CPAP for paediatric patients in Aotearoa New Zealand: audit of a developing service at Capital and Coast DHB 2005-2020.

AIMS: To document the establishment of a Paediatric Continuous Positive Airway Pressure (CPAP) service within the Wellington Region, and review outcomes over the last 15 years. METHODS: A retrospective audit of the Paediatric Sleep Service records including clinic letters and polysomnography (PSG) studies for all paediatric patients commenced on CPAP treatment, or for whom CPAP treatment was offered, from November 2005 to December 2020. Data were collected on demographics, medical diagnoses, indications for respiratory support, ENT involvement and surgery. Factors related to CPAP use were also recorded. RESULTS: Seventy-four children were offered CPAP in the time frame, 52 (70%) male. The age range at onset of CPAP treatment was <1 year of age to 23 years with 12 cases ≥16 years of age. There were 3 (4%) cases presenting before 2006, 11 (15%) cases from 2006-2010, 16 (22%) cases from 2011-2015 and 44 (59%) cases between 2016-2020. Ethnicities included were, 32 (43%) NZ European, 18 (24%) Maori, 19 (26%) Pacific and 5 (7%) Indian/Asian. The most common primary diagnoses were Obesity 21 (28%), Down Syndrome 10 (14%) and Craniofacial abnormalities 8 (11%). One family declined a CPAP trial and there were eight failed CPAP trials. For the remaining 65 patients, compliance with treatment was good/usually good for 25, variable for 19, and poor for 21. Maori patients were less likely to have good/usually good compliance than NZ European and Pacific patients (25% versus 44% and 47% respectively). CONCLUSION: Referrals for CPAP treatment in the paediatric age range are increasing and obesity is the commonest co-morbidity. Services need to be culturally appropriate to ensure the best outcomes.

Diabetes induces dysregulation of microRNAs associated with survival, proliferation and self-renewal in cardiac progenitor cells.

AIMS/HYPOTHESIS: Diabetes mellitus causes a progressive loss of functional efficacy in stem cells, including cardiac progenitor cells (CPCs). The underlying molecular mechanism is still not known. MicroRNAs (miRNAs) are small, non-coding RNA molecules that regulate genes at the post-transcriptional level. We aimed to determine if diabetes mellitus induces dysregulation of miRNAs in CPCs and to test if in vitro therapeutic modulation of miRNAs would improve the functions of diabetic CPCs. METHODS: CPCs were isolated from a mouse model of type 2 diabetes (db/db), non-diabetic mice and human right atrial appendage heart tissue. Total RNA isolated from mouse CPCs was miRNA profiled using Nanostring analysis. Bioinformatic analysis was employed to predict the functional effects of altered miRNAs. MS analysis was applied to determine the targets, which were confirmed by western blot analysis. Finally, to assess the beneficial effects of therapeutic modulation of miRNAs in vitro and in vivo, prosurvival miR-30c-5p was overexpressed in mouse and human diabetic CPCs, and the functional consequences were determined by measuring the level of apoptotic cell death, cardiac function and mitochondrial membrane potential (MMP). RESULTS: Among 599 miRNAs analysed in mouse CPCs via Nanostring analysis, 16 miRNAs showed significant dysregulation in the diabetic CPCs. Using bioinformatics tools and quantitative real-time PCR (qPCR) validation, four altered miRNAs (miR-30c-5p, miR-329-3p, miR-376c-3p and miR-495-3p) were identified to play an important role in cell proliferation and survival. Diabetes mellitus significantly downregulated miR-30c-5p, while it upregulated miR-329-3p, miR-376c-3p and miR-495-3p. MS analysis revealed proapoptotic voltage-dependent anion-selective channel 1 (VDAC1) as a direct target for miR-30c-5p, and cell cycle regulator, cyclin-dependent protein kinase 6 (CDK6), as the direct target for miR-329-3p, miR-376c-3p and miR-495-3p. Western blot analyses showed a marked increase in VDAC1 expression, while CDK6 expression was downregulated in diabetic CPCs. Finally, in vitro and in vivo overexpression of miR-30c-5p markedly reduced the apoptotic cell death and preserved MMP in diabetic CPCs via inhibition of VDAC1. CONCLUSIONS/INTERPRETATION: Our results demonstrate that diabetes mellitus induces a marked dysregulation of miRNAs associated with stem cell survival, proliferation and differentiation, and that therapeutic overexpression of prosurvival miR-30c-5p reduced diabetes-induced cell death and loss of MMP in CPCs via the newly identified target for miR-30c-5p, VDAC1.

Experiences of Weight-Loss Surgery in People With Serious Mental Illness: A Qualitative Study.

BACKGROUND: Bariatric surgery is seldom accessed by people with serious mental illness, despite high rates of obesity in this population. It is sometimes assumed that patients with complex psychiatric histories will have poor post-surgical weight loss or exacerbation of psychiatric symptoms, although this is unsubstantiated. OBJECTIVES: A qualitative descriptive study to explore personal experiences and the impact of bariatric surgery on physical and mental well-being and life-quality in individuals with serious mental illness. METHODS: Nine adults with a history of bariatric surgery and concurrent severe depressive disorder, bipolar disorder, or schizoaffective disorder were interviewed about their experiences of bariatric surgery and its outcomes using semi-structured interview schedules. Data were transcribed and inductive thematic analysis undertaken. RESULTS: Five broad themes emerged: (1) surgery was highly effective for weight loss, and resulted in subjective improvements in physical health, quality of life, and mental health described as being able to live a life; (2) recovering from surgery was a tough road, notably in the post-operative period where negative sequelae often anteceded benefits; (3) post-operative support was important, but sometimes insufficient, including from families, mental health services, and surgical teams; (4) most considered surgery life-changing, recommending it to others with mental illness and obesity, two had different experiences; (5) participants considered it discriminatory that people with mental illness were not referred or declined weight loss surgery. CONCLUSIONS: Participants benefited from bariatric surgery and felt it should be offered to others with mental illness, but with additional care and support.

Diabetes induces the activation of pro-ageing miR-34a in the heart, but has differential effects on cardiomyocytes and cardiac progenitor cells.

Increased apoptosis and premature cellular ageing of the diabetic heart underpin the development of diabetic heart disease. The molecular mechanisms underlying these pathologies are still unclear. Here we determined the role of pro-senescence microRNA (miR)-34a in accelerating the ageing of the diabetic heart. RT-PCR analysis showed a significant increase in the level of circulating miR-34a from early stages in asymptomatic type-2 diabetic individuals compared to non-diabetic controls. We also observed significant upregulation of miR-34a in the type-2 human diabetic heart suggesting circulating miR-34a may be cardiac in origin. Moreover, western blot analysis identified marked downregulation of the pro-survival protein sirtuin 1 (SIRT1), a direct target of miR-34a. Analysis of cultured human adult cardiomyocytes exposed to high glucose and cardiac progenitor cells (CPCs) isolated from the diabetic heart confirmed significant upregulation of miR-34a and downregulation of SIRT1, associated with a marked increase in pro-apoptotic caspase-3/7 activity. Although therapeutic inhibition of miR-34a activity restored SIRT1 expression in both cardiomyocytes and CPCs, p53 expression was further upregulated in cardiomyocytes but conversely downregulated in CPCs. In spite of increased p53, miR-34a inhibition significantly reduced high glucose induced apoptotic cell death in cardiomyocytes. However, this effect was not observed in CPCs, which in fact showed reduced proliferation following miR-34a inhibition. Taken together, our results demonstrate upregulation of miR-34a in the diabetic heart and in the circulation from an early stage of the disease. However, inhibition of miR-34a activity has differential effects depending on the cell type, thereby warranting the need to eliminate off-target effects when introducing miR-based therapy.

The diagnostic sensitivity of circulating cardio-enriched microRNAs is increased after normalization of high-density lipoprotein levels.

BACKGROUND: Emerging evidence suggests that microRNAs (miRs) could be a potential biomarker to identify early molecular alterations in the heart. HDL are the major carriers for miRs into the circulation. This study tested whether changes in the level of HDL could affect the diagnostic sensitivity of miRs. METHODS AND RESULTS: Peripheral blood samples were collected from 20 diabetic and 22 age and gender matched non-diabetic patients undergoing coronary artery bypass graft (CABG) surgery for ischemic heart disease (IHD). Total RNA was extracted from the separated plasma and stored in -80°C. Reverse transcription and amplification using specific primers against cardio-enriched miR-1, -34a, -126, -133, and -499 showed significant correlation between HDL levels and miR-1, -133 and -499. Importantly, normalization of miR levels with HDL showed a significant downregulation of miR-1, -133 and -499 in diabetic plasma, which was not observed before normalization with HDL levels. CONCLUSION: Normalization of circulating miR levels with HDL increases the diagnostic sensitivity of circulating miRs.