Is gut microbiota a relevant and competitive dietary target for cardio-metabolic health? Proceedings of an expert workshop

Background: The gut microbiota is a putative target for dietary interventions for cardio-metabolic health (CMH), including prevention of obesity, type 2 diabetes, and cardiovascular disease. This has generated considerable interest, but the actual feasibility for diet or specific foods to induce measurable, sustained and meaningful benefits for CMH risk by this route remains uncertain. Scope and approach: This report summarises an expert workshop assessing the gut microbiota as a relevant, feasible and competitive target for CMH benefits by dietary interventions. It summarises the expert presentations and overall view of participants on the current status and outlook, considering also implications for the food industry. Key findings and conclusions: Changing the gut microbiota by diet is possible, but an assessment of the impact on CMH risk is still needed, including clarifying advantages above other known dietary routes. The individual gut microbiota composition may in part determine the impact of diet and its effects on health. Therefore, future developments may identify individuals at risk and thus possible modification of the microbiota to achieve benefits in susceptible (sub) populations depending on their initial microbiota composition. Prebiotics currently appear to be the most promising ingredients; however, required doses may be relatively high and the actual role of gut microbiota needs further assessment. Overall, causal evidence linking gut microbiota interventions with CMH benefits are developing in preclinical models but are still lacking in humans. A significant research effort is needed and ongoing to determine whether potential effects can be reliably substantiated

Optimizing fluid–structure interaction systems with immersogeometric analysis and surrogate modeling: Application to a hydraulic arresting gear

This work describes a fluid–structure interaction (FSI) design optimization framework and applies it to improving the structural performance of a water brake used to stop aircraft landing on short runways. Inside the water brake, a dissipative torque is exerted on a rotor through interactions between rotor blades and a surrounding fluid. We seek to optimize blade shape over a parameterized design space, to prevent potentially-damaging stress concentrations without compromising performance. To avoid excessive numbers of costly simulations while exploring the design space, we use a surrogate management framework that combines derivative-free pattern search optimization with automated construction of a low-fidelity surrogate model, requiring only a handful of high-fidelity FSI simulations. We avoid the difficult problem of generating fluid and structure meshes at new points in the design space by using immersogeometric FSI analysis. The structure is analyzed isogeometrically: its design geometry also serves as a computational mesh. This geometry is then immersed in an unfitted fluid mesh that does not depend on the structure’s design parameters. We use this framework to make significant improvements to a baseline design found in the literature. Specifically, there is a 35% reduction of von Mises stress variance and a 25% reduction of maximum of stress, while the resisting torque and mass of the optimized blades remain uncompromised.This article is published as Wu, Michael CH, David Kamensky, Chenglong Wang, Austin J. Herrema, Fei Xu, Marco S. Pigazzini, Aekaansh Verma, Alison L. Marsden, Yuri Bazilevs, and Ming-Chen Hsu. "Optimizing fluid–structure interaction systems with immersogeometric analysis and surrogate modeling: Application to a hydraulic arresting gear." Computer Methods in Applied Mechanics and Engineering 316 (2017): 668-693. doi: 10.1016/j.cma.2016.09.032. Posted with permission.</p

SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation

Sirtuins are NAD(+)-dependent protein deacetylases. They mediate adaptive responses to a variety of stresses, including calorie restriction and metabolic stress. Sirtuin 3 (SIRT3) is localized in the mitochondrial matrix, where it regulates the acetylation levels of metabolic enzymes, including acetyl coenzyme A synthetase 2 (refs 1, 2). Mice lacking both Sirt3 alleles appear phenotypically normal under basal conditions, but show marked hyperacetylation of several mitochondrial proteins. Here we report that SIRT3 expression is upregulated during fasting in liver and brown adipose tissues. During fasting, livers from mice lacking SIRT3 had higher levels of fatty-acid oxidation intermediate products and triglycerides, associated with decreased levels of fatty-acid oxidation, compared to livers from wild-type mice. Mass spectrometry of mitochondrial proteins shows that long-chain acyl coenzyme A dehydrogenase (LCAD) is hyperacetylated at lysine 42 in the absence of SIRT3. LCAD is deacetylated in wild-type mice under fasted conditions and by SIRT3 in vitro and in vivo; and hyperacetylation of LCAD reduces its enzymatic activity. Mice lacking SIRT3 exhibit hallmarks of fatty-acid oxidation disorders during fasting, including reduced ATP levels and intolerance to cold exposure. These findings identify acetylation as a novel regulatory mechanism for mitochondrial fatty-acid oxidation and demonstrate that SIRT3 modulates mitochondrial intermediary metabolism and fatty-acid use during fasting

Incidence of severe critical events in paediatric anaesthesia (APRICOT): a prospective multicentre observational study in 261 hospitals in Europe

Background Little is known about the incidence of severe critical events in children undergoing general anaesthesia in Europe. We aimed to identify the incidence, nature, and outcome of severe critical events in children undergoing anaesthesia, and the associated potential risk factors. Methods The APRICOT study was a prospective observational multicentre cohort study of children from birth to 15 years of age undergoing elective or urgent anaesthesia for diagnostic or surgical procedures. Children were eligible for inclusion during a 2-week period determined prospectively by each centre. There were 261 participating centres across 33 European countries. The primary endpoint was the occurence of perioperative severe critical events requiring immediate intervention. A severe critical event was defined as the occurrence of respiratory, cardiac, allergic, or neurological complications requiring immediate intervention and that led (or could have led) to major disability or death. This study is registered with ClinicalTrials.gov, number NCT01878760. Findings Between April 1, 2014, and Jan 31, 2015, 31â127 anaesthetic procedures in 30â874 children with a mean age of 6·35 years (SD 4·50) were included. The incidence of perioperative severe critical events was 5·2% (95% CI 5·0â5·5) with an incidence of respiratory critical events of 3·1% (2·9â3·3). Cardiovascular instability occurred in 1·9% (1·7â2·1), with an immediate poor outcome in 5·4% (3·7â7·5) of these cases. The all-cause 30-day in-hospital mortality rate was 10 in 10â000. This was independent of type of anaesthesia. Age (relative risk 0·88, 95% CI 0·86â0·90; p<0·0001), medical history, and physical condition (1·60, 1·40â1·82; p<0·0001) were the major risk factors for a serious critical event. Multivariate analysis revealed evidence for the beneficial effect of years of experience of the most senior anaesthesia team member (0·99, 0·981â0·997; p<0·0048 for respiratory critical events, and 0·98, 0·97â0·99; p=0·0039 for cardiovascular critical events), rather than the type of health institution or providers. Interpretation This study highlights a relatively high rate of severe critical events during the anaesthesia management of children for surgical or diagnostic procedures in Europe, and a large variability in the practice of paediatric anaesthesia. These findings are substantial enough to warrant attention from national, regional, and specialist societies to target education of anaesthesiologists and their teams and implement strategies for quality improvement in paediatric anaesthesia. Funding European Society of Anaesthesiology

Incidence of severe critical events in paediatric anaesthesia (APRICOT): a prospective multicentre observational study in 261 hospitals in Europe

Background Little is known about the incidence of severe critical events in children undergoing general anaesthesia in Europe. We aimed to identify the incidence, nature, and outcome of severe critical events in children undergoing anaesthesia, and the associated potential risk factors. Methods The APRICOT study was a prospective observational multicentre cohort study of children from birth to 15 years of age undergoing elective or urgent anaesthesia for diagnostic or surgical procedures. Children were eligible for inclusion during a 2-week period determined prospectively by each centre. There were 261 participating centres across 33 European countries. The primary endpoint was the occurence of perioperative severe critical events requiring immediate intervention. A severe critical event was defined as the occurrence of respiratory, cardiac, allergic, or neurological complications requiring immediate intervention and that led (or could have led) to major disability or death. This study is registered with ClinicalTrials.gov, number NCT01878760. Findings Between April 1, 2014, and Jan 31, 2015, 31 127 anaesthetic procedures in 30 874 children with a mean age of 6.35 years (SD 4.50) were included. The incidence of perioperative severe critical events was 5.2% (95% CI 5.0-5.5) with an incidence of respiratory critical events of 3.1% (2.9-3.3). Cardiovascular instability occurred in 1.9% (1.7-2.1), with an immediate poor outcome in 5.4% (3.7-7.5) of these cases. The all-cause 30-day in-hospital mortality rate was 10 in 10 000. This was independent of type of anaesthesia. Age (relative risk 0.88, 95% CI 0.86-0.90; p<0.0001), medical history, and physical condition (1.60, 1.40-1.82; p<0.0001) were the major risk factors for a serious critical event. Multivariate analysis revealed evidence for the beneficial effect of years of experience of the most senior anaesthesia team member (0.99, 0.981-0.997; p<0.0048 for respiratory critical events, and 0.98, 0.97-0.99; p=0.0039 for cardiovascular critical events), rather than the type of health institution or providers. Interpretation This study highlights a relatively high rate of severe critical events during the anaesthesia management of children for surgical or diagnostic procedures in Europe, and a large variability in the practice of paediatric anaesthesia. These findings are substantial enough to warrant attention from national, regional, and specialist societies to target education of anaesthesiologists and their teams and implement strategies for quality improvement in paediatric anaesthesia