Long-term glycaemic control with metformin– sulphonylurea–pioglitazone triple therapy in PROactive (PROactive 17)

peer reviewedAims We assessed the long-term glycaemic effects and the safety profile of triple therapy with the addition of pioglitazone vs. placebo in patients with Type 2 diabetes treated with combined metformin–sulphonylurea therapy in the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive). Methods In a post-hoc analysis, we identified patients treated with metformin plus sulphonylurea combination therapy and not receiving insulin at baseline (n = 1314). In those patients, we compared the effects of pioglitazone (force-titrated to 45 mg⁄ day, n = 654) vs. placebo (n = 660) on glycated haemoglobin (HbA1c) reduction, concomitant changes in medications and initiation of permanent insulin use (defined as daily insulin use for a period of ‡ 90 days or ongoing use at death ⁄ final visit). Results Significantly greater reductions in HbA1c and greater proportions of patients with HbA1c at target were noted with pioglitazone vs, placebo, despite a decrease in the use of other oral glucose-lowering agents. Therewas an approximate twofold increase in progression to permanent insulin use in the placebo group vs. the pioglitazone group: 31.1 vs. 16.1%, respectively, when added to combination therapy. The overall safety of themetformin–sulphonylurea–pioglitazone triple therapy was good. Conclusions Intensifying an existing dual oral therapy regimen to a triple oral regimen by adding pioglitazone to the classical metformin–sulphonylurea combination resulted in sustained improvements in glycaemic control and reduced progression to insulin therapy. The advantages and disadvantages of adding pioglitazone instead of adding basal insulin should be assessed further

Quantum Chessboards in the Deuterium Molecular Ion

We present a new algorithm for vibrational control in deuterium molecules that is feasible with current experimental technology. A pump mechanism is used to create a coherent superposition of the D2+ vibrations. A short, intense infrared control pulse is applied after a chosen delay time to create selective interferences. A `chessboard' pattern of states can be realized in which a set of even- or odd-numbered vibrational states can be selectively annihilated or enhanced. A technique is proposed for experimental realization and observation of this effect using 5 fs pulses of 790 nm radiation, with intermediate intensity (5e13 W/cm2)Comment: 12 pages, 5 figure

Ricci-flat Metrics with U(1) Action and the Dirichlet Boundary-value Problem in Riemannian Quantum Gravity and Isoperimetric Inequalities

The Dirichlet boundary-value problem and isoperimetric inequalities for positive definite regular solutions of the vacuum Einstein equations are studied in arbitrary dimensions for the class of metrics with boundaries admitting a U(1) action. We show that in the case of non-trivial bundles Taub-Bolt infillings are double-valued whereas Taub-Nut and Eguchi-Hanson infillings are unique. In the case of trivial bundles, there are two Schwarzschild infillings in arbitrary dimensions. The condition of whether a particular type of filling in is possible can be expressed as a limitation on squashing through a functional dependence on dimension in each case. The case of the Eguchi-Hanson metric is solved in arbitrary dimension. The Taub-Nut and the Taub-Bolt are solved in four dimensions and methods for arbitrary dimension are delineated. For the case of Schwarzschild, analytic formulae for the two infilling black hole masses in arbitrary dimension have been obtained. This should facilitate the study of black hole dynamics/thermodynamics in higher dimensions. We found that all infilling solutions are convex. Thus convexity of the boundary does not guarantee uniqueness of the infilling. Isoperimetric inequalities involving the volume of the boundary and the volume of the infilling solutions are then investigated. In particular, the analogues of Minkowski's celebrated inequality in flat space are found and discussed providing insight into the geometric nature of these Ricci-flat spaces.Comment: 40 pages, 3 figure

MARCH WET AVALANCHE PREDICTION AT BRIDGER BOWL SKI AREA, MONTANA

ABSTRACT: Few avalanche forecast models are tailored specifically for wet avalanche forecasting. Bridger Bowl (intermountain climate) is a good area to develop a wet avalanche probability model. The primary archived data consists of eight variables. The archived data for March from 1968 to 2001 (1996 data unavailable) were used to develop 68 predictor variables related to temperature, snowpack settlement, and precipitation. The original dataset was divided into days with snowfall in the past 48 hours (new snow) and days without (old snow). There were 33 significant old snow variables and 22 significant new snow variables. Six variables are common to both old and new snow. The best predictor variables for old and new snow are different. The variables were analyzed with binomial logistic regression to produce probability models for old snow and for new snow wet avalanche conditions. The old snow model uses the prediction day minimum temperature and the two-day change in total snow depth as predictor variables and has a 89% overall success rate. However, the majority of this success is due to correct prediction of days without wet avalanches (96% of all correct predictions). The new snow model uses the prediction day minimum temperature and three-day cumulative new snow water equivalent as predictor variables, but is less useful. The models are applicable only to Bridger Bowl. The numerical forecast models can be used as one of the tools in the forecasting toolbox but limited data and complexity of process require that the decisions about closure remain in the hands of the ski patrol

MARCH WET AVALANCHE PREDICTION AT BRIDGER BOWL SKI AREA, MONTANA

ABSTRACT: Few avalanche forecast models are tailored specifically for wet avalanche forecasting. Bridger Bowl (intermountain climate) is a good area to develop a wet avalanche probability model. The primary archived data consists of eight variables. The archived data for March from 1968 to 2001 (1996 data unavailable) were used to develop 68 predictor variables related to temperature, snowpack settlement, and precipitation. The original dataset was divided into days with snowfall in the past 48 hours (new snow) and days without (old snow). There were 33 significant old snow variables and 22 significant new snow variables. Six variables are common to both old and new snow. The best predictor variables for old and new snow are different. The variables were analyzed with binomial logistic regression to produce probability models for old snow and for new snow wet avalanche conditions. The old snow model uses the prediction day minimum temperature and the two-day change in total snow depth as predictor variables and has a 89% overall success rate. However, the majority of this success is due to correct prediction of days without wet avalanches (96% of all correct predictions). The new snow model uses the prediction day minimum temperature and three-day cumulative new snow water equivalent as predictor variables, but is less useful. The models are applicable only to Bridger Bowl. The numerical forecast models can be used as one of the tools in the forecasting toolbox but limited data and complexity of process require that the decisions about closure remain in the hands of the ski patrol

Observation of confined current ribbon in JET plasmas

we report the identification of a localised current structure inside the JET plasma. It is a field aligned closed helical ribbon, carrying current in the same direction as the background current profile (co-current), rotating toroidally with the ion velocity (co-rotating). It appears to be located at a flat spot in the plasma pressure profile, at the top of the pedestal. The structure appears spontaneously in low density, high rotation plasmas, and can last up to 1.4 s, a time comparable to a local resistive time. It considerably delays the appearance of the first ELM.Comment: 10 pages, 6 figure

The molecular landscape of the University of Michigan laryngeal squamous cell carcinoma cell line panel

BackgroundLaryngeal squamous cell carcinomas (LSCCs) have a high risk of recurrence and poor prognosis. Patient‐derived cancer cell lines remain important preclinical models for advancement of new therapeutic strategies, and comprehensive characterization of these models is vital in the precision medicine era.MethodsWe performed exome and transcriptome sequencing as well as copy number analysis of a panel of LSCC‐derived cell lines that were established at the University of Michigan and are used in laboratories worldwide.ResultsWe observed a complex array of alterations consistent with those reported in The Cancer Genome Atlas head and neck squamous cell carcinoma project, including aberrations in PIK3CA, EGFR, CDKN2A, TP53, and NOTCH family and FAT1 genes. A detailed analysis of FAT family genes and associated pathways showed disruptions to these genes in most cell lines.ConclusionsThe molecular profiles we have generated indicate that as a whole, this panel recapitulates the molecular diversity observed in patients and will serve as useful guides in selecting cell lines for preclinical modeling.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151290/1/hed25803.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151290/2/hed25803_am.pd

Lower Cardiorenal Risk with Sodium-Glucose Cotransporter-2 Inhibitors versus Dipeptidyl Peptidase-4 Inhibitors in Type 2 Diabetes Patients without Cardiovascular and Renal Diseases: A large multinational observational study

BACKGROUND: We compared new use of sodium-glucose cotransporter-2 inhibitor (SGLT2i) vs. dipeptidyl peptidase-4 inhibitor (DPP4i) and the risk of cardiorenal disease, heart failure (HF) or chronic kidney disease (CKD), in type 2 diabetes patients without history of prevalent cardiovascular and renal disease, defined as cardiovascular- and renal disease (CVRD) free, managed in routine clinical practice. METHODS: In this observational cohort study, patients were identified in electronic health records in England, Germany, Japan, Norway, South Korea and Sweden, from 2012 to 2018. A total of 1 006 577 CVRD-free new users of SGLT2i or DPP4i were propensity score matched 1:1. Unadjusted Cox regression was used to estimate hazard ratios (HRs) for outcomes; cardiorenal disease, HF, CKD, stroke, myocardial infarction (MI) cardiovascular- and all-cause death. RESULTS: Baseline characteristics were well-balanced between the treatment groups (n = 105 130 in each group) with total follow up of 187 955 patient years. Patients were mean 56 years, 43% women and indexed between 2013 and 2018. The most commonly used agents were dapagliflozin (91.7% of exposure time) and sitagliptin/linagliptin (55.0%), in the SGLT2i and DPP4i groups respectively. SGLT2i was associated with lower risk of cardiorenal disease, HF, CKD, all-cause- and cardiovascular death; HR (95% CI) 0.56 (0.42-0.74), 0.71 (0.59-0.86), 0.44 (0.28-0.69), 0.67 (0.59-0.77) and 0.61 (0.44-0.85) respectively. No differences were observed for stroke (0.87 [0.69-1.09]) and MI (0.94 [0.80-1.11]). CONCLUSION: In this multinational observational study, SGLT2i was associated with lower risk of heart failure and chronic kidney disease versus DPP4i in T2D patients otherwise free from both cardiovascular and renal disease

No straight lines – young women’s perceptions of their mental health and wellbeing during and after pregnancy: a systematic review and meta-ethnography

Background: Young mothers face mental health challenges during and after pregnancy including increased rates of depression compared to older mothers. While the prevention of teenage pregnancy in countries such as the United States and the United Kingdom has been a focus for policy and research in recent decades, the need to understand young women’s own experiences has been highlighted. The aim of this meta-ethnography was to examine young women’s perceptions of their mental health and wellbeing during and after pregnancy to provide new understandings of those experiences. Methods: A systematic review and meta-ethnographic synthesis of qualitative research was conducted. Seven databases were systematically searched and forward and backward searching conducted. Papers were included if they were from Organisation for Economic Co-operation and Development countries and explored mental health and wellbeing experiences of young mothers (age under 20 in pregnancy; under 25 at time of research) as a primary research question – or where evidence about mental health and wellbeing from participants was foregrounded. Nineteen papers were identified and the Critical Appraisal Skills Programme checklist for qualitative research used to appraise the evidence. Following the seven-step process of meta-ethnography, key constructs were examined within each study and then translated into one another. Results: Seven translated themes were identified forming a new line of argument wherein mental health and wellbeing was analysed as relating to individual bodily experiences; tied into past and present relationships; underpinned by economic insecurity and entangled with feelings of societal surveillance. There were ‘no straight lines’ in young women’s experiences, which were more complex than dominant narratives around overcoming adversity suggest. Conclusions: The synthesis concludes that health and social care professionals need to reflect on the operation of power and stigma in young women’s lives and its impact on wellbeing. It adds to understanding of young women’s mental health and wellbeing during and after pregnancy as located in physical and structural factors rather than individual capacities alone