Sex Disparities in Operating Room use Among Cataract Surgeons: A 10-Year Retrospective Population-Based Analysis.

PURPOSE: To evaluate sex differences in operating room (OR) time and case volumes among comprehensive cataract surgeons in Ontario, Canada's most populated province. DESIGN: Retrospective, population-based cohort study. METHODS: Physician billing data of active comprehensive cataract surgeons between 2010 and 2019 were analyzed to identify all cataract surgeries in this timeframe. The number of OR days and case volume were the primary outcomes. Data were stratified by surgeon sex and career stage. RESULTS: Between 2010 and 2019, approximately 1.05 million cataract surgeries were performed in Ontario. There were an average of 195 ± 3 comprehensive cataract surgeons per year, of which 39 ± 5 were female. The proportion of female surgeons increased from 16.8% of all surgeons in 2010 to 24.4% in 2019. The greatest proportion of male surgeons were in the late phase of their career, whereas the greatest proportion of female surgeons were in the early stage of their career. On average, male surgeons had 44.9 ± 1.90 OR days per year and females had 32 ± 1.90 OR days per year, resulting in female surgeons averaging 12.45 ± 1.90 fewer OR days per year. This OR distribution remained consistent across career stages. Average case volumes per OR day were similar across sexes, but male surgeons performed on average 172.7 ± 30.6 more surgeries per year. CONCLUSIONS: Despite performing similar average case volumes per OR day, female surgeons had less OR time compared to their male counterparts per year, and this remained consistent across career stages and over the 10-year period. Metrics for OR allocation and use should be well defined and transparent.

Twelve tips for improving the quality of assessor judgements in senior medical student clinical assessments.

Assessment of senior medical students is usually calibrated at the level of achieving expected learning outcomes for graduation. Recent research reveals that clinical assessors often balance two slightly different perspectives on this benchmark. The first is the formal learning outcomes at graduation, ideally as part of a systematic, program-wide assessment approach that measures learning achievement, while the second is consideration of the candidate's contribution to safe care and readiness for practice as a junior doctor. The second is more intuitive to the workplace, based on experience working with junior doctors. This perspective may enhance authenticity in assessment decisions made in OSCEs and work-based assessments to better align judgements and feedback with professional expectations that will guide senior medical students and junior doctors' future career development. Modern assessment practices should include consideration of qualitative as well as quantitative information, overtly including perspectives of patients, employers, and regulators. This article presents 12 tips for how medical education faculty might support clinical assessors by capturing workplace expectations of first year medical graduates and develop graduate assessments based on a shared heuristic of 'work-readiness'. Peer-to-peer assessor interaction should be facilitated to achieve correct calibration that 'merges' the differing perspectives to produce a shared construct of an acceptable candidate.

"Could You Work in My Team?": Exploring How Professional Clinical Role Expectations Influence Decision-Making of Assessors During Exit-Level Medical School OSCEs.

Decision-making in clinical assessment, such as exit-level medical school Objective Structured Clinical Examinations (OSCEs), is complex. This study utilized an empirical phenomenological qualitative approach with thematic analysis to explore OSCE assessors' perceptions of the concept of a "prototypical intern" expressed during focus group discussions. Topics discussed included the concept of a prototypical intern, qualities to be assessed, and approaches to clinical assessment decision-making. The thematic analysis was then applied to a theoretical framework (Cultural Historical Activity Theory-CHAT) that explored the complexity of making assessment decisions amidst potentially contradicting pressures from academic and clinical perspectives. Ten Australasian medical schools were involved with 15 experienced and five less experienced assessors participating. Thematic analysis of the data revealed four major themes in relation to how the prototypical intern concept influences clinical assessors' judgements: (a) Suitability of marking rubric based on assessor characteristics and expectations; (b) Competence as final year student vs. performance as a prototypical intern; (c) Safety, trustworthiness and reliability as constructs requiring assessment and (d) Contradictions in decision making process due to assessor differences. These themes mapped well within the interaction between two proposed activity systems in the CHAT model: academic and clinical. More clinically engaged and more experienced assessors tend to fall back on a heuristic, mental construct of a "prototypical intern," to calibrate judgements, particularly, in difficult situations. Further research is needed to explore whether consensus on desirable intern qualities and their inclusion into OSCE marksheets decreases the cognitive load and increases the validity of assessor decision making.

Supply and demographic characteristics of Ontario's ophthalmologists from 2010 to 2019: a population-based analysis.

BACKGROUND: With an aging population in Ontario, ophthalmologists provide most of their care to older adults, which has prominent human resource implications. In this study, we sought to investigate the supply and demographic characteristics of Ontario's ophthalmologists. METHODS: In this retrospective, population-based analysis, we evaluated cohort demographics, including sex and career stage, of Ontario's ophthalmologists from 2010 to 2019, which we reported using descriptive statistics. Similarly, we detailed ophthalmologist supply within different areas of care using descriptive statistics. RESULTS: Over the study period, a median of 464 ophthalmologists were practising in Ontario each year. The proportion of female ophthalmologists increased from 18.7% in 2010 to 24.1% in 2019. The proportion of late-career ophthalmologists (aged > 55 yr) significantly increased by 6.4% over the study period and constituted 45.3% of the workforce in 2019. Comprehensive cataract surgery was the most common area of care. Although the number of ophthalmologists per 100 000 people remained stable over the study period (3.27 ophthalmologists/100 000 people in 2019), the number of ophthalmologists per 100 000 people aged 65 years and older fell by 18.4% from 2010 to 2019. The greatest supply reduction was among moderate-volume comprehensive cataract surgeons (-20.2% overall and -35.4% relative to the population aged ≥ 65 yr). INTERPRETATION: Between 2010 and 2019, the overall number of ophthalmologists in Ontario remained stable; however, we observed declines in the number of ophthalmologists per 100 000 people aged 65 years and older for most areas of care. Nearly half of the ophthalmology workforce is now older than 55 years and female representation is increasing.

Deep-learning-based direct synthesis of low-energy virtual monoenergetic images with multi-energy CT.

Purpose: We developed a deep learning method to reduce noise and beam-hardening artifact in virtual monoenergetic image (VMI) at low x-ray energy levels. Approach: An encoder-decoder type convolutional neural network was implemented with customized inception modules and in-house-designed training loss (denoted as Incept-net), to directly estimate VMI from multi-energy CT images. Images of an abdomen-sized water phantom with varying insert materials were acquired from a research photon-counting-detector CT. The Incept-net was trained with image patches ( 64 × 64 pixels ) extracted from the phantom data, as well as synthesized, random-shaped numerical insert materials. The whole CT images ( 512 × 512 pixels ) with the remaining real insert materials that were unseen in network training were used for testing. Seven contrast-enhanced abdominal CT exams were used for preliminary evaluation of Incept-net generalizability over anatomical background. Mean absolute percentage error (MAPE) was used to evaluate CT number accuracy. Results: Compared to commercial VMI software, Incept-net largely suppressed beam-hardening artifact and reduced noise (53%) in phantom study. Incept-net presented comparable CT number accuracy at higher-density ( P -value [0.0625, 0.999]) and improved it at lower-density inserts ( P - value = 0.0313 ) with overall MAPE: Incept-net [2.9%, 4.6%]; commercial-VMI [6.7%, 10.9%]. In patient images, Incept-net suppressed beam-hardening artifact and reduced noise (up to 50%, P - value = 0.0156 ). Conclusion: In this preliminary study, Incept-net presented the potential to improve low-energy VMI quality.

Operational Recommendations for Scarce Resource Allocation in a Public Health Crisis.

The coronavirus disease 2019 pandemic may require rationing of various medical resources if demand exceeds supply. Theoretical frameworks for resource allocation have provided much needed ethical guidance, but hospitals still need to address objective practicalities and legal vetting to operationalize scarce resource allocation schemata. To develop operational scarce resource allocation processes for public health catastrophes, including the coronavirus disease 2019 pandemic, five health systems in Maryland formed a consortium-with diverse expertise and representation-representing more than half of all hospitals in the state. Our efforts built on a prior statewide community engagement process that determined the values and moral reference points of citizens and health-care professionals regarding the allocation of ventilators during a public health catastrophe. Through a partnership of health systems, we developed a scarce resource allocation framework informed by citizens' values and by general expert consensus. Allocation schema for mechanical ventilators, ICU resources, blood components, novel therapeutics, extracorporeal membrane oxygenation, and renal replacement therapies were developed. Creating operational algorithms for each resource posed unique challenges; each resource's varying nature and underlying data on benefit prevented any single algorithm from being universally applicable. The development of scarce resource allocation processes must be iterative, legally vetted, and tested. We offer our processes to assist other regions that may be faced with the challenge of rationing health-care resources during public health catastrophes.

Examiners' decision-making processes in observation-based clinical examinations.

BACKGROUND: Objective structured clinical examinations (OSCEs) are commonly used to assess the clinical skills of health professional students. Examiner judgement is one acknowledged source of variation in candidate marks. This paper reports an exploration of examiner decision making to better characterise the cognitive processes and workload associated with making judgements of clinical performance in exit-level OSCEs. METHODS: Fifty-five examiners for exit-level OSCEs at five Australian medical schools completed a NASA Task Load Index (TLX) measure of cognitive load and participated in focus group interviews immediately after the OSCE session. Discussions focused on how decisions were made for borderline and clear pass candidates. Interviews were transcribed, coded and thematically analysed. NASA TLX results were quantitatively analysed. RESULTS: Examiners self-reported higher cognitive workload levels when assessing a borderline candidate in comparison with a clear pass candidate. Further analysis revealed five major themes considered by examiners when marking candidate performance in an OSCE: (a) use of marking criteria as a source of reassurance; (b) difficulty adhering to the marking sheet under certain conditions; (c) demeanour of candidates; (d) patient safety, and (e) calibration using a mental construct of the 'mythical [prototypical] intern'. Examiners demonstrated particularly higher mental demand when assessing borderline compared to clear pass candidates. CONCLUSIONS: Examiners demonstrate that judging candidate performance is a complex, cognitively difficult task, particularly when performance is of borderline or lower standard. At programme exit level, examiners intuitively want to rate candidates against a construct of a prototypical graduate when marking criteria appear not to describe both what and how a passing candidate should demonstrate when completing clinical tasks. This construct should be shared, agreed upon and aligned with marking criteria to best guide examiner training and calibration. Achieving this integration may improve the accuracy and consistency of examiner judgements and reduce cognitive workload.

Correction: Micro-anatomic alterations of the placenta in a non-human primate model of gestational protein-restriction.

[This corrects the article DOI: 10.1371/journal.pone.0235840.].

Micro-anatomic alterations of the placenta in a non-human primate model of gestational protein-restriction.

OBJECTIVES: Maternal protein malnutrition is associated with impaired fetal growth, and lifetime consequences for the offspring. Our group has previously developed a model of protein-restriction in the non-human primate, which was associated with fetal growth restriction, stillbirth, decreased placental perfusion, and evidence of fetal hypoxia, suggesting perturbed vascular development. Our objective was to histologically characterize the micro-anatomic alterations associated with adverse pregnancy outcomes taking an approach that permits investigation of the 3D vascular structure and surrounding histology without the requirement for 3D vascular casting or relying on 2D stereology which both have methodological limitations. METHODS: Rhesus macaques were assigned in the pre-gestational period to a control diet that contained 26% protein, or study diet containing 13% protein (50% PR diet). Placental tissue was collected at delivery and processed using a clarification, immunohistochemistry, and confocal microscopy protocol published previously by our group. Three dimensional reconstructions and quantitative assessment of the vascular micro-anatomy was performed using analysis software (Imaris®) and statistical analysis accounted for maternal and fetal confounders. RESULTS: In unadjusted analysis, when comparing those pregnancies on a 50% PR diet (n = 4) with those on a control diet (n = 4), protein-restriction diet was associated with decreased maternal pre-pregnancy weight (difference of -1.975kg, 95% CI -3.267 to -0.6826). When controlling for maternal pre-pregnancy weight, fetal sex, and latency from tissue collection to imaging, a gestational protein-restriction diet was associated with decreases in total vascular length, total vascular surface area, total vascular volume, and vascular density. CONCLUSION: In this pilot study, a gestational protein-restriction diet altered the placental micro-vasculature with decreased vascular caliber and density, which may be related to the observed adverse pregnancy outcomes and perturbed placental perfusion previously demonstrated in this model.

Endothelial Immune Activation by Medin: Potential Role in Cerebrovascular Disease and Reversal by Monosialoganglioside-Containing Nanoliposomes.

Background The function of medin, one of the most common human amyloid proteins that accumulates in the vasculature with aging, remains unknown. We aim to probe medin's role in cerebrovascular disease by comparing cerebral arterial medin content between cognitively normal and vascular dementia (VaD) patients and studying its effects on endothelial cell (EC) immune activation and neuroinflammation. We also tested whether monosialoganglioside-containing nanoliposomes could reverse medin's adverse effects. Methods and Results Cerebral artery medin and astrocyte activation were measured and compared between VaD and cognitively normal elderly brain donors. ECs were exposed to physiologic dose of medin (5 µmol/L), and viability and immune activation (interleukin-8, interleukin-6, intercellular adhesion molecule-1, and plasminogen activator inhibitor-1) were measured without or with monosialoganglioside-containing nanoliposomes (300 µg/mL). Astrocytes were exposed to vehicle, medin, medin-treated ECs, or their conditioned media, and interleukin-8 production was compared. Cerebral collateral arterial and parenchymal arteriole medin, white matter lesion scores, and astrocyte activation were higher in VaD versus cognitively normal donors. Medin induced EC immune activation (increased interleukin-8, interleukin-6, intercellular adhesion molecule-1, and plasminogen activator inhibitor-1) and reduced EC viability, which were reversed by monosialoganglioside-containing nanoliposomes. Interleukin-8 production was augmented when astrocytes were exposed to medin-treated ECs or their conditioned media. Conclusions Cerebral arterial medin is higher in VaD compared with cognitively normal patients. Medin induces EC immune activation that modulates astrocyte activation, and its effects are reversed by monosialoganglioside-containing nanoliposomes. Medin is a candidate novel risk factor for aging-related cerebrovascular disease and VaD.

Activator protein-1 and caspase 8 mediate p38α MAPK-dependent cardiomyocyte apoptosis induced by palmitic acid.

Lipoapoptosis of cardiomyocytes may underlie diabetic cardiomyopathy. Numerous forms of cardiomyopathies share a common end-pathway in which apoptotic loss of cardiomyocytes is mediated by p38α mitogen activated protein kinase (MAPK). Although we have previously shown that palmitic acid (PA), a saturated fatty acid (SFA) elevated in plasma of type 2 diabetes mellitus and morbid obesity, induces apoptosis in cardiomyocytes via p38α MAPK-dependent signaling, the downstream cascade events that cause cell death remain unknown. The objective of this study was to investigate mechanisms involved in palmitic acid-induced cardiomyocyte apoptosis. Human adult ventricular cardiomyocyte line (AC16 cells) exposed to high physiological levels of PA for 16 h showed enhanced transcription and phosphorylation of c-fos and c-jun subunits of AP-1 and transcription of caspase 8. When AC16 cells were transfected with small interfering RNA specific against p38α MAPK (si-p38α) for 24 or 48 h, the amplified phosphorylation of c-fos was dose-dependently attenuated, and procaspase 8 was dose-dependently reduced. With translational knockdown of c-fos, PA-induced apoptosis was diminished. Inhibition of caspase 8 for 24 h reduced apoptosis in PA-treated cardiomyocytes. These findings provide evidence for induction of apoptosis in cardiomyocytes exposed to high SFA by a novel pathway requiring activation of c-fos/AP-1 and caspase 8. These results demonstrate how elevated plasma SFA may lead to continual and cumulative loss of cardiomyocytes and potentially contribute to the development of diabetic cardiomyopathy.

A snapshot of current Objective Structured Clinical Examination (OSCE) practice at Australian medical schools.

Objective: The objective of this collaborative study was to compare current practices of conducting high-stake, exit-level Objective Structured Clinical Examinations (OSCEs) at all Australian medical schools. We aimed to document similarities and differences between schools, and compare existing practice against available gold standard, evidence-based practice. We also aimed to identify areas where gold standards do not currently exist, and could be developed in the future. Methods: A 72-item semi-structured questionnaire was sent to all 19 Australian medical schools with graduating students. Results: A total of 18/19 schools responded. Of these, 16/18 schools had summative exit-level OSCEs representing content from multiple medical specialties. The total number of OSCE stations varied from 8 to 16, with total OSCE testing time ranging from 70 to 160 min. All schools blueprinted their OSCE to their curriculum, and trained simulated patients and examiners. There was variation in the format of marking rubric used. Conclusions: This study has provided insight into the current OSCE practices of the majority of medical schools in Australia. Whilst the comparative data reveal a wide variation in OSCE practices between schools, many recommended "gold standard" OSCE practices are implemented. The collective awareness of our similarities and differences provides us with a baseline platform, as well as an impetus for iterative quality improvement. Such discourse also serves to develop new gold standards in practice where none have previously existed.

Effect of liraglutide on dietary lipid-induced insulin resistance in humans.

AIMS: To test whether liraglutide suppresses postprandial elevations in lipids and thus protects against high saturated fatty acid (SFA) diet-induced insulin resistance. METHODS: In a randomized placebo-controlled crossover study, 32 participants with normal or mildly impaired glucose tolerance received liraglutide and placebo for 3 weeks each. Insulin suppression tests (IST) were conducted at baseline and after a 24-hour SFA-enriched diet after each treatment. Plasma glucose, insulin, triglycerides and non-esterified fatty acids (NEFA) were measured over the initial 8 hours (breakfast and lunch) on the SFA diet. A subset of participants underwent ex vivo measurements of insulin-mediated vasodilation of adipose tissue arterioles and glucose metabolism regulatory proteins in skeletal muscle. RESULTS: Liraglutide reduced plasma glucose, triglycerides and NEFA concentrations during the SFA diet (by 50%, 25% and 9%, respectively), and the SFA diet increased plasma glucose during the IST (by 36%; all P < .01 vs placebo). The SFA diet-induced impairment of vasodilation on placebo (-9.4% vs baseline; P < .01) was ameliorated by liraglutide (-4.8%; P = .1 vs baseline). In skeletal muscle, liraglutide abolished the SFA-induced increase in thioredoxin-interacting protein (TxNIP) expression (75% decrease; P < .01 vs placebo) and increased 5'AMP-activated protein kinase (AMPK) phosphorylation (50% vs -3%; P = .04 vs placebo). CONCLUSIONS: Liraglutide blunted the SFA-enriched diet-induced peripheral insulin resistance. This effect may be related to improved microvascular function and modulation of TxNIP and AMPK pathways in skeletal muscle.

A collaborative comparison of objective structured clinical examination (OSCE) standard setting methods at Australian medical schools.

BACKGROUND: A key issue underpinning the usefulness of the OSCE assessment to medical education is standard setting, but the majority of standard-setting methods remain challenging for performance assessment because they produce varying passing marks. Several studies have compared standard-setting methods; however, most of these studies are limited by their experimental scope, or use data on examinee performance at a single OSCE station or from a single medical school. This collaborative study between 10 Australian medical schools investigated the effect of standard-setting methods on OSCE cut scores and failure rates. METHODS: This research used 5256 examinee scores from seven shared OSCE stations to calculate cut scores and failure rates using two different compromise standard-setting methods, namely the Borderline Regression and Cohen's methods. RESULTS: The results of this study indicate that Cohen's method yields similar outcomes to the Borderline Regression method, particularly for large examinee cohort sizes. However, with lower examinee numbers on a station, the Borderline Regression method resulted in higher cut scores and larger difference margins in the failure rates. CONCLUSION: Cohen's method yields similar outcomes as the Borderline Regression method and its application for benchmarking purposes and in resource-limited settings is justifiable, particularly with large examinee numbers.

HDL inhibits saturated fatty acid mediated augmentation of innate immune responses in endothelial cells by a novel pathway.

BACKGROUND AND AIMS: Peripheral insulin resistance is associated with several metabolic abnormalities, including elevated serum fatty acids that contribute to vascular injury and atherogenesis. Our goals were to examine whether saturated fatty acids can modify innate immune responses to subclinical concentrations of lipopolysaccharide (LPS) in endothelial cells, and to explore the underlying pathway and determine whether it is modified by high density lipoprotein (HDL) and other factors commonly altered in insulin resistance. METHODS: Physiologic concentrations of palmitic acid were added to human aortic endothelial cells with and without a variety of inhibitors or HDL and measures of cell inflammation and function assessed. RESULTS: Palmitic acid significantly amplified human aortic endothelial cell inflammatory responses to LPS. Similar results were obtained from lipolysis products of triglyceride rich lipoproteins. Metabolism of palmitic acid to ceramide and subsequent activation of PKC-ζ, MAPK and ATF3 appeared critical in amplifying LPS induced inflammation. The amplified response to palmitic acid/LPS was decreased by HDL, dose dependently, and this inhibition was dependent on activation of PI3K/AKT and reduction in ATF3. CONCLUSIONS: These results indicate that endothelial cell innate immune responses are modified by metabolic abnormalities commonly present in insulin resistance and provide evidence for a novel mechanism by which HDL may reduce vascular inflammation.

Time course of cardiac inflammation during nitric oxide synthase inhibition in SHR: impact of prior transient ACE inhibition.

We have previously demonstrated that angiotensin-converting enzyme (ACE) inhibition with enalapril produces persistent effects that protect against future nitric oxide synthase (NOS) inhibitor (L-arginine methyl ester, L-NAME)-induced cardiac dysfunction and outer wall collagen deposition in spontaneously hypertensive rats (SHR). In the present study, we dissect the cytokine/chemokine release profile during NOS inhibition, its correlation to pathological cardiac remodeling and the impact of transient ACE inhibition on these effects. Adult male SHR were treated with enalapril (E+L) or tap water (C+L) for 2 weeks followed by a 2-week washout period. Rats were then subjected to 0, 3, 7 or 10 days of L-NAME treatment. The temporal response to NOS inhibition was evaluated by measuring arterial pressure, cardiac remodeling and cytokine/chemokine levels. L-NAME equivalently increased blood pressure and myocardial and vascular injury in C+L and E+L rats. However, pulse pressure (PP) was only transiently altered in C+L rats. The levels of several inflammatory mediators were increased during L-NAME treatment. However, interleukin-6 (IL-6) and IL-10 and monocyte chemoattractant protein-1 were uniquely increased in C+L hearts; whereas IL-4 and fractalkine were only elevated in E+L hearts. By days 7 and 10 of L-NAME treatment, there was a significant increase in the cardiac density of macrophages and proliferating cells, respectively only in C+L rats. Although myocardial injury was similar in both treatment groups, PP was not changed and there was a distinct cardiac chemokine/cytokine signature in rats previously treated with enalapril that may be related to the lack of proliferative response and macrophage infiltration in these hearts.

Improving assessment practice through cross-institutional collaboration: An exercise on the use of OSCEs.

BACKGROUND: This study was undertaken to improve assessment practice on OSCEs through collaboration across geographically dispersed medical schools in Australia. METHODS: A total of eleven OSCE stations were co-developed by four medical schools and used in summative 2011 and 2012 examinations for the assessment of clinical performance in the early clinical and exit OSCEs in each school's medical course. Partial Credit Rasch Model was used to evaluate the psychometric properties of the shared OSCE data. Evaluation of the quality assurance reports was used to determine the beneficial impact of the collaborative benchmarking exercise on learning and teaching outcomes. RESULTS: The data for each examination demonstrated sufficient fit to the Rasch model with infit mean square values ranging from 0.88 to 0.99. Person separation (1.25-1.63) indices indicated good reliability. Evaluation of perceived benefits showed that the benchmarking process was successful as it highlighted common curriculum areas requiring specific focus and provided comparable data on the quality of teaching at the participating medical schools. CONCLUSION: This research demonstrates the validity of the psychometric data and benefits of evaluating clinical competence across medical schools without the enforcement of a prescriptive national curriculum or assessment.

Exenatide Protects Against Glucose- and Lipid-Induced Endothelial Dysfunction: Evidence for Direct Vasodilation Effect of GLP-1 Receptor Agonists in Humans.

GLP-1 receptor (GLP-1R) agonists may improve endothelial function (EF) via metabolic improvement and direct vascular action. The current study determined the effect of GLP-1R agonist exenatide on postprandial EF in type 2 diabetes and the mechanisms underlying GLP-1R agonist-mediated vasodilation. Two crossover studies were conducted: 36 participants with type 2 diabetes received subcutaneous exenatide or placebo for 11 days and EF, and glucose and lipid responses to breakfast and lunch were determined; and 32 participants with impaired glucose tolerance (IGT) or diet-controlled type 2 diabetes had EF measured before and after intravenous exenatide, with or without the GLP-1R antagonist exendin-9. Mechanisms of GLP-1R agonist action were studied ex vivo on human subcutaneous adipose tissue arterioles and endothelial cells. Subcutaneous exenatide increased postprandial EF independent of reductions in plasma glucose and triglycerides. Intravenous exenatide increased fasting EF, and exendin-9 abolished this effect. Exenatide elicited eNOS activation and NO production in endothelial cells, and induced dose-dependent vasorelaxation and reduced high-glucose or lipid-induced endothelial dysfunction in arterioles ex vivo. These effects were reduced with AMPK inhibition. In conclusion, exenatide augmented postprandial EF in subjects with diabetes and prevented high-glucose and lipid-induced endothelial dysfunction in human arterioles. These effects were largely direct, via GLP-1R and AMPK activation.