Contemporary reproductive outcomes for patients with polycystic ovary syndrome: a retrospective observational study

Context Polycystic ovary syndrome (PCOS) is the commonest cause of anovulatory infertility and may be associated with adverse pregnancy and neonatal outcomes. However, it is difficult to establish how much of this risk is due to PCOS and how much to obesity. Objective To determine the impact of PCOS upon fertility, pregnancy and neonatal outcomes. Design and setting Data were extracted from the Clinical Practice Research Datalink (CPRD), a longitudinal anonymized primary care research database in the UK. Patients with a diagnosis of PCOS were matched to controls (1:2) by age (+/-1 year), BMI (+/- 3 units) and CPRD practice. Standardised fertility ratios (SFR) before and after diagnosis (index date) were calculated. Rates of miscarriage, pre-eclampsia, gestational diabetes, premature delivery, delivery method and neonatal outcomes were compared. Results 9,068 women with PCOS matched study criteria. Prior to index date the SFR for patients with PCOS was 0.80 (95% CI 0.77-0.83); following index date it was 1.16 (1.12-1.20). The adjusted odds ratios (OR) for miscarriage (1.70; 1.56-1.84), pre-eclampsia (1.32; 1.16-1.49), gestational diabetes (1.41; 1.2-1.66) and premature delivery (1.25; 1.1-1.43) were all increased compared to controls. Of PCOS births, 27.7% were by Caesarean section compared with 23.7% of controls (1.13; 1.05-1.21). Infants born to mothers with PCOS had an increased risk of neonatal jaundice (1.20; 1.03-1.39) and respiratory complications (1.20; 1.06-1.37). Conclusions PCOS is associated with subfertility but fertility rates are restored to those of the background population following diagnosis. Pregnancy complications and adverse neonatal outcomes are more prevalent for women with PCOS independently of obesity

Bariatric surgery is accompanied by changes in extracellular vesicle-associated and plasma Fatty Acid Binding Protein 4

BACKGROUND: Bariatric surgery markedly reduces fat mass with beneficial effects on cardiometabolic health but the mechanisms involved are not fully understood. Extracellular vesicles (EVs) are secreted by a variety of cells, including adipocytes, and may mediate some of these benefits. However, the effects of bariatric surgery on circulating EVs are unclear. METHODS: Concentration of plasma EVs isolated by ultracentrifugation at baseline, 1 and 6 months post-bariatric surgery (n = 20) was established using Nanoparticle Tracking Analysis. EV origin (CD9: exosome; CD41: platelet; CD235a: erythrocyte; CD11b: leukocyte; CD144: endothelial), cytokine (interferon γ, interleukin-6, TNF-α) and adipocyte marker (adiponectin, FABP4, PPARγ) expression was measured by time-resolved fluorescence immunoassay. RESULTS: EV concentration and cell-of-origin markers (CD41, CD235a, CD11b, CD144) did not alter in response to surgery, neither did EV-expressed interferon γ, IL-6, TNF-α, adiponectin, PPARγ or CD9. EV-derived fatty acid binding protein 4 (FABP4) increased at 1 month (+ 49%) before returning to baseline by 6 months (- 51%, p < 0.05), corresponding to similar changes in circulating plasma FABP4 (+ 22 and - 24% at 1 and 6 months, respectively; p < 0.001). Patients who underwent biliopancreatic diversion had lower FABP4-expressing EVs at 6 months compared to those who underwent sleeve gastrectomy/gastric banding (p < 0.05), despite similar percentage weight reduction (- 19 vs - 20%, respectively). CD9 expression correlated with EV-expressed FABP4, adiponectin, TNF-α and interferon γ (r = 0.5, r = 0.59, r = 0.53, r = 0.41, respectively, p < 0.005), suggesting transport by an EV population of exosomal rather than microvesicular origin. CONCLUSIONS: Bariatric surgery leads to a transient change in circulating EV- and plasma-derived FABP4, reflecting alterations in adipose tissue homeostasis

Oxytocin therapy in hypopituitarism: Challenges and opportunities

SummaryPatients with hypopituitarism display impaired quality of life and excess morbidity and mortality, despite apparently optimal pituitary hormone replacement. Oxytocin is a neuropeptide synthesized in the anterior hypothalamus which plays an important role in controlling social and emotional behaviour, body weight and metabolism. Recent studies have suggested that a deficiency of oxytocin may be evident in patients with hypopituitarism and craniopharyngioma, and that this may be associated with deficits in cognitive empathy. Preliminary data hint at potential benefits of oxytocin therapy in improving these deficits and the accompanying metabolic disturbances that are common in these conditions. However, several challenges remain, including an incomplete understanding of the regulation and mechanisms of action of oxytocin, difficulties in accurately measuring oxytocin levels and in establishing a diagnosis of oxytocin deficiency, and a need to determine both the optimal mode of administration for oxytocin therapy and an acceptable safety profile with long‐term use. This review considers the data linking oxytocin to the neuropsychological and metabolic disturbances evident in patients with craniopharyngioma and hypopituitarism, and describes the challenges that need to be overcome before replacement therapy can be considered as a therapeutic option in clinical practice.</jats:p

Nuclear hyaluronidase 2 drives alternative splicing of CD44 pre-mRNA to determine profibrotic or antifibrotic cell phenotype

The cell surface protein CD44 is involved in diverse physiological processes, and its aberrant function is linked to various pathologies such as cancer, immune dysregulation, and fibrosis. The diversity of CD44 biological activity is partly conferred by the generation of distinct CD44 isoforms through alternative splicing. We identified an unexpected function for the ubiquitous hyaluronan-degrading enzyme, hyaluronidase 2 (HYAL2), as a regulator of CD44 splicing. Standard CD44 is associated with fibrotic disease, and its production is promoted through serine-arginine–rich (SR) protein–mediated exon exclusion. HYAL2 nuclear translocation was stimulated by bone morphogenetic protein 7, which inhibits the myofibroblast phenotype. Nuclear HYAL2 displaced SR proteins from the spliceosome, thus enabling HYAL2, spliceosome components (U1 and U2 small nuclear ribonucleoproteins), and CD44 pre-mRNA to form a complex. This prevented double-exon splicing and facilitated the inclusion of CD44 exons 11 and 12, which promoted the accumulation of the antifibrotic CD44 isoform CD44v7/8 at the cell surface. These data demonstrate previously undescribed mechanisms regulating CD44 alternative splicing events that are relevant to the regulation of cellular phenotypes in progressive fibrosis

Cardiovascular and renal outcomes following percutaneous coronary intervention in a population with renal disease: a case-control study

Background Patients with renal disease are less likely to undergo percutaneous coronary intervention (PCI) due to concerns about poor outcomes. Aim We describe outcomes following PCI in individuals with chronic kidney disease (CKD), as compared with matched controls with comparable CKD who did not undergo PCI. We also identified factors predictive of poor outcomes following PCI amongst patients with CKD. Design Retrospective observational case-control study. Methods Cases were individuals with CKD (stages 1–5) undergoing PCI between 2008 and 2014. Controls were age, gender and creatinine-matched individuals not requiring PCI. We compared mortality between groups using Kaplan–Meier curves and Cox regression modelling. We assessed changes in serum creatinine using Wilcoxon Rank testing. We explored the relationship between biochemical and haematological measures (baseline creatinine, calcium, phosphate, calcium-phosphate product, parathyroid hormone, white cell count, haemoglobin, platelet count, c-reactive protein and total cholesterol) and post-PCI mortality, using logistic regression. Results We identified 144 cases and 144 controls. Mortality was significantly lower amongst cases compared with controls [hazard ratio 0.46 (95% confidence intervals 0.31, 0.69)]. PCI did not result in a significant change in renal function (P=0.52). Amongst cases, serum creatinine and calcium-phosphate product were predictors of mortality following PCI. Conclusion Cases undergoing PCI had lower mortality, and PCI was not associated with accelerated CKD progression. On this data, PCI should not be deferred as a treatment option in patients with CKD. Serum creatinine and calcium-phosphate product predict mortality following PCI in this cohort, and may be useful in risk-stratifying patients with CKD being considered for PCI

A New Spin on Galactic Dust

We present a new puzzle involving Galactic microwave emission and attempt to resolve it. On one hand, a cross-correlation analysis of the WHAM H-alpha map with the Tenerife 10 and 15 GHz maps shows that the well-known DIRBE correlated microwave emission cannot be dominated by free-free emission. On the other hand, recent high resolution observations in the 8-10 GHz range with the Green Bank 140 ft telescope by Finkbeiner et al. failed to find the corresponding 8 sigma signal that would be expected in the simplest spinning dust models. So what physical mechanism is causing this ubiquitous dust-correlated emission? We argue for a model predicting that spinning dust is the culprit after all, but that the corresponding small grains are well correlated with the larger grains seen at 100 micron only on large angular scales. In support of this grain segregation model, we find the best spinning dust template to involve higher frequency maps in the range 12-60 micron, where emission from transiently heated small grains is important. Upcoming CMB experiments such as ground-based interferometers, MAP and Planck LFI with high resolution at low frequencies should allow a definitive test of this model.Comment: Minor revisions to match accepted ApJ version. 6 pages, 4 figs. Color figures and more foreground information at http://www.hep.upenn.edu/~angelica/foreground.html#spin or from [email protected]

Women with Polycystic Ovary Syndrome have an increased risk of major cardiovascular events: a population study

Context The effects of Polycystic Ovary Syndrome (PCOS) on cardiovascular morbidity and mortality are unclear. Objective To establish the relative risk of myocardial infarction (MI), stroke, angina, revascularization and cardiovascular mortality for women with PCOS. Design Data were extracted from the Clinical Practice Research Datalink Aurum database. Patients with PCOS were matched to controls (1:1) by age, body mass index (BMI) category and primary care practice. The primary outcome was the time to major adverse cardiovascular event (MACE); a composite endpoint incorporating MI, stroke, angina, revascularization and cardiovascular mortality. Secondary outcomes were the individual MACE endpoints. Results Of 219,034 with a diagnosis of PCOS, 174,660 (79.7%) met the eligibility criteria and were matched. Crude rates of the composite endpoint, MI, stroke, angina, revascularization and cardiovascular mortality were respectively 82.7, 22.7, 27.4, 32.8, 10.5 and 6.97 per 100,000 patient-years for cases, and 64.3, 15.9, 25.7, 19.8, 7.13 and 7.75 per 100,000 patient-years for controls. In adjusted cox proportional hazard models (CPHM), the hazard ratios [HR] were 1.26 (95% confidence interval=1.13-1.41), 1.38 (1.11-1.72), 1.60 (1.32-1.94) and 1.50 (1.08-2.07) for the composite outcome, MI, angina and revascularization, respectively. In a time-dependent CPHM, weight gain (HR 1.01 [1.00-1.01]), prior type 2 diabetes (T2DM) (HR 2.40 [1.76-3.30]) and social deprivation (HR 1.53 [1.11-2.11]) increased risk of progression to the composite endpoint. Conclusions The risk of incident MI, angina and revascularization is increased in young women with PCOS. Weight and T2DM are potentially modifiable risk factors amenable to intervention

Evaluation of the clinical effectiveness of a work-based mentoring programme to develop clinical reasoning on patient outcome: A stepped wedge cluster randomised controlled trial

BackgroundDespite persistent calls to measure the effectiveness of educational interventions on patient outcomes, few studies have been conducted. Within musculoskeletal physiotherapy, the effects of clinical mentoring on postgraduate physiotherapists have been explored, but its impact on patient outcomes is unknown. The objective of this trial was to assess the effectiveness of a work-based mentoring programme to facilitate physiotherapist clinical reasoning on patient outcomes.MethodsIn a stepped-wedge cluster RCT in the musculoskeletal physiotherapy outpatient departments of a large NHS organisation, 16 physiotherapists were randomised by cluster to receive the intervention-150 hours of mentored clinical practice-at one of 3 time periods; control was usual training. 441 patients submitted outcome measures: Patient-Specific Functional Scale (PSFS) (primary outcome measure), EQ-5D-5L, patient activation and patient satisfaction (secondary outcome measures). A further secondary outcome measure of physiotherapist performance was collected by an independent assessor observing the physiotherapists practice.Results80.0% of intervention patients achieved clinically significant PSFS scores compared with 63.8% of control patients. Binary logistic regression analysis modelling for time, cluster and patient characteristics showed strong statistical evidence for this difference (p = 0.023; odds ratio 4.24, 95%CI 1.22, 14.79). Physiotherapist performance scores improved from a mean of 47.8% (SD 3.60) pre-intervention to a mean of 56.0% (SD 4.24) (pConclusionThis is the first study that we aware of that provides patient outcomes measurement of an established educational intervention in physiotherapy, providing evidence that this type of intervention positively impacts patient outcomes and physiotherapist performance. This provides a basis for further research in education across other healthcare disciplines and outcome measures

Diabetic Retinopathy in Newly Diagnosed Subjects With Type 2 Diabetes Mellitus: Contribution of β-Cell Function

Purpose: The association of hyperglycemia and diabetic retinopathy (DR) in established type 2 diabetes mellitus (T2DM) subjects is well accepted. However, the association between β-cell responsiveness and insulin sensitivity leading to fasting and postprandial hyperglycemia with DR in newly diagnosed treatment-naïve T2DM subjects remain unreported. Methods: A total of 544 newly diagnosed treatment-naïve T2DM subjects were screened for DR (digital photography) and underwent a standardized meal tolerance test. Serial plasma glucose and insulin levels were measured, and fasting (M0) and postprandial β-cell responsiveness calculated Calculating Pancreatic Response Program along with homeostasis model assessment-β cell function (HOMA-B) and HOMA-Insulin Sensitivity. A subgroup of 201 subjects also underwent a frequently sampled IV glucose tolerance test and the acute insulin response to glucose, insulin sensitivity, and glucose effectiveness (SG) estimated (MINMOD model). Results: A total of 16.5% (90) subjects had DR at diagnosis. Subjects with DR had significantly reduced M0, HOMA-B and SG leading to higher fasting and postprandial (2 hour) glucose and significantly lower fasting and postprandial (2 hour) insulin. Factors independently associated with DR in multivariate logistic regression analysis were M0, HOMA-B, and SG with fasting and postprandial (2 hour) glucose and insulin. There was no statistical difference in glycated hemoglobin, systolic blood pressure, acute insulin response to glucose, and insulin sensitivity between those with or without DR. Principal Conclusions: In this cohort of newly diagnosed T2DM subjects, DR is associated with reduced β-cell responsiveness, resulting from β-cell failure rather than insulin resistance, leading to fasting and postprandial hyperglycemia and hypoinsulinemi

What are the key issues regarding the role of geothermal energy in meeting energy needs in the global south?

Globally, the potential of geothermal far exceeds that of all other renewable sources together, although investment in the other sources to date has far exceeded investment in geothermal. World Energy Assessment estimates in 2000 for the global potential of all renewables (EJ/yr) were Geothermal 5000, Solar 1575, Wind 640, Biomass 276, Hydro 50, giving a total of 7541 (UNDP, 2000). When installed, geothermal plants have a far higher capacity factor than other sources (solar depends on the level of direct insolation, wind power on wind, etc.); estimates (REN21, 2009) give wind-power 21%, solar PV 14% but geothermal is at least as high as 75% and often more than 95%, given that once a plant is established it operates continuously except for routine down-time for maintenance and rare break-downs