Pioglitazone Alters Ace/Ace 2 Balance to Favour Ace2 Independently Of Glycaemia Levels in Diabetic Rat Heart.

The activation of the renin-angiotensin system (RAS) contributes to the pathogenesis of cardiac damage during diabetes. In the present study, we investigated the role of pioglitazone, dapagliflozin and their combination on RAS components in streptozotocin-induced diabetic cardiomyopathy in Wistar rats. Blood glucose, serum lipids, and ACE (angiotensin-converting enzyme), ACE2 levels were determined. mRNA levels of Myh6 (myosins heavy chain), Myh7, Ace, Ace2, Nppa, Nppb (natriuretic peptide A, B) and Ppars (peroxisome proliferator activating receptors) genes in the heart were determined by real-time PCR (polymerase chain reaction). Protein expression of ACE and ACE2 was assessed by western blotting. After six weeks pioglitazone suppressed Ace mRNA and protein levels (p<0.05) and modified the Ace/Ace2 ratio (p<0.05) in the cardiac tissue of diabetic rats. Pioglitazone significantly decreased serum lipids (p<0.05) but did not significantly influence blood glucose and ACE serum levels of diabetic animals. Dapagliflozin had a significant glucose-lowering action (p<0.05) however, it had no impact on the Ace/Ace2 ratio. The combination of both compounds markedly improved blood glucose (p<0.05) as well as the Myh6/Myh7 ratio (p<0.05) but had no further impact on the Ace to Ace2 balance in cardiac tissue compared to pioglitazone monotherapy. We found that pioglitazone improves the cardiac Ace/ Ace2 ratio in diabetic rats suggesting a potential cardioprotective effect. This effect is independent of its antidiabetic and metabolic effects.

Early Career Training in Addiction Medicine: A Qualitative Study with Health Professions Trainees Following a Specialized Training Program in a Canadian Setting.

Background: There has been a notable deficiency in the implementation of addiction science in clinical practice and many healthcare providers feel unprepared to treat patients with substance use disorders (SUD) following training. However, the perceptions of addiction medicine training by learners in health professions have not been fully investigated. This qualitative study explored perceptions of prior training in SUD care among early-career trainees enrolled in Addiction Medicine fellowships and electives in Vancouver, Canada. Methods: From April 2015 - August 2018, we interviewed 45 early-career physicians, social workers, nurses, and 17 medical students participating in training in addiction medicine. We coded transcripts inductively using qualitative data analysis software (NVivo 11.4.3). Results: Findings revealed six key themes related to early-career training in addiction medicine: (1) Insufficient time spent on addiction education, (2) A need for more structured addictions training, (3) Insufficient hands-on clinical training and skill development, (4) Lack of patient-centeredness and empathy in the training environment, (5) Insufficient implementation of evidence-based medicine, and (6) Prevailing stigmas toward addiction medicine. Conclusion: Early clinical training in addiction medicine appears insufficient and largely focused on symptoms, rather than etiology or evidence. Early career learners in health professions perceived benefit to expanding access to quality education and reported positive learning outcomes after completing structured training programs.

Individualized prescribing portraits to reduce inappropriate initiation of opioid analgesics to opioid naïve patients in primary care: Protocol for a randomized controlled trial.

Background Opioid analgesics are frequently initiated for chronic and acute pain despite weak evidence of benefit, although prescribing rates of some analgesics decreased in the context of the epidemic. In some populations, up to a quarter of opioid naïve persons prescribed opioids for non-cancer pain develop prescription opioid use disorder (OUD). Audit and feedback interventions rely on constructive use of routinely collected data to align professional behaviours and clinical practice with best evidence. These interventions have been shown to help reduce inappropriate initiation. However, effectiveness and acceptability of individualized "portraits" of physicians' prescribing patterns, to reduce inappropriate initiation of opioid analgesics to opioid naïve persons, have not been evaluated. Methods REDONNA is a mixed-methods randomized study testing the effectiveness of individualized prescribing Portraits to reduce inappropriate initiation of opioid analgesics. This intervention to improve safety of opioid prescribing in primary care in British Columbia (BC), Canada involves mailing individual prescribing portraits to an 'early group' of 2604 family physicians, followed in 6 months by a mailing to 2553 family physicians in the 'delayed group'. Primary outcome is number of new opioid prescriptions initiated in opioid naïve people, measured using administrative data from a centralized medication monitoring database covering all prescription opioids dispensed from BC community pharmacies. Secondary endpoints will compare prescribing impact between the two groups. A qualitative sub-study will examine feasibility among a purposive sample of physicians and patients. Discussion This trial provides important evidence on the intervention's potential to steer policy and practice on inappropriate opioid analgesics initiation. Trial registration: The study was registered prospectively on 30 March 2020 at the ISRCTN Register (https://www.isrctn.com/ISRCTN34246811).

Altered serum levels of neprilysin in heart failure patients with reduced ejection fraction.

OBJECTIVE: In addition to the recent success of neprilysin inhibition in treatment of heart failure, elevated soluble neprilysin (sNEP) in circulation has been suggested to be a prognostic biomarker in heart failure with a reduced ejection fraction (HFrEF). However, the diagnostic performance of sNEP is nebulous and its levels in HFrEF have not been compared with controls. For the purpose of this study, we determined the role of sNEP levels as a biomarker in routine ambulatory care of HFrEF patients, when compared to the control subjects. METHODS: Ambulant patients with chronic HFrEF (n = 18) were included. Apparently healthy volunteers - hospital physicians (n = 9) were included as the controls. Besides standard diagnostic tools (echocardiographic examination and laboratory biochemical diagnostic tests including NT-proBNP assessment), we analysed serum levels of neprilysin with a commercially available human soluble neprilysin ultrasensitive ELISA kit (Aviscera Bioscience, USA). RESULTS: Concentrations of sNEP were significantly reduced in HFrEF patients (average ± S.E.M.=1038 ± 464 pg/ml) when compared to the controls (1947 ± 613 pg/ml; p < 0.05). Two of eighteen HFrEF samples were below, while two of ten control samples were above the detection limit of the immunoassay. We documented a lack of significant correlation between sNEP and left ventricular ejection fraction (LVEF) and other echocardiographic features as well as NT-proBNP. However, sNEP significantly negatively correlated to serum natrium levels (Spearman r = ‒0.6112, p < 0.05) and to systolic blood pressure (Spearman r = ‒0.4746, p < 0.05) in HFrEF. CONCLUSION: Levels of sNEP were significantly reduced in HFrEF, when compared to the controls, with absent correlations to relevant HF-related features (e.g. LVEF). These findings might contribute to clarification of the diagnostic value of sNEP in HF (Tab. 2, Fig. 2, Ref. 30) Keywords: soluble neprilysin, heart failure, reduced ejection fraction, pharmacotherapy.

Opiate use disorders and overdose: Medical students' experiences, satisfaction with learning, and attitudes toward community naloxone provision.

INTRODUCTION: Opiate use disorder is a common condition in healthcare services in Ireland, where over 200 opiate overdose deaths occur annually. There is limited addiction medicine education at undergraduate level and medical graduates may not be adequately prepared to diagnose and manage opioid use disorders and emergency drug overdose presentations. Therefore, we examined final-year medical students' learning experiences and attitudes toward opioid use disorder, overdose and community naloxone provision as an emerging overdose treatment. METHODS: We administered an anonymous paper-based survey to 243 undergraduate medical students undertaking their final professional completion module prior to graduation from University College Dublin, Ireland. Results were compared with parallel surveys of General Practitioners (GPs) and GP trainees. RESULTS: A total of 197 (82.1%) completed the survey. Just under half were male, and most were aged under 25 (63.3%) and of Irish nationality (76.7%). The students felt moderately prepared to recognise opioid use disorder, but felt less prepared to manage other aspects of its care. Most had taken a history from a patient with an opioid use disorder (82.8%), and a third had witnessed at least one opioid overdose. Although 10.3% had seen naloxone administered, most had never administered naloxone themselves (98.5%). Half supported wider naloxone availability; this was lower than support rates among GPs (63.6%) and GP trainees (66.1%). CONCLUSIONS: Our findings suggest an unmet learning need in undergraduate training on opioid use disorder, with potential consequences for patient care.

Barriers and facilitators to implementing addiction medicine fellowships: a qualitative study with fellows, medical students, residents and preceptors.

BACKGROUND: Although progress in science has driven advances in addiction medicine, this subject has not been adequately taught to medical trainees and physicians. As a result, there has been poor integration of evidence-based practices in addiction medicine into physician training which has impeded addiction treatment and care. Recently, a number of training initiatives have emerged internationally, including the addiction medicine fellowships in Vancouver, Canada. This study was undertaken to examine barriers and facilitators of implementing addiction medicine fellowships. METHODS: We interviewed trainees and faculty from clinical and research training programmes in addiction medicine at St Paul's Hospital in Vancouver, Canada (N = 26) about barriers and facilitators to implementation of physician training in addiction medicine. We included medical students, residents, fellows and supervising physicians from a variety of specialities. We analysed interview transcripts thematically by using NVivo software. RESULTS: We identified six domains relating to training implementation: (1) organisational, (2) structural, (3) teacher, (4) learner, (5) patient and (6) community related variables either hindered or fostered addiction medicine education, depending on context. Human resources, variety of rotations, peer support and mentoring fostered implementation of addiction training. Money, time and space limitations hindered implementation. Participant accounts underscored how faculty and staff facilitated the implementation of both the clinical and the research training. CONCLUSIONS: Implementation of addiction medicine fellowships appears feasible, although a number of barriers exist. Research into factors within the local/practice environment that shape delivery of education to ensure consistent and quality education scale-up is a priority.

Two birds with one stone: experiences of combining clinical and research training in addiction medicine.

BACKGROUND: Despite a large evidence-base upon which to base clinical practice, most health systems have not combined the training of healthcare providers in addiction medicine and research. As such, addiction care is often lacking, or not based on evidence or best practices. We undertook a qualitative study to assess the experiences of physicians who completed a clinician-scientist training programme in addiction medicine within a hospital setting. METHODS: We interviewed physicians from the St. Paul's Hospital Goldcorp Addiction Medicine Fellowship and learners from the hospital's academic Addiction Medicine Consult Team in Vancouver, Canada (N = 26). They included psychiatrists, internal medicine and family medicine physicians, faculty, mentors, medical students and residents. All received both addiction medicine and research training. Drawing on Kirkpatrick's model of evaluating training programmes, we analysed the interviews thematically using qualitative data analysis software (Nvivo 10). RESULTS: We identified five themes relating to learning experience that were influential: (i) attitude, (ii) knowledge, (iii) skill, (iv) behaviour and (v) patient outcome. The presence of a supportive learning environment, flexibility in time lines, highly structured rotations, and clear guidance regarding development of research products facilitated clinician-scientist training. Competing priorities, including clinical and family responsibilities, hindered training. CONCLUSIONS: Combined training in addiction medicine and research is feasible and acceptable for current doctors and physicians in training. However, there are important barriers to overcome and improved understanding of the experience of addiction physicians in the clinician-scientist track is required to improve curricula and research productivity.

Using electronic medical records to determine prevalence and treatment of mental disorders in primary care: a database study.

OBJECTIVES: With prevention and treatment of mental disorders a challenge for primary care and increasing capability of electronic medical records (EMRs) to facilitate research in practice, we aim to determine the prevalence and treatment of mental disorders by using routinely collected clinical data contained in EMRs. METHODS: We reviewed EMRs of patients randomly sampled from seven general practices, by piloting a study instrument and extracting data on mental disorders and their treatment. RESULTS: Data were collected on 690 patients (age range 18-95, 52% male, 52% GMS-eligible). A mental disorder (most commonly anxiety/stress, depression and problem alcohol use) was recorded in the clinical records of 139 (20%) during the 2-year study period. While most patients with the common disorders had been prescribed medication (i.e. antidepressants or benzodiazepines), a minority had been referred to other agencies or received psychological interventions. 'Free text' consultation notes and 'prescriptions' were how most patients with disorders were identified. Diagnostic coding alone would have failed to identify 92% of patients with a disorder. CONCLUSIONS: Although mental disorders are common in general practice, this study suggests their formal diagnosis, disease coding and access to psychological treatments are priorities for future research efforts.

Problem alcohol use among problem drug users: development and content of clinical guidelines for general practice.

BACKGROUND: Problem alcohol use is common and associated with considerable adverse outcomes among patients who attend primary care in Ireland and other European countries for opiate substitution treatment. AIMS: This paper aims to describe the development and content of clinical guidelines for the management of problem alcohol use among this population. METHODS: The guidelines were developed in three stages: (1) identification of key stakeholders, (2) development of evidence-based draft guidelines, and (3) determination of a modified 'Delphi-facilitated' consensus among the group members. RESULTS: The guidelines incorporate advice for physicians on all aspects of care, including (1) definition of problem alcohol use among problem drug users, (2) alcohol screening, (3) brief intervention, and (4) subsequent management of patients with alcohol dependence. CONCLUSIONS: Primary care has an important role to play in the care of problem alcohol use among problem drug users, especially opiate substitution patients. Further research on strategies to inform the implementation of these guidelines is a priority.

Chronotherapy of hypertension with combination treatment.

In the last decade, a number of clinical studies identified an additional improvement of blood pressure control if the single drug treatment is time-targeted in hypertensive individuals. On the other hand, only a few of them investigated whether any different antihypertensive effects with combination therapy can be confirmed between morning and evening dosing. This article reviews those studies employed various combinations of antihypertensive agents including calcium channel blocker with angiotensin-receptor blocker, calcium channel blocker with diuretic, angiotensin-receptor blocker with diuretic, angiotensin-receptor blocker with angiotensin-converting enzyme inhibitor and angiotensin-converting enzyme inhibitor with diuretic. Interestingly, the majority of studies confirmed that evening dosing is more effective in reducing asleep and/or mean systolic and/or diastolic blood pressure, one study found no difference and one study suggested that morning dosing could be more effective. Three studies showed a positive shift from non-dipping to dipping pattern with evening dosing and an opposite effect was found with morning dosing. Importantly, while the data strongly suggest that efficacy can be improved with evening dosing when drug combination is used, no thought was given to safety comparison. Thus, the complex benefit-risk ratio comparison between morning and evening dosing of blood pressure reducing drug combinations remains to be elucidated.

Alcohol screening and brief intervention among drug users in primary care: a discussion paper.

BACKGROUND: Problem alcohol use is common among problem drug users (PDU) and associated with adverse health outcomes. Primary care has an important role in the overall stepped approach to alcohol treatment, especially screening and brief intervention (SBI). AIM: To discuss three themes that emerged from an exploration of the literature on SBI for problem alcohol use in drug users attending primary care. METHODS: Material for this discussion paper was gathered from three biomedical databases (PubMed, PsycINFO and Cochrane library), conference proceedings and online resources of professional organisations or national health agencies. RESULTS: Themes discussed in this paper are: (a) the potential of primary care for delivery of alcohol SBIs to PDUs, (b) screening methods and (c) application of brief interventions to PDUs. CONCLUSIONS: Although SBI improves health outcomes associated with problem alcohol use in the general population, further research is needed among high-risk patient groups, especially PDUs.

Elevated pulse pressure in treated hypertensive patients during 24-hour ambulatory blood pressure monitoring.

OBJECTIVES: We tested whether antihypertensive therapy may alter PP independently from other blood pressure parameters. METHODS: Data from 24-hour ambulatory blood pressure monitoring (24-h ABPM) were compared between healthy normotensive controls and hypertensive subjects successfully treated (sBP/dBP 24-hour average bellow 130/80 mmHg) with antihypertensive medication either with absence (Treated) or presence of additional risk factors (Treated + R). These groups were compared with poorly treated hypertensives (sBP/dBP over 130/80 mmHg) with absence (Uncontrolled) or presence of additional risk factors (Uncontrolled + R). We studied mean 24-hour systolic and diastolic blood pressure (sBP and dBP), mean arterial pressure (MAP) and pulse pressure (PP). RESULTS: In Treated and Treated + R groups, sBP and dBP were appropriately controlled by antihypertensive medication, however PP was significantly increased in both groups (49 +/- 1 mmHg and 51 +/- 2 mmHg, resp., in both p < 0.05) as compared to the controls (43 +/- 1 mmHg). In Uncontrolled and Uncontrolled + R groups, values of PP were even significantly higher (60 +/- 2 mmHg and 76 +/- 3, resp.) as compared to controls as well as to successfully treated groups (p < 0.05). PP was significantly positively correlated to sBP in all groups (p < 0.05), except Treated + R. Other parameters (age, body mass index, MAP) showed overall significant positive relationship only in pooled hypertensive population. CONCLUSION: 24-h ABPM revealed significantly increased PP, in spite of proper control of sBP and dBP in treated hypertensive patients. We propose that 24-h PP could provide additional information in the evaluation of antihypertensive therapy, even when depending on sBP (Tab. 3, Fig. 2, Ref. 39).

Pycnogenol efficiency on glycaemia, motor nerve conduction velocity and markers of oxidative stress in mild type diabetes in rats.

The aim of this study was to describe the effects of Pycnogenol at various doses on preprandial and postprandial glucose levels, the levels of thiobarbituric acid reactive substances (TBARs) and N-acetyl-beta-d-glucosaminidase (NAGA) and on motor nerve conduction velocity (MNCV) in streptozotocin (STZ)-induced diabetic rats. Pycnogenol treatment (10, 20, 50 mg/kg body weight (b.w.)/day) lasted for 8 weeks after induction of diabetes. Pycnogenol significantly decreased elevated levels of preprandial glycaemia in treated animals at all doses. At doses of 10 mg/kg b.w./day and 20 mg/kg b.w./day it significantly decreased elevated levels of postprandial glycaemia compared with diabetic non-treated animals. Pycnogenol failed to induce a significant decrease of postprandial glycaemia at a dose of 50 mg/kg b.w./day. Pycnogenol improved significantly the impaired MNCV at doses of 10 and 20 mg/kg b.w./day compared with non-treated animals. The levels of TBARs were elevated in diabetic rats. The levels of NAGA increased gradually despite the treatment. Pycnogenol failed to affect the increased levels of TBARs and NAGA. Pycnogenollowered the elevated levels of glycaemia and reduced the decline in motor nerve conduction velocity in STZ-induced diabetic rats. The effect of Pycnogenol on postprandial glycaemic levels and MNCV was not dose-dependent.

Increased expression of endothelial nitric oxide synthase and caveolin-1 in the aorta of rats with isoproterenol-induced cardiac hypertrophy.

Isoproterenol-induced cardiac hypertrophy is associated with increased expression of endothelial nitric oxide synthase in the aorta but without signs of improved endothelial function. The aim was to examine the hypothesis that increased expression of eNOS allosteric inhibitor caveolin-1 could be associated with unimproved endothelium-dependent relaxations. Rats received isoproterenol (5 mg/kg body mass, i.p., n = 13) or its vehicle (n = 14) during 1 week. Systolic blood pressure (SBP) and heart rate (HR) were measured by the tail-cuff method. Expression of eNOS and caveolin-1 was measured using immunoblotting analysis. Relaxations of isolated aorta to acetylcholine and sodium nitroprusside were evaluated ex vivo. After 1 week of isoproterenol administration, basal SBP and HR were decreased (SBP 110 +/- 3 vs. 126 +/- 3 mmHg, p < 0.05; HR 342 +/- 8 vs. 366 +/- 6 beats/min, p < 0.05). Isoproterenol increased the mass of the left ventricle (+33% +/- 4% vs. control; p < 0.05) and right ventricle (+40% +/- 9%; p < 0.05). Isoproterenol administration increased the expression of eNOS (+53% +/- 12%; p < 0.05) and caveolin-1 (+54% +/- 20%, p < 0.05) in the aorta. Relaxation of isolated aorta to acetylcholine and sodium nitroprusside showed a trend towards a worsened endothelial function and a lower sensitivity to exogenous NO. Thus, 1 week of isoproterenol administration led to increased eNOS expression in the aorta without amelioration of endothelial vasorelaxation function. Concomitant increase in caveolin-1 expression may be responsible for this paradox.

Fetal alcohol syndrome: seven new cases.

In one year, the "fetal alcohol syndrome" (FAS) was recognized in seven newborn and older infants, bringing the total in the current literature to 26 cases. This recently rediscovered disorder consists of severe prenatal and postnatal growth failure, mental deficiency, and characteristic hypoplasia of the middle face and orbits with minor malformations of the heart and joints. The mothers have chronic alcoholism. By identifying and counseling such women, obstetricians and gynecologists may prevent the occurrence of the syndrome or diagnose it in the neonate.