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Summary: Obesity derives from an extended period of positive energy imbalance due to a complex interplay of environmental and biological factors. Muscle fiber type and physiology have been hypothesized to affect metabolism and energy expenditure and thus to affect an individual's propensity to gain weight. However, there have been conflicting reports regarding a relationship between muscle fiber type and obesity. Here, we systematically reviewed literature investigating this topic from PubMed, Web of Science, and EMBASE. Of these, 32 articles were included in our final review and analysis. Most studies (22/32) reported a significant relationship between muscle fiber‐type proportion and a measure of obesity. Overall, there was a significant negative relationship between the proportion of type I fibers and body mass index (BMI) and a significant positive relationship between the proportion of type IIX fibers and BMI. Moreover, between‐group comparisons indicated a greater prevalence of type IIX fibers and a lower prevalence of type I fibers in patients living with obesity relative to lean individuals. These significant relationships were confirmed in a meta‐analysis of these data. The causal nature of these associations remains to be evaluated. [ABSTRACT FROM AUTHOR]

Common multi-allelic copy number variants (CNVs) appear enriched for phenotypic associations compared to their biallelic counterparts. Here we investigated the influence of gene dosage effects on adiposity through a CNV association study of gene expression levels in adipose tissue. We identified significant association of a multi-allelic CNV encompassing the salivary amylase gene (AMY1) with body mass index (BMI) and obesity, and we replicated this finding in 6,200 subjects. Increased AMY1 copy number was positively associated with both amylase gene expression (P = 2.31 × 10−14) and serum enzyme levels (P < 2.20 × 10−16), whereas reduced AMY1 copy number was associated with increased BMI (change in BMI per estimated copy = −0.15 (0.02) kg/m2; P = 6.93 × 10−10) and obesity risk (odds ratio (OR) per estimated copy = 1.19, 95% confidence interval (CI) = 1.13-1.26; P = 1.46 × 10−10). The OR value of 1.19 per copy of AMY1 translates into about an eightfold difference in risk of obesity between subjects in the top (copy number > 9) and bottom (copy number < 4) 10% of the copy number distribution. Our study provides a first genetic link between carbohydrate metabolism and BMI and demonstrates the power of integrated genomic approaches beyond genome-wide association studies. [ABSTRACT FROM AUTHOR]

Abstract: Background context: Low back pain (LBP) is a prevalent and costly condition. Although its etiology is largely unknown, a link to obesity is suspected, and weight loss programs are often recommended to obese patients with LBP. Purpose: To assess the efficacy of a pilot, multidisciplinary, medically supervised, nonsurgical weight loss program involving meal replacement, caloric restriction, education, exercise, and group therapy at reducing the severity of LBP in obese adults. Study design: Pilot prospective cohort study. Patient sample: A total of 46 obese adults (mean body mass index [BMI] 44.7±7.6 kg/m2) referred to an academic hospital for a multidisciplinary, medically supervised, nonsurgical weight loss program who reported LBP were enrolled. Outcome measures: The severity of LBP was measured using the Numerical Pain Scale (NPS) and modified Oswestry Disability Index (ODI) at baseline (Week 1), Week 14, and Week 53; weight, BMI, dietary adherence, and physical activity levels were also measured. Methods: The 52-week weight loss program was administered by a team of physicians, dieticians, exercise specialists, and nurses and included liquid meal replacements for 12 weeks, followed by supervised caloric restriction diets for 13 weeks. Participants also attended weekly group therapy and educational meetings for the first 26 weeks, after which they were instructed to continue caloric restriction diets, engage in 60 to 90 minutes of daily physical activity, and attend monthly group meetings for an additional 26 weeks. Results: At baseline, NPS was mild in 61% (n=28), moderate in 30% (n=14), and severe in 9% (n=4), whereas ODI was moderate in 48% (n=22), severe in 17% (n=8), and crippling in 4% (n=2). At Week 14 (n=42; 92% follow-up), there were significant improvements in NPS (p=.001) and ODI (p=.0005), and significant weight loss (p<.0001). At Week 53 (n=28; 61% follow-up), there was a trend toward improvement in NPS (p=.07), significant improvement in ODI (p=.0009), and significant weight loss (p=.0005); reduction in BMI was significantly associated with clinically important improvements in ODI (p=.046). Conclusions: This pilot prospective cohort study suggests that a 52-week multidisciplinary, medically supervised, nonsurgical weight loss program in obese patients with LBP improved both pain and function. [Copyright &y& Elsevier]

Body weight is a quantitative trait with significant heritability in humans. To identify potential genetic contributors to this phenotype, we resequenced the coding exons and splice junctions of 58 genes in 379 obese and 378 lean individuals. Our 96-Mb survey included 21 genes associated with monogenic forms of obesity in humans or mice, as well as 37 genes that function in body weight-related pathways. We found that the monogenic obesity-associated gene group was enriched for rare nonsynonymous variants unique to the obese population compared with the lean population. In addition, computational analysis predicted a greater fraction of deleterious variants within the obese cohort. Together, these data suggest that multiple rare alleles contribute to obesity in the population and provide a medical sequencing-based approach to detect them. [ABSTRACT FROM AUTHOR]

Accurate weight predictions are essential for weight management program patients. The freely available National Institutes of Health Body Weight Planner (NIH-BWP) returns expected weights over time but overestimates weight when patients consume a low-calorie diet. This study sought to increase the accuracy of NIH-BWP predicted weights for people on low-calorie diets. People enrolled in a weight management program were included if they received meal replacements with defined caloric content for the 3 months of the weight loss phase of the program. The Ottawa Weight Loss Prediction Model (OWL-PM) modelled the relative difference between observed and NIH-BWP predicted weights using longitudinal analysis methods based on patient factors. OWL-PM was externally validated. 1761 people were included (mean age 46 years, 73.3% women) with a mean (SD) baseline weight in pounds and body mass index of 271.9 (55.6) and 43.9 (7.4), respectively. At the end of the program's weight loss phase, people lost a median (IQR) of 17.1% (14.8-19.5) of their baseline weight. Observed weight relative to NIH-BWP predicted weights had a median value of - 4.9% but ranged from - 32.1% to + 28.5%. After adjustment, weight overestimation by NIH-BWP was most pronounced in male patients, people without diabetes and with increased observation time. OWL-PM returned expected weights at 3 months that were significantly more accurate than those from NIH-BWP alone (mean difference observed vs. expected [95% CI] 6.7lbs [6.4-7.0] vs. 12.6lbs [12.1-13.0]). In the external validation cohort (n = 106), OWL-PM was significantly more accurate than NIH-BWP (mean squared error 24.3 vs. 40.0, p = 0.0018). OWL-PM incorporated patient-level covariates to significantly increase weight prediction accuracy of NIH-BWP in patients consuming a low-calorie diet., (© 2024. The Author(s).)

Abstract: The weapons of mass destruction-civil support team (WMD-CST) physician associate/assistant (PA) is an autonomous PA who balances military and civilian roles to achieve mission success and support the safety of the US public. This article by multiple WMD-CST PAs across the nation describes the WMD-CST PA profession and how traditional PA roles continue to advance., (Copyright © 2024 American Academy of Physician Associates.)

Objective: Full meal replacement (FMR) Intensive Lifestyle Interventions (ILI) have been used for weight management. However, predictors of efficacy with these programs are less clear. The primary objective was to assess weight loss predictors in a community-based FMR ILI program. A secondary objective was to determine if weight loss was different between virtual and in person ILI., Methods: This was a retrospective cohort study involving 234 patients who started the program between 1 January 2016 and 3 March 2021. In the 24-week program, patients spent 12 weeks on FMR and then transitioned back to food for the remainder, with weekly follow up with a physician and group sessions with a dietitian. Visits were in person prior to March 2020 and virtual afterward., Results: Patients' average age was 47.5 years (SD = 12.0) and 73.5% were female. Average weight loss was 14.3% (SD = 6.2%). There was no significant difference in weight loss between virtual and in person programs. Patients on a Glucagon-like Peptide-1 Receptor Agonist prior lost less weight. Other significant associations between groups were baseline Hemoglobin A 1 C, classes attended, as well as the age since peak weight., Conclusion: Weight loss from virtual ILI was not significantly different from person ILI. More research is needed to determine how to best stratify care as virtual or in person using FMR programs., Competing Interests: We have no conflicts of interest to disclose., (© 2023 The Authors. Obesity Science & Practice published by World Obesity and The Obesity Society and John Wiley & Sons Ltd.)

Models predicting individual body weights over time clarify patient expectations in weight loss programs. The accuracy of two commonly used weight prediction models in community living people is unclear. All eligible people entering a weight management program between 1992 and 2015 were included. Patients' diet was 1200 kcal/day for week 0 followed by 900 kcal/day for weeks 1-7 and were excluded from the analysis if they were nonadherent. We generated expected weights using the National Institutes of Health Body Weight Planner (NIH-BWP) and the Pennington Biomedical Research Center Weight Loss Predictor (PBRC-WLP). 3703 adherent people were included (mean age 46 years, 72.6% women, mean [SD] weight 262.3 pounds [54.2], mean [SD] BMI 42.4 [7.6]). Mean (SD) relative body weight differences (100*[observed-expected]/expected) for NIH-BWP and PBRC-WLP models was - 1.5% (3.8) and - 2.9% (3.2), respectively. At week 7, mean squared error with NIH-BWP (98.8, 83%CI 89.7-108.8) was significantly lower than that with PBRC-WLP (117.7, 83%CI 112.4-123.4). Notable variation in relative weight difference were seen (for NIH-BWP, 5th-95th percentile was - 6.2%, + 3.7%; Δ 9.9%). During the first 7 weeks of a weight loss program, both weight prediction models returned expected weights that were very close to observed values with the NIH-BWP being more accurate. However, notable variability between expected and observed weights in individual patients were seen. Clinicians can monitor patients in weight loss programs by comparing their progress with these data., (© 2023. The Author(s).)

There is a significant threat to global health security due to synthetic opioids, illicitly manufactured fentanyl (IMF), and nefarious uses of pharmaceutical based agents (PBA). Since 2014, increased distribution of synthetic opioids including IMF into the US through China, India, and Mexico has resulted in devastating consequences to the average street drug user. Additionally, clandestine lab operations for pill manufacturing and distribution have increased, along with unintentional drug overdoses due to drugs being laced with fentanyl or some other synthetic opioid derivative. Naloxone has been shown to be an effective and useful tool for reversing signs and symptoms of synthetic opioid overdose, though additional doses may be required depending on the analog. In addition to the risk of overdose in US civilians, other state actors have utilized fentanyl and its analogs as incapacitants resulting in significant numbers of casualties. The National Guard Weapons of Mass Destruction-Civil Support Teams (WMD-CST) have been on the front lines supporting federal law enforcement agencies with hazard identification and assessment. Physician Assistants (PA) are assigned to these units and provide the necessary skills and expertise to keep on scene personnel safe. This article aims to dispel some of the rumors and myths surrounding fentanyl in an effort to educate first receivers, first responders, and hospital providers. Lastly, this article provides a review of synthetic opioid production, overdose, hazards, treatment/countermeasures, decontamination for responders, and the potential use of synthetic opioids as WMDs.

Background: Current paradigms for predicting weight loss in response to energy restriction have general validity but a subset of individuals fail to respond adequately despite documented diet adherence. Patients in the bottom 20% for rate of weight loss following a hypocaloric diet (diet-resistant) have been found to have less type I muscle fibres and lower skeletal muscle mitochondrial function, leading to the hypothesis that physical exercise may be an effective treatment when diet alone is inadequate. In this study, we aimed to assess the efficacy of exercise training on mitochondrial function in women with obesity with a documented history of minimal diet-induced weight loss., Methods: From over 5000 patient records, 228 files were reviewed to identify baseline characteristics of weight loss response from women with obesity who were previously classified in the top or bottom 20% quintiles based on rate of weight loss in the first 6 weeks during which a 900 kcal/day meal replacement was consumed. A subset of 20 women with obesity were identified based on diet-resistance (n=10) and diet sensitivity (n=10) to undergo a 6-week supervised, progressive, combined aerobic and resistance exercise intervention., Findings: Diet-sensitive women had lower baseline adiposity, higher fasting insulin and triglycerides, and a greater number of ATP-III criteria for metabolic syndrome. Conversely in diet-resistant women, the exercise intervention improved body composition, skeletal muscle mitochondrial content and metabolism, with minimal effects in diet-sensitive women. In-depth analyses of muscle metabolomes revealed distinct group- and intervention- differences, including lower serine-associated sphingolipid synthesis in diet-resistant women following exercise training., Interpretation: Exercise preferentially enhances skeletal muscle metabolism and improves body composition in women with a history of minimal diet-induced weight loss. These clinical and metabolic mechanism insights move the field towards better personalised approaches for the treatment of distinct obesity phenotypes., Funding: Canadian Institutes of Health Research (CIHR-INMD and FDN-143278; CAN-163902; CIHR PJT-148634)., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: Roux-en-Y gastric bypass (RYGB) surgery produces significant weight loss. However, a number of patients experience weight regain years after surgery. Factors driving weight regain after surgical interventions are currently being explored. Our objective was to investigate appetite-related measures associated with weight regain after RYGB surgery., Materials and Methods: Using a cross-sectional design, 29 participants (49.6 ± 9.1 years of age; current BMI 32.4 ± 4.7 kg/m 2 , 43.6 ± 8.9 months post-RYGB) were stratified into tertiles according to weight regain per month after nadir (weight maintenance (WM), n = 9; low weight regain (LWR), n = 10; and high weight regain (HWR), n = 10). The average weight regain was, by design, significantly different between the groups (WM = 2.2 ± 2.5 kg; LWR = 10.0 ± 3.4 kg; HWR = 14.9 ± 6.3 kg regained, p < 0.05). Appetite (visual analog scales), olfactory performance ("sniffin sticks"), eating behaviors (Three Factor Eating Questionnaire), food reward (Leeds Food Preference Questionnaire), and appetite-related hormones (ghrelin, PYY, GLP-1 and leptin) were measured fasting and in response to a standardized test meal., Results: Dietary restraint was significantly higher than clinical cutoffs in WM and LWR (p < 0.05). As expected, significant time effects were noted for ghrelin, PYY, and GLP-1, but there were no group differences., Conclusion: The results suggest that appetite-related outcomes are similar across individuals who have maintained weight loss and experienced regain following RYGB., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: Our aim in this study was to compare the change in waist circumference given the same degree of weight loss in patients who meet the criteria for metabolic syndrome or type 2 diabetes and those who do not meet these criteria. Because visceral adiposity is a key feature of both conditions and intra-abdominal adipocytes show higher lipolytic activity, we sought to determine whether changes in waist circumference differed in individuals with and without these conditions., Methods: The Ottawa Hospital Weight Management Clinic offers a course in lifestyle modification and uses 12 weeks of total meal replacement. We compared the decrease in waist circumference between patients with metabolic syndrome or diabetes and those without these conditions who had lost a similar amount of weight using measurements from the first 6 weeks of meal replacement., Results: We evaluated 3,559 patients who attended the program between September 1992 and April 2015. The patient population was largely Caucasian and of European descent and all meetings were face to face. The mean weight loss for men was 15.1±20.2 kg, and the mean weight loss for women was 9.7±2.4 kg. There were no significant differences in decrease in waist circumference between those with and without metabolic syndrome in both men (11.7±3.9 cm vs 11.4±3.8 cm, p=0.48) and women (9.0±3.6 cm vs 9.1±3.7 cm, p=0.26)., Conclusions: Our results show that, given the same degree of weight loss, patients with and without diabetes or metabolic syndrome experience a similar change in waist circumference., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

Here, we performed a genome-wide search for methylation sites that contribute to the risk of obesity. We integrated methylation quantitative trait locus (mQTL) data with BMI GWAS information through a SNP-based multiomics approach to identify genomic regions where mQTLs for a methylation site co-localize with obesity risk SNPs. We then tested whether the identified site contributed to BMI through Mendelian randomization. We identified multiple methylation sites causally contributing to the risk of obesity. We validated these findings through a replication stage. By integrating expression quantitative trait locus (eQTL) data, we noted that lower methylation at cg21178254 site upstream of CCNL1 contributes to obesity by increasing the expression of this gene. Higher methylation at cg02814054 increases the risk of obesity by lowering the expression of MAST3 , whereas lower methylation at cg06028605 contributes to obesity by decreasing the expression of SLC5A11 . Finally, we noted that rare variants within 2p23.3 impact obesity by making the cg01884057 site more susceptible to methylation, which consequently lowers the expression of POMC , ADCY3 and DNAJC27 . In this study, we identify methylation sites associated with the risk of obesity and reveal the mechanism whereby a number of these sites exert their effects. This study provides a framework to perform an omics-wide association study for a phenotype and to understand the mechanism whereby a rare variant causes a disease.

Current obesity treatment strategies include diet, exercise, bariatric surgery, and a limited but growing repertoire of medications. Individual weight loss in response to each of these strategies is highly variable. Here we review research into factors potentially contributing to inter-individual variability in response to treatments for obesity, with a focus on studies in humans. Well-recognized factors associated with weight loss capacity include diet adherence, physical activity, sex, age, and specific medications. However, following control for each of these, differences in weight loss appear to persist in response to behavioral, pharmacological and surgical interventions. Adaptation to energy deficit involves complex feedback mechanisms, and inter-individual differences likely to arise from a host of poorly defined genetic factors, as well as differential responses in neurohormonal mechanisms (including gastrointestinal peptides), metabolic efficiency and capacity of tissues, non-exercise activity thermogenesis, thermogenic response to food, and in gut microbiome. A better understanding of the factors involved in inter-individual variability in response to therapies will guide more personalized approaches to the treatment of obesity., Competing Interests: Declaration of competing interest None of the authors has any financial or personal relationships with people or organizations that could inappropriately influence this work., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Chronic inflammation is a common feature of obesity, with elevated cytokines such as interleukin-1 (IL-1) in the circulation and tissues. Here, we report an unconventional IL-1R-MyD88-IRAK2-PHB/OPA1 signaling axis that reprograms mitochondrial metabolism in adipocytes to exacerbate obesity. IL-1 induced recruitment of IRAK2 Myddosome to mitochondria outer membranes via recognition by TOM20, followed by TIMM50-guided translocation of IRAK2 into mitochondria inner membranes, to suppress oxidative phosphorylation and fatty acid oxidation, thereby attenuating energy expenditure. Adipocyte-specific MyD88 or IRAK2 deficiency reduced high-fat-diet-induced weight gain, increased energy expenditure and ameliorated insulin resistance, associated with a smaller adipocyte size and increased cristae formation. IRAK2 kinase inactivation also reduced high-fat diet-induced metabolic diseases. Mechanistically, IRAK2 suppressed respiratory super-complex formation via interaction with PHB1 and OPA1 upon stimulation of IL-1. Taken together, our results suggest that the IRAK2 Myddosome functions as a critical link between inflammation and metabolism, representing a novel therapeutic target for patients with obesity.

Background: Obesity is increasing globally. Chronic kidney disease (CKD) is strongly associated with obesity. Kidney function is commonly estimated with equations using creatinine (such as CKD-EPI equation) which is a product of muscle metabolism. Decisions about categorizing CKD, planning modality of renal replacement therapies, and adjusting dosages of medications excreted by the kidneys are done using these equations. However, it is not well appreciated that creatinine-based equations may not accurately estimate kidney function in obese individuals. We plan a systematic review of diagnostic studies which will compare estimating equations to actual measured kidney function., Methods: We will systematically search electronic bibliographic databases including MEDLINE, EMBASE, and the Cochrane Library with no restrictions on language or specific dates. The search terms will be adapted for the different databases using a combination of Medical Subject Heading and relevant keywords contained in titles and abstracts. Our preliminary search strategy using Cochrane, MEDLINE, and EMBASE databases have identified 190, 1246, and 1660 citations, respectively. For all studies selected, we will extract information on general study characteristics, study participant (age, sex, ethnicity, weight, height, BMI, BSA), type and protocol of reference standard utilized, the index test studied, the methodology of measurement of index test, categories of GFR, the proportion of eGFR within 10, 20, 30, 40, and 50% of measured GFR, and bias between eGFR and measured GFR. If the quality of methods and risk of bias are adequate, we will perform a meta-analysis. We will assess the heterogeneity using the χ 2 and the I 2 statistics to examine whether the estimates from studies included could be pooled. Sensitivity and multivariate meta-regression analyses will be performed to assess the effects of clinical factors and socio-demographic characteristics reported in included studies on the meta-analytic estimates. All analysis will be performed using the Comprehensive Meta-analysis software., Discussion: This systematic review might help to inform clinicians on the best equation to use in patients with obesity and CKD for staging of CKD and for medication dosing. If no equation is deemed suitable, this review will form a basis for future studies of GFR in obese individuals., Systematic Review Registration: PROSPERO CRD42018104345.

Hundreds of genetic variants have been associated with Body Mass Index (BMI) through genome-wide association studies (GWAS) using observational cohorts. However, the genetic contribution to efficient weight loss in response to dietary intervention remains unknown. We perform a GWAS in two large low-caloric diet intervention cohorts of obese participants. Two loci close to NKX6.3/MIR486 and RBSG4 are identified in the Canadian discovery cohort (n = 1166) and replicated in the DiOGenes cohort (n = 789). Modulation of HGTX (NKX6.3 ortholog) levels in Drosophila melanogaster leads to significantly altered triglyceride levels. Additional tissue-specific experiments demonstrate an action through the oenocytes, fly hepatocyte-like cells that regulate lipid metabolism. Our results identify genetic variants associated with the efficacy of weight loss in obese subjects and identify a role for NKX6.3 in lipid metabolism, and thereby possibly weight control.

Background: Acyl-CoA Synthetase Long Chain 5 (ACSL5) gene's rs2419621 T/C polymorphism was associated with ACSL5 mRNA expression and response to lifestyle interventions. However, the mechanistic understanding of the increased response in T allele carriers is lacking. Study objectives were to investigate the effect of rs2419621 genotype and ACSL5 human protein isoforms on fatty acid oxidation and respiration., Methods: Human ACSL5 overexpression in C2C12 mouse myoblasts was conducted to measure 14 C palmitic acid oxidation and protein isoform localization in vitro. 14 C palmitic acid oxidation studies and Western blot analysis of ACSL5 proteins were carried out in rectus abdominis primary myotubes from 5 rs2419621 T allele carriers and 4 non-carriers. In addition, mitochondrial high-resolution respirometry was conducted on vastus lateralis muscle biopsies from 4 rs2419621 T allele carriers and 4 non-carriers. Multiple linear regression analysis was conducted to test the association between rs2419621 genotype and respiratory quotient related pre- and post-lifestyle intervention measurements in postmenopausal women with overweight or obesity., Results: In comparison to rs2419621 non-carriers, T allele carriers displayed higher levels of i) 683aa ACSL5 isoform, localized mainly in the mitochondria, playing a greater role in fatty acid oxidation in comparison to the 739aa protein isoform ii) in vitro CO 2 production in rectus abdominis primary myotubes iii) in vivo fatty acid oxidation and lower carbohydrate oxidation post-intervention iv) ex vivo complex I and II tissue respiration in vastus lateralis muscle., Conclusions: These results support the conclusion that rs2419621 T allele carriers, are more responsive to lifestyle interventions partly due to an increase in the short ACSL5 protein isoform, increasing cellular, tissue and whole-body fatty acid utilization. With the increasing effort to develop personalized medicine to combat obesity, our findings provide additional insight into genotypes that can significantly affect whole body metabolism and response to lifestyle interventions., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: A 6-month weight-management program with full meal replacement, low-calorie diet (full MR-LCD) (900 kcal/day for 6 to 12 weeks) follows a protocol for patients with diabetes for decreasing or discontinuing weight-gaining diabetes medications first (Group WG) and then titrating weight-neutral medications (Group WN)., Methods: This is a retrospective cohort study (1992 to 2009) of weight, glycemic control and diabetes medications changes in 317 patients with obesity and type 2 diabetes who were taking medications., Results: Group WG and Group WN were similar at baseline, except that glycated hemoglobin (A1C) levels were significantly lower in Group WN (7.5% vs. 6.6%; p<0.001). At 6 months, both groups had lost 16% of their weight, and the decreases or discontinuations of medications were 92.1% sulfonureas, 86.5% insulins, 78.8% thiazolidinediones, 77.8% alpha-glucosidase inhibitors, 50% meglitinides, 33.3% dipeptidyl peptidase-4 (DPP-4) inhibitors and 32.8% metformin. At 6 months, compared with baseline, A1C levels improved in Group WG and Group WN (6-month A1C levels 6.7% and 5.8%, respectively; p<0.0001), and Group WN had significantly better A1C levels than Group WG. At 6 months, 30% of patients were no longer taking diabetes medications and had significantly better percentages of weight loss compared with those taking medications (18.6% vs. 16%; p=0.002); both groups had improved glycemic control at 6 months (A1C 6.0% vs. A1C 6.6%; NS)., Conclusions: In patients with obesity and type 2 diabetes taking medications, a full MR-LCD program appears to be safe and includes improvement in A1C levels. At 6 months, the percentage of weight loss can be significantly better in patients who no longer require diabetes medications, and A1C levels are best controlled in patients who are on WN medications., (Copyright © 2017 Diabetes Canada. Published by Elsevier Inc. All rights reserved.)

Background: The effects of β-blockers on metabolic parameters including weight loss are poorly understood., Methods: From a database of 3582 patients who completed The Ottawa Hospital Weight Management Program between 1992 and 2011, a total of 173 patients were receiving β-blockers and were eligible for the study. We determined differences in rate of weight loss in the first 6 weeks of this 900 kcal/d Optifast (Nestlé Health Science, Vevey, Switzerland) meal replacement program for patients treated with β-blockers compared with (1) matched controls and (2) all participants in the program not being treated with β-blockers. Secondary outcomes included changes in waist circumference., Results: Mean percent weight loss in the β-blocker group was reduced compared with the rest of the group (9.7% vs 10.0%; P = 0.0001) as well as with matched controls (9.7% vs 10.3%; P = 0.004). Results were the same after adjusting for prevalent cardiovascular disease (9.7% vs 10.0%; P = 0.006). Similarly, a smaller decrease in waist circumference at 6 weeks was observed in the β-blocker-treated group compared with the rest of the group (-24.2 vs -26.3 cm; P = 0.002) and with matched controls (-24.2 vs -25.2 cm; P = 0.04) and was not altered by adjustment for cardiovascular disease (-24.2 vs 26.3 cm; P = 0.004)., Conclusions: In the absence of a clear medical indication, alternatives to β-blockers should be considered for the treatment of hypertension in obese individuals., (Copyright © 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Aims/hypothesis: Skeletal muscle mitochondrial dysfunction has been documented in patients with type 2 diabetes mellitus; however, specific respiratory defects and their mechanisms are poorly understood. The aim of the current study was to examine oxidative phosphorylation and electron transport chain (ETC) supercomplex assembly in rectus abdominis muscles of 10 obese diabetic and 10 obese non-diabetic individuals., Methods: Twenty obese women undergoing Roux-en-Y gastric bypass surgery were recruited for this study. Muscle samples were obtained intraoperatively and subdivided for multiple analyses, including high-resolution respirometry and assessment of supercomplex assembly. Clinical data obtained from referring physicians were correlated with laboratory findings., Results: Participants in both groups were of a similar age, weight and BMI. Mitochondrial respiration rates were markedly reduced in diabetic vs non-diabetic patients. This defect was observed during maximal ADP-stimulated respiration in the presence of complex I-linked substrates and complex I- and II-linked substrates, and during maximal uncoupled respiration. There were no differences in fatty acid (octanoyl carnitine) supported respiration, leak respiration or isolated activity of cytochrome c oxidase. Intriguingly, significant correlations were found between glycated haemoglobin (HbA1c) levels and maximal respiration or respiration supported by complex I, complex I and II or fatty acid. In the muscle of diabetic patients, blue native gel electrophoresis revealed a striking decrease in complex I, III and IV containing ETC supercomplexes., Conclusions/interpretation: These findings support the hypothesis that ETC supercomplex assembly may be an important underlying mechanism of muscle mitochondrial dysfunction in type 2 diabetes mellitus.

The inverse relationship between obesity and adverse cardiovascular outcomes has been coined the 'obesity-paradox'. We sought to determine the relationship between measures of obesity [body mass index (BMI), body surface area (BSA) and body fat percentage (BF%)] and coronary artery calcification (CAC). We retrospectively analyzed patients who underwent CAC using the Agatston score. Baseline demographics were collected and BMI, BSA and BF% were calculated. A two-stage regression modeling approach was used to evaluate the association between BMI, BSA, BF% and Agatston score. Of the 6661 patients [mean age = 57.1 ± 10.8 years, men = 54.3%, median Agatston score = 14 (0, 163)], 0.1% were underweight, 21.3% had normal BMI, 39.1% were overweight and 39.4% were obese. The mean BMI, BSA and BF% were 29.6 ± 6.1 kg/m(2), 1.97 ± 0.25 m(2) and 37 ± 10 %, respectively. There was an independent association between the presence of CAC and BMI (5 kg/m(2) increments) (OR 1.05, CI 1.00-1.11, P = 0.038) and BF% (OR 2.38, CI 1.05-5.41, P = 0.038). Neither BMI categories nor large BSA independently predicted the presence of CAC. BF% predicted the extent of CAC in men but not in women, and higher BF% was associated with higher category of CAC severity in men only. BMI and BF% were independent predictors of the presence of CAC. BF% was associated with the extent of CAC and higher BF% was associated with higher category of CAC severity in men only. These results suggest that further study is needed to better understand the obesity-paradox.

Context: Weight loss success in response to energy restriction is highly variable. This may be due in part to differences in mitochondrial function and oxidative stress., Objective: The objective of the study was to determine whether mitochondrial function, content, and oxidative stress differ in well-matched obese individuals in the upper [obese diet sensitive (ODS)] vs lower quintiles [obese diet resistant (ODR)] for rate of weight loss., Design: Primary myotubes derived from muscle biopsies of individuals identified as ODS or ODR were studied., Setting: Compliant ODS and ODR females who completed in the Ottawa Hospital Weight Management Program and identified as ODS and ODR participated in this study., Patients or Other Participants: Eleven ODS and nine ODR weight-stable females matched for age, body mass, and body mass index participated in this study., Intervention: Vastus lateralis muscle biopsies were obtained and processed for muscle satellite cell isolation., Main Outcome Measures: Mitochondrial respiration, content, reactive oxygen species, and glutathione redox ratios were measured in the myotubes of ODS and ODR individuals., Results: Mitochondrial proton leak was increased in myotubes of ODS compared with ODR (P < .05). Reduced and oxidized glutathione was decreased in the myotubes of ODR vs ODS (P < .05), indicating a more oxidized glutathione redox state. There were no differences in myotube mitochondrial content, uncoupling protein 3, or adenine nucleotide translocase levels., Conclusions: Lower rate of mitochondrial proton leak in muscle is a cell autonomous phenomenon in ODR vs ODS individuals, and this is associated with a more oxidized glutathione redox state in ODR vs ODS myotubes. The muscle of ODR subjects may thus have a lower capacity to adapt to oxidative stress as compared with ODS.

The Patient Protection and Affordable Care Act (PPACA, 2010) and the Institute of Medicine's (IOM, 2011) Future of Nursing report have prompted changes in the U.S. health care system. This has also stimulated a new direction of thinking for the profession of nursing. New payment and priority structures, where value is placed ahead of volume in care, will start to define our health system in new and unknown ways for years. One thing we all know for sure: we cannot afford the same inefficient models and systems of care of yesterday any longer. The Data-Driven Model for Excellence in Staffing was created as the organizing framework to lead the development of best practices for nurse staffing across the continuum through research and innovation. Regardless of the setting, nurses must integrate multiple concepts with the value of professional nursing to create new care and staffing models. Traditional models demonstrate that nurses are a commodity. If the profession is to make any significant changes in nurse staffing, it is through the articulation of the value of our professional practice within the overall health care environment. This position paper is organized around the concepts from the Data-Driven Model for Excellence in Staffing. The main concepts are: Core Concept 1: Users and Patients of Health Care, Core Concept 2: Providers of Health Care, Core Concept 3: Environment of Care, Core Concept 4: Delivery of Care, Core Concept 5: Quality, Safety, and Outcomes of Care. This position paper provides a comprehensive view of those concepts and components, why those concepts and components are important in this new era of nurse staffing, and a 3-year challenge that will push the nursing profession forward in all settings across the care continuum. There are decades of research supporting various changes to nurse staffing. Yet little has been done to move that research into practice and operations. While the primary goal of this position paper is to generate research and innovative thinking about nurse staffing across all health care settings, a second goal is to stimulate additional publications. This includes a goal of at least 20 articles in Nursing Economic$ on best practices in staffing and care models from across the continuum over the next 3 years.

One of the first encounters many people have with a health care institution occurs in the emergency department. If that area presents a poor picture to patients and their families, the whole institution can be seen as negative. How a tertiary care facility identified a way to improve the appropriate use of the emergency dept is the focus of this article., (Copyright 2010 Elsevier Inc. All rights reserved.)

Tumor suppressor candidate 5 (TUSC5) is a gene expressed abundantly in white adipose tissue (WAT), brown adipose tissue (BAT), and peripheral afferent neurons. Strong adipocyte expression and increased expression following peroxisome proliferator activated receptor gamma (PPARgamma) agonist treatment of 3T3-L1 adipocytes suggested a role for Tusc5 in fat cell proliferation and/or metabolism. However, the regulation of Tusc5 in WAT and its potential association with obesity phenotypes remain unclear. We tested the hypothesis that the TUSC5 gene is a bona fide PPARgamma target and evaluated whether its WAT expression or single-nucleotide polymorphisms (SNPs) in the TUSC5 coding region are associated with human obesity. Induction of Tusc5 mRNA levels in 3T3-L1 adipocytes by troglitazone and GW1929 followed a dose-response consistent with these agents' binding affinities for PPARgamma. Chromatin immunoprecipitation (ChIP) experiments confirmed that PPARgamma protein binds a approximately -1.1 kb promotor sequence of murine TUSC5 transiently during 3T3-L1 adipogenesis, concurrent with histone H3 acetylation. No change in Tusc5 mRNA or protein levels was evident in type 2 diabetic patients treated with pioglitazone. Tusc5 expression was not induced appreciably in liver preparations overexpressing PPARs, suggesting that tissue-specific factors regulate PPARgamma responsiveness of the TUSC5 gene. Finally, we observed no differences in Tusc5 WAT expression or prevalence of coding region SNPs in lean versus obese human subjects. These studies firmly establish the murine TUSC5 gene locus as a PPARgamma target, but the significance of Tusc5 in obesity phenotypes or in the pharmacologic actions of PPARgamma agonists in humans remains equivocal.

Background: AMP-activated protein kinase (AMPK) is a heterotrimeric enzyme that is evolutionarily conserved from yeast to mammals and functions to maintain cellular and whole body energy homeostasis. Studies in experimental animals demonstrate that activation of AMPK in skeletal muscle protects against insulin resistance, type 2 diabetes and obesity. The regulatory gamma(3) subunit of AMPK is expressed exclusively in skeletal muscle; however, its importance in controlling overall AMPK activity is unknown. While evidence is emerging that gamma subunit mutations interfere specifically with AMP activation, there remains some controversy regarding the impact of gamma subunit mutations. Here we report the first gain-of-function mutation in the muscle-specific regulatory gamma(3) subunit in humans., Methods and Findings: We sequenced the exons and splice junctions of the AMPK gamma(3) gene (PRKAG3) in 761 obese and 759 lean individuals, identifying 87 sequence variants including a novel R225W mutation in subjects from two unrelated families. The gamma(3) R225W mutation is homologous in location to the gamma(2)R302Q mutation in patients with Wolf-Parkinson-White syndrome and to the gamma(3)R225Q mutation originally linked to an increase in muscle glycogen content in purebred Hampshire Rendement Napole (RN-) pigs. We demonstrate in differentiated muscle satellite cells obtained from the vastus lateralis of R225W carriers that the mutation is associated with an approximate doubling of both basal and AMP-activated AMPK activities. Moreover, subjects bearing the R225W mutation exhibit a approximately 90% increase of skeletal muscle glycogen content and a approximately 30% decrease in intramuscular triglyceride (IMTG)., Conclusions: We have identified for the first time a mutation in the skeletal muscle-specific regulatory gamma(3) subunit of AMPK in humans. The gamma(3)R225W mutation has significant functional effects as demonstrated by increases in basal and AMP-activated AMPK activities, increased muscle glycogen and decreased IMTG. Overall, these findings are consistent with an important regulatory role for AMPK gamma(3) in human muscle energy metabolism.

Peroxisome proliferator-activated receptor gamma (PPARgamma) and its response gene, Acyl CoA synthetase 5 (ACSL5), which has an important role in fatty acid metabolism, may affect weight loss in response to caloric restriction. Therefore, we aimed to determine whether these genes were involved in the interindividual response to dietary treatment. Genotypic/phenotypic comparisons were made between selected obese women from the quintiles losing the most (diet responsive, n = 74) and the quintiles losing the least (diet-resistant, n = 67) weight in the first 6 weeks of a 900-kcal formula diet. Two common PPARgamma single nucleotide polymorphisms, Pro(12)Ala and C1431T, and eight polymorphisms across the ACSL5 gene were selected for single locus and haplotypic association analyses. The PPARgamma Pro(12)Ala single nucleotide polymorphism was associated with diet resistance (odds ratio = 3.48, 95% confidence interval = 1.41 to 8.56, p = 0.03), and the rs2419621, located in the 5'untranslated region of the ACSL5 gene, displayed the strongest association with diet response (odds ratio = 3.45, 95% confidence interval = 1.61 to 7.69, p = 0.001). Skeletal muscle ACSL5 mRNA expression was significantly lower in carriers of the wildtype compared with the variant rs2419621 allele (p = 0.03). Our results suggest a link between PPARgamma2 and ACSL5 genotype and diet responsiveness.