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Background: Screening first-degree relatives (FDRs) of patients with premature coronary artery disease (CAD) is recommended but not routinely performed., Objectives: To assess the diagnostic yield and impact on clinical management of a clinical and imaging-based screening program of FDRs delivered in the setting of routine clinical care., Methods: We recruited FDRs of patients with premature CAD with no personal history of CAD and prospectively assessed for: 1) cardiovascular risk and presence of significant subclinical atherosclerosis (SA) defined as plaque on carotid ultrasound, stenosis >50% or extensive atherosclerosis on coronary computed tomography angiography, or coronary artery calcium scores >100 Agatston units or >75% percentile for age and sex; 2) utilization of preventive medications and lipid levels prior enrolment and after completion of the assessment., Results: We assessed 132 FDRs (60.6% females), mean (SD) age 47(17) years old. Cardiovascular risk was high in 38.2%, moderate in 12.2%, and low in 49.6% of FDRs. SA was present in 34.1% of FDRs, including 12.5% in low, 51.9% in moderate, and 55.0% in high calculated risk groups. After assessment, LLT was initiated in 32.6% of FDRs and intensified in 16.0% leading to mean (SD) LDL-C decrease of 1.07(1.10) mmol/L in patients with high calculated risk or SA. LLT was recommended to all patients with high calculated risk, but those with SA were more likely to receive the medications from pharmacies (93.3% vs 60.0%, p = 0.006)., Conclusion: Screening the FDRs of patients with premature CAD is feasible, may have high diagnostic yield and impact risk factor management., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Liam Brunham reports financial support was provided by Canadian Institutes of Health Research. Liam Brunham reports financial support was provided by Genome British Columbia. Liam Brunham reports a relationship with Amgen Canada Inc that includes: board membership. Liam Brunham reports a relationship with Ultragenyx Pharmaceutical Inc that includes: board membership. Liam Brunham reports a relationship with Novartis that includes: board membership. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Objective: To assess patients' and providers' attitudes about the online weight management program and population health management approach in the PROPS Study, which examined the effectiveness of these strategies in primary care., Methods: We conducted semi-structured interviews with 22 patients and nine providers. Using thematic analysis, we analyzed transcripts of the interviews to identify key themes., Results: Most patients found the online program to be well-structured and easy to use, although a few noted that the information was overwhelming or could be more personalized. Patients mentioned that the support from the population health managers was critical for their success, and several reported that they would have liked more involvement from their primary care provider or a dietitian. Providers also were satisfied with the interventions, and several stated that the population health management support was helpful because it added accountability. Providers suggested that the interventions could be improved by tailoring the information and integrating the online program with the electronic health record., Conclusion: Most patients and providers were satisfied with the interventions, with several recommendations for improvements., Innovation: These findings give additional information about patients' and providers' experience with this innovative approach for managing overweight and obesity in primary care., Competing Interests: Dr. Bates consults for EarlySense, which makes patient safety monitoring systems. He receives cash compensation from CDI (Negev), Ltd, which is a not-for-profit incubator for health IT startups. He receives equity from ValeraHealth which makes software to help patients with chronic diseases. He receives equity from Clew which makes software to support clinical decision-making in intensive care. He receives equity from MDClone which takes clinical data and produces deidentified versions of it. He will be receiving research funding from IBM Watson Health. Dr. Rozenblum reports having an equity in Hospitech Respiration Ltd, which makes Airway Management Solutions. He is also receiving research funding from IBM, Boston Scientific Corporation, and MedAware. Dr. Halperin receives cash compensation and equity from Form Health, Inc., (© 2022 The Authors.)

Aims: Insulin potentiates glucose-stimulated insulin secretion. These effects are attenuated in beta cell-specific insulin receptor knockout mice and insulin resistant humans. This investigation examines whether short duration insulin exposure regulates beta cell responsiveness to arginine, a non-glucose secretagogue, in healthy humans., Materials and Methods: Arginine-stimulated insulin secretion was studied in 10 healthy humans. In each subject arginine was administered as a bolus followed by continuous infusion on two occasions one month apart, after sham/saline or hyperinsulinemic-isoglycemic clamp, respectively providing low and high insulin pre-exposure conditions. Arginine-stimulated insulin secretion was measured by C-peptide deconvolution, and by a selective immunogenic (DAKO) assay for direct measurement of endogenous but not exogenous insulin., Results: Pre-exposure to exogenous insulin augmented arginine-stimulated insulin secretion. The effect was seen acutely following arginine bolus (endogenous DAKO insulin incremental AUC 240-255min 311.6 ± 208.1 (post-insulin exposure) versus 120.6 ± 42.2 μU/ml•min (sham/saline) (t-test P = 0.021)), as well as in response to continuous arginine infusion (DAKO insulin incremental AUC 260-290min 1095.3 ± 592.1 (sham/saline) versus 564.8 ± 207.1 μU/ml•min (high insulin)(P = 0.009)). Findings were similar when beta cell response was assessed using C-peptide, insulin secretion rates by deconvolution, and the C-peptide to glucose ratio., Conclusions: We demonstrate a physiologic role of insulin in regulation of the beta cell secretory response to arginine., Competing Interests: Declaration of competing interest The authors have declared that no conflict of interest exists. Dr. Goldfine completed the work when employed at the Joslin Diabetes Center and is now an employee of Novartis Institutes of Biomedical Research. Dr. Halperin completed the work when employed at Brigham and Women's Hospital and Joslin Diabetes Center and now works at Brigham and Women's Hospital and Form Health, Inc., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Glycemic control through titration of insulin dosing remains the mainstay of diabetes mellitus treatment. Insulin therapy is generally divided into dosing with long- and short-acting insulin, where long-acting insulin provides basal coverage and short-acting insulin supports glycemic excursions associated with eating. The dosing of short-acting insulin often involves several steps for the user including blood glucose measurement and integration of potential carbohydrate loads to inform safe and appropriate dosing. The significant burden placed on the user for blood glucose measurement and effective carbohydrate counting can manifest in substantial effects on adherence. Through the application of computer vision, we have developed a smartphone-based system that is able to detect the carbohydrate load of food by simply taking a single image of the food and converting that information into a required insulin dose by incorporating a blood glucose measurement. Moreover, we report the development of comprehensive all-in-one insulin delivery systems that streamline all operations that peripheral devices require for safe insulin administration, which in turn significantly reduces the complexity and time required for titration of insulin. The development of an autonomous system that supports maximum ease and accuracy of insulin dosing will transform our ability to more effectively support patients with diabetes., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Importance: Persistently depressed left ventricular ejection fraction (LVEF) after myocardial infarction (MI) is associated with adverse prognosis and directs the use of evidence-based treatments to prevent sudden cardiac death and/or progressive heart failure., Objective: To assess adherence with guideline-recommended LVEF reassessment and to study the evolution of LVEF over 6 months of follow-up., Design, Setting, and Participants: This was a multicenter cohort study at Canadian academic and community hospitals with on-site cardiac catheterization services. Patients with type 1 acute MI and LVEF less than or equal to 45% during the index hospitalization were enrolled between January 2018 and August 2019 and were followed-up for 6 months. Data analysis was performed from May 2020 to September 2021., Exposures: Baseline clinical factors, in-hospital care and LVEF, and site-specific features., Main Outcomes and Measures: The main outcomes were receipt of repeat LVEF assessment by 6 months and the presence of a persistent LVEF reduction at 2 thresholds: LVEF less than or equal to 40%, prompting consideration of additional medical therapy for heart failure, or LVEF less than or equal to 35%, prompting referral for implanted cardioverter defibrillator in addition to medical therapy., Results: This study included 501 patients (mean [SD] age, 63.3 [13.0] years; 113 women [22.6%]). Overall, 370 patients (73.4%) presented with STEMI, and 454 (90.6%) had in-hospital revascularization. The median (IQR) baseline LVEF was 40% (34%-43%). Of 458 patients (91.4%) who completed the 6-month follow-up, 303 (66.2%; 95% CI, 61.7%-70.5%) had LVEF reassessment, with a range of 46.7% to 90.0% across sites (χ213 = 19.6; P = .11). Participants from community hospitals were more likely than those from academic hospitals to undergo LVEF reassessment (73.6% vs 63.2%; χ21 = 4.50; P = .03), as were those with worse LVEF at baseline. Follow-up LVEF improved by an absolute median (IQR) of 8% (3%-15%). However, 103 patients (34.1%) met the definitions of clinically relevant LVEF reduction, including 52 patients (17.2%) with LVEF less than or equal to 35% and 51 patients (16.9%) with LVEF of 35.1% to 40.0%., Conclusions and Relevance: In this cohort study, approximately 1 in 3 patients with at least mild LVEF reduction after acute MI did not undergo indicated LVEF reassessment within 6 months, suggesting that programs to improve the quality of post-MI care should include measures to ensure that indicated repeat cardiac imaging is performed. In those with follow-up imaging, clinically relevant persistent LVEF reduction was identified in more than one-third of patients.

To improve the power of mediation in high-throughput studies, here we introduce High-throughput mediation analysis (Hitman), which accounts for direction of mediation and applies empirical Bayesian linear modeling. We apply Hitman in a retrospective, exploratory analysis of the SLIMM-T2D clinical trial in which participants with type 2 diabetes were randomized to Roux-en-Y gastric bypass (RYGB) or nonsurgical diabetes/weight management, and fasting plasma proteome and metabolome were assayed up to 3 years. RYGB caused greater improvement in HbA1c, which was mediated by growth hormone receptor (GHR). GHR's mediation is more significant than clinical mediators, including BMI. GHR decreases at 3 months postoperatively alongside increased insulin-like growth factor binding proteins IGFBP1/BP2; plasma GH increased at 1 year. Experimental validation indicates (1) hepatic GHR expression decreases in post-bariatric rats; (2) GHR knockdown in primary hepatocytes decreases gluconeogenic gene expression and glucose production. Thus, RYGB may induce resistance to diabetogenic effects of GH signaling.Trial Registration: Clinicaltrials.gov NCT01073020., (© 2021. The Author(s).)

Importance: Online programs may help with weight loss but have not been widely implemented in routine primary care., Objective: To compare the effectiveness of a combined intervention, including an online weight management program plus population health management, with the online program only and with usual care., Design, Setting, and Participants: Cluster randomized trial with enrollment from July 19, 2016, through August 10, 2017, at 15 primary care practices in the US. Eligible participants had a scheduled primary care visit and were aged 20 to 70 years, had a body mass index between 27 and less than 40, and had a diagnosis of hypertension or type 2 diabetes. Follow-up ended on May 8, 2019., Interventions: Participants in the usual care group (n = 326) were mailed general information about weight management. Participants in the online program only group (n = 216) and the combined intervention group (n = 298) were registered for the online program. The participants in the combined intervention group also received weight-related population health management, which included additional support from nonclinical staff who monitored their progress in the online program and conducted periodic outreach., Main Outcomes and Measures: The primary outcome was weight change at 12 months based on measured weights recorded in the electronic health record. Weight change at 18 months was a secondary outcome., Results: Among the 840 participants who enrolled (mean age, 59.3 years [SD, 8.6 years]; 60% female; 76.8% White), 732 (87.1%) had a recorded weight at 12 months and the missing weights for the remaining participants were imputed. There was a significant difference in weight change at 12 months by group with a mean weight change of -1.2 kg (95% CI, -2.1 to -0.3 kg) in the usual care group, -1.9 kg (95% CI, -2.6 to -1.1 kg) in the online program only group, and -3.1 kg (95% CI, -3.7 to -2.5 kg) in the combined intervention group (P < .001). The difference in weight change between the combined intervention group and the usual care group was -1.9 kg (97.5% CI, -2.9 to -0.9 kg; P < .001) and the difference between the combined intervention group and the online program only group was -1.2 kg (95% CI, -2.2 to -0.3 kg; P = .01). At 18 months, the mean weight change was -1.9 kg (95% CI, -2.8 to -1.0 kg) in the usual care group, -1.1 kg (95% CI, -2.0 to -0.3 kg) in the online program only group, and -2.8 kg (95% CI, -3.5 to -2.0 kg) in the combined intervention group (P < .001)., Conclusions and Relevance: Among primary care patients with overweight or obesity and hypertension or type 2 diabetes, combining population health management with an online program resulted in a small but statistically significant greater weight loss at 12 months compared with usual care or the online program only. Further research is needed to understand the generalizability, scalability, and durability of these findings., Trial Registration: ClinicalTrials.gov Identifier: NCT02656693.

Background: Scalable, low-cost weight management strategies are needed in primary care. We conducted a pragmatic, cluster-randomized controlled trial to examine the effectiveness of an online weight management program integrated with population health management support., Methods: We adapted an online weight management program and integrated it with population health management support in 15 primary care practices (24 clinics). We randomized the 24 clinics to usual care (UC), online program alone (OP), or combined intervention (CI). Eligible participants had to be ages 20 to 70 and have a recent primary care visit, body mass index (BMI) ≥ 27 and < 40 kg/m 2 , and a diagnosis of hypertension or type 2 diabetes. Participants attended routine visits and completed surveys over 18 months. The primary outcome is absolute weight change at 12 months (± 90 days) after enrollment, calculated from weights measured at primary care visits and recorded in the electronic health record., Results: We enrolled 840 participants between July 2016 and August 2017 (326 UC, 216 OP, and 298 CI.) At enrollment, participants' mean age was 59.3 years, their mean weight was 203.1 pounds, and their mean BMI was 32.5 kg/m 2 ; 60% of participants were female, 76.8% were white, 96.4% had hypertension, and 24.4% had type 2 diabetes., Conclusion: It is feasible to adapt an online weight management program and integrate it with population health management support in primary care. The results of this trial will provide valuable information about the effectiveness of these strategies in primary care settings. ClinicalTrials.govregistration number:NCT02656693., Competing Interests: Declaration of Competing Interest Dr. Rozenblum received equity from Hospitech Respiration Ltd., which makes medical devices to reduce complications related to prolonged mechanical ventilation in the ICU. Dr. Bates consults for EarlySense, which makes patient safety monitoring systems. He receives cash compensation from CDI (Negev), Ltd., which is a not-for-profit incubator for health IT startups. He receives equity from ValeraHealth which makes software to help patients with chronic diseases. He receives equity from Clew which makes software to support clinical decision-making in intensive care. He receives equity from MDClone which takes clinical data and produces deidentified versions of it. He will be receiving research funding from IBM Watson Health. Dr. Aronne reports receiving consulting fees from and/or serving on advisory boards for Jamieson Laboratories, Pfizer, Novo Nordisk, Eisai, Real Appeal, Janssen Pharmaceuticals, and Gelesis; receiving research funding from Aspire Bariatrics, Allurion, Eisai, AstraZeneca, Gelesis, Janssen Pharmaceuticals, Eli Lilly, and Novo Nordisk; having an equity interest in Allurion, Intellihealth/BMIQ, ERX, Zafgen, Gelesis, MYOS, and Jamieson Laboratories; and serving on a board of directors for MYOS, Intellihealth/BMIQ and Jamieson Laboratories. Ms. Minero reports being employed and having an equity interest in Intellihealth/BMIQ., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: The primary objective of this study was to ascertain the reasons for emergency department (ED) attendance among patients with a history of atrial fibrillation (AF)., Design: Appropriate ED attendance was defined by the requirement for an electrical or chemical cardioversion and/or an attendance resulting in hospitalisation or administration of intravenous medications for ventricular rate control. Quantitative and qualitative responses were recorded and analysed using descriptive statistics and content analysis, respectively. Random effects logistic regression was performed to estimate the OR of inappropriate ED attendance based on clinically relevant patient characteristics., Participants: Participants ≥18 years with a documented history of AF were approached in one of eight centres partaking in the study across Canada (Ontario, Nova Scotia, Alberta and British Columbia)., Results: Of the 356 patients enrolled (67±13, 45% female), the majority (271/356, 76%) had inappropriate reasons for presentation and did not require urgent ED treatment. Approximately 50% of patients(172/356, 48%) were driven to the ED due to symptoms, while the remainder presented on the basis of general fear or anxiety (67/356, 19%) or prior medical advice (117/356, 33%). Random effects logistic regression analysis showed that patients with a history of congestive heart failure were significantly more likely to seek urgent care for appropriate reasons (p=0.03). Likewise, symptom-related concerns for ED presentation were significantly less likely to result in inappropriate visitation (p=0.02). When patients were surveyed on alternatives to ED care, the highest proportion of responses among both groups was in favour of specialised rapid assessment outpatient clinics (186/356, 52%). Qualitative content analysis confirmed these results., Conclusions: Improved education focused on symptom management and alleviating disease-related anxiety as well as the institution of rapid access arrhythmias clinics may reduce the need for unnecessary healthcare utilisation in the ED and subsequent hospitalisation., Trial Registration Number: NCT03127085., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Coronary artery disease (CAD) is the most common health problem worldwide and remains the leading cause of morbidity and mortality. Over the past decade, it has become clear that the inhabitants of our gut, the gut microbiota, play a vital role in human metabolism, immunity, and reactions to diseases, including CAD. Although correlations have been shown between CAD and the gut microbiota, demonstration of potential causal relationships is much more complex and challenging. In this review, we will discuss the potential direct and indirect causal roots between gut microbiota and CAD development via microbial metabolites and interaction with the immune system. Uncovering the causal relationship of gut microbiota and CAD development can lead to novel microbiome-based preventative and therapeutic interventions. However, an interdisciplinary approach is required to shed light on gut bacterial-mediated mechanisms (e.g., using advanced nanomedicine technologies and incorporation of demographic factors such as age, sex, and ethnicity) to enable efficacious and high-precision preventative and therapeutic strategies for CAD.

Objective: Deposit contracts, where participants "bet" on achieving a goal and get their money back only if successful, have been shown to be effective for short-term weight-loss. This pilot study examined their effect on weight-loss maintenance., Methods: From 2016 to 2018, we conducted a pilot, 50-week randomized controlled trial among 42 hospital employees (19 intervention and 23 control), in Boston, Massachusetts, who lost ≥10 lb (4.5 kg) in the two years prior to enrollment. Participants were recruited primarily in-person. Both control and intervention participants were asked to attend a weigh in weekly and received weekly email communication. Intervention participants also entered into a deposit contract to maintain baseline weight within ≤2 lb (0.9 kg). We examined weight change from baseline to 50 weeks (primary outcome) and maintenance of baseline weight at 50 weeks (secondary outcome; binary - yes v. no). Participants completed baseline and follow-up surveys and received incentives for completion., Results: At baseline, mean (SD) weight was 83.2 (15.5 kg) among intervention and 80.7 (14.5 kg) among control participants. After 50 weeks, intervention participants had slightly less but non-significant weight gain (adjusted β -1.12 kg; 95% CI -5.28, 3.05) than control participants; 73.7% of intervention v. 39.1% of control participants met their weight-loss maintenance goal by study end (adjusted OR 4.78; 95% CI 1.01, 22.71)., Conclusions: A deposit contract was not associated with differences in weight but led to more participants meeting their weight-loss maintenance goals; a deposit contract for weight-loss maintenance should be tested in a full-scale intervention. Most intervention participants viewed the deposit contract as acceptable., (© 2020 Published by Elsevier Inc.)

Eliciting a weight history can provide clinically important information to aid in treatment decision-making. This view is consistent with the life course perspective of obesity and the aim of patient-centered care, one of six domains of health care quality. However, thus far, the value and practicality of including a weight history in the clinical assessment and treatment of patients with obesity have not been systematically explored. For these reasons, the Clinical Committee of The Obesity Society established a task force to review and assess the available evidence to address five key questions. It is concluded that weight history is an essential component of the medical history for patients presenting with overweight or obesity, and there are strong and emerging data that demonstrate the importance of life stage, duration of exposure to obesity, maximum BMI, and group-based trajectory modeling in predicting risk for increased morbidity and mortality. Consideration of these and other patient-specific factors may improve risk stratification and clinical decision-making for screening, counseling, and management. Recommendations are provided for the key elements that should be included in a weight history, and several needs for future clinical research are outlined., (© 2019 The Obesity Society.)

Background: Few randomized trials have compared surgical versus lifestyle and pharmacologic approaches for type 2 diabetes (T2D) patients with mild to moderate obesity., Objectives: This study examined resolution of hyperglycemia (A1C <6.5% and fasting glucose <126 mg/dL) 3 years after randomization to either a laparoscopic adjustable gastric band (LAGB) or 1-year diabetes and weight management (DWM) program., Setting: University medical center, United States., Methods: Forty T2D patients (mean ± SD: age, 51.3 ±10.0 yr; weight 109.5 ± 15.0 kg; body mass index [BMI] 36.5 ± 3.7 kg/m 2 ; HBA1C 8.2% ± 1.2%) were randomized to LAGB (n = 18) or DWM (n = 22)., Results: At 3 years, 13% of 16 patients in LAGB and 5% of 17 patients in DWM achieved resolution of hyperglycemia (P = .601), with a modestly greater reduction in antidiabetic medications in the surgical group (P = .054). Reductions from baseline in A1C were sustained at 3 years in LAGB (-.82% [95% CI: -1.62 to -.01], P = .046) compared with DWM (+.23% [95% CI: -.57 to 1.03], P = .567). The surgical group had greater weight loss (-12.0 kg [95% CI: -15.9 to -8.1] versus -4.8 [95% CI: -8.6 to -.9], P = .010). HDL-cholesterol increased more after surgery (P = .003), but changes in triglycerides, LDL-cholesterol, and blood pressure did not differ between treatments. Diabetes- and obesity-specific quality of life improved comparably with both therapies., Conclusions: Achievement of American Diabetes Association targets for glucose, lipids, and blood pressure was similar with both treatment strategies. LAGB leads to greater sustained weight loss and higher HDL cholesterol compared with a DWM program. These findings may help guide patients with T2D and obesity when exploring options for diabetes and weight management., (Copyright © 2019. Published by Elsevier Inc.)

Oral semaglutide, which has undergone multiple phase 3 clinical trials, represents the first oral biologic medication for type 2 diabetes in the form of a daily capsule. It provides similar efficacy compared with its weekly injection counterpart, but it demands a dose on the order of 100 times as high and requires more frequent administration. We perform a cost effectiveness analysis using a first and second order Monte Carlo simulation to estimate quality-adjusted life expectancies associated with an oral daily capsule, oral weekly capsule, daily injection, and weekly injection of semaglutide. We conclude that the additional costs incurred to produce extra semaglutide for the oral formulation are cost effective, given the greater quality of life experienced when taking a capsule over a weekly injection. We also demonstrate that the potency of semaglutide allows the formulation to be cost effective, and less potent drugs will require increased oral bioavailability to make a cost effective oral formulation., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Background: Primary care providers (PCPs) often take the lead role in caring for patients with overweight and obesity; however, few PCPs counsel patients about weight loss. Online weight management programs that are integrated within primary care may help address this gap in care., Objective: To identify perceptions of and experience with online weight management programs in general and with a proposed online program, to identify barriers to use, and to improve the design and content of our intervention, which included an online program plus population health management (PHM) support from primary care practices., Design: A mixed qualitative methods study including three patient focus groups and seven semi-structured interviews with healthcare providers., Participants: A total of 13 adult patients (age range, 20-70) with body mass index (BMI) 27-35 kg/m 2 attended the focus groups. In-person semi-structured interviews were conducted with seven healthcare providers (three PCPs, two population health managers, one primary care nurse, and one registered dietitian)., Main Measures: We developed and used semi-structured focus groups and interview guides. The focus group and interviews were recorded and transcribed. Using grounded theory, we analyzed the transcripts to identify and extract common concepts and themes., Key Results: Although patients and healthcare providers expressed positive opinions about online weight management programs, few patients had experience with them, and providers stated that such programs are not being widely implemented in primary care settings. Some participants highlighted the flexibility and low cost as strengths of online weight management tools compared with in-person programs. All participants had favorable opinions about our proposed intervention and were overwhelmingly positive about the combination of an online program and PHM support., Conclusions: This study highlights the potential value of online weight management programs and PHM support in primary care., Clinical Trials Registration: NCT02656693.

Objective: To compare the effect of Roux-en-Y gastric bypass (RYGB) surgery versus intensive medical diabetes and weight management (IMWM) on clinical and patient-reported outcomes in obese patients with type 2 diabetes., Research Design and Methods: We prospectively randomized 38 obese patients with type 2 diabetes (15 male and 23 female, with mean ± SD weight 104 ± 16 kg, BMI 36.3 ± 3.4 kg/m 2 , age 52 ± 6 years, and HbA 1c 8.5 ± 1.3% [69 ± 14 mmol/mol]) to laparoscopic RYGB ( n = 19) or IMWM ( n = 19). Changes in weight, HbA 1c , cardiovascular risk factors (UKPDS risk engine), and self-reported health status (the 36-Item Short-Form [SF-36] survey, Impact of Weight on Quality of Life [IWQOL] instrument, and Problem Areas in Diabetes Survey [PAID]) were assessed., Results: After 3 years, the RYGB group had greater weight loss (mean -24.9 kg [95% CI -29.5, -20.4] vs. -5.2 [-10.3, -0.2]; P < 0.001) and lowering of HbA 1c (-1.79% [-2.38, -1.20] vs. -0.39% [-1.06, 0.28] [-19.6 mmol/mol {95% CI -26.0, -13.1} vs. -4.3 {-11.6, 3.1}]; P < 0.001) compared with the IMWM group. Changes in cardiometabolic risk for coronary heart disease and stroke were all more favorable in RYGB versus IMWM ( P < 0.05 to P < 0.01). IWQOL improved more after RYGB ( P < 0.001), primarily due to subscales of physical function, self-esteem, and work performance. SF-36 and PAID scores improved in both groups, with no difference between treatments. A structural equation model demonstrated that improvement in overall quality of life was more strongly associated with weight loss than with improved HbA 1c and was manifest by greater improvements in IWQOL than with either SF-36 or PAID., Conclusions: Three years after randomization to RYGB versus IMWM, surgery produced greater weight loss, lower HbA 1c , reduced cardiovascular risk, and improvements in obesity-related quality of life in obese patients with type 2 diabetes., (© 2018 by the American Diabetes Association.)

Objective: To evaluate the association between weight loss and rheumatoid arthritis (RA) disease activity., Methods: We conducted a retrospective cohort study of RA patients seen at routine clinic visits at an academic medical center, 2012-2015. We included patients who had ≥2 clinical disease activity index (CDAI) measures. We identified visits during follow-up where the maximum and minimum weights occurred and defined weight change and CDAI change as the differences of these measures at these visits. We defined disease activity improvement as CDAI decrease of ≥5 and clinically relevant weight loss as ≥5 kg. We performed logistic regression analyses to establish the association between improved disease activity and weight loss and baseline BMI category (≥25 kg/m 2 or <25 kg/m 2 ). We built linear regression models to investigate the association between continuous weight loss and CDAI change among patients who were overweight/obese at baseline and who lost weight during follow-up., Results: We analyzed data from 174 RA patients with a median follow-up of 1.9 years (IQR 1.3-2.4); 117 (67%) were overweight/obese at baseline, and 53 (31%) lost ≥5 kg during follow-up. Patients who were overweight/obese and lost ≥5 kg had three-fold increased odds of disease activity improvement compared to those who did not (OR 3.03, 95%CI 1.18-7.83). Among those who were overweight/obese at baseline, each kilogram weight loss was associated with CDAI improvement of 1.15 (95%CI 0.42-1.88). Our study was limited by using clinical data from a single center without fixed intervals for assessments., Conclusion: Clinically relevant weight loss (≥5 kg) was associated with improved RA disease activity in the routine clinical setting. Further studies are needed for replication and to evaluate the effect of prospective weight loss interventions on RA disease activity.

Background: The purpose of this study was to compare effects of Roux-en-Y gastric bypass versus a multidisciplinary, group-based medical diabetes and weight management program on physical fitness and behaviors., Methods: Physical behavior and fitness were assessed in participants of the study Surgery or Lifestyle With Intensive Medical Management in the Treatment of Type 2 Diabetes (SLIMM-T2D) (NCT01073020), a randomized, parallel-group trial conducted at a US academic hospital and diabetes clinic with 18- to 24-month follow-up. Thirty-eight type 2 diabetes patients with hemoglobin A 1c ≥6.5% and body mass index 30-42 kg/m 2 were randomized to Roux-en-Y gastric bypass or the medical program. A 6-minute walk test to evaluate fitness, self-reported physical activity, standardized physical surveys, and cardiometabolic risk assessment were performed at baseline and after intervention., Results: Both groups similarly improved 6-minute walk test distance, with greater improvements in oxygen saturation and reduced heart rate after surgery. Self-reported physical activity improved similarly at 18-24 months after interventions, although exercise increased gradually after surgery, whereas early substantial increases in the medical group were not fully sustained. Self-reported total and physical health were similar by Short Form-36 but improved more in the Impact of Weight on Quality of Life survey after surgery. Improvement in cardiovascular risk scores, HbA 1c , and body mass index were greater after surgery., Conclusion: In this small, randomized study, both interventions led to therapeutic lifestyle changes and improved objective and self-reported physical fitness. Greater improvements in heart rate, oxygen saturation, and perceived impact of weight on health were seen after surgery, which could be attributable to greater weight loss. The clinical importance of these improvements with greater weight loss warrants further investigation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The effects of ethylene oxide (EO), vaporized hydrogen peroxide (VHP), gamma (γ) radiation, and electron-beam (E-beam) on the physiochemical and morphological properties of medical device polymers are investigated. Polymers with ether, carbonate, carboxylic acid, amide and ester functionalities are selected from a family of poly(ethylene glycol) (PEG) containing tyrosine-derived polycarbonates (TyrPCs) to include slow, medium, fast, and ultrafast degrading polymers. Poly(lactic acid) (PLA) is used for comparison. Molecular weight ( M w ) of all tested polymers decreases upon gamma and E-beam, and this effect becomes more pronounced at higher PEG content. Gamma sterilization increases the glass transition temperature of polymers with high PEG content. EO esterifies the carboxylic acid groups in desaminotyrosol-tyrosine (DT) and causes significant degradation. VHP causes hydroxylation of the phenyl ring, and hydrolytic degradation. This study signifies the importance of the chemical composition when selecting a sterilization method, and provides suggested conditions for each of the sterilization methods.

Context: Roux-en-Y gastric bypass (RYGB) leads to high-turnover bone loss, but little is known about skeletal effects of laparoscopic adjustable gastric banding (LAGB) or mechanisms underlying bone loss after bariatric surgery., Objective: To evaluate effects of RYGB and LAGB on fasting and postprandial indices of bone remodeling., Design and Setting: Ancillary investigation of a prospective study at 2 academic institutions., Participants: Obese adults aged 21-65 years with type 2 diabetes who underwent RYGB (n = 11) or LAGB (n = 8)., Outcomes: Serum C-terminal telopeptide (CTX), procollagen type 1 N-terminal propeptide (P1NP), and PTH were measured during a mixed meal tolerance test at baseline, 10 days and 1 year after surgery. Changes in 25-hydroxyvitamin D, polypeptide YY (PYY), glucagon-like peptide-1, glucose-dependent insulinotropic peptide, and insulin were also assessed., Results: Fasting CTX increased 10 days after RYGB but not LAGB (+69 ± 23% vs +12±12%, P < .001), despite comparable weight loss at that time. By 1 year, fasting CTX and P1NP increased more after RYGB than LAGB (CTX +221 ± 60% vs +15 ± 6%, P<0.001; P1NP +93 ± 25% vs -9 ± 10%, P < .001) and weight loss was greater with RYGB. Changes in CTX were independent of PTH and 25-hydroxyvitamin D but were associated with increases in fasting PYY. Postprandial suppression of CTX was more pronounced after RYGB than LAGB at 10 days and 1 year postoperatively., Conclusions: RYGB is accompanied by early increases in fasting indices of bone remodeling, independent of weight loss or changes in PTH or 25-hydroxyvitamin D. LAGB did not affect bone markers. PYY and other enterohormonal signals may play a role in RYGB-specific skeletal changes.

Objective: To investigate the effect of weight loss after bariatric surgery among patients with rheumatoid arthritis (RA)., Methods: We conducted a retrospective cohort study of RA patients who underwent bariatric surgery (Roux-en-Y gastric bypass, laparoscopic adjustable gastric banding, or sleeve gastrectomy) at 2 medical centers. We obtained information on anthropometrics, laboratory values, RA disease activity, and medication use at baseline (prior to surgery), at 6 and 12 months following surgery, and at the most recent followup visits. RA disease activity was determined by clinical or validated measures. At each postsurgical visit, characteristics were compared to baseline., Results: We identified 53 RA patients who underwent bariatric surgery. At baseline prior to surgery, mean ± SD body mass index was 47.8 ± 7.7 kg/m(2), mean ± SD weight was 128.2 ± 24.1 kg, and 57% had moderate to high RA disease activity. Twelve months following surgery, subjects lost a mean ± SD weight of 41.0 ± 17.3 kg, mean ± SD 70% ± 24% excess weight (P < 0.001). RA disease activity significantly improved at postsurgical visits (P < 0.001). At 12 months following surgery, 6% had moderate to high disease activity, compared to 57% at baseline (P < 0.001). At the most recent followup (mean ± SD 5.8 ± 3.2 years after surgery), 74% were in remission, compared to 26% at baseline (P < 0.001). Subjects had significantly lower erythrocyte sedimentation rate, C-reactive protein level, and RA-related medication use at followup visits compared to baseline (P < 0.05)., Conclusion: After substantial weight loss from bariatric surgery, RA patients had lower disease activity, decreased serum inflammatory markers, and less RA-related medication use. Weight loss may be an important nonpharmacologic strategy to reduce RA disease activity. However, other factors, such as improved efficacy of medications, improved physical activity, and metabolic changes, may also have contributed to these postsurgical improvements., (© 2015, American College of Rheumatology.)

Context: Recommendations for surgical, compared with lifestyle and pharmacologically based, approaches for type 2 diabetes (T2D) management remain controversial., Objective: The objective was to compare laparoscopic adjustable gastric band (LAGB) to an intensive medical diabetes and weight management (IMWM) program for T2D., Design: This was designed as a prospective, randomized clinical trial., Setting: The setting was two Harvard Medical School-affiliated academic institutions. INTERVENTIONS AND PARTICIPANTS: A 12-month randomized trial comparing LAGB (n = 23) vs IMWM (n = 22) in persons aged 21-65 years with body mass index of 30-45 kg/m(2), T2D diagnosed more than 1 year earlier, and glycated hemoglobin (HbA(1c)) ≥ 6.5% on antihyperglycemic medication(s)., Main Outcome Measure: The proportion meeting the prespecified primary glycemic endpoint, defined as HbA(1c) < 6.5% and fasting glucose < 7.0 mmol/L at 12 months, on or off medication., Results: After randomization, five participants did not undergo the surgical intervention. Of the 40 initiating intervention (22 males/18 females; age, 51 ± 10 y; body mass index, 36.5 ± 3.7 kg/m(2); diabetes duration, 9 ± 5 y; HbA(1c), 8.2 ± 1.2%; 40% on insulin), the proportion meeting the primary glycemic endpoint was achieved in 33% of the LAGB patients and 23% of the IMWM patients (P = .457). HbA(1c) reduction was similar between groups at both 3 and 12 months (-1.2 ± 0.3 vs -1.0 ± 0.3%; P = .496). Weight loss was similar at 3 months but greater 12 months after LAGB (-13.5 ± 1.7 vs -8.5 ± 1.6 kg; P = .027). Systolic blood pressure reduction was greater after IMWM than LAGB, whereas changes in diastolic blood pressure, lipids, fitness, and cardiovascular risk scores were similar between groups. Patient-reported health status, assessed using the Short Form-36, Impact of Weight on Quality of Life, and Problem Areas in Diabetes, all improved similarly between groups., Conclusions: LAGB and a multidisciplinary IMWM program have similar 1-year benefits on diabetes control, cardiometabolic risk, and patient satisfaction, which should be considered in the context of other factors, such as personal preference, when selecting treatment options with obese T2D patients. Longer duration studies are important to understand emergent differences.

Background: During Roux-en-Y gastric bypasses (RYGB), some surgeons elect to perform a vagotomy to reduce symptoms of gastro-oesophageal reflux (GER). Routine vagotomy during RYGB may independently affect weight loss and metabolic outcomes following bariatric surgery. We aimed to determine whether vagotomy augments percent excess weight loss in obese patients after RYGB., Methods: We examined the effect of vagotomy in 1278 patients undergoing RYGB at our institution from 2003 to 2009. Weight and percent excess weight loss (%EWL) were modelled at three months and annually up to five years using a longitudinal linear mixed model controlling for differences in age, gender, initial body mass index (BMI), ideal body weight, and presence of vagotomy., Results: Vagotomy was performed on 40.3% of our cohort. Vagotomy patients had significantly lower initial BMI (46.4±6.2 vs. 48.3±7.7kg/m(2), p<0.001), but there were no other significant differences at baseline. The strongest predictor of %EWL over time was initial BMI, with lower BMI patients exhibiting greater %EWL (p<0.001). Age and gender effects were also significant, with younger patients (p<0.04) and males (p<0.002) attaining greater %EWL. Vagotomy had no effect on %EWL in either simple or multiple regression models., Conclusion: Our series suggest that vagotomy does not augment %EWL when performed with RYGB., (Copyright © 2014 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.)

Importance: Emerging data support bariatric surgery as a therapeutic strategy for management of type 2 diabetes mellitus., Objective: To test the feasibility of methods to conduct a larger multisite trial to determine the long-term effect of Roux-en-Y gastric bypass (RYGB) surgery compared with an intensive diabetes medical and weight management (Weight Achievement and Intensive Treatment [Why WAIT]) program for type 2 diabetes., Design, Setting, and Participants: A 1-year pragmatic randomized clinical trial was conducted in an academic medical institution. Participants included persons aged 21 to 65 years with type 2 diabetes diagnosed more than 1 year before the study; their body mass index was 30 to 42 (calculated as weight in kilograms divided by height in meters squared) and hemoglobin A1c (HbA1c) was greater than or equal to 6.5%. All participants were receiving antihyperglycemic medications., Interventions: RYGB (n = 19) or Why WAIT (n = 19) including 12 weekly multidisciplinary group lifestyle, medical, and educational sessions with monthly follow-up thereafter., Main Outcomes and Measures: Proportion of patients with fasting plasma glucose levels less than 126 mg/dL and HbA1c less than 6.5%, measures of cardiometabolic health, and patient-reported outcomes., Results: At 1 year, the proportion of patients achieving HbA1c below 6.5% and fasting glucose below 126 mg/dL was higher following RYGB than Why WAIT (58% vs 16%, respectively; P = .03). Other outcomes, including HbA1c, weight, waist circumference, fat mass, lean mass, blood pressure, and triglyceride levels, decreased and high-density lipoprotein cholesterol increased more after RYGB compared with Why WAIT. Improvement in cardiovascular risk scores was greater in the surgical group. At baseline the participants exhibited moderately low self-reported quality-of-life scores reflected by Short Form-36 total, physical health, and mental health, as well as high Impact of Weight on Quality of Life-Lite and Problem Areas in Diabetes health status scores. At 1 year, improvements in Short Form-36 physical and mental health scores and Problem Areas in Diabetes scores did not differ significantly between groups. The Impact of Weight on Quality of Life-Lite score improved more with RYGB and correlated with greater weight loss compared with Why WAIT., Conclusions and Relevance: In obese patients with type 2 diabetes, RYGB produces greater weight loss and sustained improvements in HbA1c and cardiometabolic risk factors compared with medical management, with emergent differences over 1 year. Both treatments improve general quality-of-life measures, but RYGB provides greater improvement in the effect of weight on quality of life. These differences may help inform therapeutic decisions for diabetes and weight loss strategies in obese patients with type 2 diabetes until larger randomized trials are performed., Trial Registration: clinicaltrials.gov Identifier: NCT01073020.

Purpose of Review: Bariatric surgery has emerged as a highly effective treatment for obesity and is increasingly recognized to have benefits for glycemic management in patients with pre-existing type 2 diabetes mellitus (T2DM), and for diabetes prevention. This article will review the efficacy and mechanisms of metabolic surgery for the treatment of T2DM., Recent Findings: Recent small randomized studies with 1-2 years of follow-up begin to provide level 1 data of the effects of surgical procedures compared to medical management on glycemic control. Physiology studies using sophisticated metabolic techniques to evaluate insulin secretion, action, and entero-endocrine changes in patients preoperatively and postoperatively have shed light on the mechanisms that lead to changes in glycemia observed after bariatric surgery., Summary: Understanding the efficacy and physiologic effects of bariatric surgery on metabolism will help guide patient management in the context of a growing epidemic of obesity and T2DM, and may also ultimately enable us to develop less invasive but equally effective therapeutic strategies for weight loss and metabolic control.

An amphiphilic macromolecule (AM) was exposed to ionizing radiation (both electron beam and gamma) at doses of 25 kGy and 50 kGy to study the impact of these sterilization methods on the physicochemical properties and bioactivity of the AM. Proton nuclear magnetic resonance and gel permeation chromatography were used to determine the chemical structure and molecular weight, respectively. Size and zeta potential of the micelles formed from AMs in aqueous media were evaluated by dynamic light scattering. Bioactivity of irradiated AMs was evaluated by measuring inhibition of oxidized low-density lipoprotein uptake in macrophages. From these studies, no significant changes in the physicochemical properties or bioactivity were observed after the irradiation, demonstrating that the AMs can withstand typical radiation doses used to sterilize materials.

Type 2 diabetes (T2D) is characterized by insulin resistance and pancreatic β-cell dysfunction, the latter possibly caused by a defect in insulin signaling in β-cells. We hypothesized that insulin's effect to potentiate glucose-stimulated insulin secretion (GSIS) would be diminished in insulin-resistant persons. To evaluate the effect of insulin to modulate GSIS in insulin-resistant compared with insulin-sensitive subjects, 10 participants with impaired glucose tolerance (IGT), 11 with T2D, and 8 healthy control subjects were studied on two occasions. The insulin secretory response was assessed by the administration of dextrose for 80 min following a 4-h clamp with either saline infusion (sham) or an isoglycemic-hyperinsulinemic clamp using B28-Asp-insulin (which can be distinguished immunologically from endogenous insulin) that raised insulin concentrations to high physiologic concentrations. Pre-exposure to insulin augmented GSIS in healthy persons. This effect was attenuated in insulin-resistant cohorts, both those with IGT and those with T2D. Insulin potentiates glucose-stimulated insulin secretion in insulin-resistant subjects to a lesser degree than in normal subjects. This is consistent with an effect of insulin to regulate β-cell function in humans in vivo with therapeutic implications.

The effect of electron beam and gamma radiation on the physicochemical properties of a salicylate-based poly(anhydride-ester) was studied by exposing polymers to 0 (control), 25 and 50 kGy. After radiation exposure, salicylic acid release in vitro was monitored to assess any changes in drug release profiles. Molecular weight, glass transition temperature and decomposition temperature were evaluated for polymer chain scission and/or crosslinking as well as changes in thermal properties. Proton nuclear magnetic resonance and infrared spectroscopies were also used to determine polymer degradation and/or chain scission. In vitro cell studies were performed to identify cytocompatibility following radiation exposure. These studies demonstrate that the physicochemical properties of the polymer are not substantially affected by exposure to electron beam and gamma radiation.

Glucocorticoid-remediable aldosteronism (GRA) is a hereditary form of primary hyperaldosteronism and the most common monogenic cause of hypertension. A chimeric gene duplication leads to ectopic aldosterone synthase activity in the cortisol-producing zona fasciculata of the adrenal cortex, under the regulation of adrenocorticotropin (ACTH). Hypertension typically develops in childhood, and may be refractory to standard therapies. Hypokalemia is uncommon in the absence of treatment with diuretics. The discovery of the genetic basis of the disorder has permitted the development of accurate diagnostic testing. Glucocorticoid suppression of ACTH is the mainstay of treatment; alternative treatments include mineralocorticoid receptor antagonists., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background. Hyperinsulinemic hypoglycemia with neuroglycopenia is a rare complication of Roux-en-Y gastric bypass (RYGB). We hypothesized that continuous glucose monitoring (CGM) would be useful to characterize glycemic variability after RYGB. Methods. CGM and mixed meal tolerance testing (MMTT) were performed on sixteen post-RYGB subjects, ten with a history of neuroglycopenia on medical treatment and six asymptomatic controls. Results. 9 of 10 subjects with neuroglycopenia developed hypoglycemia defined by glucose <70 mg/dL on CGM, and 3 of 9 on MMTT. In asymptomatic subjects, 3 of 6 had asymptomatic hypoglycemia during CGM, and 3 of 5 on MMTT. Therefore, the sensitivity and specificity to detect clinically significant hypoglycemia was 90% and 50% for CGM and 33% and 40% for MMTT. Conclusions. Asymptomatic hypoglycemia after RYGB is more frequent than commonly recognized. For clinicians evaluating patients for postbypass neuroglycopenia, CGM may be a valuable diagnostic tool.

Hyperinsulinemic hypoglycemia is a recently described complication of Roux-en-Y gastric bypass (RYGB). We hypothesized that glucagon administration would help maintain normal postprandial plasma glucose concentrations by stimulating hepatic glucose output, and if so, represent a new therapeutic option for postbypass hypoglycemia. In this study, we compared the insulin and glycemic response to a mixed meal with and without concomitant glucagon infusion in a patient with severe recurrent hypoglycemia after RYGB. Although effective in transiently raising postprandial plasma glucose values, glucagon infusion was also associated with higher insulin concentrations, and failed to prevent symptomatic hypoglycemia. This case demonstrates that glucagon may have limited clinical utility in the treatment of post-RYGB hyperinsulinemic hypoglycemia.

Background: A previously healthy 32-year-old man presented with pain in his chest, ankle, and hip. His musculoskeletal pain progressed over the course of 6 months to the point of difficulty with ambulation., Investigations: Radiographic studies included chest and ankle X-rays, multiple bone scans, and foot and pelvic MRI. Laboratory evaluation comprised a serum chemistry panel (including electrolyte levels, renal function tests and liver function tests), and measuring serum levels of phosphorus, parathyroid hormone, vitamin D, alkaline phosphatase, and fibroblast growth factor 23, as well as urine levels of calcium and phosphorus., Diagnosis: Tumor-induced osteomalacia., Management: The patient received phosphate and vitamin D supplementation in the form of potassium-phosphorus (500 mg, three times daily) and calcitriol (0.5 microg, three times daily). Six months after his first presentation, he underwent surgical resection of a rib mass, with subsequent normalization of phosphorus concentration.

The goal of this study was to evaluate whether sodium bicarbonate might be a useful form of therapy for hypoxic L-lactic acidosis; our aim was to determine if alkali could extend the time of survival in this setting. Hypoxia was induced in anesthetized, paralyzed, artificially ventilated rats by lowering inspired O2 to 5.5%, an amount sufficient to develop a severe degree of L-lactic acidosis. Measuring arterial blood gases frequently permitted maintenance of a near-constant arterial O2 content. Three groups of hypoxic rats were studied: first, no infusions (n = 10); second, sodium bicarbonate at a rate equal to H+ production in the no-infusion group (n = 12); and third, a control for the Na load in the second group as NaCl (n = 17). Survival was close to twofold longer in the sodium bicarbonate group. Part of this beneficial effect seemed to be increased anaerobic glycolysis, producing ATP along with L-lactic acid. In addition, there was a large decrease in the metabolic demand (consumption of O2) in the 7- to 15-min period in the sodium bicarbonate group. Rats exposed to hypoxia and infused with NaCl for 15 min or alkali for 15, 27, or 40 min were then returned to room air; all survived for the subsequent experimental period of 150 min. We found that there is both a rationale and experimental evidence for giving sodium bicarbonate to prolong survival during hypoxia.

The purpose of these experiments was to examine the factors which regulate ethanol metabolism in vivo. Since the major pathway for ethanol removal requires flux through hepatic alcohol dehydrogenase, the activity of this enzyme was measured and found to be 2.9 mumol/(min X g liver). Ethanol disappearance was linear for over 120 min in vivo and the blood ethanol fell 0.1 mM/min; this is equivalent to removing 20 mumol ethanol/min and would require that flux through alcohol dehydrogenase be about 60% of its measured maximum velocity. To test whether ethanol metabolism was limited by the rate of removal of one of the end products (NADH) of alcohol dehydrogenase, fluoropyruvate was infused to reoxidize hepatic NADH and to prevent NADH generation via flux through pyruvate dehydrogenase. There was no change in the rate of ethanol clearance when fluoropyruvate was metabolized. Furthermore, enhancing endogenous hepatic NADH oxidation by increasing the rate of urea synthesis (converting ammonium bicarbonate to urea) did not augment the steady-state rate of ethanol oxidation. Hence, transport of cytoplasmic reducing power from NADH into the mitochondria was not rate limiting for ethanol oxidation. In contrast, ethanol oxidation at the earliest time periods could be augmented by increasing hepatic urea synthesis.