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Background: Longevity clusters in families, and parental longevity may be associated with lower risk of chronic diseases in their children. It is unknown if diabetes risk is associated with parental longevity.Methods: We evaluated participants in the Diabetes Prevention Program with a parental history questionnaire at study entry. We classified them into five groups: premature death (parental death at age < 50 years), parental longevity (living to at least 80 years), and three intermediate groups (alive by age 49 but dying at age 50-59, 60-69, or 70-79). Those with alive parents and younger than 80 years were excluded. We analyzed separately effects of paternal (n = 2,165) and maternal (n = 1,739) longevity on diabetes incidence and risk after an average follow-up of 3.2 years.Results: At baseline, more diabetes risk factors (parental history of diabetes, coronary heart disease, higher body mass index, homeostasis model assessment for insulin resistance, and corrected insulin response) were found in participants whose parents died prematurely. Diabetes incidence was 9.5 cases/100 person-years in the 229 whose fathers died prematurely. In the 618 with paternal longevity, the rate was 6.6 cases/100 person-years (hazard ratio [95% confidence interval] = 0.68 [0.49-0.94]). The rates were 10.7 cases/100 person-years (n = 156) and 7.3 cases/100 person-years (n = 699, hazard ratio = 0.67 [95% confidence interval 0.47-0.95]) for those with maternal premature death or longevity, respectively. Associations with demographic and diabetes risk factors had minimal influence on the reduced risk found in those with paternal (adjusted hazard ratio = 0.78, 95% confidence interval 0.52-1.16) and maternal (adjusted hazard ratio = 0.64, 95% confidence interval 0.41-1.01) longevity.Conclusion: Parental longevity is associated with lower diabetes incidence in adults at high risk of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to determine the dose-response relationships for edrophonium antagonism of mivacurium-induced neuromuscular block.Method: Seventy-five ASA physical status I or II adults were given mivacurium 0.15 mg.kg-1 followed by an infusion (7 micrograms.kg-1.min-1) during alfentanil-propofol-N2O anaesthesia. Train-of-four stimulation (TOF) was applied to the ulnar nerve every 20 sec and the response of the adductor digiti minimi was recorded (Relaxograph NMT-100, DATEX, Helsinki, Finland). Mivacurium infusion was adjusted at five minutes intervals in order to keep the height of the first twitch in TOF (T1) at 5% of its control value. At the end of surgery, the mivacurium infusion was stopped and edrophonium 0.0, 0.05, 0.1, 0.5 or 1.0 mg.kg-1 combined respectively with glycopyrrolate 0.0, 0.0005, 0.001, 0.005 or 0.01 mg.kg-1 were administered by random allocation.Results: All four edrophonium doses tested were statistically different from placebo with regard to time to attain a TOF ratio (fourth twitch in TOF/T1) = 0.7 (0.05:780 +/- 179, 0.1:727 +/- 216, 0.5:547 +/- 287 and 1.0:640 +/- 236 vs 0.0 mg.kg-1:1089 +/- 323 sec P < 0.05). Does of 0.1, 0.5 and 1.0 mg.kg-1 permitted faster recovery time of T1 from 10 to 95% (T10-95) (567 +/- 236, 419 +/- 166, 555 +/- 288 vs 861 +/- 224 sec P < 0.05) and from 25 to 75% (T25-75) (253 +/- 121, 147 +/- 92, 217 +/- 175 vs 429 +/- 154 sec P < 0.05) than did placebo. However, data showed considerable variability for all neuromuscular indices, no matter the dose of edrophonium used.Conclusion: Edrophonium in doses of 0.1 mg.kg-1 and higher permitted faster recovery of all indices from a mivacurium-induced block during alfentanil-propofol-N2O anaesthesia than did placebo. [ABSTRACT FROM AUTHOR]

Copyright of Canadian Journal of Anaesthesia / Journal Canadien d'Anesthésie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Canadian Journal of Anaesthesia / Journal Canadien d'Anesthésie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The Law on End of Life Care is now effective in Quebec. This law provides for a system of advanced medical directives. Respecting advanced directives (AD) issued in anticipation of incapacity can be a beneficial ethical way to ensure self-determination of the patient in a context where a person’s incapacity is total and of short duration (e.g., terminal cancer). But what about when the loss of decision- making abilities is gradual and spread over a long period of time, as is the case of people with Alzheimer’s type dementia (ATD)? Although the cognitive decline associated with ATD legitimizes the use of AD to promote self- determination of these people, relying solely on a person’s wishes expressed verbally or in writing to their relatives or physician to guide care is an approach that can be ethically risky. A review of the literature on AD, a study of the clinical features associated with ATD, and a critical analysis of a fictitious clinical case will help demonstrate the need for developing a gradual approach to revalidate agreements that take into consideration the AD of the person with a ATD while weighing their wishes and views in real time, their current quality of life and that of their caregiver. The beneficial deployment of AD relies on the ability of the actors involved to consider this as a process of revalidation of agreements. This necessary paradigm shift will ensure that actualising the self-determination of people with ATD does not come at the expense of their dignity, safety and integrity. Such an approach remains to be developed and promoted for people with ATD in Quebec. Health policies that move in this direction, as well as specific normative benchmarks for this clientele, are needed rapidly in the current Quebec context, which is joining the development of a system of “advanced medical directives” with a Law on End of Life Care.

Background: Obesity is chronic disease and causal precursor to myriad other conditions, including type 2 diabetes. In an earlier analysis of the SURMOUNT-1 trial, tirzepatide was shown to provide substantial and sustained reductions in body weight in persons with obesity over a 72-week period. Here, we report the 3-year safety outcomes with tirzepatide and its efficacy in reducing weight and delaying progression to type 2 diabetes in persons with both obesity and prediabetes., Methods: We performed a phase 3, double-blind, randomized, controlled trial in which 2539 participants with obesity, of whom 1032 also had prediabetes, were assigned in a 1:1:1:1 ratio to receive tirzepatide at a once-weekly dose of 5 mg, 10 mg, or 15 mg or placebo. The current analysis involved the participants with both obesity and prediabetes, who received their assigned dose of tirzepatide or placebo for a total of 176 weeks, followed by a 17-week off-treatment period. The three key secondary end points, which were controlled for type I error, were the percent change in body weight from baseline to week 176 and onset of type 2 diabetes during the 176-week and 193-week periods., Results: At 176 weeks, the mean percent change in body weight among the participants who received tirzepatide was -12.3% with the 5-mg dose, -18.7% with the 10-mg dose, and -19.7% with the 15-mg dose, as compared with -1.3% among those who received placebo (P<0.001 for all comparisons with placebo). Fewer participants received a diagnosis of type 2 diabetes in the tirzepatide groups than in the placebo group (1.3% vs. 13.3%; hazard ratio, 0.07; 95% confidence interval [CI], 0.0 to 0.1; P<0.001). After 17 weeks off treatment or placebo, 2.4% of the participants who received tirzepatide and 13.7% of those who received placebo had type 2 diabetes (hazard ratio, 0.12; 95% CI, 0.1 to 0.2; P<0.001). Other than coronavirus disease 2019, the most common adverse events were gastrointestinal, most of which were mild to moderate in severity and occurred primarily during the dose-escalation period in the first 20 weeks of the trial. No new safety signals were identified., Conclusions: Three years of treatment with tirzepatide in persons with obesity and prediabetes resulted in substantial and sustained weight reduction and a markedly lower risk of progression to type 2 diabetes than that with placebo. (Funded by Eli Lilly; SURMOUNT-1 ClinicalTrials.gov number, NCT04184622.)., (Copyright © 2024 Massachusetts Medical Society.)

Aims/hypothesis: Intracellular ceramide accumulation in specific cellular compartments is a potential mechanism explaining muscle insulin resistance in the pathogenesis of type 2 diabetes. Muscle sarcolemmal ceramide accumulation negatively impacts insulin sensitivity in humans, but the mechanism explaining this localised accumulation is unknown. Previous reports revealed that circulating oxidised LDL is elevated in serum of individuals with obesity and type 2 diabetes. Oxidised phosphatidylcholine, which is present in oxidised LDL, has previously been linked to ceramide pathway activation, and could contribute to localised ceramide accumulation in skeletal muscle. We hypothesised that oxidised phosphatidylcholine inversely correlates with insulin sensitivity in serum, and induces sarcolemmal ceramide accumulation and decreases insulin sensitivity in muscle., Methods: We used LC-MS/MS to quantify specific oxidised phosphatidylcholine species in serum from a cross-sectional study of 58 well-characterised individuals spanning the physiological range of insulin sensitivity. We also performed in vitro experiments in rat L6 myotubes interrogating the role of specific oxidised phosphatidylcholine species in promoting sarcolemmal ceramide accumulation, inflammation and insulin resistance in skeletal muscle cells., Results: Human serum oxidised phosphatidylcholine levels are elevated in individuals with obesity and type 2 diabetes, inversely correlated with insulin sensitivity, and positively correlated with sarcolemmal C18:0 ceramide levels in skeletal muscle. Specific oxidised phosphatidylcholine species, particularly 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC), increase total ceramide and dihydroceramide and decrease total sphingomyelin in the sarcolemma of L6 myotubes by de novo ceramide synthesis and sphingomyelinase activation. POVPC also increases inflammatory signalling and causes insulin resistance in L6 myotubes., Conclusions/interpretation: These data suggest that circulating oxidised phosphatidylcholine species promote ceramide accumulation and decrease insulin sensitivity in muscle, help explain localised sphingolipid accumulation and muscle inflammatory response, and highlight oxidised phosphatidylcholine species as potential targets to combat insulin resistance., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The quantitative effects of congenital heart disease (CHD) risk factors are not fully understood. We conducted a meta-analysis of all CHD risk factors. This report explores maternal medication, assisted reproductive technologies (ART), and familial and fetal factors., Methods: Relevant studies were identified using a search strategy encompassing the concepts of CHD and prenatal risk factors with the following inclusion criteria: (1) peer-reviewed articles, (2) quantifying the effects of CHD risk factors, and (3) between 1989 and 2022. Pooled odds ratios (OR) and 95% confidence intervals (CIs) were calculated using a random effect model., Results: There were 131 articles that met the inclusion criteria. Associations were found between CHDs and extracardiac anomalies (OR, 3.41; 95% CI, 1.72-6.77), increased nuchal translucency (OR, 6.87; 95% CI, 2.42-19.53), family history of CHD (OR, 2.90; 95% CI, 2.25-3.75), maternal antidepressants (OR, 1.23; 95% CI, 1.09-1.38), and antihypertensives (OR, 2.07; 95% CI, 1.80-2.38). A positive association was observed between severe CHDs and lithium, but with a very wide CI encompassing the null effect. A positive association was observed between severe CHDs and ARTs (OR, 1.98; 95% CI, 1.30-3.02). The data were insufficient for anomalies of the umbilical cord, anticonvulsants, and retinoid medication., Conclusions: There were strong associations among CHDs and increased nuchal translucency, extracardiac anomalies, and family history of CHD. Effect sizes were modest for maternal medication and ART. Data were scarce and sometimes inconclusive for some risk factors commonly cited as being associated with CHD such as lithium, anomalies of the umbilical cord, anticonvulsants, and retinoid medication., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Little is known about the trends in morbidity and mortality at the population level that followed the introduction of newer once-daily long-acting bronchodilators for COPD. The purpose of the study was to evaluate whether the availability of new bronchodilators was associated with changes in the temporal trends in severe COPD exacerbations and mortality between 2007 and 2018 in the older population with COPD; and whether this association was homogeneous across sex and socioeconomic status classes., Methods: We used an interrupted time-series and three segments multivariate autoregressive models to evaluate the adjusted changes in slopes (i.e., trend effect) in monthly severe exacerbation and mortality rates after 03/2013 and 02/2015 compared to the tiotropium period (04/2007 to 02/2013). Cohorts of individuals > 65 years with COPD were created from the nationally representative database of the Quebec Integrated Chronic Disease Surveillance System in the province of Quebec, Canada. Whether these trends were similar for men and women and across different socioeconomic status classes was also assessed., Results: There were 130,750 hospitalizations for severe exacerbation and 104,460 deaths, including 24,457 (23.4%) respiratory-related deaths, over the study period (928,934 person-years). Significant changes in trends were seen after 03/2013 for all-cause mortality (-1.14%/month;95%CI -1.90% to -0.38%), which further decreased after 02/2015 (-1.78%/month;95%CI -2.70% to -0.38%). Decreases in respiratory-related mortality (-2.45%/month;95%CI -4.38% to -0.47%) and severe exacerbation (-1,90%/month;95%CI -3.04% to -0.75%) rates were only observed after 02/2015. These observations tended to be more pronounced in women than in men and in higher socioeconomic status groups (less deprived) than in lower socioeconomic status groups (more deprived)., Conclusions: The arrival of newer bronchodilators was chronologically associated with reduced trends in severe exacerbation, all-cause and respiratory-related mortality rates among people with COPD > 65 years. Our findings document population benefits on key patient-relevant outcomes in the years following the introduction of newer once-daily long-acting bronchodilators and their combinations, which were likely multifactorial. Public health efforts should focus on closing the gap between lower and higher socioeconomic status groups., (© 2024. The Author(s).)

Elevated skeletal muscle diacylglycerols (DAGs) and ceramides can impair insulin signaling, and acylcarnitines (acylCNs) reflect impaired mitochondrial fatty acid oxidation, thus, the intramuscular lipid profile is indicative of insulin resistance. Acute (i.e., postprandial) hyperinsulinemia has been shown to elevate lipid concentrations in healthy muscle and is an independent risk factor for type 2 diabetes (T2D). However, it is unclear how the relationship between acute hyperinsulinemia and the muscle lipidome interacts across metabolic phenotypes, thus contributing to or exacerbating insulin resistance. We therefore investigated the impact of acute hyperinsulinemia on the skeletal muscle lipid profile to help characterize the physiological basis in which hyperinsulinemia elevates T2D risk. In a cross-sectional comparison, endurance athletes ( n = 12), sedentary lean adults ( n = 12), and individuals with obesity ( n = 13) and T2D ( n = 7) underwent a hyperinsulinemic-euglycemic clamp with muscle biopsies. Although there were no significant differences in total 1,2-DAG fluctuations, there was a 2% decrease in athletes versus a 53% increase in T2D during acute hyperinsulinemia ( P = 0.087). Moreover, C18 1,2-DAG species increased during the clamp with T2D only, which negatively correlated with insulin sensitivity ( P < 0.050). Basal muscle C18:0 total ceramides were elevated with T2D ( P = 0.029), but not altered by clamp. Acylcarnitines were universally lowered during hyperinsulinemia, with more robust reductions of 80% in athletes compared with only 46% with T2D (albeit not statistically significant, main effect of group, P = 0.624). Similar fluctuations with acute hyperinsulinemia increasing 1,2 DAGs in insulin-resistant phenotypes and universally lowering acylcarnitines were observed in male mice. In conclusion, acute hyperinsulinemia elevates muscle 1,2-DAG levels with insulin-resistant phenotypes. This suggests a possible dysregulation of intramuscular lipid metabolism in the fed state in individuals with low insulin sensitivity, which may exacerbate insulin resistance. NEW & NOTEWORTHY Postprandial hyperinsulinemia is a risk factor for type 2 diabetes and may increase muscle lipids. However, it is unclear how the relationship between acute hyperinsulinemia and the muscle lipidome interacts across metabolic phenotypes, thus contributing to insulin resistance. We observed that acute hyperinsulinemia elevates muscle 1,2-DAGs in insulin-resistant phenotypes, whereas ceramides were unaltered. Insulin-mediated acylcarnitine reductions are also hindered with high-fat feeding. The postprandial period may exacerbate insulin resistance in metabolically unhealthy phenotypes.

Background: There is considerable heterogeneity in studies on prenatal risk factors for congenital heart diseases (CHDs). We performed a meta-analysis of all nongenetic factors of CHDs. This report presents results of factors related to maternal chronic diseases and parental exposures., Methods: A systematic search encompassing concepts of CHD and risk factors was used, using the following inclusion criteria: (1) original peer-reviewed articles, (2) quantifying the effects of risk factors for CHDs, (3) between 1989 and 2022. Pooled odds ratios (ORs) and 95% confidence interval (CI) were calculated using a random-effect model., Results: Inclusion criteria were met for 170 studies. There was an association between being overweight or obese and CHDs (OR, 1.26; 95% CI, 1.15-1.37), with a dose-effect relationship. Pregestational diabetes (PGDM) was associated with CHDs (OR, 3.51; 95% CI, 2.86-4.3), without difference between type 1 and type 2 PGDM. The effect size of gestational diabetes was less than that of PGDM (OR, 1.38; 95% CI, 1.18-1.61). There was an association between CHDs and pre-eclampsia (OR, 2.01; 95% CI, 1.32-3.05), paternal smoking (OR, 1.32; 95% CI, 1.03-1.70), and alcohol use (OR, 1.50; 95% CI, 1.08-2.08). A smaller association was found with maternal smoking and advanced maternal age., Conclusions: There exists robust evidence for increased risk of CHD in the presence of obesity, maternal diabetes, maternal smoking, and increased maternal age. The effect sizes were relatively modest, except for PGDM. The robustness of the evidence decreased when CHDs were divided into subgroups or when the analyses were restricted to severe CHDs., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Sphingolipids are thought to promote skeletal muscle insulin resistance. Deoxysphingolipids (dSLs) are atypical sphingolipids that are increased in the plasma of individuals with type 2 diabetes and cause β-cell dysfunction in vitro. However, their role in human skeletal muscle is unknown. We found that dSL species are significantly elevated in muscle of individuals with obesity and type 2 diabetes compared with athletes and lean individuals and are inversely related to insulin sensitivity. Furthermore, we observed a significant reduction in muscle dSL content in individuals with obesity who completed a combined weight loss and exercise intervention. Increased dSL content in primary human myotubes caused a decrease in insulin sensitivity associated with increased inflammation, decreased AMPK phosphorylation, and altered insulin signaling. Our findings reveal a central role for dSL in human muscle insulin resistance and suggest dSLs as therapeutic targets for the treatment and prevention of type 2 diabetes., Article Highlights: Deoxysphingolipids (dSLs) are atypical sphingolipids elevated in the plasma of individuals with type 2 diabetes, and their role in muscle insulin resistance has not been investigated. We evaluated dSL in vivo in skeletal muscle from cross-sectional and longitudinal insulin-sensitizing intervention studies and in vitro in myotubes manipulated to synthesize higher dSLs. dSLs were increased in the muscle of people with insulin resistance, inversely correlated to insulin sensitivity, and significantly decreased after an insulin-sensitizing intervention; increased intracellular dSL concentrations cause myotubes to become more insulin resistant. Reduction of muscle dSL levels is a potential novel therapeutic target to prevent/treat skeletal muscle insulin resistance., (© 2023 by the American Diabetes Association.)

Aims/hypothesis: Although insulin resistance often leads to type 2 diabetes mellitus, its early stages are often unrecognised, thus reducing the probability of successful prevention and intervention. Moreover, treatment efficacy is affected by the genetics of the individual. We used gene expression profiles from a cross-sectional study to identify potential candidate genes for the prediction of diabetes risk and intervention response., Methods: Using a multivariate regression model, we linked gene expression profiles of human skeletal muscle and intermuscular adipose tissue (IMAT) to fasting glucose levels and glucose infusion rate. Based on the expression patterns of the top predictive genes, we characterised and compared individual gene expression with clinical classifications using k-nearest neighbour clustering. The predictive potential of the candidate genes identified was validated using muscle gene expression data from a longitudinal intervention study., Results: We found that genes with a strong association with clinical measures clustered into three distinct expression patterns. Their predictive values for insulin resistance varied substantially between skeletal muscle and IMAT. Moreover, we discovered that individual gene expression-based classifications may differ from classifications based predominantly on clinical variables, indicating that participant stratification may be imprecise if only clinical variables are used for classification. Of the 15 top candidate genes, ST3GAL2, AASS, ARF1 and the transcription factor SIN3A are novel candidates for predicting a refined diabetes risk and intervention response., Conclusion/interpretation: Our results confirm that disease progression and successful intervention depend on individual gene expression states. We anticipate that our findings may lead to a better understanding and prediction of individual diabetes risk and may help to develop individualised intervention strategies., (© 2023. The Author(s).)

Purpose: To describe the characteristics of patients and practice of clinicians during standard-of-care for weight management in a large, multiclinic health system before the implementation of PATHWEIGH, a pragmatic weight management intervention., Methods: We analyzed baseline characteristics of patients, clinicians, and clinics during standard-of-care for weight management before the implementation of PATHWEIGH, which will be evaluated for effectiveness and implementation in primary care using an effectiveness-implementation hybrid type-1 cluster randomized stepped-wedge clinical trial design. A total of 57 primary care clinics were enrolled and randomized to 3 sequences. Patients included in the analysis met the eligibility requirements of age ≥18 years and body mass index (BMI) ≥25 kg/m 2 and had a weight-prioritized visit (defined a priori) during the period March 17, 2020 to March 16, 2021., Results: A total of 12% of patients aged ≥18 years and with a BMI ≥25 kg/m 2 seen in the 57 practices during the baseline period (n = 20,383) had a weight-prioritized visit. The 3 randomization sequences of 20, 18, and 19 sites were similar, with an overall mean patient age of 52 (SD 16) years, 58% women, 76% non-Hispanic White patients, 64% with commercial insurance, and with a mean BMI of 37 (SD 7) kg/m 2 . Documented referral for anything weight related was low (<6%), and 334 prescriptions of an antiobesity drug were noted., Conclusions: Of patients aged ≥18 years and with a BMI ≥25 kg/m 2 in a large health system, 12% had a weight-prioritized visit during the baseline period. Despite most patients being commercially insured, referral to any weight-related service or prescription of antiobesity drug was uncommon. These results fortify the rationale for trying to improve weight management in primary care., (© 2023 Annals of Family Medicine, Inc.)

Importance: Prediabetes, an intermediate stage between normal glucose regulation and diabetes, affects 1 in 3 adults in the US and approximately 720 million individuals worldwide., Observations: Prediabetes is defined by a fasting glucose level of 100 to 125 mg/dL, a glucose level of 140 to 199 mg/dL measured 2 hours after a 75-g oral glucose load, or glycated hemoglobin level (HbA1C) of 5.7% to 6.4% or 6.0% to 6.4%. In the US, approximately 10% of people with prediabetes progress to having diabetes each year. A meta-analysis found that prediabetes at baseline was associated with increased mortality and increased cardiovascular event rates (excess absolute risk, 7.36 per 10 000 person-years for mortality and 8.75 per 10 000 person-years for cardiovascular disease during 6.6 years). Intensive lifestyle modification, consisting of calorie restriction, increased physical activity (≥150 min/wk), self-monitoring, and motivational support, decreased the incidence of diabetes by 6.2 cases per 100 person-years during a 3-year period. Metformin decreased the risk of diabetes among individuals with prediabetes by 3.2 cases per 100 person-years during 3 years. Metformin is most effective for women with prior gestational diabetes and for individuals younger than 60 years with body mass index of 35 or greater, fasting plasma glucose level of 110 mg/dL or higher, or HbA1c level of 6.0% or higher., Conclusions and Relevance: Prediabetes is associated with increased risk of diabetes, cardiovascular events, and mortality. First-line therapy for prediabetes is lifestyle modification that includes weight loss and exercise or metformin. Lifestyle modification is associated with a larger benefit than metformin.

Objective: Treatment of obesity-related diseases, rather than obesity itself, remains the mainstay of medical care. The current study examined a novel approach that prioritizes weight management in primary care to shift this paradigm., Methods: PATHWEIGH is a weight management approach consisting of staff team training, workflow system management, and data capture from tools built into the electronic medical record (EPIC). PATHWEIGH was compared to standard of care (SOC) using two family medicine clinics in the same US healthcare system. Descriptive statistics compared patient-, provider-, and clinic-level factors between the groups among those with at least one weight-prioritized visit (WPV) and one follow-up weight over 14 months., Results: Groups were similar in terms of total patient visits (7,353 vs. 7,984) and patients eligible for a WPV (i.e. >18 years + body mass index >25 kg/m2; 3,746 vs. 3,008, PATHWEIGH vs. SOC, respectively). However, more PATHWEIGH clinic patients (15.9% vs. 8.4%; P < 0.001) received at least one WPV. Although no difference was observed for average patient weight loss over 14 months (P = 0.991), the number of WPVs per patient was higher in PATHWEIGH (P < 0.001) and significantly associated with weight loss (P = 0.001), with an average decrease in weight of 0.55 kg per additional visit., Conclusions: Results from the current study demonstrate early success in changing the paradigm from treating weight-related comorbidities to treating weight in primary care., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Primary care practices can help patients address obesity through weight loss; however, there are many barriers to doing so. This study examined weight management services provided and factors associated with higher reported provision of services., Methods: A survey was given to practice members in 18 primary care practices in a Colorado-based health system. The survey assessed weight management services to determine the amount and type of weight loss assistance provided and other factors that may be important. We used descriptive statistics to summarize responses and linear regression with generalized estimating equations to assess the association between the practice and practice member characteristics and the amount of weight management services provided., Results: The overall response rate was 64% (254/399). On average, clinicians reported performing 73% of the services, and when grouped into minimal, basic, and extensive, the clinicians on average performed 87%, 68%, and 69% of them, respectively. In a multivariable model adjusted for demographics, factors associated with performing more services included perception of overall better practice culture and perception of weight management implementation climate., Conclusions: Practice-associated factors such as culture and implementation climate may be worth examining to understand how to implement weight management in primary care., Competing Interests: Conflict of interest: None., (© Copyright by the American Board of Family Medicine.)

Serum ceramides, especially C16:0 and C18:0 species, are linked to CVD risk and insulin resistance, but details of this association are not well understood. We performed this study to quantify a broad range of serum sphingolipids in individuals spanning the physiologic range of insulin sensitivity and to determine if dihydroceramides cause insulin resistance in vitro. As expected, we found that serum triglycerides were significantly greater in individuals with obesity and T2D compared with athletes and lean individuals. Serum ceramides were not significantly different within groups but, using all ceramide data relative to insulin sensitivity as a continuous variable, we observed significant inverse relationships between C18:0, C20:0, and C22:0 species and insulin sensitivity. Interestingly, we found that total serum dihydroceramides and individual species were significantly greater in individuals with obesity and T2D compared with athletes and lean individuals, with C18:0 species showing the strongest inverse relationship to insulin sensitivity. Finally, we administered a physiological mix of dihydroceramides to primary myotubes and found decreased insulin sensitivity in vitro without changing the overall intracellular sphingolipid content, suggesting a direct effect on insulin resistance. These data extend what is known regarding serum sphingolipids and insulin resistance and show the importance of serum dihydroceramides to predict and promote insulin resistance in humans., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: This analysis of 3,375 adults with overweight/obesity across the Semaglutide Treatment Effect in People with obesity (STEP) 1, 3, and 4 trials evaluated whether more participants with prediabetes had normoglycemia after 68 weeks' treatment with once-weekly semaglutide 2.4 mg plus lifestyle intervention versus placebo and assessed changes in glucose metabolism in participants with prediabetes., Research Design and Methods: STEP 1, 3, and 4 were phase 3, 68-week, randomized, placebo-controlled, multinational trials; STEP 4 had a 20-week semaglutide run-in and 48-week randomized period. Analyses included changes (week 0-68; before the washout period) in glycemic status (prespecified: STEP 1 and 3; post hoc: STEP 4), and in HbA1c, fasting plasma glucose (FPG), and HOMA insulin resistance (HOMA-IR) among participants with prediabetes (post hoc)., Results: Significantly more participants with baseline (week 0) prediabetes (n = 1,536) had normoglycemia at week 68 with semaglutide versus placebo (STEP 1, 84.1% vs. 47.8%; STEP 3, 89.5% vs. 55.0%; STEP 4, 89.8% vs. 70.4%; all P < 0.0001). Fewer participants with baseline normoglycemia had prediabetes at week 68 with semaglutide versus placebo (STEP 1, 2.9% vs. 10.9%; STEP 3, 3.2% vs. 5.8%; STEP 4, 1.1% vs. 5.0%). Semaglutide resulted in greater improvements in HbA1c, FPG, and HOMA-IR than placebo among participants with baseline prediabetes (all P < 0.01)., Conclusions: STEP 1, 3, and 4 collectively provide a robust assessment of the effects of semaglutide on glucose metabolism and prediabetes in a large cohort of adults with overweight/obesity while on treatment. Among participants with baseline prediabetes, 68 weeks' treatment with semaglutide versus placebo led to significant improvements in glucose metabolism and a higher likelihood of normoglycemia., (© 2022 by the American Diabetes Association.)

In October 2020, KDIGO (Kidney Disease: Improving Global Outcomes) published its first clinical practice guideline directed specifically to the care of patients with diabetes and chronic kidney disease (CKD). This commentary presents the views of the KDOQI (Kidney Disease Outcomes Quality Initiative) work group for diabetes in CKD, convened by the National Kidney Foundation to provide an independent expert perspective on the new guideline. The KDOQI work group believes that the KDIGO guideline takes a major step forward in clarifying glycemic targets and use of specific antihyperglycemic agents in diabetes and CKD. The purpose of this commentary is to carry forward the conversation regarding optimization of care for patients with diabetes and CKD. Recent developments for prevention of CKD progression and cardiovascular events in people with diabetes and CKD, particularly related to sodium/glucose cotransporter 2 (SGLT2) inhibitors, have filled a longstanding gap in nephrology's approach to the care of persons with diabetes and CKD. The multifaceted benefits of SGLT2 inhibitors have facilitated interactions between nephrology, cardiology, endocrinology, and primary care, underscoring the need for innovative approaches to multidisciplinary care in these patients. We now have more interventions to slow kidney disease progression and prevent or delay kidney failure in patients with diabetes and kidney disease, but methods to streamline their implementation and overcome barriers in access to care, particularly cost, are essential to ensuring all patients may benefit., (Copyright © 2021 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Despite the overwhelming prevalence and health implications of obesity, it is rarely adequately addressed in a health care setting. PATHWEIGH is a pragmatic approach to weight management that uses tools built into the electronic medical record to overcome barriers and guide care. Implementation strategies are employed to facilitate adoption and use of the PATHWEIGH tools and processes. The current study will compare the effectiveness of PATHWEIGH versus standard of care (SOC) on patient weight loss in primary care and explore factors for its successful implementation., Methods: A stepped wedge cluster randomized trial design will be used within an effectiveness-implementation hybrid study. Adult patient weight loss and weight loss maintenance will be compared in PATHWEIGH versus SOC in 57 family and internal medicine clinics in a large health system in Colorado, USA. Effectiveness will be evaluated using generalized linear mixed models to determine statistical differences in weight loss and weight loss maintenance at 6, 12, and 18 months. Patient-, provider-, and clinic-level predictors will be identified using mediator and moderator analyses. Conceptually guided by the Practical, Robust, Implementation and Sustainability Model (PRISM), a mixed methods approach including quantitative (practice surveys, use tracking) and qualitative (interviews, observations) data collection will be used to determine factors impeding and facilitating adoption, implementation, and maintenance of PATHWEIGH and evaluate specified implementation strategies. A cost analysis of the practice and system costs and resources required by PATHWEIGH relative to the reimbursement collected will be performed., Discussion: The effectiveness and implementation of PATHWEIGH, and their interrelatedness, for patient weight loss are collectively the focus of the current trial. Findings from this study are expected to serve as a blueprint for available and effective weight management in primary care medical practice., Trial Registration: ClinicalTrials.gov NCT04678752 . Registered on December 21, 2020., (© 2022. The Author(s).)

Study Objectives: Insufficient sleep is believed to promote positive energy balance (EB) and weight gain. Increasing weekend sleep duration to "recover" from weekday sleep loss is common, yet little is known regarding how weekend recovery sleep influences EB. We conducted a randomized controlled trial to assess how: (1) 2 days and 8 days of insufficient sleep and (2) ad libitum weekend recovery sleep impact EB (energy intake [EI] - energy expenditure [EE])., Methods: Following ten baseline days with 9 h per night sleep opportunities, participants completed one of three 10-day experimental protocols with ad libitum EI: control (9 h sleep opportunities; n = 8; 23 ± 5 years [mean ± SD]); sleep restriction (SR; 5 h sleep opportunities; n = 14; 25 ± 5 years); sleep restriction with weekend recovery sleep (SR + WR; 5 days insufficient sleep, 2 days ad libitum weekend recovery sleep, 3 days recurrent insufficient sleep; n = 14; 27 ± 4 years)., Results: Twenty-four hour EB increased (p < 0.001; main effect) by an average of 797.7 ± 96.7 (±SEM) kcal during the 10-day experimental protocol versus baseline with no significant differences between groups. Percent change from baseline in 24 h-EE was higher (p < 0.05) on day 2 of insufficient sleep (SR and SR + WR groups; 10 ± 1%) versus adequate sleep (control group; 4 ± 3%)., Conclusions: In this between-group study, the effects of adequate sleep and insufficient sleep, with or without or weekend recovery sleep, on 24 h-EB were similar. Examining EB and body weight changes using within-subject cross-over designs and "free-living" conditions outside the laboratory (e.g. sleep extension) are needed to advance our understanding of the links between insufficient sleep, weekend recovery sleep and weight-gain., (© Sleep Research Society 2021. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Difficulty achieving preset goals (e.g., ≥5% weight loss, ≥150 min of weekly physical activity) in the yearlong National Diabetes Prevention Program (NDPP) can prompt dropout and diminish benefits. We piloted a more patient-centered NDPP adaptation (NDPP-Flex) that promotes a variety of attainable and individually tailored goals to reduce diabetes risks, along with flexibility to adjust goals each week as needed., Research Design and Methods: Retention, physical activity, weight, and glycated hemoglobin (HbA 1c ) were evaluated among diverse participants with diabetes risks who received our pilot of NDPP-Flex beginning in January and July 2018 ( n = 95), with a planned comparison with standard NDPP delivery in preceding cohorts that launched between September 2016 and October 2017 ( n = 245). Both the standard NDPP and NDPP-Flex interventions were 1 year in duration and implemented in phases (i.e., nonrandomized)., Results: Average adjusted retention (e.g., 158.90 ± 15.20 vs. 166.71 ± 9.38 days; P = 0.674), physical activity (157.97 ± 11.91 vs. 175.64 ± 7.54 weekly min; P = 0.231), and weight loss (1.46 ± 0.38% vs. 1.90 ± 0.24%; P = 0.396) were similar between NDPP-Flex versus standard NDPP. However, NDPP-Flex participants had greater HbA 1c reduction on average (0.22 ± 0.05% vs. 0.06 ± 0.03%; P = 0.018) and were more likely to have normoglycemia at follow-up (odds ratio 4.62; P = 0.013 [95% CI 1.38-15.50]) than participants in the standard NDPP., Conclusions: An adapted, more patient-centered NDPP that focuses on flexible, self-selected goals may be a promising strategy to improve glycemia even in the absence of substantial weight loss., (© 2021 by the American Diabetes Association.)

Context: There is little information about fatty liver in prediabetes as it transitions to early diabetes., Objective: This study is aimed at evaluating the prevalence and determinants of fatty liver in the Diabetes Prevention Program (DPP)., Methods: We measured liver fat as liver attenuation (LA) in Hounsfield units (HU) in 1876 participants at ~14 years following randomization into the DPP, which tested the effects of lifestyle or metformin interventions versus standard care to prevent diabetes. LA was compared among intervention groups and in those with versus without diabetes, and associations with baseline and follow-up measurements of anthropometric and metabolic covariates were assessed., Results: There were no differences in liver fat between treatment groups at 14 years of follow-up. Participants with diabetes had lower LA (mean ± SD: 46 ± 16 vs 51 ± 14 HU; P < 0.001) and a greater prevalence of fatty liver (LA < 40 HU) (34% vs 17%; P < 0.001). Severity of metabolic abnormalities at the time of LA evaluation was associated with lower LA categories in a graded manner and more strongly in those with diabetes. Averaged annual fasting insulin (an index of insulin resistance [OR, 95% CI 1.76, 1.41-2.20]) waist circumference (1.63, 1.17-2.26), and triglyceride (1.42, 1.13-1.78), but not glucose, were independently associated with LA < 40 HU prevalence., Conclusion: Fatty liver is common in the early phases of diabetes development. The association of LA with insulin resistance, waist circumference, and triglyceride levels emphasizes the importance of these markers for hepatic steatosis in this population and that assessment of hepatic fat in early diabetes development is warranted., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Type 2 diabetes mellitus (T2DM) is one of the greatest health crises of our time and its prevalence is projected to increase by >50% globally by 2045. Currently, 10 classes of drugs are approved by the US Food and Drug Administration for the treatment of T2DM. Drugs in development for T2DM must show meaningful reductions in glycaemic parameters as well as cardiovascular safety. Results from an increasing number of cardiovascular outcome trials using modern T2DM therapeutics have shown a reduced risk of atherosclerotic cardiovascular disease, congestive heart failure and chronic kidney disease. Hence, guidelines have become increasingly evidence based and more patient centred, focusing on reaching individualized glycaemic goals while optimizing safety, non-glycaemic benefits and the prevention of complications. The bar has been raised for novel therapies under development for T2DM as they are now expected to achieve these aims and possibly even treat concurrent comorbidities. Indeed, the pharmaceutical pipeline for T2DM is fertile. Drugs that augment insulin sensitivity, stimulate insulin secretion or the incretin axis, or suppress hepatic glucose production are active in more than 7,000 global trials using new mechanisms of action. Our collective goal of being able to truly personalize medicine for T2DM has never been closer at hand.