Evidence that stimulation of gluconeogenesis by fatty acid is mediated through thermodynamic mechanisms

AbstractWe have studied the stimulatory effects of palmitate on the rate of glucose synthesis from lactate in isolated hepatocytes. Control of the metabolic flow was achieved by modulating the activity of enolase using graded concentrations of fluoride. Unexpectedly, palmitate stimulated gluconeogenesis even when enolase was rate-limiting. This stimulation was also observed when the activities of phosphoenolpyruvate carboxykinase and aspartate aminotransferase were modulated using graded concentrations of quinolinate and aminooxyacetate, respectively. Linear force-flow relationships were found between the rate of gluconeogenesis and indicators of cellular energy status (i.e. mitochondrial membrane and redox potentials and cellular phosphorylation potential). These findings suggest that the fatty acid stimulation of glucose synthesis is in part mediated through thermodynamic mechanisms

Skin and subcutaneous fascia closure at caesarean section to reduce wound complications: the closure randomised trial

Background: Wound infection is a common complication following caesarean section. Factors influencing the risk of infection may include the suture material for skin closure, and closure of the subcutaneous fascia. We assessed the effect of skin closure with absorbable versus non-absorbable suture, and closure versus non-closure of the subcutaneous fascia on risk of wound infection following Caesarean section. Methods: Women undergoing caesarean birth at an Adelaide maternity hospital were eligible for recruitment to a randomised trial using a 2 × 2 factorial design. Women were randomised to either closure or non-closure of the subcutaneous fascia and to subcuticular skin closure with an absorbable or non-absorbable suture. Participants were randomised to each of the two interventions into one of 4 possible groups: Group 1 - non-absorbable skin suture and non-closure of the subcutaneous fascia; Group 2 - absorbable skin suture and non-closure of the subcutaneous fascia; Group 3 - non-absorbable skin suture and closure of the subcutaneous fascia; and Group 4 - absorbable skin suture and closure of the subcutaneous fascia. The primary outcomes were reported wound infection and wound haematoma or seroma within the first 30 days after birth. Results: A total of 851 women were recruited and randomised, with 849 women included in the analyses (Group 1: 216 women; Group 2: 212 women; Group 3: 212 women; Group 4: 211 women). In women who underwent fascia closure, there was a statistically significant increase in risk of wound infection within 30 days post-operatively for those who had skin closure with an absorbable suture (Group 4), compared with women who had skin closure with a non-absorbable suture (Group 3) (adjusted RR 2.17; 95% CI 1.05, 4.45; p = 0.035). There was no significant difference in risk of wound infection for absorbable vs non-absorbable sutures in women who did not undergo fascia closure. Conclusion: The combination of subcutaneous fascia closure and skin closure with an absorbable suture may be associated with an increased risk of reported wound infection after caesarean section.Amanda J. Poprzeczny, Rosalie M. Grivell, Jennie Louise, Andrea R. Deussen and Jodie M. Dod

A generic estimate of trans-Planckian modifications to the primordial power spectrum in inflation

We derive a general expression for the power spectra of scalar and tensor fluctuations generated during inflation given an arbitrary choice of boundary condition for the mode function at a short distance. We assume that the boundary condition is specified at a short-distance cutoff at a scale $M$ which is independent of time. Using a particular prescription for the boundary condition at momentum $p = M$, we find that the modulation to the power spectra of density and gravitational wave fluctuations is of order $(H/M)$, where $H$ is the Hubble parameter during inflation, and we argue that this behavior is generic, although by no means inevitable. With fixed boundary condition, we find that the shape of the modulation to the power spectra is determined entirely by the deviation of the background spacetime from the de Sitter limit.Comment: 15 pages (RevTeX), 2 figure

Monte Carlo reconstruction of the inflationary potential

We present Monte Carlo reconstruction, a new method for ``inverting'' observational data to constrain the form of the scalar field potential responsible for inflation. This stochastic technique is based on the flow equation formalism and has distinct advantages over reconstruction methods based on a Taylor expansion of the potential. The primary ansatz required for Monte Carlo reconstruction is simply that inflation is driven by a single scalar field. We also require a very mild slow roll constraint, which can be made arbitrarily weak since Monte Carlo reconstruction is implemented at arbitrary order in the slow roll expansion. While our method cannot evade fundamental limits on the accuracy of reconstruction, it can be simply and consistently applied to poor data sets, and it takes advantage of the attractor properties of single-field inflation models to constrain the potential outside the small region directly probed by observations. We show examples of Monte Carlo reconstruction for data sets similar to that expected from the Planck satellite, and for a hypothetical measurement with a factor of five better parameter discrimination than Planck.Comment: 10 pages, 5 figures (RevTeX 4) Version submitted to PRD: references added, minor clarification

The cost-effectiveness of providing antenatal lifestyle advice for women who are overweight or obese: the LIMIT randomised trial

BACKGROUND: Overweight and obesity during pregnancy is common, although robust evidence about the economic implications of providing an antenatal dietary and lifestyle intervention for women who are overweight or obese is lacking. We conducted a health economic evaluation in parallel with the LIMIT randomised trial. Women with a singleton pregnancy, between 10(+0)-20(+0) weeks, and BMI ≥25 kg/m(2) were randomised to Lifestyle Advice (a comprehensive antenatal dietary and lifestyle intervention) or Standard Care. The economic evaluation took the perspective of the health care system and its patients, and compared costs encountered from the additional use of resources from time of randomisation until six weeks postpartum. Increments in health outcomes for both the woman and infant were considered in the cost-effectiveness analysis. Mean costs and effects in the treatment groups allocated at randomisation were compared, and incremental cost effectiveness ratios (ICERs) and confidence intervals (95%) calculated. Bootstrapping was used to confirm the estimated confidence intervals, and to generate acceptability curves representing the probability of the intervention being cost-effective at alternative monetary equivalent values for the outcomes avoiding high infant birth weight, and respiratory distress syndrome. Analyses utilised intention to treat principles. RESULTS: Overall, the increase in mean costs associated with providing the intervention was offset by savings associated with improved immediate neonatal outcomes, rendering the intervention cost neutral (Lifestyle Advice Group $11261.19±$14573.97 versus Standard Care Group $11306.70±$14562.02; p=0.094). Using a monetary value of $20,000 as a threshold value for avoiding an additional infant with birth weight above 4 kg, the probability that the antenatal intervention is cost-effective is 0.85, which increases to 0.95 when the threshold monetary value increases to$45,000. CONCLUSIONS: Providing an antenatal dietary and lifestyle intervention for pregnant women who are overweight or obese is not associated with increased costs or cost savings, but is associated with a high probability of cost effectiveness. Ongoing participant follow-up into childhood is required to determine the medium to long-term impact of the observed, short-term endpoints, to more accurately estimate the value of the intervention on risk of obesity, and associated costs and health outcomes. TRIALS REGISTRATION: Australian and New Zealand Clinical Trials Registry (ACTRN12607000161426).Jodie M Dodd, Sharmina Ahmed, Jonathan Karnon, Wendy Umberger, Andrea R Deussen, Thach Tran, Rosalie M Grivell, Caroline A Crowther, Deborah Turnbull, Andrew J McPhee, Gary Wittert, Julie A Owens, Jeffrey S Robinson and For the LIMIT Randomised Trial Grou

Cosmological parameter estimation and the inflationary cosmology

We consider approaches to cosmological parameter estimation in the inflationary cosmology, focussing on the required accuracy of the initial power spectra. Parametrizing the spectra, for example by power-laws, is well suited to testing the inflationary paradigm but will only correctly estimate cosmological parameters if the parametrization is sufficiently accurate, and we investigate conditions under which this is achieved both for present data and for upcoming satellite data. If inflation is favoured, reliable estimation of its physical parameters requires an alternative approach adopting its detailed predictions. For slow-roll inflation, we investigate the accuracy of the predicted spectra at first and second order in the slow-roll expansion (presenting the complete second-order corrections for the tensors for the first time). We find that within the presently-allowed parameter space, there are regions where it will be necessary to include second-order corrections to reach the accuracy requirements of MAP and Planck satellite data. We end by proposing a data analysis pipeline appropriate for testing inflation and for cosmological parameter estimation from high-precision data.Comment: 15 pages RevTeX file with figures incorporated. Slow-roll inflation module for use with the CAMB program can be found at http://astronomy.cpes.susx.ac.uk/~sleach/inflation/ This version corrects a typo in the definition of z_S (after Eq.1) and supersedes the journal versio

Metformin for women who are overweight or obese during pregnancy for improving maternal and infant outcomes

Publication status and date: New, published in Issue 7, 2018.BACKGROUND:There has been considerable interest in providing antenatal dietary and lifestyle advice for women with obesity or who are overweight during pregnancy, as a strategy to limit gestational weight gain and improve maternal and infant health. However, such antenatal interventions appear to have a modest effect on gestational weight gain and other clinical pregnancy and birth outcomes and additional strategies are required.Metformin is an oral insulin-sensitising medication that acts to decrease blood glucose concentrations. Metformin is commonly used in the treatment of type 2 diabetes mellitus and polycystic ovarian syndrome, and is being used increasingly in the treatment of gestational diabetes, having been shown to result in decreased rates of caesarean birth and neonatal hypoglycaemia. Metformin may be an adjuvant therapy to current antenatal strategies in pregnant women with obesity or who are overweight, acting to reduce glucose production in the liver and improve glucose uptake in smooth muscle cells, and therefore improve the overall metabolic health of women in pregnancy and reduce the risk of known adverse pregnancy outcomes. OBJECTIVES:To evaluate the role of metformin in pregnant women with obesity or who are overweight, on maternal and infant outcomes, including adverse effects of treatment and costs. SEARCH METHODS:We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (11 October 2017), and reference lists of retrieved studies. SELECTION CRITERIA:All published and unpublished randomised controlled trials evaluating metformin use (compared with placebo or no metformin) in women with obesity or who are overweight in pregnancy for improving outcomes, alone or in combination with other interventions were eligible for inclusion. DATA COLLECTION AND ANALYSIS:Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We used the GRADE approach to assess the quality of the evidence. MAIN RESULTS:We included three studies which randomised women (1099) with a body mass index (BMI) of 30 kg/m2 (1 study) and 35 kg/m2 (2 studies), with outcomes available for 1034 participants. None of the studies assessed women with a BMI between 25 kg/m2and 29.9 kg/m2, therefore we could not assess the use of metformin in women considered overweight. We did not identify studies of metformin in combination with another treatment. Two other studies are ongoing.All three included studies were randomised controlled trials and compared metformin with placebo, commencing early in the second trimester. Doses ranged from 500 mg twice daily to 3.0 g per day. All three studies (two in the UK, one in Egypt) included women attending hospitals for antenatal care.Two studies were generally at a low risk of bias across the majority of domains. We assessed the third study as being at an unclear risk of selection bias, performance and detection bias due to insufficient information in the report. We assessed the trial as being at a low risk of attrition bias and other bias; we felt it was at a high risk of reporting bias.The primary outcome for this review was infant birthweight large-for-gestational-age (> 90th centile for gestational age and infant sex). Women who received metformin or placebo had a similar risk of their baby being born large for his or her gestational age (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.70 to 1.30; 2 studies, 831 infants; high-quality evidence).Women who received metformin may have a slightly lower gestational weight gain (mean difference (MD) -2.60 kg, 95% CI -5.29 to 0.10; 3 studies, 899 women; low-quality evidence).Metformin may make little or no difference in the risk of women developing gestational hypertension (average RR 1.02, 95% CI 0.54 to 1.94; 3 studies, 1040 women; low-quality evidence) or pre-eclampsia (RR 0.74, 95% CI 0.09 to 6.28; 2 studies, 840 women; low-quality evidence). Metformin probably makes little or no difference in the risk of women developing gestational diabetes (RR 0.85, 95% CI 0.61 to 1.19; 3 studies, 892 women; moderate-quality evidence).One study of 400 women reported women receiving metformin were more likely to experience any adverse effect compared with women receiving placebo (RR 1.63, 95% CI 1.27 to 2.08; 1 study, 400 women). Adverse effects included abdominal pain, diarrhoea, or headache. When considering individual side effects, women receiving metformin were more likely to experience diarrhoea than women receiving placebo (RR 2.34, 95% CI 1.74 to 3.14; 797 women; 2 studies, 797 women; high-quality evidence). No other important differences were identified between Metformin and placebo for other maternal secondary outcomes, including: caesarean birth, birth before 37 weeks of pregnancy, shoulder dystocia, perineal tear, or postpartum haemorrhage.In terms of other infant outcomes, there was little or no difference in the infant birthweight (MD 6.39 g, 95% CI -81.15 to 93.92; 2 studies, 834 infants; high-quality evidence). There were no other important differences identified for other infant secondary outcomes in this review: hypoglycaemia (low blood sugar); hyperbilirubinaemia (jaundice); Apgar score less than 7 at five minutes; or stillbirth and neonatal death. Only one study reported admission to the neonatal intensive care unit (NICU), indicating similar rates of admission between women receiving metformin or placebo; no other admission data were reported to assess differences in costs. AUTHORS' CONCLUSIONS:There is insufficient evidence to support the use of metformin for women with obesity in pregnancy for improving maternal and infant outcomes. Metformin was, however, associated with increased risk of adverse effects, particularly diarrhoea. The quality of the evidence in this review varied from high to low, with downgrading decisions based on study limitations and inconsistency.There were only a small number of studies included in this review. Furthermore, none of the included studies included women categorised as 'overweight' and no trials looked at metformin in combination with another treatment.Future research is required in order to further evaluate the role of metformin therapy in pregnant women with obesity or who are overweight, as a strategy to improve maternal and infant health, alone or as an adjuvant to dietary and lifestyle advice.Jodie M Dodd, Rosalie M Grivell, Andrea R Deussen, William M Hagu

Nutrition during pregnancy, lactation and early childhood and its implications for maternal and long-term child health: the early nutrition project recommendations

BACKGROUND:A considerable body of evidence accumulated especially during the last decade, demonstrating that early nutrition and lifestyle have long-term effects on later health and disease ("developmental or metabolic programming"). METHODS:Researchers involved in the European Union funded international EarlyNutrition research project consolidated the scientific evidence base and existing recommendations to formulate consensus recommendations on nutrition and lifestyle before and during pregnancy, during infancy and early childhood that take long-term health impact into account. Systematic reviews were performed on published dietary guidelines, standards and recommendations, with special attention to long-term health consequences. In addition, systematic reviews of published systematic reviews on nutritional interventions or exposures in pregnancy and in infants and young children aged up to 3 years that describe effects on subsequent overweight, obesity and body composition were performed. Experts developed consensus recommendations incorporating the wide-ranging expertise from additional 33 stakeholders. FINDINGS:Most current recommendations for pregnant women, particularly obese women, and for young children do not take long-term health consequences of early nutrition into account, although the available evidence for relevant consequences of lifestyle, diet and growth patterns in early life on later health and disease risk is strong. INTERPRETATION:We present updated recommendations for optimized nutrition before and during pregnancy, during lactation, infancy and toddlerhood, with special reference to later health outcomes. These recommendations are developed for affluent populations, such as women and children in Europe, and should contribute to the primary prevention of obesity and associated non-communicable diseases.Berthold Koletzko, K.M. Godfrey, Lucilla Poston, Hania Szajewska, Johannes B. van Goudoever, Marita de Waard, Brigitte Brands, Rosalie M. Grivell, Andrea R. Deussen, Jodie M. Dodd, Bernadeta Patro-Golab, Bartlomiej M. Zalewski, EarlyNutrition Project Systematic Review Grou