%) were still deprescribed. Proton pump inhibitors and benzodiazepines or Z-drugs were the most common inappropriate medications, and allopurinol was the most deprescribed medication. CONCLUSION: A pharmacist-led intervention with a patient-partnership approach and using deprescribing algorithms reduced the number of inappropriate medications in patients on hemodialysis.

Clinical disease characteristics of patients with Niemann-Pick Disease Type C: findings from the International Niemann-Pick Disease Registry (INPDR).

BACKGROUND: Niemann-Pick Disease Type C (NPC) is an autosomal recessive rare disease characterised by progressive neurovisceral manifestations. The collection of on-going large-scale NPC clinical data may generate better understandings of the natural history of the disease. Here we report NPC patient data from the International Niemann-Pick Disease Registry (INPDR). METHOD: The INPDR is a web-based, patient-led independent registry for the collection of prospective and retrospective clinical data from Niemann-Pick Disease patients. Baseline data from NPC patients enrolled into the INPDR from September 2014 to December 2019 was extracted to analyse the demographic, genetic and clinical features of the disease. RESULTS: A total of 203 NPC patients from six European countries were included in this study. The mean age (SD) at diagnosis was 11.2 years (14.2). Among enrolled patients, 168 had known neurological manifestations: 43 (24.2%) had early-infantile onset, 47 (26.4%) had late-infantile onset, 41 (23.0%) had juvenile onset, and 37 (20.8%) had adult onset. 10 (5.6%) patients had the neonatal rapidly fatal systemic form. Among the 97 patients with identified NPC1 variants, the most common variant was the c. 3182T > C variant responsible for the p.lle1061Thr protein change, reported in 35.1% (N = 34) of patients. The frequencies of hepatomegaly and neonatal jaundice were greatest in patients with early-infantile and late-infantile neurological onset. Splenomegaly was the most commonly reported observation, including 80% of adult-onset patients. The most commonly reported neurological manifestations were cognitive impairment (78.5%), dysarthria (75.9%), ataxia (75.9%), vertical supranuclear gaze palsy (70.9%) and dysphagia (69.6%). A 6-domain composite disability scale was used to calculate the overall disability score for each neurological form. Across all with neurological onset, the majority of patients showed moderate to severe impairments in all domains, except for 'swallowing' and 'seizure'. The age at diagnosis and death increased with increased age of neurological symptom onset. Miglustat use was recorded in 62.4% of patients and the most common symptomatic therapies used by patients were antiepileptics (32.9%), antidepressants (11.8%) and antacids (9.4%). CONCLUSION: The proportion of participants at each age of neurological onset was relatively equal across the cohort. Neurological manifestations, such as ataxia, dysphagia, and dysarthria, were frequently observed across all age categories.

Pharmacists practising in family medicine groups: An evaluation 2 years after experiencing a virtual community of practice.

BACKGROUND: In 2018, a virtual community of practice (CoP) for pharmacists working in family medicine groups (FMGs) in Quebec province was developed. The aim of this CoP-called Réseau Québécois des Pharmaciens GMF (RQP GMF)-was to foster best practices by supporting FMG pharmacists. This study assesses the processes and outcomes of this CoP 2 years after its creation. METHODS: We performed a cross-sectional web-based study from March to May 2020. All FMG pharmacists who were registered as members of the RQP GMF (n = 326) were sent an invitation via a newsletter. The link to the questionnaire was also publicized in the CoP Facebook group. The questionnaire comprised a 38-item validated instrument assessing 8 dimensions of the CoP. A descriptive analysis was performed. RESULTS: A total of 112 FMG pharmacists (34.4%) completed the questionnaire. Respondents agreed that the RQP GMF was a joint enterprise (mean score, 4.18/5), that members shared their knowledge (mean score, 3.94/5) and engaged mutually (mean score, 3.50/5) and that the RQP GMF provided support (mean score, 3.92/5) and capacity building (mean score, 4.01/5). In general, they were satisfied with the implementation process (mean score, 3.68/5) and with activities proposed (mean score, 3.79/5). A lower proportion of respondents agreed that their participation in the RQP GMF generated external impacts, which led to a smaller mean score (3.37/5) for this dimension. CONCLUSION: The RQP GMF, one of the first communities of practice for pharmacists practising in family medicine groups, attained most of the objectives initially intended by the CoP. These results will facilitate the adaptation of processes and activities to better fulfil members' needs. Can Pharm J (Ott) 2021;154:xx-xx.

Prevalence of Cancer in Acid Sphingomyelinase Deficiency.

Acid sphingomyelinase deficiency (ASMD) is an inherited lysosomal disease characterised by a diffuse accumulation of sphingomyelin that cannot be catabolised into ceramide and phosphocholine. We studied the incidence of cancer in ASMD patients. We retrospectively reviewed the medical records of the adult chronic visceral ASMD patients in our cohort. Thirty-one patients (12 females, 19 males) were included with a median age of 48.7 y. (IQ: 30.3-55.1). Five cancers were observed in 1 female (breast cancer) and 4 males (two lung cancers, one thyroid cancer and one bladder cancer), resulting in a prevalence of 16.1%. The existence of cancer was associated with a more severe ASMD characterised by a larger spleen (25 cm (22.5-25) vs. 18 cm (17-20); p = 0.042); lower diffusing capacity of the lung for carbon monoxide (DLCO; 29.5 % (17.8-43.0) vs. 58.5 % (49.8-69.5%); p = 0.01) and tobacco use (100% vs. 45%; p = 0.04). Three patients died, all from cancer (p = 0.002). The prevalence of cancer appeared to be strikingly elevated in our cohort of patients, without any specificity in the type of cancer. Systematic screening for cancer should be performed, and carcinogenic substances such as tobacco should be avoided in patients with ASMD.

Prospective study of the natural history of chronic acid sphingomyelinase deficiency in children and adults: eleven years of observation.

BACKGROUND: Acid sphingomyelinase deficiency (ASMD) (also known as Niemann-Pick disease types A and B) is a rare and debilitating lysosomal storage disorder. This prospective, multi-center, multinational longitudinal study aimed to characterize the clinical features of chronic forms of ASMD and disease burden over time in children and adults. RESULTS: Fifty-nine patients (31 males/28 females) ranging in age from 7 to 64 years with chronic ASMD types A/B and B and at least two disease symptoms participated from 5 countries. Disease characteristics were assessed at baseline, after 1 year, and at the final visit (ranging from 4.5 to 11 years). Thirty patients (51%) were < 18 years at baseline (median age 12 years), and 29 were adults (median age 32 years). Overall, 32/59 patients completed the final visit, 9 died, 9 discontinued, and 9 were lost to follow up. Common clinical characteristics that tended to worsen gradually with time were splenomegaly, hepatomegaly, interstitial lung disease, lung diffusion capacity (DLCO), and dyslipidemia. Spleen volumes ranged from 4 to 29 multiples of normal at baseline, and splenomegaly was moderate or severe in 86%, 83%, and 90% of individuals at baseline, year 1, and final visits, respectively. The proportion of all individuals with interstitial lung disease was 66% (39/59) at baseline and 78% (25/32) at the final visit, while median % predicted DLCO decreased by > 10% from baseline to the final visit. Nine patients died (15%), eight of causes related to ASMD (most commonly pneumonia); of these eight patients, five (63%) had symptom onset at or before age 2. Overall, six of the nine deaths occurred before age 50 with three occurring before age 20. Individuals with either severe splenomegaly or prior splenectomy were ten times more likely to have died during the follow-up period than those with smaller or intact spleens (odds ratio 10.29, 95% CI 1.7, 62.7). Most children had growth deficits that persisted into adulthood. CONCLUSIONS: This study provides important information about the natural history of chronic ASMD and provides a longitudinal view of the spectrum of disease manifestations and major morbidities in children and adults and supports the selection of clinically meaningful endpoints in therapeutic trials.

How interprofessional teams of students mobilized collaborative practice competencies and the patient partnership approach in a hybrid IPE course.

To develop collaborative competencies of future health and social services professionals, the Université de Montréal (UdeM) offers interprofessional education (IPE) in partnership with patients. To meet the challenges of IPE, UdeM turned to digital tools to enable interprofessional teams of students to collaborate online and face-to-face. The collaborative flipped classroom for IPE with patient partnership is the conceptual framework for the pedagogical method used for this study. It is based on: 1) a competency framework and 2) collaborative learning concept and dimensions. The study aimed to: 1) demonstrate how interprofessional teams of students mobilize framework competencies and care approaches during online and face-to-face collaborative learning activities; and 2) analyze how students collaborate during a hybrid IPE course using a patient partnership approach. Using a qualitative methodology, the contents of the online collaborative journals (OCJs) of 12 interprofessional student teams were analyzed, along with the individual comments (n = 994) of IPE course learners collected through the Interprofessional Team Collaboration questionnaire (n = 321). The results suggest that the course under study enabled teams to collaborate online and face-to-face throughout the term, and indicate that students were better prepared to adopt a patient partnership approach.

Issues with deprescribing in haemodialysis: a qualitative study of patient and provider experiences.

RATIONALE, AIMS AND OBJECTIVES: Patients undergoing haemodialysis receive on average 10-17 medications, which increase the risk of falls, adverse drug reactions and hospitalizations. Supervised discontinuation of potentially inappropriate medications may lower these risks. Although many calls have been made for deprescribing in the haemodialysis setting, little is known about how patients and providers in this setting experience it. The aim of this study is to explore patient and provider experiences and perceptions of one of the rare deprescribing intervention in haemodialysis. METHODS: Ten semi-structured interviews were held with patients, and a focus group was done with dialysis clinic team members at a Montreal area health network's haemodialysis clinic after the implementation of a standardized deprescribing intervention using the patient-as-partner approach. The interviews and focus group were recorded, and verbatims were coded to determine emerging themes. Grounded theory was used for interview guide design and data analysis. RESULTS: The three emerging themes were (1) ambivalence towards medication creating a favourable context for deprescribing, (2) the empowering elements of the deprescribing process and (3) the uncertain future of deprescribing in the clinics even though the intervention was considered successful. CONCLUSION: Haemodialysis patients and providers viewed deprescribing favourably, believed the intervention was valuable, and offered suggestions for long term implementation while expressing concerns about feasibility. Notwithstanding the underlying uncertainties, a structured and integrated approach in routine practice involving all members of the care team may facilitate the continuity of deprescribing as an intervention in the setting of a haemodialysis clinic.

Pharmaceutical practices before and throughout the opioid crisis: A scoping review.

METHODS: Opioid misuse has reached epidemic status in many countries. This crisis-recognized since 2014-questions the practices of prescribing and dispensing. Did this public health issue change pharmaceutical practices? This literature review presents pharmaceutical practices regarding treatment of noncancer pain. We will assess whether these practices changed after the declaration of the crisis. We will also present barriers and facilitators to their implementation in real life to understand the distance between them and current practices. A scoping review of the literature was conducted on PubMed, Medline, and Embase for references dealing with pharmaceutical practices regarding noncancer pain management, in French and English, from 2000 to 2018. RESULTS: The search yielded 250 results, with 25 studies surviving the exclusion process. Twenty studies took place in the United States, the country most affected by the crisis. Interventions took place as interprofessional collaboration (n = 14), patient counseling (6), or a combination of these (5). Although the nature of the interventions remained constant through the crisis, the number of publications greatly increased over time. The studies demonstrated pharmacists' upstream contributions regarding pain management and opioid use. Several large-scale implementation issues, including knowledge gaps and communication barriers, have been reported in these studies and in others that gathered opinions and perspectives of prescribers, pharmacists, and patients. CONCLUSION: Our review showed that the opioid crisis did not modify the nature of pharmaceutical practices regarding pain treatment and opioid management, but the number of studies reporting these practices greatly increased since its onset. Barriers to implementing the best practices to reduce opioid harm have been identified to explain slow integration in daily practice. Adjustments to teaching and practice methods such as a reviewed pain treatment curriculum, standardized tools, and decision-making algorithms could prove beneficial.

Treatment outcomes following continuous miglustat therapy in patients with Niemann-Pick disease Type C: a final report of the NPC Registry.

BACKGROUND: Niemann-Pick disease Type C (NP-C) is a rare, progressive neurodegenerative disorder characterized by progressive neurodegeneration and premature death. We report data at closure of the NPC Registry that describes the natural history, disease course and treatment experience of NP-C patients in a real-world setting. METHODS: The NPC Registry was a prospective observational cohort study that ran between September 2009 and October 2017. Patients with a confirmed diagnosis of NP-C were enrolled regardless of treatment status. All patients underwent clinical assessments and medical care as determined by their physicians; data were collected through a secure internet-based portal. RESULTS: At closure on October 19, 2017, 472 patients from 22 countries were enrolled in the NPC Registry. Mean (standard deviation) age at enrollment was 21.2 (15.0) years, and 51.9% of patients were male. First neurological symptom onset occurred during the early-infantile (< 2 years), late-infantile (2 to < 6 years), juvenile (6 to < 15 years), or adolescent/adult (≥ 15 years) periods in 13.5, 25.6, 31.8, and 29.1% of cases, respectively. The most frequent neurological manifestations prior to enrollment included ataxia (67.9%), vertical supranuclear gaze palsy (67.4%), dysarthria (64.7%), cognitive impairment (62.7%), dysphagia (49.1%), and dystonia (40.2%). During infancy, splenomegaly and hepatomegaly were frequent (n = 199/398 [50%] and n = 147/397 [37.0%], respectively) and persisted in most affected patients. Of the 472 enrolled patients, 241 were continuously treated with miglustat during the NPC Registry observation period, of whom 172 of these 241 patients were treated continuously for ≥12 months. A composite disability score that assesses impairment of ambulation, manipulation, language, and swallowing was highest in the early-infantile population and lowest in the adolescent/adult population. Among the continuous miglustat therapy population, 70.5% of patients had improved or had stable disease (at least 3 of the 4 domains having a decreased or unchanged score between enrollment and last follow-up). The NPC Registry did not identify any new safety signals associated with miglustat therapy. CONCLUSIONS: The profiles of clinical manifestations in the final NPC Registry dataset agreed with previous clinical descriptions. Miglustat therapy was associated with a stabilization of neurological manifestations in most patients. The safety and tolerability of miglustat therapy was consistent with previous reports.

Long-term survival outcomes of patients with Niemann-Pick disease type C receiving miglustat treatment: A large retrospective observational study.

Miglustat has been indicated for the treatment of Niemann-Pick disease type C (NP-C) since 2009. The aim of this observational study was to assess the effect of miglustat on long-term survival of patients with NP-C. Data for 789 patients from five large national cohorts and from the NPC Registry were collected and combined. Miglustat-treated and untreated patients overall and within sub-groups according to age-at-neurological-onset, that is, early infantile-onset (<2 years), late infantile-onset (2 to <6 years), juvenile-onset (6 to <15 years), and adolescent/adult-onset (≥15 years) were analysed and compared. Survival was analysed from the time of first neurological manifestation (Neurological onset group, comprising 669 patients) and from diagnosis (Diagnosis group, comprising 590 patients) using a Cox proportional hazard model adjusted for various covariates. Overall, 384 (57.4%) patients in the Neurological onset group and 329 (55.8%) in the Diagnosis group were treated with miglustat. Miglustat treatment was associated with a significant reduction in risk of mortality in both groups (entire Neurological onset group, Hazard ratio [HR] = 0.51; entire Diagnosis group, HR = 0.44; both P < .001). The effect was observed consistently in all age-at-neurological-onset sub-groups (HRs = 0.3 to 0.7) and was statistically significant for late infantile-onset patients in both groups (Neurological onset group, HR = 0.36, P < .05; Diagnosis group, HR = 0.32, P < .01), and juvenile-onset patients in the Diagnosis group only (HR = 0.30, P < .05). Despite the limitations of the data that urge cautious interpretation, the findings are consistent with a beneficial effect of miglustat on survival in patients with NP-C.

Transcript, protein, metabolite and cellular studies in skin fibroblasts demonstrate variable pathogenic impacts of NPC1 mutations.

BACKGROUND: Niemann-Pick type C (NP-C) is a rare neurovisceral genetic disorder caused by mutations in the NPC1 or the NPC2 gene. NPC1 is a multipass-transmembrane protein essential for egress of cholesterol from late endosomes/lysosomes. To evaluate impacts of NPC1 mutations, we examined fibroblast cultures from 26 NP-C1 patients with clinical phenotypes ranging from infantile to adult neurologic onset forms. The cells were tested with multiple assays including NPC1 mRNA expression levels and allele expression ratios, assessment of NPC1 promoter haplotypes, NPC1 protein levels, cellular cholesterol staining, localization of the mutant NPC1 proteins to lysosomes, and cholesterol/cholesteryl ester ratios. These results were correlated with phenotypes of the individual patients. RESULTS: Overall we identified 5 variant promoter haplotypes. Three of them showed reporter activity decreased down to 70% of the control sequence. None of the haplotypes were consistently associated with more severe clinical presentation of NP-C. Levels of transcripts carrying null NPC1 alleles were profoundly lower than levels of the missense variants. Low levels of the mutant NPC1 protein were identified in most samples. The protein localised to lysosomes in cultures expressing medium to normal NPC1 levels. Fibroblasts from patients with severe infantile phenotypes had higher cholesterol levels and higher cholesterol/cholesteryl ester ratios. On the contrary, cell lines from patients with juvenile and adolescent/adult phenotypes showed values comparable to controls. CONCLUSION: No single assay fully correlated with the disease severity. However, low residual levels of NPC1 protein and high cholesterol/cholesteryl ester ratios associated with severe disease. The results suggest not only low NPC1 expression due to non-sense mediated decay or low mutant protein stability, but also dysfunction of the stable mutant NPC1 as contributors to the intracellular lipid transport defect.

Pharmacists practising in family medicine groups: What are their activities and needs?

WHAT IS KNOWN AND OBJECTIVE: Pharmacists' responsibilities and practices have expanded over the years to be more clinical. Working in other settings and collaborating with other healthcare professionals can lead to new needs that are unmet by actual training. This study was performed to describe the characteristics and practices of pharmacists working in family medicine groups (FMGs) and to assess their needs to develop a practice-based network fostering best practices. METHODS: A Quebec province-wide cross-sectional study was performed from May to August 2018. Pharmacists practising in FMGs were identified through phone calls to all listed FMGs and via direct emails. All identified pharmacists were emailed an invitation to complete an online questionnaire comprising questions to assess their sociodemographic characteristics, to describe their FMG and to assess their needs to reach an optimal practice. The link to the questionnaire was also publicized in a Facebook group of FMG pharmacists and by several professional organizations. A descriptive analysis was performed and discussed with two committees: a working group of FMG pharmacists and an advisory committee comprising key stakeholders. RESULTS AND DISCUSSION: A total of 299 FMG pharmacists were identified, and 178 (59.5%) completed the online questionnaire. Most were women (71.9%), were less than 40 years old (71.9%) and also practised as community pharmacists (76.4%). Reviewing medication to optimize pharmacotherapy and answering questions related to specific issues were the most frequent activities, with 86.0% and 90.4% of pharmacists, respectively, reporting that they performed these often or very often. The most frequently mentioned needs were training and mentorship adapted to the FMG practice and improvement in the understanding that other healthcare professionals have about the role of the FMG pharmacist. Performing comprehensive medication assessments and developing thorough pharmaceutical care plans were among the clinical competencies that pharmacists wanted to develop. Scientific and interprofessional communication was also among the abilities they wished to optimize. WHAT IS NEW AND CONCLUSION: This study provided unique information about pharmacists practising in FMGs and elicited several needs. The results will inform the development of a practice-based network aimed at fulfilling these needs.

The Creation of a Practice-Based Network of Pharmacists Working in Family Medicine Groups (FMG).

A needs assessment study of pharmacists working in family medicine groups (FMG) demonstrated the necessity to build a practice-based network. This network would foster a faster integration into FMG and a more efficient collaborative practice. It would also take advantage of an existing practice-based research network (PBRN)-the STAT (Soutien Technologique pour l'Application et le Transfert des pratiques novatrices en pharmacie) network. A working group of nine FMG pharmacists from the different regions of the province of Quebec, Canada, and a committee of partners, including the key pharmacy organizations, were created. Between January 2018 and May 2019, nine meetings took place to discuss the needs assessment results and deploy an action plan. The practice-based network first year activities allowed identifying pharmacists working in FMGs across the province. A directory of these pharmacists was published on the STAT network. The vision, mission, mandate, name («Réseau Québécois des Pharmaciens GMF¼) and logo were developed. The first few activities include: Bi-monthly newsletters; a mentorship program; short evidence-based therapeutic letters (pharmacotherapeutic capsules) and a start-up kit to facilitate integration of these pharmacists. The Quebec FMG pharmacist practice-based network has been launched. It is planned to evaluate the members' satisfaction in late Spring 2020 with regards to activities and resources provided.

Psychiatric and neurological symptoms in patients with Niemann-Pick disease type C (NP-C): Findings from the International NPC Registry.

Objectives: Niemann-Pick disease type C (NP-C) is a rare inherited neurovisceral disease that should be recognised by psychiatrists as a possible underlying cause of psychiatric abnormalities. This study describes NP-C patients who had psychiatric manifestations at enrolment in the international NPC Registry, a unique multicentre, prospective, observational disease registry. Methods: Treating physicians' data entries describing psychiatric manifestations in NPC patients were coded and grouped by expert psychiatrists. Results: Out of 386 NP-C patients included in the registry as of October 2015, psychiatric abnormalities were reported to be present in 34% (94/280) of those with available data. Forty-four patients were confirmed to have identifiable psychiatric manifestations, with text describing these psychiatric manifestations. In these 44 patients, the median (range) age at onset of psychiatric manifestations was 17.9 years (2.5-67.9; n = 15), while the median (range) age at NP-C diagnosis was 23.7 years (0.2-69.8; n = 34). Almost all patients (43/44; 98%) had an occurrence of ≥1 neurological manifestation at enrolment. Conclusions: These data show that substantial delays in diagnosis of NP-C are long among patients with psychiatric symptoms and, moreover, patients presenting with psychiatric features and at least one of cognitive impairment, neurological manifestations, and/or visceral symptoms should be screened for NP-C.

Adult Niemann-Pick disease type C in France: clinical phenotypes and long-term miglustat treatment effect.

BACKGROUND: Niemann-Pick disease type C (NP-C) is a neurodegenerative lysosomal lipid storage disease caused by autosomal recessive mutations in the NPC1 or NPC2 genes. The clinical presentation and evolution of NP-C and the effect of miglustat treatment are described in the largest cohort of patients with adolescent/adult-onset NP-C studied to date. METHODS: Observational study based on clinical chart data from adult patients with NP-C (> 18 year old) diagnosed in France between 1990 and 2015. Retrospective data from patients at diagnosis, onset of miglustat therapy (if applicable), and last follow up were analysed. RESULTS: In France, patients with an adolescent-adult neurological form constituted approximately 25% of all NP-C cases diagnosed during the study period. Forty-seven patients (46 with NP-C1 and one with NP-C2; 53% female) were included. Mean ± SD (range) ages at neurological onset and diagnosis were 23.9 ± 12.5 (8-56) years and 34 ± 13.5 (15-65) years, respectively. At presentation, patients mainly had 1) impaired gait due to cerebellar ataxia and/or dystonia, 2) and/or cognitive/behavioural manifestations, 3) and/or psychotic signs. Initially, almost half of patients had only one of the above three neuro-psychiatric manifestations. Vertical supranuclear gaze palsy, usually occurring without patient complaint, was only detected on careful clinical examination and was recorded in most patients (93%) at the time of diagnosis, several years after neurological onset. Thirty-seven patients (79%) received miglustat, among whom seventeen (46%) continued beyond 2 years (at last follow up) to a maximum of 9.8 years. Eight patients (22%) discontinued treatment early due to side effects (n = 3) or perceived lack of efficacy (n = 5).Miglustat treatment duration correlated significantly with reduced neurological worsening (p < 0.001). Treatment for≥2 years was associated with improved patient survival (p = 0.029). Good responses to miglustat were associated with less severe neurological disability at the start of miglustat treatment (p = 0.02). CONCLUSION: The proportion of adolescent/adult-onset NP-C cases diagnosed in France increased 2.5-fold since 2009 compared with the 2000-2008 period due to improved awareness. Adolescent/adult-onset NP-C frequently presented initially with a non-specific isolated neuro-psychiatric manifestation (motor, cognitive or psychotic). Patients with less severe neurological disability responded better to miglustat therapy.