Partially clustered designs for clinical trials: Unifying existing designs using consistent terminology.

INTRODUCTION: Clinical trial designs based on the assumption of independent observations are well established. Clustered clinical trial designs, where all observational units belong to a cluster and outcomes within clusters are expected to be correlated, have also received considerable attention. However, many clinical trials involve partially clustered data, where only some observational units belong to a cluster. Examples of such trials occur in neonatology, where participants include infants from both singleton and multiple births, and ophthalmology, where one or two eyes per participant may need treatment. Partial clustering can also arise in trials of group-based treatments (e.g. group education or counselling sessions) or treatments administered individually by a discrete number of health care professionals (e.g. surgeons or physical therapists), when this is compared to an unclustered control arm. Trials involving partially clustered data have received limited attention in the literature and the current lack of standardised terminology may be hampering the development and dissemination of methods for designing and analysing these trials. METHODS AND EXAMPLES: In this article, we present an overarching definition of partially clustered trials, bringing together several existing trial designs including those for group-based treatments, clustering due to facilitator effects and the re-randomisation design. We define and describe four types of partially clustered trial designs, characterised by whether the clustering occurs pre-randomisation or post-randomisation and, in the case of pre-randomisation clustering, by the method of randomisation that is used for the clustered observations (individual randomisation, cluster randomisation or balanced randomisation within clusters). Real life examples are provided to highlight the occurrence of partially clustered trials across a variety of fields. To assess how partially clustered trials are currently reported, we review published reports of partially clustered trials. DISCUSSION: Our findings demonstrate that the description of these trials is often incomplete and the terminology used to describe the trial designs is inconsistent, restricting the ability to identify these trials in the literature. By adopting the definitions and terminology presented in this article, the reporting of partially clustered trials can be substantially improved, and we present several recommendations for reporting these trial designs in practice. Greater awareness of partially clustered trials will facilitate more methodological research into their design and analysis, ultimately improving the quality of these trials.

Patient Acceptability of a Novel Technological Solution (Ambient Intelligent Geriatric Management System) to Prevent Falls in Geriatric and General Medicine Wards: A Mixed-Methods Study.

INTRODUCTION: As effective interventions to prevent inpatient falls are lacking, a novel technological intervention was trialed. The Ambient Intelligent Geriatric Management (AmbIGeM) system used wearable sensors that detected and alerted staff of patient movements requiring supervision. While the system did not reduce falls rate, it is important to evaluate the acceptability, usability, and safety of the AmbIGeM system, from the perspectives of patients and informal carers. METHODS: We conducted a mixed-methods study using semistructured interviews, a pre-survey and post-survey. The AmbIGeM clinical trial was conducted in two geriatric evaluation and management units and a general medical ward, in two Australian hospitals, and a subset of participants were recruited. Within 3 days of being admitted to the study wards and enrolling in the trial, 31 participants completed the pre-survey. Prior to discharge (post-intervention), 30 participants completed the post-survey and 27 participants were interviewed. Interview data were thematically analyzed and survey data were descriptively analyzed. RESULTS: Survey and interview participants had an average age of 83 (SD 9) years, 65% were female, and 41% were admitted with a fall. Participants considered the AmbIGeM system a good idea. Most but not all thought the singlet and sensor component as acceptable and comfortable, with no privacy concerns. Participants felt reassured with extra monitoring, although sometimes misunderstood the purpose of AmbIGeM as detecting patient falls. Participants' acceptability was strongly positive, with median 8+ (0-10 scale) on pre- and post-surveys. DISCUSSION/CONCLUSION: Patients' acceptability is important to optimize outcomes. Overall older patients considered the AmbIGeM system as acceptable, usable, and improving safety. The findings will be important to guide refinement of this and other similar technology developments.

Acute effects of whey protein, alone and mixed with other macronutrients, on blood pressure and heart rate in older men.

BACKGROUND: Caloric supplements are increasingly used by older people, aiming to increase their daily protein intake. These high caloric drinks, rich in glucose and whey-protein in particular, may result in potential harmful decreases in blood pressure (BP). The effect of ingesting whey-protein with glucose and fat on BP is unknown. It has also been assumed that the maximum fall in systolic blood pressure occurs within 2 h of a meal. METHODS: This study aimed to determine in older men, the effects of whey-protein, alone and mixed with other macronutrients, on systolic (SBP) and diastolic (DBP) blood pressure and heart rate (HR) in older men for 3 h. Thirteen older men (age 75 ± 2yrs; body mass index (BMI) 25.6 ± 0.6 kg/m2) ingested a drink on separate study days: (i) 70 g whey-protein (P280); (ii) 14 g whey-protein, 28 g carbohydrate, 12.4 g fat (M280); (iii) 70 g whey-protein, 28 g carbohydrate, 12.4 g fat (M504); or (iv) a non-caloric control drink (C). RESULTS: SBP decreased after all three nutrient drinks compared to the C, with the greatest reduction after the M504 drink (P = 0.008). Maximal decreases in SBP (C: -14 ± 2 mmHg, P280: -22 ± 2 mmHg, M280: -22 ± 4 mmHg, M504: -24 ± 3 mmHg) occurred about 2 h after drink ingestion and this fall was sustained thereafter (120-180 min: P280 and M504 vs. C P < 0.05). Maximum DBP decreases and HR increases occurred after M504, with no differences between the effects of the P280 and M280 drinks. CONCLUSIONS: The effects of whey-protein containing drinks to lower BP and increase HR appear to be primarily dependent on their energy content rather than macronutrient composition and may persist for at least 3 h after ingestion,. Pure whey-protein drinks may represent the best approach to maximize protein intake without increasing the potential for deleterious BP falls in older people. TRIAL REGISTRATION: ACTRN12614000846628 , 14/03/2019.

Energy-Dense versus Routine Enteral Nutrition in the Critically Ill.

BACKGROUND: The effect of delivering nutrition at different calorie levels during critical illness is uncertain, and patients typically receive less than the recommended amount. METHODS: We conducted a multicenter, double-blind, randomized trial, involving adults undergoing mechanical ventilation in 46 Australian and New Zealand intensive care units (ICUs), to evaluate energy-dense (1.5 kcal per milliliter) as compared with routine (1.0 kcal per milliliter) enteral nutrition at a dose of 1 ml per kilogram of ideal body weight per hour, commencing at or within 12 hours of the initiation of nutrition support and continuing for up to 28 days while the patient was in the ICU. The primary outcome was all-cause mortality within 90 days. RESULTS: There were 3957 patients included in the modified intention-to-treat analysis (1971 in the 1.5-kcal group and 1986 in the 1.0-kcal group). The volume of enteral nutrition delivered during the trial was similar in the two groups; however, patients in the 1.5-kcal group received a mean (±SD) of 1863±478 kcal per day as compared with 1262±313 kcal per day in the 1.0-kcal group (mean difference, 601 kcal per day; 95% confidence interval [CI], 576 to 626). By day 90, a total of 523 of 1948 patients (26.8%) in the 1.5-kcal group and 505 of 1966 patients (25.7%) in the 1.0-kcal group had died (relative risk, 1.05; 95% CI, 0.94 to 1.16; P=0.41). The results were similar in seven predefined subgroups. Higher calorie delivery did not affect survival time, receipt of organ support, number of days alive and out of the ICU and hospital or free of organ support, or the incidence of infective complications or adverse events. CONCLUSIONS: In patients undergoing mechanical ventilation, the rate of survival at 90 days associated with the use of an energy-dense formulation for enteral delivery of nutrition was not higher than that with routine enteral nutrition. (Funded by National Health and Medical Research Institute of Australia and the Health Research Council of New Zealand; TARGET ClinicalTrials.gov number, NCT02306746 .).

Nocturnal Hypoglycemia in Patients With Diabetes Discharged From ICUs: A Prospective Two-Center Cohort Study.

OBJECTIVES: There is very limited information about glycemic control after discharge from the ICU. The aims of this study were to evaluate the prevalence of hypoglycemia in ICU survivors with type-2 diabetes and determine whether hypoglycemia is associated with cardiac arrhythmias. DESIGN: Prospective, observational, two-center study. Participants underwent up to 5 days of simultaneous blinded continuous interstitial glucose monitoring and ambulatory 12-lead electrocardiogram monitoring immediately after ICU discharge during ward-based care. Frequency of arrhythmias, heart rate variability, and cardiac repolarization markers were compared between hypoglycemia (interstitial glucose ≤ 3.5 mmol/L) and euglycemia (5-10 mmol/L) matched for time of day. SETTING: Mixed medical-surgical ICUs in two geographically distinct university-affiliated hospitals. PATIENTS: Patients with type-2 diabetes who were discharged from ICU after greater than or equal to 24 hours with greater than or equal to one organ failure and were prescribed subcutaneous insulin were eligible. MEASUREMENTS AND MAIN RESULTS: Thirty-one participants (mean ± sd, age 65 ± 13 yr, glycated hemoglobin 64 ± 22 mmol/mol) were monitored for 101 ± 32 hours post-ICU (total 3,117 hr). Hypoglycemia occurred in 12 participants (39%; 95% CI, 22-56%) and was predominantly nocturnal (40/51 hr) and asymptomatic (25/29 episodes). Participants experiencing hypoglycemia had 2.4 ± 0.7 discrete episodes lasting 45 minutes (interquartile range, 25-140 min). Glucose nadir was less than or equal to 2.2 mmol/L in 34% of episodes. The longest episode of nocturnal hypoglycemia was 585 minutes with glucose nadir less than 2.2 mmol/L. Simultaneous electrocardiogram and continuous interstitial glucose monitoring recordings were obtained during 44 hours of hypoglycemia and 991 hours of euglycemia. Hypoglycemia was associated with greater risk of bradycardia but did not affect atrial or ventricular ectopics, heart rate variability, or cardiac repolarization. CONCLUSIONS: In ICU survivors with insulin-treated type-2 diabetes, hypoglycemia occurs frequently and is predominantly nocturnal, asymptomatic, and prolonged.

Suppression of Energy Intake by Intragastric l-Tryptophan in Lean and Obese Men: Relations with Appetite Perceptions and Circulating Cholecystokinin and Tryptophan.

BACKGROUND: l-Tryptophan reduces energy intake in healthy men. The underlying mechanisms, including appetite, plasma cholecystokinin (CCK), tryptophan (Trp), and the ratio of Trp to large neutral amino acids (Trp:LNAAs ratio), and whether responses differ in lean and obese individuals, are uncertain. OBJECTIVES: We evaluated the effects of intragastric Trp on energy intake (primary outcome) and their potential mechanisms, pre- and postmeal, in lean men and those with obesity. METHODS: Twelve lean men [mean ± SD age: 30 ± 3 y; BMI (in kg/m2): 23 ± 1] and 13 men with obesity (mean ± SD age: 31 ± 3 y; BMI: 33 ± 1) received, on 3 separate occasions, in double-blind, randomized order, 3 g ("Trp-3") or 1.5 g ("Trp-1.5") Trp, or control ("C"), intragastrically, 30 min before a buffet-meal. Energy intake from the buffet-meal, hunger, fullness, and plasma CCK and amino acid concentrations were measured in response to Trp alone and for 2 h postmeal. Data were analyzed using maximum likelihood mixed-effects models, with treatment, group, and treatment-by-group interaction as fixed effects. RESULTS: Trp alone increased plasma CCK, Trp, and the Trp:LNAAs ratio (all P < 0.001), with no difference between groups. Trp suppressed energy intake (P < 0.001), with no difference between groups (lean, C: 1085 ± 102 kcal, Trp-1.5: 1009 ± 92 kcal, Trp-3: 868 ± 104 kcal; obese, C: 1249 ± 98 kcal, Trp-1.5: 1217 ± 90 kcal, Trp-3: 1012 ± 100 kcal). Postmeal, fullness was greater after Trp-3 than after C and Trp-1.5 (all P < 0.05), and in men with obesity than in lean men (P < 0.05). Plasma Trp and the Trp:LNAAs ratio were greater after Trp-3 and Trp-1.5 than after C (all P < 0.001), and tended to be less in men with obesity than in the lean (P = 0.07) (Trp:LNAAs ratio: lean, C: 1.5 ± 0.2, Trp-1.5: 6.9 ± 0.7, Trp-3: 10.7 ± 1.4; obese, C: 1.4 ± 0.1, Trp-1.5: 4.6 ± 0.7, Trp-3: 7.8 ± 1.3). There were inverse correlations of energy intake with plasma Trp and the Trp:LNAAs ratio in both groups (lean, both r = -0.50, P < 0.01; obese, both r = -0.40, P < 0.05). CONCLUSIONS: Intragastric Trp has potent energy intake-suppressant effects, in both lean men and those with obesity, apparently related to the Trp:LNAAs ratio.

Outcomes Six Months after Delivering 100% or 70% of Enteral Calorie Requirements during Critical Illness (TARGET). A Randomized Controlled Trial.

Rationale: The long-term effects of delivering approximately 100% of recommended calorie intake via the enteral route during critical illness compared with a lesser amount of calories are unknown.Objectives: Our hypotheses were that achieving approximately 100% of recommended calorie intake during critical illness would increase quality-of-life scores, return to work, and key life activities and reduce death and disability 6 months later.Methods: We conducted a multicenter, blinded, parallel group, randomized clinical trial, with 3,957 mechanically ventilated critically ill adults allocated to energy-dense (1.5 kcal/ml) or routine (1.0 kcal/ml) enteral nutrition.Measurements and Main Results: Participants assigned energy-dense nutrition received more calories (percent recommended energy intake, mean [SD]; energy-dense: 103% [28] vs. usual: 69% [18]). Mortality at Day 180 was similar (560/1,895 [29.6%] vs. 539/1,920 [28.1%]; relative risk 1.05 [95% confidence interval, 0.95-1.16]). At a median (interquartile range) of 185 (182-193) days after randomization, 2,492 survivors were surveyed and reported similar quality of life (EuroQol five dimensions five-level quality-of-life questionnaire visual analog scale, median [interquartile range]: 75 [60-85]; group difference: 0 [95% confidence interval, 0-0]). Similar numbers of participants returned to work with no difference in hours worked or effectiveness at work (n = 818). There was no observed difference in disability (n = 1,208) or participation in key life activities (n = 705).Conclusions: The delivery of approximately 100% compared with 70% of recommended calorie intake during critical illness does not improve quality of life or functional outcomes or increase the number of survivors 6 months later.

Effects of sitagliptin on gastric emptying of, and the glycaemic and blood pressure responses to, a carbohydrate meal in type 2 diabetes.

AIMS: To determine the effects of the dipeptidyl peptidase-4 inhibitor, sitagliptin, on gastric emptying (GE) of a high-carbohydrate meal and associated glycaemic and blood pressure (BP) responses in type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: Fourteen patients with T2DM (nine men, five women; age 67.8 ± 1.5 years; body mass index 31.2 ± 0.9 kg/m2 ; T2DM duration: 4.2 ± 0.9 years; glycated haemoglobin: 46 ± 1.8 mmol/mol [6.4% ± 0.2%]), managed by diet and/or metformin, underwent concurrent measurements of GE, BP and plasma glucose for 240 minutes after ingestion of a radiolabelled mashed potato meal after receiving sitagliptin (100 mg) or placebo in randomized, double-blind, crossover fashion on 2 consecutive days. RESULTS: Sitagliptin reduced postprandial plasma glucose (P < .005) without affecting GE (P = .88). The magnitude of the glucose-lowering effect (change in incremental area under the curve0-240 min from placebo to sitagliptin) was related to GE (kcal/min) on placebo (r = 0.68, P = .008) There was a comparable fall in systolic BP (P = .80) following the meal, with no difference between the 2 days. CONCLUSIONS: In T2DM, while sitagliptin has no effect on either GE or postprandial BP, its ability to lower postprandial glucose are dependent on the basal rate of GE.

Exenatide once weekly slows gastric emptying of solids and liquids in healthy, overweight people at steady-state concentrations.

AIMS: To evaluate the effects of 8 weeks' administration of exenatide (EXE) once weekly on gastric emptying of solids and liquids (using the "gold standard" technique, scintigraphy), glucose absorption and postprandial glycaemia in healthy people. MATERIAL AND METHODS: A total of 32 healthy participants were randomized to receive either EXE once weekly (2 mg/wk subcutaneously; six men, 10 women, mean age 59.9 ± 0.9 years, mean body mass index [BMI] 29.6 ± 0.6 kg/m2 ) or matching placebo (PBO; six men, 10 women, mean age 60.6 ± 1.2 years, mean BMI 29.5 ± 1.0 kg/m2 ) for 8 weeks. Gastric emptying, nausea (visual analogue scale), and plasma glucose, insulin, C-peptide and glucagon were measured for 120 min after a solid/liquid meal, comprising 100 g ground beef (radiolabelled with 20 MBq 99m Tc-sulphur colloid) and 150 mL 10% glucose (radiolabelled with 7 MBq 67 Ga-EDTA), and containing 5 g 3-O-methyl-glucose (3-OMG) as a marker of glucose absorption, at baseline and after 8 weeks' treatment. RESULTS: The study treatments were well tolerated. Scores for nausea were consistently low, with no difference between the EXE once weekly and PBO groups. EXE once weekly slowed gastric emptying of solids (area under the curve [AUC]0-120min : P < 0.05) and liquids (AUC0-120min : P = 0.01) substantially, and attenuated glucose absorption (3-OMG incremental AUC [iAUC]0-30min : P = 0.001) and the postprandial rise in plasma glucose (iAUC0-30min : P = 0.008). Plasma glucagon at 2 h was reduced by EXE once weekly (P = 0.001). The magnitude of the reduction in plasma glucose at t = 30 min from baseline to 8 weeks with EXE once weekly was related inversely to the 50% emptying time of the glucose drink (r = -0.55, P = 0.03). CONCLUSIONS: In healthy participants, 8 weeks' administration of the "long-acting" glucagon-like peptide-1 receptor agonist EXE, slowed gastric emptying of solids and liquids substantially, with consequent reductions in glucose absorption and postprandial glycaemia.

Effects of lixisenatide on postprandial blood pressure, gastric emptying and glycaemia in healthy people and people with type 2 diabetes.

AIM: To evaluate the effects of the prandial glucagon-like peptide-1 receptor agonist lixisenatide on gastric emptying and blood pressure (BP) and superior mesenteric artery (SMA) blood flow, and the glycaemic responses to a 75-g oral glucose load in healthy people and those with type 2 diabetes (T2DM). MATERIALS AND METHODS: Fifteen healthy participants (nine men, six women; mean ± SEM age 67.2 ± 2.3 years) and 15 participants with T2DM (nine men, six women; mean ± SEM age 61.9 ± 2.3 years) underwent measurement of gastric emptying, BP, SMA flow and plasma glucose 180 minutes after a radiolabelled 75-g glucose drink on two separate days. All participants received lixisenatide (10 µg subcutaneously) or placebo in a randomized, double-blind, crossover fashion 30 minutes before the glucose drink. RESULTS: Lixisenatide slowed gastric emptying (retention at 120 minutes, P < 0.01), attenuated the rise in SMA flow (P < 0.01) and markedly attenuated the decrease in systolic BP (area under the curve [AUC] 0-120 minutes, P < 0.001) compared to placebo in healthy participants and those with T2DM. Plasma glucose (incremental AUC 0-120 minutes) was greater in participants with T2DM (P < 0.005) than in healthy participants, and lower after lixisenatide in both groups (P < 0.001). CONCLUSIONS: In healthy participants and those with T2DM, the marked slowing of gastric emptying of glucose induced by lixisenatide was associated with attenuation of the increments in glycaemia and SMA flow and decrease in systolic BP. Accordingly, lixisenatide may be useful in the management of postprandial hypotension.

Effectiveness of an Ambient Intelligent Geriatric Management system (AmbIGeM) to prevent falls in older people in hospitals: protocol for the AmbIGeM stepped wedge pragmatic trial.

BACKGROUND: Although current best practice recommendations contribute to falls prevention in hospital, falls and injury rates remain high. There is a need to explore new interventions to reduce falls rates, especially in geriatric and general medical wards where older patients and those with cognitive impairment are managed. DESIGN AND METHODS: A three-cluster stepped wedge pragmatic trial, with an embedded qualitative process, of the Ambient Intelligent Geriatric Management (AmbIGeM) system (wearable sensor device to alert staff of patients undertaking at-risk activities), for preventing falls in older patients compared with standard care. The trial will occur on three acute/subacute wards in two hospitals in Adelaide and Perth, Australia. PARTICIPANTS: Patients aged >65 years admitted to study wards. A waiver (Perth) and opt-out of consent (Adelaide) was obtained for this study. Patients requiring palliative care will be excluded. OUTCOMES: The primary outcome is falls rate; secondary outcome measures are: (1) proportion of participants falling; (2) rate of injurious inpatient falls/1000 participant bed-days; (3) acceptability and safety of the interventions from patients and clinical staff perspectives; and (4) hospital costs, mortality and use of residential care to 3 months postdischarge. DISCUSSION: This study investigates a novel technological approach to preventing falls in hospitalised older people. We hypothesise that the AmbIGeM intervention will reduce falls and injury rates, with an economic benefit attributable to the intervention. If successful, the AmbIGeM system will be a useful addition to falls prevention in hospital wards with high proportions of older people and people with cognitive impairment. : Trial registration NUMBER: Australian and New Zealand Clinical Trial Registry: ACTRN 12617000981325; Pre-results.

A retrospective evaluation of nutrition support in relation to clinical outcomes in critically ill patients with an open abdomen.

BACKGROUND: Optimising nutrition support in critically ill patients with an open abdomen is challenging. OBJECTIVES: The aims of this study were to (i) quantify the amount and adequacy of nutrition support administered and (ii) determine any relationships that exist between mode of nutrition support delivery and clinical outcomes in critically ill patients with an open abdomen. METHODS: A retrospective review of critically ill patients mechanically ventilated for at least 48 h with an open abdomen in a mixed quaternary referral intensive care unit. Enteral and parenteral nutrition (ml) administered daily to patients was recorded for up to 21 days. Length of stay in the intensive care unit and hospital and duration of mechanical ventilation (days) were reported. RESULTS: Thirty patients were studied [14 male, 68 y (15-90 y), body mass index 25 kg/m2 (11-51 kg/m2), Acute Physiology and Chronic Health Evaluation II score 20 (7-41), energy goal 1860 kcal/d (1250-2712 kcal/d)]. Patients received 55% (0-117%) of energy goal and 56% (0-105%) protein goal from either enteral or parenteral nutrition. When enteral nutrition was delivered alone or in combination with parenteral nutrition, patients received 48% (0-146%) of their energy and 59% (19-105%) of their protein goal. Patients fed parenteral nutrition, either alone or as supplementary to enteral nutrition (n = 18), received more energy when compared with those who only received enteral nutrition (n = 9) [65 (27-117) vs 49 (15-89) % energy goal, P = 0.025]. Parenteral nutrition was associated with an increased length of stay in hospital [63 (45-156) vs 45 (17-93) d, P = 0.037]. CONCLUSION: Patients with an open abdomen receive about half of their nutrition requirements when fed exclusively via the enteral route. Providing combination enteral and parenteral nutrition to reach nutritional goals may not result in better clinical outcomes for patients with an open abdomen.

Wide Disagreement Between Alternative Assessments of Premorbid Physical Activity: Subjective Patient and Surrogate Reports and Objective Smartphone Data.

OBJECTIVES: Surrogate-decision maker and patient self-reported estimates of the distances walked prior to acute illness are subjective and may be imprecise. It may be possible to extract objective data from a patient's smartphone, specifically, step and global position system data, to quantify physical activity. The objectives were to 1) assess the agreement between surrogate-decision maker and patient self-reported estimates of distance and time walked prior to resting and daily step-count and 2) determine the feasibility of extracting premorbid physical activity (step and global position system) data from critically ill patients. DESIGN: Prospective cohort study. SETTING: Quaternary ICU. PATIENTS: Fifty consecutively admitted adult patients who owned a smartphone, who were ambulatory at baseline, and who remained in ICU for more than 48 hours participated. MEASURMENTS AND MAIN RESULTS: There was no agreement between patients and surrogates for all premorbid walking metrics (mean bias 108% [99% lower to 8,700% higher], 83% [97% to 2,100%], and 71% [96% to 1,080%], for distance, time, and steps, respectively). Step and/or global position system data were successfully extracted from 24 of 50 phones (48%; 95% CI, 35-62%). Surrogate-decision makers, but not patient self-reported, estimates of steps taken per day correlated with smartphone data (surrogates: n = 13, ρ = 0.56, p < 0.05; patients: n = 13, ρ = 0.30, p = 0.317). CONCLUSION: There was a lack of agreement between surrogate-decision maker and patient self-reported subjective estimates of distance walked. Obtaining premorbid physical activity data from the current-generation smartphones was feasible in approximately 50% of patients.

The insulinotropic effect of pulsatile compared with continuous intravenous delivery of GLP-1.

AIMS/HYPOTHESIS: In healthy individuals, both insulin and glucagon-like peptide 1 (GLP-1) are secreted in a pulsatile fashion. Insulin has greater glucose-lowering properties when administered in pulses compared with a constant i.v. infusion. The primary aim of this randomised double-dummy cross-over study was to compare the insulinotropic response to pulsatile and continuous i.v. infusions of equivalent doses of GLP-1. METHODS: Twelve healthy participants aged 18-35 years were randomised to three different treatments on separate days: a continuous infusion day (GLP-1 at 0.6 pmol kg(-1) min(-1) [1 ml/min] and a 1 ml placebo bolus every 6 min); a pulsatile infusion day (placebo at 1 ml/min and a 3.6 pmol/kg GLP-1 bolus every 6 min); and a placebo day (placebo at 1 ml/min and a 1 ml placebo bolus every 6 min). Between 45 and 120 min, a hyperglycaemic clamp was used to maintain blood glucose at 9 mmol/l. Venous blood glucose and plasma insulin concentrations were measured every 5 min from 0 to 45 min and every 1 min from 45 to 120 min; plasma glucagon was measured every 15 min. The order of treatment was randomised by the Pharmacy Department and both study investigators and participants were blinded to the treatment arm. The dextrose requirement and glucagon data were analysed using repeated measures ANOVA and insulin data were analysed with a linear mixed effects maximum likelihood model. RESULTS: Continuous and pulsatile infusions of GLP-1 increased the dextrose requirement by ~threefold (p < 0.001) and increased insulin secretion by ~ninefold (p < 0.001). There was no difference in the effect of both treatments. Although hyperglycaemia reduced plasma glucagon concentrations, there was no difference between the treatment days. CONCLUSIONS/INTERPRETATION: In healthy individuals, pulsatile and continuous administration of i.v. GLP-1 appears to have comparable insulinotropic effects. TRIAL REGISTRATION: ACTRN12612001040853 FUNDING: This study was supported by the National Health and Medical Research Council (NHMRC) of Australia.

Critical Illness Is Associated With Impaired Gallbladder Emptying as Assessed by 3D Ultrasound.

OBJECTIVE: To quantify gallbladder dysfunction during critical illness. DESIGN: Prospective observational comparison study of nutrient-stimulated gallbladder emptying in health and critical illness. SETTING: Single-centre mixed medical/surgical ICU. PATIENTS: Twenty-four mechanically ventilated critically ill patients suitable to receive enteral nutrition were compared with 12 healthy subjects. INTERVENTIONS: Participants were studied after an 8-hour fast. Between 0 and 120 minutes, high-fat nutrient (20% intralipid) was infused via a postpyloric catheter into the duodenum at 2 kcal/min. MEASUREMENTS AND MAIN RESULTS: Three-dimensional images of the gallbladder were acquired at 30-minute intervals from -30 to 180 minutes. Ejection fraction (%) was calculated as changes between 0 and 120 minutes. Blood samples were obtained at 30-minute intervals for plasma cholecystokinin. Data are mean (SD) or median [interquartile range]. In the critically ill, fasting gallbladder volumes (critically ill, 61 mL [36-100 mL] vs healthy, 22 mL [15-25] mL; p < 0.001] and wall thickness (0.45 mm [0.15 mm] vs 0.26 mm [0.08 mm]; p < 0.001] were substantially greater, and sludge was evident in the majority of patients (71% vs 0%). Nutrient-stimulated emptying was incomplete in the critically ill after 120 minutes but was essentially complete in the healthy individuals (22 mL [9-66 mL] vs 4 mL [3-5 mL]; p < 0.01]. In five critically ill patients (21%), there was no change in gallbladder volume in response to nutrient, and overall ejection fraction was reduced in the critically ill (50% [8-83%] vs 77 [72-84%]; p = 0.01]. There were no differences in fasting or incremental cholecystokinin concentrations. CONCLUSIONS: Fasted critically ill patients have larger, thicker-walled gallbladders than healthy subjects and nutrient-stimulated gallbladder emptying is impaired with "gallbladder paresis" occurring in approximately 20%.

Nutrition support practices in critically ill head-injured patients: a global perspective.

BACKGROUND: Critical illness following head injury is associated with a hypermetabolic state but there are insufficient epidemiological data describing acute nutrition delivery to this group of patients. Furthermore, there is little information describing relationships between nutrition and clinical outcomes in this population. METHODS: We undertook an analysis of observational data, collected prospectively as part of International Nutrition Surveys 2007-2013, and extracted data obtained from critically ill patients with head trauma. Our objective was to describe global nutrition support practices in the first 12 days of hospital admission after head trauma, and to explore relationships between energy and protein intake and clinical outcomes. Data are presented as mean (SD), median (IQR), or percentages. RESULTS: Data for 1045 patients from 341 ICUs were analyzed. The age of patients was 44.5 (19.7) years, 78% were male, and median ICU length of stay was 13.1 (IQR 7.9-21.6) days. Most patients (94%) were enterally fed but received only 58% of estimated energy and 53% of estimated protein requirements. Patients from an ICU with a feeding protocol had greater energy and protein intakes (p <0.001, 0.002 respectively) and were more likely to survive (OR 0.65; 95% CI 0.42-0.99; p = 0.043) than those without. Energy or protein intakes were not associated with mortality. However, a greater energy and protein deficit was associated with longer times until discharge alive from both ICU and hospital (all p <0.001). CONCLUSION: Nutritional deficits are commonplace in critically ill head-injured patients and these deficits are associated with a delay to discharge alive.

Randomized trial investigating the safety and efficacy of influenza vaccination in patients with antineutrophil cytoplasmic antibody-associated vasculitis.

AIM: This study evaluated the safety and efficacy of influenza vaccination in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis. METHODS: Thirty-one patients who were in remission were randomized to receive either a trivalent influenza vaccine or no vaccine. Vaccine efficacy was assessed at 28 days. Patients were followed for 6 months for signs of reactivation of disease. In addition, 67 healthy individuals were randomized to receive either the influenza vaccine or no vaccine to assess its potential for triggering the formation of autoantibodies. RESULTS: Compared with patients who did not receive the vaccine, vaccinated patients achieved effective responses to all three influenza vaccine antigens. There was no significant change in levels of anti-neutrophil cytoplasmic antibody post-vaccination. There was no significant change in disease activity in vaccinated patients compared with non-vaccinated patients. Among vaccinated healthy individuals, we did not observe any significant change in the level of autoantibodies measured. CONCLUSION: This study shows that the administration of influenza vaccine to patients in remission with anti-neutrophil cytoplasmic antibody-associated vasculitis is both safe and modestly efficacious.

Risk factors for progression or improvement of lower urinary tract symptoms in a prospective cohort of men.

PURPOSE: We determined the metabolic, lifestyle and physical factors associated with progression or improvement of storage and voiding lower urinary tract symptoms in a population based cohort of men. MATERIALS AND METHODS: After the exclusion of men with prostate or bladder cancer and/or surgery from the study, progression and improvement of storage and voiding lower urinary tract symptoms was assessed using the AUA-SI (American Urological Association symptom index) in 780 men, age 35 to 80 years at baseline, who attended 5-year followup clinics. RESULTS: Storage and voiding lower urinary tract symptoms progressed in 39.8% (308) and 32.3% (250) of men, and improved in 33.1% (256) and 23.4% (181), respectively. In final adjusted regression models greater bother and physical activity at baseline predicted improvement in storage and voiding lower urinary tract symptoms, while greater income, high-density lipoprotein cholesterol and lower triglycerides predicted improvement of storage lower urinary tract symptoms only. Being widowed, higher plasma estradiol and depression at baseline predicted the progression of storage and voiding lower urinary tract symptoms, while greater abdominal fat mass and obstructive sleep apnea risk predicted the progression of storage lower urinary tract symptoms only. Older age, lower high-density lipoprotein cholesterol, testosterone, income, previous benign prostatic hyperplasia and erectile dysfunction at baseline predicted the progression of voiding lower urinary tract symptoms only. The initiation or continued use of α-blockers or anticholinergics (storage lower urinary tract symptoms), and 5α-reductase inhibitors (voiding lower urinary tract symptoms), were associated with symptom improvement. CONCLUSIONS: Lower urinary tract symptoms may progress or remit. Even accounting for medication use, progression may be associated with modifiable disease, or metabolic or behavioral factors, which are also risk factors for type 2 diabetes and cardiovascular disease. These factors should be looked for and managed.

Predictors of sexual dysfunction incidence and remission in men.

INTRODUCTION: The progress and determinants of sexual dysfunction in middle-aged and elderly men remain unclear. AIM: To describe the incidence or remission and biopsychosocial predictors of erectile dysfunction (ED) and low sexual desire (SD). MAIN OUTCOME MEASURES: Erectile function (International Index of Erectile Function) and sexual desire (Sexual Desire Inventory 2) were assessed at follow-up. Sociodemographic, lifestyle, and health-related factors were examined in multivariate models of ED and low SD. METHODS: Data were collected from 810 randomly selected men residing in northern and western Adelaide, Australia, and aged 35-80 years at baseline, who made clinic visits 5 years apart. RESULTS: At baseline, 23.2% (n = 123) of men had ED. ED incidence and remission were observed in 31.7% (n = 179) and 29.0% (n = 71) of eligible men, respectively. At baseline, 19.2% (n = 165) had low solitary sexual desire, and 6.0% (n = 50) had low dyadic sexual desire; incidence of low sexual desire occurred in 17.6% (n = 83) (solitary) and 8.3% (n = 51) (dyadic), while remission occurred in 15.4% (n = 68) (solitary) and 22.6% (n = 40) (dyadic) of men. In the final regression models, predictors of incident ED were higher age, lower income, higher abdominal fat mass, low alcohol intake, higher risk of obstructive sleep apnea (OSA) risk, voiding lower urinary tract symptoms (LUTS), depression, and diabetes. Predictors of ED remission were lower age, current employment, and absence of voiding LUTS, angina, diabetes, and dyslipidemia. Predictors of low dyadic SD incidence included higher age, never having been married, widowhood, being unemployed, being retired, insufficient physical activity, and low alcohol intake. Predictors of low dyadic SD remission were being married, not being widowed, higher income, lower abdominal fat mass, lower OSA risk, and higher plasma testosterone. Predictors of low solitary SD included never having been married, being unemployed, low alcohol intake, lower testosterone, storage LUTS, and hypertension. Predictors of low solitary SD remission were being married, being employed, higher income, higher physical activity, moderate alcohol intake, and depression. CONCLUSIONS: Sexual dysfunction in aging men is a dynamic disorder whose incidence and remission are predicted by a range of modifiable risk factors.