Fibroblast Growth Factor-Based Pharmacotherapies for the Treatment of Obesity-Related Metabolic Complications.

The fibroblast growth factor (FGF) family, which comprises 22 structurally related proteins, plays diverse roles in cell proliferation, differentiation, development, and metabolism. Among them, two classical members (FGF1 and FGF4) and two endocrine members (FGF19 and FGF21) are important regulators of whole-body energy homeostasis, glucose/lipid metabolism, and insulin sensitivity. Preclinical studies have consistently demonstrated the therapeutic benefits of these FGFs for the treatment of obesity, diabetes, dyslipidemia, and nonalcoholic steatohepatitis (NASH). Several genetically engineered FGF19 and FGF21 analogs with improved pharmacodynamic and pharmacokinetic properties have been developed and progressed into various stages of clinical trials. These FGF analogs are effective in alleviating hepatic steatosis, steatohepatitis, and liver fibrosis in biopsy-confirmed NASH patients, whereas their antidiabetic and antiobesity effects are mildand vary greatly in different clinical trials. This review summarizes recent advances in biopharmaceutical development of FGF-based therapies against obesity-related metabolic complications, highlights major challenges in clinical implementation, and discusses possible strategies to overcome these hurdles.

Lipid and glucose profiles in pregnant women with HIV on tenofovir-based antiretroviral therapy.

OBJECTIVE: Tenofovir alafenamide (TAF)-based antiretroviral therapy (ART) regimens have been associated with adverse changes in lipid and glucose profiles compared with tenofovir disoproxil fumarate (TDF)-based ART, but data in pregnancy is limited. We evaluated metabolic markers in pregnant women with HIV after starting TAF- vs TDF-based ART. METHODS: We analyzed data within the IMPAACT 2010/VESTED trial, which demonstrated better pregnancy outcomes in pregnant women randomized to initiate TAF/Emtricitabine/Dolutegravir (TAF/FTC+DTG; n=217) or TDF/FTC+DTG (n=215). We measured non-fasting plasma concentrations of glucose, total-cholesterol, low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), lipoprotein (a), and triglycerides from samples collected eight weeks after enrollment. We employed linear regression models to estimate by-arm mean differences. RESULTS: 219 participants enrolled in the DTG arms in Zimbabwe and Uganda: 109 in the TAF/FTC+DTG and 110 in the TDF/FTC+DTG arms. At study entry, mean gestational age was 22.6 weeks, median HIV-1 RNA was 711 copies/mL, and mean age was 25.8 years. By eight weeks, mean total cholesterol was 12 mg/dL higher in women randomized to TAF/FTC+DTG versus TDF/FTC+DTG (95% CI 3.8, 21.1). Pregnant women in the TAF/FTC+DTG arm had higher mean LDL-C (7.1 mg/dL, 95% CI 0.2, 14.0), triglycerides (12.3 mg/dL, 95% CI 1.8, 22.7), lipoprotein (a) (7.3 mg/dL, 95% CI 1.1, 13.6), and lower mean HDL-C (2.8 mg/dL, 95% CI 0.1, 5.6) compared to the TDF/FTC+DTG arm. CONCLUSION: Pregnant women randomized to start TAF/FTC+DTG had higher lipids than those randomized to TDF/FTC+DTG within eight weeks of ART initiation. However, lipid levels were within normal reference ranges.

Safety and Feasibility of Regional Citrate Anticoagulation for Continuous Renal Replacement Therapy With Calcium-Containing Solutions: A Randomized Controlled Trial.

BACKGROUND: Calcium-free (Ca-free) solutions are theoretically the most ideal for regional citrate anticoagulation (RCA) in continuous renal replacement therapy (CRRT). However, the majority of medical centers in China had to make a compromise of using commercially available calcium-containing (Ca-containing) solutions instead of Ca-free ones due to their scarcity. This study was designed to probe into the potential of Ca-containing solution as a secure and efficient substitution for Ca-free solutions. METHODS: In this prospective, randomized single-center trial, 99 patients scheduled for CRRT were randomly assigned in a 1:1:1 ratio to one of three treatment groups: continuous veno-venous hemodialysis Ca-free dialysate (CVVHD Ca-free) group, continuous veno-venous hemodiafiltration calcium-free dialysate (CVVHDF Ca-free) group, and continuous veno-venous hemodiafiltration Ca-containing dialysate (CVVHDF Ca-containing) group at cardiac intensive care unit (CICU). The primary endpoint was the incidence of metabolic complications. The secondary endpoints included premature termination of treatment, thrombus of filter, and bubble trap after the process. RESULTS: The incidence of citrate accumulation (18.2% vs. 12.1% vs. 21.2%) and metabolic alkalosis (12.1% vs. 0% vs. 9.1%) did not significantly differ among three groups (p > 0.05 for both). The incidence of premature termination was comparable among the groups (18.2% vs. 9.1% vs. 9.1%, p = 0.582). The thrombus level of the filter and bubble trap was similar in the three groups (p > 0.05 for all). CONCLUSIONS: In RCA-CRRT for CICU population, RCA-CVVHDF with Ca-containing solutions and traditional RCA with Ca-free solutions had a comparable safety and feasibility. TRIAL REGISTRATION: ChiCTR2100048238 in the Chinese Clinical Trial Registry.

The age of the obesity onset is a very important factor for the development of metabolic complications and cardiovascular risk in children and adolescents with severe obesity.

Severe obesity defined as BMI value corresponding to an adult > 40 kg/m2 affects 1-5% of children and adolescents in Europe. The purpose of this study was to assess the occurrence of cardiovascular risk factors in children and adolescents with severe obesity. The analysis included 140 patients (75 female) at the mean age of 14 ± 2.1 SD (range 10-18) years (all recruited in 4 regional reference centers in Poland). Severe obesity was defined as BMI > 35 kg/m2 (children 6-14 years), and BMI > 40 kg/m2 (> 14 years). Fasting plasma samples have been obtained in all patients, and OGTT was performed in all patients. The metabolic risk factors were defined as high blood pressure (BP > 90 percentile for height, age, and sex), HDL cholesterol < 1.03 mmol/L, TG ≥ 1.7 mmol/L, and hyperglycemic state (fasting blood glucose > 5.6 mmol/L, or blood glucose 120' after oral glucose load > 7.8 mmol/L). Additionally, the MetS z-score was calculated using Metabolic Syndrome Severity Calculator. One hundred twenty-four (89%) participants presented with high BP, 117 (84%) with abnormal lipid profile, and 26 with the hyperglycemic. Only 12 (9%) were free of metabolic complications. More than 60% of patients had more than one cardiovascular risk factor. The high BP was significantly associated with the severity of obesity (F = 9.9, p = 0.002). Patients with at least one metabolic complication presented with significantly younger age of the onset of obesity (the mean age of the patients with no overt obesity complications was 10 years, while the mean age of those who presented at least one was 4.7 ± 3.5 SD years (p = 0.002)). A significant positive association between in the value of the Mets BMI z-score with age was observed (R = 0.2, p < 0.05). There were no differences between girls and boys regarding Mets BMI z-score (1.7 ± 0.8 vs 1.7 ± 0.7, p = 0.8).Conclusions: The most common metabolic risk factor in children and adolescents with severe obesity was high BP. The most important factor determining presence of obesity complications, and thus the total metabolic risk, seems to be younger (< 5 years) age of onset of obesity. What is Known? • It is estimated that 1-5% of children and adolescents in Europe suffer from severe obesity corresponding to an adult BMI > 40 kg/m2, and it is the fastest growing subcategory of childhood obesity. • Children with severe obesity face substantial health risk that may persist into adulthood, encompassing chronic conditions, psychological disorders and premature mortality. What is new: • The most common complication is high BP that is significantly associated with the severity of obesity (BMI z-score), contrary to dyslipidemia and hyperglycemic state, which do not depend on BMI z-score value. • The most important factor determining presence of obesity complications, and thus the total metabolic risk, seems to be younger (< 5 years) age of onset of obesity.

Impact of living donor liver transplantation on long-term cardiometabolic and graft outcomes in cirrhosis due to nonalcoholic steatohepatitis.

BACKGROUND AND AIM: Non-alcoholic steatohepatitis (NASH) is a leading indication for liver transplantation (LT). This study aimed to determine whether living donor LT (LDLT) recipients experienced less recurrent NASH, cirrhosis, and cardiometabolic complications compared to deceased donor LT (DDLT). METHOD: Patients with LDLT and DDLT for NASH between February 2002 and May 2018 at University Health Network (UHN) were compared. Cox Proportional Hazard model was used to analyze overall survival (OS), Fine and Gray's Competing Risk models were conducted to analyze cumulative incidence of post LT outcomes. RESULTS: One hundred and ninety-nine DDLTs and 66 LDLTs were performed for NASH cirrhosis. Time and rate of recurrence of NAFLD and NASH were comparable in both groups. Graft cirrhosis was more common in DDLT recipients (n = 14) versus LDLT (n = 0) (p < .0001). Significant fibrosis (Fibrosis ≥ F2) developed in 50 recipients (12 LDLT and 38 DDLT) post LT (DDLT vs. LDLT: HR = 1.00, 95% CI = (.52-1.93), p = .91) and there was no difference in time to significant fibrosis (p = .57). There was no difference in development of post-transplant diabetes, dyslipidemia, metabolic syndrome, cardiovascular disease, and cancers. LDLT group had better renal function at 10 years (MDRD eGFR of 57.0 mL/min vs. 48.5 mL/min, p = .047). Both groups had a comparable OS (HR = 1.83 (95% CI = .92-3.62), p = .08). CONCLUSION: Overall, LDLT recipients had significantly better renal function by virtue of having early transplantation in their disease course. LDLT was also associated with significantly less graft cirrhosis, although OS and cardiometabolic outcomes were comparable between LDLT and DDLT.

Obesity, metabolic risk and adherence to healthy lifestyle behaviours: prospective cohort study in the UK Biobank.

BACKGROUND: Contested evidence suggests that obesity confers no risk to health in people who have a healthy lifestyle, particularly if there are no metabolic complications of obesity. The aim was to examine the association between adherence to lifestyle recommendations and the absence of metabolic complications on the incident or fatal cardiovascular disease and all-cause mortality across different categories of body mass index (BMI). METHODS: This contemporary prospective cohort study included 339,902 adults without cardiovascular disease at baseline, recruited between 2006 and 2010 from the UK Biobank and followed until 2018-2020. The main exposures were four healthy lifestyle behaviours: never smoker, alcohol intake ≤ 112g/ week, 150 min moderate physical activity or 75 min vigorous activity/week, ≥ 5 servings of fruit or vegetables/day, and we assessed these overall and across the BMI groups. Metabolic complications of excess adiposity were hypertension, diabetes and hyperlipidaemia, and we examined whether obesity was associated with increased risk in the absence of these complications. The outcomes were all-cause mortality, death from, and incident cardiovascular disease (CVD). RESULTS: Individuals who met four lifestyle recommendations but had excess weight had higher all-cause mortality; for BMI 30-34.9 kg/m2, the hazard ratio (HR) was 1.42 (95% confidence interval 1.20 to 1.68), and for BMI ≥ 35 kg/m2, HR was 2.17 (95% CI 1.71 to 2.76). The risk was lower, but still increased for people with no metabolic complications; for all-cause mortality, BMI 30-34.9 kg/m2 had an HR of 1.09 (95% CI 0.99 to 1.21), and BMI ≥ 35 kg/m2 had an HR of 1.44 (95% CI 1.19 to 1.74) for all-cause mortality. Similar patterns were found for incident and fatal CVD. CONCLUSIONS: Meeting healthy lifestyle recommendations, or the absence of metabolic complications of obesity offsets some, but not all, of the risk of subsequent CVD, and premature mortality in people with overweight or obesity. Offering support to achieve and maintain a healthy weight and to adopt healthy behaviours are likely to be important components in effective preventative healthcare.

Characterization and predictive functional profiles on metagenomic 16S rRNA data of liver transplant recipients: A longitudinal study.

Long-term survival after Liver Transplantation (LT) is often compromised by infectious and metabolic complications. We aimed to delineate alterations in intestinal microbiome (IM) over time that could contribute to medical complications compromising long-term survival following LT. Fecal samples from LT recipients were collected at 3 months (3 M) and 6 months (6 M) post-LT. The bacterial DNA was extracted using E.Z.N.A. Stool DNA Kit and 16S rRNA gene sequencing at V4 hypervariable region was performed. DADA2 and Phyloseq was implemented to analyze the taxonomic composition. Differentially abundant taxa were identified by metagenomeSeq and LEfSe. Piphillin, an Inferred functional metagenomic analysis tool was used to study the bacterial functional content. For comparison, healthy samples were extracted from NCBI and analyzed similarly. The taxonomic & functional profiles of LT recipients were validated with metagenomic sequencing data from animals exposed to immunosuppressants using Venny. Our findings provide a new perspective on longitudinal increase in specific IM communities post-LT along with an increase in bacterial genes associated with metabolic and infectious disease.

A prospective longitudinal assessment of de novo metabolic syndrome after liver transplantation.

BACKGROUND: De novo metabolic syndrome (MS) is a frequent complication after liver transplantation (LT). The aim of this prospective study is to identify potential risk factors longitudinally associated to post-LT de novo MS. Patients without pre-LT MS who underwent LT between April 2013 and October 2017 were prospectively included. Metabolic variables were collected at LT and at 6, 12, and 24 months post-LT. RESULTS: Sixty-three patients fulfilled the inclusion criteria (76% male, mean age 53.6±9.5 years). The prevalence of de novo MS was 46%, 43%, and 49% at 6, 12, and 24 months after LT, respectively. Among other MS components, the prevalence of type 2 diabetes, hypertension and hypertriglyceridemia significantly increased after LT. Considering the baseline characteristics at the adjusted analysis, alcoholic liver disease (OR 4.17, 95%CI 1.20-14.51; p = .03) and hypertension pre-LT (OR 11.3, 95% CI 1.49-85.46; p = .02) were confirmed as independent risk factors of post-LT de novo MS. In the time-varying analysis, only eGFR (OR .97, 95% CI .97-.98; p < .0001) was found associated with post-LT de novo MS. CONCLUSIONS: De novo MS frequently occurs shortly after LT, affecting nearly half of patients at 24 months post-LT. Lifestyle modifications should be recommended starting early post-LT, particularly for patients with established risk factors.

Nutritional status of the elderly in Poland.

Background: The elderly are at greater risk of underweight and the associated risk of protein and energy malnutrition. On the other hand, the lower energy requirement with an often too high intake from the diet leads to the development of overweight and obesity. Objective: The aim of the study was to assess the prevalence of underweight, overweight and obesity, including abdominal obesity in Polish elderly. Material and methods: The study included 300 men and 304 women aged 65 and over from all over the country. The nutritional status was assessed on the basis of anthropometric measurements: body height and weight as well as waist and hip circumferences. Based on BMI (Body Mass Index), the prevalence of underweight (<20.0), overweight (25.0-29.9) and obesity (≥30.0) was assessed. WHR (Waist-to-Hip Ratio) was used to assess abdominal obesity (≥1.0 in men and ≥0.85 in women). Waist circumference was also analysed with regard to increased risk of metabolic complications (≥94 cm in men and ≥80 cm in women). Results: Underweight was found in 1.3% of men and 4.3% of women. 55.3% of men and 40.1% of women were overweight, 20.3% and 21.7% were obese, respectively. In the case of people with excess body weight, abdominal obesity was observed in 50% of men and 70.1% of women. Waist circumference indicating an increased risk of metabolic complications was found in 44.1% of men and 67.5% of women. Conclusions: The prevalence of overweight and obesity in Polish elderly was high, especially in men. Overweight and obese people often had abdominal obesity. This type of obesity was more common in women. Elderly people, especially women, often have an increased risk of metabolic complications due to high fat accumulation in the abdomen. It was even found in elderly who were not overweight nor obese. Some elderly, mostly women, were underweight which increased the risk of protein and energy malnutrition.

Regional Citrate Anticoagulation for Continuous Kidney Replacement Therapy With Calcium-Containing Solutions: A Cohort Study.

OBJECTIVE: Regional citrate anticoagulation (RCA) is the preferred anticoagulation method for continuous kidney replacement therapy (CKRT) recommended by KDIGO. Limited availability of calcium-free solutions often imposes challenges to the implementation of RCA for CKRT (RCA-CKRT). The principal purpose of this study was to characterize the outcomes of RCA-CKRT using calcium-containing solutions. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: We evaluated the safety and efficacy of RCA-CKRT with calcium-containing dialysate and replacement fluid used for 128 patients. A total of 571 filters and 1,227 days of CKRT were analyzed. EXPOSURES: Liver disease, sepsis in the absence of liver disease, and sepsis with liver disease. OUTCOMES: Filter life and metabolic complications per 100 CKRT days. ANALYTICAL APPROACH: Linear mixed-effects model and generalized linear mixed-effects models. RESULTS: The majority of patients were male (91; 71.1%), 32 (25%) had liver disease, and 29 (22.7%) had sepsis without liver disease. Median filter life was 50.0 (interquartile range, 22.0-118.0) hours, with a maximum of 322 hours, and was significantly lower (33.5 [interquartile range, 17.5-60.5] h) in patients with liver disease. Calcium-containing replacement solutions were used in 41.6% of all CKRT hours and reduced intravenous calcium requirements by 31.7%. Hypocalcemia (ionized calcium<0.85mmol/L) and hypercalcemia (total calcium>10.6mg/dL) were observed in 6.0 and 6.7 per 100 CKRT days, respectively. Citrate accumulation was observed in 13.3% of all patients and was associated with metabolic acidosis in 3.9%, which was not significantly different in patients with liver disease (9.3%; P = 0.2). LIMITATIONS: Lack of control groups that used calcium-free dialysate and replacement solutions with RCA-CKRT. Possible overestimation of filter life from incomplete data on cause of filter failure. CONCLUSIONS: Our study suggests that RCA-CKRT with calcium-containing solutions is feasible and safe in critically ill patients, including those with sepsis and liver disease.

The metabolic and immunological characteristics of pregnant women with COVID-19 and their neonates.

Our aim was to investigate whether SARS-CoV-2 infection raised high risks of late pregnancy complications, and posed health problems in fetuses and neonates. We analyzed the data of COVID-19 pregnant women with COVID-19 during late pregnancy and their neonates. Eleven out of 16 (69%) pregnant women with COVID-19 had ++ or +++ of ketone body in urine. The blood uric acid of pregnant patients was 334 µmol/L (IQR, 269-452). D-dimer and FDP in pregnant patients were 3.32 mg/L (IQR, 2.18-4.21) and 9.6 mg/L (IQR, 5.9-12.4). Results of blood samples collected at birth showed that 16 neonates had leukocytes (15.7 × 109/L (IQR, 13.7-17.2)), neutrophils (11.1 × 109/L (IQR, 9.2-13.2)), CK (401 U/L (IQR, 382-647)), and LDH (445 U/L (IQR, 417-559)). Twenty-four hours after birth, a neonate from COVID-19 woman had fever and positive of SARS-CoV-2 gene. Another woman had strongly positive for SARS-CoV-2 gene (+++) for 4 weeks, and delivered one neonate who had SARS-CoV-2 IgM (46 AU/mL) and IgG (140 AU/mL) on day 1 after birth. In the third trimester, COVID-19 infection in pregnant patients raised high risks of ketonuria, hypercoagulable state, and hyperfibrinolysis, which may lead to severe complications. COVID-19 increased the inflammatory responses of placenta, and fetuses and neonates had potential organ dysregulation and coagulation disorders. There was a potential intrauterine transmission while pregnant women had high titer of SARS-CoV-2, but it is necessary to detect SARS-CoV-2 in the blood cord, placenta, and amniotic fluid to further confirm intrauterine infection of fetuses.

An Association between Diet and MC4R Genetic Polymorphism, in Relation to Obesity and Metabolic Parameters-A Cross Sectional Population-Based Study.

The melanocortin-4 receptor (MC4R) gene harbours one of the strongest susceptibility loci for obesity and obesity-related metabolic consequences. We analysed whether dietary factors may attenuate the associations between MC4R genotypes and obesity and metabolic parameters. In 819 participants genotyped for common MC4R polymorphisms (rs17782313, rs12970134, rs633265, and rs135034), the anthropometric measurements, body fat content and distribution (visceral and subcutaneous adipose tissue, VAT and SAT, respectively), and blood glucose, insulin, total-, LDL-, HDL-cholesterol, triglycerides concentrations, and daily macronutrient intake were assessed. ANOVA or Kruskal-Wallis tests were used, and multivariate linear regression models were developed. We observed that the CC genotype carriers (rs17782313) presented higher VAT, VAT/SAT ratio, fasting blood glucose and triglyceride concentrations when they were stratified to the upper quantiles of protein intake. An increase in energy derived from proteins was associated with higher BMI (Est. 5.74, R2 = 0.12), body fat content (Est. 8.44, R2 = 0.82), VAT (Est. 32.59, R2 = 0.06), and VAT/SAT ratio (Est. 0.96, R2 = 0.05). The AA genotype carriers (rs12970134) presented higher BMI, body fat, SAT and VAT, fasting blood glucose, triglycerides and total cholesterol concentrations. An increase in energy derived from proteins by AA carriers was associated with higher VAT (Est.19.95, R2 = 0.06) and VAT/SAT ratio (Est. 0.64, R2 = 0.05). Our findings suggest that associations of the common MC4R SNPs with obesity and its metabolic complications may be dependent on the daily dietary intake, which may open new areas for developing personalised diets for preventing and treating obesity and obesity-related comorbidities.

Greater Weight Gain in Treatment-naive Persons Starting Dolutegravir-based Antiretroviral Therapy.

BACKGROUND: Recent studies have reported weight gain in virologically suppressed persons living with human immunodeficiency virus (PLWH) switched from older antiretroviral therapy (ART) to newer integrase strand transfer inhibitor (INSTI)-based regimens. In this study, we investigated whether weight gain differs among treatment-naive PLWH starting INSTI-based regimens compared to other ART regimens. METHODS: Adult, treatment-naive PLWH in the Vanderbilt Comprehensive Care Clinic cohort initiating INSTI-, protease inhibitor (PI)-, and nonnucleoside reverse transcriptase inhibitor (NNRTI)-based ART between January 2007 and June 2016 were included. We used multivariable linear mixed-effects models to generate marginal predictions of weights over time, adjusting for baseline clinical and demographic characteristics. We used restricted cubic splines to relax linearity assumptions and bootstrapping to generate 95% confidence intervals. RESULTS: Among 1152 ART-naive PLWH, 351 initiated INSTI-based regimens (135 dolutegravir, 153 elvitegravir, and 63 raltegravir), 86% were male, and 49% were white. At ART initiation, median age was 35 years, body mass index was 25.1 kg/m2, and CD4+ T-cell count was 318 cells/µL. Virologic suppression at 18 months was similar between different ART classes. At all examined study time points, weight gain was highest among PLWH starting dolutegravir. At 18 months, PLWH on dolutegravir gained 6.0 kg, compared to 2.6 kg for NNRTIs (P < .05), and 0.5 kg for elvitegravir (P < .05). PLWH starting dolutegravir also gained more weight at 18 months compared to raltegravir (3.4 kg) and PIs (4.1 kg), though these differences were not statistically significant. CONCLUSIONS: Treatment-naive PLWH starting dolutegravir-based regimens gained significantly more weight at 18 months than those starting NNRTI-based and elvitegravir-based regimens.

Association between obesity after liver transplantation and steatosis, inflammation, and fibrosis of the graft.

BACKGROUND: Nonalcoholic steatohepatitis has become one of the leading causes of liver transplantation. The development of steatosis, as well as the link to inflammation and fibrosis, after transplantation remain poorly understood. The aim of this analysis was to evaluate the influence of obesity on histopathological changes of the graft during long-term follow-up. METHODS: A total of 1494 longitudinal liver biopsies of 271 recipients were evaluated during a follow-up period of 5 to 10 years. Clinical and laboratory parameters as well as histopathological categories of steatosis, inflammation, and fibrosis were explored by routine protocol biopsies. RESULTS: The BMI and prevalence of diabetes mellitus significantly increased after transplantation (P < .01). Diabetes and de novo obesity were significantly associated with the degree of graft steatosis. There was no correlation between former steatosis and inflammation or fibrosis. Inflammation was a precursor of fibrosis, and fibrosis increased over the first 3 years (P < .01). No severe graft dysfunction was observed. CONCLUSION: Obesity and diabetes mellitus correlated with higher grades of steatosis and de novo steatosis after transplantation. Metabolic syndrome must be considered as a serious post-transplant complication that can cause histopathological alteration. However, the progress from steatosis to steatohepatitis is not as common as expected.

Complications of Regional Citrate Anticoagulation for Continuous Renal Replacement Therapy: An Observational Study.

INTRODUCTION: Regional citrate anticoagulation (RCA) is the recommended anticoagulation modality for continuous renal replacement therapy (CRRT). RCA was associated with a low rate of complications in randomized controlled trials. However, little is known about the type and rate of complications in real life. We sought to describe complications associated with RCA in comparison with those associated with heparin anticoagulation. METHODS: In our institution, RCA has been the default anticoagulation modality for CRRT in all patients without contraindications since 2013. We have retrospectively reviewed all consecutive patients who received CRRT between January and December 2016 in our institution. For each CRRT session, we have assessed circuit duration, administered dose, as well as therapy-associated complications. Those parameters were compared according to whether the circuit was run in continuous veno-venous hemodialysis (CVVHD) mode with RCA or continuous veno-venous hemofiltration (CVVH) mode with heparin anticoagulation. RESULTS: We analyzed 691 CRRT sessions in 121 patients. Of those 400 (57.9%) were performed in CVVHD-RCA mode and 291 (42.1%) in CVVH-Heparin Mode. Compared with -CVVH-Heparin mode, CVVHD-RCA mode was associated with a longer circuit lifespan (median duration 54.9 interquartile range [IQR 44.6] vs. 15.3 h [IQR 22.4], p < 0.0001). It was associated with a higher rate of metabolic acidosis 77 (20.2%) vs. 18 (7.2%), (p < 0.0001), alkalosis 186 (48.7%) vs. 43 (17.1%), (p= 0.0001), and hypocalcemia 96 (25.07%) vs. 26 events (10.79%), p < 0.0001. However, the majority of these alterations were of benign or moderate severity. Only one possible citrate intoxication was observed. CONCLUSIONS: CVVHD-RCA was associated with a much longer circuit life but an increased rate of minor metabolic complications, in particular acid-base derangements. Some of these complications might have been prevented by therapy adaptation. Medical and nursing staff education is of major importance in the implementation of an RCA protocol.

Non-exercise based estimation of cardiorespiratory fitness is inversely associated with metabolic syndrome in a representative sample of Korean adults.

BACKGROUND: This study investigated the association between non-exercise based estimation of cardiorespiratory fitness (eCRF) and metabolic syndrome (Mets) in Korean adults aged 18 years and older (13,400 women and 9885 men). METHODS: Data from the 2008 and 2011 Korea National Health and Nutrition Examination Surveys IV and V in South Korea were analyzed. eCRF was assessed with a previously validated procedure. Participants were classified into 5 categories from the lowest quantile to the highest quantile based on individual eCRF distributions. RESULTS: The findings showed an independent and inverse association between eCRF and Mets in women and men separately. Individuals in the highest eCRF category (quantile 5) had a significantly lower prevalence of Mets (14.5 and 14.8% for women and men, respectively) compared with their counterparts (40.4 and 46.4% for women and men, respectively) in the lowest eCRF category (quantile 1), and the association showed a graded response, with the quantiles 2, 3, and 4 also significantly associated with a lower prevalence of Mets compared with the quantile 1. Furthermore, the prevalence of Mets in the highest quantile compared with the lowest quantile remained statistically significant in both men (p < 0.05) and women (p < 0.05) even after adjustments for age, body mass index, skeletal muscle index, smoking, heavy drinking, vitamin D, caloric intake, and dietary intakes of carbohydrates, fats, and proteins. CONCLUSION: The findings support a preventive role for eCRF against Mets in Korean adults.

Coenzyme Q10 Supplementation Improves Adipokine Levels and Alleviates Inflammation and Lipid Peroxidation in Conditions of Metabolic Syndrome: A Meta-Analysis of Randomized Controlled Trials.

Evidence from randomized controlled trials (RCTs) suggests that coenzyme Q10 (CoQ10) can regulate adipokine levels to impact inflammation and oxidative stress in conditions of metabolic syndrome. Here, prominent electronic databases such as MEDLINE, Cochrane Library, and EMBASE were searched for eligible RCTs reporting on any correlation between adipokine levels and modulation of inflammation and oxidative stress in individuals with metabolic syndrome taking CoQ10. The risk of bias was assessed using the modified Black and Downs checklist, while the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool was used to evaluate the quality of evidence. Results from the current meta-analysis, involving 318 participants, showed that CoQ10 supplementation in individuals with metabolic syndrome increased adiponectin levels when compared to those on placebo (SMD: 1.44 [95% CI: -0.13, 3.00]; I2 = 96%, p < 0.00001). Moreover, CoQ10 supplementation significantly lowered inflammation markers in individuals with metabolic syndrome in comparison to those on placebo (SMD: -0.31 [95% CI: -0.54, -0.08]; I2 = 51%, p = 0.07). Such benefits with CoQ10 supplementation were related to its ameliorative effects on lipid peroxidation by reducing malondialdehyde levels, concomitant to improving glucose control and liver function. The overall findings suggest that optimal regulation of adipokine function is crucial for the beneficial effects of CoQ10 in improving metabolic health.

Islet Transplantation Alone Versus Solitary Pancreas Transplantation: an Outcome-Driven Choice?

PURPOSE OF REVIEW: In patients with type 1 diabetes with extreme glycemic variability, the restoration of pancreas endocrine function is potentially and completely achieved with islets of Langerhans (tissue derived from whole organ) or pancreas (whole organ) transplantation. The aim of our review is to report on the latest studies and to highlight the benefits and risks of the two procedures, providing clearer, more selective, evidence-based clinical indications that also consider the impact on the degenerative complications of diabetes as a potential benefit. RECENT FINDINGS: Clinical experience in this field has been dynamic over the last three decades, and has been characterized by the development of more standardized protocols and a clearer definition of clinical outcome. On the contrary, the recommendations thus far are not well delineated and tend to overlap, and the past ADA position statement for pancreas transplant alone has also been applied to islet transplant alone, without differentiation. Both outcome-driven and non-outcome-driven criteria are considered in the conclusions, in an attempt to streamline indications for islet-alone or pancreas-alone transplantation.

The beneficial effects of N-acetyl cysteine (NAC) against obesity associated complications: A systematic review of pre-clinical studies.

Excessive adiposity in an obese state is known to drive the onset of metabolic dysregulations, mostly involving chronic immune activation and oxidative stress. Prolonged inflammation and oxidative stress have been linked to impaired adipose tissue function and the development of the metabolic syndrome. Currently available therapies offer minimal prophylactic effects, while substantial experimental evidence supports the ameliorative effects of N-acetylcysteine (NAC) against various metabolic complications associated with obesity. The current review provides a comprehensive synthesis of studies published in major search engines such as PubMed, Cochrane library, Embase, and Google Scholar assessing the therapeutic effect of NAC against obesity associated complications. Overwhelming literature included in this review supports the ameliorative effects of NAC against such complications in both in vitro and in vivo models of obesity. In addition to attenuating an abnormal pro-inflammatory response and limiting oxidative damage, NAC could inhibit lipid accumulation by targeting adipogenic transcription factors such as peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer binding protein beta (C/EBPß), and improve insulin sensitivity through augmenting phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway. Although necessary evidence informing on its optimal dose and its comparative effect with other well-studied pharmacological compounds is demonstrated, it is clear that future investigations are required to confirm the therapeutic effect of NAC in obese human subjects.

Inflammation and Metabolic Complications in HIV.

PURPOSE OF REVIEW: We aim to provide an in-depth review of recent literature highlighting the role of inflammation involving the adipose tissue, liver, skeletal muscles, and gastrointestinal tract in the development of metabolic complications among persons living with HIV (PLWH). RECENT FINDINGS: Recent studies in PLWH have demonstrated a significant association between circulating inflammatory markers and development of insulin resistance and metabolic complications. In adipose tissue, pro-inflammatory cytokine expression inhibits adipocyte insulin signaling, which alters lipid and glucose homeostasis. Increased lipolysis and lipogenesis elevate levels of circulating free fatty acids and promote ectopic fat deposition in liver and skeletal muscles. This leads to lipotoxicity characterized by a pro-inflammatory response with worsening insulin resistance. Finally, HIV is associated with gastrointestinal tract inflammation and changes in the gut microbiome resulting in reduced diversity, which is an additional risk factor for diabetes. Metabolic complications in PLWH are in part due to chronic, multisite tissue inflammation resulting in dysregulation of glucose and lipid trafficking, utilization, and storage.