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BACKGROUND: Acetaminophen is metabolized through a nontoxic sulfation and glucuronidation pathway and toxic oxidation pathway (via CYP2E1 and CYP1A2). A short-term high-fat diet induces alterations in the steatotic liver and may alter hepatic drug enzyme activity. In the case of acetaminophen, these alterations may result in an increased risk of hepatotoxicity. Therefore, this study was conducted to assess the effect of a 3-day hypercaloric high-fat diet on the plasma levels of acetaminophen metabolites. METHODS: Nine healthy subjects participated in this randomized, crossover intervention study. The subjects consumed a regular diet or a regular diet supplemented with 500 mL of cream (1700 kcal) for 3 days and then fasted overnight. After ingesting 1000-mg acetaminophen, the plasma concentration of acetaminophen (APAP) and its metabolites [acetaminophen glucuronide, acetaminophen sulfate, 3-cysteinyl-acetaminophen, and 3-(N-acetyl-L-cystein-S-yl)-acetaminophen, and 3-methoxy-acetaminophen] were measured. RESULTS: The 3-day high-fat diet increased the extrapolated area under the concentration-time curve from 0 to infinity (area under the curve 0-inf ) of APAP-Cys by approximately 20% ( P = 0.02) and that from 0 to 8 hours (area under the curve 0-8 ) of APAP-Cys-NAC by approximately 39% ( P = 0.01). The 3-day high-fat diet did not alter the pharmacokinetic parameters of the parent compound acetaminophen and other metabolites. CONCLUSIONS: A short-term, hypercaloric, high-fat diet increases the plasma levels of the APAP metabolites formed by the oxidation pathway, which may increase the risk of hepatotoxicity.

Objective Pituitary tumours that compress the optic chiasm are associated with long-term alterations in sleep–wake rhythm. This may result from damage to intrinsically photosensitive retinal ganglion cells (ipRGCs) projecting from the retina to the hypothalamic suprachiasmatic nucleus via the optic chiasm to ensure photoentrainment (i.e. synchronisation to the 24-h solar cycle through light). To test this hypothesis, we compared the post-illumination pupil response (PIPR), a direct indicator of ipRGC function, between hypopituitarism patients with and without a history of optic chiasm compression. Design Observational study, comparing two predefined groups. Methods We studied 49 patients with adequately substituted hypopituitarism: 25 patients with previous optic chiasm compression causing visual disturbances (CC+ group) and 24 patients without (CC– group). The PIPR was assessed by chromatic pupillometry and expressed as the relative change between baseline and post-blue-light stimulus pupil diameter. Objective and subjective sleep parameters were obtained using polysomnography, actigraphy, and questionnaires. Results Post-blue-light stimulus pupillary constriction was less sustained in CC+ patients compared with CC– patients, resulting in a significantly smaller extended PIPR (mean difference: 8.1%, 95% CI: 2.2–13.9%, P = 0.008, Cohen's d = 0.78). Sleep–wake timing was consistently later in CC+ patients, without differences in sleep duration, efficiency, or other rest–activity rhythm features. Subjective sleep did not differ between groups. Conclusion Previous optic chiasm compression due to a pituitary tumour in patients with hypopituitarism is associated with an attenuated PIPR and delayed sleep timing. Together, these data suggest that ipRGC function and consequently photoentrainment of the central biological clock is impaired in patients with a history of optic chiasm compression.

Objective: Fall prevention is important in many hospitals. Current fall-risk-screening tools have limited predictive accuracy specifically for older inpatients. Their administration can be time-consuming. A reliable and easy-to-administer tool is desirable to identify older inpatients at higher fall risk. We aimed to develop and internally validate a prognostic prediction model for inpatient falls for older patients. Design: Retrospective analysis of a large cohort drawn from hospital electronic health record data. Setting and Participants: Older patients (≥70 years) admitted to a university medical center (2016 until 2021). Methods: The outcome was an inpatient fall (≥24 hours of admission). Two prediction models were developed using regularized logistic regression in 5 imputed data sets: one model without predictors indicating missing values (Model-without) and one model with these additional predictors indicating missing values (Model-with). We internally validated our whole model development strategy using 10-fold stratified cross-validation. The models were evaluated using discrimination (area under the receiver operating characteristic curve) and calibration (plot assessment). We determined whether the areas under the receiver operating characteristic curves (AUCs) of the models were significantly different using DeLong test. Results: Our data set included 21,286 admissions. In total, 470 (2.2%) had a fall after 24 hours of admission. The Model-without had 12 predictors and Model-with 13, of which 4 were indicators of missing values. The AUCs of the Model-without and Model-with were 0.676 (95% CI 0.646-0.707) and 0.695 (95% CI 0.667-0.724). The AUCs between both models were significantly different (P = .013). Calibration was good for both models. Conclusions and Implications: Both the Model-with and Model-without indicators of missing values showed good calibration and fair discrimination, where the Model-with performed better. Our models showed competitive performance to well-established fall-risk-screening tools, and they have the advantage of being based on routinely collected data. This may substantially reduce the burden on nurses, compared with nonautomatic fall-risk-screening tools.

ObjectivesPhysician gaze towards patients is fundamental for medical consultations. Physicians’ use of Electronic Health Records (EHR) affects their gaze towards patients, and may negatively influence this interaction. We aimed to study conversation patterns during gaze shifts of physicians from the patient towards the EHR.MethodsOutpatient consultations (N=8) were eye-tracked. Interactions around physician gaze shifts towards the computer were transcribed.ResultsWe found that physician gaze shifts have different interactional functions, e.g., introducing a topic switch or entering data into the EHR. Furthermore, physicians differ in how they account for their gaze shifts, i.e., both implicitly and explicitly. Third, patients vary in treating the gaze shift as an indication to continue their turn or not.ConclusionsOur results suggest that physician gaze shifts vary in function, in how physicians account for them, and in how they influence the conversation. Future research should take into account distinctions when relating gaze to patient outcomes.Practice implicationsPhysicians may be aware of the interactional context of their gaze behaviour. Patients respond differently to various types of gaze shifts. How physicians handle gaze shifts can therefore have different consequences for the interaction.

Background & aims: To investigate the acute effects of intravenous vs enteral meal administration on circulating bile acid and gut hormone responses.Methods: In a randomized crossover design, we compared the effects of duodenal (via a nasoduodenal tube) vs parenteral (intravenous) administration over 180 min of identical mixed meals on circulating bile acid and gut hormone concentrations in eight healthy lean men. We analysed the bile acid and gut hormone responses in two periods: the intraprandial period from time point (T) 0 until T180 during meal administration and the postprandial period from T180 until T360, after discontinuation of meal administration.Results: Intravenous meal administration decreased the intraprandial (AUC (mmol/L*min) duodenal 1469 +/- 284 vs intravenous 240 +/- 39, p < 0.01) and postprandial bile acid response (985 +/- 240 vs 223 +/- 5, p < 0.05) and was accompanied by decreased gut hormone responses including glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, glucagon-like peptide 2 and fibroblast growth factor 19. Furthermore, intravenous meal administration elicited greater glucose concentrations, but similar insulin concentrations compared to enteral administration.Conclusions: Compared to enteral administration, parenteral nutrition results in lower postprandial bile acid and gut hormone responses in healthy lean men. This was accompanied by higher glucose concentrations in the face of similar insulin concentrations exposing a clear incretin effect of enteral mixed meal administration. The alterations in bile acid homeostasis were apparent after only one intravenous meal. (C) 2020 The Authors. Published by Elsevier Ltd.

Retinol‐binding protein‐4 (RBP4) is elevated in serum and adipose tissue (AT) in obesity‐induced insulin resistance and correlates inversely with insulin‐stimulated glucose disposal. But its role in insulin‐mediated suppression of lipolysis, free fatty acids (FFA), and endogenous glucose production (EGP) in humans is unknown. RBP4 mRNA or protein levels were higher in liver, subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) in morbidly obese subjects undergoing Roux‐en‐Y gastric bypass surgery compared to lean controls undergoing elective laparoscopic cholecystectomy. RBP4 mRNA expression in SAT correlated with the expression of several macrophage and other inflammation markers. Serum RBP4 levels correlated inversely with glucose disposal and insulin‐mediated suppression of lipolysis, FFA, and EGP. Mechanistically, RBP4 treatment of human adipocytes in vitro directly stimulated basal lipolysis. Treatment of adipocytes with conditioned media from RBP4‐activated macrophages markedly increased basal lipolysis and impaired insulin‐mediated lipolysis suppression. RBP4 treatment of macrophages increased TNFα production. These data suggest that elevated serum or adipose tissue RBP4 levels in morbidly obese subjects may cause hepatic and systemic insulin resistance by stimulating basal lipolysis and by activating macrophages in adipose tissue, resulting in release of pro‐inflammatory cytokines that impair lipolysis suppression. While we have demonstrated this mechanism in human adipocytes in vitro, and correlations from our flux studies in humans strongly support this, further studies are needed to determine whether this mechanism explains RBP4‐induced insulin resistance in humans.

Eye contact is a fundamental aspect of nonverbal communication and therefore important for understanding human interaction. Eye contact has been the subject of research in many disciplines, including communication sciences, social psychology, and psychiatry, and a variety of techniques have been used to measure it. The choice of measurement method has consequences for research outcomes and their interpretation. To ensure that research findings align with study aims and populations, it is essential that methodological choices are well substantiated. Therefore, to enhance the effective examination of eye contact, we performed a literature review of the methods used to study eye contact. We searched Medline, PsycINFO and Web of Science for empirical peer-reviewed articles published in English that described quantitative studies on human eye contact and included a methodological description. The identified studies (N = 109) used two approaches to assess eye contact: direct, i.e., assessing eye contact while it is occurring, and indirect, i.e., assessing eye contact retrospectively (e.g., from video recordings). Within these categories, eight specific techniques were distinguished. Variation was found regarding the reciprocity of eye contact between two individuals, the involvement of an assessor and the behavior of participants while being studied. Measures not involving the interactors in assessment of eye contact and have a higher spatial and temporal resolution, such as eye tracking, have gained popularity. Our results show wide methodological diversity regarding the measurement of eye contact. Although studies often define eye contact as gaze towards an exact location, this may not do justice to the subjective character of eye contact. The various methodologies have hardly ever been compared, limiting the ability to compare findings between studies. Future studies should take notice of the controversy surrounding eye contact measures.

Objective to investigate the effect of potentially inappropriate medications (PIMs) on inpatient falls and to identify whether PIMs as defined by STOPPFall or the designated section K for falls of STOPP v2 have a stronger association with inpatient falls when compared to the general tool STOPP v2. Methods a retrospective observational matching study using an electronic health records dataset of patients (≥70 years) admitted to an academic hospital (2015–19), including free text to identify inpatient falls. PIMs were identified using the STOPP v2, section K of STOPP v2 and STOPPFall. We first matched admissions with PIMs to those without PIMs on confounding factors. We then applied multinomial logistic regression analysis and Cox proportional hazards analysis on the matched datasets to identify effects of PIMs on inpatient falls. Results the dataset included 16,678 hospital admissions, with a mean age of 77.2 years. Inpatient falls occurred during 446 (2.7%) admissions. Adjusted odds ratio (OR) (95% confidence interval (CI)) for the association between PIM exposure and falls were 7.9 (6.1–10.3) for STOPP section K, 2.2 (2.0–2.5) for STOPP and 1.4 (1.3–1.5) for STOPPFall. Adjusted hazard ratio (HR) (95% CI) for the effect on time to first fall were 2.8 (2.3–3.5) for STOPP section K, 1.5 (1.3–1.6) for STOPP and 1.3 (1.2–1.5) for STOPPFall. Conclusions we identified an independent association of PIMs on inpatient falls for all applied (de)prescribing tools. The strongest effect was identified for STOPP section K, which is restricted to high-risk medication for falls. Our results suggest that decreasing PIM exposure during hospital stay might benefit fall prevention, but intervention studies are warranted.

Purpose: Fall prevention is a safety goal in many hospitals. The performance of the Johns Hopkins Fall Risk Assessment Tool (JHFRAT) in older inpatients is largely unknown. We aimed to assess the JHFRAT performance in a large sample of Dutch older inpatients, including its trend over time. Methods: We used an Electronic Health Records (EHR) dataset with hospitalized patients (≥ 70), admitted for ≥ 24 h between 2016 and 2021. Inpatient falls were extracted from structured and free-text data. We assessed the association between JHFRAT and falls using logistic regression. For test accuracy, we calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Discrimination was measured by the AUC. For calibration, we plotted the predicted fall probability with the actual probability of falls. For time-related effects, we calculated the AUC per 6 months (using data of patients admitted during the 6 months’ time interval) and plotted these different AUC values over time. Furthermore, we compared the model (JHFRAT and falls) with and without adjusting for seasonal influenza, COVID-19, spring, summer, fall or winter periods. Results: Data included 17,263 admissions with at least 1 JHFRAT measurement, a median age of 76 and a percentage female of 47%. The in-hospital fall prevalence was 2.5%. JHFRAT [OR = 1.11 (1.03–1.20)] and its subcategories were significantly associated with falls. For medium/high risk of falls (JHFRAT > 5), sensitivity was 73%, specificity 51%, PPV 4% and NPV 99%. The overall AUC was 0.67, varying over time between 0.62 and 0.71 (for 6 months’ time intervals). Seasonal influenza did affect the association between JHFRAT and falls. COVID-19, spring, summer, fall or winter did not affect the association. Conclusions: Our results show an association between JHFRAT and falls, a low discrimination by JHFRAT for older inpatients and over-prediction in the calibration. Improvements in the fall-risk assessment are warranted to improve efficiency.

Frontiers in physiology 12, 771944 (2022). doi:10.3389/fphys.2021.771944, Published by Frontiers Research Foundation, Lausanne

Face gaze is a fundamental non-verbal behaviour and can be assessed using eye-tracking glasses. Methodological guidelines are lacking on which measure to use to determine face gaze. To evaluate face gaze patterns we compared three measures: duration, frequency and dwell time. Furthermore, state of the art face gaze analysis requires time and manual effort. We tested if face gaze patterns in the first 30, 60 and 120 s predict face gaze patterns in the remaining interaction. We performed secondary analyses of mobile eye-tracking data of 16 internal medicine physicians in consultation with 100 of their patients. Duration and frequency of face gaze were unrelated. The lack of association between duration and frequency suggests that research may yield different results depending on which measure of face gaze is used. Dwell time correlates both duration and frequency. Face gaze during the first seconds of the consultations predicted face gaze patterns of the remaining consultation time (R2 0.26 to 0.73). Therefore, face gaze during the first minutes of the consultations can be used to predict face gaze patterns over the complete interaction. Researchers interested to study face gaze may use these findings to make optimal methodological choices.

The aim of this scoping review is to summarize approaches and outcomes of clinical validation studies of clinical decision support systems (CDSSs) to support (part of) a medication review. A literature search was conducted in Embase and Medline. In total, 30 articles validating a CDSS were ultimately included. Most of the studies focused on detection of adverse drug events, potentially inappropriate medications and drug-related problems. We categorized the included articles in three groups: studies subjectively reviewing the clinical relevance of CDSS's output (21/30 studies) resulting in a positive predictive value (PPV) for clinical relevance of 4–80%; studies determining the relationship between alerts and actual events (10/30 studies) resulting in a PPV for actual events of 5–80%; and studies comparing output of CDSSs to chart/medication reviews in the whole study population (10/30 studies) resulting in a sensitivity of 28–85% and specificity of 42–75%. We found heterogeneity in the methods used and in the outcome measures. The validation studies did not report the use of a published CDSS validation strategy. To improve the effectiveness and uptake of CDSSs supporting a medication review, future research would benefit from a more systematic and comprehensive validation strategy.

Background Falls and delirium are common complications in older inpatients. Implementation of fall and delirium guidelines is complex and may be facilitated by Clinical Decision Support Systems (CDSSs). Our study aimed to understand the differences between guidelines (work-as-imagined) and actual care (work-as-done) and how these can impact the design of a CDSS. Methods We used Functional Resonance Analysis Method (FRAM) as structured method to visualize work-as-imagined and work-as-done and to develop an initial CDSS design. As input for work-as-imagined, we used national guidelines. To identify work-as-done and CDSS preferences, we conducted semi-structured interviews in two rounds. We identified differences between guidelines and actual care by creating a FRAM model for work-as-imagined and one for work-as-done. CDSS preferences were coupled to activities in the FRAM models and to the identified barriers and facilitators for following guidelines. Results Eighteen clinicians participated in 24 individual and small-group interviews. For both falls and delirium, we found substantial differences between work-as-imagined and work-as-done. Several CDSS opportunities to improve fall and delirium care were identified including reminders for screening, an order set to facilitate risk assessment, automatically-generated advice with personalized preventive interventions and support to facilitate medication reviews. The required CDSSs addressed both barriers and facilitators. Conclusion In our study, work-as-done for falls and delirium differed substantially from work-as-imagined and the preferred CDSSs would address both barriers and facilitators. Furthermore, our study showed that FRAM is a suitable tool to identify differences between actual care and guidelines and to design CDSSs from a user-centred approach.

The patient-physician relationship is a critical determinant for patient health outcomes. Verbal and non-verbal communication, such as eye gaze, are vital aspects of this bond. Neurobiological studies indicate that oxytocin may serve as a link between increased eye gaze and social bonding. Therefore, oxytocin signaling could serve as a key factor influencing eye gaze as well as the patient-physician relationship. We aimed to test the effects of oxytocin on gaze to the eyes of the physician and the patient-physician relationship by conducting a randomized placebo-controlled crossover trial in healthy volunteers with intranasally administered oxytocin (24IU, number 2018-004081-34). Eye gaze of sixty-eight male volunteers was studied using eye-tracking. Volunteers engaged in a simulated video call consultation with a physician who provided information about vaccination against the human papilloma virus. Relationship outcomes, including trust, satisfaction and perceived physician communication style, were measured using questionnaires and corrected for possible confounders (social anxiety and attachment orientation). Additional secondary outcome measures were recall of information and pupil diameter and exploratory outcomes were mood and anxiety. Oxytocin did not affect eye tracking parameters of volunteers’ gaze towards the eyes of the physician. Moreover, oxytocin did not affect parameters of bonding between volunteers and the physician, nor other secondary and exploratory outcomes. Bayesian hypothesis testing provided evidence for the absence of effects. These results contradict the notion that oxytocin affects eye gaze patterns or bonding.

BackgroundClinical decision support systems (CDSSs) form an implementation strategy that can facilitate and support health care professionals in the care of older hospitalized patients.ObjectiveOur study aims to systematically review the effects of CDSS interventions in older hospitalized patients. As a secondary aim, we aim to summarize the implementation and design factors described in effective and ineffective interventions and identify gaps in the current literature.MethodsWe conducted a systematic review with a search strategy combining the categories older patients, geriatric topic, hospital, CDSS, and intervention in the databases MEDLINE, Embase, and SCOPUS. We included controlled studies, extracted data of all reported outcomes, and potentially beneficial design and implementation factors. We structured these factors using the Grol and Wensing Implementation of Change model, the GUIDES (Guideline Implementation with Decision Support) checklist, and the two-stream model. The risk of bias of the included studies was assessed using the Cochrane Collaboration’s Effective Practice and Organisation of Care risk of bias approach.ResultsOur systematic review included 18 interventions, of which 13 (72%) were effective in improving care. Among these interventions, 8 (6 effective) focused on medication review, 8 (6 effective) on delirium, 7 (4 effective) on falls, 5 (4 effective) on functional decline, 4 (3 effective) on discharge or aftercare, and 2 (0 effective) on pressure ulcers. In 77% (10/13) effective interventions, the effect was based on process-related outcomes, in 15% (2/13) interventions on both process- and patient-related outcomes, and in 8% (1/13) interventions on patient-related outcomes. The following implementation and design factors were potentially associated with effectiveness: a priori problem or performance analyses (described in 9/13, 69% effective vs 0/5, 0% ineffective interventions), multifaceted interventions (8/13, 62% vs 1/5, 20%), and consideration of the workflow (9/13, 69% vs 1/5, 20%).ConclusionsCDSS interventions can improve the hospital care of older patients, mostly on process-related outcomes. We identified 2 implementation factors and 1 design factor that were reported more frequently in articles on effective interventions. More studies with strong designs are needed to measure the effect of CDSS on relevant patient-related outcomes, investigate personalized (data-driven) interventions, and quantify the impact of implementation and design factors on CDSS effectiveness.Trial RegistrationPROSPERO (International Prospective Register of Systematic Reviews): CRD42019124470; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=124470.

Introduction: There is considerable variability in the rates and extent of drug metabolism between patients due to physiological, genetic, pharmacologic, environmental and nutritional factors such as fasting. This variability in drug metabolism may result in treatment failure or, conversely, in increased side effects or toxicity. Preclinical studies have shown that fasting alters drug metabolism by modulating the activity of drug metabolizing enzymes involved. However, until recently little was known about the effects of fasting on drug metabolism in humans. Areas covered: This review describes the effects of fasting on drug metabolism based on both preclinical studies and studies performed in humans. Expert opinion: A better understanding of the effects of fasting may improve the efficacy and safety of pharmacotherapy for individual patients. Fasting contributes to variability in human drug metabolism by differentially affecting drug metabolizing enzymes. Although the effects of fasting on drug metabolism appear to be small (between 10-20%), fasting may be relevant for drugs with a small therapeutic range and/or in combination with other factors that contribute to variability in drug metabolism such as physiological, genetic or pharmacological factors. Therefore, additional research on this topic is warranted.

Background and Aims: Placement of the duodenal-jejunal bypass liner (DJBL) leads to rapid weight loss and restoration of insulin sensitivity in a similar fashion to bariatric surgery. Increased systemic bile add levels are candidate effectors for these effects through postprandial activation of their receptors TGR5 and FXR. We aimed to quantify postprandial bile acid, GLP-1 and FGF19 responses and assess their temporal relation to the weight loss and metabolic and hormonal changes seen after DJBL placement.Methods: We performed mixed meal testing in 17 obese patients with type 2 diabetes mellitus (DM2) directly before, one week after and 6 months after DJBL placement.Results: Both fasting and postprandial bile add levels were unchanged at 1 week after implantation, and greatly increased 6 months after implantation. The increase consisted of unconjugated bile add species. 3 hour-postprandial GLP-1 levels increased after 1 week and were sustained, whereas FGF19 levels and postprandial plasma courses were unaffected.Conclusions: DJBL placement leads to profound increases in unconjugated bile add levels after 6 months, similar to the effects of bariatric surgery. The temporal dissociation between the changes in bile adds, GLP-1 and FGF19 and other gut hormone responses warrant caution about the beneficial role of bile acids after DJBL placement. This observational uncontrolled study emphasizes the need for future controlled studies. (C) 2019 Elsevier Inc. All rights reserved.

BACKGROUND Clinical decision support systems (CDSSs) form an implementation strategy that can facilitate and support health care professionals in the care of older hospitalized patients. OBJECTIVE Our study aims to systematically review the effects of CDSS interventions in older hospitalized patients. As a secondary aim, we aim to summarize the implementation and design factors described in effective and ineffective interventions and identify gaps in the current literature. METHODS We conducted a systematic review with a search strategy combining the categories older patients, geriatric topic, hospital, CDSS, and intervention in the databases MEDLINE, Embase, and SCOPUS. We included controlled studies, extracted data of all reported outcomes, and potentially beneficial design and implementation factors. We structured these factors using the Grol and Wensing Implementation of Change model, the GUIDES (Guideline Implementation with Decision Support) checklist, and the two-stream model. The risk of bias of the included studies was assessed using the Cochrane Collaboration’s Effective Practice and Organisation of Care risk of bias approach. RESULTS Our systematic review included 18 interventions, of which 13 (72%) were effective in improving care. Among these interventions, 8 (6 effective) focused on medication review, 8 (6 effective) on delirium, 7 (4 effective) on falls, 5 (4 effective) on functional decline, 4 (3 effective) on discharge or aftercare, and 2 (0 effective) on pressure ulcers. In 77% (10/13) effective interventions, the effect was based on process-related outcomes, in 15% (2/13) interventions on both process- and patient-related outcomes, and in 8% (1/13) interventions on patient-related outcomes. The following implementation and design factors were potentially associated with effectiveness: a priori problem or performance analyses (described in 9/13, 69% effective vs 0/5, 0% ineffective interventions), multifaceted interventions (8/13, 62% vs 1/5, 20%), and consideration of the workflow (9/13, 69% vs 1/5, 20%). CONCLUSIONS CDSS interventions can improve the hospital care of older patients, mostly on process-related outcomes. We identified 2 implementation factors and 1 design factor that were reported more frequently in articles on effective interventions. More studies with strong designs are needed to measure the effect of CDSS on relevant patient-related outcomes, investigate personalized (data-driven) interventions, and quantify the impact of implementation and design factors on CDSS effectiveness. CLINICALTRIAL PROSPERO (International Prospective Register of Systematic Reviews): CRD42019124470; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=124470.

The assessment of gaze behaviour is essential for understanding the psychology of communication. Mobile eye-tracking glasses are useful to measure gaze behaviour during dynamic interactions. Eye-tracking data can be analysed by using manually annotated areas-of-interest. Computer vision algorithms may alternatively be used to reduce the amount of manual effort, but also the subjectivity and complexity of these analyses. Using additional re-identification (Re-ID) algorithms, different participants in the interaction can be distinguished. The aim of this study was to compare the results of manual annotation of mobile eye-tracking data with the results of a computer vision algorithm. We selected the first minute of seven randomly selected eye-tracking videos of consultations between physicians and patients in a Dutch Internal Medicine out-patient clinic. Three human annotators and a computer vision algorithm annotated mobile eye-tracking data, after which interrater reliability was assessed between the areas-of-interest annotated by the annotators and the computer vision algorithm. Additionally, we explored interrater reliability when using lengthy videos and different area-of-interest shapes. In total, we analysed more than 65 min of eye-tracking videos manually and with the algorithm. Overall, the absolute normalized difference between the manual and the algorithm annotations of face-gaze was less than 2%. Our results show high interrater agreements between human annotators and the algorithm with Cohen’s kappa ranging from 0.85 to 0.98. We conclude that computer vision algorithms produce comparable results to those of human annotators. Analyses by the algorithm are not subject to annotator fatigue or subjectivity and can therefore advance eye-tracking analyses.

OBJECTIVE Both glucose and triglyceride production are increased in type 2 diabetes and nonalcoholic fatty liver disease (NAFLD). For decades, the leading hypothesis to explain these paradoxical observations has been selective hepatic insulin resistance wherein insulin drives de novo lipogenesis (DNL) while failing to suppress glucose production. Here, we aimed to test this hypothesis in humans. RESEARCH DESIGN AND METHODS We recruited obese subjects who met criteria for bariatric surgery with (n = 16) or without (n = 15) NAFLD and assessed 1) insulin-mediated regulation of hepatic and peripheral glucose metabolism using hyperinsulinemic-euglycemic clamps with [6,6-2H2]glucose, 2) fasting and carbohydrate-driven hepatic DNL using deuterated water (2H2O), and 3) hepatocellular insulin signaling in liver biopsy samples collected during bariatric surgery. RESULTS Compared with subjects without NAFLD, those with NAFLD demonstrated impaired insulin-mediated suppression of glucose production and attenuated—not increased—glucose-stimulated/high-insulin lipogenesis. Fructose-stimulated/low-insulin lipogenesis was intact. Hepatocellular insulin signaling, assessed for the first time in humans, exhibited a proximal block in insulin-resistant subjects: Signaling was attenuated from the level of the insulin receptor through both glucose and lipogenesis pathways. The carbohydrate-regulated lipogenic transcription factor ChREBP was increased in subjects with NAFLD. CONCLUSIONS Acute increases in lipogenesis in humans with NAFLD are not explained by altered molecular regulation of lipogenesis through a paradoxical increase in lipogenic insulin action; rather, increases in lipogenic substrate availability may be the key.

Background Glucagon-like peptide-1 (GLP-1) receptor agonist treatment is beneficial for human glucose metabolism, and GLP-1 secretion is greatly enhanced following Roux-en-Y gastric bypass (RYGB). Objectives The objectives of this study were to elucidate the relationship between GLP-1 concentrations and insulin sensitivity in subjects with class II/III obesity without diabetes, and to assess the relation between GLP-1 and the improvements in glucose metabolism following RYGB. Setting Clinical research facility in university hospital. Methods We recruited 35 patients scheduled for RYGB and assessed the plasma GLP-1, insulin, and glucose responses to a high-fat mixed meal. Basal and insulin-mediated glucose fluxes were determined during a two-step hyperinsulinemic-euglycemic clamp with stable isotope-labeled tracers. Ten out of 35 subjects were studied both before surgery and at one-year follow-up. Results Plasma GLP-1 increased following the high-fat mixed meal. Postprandial GLP-1 excursions correlated positively with hepatic and peripheral insulin sensitivity, but not with body mass index (BMI). One year after RYGB, participants had lost 24±6% of body weight. Plasma GLP-1, insulin, and glucose levels peaked earlier and higher after the mixed meal. The positive association between the postprandial GLP-1 response and peripheral insulin sensitivity persisted. Conclusions Postprandial GLP-1 concentrations correlate with insulin sensitivity in subjects with class II/III obesity without diabetes before and one year after RYGB. Increased GLP-1 signaling in postbariatric patients may, directly or indirectly, contribute to the observed improvements in insulin sensitivity and metabolic health.

Animal studies indicate that hypothalamic dysfunction plays a major role in type 2 diabetes mellitus (T2DM) development, and that insulin resistance and inflammation are important mechanisms involved in this disorder. However, it remains unclear how T2DM and antidiabetic treatments affect the human hypothalamus. Here, we characterized the proopiomelanocortin (POMC) immunoreactive (-ir) neurons, the neuropeptide-Y–ir (NPY-ir) neurons, the ionized calcium-binding adapter molecule 1–ir (iba1-ir) microglia, and the transmembrane protein 119–ir (TMEM119-ir) microglia in the infundibular nucleus (IFN) of human postmortem hypothalamus of 32 T2DM subjects with different antidiabetic treatments and 17 matched nondiabetic control subjects. Compared with matched control subjects, T2DM subjects showed a decrease in the number of POMC-ir neurons, but no changes in NPY-ir neurons or microglia. Interestingly, T2DM subjects treated with the antidiabetic drug metformin had fewer NPY-ir neurons and microglia than T2DM subjects not treated with metformin. We found that the number of microglia correlated with the number of NPY-ir neurons, but only in T2DM subjects. These results indicate that different changes in POMC and NPY neurons and microglial cells in the IFN accompany T2DM. In addition, T2DM treatment modality is associated with highly selective changes in hypothalamic neurons and microglial cells., Type 2 diabetes impacts energy homeostasis-regulatory neurons and the surrounding microglia in the hypothalamus, and these effects are modulated by metformin.

Purpose To investigate prevalence, independent associations, and variation over time of potentially inappropriate prescriptions in a population of older hospitalized patients. Methods A longitudinal study using a large dataset of hospital admissions of older patients (≥ 70 years) based on an electronic health records cohort including data from 2015 to 2019. Potentially inappropriate medication (PIM) and potential prescribing omission (PPO) prevalence during hospital stay were identified based on the Dutch STOPP/START criteria v2. Univariate and multivariate logistic regression were used for analyzing associations and trends over time. Results The data included 16,687 admissions. Of all admissions, 56% had ≥ 1 PIM and 58% had ≥ 1 PPO. Gender, age, number of medications, number of diagnoses, Charlson score, and length of stay were independently associated with both PIMs and PPOs. Additionally, number of departments and number of prescribing specialties were independently associated with PIMs. Over the years, the PIM prevalence did not change (OR = 1.00, p = .95), whereas PPO prevalence increased (OR = 1.08, p p Conclusion We found potentially inappropriate prescriptions in the majority of admissions of older patients. Prescribing relatively improved over time when considering complexity of the admissions. Nevertheless, the high prevalence shows a clear need to better address this issue in clinical practice. Studies seeking effective (re)prescribing interventions are warranted.

Purpose of Review The global prevalence of obesity has increased rapidly over the last decades, posing a severe threat to human health. Currently, bariatric surgery is the most effective therapy for patients with morbid obesity. It is unknown whether this treatment is also suitable for patients with obesity due to a confirmed genetic defect (genetic obesity disorders). Therefore, this review aims to elucidate the role of bariatric surgery in the treatment of genetic obesity. Recent Findings In monogenic non-syndromic obesity, an underlying genetic defect seems to be the most important factor determining the efficacy of bariatric surgery. In syndromic obesity, bariatric surgery result data are scarce, and even though some promising follow-up results have been reported, caution is required as patients with more severe behavioral and developmental disorders might have poorer outcomes. Summary There is limited evidence in support of bariatric surgery as a treatment option for genetic obesity disorders; hence, no strong statements can be made regarding the efficacy and safety of these procedures for these patients. However, considering that patients with genetic obesity often present with life-threatening obesity-related comorbidities, we believe that bariatric surgery could be considered a last-resort treatment option in selected patients.

Background Bile acids are multifaceted metabolic compounds that signal to cholesterol, glucose, and lipid homeostasis via receptors like the Farnesoid X Receptor (FXR) and transmembrane Takeda G protein‐coupled receptor 5 (TGR5). The postprandial increase in plasma bile acid concentrations is therefore a potential metabolic signal. However, this postprandial response has a high interindividual variability. Such variability may affect bile acid receptor activation. Methods In this study, we analyzed the inter‐ and intraindividual variability of fasting and postprandial bile acid concentrations during three identical meals on separate days in eight healthy lean male subjects using a statistical and mathematical approach. Main findings The postprandial bile acid responses exhibited large interindividual and intraindividual variability. The individual mathematical models, which represent the enterohepatic circulation of bile acids in each subject, suggest that interindividual variability results from quantitative and qualitative differences of distal active uptake, colon transit, and microbial bile acid transformation. Conversely, intraindividual variations in gallbladder kinetics can explain intraindividual differences in the postprandial responses. Conclusions We conclude that there is considerable inter‐ and intraindividual variation in postprandial plasma bile acid levels. The presented personalized approach is a promising tool to identify unique characteristics of underlying physiological processes and can be applied to investigate bile acid metabolism in pathophysiological conditions., The data presented here characterize the inter‐ and intraindividual variability of the postprandial bile acid response. More so, the mathematical models allocated the interindividual variability to distal active uptake, colon transit, and microbial bile acid transformation, whereas for intraindividual variability, it was sufficient to allow variation in gallbladder kinetics

Fasting induces profound changes in the hypothalamus-pituitary-thyroid axis and peripheral thyroid hormone (TH) metabolism, ultimately leading to lower serum thyroid hormone (TH) concentrations. In the present study, we aimed to investigate the regulation of type 3 deiodinase (D3) during fasting in two metabolic tissues: liver and white adipose tissue (WAT). To this end, we studied the effect of modulation of the mammalian target of rapamycin (mTOR) and hypoxia inducible factor 1α (HIF1α) on D3 expression in primary rat hepatocytes and in 3T3-L1 adipocytes. In addition, we studied the role of the constitutive androstane receptor (CAR) on liver TH metabolism using primary hepatocytes and CAR-/- mice. Twenty-four-hour fasting increased liver Dio3 expression in mice. Inhibition of mTOR using mTOR inhibitors markedly induced Dio3 mRNA expression in primary hepatocytes; this increase was accompanied by a small increase in D3 activity. Stimulation of these cells with a CAR agonist induced both Dio3 mRNA expression and activity. Fasting increased hepatic D3 expression in WT but not in CAR-/- mice. In WAT, Dio3 mRNA expression increased five-fold after 48-h fasting. Treatment of 3T3-L1 adipocytes with mTOR inhibitors induced Dio3 mRNA expression, whereas stimulation of these cells with cobalt chloride, a compound that mimics hypoxia and stabilizes HIF1α, did not induce Dio3 mRNA expression. In conclusion, our results indicate an important role of mTOR in the upregulation of D3 in WAT and liver during fasting. Furthermore, CAR plays a role in the fasting induced D3 increase in the liver.

Background & aims: Bile acids (BAs) play a key role in lipid uptake and metabolic signalling in different organs including gut, liver, muscle and brown adipose tissue. Portal and peripheral plasma BA concentrations increase after a meal. However, the exact kinetics of postprandial BA metabolism have never been described in great detail. We used a conscious porcine model to investigate postprandial plasma concentrations and transorgan fluxes of BAs, glucose and insulin using the para-aminohippuric acid dilution method.Methods: Eleven pigs with intravascular catheters received a standard mixed-meal while blood was sampled from different veins such as the portal vein, abdominal aorta and hepatic vein. To translate the data to humans, fasted venous and portal blood was sampled from non-diabetic obese patients during gastric by-pass surgery.Results: The majority of the plasma bile acid pool and postprandial response consisted of glycine-conjugated forms of primary bile acids. Conjugated bile acids were more efficiently cleared by the liver than unconjugated forms. The timing and size of the postprandial response showed large interindividual variability for bile acids compared to glucose and insulin.Conclusions: The liver selectively extracts most BAs and BAs with highest affinity for the most important metabolic BA receptor, TGR5, are typically low in both porcine and human peripheral circulation. Our findings raise questions about the magnitude of a peripheral TGR5 signal and its ultimate clinical application. (C) 2017 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Introduction: Fasting, as well as a high-fat diet, might increase the risk on acetaminophen-induced toxicity after an acute overdose. Therefore, it has been suggested to lower the threshold for acetylcysteine treatment to prevent liver injury in case of fasting. This study aims to investigate the effects of 36 hours of fasting and three days of a hypercaloric high-fat diet on acetaminophen measurement and exposure. Methods: Nine healthy male subjects were enrolled in a randomized crossover intervention study. Subjects received 1000mg oral acetaminophen after an overnight fast following: (1) regular diet,(2) 36h of fasting and (3) three days of a hypercaloric high-fat diet consisting of 500ml of cream (1715 kcal) supplemented to their regular diet. Pharmacokinetic parameters were determined by non-compartmental analysis. Samples were analyzed by an enzymatic colorimetric method used in routine practice and by LC-MS/MS being the gold standard. Agreement between these methods was assessed by the Bland–Altman method. Results: Short-term fasting increased acetaminophen exposure by 20% (ΔAUC0-8 hours, p = .04) in comparison with the control diet. Three days of hypercaloric high-fat diet did not affect acetaminophen exposure (ΔAUC0–8 hours= 9%, p = .67). The intraclass correlation coefficient between the enzymatic assay and LC-MS/MS methods of the fasting samples was 0.46 (0.28–0.61), compared to 0.87 (0.81–0.92) and 0.87 (0.79–0.91) in the control and high-fat samples respectively. Conclusions: Short-term fasting increases acetaminophen exposure in healthy subjects, whereas no effect is observed after a high-fat diet. Furthermore, short-term fasting decreases the accuracy of the enzymatic colorimetric method when measuring relatively low acetaminophen concentrations. This suggests considering nutritional status when assessing the risk of acetaminophen-induced toxicity, although further research at toxic doses is needed.

A recent study in rheumatoid arthritis (RA) patients using electrical vagus nerve stimulation (VNS) to activate the inflammatory reflex has shown promising effects on disease activity. Innervation by the autonomic nerve system might be involved in the regulation of many endocrine and metabolic processes and could therefore theoretically lead to unwanted side effects. Possible effects of VNS on secretion of hormones are currently unknown. Therefore, we evaluated the effects of a single VNS on plasma levels of pituitary hormones and parameters of postprandial metabolism. Six female patients with RA were studied twice in balanced assignment (crossover design) to either VNS or no stimulation. The patients selected for this substudy had been on VNS therapy daily for at least 3 months and at maximum of 24 months. We compared 10-, 20-, and 30-min poststimulus levels to baseline levels, and a 4-h mixed meal test was performed 30 min after VNS. We also determined energy expenditure (EE) by indirect calorimetry before and after VNS. VNS did not affect pituitary hormones (growth hormone, thyroid stimulating hormone, adrenocorticotropic hormone, prolactin, follicle-stimulating hormone, and luteinizing hormone), postprandial metabolism, or EE. Of note, VNS reduced early postprandial insulin secretion, but not AUC of postprandial plasma insulin levels. Cortisol and catecholamine levels in serum did not change significantly. Short stimulation of vagal activity by VNS reduces early postprandial insulin secretion, but not other hormone levels and postprandial response. This suggests VNS as a safe treatment for RA patients.

Background and Objectives Short-term fasting differentially alters cytochrome P450 (CYP) mediated drug metabolism. This has been established by using CYP-enzyme selective probe drugs. However, the observed effects of fasting on the pharmacokinetics of these probe drugs may also include the effects of altered plasma protein binding of these drugs. Therefore, we studied the effect of short-term fasting on protein binding of five commonly used probe drugs [caffeine (CYP1A2), metoprolol (CYP2D6), midazolam (CYP3A4), omeprazole (CYP2C19) and S-warfarin (CYP2C9)]. Methods The free and total plasma concentrations of the five probe drugs were analyzed by LC–MS/MS in samples retrieved in a cross-over study in which nine healthy subjects received an intravenous administration of the cocktail after an overnight fast (control) and after 36 h of fasting. Results Short-term fasting increased plasma free fatty acid concentrations from 0.48 mmol/L (control) to 1.29 mmol/L (36 h fasting) (p = 0.012). Short-term fasting did not alter the free fractions of caffeine, metoprolol and omeprazole compared to the control intervention (p > 0.05). Power to detect a difference for midazolam and S-warfarin was low since the majority of free concentrations were below the limit of quantification. Conclusions This study demonstrates that short-term fasting does not alter protein binding of the probe drugs caffeine, metoprolol and omeprazole. Electronic supplementary material The online version of this article (doi:10.1007/s13318-017-0437-7) contains supplementary material, which is available to authorized users.

Background & aims: Bile acids (BA) are pleiotropic hormones affecting glucose and lipid metabolism. The physiochemical properties of different BA species affect their enterohepatic dynamics and their affinity for bile acid receptors. The BA pool composition is altered in patients with type 2 diabetes and obesity. In this study we used a 2-week very-low-calorie diet (VLCD) to investigate the effects of weight loss on BA pool composition and postprandial dynamics.Methods: We performed mixed meal tests in obese, insulin resistant subjects before and after the VLCD. We measured postprandial plasma levels of glucose, insulin, BA and the BA-induced enterokine fibroblast growth factor 19 (FGF19).Results: The VLCD decreased weight by 4.5 +/- 2.3 kg (p Conclusions: VLCD induced weight loss increased postprandial DCA peak levels and decreased resting energy expenditure in obese insulin resistant subjects. (C) 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Desynchronization between the master clock in the brain, which is entrained by (day) light, and peripheral organ clocks, which are mainly entrained by food intake, may have negative effects on energy metabolism. Bile acid metabolism follows a clear day/night rhythm. We investigated whether in rats on a normal chow diet the daily rhythm of plasma bile acids and hepatic expression of bile acid metabolic genes is controlled by the light/dark cycle or the feeding/fasting rhythm. In addition, we investigated the effects of high caloric diets and time-restricted feeding on daily rhythms of plasma bile acids and hepatic genes involved in bile acid synthesis. In experiment 1 male Wistar rats were fed according to three different feeding paradigms: food was available ad libitum for 24 h (ad lib) or time-restricted for 10 h during the dark period (dark fed) or 10 h during the light period (light fed). To allow further metabolic phenotyping, we manipulated dietary macronutrient intake by providing rats with a chow diet, a free choice high-fat-high-sugar diet or a free choice high-fat (HF) diet. In experiment 2 rats were fed a normal chow diet, but food was either available in a 6-meals-a-day (6M) scheme or ad lib. During both experiments, we measured plasma bile acid levels and hepatic mRNA expression of genes involved in bile acid metabolism at eight different time points during 24 h. Time-restricted feeding enhanced the daily rhythm in plasma bile acid concentrations. Plasma bile acid concentrations are highest during fasting and dropped during the period of food intake with all diets. An HF-containing diet changed bile acid pool composition, but not the daily rhythmicity of plasma bile acid levels. Daily rhythms of hepatic Cyp7a1 and Cyp8b1 mRNA expression followed the hepatic molecular clock, whereas for Shp expression food intake was leading. Combining an HF diet with feeding in the light/inactive period annulled CYp7a1 and Cyp8b1 gene expression rhythms, whilst keeping that of Shp intact. In conclusion, plasma bile acids and key genes in bile acid biosynthesis are entrained by food intake as well as the hepatic molecular clock. Eating during the inactivity period induced changes in the plasma bile acid pool composition similar to those induced by HF feeding.

BACKGROUND/OBJECTIVES: Insulin resistance of adipose tissue is an important feature of obesity-related metabolic disease. However, assessment of lipolysis in humans requires labor-intensive and expensive methods, and there is limited validation of simplified measurement methods. We aimed to validate simplified methods for the quantification of adipose tissue insulin resistance against the assessment of insulin sensitivity of lipolysis suppression during hyperinsulinemic-euglycemic clamp studies. SUBJECTS/METHODS: We assessed the insulin-mediated suppression of lipolysis by tracer-dilution of [1,1,2,3,3-H-2(5)] glycerol during hyperinsulinemic-euglycemic clamp studies in 125 overweight or obese adults (85 men, 40 women; age 50 +/- 11 years; body mass index 38 +/- 7 kg m(-2)). Seven indices of adipose tissue insulin resistance were validated against the reference measurement method. RESULTS: Low-dose insulin infusion resulted in suppression of the glycerol rate of appearance ranging from 4% (most resistant) to 85% (most sensitive), indicating a good range of adipose tissue insulin sensitivity in the study population. The reference method correlated with (1) insulin-mediated suppression of plasma glycerol concentrations (r = 0.960, P = 0.801, P

Background and Objective Short-term fasting can alter drug exposure but it is unknown whether this is an effect of altered oral bioavailability and/or systemic clearance. Therefore, the aim of our study was to assess the effect of short-term fasting on oral bioavailability and systemic clearance of different drugs. Methods In a randomized, controlled, crossover trial, 12 healthy subjects received a single administration of a cytochrome P450 (CYP) probe cocktail, consisting of caffeine (CYP1A2), metoprolol (CYP2D6), midazolam (CYP3A4), omeprazole (CYP2C19) and warfarin (CYP2C9), on four occasions: an oral (1) and intravenous (2) administration after an overnight fast (control) and an oral (3) and intravenous (4) administration after 36 h of fasting. Pharmacokinetic parameters of the probe drugs were analyzed using the nonlinear mixed-effects modeling software NONMEM. Results Short-term fasting increased systemic caffeine clearance by 17% (p = 0.04) and metoprolol clearance by 13% (p

Aims/hypothesis The central pacemaker of the mammalian biological timing system is located within the suprachiasmatic nucleus (SCN) in the anterior hypothalamus. Together with the peripheral clocks, this central brain clock ensures a timely, up-to-date and proper behaviour for an individual throughout the day–night cycle. A mismatch between the central and peripheral clocks results in a disturbance of daily rhythms in physiology and behaviour. It is known that the number of rhythmically expressed genes is reduced in peripheral tissue of individuals with type 2 diabetes mellitus. However, it is not known whether the central SCN clock is also affected in the pathogenesis of type 2 diabetes. In the current study, we compared the profiles of the SCN neurons and glial cells between type 2 diabetic and control individuals. Methods We collected post-mortem hypothalamic tissues from 28 type 2 diabetic individuals and 12 non-diabetic control individuals. We performed immunohistochemical analysis for three SCN neuropeptides, arginine vasopressin (AVP), vasoactive intestinal polypeptide (VIP) and neurotensin (NT), and for two proteins expressed in glial cells, ionised calcium-binding adapter molecule 1 (IBA1, a marker of microglia) and glial fibrillary acidic protein (GFAP, a marker of astroglial cells). Results The numbers of AVP immunoreactive (AVP-ir) and VIP-ir neurons and GFAP-ir astroglial cells in the SCN of type 2 diabetic individuals were significantly decreased compared with the numbers in the SCN of the control individuals. In addition, the relative intensity of AVP immunoreactivity was reduced in the individuals with type 2 diabetes. The number of NT-ir neurons and IBA1-ir microglial cells in the SCN was similar in the two groups. Conclusions/interpretation Our data show that type 2 diabetes differentially affects the numbers of AVP- and VIP-expressing neurons and GFAP-ir astroglial cells in the SCN, each of which could affect the daily rhythmicity of the SCN biological clock machinery. Therefore, for effectively treating type 2 diabetes, lifestyle changes and/or medication to normalise central biological clock functioning might be helpful. Electronic supplementary material The online version of this article (10.1007/s00125-019-4953-7) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Aim: Vitamin D deficiency has been proposed to be involved in obesity-induced metabolic disease. However, data on the relationship between 25-hydroxycholecalciferol (25(OH)D) and insulin resistance have been inconsistent, and few studies have investigated the active vitamin D metabolite, 1,25-dihydroxycholecalciferol (1,25(OH)2D). This study aimed to determine the relationship between circulating levels of both 25(OH)D and 1,25(OH)2D and direct measures of glucose metabolism and insulin action in obese women. Methods: Serum levels of 25(OH)D and 1,25(OH)2D, and glucose metabolism and tissue-specific insulin action, as assessed in the basal state and during a two-step euglycaemic-hyperinsulinaemic clamp study with [6,6-2H2]glucose infusion, were measured in 37 morbidly obese women (age: 43±10 years; body mass index: 44±6kg/m2). Results: Sixteen subjects had circulating 25(OH)D levels2D, was negatively correlated with both body mass index (r =-0.42, P =0.01) and total body fat (r =-0.46, P 2D levels were related to any measured metabolic parameters, including fasting glucose, fasting insulin, basal endogenous glucose production, and hepatic, adipose-tissue and skeletal muscle insulin sensitivity. Conclusion: Obesity was associated with lower levels of circulating 25(OH)D, but not with the hormonally active metabolite 1,25(OH)2D. Neither 25(OH)D nor 1,25(OH)2D were related to glucose metabolism and tissue-specific insulin sensitivity in obese women, suggesting that vitamin D does not play a major role in obesity-related insulin resistance.

SummaryWhile experimental data state that protamine exerts intrinsic anticoagulation effects, protamine is still frequently overdosed for heparin neutralisation during cardiac surgery with cardiopulmonary bypass (CPB). Since comparative studies are lacking, we assessed the influence of two protamine-to-heparin dosing ratios on perioperative haemostasis and bleeding, and hypothesised that protamine overdosing impairs the coagulation status following cardiac surgery. In this open-label, multicentre, single-blinded, randomised controlled trial, patients undergoing on-pump coronary artery bypass graft surgery were assigned to a low (0.8; n=49) or high (1.3; n=47) protamine-to-heparin dosing group. The primary outcome was 24-hour blood loss. Patient haemostasis was monitored using rotational thromboelastometry and a thrombin generation assay. The low protamine-to-heparin dosing ratio group received less protamine (329 ± 95 vs 539 ± 117 mg; p

Ultimately, almost all patients who are appropriately treated for pituitary tumours enter a chronic phase with control or cure of hormonal excess, adequate treatment of pituitary insufficiency and relief of mass effects. This phase is associated with improvement of initial signs and symptoms, but also with the persistent consequences of the initial disease and associated treatments. Pituitary insufficiency is a common denominator in many of these patients, and is associated with a reduction in quality of life, despite adequate endocrine substitution. Hypothalamic dysfunction can be present in patients previously treated for visual impairments caused by large suprasellar adenomas, or craniopharyngiomas. In addition to hypopituitarism, these patients can have multisystem morbidities caused by altered hypothalamic function, including weight gain and disturbed regulation of sleep-wake cycles. Mortality can also be affected. Patients cured of Cushing disease or acromegaly have chronic multisystem morbidities (in the case of Cushing disease, also affecting mortality) caused by irreversible effects of the previous excesses of cortisol in Cushing disease and growth hormone and insulin-like growth factor 1 in acromegaly. In addition to early diagnosis and treatment of pituitary tumours, research should focus on the amenability of these chronic post-treatment syndromes to therapeutic intervention, to improve quality of life and clinical outcomes.