Acute activation of SERCA with CDN1163 attenuates IgE-mediated mast cell activation through selective impairment of ROS and p38 signaling.

Mast cells are granulocytic immune sentinels present in vascularized tissues that drive chronic inflammatory mechanisms characteristic of allergic pathologies. IgE-mediated mast cell activation leads to a rapid mobilization of Ca2+ from intracellular stores, which is essential for the release of preformed mediators via degranulation and de novo synthesized proinflammatory cytokines and chemokines. Given its potent signaling capacity, the dynamics of Ca2+ localization are highly regulated by various pumps and channels controlling cytosolic Ca2+ concentrations. Among these is sarco/endoplasmic reticulum Ca2+ -ATPase (SERCA), which functions to maintain low cytosolic Ca2+ concentrations by actively transporting cytosolic Ca2+ ions into the endoplasmic reticulum. In this study, we characterized the role of SERCA in allergen-activated mast cells using IgE-sensitized bone marrow-derived mast cells (BMMCs) treated with the SERCA activating compound, CDN1163, and simultaneously stimulated with allergen through FcεRI under stem cell factor (SCF) potentiation. Acute treatment with CDN1163 was found to attenuate early phase mast cell degranulation along with reactive oxygen species (ROS) production. Additionally, treatment with CDN1163 significantly reduced secretion of IL-6, IL-13, and CCL3, suggesting a role for SERCA in the late phase mast cell response. The protective effects of SERCA activation via CDN1163 treatment on the early and late phase mast cell response may be driven by the selective suppression of p38 MAPK signaling. Together, these findings implicate SERCA as an important regulator of the mast cell response to allergen and suggest SERCA activity may offer therapeutic potential targeting allergic pathologies, warranting further investigation.

Tafazzin Modulates Allergen-Induced Mast Cell Inflammatory Mediator Secretion.

Allergic inflammatory diseases are a steadily growing health concern. Mast cells, a driving force behind allergic pathologies, modulate metabolic pathways to carry out various functions following IgE-FcεRI-mediated activation. Tafazzin (TAZ) is a cardiolipin transacylase that functions to remodel, and thereby mature, cardiolipin, which is important for efficient energy production through oxidative phosphorylation. In this study, we aimed to evaluate the contribution of TAZ in IgE-mediated mast cell activation. Fetal liver-derived mast cells (FLMCs) were differentiated from mice with a doxycycline (dox)-inducible TAZ short hairpin RNA (shRNA) cassette (TAZ shRNA+/+) and littermate wild-types (WTs). TAZ knockdown in FLMCs following dox treatment was confirmed by Western blotting (99.1% by day 5), whereas flow cytometry confirmed FLMC phenotype (c-kit+ FcεRI+) and retention of receptor expression post-dox. Five-day dox-treated WT and TAZ shRNA+/+ FLMCs were activated via allergen-bound IgE cross-linking of FcεRI under stem cell factor potentiation. With dox, and in response to allergen, TAZ shRNA+/+ FLMCs displayed a 25% reduction in oxygen consumption and a significant 31% reduction in mast cell degranulation compared with dox-treated WT FLMCs. Secretion of TNF, CCL1, and CCL2 were significantly reduced, with CCL9 also impaired. Notably, gene expression was not impaired for any inflammatory mediator measured. Functionally, this suggests that TAZ is a contributor to mast cell degranulation and inflammatory mediator secretion. Given unimpacted induced gene expression for mediators measured, we propose that TAZ reduction impairs mast cell exocytosis mechanisms. We thus identify a potential new contributor to immunometabolism that enhances our understanding of mast cell signaling metabolic pathway interactions during allergic inflammation.

Influential factors in patient uptake of influenza vaccination during pregnancy; a survey-based audit in a tertiary hospital setting.

AIM: The aim of this study was to determine the key influential factors for pregnant or recently pregnant women in deciding on influenza vaccination. METHOD: This study was conducted in a single tertiary hospital in New Zealand using an anonymous and voluntary patient survey. Ethnicity, age and stage of pregnancy along with self-reported data on factors that influenced the decision to vaccinate against influenza during pregnancy were recorded. RESULTS: We included 101 participants over the one-week study period, 76% of whom had received the influenza vaccination. The most commonly reported reason for vaccination was the desire for neonatal protection, the common reasons for not being vaccinated were not receiving information on vaccination or safety concerns. CONCLUSION: There are a variety of factors influencing women when deciding on antenatal influenza vaccination. Further studies are needed to expand on the findings of this small local study in order to be able to improve vaccination uptake through empathetic delivery of evidence-based recommendations.

Experimental manipulation of visual attention affects body size adaptation but not body dissatisfaction.

OBJECTIVE: Prolonged exposure to large/small bodies causes aftereffects in perceived body size. Outside the laboratory, individuals repeatedly exposed to small (large) bodies tend to over- (under-) estimate their size and exhibit increased (decreased) body dissatisfaction. Why, among individuals exposed to approximately equivalent distributions of body sizes, only some develop body size and shape misperception and/or body dissatisfaction is not yet fully understood. METHOD: We exposed 61 women to high and low adiposity bodies simultaneously, instructing half to attend to high, and half to low adiposity bodies. RESULTS: Participants in the high adiposity attention condition's perception of "normal" body size significantly increased in adiposity, and vice versa. DISCUSSION: This suggests that visual attention moderates body size aftereffects. Interventions encouraging visual attention to more realistic ranges of bodies may therefore reduce body misperception. No change in body dissatisfaction was found, suggesting that changes in the perceptual component (misperception) may not necessarily affect the attitudinal component (dissatisfaction) of body image distortion.

Developing a set of indicators to monitor quality in ambulatory diabetes care using a modified Delphi panel process.

OBJECTIVE: There is a large evidence to practice gap in diabetes care with limited performance assessments that capture the full spectrum of care delivery. Our study aimed to develop a set of ambulatory diabetes quality indicators across six domains (effectiveness, safety, patient-centered, timely, equitable and efficient) to provide a broad view of quality. DESIGN: A modified Delphi panel process was conducted. Phase I involved compiling a list of indicators through literature review and generation of patient and healthcare provider-derived indicators through interviews and surveys, respectively. Phase II involved panelists rating indicators using the Agency for Healthcare Research and Quality measure attributes on 9-point Likert scale, attending a face-to-face meeting followed by re-rating, and final ranking. SETTING: This study was conducted across five adult academic medical centers affiliated with the University of Toronto. PARTICIPANTS: A multi-disciplinary Delphi panel (n = 16) including patients was assembled. MAIN OUTCOME MEASURE: For indicator advancement for ranking, ≥75% of panelists' responses in the top tertile (between 7 and 9) with a median composite score of ≥7 was required. RESULTS: There were 202 indicators included in the Delphi panel process including 171 from a comprehensive literature review, 14 from patient interviews, and 17 from healthcare provider surveys. Following the first round, 40 indicators proceeded directly to ranking, while 162 indicators were re-rated and distilled down to 12 for ranking. In the final ranking round, the 52 indicators were reduced to 35 including 13 effective, 10 safe, 6 patient-centered, 1 equitable, 3 efficient and 2 timely indicators. CONCLUSION: Thirty-five selected indicators developed with broad stakeholder engagement can be used to monitor quality in diabetes care.

How to adapt existing evidence-based clinical practice guidelines: a case example with smoking cessation guidelines in Canada.

OBJECTIVE: To develop and encourage the adoption of clinical practice guidelines (CPGs) for smoking cessation in Canada by engaging stakeholders in the adaptation of existing high-quality CPGs using principles of the ADAPTE framework. METHODS: An independent expert body in guideline review conducted a review and identified six existing CPGs, which met a priori criteria for quality and potential applicability to the local context. Summary statements were extracted and assigned a grade of recommendation and level of evidence by a second expert panel. Regional knowledge exchange brokers recruited additional stakeholders to build a multidisciplinary network of over 800 clinicians, researchers and decision-makers from across Canada. This interprofessional network and other stakeholders were offered various opportunities to provide input on the guideline both online and in person. We actively encouraged end-user input into the development and adaptation of the guidelines to ensure applicability to various practice settings and to promote adoption. RESULTS: The final guideline contained 24 summary statements along with supporting clinical considerations, across six topic area sections. The guideline was adopted by various provincial/territorial and national government and non-governmental organisations. CONCLUSIONS: This method can be applied in other jurisdictions to adapt existing high-quality smoking cessation CPGs to the local context and to facilitate subsequent adoption by various stakeholders.

Quality indicators for the detection and management of chronic kidney disease in primary care in Canada derived from a modified Delphi panel approach.

BACKGROUND: The detection and management of chronic kidney disease lies within primary care; however, performance measures applicable in the Canadian context are lacking. We sought to develop a set of primary care quality indicators for chronic kidney disease in the Canadian setting and to assess the current state of the disease's detection and management in primary care. METHODS: We used a modified Delphi panel approach, involving 20 panel members from across Canada (10 family physicians, 7 nephrologists, 1 patient, 1 primary care nurse and 1 pharmacist). Indicators identified from peer-reviewed and grey literature sources were subjected to 3 rounds of voting to develop a set of quality indicators for the detection and management of chronic kidney disease in the primary care setting. The final indicators were applied to primary care electronic medical records in the Electronic Medical Record Administrative data Linked Database (EMRALD) to assess the current state of primary care detection and management of chronic kidney disease in Ontario. RESULTS: Seventeen indicators made up the final list, with 1 under the category Prevalence, Incidence and Mortality; 4 under Screening, Diagnosis and Risk Factors; 11 under Management; and 1 under Referral to a Specialist. In a sample of 139 993 adult patients not on dialysis, 6848 (4.9%) had stage 3 or higher chronic kidney disease, with the average age of patients being 76.1 years (standard deviation [SD] 11.0); 62.9% of patients were female. Diagnosis and screening for chronic kidney disease were poorly performed. Only 27.1% of patients with stage 3 or higher disease had their diagnosis documented in their cumulative patient profile. Albumin-creatinine ratio testing was only performed for 16.3% of patients with a low estimated glomerular filtration rate (eGFR) and for 28.5% of patients with risk factors for chronic kidney disease. Family physicians performed relatively better with the management of chronic kidney disease, with 90.4% of patients with stage 3 or higher disease having an eGFR performed in the previous 18 months and 83.1% having a blood pressure recorded in the previous 9 months. INTERPRETATION: We propose a set of measurable indicators to evaluate the quality of the management of chronic kidney disease in primary care. These indicators may be used to identify opportunities to improve current practice in Canada.

The impact of endothelin-1 genetic analysis and job strain on ambulatory blood pressure.

OBJECTIVE: An interaction between the endothelin-1 gene (EDN1), blood pressure (BP) and social determinants has been previously found. Using a well-characterized cohort of participants, the impact of associations between genetic factors and job strain on BP was evaluated. METHODS: A cross-sectional analysis of five polymorphisms covering the EDN1, of which 2 were previously reported to be associated with BP, was performed. Study subjects had previously completed a baseline evaluation including 24-h ambulatory BP monitoring and an assessment of job strain. This report presents the findings for 184 subjects who gave DNA samples for genetic analysis. One-way analysis of variance (ANOVA) was performed between each genetic marker and 24-h systolic blood pressure (SBP) and diastolic blood pressure (DBP), as well as two-way ANOVAs to test the interaction effect with job strain. RESULTS: Trends for relationships were observed between SBP and two polymorphisms: rs10478694 and rs5369. An interaction between job strain and those heterozygous for two polymorphisms showed higher SBP (P=.029 and .008) and a tendency for higher DBP. All findings were more significant when analyses were confined to the 139 Caucasian subjects. CONCLUSION: This is the first study to report an interaction between the EDN1 gene, job strain and BP, supporting previous evidence of a role of this gene in the interaction between environmental stress and ambulatory BP. Given the limited sample size, the results should be considered preliminary, and further studies are required.

Blood pressure 2 years after a chronic disease management intervention study.

OBJECTIVES: To follow blood pressure change over time in participants who had participated in a 1- year chronic disease management program focused on blood pressure reduction. The expectation was that blood pressure would return back to the baseline once the study was completed. STUDY DESIGN: Prospective, single-arm observational study. METHODS: Study participants were Status Indians living on-reserve with type 2 diabetes and persistent hypertension who had participated in the DREAM3 study. Blood pressure was measured with the BpTRU automated device every 6 months for 2 years. The primary endpoint was the change in systolic blood pressure over the follow-up period. RESULTS: Sixty of the original 96 participants agreed to participate in the follow-up. Mean blood pressure at the beginning of the follow-up was 130/76 (SD 18/12) mmHg. Mean blood pressure at the end of the follow-up period was 132/76 (17/9 SD) mmHg. Target blood pressure (<130/80 mmHg) was present in 53%. The 99% confidence limit around change of blood pressure over the 24 months of follow-up was +/-4.7 mmHg. CONCLUSIONS: Contrary to expectations, the participants maintained their blood pressure control and did not revert to baseline levels. Community awareness and engagement resulting from the chronic disease management program led to a sustainable improvement in the health parameters of the participants and the community that lasted beyond the duration of the 1-year DREAM3 project.

IMPPACT: Investigation of Medical Professionals and Patients Achieving Control Together.

OBJECTIVE: To determine whether home blood pressure monitoring (HBPM) led to physician-initiated medication titration and improved achievement of target BP levels compared with standard, office-based management. METHODS: Physicians were randomly assigned to a treatment group or a control group. Patients in the control group were monitored by their physician and were drug-adjusted according to the usual approach. In the treatment group, patients were given home BP monitors (UA-767P [A&D Medical/Lifesource, USA]), and drug dosing was adjusted according to HBPM readings and protocol. Long-acting diltiazem (240 mg/day) was added at baseline, which was adjusted as necessary (other medications were added if more than 360 mg/day of diltiazem was required). A final BP measurement was taken in the office after six weeks. RESULTS: Nineteen physicians were randomly assigned to the office BP monitoring group and 34 were assigned to the HBPM group. Of the 270 subjects recruited, 97 were in the office BP monitoring group and 173 were in the HBPM group. From baseline to the final visit, there was a statistically significant time by group interaction with lower BP in the HBPM group (P=0.034 for both systolic BP and diastolic BP). BP fell from 159/91+/-11/10 mmHg at baseline in the HBPM group to 138/80+/-13/8 mmHg on the final visit, and from 160/88+/-14/10 mmHg to 141/78+/-10/9 mmHg in the control group. CONCLUSIONS: BP was lowered significantly in both groups, and to a statistically greater degree in the HBPM group. The Hawthorne effect might have led to altered care by the physicians with improvement in BP control in both groups.