Bariatric Surgery in Patients with Achondroplasia, a Feasibility Study of Two Case Studies.

BACKGROUND: Achondroplasia is a common skeletal dysplasia with a high prevalence of obesity in adulthood. Bariatric surgery has been shown to be effective in treating obesity and related comorbidities, but its feasibility and effectiveness in patients with achondroplasia have not been clearly established. OBJECTIVES: The objective of this study was to evaluate the feasibility and effectiveness of bariatric surgery in patients with achondroplasia. SETTING: This study was performed in France, and bariatric surgeons from the Société Française et Francophone de Chirurgie de l'Obésité et des Maladies Métaboliques (French Francophone Society of Surgery for Obesity or Metabolic Diseases) were asked to participate. METHODS: Two adult women with confirmed achondroplasia and a high BMI were selected for laparoscopic sleeve gastrectomy. Preoperative data were collected, including demographic information, comorbidities, and follow-up at 1, 3, and 6 months and 1 year after surgery. Complications were monitored and recorded. RESULTS: Both patients had good excess weight loss outcomes, with an average excess weight loss of 60.5% 1 year after surgery. One patient had a follow-up of 3 years and an excess weight loss of 44%. The surgery was well-tolerated, and no major complications were observed. CONCLUSIONS: Bariatric surgery is feasible and effective in patients with achondroplasia, with good outcomes for excess weight loss and related comorbidities. These findings suggest that bariatric surgery should be considered a treatment option for patients with achondroplasia and obesity.

Adjuvant Glucose-Like Peptide 1 Receptor Agonist Therapy for Suboptimal Weight Loss After Bariatric Surgery: a Systematic Review.

Addressing suboptimal weight loss post-bariatric surgery poses a challenge. While glucagon-like peptide 1 receptor agonists (GLP1-RA) show promise in managing obesity, their role as an adjuvant treatment after bariatric surgery remains uncertain. We conducted a systematic literature review focused on the efficacy and safety of GLP1-RA in bariatric surgery patients with insufficient weight loss or distant weight regain. Our literature search identified 1167 articles, with 10 (involving 594 patients) meeting inclusion/exclusion criteria for detailed review. GLP1-RA therapy resulted in 5 to 17% weight loss over 6 to 12 months, with 10-50% experiencing non-severe side effects like nausea. Overall, GLP1-RA emerges as an effective adjuvant therapy for patients experiencing inadequate weight loss or regain after bariatric surgery, offering a viable alternative to revision surgery.

Precision medicine in endocrinology: Unraveling metabolic health through time-restricted eating.

As a promising avenue in nutrition, intermittent fasting, particularly time-restricted eating like the 8/16 protocol, requires careful individualization. This approach involves voluntary food restriction interspersed with normal eating, aiming to align with inner circadian rhythms for potential benefits in metabolism and weight management. Endocrinologists, responding to patient interest and backed by evidence-based medicine, can now delve into the intricacies of time-restricted eating. They consider each patient's unique medical history and expectations, integrating this approach into tailored treatment plans in a personalized medicine approach. Ongoing research is essential to deepen our comprehension of how time-restricted eating influences metabolic health, enabling the development of precise recommendations suitable for diverse populations and various clinical conditions. While time-restricted eating is a relevant metabolic approach, endocrinologists should exercise caution to prevent the promotion of eating disorders due to its restrictive nature.

Out-of-Pocket Expenses in Households of People Living with Obesity in France.

BACKGROUND/OBJECTIVES: Overweight and obesity result in a substantial economic burden in both low- and high-income countries. Moreover, this burden is often underestimated because it only partially accounts for unreimbursed out-of-pocket expenses (OOPE) related to obesity. The objective of our study was not only to evaluate OOPE incurred by people with obesity in relation to their disease with respect to direct medical expenditures and direct non-medical expenditures but also the proportion of people living with obesity who have forgone obesity-related healthcare due to the costs of such care. METHODS: An observational descriptive survey was conducted among people with class II/III obesity attending six obesity treatment centers in France. Volunteer adult participants completed a written/phone questionnaire on their related expenditures over the last 6 months for current expenditures and over the last 5 years for occasional ones. The costs were expressed in 2022 EUR. RESULTS: 299 people participated (age: 46 years [SD: 13.9], women: 72%, BMI ≥40 kg/m2: 62% and 48% with comorbidities). 65% had a professional activity. 83% declared that they had OOPE related to obesity representing annually EUR 2027/individual on average (5% of the household revenue), including weight loss and nutritional products, vitamins, meal programs, gym memberships, psychologists, but mainly adapted clothing, additional travel costs, and others. 15% of the respondents had to modify their professional activity due to obesity and 15% forwent some medical care in the last 12 months. CONCLUSIONS: OOPE is a significant part of the economic burden of obesity. Despite some limitations due to the specificities of the participants and because some costs may be more related to social activities affected by obesity than to healthcare, it seems important to consider these expenditures in cost estimates for obesity.

Nutritional biomarkers and heart failure requiring hospitalization in patients with type 2 diabetes: the SURDIAGENE cohort.

BACKGROUND: Heart failure (HF) is a growing complication and one of the leading causes of mortality in people living with type 2 diabetes (T2D). Among the possible causes, the excess of red meat and the insufficiency of vegetables consumption are suspected. Such an alimentation is associated with nutritional biomarkers, including trimethylamine N-oxide (TMAO) and its precursors. Here, we aimed to study these biomarkers as potential prognostic factors for HF in patients with T2D. METHODS: We used the SURDIAGENE (SURvival DIAbetes and GENEtics) study, a large, prospective, monocentric cohort study including 1468 patients with T2D between 2001 and 2012. TMAO and its precursors (trimethylamine [TMA], betaine, choline, and carnitine) as well as thio-amino-acids (cysteine, homocysteine and methionine) were measured by liquid chromatography-tandem mass spectrometry. The main outcome was HF requiring Hospitalization (HFrH) defined as the first occurrence of acute HF leading to hospitalization and/or death, established by an adjudication committee, based on hospital records until 31st December 2015. The secondary outcomes were the composite event HFrH and/or cardiovascular death and all-cause death. The association between the biomarkers and the outcomes was studied using cause-specific hazard-models, adjusted for age, sex, history of coronary artery disease, NT-proBNP, CKD-EPI-derived eGFR and the urine albumin/creatinine ratio. Hazard-ratios (HR) are expressed for one standard deviation. RESULTS: The data of interest were available for 1349/1468 of SURDIAGENE participants (91.9%), including 569 (42.2%) women, with a mean age of 64.3 ± 10.7 years and a median follow-up of 7.3 years [25th-75th percentile, 4.7-10.8]. HFrH was reported in 209 patients (15.5%), HFrH and/or cardiovascular death in 341 (25.3%) and all-cause death in 447 (33.1%). In unadjusted hazard-models, carnitine (HR = 1.20, 95% CI [1.05; 1.37]), betaine (HR = 1.34, [1.20; 1.50]), choline (HR = 1.35, [1.20; 1.52]), TMAO (HR = 1.32, [1.16; 1.50]), cysteine (HR = 1.38, [1.21; 1.58]) and homocysteine (HR = 1.28, [1.17; 1.39]) were associated with HFrH, but not TMA and methionine. In the fully adjusted models, none of these associations was significant, neither for HFrH nor for HFrH and/or CV death, when homocysteine only was positively associated with all-cause death (HR = 1.16, [1.06; 1.27]). CONCLUSIONS: TMAO and its precursors do not appear to be substantial prognosis factors for HFrH, beyond usual cardiac- and kidney-related risk factors, whereas homocysteine is an independent risk factor for all-cause death in patients with T2D.

Hepatic Fis1 regulates mitochondrial integrated stress response and improves metabolic homeostasis.

Mitophagy and mitochondrial integrated stress response (ISR) are 2 primary protective mechanisms to maintain functional mitochondria. Whether these 2 processes are coordinately regulated remains unclear. Here we show that mitochondrial fission 1 protein (Fis1), which is required for completion of mitophagy, serves as a signaling hub linking mitophagy and ISR. In mouse hepatocytes, high fat diet (HFD) feeding induces unresolved oxidative stress, defective mitophagy and enhanced type I interferon (IFN-I) response implicated in promoting metabolic inflammation. Adenoviral-mediated acute hepatic Fis1 overexpression is sufficient to reduce oxidative damage and improve glucose homeostasis in HFD-fed mice. RNA-Seq analysis reveals that Fis1 triggers a retrograde mitochondria-to-nucleus communication upregulating ISR genes encoding anti-oxidant defense, redox homeostasis, and proteostasis pathways. Fis1-mediated ISR also suppresses expression of IFN-I-stimulated genes through activating transcription factor 5 (Atf5), which inhibits the transactivation activity of interferon regulatory factor 3 (Irf3) known to control IFN-I production. Metabolite analysis demonstrates that Fis1 activation leads to accumulation of fumarate, a TCA cycle intermediate capable of increasing Atf5 activity. Consequently, hepatic Atf5 overexpression or monomethyl fumarate (MMF) treatment improves glucose homeostasis in HFD-fed mice. Collectively, these results support the potential use of small molecules targeting the Fis1-Atf5 axis, such as MMF, to treat metabolic diseases.

Timing of Kidney Clamping and Deceased Donor Kidney Transplant Outcomes.

BACKGROUND AND OBJECTIVES: The fact that metabolism and immune function are regulated by an endogenous molecular clock that generates circadian rhythms suggests that the magnitude of ischemia reperfusion, and subsequent inflammation on kidney transplantation, could be affected by the time of the day. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We evaluated 5026 individuals who received their first kidney transplant from deceased heart-beating donors. In a cause-specific multivariable analysis, we compared delayed graft function and graft survival according to the time of kidney clamping and declamping. Participants were divided into those clamped between midnight and noon (ante meridiem [am] clamping group; 65%) or clamped between noon and midnight (post meridiem [pm] clamping group; 35%), and, similarly, those who underwent am declamping (25%) or pm declamping (75%). RESULTS: Delayed graft function occurred among 550 participants (27%) with am clamping and 339 (34%) with pm clamping (adjusted odds ratio, 0.81; 95% confidence interval, 0.67 to 0.98; P=0.03). No significant association was observed between clamping time and overall death-censored graft survival (hazard ratio, 0.92; 95% confidence interval, 0.77 to 1.10; P=0.37). No significant association of declamping time with delayed graft function or graft survival was observed. CONCLUSIONS: Clamping between midnight and noon was associated with a lower incidence of delayed graft function, whereas declamping time was not associated with kidney graft outcomes.

Knowledge and competency standards for specialized cognitive behavior therapy for adult obsessive-compulsive disorder.

Obsessive-Compulsive Disorder (OCD) is a leading cause of disability world-wide (World Health Organization, 2008). Treatment of OCD is a specialized field whose aim is recovery from illness for as many patients as possible. The evidence-based psychotherapeutic treatment for OCD is specialized cognitive behavior therapy (CBT, NICE, 2005, Koran and Simpson, 2013). However, these treatments are not accessible to many sufferers around the world. Currently available guidelines for care are deemed to be essential but insufficient because of highly variable clinician knowledge and competencies specific to OCD. The phase two mandate of the 14 nation International OCD Accreditation Task Force (ATF) created by the Canadian Institute for Obsessive Compulsive Disorders is development of knowledge and competency standards for specialized treatments for OCD through the lifespan deemed by experts to be foundational to transformative change in this field. This paper presents knowledge and competency standards for specialized CBT for adult OCD developed to inform, advance, and offer a model for clinical practice and training for OCD. During upcoming ATF phases three and four criteria and processes for training in specialized treatments for OCD through the lifespan for certification (individuals) and accreditation (sites) will be developed based on the ATF standards.

Changes in Key Mitochondrial Lipids Accompany Mitochondrial Dysfunction and Oxidative Stress in NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is a dysmetabolic hepatic damage of increasing severity: simple fat accumulation (steatosis), nonalcoholic steatohepatitis (NASH), and hepatic fibrosis. Oxidative stress is considered an important factor in producing hepatocyte injury associated with NAFLD progression. Studies also suggest a link between the accumulation of specific hepatic lipid species, mitochondrial dysfunction, and the progression of NAFLD. However, it is unclear whether mitochondrial lipid modifications are involved in NAFLD progression. To gain insight into the relationship between mitochondrial lipids and disease progression through different stages of NAFLD, we performed lipidomic analyses on mouse livers at different stages of western diet-induced NAFLD, with or without hepatic fibrosis. After organelle separation, we studied separately the mitochondrial and the "nonmitochondrial" hepatic lipidomes. We identified 719 lipid species from 16 lipid families. Remarkably, the western diet triggered time-dependent changes in the mitochondrial lipidome, whereas the "nonmitochondrial" lipidome showed little difference with levels of hepatic steatosis or the presence of fibrosis. In mitochondria, the changes in the lipidome preceded hepatic fibrosis. In particular, two critical phospholipids, phosphatidic acid (PA) and cardiolipin (CL), displayed opposite responses in mitochondria. Decrease in CL and increase in PA were concurrent with an increase of coenzyme Q. Electron paramagnetic resonance spectroscopy superoxide spin trapping and Cu2+ measurement showed the progressive increase in oxidative stress in the liver. Overall, these results suggest mitochondrial lipid modifications could act as an early event in mitochondrial dysfunction and NAFLD progression.

Daily Timing of Meals and Weight Loss After Bariatric Surgery: a Systematic Review.

The timing of food intake throughout the day can alter circadian clocks and metabolism to modulate the course of obesity. We conducted a systematic literature review to determine whether the timing of meals could alter the change in body weight after bariatric surgery in adults. Twelve cohort studies examined the association between meal timing and changes in body weight after bariatric surgery. Eight studies suggested an association between meal timing and weight loss. All studies examined simple exposure variables such as frequency of breakfast or dinner consumption and overnight meals. Overall, the low-quality evidence that food consumption at the end of the day is associated with lower weight loss after bariatric surgery in adults warrants further research.

Bmal1 integrates mitochondrial metabolism and macrophage activation.

Metabolic pathways and inflammatory processes are under circadian regulation. Rhythmic immune cell recruitment is known to impact infection outcomes, but whether the circadian clock modulates immunometabolism remains unclear. We find that the molecular clock Bmal1 is induced by inflammatory stimulants, including Ifn-γ/lipopolysaccharide (M1) and tumor-conditioned medium, to maintain mitochondrial metabolism under metabolically stressed conditions in mouse macrophages. Upon M1 stimulation, myeloid-specific Bmal1 knockout (M-BKO) renders macrophages unable to sustain mitochondrial function, enhancing succinate dehydrogenase (SDH)-mediated mitochondrial production of reactive oxygen species as well as Hif-1α-dependent metabolic reprogramming and inflammatory damage. In tumor-associated macrophages, aberrant Hif-1α activation and metabolic dysregulation by M-BKO contribute to an immunosuppressive tumor microenvironment. Consequently, M-BKO increases melanoma tumor burden, whereas administering the SDH inhibitor dimethyl malonate suppresses tumor growth. Therefore, Bmal1 functions as a metabolic checkpoint that integrates macrophage mitochondrial metabolism, redox homeostasis and effector functions. This Bmal1-Hif-1α regulatory loop may provide therapeutic opportunities for inflammatory diseases and immunotherapy.

Interleukin-13 drives metabolic conditioning of muscle to endurance exercise.

Repeated bouts of exercise condition muscle mitochondria to meet increased energy demand-an adaptive response associated with improved metabolic fitness. We found that the type 2 cytokine interleukin-13 (IL-13) is induced in exercising muscle, where it orchestrates metabolic reprogramming that preserves glycogen in favor of fatty acid oxidation and mitochondrial respiration. Exercise training-mediated mitochondrial biogenesis, running endurance, and beneficial glycemic effects were lost in Il13-/- mice. By contrast, enhanced muscle IL-13 signaling was sufficient to increase running distance, glucose tolerance, and mitochondrial activity similar to the effects of exercise training. In muscle, IL-13 acts through both its receptor IL-13Rα1 and the transcription factor Stat3. The genetic ablation of either of these downstream effectors reduced running capacity in mice. Thus, coordinated immunological and physiological responses mediate exercise-elicited metabolic adaptations that maximize muscle fuel economy.

Bariatric Surgery is feasible in patients with Ehlers-Danlos Syndrome.

BACKGROUND: Ehlers-Danlos syndrome (EDS) is a heterogeneous disease affecting connective tissues. EDS patients have a high susceptibility for developing anastomotic leak after visceral surgery. Although patients with EDS can also develop severe obesity and might be referred to bariatric surgery, there is just 1 case report in the literature regarding the outcomes of bariatric surgery in this specific context. OBJECTIVE: To report the cases of patients with EDS and severe obesity that underwent bariatric surgery. SETTING: Five French hospitals (University Hospital of Nantes, APHP Pitié Salpêtrière Hospital, APHP Bichat Hospital, Clinique St Gregoire Rennes, and Clinique Mutualiste de l'Estuaire St Nazaire). METHODS: We report the cases of 7 patients with EDS and severe obesity who underwent surgery. RESULTS: All patients showed classical postoperative course except for 1 case of excessive bleeding. There was no increased pain, leak, and solid parietal healing was achieved in all patients at 1 month postoperatively. The percent excess weight loss at 1 and 6 months were 13.9 ± 3.8% and 45.3 ± 16%, respectively. CONCLUSION: Our study shows that bariatric surgery is a relevant and apparently safe surgical option to consider in severely obese patients with EDS.

Predictive value of preoperative DeMeester score on conversion to Roux-en-Y gastric bypass for gastroeosophageal reflux disease after sleeve gastrectomy.

BACKGROUND: Obesity is well known to increase the risk of gastroesophageal reflux disease (GERD). The impact of sleeve gastrectomy (SG) on GERD is still discussed but seems to be associated with the development of de novo GERD or the exacerbation of preexisting GERD. OBJECTIVE: The objective of this study was to evaluate the impact of preoperative pH monitoring, using the DeMeester score (DMS), on the risk of conversion to Roux-en-Y gastric bypass (RYGB) after SG. SETTING: University Hospital in Nantes, France. METHODS: This monocentric study reported the results of a retrospective chart review of 523 obese individuals treated between 2011 and 2018. All patients underwent primary bariatric surgery; 95% had undergone an SG. GERD diagnosis was established with preoperative DMS based on 24-hour esophageal pH monitoring. RESULTS: Preoperative DMS was identified in 423 patients (86%). Sixty-seven patients (14%) underwent a second bariatric procedure; among them, 36 (54%) have been converted to RYGB because of GERD. There was no significant difference between preoperative DMS (16.1 ± 22 versus 13.7 ± 14, P = .37) in patients undergoing conversion for GERD and the nonconverted ones. The sensitivity, specificity, positive predictive, and negative predictive values of the preoperative DMS for predicting conversion to RYGB were 25%, 66%, 7%, and 4%, respectively. In patients who underwent a conversion for GERD, DMS (P < .002), rates of esophagitis (P = .035), and hiatal hernia (P = .039) significantly increased after SG. CONCLUSION: Preoperative DMS alone is not predictive of the risk of conversion of SG to RYGB for GERD.

Improvement in arterial stiffness (pOpmètre®) after bariatric surgery. Results from a prospective study.

BACKGROUND: Arterial stiffness (AS) is an independent predictor of cardiovascular risk, and could be used as a surrogate marker of improvement in cardiovascular risk following bariatric surgery. The aim of this study was to compare AS before and after surgery. METHODS: One hundred and thirty-four patients undergoing bariatric surgery between May 2016 and January 2019 were prospectively included. AS was measured on pulse wave velocity (PWV) with the pOpmètre® device pre- and postoperatively. The main endpoint was change in PWV between baseline and 3 months post-surgery. RESULTS: Overall, mean PWV was 6.87m/s preoperatively and 6.71m/s at 3 months (P=0.7148). Patients with pathologic PWV (>2 standard deviations from expected value for age) showed significant improvement at 3 months (31 patients; 10.1m/s preoperatively vs 7.5m/s at 3 months; P=0.007). These results did not correlate with improvement in other clinical or biological parameters following surgery (excess weight loss, mean blood pressure, fasting blood glucose, waist circumference, body composition). CONCLUSION: These results suggest that pathological arterial stiffness may resolve following bariatric surgery independently of the other factors influencing cardiovascular risk in obesity.

OBEDIS Core Variables Project: European Expert Guidelines on a Minimal Core Set of Variables to Include in Randomized, Controlled Clinical Trials of Obesity Interventions.

Heterogeneity of interindividual and intraindividual responses to interventions is often observed in randomized, controlled trials for obesity. To address the global epidemic of obesity and move toward more personalized treatment regimens, the global research community must come together to identify factors that may drive these heterogeneous responses to interventions. This project, called OBEDIS (OBEsity Diverse Interventions Sharing - focusing on dietary and other interventions), provides a set of European guidelines for a minimal set of variables to include in future clinical trials on obesity, regardless of the specific endpoints. Broad adoption of these guidelines will enable researchers to harmonize and merge data from multiple intervention studies, allowing stratification of patients according to precise phenotyping criteria which are measured using standardized methods. In this way, studies across Europe may be pooled for better prediction of individuals' responses to an intervention for obesity - ultimately leading to better patient care and improved obesity outcomes.