Individuality and ethnicity eclipse a short-term dietary intervention in shaping microbiomes and viromes.

Many diseases linked with ethnic health disparities associate with changes in microbial communities in the United States, but the causes and persistence of ethnicity-associated microbiome variation are not understood. For instance, microbiome studies that strictly control for diet across ethnically diverse populations are lacking. Here, we performed multiomic profiling over a 9-day period that included a 4-day controlled vegetarian diet intervention in a defined geographic location across 36 healthy Black and White females of similar age, weight, habitual diets, and health status. We demonstrate that individuality and ethnicity account for roughly 70% to 88% and 2% to 10% of taxonomic variation, respectively, eclipsing the effects a short-term diet intervention in shaping gut and oral microbiomes and gut viromes. Persistent variation between ethnicities occurs for microbial and viral taxa and various metagenomic functions, including several gut KEGG orthologs, oral carbohydrate active enzyme categories, cluster of orthologous groups of proteins, and antibiotic-resistant gene categories. In contrast to the gut and oral microbiome data, the urine and plasma metabolites tend to decouple from ethnicity and more strongly associate with diet. These longitudinal, multiomic profiles paired with a dietary intervention illuminate previously unrecognized associations of ethnicity with metagenomic and viromic features across body sites and cohorts within a single geographic location, highlighting the importance of accounting for human microbiome variation in research, health determinants, and eventual therapies. Trial Registration: ClinicalTrials.gov ClinicalTrials.gov Identifier: NCT03314194.

Gut Microbiota and Microbial Metabolism in Early Risk of Cardiometabolic Disease.

Cardiometabolic disease comprises cardiovascular and metabolic dysfunction and underlies the leading causes of morbidity and mortality, both within the United States and worldwide. Commensal microbiota are implicated in the development of cardiometabolic disease. Evidence suggests that the microbiome is relatively variable during infancy and early childhood, becoming more fixed in later childhood and adulthood. Effects of microbiota, both during early development, and in later life, may induce changes in host metabolism that modulate risk mechanisms and predispose toward the development of cardiometabolic disease. In this review, we summarize the factors that influence gut microbiome composition and function during early life and explore how changes in microbiota and microbial metabolism influence host metabolism and cardiometabolic risk throughout life. We highlight limitations in current methodology and approaches and outline state-of-the-art advances, which are improving research and building toward refined diagnosis and treatment options in microbiome-targeted therapies.

Microbiome-associated human genetic variants impact phenome-wide disease risk.

Human genetic variation associates with the composition of the gut microbiome, yet its influence on clinical traits remains largely unknown. We analyzed the consequences of nearly a thousand gut microbiome-associated variants (MAVs) on phenotypes reported in electronic health records from tens of thousands of individuals. We discovered and replicated associations of MAVs with neurological, metabolic, digestive, and circulatory diseases. Five significant MAVs in these categories correlate with the relative abundance of microbes down to the strain level. We also demonstrate that these relationships are independently observed and concordant with microbe by disease associations reported in case-control studies. Moreover, a selective sweep and population differentiation impacted some disease-linked MAVs. Combined, these findings establish triad relationships among the human genome, microbiome, and disease. Consequently, human genetic influences may offer opportunities for precision diagnostics of microbiome-associated diseases but also highlight the relevance of genetic background for microbiome modulation and therapeutics.

Comparing the clinical practice and prescribing safety of locum and permanent doctors: observational study of primary care consultations in England.

BACKGROUND: Temporary doctors, known as locums, are a key component of the medical workforce in the NHS but evidence on differences in quality and safety between locum and permanent doctors is limited. We aimed to examine differences in the clinical practice, and prescribing safety for locum and permanent doctors working in primary care in England. METHODS: We accessed electronic health care records (EHRs) for 3.5 million patients from the CPRD GOLD database with linkage to Hospital Episode Statistics from 1st April 2010 to 31st March 2022. We used multi-level mixed effects logistic regression to compare consultations with locum and permanent GPs for several patient outcomes including general practice revisits; prescribing of antibiotics; strong opioids; hypnotics; A&E visits; emergency hospital admissions; admissions for ambulatory care sensitive conditions; test ordering; referrals; and prescribing safety indicators while controlling for patient and practice characteristics. RESULTS: Consultations with locum GPs were 22% more likely to involve a prescription for an antibiotic (OR = 1.22 (1.21 to 1.22)), 8% more likely to involve a prescription for a strong opioid (OR = 1.08 (1.06 to 1.09)), 4% more likely to be followed by an A&E visit on the same day (OR = 1.04 (1.01 to 1.08)) and 5% more likely to be followed by an A&E visit within 1 to 7 days (OR = 1.05 (1.02 to 1.08)). Consultations with a locum were 12% less likely to lead to a practice revisit within 7 days (OR = 0.88 (0.87 to 0.88)), 4% less likely to involve a prescription for a hypnotic (OR = 0.96 (0.94 to 0.98)), 15% less likely to involve a referral (OR = 0.85 (0.84 to 0.86)) and 19% less likely to involve a test (OR = 0.81 (0.80 to 0.82)). We found no evidence that emergency admissions, ACSC admissions and eight out of the eleven prescribing safety indicators were different if patients were seen by a locum or a permanent GP. CONCLUSIONS: Despite existing concerns, the clinical practice and performance of locum GPs did not appear to be systematically different from that of permanent GPs. The practice and performance of both locum and permanent GPs is likely shaped by the organisational setting and systems within which they work.

The consumption of animal products is associated with plasma levels of alpha-aminoadipic acid (2-AAA).

BACKGROUND AND AIMS: The cardiometabolic disease-associated metabolite, alpha-aminoadipic acid (2-AAA) is formed from the breakdown of the essential dietary amino acid lysine. However, it was not known whether elevated plasma levels of 2-AAA are related to dietary nutrient intake. We aimed to determine whether diet is a determinant of circulating 2-AAA in healthy individuals, and whether 2-AAA is altered in response to dietary modification. METHODS AND RESULTS: We investigated the association between 2-AAA and dietary nutrient intake in a cross-sectional study of healthy individuals (N = 254). We then performed a randomized cross-over dietary intervention trial to investigate the effect of lysine supplementation (1 week) on 2-AAA in healthy individuals (N = 40). We further assessed the effect of a vegetarian diet on 2-AAA in a short-term (4-day) dietary intervention trial in healthy omnivorous women (N = 35). We found that self-reported dietary intake of animal products, including meat, poultry, and seafood, was associated with higher plasma 2-AAA cross-sectionally (P < 0.0001). Supplementary dietary lysine (5g/day) caused no significant increase in plasma 2-AAA; however, plasma 2-AAA was altered by general dietary modification. Further, plasma 2-AAA was significantly reduced by a short-term vegetarian diet (P = 0.003). CONCLUSION: We identified associations between plasma 2-AAA and consumption of animal products, which were validated in a vegetarian dietary intervention trial, but not in a trial designed to specifically increase the 2-AAA amino acid precursor lysine. Further studies are warranted to investigate whether implementation of a vegetarian diet improves cardiometabolic risk in individuals with elevated 2-AAA.

Providing technical assistance: lessons learned from the first three years of the WHO Adolescent and Youth Sexual and Reproductive Health and Rights Technical Assistance Coordination Mechanism.

Young people's sexual and reproductive health (SRH) continues to be a major challenge in low and middle-income countries, with implications for public health now and in the future. Fortunately there is a growing array of evidence-based interventions, and commitments from governments, development partners and donors, to support programmes that aim to improve young people's SRH.However, in some situations, the technical assistance that governments feel that they need to strengthen and implement national policies and strategies, to move from words to action, is not available. The WHO Adolescent and Youth Sexual and Reproductive Health and Rights (AYSRHR) Technical Assistance (TA) Coordination Mechanism was initiated to help fill this technical assistance gap; to respond to TA requests from ministries of health in ways that are timely, efficient, effective and contribute to strengthening capacity.This paper describes the process of developing the Technical Assistance Coordination Mechanism (TA Mechanism) and the outcomes, experiences and lessons learned after three years of working. It triangulates the findings from a preliminary review of the literature and discussions with selected key informants; the outcomes from a series of structured review meetings; and the documented processes and results of the technical assistance provided to countries.The lessons learned focus on three aspects of the TA Mechanism. How it was conceptualized and designed: through listening to people who provide and receive AYSRHR TA and by reviewing and synthesizing past experiences of TA provision. What the TA Mechanism has achieved: a standardized process for TA provision, at different stages for a range of AYSRHR issues in ten countries in three geographic regions. And what worked well and what did not: which common challenges was the TA Mechanism able to address and which ones persisted despite efforts to avoid or resolve them. The paper ends with the implications of the lessons learned for future action.

Heart Disease and Stroke Statistics-2022 Update: A Report From the American Heart Association.

BACKGROUND: The American Heart Association, in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health. The Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, heart failure, valvular disease, venous disease, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs). METHODS: The American Heart Association, through its Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States to provide the most current information available in the annual Statistical Update. The 2022 Statistical Update is the product of a full year's worth of effort by dedicated volunteer clinicians and scientists, committed government professionals, and American Heart Association staff members. This year's edition includes data on the monitoring and benefits of cardiovascular health in the population and an enhanced focus on social determinants of health, adverse pregnancy outcomes, vascular contributions to brain health, and the global burden of cardiovascular disease and healthy life expectancy. RESULTS: Each of the chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics. CONCLUSIONS: The Statistical Update represents a critical resource for the lay public, policymakers, media professionals, clinicians, health care administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.

Second ionization constant of sulfuric acid in H2O and D2O from 150 to 300 °C at p = 11.5 MPa using flow AC conductivity.

A custom-built flow-through AC conductivity instrument was used to measure the deuterium isotope effect on the ionization quotient of bisulfate from 150 to 300 °C, at p = 11.5 MPa. Standardized solutions of KCl, HCl, KOH, KHSO4, K2SO4, and H2SO4 were prepared in light and heavy waters and their conductivities were measured and fitted with the Quint-Viallard conductivity model to obtain single ion conductivities at infinite dilution for K+, Cl-, H+, OH-, HSO4-, and SO42-. These are the first conductivities of DSO4- and SO42- measured in heavy water at any temperature, and the first ionization constants for bisulfate reported in heavy water above 225 °C. The deuterium isotope effect on the chemical equilibrium constant, ΔpK2a = pK2a,D - pK2a,H, was found to increase with temperature, in contrast to the behaviour seen for other simple oxyacids.

The use of locum doctors in the NHS - results of a national survey of NHS Trusts in England.

BACKGROUND: Locum working in healthcare organisations has benefits for individual doctors and organisations but there are concerns about the impact of locum working on continuity of care, patient safety, team function and cost. We conducted a national survey of NHS Trusts in England to explore locum work, and better understand why and where locum doctors were needed; how locum doctors were engaged, supported, perceived and managed; and any changes being made in the way locums are used. METHODS: An online survey was sent to 191 NHS Trusts and 98 were returned (51%) including 66 (67%) acute hospitals, 26 (27%) mental health and six (6%) community health providers. Data was analysed using frequency tables, t-tests and correlations. Free-text responses were analysed using thematic analysis. RESULTS: Most NHS Trusts use locums frequently and for varying lengths of time. Trusts prefer to use locums from internal locum banks but frequently rely on locum agencies. The benefits of using locums included maintaining workforce capacity and flexibility. Importantly, care provided by locums was generally viewed as the same or somewhat worse when compared to care provided by permanent doctors. The main disadvantages of using locum agencies included cost, lack of familiarity and impact on organisational development. Some respondents felt that locums could be unreliable and less likely to be invested in quality improvement. NHS Trusts were broadly unfamiliar with the national guidance from NHS England for supporting locums and there was a focus on processes like compliance checks and induction, with less focus on providing feedback and support for appraisal. CONCLUSIONS: Locum doctors provide a necessary service within NHS Trusts to maintain workforce capacity and provide patient care. There are potential issues related to the way that locums are perceived, utilised, and supported which might impact the quality of the care that they provide. Future research should consider the arrangements for locum working and the performance of locums and permanent doctors, investigating the organisation of locums in order to achieve safe and high-quality care for patients.

Heart Disease and Stroke Statistics-2021 Update: A Report From the American Heart Association.

BACKGROUND: The American Heart Association, in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health. The Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, heart failure, valvular disease, venous disease, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs). METHODS: The American Heart Association, through its Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States to provide the most current information available in the annual Statistical Update. The 2021 Statistical Update is the product of a full year's worth of effort by dedicated volunteer clinicians and scientists, committed government professionals, and American Heart Association staff members. This year's edition includes data on the monitoring and benefits of cardiovascular health in the population, an enhanced focus on social determinants of health, adverse pregnancy outcomes, vascular contributions to brain health, the global burden of cardiovascular disease, and further evidence-based approaches to changing behaviors related to cardiovascular disease. RESULTS: Each of the 27 chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics. CONCLUSIONS: The Statistical Update represents a critical resource for the lay public, policy makers, media professionals, clinicians, health care administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.

Genome-wide analysis identifies novel susceptibility loci for myocardial infarction.

AIMS: While most patients with myocardial infarction (MI) have underlying coronary atherosclerosis, not all patients with coronary artery disease (CAD) develop MI. We sought to address the hypothesis that some of the genetic factors which establish atherosclerosis may be distinct from those that predispose to vulnerable plaques and thrombus formation. METHODS AND RESULTS: We carried out a genome-wide association study for MI in the UK Biobank (n∼472 000), followed by a meta-analysis with summary statistics from the CARDIoGRAMplusC4D Consortium (n∼167 000). Multiple independent replication analyses and functional approaches were used to prioritize loci and evaluate positional candidate genes. Eight novel regions were identified for MI at the genome wide significance level, of which effect sizes at six loci were more robust for MI than for CAD without the presence of MI. Confirmatory evidence for association of a locus on chromosome 1p21.3 harbouring choline-like transporter 3 (SLC44A3) with MI in the context of CAD, but not with coronary atherosclerosis itself, was obtained in Biobank Japan (n∼165 000) and 16 independent angiography-based cohorts (n∼27 000). Follow-up analyses did not reveal association of the SLC44A3 locus with CAD risk factors, biomarkers of coagulation, other thrombotic diseases, or plasma levels of a broad array of metabolites, including choline, trimethylamine N-oxide, and betaine. However, aortic expression of SLC44A3 was increased in carriers of the MI risk allele at chromosome 1p21.3, increased in ischaemic (vs. non-diseased) coronary arteries, up-regulated in human aortic endothelial cells treated with interleukin-1ß (vs. vehicle), and associated with smooth muscle cell migration in vitro. CONCLUSIONS: A large-scale analysis comprising ∼831 000 subjects revealed novel genetic determinants of MI and implicated SLC44A3 in the pathophysiology of vulnerable plaques.

Heart Disease and Stroke Statistics-2020 Update: A Report From the American Heart Association.

BACKGROUND: The American Heart Association, in conjunction with the National Institutes of Health, annually reports on the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health. The Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, heart failure, valvular disease, venous disease, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs). METHODS: The American Heart Association, through its Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States to provide the most current information available in the annual Statistical Update. The 2020 Statistical Update is the product of a full year's worth of effort by dedicated volunteer clinicians and scientists, committed government professionals, and American Heart Association staff members. This year's edition includes data on the monitoring and benefits of cardiovascular health in the population, metrics to assess and monitor healthy diets, an enhanced focus on social determinants of health, a focus on the global burden of cardiovascular disease, and further evidence-based approaches to changing behaviors, implementation strategies, and implications of the American Heart Association's 2020 Impact Goals. RESULTS: Each of the 26 chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics. CONCLUSIONS: The Statistical Update represents a critical resource for the lay public, policy makers, media professionals, clinicians, healthcare administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.

Gut Microbiota-Derived Short-Chain Fatty Acids Facilitate Microbiota:Host Cross talk and Modulate Obesity and Hypertension.

PURPOSE OF REVIEW: The purpose of this review is to summarize the evidence supporting a role of short-chain fatty acids (SCFAs) as messengers facilitating cross talk between the host and gut microbiota and discuss the effects of altered SCFA signaling in obesity and hypertension. RECENT FINDINGS: Recent evidence suggests there to be a significant contribution of gut microbiota-derived SCFAs to microbe:host communication and host metabolism. SCFA production within the intestine modulates intestinal pH, microbial composition, and intestinal barrier integrity. SCFA signaling through host receptors, such as PPARγ and GPCRs, modulates host health and disease physiology. Alterations in SCFA signaling and downstream effects on inflammation are implicated in the development of obesity and hypertension. SCFAs are crucial components of the holobiont relationship; in the proper environment, they support normal gut, immune, and metabolic function. Dysregulation of microbial SCFA signaling affects downstream host metabolism, with implications in obesity and hypertension.

A metabolome and microbiome wide association study of healthy eating index points to the mechanisms linking dietary pattern and metabolic status.

BACKGROUND: Healthy eating index (HEI), a measure of diet quality, associates with metabolic health outcomes; however, the molecular basis is unclear. We conducted a multi-omic study to examine whether HEI associates with the circulatory and gut metabolome and investigated the gut microbiome-HEI interaction on circulating and gut metabolites. METHODS: Through a cross-sectional study, we evaluated diet quality in healthy individuals [the ABO Glycoproteomics in Platelets and Endothelial Cells (ABO) Study, n = 73], metabolites (measured at Metabolon Inc.) in plasma (n = 800) and gut (n = 767) and the gut microbiome at enterotype and microbial taxa (n = 296) levels. Pathway analysis was conducted using Metaboanalyst 4.0. We performed multi-variable linear regression to explore both the HEI-metabolites and HEI-microbiome associations and how metabolites were affected by the HEI-microbiome interaction. In the Fish oils and Adipose Inflammation Reduction (FAIR) Study (n = 25), analyses on HEI and plasma metabolites were replicated. Estimates of findings from both studies were pooled in random-effects meta-analysis. RESULTS: The HEI-2015 was associated with 74 plasma and 73 gut metabolites (mostly lipids) and with 47 metabolites in the meta-analysis of the ABO and FAIR Studies. Compared to Enterotype-1 participants, those with Enterotype-2 had higher diet quality (p = 0.01). We also identified 9 microbial genera associated with HEI, and 35 plasma and 40 gut metabolites linked to the HEI-gut microbiome interaction. Pathways involved in the metabolism of polar lipids, amino acids and caffeine strongly associated with diet quality. However, the HEI-microbiome interaction not only influenced the pathways involved in the metabolism of branch-chain amino acids, it also affected upstream pathways including nucleotide metabolism and amino acids biosynthesis. CONCLUSIONS: Our multi-omic analysis demonstrated that changes in metabolism, measured by either circulatory/gut metabolites or metabolic pathways, are influenced by not only diet quality but also gut microbiome alterations shaped by the quality of diet consumed. Future work is needed to explore the causality in the interplay between HEI and gut-microbiome composition in metabolism.

New-onset vegetarian diet shows differences in fatty acid metabolites in European American and African American women.

BACKGROUND AND AIMS: The type of fat consumed in animal-based western diets, typically rich in the saturated fat palmitate, has been implicated in cardiometabolic disease risk. In contrast, the most abundant mono- and polyunsaturated fats, more typical in a vegetarian or plant-based diet, potentiate less deleterious effects. This study determined differences in plasma and urine metabolites when switching from omnivorous to vegetarian diet, including metabolites involved in fatty acid utilization. METHODS AND RESULTS: A prospective cohort of 38 European (EA) and African American (AA) omnivorous females were matched by age (25.7 ± 5.3y) and BMI (22.4 ± 1.9 kg/m2). Pre-intervention samples were collected while subjects consumed habitual animal-based diet. Changes in metabolites were assessed by ultra-high-performance liquid chromatography-tandem mass spectroscopy (Metabolon, Inc.) upon completing four days of novel vegetarian diet provided by the Vanderbilt Metabolic Kitchen. Changes in several diet-derived metabolites were observed, including increases in compounds derived from soy food metabolism along with decreases in metabolites of xanthine and histidine. Significant changes occurred in metabolites of saturated, monounsaturated and polyunsaturated fatty acids along with significant differences between EA and AA women in changes in plasma concentrations of acylcarnitines, which reflect the completeness of fatty acid oxidation (versus storage). CONCLUSION: These data suggest improvements in fatty acid metabolism (oxidation vs storage), a key factor in energy homeostasis, may be promoted rapidly by adoption of a vegetarian (plant-based) diet. Mechanistic differences in response to diet interventions must be understood to effectively provide protection against the widespread development of obesity and cardiometabolic disease in population subgroups, such as AA women.

'You're just a locum': professional identity and temporary workers in the medical profession.

Internationally, there has been substantial growth in temporary working, including in the medical profession where temporary doctors are known as locums. There is little research into the implications of temporary work in health care. In this paper, we draw upon theories concerning the sociology of the medical profession to examine the implications of locum working for the medical profession, healthcare organisations and patient safety. We focus particularly on the role of organisations in professional governance and the positioning of locums as peripheral to or outside the organisation, and the influence of intergroup relationships (in this case between permanent and locum doctors) on professional identity. Qualitative semi-structured interviews were conducted between 2015 and 2017 in England with 79 participants including locum doctors, locum agency staff, and representatives of healthcare organisations who use locums. An abductive approach to analysis combined inductive coding with deductive, theory-driven interpretation. Our findings suggest that locums were perceived to be inferior to permanently employed doctors in terms of quality, competency and safety and were often stigmatised, marginalised and excluded. The treatment of locums may have negative implications for collegiality, professional identity, group relations, team functioning and the way organisations deploy and treat locums may have important consequences for patient safety.

High-fidelity simulation-based education in pre-registration healthcare programmes: a systematic review of reviews to inform collaborative and interprofessional best practice.

Simulation-based education (SBE) is recognized as an effective interprofessional teaching and learning method. Whilst there is a large volume of research evidence concerning elements of SBE there is a lack of clarity concerning foundational principles of best practice. This is important for educators wishing to utilize high-quality SBE to deliver interprofessional education. The aim of this review is to synthesize review evidence of SBE best practice in a broad range of pre-registration healthcare programs and contextualize findings in light of relevant educational theory. A systematic search of PubMed, Scopus, Medline/Ovid, British Nursing Index, and the Cochrane Library databases was undertaken in February 2020. Data extraction and quality evaluation were undertaken by two authors. Fifteen reviews were included. In addition to identifying barriers and enablers to implementation, three interdependent themes regarding SBE best practice were found: curriculum level integration and planning (curriculum level integration, the opportunity for deliberate repeated practice, distribution, and sequencing); simulation design and delivery (clearly defined learning outcomes and benchmarks, pre-brief, multiple learning strategies, interactivity and individualized learning, feedback, and debrief); and resources (facilitator competency, controlled environments). These themes broadly align with the social constructivist theory of experiential learning whereby structured opportunities to learn via concrete experience, reflective observation, abstract conceptualization, and active experimentation are provided through effective planning, design, and delivery of SBE. Interdependencies suggest that integration of SBE at curriculum-level enables planning and implementation of best practice principles which are associated with effective learning, which also inform and facilitate the availability of adequate simulation resources.

Metabolomics reveals the impact of Type 2 diabetes on local muscle and vascular responses to ischemic stress.

OBJECTIVE: Type 2 diabetes mellitus (T2DM) reduces exercise capacity, but the mechanisms are incompletely understood. We probed the impact of ischemic stress on skeletal muscle metabolite signatures and T2DM-related vascular dysfunction. METHODS: we recruited 38 subjects (18 healthy, 20 T2DM), placed an antecubital intravenous catheter, and performed ipsilateral brachial artery reactivity testing. Blood samples for plasma metabolite profiling were obtained at baseline and immediately upon cuff release after 5 min of ischemia. Brachial artery diameter was measured at baseline and 1 min after cuff release. RESULTS: as expected, flow-mediated vasodilation was attenuated in subjects with T2DM (P<0.01). We confirmed known T2DM-associated baseline differences in plasma metabolites, including homocysteine, dimethylguanidino valeric acid and ß-alanine (all P<0.05). Ischemia-induced metabolite changes that differed between groups included 5-hydroxyindoleacetic acid (healthy: -27%; DM +14%), orotic acid (healthy: +5%; DM -7%), trimethylamine-N-oxide (healthy: -51%; DM +0.2%), and glyoxylic acid (healthy: +19%; DM -6%) (all P<0.05). Levels of serine, betaine, ß-aminoisobutyric acid and anthranilic acid were associated with vessel diameter at baseline, but only in T2DM (all P<0.05). Metabolite responses to ischemia were significantly associated with vasodilation extent, but primarily observed in T2DM, and included enrichment in phospholipid metabolism (P<0.05). CONCLUSIONS: our study highlights impairments in muscle and vascular signaling at rest and during ischemic stress in T2DM. While metabolites change in both healthy and T2DM subjects in response to ischemia, the relationship between muscle metabolism and vascular function is modified in T2DM, suggesting that dysregulated muscle metabolism in T2DM may have direct effects on vascular function.

The Gut Microbiome, Inflammation, and Salt-Sensitive Hypertension.

PURPOSE OF REVIEW: Salt sensitivity of blood pressure (SSBP) is an independent predictor of death due to cardiovascular events and affects nearly 50% of the hypertensive and 25% of the normotensive population. Strong evidence indicates that reducing sodium (Na+) intake decreases blood pressure (BP) and cardiovascular events. The precise mechanisms of how dietary Na+ contributes to elevation and cardiovascular disease remain unclear. The goal of this review is to discuss mechanisms of salt-induced cardiovascular disease and how the microbiome may play a role. RECENT FINDINGS: The innate and adaptive immune systems are involved in the genesis of salt-induced hypertension. Mice fed a high-salt diet exhibit increased inflammation with a marked increase in dendritic cell (DC) production of interleukin (IL)-6 and formation of isolevuglandins (IsoLG)-protein adducts, which drive interferon-gamma (IFN-γ) and IL-17A production by T cells. While prior studies have mainly focused on the brain, kidney, and vasculature as playing a role in salt-induced hypertension, the gut is the first and largest location for Na+ absorption. Research from our group and others strongly suggests that the gut microbiome contributes to salt-induced inflammation and hypertension. Recent studies suggest that alterations in the gut microbiome contribute to salt-induced hypertension. However, the contribution of the microbiome to SSBP and its underlying mechanisms are not known. Targeting the microbiota and the associated immune cell activation could conceivably provide the much-needed therapy for SSBP.

Soy food intake associates with changes in the metabolome and reduced blood pressure in a gut microbiota dependent manner.

BACKGROUND AND AIMS: Consumption of soy foods has been associated with protection against cardiometabolic disease, but the mechanisms are incompletely understood. We hypothesized that habitual soy food consumption associates with gut microbiome composition, metabolite production, and the interaction between diet, microbiota and metabolites. METHODS AND RESULTS: We analyzed dietary soy intake, plasma and stool metabolites, and gut microbiome data from two independent cross-sectional samples of healthy US individuals (N = 75 lean or overweight, and N = 29 obese). Habitual soy intake associated with several circulating metabolites. There was a significant interaction between soy intake and gut microbiome composition, as defined by gut enterotype, on metabolites in plasma and stool. Soy consumption associated with reduced systolic blood pressure, but only in a subset of individuals defined by their gut microbiome enterotype, suggesting that responsiveness to soy may be dependent on microbiome composition. Soy intake was associated with differences in specific microbial taxa, including two taxa mapping to genus Dialister and Prevotella which appeared to be suppressed by high soy intake We identified context-dependent effects of these taxa, where presence of Prevotella was associated with higher blood pressure and a worse cardiometabolic profile, but only in the absence of Dialister. CONCLUSIONS: The gut microbiome is an important intermediate in the interplay between dietary soy intake and systemic metabolism. Consumption of soy foods may shape the microbiome by suppressing specific taxa, and may protect against hypertension only in individuals with soy-responsive microbiota. CLINICAL TRIALS REGISTRY: NCT02010359 at clinicaltrials.gov.