Pharmacodynamic characterization of rytvela, a novel allosteric anti-inflammatory therapeutic, to prevent preterm birth and improve fetal and neonatal outcomes.

BACKGROUND: Preterm birth is the leading cause of neonatal morbidity and mortality. Studies have shown that interleukin 1 plays a major role in the pathophysiology of preterm birth by inducing the production of proinflammatory mediators and uterine activation proteins leading to labor. More importantly, uteroplacental inflammation, associated with preterm birth parturition pathways, is detrimental to fetal tissues and leads to long-term sequelae. Our group has developed an allosteric antagonist of the interleukin 1 receptor, rytvela, found to be potent and safe in preventing preterm birth by suppressing inflammation via the inhibition of the mitogen-activated protein kinase pathway while preserving the Nuclear factor kappa B pathway (important in immune vigilance). Rytvela has been shown to inhibit inflammatory up-regulation and uterine activation while preserving fetal development. OBJECTIVE: This study aimed to further the preclinical development of rytvela by evaluating its optimal dose and minimal duration of treatment to inhibit the inflammatory cascade, prolong gestation, and promote neonatal outcomes. STUDY DESIGN: Pregnant CD-1 mice were administered with lipopolysaccharide (10 µg, intraperitoneal administration) or interleukin 1 (1 µg/kg, intrauterine administration) on gestational day 16 to induce preterm labor. Rytvela was administered at different doses (0.1, 0.5, 1.0, 2.0, 4.0 mg/kg/d subcutaneously) from gestational days 16 to 18.5. To evaluate the minimal duration of treatment, the mice were administered with rytvela (2 mg/kg/d subcutaneously) for 24, 36, or 48 hours. The rate of prematurity (gestational day <18.5) and neonate survival and weight were evaluated. Gestational tissues were collected at gestational day 17.5 to quantify cytokines, proinflammatory mediators, and uterine activating proteins by real-time quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. The neonatal lungs and intestines were collected from postnatal days 5 to 7 and analyzed by histology. RESULTS: Rytvela exhibited a dose-response profile and achieved maximum efficacy at a dose of 2 mg/kg/d by reducing 70% of lipopolysaccharide-induced preterm births and 60% of interleukin 1ß-induced preterm births. In addition, rytvela attained maximum efficacy at a dose of 1 mg/kg/d by increasing neonate survival by up to 65% in both models of preterm birth. Rytvela protected fetuses from inflammatory insult as of 24 hours, preserving lung and intestinal integrity, and prevented preterm birth and fetal mortality by 60% and 50%, respectively, as of 36 hours of treatment. CONCLUSION: The maximum efficacy of rytvela was achieved at 2 mg/kg/d with improved birth outcomes and prevented inflammatory up-regulation upon 36 hours (only) of treatment. Rytvela exhibited desirable properties for the safe prevention of preterm birth and fetal protection.

Evaluation of supervised multimodal prehabilitation programme in cancer patients undergoing colorectal resection: a randomized control trial.

BACKGROUND: Prehabilitation has been previously shown to be more effective in enhancing postoperative functional capacity than rehabilitation alone. The purpose of this study was to determine whether a weekly supervised exercise session could provide further benefit to our current prehabilition program, when comparing to standard post-surgical rehabilitation. METHODS: A parallel-arm single-blind randomized control trial was conducted in patients scheduled for non-metastatic colorectal cancer resection. Patients were assigned to either a once weekly supervised prehabilitation (PREHAB+, n = 41) or standard rehabilitation (REHAB, n = 39) program. Both multimodal programs were home-based program and consisted of moderate intensity aerobic and resistance exercise, nutrition counseling with daily whey protein supplementation and anxiety-reduction strategies. Perioperative care was standardized for both groups as per enhanced recovery after surgery (ERAS®) guidelines. Functional exercise capacity, as determined by the 6-minute walk test distance (6MWD), was the primary outcome. Exercise quantity, intensity and energy expenditure was determined by the CHAMPS questionnaire. RESULTS: Both groups were comparable for baseline walking capacity (PREHAB+: 448 m [IQR 375-525] vs. REHAB: 461 m [419-556], p=.775) and included a similar proportion of patients who improved walking capacity (>20 m) during the preoperative period (PREHAB+: 54% vs. REHAB: 38%, p = .222). After surgery, changes in 6MWD were also similar in both groups. In PREHAB+, however, there was a significant association between physical activity energy expenditure and 6MWD (p < .01). Previously inactive patients were more likely to improve functional capacity due to PREHAB+ (OR 7.07 [95% CI 1.10-45.51]). CONCLUSIONS: The addition of a weekly supervised exercise session to our current prehabilitation program did not further enhance postoperative walking capacity when compared to standard REHAB care. Sedentary patients, however, seemed more likely to benefit from PREHAB+. An association was found between energy spent in physical activity and 6MWD. This information is important to consider when designing cost-effective prehabilitation programs.

Changes in Adiposity without Impacting Bone Health in Nine- to Twelve-Year-Old Children with Overweight and Obesity after a One-Year Family-Centered Lifestyle Behavior Intervention.

Background: Few family-centered lifestyle interventions (FCLIs) for children with overweight or obesity (OW/OB) have assessed regional adiposity and bone health. This study assessed changes in adiposity in 9- to 12-year olds with OW/OB in a 1-year FCLI. Methods: Children were randomized to FCLI (six registered dietitian-led sessions) or no intervention (Control, CTRL). The FCLI focused on physical activity, nutrition education, and behavioral counseling children with families present. Assessments occurred at baseline and every 3 months for 1 year to assess changes in waist circumference (WC), body mass index for age-and-sex Z-scores (BAZ), body composition (dual-energy x-ray absorptiometry), and cardiometabolic biomarkers. Mixed models were used to determine the effects of group and time or group-by-time interactions for all outcomes. Results: Sixty children (age: 11.1 ± 1.1 years, BAZ: 2.7 ± 0.6) were enrolled; 55 participants (n = 28 CTRL, n = 27 FCLI) completed the study. There were no between group differences from baseline to follow-up for any measure. The FCLI group had significant decreases in BAZ over 12 months (-0.18 ± 0.27, p = 0.03) but not CTRL (-0.05 ± 0.32, p = 0.92). WC and android fat mass did not change in FCLI (p > 0.20) but increased in CTRL (p < 0.02). Whole body bone area, content, and areal bone mineral density (aBMD) increased in both groups (p < 0.010); whole body aBMD Z-score decreased by 5.8% and 1.6% in CTRL and FCLI, respectively (p < 0.001). There were no significant within group changes in biomarkers. Conclusion: The FCLI resulted in small reductions in BAZ and a plateau in android fat mass, which suggest that FCLIs are suitable as an intervention for 9- to 12-year-old children with OW/OB. Clinical Trial Registration number: NCT01290016.

SMART goals of children of 6-12 years enrolled in a family-centred lifestyle intervention for childhood obesity: Secondary analysis of a randomized controlled trial.

This study demonstrates how SMART (Specific, Measurable, Attainable, Realistic and Timely) goals set by children in a lifestyle intervention contributed favorably to weight outcomes. Children (6-12 years) set goals with a registered dietitian over six months. Goals were classified according to their type (diet or activity), direction, (increase healthy or decrease unhealthy), and theoretical constructs. Theoretical constructs included the Theory of Planned Behavior's attitudes (i.e., changing beliefs about behaviour outcomes), subjective norm (i.e., incorporation of health recommendations) and perceived behavioural control (i.e., over goal barriers and facilitators). Constructs from a Socio-Ecological Model (family or individual) were also applied. Participants who maintained or decreased their body mass index for-age-and-sex z-scores (BAZ) after six months created significantly more goals related to the subjective norm compared to those whose BAZ increased (p = 0.003). Future interventions using SMART goals should incorporate health recommendations (i.e., the subjective norm) through actionable items among children to promote success.

Associations between Body Composition and Vitamin D Status in Children with Overweight and Obesity Participating in a 1-Year Lifestyle Intervention.

Background: To examine associations between body composition and vitamin D status in children participating in a lifestyle intervention. Methods: Children (6−12 y, n = 101) with a body mass index (BMI)-for-age >85th percentile were randomized to six dietitian-led behavior counselling sessions or no intervention. Plasma 25-hydroxyvitamin D (25(OH)D), anthropometry, and body composition using dual-energy X-ray absorptiometry were assessed every 3 months for 1 year. For each anthropometry variable (z-scores), tertiles were created to test for differences in 25(OH)D over time (tertile-by-time), and for changes in the z-score (loss, maintain, gain)-by-time, and according to fat patterning (android vs. gynoid) using mixed effects models. Results: The baseline plasma 25(OH)D was 62.2 nmol/L (95%CI: 58.7−65.7), and none < 30 nmol/L. At 6 mo, children with gynoid fat patterning had higher 25(OH)D concentrations than in those with android fat patterning (64.5 ± 1.1 nmol/L vs. 50.4 ± 1.0 nmol/L, p < 0.003, Cohen's f = 0.20). Children with the lowest lean mass index z-score at 9 mo had higher plasma 25(OH)D concentrations than children with the highest z-score at baseline, 3 mo, and 6 mo (p < 0.05, Cohen's f = 0.20). No other significant differences were observed. Conclusion: In this longitudinal study, vitamin D deficiency was not present in children 6−12 y of age with obesity. Reductions in adiposity did not alter the vitamin D status.

Propranolol Attenuates Proangiogenic Activity of Mononuclear Phagocytes: Implication in Choroidal Neovascularization.

Purpose: Targeting ß-adrenergic receptor signaling with propranolol has emerged as a potential candidate to counteract choroidal neovascularization (CNV). Little is known of its effect on macrophages, which play a critical role in CNV. We investigated the effect of propranolol on angiogenic response of mononuclear phagocytes (MPs). Methods: The angiogenic effect of propranolol was evaluated in laser-induced CNV model. Mice received intraperitoneal injections of propranolol (6 mg/kg/d) or vehicle. CNV area and inflammatory cells were determined respectively by using lectin staining and an anti-IBA-1 antibody on RPE/choroid flat mounts. Inflammatory gene expression was evaluated by quantitative (q) PCR analysis. Mechanisms of propranolol was studied in MP cell lines J774 and RAW264.7 and in primary peritoneal macrophages. Expression of pro- and antiangiogenic mediators was studied. In addition, effects of propranolol treatment of MPs was assessed on choroidal explant. Results: CNV was attenuated by propranolol and concomitantly associated with decreased inflammatory mediators IL-6 and TNFα, albeit with accumulation of (ß-adrenoceptor harboring) MPs in the CNV area. Conditioned media from MPs preincubated with propranolol exerted antiangiogenic effects. Treatment of J774 confirmed the attenuation of inflammatory response to propranolol and increased cleaved caspase-3 on choroidal explant. We found that propranolol increased pigment epithelium-derived factor (PEDF) expression in MPs. Trapping of PEDF with an antibody abrogated antiangiogenic effects of propranolol. PEDF was also detected in CNV-associated MPs. Conclusions: We hereby show that propranolol confers on MPs antiangiogenic properties by increasing PEDF expression, which complements its effects on vascular tissue resulting in inhibition of choroidal vasoproliferation in inflammatory conditions. The study supports possible use of propranolol as a therapeutic modality for CNV.

Trimodal prehabilitation for colorectal surgery attenuates post-surgical losses in lean body mass: A pooled analysis of randomized controlled trials.

BACKGROUND & AIMS: Preservation of lean body mass is an important cancer care objective. The capacity for prehabilitation interventions to modulate the lean body mass (LBM) of colorectal cancer patients before and after surgery is unknown. METHODS: A pooled analysis of two randomized controlled trials of trimodal prehabilitation vs. trimodal rehabilitation at a single university-affiliated tertiary center employing Enhanced Recovery After Surgery (ERAS) care was conducted. The prehabilitation interventions included exercise, nutrition, and anxiety-reduction elements that began approximately four weeks before surgery and continued for eight weeks after surgery. The rehabilitation interventions were identical to the prehabilitation interventions but were initiated only after surgery. Body composition, measured using multifrequency bioelectrical impedance analysis, was recorded at baseline, pre-surgery, 4 and 8 weeks after surgery. The primary outcome was change in LBM before and after colorectal surgery for cancer. A mixed effects regression model was used to estimate changes in body mass and body composition over time controlling for age, sex, baseline body mass index (BMI), baseline six-minute walk test (6MWT), and postoperative compliance to the interventions. NCT02586701 &NCT01356264. RESULTS: Pooled data included 76 patients who followed prehabilitation and 63 patients who followed rehabilitation (n = 139). Neither group experienced changes in preoperative LBM. Compared to rehabilitated patients, prehabilitated patients had significantly more absolute and relative LBM at four and eight-weeks post-surgery in models controlling for age, sex, baseline BMI, baseline 6MWT, and compliance to the postoperative intervention. CONCLUSION: Trimodal prehabilitation attenuated the post-surgical LBM loss compared to the loss observed in patients who received the rehabilitation intervention. Patients who receive neither intervention (i.e., standard of care) would be likely to lose more LBM. Offering a prehabilitation program to colorectal cancer patients awaiting resection is a useful strategy to mitigate the impact of the surgical stress response on lean tissue in an ERAS setting, and, in turn, might have a positive impact on the cancer care course. CLINICAL TRIAL REGISTRATION: NCT02586701 &NCT01356264 (clinicaltrials.gov).

Variability in Bariatric Surgical Care Among Various Centers: a Survey of All Bariatric Surgeons in the Province of Quebec, Canada.

BACKGROUND: Despite an increase in bariatric surgery across Quebec, Canada, access is still limited. Furthermore, there are differences in resources and multidisciplinary capabilities of providing centers that may impact quality of care and outcomes. METHODS: We performed an online survey of all bariatric surgeons in the province of Quebec, Canada, using the LimeSurvey software. RESULTS: Forty-six surgeons from 15 centers were surveyed. Response rate was 87% (n = 40). Only 13 (35%) surgeons have any formal fellowship training in bariatric surgery and 74% perform > 50 cases/year. All surgeons perform sleeve gastrectomy, 34% do duodenal switch, and 44% provide major revisions. Thirty-one surgeons (77%) identified access to operating room as the main cause for surgical delays. While most surgeons (52%) considered < 6 months as an acceptable wait-time, only 33% achieved this in their practice. Majority (70%) favored a centralized provincial referral system. Patient's geographical convenience, procedural choice, and multidisciplinary capabilities of providing centers are identified as important determinants for centralized referrals (93, 78, and 55%, respectively). Virtually, all supported accreditation/designation of centers and creation of Quebec Bariatric Network for quality control and research (85 and 98%, respectively). CONCLUSION: Bariatric surgical patterns vary among designated centers in Quebec, Canada. Access to multidisciplinary care and surgeon's fellowship training may be contributing factors for the observed variability. Wait-lists are long and timely access to surgery remains an issue. There is near consensus for establishing a centralized referral system, designation of referral vs. primary centers, and creating Quebec Bariatric Network for research and quality control.

Medium to long-term outcomes of bariatric surgery in older adults with super obesity.

BACKGROUND: Indications and outcomes of bariatric surgery in older adults suffering from morbid obesity remain controversial. We aimed to evaluate safety and medium to long-term outcomes of bariatric procedures in this patient population. SETTING: University Hospital, Canada. METHODS: This is a single-center retrospective study of a prospectively collected database. We included patients aged ≥60 years who underwent sleeve gastrectomy, Roux-en-Y gastric bypass, or biliopancreatic diversion with duodenal switch between January 2006 and December 2014 and had at least 2 years of follow-up. RESULTS: Of patients, 115 underwent bariatric surgeries (11 patients had 2 procedures). There were 66 were super-obese patients (body mass index>50 kg/m2). Of patients, 74% had sleeve gastrectomy, 16% Roux-en-Y gastric bypass, and 8% underwent biliopancreatic diversion with duodenal switch. Mean age and body mass index were 63.3 ± 2.6 years and 51.7 ± 8.1 kg/m2, respectively. Average follow-up time was 42 ± 19 months. At baseline, 78% had hypertension, 60% had type 2 diabetes, and 30% had obstructive sleep apnea. There was no 30-day mortality. Complication rate was 14% (n = 16): 2 leaks post-Roux-en-Y gastric bypass, 1 leak post-biliopancreatic diversion with duodenal switch, 1 obstruction post-sleeve gastrectomy, 1 bleeding requiring transfusion, 1 liver injury with bile leak, 2 port-site hernias, 1 myocardial infarction, 2 gastrojejunal strictures, 1 wound infection, 1 urinary tract infection, and 3 gastric reflux exacerbations. Mean percent excess weight loss at 2 years was 52.2 ± 23.8. Remission rates of hypertension, type-2 diabetes, and obstructive sleep apnea were 26%, 44%, and 38%, respectively. CONCLUSION: Bariatric surgery is safe and effective in improving obesity-related co-morbidities in older patients suffering from morbid obesity. Age alone should not preclude older patients from getting the best bariatric procedure for obesity and related co-morbidities.

Effect of Exercise and Nutrition Prehabilitation on Functional Capacity in Esophagogastric Cancer Surgery: A Randomized Clinical Trial.

Importance: Preserving functional capacity is a key element in the care continuum for patients with esophagogastric cancer. Prehabilitation, a preoperative conditioning intervention aiming to optimize physical status, has not been tested in upper gastrointestinal surgery to date. Objective: To investigate whether prehabilitation is effective in improving functional status in patients undergoing esophagogastric cancer resection. Design, Setting, and Participants: A randomized clinical trial (available-case analysis based on completed assessments) was conducted at McGill University Health Centre (Montreal, Quebec, Canada) comparing prehabilitation with a control group. Intervention consisted of preoperative exercise and nutrition optimization. Participants were adults awaiting elective esophagogastric resection for cancer. The study dates were February 13, 2013, to February 10, 2017. Main Outcomes and Measures: The primary outcome was change in functional capacity, measured with absolute change in 6-minute walk distance (6MWD). Preoperative (end of the prehabilitation period) and postoperative (from 4 to 8 weeks after surgery) data were compared between groups. Results: Sixty-eight patients were randomized, and 51 were included in the primary analysis. The control group were a mean (SD) age, 68.0 (11.6) years and 20 (80%) men. Patients in the prehabilitation group were a mean (SD) age, 67.3 (7.4) years and 18 (69%) men. Compared with the control group, the prehabilitation group had improved functional capacity both before surgery (mean [SD] 6MWD change, 36.9 [51.4] vs -22.8 [52.5] m; P < .001) and after surgery (mean [SD] 6MWD change, 15.4 [65.6] vs -81.8 [87.0] m; P < .001). Conclusions and Relevance: Prehabilitation improves perioperative functional capacity in esophagogastric surgery. Keeping patients from physical and nutritional status decline could have a significant effect on the cancer care continuum. Trial Registration: ClinicalTrials.gov Identifier: NCT01666158.

Prehabilitation with Whey Protein Supplementation on Perioperative Functional Exercise Capacity in Patients Undergoing Colorectal Resection for Cancer: A Pilot Double-Blinded Randomized Placebo-Controlled Trial.

BACKGROUND: A previous comprehensive prehabilitation program, providing nutrition counseling with whey protein supplementation, exercise, and psychological care, initiated 4 weeks before colorectal surgery for cancer, improved functional capacity before surgery and accelerated functional recovery. Those receiving standard of care deteriorated. The specific role of nutritional prehabilitation alone on functional recovery is unknown. OBJECTIVE: This study was undertaken to estimate the impact of nutrition counseling with whey protein on preoperative functional walking capacity and recovery in patients undergoing colorectal resection for cancer. DESIGN: We conducted a double-blinded randomized controlled trial at a single university-affiliated tertiary center located in Montreal, Quebec, Canada. Colon cancer patients (n=48) awaiting elective surgery for nonmetastatic disease were randomized to receive either individualized nutrition counseling with whey protein supplementation to meet protein needs or individualized nutrition counseling with a nonnutritive placebo. Counseling and supplementation began 4 weeks before surgery and continued for 4 weeks after surgery. MAIN OUTCOME MEASURE: The primary outcome was change in functional walking capacity as measured with the 6-minute walk test. The distance was recorded at baseline, the day of surgery, and 4 weeks after surgery. A change of 20 m was considered clinically meaningful. RESULTS: The whey group experienced a mean improvement in functional walking capacity before surgery of +20.8 m, with a standard deviation of 42.6 m, and the placebo group improved by +1.2 (65.5) m (P=0.27). Four weeks after surgery, recovery rates were similar between groups (P=0.81). CONCLUSION: Clinically meaningful improvements in functional walking capacity were achieved before surgery with whey protein supplementation. These pilot results are encouraging and justify larger-scale trials to define the specific role of nutrition prehabilitation on functional recovery after surgery.

Foot-to-foot bioelectrical impedance accurately tracks direction of adiposity change in overweight and obese 7- to 13-year-old children.

Body composition measurements are valuable when evaluating pediatric obesity interventions. We hypothesized that foot-to-foot bioelectrical impedance analysis (BIA) will accurately track the direction of adiposity change, but not magnitude, in part due to differences in fat patterning. The purposes of this study were to examine the accuracy of body composition measurements of overweight and obese children over time using dual-energy x-ray absorptiometry (DXA) and BIA and to determine if BIA accuracy was affected by fat patterning. Eighty-nine overweight or obese children (48 girls, 41 boys, age 7-13 years) participating in a randomized controlled trial providing a family-centered, lifestyle intervention, underwent DXA and BIA measurements every 3 months. Bland-Altman plots showed a poor level of agreement between devices for baseline percent body fat (%BF; mean, 0.398%; +2SD, 8.685%; -2SD, -7.889%). There was overall agreement between DXA and BIA in the direction of change over time for %BF (difference between visits 3 and 1: DXA -0.8 ± 0.5%, BIA -0.7 ± 0.5%; P = 1.000) and fat mass (FM; difference between visits 3 and 1: DXA 0.7 ± 0.5 kg, BIA 0.6 ± 0.5 kg; P = 1.000). Bioelectrical impedance analysis measurements of %BF and FM at baseline were significantly different in those with android and gynoid fat (%BF: 35.9% ± 1.4%, 32.2% ± 1.4%, P < .003; FM: 20.1 ± 0.8 kg, 18.4 ± 0.8, P < .013). Bioelectrical impedance analysis accurately reports the direction of change in FM and FFM in overweight and obese children; inaccuracy in the magnitude of BIA measurements may be a result of fat patterning differences.