Rosacea in Older Adults and Pharmacologic Treatments.

Rosacea is a chronic inflammatory skin condition that is often more severe in older patients. The main clinical features are erythema, telangiectasia, and inflammatory lesions of the face. The pathogenesis of this condition is not fully understood but certainly multifaceted. Immune and inflammatory dysregulation, genetics, neurogenic dysregulation, microbiome dysbiosis, and systemic disease have all been implicated in rosacea pathogenesis. As we better understand the various pathways that lead to rosacea, we acknowledge that the different symptoms may have unique underlying triggers and mechanisms. Aging also impacts rosacea diagnosis and treatment. Older adults have more severe rosacea symptoms while also having more sensitive and fragile skin than younger patients; therefore, rosacea treatments for older patients require a balance between delivering adequate potency while also minimizing skin irritation and other adverse effects. Until recently, rosacea diagnoses were based on concrete subtypes that did not necessarily capture each patient's manifestation of rosacea. There is now an emphasis on more personalized phenotype-based diagnoses and treatments, which allows for more emphasis on treating individual symptoms and accounting for the unique characteristics of older patients. Centrofacial erythema is best treated with brimonidine and oxymetazoline, while phymatous change and telangiectasia are best treated with surgery and laser ablation. Treatment for rosacea papules and pustules ranges from topicals, such as azelaic acid, ivermectin, metronidazole, minocycline, and encapsulated benzoyl peroxide, to systemics, such as doxycycline and isotretinoin. It is important to understand these treatments in relation to adverse effects and drug interactions that may specifically arise in older populations to provide optimal care. As we advance in understanding rosacea's pathogenesis and adopt personalized phenotype-based approaches, optimizing care for older patients becomes crucial. Continued research into novel treatments is essential to address their unique needs.

Disruption of G-quadruplex dynamicity by BRCA2 abrogation instigates phase separation and break-induced replication at telomeres.

Dynamic interaction between BRCA2 and telomeric G-quadruplexes (G4) is crucial for maintaining telomere replication homeostasis. Cells lacking BRCA2 display telomeric damage with a subset of these cells bypassing senescence to initiate break-induced replication (BIR) for telomere synthesis. Here we show that the abnormal stabilization of telomeric G4 following BRCA2 depletion leads to telomeric repeat-containing RNA (TERRA)-R-loop accumulation, triggering liquid-liquid phase separation (LLPS) and the assembly of Alternative Lengthening of Telomeres (ALT)-associated promyelocytic leukemia (PML) bodies (APBs). Disruption of R-loops abolishes LLPS and impairs telomere synthesis. Artificial engineering of telomeric LLPS restores telomere synthesis, underscoring the critical role of LLPS in ALT. TERRA-R-loops also recruit Polycomb Repressive Complex 2 (PRC2), leading to tri-methylation of Lys27 on histone H3 (H3K27me3) at telomeres. Half of paraffin-embedded tissue sections from human breast cancers exhibit APBs and telomere length heterogeneity, suggesting that BRCA2 mutations can predispose individuals to ALT-type tumorigenesis. Overall, BRCA2 abrogation disrupts the dynamicity of telomeric G4, producing TERRA-R-loops, finally leading to the assembly of telomeric liquid condensates crucial for ALT. We propose that modulating the dynamicity of telomeric G4 and targeting TERRA-R-loops in telomeric LLPS maintenance may represent effective therapeutic strategies for treating ALT-like cancers with APBs, including those with BRCA2 disruptions.

Health Service Utilization of Black Immigrant Women Residing in the United States: A Systematic Review.

Black immigrants constitute a rapidly growing population group in the U.S. A comprehensive understanding of health services used by Black immigrant women is necessary to support the complex needs of this population. We conducted a systematic review to (1) understand the types of health services used by Black immigrant women living in the U.S. and (2) examine barriers and motivators to using health services. Relevant studies were identified in the following databases: PubMed, PsychInfo, CINAHL, and Embase. Articles published until October 2022 were included in the review. From a total of 15,245 records, 47 articles that reported on health service utilization practices of Black immigrant women were included in the review. A variety of different health services were accessed by Black immigrant women, such as hepatitis screening, reproductive health services, cancer screenings, substance abuse treatment, mental health services, HIV services, dental services, genetic testing, cardiovascular risk testing, and general health services/ hospitalizations. Motivators for using health services included possession of health insurance, knowledge of health resources and conditions, and positive experiences with providers. Barriers to using health services included challenges navigating the health system, language barriers, and cultural beliefs. Factors that positively influence health service utilization must be expanded at the institutional, societal, and policy levels to improve access to health services for Black immigrant women.

Addressing Suicide Risk Among Immigrant Women Survivors of Intimate Partner Violence.

Intimate partner violence (IPV) is a significant public health problem contributing to multiple morbidities. Immigrant women who experience IPV may be disproportionately vulnerable to poor mental health outcomes, including self-harm and suicidal ideation, due to cultural experiences and contextual factors that prevent them from accessing services. While existing studies identify the risks for suicidal ideation amongst survivors of IPV, there is limited knowledge on how to tailor strategies to support immigrant women survivors of IPV who experience suicidal ideation. This study was conducted as part of the formative phase of a longitudinal research project designed to develop and evaluate a safety planning intervention for immigrant women survivors of IPV. Using qualitative in-depth interviews, we explored the perspectives of immigrant women survivors of IPV (n = 46) from various countries of origin, ages, and educational backgrounds on effective strategies for supporting immigrant women who disclose suicidal ideation. Study participants discussed various strategies for supporting survivors including building trust, providing encouragement, strengthening social support networks, and reminding survivors of parental responsibilities. Participants also pointed to the importance of the following services: domestic violence support, faith-based health resources, supportive immigration programs, mental health support, and emergency and medical treatment. These findings are informative for researchers and practitioners who work with immigrant women survivors of IPV, and they can be used to develop appropriate safety protocols and support strategies for survivors who are experiencing or have previously experienced suicidal ideation to mitigate the risk of self-harm.

Sedation Research in Critically Ill Pediatric Patients: Proposals for Future Study Design From the Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research IV Workshop.

OBJECTIVES: Sedation and analgesia for infants and children requiring mechanical ventilation in the PICU is uniquely challenging due to the wide spectrum of ages, developmental stages, and pathophysiological processes encountered. Studies evaluating the safety and efficacy of sedative and analgesic management in pediatric patients have used heterogeneous methodologies. The Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research (SCEPTER) IV hosted a series of multidisciplinary meetings to establish consensus statements for future clinical study design and implementation as a guide for investigators studying PICU sedation and analgesia. DESIGN: Twenty-five key elements framed as consensus statements were developed in five domains: study design, enrollment, protocol, outcomes and measurement instruments, and future directions. SETTING: A virtual meeting was held on March 2-3, 2022, followed by an in-person meeting in Washington, DC, on June 15-16, 2022. Subsequent iterative online meetings were held to achieve consensus. SUBJECTS: Fifty-one multidisciplinary, international participants from academia, industry, the U.S. Food and Drug Administration, and family members of PICU patients attended the virtual and in-person meetings. Participants were invited based on their background and experience. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Common themes throughout the SCEPTER IV consensus statements included using coordinated multidisciplinary and interprofessional teams to ensure culturally appropriate study design and diverse patient enrollment, obtaining input from PICU survivors and their families, engaging community members, and using developmentally appropriate and validated instruments for assessments of sedation, pain, iatrogenic withdrawal, and ICU delirium. CONCLUSIONS: These SCEPTER IV consensus statements are comprehensive and may assist investigators in the design, enrollment, implementation, and dissemination of studies involving sedation and analgesia of PICU patients requiring mechanical ventilation. Implementation may strengthen the rigor and reproducibility of research studies on PICU sedation and analgesia and facilitate the synthesis of evidence across studies to improve the safety and quality of care for PICU patients.

A decade of progress in juvenile idiopathic athritis treatments and outcomes in Canada: results from ReACCh-Out and the CAPRI registry.

OBJECTIVE: To assess changes in juvenile idiopathic arthritis (JIA) treatments and outcomes in Canada, comparing a 2005-2010 and a 2017-2021 inception cohorts. METHODS: Patients enrolled within three months of diagnosis in the Research in Arthritis in Canadian Children Emphasizing Outcomes (ReACCh-Out) and the Canadian Alliance of Pediatric Rheumatology Investigators Registry (CAPRI) cohorts were included. Cumulative incidences of drug starts and outcome attainment within 70 weeks of diagnosis were compared with Kaplan Meier survival analysis and multivariable Cox regression. RESULTS: The 2005-2010 and 2017-2021 cohorts included 1128 and 721 patients, respectively. JIA category distribution and baseline clinical juvenile idiopathic arthritis disease activity (cJADAS10) scores at enrolment were comparable. By 70 weeks, 6% of patients (95% CI 5, 7) in the 2005-2010 and 26% (23, 30) in the 2017-2021 cohort had started a biologic DMARD (bDMARD), and 43% (40, 47) and 60% (56, 64) had started a conventional DMARD (cDMARD), respectively. Outcome attainment was 64% (61, 67) and 83% (80, 86) for Inactive disease (Wallace criteria), 69% (66, 72) and 84% (81, 87) for minimally active disease (cJADAS10 criteria), 57% (54, 61) and 63% (59, 68) for pain control (<1/10), and 52% (47, 56) and 54% (48, 60) for a good health-related quality of life. CONCLUSION: Although baseline disease characteristics were comparable in the 2005-2010 and 2017-2021 cohorts, cDMARD and bDMARD use increased with a concurrent increase in minimally active and inactive disease. Improvements in parent and patient reported outcomes were smaller than improvements in disease activity.

A content and quality analysis of free, popular mHealth apps supporting 'plant-based' diets.

There has been an increased emphasis on plant-based foods and diets. Although mobile technology has the potential to be a convenient and innovative tool to help consumers adhere to dietary guidelines, little is known about the content and quality of free, popular mobile health (mHealth) plant-based diet apps. The objective of the study was to assess the content and quality of free, popular mHealth apps supporting plant-based diets for Canadians. Free mHealth apps with high user ratings, a high number of user ratings, available on both Apple App and GooglePlay stores, and primarily marketed to help users follow plant-based diet were included. Using pre-defined search terms, Apple App and GooglePlay App stores were searched on December 22, 2020; the top 100 returns for each search term were screened for eligibility. Included apps were downloaded and assessed for quality by three dietitians/nutrition research assistants using the Mobile App Rating Scale (MARS) and the App Quality Evaluation (AQEL) scale. Of the 998 apps screened, 16 apps (mean user ratings±SEM: 4.6±0.1) met the eligibility criteria, comprising 10 recipe managers and meal planners, 2 food scanners, 2 community builders, 1 restaurant identifier, and 1 sustainability assessor. All included apps targeted the general population and focused on changing behaviors using education (15 apps), skills training (9 apps), and/or goal setting (4 apps). Although MARS (scale: 1-5) revealed overall adequate app quality scores (3.8±0.1), domain-specific assessments revealed high functionality (4.0±0.1) and aesthetic (4.0±0.2), but low credibility scores (2.4±0.1). The AQEL (scale: 0-10) revealed overall low score in support of knowledge acquisition (4.5±0.4) and adequate scores in other nutrition-focused domains (6.1-7.6). Despite a variety of free plant-based apps available with different focuses to help Canadians follow plant-based diets, our findings suggest a need for increased credibility and additional resources to complement the low support of knowledge acquisition among currently available plant-based apps. This research received no specific grant from any funding agency.

Safety and Health Care Use Following COVID-19 Vaccination Among Adults With Rheumatoid Arthritis: A Population-Based Self-Controlled Case Series Analysis.

OBJECTIVE: To determine if coronavirus disease 2019 (COVID-19) vaccines were associated with adverse events of special interest (AESIs) and healthcare use among adults with rheumatoid arthritis (RA). METHODS: Among adults with RA who received at least 1 COVID-19 vaccine, a self-controlled case series (SCCS) analysis was conducted to evaluate relative incidence (RI) rates of AESIs (Bell palsy, idiopathic thrombocytopenia, acute disseminated encephalomyelitis, pericarditis/myocarditis, Guillain-Barré syndrome, transverse myelitis, myocardial infarction, anaphylaxis, stroke, deep vein thrombosis, pulmonary embolism, narcolepsy, appendicitis, and disseminated intravascular coagulation) in any 21-day period following vaccination compared to control periods. Secondary outcomes included emergency department (ED) visits, hospitalizations, and rheumatology visits. A matched non-RA comparator group was created and a separate SCCS analysis was conducted. RI ratios (RIRs) were used to compare RA and non-RA groups. RESULTS: Among 123,466 patients with RA and 493,864 comparators, the majority received mRNA vaccines. For patients with RA, relative to control periods, AESIs were not increased. ED visits increased after dose 2 (RI 1.06, 95% CI 1.03-1.10) and decreased after dose 3 (RI 0.93, 95% CI 0.89-0.96). Hospitalizations were lower after the first (RI 0.83, 95% CI 0.78-0.88), second (RI 0.86, 95% CI 0.81-0.92), and third (RI 0.89, 95% CI 0.83-0.95) doses. Rheumatology visits increased after dose 1 (RI 1.08, 95% CI 1.07-1.10), and decreased after doses 2 and 3. Relative to comparators, patients with RA had a higher AESI risk after dose 3 (RIR 1.28, 95% CI 1.05-1.56). Patients with RA experienced fewer ED visits (RIR 0.73, 95% CI 0.58-0.90) and hospitalizations (RIR 0.52, 95% CI 0.36-0.75) after dose 4. CONCLUSION: COVID-19 vaccines in patients with RA were not associated with an increase in AESI risk or healthcare use after every dose.

Choosing Wisely: The Canadian Rheumatology Association Pediatric Committee's List of Items Physicians and Patients Should Question.

OBJECTIVE: To develop a list of tests or treatments frequently used in pediatric rheumatology practice that may be unnecessary based on existing evidence. METHODS: A Choosing Wisely (CW) working group composed of 16 pediatric rheumatologists, 1 allied health professional, 1 parent, and 1 patient used the Delphi method to generate, rank, and refine a list of tests and treatments that may be unnecessary or harmful. The items with the highest content agreement and perceived impact were presented in a survey to all Canadian Rheumatology Association (CRA) physicians who practice pediatric rheumatology. Respondents were asked to rate their agreement and impact, and to rank the items. Five items with the highest composite scores and 2 additional items selected by the CW working group were put forward for literature review. RESULTS: The initial Delphi procedure generated 80 items. After 3 rounds, the list was narrowed to 13 items. The survey was completed by 41/81 (51%) CRA pediatric members across Canada. Respondent characteristics were similar to those of the CRA pediatric membership for self-reported gender, geographical location, and career stage. The highest composite score items were antinuclear antibody testing, drug toxicity monitoring, HLA-B27 testing, rheumatoid factor/anticyclic citrullinated peptide testing, and Lyme serology testing. Two additional items (numerous or repeated intraarticular corticosteroid injections, and autoinflammatory diseases genetic testing) were also selected. Literature review was performed for these 7 highest priority items. CONCLUSION: We have identified areas for quality improvement in the evaluation and treatment of rheumatic diseases in Canadian children.

An Overview of Reviews to Inform Organization-Level Interventions to Address Burnout in Rheumatologists.

OBJECTIVE: To identify organization-directed strategies that could be implemented to prevent burnout among rheumatologists. METHODS: A search of English language articles published 2011 or later was conducted on Cochrane Database of Systematic Reviews, Embase, Medline, and PsycInfo on January 25, 2022. Included reviews had ≥ 1 primary studies with ≥ 10% of participants who were physicians, recorded burnout as an outcome, and described an organization-directed intervention to prevent burnout. Overlap of primary studies across reviews was assessed. The final review inclusion was determined by study quality, minimization of overlap, and maximization of intervention breadth. The A Measurement Tool to Assess Systematic Reviews (AMSTAR) 2 tool was used for quality assessment. Included studies and interventions were assessed by rheumatologists for their applicability to rheumatology. RESULTS: A total of 17 reviews, including 15 systematic reviews, 1 realist review, and 1 umbrella review were included. AMSTAR 2 quality ratings classified 5 systematic reviews as low quality, 1 as moderate, and 9 as critically low. There was significant heterogeneity between and within reviews. Six conducted a metaanalysis and 11 provided a qualitative summary of findings. The following intervention types were identified as having possible applicability to rheumatology: physician workflow and organizational strategies; peer support and formal communication training; leadership support; and addressing stress, mental health, and mindfulness. Across interventions, mindfulness had the highest quality of evidence to support its effectiveness. CONCLUSION: Although the quality of evidence for interventions to prevent burnout in physicians is low, promising strategies such as mindfulness have been identified.

The estimated dietary and health impact of implementing the recently approved 'high in' front-of-package nutrition symbol in Canada: a food substitution scenario modeling study.

Background: Front-of-pack labeling (FOPL) has been identified as a cost-effective policy to promote healthy food environments and to help consumers make healthier food choices. Consumer surveys report that after implementation of mandatory 'high in' FOPL symbols between 30 and 70% of consumers choose or were willing to choose products with fewer 'high in' symbols. Health Canada has recently published FOPL regulations that will require prepackaged food and beverages that meet or exceed thresholds for sodium, total sugars, or saturated fat to display a 'high in' FOPL nutrition symbol. Objectives: The aims were to estimate the potential (1) dietary impact of substituting foods with similar foods that would display at least one less 'high in' symbol, and (2) the number of diet-related noncommunicable disease (NCD) deaths that could be averted or delayed due to estimated dietary changes. Methods: Baseline and counterfactual intakes of sodium, total sugars, saturated fats, and energy were estimated among Canadian adults (n = 11,992) using both available days of 24 h-recall data from the 2015 Canadian Community Health Survey-Nutrition (CCHS). Similar foods to those reported in CCHS that would display at least one less 'high in' symbol (n = 239) were identified using a Canadian branded food composition database. Based on current FOPL consumer research, identified foods were substituted for 30, 50, and 70% of randomly selected CCHS-Nutrition adult participants and for all adult participants. Potential health impacts were estimated using the Preventable Risk Integrated ModEl. Results: Mean dietary reductions of between 73 and 259 mg/day of sodium, 2.0 and 6.9 g/day of total sugars, 0.2 and 0.5 g/day of saturated fats, and 14 and 46 kcal/day of energy were estimated. Between 2,148 (95% UI 1,913-2,386) and 7,047 (95% UI 6,249-7,886) of deaths due to diet-related NCDs, primarily from cardiovascular diseases (70%), could potentially be averted or delayed if Canadians choose products with fewer 'high in' symbols. Conclusion: Results suggest that FOPL could significantly reduce sodium and total sugar intakes among Canadian adults, the consequences of which could avert or delay an important number of diet-related NCD deaths. These findings provide relevant data to support the importance of the impending FOPL regulations.

Nutritional quality and price of plant-based dairy and meat analogs in the Canadian food supply system.

There has been an increased consumer interest and public health emphasis on plant-based protein foods, resulting in a rise in the availability of highly processed plant-based analogs. The objectives of this study were to assess the nutritional quality and the price of plant-based dairy and meat analogs compared to their respective animal-derived products and to examine the association between processing levels and the nutritional quality among these products. Using a branded food composition database, products in cheese, yogurt, milk, and meat categories were examined (n = 3231). Products were categorized as plant-based analogs versus animal-derived products using the ingredient list. Products were examined for their nutrient content, overall nutritional quality using the Food Standards Australia New Zealand nutrient profiling model, price, and processing levels using the NOVA classification. All plant-based analogs had lower protein and higher total carbohydrate, sugar, and fiber content compared to their respective animal-derived products. Compared to their respective animal-derived products, plant-based milk and meat analogs had lower energy, total fat, and saturated fat content; plant-based yogurt and meat analogs had lower sodium content; and all plant-based dairy analogs had lower calcium content. Plant-based cheese and yogurt analogs were more expensive than animal-based products; however, there was no significant difference among milk and meat products. There was no association between processing levels and overall nutritional quality among dairy and meat products. Plant-based analogs may be part of a healthy and affordable diet to reduce the intakes of nutrients of concern; however, additional compositional guidelines and/or labeling may be needed to highlight the differences in the levels of nutrients to encourage.

Examining the diet quality of Canadian adults and the alignment of Canadian front-of-pack labelling regulations with other front-of-pack labelling systems and dietary guidelines.

Introduction: Canada promulgated mandatory front-of-pack labelling (FOPL) regulations in 2022, requiring pre-packaged foods meeting and/or exceeding recommended thresholds for nutrients-of-concern (i.e., saturated fat, sodium, sugars) to display a "high-in" nutrition symbol. However, there is limited evidence on how Canadian FOPL (CAN-FOPL) regulations compare to other FOPL systems and dietary guidelines. Therefore, the objectives of the study were to examine the diet quality of Canadians using the CAN-FOPL dietary index system and its alignment with other FOPL systems and dietary guidelines. Methods: Nationally representative dietary data from the 2015 Canadian Community Health Survey-Nutrition survey (n = 13,495) was assigned dietary index scores that underpin CAN-FOPL, Diabetes Canada Clinical Practice (DCCP) Guidelines, Nutri-score, Dietary Approaches to Stop Hypertension (DASH) and Canada's Food Guide (Healthy Eating Food Index-2019 [HEFI-2019]). Diet quality was examined by assessing linear trends of nutrient intakes across quintile groups of CAN-FOPL dietary index scores. The alignment of CAN-FOPL dietary index system compared with other dietary index systems, with HEFI as the reference standard, was examined using Pearson's correlations and к statistics. Results: The mean [95% CI] dietary index scores (range: 0-100) for CAN-FOPL, DCCP, Nutri-score, DASH, and HEFI-2019 were 73.0 [72.8, 73.2], 64.2 [64.0, 64.3], 54.9 [54.7, 55.1], 51.7 [51.4, 51.9], and 54.3 [54.1, 54.6], respectively. Moving from the "least healthy" to the "most healthy" quintile in the CAN-FOPL dietary index system, intakes of protein, fiber, vitamin A, vitamin C, and potassium increased, while intakes of energy, saturated fat, total and free sugars, and sodium decreased. CAN-FOPL showed moderate association with DCCP (r = 0.545, p < 0.001), Nutri-score (r = 0.444, p < 0.001), and HEFI-2019 (r = 0.401, p < 0.001), but poor association with DASH (r = 0.242, p < 0.001). Slight to fair agreement was seen between quintile combinations of CAN-FOPL and all dietary index scores (к = 0.05-0.38). Discussion: Our findings show that CAN-FOPL rates the dietary quality of Canadian adults to be healthier than other systems. The disagreement between CAN-FOPL with other systems suggest a need to provide additional guidance to help Canadians select and consume 'healthier' options among foods that would not display a front-of-pack nutrition symbol.

Nutrient intakes and top food categories contributing to intakes of energy and nutrients-of-concern consumed by Canadian adults that would require a 'high-in' front-of-pack symbol according to Canadian labelling regulations.

Canada recently mandated front-of-pack (FOP) labelling regulations, where foods meeting and/or exceeding recommended thresholds for nutrients-of-concern (i.e., saturated fat, sodium, and sugars) must display a 'high-in' FOP nutrition symbol. However, there is limited research on the amounts and sources of foods consumed by Canadians that would require a FOP symbol. The objective was to examine the intakes of nutrients-of-concern from foods that would display a FOP symbol and to identify the top food categories contributing to intakes for each nutrient-of-concern. Using the first day 24-hour dietary recall from the nationally representative 2015 Canadian Community Health Survey-Nutrition (CCHS), Canadian adults' intakes of nutrients-of-concern from foods that would display a FOP symbol was examined. Foods were assigned to 1 of 62 categories to identify the top food categories contributing to intakes of energy and nutrient-of-concern that would display a FOP symbol for each nutrient-of-concern. Canadian adults (n = 13,495) consumed approximately 24% of total calories from foods that would display a FOP symbol. Foods that would display a FOP symbol for exceeding thresholds for nutrients-of-concern accounted for 16% of saturated fat, 30% of sodium, 25% of total sugar, and 39% of free sugar intakes among Canadian adults. The top food category contributing intakes of each nutrient-of-concern that would display a FOP symbol were nutrient-specific: Processed meat and meat substitutes for saturated fat; Breads for sodium; and Fruit juices & drinks for total and free sugars. Our findings show that Canadian FOP labelling regulations have the potential to influence the intakes of nutrients-of-concern for Canadian adults. Using the findings as baseline data, future studies are warranted to evaluate the impact of FOP labelling regulations.

Heterogeneity in Lowe Syndrome: Mutations Affecting the Phosphatase Domain of OCRL1 Differ in Impact on Enzymatic Activity and Severity of Cellular Phenotypes.

Lowe Syndrome (LS) is a condition due to mutations in the OCRL1 gene, characterized by congenital cataracts, intellectual disability, and kidney malfunction. Unfortunately, patients succumb to renal failure after adolescence. This study is centered in investigating the biochemical and phenotypic impact of patient's OCRL1 variants (OCRL1VAR). Specifically, we tested the hypothesis that some OCRL1VAR are stabilized in a non-functional conformation by focusing on missense mutations affecting the phosphatase domain, but not changing residues involved in binding/catalysis. The pathogenic and conformational characteristics of the selected variants were evaluated in silico and our results revealed some OCRL1VAR to be benign, while others are pathogenic. Then we proceeded to monitor the enzymatic activity and function in kidney cells of the different OCRL1VAR. Based on their enzymatic activity and presence/absence of phenotypes, the variants segregated into two categories that also correlated with the severity of the condition they induce. Overall, these two groups mapped to opposite sides of the phosphatase domain. In summary, our findings highlight that not every mutation affecting the catalytic domain impairs OCRL1's enzymatic activity. Importantly, data support the inactive-conformation hypothesis. Finally, our results contribute to establishing the molecular and structural basis for the observed heterogeneity in severity/symptomatology displayed by patients.

Estimating the dietary and health impact of implementing front-of-pack nutrition labeling in Canada: A macrosimulation modeling study.

Background: Front-of-pack labeling (FOPL) has been identified as a cost-effective policy to promote healthy diets. Health Canada has recently published FOPL regulations that will require food and beverages that meet or exceed set thresholds for sodium, sugars, or saturated fat to display a 'high in' symbol on the front of the package. Although a promising measure, its potential impact on dietary intakes and health have not yet been estimated in Canada. Objective: This study aims to estimate (1) the potential dietary impact of implementing a mandatory FOPL among Canadian adults; and (2) the number of diet-related non-communicable disease (NCD) deaths that could be averted or delayed due to these estimated dietary changes. Methods: Baseline and counterfactual usual intakes of sodium, total sugars, saturated fats, and calories were estimated among Canadian adults (n = 11,992) using both available days of 24 h recalls from the 2015 Canadian Community Health Survey-Nutrition. The National Cancer Institute method was used to estimate usual intakes, and adjusted for age, sex, misreporting status, weekend/weekday, and sequence of recall. Estimated counterfactual dietary intakes were modeled from reductions observed in experimental and observational studies that examined changes in sodium, sugars, saturated fat, and calorie content of food purchases in the presence of a 'high in' FOPL (four counterfactual scenarios). The Preventable Risk Integrated ModEl was used to estimate potential health impacts. Results: Estimated mean dietary reductions were between 31 and 212 mg/day of sodium, 2.3 and 8.7 g/day of total sugars, 0.8 and 3.7 g/day of saturated fats, and 16 and 59 kcal/day of calories. Between 2,183 (95% UI 2,008-2,361) and 8,907 (95% UI 8,095-9,667) deaths due to diet-related NCDs, mostly from cardiovascular diseases (~70%), could potentially be averted or delayed by implementing a 'high in' FOPL in Canada. This estimation represents between 2.4 and 9.6% of the total number of diet-related NCD deaths in Canada. Conclusion: Results suggest that implementing a FOPL could significantly reduce sodium, total sugar, and saturated fat intakes among Canadian adults and subsequently prevent or postpone a substantial number of diet-related NCD deaths in Canada. These results provide critical evidence to inform policy decisions related to implementing FOPL in Canada.