Extreme Obesity Research Articles

Reduced Free Fatty Acid Receptor 4 Gene Expression is Associated With Extreme Obesity and Insulin Resistance in Children.

Free fatty acid receptor 4 (FFAR4) is a G-protein-coupled membrane receptor highly expressed in macrophages that triggers anti-inflammatory effects and promotes insulin sensitization. We have previously found significant associations between the FFAR4 rs11187533 single nucleotide polymorphism (SNP) and various obesity comorbidity parameters. We aimed to verify the FFAR4 expression levels in children with obesity and the associated comorbidities. Thirty-eight children with obesity were studied. Clinical and anthropometric evaluation was performed. A venous sample under fasting conditions was obtained. Biochemical study included parameters of metabolic risk. DNA was extracted and genotyped for the rs11187533 FFAR4 SNP. Real-time PCR technique was performed to investigate the gene expression. Relative FFAR4 mRNA levels were determined according to the 2-ΔΔCt method. Significant differences in FFAR4 expression levels between the CC and CT-TT genotypes of the rs11187533 FFAR4 SNP were observed (P = 0.034). The minor allele T presented higher levels of FFAR4 expression. We found that a loss of FFAR4 expression was associated with extreme obesity (P = 0.032). The lowest FFAR4 expression levels were observed in children who had higher insulin (P = 0.008) and homeostasis model assessment insulin resistance values (P = 0.012) and lower quantitative insulin-sensitivity check index (P = 0.033). The underexpression of FFAR4 was associated with extreme obesity and parameters indicative of obesity comorbidities in children. This under expression could be partially influenced by the presence of the C allele rs11187533 FFAR4 SNP.

Impact of Fatty Acids on Obesity-Associated Diseases and Radical Weight Reduction

PurposeFatty acids (FA), particularly polyunsaturated (PUFA) ones, are involved in the regulation of glycemic control, lipid metabolism, and inflammation. The aim of the study was to assess patient FA profile in relation to obesity, lipid and carbohydrate metabolism disturbances, and weight loss.Materials and MethodsThe studied group consisted of 51 patients with extreme obesity, 23 of whom achieved radical weight reduction within 1 year after a laparoscopic sleeve gastrectomy (LSG). FA levels were determined using gas chromatography with flame ionization detection.ResultsPatients with extreme obesity and higher serum PUFA content have lower serum levels of SFA and MUFA (especially myristic, palmitic, lignoceric acids and palmitoleic, oleic acids), as well as lower triglyceride and higher HDL-cholesterol concentrations and it was not influenced by CEPT Taq1B variant. At baseline, the fatty acid profile of patients with type II diabetes differ from patients with dyslipidemia. In patients who had lost weight, significantly lower levels of selected saturated FA and major trans-fatty acid, elaidic, were found. Moreover, the proportion of PUFA was increased.ConclusionIn extreme obesity, higher PUFA exert their favorable effects on serum lipids. Significant weight reduction after the bariatric surgery is associated with beneficial changes in the fatty acid profile.Graphical

Effect of intraperitoneal local anesthesia on enhanced recovery outcomes after bariatric surgery: a randomized controlled pilot study.

Background:Patients with extreme obesity are at high risk for adverse perioperative events, especially when opioid-centric analgesic protocols are used, and perioperative pain management interventions in bariatric surgery could improve safety, outcomes and satisfaction. We aimed to evaluate the impact of intraperitoneal local anesthesia (IPLA) on enhanced recovery after bariatric surgery (ERABS) outcomes.Methods:We conducted a prospective double-blind randomized controlled pilot study in adherence to an a priori peer-reviewed protocol. Patients undergoing laparoscopic Roux-en-Y gastric bypass surgery (LRYGB) with an established ERABS protocol between July 2014 and February 2015 were randomly allocated to receive either IPLA with 0.2% ropivacaine (intervention group) or normal saline (control group). We measured pain scores, analgesic consumption and adverse effects. Functional prehabilitation outcomes, including peak expiratory flow (PEF) and the Six Minute Walk Test (6MWT) and Quality of Recovery Survey-40 (QoR-40) scores, were assessed before surgery, and 1 day and 7 days postoperatively.Results:One hundred patients were randomly allocated to the study groups, of whom 92 completed the study, 46 in each group. There were no statistically significant differences between the 2 groups in baseline characteristics or any primary or secondary outcomes. Pain scores and analgesic consumption were low in both groups. There were no adverse events. Significant declines in PEF and 6MWT and QoR-40 scores were noted on postoperative day 1 in both groups; the values returned to baseline on postoperative day 7 in both groups.Conclusion:Intraperitoneal local anesthesia with ropivacaine did not reduce postoperative pain or analgesic consumption when administered intraoperatively to patients undergoing LRYGB. Standardization of the ERABS protocol benefited patients, with functional prehabilitation outcomes returning to baseline postoperatively. Trial registration: ClinicalTrials.gov no. NCT 02154763

Obesity Is Associated with Increased Relapse Risk in Diffuse Large B-Cell Lymphoma

Introduction: Diffuse Large B-Cell Lymphoma (DLBCL) is an aggressive Non-Hodgkin's lymphoma (NHL) characterized by clinical, biological and genetic heterogeneity. Despite the tremendous advancement in anticancer therapy against DLBCL, up to 40% of patients are refractory and/or relapse after first-line chemo-immunotherapy. Mechanisms responsible for chemo-immunotherapy failure are largely uncharacterized; however, it is believed the microenvironment contributes to tumor adaptation and survival. Several studies have shown that high body mass index (BMI) is associated with increased risk of developing DLBCL and obesity is an independent prognostic indicator of worse outcome when compared to non-obese patients. Weight gain alters the metabolic landscape of tumor microenvironment to inhibit T cell function and promote cellular growth. Obesity induced proinflammatory mediators can activate numerous signaling pathways including nuclear factor (NF)-KB that result in anti-apoptotic and increased proliferative efficiency in B-cells Here, we report the results of our retrospective study from two hospital systems in Houston, Texas evaluating the impact of BMI on progression-free-survival (PFS) in DLBCL patients receiving standard induction chemotherapy.Methods: After Institutional Review Boards (IRB) approval, patients (pts) were identified by electronic medical record database query. Inclusion criteria included: (a) age>18 years old, (b) DLBCL diagnosis confirmed by pathology review at Ben Taub Medical Center and Baylor St. Luke's Medical Center. BMI was calculated using patient's height and weight at diagnosis. For all comparison, we selected DLBCL pts with World Health Organization (WHO) predefined overweight, class I, II, III obesity to better capture effect of extreme BMI on DLBCL PFS. Cell-of-origin (COO) was determined by Hans classification. R-CHOP/R-EPOCH were classified as intense therapy whereas R-CVP/R-CEOP as non-intense therapy. Descriptive statistics was used to evaluate differential expression of clinical and laboratory variables. PFS among pts with BMI <35 and BMI >35 was estimated with Kaplan Meier Method. Cox regression model evaluated effect of independent variables on PFS for pts with DLBCL exhibiting obesity. SAS was used for all analysis.Results: 123 pts were identified. Demographic, clinical and laboratory data was balanced among DLBCL pts with and without BMI >35 (Table 1). Median BMI was 25.9 for pts with BMI<35 v 37.3 in pts with BMI >35. In the pts with BMI <35, 36.9% were classified as germinal center b-cell (GCB) subtype and 63.1% were classified as non-GCB subtype (p= NS). Within the BMI >35, 46.2% were GCB subtype and 53.9% were non-GCB subtype. 45.9% of pts had low International Prognostic Index (IPI) score in BMI<35 compared to 56.52% in BMI>35, whereas 54% had high IPI in BMI<35 compared to 43.48% in BMI>35. PFS was 2,864 days vs 763 days in patients with BMI <35 and >35, respectively (p=0.02). (Fig 1). To address effect of “type of therapy administered” (low v high intensity), COO, and age as confounders for our observation that PFS is inferior in DLBCL pts with BMI >35, Cox regression model was performed confirming the independent predictive role for BMI >35 only on DLBCL PFS.Conclusions: Our study demonstrates that obesity (BMI >35) results in increased relapse risk in DLBCL patients. In our population, risk of relapse was enhanced by higher BMI independent of age, therapy administered and COO. Obesity, by itself, especially BMI>35 (Class II and Class III) may represent a unique factor for adverse outcome in DLBCL. The mechanism for which extreme obesity leads to inferior PFS in DLBCL is unclear. It is possible that obesity induces “high risk” mutations acquisition and/or adversely modifies tumor microenvironment resulting in chemotherapy cytotoxic attenuation. Larger studies are needed to externally validate our observation. [Display omitted] DisclosuresMims: Biogen: Current holder of individual stocks in a privately-held company; Incyte: Research Funding; IDEC: Current holder of individual stocks in a privately-held company; Celgene: Research Funding; Pfizer: Research Funding; AVEO: Research Funding.

Gut Microbiota Metabolism of Bile Acids Could Contribute to the Bariatric Surgery Improvements in Extreme Obesity.

Bariatric surgery is the only procedure to obtain and maintain weight loss in the long term, although the mechanisms driving these benefits are not completely understood. In the last years, gut microbiota has emerged as one of the drivers through its metabolites, especially secondary bile acids. In the current study, we have compared the gut microbiota and the bile acid pool, as well as anthropometric and biochemical parameters, of patient with morbid obesity who underwent bariatric surgery by two different techniques, namely Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG). Gut microbiota populations differed after the respective procedures, particularly with respect to the Enterobacteriaceae family. Both techniques resulted in changes in the bile acids pool, but RYGB was the procedure which suffered the greatest changes, with a reduction in most of their levels. Blautia and Veillonella were the two genera that more relationships showed with secondary bile acids, indicating a possible role in their formation and inhibition, respectively. Correlations with the anthropometric and biochemical variables showed that secondary bile acids could have a role in the amelioration of the glucose and HDL-cholesterol levels. Thus, we have observed a possible relationship between the interaction of the bile acids pool metabolized by the gut microbiota in the metabolic improvements obtained by bariatric surgery in the frame of morbid obesity, deserving further investigation in greater cohorts to decipher the role of each bile acid in the homeostasis of the host for their possible use in the development of microbiota-based therapeutics, such as new drugs, postbiotics or probiotics.

Melanin-concentrating hormone neurons affect adipose tissues and modulate weight gain.

Melanin-concentrating hormone neurons affect adipose tissues and modulate weight gain.

Adenotonsillectomy for the treatment of obstructive sleep apnoea in extreme paediatric obesity.

Adenotonsillectomy is a recognised treatment for paediatric obstructive sleep apnoea. Recent literature highlights the need to assess outcomes in the extremely obese subpopulation. This study reviewed the efficacy of adenotonsillectomy performed in patients with extreme obesity. A retrospective analysis of attendees at a tertiary paediatric obesity clinic was performed, identifying patients with a body mass index z-score equal to or more than three who had undergone adenotonsillectomy for obstructive sleep apnoea. Electronic patient records, including respiratory polygraphy, were analysed. Nine patients met the study criteria. All required nocturnal non-invasive ventilation pre-operatively. Mean age at referral was 6.9 years, and average age of non-invasive ventilation commencement was 7.8 years. Post-operatively, 8 patients (89 per cent) required non-invasive ventilation with evidence of post-operative obstructive sleep apnoea. In extreme obesity, adenotonsillectomy does not prevent the need for non-invasive ventilation. Management of this patient group requires treatment of obesity alongside potential surgical intervention. Poor efficacy in treating obstructive sleep apnoea may influence the decision to proceed with adenotonsillectomy.

Outcomes of bariatric surgery in extreme obesity: results from the United Kingdom National Bariatric Surgery Registry for patients with a body mass index &gt;70 kg/m2

Bariatric and metabolic surgery (BMS) is an established safe, effective, and durable treatment for obesity and its complications. However, there is still a paucity of evidence on surgery outcomes in patients suffering from extreme obesity.This study aimed to evaluate outcomes of BMS in weight loss and the resolution of co-morbidities in patients with a body mass index (BMI) ≥70kg/m2.National Health Service and private hospitals in the United Kingdom.This cohort study analyzed prospectively collected records from the UK National Bariatric Surgery Registry of patients with a BMI ≥70 kg/m2 undergoing Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), or adjustable gastric band (AGB) between January 2009 and June 2014.There were 230 patients (64% female) eligible for inclusion in the study: 22 underwent AGB; 102 underwent SG, and 106 underwent RYGB. Preoperative weight and BMI values were comparable (76 ± 7 kg/m2 for AGB; 75 ± 5 kg/m2 for SG; 74 ± 5 kg/m2 for RYGB). The median postoperative follow-up was 13 months for AGB (10-22 mo), 18 for SG (6-28 mo), and 15 for RYGB (6-24 mo). Patients undergoing RYGB and SG exhibited the greatest postoperative total body weight loss (35 ± 13% and 31 ± 15%, respectively; P = .14), which led to postoperative BMIs of 48 ± 10 kg/m2 and 51 ± 11 kg/m2, respectively (P = .14). All procedures conferred a reduction in the incidence of co-morbidities, including type 2 diabetes, and led to improved functional statuses. The overall complication rate was 7%, with 3 deaths (1%) within 30 days of surgery.This study found that primary BMS in patients with a BMI >70kg/m2 has an acceptable safety profile and is associated with good medium-term clinical outcomes. RYGB and SG are associated with better weight loss and great improvements in co-morbidities than AGB. Given the noninferiority of SG outcomes and SG's potential for further conversion to other BMS procedures if required, SG may be the best choice for primary BMS in patients with extreme obesity.

Diabetes, hypertension, body mass index, smoking and COVID-19-related mortality: a systematic review and meta-analysis of observational studies

ObjectivesWe conducted a systematic literature review and meta-analysis of observational studies to investigate the association between diabetes, hypertension, body mass index (BMI) or smoking with the risk of death in...

Subtyping youngsters with obesity: A theory-based cluster analysis

Psychological mechanisms play a crucial role in explaining weight gain. Aim of the present study was to identify subtypes in youngsters with obesity in line with these mechanisms. Defining homogeneous clusters within this heterogeneous group provides relevant information for personalized treatments.Data were collected in N = 572 participants (51% boys, aged 7–19) with extreme obesity (%BMI M = 187.8; SD = 30.9) recruited in an inpatient treatment centre. Based on psychological models of overweight/obesity, the Affect Regulation Model, the Reward Deficiency Model and The Dual Pathway Model, cluster variables were selected assessing emotional eating, reward reactivity and regulative capacities. Youngsters reported on emotional eating (DEBQ Emotional Eating) and reward sensitivity (BAS), while parents reported on children's regulative Executive Functions (BRIEF). Characteristics of the different clusters were examined concerning weight variables (pre and post treatment) and variables indexing problematic eating (DEBQ External Eating, Ch-EDE), affect regulation (FEEL-KJ) and depressive symptoms (CDI). Hierarchical cluster analyses supported the presence of three clusters, further evaluated by K-means cluster analyses. The cluster solutions differed according to age and sex (boys 7–13, boys 14–19, girls 7–13, girls 14–19). In all four age and gender subsamples, an “Emotional Eating” cluster displaying a vulnerable profile (high depression, maladaptive emotion regulation, problematic eating) and a “Reward Deficiency” cluster displaying a more resilient profile were detected. In girls 7–13, a “Weak Executive Functioning” indicative of insufficient self-regulative capacities, showed moderate to high emotional problems and problematic eating. In the other subgroups, the “Mean Level Functioning” cluster also showed elevated emotional problems and problematic eating. Given that different clusters can be identified, and given that these clusters have different profiles on emotional problems and problematic eating, subtyping youngsters with severe obesity is indicated, setting the stage for personalized treatments.

New DXA Diagnostic Indexes of Abdominal Obesity.

Aim: Cushing's syndrome (CS) is associated with weight gain and extreme central, visceral, abdominal obesity which is confirmed with dual-energy X-rays absorptiometric (DXA) diagnostic cut-off point (CP) values of central obesity indexes (COI), determined as an android to gynoid tissue and fat mass ratios. These best differentiate CS from non-CS obese women matched with CS according to their age and BMI. The aim of this study was to determine the CP values of new DXA indexes of central, abdominal obesity as a ratio of android and trunk to legs as well as trunk and legs to total tissue and fat mass that best differentiate CS and matched non-CS obese women in order to confirm central abdominal obesity, and to determine their normal CP values that best differentiate healthy non-obese women from CS and non-CS obese women, and to exclude abdominal obesity completely. Material and Methods: DXA indexes of abdominal obesity, calculated as а ratio of regional body fat and tissue mass compartments android to legs (A/L), trunk to legs (Tr/L), trunk to total (Tr/To) and legs to total (L/To) values were determined among 4 groups. Each group consisted of 18 women: 1st group of CS, 2nd group of obese women (O1) not different according to their age and BMI from CS, 3rd group of obese women (O2) with higher BMI of 35 ± 1.2 kg and a 4th group of non-obese, healthy women (C) with a normal BMI. Diagnostic accuracy (DG) of CP values of DXA indexes of abdominal obesity and indexes of normal body fat distribution (BFD) were determined. Results: A/L, Tr/L, Tr/To, and L/To DXA indexes were significantly different between CS and O1 as well as between non-CS women O2 compared to O1 and C. These indexes had a highly significant correlation among each other and also in relation to their BMI (p < 0.0001). A/L-Tm CP value of 0.3 best differentiated the CS from group O1, with the highest DG of 100 % and an A/L-Fm CP value of 0.26 differentiated them with a DG of 94.44% and sensitivity of 100 %. An A/L-Tn CP value of 0.23 and an A/L-Fn CP value of 0.25 best differentiated CS and C as well as O2 and C for the highest DG of 100 %. Conclusions: DXA indexes A/L, Tr/L, Tr/To and L/To values were significantly different among the four groups. These values correlated significantly among them and with their BMI in non-CS groups, thus confirming a BMI increase association with a more pronounced abdominal BFD. An A/L-Tm CP value of 0.3 and an A/L-Fm CP value of 0.26 were discovered as the best DXA diagnostic indexes of extreme abdominal obesity in CS and these could also be used in discovering abdominal BFD in non-CS obese women with metabolic syndrome (MS). An A/L-Tn CP value of 0.23 and an A/L-Fn CP value of 0.25 were discovered as the best DXA diagnostic indexes of normal BFD which completely excluded abdominal obesity.

SUCCESSFUL USE OF EXTRACORPOREAL MEMBRANE OXYGENATION (ECMO) IN MORBIDLY OBESE PATIENTS

TOPIC: Critical Care TYPE: Original Investigations PURPOSE: In 2020, ELSO published guidelines to assist providers with patient selection for ECMO in COVID ARDS. A BMI > 40 was listed as a relative contraindication for ECMO support without any supporting data in this specific patient population. Two major reports on ECMO patients from France and the ELSO database that included a total of 1118 patients with COVID ARDS, all with BMIs of 40 to be ECMO candidates. We aim to demonstrate the outcomes and feasibility of using ECMO in ARDS patients with extreme obesity METHODS: Data was collected from the ELSO database outlining outcomes of patients cannulated at Advent Health-Orlando for ECMO due to COVID ARDS between March 2020 – April 2021. The data included only patients with a BMI > 40. Data collected included age, length of stay, survival, discharge disposition, and expiration RESULTS: We have cannulated a total of 33 morbidly obese patients (BMI >40). 19/33 (57%) have survived and transitioned to either home, long-term acute care facility, rehab, or original referring hospital. 11/33 (33%) expired while on ECMO, 1/33 (3%) expired post-ECMO, resulting in an overall mortality of (12/33) 36%. The average LOS for all patients was 39.9 days. The survival group had an average LOS of 46.1 days. The average age for our cohort was 41 years CONCLUSIONS: It is our experience at Advent Health Orlando, that providing ECMO support to patients with BMI >40 has similar outcomes to patients who are not morbidly obese, our 59% survival rate compares to 60% in the ELSO historical database. Our 36% mortality rate compared to a range of 31-37% reported in the recent literature for COVID ARDS. Based on our results, we suggest that BMI > 40 be removed as a relative contraindication to ECMO. We also urge other centers to re-consider denying morbidly obese patients ECMO support based on the assumption that they may have a worse outcome than the rest of the population CLINICAL IMPLICATIONS: Based on our data, we demonstrate patients with COVID-19 ARDS with BMI > 40 benefited from ECMO support. In order to effectively ventilate morbidly obese patients, higher plateau pressures are required and may result in barotrauma and hemodynamic compromise. Supporting obese patients with ECMO to maintain protective lung settings can ultimately lead to better long-term outcomes. More data is needed to fully assess the survivability and overall quality of life in morbidly obese patients who are placed on ECMO, however, while this information is collected, we hope that the medical community will start offering the same opportunities to all patients regardless of weight DISCLOSURES: No relevant relationships by Nicholas Cavarocchi, source=Web Response No relevant relationships by Sergio Ramirez, source=Web Response No relevant relationships by Mai Vo, source=Web Response

Perioperative Challenges in Patients Transplanted with Livers from Extreme Obese Donors.

The combination of rising rates of obesity and the shortage of deceased donor livers have forced the consideration of marginal liver donors in terms of body mass index (BMI) for liver transplantation (LT). To date, there are still conflicting data on the impact of donor obesity on post-LT outcomes. We analyzed all patients undergoing LT alone in the United States (US) from October 2005 through December 2019 using the United Network of Organ Sharing (UNOS) data set. We categorized donor BMI >40kg/m2 as extremely obese (EO). Primary endpoints included 30-day perioperative mortality and early graft loss (EGL) within 7days. A subgroup analysis was performed for the EO donor group to assess how macrovesicular steatosis (MaS) >30% affects 30-day mortality and EGL within 7days. A total of 72,616 patients underwent LT during the study period. The 30-day perioperative mortality was significantly higher in the EO donor group (P=0.02). On multivariate analysis, recipients undergoing LT with EO donors had a 38% higher 30-day mortality risk (odds ratio [OR], 1.38; 95% confidence interval [CI], 1.21-1.69) and 53% increased risk of EGL (OR, 1.53; 95%CI, 1.22-1.90). MaS >30% was independently associated with a 2-fold increased risk of 30-day mortality (P=0.003) and 3.5-fold increased risk of EGL within 7days (P<0.001). The impact of MaS >30% in EGL was 2-fold for all patients transplanted during the study period compared with 3.5-fold in the EO donor group. There is an increased risk of EGL and 30-day perioperative mortality in recipients transplanted with EO donors. Future studies are warranted in morbid and super obese donors to assess the possible effect of obesity-related proinflammatory factors in EGL.

Weight Loss Outcomes and Lifestyle Patterns Following Sleeve Gastrectomy: an 8-Year Retrospective Study of 212 Patients.

Sleeve gastrectomy (SG) is an effective treatment for extreme obesity; however, long-term weight loss outcomes remain largely understudied. We aimed to examine the long-term weight changes following SG and patient characteristics and lifestyle patterns related to weight loss outcomes. Data from medical records of patients operated in a tertiary university medical center between 2008 and 2014 were reviewed, along with information derived from a telephone questionnaire. Information included the following: current medical status, medications, side effects, behavior, lifestyle habits, and weight changes. A total of 212 patients (69.3% females) were included, with a median follow-up duration of 8years post-SG. Mean age and baseline body mass index (BMI) of participants were 39.7 ± 12.0years and 42.2 ± 4.9kg/m2, respectively. Mean BMI, percentage excess weight loss, and percentage total body weight loss were 33.1 ± 6.1, 55.5 ± 27.5%, and 21.7 ± 10.7%, respectively. Higher baseline BMI was found to be the strongest independent predictor for insufficient weight loss (OR = 0.90, P = 0.001, 95% CI 0.85, 0.96). Sweetened beverage intake, usage of psychiatric medications, higher initial BMI, and lower age were significant predictors for increased weight gain from nadir weight (P < 0.0001, P = 0.005, P = 0.035, and P < 0.0001, respectively). SG patients were found to maintain a notable long-term weight loss. Nevertheless, weight regain and insufficient weight loss were prevalent in the long-term post-operative period, and were related to certain lifestyle patterns. Clinical practice should emphasize the relationship between post-operative weight loss outcomes and specific behaviors. Efforts should be made to educate patients on the need for lifelong follow-up and support.

Pharmacokinetics of Direct Oral Anticoagulants in Patients With Atrial Fibrillation and Extreme Obesity

PurposeDirect oral anticoagulants (DOACs) are recommended in preference to vitamin K antagonists (VKAs) for stroke prevention in patients with atrial fibrillation (AF) eligible for oral anticoagulation therapy; however, data and clinical experiences supporting the use of DOACs in patients with a body mass index ≥40 kg/m2 or weight >120 kg remain limited. The aim of this study was to evaluate the pharmacokinetic properties of DOACs in patients with AF and extreme obesity. MethodsWe enrolled all consecutive patients with AF and extreme obesity undergoing treatment with DOACs followed up at Monaldi Hospital, Naples, Italy. To determine peak plasma and trough levels of DOACs, plasma samples were collected at 2nd, 4th, 6th, and 12th hours from the last dose intake in patients receiving apixaban and dabigatran and at the 2nd, 4th, 6th, and 24th hours in those receiving edoxaban and rivaroxaban. The DOACs’ peak and trough plasma levels obtained from our study population were compared with those sourced from pharmacokinetic studies among patients without obesity, defined as a normal reference range in the literature. If at least 1 peak or trough plasma level was found ​​below or above the normal reference ranges, the patients were classified as having out-of-range DOAC plasma levels. Study population was then divided into in-range and out-of-range groups. Baseline characteristics, including DOAC treatment, were compared between the 2 groups. Univariate and multivariate logistic regression analysis were performed to identify baseline variables associated with DOACs’ plasma concentration out of the expected range. FindingsA total of 58 patients (mean [SD] age, 70.93 [8.73] years; 40% female) with extreme obesity (mean [SD] body mass index. 44.43 [3.54] kg/m2) and AF while undergoing DOAC treatment were included in the present study. In 9 patients (15.5 %), the DOAC plasma concentrations were out of the expected ranges (out-of-range group);, indicating a greater likelihood of edoxaban 30 mg treatment (33% vs 2%; P < 0.01) and inappropriate DOAC underdosing (56% vs 4%; P < 0.005) compared with the in-range group. According to the multivariate logistic analysis (P = 0.0011), the inappropriate DOAC underdosing (hazard ratio = 29.37; P = 0.0002) was an independent predictor of DOAC plasma levels out of the expected ranges. ImplicationsPatients with extreme obesity and AF who were receiving DOAC therapy had DOAC plasma concentrations in the expected range. The inappropriate DOAC underdosing seems to be the only independent clinical factor associated with a plasma concentration of the drug out of the expected range.

P–110 Does the Body Mass Index affect sperm quality?

Abstract Study question Does the body mass index (BMI) have an impact on semen analysis results? Summary answer The increase in BMI has a negative impact on sperm motility. What is known already Obesity is an increasingly prevalent health condition worldwide and can affect male fertility in various ways. It is known that obesity can cause testicular inflammation, higher testicular temperature, hypogonadism, sperm DNA fragmentation, and erectile dysfunction. However, there are still conflicting data regarding the correlation between BMI and semen parameters in the seminal analysis. Study design, size, duration Observational, cross-sectional, retrospective study using data from 1147 patients seen at a private infertility clinic between 2010 and 2020. The data were collected from electronic records in a prospective database. Participants/materials, setting, methods Patients were divided according to BMI (healthy weight, overweight, obesity classes I, II, III), and their seminal profiles were compared, according to 2010’s World Health Organization’s parameters. Cancer, cryptorchidism, viral orchitis, altered karyotype, Y chromosome microdeletions, vasectomy reversion, and testosterone use were excluding factors. Student t-tests and multiple linear regression were used for statistical analysis. The results were adjusted for age, alcohol, tobacco, and drug use, medication intake, physical activity, comorbidities, and scrotum heat factors. Main results and the role of chance From a total of 1384 patients, 219 were excluded. The BMI varied between 18,9 and 50,8 kg/m². From the 1147 patients, 297 had BMI 18.5–24.9 kg/m² (healthy weight, group 1), 611 had BMI 25–29.9 kg/m² (overweight, group 2), 179 had BMI 30–34.5 kg/m² (obese, group 3), 60 had BMI ≥ 35 kg/m² (extremely obese, group 4). The mean age for groups 1 through 4 was 37.6, 38.5, 38.2, and 36.5 years old. The comparison of the groups’ seminal parameters shows a significant decrease in progressive and total motility in patients with BMI ≥ 35 kg/m².The progressive motility was 43.8% in group 1, 44.1% in group 2, 42.4% in group 3, and 35.2% in group 4 (p = 0.07) and the total motility was 54.4%, 54.1%, 53.6%, and 45.9%, respectively (p = 0.012). The complementary analysis determined BMI 29 kg/m² as the cutoff for negative impact on progressive motility (p = 0.044) and 31 kg/m² on total motility (p = 0.036). The results were still significant after age, use of cannabis, and hypertension adjustments – the other possible interfering factors were not significant. Limitations, reasons for caution Besides the fact that this was a retrospective study, it also has a smaller sample size of patients with extreme obesity. This is probably related to the fact that the patients seeking reproductive treatment in a private clinic have a greater purchasing power and lower prevalence of obesity. Wider implications of the findings: In this study, sperm quality is negatively affected by BMI, with impairment since 29 kg/m² for progressive and 31 kg/m² for total motility. Our data support the potential deleterious role of obesity on semen parameters, reinforcing the importance of weight control in infertility prevention. Trial registration number Not applicable

Adult-born proopiomelanocortin neurons derived from Rax-expressing precursors mitigate the metabolic effects of congenital hypothalamic proopiomelanocortin deficiency

ObjectiveProopiomelanocortin (POMC) neurons of the hypothalamic arcuate nucleus are essential regulators of energy balance. Selective loss of POMC production in these cells results in extreme obesity and metabolic comorbidities. Neurogenesis occurs in the adult hypothalamus, but it remains uncertain whether functional POMC neurons emerge in physiologically significant numbers during adulthood. Here, we tested whether Rax-expressing precursors generate POMC neurons in adult mice and rescue the metabolic phenotype caused by congenital hypothalamic POMC deficiency. MethodsInitially, we identified hypothalamic Rax-expressing cell types using wild-type and Rax-CreERT2:Ai34D mice. Then we generated compound Rax-CreERT2:ArcPomcloxTB/loxTB mice in which endogenous hypothalamic Pomc expression is silenced, but can be restored by tamoxifen administration selectively in neurons derived from Rax+ progenitors. The number of POMC neurons generated by Rax+ progenitors in adult mice and their axonal projections was determined. The metabolic effects of these neurons were assessed by measuring food intake, bodyweight, and body composition, along with glucose and insulin levels. ResultsWe found that Rax is expressed by tanycytes and a previously unrecognized cell type in the hypothalamic parenchyma of adult mice. Rax+ progenitors generated ~10% of the normal adult hypothalamic POMC neuron population within two weeks of tamoxifen treatment. The same rate and steady state of POMC neurogenesis persisted from young adult to aged mice. These new POMC neurons established terminal projections to brain regions that were involved in energy homeostasis. Mice with Rax+ progenitor-derived POMC neurons had reduced body fat mass, improved glucose tolerance, increased insulin sensitivity, and decreased bodyweight in proportion to the number of new POMC neurons. ConclusionsThese data demonstrate that Rax+ progenitors generate POMC neurons in sufficient numbers during adulthood to mitigate the metabolic abnormalities of hypothalamic POMC-deficient mice. The findings suggest that adult hypothalamic neurogenesis is a robust phenomenon in mice that can significantly impact energy homeostasis.

The relationship and significance between lipoprotein abnormalities and HDL dysfunction in severely obese people

Obesity and dyslipidemia may have a role in the development of cardiovascular disease. Neuropathy has also been linked to obesity. The existence of peripheral nerve injury and the presence of metabolic syndrome and lipoprotein abnormalities were evaluated in patients with severe obesity who did not have type 2 diabetes. Detailed proteomics of neuropathic and an evaluation of lipoproteins and HDL-functionality were performed on 49 patients with extreme obesity and 35 age-matched healthy controls. Compared to healthy controls, participants with extreme obesity exhibited a more excellent neuropathy symptom portfolio, lower sural and peroneal nerve impedance, aberrant temperature thresholds, heart rate with controlled breathing, and corneal nerve characteristics. People with significant obesity suffer from little nerve fiber injury. In comparison to controls, obese patients have abnormal lipoproteins and impaired HDL activity. Obese patients with minor nerve fiber injury showed significantly higher serum triglycerides, decreased PON-1 activity, and a higher frequency of obesity than those without.

Genetic association of the PERIOD3 (PER3) Clock gene with extreme obesity

BackgroundObesity has reached epidemic proportions worldwide, affecting life quality and span. Susceptibility to obesity is partly mediated by genetic differences. Indeed, several genes from the clock gene family have already been shown to be intimately associated with obesity in diverse ethnic groups. In the present study, an association between BMI and the rs707467, rs228697 and rs228729 PER3 (Period Circadian Clock 3) polymorphisms in subjects with class II (BMI ≥ 35.0–39.9 kg/m2) and class III obesity (>40 kg/m2, extreme obesity) were carried out using TaqMan real-time PCR. Overall, 259 Brazilian adults were genotyped, of whom 122 had class II or III obesity (BMI ≥ 35.0 kg/m2) and 137 were controls having normal weight (BMI > 18.5 and <24.9 kg/m2). ResultsPER3 tag SNP (rs228729) shows a significant association with extreme obesity (1000 permutation p = 0.03 and p = 0.04), for genotype and allele frequency respectively) and a haplotype among the three assessed SNPs (alleles G/T/A, rs228697, rs228729, and rs707467, respectively, 1000 permutation p = 0.03) was significantly more prevalent in the group with obesity. ConclusionThis exploratory association study suggests that PER3 rs228729 may be associated with extreme obesity in Brazilian adults, however, replication is needed.

Does the severity of obesity influence bone density, geometry and strength in adolescents?

Relationships between the severity of obesity and bone health remain underexplored. To compare whole-body and localized bone mineral content (BMC) and density (BMD), trabecular bone score (TBS) and hip geometry and strength between adolescents with obesity versus extreme obesity. This cross-sectional study included 154 adolescents (12-15 years, 62% females) who were classified as having obesity (OG, [95th-99th] percentile) or extreme obesity (EOG, >99th percentile). Fat mass (FM), lean mass (LM), BMC, BMD for total-body-less-head (TBLH), lumbar spine (LS), hip, TBS and geometric and strength indices at the narrow-neck (NN), femoral shaft (FS) and intertrochanteric regions (IT) were assessed by Dual-X-ray Absorptiometry (DXA). There was no significant sex-interaction. For both sexes, TBLH BMC and BMD were not different between groups. TBS was lower in EOG compared with OG in both sexes in univariate analysis and after adjustment with maturation and body weight (p < 0.05). Hip BMD was significantly higher in the EOG compared to OG only after adjustment with maturation and fat mass percentage (p < 0.05 for men, p < 0.01 for women). For both sexes, TBLH, LS and hip BMC and BMD positively correlated with weight, BMI, LM and FM. TBS negatively correlated with BMI-percentile in both sexes, with a negative correlation with FM for males alone. Hip BMC and BMD, BMD, ACT and CSA at the three hip sites positively correlated with BMI-percentile in males. Extreme obesity impacts bone health depending on anatomical sites, altering lumbar trabecular bone in both males and females adolescents.