Contractile Effects of Semaglutide in the Human Atrium.

Semaglutide is a glucagon-like peptide 1 receptor (GLP-1R) agonist. GLP-1R agonists are used to treat type 2 diabetes and obesity. It is currently unknown whether semaglutide can directly increase force of contraction (FOC) in the human heart. We tested the hypothesis that semaglutide might increase the FOC in the isolated human atrium. To this end, we conducted contraction experiments in isolated human right atrial muscle preparations (HAP). HAP were obtained during open-heart surgery. We detected a concentration- and time-dependent positive inotropic effect (PIE) of semaglutide in HAP. These PIEs were accompanied by increases in the rates of tension development and tension relaxation and a reduction in muscle relaxation time. The PIE of semaglutide in HAP was attenuated by H89, an inhibitor of the cyclic AMP-dependent protein kinase and by ryanodine, an inhibitor of sarcoplasmic Ca2+ release. Semaglutide up to 100 nM failed to exert a PIE in isolated electrically paced (1 Hz) wild-type mouse left atrial preparations studied for comparison. Our data suggest that semaglutide can increase the FOC in the atria of patients at therapeutic drug concentrations.

NGF increases Connexin-43 expression and function in pulmonary arterial smooth muscle cells to induce pulmonary artery hyperreactivity.

AIMS: Pulmonary hypertension (PH) is characterised by an increase in pulmonary arterial pressure, ultimately leading to right ventricular failure and death. We have previously shown that nerve growth factor (NGF) plays a critical role in PH. Our objectives here were to determine whether NGF controls Connexin-43 (Cx43) expression and function in the pulmonary arterial smooth muscle, and whether this mechanism contributes to NGF-induced pulmonary artery hyperreactivity. METHODS AND RESULTS: NGF activates its TrkA receptor to increase Cx43 expression, phosphorylation, and localization at the plasma membrane in human pulmonary arterial smooth muscle cells, thus leading to enhanced activity of Cx43-dependent GAP junctions as shown by Lucifer Yellow dye assay transfer and fluorescence recovery after photobleaching -FRAP- experiments. Using both in vitro pharmacological and in vivo SiRNA approaches, we demonstrate that NGF-dependent increase in Cx43 expression and activity in the rat pulmonary circulation causes pulmonary artery hyperreactivity. We also show that, in a rat model of PH induced by chronic hypoxia, in vivo blockade of NGF or of its TrkA receptor significantly reduces Cx43 increased pulmonary arterial expression induced by chronic hypoxia and displays preventive effects on pulmonary arterial pressure increase and right heart hypertrophy. CONCLUSIONS: Modulation of Cx43 by NGF in pulmonary arterial smooth muscle cells contributes to NGF-induced alterations of pulmonary artery reactivity. Since NGF and its TrkA receptor play a role in vivo in Cx43 increased expression in PH induced by chronic hypoxia, these NGF/Cx43-dependent mechanisms may therefore play a significant role in human PH pathophysiology.

Initial Characterization of a Transgenic Mouse with Overexpression of the Human H1-Histamine Receptor on the Heart.

There is a debate on whether H1-histamine receptors can alter contractility in the mammalian heart. We studied here a new transgenic mouse model where we increased genetically the cardiac level of the H1-histamine receptor. We wanted to know if histamine could augment or decrease contractile parameters in mice with cardiac-specific overexpression of human H1-histamine receptors (H1-TG) and compared these findings with those in littermate wild-type mice (WT). In H1-TG mice, we studied the presence of H1-histamine receptors by autoradiography of the atrium and ventricle using [3H]mepyramine. The messenger RNA for human H1-histamine receptors was present in the heart from H1-TG and absent from WT. Using in situ hybridization, we noted mRNA for the human H1-histamine receptor in cardiac cells from H1-TG. We noted that histamine (1 nM-10 µM) in paced (1 Hz) left atrial preparations from H1-TG, exerted at each concentration of histamine initially reduced force of contraction and then raised contractile force. Likewise, in spontaneously beating left atrial preparations from H1-TG, we noted that histamine led to a transient reduction in the spontaneous beating rate followed by an augmentation in the beating rate. The negative inotropic and chronotropic and the positive inotropic effects on histamine in isolated atrial muscle strips from H1-TG were attenuated by the H1-histamine receptor antagonist mepyramine. Histamine failed to exert an increased force or reduce the heartbeat in atrial preparations from WT. We concluded that stimulation of H1-histamine-receptors can decrease and then augment contractile force in the mammalian heart and stimulation of H1-histamine receptors exerts a negative chronotropic effect. SIGNIFICANCE STATEMENT: We made novel transgenic mice with cardiomyocyte-specific high expressional levels of the human H1-histamine receptor to contribute to the clarification of the controversy on whether H1-histamine receptors increase or decrease contractility and beating rate in the mammalian heart. From our data, we conclude that stimulation of H1-histamine receptors first decrease and then raise contractile force in the mammalian heart but exert solely negative chronotropic effects.

Initial characterization of a transgenic mouse with overexpression of the human D1-dopamine receptor in the heart.

Dopamine can exert effects in the mammalian heart via five different dopamine receptors. There is controversy whether dopamine receptors increase contractility in the human heart. Therefore, we have generated mice that overexpress the human D1-dopamine receptor in the heart (D1-TG) and hypothesized that dopamine increases force of contraction and beating rate compared to wild-type mice (WT). In D1-TG hearts, we ascertained the presence of D1-dopamine receptors by autoradiography using [3H]SKF 38393. The mRNA for human D1-dopamine receptors was present in D1-TG hearts and absent in WT. We detected by in-situ-hybridization mRNA for D1-dopamine receptors in atrial and ventricular D1-TG cardiomyocytes compared to WT but also in human atrial preparations. We noted that in the presence of 10 µM propranolol (to antagonize ß-adrenoceptors), dopamine alone and the D1- and D5-dopamine receptor agonist SKF 38393 (0.1-10 µM cumulatively applied) exerted concentration- and time-dependent positive inotropic effects and positive chronotropic effects in left or right atrial preparations from D1-TG. The positive inotropic effects of SKF 38393 in left atrial preparations from D1-TG led to an increased rate of relaxation and accompanied by and probably caused by an augmented phosphorylation state of the inhibitory subunit of troponin. In the presence of 0.4 µM propranolol, 1 µM dopamine could increase left ventricular force of contraction in isolated perfused hearts from D1-TG. In this model, we have demonstrated a positive inotropic and chronotropic effect of dopamine. Thus, in principle, the human D1-dopamine receptor can couple to contractility in the mammalian heart.

Access to episodic primary care: a cross-sectional comparison of walk-in clinics and urgent primary care centers in British Columbia.

AIM: This study aimed to identify publicly reported access characteristics for episodic primary care in BC and provided a clinic-level comparison between walk-in clinics and UPCCs. BACKGROUND: Walk-in clinics are non-hospital-based primary care facilities that are designed to operate without appointments and provide increased healthcare access with extended hours. Urgent and Primary Care Centres (UPCCs) were introduced to British Columbia (BC) in 2018 as an additional primary care resource that provided urgent, but not emergent care during extended hours. METHODS: This cross-sectional study used publicly available data from all walk-in clinics and UPCCs in BC. A structured data collection form was used to record access characteristics from clinic websites, including business hours, weekend availability, attachment to a longitudinal family practice, and provision of virtual services. FINDINGS: In total, 268 clinics were included in the analysis (243 walk-in clinics, 25 UPCCs). Of those, 225 walk-in clinics (92.6%) and two UPCCs (8.0%) were attached to a longitudinal family practice. Only 153 (63%) walk-in clinics offered weekend services, compared to 24 (96%) of UPCCs. Walk-in clinics offered the majority (8,968.6/ 78.4%) of their service hours between 08:00 and 17:00, Monday to Friday. UPCCs offered the majority (889.3/ 53.7%) of their service hours after 17:00. CONCLUSION: Most walk-in clinics were associated with a longitudinal family practice and provided the majority of clinic services during typical business hours. More research that includes patient characteristics and care outcomes, analyzed at the clinic level, may be useful to support the optimization of episodic primary healthcare delivery.

Adding SGLT2 Cotransporter Inhibitor to PPARγ Activator Does Not Provide an Additive Effect in the Management of Diabetes-Induced Vascular Dysfunction.

INTRODUCTION: Endothelial dysfunction (ED) plays a key role in the pathogenesis of diabetic vascular complications. In monotherapy, dapagliflozin (Dapa) as well as pioglitazone (Pio) prevent the progression of target organ damage in both type 1 (T1DM) and type 2 diabetes. We investigated whether the simultaneous PPAR-γ activation and SGLT2 cotransporter inhibition significantly alleviate ED-related pathological processes and thus normalize vascular response in experimental T1DM. METHODS: Experimental diabetes was induced by streptozotocin (STZ; 55 mg/kg, i.p.) in Wistar rats. Dapa (10 mg/kg), Pio (12 mg/kg), or their combination were administrated to the STZ rats orally. Six weeks after STZ administration, the aorta was excised for functional studies and real-time qPCR analysis. RESULTS: In the aorta of diabetic rats, impaired endothelium-dependent and independent relaxation were accompanied by the imbalance between vasoactive factors (eNos, Et1) and overexpression of inflammation (Tnfα, Il1b, Il6, Icam, Vcam) and oxidative stress (Cybb) markers. Pio monotherapy normalized response to vasoactive substances and restored balance between Et1-eNos expression, while Dapa treatment was ineffective. Nevertheless, Dapa and Pio monotherapy significantly reverted inflammation and oxidative stress markers to normal values. The combination treatment exhibited an additive effect in modulating Il6 expression, reaching the effect of Pio monotherapy in other measured parameters. CONCLUSION: Particularly, Pio exerts a vasoprotective character when used in monotherapy. When combined with Dapa, it does not exhibit an expected additive effect within modulating vasoreactivity or oxidative stress, though having a significant influence on IL6 downregulation.

Evaluation of audit and feedback to family physicians on prescribing of opioid analgesics to opioid-naïve patients: A pragmatic randomized delay trial.

BACKGROUND: Exposure to opioid analgesics have historically raised concern for a risk of developing opioid use disorder. Prescriber audit-and-feedback interventions may reduce opioid prescribing, but some studies have shown detrimental effects for current users. We examined the effectiveness of an audit and feedback intervention, named Portrait, to reduce initiation of opioid analgesics among opioid-naïve patients experiencing pain. METHODS: REDONNA was a single-blinded, two-arm (Early vs Delayed mailing) randomized trial of a portrait for eligible family physicians (FPs) in British Columbia (BC), Canada. The primary outcome was the change in the number of initiations of opioid analgesic prescriptions written by FPs for acute/chronic pain management. We compared outcomes for a 6-month window before vs. after each mailed intervention, using differences in percent differences (DPD) with 95% confidence intervals (CI) and odds ratios (OR) from logistic regressions adjusted for clustering of patients by FP. RESULTS: In the Early (n = 2260) and Delayed (n = 2156) groups, opioid initiations per month were the same in the Before (2.10 Early; 2.06 Delayed) and After (1.94 Early; 1.95 Delayed) windows. The DPD was -2.1% (CI: -4.4% to 0.3%), and ORs were: 0.98 (CI: 0.96 to 1.01) for any opioid, 0.97 (CI: 0.94 to 1.01) for codeine (62% of initiations), and 1.0 (CI: 0.97 to 1.07) for tramadol (25% of initiations). There were no differences in mean quantity of tablets, mean milligrams of morphine equivalents (MME), or mean number of days. CONCLUSION: Portrait had no impact on FPs' rates of prescribing opioid analgesics to opioid-naïve patients experiencing pain. TRIAL REGISTRATION: The study was registered prospectively on 30 March 2020 at the ISRCTN Register (https://www.isrctn.com/ISRCTN34246811).

Assessment of potentially inappropriate medication use among geriatric outpatients in the Slovak Republic.

BACKGROUND: Potentially inappropriate medication (PIM) use is a highly prevalent problem among older people, making it challenging to improve patient safety. The aim of this study was to assess the use of PIMs among geriatric outpatients (OUTs) in the Slovak Republic according to the EU(7) PIM list and to identify the differences in PIM prescriptions among general practitioners (GPs), internists (INTs) and geriatricians (GERs). METHODS: In total, 449 patients (65 years and older) from 4 medical centres who were in the care of GPs (32.5%), INTs (22.7%) or GERs (44.8%) were included in this retrospective analysis. Data were collected from 1.12.2019-31.3.2020. PIMs were identified according to the EU(7) PIM list from patients' records. PIM prescriptions by GPs, INTs and GERs were assessed. All obtained data were statistically analysed. RESULTS: Polypharmacy (68.8% of patients), and PIM use (73% of patients) were observed. The mean number of all prescribed drugs was 6.7 ± 0.2 drugs per day/patient. The mean number of prescribed PIMs was 1.7 ± 0.1 PIMs per day/patient. Drugs from Anatomical Therapeutic Chemical (ATC) classes C, N and A accounted for the greatest number of PIMs. Significantly higher numbers of prescribed drugs as well as PIMs were prescribed by GPs than INTs or GERs. There were 4.2 times higher odds of being prescribed PIMs by GPs than by GERs (p < 0.001). CONCLUSIONS: Polypharmacy and overprescription of PIMs were identified among geriatric patients in our study. We found a positive relationship between the number of prescribed drugs and PIMs. The lowest odds of being prescribed PIMs were observed among those who were in the care of a geriatrician. The absence of geriatricians and lack of information about PIMs among general practitioners leads to high rates of polypharmacy and overuse of potentially inappropriate medications in geriatric patients in the Slovak Republic.

Rapid changes of mRNA expressions of cardiac ion channels affected by Torsadogenic drugs influence susceptibility of rat hearts to arrhythmias induced by Beta-Adrenergic stimulation.

Drug-induced long QT syndrome (LQTS) and Torsades de Pointes (TdP) are serious concerns in drug development. Although rats are a useful scientific tool, their hearts, unlike larger species, usually do not respond to torsadogenic drugs. Consequently, their resistance to drug-induced arrhythmias is poorly understood. Here, we challenged rats with rapid delayed rectifier current (Ikr)-inhibiting antibiotic clarithromycin (CLA), loop diuretic furosemide (FUR) or their combination (CLA + FUR), and examined functional and molecular abnormalities after stimulation with isoproterenol. Clarithromycin and furosemide were administered orally at 12-h intervals for 7 days. To evaluate electrical instability, electrocardiography (ECG) was recorded either in vivo or ex vivo using the Langendorff-perfused heart method under basal conditions and subsequently under beta-adrenergic stimulation. Gene expression was measured using real-time quantitative PCR in left ventricular tissue. Indeed, FUR and CLA + FUR rats exhibited hypokalemia. CLA and CLA + FUR treatment resulted in drug-induced LQTS and even an episode of TdP in one CLA + FUR rat. The combined treatment dysregulated gene expression of several ion channels subunits, including KCNQ1, calcium channels and Na+/K + -ATPase subunits, while both monotherapies had no impact. The rat with recorded TdP exhibited differences in the expression of ion channel genes compared to the rest of rats within the CLA + FUR group. The ECG changes were not detected in isolated perfused hearts. Hence, we report rapid orchestration of ion channel reprogramming of hearts with QT prolongation induced by simultaneous administration of clarithromycin and furosemide in rats, which may account for their ability to avoid arrhythmias triggered by beta-adrenergic stimulation.

Living with prostate cancer: a mixed-method evaluation of group therapy intervention to alleviate psychological distress in a Canadian setting.

PURPOSE: To assess the effects of group therapy focused on the experience of living with prostate cancer (PC) on depression and mental well-being among men with the disease and to explore participant experiences of a guided opportunity to 'speak the unspeakable' as it pertains to living with PC. METHODS: We used a mixed-method convergent design. Participants completed four validated self-report questionnaires at baseline, immediately after the final session, and at three, six, and 12 months follow-up. A repeated measures mixed-effect model examined the effects of the program on depression, mental well-being, and masculinity. Seven focus groups (n = 37) and 39 semi-structured individual interviews explored participant reactions at follow-up. RESULTS: Thirty-nine (93%) participants completed the questionnaires at all follow-ups. Responses indicated improved mental well-being up to three months (p < 0.01) and a decrease in depressive symptoms to 12 months (p < 0.05). Qualitative analysis revealed how the cohesive group environment alleviated psychological stress, enabled participants to identify significant issues and concerns in their lives, and improved communication and relationship skills that were of value in the group as well as with family and friends. The facilitation was essential to guiding participants to 'speak the unspeakable.' CONCLUSION: Men with PC who speak of their experience in a group setting with a guided process incorporating features of a life review appear to gain insight into the impact of PC in their lives, experience diminished features of depression and isolation, and enhance their communication skills within the groups as well as with family members and friends.

"I'm almost opioid-a-phobic": family medicine residents' perceptions of enhancing opioid analgesic and agonist treatment training in a Canadian setting.

PURPOSE: As deaths from the illicit drug poisoning crisis continue to rise in Canada, increasing the number of healthcare professionals qualified to effectively prescribe opioids could be beneficial. The willingness of family medicine residents to undertake structured training in prescribing opioids for Opioid Agonist Treatment (OAT) and pain management have not been well described. MATERIALS AND METHODS: Family medicine residents (n = 20) in British Columbia, Canada, were asked about their experience with and willingness to enrol in OAT training. Informed by the Consolidated Framework for Implementation Research, data were analysed thematically using NVivo software. RESULTS: Four themes were identified: (1) challenges to training implementation, (2) feelings and attitudes on prescribing practices, (3) helpful learning spaces and places of substance use training, and (4) recommendations for implementing training. Preparedness, exposure, and supportive learning environments for substance use education increased willingness to pursue OAT accreditation, while ineffective learning experiences, mixed feelings about opioid prescribing, and lack of protected time were the most common reasons for unwillingness. CONCLUSIONS: Protected time and a range of clinical experiences appear to facilitate residents' willingness to complete OAT and opioid training. Implementation strategies to enhance the uptake of OAT accreditation in family medicine residency must be prioritised.

Identification of a Link between Suspected Metabolic Syndrome and Cognitive Impairment within Pharmaceutical Care in Adults over 75 Years of Age.

The prevalence of metabolic syndrome (MetS) and cognitive impairment (CI) is increasing with age. MetS reduces overall cognition, and CI predicts an increased risk of drug-related problems. We investigated the impact of suspected MetS (sMetS) on cognition in an aging population receiving pharmaceutical care in a different state of old age (60-74 vs. 75+ years). Presence or absence of sMetS (sMetS+ or sMetS-) was assessed according to criteria modified for the European population. The Montreal Cognitive Assessment (MoCA) score, being ≤24 points, was used to identify CI. We found a lower MoCA score (18.4 ± 6.0) and a higher rate of CI (85%) in the 75+ group when compared to younger old subjects (23.6 ± 4.3; 51%; p < 0.001). In the age group of 75+, a higher occurrence, of MoCA ≤ 24 points, was in sMetS+ (97%) as compared to sMetS- (80% p < 0.05). In the age group of 60-74 years, a MoCA score of ≤24 points was identified in 63% of sMetS+ when compared to 49% of sMetS- (NS). Conclusively, we found a higher prevalence of sMetS, the number of sMetS components and lower cognitive performance in subjects aged 75+. This age, the occurrence of sMetS and lower education can predict CI.

Advancing virtual primary care for people with opioid use disorder (VPC OUD): a mixed-methods study protocol.

INTRODUCTION: The emergence of COVID-19 introduced a dual public health emergency in British Columbia, which was already in the fourth year of its opioid-related overdose crisis. The public health response to COVID-19 must explicitly consider the unique needs of, and impacts on, communities experiencing marginalisation including people with opioid use disorder (PWOUD). The broad move to virtual forms of primary care, for example, may result in changes to healthcare access, delivery of opioid agonist therapies or fluctuations in co-occurring health problems that are prevalent in this population. The goal of this mixed-methods study is to characterise changes to primary care access and patient outcomes following the rapid introduction of virtual care for PWOUD. METHODS AND ANALYSIS: We will use a fully integrated mixed-methods design comprised of three components: (a) qualitative interviews with family physicians and PWOUD to document experiences with delivering and accessing virtual visits, respectively; (b) quantitative analysis of linked, population-based administrative data to describe the uptake of virtual care, its impact on access to services and downstream outcomes for PWOUD; and (c) facilitated deliberative dialogues to co-create educational resources for family physicians, PWOUD and policymakers that promote equitable access to high-quality virtual primary care for this population. ETHICS AND DISSEMINATION: Approval for this study has been granted by Research Ethics British Columbia. We will convene PWOUD and family physicians for deliberative dialogues to co-create educational materials and policy recommendations based on our findings. We will also disseminate findings via traditional academic outputs such as conferences and peer-reviewed publications.

Physical activity enhances fecal lactobacilli in rats chronically drinking sweetened cola beverage.

Overweight and obesity have been linked with increased intake of sugar-sweetened beverages. On the other hand, physical activity has been known to lead to weight loss. Therefore, we hypothesized that exercise might influence the Lactobacillus population in fecal microbiota as their changed abundance is often associated with shifts in the physical activity and diet. In our experiment, Wistar rats were allocated into groups with normal feed or added sugar-sweetened beverages with or without access to a running wheel. Interestingly, only a combination of physical activity and sweetened beverage intake was associated with a significant increase in fecal lactobacilli abundance, suggesting a connection between exercise and a rise in lactobacilli abundance. Moreover, physical activity has improved weight-related parameters and led to increased plasma and mRNA adiponectin levels. Ghrelin and leptin plasma levels were unaltered. Taken together, our results demonstrate that effect of physical activity on adiposity even during unhealthy feeding patterns is accompanied by increased lactobacilli abundance in the fecal microbiota population.

Finding Primary Care-Repurposing Physician Registration Data to Generate a Regionally Accurate List of Primary Care Clinics: Development and Validation of an Open-Source Algorithm.

BACKGROUND: Some Canadians have limited access to longitudinal primary care, despite its known advantages for population health. Current initiatives to transform primary care aim to increase access to team-based primary care clinics. However, many regions lack a reliable method to enumerate clinics, limiting estimates of clinical capacity and ongoing access gaps. A region-based complete clinic list is needed to effectively describe clinic characteristics and to compare primary care outcomes at the clinic level. OBJECTIVE: The objective of this study is to show how publicly available data sources, including the provincial physician license registry, can be used to generate a verifiable, region-wide list of primary care clinics in British Columbia, Canada, using a process named the Clinic List Algorithm (CLA). METHODS: The CLA has 10 steps: (1) collect data sets, (2) develop clinic inclusion and exclusion criteria, (3) process data sets, (4) consolidate data sets, (5) transform from list of physicians to initial list of clinics, (6) add additional metadata, (7) create working lists, (8) verify working lists, (9) consolidate working lists, and (10) adjust processing steps based on learnings. RESULTS: The College of Physicians and Surgeons of British Columbia Registry contained 13,726 physicians, at 2915 unique addresses, 6942 (50.58%) of whom were family physicians (FPs) licensed to practice in British Columbia. The CLA identified 1239 addresses where primary care was delivered by 4262 (61.39%) FPs. Of the included addresses, 84.50% (n=1047) were in urban locations, and there was a median of 2 (IQR 2-4, range 1-23) FPs at each unique address. CONCLUSIONS: The CLA provides a region-wide description of primary care clinics that improves on simple counts of primary care providers or self-report lists. It identifies the number and location of primary care clinics and excludes primary care providers who are likely not providing community-based primary care. Such information may be useful for estimates of capacity of primary care, as well as for policy planning and research in regions engaged in primary care evaluation or transformation.

Prevalence and correlates of intentional substance use to reduce illicit opioid use in a Canadian setting.

Background: While preliminary evidence has begun to document intentional use of one substance to reduce the use of another, the phenomenon of drug substitution among people who use illicit opioids remains understudied. Therefore, we sought to estimate the prevalence and correlates of intentional substance use to reduce illicit opioid use among persons who use drugs (PWUD). Methods: We analysed data from three prospective cohorts of PWUD in Vancouver, Canada, using multivariable generalized estimating equations (GEE). Results: Between June 2012 and June 2016, 1527 participants were recruited and contributed 4991 interviews. Of those, 336 (22%) illicit opioid-using participants self-reported substitution to reduce illicit opioid use at least once during study period contributing 467 (9.4%) interviews. Among those interviews, substances substituted for opioids were alcohol (15 participants, 3.2%), stimulants (235, 50.3%), cannabis (129, 27.6%), benzodiazepines (21, 4.5%), and others (20, 4.3%). In multivariable GEE model adjusted for socio-demographic factors, reporting substitution to reduce illicit opioid use was positively associated with greater likelihood of daily cannabis use (Adjusted Odds Ratio = 1.56, 95% Confidence Interval: 1.24-1.96]. Conclusions: While daily cannabis use was associated with reporting opioid substitution attempts, additional study is needed to examine potential of cannabis/cannabinoids to reduce illicit opioid use.

Development and pilot evaluation of an educational session to support sparing opioid prescriptions to opioid naïve patients in a Canadian primary care setting.

BACKGROUND: Prescribing rates of some analgesics decreased during the public health crisis. Yet, up to a quarter of opioid-naïve persons prescribed opioids for noncancer pain develop prescription opioid use disorder. We, therefore, sought to evaluate a pilot educational session to support primary care-based sparing of opioid analgesics for noncancer pain among opioid-naïve patients in British Columbia (BC). METHODS: Therapeutics Initiative in BC has launched an audit and feedback intervention. Individual prescribing portraits were mailed to opioid prescribers, followed by academic detailing webinars. The webinars' learning outcomes included defining the terms opioid naïve and opioid sparing, and educating attendees on the (lack of) evidence for opioid analgesics to treat noncancer pain. The primary outcome was change in knowledge measured by four multiple-choice questions at the outset and conclusion of the webinar. RESULTS: Two hundred participants attended four webinars; 124 (62%) responded to the knowledge questions. Community-based primary care professionals (80/65%) from mostly urban settings (77/62%) self-identified as family physicians (46/37%), residents (22/18%), nurse practitioners (24/19%), and others (32/26%). Twelve participants (10%) recalled receiving the individualized portraits. While the correct identification of opioid naïve definitions increased by 23%, the correct identification of opioid sparing declined by 7%. Knowledge of the gaps in high-quality evidence supporting opioid analgesics and risk tools increased by 26% and 35%, respectively. CONCLUSION: The educational session outlined in this pilot yielded mixed results but appeared acceptable to learners and may need further refinement to become a feasible way to train professionals to help tackle the current toxic drugs crisis.

Analysis of necroptosis and its association with pyroptosis in organ damage in experimental pulmonary arterial hypertension.

In this study, a role of cell loss due to necroptosis and its linkage with pyroptosis in organ damage under the conditions of pulmonary arterial hypertension (PAH) was examined. Monocrotaline (MCT) was used to induce PAH in Wistar rats, and depending on the severity of the disease progression, they were further divided into two subgroups: MCT group-sacrificed 4 weeks after MCT administration and ptMCT group-prematurely sacrificed due to rapid deterioration in vital functions (on Day 24,11 ± 0,7). The elevation of respiratory rate and right ventricular (RV) hypertrophy were more evident in ptMCT group, while the heart rate and cardiac haemodynamic stress markers were comparably higher in both diseased groups. Detailed immunoblotting analysis revealed that the upregulation of pThr231 /Ser232 -RIP3 proceeded into necroptosis execution in the RVs, unlike in the lungs of both PAH stages. The elevated pulmonary pThr231 /Ser232 -RIP3 levels in both PAH subgroups were associated rather with GSDMD-mediated pyroptosis. On the contrary, other inflammasome forms, such as AIM2 and NLRC4, were higher in the RV, unlike in the lungs, of diseased groups. The PAH-induced increase in the plasma RIP3 levels was more pronounced in ptMCT group, and positively correlated with RV hypertrophy, but not with haemodynamic stress. Taken together, we indicated for the first time that pThr231 /Ser232 -RIP3 upregulation resulting in two different necrosis-like cell death modes might underlie the pathomechanisms of PAH and that the plasma RIP3 might serve as an additional diagnostic and prognostic marker of cardiac injury under these conditions.

Impact of the international collaborative addiction medicine research fellowship on physicians' future engagement in addiction research.

Background: To evaluate how an international one-year intensive research training program for addiction medicine physicians contributed to subsequent research involvement and productivity. Methods: We prospectively compared addiction medicine physician fellows admitted to a one-year training program with non-admitted controls, using baseline questionnaire and peer-reviewed publication data. Participants' publication activity was assessed from fellowship application date onwards using biomedical databases (e.g., PubMed, Embase). Results: Between July 2014 and June 2020, which is six years of cohorts, 56 (39 women) physicians, both fellows (n = 25) and non-admitted applicants (n = 31), were observed and included in the study, contributing 261 person-years of observation. At baseline, in the fellows' cohort: 76% of participants (19/25) reported past research involvement, 24% (6/25) had one or more advanced graduate degrees (e.g., MPH), and the median number of peer-reviewed, first author publications was one (Interquartile Range [IQR] = 0-2). At baseline, in the controls' cohort: 84% of participants (26/31) reported past research involvement, 39% (12/31) had one or more advanced graduate degrees, and the median number of peer-reviewed, first author publications was zero. The physicians' training included internal medicine (n = 8), family medicine (n = 33), psychiatry (n = 5) and others (n = 4). At follow up, there was a significant difference between fellows (n = 25) and controls (n = 31) in total number of publications (Rate Ratio [RR] = 13.09, 95% Confidence Interval [CI], 5.01 - 34.21, p < 0.001), as well as first author publications (RR = 5.59, 95% CI, 2.23 - 14.06, p < 0.001). Conclusion: In the six-year observation period, fellows' productivity indicates undertaking this fellowship was associated with significant research outputs in comparison to controls, signaling successful training of addiction physicians to help recruit addiction medicine physicians to participate in addiction research.

Pioglitazone restores phosphorylation of downregulated caveolin-1 in right ventricle of monocrotaline-induced pulmonary hypertension.

BACKGROUND: Caveolin-1 (cav-1) plays a role in pulmonary arterial hypertension (PAH). Monocrotaline (MCT)-induced PAH is characterized by a loss of cav-1 in pulmonary arteries; however, less is known regarding its role in the hypertrophied right ventricle (RV). We aimed to characterize the role of cav-1 and Hsp90 in the RV of MCT-induced PAH and their impact on endothelial nitric oxide synthase (eNOS). Additionally, we focused on restoration of cav-1 expression with pioglitazone administration. METHODS: Male 12-week-old Wistar rats were injected subcutaneously with monocrotaline (60 mg/kg). Selected proteins (cav-1, eNOS, pSer1177eNOS, Hsp90) and mRNAs (cav-1α, cav-1ß, eNOS) were determined in the RV and left ventricle (LV) 4 weeks later. In a separate MCT-induced PAH study, pioglitazone (10 mg/kg/d, orally) administration started on day 14 after MCT. RESULTS: MCT induced RV hypertrophy and lung enlargement. Cav-1 and pTyr14cav-1 were decreased in RV. Caveolin-1α (cav-1α) and caveolin-1ß (cav-1ß) mRNAs were decreased in both ventricles. Hsp90 protein was increased in RV. eNOS and pSer1177eNOS proteins were unchanged in the ventricles. eNOS mRNA was reduced in RV. Pioglitazone treatment increased oxygen saturation and pTyr14cav-1 vs. MCT group. CONCLUSIONS: Restoration of pTyr14cav-1 did not lead to amelioration of the disease, nor did it prevent RV hypertrophy and fibrosis, which was indicated by an increase in Acta2, Nppb, Col3a1, and Tgfß1 mRNA.