Investigating the Degree to Which Unstructured Socializing With Peers and Delinquency Are Nonlinear.

Since the formulation of Cohen and Felson's (1979) routine activity theory (RAT), Osgood et al. (1996) established a reformulated theory to better explain patterns of situational offense and coined the RAT of general deviance or more commonly known as unstructured socializing with peers (USWP). The present study seeks to explore whether spending more time in USWP may increase antisocial behavior in a nonlinear manner, either accelerating or decelerating. Results showed that the relationship between USWP and property delinquency was found to be nonlinear in a decelerating manner. Similar results were found for the association between USWP and substance use. Finally, the relationship between USWP and violent delinquency was significant, although no evidence was found for nonlinearity. The present study concludes with theoretical implications, limitations, and directions for future research.

Hot Mail: Temperature Exposure during Mail Return of an Immunochemical Fecal Occult Blood Test.

BACKGROUND: Fecal immunochemical tests (FITs) are widely used for colorectal cancer (CRC) screening; however, high ambient temperatures were found to reduce test accuracy. More recently, proprietary globin stabilizers were added to FIT sample buffers to prevent temperature-associated hemoglobin (Hb) degradation, but their effectiveness remains uncertain. We aimed to determine the impact of high temperature (>30°C) on OC-Sensor FIT Hb concentration with current FITs, characterize FIT temperatures during mail transit, and determine impact of ambient temperature on FIT Hb concentration using data from a CRC screening program. METHODS: FITs were analyzed for Hb concentration after in vitro incubation at different temperatures. Data loggers packaged alongside FITs measured temperatures during mail transit. Separately, screening program participants completed and mailed FITs to the laboratory for Hb analysis. Regression analyses compared the impact of environmental variables on FIT temperatures and separately on FIT sample Hb concentration. RESULTS: In vitro incubation at 30 to 35°C reduced FIT Hb concentration after >4 days. During mail transit, maximum FIT temperature averaged 6.4°C above maximum ambient temperature, but exposure to temperature above 30°C was for less than 24 hours. Screening program data showed no association between FIT Hb concentration and maximum ambient temperatures. CONCLUSIONS: Although FIT samples are exposed to elevated temperatures during mail transit, this is brief and does not significantly reduce FIT Hb concentration. These data support continuation of CRC screening during warm weather with modern FITs with a stabilizing agent when mail delivery is ≤4 days.

Use of a Multiplex PCR Assay To Assess the Presence of Treponema pallidum in Mucocutaneous Ulcerations in Patients with Suspected Syphilis.

We evaluated the utility of the commercial Allplex genital ulcer real-time PCR multiplex assay for detecting Treponema pallidum, herpes simplex virus 1 (HSV-1) and 2 (HSV-2), and Chlamydia trachomatis serovar L (lymphogranuloma venereum [LGV]) DNA in mucosal and genital ulcers in the context of suspected syphilis. In total, 374 documented genital and mucosal ulcers from patients with and without syphilis presenting at several sexually transmitted infection (STI) centers in France from October 2010 to December 2016 were analyzed at the National Reference Center (CNR) for Bacterial STIs at Cochin Hospital in Paris. T. pallidum subsp. pallidum detection results were compared with the final diagnosis based on a combination of clinical examination, serological results, and in-house nested PCR (nPCR). Detections of HSV and LGV were validated against reference methods. We found that 44.6% of the 374 samples tested were positive for T. pallidum subsp. pallidum, 21% for HSV, and 0.8% for LGV. No positive results were obtained for 30.7% of samples, and 4.8% presented coinfections. For T. pallidum subsp. pallidum detection, the overall sensitivity was 80% (95% confidence interval [CI], 76.1 to 84.1%), specificity was 98.8% (95% CI, 97.7 to 99.9%), positive predictive value was 98.8% (95% CI, 97.7 to 99.9%) and negative predictive value was 80.2% (95% CI, 76.2 to 84.2%), with a rate of concordance with the reference method of 92.5% (k = 0.85). This PCR multiplex assay is suitable for T. pallidum subsp. pallidum detection in routine use and facilitates the simultaneous rapid detection of a broad panel of pathogens relevant in a context of suspected syphilis lesions.

The association between nutritional adequacy and 28-day mortality in the critically ill is not modified by their baseline nutritional status and disease severity.

BACKGROUND: During the initial phase of critical illness, the association between the dose of nutrition support and mortality risk may vary among patients in the intensive care unit (ICU) because the prevalence of malnutrition varies widely (28 to 78%), and not all ICU patients are severely ill. Therefore, we hypothesized that a prognostic model that integrates nutritional status and disease severity could accurately predict mortality risk and classify critically ill patients into low- and high-risk groups. Additionally, in critically ill patients placed on exclusive nutritional support (ENS), we hypothesized that their risk categories could modify the association between dose of nutrition support and mortality risk. METHODS: A prognostic model that predicts 28-day mortality was built from a prospective cohort study of 440 patients. The association between dose of nutrition support and mortality risk was evaluated in a subgroup of 252 mechanically ventilated patients via logistic regressions, stratified by low- and high-risk groups, and days of exclusive nutritional support (ENS) [short-term (≤ 6 days) vs. longer-term (≥ 7 days)]. Only the first 6 days of ENS was evaluated for a fair comparison. RESULTS: The prognostic model demonstrated good discrimination [AUC 0.78 (95% CI 0.73-0.82), and a bias-corrected calibration curve suggested fair accuracy. In high-risk patients with short-term ENS (≤ 6 days), each 10% increase in goal energy and protein intake was associated with an increased adjusted odds (95% CI) of 28-day mortality [1.60 (1.19-2.15) and 1.47 (1.12-1.86), respectively]. In contrast, each 10% increase in goal protein intake during the first 6 days of ENS in high-risk patients with longer-term ENS (≥ 7 days) was associated with a lower adjusted odds of 28-day mortality [0.75 (0.57-0.99)]. Despite the opposing associations, the mean predicted mortality risks and prevalence of malnutrition between short- and longer-term ENS patients were similar. CONCLUSIONS: Combining baseline nutritional status and disease severity in a prognostic model could accurately predict 28-day mortality. However, the association between the dose of nutrition support during the first 6 days of ENS and 28-day mortality was independent of baseline disease severity and nutritional status.

Low Sensitivity of Fecal Immunochemical Tests and Blood-Based Markers of DNA Hypermethylation for Detection of Sessile Serrated Adenomas/Polyps.

BACKGROUND: Early detection and removal of precursor lesions reduce colorectal cancer morbidity and mortality. Sessile serrated adenomas/polyps (SSP) are a recognized precursor of cancer, but there are limited studies on whether current screening techniques detect this pathology. AIMS: To investigate the sensitivity of fecal immunochemical tests (FIT) and epigenetic biomarkers in blood for detection of SSP. METHODS: A prospective study offered FIT and a blood test (Colvera for methylated BCAT1 and IKZF1) to adults referred for colonoscopy. Sensitivity of FIT and the blood test were determined for four types of pathology: low-risk conventional adenoma, high-risk adenoma, SSP, and absence of neoplasia. Comparisons were made for FIT positivity at 10 and 20 µg hemoglobin (Hb)/g feces. RESULTS: One thousand eight hundred and eighty-two subjects completed FIT and underwent colonoscopy. One thousand four hundred and three were also tested for methylated BCAT1/IKZF1. The sensitivity of FIT (20 µg Hb/g feces) for SSP was 16.3%. This was lower than the sensitivity for high-risk adenomas (28.7%, p < 0.05), but no different to that for low-risk adenomas (13.1%) or no neoplasia (8.4%). A positive FIT result for SSP was not associated with demographics, morphology, concurrent pathology or intake of medications that increase bleeding risk. FIT sensitivity for SSP did not significantly increase through lowering the positivity threshold to 10 µg Hb/g feces (20.4%, p > 0.05). Sensitivity of the blood test for SSP was 8.8%, and 26.5% when combined with FIT. CONCLUSIONS: Both FIT and blood-based markers of DNA hypermethylation have low sensitivity for detection of SSP. Further development of sensitive screening tests is warranted.

Toward More Efficient Surveillance of Barrett's Esophagus: Identification and Exclusion of Patients at Low Risk of Cancer.

BACKGROUND: Endoscopic surveillance of Barrett's esophagus (BE) is probably not cost-effective. A sub-population with BE at increased risk of high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) who could be targeted for cost-effective surveillance was sought. METHODS: The outcome for BE surveillance from 2003 to 2012 in a structured program was reviewed. Incidence rates and incidence rate ratios for developing HGD or EAC were calculated. Risk stratification identified individuals who could be considered for exclusion from surveillance. A health-state transition Markov cohort model evaluated the cost-effectiveness of focusing on higher-risk individuals. RESULTS: During 2067 person-years of follow-up of 640 patients, 17 individuals progressed to HGD or EAC (annual IR 0.8%). Individuals with columnar-lined esophagus (CLE) ≥2 cm had an annual IR of 1.2% and >8-fold increased relative risk of HGD or EAC, compared to CLE <2 cm [IR-0.14% (IRR 8.6, 95% CIs 4.5-12.8)]. Limiting the surveillance cohort after the first endoscopy to individuals with CLE ≥2 cm, or dysplasia, followed by a further restriction after the second endoscopy-exclusion of patients without intestinal metaplasia-removed 296 (46%) patients, and 767 (37%) person-years from surveillance. Limiting surveillance to the remaining individuals reduced the incremental cost-effectiveness ratio from US$60,858 to US$33,807 per quality-adjusted life year (QALY). Further restrictions were tested but failed to improve cost-effectiveness. CONCLUSIONS: Based on stratification of risk, the number of patients requiring surveillance can be reduced by at least a third. At a willingness-to-pay threshold of US$50,000 per QALY, surveillance of higher-risk individuals becomes cost-effective.

The effect of camicinal (GSK962040), a motilin agonist, on gastric emptying and glucose absorption in feed-intolerant critically ill patients: a randomized, blinded, placebo-controlled, clinical trial.

BACKGROUND: The promotility agents currently available to treat gastroparesis and feed intolerance in the critically ill are limited by adverse effects. The aim of this study was to assess the pharmacodynamic effects and pharmacokinetics of single doses of the novel gastric promotility agent motilin agonist camicinal (GSK962040) in critically ill feed-intolerant patients. METHODS: A prospective, randomized, double-blind, parallel-group, placebo-controlled, study was performed in mechanically ventilated feed-intolerant patients [median age 55 (19-84), 73 % male, APACHE II score 18 (5-37) with a gastric residual volume ≥200 mL]. Gastric emptying and glucose absorption were measured both pre- and post-treatment after intragastric administration of 50 mg (n = 15) camicinal and placebo (n = 8) using the (13)C-octanoic acid breath test (BTt1/2), acetaminophen concentrations, and 3-O-methyl glucose concentrations respectively. RESULTS: Following 50 mg enteral camicinal, there was a trend to accelerated gastric emptying [adjusted geometric means: pre-treatment BTt1/2 117 minutes vs. post- treatment 76 minutes; 95 % confidence intervals (CI; 0.39, 1.08) and increased glucose absorption (AUC240min pre-treatment: 28.63 mmol.min/L vs. post-treatment: 71.63 mmol.min/L; 95 % CI (1.68, 3.72)]. When two patients who did not have detectable plasma concentrations of camicinal were excluded from analysis, camicinal accelerated gastric emptying (adjusted geometric means: pre-treatment BTt1/2 121 minutes vs. post-treatment 65 minutes 95 % CI (0.32, 0.91) and increased glucose absorption (AUC240min pre-treatment: 33.04 mmol.min/L vs. post-treatment: 74.59 mmol.min/L; 95 % CI (1.478, 3.449). In those patients receiving placebo gastric emptying was similar pre- and post-treatment. CONCLUSIONS: When absorbed, a single enteral dose of camicinal (50 mg) accelerates gastric emptying and increases glucose absorption in feed-intolerant critically ill patients. TRIAL REGISTRATION: The study protocol was registered with the US NIH clinicaltrials.gov on 23 December 2009 (Identifier NCT01039805 ).

Percutaneous thermal ablation for primary hepatocellular carcinoma: A systematic review and meta-analysis.

BACKGROUND AND AIM: Percutaneous thermal ablation using radiofrequency ablation (RFA) and microwave ablation (MWA) are both widely available curative treatments for hepatocellular carcinoma. Despite significant advances, it remains unclear which modality results in better outcomes. This meta-analysis of randomized controlled trials (RCT) and observational studies was undertaken to compare the techniques in terms of effectiveness and safety. METHODS: Electronic reference databases (Medline, EMBASE and Cochrane Central) were searched between January 1980 and May 2014 for human studies comparing RFA and MWA. The primary outcome was the risk of local tumor progression (LTP). Secondary outcomes were complete ablation (CA), overall survival, and major adverse events (AE). The ORs were combined across studies using the random-effects model. RESULTS: Ten studies (two prospective and eight retrospective) were included, and the overall LTP rate was 13.6% (176/1298). There was no difference in LTP rates between RFA and MWA [OR (95% CI): 1.01(0.67-1.50), P = 0.9]. The CA rate, 1- and 3-year overall survival and major AE were similar between the two modalities (P > 0.05 for all). In subgroup analysis, there was no difference in LTP rates according to study quality, but LTP rates were lower with MWA for treatment of larger tumors [1.88(1.10-3.23), P = 0.02]. There was no significant publication bias or inter-study heterogeneity (I(2) < 50% and P > 0.1) observed in any of the measured outcomes. CONCLUSION: Overall, both RFA and MWA are equally effective and safe, but MWA may be more effective compared to RFA in preventing LTP when treating larger tumors. Well-designed, larger, multicentre RCTs are required to confirm these findings.

Hip Resurfacing Implant Orientation Analysis: A Comparison of a Computer-Added Design Technique and Computed Tomography.

BACKGROUND: Accurate acetabular component orientation in hip resurfacing is mandatory. The aim of this study is to analyze if interpretation of pelvic radiographs with computer-added design (CAD) software is comparable to computed tomography (CT) in measurement of acetabular anteversion and inclination of a Birmingham Hip Resurfacing (BHR) hip. METHODS: A consecutive series of 49 patients (50 hips) who underwent hip resurfacing arthroplasty between 2005 and 2007 with the BHR system were retrospectively included. The surgical procedure was performed by 1 orthopedic surgeon in the beginning of his learning curve. Computer-added design software was used to measure acetabular component orientation on an anteroposterior pelvic radiograph. These measurements were compared with CT measurements. We calculated the correlation between the CAD software and CT analysis. The degree of underestimation or overestimation was determined, and a Bland-Altman plot was created to visualize the agreement between CAD software and CT results. RESULTS: We analyzed 50 BHR hips with mean inclination of 54.6° and 55.6° and mean anteversion of 24.8° and 13.3° measured by CT and CAD, respectively. Pearson correlation coefficient for inclination was 0.69 (P < .001) and for anteversion 0.81 (P < .001). Computer-added design showed a mean underestimated anteversion of 11.6° (P < .001). There was no significant underestimation or overestimation of inclination with CAD analysis compared to CT measurements. CONCLUSION: The CAD software is useful to assess acetabular inclination in hip resurfacing but underestimates anteversion.

Sucrose malabsorption and impaired mucosal integrity in enterally fed critically ill patients: a prospective cohort observational study.

OBJECTIVE: Inadequate nutrition is common in critical illness due in part to gastric stasis. However, recent data suggest that altered small intestinal mucosal function may be a contributing factor. The aim of this study was to examine the effects of critical illness on sucrose absorption, permeability, and mucosal morphology. DESIGN: Prospective, observational study. SETTING: Tertiary critical care unit. SUBJECTS: Twenty mechanically ventilated patients (19 men; 52.2 ± 20.5 yr; 9 feed intolerant; Acute Physiology and Chronic Health Evaluation II score 16.2 ± 6.0) and 20 healthy subjects (14 men; 51.6 ± 21.5 yr). INTERVENTIONS: Following a 4-hr fast, a "meal" (100 kcal Ensure, 20-g enriched C-sucrose, 1.1 g rhamnose, 7.5 mL lactulose) was administered into the small intestine. Sucrose absorption was evaluated by analyzing 13CO2 concentration (cumulative percent of administered 13C dose recovered) in expiratory breath samples taken at timed intervals. At 90 minutes, a plasma lactulose/rhamnose concentration was also measured, with lactulose/rhamnose ratio, a marker of small intestinal mucosal permeability. When possible duodenal biopsies were taken in critically ill patients on insertion of the small intestinal feeding catheter and examined for disaccharidase levels and histology. Data are mean ± SD. RESULTS: When compared with healthy subjects, critically ill patients had significantly reduced cumulative CO2 recovery (90 min: 1.78% ± 1.98% vs. 8.04% ± 2.55%; p < 0.001) and increased lactulose/rhamnose ratio (2.77 ± 4.24 vs.1.10 ± 0.98; p = 0.03). The lactulose/rhamnose ratio was greater in feed-intolerant patients (4.06 ± 5.38; p = 0.003). In five patients, duodenal mucosal biopsy showed mild to moderate epithelial injury. Sucrase levels were normal in all patients. CONCLUSIONS: Sucrose absorption is reduced and intestinal permeability increased in critically ill patients, possibly indicating an impairment of small intestinal mucosal function. These results, however, are discordant with duodenal mucosal histology and sucrase levels. This may reflect an inactivation of sucrase in vivo or inadequate nutrient exposure to the brush border due to small intestinal dysmotility.

Shift to earlier stage at diagnosis as a consequence of the National Bowel Cancer Screening Program.

OBJECTIVE: To assess the impact of the National Bowel Cancer Screening Program (NBCSP) in South Australia. DESIGN, SETTING AND PARTICIPANTS: A cohort comparison of colorectal cancer (CRC) patient data from the NBCSP register and the South Australian Cancer Registry. Patient records of those invited to take part in screening through the NBCSP, those who participated in the program, and those with positive test results were compared with those of the rest of the study population (excluding the group of interest) on an intention-to-screen basis. MAIN OUTCOME MEASURE: Stage of CRC at diagnosis as a surrogate marker for effect on CRC mortality. RESULTS: Of 3481 eligible patients, 221 had been invited to the NBCSP. Invitees were more likely to have stage A lesions compared with all other patients (34.8% versus 19.2%; P < 0.001), and half as likely to have stage D CRC (5.4% versus 12.4%; P < 0.001). A further shift towards earlier stage was seen in those who participated in screening and those with positive test results compared with all other patients (38.8% stage A and 3.0% stage D in screening participants versus 19.3% stage A and 12.4% stage D in all other patients; and 39.7% stage A and 2.6% stage D in those with positive test results versus 19.3% stage A and 12.4% stage D in all other patients; P < 0.001). CONCLUSIONS: CRCs were diagnosed at a significantly earlier stage in people invited to the NBCSP compared with those who were not invited, regardless of participation status or test result. The NBCSP should lead to reductions in CRC mortality in Australia.

The child's right to an open future: is the principle applicable to non-therapeutic circumcision?

The principle of the child's right to an open future was first proposed by the legal philosopher Joel Feinberg and developed further by bioethicist Dena Davis. The principle holds that children possess a unique class of rights called rights in trust-rights that they cannot yet exercise, but which they will be able to exercise when they reach maturity. Parents should not, therefore, take actions that permanently foreclose on or pre-empt the future options of their children, but leave them the greatest possible scope for exercising personal life choices in adulthood. Davis particularly applies the principle to genetic counselling, arguing that parents should not take deliberate steps to create physically abnormal children, and to religion, arguing that while parents are entitled to bring their children up in accordance with their own values, they are not entitled to inflict physical or mental harm, neither by omission nor commission. In this paper, I aim to elucidate the open future principle, and consider whether it is applicable to non-therapeutic circumcision of boys, whether performed for cultural/religious or for prophylactic/health reasons. I argue that the principle is highly applicable to non-therapeutic circumcision, and conclude that non-therapeutic circumcision would be a violation of the child's right to an open future, and thus objectionable from both an ethical and a human rights perspective.

Delayed enteral feeding impairs intestinal carbohydrate absorption in critically ill patients.

OBJECTIVES: Delay in initiating enteral nutrition has been reported to disrupt intestinal mucosal integrity in animals and to prolong the duration of mechanical ventilation in humans. However, its impact on intestinal absorptive function in critically ill patients is unknown. The aim of this study was to examine the impact of delayed enteral nutrition on small intestinal absorption of 3-O-methyl-glucose. DESIGN: Prospective, randomized study. SETTING: Tertiary critical care unit. PATIENTS: Studies were performed in 28 critically ill patients. INTERVENTIONS: Patients were randomized to either enteral nutrition within 24 hrs of admission (14 "early feeding": 8 males, 6 females, age 54.9 ± 3.3 yrs) or no enteral nutrition during the first 4 days of admission (14 "delayed feeding": 10 males, 4 females, age 56.1 ± 4.2 yrs). MEASUREMENTS AND MAIN RESULTS: Gastric emptying (scintigraphy, 100 mL of Ensure (Abbott Australia, Kurnell, Australia) with 20 MBq Tc-suphur colloid), intestinal absorption of glucose (3 g of 3-O-methyl-glucose), and clinical outcomes were assessed 4 days after intensive care unit admission. Although there was no difference in gastric emptying, plasma 3-O-methyl-glucose concentrations were less in the patients with delayed feeding compared to those who were fed earlier (peak: 0.24 ± 0.04 mmol/L vs. 0.37 ± 0.04 mmol/L, p < .02) and integrated (area under the curve at 240 mins: 38.5 ± 7.0 mmol/min/L vs. 63.4 ± 8.3 mmol/min/L, p < .04). There was an inverse correlation between integrated plasma concentrations of 3-O-methyl-glucose (area under the curve at 240 mins) and the duration of ventilation (r = -.51; p = .006). In the delayed feeding group, both the duration of mechanical ventilation (13.7 ± 1.9 days vs. 9.2 ± 0.9 days; p = .049) and length of stay in the intensive care unit (15.9 ± 1.9 days vs. 11.3 ± 0.8 days; p = .048) were greater. CONCLUSIONS: In critical illness, delaying enteral feeding is associated with a reduction in small intestinal glucose absorption, consistent with the reduction in mucosal integrity after nutrient deprivation evident in animal models. The duration of both mechanical ventilation and length of stay in the intensive care unit are prolonged. These observations support recommendations for "early" enteral nutrition in critically ill patients.

Glucose absorption and small intestinal transit in critical illness.

OBJECTIVES: Although enteral nutrition is standard care for critically ill patients, nutrient absorption has not been quantified in this group and may be impaired due to intestinal dysmotility. The objectives of this study were to measure small intestinal glucose absorption and duodenocecal transit and determine their relationship with glycemia in the critically ill. DESIGN: Prospective observational study of healthy and critically ill subjects. SETTING: Tertiary mixed medical-surgical adult intensive care unit. SUBJECTS: Twenty-eight critically ill patients and 16 healthy subjects were studied. MATERIALS AND MAIN RESULTS: Liquid feed (100 kcal/100 mL), labeled with Tc-sulfur colloid and including 3 g of 3-O-methylglucose, was infused into the duodenum. Glucose absorption and duodenocecal transit were measured using the area under the 3-O-methylglucose concentration curve and scintigraphy, respectively. Data are median (range). RESULTS AND DISCUSSION: Glucose absorption was reduced in critical illness when compared to health (area under the concentration curve: 16 [1-32] vs. 20 [14-34] mmol/L·min; p = .03). Small intestinal transit times were comparable in patients and healthy subjects (192 [9-240] vs. 168 [6-240] min; p = .99) and were not related to glucose absorption. Despite higher fasting blood glucose concentrations (6.3 [5.1-9.3] vs. 5.7 [4.6-7.6] mmol/L; p < .05), the increment in blood glucose was sustained for longer in the critically ill (Δ glucose at t = 60; 1.9 [-2.1-5.0] mmol/L vs. -0.2 [-1.3-2.3] mmol/L; p < .01). CONCLUSIONS: Critical illness is associated with reduced small intestinal glucose absorption, but despite this, the glycemic response to enteral nutrient is sustained for longer.

Plasma erythromycin concentrations predict feeding outcomes in critically ill patients with feed intolerance.

OBJECTIVE: Motilin receptors are rapidly down-regulated by exposure to erythromycin, and its progressive loss of clinical prokinetic effect may relate to higher plasma drug concentrations. This study aimed to evaluate the relationship between plasma erythromycin concentrations and feeding outcomes in critically ill patients. DESIGN: Observational comparative study. SETTING: Tertiary critical care unit. PATIENTS: Twenty-nine feed-intolerant (gastric residual volume >250 mL) mechanically ventilated, medical critically ill patients. INTERVENTIONS: Patients received intravenous erythromycin 200 mg twice daily for feed intolerance. MEASUREMENTS: Plasma erythromycin concentrations were measured 1 and 7 hrs after drug administration on day 1. Success of enteral feeding, defined as 6-hourly gastric residual volume of ≤ 250 mL with a feeding rate ≥ 40 mL/h, was recorded over 7 days. RESULTS: At day 7, 38% (11 of 29) of patients were feed tolerant. Age, Acute Physiology and Chronic Health Evaluation scores, serum glucose concentrations, and creatinine clearance were comparable between successful and failed feeders. Both plasma erythromycin concentrations at 1 and 7 hrs after drug administration were significantly lower in successfully treated patients compared to treatment failures (1 hr: 3.7 ± 0.8 mg/L vs. 7.0 ± 1.0 mg/L, p = .02; and 7 hr: 0.7 ± 0.3 mg/L vs. 2.8 ± 0.6 mg/L, p = .01). There was a negative correlation between the number of days to failure of feeding and both the 1-hr (r = -.47, p = .049) and 7-hr (r = -.47, p = .050) plasma erythromycin concentrations. A 1-hr plasma concentration of >4.6 mg/L had 72% sensitivity and 72% specificity, and a 7-hr concentration of ≥ 0.5 mg/L had 83% sensitivity and 72% specificity in predicting loss of response to erythromycin. CONCLUSIONS: In critically ill feed-intolerant patients, there is an inverse relationship between plasma erythromycin concentrations and the time to loss of clinical motor effect. This suggests that erythromycin binding to motilin receptors contributes to variations in the duration of prokinetic response. The use of lower doses of erythromycin and tailoring the dose of erythromycin according to plasma concentrations may be useful strategies to reduce erythromycin tachyphylaxis.

Exogenous glucagon-like peptide-1 attenuates the glycaemic response to postpyloric nutrient infusion in critically ill patients with type-2 diabetes.

INTRODUCTION: Glucagon-like peptide-1 (GLP-1) attenuates the glycaemic response to small intestinal nutrient infusion in stress-induced hyperglycaemia and reduces fasting glucose concentrations in critically ill patients with type-2 diabetes. The objective of this study was to evaluate the effects of acute administration of GLP-1 on the glycaemic response to small intestinal nutrient infusion in critically ill patients with pre-existing type-2 diabetes. METHODS: Eleven critically ill mechanically-ventilated patients with known type-2 diabetes received intravenous infusions of GLP-1 (1.2 pmol/kg/minute) and placebo from t = 0 to 270 minutes on separate days in randomised double-blind fashion. Between t = 30 to 270 minutes a liquid nutrient was infused intraduodenally at a rate of 1 kcal/min via a naso-enteric catheter. Blood glucose, serum insulin and C-peptide, and plasma glucagon were measured. Data are mean ± SEM. RESULTS: GLP-1 attenuated the overall glycaemic response to nutrient (blood glucose AUC30-270 min: GLP-1 2,244 ± 184 vs. placebo 2,679 ± 233 mmol/l/minute; P = 0.02). Blood glucose was maintained at < 10 mmol/l in 6/11 patients when receiving GLP-1 and 4/11 with placebo. GLP-1 increased serum insulin at 270 minutes (GLP-1: 23.4 ± 6.7 vs. placebo: 16.4 ± 5.5 mU/l; P < 0.05), but had no effect on the change in plasma glucagon. CONCLUSIONS: Exogenous GLP-1 in a dose of 1.2 pmol/kg/minute attenuates the glycaemic response to small intestinal nutrient in critically ill patients with type-2 diabetes. Given the modest magnitude of the reduction in glycaemia the effects of GLP-1 at higher doses and/or when administered in combination with insulin, warrant evaluation in this group. TRIAL REGISTRATION: ANZCTR:ACTRN12610000185066.

Effects of metoclopramide on duodenal motility and flow events, glucose absorption, and incretin hormone release in response to intraduodenal glucose infusion.

The contribution of small intestinal motor activity to nutrient absorption is poorly defined. A reduction in duodenal flow events after hyoscine butylbromide, despite no change in pressure waves, was associated with reduced secretion of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) and a delay in glucose absorption. The aim of this study was to investigate the effect of metoclopramide on duodenal motility and flow events, incretin hormone secretion, and glucose absorption. Eight healthy volunteers (7 males and 1 female; age 29.8 ± 4.6 yr; body mass index 24.5 ± 0.9 kg/m²) were studied two times in randomized order. A combined manometry and impedance catheter was used to measure pressure waves and flow events in the same region of the duodenum simultaneously. Metoclopramide (10 mg) or control was administered intravenously as a bolus, followed by an intraduodenal glucose infusion for 60 min (3 kcal/min) incorporating the ¹4C-labeled glucose analog 3-O-methylglucose (3-OMG). We found that metoclopramide was associated with more duodenal pressure waves and propagated pressure sequences than control (P < 0.05 for both) during intraduodenal glucose infusion. However, the number of duodenal flow events, blood glucose concentration, and plasma 3-[¹4C]OMG activity did not differ between the two study days. Metoclopramide was associated with increased plasma concentrations of GLP-1 (P < 0.05) and GIP (P = 0.07) but lower plasma insulin concentrations (P < 0.05). We concluded that metoclopramide was associated with increased frequency of duodenal pressure waves but no change in duodenal flow events and glucose absorption. Furthermore, GLP-1 and GIP release increased with metoclopramide, but insulin release paradoxically decreased.

Effects of exogenous glucagon-like peptide-1 on gastric emptying and glucose absorption in the critically ill: relationship to glycemia.

OBJECTIVE: To determine the acute effects of exogenous glucagon-like peptide-1 on gastric emptying, glucose absorption, glycemia, plasma insulin, and glucagon in critically ill patients. DESIGN: Randomized, double-blind, crossover study. SETTING: Intensive care unit. SUBJECTS: Twenty-five mechanically ventilated patients, without known diabetes, studied on consecutive days. INTERVENTIONS: Intravenous glucagon-like peptide-1 (1.2 pmol/kg/min) or placebo was infused between -30 and 330 mins. At 0 min, 100 mL liquid nutrient (1 kcal/mL) including 100 microg of 13C-octanoic acid and 3 grams of 3-O-methyl-glucose was administered. MEASUREMENTS AND MAIN RESULTS: Blood glucose, serum 3-O-methyl-glucose (as an index of glucose absorption), insulin and glucagon concentrations, as well as exhaled 13CO2 were measured. The gastric emptying coefficient was calculated to quantify gastric emptying. Data are presented as mean (sd). There was a nonsignificant trend for glucagon-like peptide-1 to slow gastric emptying (gastric emptying coefficient) (glucagon-like peptide-1, 2.45 [0.93] vs. placebo, 2.75 [0.83]; p = .09). In 11 of the 25 patients, gastric emptying was delayed during placebo infusion and glucagon-like peptide-1 had no detectable effect on gastric emptying in this group (1.92 [0.82] vs. 1.90 [0.68]; p = .96). In contrast, in patients who had normal gastric emptying during placebo, glucagon-like peptide-1 slowed gastric emptying substantially (2.86 [0.58] vs. 3.41 [0.37]; p = .006). Glucagon-like peptide-1 markedly reduced the rate of glucose absorption (3-O-methyl-glucose area under the curve(0-330), 37 [35] vs. 76 [51] mmol/L/min; p < .001), decreased preprandial glucagon (at 0 min change in glucagon, -15 [15] vs. -3 [14] pmol/L; p < .001), increased the insulin/glucose ratio throughout the infusion (area under the curve(-30-330), 1374 [814] vs. 1172 [649] mU/mmol/min; p = .041), and attenuated the glycemic response to the meal (glucose area under the curve(0-330), 2071 [353] vs. 2419 [594] mmol/L/min; p = .001). CONCLUSIONS: Exogenous glucagon-like peptide-1 lowers postprandial glycemia in the critically ill. This may occur, at least in part, by slowing gastric emptying when the latter is normal but not when it is delayed.

Bench-to-bedside review: the gut as an endocrine organ in the critically ill.

In health, hormones secreted from the gastrointestinal tract have an important role in regulating gastrointestinal motility, glucose metabolism and immune function. Recent studies in the critically ill have established that the secretion of a number of these hormones is abnormal, which probably contributes to disordered gastrointestinal and metabolic function. Furthermore, manipulation of endogenous secretion, physiological replacement and supra-physiological treatment (pharmacological dosing) of these hormones are likely to be novel therapeutic targets in this group. Fasting ghrelin concentrations are reduced in the early phase of critical illness, and exogenous ghrelin is a potential therapy that could be used to accelerate gastric emptying and/or stimulate appetite. Motilin agonists, such as erythromycin, are effective gastrokinetic drugs in the critically ill. Cholecystokinin and peptide YY concentrations are elevated in both the fasting and postprandial states, and are likely to contribute to slow gastric emptying. Accordingly, there is a rationale for the therapeutic use of their antagonists. So-called incretin therapies (glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide) warrant evaluation in the management of hyperglycaemia in the critically ill. Exogenous glucagon-like peptide-2 (or its analogues) may be a potential therapy because of its intestinotropic properties.