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Background: Many self-attending patients make inappropriate use of accident and emergency departments.Aim: To determine whether a new care method consisting of the involvement of a GP during the day with the staff of the accident and emergency department of an academic city hospital and application of the Nederlands Triage System by a practice nurse is more effective than usual care.Design: Before and after intervention design.Setting: Accident and emergency department in the VU University Medical Center in Amsterdam.Method: Participants were patients (n = 1527) attending the accident and emergency department without a referral, on weekdays from 10.00-17.00 hours, from 1 November 2006 to 30 April 2007. The intervention consisted of a new care method that combined the involvement of a GP in the accident and emergency department and allocation of patients by triage to either the GP or the accident and emergency department physician. Main outcome measures were patient satisfaction, number and type of additional examinations, quality of diagnosis, process time, and treatment time.Results: Patient satisfaction with the treatment increased significantly. Compared to the usual care method, this new care method resulted in a 13% decrease in additional examinations. The percentage of incorrect diagnoses (1 %), as a measure of quality of care, was similar with the two methods. The mean process time decreased from 93 to 69 minutes (P<0.001). The mean treatment time decreased from 60 to 35 minutes (P<0.001).Conclusion: The new care method resulted in greater patient satisfaction and maintained the quality of care, with fewer additional examinations. It reduced both the process time and the treatment time. [ABSTRACT FROM AUTHOR]

Objective: Recently, results from a meta-analysis of genome-wide association studies have yielded a number of novel type 2 diabetes loci. However, conflicting results have been published regarding their effects on insulin secretion and insulin sensitivity. In this study we used hyperglycemic clamps with three different stimuli to test associations between these novel loci and various measures of beta-cell function.Research Design and Methods: For this study, 336 participants, 180 normal glucose tolerant and 156 impaired glucose tolerant, underwent a 2-h hyperglycemic clamp. In a subset we also assessed the response to glucagon-like peptide (GLP)-1 and arginine during an extended clamp (n = 123). All subjects were genotyped for gene variants in JAZF1, CDC123/CAMK1D, TSPAN8/LGR5, THADA, ADAMTS9, NOTCH2/ADAMS30, DCD, VEGFA, BCL11A, HNF1B, WFS1, and MTNR1B.Results: Gene variants in CDC123/CAMK1D, ADAMTS9, BCL11A, and MTNR1B affected various aspects of the insulin response to glucose (all P < 6.9 x 10(-3)). The THADA gene variant was associated with lower beta-cell response to GLP-1 and arginine (both P < 1.6 x 10(-3)), suggesting lower beta-cell mass as a possible pathogenic mechanism. Remarkably, we also noted a trend toward an increased insulin response to GLP-1 in carriers of MTNR1B (P = 0.03), which may offer new therapeutic possibilities. The other seven loci were not detectably associated with beta-cell function.Conclusions: Diabetes risk alleles in CDC123/CAMK1D, THADA, ADAMTS9, BCL11A, and MTNR1B are associated with various specific aspects of beta-cell function. These findings point to a clear diversity in the impact that these various gene variants may have on (dys)function of pancreatic beta-cells. [ABSTRACT FROM AUTHOR]

BACKGROUND: Pulmonary embolism (PE) is a potentially fatal disease with risks of recurrent venous thrombotic events (venous thromboembolism [VTE]) and major bleeding from anticoagulant therapy. Identifying risk factors for recurrent VTE, bleeding, and mortality may guide clinical decision making. OBJECTIVE: To evaluate the incidence of recurrent VTE, hemorrhagic complications, and mortality in patients with PE, and to identify risk factors and the time course of these events. DESIGN: We evaluated consecutive patients with PE derived from a prospective management study, who were followed for 3 months, treated with anticoagulants, and underwent objective diagnostic testing for suspected recurrent VTE or bleeding. RESULTS: Of 673 patients with complete follow-up, 20 patients (3.0%; 95% confidence interval [CI], 1.8 to 4.6%) had recurrent VTE. Eleven of 14 patients with recurrent PE had a fatal PE (79%; 95% CI, 49 to 95%), occurring mostly in the first week after diagnosis of initial PE. In 23 patients (3.4%; 95% CI, 2.2 to 5.1%), a hemorrhagic complication occurred, 10 of which were major bleeds (1.5%; 95% CI, 0.7 to 2.7%), and 2 were fatal (0.3%; 95% CI, 0.04 to 1.1%). During the 3-month follow-up, 55 patients died (8.2%; 95% CI, 6.2 to 10.5%). Risk factors for recurrent VTE were immobilization for > 3 days and being an inpatient; having COPD or malignancies were risk factors for bleeding. Higher age, immobilization, malignancy, and being an inpatient were risk factors for mortality. CONCLUSIONS: Recurrent VTE occurred in a small percentage of patients treated for an acute PE, and the majority of recurrent PEs were fatal. Immobilization, hospitalization, age, COPD, and malignancies were risk factors for recurrent VTE, bleeding, and mortality. Close monitoring may be indicated in these patients, precluding them from out-of-hospital start of treatment. [ABSTRACT FROM AUTHOR]

Purpose: Clonal hematopoiesis (CH) is thought to be the origin of myeloid neoplasms (MN). Yet, our understanding of the mechanisms driving CH progression to MN and clinical risk prediction of MN remains limited. The human proteome reflects complex interactions between genetic and epigenetic regulation of biological systems. We hypothesized that the plasma proteome might predict MN risk and inform our understanding of the mechanisms promoting MN development., Experimental Design: We jointly characterized CH and plasma proteomic profiles of 46,237 individuals in the UK Biobank at baseline study entry. During 500,036 person-years of follow-up, 115 individuals developed MN. Cox proportional hazard regression was used to test for an association between plasma protein levels and MN risk., Results: We identified 115 proteins associated with MN risk, of which 30% (N = 34) were also associated with CH. These were enriched for known regulators of the innate and adaptive immune system. Plasma proteomics improved the prediction of MN risk (AUC = 0.85; P = 5×10-9) beyond clinical factors and CH (AUC = 0.80). In an independent group (N = 381,485), we used inherited polygenic risk scores (PRS) for plasma protein levels to validate the relevance of these proteins toMNdevelopment. PRS analyses suggest that most MN-associated proteins we identified are not directly causally linked toMN risk, but rather represent downstream markers of pathways regulating the progression of CH to MN., Conclusions: These data highlight the role of immune cell regulation in the progression of CH to MN and the promise of leveraging multi-omic characterization of CH to improveMN risk stratification. See related commentary by Bhalgat and Taylor, p. 3095., (©2024 The Authors; Published by the American Association for Cancer Research.)

Previous work has shown that inhibition of abundant myeloid azurophil granule-associated serine proteases (ELANE [neutrophil elastase], PRTN3 [protease 3], and CTSG [Cathepsin G]) is required to stabilize some proteins in myeloid cells. We therefore hypothesized that effective inhibition of these proteases may be necessary for quantitative proteomic analysis of samples containing myeloid cells. To test this hypothesis, we thawed viably preserved acute myeloid leukemia cells from cryovials in the presence or the absence of diisopropyl fluorophosphate (DFP), a cell-permeable and irreversible serine protease inhibitor. Global proteomic analysis was performed, using label-free and isobaric peptide-labeling quantitation. The presence of DFP resulted in an increase of tryptic peptides (14-57%) and proteins (9-31%). In the absence of DFP, 11 to 31% of peptide intensity came from nontryptic peptides; 52 to 75% had cleavage specificity consistent with activities of ELANE-PRTN3. Treatment with DFP reduced the intensity of nontryptic peptides to 4-8% of the total. ELANE inhibition was 95%, based on diisopropyl phosphate modification of active site serine residue. Overall, the relative abundance of 20% of proteins was significantly altered by DFP treatment. These results suggest that active myeloid serine proteases, released during sample processing, can skew quantitative proteomic measurements. Finally, significant ELANE activity was also detected in Clinical Proteomics Tumor Analysis Consortium datasets of solid tumors (many of which have known myeloid infiltration). In the pancreatic cancer dataset, the median percentage of nontryptic intensity detected across patient samples was 34%, with many patient samples having more than half of their detected peptide intensity from nontryptic cleavage events consistent with ELANE-PRTN3 cleavage specificity. Our study suggests that in vitro cleavage of proteins by myeloid serine proteases may be relevant for proteomic studies of any tumor that contains infiltrating myeloid cells., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Recreational drug use is common at large-scale dance events such as the Amsterdam Dance Event (ADE) and severe drug-related complications and deaths occur. Increasing concentrations of cocaine, amphetamine and MDMA have been observed in samples from dance events. Therefore, large dance events are expected to cause an increasing amount of recreational drug related complaints (RDRC) and an increased demand on emergency medical services., Aim: To evaluate the impact of recreational drug related complaints (RDRC) during ADE 2016, compared to regular weeks, and to evaluate the requirement for additional medical personnel., Methods: For this prospective, observational cohort study, patients >12 years old presenting with RDRC at first aid stations (FAS), ambulance service (AA) and ED during ADE, between October 19th and October 24th 2016 were included. From 2 EDs and AA, the RDRC 2 weeks before and after ADE were also collected., Results: An estimated 375.000 people attended ADE. The number of patients with RDRC was 459 at the FAS, 113 at AA and 81 at the ED, and increased significantly during ADE with 225% at AA and with 236% at OLVG ED. Eight patients were admitted. A higher percentage of poly-drug use among ED patients (58%) was found, compared to FAS patients (25%). Also, the proportion of tourists in ED's (51%) was higher compared to FAS (30%)., Conclusions: During ADE 2016, the number of intoxicated patients increased significantly. Eight patients were admitted to the hospital, without any deaths. The absolute number of patients stayed within normal range of emergency medical services capacity., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

We have developed a deep-scale proteome and phosphoproteome database from 44 representative acute myeloid leukemia (AML) patients from the LAML TCGA dataset and 6 healthy bone marrow-derived controls. After confirming data quality, we orthogonally validated several previously undescribed features of AML revealed by the proteomic data. We identified examples of posttranscriptionally regulated proteins both globally (ie, in all AML samples) and also in patients with recurrent AML driver mutations. For example, samples with IDH1/2 mutations displayed elevated levels of the 2-oxoglutarate-dependent histone demethylases KDM4A/B/C, despite no changes in messenger RNA levels for these genes; we confirmed this finding in vitro. In samples with NPMc mutations, we identified several nuclear importins with posttranscriptionally increased protein abundance and showed that they interact with NPMc but not wild-type NPM1. We identified 2 cell surface proteins (CD180 and MRC1/CD206) expressed on AML blasts of many patients (but not healthy CD34+ stem/progenitor cells) that could represent novel targets for immunologic therapies and confirmed these targets via flow cytometry. Finally, we detected nearly 30 000 phosphosites in these samples; globally, AML samples were associated with the abnormal phosphorylation of specific residues in PTPN11, STAT3, AKT1, and PRKCD. FLT3-TKD samples were associated with increased phosphorylation of activating tyrosines on the cytoplasmic Src-family tyrosine kinases FGR and HCK and related signaling proteins. PML-RARA-initiated AML samples displayed a unique phosphorylation signature, and TP53-mutant samples showed abundant phosphorylation of serine-183 on TP53 itself. This publicly available database will serve as a foundation for further investigations of protein dysregulation in AML pathogenesis., (© 2022 by The American Society of Hematology.)

Objectives: To develop predictive models for blood culture (BC) outcomes in an emergency department (ED) setting., Design: Retrospective observational study., Setting: ED of a large teaching hospital in the Netherlands between 1 September 2018 and 24 June 2020., Participants: Adult patients from whom BCs were collected in the ED. Data of demographic information, vital signs, administered medications in the ED and laboratory and radiology results were extracted from the electronic health record, if available at the end of the ED visits., Main Outcome Measures: The primary outcome was the performance of two models (logistic regression and gradient boosted trees) to predict bacteraemia in ED patients, defined as at least one true positive BC collected at the ED., Results: In 4885 out of 51 399 ED visits (9.5%), BCs were collected. In 598/4885 (12.2%) visits, at least one of the BCs was true positive. Both a gradient boosted tree model and a logistic regression model showed good performance in predicting BC results with area under curve of the receiver operating characteristics of 0.77 (95% CI 0.73 to 0.82) and 0.78 (95% CI 0.73 to 0.82) in the test sets, respectively. In the gradient boosted tree model, the optimal threshold would predict 69% of BCs in the test set to be negative, with a negative predictive value of over 94%., Conclusions: Both models can accurately identify patients with low risk of bacteraemia at the ED in this single-centre setting and may be useful to reduce unnecessary BCs and associated healthcare costs. Further studies are necessary for validation and to investigate the potential clinical benefits and possible risks after implementation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

To clarify the mechanism underlying the described U-shaped relation of both low and high levels of IGF-1 with cardiovascular disease this study explores the effect of decreasing and increasing growth hormone dose in GH deficient adults on (micro)vascular function, body composition and insulin resistance. In this randomized clinical trial, thirty-two subjects receiving GH therapy with an IGF-1 concentration between -1 and 1 SD score (SDS) for at least one year were randomized to receive either a decrease (IGF-1 target level of -2 to -1 SDS) or an increase of their daily GH dose (IGF-1 target level of 1 to 2 SDS) for a period of 24 weeks. Microvascular endothelium (in)dependent vasodilatation and vasomotion, vascular stiffness by pulse wave analysis, and HOMA-IR were measured. At the end of the study 30 subjects (65.6% men, mean age 46.6 (SD 9.9) years) were analyzed. There was a favorable effect of increasing the IGF-1 level on waist circumference compared to decreasing the IGF-1 level (p=0.05), but a detrimental effect on insulin resistance (p=0.03). Decreasing IGF-1 level significantly lowered the endothelial domain of vasomotion (p=0.03), whereas increasing IGF-1 level increased the contribution of the neurogenic domain (p=0.05). This change was related to the favorable change in waist circumference. In conclusion, increasing IGF-1 levels was beneficial for body composition but detrimental with respect to insulin resistance. The contribution of the neurogenic vasomotion domain increased in parallel, and could be explained by the favorable change in waist circumference., Clinical Trial Registration: ClinicalTrials.gov, identifier NCT01877512., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 van Bunderen, Meijer, Lips, Kramer, Serné and Drent.)

Aim: Increased plasma uric acid (PUA) concentrations are associated with chronic kidney disease in type 2 diabetes (T2D) patients. The mechanisms involved remain unclear. We investigated the relation between PUA and (intra)renal haemodynamics in T2D patients without overt kidney disease., Methods: Eighty-eight white men and women with T2D were included (age 64 (58-68) years; body mass index 30.9 (28.3-33.6) kg/m 2 ; glycated haemoglobin 7.1 (6.8-7.6)%). Plasma UA and fractional excretion of UA were measured, while glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were assessed by inulin and PAH-clearance techniques, respectively. Effective renal vascular resistance was calculated (ERVR). Renal afferent and efferent arteriolar resistances and glomerular hydrostatic pressure were estimated. Relationships between PUA and fractional excretion of UA and (intra)renal haemodynamic parameters were evaluated by multivariable linear regression analyses., Results: Plasma UA concentrations were at the higher end of the normal range in most participants: 342 ± 68 μmol/L or 5.7 ± 1.1 mg/dL (mean ± SD). In multivariable analyses, PUA concentrations were negatively associated with GFR (r = -0.471; P = 0.001), ERPF (r = -0.436; P = 0.003) and glomerular hydrostatic pressure (r = -0.427; P = 0.003). In contrast, PUA concentrations had a positive correlation with ERVR (r = 0.474; P = 0.001), but not with efferent vascular resistance. Fractional excretion of UA was not related to renal haemodynamics., Conclusion: Plasma UA was negatively associated to GFR, ERPF but positively related to ERVR in T2D patients without overt renal impairment. Plasma UA-related increase in ERVR may be related to increased arterial afferent tone, which may put the kidney at risk for renal damage through ischaemia., (© 2019 The Authors. Nephrology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Nephrology.)

Objectives: Because of fundamental differences in healthcare systems, US readmission data cannot be extrapolated to the European setting: To investigate the opinions of readmitted patients, their carers, nurses and physicians on predictability and preventability of readmissions and using majority consensus to determine contributing factors that could potentially foresee (preventable) readmissions., Design: Prospective observational study. Readmitted patients, their carers, and treating professionals were surveyed during readmission to assess the discharge process and the predictability and preventability of the readmission. Cohen's Kappa measured pairwise agreement of considering readmission as predictable/preventable by patients, carers and professionals. Subsequently, multivariable logistic regressionidentified factors associated with predictability/preventability., Setting: 15 hospitals in four European countries PARTICIPANTS: 1398 medical patients readmitted unscheduled within 30 days MAIN OUTCOMES AND MEASURES: (1) Agreement between the interviewed groups on considering readmissions likely predictable or preventable;(2) Factors distinguishing predictable from non-predictable and preventable from non-preventable readmissions., Results: The majority deemed 27.8% readmissions potentially predictable and 14.4% potentially preventable. The consensus on predictability and preventability was poor, especially between patients and professionals (kappas ranged from 0.105 to 0.173). The interviewed selected different factors as potentially associated with predictability and preventability. When a patient reported that he was ready for discharge during index admission, the readmission was deemed less likely by the majority (predictability: OR 0.55; 95% CI 0.40 to 0.75; preventability: OR 0.35; 95% CI 0.24 to 0.49)., Conclusions: There is no consensus between readmitted patients, their carers and treating professionals about predictability and preventability of readmissions, nor associated risk factors. A readmitted patient reporting not feeling ready for discharge at index admission was strongly associated with preventability/predictability. Therefore, healthcare workers should question patients' readiness to go home timely before discharge., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: This study investigated whether the relationship between neuropathy and microvascular dysfunction in patients with type 2 diabetes is independent of diabetes-related factors. For this purpose, we compared skin microvascular function in patients with type 2 diabetes with that of patients with cryptogenic axonal polyneuropathy (CAP), a polyneuropathy of unknown etiology., Research Design and Methods: Cross-sectional information was collected from 16 healthy controls (HCs), 16 patients with CAP, 15 patients with type 2 diabetes with polyneuropathy (DPN), and 11 patients with type 2 diabetes without polyneuropathy. Axonal degeneration was assessed with skin biopsy and nerve conduction studies. Microvascular skin vasodilation was measured using laser Doppler fluxmetry combined with iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP)., Results: Patients with CAP and DPN demonstrated a similar decrease in intraepidermal nerve fiber density and sural sensory nerve action potential compared with HCs. The vasodilator response to ACh was similar among patients with CAP (relative mean difference based on log values 13.3%; 95% CI -35.0 to 97.7%; P = 0.652) but was lower in the patients with diabetes with neuropathy (157.5%; 42.0-366.7%; P = 0.003) and without neuropathy (174.2%; 44.2-421.3%; P = 0.003) compared with HCs. No significant differences were found between the groups of patients with diabetes ( P = 0.845). The vasodilator response to SNP was not significantly different among the groups ( P = 0.082)., Conclusions: In this study, endothelium-dependent vasodilation was reduced in patients with type 2 diabetes regardless of the presence of polyneuropathy, whereas microvascular vasodilation was normal in patients with CAP. These data suggest that in type 2 diabetes, neuropathy does not contribute to impaired microvascular endothelium-dependent vasodilation and vice versa. In addition, this study suggests that impaired microvascular vasodilation does not contribute to CAP., (© 2017 by the American Diabetes Association.)

Background: Acute healthcare chains in the Netherlands are increasingly under pressure because of rising emergency department (ED) admissions, relative bed shortages and government policy changes. In order to improve acute patient flow and quality of care through hospitals, an acute medical unit (AMU) might be a solution, as demonstrated in the UK. However, limited information is available concerning AMUs in the Netherlands. Therefore, the aims of this study were to METHODS: A systematic literature search was performed searching 3 electronic databases: PubMed, Cochrane and EMBASE. All 106 hospitals in the Netherlands were contacted, inquiring about the status of an ED, the AMU or future plans to start one., Results: The literature search resulted in 31 studies that met inclusion criteria. In general, these studies reported significant benefits on number of admissions, hospital length of stay (LOS), mortality, other wards and readmissions. Among the Dutch hospitals with an ED, 33 out of 93 implemented an AMU or similar ward, these are however organized heterogeneously. Following current trends, more AMUs are expected to be realized in the future., Conclusion: In order to improve the current strain on the Dutch acute healthcare system, an AMU could potentially provide benefits. However, uniform guideline is warranted to optimize and compare quality of care throughout the Netherlands., (Copyright © 2016 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Objective: To assess the mechanistic effects of the glucagon-like peptide 1 (GLP-1) receptor agonist liraglutide and the dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin on (exocrine) pancreatic physiology and morphology., Research Design and Methods: For this randomized, double-blind, parallel-group trial, 55 patients with type 2 diabetes treated with metformin and/or sulfonylurea agents were included. Participants received liraglutide 1.8 mg ( n = 19), sitagliptin 100 mg ( n = 19), or matching placebos ( n = 17) once daily for 12 weeks. The primary end point was change in exocrine function (intraduodenal pancreatic fluid secretion, lipase activity, fecal elastase-1, and chymotrypsin). Secondary end points included changes in plasma enzyme concentrations and pancreatic morphology (per MRI)., Results: No patient developed pancreatitis. Sitagliptin increased intraduodenal pancreatic fluid secretion by 16.3 mL (95% CI -0.3 to 32.9; P = 0.05), whereas liraglutide did not change exocrine pancreatic function. Neither therapy increased lipase/amylase levels after 12 weeks. However, liraglutide increased lipase levels after 6 weeks (23.5 U/L [95% CI 2.1-44.8]; P = 0.03) and sitagliptin increased amylase levels after 2 and 6 weeks (13.7 U/L [95% CI 3.4-23.9]; P = 0.03). Both drugs increased plasma trypsinogen after 12 weeks (liraglutide: 34.6 µg/mL [95% CI 15.1-54.2], P = 0.001; sitagliptin: 23.9 µg/mL [95% CI 4.9-42.9], P = 0.01). Neither changed pancreatic morphology, although liraglutide tended to increase pancreatic volume (7.7 cm 3 [95% CI -1.2 to 16.6]; P = 0.09). Treatment-induced volume expansion was associated with increased amylase levels., Conclusions: A 12-week treatment with liraglutide or sitagliptin only resulted in a brief and modest increase of plasma pancreatic enzyme concentrations in patients with type 2 diabetes. Apart from a minimal sitagliptin-induced increase in intraduodenal fluid secretion, pancreatic exocrine function was unaffected. The long-term clinical consequences of these discrete changes require further study., (© 2017 by the American Diabetes Association.)

We have developed a general progressive procedure, Active Interaction Mapping, to guide assembly of the hierarchy of functions encoding any biological system. Using this process, we assemble an ontology of functions comprising autophagy, a central recycling process implicated in numerous diseases. A first-generation model, built from existing gene networks in Saccharomyces, captures most known autophagy components in broad relation to vesicle transport, cell cycle, and stress response. Systematic analysis identifies synthetic-lethal interactions as most informative for further experiments; consequently, we saturate the model with 156,364 such measurements across autophagy-activating conditions. These targeted interactions provide more information about autophagy than all previous datasets, producing a second-generation ontology of 220 functions. Approximately half are previously unknown; we confirm roles for Gyp1 at the phagophore-assembly site, Atg24 in cargo engulfment, Atg26 in cytoplasm-to-vacuole targeting, and Ssd1, Did4, and others in selective and non-selective autophagy. The procedure and autophagy hierarchy are at http://atgo.ucsd.edu/., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Aims: To assess the effects of glucagon-like peptide (GLP)-1 receptor agonists and dipeptidyl peptidase (DPP)-4 inhibitors on postprandial haemodynamics., Methods: 57 patients with type 2 diabetes (mean±SD age 62.8±6.9years; BMI 31.8±4.1kg/m 2 ; HbA 1c 7.3±0.6%) were included in an acute (exenatide- or placebo-infusion) and 12-week (liraglutide, sitagliptin or placebo) randomised, placebo-controlled, double-blind trial. Systemic haemodynamics (oscillometric technique and finger photoplethysmography), vascular stiffness (tonometry), and sympathetic nervous system (SNS)-activity (heart rate variability) were determined in the fasting state and following a standardised mixed meal., Results: In both studies, postprandial blood pressure (BP) decreased during placebo-intervention. Compared with placebo, acute exenatide-infusion increased postprandial diastolic BP (6.7 [95%-confidence interval 3.6-9.9]mmHg, p<0.001) and vascular resistance (683.6 [438.5-928.8]dyn*s/cm 5 /1.73m 2 , p<0.001), while cardiac index decreased (0.6 [0.40.8]L/min/1.73m 2 ; p<0.001). Systolic BP, augmentation index and SNS-activity were unaffected. Twelve-week liraglutide-treatment did not affect postprandial haemodynamics, while sitagliptin decreased diastolic BP (3.5 [0.0-6.9] mmHg; p=0.050), vascular resistance (309.9 [66.6-553.1]dyn*s/cm 5 /1.73m 2 ; p=0.013) and cardiac index (0.3 [0.0-0.6]L/min/1.73m 2 ; p=0.040), compared with placebo. Neither liraglutide nor sitagliptin affected SNS-activity or augmentation index. All treatments significantly lowered postprandial glucose levels., Conclusions: Acute exenatide-infusion prevented the meal-induced decline in diastolic BP, although prolonged liraglutide intervention did not affect postprandial haemodynamics. The meal-induced drop in BP was augmented during sitagliptin-treatment., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: To examine mechanisms underlying resting heart rate (RHR) increments of GLP-1 receptor agonists in type 2 diabetes patients., Design: Acute and 12-week randomised, placebo-controlled, double-blind, single-centre, parallel-group trial., Methods: In total, 57 type 2 diabetes patients (mean ± s.d. age: 62.8 ± 6.9 years; BMI: 31.8 ± 4.1 kg/m 2 ; HbA1c: 7.3 ± 0.6%), treated with metformin and/or sulfonylureas, were included between July 2013 and August 2015. In the acute study, the GLP-1 receptor agonist exenatide (n = 29) or placebo (saline 0.9%; n = 28) was infused intravenously. Subsequently, patients were again randomised to receive the GLP-1 receptor agonist liraglutide (n = 19) or matching placebo (n = 17) for 12 weeks. RHR and blood pressure (BP) were measured by oscillometric technique, systemic haemodynamics by finger photoplethysmography, sympathetic nervous system (SNS) activity by heart rate variability and arterial stiffness by applanation tonometry. This trial was registered at ClinicalTrials.gov (Nbib1744236)., Results: Exenatide-infusion increased RHR (mean ± s.e.m. +7.5 ± 0.9 BPM, P < 0.001), and systolic and diastolic BP (both P < 0.05), compared with placebo. Vascular resistance increased during exenatide-infusion, whereas stroke volume and arterial stiffness decreased (P < 0.05). SNS activity and cardiac output were unaffected. Twelve-week treatment with liraglutide increased RHR (+6.6 ± 2.1 BPM), while reducing systolic BP (-12.6 ± 4.7 mmHg) and stroke volume (all P < 0.01). Cardiac output, vascular resistance, arterial stiffness and SNS activity remained unchanged (all P > 0.05)., Conclusions: RHR acceleration with acute and 12-week GLP-1 receptor agonist treatment in type 2 diabetes patients is not explained by changes in SNS activity, and our data argue against vasodilation. In line with pre-clinical data, direct sino-atrial stimulation may be involved., (© 2017 European Society of Endocrinology.)

Background: Policy makers struggle with unplanned readmissions as a quality indicator since integrating preventability in such indicators is difficult. Most studies on the preventability of readmissions questioned physicians whether they consider a given readmission to be preventable, from which conclusions on factors predicting preventable readmissions were derived. There is no literature on the interobserver agreement of physician judgement., Aim: To assess the degree of agreement among physicians regarding predictability and preventability of medical readmissions., Design: An online survey based on eight real-life case scenarios was distributed to European physicians., Methods: Physicians were requested to rate from the first four (index admission) scenarios whether they expected these patients to be readmitted within 30 days (the predictability). The remaining four cases, describing a readmission, were used to assess the preventability. The main outcome was the degree of agreement among physicians determined using the intra class correlation coefficient (ICC)., Results: 526 European medical physicians completed the survey. Most physicians had internal medicine as primary specialism. The median years of clinical experience was 11. ICC for predictability of readmission was 0.67 (moderate to good) and ICC for preventability of readmission was 0.13 (poor)., Conclusion: There was moderate to good agreement among physicians on the predictability of readmissions while agreement on preventability was poor. This study indicates that assessing preventability of readmissions based solely on the judgement of physicians is far from perfect. Current literature on the preventability of readmissions and conclusions derived on the basis of physician opinion should be interpreted with caution.

Aims: Treatment with glucagon-like peptide (GLP)-1 receptor agonists or dipeptidyl peptidase (DPP)-4 inhibitors might increase gallstone formation; however, the mechanisms involved are unknown. We aimed to assess the effects of these drugs on gallbladder volume and bile acid profile., Materials and Methods: A total of 57 type 2 diabetes patients (mean ± SD age, 62.8 ± 6.9 years; BMI, 31.8 ± 4.1 kg/m 2 ; HbA1c, 7.3% ± 0.6%), treated with metformin and/or sulfonylureas, were included in this 12-week randomized, placebo-controlled, double-blind, single-centre trial between July 2013 and August 2015 at the VU University Medical Center, the Netherlands. Patients received the GLP-1 receptor agonist liraglutide, the DPP-4 inhibitor sitagliptin or matching placebo for 12 weeks. Gallbladder fasting volume and ejection fraction were measured using ultrasonography after a high-fat meal. Serum bile acids were measured in the fasting and postprandial state and in faecal samples. The trial was registered at ClinicalTrials.gov (NCT01744236)., Results: Neither liraglutide nor sitagliptin had an effect on gallbladder fasting volume and ejection fraction (p > .05). Liraglutide increased serum levels of deoxycholic acid in the fasting state [0.20 µmol/L (95% CI 0.027-0.376), p = 0.024] and postprandial state [AUC 40.71 (13.22-68.21), p = 0.005] and in faeces [ratio 1.5 (1.03-2.19); p = 0.035]. Sitagliptin had no effect on serum bile acids, but increased faecal levels of chenodeoxycholic acid [ratio 3.42 (1.33-8.79), p = 0.012], cholic acid [ratio 3.32 (1.26-8.87), p = 0.017] and ursodeoxycholic acid [ratio 3.81 (1.44-10.14), p = 0.008]., Conclusions: Neither liraglutide nor sitagliptin has an effect on gallbladder volume. Observed changes in bile acids with liraglutide suggest alterations in the intestinal microbiome, while sitagliptin appears to increase hepatic bile acid production., (© 2016 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Objectives: To study the associations between protein energy malnutrition, micronutrient malnutrition, brain atrophy, and cerebrovascular lesions., Design: Cross-sectional., Setting: Geriatric outpatient clinic., Participants: Older adults (N = 475; mean age 80 ± 7)., Measurements: Nutritional status was assessed using the Mini Nutritional Assessment (MNA) and according to serum micronutrient levels (vitamins B1, B6, B12, D; folic acid). White matter hyperintensities (WMHs), global cortical brain atrophy, and medial temporal lobe atrophy on magnetic resonance imaging (MRI) were rated using visual rating scales. Logistic regression analyses were performed to assess associations between the three MNA categories (<17, 17-23.5, ≥23.5) and micronutrients (per SD decrease) and WMHs and measures of brain atrophy., Results: Included were 359 participants. Forty-eight participants (13%) were malnourished (MNA <17), and 197 (55%) were at risk of malnutrition (MNA = 17-23.5). Participants at risk of malnutrition (odds ratio (OR) = 1.93, 95% confidence interval (CI) = 1.01-3.71) or who were malnourished (OR = 2.80, 95% CI = 1.19-6.60) had a greater probability of having severe WMHs independent of age and sex than those with adequate nutritional status. Results remained significant after further adjustments for cognitive function, depressive symptoms, cardiovascular risk factors, history of cardiovascular disease, smoking and alcohol use, and micronutrient levels. Lower vitamin B1 (OR = 1.51, 95% CI = 1.11-2.08) and B12 (OR = 1.45, 95% CI = 1.02-2.04) levels were also related to greater risk of severe WMHs, independent of age and sex. Results remained significant after additional adjustments. MNA and vitamin levels were not associated with measures of brain atrophy., Conclusion: Malnutrition and lower vitamin B1 and B12 levels were independently associated with greater risk of WMHs. Underlying mechanisms need to be further clarified, and whether nutritional interventions can modify these findings also needs to be studied., (© 2016, Copyright the Authors Journal compilation © 2016, The American Geriatrics Society.)

Aims/hypothesis: Glucagon-like peptide (GLP)-1-based therapies have been suggested to improve hepatic steatosis. We assessed the effects of the GLP-1 receptor agonist liraglutide and the dipeptidyl peptidase (DPP)-4 inhibitor sitagliptin on hepatic steatosis and fibrosis in patients with type 2 diabetes., Methods: In this 12 week, parallel, randomised, placebo-controlled trial, performed at the VU University Medical Center between July 2013 and August 2015, 52 overweight patients with type 2 diabetes treated with metformin and/or sulphonylurea agent ([mean ± SD] age 62.7 ± 6.9 years, HbA 1c 7.3 ± 0.7% or 56 ± 1 mmol/mol) were allocated to once daily liraglutide 1.8 mg (n = 17), sitagliptin 100 mg (n = 18) or matching placebos (n = 17) by computer generated numbers. Both participants and researchers were blinded to group assignment. Hepatic fat content was measured using proton magnetic resonance spectroscopy ( 1 H-MRS). Hepatic fibrosis was estimated using three validated formulae., Results: One patient dropped out in the sitagliptin group owing to dizziness, but no serious adverse events occurred. At week 12, no between-group differences in hepatic steatosis were found. Liraglutide reduced steatosis by 10% (20.9 ± 3.4% to 18.8 ± 3.3%), sitagliptin reduced steatosis by 12.1% (23.9 ± 3.0% to 21.0 ± 2.7%) and placebo lessened it by 9.5% (18.7 ± 2.7% to 16.9 ± 2.7%). Neither drug affected hepatic fibrosis scores compared with placebo., Conclusions/interpretation: Twelve-week liraglutide or sitagliptin treatment does not reduce hepatic steatosis or fibrosis in type 2 diabetes., Trial Registration: ClinicalTrials.gov NCT01744236 FUNDING : Funded by the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 282521 - the SAFEGUARD project.

Background: Ganciclovir can be used to treat a primary cytomegalovirus (CMV) infection, however it can cause side effects., Case Description: We describe a 60-year-old immunocompromised woman with a primary CMV infection who was treated with ganciclovir. She developed an encephalopathy which resolved after discontinuation of ganciclovir., Conclusion: A reversible encephalopathy as a side effect of ganciclovir.

Objective: To investigate effects of dipeptidyl peptidase-4 inhibitor (DPP-4I) sitagliptin or glucagon-like peptide 1 (GLP-1) receptor agonist liraglutide treatment on renal hemodynamics, tubular functions, and markers of renal damage in overweight patients with type 2 diabetes without chronic kidney disease (CKD)., Research Design and Methods: In this 12-week, randomized, double-blind trial, 55 insulin-naïve patients with type 2 diabetes (mean ± SEM: age 63 ± 7 years, BMI 31.8 ± 4.1 kg/m 2 , glomerular filtration rate [GFR] 83 ± 16 mL/min/1.73 m 2 ; median [interquartile range]: albumin-to-creatinine ratio (ACR) 1.09 mg/mmol [0.47-3.31]) received sitagliptin (100 mg/day), liraglutide (1.8 mg/day), or matching placebos. GFR (primary end point) and effective renal plasma flow (ERPF) were determined by inulin and para-aminohippuric acid clearance, respectively. Intrarenal hemodynamic variables were estimated. Absolute and fractional excretions of sodium (FE Na ), potassium, and urea (FE U ) and renal damage markers (ACR, neutrophil gelatinase-associated lipocalin [NGAL], and kidney injury molecule-1 [KIM-1]) were measured. Plasma renin concentration (PRC) and glycated hemoglobin (HbA 1c ) were assessed. At weeks 2 and 6, estimated GFR and fractional electrolyte excretions were determined., Results: At week 12, GFR was not affected by sitagliptin (-6 mL/min/1.73 m 2 [95% CI -14 to 3], P = 0.17) or liraglutide (+3 mL/min/1.73 m 2 [-5 to 11], P = 0.46), compared with placebo. Sitagliptin modestly reduced estimated glomerular hydraulic pressure (P GLO ; P = 0.043). ERPF, other intrarenal hemodynamic variables, renal damage markers, and PRC did not change for both treatments. Both agents reduced HbA 1c . Only at week 2, sitagliptin increased FE Na and FE U (P = 0.005)., Conclusions: Twelve-week treatment with sitagliptin or liraglutide does not affect measured renal hemodynamics. No sustained changes in tubular functions or alteration in renal damage markers were observed. The validity and clinical relevance of the slight sitagliptin-induced P GLO reduction remains speculative., (© 2016 by the American Diabetes Association.)

Background: Patients with type 1 diabetes who have impaired awareness of hypoglycaemia have a three to six times increased risk of severe hypoglycaemia. We aimed to assess whether continuous glucose monitoring (CGM) improves glycaemia and prevents severe hypoglycaemia compared with self-monitoring of blood glucose (SMBG) in this high-risk population., Methods: We did a randomised, open-label, crossover trial (IN CONTROL) at two medical centres in the Netherlands. Eligible participants were patients diagnosed with type 1 diabetes according to American Diabetes Association criteria, aged 18-75 years, with impaired awareness of hypoglycaemia as confirmed by a Gold score of at least 4, and treated with either continuous subcutaneous insulin infusion or multiple daily insulin injections and doing at least three SMBG measurements per day. After screening, re-education about diabetes management, and a 6-week run-in phase (to obtain baseline CGM data), we randomly assigned patients (1:1) with a computer-generated allocation sequence (block size of four) to either 16 weeks of CGM followed by 12 weeks of washout and 16 weeks of SMBG, or 16 weeks of SMBG followed by 12 weeks of washout and 16 weeks of CGM (where the SMBG phase was the control). During the CGM phase, patients used a real-time CGM system consisting of a Paradigm Veo system with a MiniLink transmitter and an Enlite glucose sensor (Medtronic, CA, USA). During the SMBG phase, patients were equipped with a masked CGM device, consisting of an iPro 2 continuous glucose monitor and an Enlite glucose sensor, which does not display real-time glucose values. The number of SMBG measurements per day and SMBG systems were not standardised between patients, to mimic real-life conditions. During both intervention periods, patients attended follow-up visits at the centres each month and had telephone consultations 2 weeks after each visit inquiring about adverse events, episodes of hypoglycaemia, etc. The primary endpoint was the mean difference in percentage of time spent in normoglycaemia (4-10 mmol/L) over the total intervention periods, analysed on an intention-to-treat basis. Severe hypoglycaemia (requiring third party assistance) was a secondary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01787903., Findings: Between March 4, 2013, and Feb 9, 2015, we recruited and randomly assigned 52 patients to either the CGM-SMBG sequence (n=26) or the SMBG-CGM sequence (n=26). The last patient visit was on March 21, 2016. Time spent in normoglycaemia was higher during CGM than during SMBG: 65·0% (95% CI 62·8-67·3) versus 55·4% (53·1-57·7; mean difference 9·6%, 95% CI 8·0-11·2; p<0·0001), with reductions in both time spent in hypoglycaemia (ie, blood glucose ≤3·9 mmol/L [6·8% vs 11·4%, mean difference 4·7%, 3·4-5·9; p<0·0001]) and time spent in hyperglycaemia (ie, blood glucose >10 mmol/L [28·2% vs 33·2%, mean difference 5·0%, 3·1-6·9; p<0·0001]). During CGM, the number of severe hypoglycaemic events was lower (14 events vs 34 events, p=0·033). Five serious adverse events other than severe hypoglycaemia occurred during the trial, but all were deemed unrelated to the trial intervention. Additionally, no mild to moderate adverse events were related to the trial intervention., Interpretation: CGM increased time spent in normoglycaemia and reduced severe hypoglycaemia in patients with type 1 diabetes and impaired awareness of hypoglycaemia, compared with SMBG. Our results support the concept of using CGM in this high-risk population., Funding: Eli Lilly and Sanofi., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objective: To assess the effects of glucagon-like peptide (GLP)-1-based therapies (ie, GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors) on microvascular function in patients with type 2 diabetes mellitus., Approach and Results: We studied 57 patients with type 2 diabetes mellitus (mean±SD age: 62.8±6.9 years; body mass index: 31.8±4.1 kg/m(2); HbA1c [glycated hemoglobin] 7.3±0.6%) in an acute and 12-week randomized, placebo-controlled, double-blind trial conducted at the Diabetes Center of the VU University Medical Center. In the acute study, the GLP-1 receptor agonist exenatide (therapeutic concentrations) or placebo (saline 0.9%) was administered intravenously. During the 12-week study, patients received the GLP-1 receptor agonist liraglutide (1.8 mg daily), the dipeptidyl peptidase-4 inhibitor sitagliptin (100 mg daily), or matching placebos. Capillary perfusion was assessed by nailfold skin capillary videomicroscopy and vasomotion by laser Doppler fluxmetry, in the fasting state and after a high-fat mixed meal. In neither study, treatment affected fasting or postprandial capillary perfusion compared with placebo (P>0.05). In the fasting state, acute exenatide infusion increased neurogenic vasomotion domain power, while reducing myogenic domain power (both P<0.05). After the meal, exenatide increased endothelial domain power (P<0.05). In the 12-week study, no effects on vasomotion were observed., Conclusions: Despite modest changes in vasomotion, suggestive of sympathetic nervous system activation and improved endothelial function, acute exenatide infusion does not affect skin capillary perfusion in type 2 diabetes mellitus. Twelve-week treatment with liraglutide or sitagliptin has no effect on capillary perfusion or vasomotion in these patients. Our data suggest that the effects of GLP-1-based therapies on glucose are not mediated through microvascular responses., (© 2016 American Heart Association, Inc.)

Objectives: Little is known about the validity and reliability of expert assessments of the quality of antimicrobial prescribing, despite their importance in antimicrobial stewardship. We investigated how infectious disease doctors' assessments compared with a reference standard (modal expert opinion) and with the assessments of their colleagues., Methods: Twenty-four doctors specialized in infectious diseases or clinical microbiology (16 specialists and 8 residents) from five hospitals were asked to assess the appropriateness of antimicrobial agents prescribed for a broad spectrum of indications in 56 paper cases. They were instructed how to handle guideline applicability and deviations. We created a reference standard of antimicrobial appropriateness using the modal assessment of 16 specialists. We calculated criterion validity and interrater and intrarater overall and specific agreement with an index expert (senior infectious disease physician) and analysed the influence of doctor characteristics on validity., Results: Specialists agreed with the reference standard in 80% of cases (range 75%-86%), with a sensitivity and specificity of 75% and 84%, respectively. This did not differ by clinical specialty, hospital or years of experience, and residents had similar results. Specialists agreed with the index expert in 76% of cases and the index expert agreed with his previous assessments in 71% of cases., Conclusions: Doctors specialized in infectious diseases and clinical microbiology assess the appropriateness of antimicrobials prescribed for a broad spectrum of indications with acceptable agreement and validity, regardless of their experience or hospital of employment. However, there is room for improvement, which merits attention in multidisciplinary discussions and education., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: An unplanned ICU admission of an inpatient is a serious adverse event (SAE). So far, no in depth-study has been performed to systematically analyse the root causes of unplanned ICU-admissions. The primary aim of this study was to identify the healthcare worker-, organisational-, technical,- disease- and patient- related causes that contribute to acute unplanned ICU admissions from general wards using a Root-Cause Analysis Tool called PRISMA-medical. Although a Track and Trigger System (MEWS) was introduced in our hospital a few years ago, it was implemented without a clear protocol. Therefore, the secondary aim was to assess the adherence to a Track and Trigger system to identify deterioration on general hospital wards in patients eventually transferred to the ICU., Methods: Retrospective observational study in 49 consecutive adult patients acutely admitted to the Intensive Care Unit from a general nursing ward. 1. PRISMA-analysis on root causes of unplanned ICU admissions 2. Assessment of protocol adherence to the early warning score system., Results: Out of 49 cases, 156 root causes were identified. The most frequent root causes were healthcare worker related (46%), which were mainly failures in monitoring the patient. They were followed by disease-related (45%), patient-related causes (7, 5%), and organisational root causes (3%). In only 40% of the patients vital parameters were monitored as was instructed by the doctor. 477 vital parameter sets were found in the 48 hours before ICU admission, in only 1% a correct MEWS was explicitly documented in the record., Conclusions: This in-depth analysis demonstrates that almost half of the unplanned ICU admissions from the general ward had healthcare worker related root causes, mostly due to monitoring failures in clinically deteriorating patients. In order to reduce unplanned ICU admissions, improving the monitoring of patients is therefore warranted.

Background: The Modified Early Warning Score (MEWS) was developed to timely recognise clinically deteriorating hospitalised patients. However, the ability of the MEWS in predicting serious adverse events (SAEs) in a general hospital population has not been examined prospectively. The aims were to (1) analyse protocol adherence to a MEWS protocol in a real-life setting and (2) to determine the predictive value of protocolised daily MEWS measurement on SAEs: death, cardiac arrests, ICU-admissions and readmissions., Methods: All adult patients admitted to 6 hospital wards in October and November 2015 were included. MEWS were checked each morning by the research team. For each critical score (MEWS ≥ 3), the clinical staff was inquired about the actions performed. 30-day follow-up for SAEs was performed to compare between patients with and without a critical score., Results: 1053 patients with 3673 vital parameter measurements were included, 200 (19.0%) had a critical score. The protocol adherence was 89.0%. 18.2% of MEWS were calculated wrongly. Patients with critical scores had significant higher rates of unplanned ICU admissions [7.0% vs 1.3%, p < 0.001], in-hospital mortality [6.0% vs 0.8%, p < 0.001], 30-day readmission rates [18.6% vs 10.8%, p < 0.05], and a longer length of stay [15.65 (SD: 15.7 days) vs 6.09 (SD: 6.9), p < 0.001]. Specificity of MEWS related to composite adverse events was 83% with a negative predicting value of 98.1%., Conclusions: Protocol adherence was high, even though one-third of the critical scores were calculated wrongly. Patients with a MEWS ≥ 3 experienced significantly more adverse events. The negative predictive value of early morning MEWS < 3 was 98.1%, indicating the reliability of this score as a screening tool.

Aims: To investigate the feasibility, safety and efficacy of the Nurse-Driven Diabetes In-Hospital Treatment protocol (N-DIABIT), which consists of nurse-driven correctional therapy, in addition to physician-guided basal therapy, and is carried out by trained ward nurses., Methods: Data on 210 patients with diabetes consecutively admitted in the 5-month period after the introduction of N-DIABIT (intervention group) were compared with the retrospectively collected data on 200 consecutive patients with diabetes admitted in the 5-month period before N-DIABIT was introduced (control group). Additional per-protocol analyses were performed in patients in whom mean patient-based protocol adherence was ≥ 70% (intervention subgroup, n = 173 vs. control subgroup, n = 196)., Results: There was no difference between the intervention and the control group in mean blood glucose levels (8.9 ± 0.1 and 9.1 ± 0.2 mmol/l, respectively; P = 0.38), consecutive hyperglycaemic (blood glucose ≥ 10.0 mmol/l) episodes; P = 0.15), admission duration (P = 0.79), mean number of blood glucose measurements (P = 0.21) and incidence of severe hypoglycaemia (P = 0.29). Per-protocol analyses showed significant reductions in mean blood glucose levels and consecutive hypoglycaemia and hyperglycaemia in the intervention compared with the control group., Conclusions: Implementation of N-DIABIT by trained ward nurses in non-intensive care unit diabetes care is feasible, safe and non-inferior to physician-driven care alone. High protocol adherence was associated with improved glycaemic control., (© 2015 Diabetes UK.)

Background: Current guidelines state that the goals of growth hormone (GH) therapy in adults should be an appropriate clinical response, avoidance of side effects, and an IGF-1 value within the age-adjusted reference range. There are no published studies on the target level for IGF-1 that offer specific guidance in this regard., Objectives: To compare low-normal and high-normal target levels of IGF-1 on efficacy and safety of GH treatment., Methods: A randomized, open-label, clinical trial including thirty-two adults from one university hospital receiving GH therapy for at least one year with a stable IGF-1 concentration between -1 and 1 SD score (SDS). Subjects were randomized to receive either a decrease (IGF-1 target level of -2 to -1 SDS) or an increase of their daily GH dose (IGF-1 target level of 1 to 2 SDS) for a period of 24weeks. The effect on cardiovascular risk factors and physical performance, next to tolerability, was compared., Results: Thirty subjects (65.6% men, mean age 46.6 (SD 9.9) years) could be analyzed. In subjects with a high-normal IGF-1 target level, waist circumference decreased (p=0.05), and overall they felt better (p=0.04), compared to subjects with a low-normal IGF-1 target level. However, increasing IGF-1 levels led to more myalgia, and decreasing IGF-1 levels to more fatigue. There was a gender-dependent difference in effect on HDL cholesterol., Conclusion: Although increasing GH dose to IGF-1 levels between 1 and 2 SDS improved waist circumference and well-being, safety was not guaranteed with the demonstrated effect on HDL cholesterol in men, and reported myalgia., (Copyright © 2016. Published by Elsevier B.V.)

The gut-derived incretin hormone, glucagon-like peptide 1 (GLP-1) lowers postprandial blood glucose levels by stimulating insulin and inhibiting glucagon secretion. Two novel antihyperglycaemic drug classes augment these effects; GLP-1 receptor agonists and inhibitors of the GLP-1 degrading enzyme dipeptidyl peptidase 4. These so called GLP-1 based or incretin based drugs are increasingly used to treat type 2 diabetes, because of a low risk of hypoglycaemia and favourable effect on body weight, blood pressure and lipid profiles. Besides glucose control, GLP-1 functions as an enterogastrone, causing a wide range of GI responses. Studies have shown that endogenous GLP-1 and its derived therapies slow down digestion by affecting the stomach, intestines, exocrine pancreas, gallbladder and liver. Understanding the GI actions of GLP-1 based therapies is clinically relevant; because GI side effects are common and need to be recognised, and because these drugs may be used to treat GI disease., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Aim: Clinical use of glucagon-like peptide-1 receptor agonists (GLP-1RA) is consistently associated with heart rate (HR) acceleration in type 2 diabetes patients. We explored the mechanisms underlying this potential safety concern., Methods: Ten healthy overweight males (aged 20-27 years) were examined in an open label, crossover study. Automated oscillometric blood pressure measurements and finger photoplethysmography were performed throughout intravenous administration of placebo (saline 0.9%), exenatide (targeting therapeutic concentrations) and a combination of exenatide and the nitric oxide synthase inhibitor L-N(G) -monomethyl arginine (L-NMMA). Sympathetic nervous system (SNS) activity was measured by heart rate variability and rate-pressure product., Results: Exenatide increased HR by a mean maximum of 6.8 (95% CI 1.7, 11.9) beats min(-1) (P < 0.05), systolic blood pressure (SBP) by 9.8 (95% CI 3.5, 16.1) mmHg (P < 0.01) and markers of SNS activity (P < 0.05). No changes in total peripheral resistance were observed. Increases in HR, SBP and sympathetic activity were preserved during concomitant L-NMMA infusion., Conclusions: Our data argue against exenatide-induced reflex tachycardia as a response to vasodilation and rather suggest the involvement of SNS activation in humans., (© 2015 The British Pharmacological Society.)

Aims: To investigate the effect of infusion of the glucagon-like peptide-1 (GLP-1) receptor agonist exenatide on exocrine pancreatic function., Methods: This was a randomized, placebo-controlled, double-blind, crossover study in 12 male patients with type 2 diabetes, treated with oral glucose-lowering agents. On two separate occasions, exenatide or placebo (saline 0.9%) were administered intravenously, in randomized order. Exocrine pancreatic function was measured using secretin-enhanced magnetic resonance cholangiopancreatography. The primary outcome measure was defined as secretin-stimulated pancreatic excretion volume. Secondary outcome measures were maximum secretion speed and the time to reach this maximum. In addition, changes in pancreatic duct (PD) diameter were measured., Results: Exenatide did not change secretin-stimulated pancreatic excretion volume, as compared with placebo (mean ± standard error of the mean 142.2 ± 15.6 ml vs 142.6 ± 8.5 ml, respectively; p = 0.590). Also, exenatide did not change the maximum secretion speed (33.1 ± 1.4 vs 36.9 ± 2.2; p = 0.221), nor the time to reach this maximum (both 4 min 30 s). No differences in PD diameter were observed between the two groups., Conclusions: Infusion of exenatide did not directly influence MRI-measured exocrine pancreatic excretion in patients with type 2 diabetes. Although long-term studies are warranted, these findings suggest that potential adverse pancreatic effects of GLP-1 receptor agonists are not mediated by changes in exocrine pancreatic secretion., (© 2015 John Wiley & Sons Ltd.)

The gastrointestinal hormone glucagon-like peptide-1 (GLP-1) lowers postprandial glucose concentrations by regulating pancreatic islet-cell function, with stimulation of glucose-dependent insulin and suppression of glucagon secretion. In addition to endocrine pancreatic effects, mounting evidence suggests that several gastrointestinal actions of GLP-1 are at least as important for glucose-lowering. GLP-1 reduces gastric emptying rate and small bowel motility, thereby delaying glucose absorption and decreasing postprandial glucose excursions. Furthermore, it has been suggested that GLP-1 directly stimulates hepatic glucose uptake, and suppresses hepatic glucose production, thereby adding to reduction of fasting and postprandial glucose levels. GLP-1 receptor agonists, which mimic the effects of GLP-1, have been developed for the treatment of type 2 diabetes. Based on their pharmacokinetic profile, GLP-1 receptor agonists can be broadly categorized as short- or long-acting, with each having unique islet-cell and gastrointestinal effects that lower glucose levels. Short-acting agonists predominantly lower postprandial glucose excursions, by inhibiting gastric emptying and intestinal glucose uptake, with little effect on insulin secretion. By contrast, long-acting agonists mainly reduce fasting glucose levels, predominantly by increased insulin and reduced glucagon secretion, with potential additional direct inhibitory effects on hepatic glucose production. Understanding these pharmacokinetic and pharmacodynamic differences may allow personalized antihyperglycaemic therapy in type 2 diabetes. In addition, it may provide the rationale to explore treatment in patients with no or little residual β-cell function., (© 2015 John Wiley & Sons Ltd.)

Aims: To determine the acute effect of glucagon-like peptide-1 (GLP-1) receptor agonist exenatide and the involvement of nitric oxide (NO) on renal haemodynamics and tubular function, in healthy overweight men., Methods: Renal haemodynamics and tubular electrolyte handling were measured in 10 healthy overweight men (aged 20-27 years; BMI 26-31 kg/m(2)) during intravenous administration of placebo (saline 0.9%), exenatide, and exenatide combined with the NO-synthase inhibitor L-N(G)-monomethyl arginine (L-NMMA). Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were determined by inulin and para-aminohippurate clearance techniques, respectively, based on timed urine sampling. Glomerular hydrostatic pressure and vascular resistance of afferent and efferent renal arterioles were calculated using the Gomez formulae. Urinary electrolytes, osmolality and pH were also measured., Results: GFR increased by a mean of 18 ± 20 (+20%; p = 0.021) and ERPF increased by a median (interquartile range) of 68 (26; 197) ml/min/1.73 m(2) (+14%; p = 0.015) during exenatide infusion versus placebo. During L-NMMA infusion, exenatide increased GFR by mean 8 ± 12 ml/min/1.73 m(2) (+9%; p = 0.049). Exenatide increased estimated glomerular pressure by +6% (p = 0.015) and reduced afferent renal vascular resistance by -33% (p = 0.038), whereas these effects were blunted during L-NMMA infusion. Exenatide increased absolute and fractional sodium excretion, urinary osmolality and urinary pH. The tubular effects of exenatide were not altered by concomitant L-NMMA infusion., Conclusions: Exenatide infusion in healthy overweight men acutely increases GFR, ERPF and glomerular pressure, probably by reducing afferent renal vascular resistance, and at least partially in an NO-dependent manner. As baseline renal haemodynamics in patients with type 2 diabetes differ from those in healthy individuals, clinical studies on the renal effects of GLP-1 receptor agonists are warranted., (© 2015 John Wiley & Sons Ltd.)

Introduction: Sepsis is one of the most frequent reasons for referral to emergency departments (EDs) worldwide. Sepsis becomes more serious when left untreated with a high mortality rate, exceeding even those of myocardial infarction and stroke. Therefore, much effort has been put in to start with appropriate therapy as early as possible. Emergency medical services (EMS) personnel have already made a significant difference in improving care for patients with acute coronary syndrome, multiple trauma and stroke. Patients with severe sepsis or septic shock could also benefit from timely prehospital care. Earlier recognition and initiation of treatment by EMS personnel may improve survival of these critically ill patients. Methods and analysis: The Prehospital Antibiotics against Sepsis (PHANTASi) trial is an investigator- initiated, multicentre, randomized controlled open-label clinical trial nested within a step wedge design. This study compares the effects of usual care to that of training EMS personnel in recognizing and initiating treatment in the prehospital setting together with early administration of antibiotics for patients suspected of (severe) sepsis and septic shock. Primary outcome is 28 day mortality. Secondary outcomes include, length of hospital stay and admission to intensive care units. Ethics and dissemination: This study has been approved by the research ethics committee of VU University Medical Centre, Amsterdam, The Netherlands (Protocol 2013.458/ NL 42001.029.13). The results of the study will be disseminated at several research conferences and international peer reviewed journals. The study will be implemented and reported in line with the CONSORT statement.

Objectives: Patients with head and neck cancer (HNC) frequently encounter weight loss with multiple negative outcomes as a consequence. Adequate treatment is best achieved by early identification of patients at risk for critical weight loss. The objective of this study was to detect predictive factors for critical weight loss in patients with HNC receiving (chemo)radiotherapy ((C)RT)., Materials and Methods: In this cohort study, 910 patients with HNC were included receiving RT (±surgery/concurrent chemotherapy) with curative intent. Body weight was measured at the start and end of (C)RT. Logistic regression and classification and regression tree (CART) analyses were used to analyse predictive factors for critical weight loss (defined as >5%) during (C)RT. Possible predictors included gender, age, WHO performance status, tumour location, TNM classification, treatment modality, RT technique (three-dimensional conformal RT (3D-RT) vs intensity-modulated RT (IMRT)), total dose on the primary tumour and RT on the elective or macroscopic lymph nodes., Results: At the end of (C)RT, mean weight loss was 5.1±4.9%. Fifty percent of patients had critical weight loss during (C)RT. The main predictors for critical weight loss during (C)RT by both logistic and CART analyses were RT on the lymph nodes, higher RT dose on the primary tumour, receiving 3D-RT instead of IMRT, and younger age., Conclusion: Critical weight loss during (C)RT was prevalent in half of HNC patients. To predict critical weight loss, a practical prediction tree for adequate nutritional advice was developed, including the risk factors RT to the neck, higher RT dose, 3D-RT, and younger age., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Introduction: General practitioners (GPs) and the emergency medical services (EMS) personnel have a pivotal role as points of entry into the acute care chain. This study was conducted to investigate the recognition of sepsis by GPs and EMS personnel and to evaluate the associations between recognition of sepsis in the pre-hospital setting and patient outcomes. Methods Design: prospective, observational study during a 12 week period in the emergency department (ED) of two academic hospitals., Study Population: Patients >18 years presenting with sepsis at the ED. The information available in the ED discharge letter and the ED charts was used to make a definite diagnosis of sepsis, severe sepsis and septic shock Outcome measures: primary: recognition/documentation of sepsis. Secondary: ED arrival time to antibiotic administration, in-hospital mortality, hospital length of stay (LOS) and intensive care unit (ICU) admission., Results: A total of 301 patients were included in the study. GPs and EMS personnel correctly identified and documented 31.6% (n=114) and 41.4% of all sepsis patients (n=140) respectively. Recognition and documentation of sepsis improved with increasing severity. The mean time to administration of antibiotics (TTA) was nearly halved for the group of patients where sepsis was documented (GP: 66,4 minutes, EMS: 65,6 minutes) compared to the group in which sepsis was not documented (GP: 123,9 minutes, EMS: 101,5 minutes; p: 0.365 and p: 0.024 respectively). Conclusions There is room for improvement in the recognition of sepsis, severe sepsis and septic shock by practitioners working in the pre-hospital setting. Documentation of sepsis prior to arrival in hospital led to a reduced time delay in administration of antibiotics.

Little is known about the epidemiology of sepsis in the Netherlands. In addition, information regarding the ability of emergency medical services (EMS) personnel to recognize sepsis is lacking. The aim of this study is to determine epidemiological characteristics of sepsis and the recognition of sepsis by EMS personnel in an urban area in the Netherlands. We conducted a retrospective cohort study using transport information from EMS Amsterdam and admission diagnoses at the emergency department gathered through discharge data from two academic hospitals in Amsterdam for the year 2012. A total of 253 patients with sepsis were evaluated, of which 131 were transported by ambulance. The in-hospital mortality rate of the total population was 21% and a mean length of hospital stay was of 13.5 days. Sixty-seven patients (26.5%) were admitted to the intensive care unit. Almost half of the patients were assigned to the internal medicine ward (117; 46.2%). The most common site of infection was the urinary tract (30%). E. coli was the most frequent cause of infections. EMS staff recognized 18/131 (13.7%) transported patients with (severe) sepsis or septic shock. In 52 cases (39.7%) sepsis went unrecognized, probably due to an incomplete primary survey. In 60 cases (45.8%) sepsis went unrecognized, although enough systemic inflammatory response syndrome criteria were present at initial presentation. Recognition of sepsis by EMS staff in the Netherlands is low, probably due to a lack of awareness of the syndrome and infrequent measurement of temperature and respiratory rate. As early initiation of treatment is crucial, the EMS staff, general practitioners, and other specialties could benefit from more education on this critical illness.

Introduction: Incretin-based therapies, that is, glucagon-like peptide (GLP)-1 receptor agonists and dipeptidyl peptidase (DPP)-4 inhibitors, are relatively novel antihyperglycaemic drugs that are frequently used in type 2 diabetes management. Apart from glucose-lowering, these agents exhibit pleiotropic actions that may have favourable and unfavourable clinical consequences. Incretin-based therapies have been associated with heart rate acceleration, heart failure, acute renal failure and acute pancreatitis. Conversely, these agents may reduce blood pressure, glomerular hyperfiltration, albuminuria and hepatic steatosis. While large-sized cardiovascular safety trials can potentially identify the clinical significance of some of these pleiotropic actions, small-sized mechanistic studies are important to understand the (patho)physiological rationale of these findings. The current protocol describes a mechanistic study to assess cardiovascular, renal and gastrointestinal effects, and mechanisms of incretin-based therapies in type 2 diabetes., Methods and Analyses: 60 patients with type 2 diabetes will undergo acute and prolonged randomised, double-blind, intervention studies. The acute intervention will consist of intravenous administration of the GLP-1 receptor agonist exenatide or placebo. For the prolonged intervention, patients will be randomised to 12-week treatment with the GLP-1 receptor agonist liraglutide, the DPP-4 inhibitor sitagliptin or matching placebos. For each examined organ system, a primary end point is defined. Primary cardiovascular end point is change in resting heart rate variability assessed by beat-to-beat heart rate monitor and spectral analyses software. Primary renal end point is change in glomerular filtration rate assessed by the classic inulin clearance methodology. Primary gastrointestinal end points are change in pancreatic exocrine function assessed by MRI-techniques (acute intervention) and faecal elastase-1 levels (12-week intervention). Secondary end points include systemic haemodynamics, microvascular function, effective renal plasma flow, renal tubular function, pancreatic volume and gallbladder emptying-rate., Medical Ethics and Dissemination: The study is approved by the local Ethics Review Board (VU University Medical Center, Amsterdam) and conducted in accordance with the Declaration of Helsinki and Good Clinical Practice., Trial Registration Number: NCT01744236., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: Hypoglycemia is the main side effect of intensified insulin therapy in type 1 diabetes and recognized as a limitation in achieving glycemic targets. Patients with impaired awareness of hypoglycemia have a threefold to sixfold increased risk of severe hypoglycemia. Real-time continuous glucose monitoring may help patients with type 1 diabetes to achieve better glycemic control with less hypoglycemic episodes. Accordingly, one may hypothesize that particularly type 1 diabetes mellitus patients with impaired awareness of hypoglycemia will profit most from this technology with improvements in their quality of life. However, this has not yet been established. This trial aims to study the effect of real-time continuous glucose monitoring on glycemia and quality of life specifically in type 1 diabetes mellitus patients with established impaired awareness of hypoglycemia., Methods/design: This is a two-center, randomized, cross-over trial with a 12-week wash-out period in between intervention periods. A total of 52 type 1 diabetes mellitus patients with impaired awareness of hypoglycemia according to Gold et al. criteria will be randomized to receive real-time continuous glucose monitoring or blinded continuous glucose monitoring for 16 weeks. After a wash-out period, patients will cross over to the other intervention. The primary outcome measure is time spent in euglycemia. Secondary outcomes include (diabetes-specific) markers of quality of life and other glycemic variables., Discussion: It remains unclear whether patients with type 1 diabetes and impaired awareness of hypoglycemia benefit from real-time continuous glucose monitoring in real-life. This study will provide insight into the potential benefits of real-time continuous glucose monitoring in this patient population., Trial Registration: Clinicaltrials.gov: NCT01787903.

Background: A long completion time in the Emergency Department (ED) is associated with higher morbidity and in-hospital mortality. A completion time of more than four hours is a frequently used cut-off point. Mostly, older and sicker patients exceed a completion time of four hours on the ED. The primary aim was to examine which factors currently contribute to overcrowding and a time to completion of more than four hours on the EDs of two different hospitals, namely: the VU Medical Center (VUmc), an academic level 1 trauma centre and the St. Antonius Hospital, a large community hospital in Nieuwegein. In addition, we compared the differences between these hospitals., Methods: In this observational study, the time steps in the process of diagnosing and treatment of all patients visiting the EDs of the two hospitals were measured for four weeks. Patients triaged as Emergency Severity Index (ESI) category 2/3 or Manchester Triage System (MTS) orange/yellow were followed more closely and prospectively by researchers for detailed information in the same period from 12.00-23.00 hrs., Results: In the VUmc, 89% of the patients had a completion time of less than four hours. The average completion time (n = 2262) was 2:10 hours, (median 1:51 hours, range: 0:05-12:08). In the St. Antonius Hospital, 77% of patients had a completion time shorter than four hours (n = 1656). The average completion time in hours was 2:49 (n = 1655, median 2:34, range: 0:08-11:04). In the VUmc, a larger percentage of ESI 1, 2 and 3 patients did not achieve the 4-hour target (14%, 20% and 19%) compared with ESI 4 and 5 patients (2.7% and 0%), p < 0.001. At the St. Antonius Hospital, a greater percentage of orange and yellow categorised patients exceeded four hours on the ED (32% and 28%) compared with red (8%) and green/blue (13%), p < 0.001. For both hospitals there was a significant dependency between exceeding four hours on the ED and the following: whether a consultation was performed (p < 0.001), the number of radiology tests performed (p < 0.001), and an age above 65 years., Conclusion: Factors leading to ED stagnation were similar in both hospitals, namely old age, treatment by more than one speciality and undergoing radiological tests. Uniform remedial measures should be taken on a nationwide level to deal with these factors to reduce stagnation in the EDs.

Objective: The insulinotropic gut-derived hormone glucagon-like peptide-1 (GLP-1) increases capillary perfusion via a nitric oxide-dependent mechanism in rodents. This improves skeletal muscle glucose use and cardiac function. In humans, the effect of clinically used GLP-1 receptor agonists (GLP-1RAs) on capillary density is unknown. We aimed to assess the effects of the GLP-1RA exenatide on capillary density as well as the involvement of nitric oxide in humans., Approach and Results: We included 10 healthy overweight men (age, 20-27 years; body mass index, 26-31 kg/m(2)). Measurements were performed during intravenous infusion of placebo (saline 0.9%), exenatide, and a combination of exenatide and the nonselective nitric oxide-synthase inhibitor L-N(G)-monomethyl arginine. Capillary videomicroscopy was performed, and baseline and postocclusive (peak) capillary densities were counted. Compared with placebo, exenatide increased baseline and peak capillary density by 20.1% and 8.3%, respectively (both P=0.016). Concomitant L-N(G)-monomethyl arginine infusion did not alter the effects of exenatide. Vasomotion was assessed using laser Doppler fluxmetry. Exenatide nonsignificantly reduced the neurogenic domain of vasomotion measurements (R=-5.6%; P=0.092), which was strongly and inversely associated with capillary perfusion (R=-0.928; P=0.036). Glucose levels were reduced during exenatide infusion, whereas levels of insulin were unchanged., Conclusions: Acute exenatide infusion increases capillary perfusion via nitric oxide-independent pathways in healthy overweight men, suggesting direct actions of this GLP-1RA on microvascular perfusion or interaction with vasoactive factors., (© 2015 American Heart Association, Inc.)