Effects of interrupting daily sedentary behavior on children's glucose metabolism: A 6-day randomized controlled trial.

BACKGROUND: Metabolic disease risk in youth is influenced by sedentary behaviors. Acute in-lab studies show that, during a single day, interrupting a sedentary period with short bouts of physical activity improves glucometabolic outcomes. OBJECTIVE: To determine if acutely improved glucose metabolism persists after multi-day interruptions of sitting with walking brief bouts. We hypothesized that children who underwent interrupting sitting on multiple days would demonstrate lower insulin area under the curve during an oral glucose tolerance test compared to uninterrupted sitting. METHODS: Healthy, normoglycemic children (N = 109) ages 7-11 years were randomized to one of two conditions: Control (3 h of daily Uninterrupted Sitting) or Interrupted Sitting (3-min of moderate-intensity walking every 30 min for 3 h daily); with dietary intake controlled through provision of foodstuffs for the entire experiment. Participants attended six consecutive daily visits at a research ambulatory unit. The primary outcome was insulin area under the curve during the oral glucose tolerance test on day 6 during interrupted or uninterrupted sitting; secondary outcomes included glucose and c-peptide area under the curve, energy intake at a buffet meal on day 6, and free-living activity. RESULTS: Among 93 children (42 uninterrupted sitting, 51 interrupted sitting), daily interrupted sitting resulted in 21% lower insulin (ß = 0.102 CI:0.032-0.172, p = 0.005) and a 10% lower C-peptide (ß = 0.043, CI:0.001-0.084, p = 0.045) area under the curve. Matsuda and Glucose Effectiveness Indices were also improved (p's < 0.05). There were no group differences in energy intake or expenditure. CONCLUSIONS: Sustained behavioral change by interrupting sedentary behaviors is a promising intervention strategy for improving metabolic risk in children.

Small intestinal immunopathology and GI-associated antibody formation in hereditary alpha-tryptasemia.

BACKGROUND: Hereditary alpha-tryptasemia (HαT) is characterized by elevated basal serum tryptase due to increased copies of the TPSAB1 gene. Individuals with HαT frequently present with multisystem complaints, including anaphylaxis and seemingly functional gastrointestinal (GI) symptoms. OBJECTIVE: We sought to determine the prevalence of HαT in an irritable bowel syndrome cohort and associated immunologic characteristics that may distinguish patients with HαT from patients without HαT. METHODS: Tryptase genotyping by droplet digital PCR, flow cytometry, cytometry by time-of-flight, immunohistochemistry, and other molecular biology techniques was used. RESULTS: HαT prevalence in a large irritable bowel syndrome cohort was 5% (N = 8/158). Immunophenotyping of HαT PBMCs (N ≥ 27) revealed increased total and class-switched memory B cells. In the small bowel, expansion of tissue mast cells with expression of CD203c, HLA-DR, and FcεRI, higher intestinal epithelial cell pyroptosis, and increased class-switched memory B cells were observed. IgG profiles in sera from individuals with HαT (N = 21) significantly differed from those in individuals with quiescent Crohn disease (N = 20) and non-HαT controls (N = 19), with increased antibodies directed against GI-associated proteins identified in individuals with HαT. CONCLUSIONS: Increased mast cell number and intestinal epithelial cell pyroptosis in the small intestine, and class-switched memory B cells in both the gut and peripheral blood associated with IgG reactive to GI-related proteins, distinguish HαT from functional GI disease. These innate and adaptive immunologic findings identified in association with HαT are suggestive of subclinical intestinal inflammation in symptomatic individuals.

Evidence of Duodenal Epithelial Barrier Impairment and Increased Pyroptosis in Patients With Functional Dyspepsia on Confocal Laser Endomicroscopy and "Ex Vivo" Mucosa Analysis.

INTRODUCTION: Duodenal epithelial barrier impairment and immune activation may play a role in the pathogenesis of functional dyspepsia (FD). This study was aimed to evaluate the duodenal epithelium of patients with FD and healthy individuals for detectable microscopic structural abnormalities. METHODS: This is a prospective study using esophagogastroduodenoscopy enhanced with duodenal confocal laser endomicroscopy (CLE) and mucosal biopsies in patients with FD (n = 16) and healthy controls (n = 18). Blinded CLE images analysis evaluated the density of epithelial gaps (cell extrusion zones), a validated endoscopic measure of the intestinal barrier status. Analyses of the biopsied duodenal mucosa included standard histology, quantification of mucosal immune cells/cytokines, and immunohistochemistry for inflammatory epithelial cell death called pyroptosis. Transepithelial electrical resistance (TEER) was measured using Ussing chambers. Epithelial cell-to-cell adhesion proteins expression was assessed by real-time polymerase chain reaction. RESULTS: Patients with FD had significantly higher epithelial gap density on CLE in the distal duodenum than that of controls (P = 0.002). These mucosal abnormalities corresponded to significant changes in the duodenal biopsy samples of patients with FD, compared with controls, including impaired mucosal integrity by TEER (P = 0.009) and increased number of epithelial cells undergoing pyroptosis (P = 0.04). Reduced TEER inversely correlated with the severity of certain dyspeptic symptoms. Furthermore, patients with FD demonstrated altered duodenal expression of claudin-1 and interleukin-6. No differences in standard histology were found between the groups. DISCUSSION: This is the first report of duodenal CLE abnormalities in patients with FD, corroborated by biopsy findings of epithelial barrier impairment and increased cell death, implicating that duodenal barrier disruption is a pathogenesis factor in FD and introducing CLE a potential diagnostic biomarker in FD.

Effect of setmelanotide, a melanocortin-4 receptor agonist, on obesity in Bardet-Biedl syndrome.

AIM: To report an analysis of ~1 year of setmelanotide treatment for obesity and hunger, as well as metabolic and cardiac outcomes, in individuals with Bardet-Biedl syndrome (BBS). MATERIALS AND METHODS: Individuals aged 12 years and older with BBS received once-daily setmelanotide. The dose was titrated every 2 weeks to establish the individual therapeutic dose (≤3 mg); treatment continued for an additional 10 weeks. Participants who lost 5 kg or more (or ≥5% of body weight if <100 kg at baseline) continued into the 52-week extension phase. The primary outcome was mean percent change from baseline in body weight at 3 months. Hunger scores and safety were secondary outcomes. RESULTS: From February 2017 and February 2018, 10 individuals were screened; eight completed the 3-month treatment phase and seven completed the extension phase. Mean percent change in body weight from baseline to 3 months was -5.5% (90% CI, -9.3% to -1.6%; n = 8); change from baseline was -11.3% (90% CI, -15.5% to -7.0%; n = 8) at 6 months and -16.3% (90% CI, -19.9% to -12.8%; n = 7) at 12 months. All participants reported at least one treatment-emergent adverse event (AE), most commonly injection-site reaction. No AEs led to study withdrawal or death. Most, morning, and average hunger scores were reduced across time points. CONCLUSIONS: Setmelanotide reduced body weight and hunger in individuals with BBS and had a safety profile consistent with previous reports. Setmelanotide may be a treatment option in individuals with BBS-associated obesity and hyperphagia.

Estimating plasma glucose with the FreeStyle Libre Pro continuous glucose monitor during oral glucose tolerance tests in youth without diabetes.

Few studies have assessed the accuracy of the FreeStyle Libre Pro (FLP) continuous glucose monitor for estimating plasma glucose (PG) in non-diabetic children. OBJECTIVE: Determine the accuracy of FLP compared to PG during OGTT in healthy children. SUBJECTS: Children (7-11.99 years) with healthy weight and overweight/obesity (n = 33; 52% male). METHODS: Participants wore the FLP before and during a 2-hour OGTT; PG was measured at 30 minutes intervals. Potential systematic- and magnitude-related biases for FLP vs PG were examined. RESULTS: FLP 15-minute averages and PG were correlated at most timepoints during OGTT (r2 = 0.35-0.69, P's < .001 for time point 30-120 minutes) and for PG area under the curve (AUC) (r2 = 0.65, P < .0001). There were no systematic biases as assessed by Bland-Altman analyses for FLP AUC or for FLP at each OGTT timepoint. However, for fasting glucose, a significant magnitude bias was noted (r2 = 0.38, P < .001), such that lower PG was underestimated, and higher PG was overestimated by FLP readings; further, there was poor correlation between fasting PG and FLP (r2 = 0.06, P = .22). BMIz was also associated with FLP accuracy: FLP overestimated PG in children with low BMIz and underestimated PG in those with overweight/obesity for OGTT AUC and OGTT PG at baseline, 60, and 120 minutes (all P's ≤ .015). No adverse events occurred with FLP. CONCLUSIONS: Among children without diabetes, the FLP was well tolerated and correlated with post-OGTT glucose, but had magnitude bias affecting fasting glucose and appeared to underestimate plasma glucose in those with overweight/obesity. These results suggest potential limitations for the utility of the FLP for research.

A Pilot Study of Confocal Laser Endomicroscopy to Predict Barrier Dysfunction and Relapse in Pediatric Inflammatory Bowel Disease.

OBJECTIVES: Probe-based confocal laser endomicroscopy (pCLE) is a novel imaging modality that enables virtual optical biopsy in vivo. Loss of barrier function of the small bowel observed via pCLE as increased density of epithelial gaps (extrusion zones left in the intestinal lining after cells are shed) is predictive of relapse in adult patients with inflammatory bowel disease (IBD). This study aims to determine whether such observations on pCLE are similarly predictive of disease relapse in pediatric patients with IBD. METHODS: Pediatric patients with biopsy-proven IBD underwent pCLE during colonoscopy and subsequent clinical follow-up every 6 months. Relapse was defined as moderate to severe flare with endoscopic evidence of inflammation during the follow-up period. The relations between epithelial gap density, disease relapse, and imaging parameters were determined using Cox models. RESULTS: Twenty-four patients with IBD (13 with Crohn disease, 11 with ulcerative colitis) with a median age of 14 years (range 10-21) were studied for a median of 13 (4-33) months. The median duration of disease was 2.9 years (range 0-9). Increased epithelial gap density in the terminal ileum on pCLE of normal endoscopic appearing terminal ileum mucosa (N = 19) was predictive of disease relapse when 3 or more areas were imaged (N = 6, log-rank P = 0.02, C-statistic = 0.94). CONCLUSIONS: In pediatric patients with IBD, barrier dysfunction observed on pCLE imaging of the small bowel was predictive of disease relapse.

Epithelial Cell Extrusion Zones Observed on Confocal Laser Endomicroscopy Correlates with Immunohistochemical Staining of Mucosal Biopsy Samples.

BACKGROUND AND AIMS: The density of epithelial cell extrusion zones in the intestinal lining, also known as gap density (number of gaps/1000 epithelial cells counted), can be quantitated using probe-based confocal laser endomicroscopy (pCLE). Gap density has been reported to be higher than normal in both inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) patients. Epithelial cells destined for extrusion from the intestinal surface would stain positive for either activated caspase-1 or caspase-3 on mucosal biopsy samples. The aim of this study was to determine whether epithelial gap density on pCLE correlates with quantitative analysis of activated caspase staining of mucosal biopsy samples from patients. METHODS: We obtained pCLE images and biopsy samples of the terminal ileum during colonoscopies of healthy controls and patients with either IBD or IBS. The pCLE images and biopsy samples were blindly analyzed for gap density and for cells staining positive for activated caspases, respectively. The degree of correlation was determined using nonparametric statistical tests. RESULTS: The median results were 10 gaps/1000 cells counted for controls versus 33 gaps/1000 cells counted for chronic intestinal disorder patients (p = 0.02). Activated caspase staining showed 13 positive cells/1000 epithelial cells counted versus 26 positive cells/1000 epithelial cells counted, respectively (p = 0.02), thus showing a strong correlation with a Spearman's coefficient ρ of 0.61 (strong correlation for ρ = 0.4-0.75, p = 0.01). CONCLUSIONS: Intestinal epithelial gap density via pCLE correlated strongly with quantitative analysis of immunohistochemical staining of mucosal biopsy samples.

Associations of anaemia and race with peripartum transfusion in three United States datasets.

BACKGROUND: Transfusion complicates a significant proportion of births in the United States, and Black women have greater prevalence of transfusion at delivery than White women. Antepartum anaemia, a risk factor for peripartum transfusion, is more common among Black women than White women. We aimed to describe the racial distribution of antepartum anaemia in three national datasets and to evaluate the peripartum transfusion rate and characteristics of transfusion recipients, to investigate disparities in haemostatic outcomes. MATERIAL AND METHODS: We performed a retrospective analysis of Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units Network Cesarean Registry (CR), NICHD Consortium on Safe Labor Registry (CSL), and a cohort of deliveries at Universal Health Services hospitals (UHS). Univariable associations and multivariable logistic regressions were calculated between race, anaemia and transfusion. Covariates included age, parity, smoking, body mass index, type of insurance, and delivery mode. RESULTS: We included n=56,964 deliveries from CR (28% Black), 87,465 from UHS (12% Black), and 140,324 from CSL (24% Black). Anaemia prevalence was 8% in CR, 7% in UHS, and 13% in CSL. Anaemia was more common among Black patients (ORs 2.52, 2.61, and 1.48 respectively) and was associated with transfusion in all databases (ORs 6.46 [95% CI 5.78-7.22]; 5.79 [4.74-7.27]; 1.27 [1.18-1.37] respectively). After adjusting for covariates, Black patients had greater odds of transfusion than non-Black patients in CR (aOR 1.32 [1.16-1.50]), but not in UHS or CSL (aORs 1.19 [0.89-1.59] and 0.40 [0.36-0.44] respectively). DISCUSSION: In our retrospective cohort study using three US registries, we emphasized the link between anaemia and transfusion. Although anaemia was more prevalent among Black patients, the race-transfusion relationship differed between databases, indicating other unexplored factors are involved.

Role of the cell wall microenvironment in expression of a heterologous SpaP-S1 fusion protein by Streptococcus gordonii.

The charge density in the cell wall microenvironment of Gram-positive bacteria is believed to influence the expression of heterologous proteins. To test this, the expression of a SpaP-S1 fusion protein, consisting of the surface protein SpaP of Streptococcus mutans and a pertussis toxin S1 fragment, was studied in the live vaccine candidate bacterium Streptococcus gordonii. Results showed that the parent strain PM14 expressed very low levels of SpaP-S1. By comparison, the dlt mutant strain, which has a mutation in the dlt operon preventing d-alanylation of the cell wall lipoteichoic acids, and another mutant strain, OB219(pPM14), which lacks the LPXTG major surface proteins SspA and SspB, expressed more SpaP-S1 than the parent. Both the dlt mutant and the OB219(pPM14) strain had a more negatively charged cell surface than PM14, suggesting that the negative charged cell wall played a role in the increase in SpaP-S1 production. Accordingly, the addition of Ca(2+), Mg(2+), and K(+), presumably increasing the positive charge of the cell wall, led to a reduction in SpaP-S1 production, while the addition of bicarbonate resulted in an increase in SpaP-S1 production. The level of SpaP-S1 production could be correlated with the level of PrsA, a peptidyl-prolyl cis/trans isomerase, in the cells. PrsA expression appears to be regulated by the cell envelope stress two-component regulatory system LiaSR. The results collectively indicate that the charge density of the cell wall microenvironment can modulate heterologous SpaP-S1 protein expression in S. gordonii and that this modulation is mediated by the level of PrsA, whose expression is regulated by the LiaSR two-component regulatory system.

Epithelial Cell Biomarkers Are Predictive of Response to Biologic Agents in Crohn's Disease.

BACKGROUND: Therapeutic efficacy of biologics has remained at about 50% for 2 decades. In Crohn's disease (CD) patients, we examined the predictive value of an epithelial cell biomarker, ileal microvillar length (MVL), for clinical response to ustekinumab (UST) and vedolizumab (VDZ) and its relationship to another biomarker, intestinal epithelial cell (IEC) pyroptosis, with respect to response to VDZ. METHOD: Ileal biopsies from the UNITI-2 randomized controlled trial were analyzed for MVL as a predictor of clinical response to UST. In a 5-center academic retrospective cohort of CD patients, ileal MVL was analyzed to determine its predictive value for response to VDZ. Correlation between ileal MVL and IEC pyroptosis was determined, and the discriminant ability of the combination of 2 biomarkers to VDZ was examined. RESULTS: Clinical response in UST was significantly higher than placebo (65% vs 39%; P = 0.03), with patients with normal MVL (>1.7 µm) having the greatest therapeutic effect: 85% vs 20% (P = 0.02). For VDZ, clinical response with MVL of 1.35 to 1.55 µm was 82% vs 44% (<1.35 µm) and 40% (>1.55 µm; P = 0.038). There was no correlation between ileal MVL and IEC pyroptosis. The combination criteria of ileal pyroptosis <14 positive cells/1000 IECs or MVL of 1.35 to 1.55 µm could identify 84% of responders and 67% of nonresponders (P = 0.001). CONCLUSION: Ileal MVL was predictive of response to UST and VDZ in prospective and retrospective CD cohorts. It was independent of ileal IEC pyroptosis, and combination of the 2 biomarkers enhanced the discriminate ability of responders from nonresponders to VDZ.

Associations between weight-based teasing and disordered eating behaviors among youth.

Weight-based teasing (WBT) is commonly reported among youth and is associated with disinhibited and disordered eating. Specifically, youth who experience WBT may engage in disordered eating behaviors to cope with the resultant negative affect. Therefore, we examined associations between WBT and disordered eating behaviors among youth and assessed whether negative affect mediated these relationships. Two hundred one non-treatment seeking youth (8-17y) completed questionnaires assessing WBT, disinhibited eating, depression, and anxiety. Disordered eating and loss-of-control (LOC) eating were assessed via semi-structured interview. Analyses of covariance were conducted to examine relationships between WBT and eating-related variables, and bootstrapping mediation models were used to evaluate negative affect (a composite of depressive and anxiety symptoms) as a mediator of these associations. All models were adjusted for sex, race, age, and adiposity. Among 201 participants (13.1 ± 2.8y; 54.2% female; 30.3% Black; 32.8% with overweight/obesity), WBT was associated with emotional eating, eating in the absence of hunger, and disordered eating attitudes and behaviors (ps ≤ 0.02). These associations were all mediated by negative affect. WBT was also associated with a threefold greater likelihood of reporting a recent LOC eating episode (p = .049). Among boys and girls across weight strata, WBT was associated with multiple aspects of disordered eating and these relationships were mediated by negative affect. Longitudinal studies are needed to clarify the directionality of these associations and to identify subgroups of youth that may be particularly vulnerable to WBT and its sequelae.

Surface nanocrystallization for bacterial control.

Stainless steel is commonly used in indwelling medical devices, food preparation, and heavy industry. Bacteria display reduced adherence to nanocrystallized stainless steel. In this article, we present quantitative information on the surface adhesive force, surface electron work function, and bacterial adherence to surfaces of nanocrystallized stainless steel with differing grain sizes. Surface nanocrystallization was achieved by sandblasting followed by recovery treatment. The adhesive force of bacterial binding to nanocrystallized surfaces was measured using an atomic force microscope with a synthetic-peptide-coated AFM tip designed to mimic the bacterial binding site of Pseudomonas aeruginosa, a common pathogen known to form biofilms. The electron work function of the steel surfaces was measured, and bacterial binding assays were performed using subinoculated P. aeruginosa cultures. It was demonstrated that for nanograined steel surfaces, the adhesive force, peptide adherence, surface electron activity, and bacterial binding all decreased with decreasing grain size.

Mucosal Biomarker of Innate Immune Activation Predicts Response to Vedolizumab in Crohn's Disease.

OBJECTIVE: Mucosal barrier dysfunction plays a crucial role in intestinal inflammation in Crohn's disease (CD). Intestinal epithelial cell (IEC) death resulting from innate immune activation, termed pyroptosis, was recently found to be a cause of this barrier defect. The aim of this study was to determine the predictive value of pretreatment ileal biopsy pyroptosis as a biomarker for clinical response to vedolizumab in CD. DESIGN: Crohn's disease patients ranging 18 to 80 years old from 5 IBD centers with pre-vedolizumab ileal biopsies during colonoscopy were enrolled. Biopsies were stained for activated caspases, and levels of ileal IEC pyroptosis levels were quantified. The primary outcome was clinical response 6 months after therapy, defined as a reduction of Harvey-Bradshaw Index (HBI) of ≥5 points from baseline. Secondary outcomes included clinical remission, defined as HBI <5, and endoscopic improvement, as measured by the Simple Endoscopic Score for Crohn's Disease (SES-CD). RESULTS: One hundred CD patients (45 male, 55 female), median age 47 (19, 78) years, were included; clinical response rate was 60%, and clinical remission was 36%. The response rate in patients with ileal pyroptosis <14 positive cells per 1000 IECs was significantly higher than those above the threshold: 89% (25 of 28) vs 49% (35 of 72), odds ratio (OR) 8.8 (95% CI, 2.3-48.6; P < 0.001). Corresponding remission rates were 54% (15 of 28) vs 29% (21 of 72; OR 2.8 [1.03-7.59; P = 0.036]). For endoscopic improvement, ileal pyroptosis of 22 positive cells per 1000 IECs was the optimal threshold that determines the magnitude SES-CD change. CONCLUSIONS: Ileal biopsy IEC pyroptosis was predictive of clinical response and endoscopic improvement to vedolizmab in CD patients.

Free Fatty Acids as an Indicator of the Nonfasted State in Children.

BACKGROUND: Ensuring children are fasting for blood draws is necessary to diagnose abnormalities in glucose homeostasis. We sought to determine if serum free fatty acid (FFA) concentrations might be a useful marker to differentiate the fed and fasted states among children. METHODS: A total of 442 inpatient (fasting) and 323 (postglucose load) oral glucose tolerance test samples of glucose, insulin, and FFA from children (age 5-18 years) who had healthy weight, overweight, or obesity were examined by receiver operating characteristic (ROC) curve analysis to identify a cut point for nonfasting. In a cross-sectional study, we compared mean FFA and percentage of FFA values below this cut point as a function of inpatient (n = 442) versus outpatient (n = 442) setting. RESULTS: The area under the curve of FFA was significantly better (P values < .001) than the area under the curve of glucose or insulin for identifying nonfasting. FFA <287 mEq/mL had 99.0% sensitivity and 98.0% specificity for nonfasting. Mean FFA was lower in outpatients than inpatients (P < .001); only 1.6% inpatient but 9.7% outpatient FFA values were consistent with nonfasting (P < .001). CONCLUSIONS: Clinicians cannot assume that pediatric patients are adequately fasted on arrival for fasting blood work. On the basis of having significantly lower outpatient than inpatient FFA values and more frequently suppressed FFA, children appeared less likely to be fasting at outpatient appointments. FFA value <287 mEq/mL was a sensitive and specific cutoff for nonfasting in children that may prove clinically useful.

Associations of Weekday and Weekend Sleep with Children's Reported Eating in the Absence of Hunger.

Insufficient average sleep duration has been inconsistently associated with poor diet and obesity risks in youth. Inconsistencies in findings across studies may be due to a general failure to examine associations in weekday versus weekend sleep. We hypothesized that greater variations in weekday and weekend sleep duration would be associated with more disinhibited eating behaviors, which, in turn, might be involved in the relationship between sleep and weight. We, therefore, examined, among healthy, non-treatment seeking youth, the associations of average weekly, weekend, and weekday sleep duration with eating in the absence of hunger (EAH), a disinhibited eating behavior associated with disordered eating and obesity. Sleep was assessed via actigraphy for 14 days. Participants completed a self-report measure of EAH. Adiposity was measured by dual-energy X-ray absorptiometry. Linear regressions were used to test the associations of sleep duration with EAH and the associations of sleep duration and EAH, with fat mass. Among 123 participants (8-17 years, 52.0% female, and 30.9% with overweight), there was no significant association between average weekly sleep and EAH. Further, there was no significant association among average weekly sleep duration or EAH and fat mass. However, average weekday sleep was negatively associated, and average weekend sleep was positively associated, with EAH (ps < 0.02). Weekend "catch-up" sleep (the difference between weekend and weekday sleep) was positively associated with EAH (p < 0.01). Findings indicate that shorter weekday sleep and greater weekend "catch-up" sleep are associated with EAH, which may place youth at risk for the development of excess weight gain over time.

Effects of Interrupting Sedentary Behavior With Short Bouts of Moderate Physical Activity on Glucose Tolerance in Children With Overweight and Obesity: A Randomized Crossover Trial.

OBJECTIVE: Sedentary children have greater risk of developing abnormalities in glucose homeostasis. We investigated whether interrupting sedentary behavior (sitting) with very short periods of walking would improve glucose metabolism without affecting dietary intake in children with overweight or obesity. We hypothesized that interrupting sitting with short bouts of moderate-intensity walking would decrease insulin area under the curve (AUC) during an oral glucose tolerance test (OGTT) compared with uninterrupted sitting. RESEARCH DESIGN AND METHODS: Overweight/obese (BMI ≥85th percentile) children 7-11 years of age underwent two experimental conditions in random order: prolonged sitting (3 h of continuous sitting) and interrupted sitting (3 min of moderate-intensity walking at 80% of ventilatory threshold every 30 min for 3 h). Insulin, C-peptide, and glucose were measured every 30 min for 3 h during an OGTT. Each session was followed by a buffet meal. Primary outcomes were differences in OGTT hormones and substrates and in buffet meal intake by condition. RESULTS: Among 35 children with complete data, mixed-model results identified lower insulin and C-peptide in the interrupted condition (P = 0.007 and P = 0.029, respectively); the intervention reduced insulin AUC by 21% (P < 0.001) and C-peptide AUC 18% (P = 0.001) and improved estimated insulin sensitivity (P = 0.013). Neither buffet total energy intake (1,262 ± 480 vs. 1,260 ± 475 kcal; P = 0.89) nor macronutrient composition of the meal (P values >0.38) differed between conditions significantly. CONCLUSIONS: Interrupting sitting with brief moderate-intensity walking improved glucose metabolism without significantly increasing energy intake in children with overweight or obesity. Interrupting sedentary behavior may be a promising intervention strategy for reducing metabolic risk in such children.

Peptide-Mediated PEGylation of Polysulfone Reduces Protein Adsorption and Leukocyte Activation.

The exposure of blood to bioincompatible materials used for dialysis triggers leukocyte activation and protein adsorption. We describe a single-step, postmanufacturing method for surface modification to create biomaterials used in medical devices and dialysis with altered surface characteristics. Peptides derived from the receptor-binding domain of the type IV pilin of Pseudomonas aeruginosa were synthesized using L and D-amino acids to generate L-K122-4, enantiomer D-K122-4, and D-retroinverso RI-K122-4 peptides. L-K122-4, D-K122-4, and RI-K122-4 peptides, but not control peptides, bound durably to the surfaces of materials used in medical devices and dialysis including silicone and polysulfone. D-K122-4 enantiomeric peptides were protease resistant on polysulfone and could remain bound to the surface for up to 28 days. To demonstrate that K122-4 peptides could be used to modify material surfaces, D-K122-4 peptide was conjugated to polyethylene glycol (D-K122-4-PEG) and applied to polysulfone. When compared with untreated material, D-K122-4-PEG reduced the surface adsorption of albumin or immunoglobulin G to polysulfone. In coincubation experiments, although uncoated polysulfone induced pro-interleukin-1ß cytokine expression in leukocytes, cellular activation was prevented when leukocytes were incubated with D-K122-4-PEG-modified polysulfone. These data demonstrate the proof of principle that K122-4 peptides can be applied to modify the surface characteristics of materials used for dialysis.

Transition to surgical residency: a multi-institutional study of perceived intern preparedness and the effect of a formal residency preparatory course in the fourth year of medical school.

PURPOSE: To evaluate interns' perceived preparedness for defined surgical residency responsibilities and to determine whether fourth-year medical school (M4) preparatory courses ("bootcamps") facilitate transition to internship. METHOD: The authors conducted a multi-institutional, mixed-methods study (June 2009) evaluating interns from 11 U.S. and Canadian surgery residency programs. Interns completed structured surveys and answered open-ended reflective questions about their preparedness for their surgery internship. Analyses include t tests comparing ratings of interns who had and had not participated in formal internship preparation programs. The authors calculated Cohen d for effect size and used grounded theory to identify themes in the interns' reflections. RESULTS: Of 221 eligible interns, 158 (71.5%) participated. Interns self-reported only moderate preparation for most defined care responsibilities in the medical knowledge and patient care domains but, overall, felt well prepared in the professionalism, interpersonal communication, practice-based learning, and systems-based practice domains. Interns who participated in M4 preparatory curricula had higher self-assessed ratings of surgical technical skills, professionalism, interpersonal communication skills, and overall preparation, at statistically significant levels (P < .05) with medium effect sizes. Themes identified in interns' characterizations of their greatest internship challenges included anxiety or lack of preparation related to performance of technical skills or procedures, managing simultaneous demands, being first responders for critically ill patients, clinical management of predictable postoperative conditions, and difficult communications. CONCLUSIONS: Entering surgical residency, interns report not feeling prepared to fulfill common clinical and professional responsibilities. As M4 curricula may enhance preparation, programs facilitating transition to residency should be developed and evaluated.

Are general surgery residents ready to practice? A survey of the American College of Surgeons Board of Governors and Young Fellows Association.

BACKGROUND: General surgery residency training has changed with adoption of the 80-hour work week, patient expectations, and the malpractice environment, resulting in decreased resident autonomy during the chief resident year. There is considerable concern that graduating residents are not prepared for independent surgical practice. STUDY DESIGN: Two online surveys were developed, one for "young surgeons" (American College of Surgeons [ACS] Fellows 45 years of age and younger) and one for "older surgeons" (ACS Fellows older than 45 years of age). The surveys were distributed by email to 2,939 young and 9,800 older surgeons. The last question was open-ended with a request to provide comments. A qualitative and quantitative analysis of all comments was performed. RESULTS: The response rate was 9.6% (282 of 2,939) of young and 10% (978 of 9,800) of older surgeons. The majority of young surgeons (94% [58.7% strongly agree, 34.9% agree]) stated they had adequate surgical training and were prepared for transition to the surgery attending role (91% [49.6% strongly agree, 41.1% agree]). In contrast, considerably fewer older surgeons believed that there was adequate surgical training (59% [18.7% strongly agree, 40.2% agree]) or adequate preparation for transition to the surgery attending role (53% [16.93% strongly agree, 36.13% agree]). The 2 groups' responses were significantly different, chi-square test of association (3) = 15.73, p = 0.0012. Older surgeons focused considerably more on residency issues (60% vs 42%, respectively), and young surgeons focused considerably more on business and practice issues (30% vs 14%, respectively). CONCLUSIONS: Young and older surgeons' perceptions of general surgery residents' readiness to practice independently after completion of general surgery residency differ significantly. Future work should focus on determination of specific efforts to improve the transition to independent surgery practice for the general surgery resident.

Evidence of extensive diversity in bacterial adherence mechanisms that exploit unanticipated stainless steel surface structural complexity for biofilm formation.

Three protease-resistant bioorganic 304 stainless steel surfaces were created through the reaction of synthetic peptides consisting of the D-enantiomeric isomer (D-K122-4), the retro-inverso D-enantiomeric isomer (RI-K122-4), and a combination of the two peptides (D+RI) of the Pseudomonas aeruginosa PilA receptor binding domain with steel surfaces. The peptides used to produce the new materials differ only in handedness of their three-dimensional structure, but they reacted with the steel to yield materials that differed in their surface electron work function (EWF) while displaying an identical chemical composition and equivalent surface adhesive force properties. These surfaces allowed for an assessment of the relative role of surface EWF in initial biofilm formation. We examined the ability of various bacteria (selected strains of Listeria monocytogenes, L. innocua, Staphylococcus aureus and S. epidermidis) to initiate biofilm formation. The D-K1224 generated surface displayed the lowest EWF (classically associated with greater molecular interactions and more extensive biofilm formation) but was observed to be least effectively colonized by bacteria (>50% decrease in bacterial adherence of all strains). The highest surface EWF with the lowest surface free energy (RI-K122-4 generated) was more extensively colonized by bacteria, with the binding of some strains being equivalent to unmodified steel. The D+RI generated surface was least effective in minimizing biofilm formation, where some strains displayed enhanced bacterial colonization. Fluorescent microscopy revealed that the D and RI peptides displayed similar but clearly different binding patterns, suggesting that the peptides recognized different sites on the steel, and that differential binding of the peptides to the steel surfaces influences the binding of different bacterial strains and species. We have demonstrated that stainless steel surfaces can be easily modified by peptides to generate surfaces with new physiochemical properties. The D-K122-4-modified surface substantially decreases biofilm formation compared to the RI-K122-4 and D+RI surfaces.