Re-Cellularization via Electroporation Therapy of the duodenum combined with GPL-1 receptor agonist to replace insulin therapy in patients with type 2 diabetes; 12 months results of a first-in-human study.

BACKGROUND AND AIMS: Studies have shown that hydrothermal duodenal mucosal ablation results in improved glycemic control. Re-Cellularization via Electroporation Therapy (ReCET) is a novel endoscopic procedure that uses electroporation to induce cellular apoptosis and subsequent reepithelization. In this study, we aimed to eliminate exogenous insulin treatment in T2D patients through a single ReCET procedure combined with a GLP-1 receptor agonist (GLP-1RA). Feasibility, safety, and (dose) efficacy of ReCET were assessed. METHODS: First-in-human study including patients with T2D on basal insulin (28-75years; BMI 24-40kg/m2, HbA1c ≤64mmol/mol; C-peptide ≥0.2nmol/L). The electroporation dose was optimized during the study, starting with single 600V and ending with double 750V treatments. All patients underwent ReCET, after which insulin was discontinued and semaglutide (GLP-1RA) was initiated. Primary endpoints were: feasibility (procedure time [catheter in-out], technical success rate), safety, and efficacy (patients off insulin at 6 months; HbA1c ≤58mmol/mol). RESULTS: Fourteen patients underwent endoscopic ReCET. Median procedure time was 58 (IQR 49-73) minutes. ReCET demonstrated a technical success rate of 100%. No device related SAEs or severe hypoglycemic events were observed. At 12 months follow up, 12 (86%) patients remained off exogenous insulin therapy with significant improvements in glycemic control, metabolic parameters. The 2 patients in whom insulin therapy was reintroduced both received ReCET at the lowest voltage (single 600V). CONCLUSION: These results suggest that ReCET is feasible and safe. In combination with semaglutide, ReCET may be a promising therapeutic option to replace insulin therapy in selected T2D patients, while improving glycemic control and metabolic health.

Ultra-low-dose CT versus chest X-ray for patients suspected of pulmonary disease at the emergency department: a multicentre randomised clinical trial.

BACKGROUND: Chest CT displays chest pathology better than chest X-ray (CXR). We evaluated the effects on health outcomes of replacing CXR by ultra-low-dose chest-CT (ULDCT) in the diagnostic work-up of patients suspected of non-traumatic pulmonary disease at the emergency department. METHODS: Pragmatic, multicentre, non-inferiority randomised clinical trial in patients suspected of non-traumatic pulmonary disease at the emergency department. Between 31 January 2017 and 31 May 2018, every month, participating centres were randomly allocated to using ULDCT or CXR. Primary outcome was functional health at 28 days, measured by the Short Form (SF)-12 physical component summary scale score (PCS score), non-inferiority margin was set at 1 point. Secondary outcomes included hospital admission, hospital length of stay (LOS) and patients in follow-up because of incidental findings. RESULTS: 2418 consecutive patients (ULDCT: 1208 and CXR: 1210) were included. Mean SF-12 PCS score at 28 days was 37.0 for ULDCT and 35.9 for CXR (difference 1.1; 95% lower CI: 0.003). After ULDCT, 638/1208 (52.7%) patients were admitted (median LOS of 4.8 days; IQR 2.1-8.8) compared with 659/1210 (54.5%) patients after CXR (median LOS 4.6 days; IQR 2.1-8.8). More ULDCT patients were in follow-up because of incidental findings: 26 (2.2%) versus 4 (0.3%). CONCLUSIONS: Short-term functional health was comparable between ULDCT and CXR, as were hospital admissions and LOS, but more incidental findings were found in the ULDCT group. Our trial does not support routine use of ULDCT in the work-up of patients suspected of non-traumatic pulmonary disease at the emergency department. TRIAL REGISTRATION NUMBER: NTR6163.

The impact of a sepsis performance improvement program in the emergency department: a before-after intervention study.

PURPOSE: The latest Surviving Sepsis Campaign guidelines advocate that all hospitals use sepsis performance improvement programs. However, there is a limited evidence about how to structure such programs and what their potential impact is on sepsis management and outcomes in the emergency department (ED). In this study, we evaluated the implementation of a sepsis performance improvement program in the ED including a dedicated sepsis response team and analyzed the management and outcomes of sepsis patients before and after. METHODS: We conducted a before-after interventional study in the ED of the Amsterdam University Medical Centers, the Netherlands. The sepsis performance improvement program included regular educational meetings, daily audits and weekly feedback, a screening tool, and a dedicated multidisciplinary sepsis response team. We studied all adult patients who presented to the ED with a suspected infection and a Modified Early Warning Score (MEWS) ≥ 3 during their stay. In the postintervention phase, these patients were seen by the sepsis team. Process-related and patient-related outcomes were measured between November 2019 and February 2020 (preintervention) and December 2021-May 2022 (postintervention). RESULTS: A total of 265 patients were included in the primary study, 132 patients preintervention and 133 patients postintervention. The postintervention phase was associated with improvements in nearly all process-related outcomes, such as a shorter time to antibiotics (66 vs. 143 min; p < 0.001), increased number of lactate measurements (72.9 vs. 46.2%; p < 0.001), and improved completeness of documented MEWS scores (85.0 vs. 62.9%; p < 0.001). Except for an improvement in the number of immediate versus delayed ICU admissions (100% immediate vs. 64.3% immediate; p = 0.012), there was no improvement in the other patient-related outcomes such as 28 days mortality (14.3 vs. 9.1%; p = 0.261), during the postintervention phase. CONCLUSION: Our program stimulated physicians to make timely decisions regarding diagnostics and treatment of sepsis in the ED. Implementing the sepsis performance improvement program was associated with significant improvements in most process-related outcomes but with minimal improvements in patient-related outcomes in our cohort.

Use of the National Early Warning Score for predicting deterioration of patients with acute pulmonary embolism: a post-hoc analysis of the YEARS Study.

BACKGROUND: The Pulmonary Embolism Severity Index (PESI) and the simplified PESI (sPESI) are validated scores for mortality prediction in patients with pulmonary embolism (PE). National Early Warning Score (NEWS) is a general prognostic risk score for multiple clinical settings. We investigated whether the NEWS had a comparable performance with the PESI and sPESI, for predicting intensive care unit (ICU) admission and death in patients with acute PE. METHODS: In haemodynamically stable patients with confirmed PE from the YEARS Study (2013-2015), we evaluated the performance of the NEWS, PESI and sPESI for predicting 7-day ICU admission and 30-day mortality. Receiver operating characteristic curves were plotted and the area under the curve (AUC) was calculated. RESULTS: Of 352 patients, 12 (3.4%) were admitted to the ICU and 5 (1.4%) died. The AUC of the NEWS for ICU admission was 0.80 (95% CI 0.66 to 0.94) and 0.92 (95% CI 0.82 to 1.00) for 30-day mortality. At a threshold of 3 points, NEWS yielded a sensitivity and specificity of 92% and 53% for ICU admission and 100% and 52% for 30-day mortality. The AUC of the PESI was 0.64 (95% CI 0.48 to 0.79) for ICU admission and 0.94 (95% CI 0.87 to 1.00) for mortality. At a threshold of 66 points, PESI yielded a sensitivity of 75% and a specificity of 38% for ICU admission. For mortality, these were 100% and 37%, respectively. The performance of the sPESI was similar to that of PESI. CONCLUSION: In comparison with PESI and sPESI, NEWS adequately predicted 7-day ICU admission as well as 30-day mortality, supporting its potential relevance for clinical practice.

Duodenal mucosal resurfacing with a GLP-1 receptor agonist increases postprandial unconjugated bile acids in patients with insulin-dependent type 2 diabetes.

Duodenal mucosal resurfacing (DMR) is a new endoscopic ablation technique aimed at improving glycemia and metabolic control in patients with type 2 diabetes mellitus (T2DM). DMR appears to improve insulin resistance, which is the root cause of T2DM, but its mechanism of action is largely unknown. Bile acids function as intestinal signaling molecules in glucose and energy metabolism via the activation of farnesoid X receptor and secondary signaling [e.g., via fibroblast growth factor 19 (FGF19)], and are linked to metabolic health. We investigated the effect of DMR and glucagon-like peptide-1 (GLP-1) on postprandial bile acid responses in 16 patients with insulin-dependent T2DM, using mixed meal tests performed at the baseline and 6 mo after the DMR procedure. The combination treatment allowed discontinuation of insulin treatment in 11/16 (69%) of patients while improving glycemic and metabolic health. We found increased postprandial unconjugated bile acid responses (all P < 0.05), an overall increased secondary bile acid response (P = 0.036) and a higher 12α-hydroxylated:non-12α-hydroxylated ratio (P < 0.001). Total bile acid concentrations were unaffected by the intervention. Postprandial FGF19 and 7-α-hydroxy-4-cholesten-3-one (C4) concentrations decreased postintervention (both P < 0.01). Our study demonstrates that DMR with GLP-1 modulates the postprandial bile acid response. The alterations in postprandial bile acid responses may be the result of changes in the microbiome, ileal bile acid uptake and improved insulin sensitivity. Controlled studies are needed to elucidate the mechanism linking the combination treatment to metabolic health and bile acids.NEW & NOTEWORTHY Glycemic and metabolic improvements are seen in patients with type 2 diabetes after replacing their insulin therapy with DMR and GLP-1. These changes are accompanied by changes in postprandial bile acid concentrations: increased unconjugated and secondary bile acids.

Comparing complaint-based triage scales and early warning scores for emergency department triage.

BACKGROUND: Emergency triage systems are used globally to prioritise care based on patients' needs. These systems are commonly based on patient complaints, while the need for timely interventions on regular hospital wards is usually assessed with early warning scores (EWS). We aim to directly compare the ability of currently used triage scales and EWS scores to recognise patients in need of urgent care in the ED. METHODS: We performed a retrospective, single-centre study on all patients who presented to the ED of a Dutch Level 1 trauma centre, between 1 September 2018 and 24 June 2020 and for whom a Netherlands Triage System (NTS) score as well as a Modified Early Warning Score (MEWS) was recorded. The performance of these scores was assessed using surrogate markers for true urgency and presented using bar charts, cross tables and a paired area under the curve (AUC). RESULTS: We identified 12 317 unique patient visits where NTS and MEWS scores were documented during triage. A paired comparison of the AUC of these scores showed that the MEWS score had a significantly better AUC than the NTS for predicting the need for hospital admission (0.65 vs 0.60; p<0.001) or 30-day all-cause mortality (0.70 vs 0.60; p<0.001). Furthermore, when non-urgent MEWS scores co-occur with urgent NTS scores, the MEWS score seems to more accurately capture the urgency level that is warranted. CONCLUSIONS: The results of this study suggest that EWSs could potentially be used to replace the current emergency triage systems.

Faecal microbiota transplantation halts progression of human new-onset type 1 diabetes in a randomised controlled trial.

OBJECTIVE: Type 1 diabetes (T1D) is characterised by islet autoimmunity and beta cell destruction. A gut microbiota-immunological interplay is involved in the pathophysiology of T1D. We studied microbiota-mediated effects on disease progression in patients with type 1 diabetes using faecal microbiota transplantation (FMT). DESIGN: Patients with recent-onset (<6 weeks) T1D (18-30 years of age) were randomised into two groups to receive three autologous or allogenic (healthy donor) FMTs over a period of 4 months. Our primary endpoint was preservation of stimulated C peptide release assessed by mixed-meal tests during 12 months. Secondary outcome parameters were changes in glycaemic control, fasting plasma metabolites, T cell autoimmunity, small intestinal gene expression profile and intestinal microbiota composition. RESULTS: Stimulated C peptide levels were significantly preserved in the autologous FMT group (n=10 subjects) compared with healthy donor FMT group (n=10 subjects) at 12 months. Small intestinal Prevotella was inversely related to residual beta cell function (r=-0.55, p=0.02), whereas plasma metabolites 1-arachidonoyl-GPC and 1-myristoyl-2-arachidonoyl-GPC levels linearly correlated with residual beta cell preservation (rho=0.56, p=0.01 and rho=0.46, p=0.042, respectively). Finally, baseline CD4 +CXCR3+T cell counts, levels of small intestinal Desulfovibrio piger and CCL22 and CCL5 gene expression in duodenal biopsies predicted preserved beta cell function following FMT irrespective of donor characteristics. CONCLUSION: FMT halts decline in endogenous insulin production in recently diagnosed patients with T1D in 12 months after disease onset. Several microbiota-derived plasma metabolites and bacterial strains were linked to preserved residual beta cell function. This study provides insight into the role of the intestinal gut microbiome in T1D. TRIAL REGISTRATION NUMBER: NTR3697.

Duodenal mucosal resurfacing combined with glucagon-like peptide-1 receptor agonism to discontinue insulin in type 2 diabetes: a feasibility study.

BACKGROUND AND AIMS: Duodenal mucosal resurfacing (DMR) is an endoscopic intervention in which the duodenal mucosa is ablated by hydrothermal energy. DMR improves glycemic control in patients with type 2 diabetes (T2D), most likely by altered duodenal signaling leading to insulin sensitization. We studied whether we could discontinue insulin use in T2D patients by combining DMR with glucagon-like peptide-1 receptor agonist (GLP-1RA) and lifestyle counseling. METHODS: In this single-arm, single-center feasibility study in 16 insulin-treated patients with T2D (hemoglobin A1c [HbA1c] ≤8.0%, basal insulin <1 U/kg/day, C-peptide ≥.5 nmol/L), patients underwent a single DMR followed by a 2-week postprocedural diet, after which GLP-1RA (liraglutide) was introduced. Lifestyle counseling was provided per American Diabetes Association guidelines. The primary endpoint was percentage of patients without insulin with an HbA1c ≤7.5% (responders) at 6 months. Secondary endpoints were changes in multiple glycemic and metabolic parameters and percentage of responders at 12 and 18 months, respectively. RESULTS: All 16 patients underwent successful DMR without procedure-related serious adverse events. At 6 months, 69% of patients were off insulin therapy with an HbA1c ≤7.5%. At 12 and 18 months 56% and 53% remained off insulin, respectively. All patients significantly improved in the glycemic and metabolic parameters of homeostatic model assessment for insulin resistance, body mass index, weight, and liver fat fraction. CONCLUSIONS: In this feasibility study, the combination of a single DMR and GLP-1RA, supported by lifestyle counseling, eliminated the need for insulin therapy in most patients with T2D through 18 months postprocedure, with adequate beta-cell capacity, while improving glucose regulation and metabolic health in all patients. A randomized-sham controlled trial is currently initiated based on these results. (Clinical trial registration number: EudraCT 2017-00349-30.).

Endoscopic duodenal mucosal resurfacing for the treatment of type 2 diabetes mellitus: one year results from the first international, open-label, prospective, multicentre study.

BACKGROUND: The duodenum has become a metabolic treatment target through bariatric surgery learnings and the specific observation that bypassing, excluding or altering duodenal nutrient exposure elicits favourable metabolic changes. Duodenal mucosal resurfacing (DMR) is a novel endoscopic procedure that has been shown to improve glycaemic control in people with type 2 diabetes mellitus (T2D) irrespective of body mass index (BMI) changes. DMR involves catheter-based circumferential mucosal lifting followed by hydrothermal ablation of duodenal mucosa. This multicentre study evaluates safety and feasibility of DMR and its effect on glycaemia at 24 weeks and 12 months. METHODS: International multicentre, open-label study. Patients (BMI 24-40) with T2D (HbA1c 59-86 mmol/mol (7.5%-10.0%)) on stable oral glucose-lowering medication underwent DMR. Glucose-lowering medication was kept stable for at least 24 weeks post DMR. During follow-up, HbA1c, fasting plasma glucose (FPG), weight, hepatic transaminases, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), adverse events (AEs) and treatment satisfaction were determined and analysed using repeated measures analysis of variance with Bonferroni correction. RESULTS: Forty-six patients were included of whom 37 (80%) underwent complete DMR and 36 were finally analysed; in remaining patients, mainly technical issues were observed. Twenty-four patients had at least one AE (52%) related to DMR. Of these, 81% were mild. One SAE and no unanticipated AEs were reported. Twenty-four weeks post DMR (n=36), HbA1c (-10±2 mmol/mol (-0.9%±0.2%), p<0.001), FPG (-1.7±0.5 mmol/L, p<0.001) and HOMA-IR improved (-2.9±1.1, p<0.001), weight was modestly reduced (-2.5±0.6 kg, p<0.001) and hepatic transaminase levels decreased. Effects were sustained at 12 months. Change in HbA1c did not correlate with modest weight loss. Diabetes treatment satisfaction scores improved significantly. CONCLUSIONS: In this multicentre study, DMR was found to be a feasible and safe endoscopic procedure that elicited durable glycaemic improvement in suboptimally controlled T2D patients using oral glucose-lowering medication irrespective of weight loss. Effects on the liver are examined further. TRIAL REGISTRATION NUMBER: NCT02413567.

Donor metabolic characteristics drive effects of faecal microbiota transplantation on recipient insulin sensitivity, energy expenditure and intestinal transit time.

OBJECTIVE: Bariatric surgery improves glucose metabolism. Recent data suggest that faecal microbiota transplantation (FMT) using faeces from postbariatric surgery diet-induced obese mice in germ-free mice improves glucose metabolism and intestinal homeostasis. We here investigated whether allogenic FMT using faeces from post-Roux-en-Y gastric bypass donors (RYGB-D) compared with using faeces from metabolic syndrome donors (METS-D) has short-term effects on glucose metabolism, intestinal transit time and adipose tissue inflammation in treatment-naïve, obese, insulin-resistant male subjects. DESIGN: Subjects with metabolic syndrome (n=22) received allogenic FMT either from RYGB-D or METS-D. Hepatic and peripheral insulin sensitivity as well as lipolysis were measured at baseline and 2 weeks after FMT by hyperinsulinaemic euglycaemic stable isotope (2H2-glucose and 2H5-glycerol) clamp. Secondary outcome parameters were changes in resting energy expenditure, intestinal transit time, faecal short-chain fatty acids (SCFA) and bile acids, and inflammatory markers in subcutaneous adipose tissue related to intestinal microbiota composition. Faecal SCFA, bile acids, glycaemic control and inflammatory parameters were also evaluated at 8 weeks. RESULTS: We observed a significant decrease in insulin sensitivity 2 weeks after allogenic METS-D FMT (median rate of glucose disappearance: from 40.6 to 34.0 µmol/kg/min; p<0.01). Moreover, a trend (p=0.052) towards faster intestinal transit time following RYGB-D FMT was seen. Finally, we observed changes in faecal bile acids (increased lithocholic, deoxycholic and (iso)lithocholic acid after METS-D FMT), inflammatory markers (decreased adipose tissue chemokine ligand 2 (CCL2) gene expression and plasma CCL2 after RYGB-D FMT) and changes in several intestinal microbiota taxa. CONCLUSION: Allogenic FMT using METS-D decreases insulin sensitivity in metabolic syndrome recipients when compared with using post-RYGB-D. Further research is needed to delineate the role of donor characteristics in FMT efficacy in human insulin-resistant subjects. TRIAL REGISTRATION NUMBER: NTR4327.

Oral butyrate does not affect innate immunity and islet autoimmunity in individuals with longstanding type 1 diabetes: a randomised controlled trial.

AIMS/HYPOTHESIS: The pathophysiology of type 1 diabetes has been linked to altered gut microbiota and more specifically to a shortage of intestinal production of the short-chain fatty acid (SCFA) butyrate, which may play key roles in maintaining intestinal epithelial integrity and in human and gut microbial metabolism. Butyrate supplementation can protect against autoimmune diabetes in mouse models. We thus set out to study the effect of oral butyrate vs placebo on glucose regulation and immune variables in human participants with longstanding type 1 diabetes. METHODS: We administered a daily oral dose of 4 g sodium butyrate or placebo for 1 month to 30 individuals with longstanding type 1 diabetes, without comorbidity or medication use, in a randomised (1:1), controlled, double-blind crossover trial, with a washout period of 1 month in between. Participants were randomly allocated to the 'oral sodium butyrate capsules first' or 'oral placebo capsules first' study arm in blocks of five. The clinical investigator received blinded medication from the clinical trial pharmacy. All participants, people doing measurements or examinations, or people assessing the outcomes were blinded to group assignment. The primary outcome was a change in the innate immune phenotype (monocyte subsets and in vitro cytokine production). Secondary outcomes were changes in blood markers of islet autoimmunity (cell counts, lymphocyte stimulation indices and CD8 quantum dot assays), glucose and lipid metabolism, beta cell function (by mixed-meal test), gut microbiota and faecal SCFA. The data was collected at the Amsterdam University Medical Centers. RESULTS: All 30 participants were analysed. Faecal butyrate and propionate levels were significantly affected by oral butyrate supplementation and butyrate treatment was safe. However, this modulation of intestinal SCFAs did not result in any significant changes in adaptive or innate immunity, or in any of the other outcome variables. In our discussion, we elaborate on this important discrepancy with previous animal work. CONCLUSIONS/INTERPRETATION: Oral butyrate supplementation does not significantly affect innate or adaptive immunity in humans with longstanding type 1 diabetes. TRIAL REGISTRATION: Netherlands Trial Register: NL4832 (www.trialregister.nl). DATA AVAILABILITY: Raw sequencing data are available in the European Nucleotide Archive repository (https://www.ebi.ac.uk/ena/browse) under study PRJEB30292. FUNDING: The study was funded by a Le Ducq consortium grant, a CVON grant, a personal ZONMW-VIDI grant and a Dutch Heart Foundation grant.

Febrile urinary tract infections: pyelonephritis and urosepsis.

PURPOSE OF REVIEW: Complicated infections of the urinary tract (UTI) including pyelonephritis and urosepsis are also called febrile UTI. This review describes insights from the literature on this topic since July 2014. RECENT FINDINGS: Recent studies regarding risk factors and consequences of febrile UTI confirmed existing knowledge. It remains difficult to obtain insight into the epidemiology of febrile UTI because urine and blood cultures are frequently missing. The relationship between host and virulence factors of Escherichia coli was further explored showing that less virulent strains can cause infection in immunocompromised patients. In contrast to obstructive uropathy, diabetes, and being older, neutropenia was not a risk factor for lower UTI or urosepsis. A randomized controlled trial revealed that ceftolozane-tazobactam was marginally superior to levofloxacin as treatment for complicated UTI. Case series supported the notion that xanthogranulomatous and emphysematous pyelonephritis are more common in diabetic patients and that drainage or surgery is often required. SUMMARY: Neutropenia was not a risk factor for lower UTI or urosepsis. When local resistance percentages to the frequently prescribed fluoroquinolones are high, the combination of ceftolozane-tazobactam may be an alternative as treatment for complicated UTI. Xanthogranulomatous and emphysematous pyelonephritis need to be considered in diabetic patients presenting with UTI symptoms.

Epidemiology of Sepsis and Its Recognition by Emergency Medical Services Personnel in the Netherlands.

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.

Epidemiology, recognition and documentation of sepsis in the pre-hospital setting and associated clinical outcomes: a prospective multicenter study.

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.

Impact of oral vancomycin on gut microbiota, bile acid metabolism, and insulin sensitivity.

BACKGROUND & AIMS: Obesity has been associated with changes in the composition and function of the intestinal microbiota. Modulation of the microbiota by antibiotics also alters bile acid and glucose metabolism in mice. Hence, we hypothesized that short term administration of oral antibiotics in humans would affect fecal microbiota composition and subsequently bile acid and glucose metabolism. METHODS: In this single blinded randomized controlled trial, 20 male obese subjects with metabolic syndrome were randomized to 7 days of amoxicillin 500 mg t.i.d. or 7 days of vancomycin 500 mg t.i.d. At baseline and after 1 week of therapy, fecal microbiota composition (Human Intestinal Tract Chip phylogenetic microarray), fecal and plasma bile acid concentrations as well as insulin sensitivity (hyperinsulinemic euglycemic clamp using [6,6-(2)H2]-glucose tracer) were measured. RESULTS: Vancomycin reduced fecal microbial diversity with a decrease of gram-positive bacteria (mainly Firmicutes) and a compensatory increase in gram-negative bacteria (mainly Proteobacteria). Concomitantly, vancomycin decreased fecal secondary bile acids with a simultaneous postprandial increase in primary bile acids in plasma (p<0.05). Moreover, changes in fecal bile acid concentrations were predominantly associated with altered Firmicutes. Finally, administration of vancomycin decreased peripheral insulin sensitivity (p<0.05). Amoxicillin did not affect any of these parameters. CONCLUSIONS: Oral administration of vancomycin significantly impacts host physiology by decreasing intestinal microbiota diversity, bile acid dehydroxylation and peripheral insulin sensitivity in subjects with metabolic syndrome. These data show that intestinal microbiota, particularly of the Firmicutes phylum contributes to bile acid and glucose metabolism in humans. This trial is registered at the Dutch Trial Register (NTR2566).

Diabetes patients' experiences with the implementation of insulin therapy and their perceptions of computer-assisted self-management systems for insulin therapy.

BACKGROUND: Computer-assisted decision support is an emerging modality to assist patients with type 2 diabetes mellitus (T2DM) in insulin self-titration (ie, self-adjusting insulin dose according to daily blood glucose levels). Computer-assisted insulin self-titration systems mainly focus on helping patients overcome barriers related to the cognitive components of insulin titration. Yet other (eg, psychological or physical) barriers could still impede effective use of such systems. OBJECTIVE: Our primary aim was to identify experiences with and barriers to self-monitoring of blood glucose, insulin injection, and insulin titration among patients with T2DM. Our research team developed a computer-assisted insulin self-titration system, called PANDIT. The secondary aim of this study was to evaluate patients' perceptions of computer-assisted insulin self-titration. We included patients who used PANDIT in a 4-week pilot study as well as patients who had never used such a system. METHODS: In-depth, semi-structured interviews were conducted individually with patients on insulin therapy who were randomly recruited from a university hospital and surrounding general practices in the Netherlands. The interviews were transcribed verbatim and analyzed qualitatively. To classify the textual remarks, we created a codebook during the analysis, in a bottom-up and iterative fashion. To support examination of the final coded data, we used three theories from the field of health psychology and the integrated model of user satisfaction and technology acceptance by Wixom and Todd. RESULTS: When starting insulin therapy, some patients feared a lifelong commitment to insulin therapy and disease progression. Also, many barriers arose when implementing insulin therapy (eg, some patients were embarrassed to inject insulin in public). Furthermore, patients had difficulties increasing the insulin dose because they fear hypoglycemia, they associate higher insulin doses with disease progression, and some were ignorant of treatment targets. Patients who never used a computer-assisted insulin self-titration system felt they had enough knowledge to know when their insulin should be adjusted, but still believed that the system advice would be useful to confirm their reasoning. Furthermore, the time and effort saved with automated insulin advice was considered an advantage. Patients who had used PANDIT found the system useful if their glycemic regulation improved. Nevertheless, for some patients, the absence of personal contact with their caregiver was a drawback. While guidelines state that adjustment of basal insulin dose based on fasting plasma glucose values is sufficient, both patients who had and those who had not used PANDIT felt that such a system should take more patient data into consideration, such as lifestyle and diet factors. CONCLUSIONS: Patients encounter multiple obstacles when implementing insulin therapy. Computer-assisted insulin self-titration can increase patient awareness of treatment targets and increase their confidence in self-adjusting the insulin dose. Nevertheless, some barriers may still exist when using computer-assisted titration systems and these systems could also introduce new barriers.

Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome.

Alterations in intestinal microbiota are associated with obesity and insulin resistance. We studied the effects of infusing intestinal microbiota from lean donors to male recipients with metabolic syndrome on the recipients' microbiota composition and glucose metabolism. Subjects were assigned randomly to groups that were given small intestinal infusions of allogenic or autologous microbiota. Six weeks after infusion of microbiota from lean donors, insulin sensitivity of recipients increased (median rate of glucose disappearance changed from 26.2 to 45.3 µmol/kg/min; P < .05) along with levels of butyrate-producing intestinal microbiota. Intestinal microbiota might be developed as therapeutic agents to increase insulin sensitivity in humans; www.trialregister.nl; registered at the Dutch Trial Register (NTR1776).