WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Human pancreatic polypeptide (hPP) is a natural pancreatic hormone that suppresses appetite after meals.
• When exogenous hPP is given to healthy human ...volunteers, it causes a reduction in food intake.
• PP 1420 is a longer acting analogue of hPP that has been developed as a novel treatment for obesity.
WHAT THIS STUDY ADDS
• PP 1420 has been shown to be well tolerated in healthy human volunteers.
• PP 1420 has been shown to have an extended terminal elimination half‐life compared with hPP.
AIMS The objectives of this phase 1 study were to confirm the tolerability of single ascending subcutaneous doses of PP 1420 in healthy subjects, to assess its adverse effects and to investigate the drug's pharmacokinetics and dose proportionality.
METHODS This was a double‐blind, placebo‐controlled, randomized study. There were three dosing periods. Each subject (n= 12) was randomized to receive one dose of placebo and two ascending doses of PP 1420, given as a subcutaneous injection. Blood samples were taken over 24 h to assess pharmacokinetics. Standard safety and laboratory data were collected. The primary endpoint was the tolerability of PP 1420. The secondary endpoint was exposure to PP 1420 as assessed by Cmax and AUC(0,∞).
RESULTS PP 1420 was well tolerated by all subjects with no serious adverse effects. Following single subcutaneous doses of PP 1420 at 2, 4 and 8 mg to male subjects, Cmax was reached at a median tmax of approximately 1 h post dose (range 0.32–2.00 h). Thereafter, plasma concentrations of PP 1420 declined with geometric mean apparent terminal elimination t1/2 ranging from 2.42–2.61 h (range 1.64–3.95 h) across all dose levels.
CONCLUSIONS Subcutaneous PP 1420 was well tolerated in healthy human subjects at single doses between 2–8 mg, with no tolerability issues arising. Where observed, adverse events were not serious, and there was no evidence of a dose‐relationship to frequency of adverse events. The results therefore support the conduct of clinical trials to investigate efficacy, tolerability and pharmacokinetics during repeated dosing.
Bloodstream infection (BSI) rates are used as comparative clinical performance indicators; however, variations in definitions and data-collection approaches make it difficult to compare and interpret ...rates. To determine the extent to which variation in indicator specifications affected infection rates and hospital performance rankings, we compared absolute rates and relative rankings of hospitals across 5 BSI indicators.
Multicenter observational study. BSI rate specifications varied by data source (clinical data, administrative data, or both), scope (hospital wide or intensive care unit specific), and inclusion/exclusion criteria. As appropriate, hospital-specific infection rates and rankings were calculated by processing data from each site according to 2-5 different specifications.
A total of 28 hospitals participating in the EPIC study.
Hospitals submitted deidentified information about all patients with BSIs from January through September 1999.
Median BSI rates for 2 indicators based on intensive care unit surveillance data ranged from 2.23 to 2.91 BSIs per 1000 central-line days. In contrast, median rates for indicators based on administrative data varied from 0.046 to 7.03 BSIs per 100 patients. Hospital-specific rates and rankings varied substantially as different specifications were applied; the rates of 8 of 10 hospitals were both greater than and less than the mean. Correlations of hospital rankings among indicator pairs were generally low (rs=0-0.45), except when both indicators were based on intensive care unit surveillance (rs = 0.83).
Although BSI rates seem to be a logical indicator of clinical performance, the use of various indicator specifications can produce remarkably different judgments of absolute and relative performance for a given hospital. Recent national initiatives continue to mix methods for specifying BSI rates; this practice is likely to limit the usefulness of such information for comparing and improving performance.
MODERNIZING DIETARY ASSESSMENT Perez, Isabel Garcia; Posma, Joram M; Gibson, Rachel ...
Annals of nutrition and metabolism,
10/2017, Volume:
71
Journal Article
Peer reviewed
Background and objectives: A cornerstone of governments' policies to reduce the risk of non communicable diseases is to encourage population change towards healthier diet and lifestyle. However, ...monitoring dietary changes in response to policy recommendations is based on self-reported dietary assessment tools, which are known to have high misreporting rates. We have developed a novel analytical pipeline capable to independently of recorded food intake, classify people into consumers of a healthy or unhealthy diet based on urinary metabolic patterns (Garcia-Perez et al., Lancet Diabetes Endocrinology, 2017). Here we aim to apply this methodology based on metabolic profiling to improve the accuracy of monitoring dietary intake and adherence to diet guidelines for free living people and evaluate its utility for establishing inter-individual variation in response to diet. Methods: We used a randomised controlled trial in 19 volunteers to develop metabolite models of eating patterns. Volunteers were admitted to a clinical research unit for four day periods. Participants were provided with all food and drink representing 25, 50, 75 and 100% of healthy eating recommendations to increase fruits, vegetables, carbohydrates, dietary fibre and to decrease total fats, sugars, and salt. A cohort of 20 volunteers collected spot urine samples once a week for six months and a matching 24-hours food diaries for each day of the sample collection. Metabolic profiles were measured by 1H-NMR spectroscopy. MetaboNetworks has been used to investigate the metabolic coverage based on inter-individual variation. Results: Analysis of 1H-NMR spectroscopy data indicated significant differences in the urinary metabolic profiles of the four diets. These were used to predict the healthiness of the dietary habits of free-living people and tracking adherence to healthy eating recommendations over time. Missreporting of dietary data has been investigated using dietary biomarkers against the food records. In addition, significant differences in metabolite concentrations were investigated to assess individual's variability in response to diet. Conclusions: This study demonstrates the utility of applying our methodology to monitor adherence to healthful diets and assess individuals' variability in response to dietary changes.
Acute bouts of high-intensity exercise modulate peripheral appetite regulating hormones to transiently suppress hunger. However, the effects of physical activity on central appetite regulation have ...yet to be fully investigated.
We used functional magnetic resonance imaging (fMRI) to compare neural responses to visual food stimuli after intense exercise and rest.
Fifteen lean healthy men mean ± SD age: 22.5 ± 3.1 y; mean ± SD body mass index (in kg/m2): 24.2 ± 2.4 completed two 60-min trials—exercise (EX; running at ∼70% maximum aerobic capacity) and a resting control trial (REST)—in a counterbalanced order. After each trial, an fMRI assessment was completed in which images of high- and low-calorie foods were viewed.
EX significantly suppressed subjective appetite responses while increasing thirst and core-body temperature. Furthermore, EX significantly suppressed ghrelin concentrations and significantly enhanced peptide YY release. Neural responses to images of high-calorie foods significantly increased dorsolateral prefrontal cortex activation and suppressed orbitofrontal cortex (OFC) and hippocampus activation after EX compared with REST. After EX, low-calorie food images increased insula and putamen activation and reduced OFC activation compared with REST. Furthermore, left pallidum activity was significantly elevated after EX when low-calorie images were viewed and was suppressed when high-calorie images were viewed, and these responses correlated significantly with thirst.
Exercise increases neural responses in reward-related regions of the brain in response to images of low-calorie foods and suppresses activation during the viewing of high-calorie foods. These central responses are associated with exercise-induced changes in peripheral signals related to appetite-regulation and hydration status. This trial was registered at www.clinicaltrials.gov as NCT01926431.
Background: Short-chain fatty acids (SCFAs), metabolites produced through the microbial fermentation of nondigestible dietary components, have key roles in energy homeostasis. Animal research ...suggests that colon-derived SCFAs modulate feeding behavior via central mechanisms. In humans, increased colonic production of the SCFA propionate acutely reduces energy intake. However, evidence of an effect of colonic propionate on the human brain or reward-based eating behavior is currently unavailable.
Objectives: We investigated the effect of increased colonic propionate production on brain anticipatory reward responses during food picture evaluation. We hypothesized that elevated colonic propionate would reduce both reward responses and ad libitum energy intake via stimulation of anorexigenic gut hormone secretion.
Design: In a randomized crossover design, 20 healthy nonobese men completed a functional magnetic resonance imaging (fMRI) food picture evaluation task after consumption of control inulin or inulin-propionate ester, a unique dietary compound that selectively augments colonic propionate production. The blood oxygen level–dependent (BOLD) signal was measured in a priori brain regions involved in reward processing, including the caudate, nucleus accumbens, amygdala, anterior insula, and orbitofrontal cortex (n = 18 had analyzable fMRI data).
Results: Increasing colonic propionate production reduced BOLD signal during food picture evaluation in the caudate and nucleus accumbens. In the caudate, the reduction in BOLD signal was driven specifically by a lowering of the response to high-energy food. These central effects were partnered with a decrease in subjective appeal of high-energy food pictures and reduced energy intake during an ad libitum meal. These observations were not related to changes in blood peptide YY (PYY), glucagon-like peptide 1 (GLP-1), glucose, or insulin concentrations.
Conclusion: Our results suggest that colonic propionate production may play an important role in attenuating reward-based eating behavior via striatal pathways, independent of changes in plasma PYY and GLP-1. This trial was registered at clinicaltrials.gov as NCT00750438.
Background:
Short-chain fatty acids (SCFAs), metabolites produced through the microbial fermentation of nondigestible dietary components, have key roles in energy homeostasis. Animal research ...suggests that colon-derived SCFAs modulate feeding behavior via central mechanisms. In humans, increased colonic production of the SCFA propionate acutely reduces energy intake. However, evidence of an effect of colonic propionate on the human brain or reward-based eating behavior is currently unavailable.
Objectives:
We investigated the effect of increased colonic propionate production on brain anticipatory reward responses during food picture evaluation. We hypothesized that elevated colonic propionate would reduce both reward responses and ad libitum energy intake via stimulation of anorexigenic gut hormone secretion.
Design:
In a randomized crossover design, 20 healthy nonobese men completed a functional magnetic resonance imaging (fMRI) food picture evaluation task after consumption of control inulin or inulin-propionate ester, a unique dietary compound that selectively augments colonic propionate production. The blood oxygen level–dependent (BOLD) signal was measured in a priori brain regions involved in reward processing, including the caudate, nucleus accumbens, amygdala, anterior insula, and orbitofrontal cortex (
n
= 18 had analyzable fMRI data).
Results:
Increasing colonic propionate production reduced BOLD signal during food picture evaluation in the caudate and nucleus accumbens. In the caudate, the reduction in BOLD signal was driven specifically by a lowering of the response to high-energy food. These central effects were partnered with a decrease in subjective appeal of high-energy food pictures and reduced energy intake during an ad libitum meal. These observations were not related to changes in blood peptide YY (PYY), glucagon-like peptide 1 (GLP-1), glucose, or insulin concentrations.
Conclusion:
Our results suggest that colonic propionate production may play an important role in attenuating reward-based eating behavior via striatal pathways, independent of changes in plasma PYY and GLP-1. This trial was registered at
clinicaltrials.gov
as NCT00750438.
Glucagon and glucagon-like peptide (GLP)-1 are the primary products of proglucagon processing from the pancreas and gut, respectively. Giving dual agonists with glucagon and GLP-1 activity to ...diabetic, obese mice causes enhanced weight loss and improves glucose tolerance by reduction of food intake and by increase in energy expenditure (EE). We aimed to observe the effect of a combination of glucagon and GLP-1 on resting EE and glycemia in healthy human volunteers. In a randomized, double-blinded crossover study, 10 overweight or obese volunteers without diabetes received placebo infusion, GLP-1 alone, glucagon alone, and GLP-1 plus glucagon simultaneously. Resting EE--measured using indirect calorimetry--was not affected by GLP-1 infusion but rose significantly with glucagon alone and to a similar degree with glucagon and GLP-1 together. Glucagon infusion was accompanied by a rise in plasma glucose levels, but addition of GLP-1 to glucagon rapidly reduced this excursion, due to a synergistic insulinotropic effect. The data indicate that drugs with glucagon and GLP-1 agonist activity may represent a useful treatment for type 2 diabetes and obesity. Long-term studies are required to demonstrate that this combination will reduce weight and improve glycemia in patients. Diabetes 62:1131-1138, 2013
Quality improvement collaboratives are used to improve health care quality, but their efficacy remains controversial.
To assess the effects of a quality improvement collaborative on preoperative ...antimicrobial prophylaxis.
Longitudinal cluster randomized trial, with the quality improvement collaborative as the intervention.
United States.
44 acute care hospitals, each of which randomly sampled approximately 100 selected surgical cases (cardiac, hip or knee replacement, and hysterectomy) at both the baseline and remeasurement phases.
All hospitals received a comparative feedback report. Hospitals randomly assigned to the intervention group (n = 22) participated in a quality improvement collaborative comprising 2 in-person meetings led by experts, monthly teleconferences, and receipt of supplemental materials over 9 months.
Change in the proportion of patients receiving at least 1 antibiotic dose within 60 minutes of surgery (primary outcome) and change in the proportions of patients given any antibiotics, given antibiotics for 24 hours or less, given an appropriate drug, and given a single preoperative dose and receipt of any of the 5 measures (secondary outcome).
The groups did not differ in the change in proportion of patients who received a properly timed antimicrobial prophylaxis dose (-3.8 percentage points 95% CI, -13.9 to 6.2 percentage points) after adjustment for region, hospital size, and surgery type. Similarly, the groups did not differ in individual measures of antibiotic duration; use of appropriate drug; receipt of a single preoperative dose; or an all-or-none measure combining timing, duration, and selection.
Hospitals volunteered for the effort, thereby resulting in selection for participants who were motivated to change. Implementation of the surgical infection prevention measure reporting requirements by the Centers for Medicare & Medicaid Services and The Joint Commission may have motivated improvement in prophylaxis performance.
At a time of heightened national attention toward measures of antimicrobial prophylaxis performance, the trial did not demonstrate a benefit of participation in a quality improvement collaborative over performance feedback for improvement of these measures.
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