Genetic glucocorticoid receptor variants differ between ethnic groups but do not explain variation in age of diabetes onset, metabolic and inflammation parameters in patients with type 2 diabetes.

Aims: The effect of excess glucocorticoid receptor (GR) stimulation through glucocorticoid medication or cortisol on glucose metabolism is well established. There are genetic GR variants that result in increased or decreased GR stimulation. We aimed to determine the prevalence of genetic GR variants in different ethnic groups in a cohort of patients with type 2 diabetes, and we aimed to determine their association with age of diabetes onset and metabolic and inflammation parameters. Methods: A cross-sectional analysis was performed in a multiethnic cohort (n = 602) of patients with established type 2 diabetes. Polymorphisms in the GR gene that have previously been associated with altered glucocorticoid sensitivity (TthIIII, ER22/23EK N363S, BclI and 9ß) were determined and combined into 6 haplotypes. Associations with age of diabetes onset, HbA1c, hs-CRP and lipid values were evaluated in multivariate regression models. Results: The prevalence of the SNPs of N363S and BclI was higher in Dutch than in non-Dutch patients. We observed a lower prevalence of the SNP 9ß in Dutch, South(East) Asian and Black African patients versus Turkish and Moroccan patients. We did not detect an association between SNPs and diabetes age of onset or metabolic parameters. We only found a trend for lower age of onset and higher HbA1c in patients with 1 or 2 copies of haplotype 3 (TthIIII + 9ß). Conclusions: The prevalence of genetic GR variants differs between patients of different ethnic origins. We did not find a clear association between genetic GR variants and age of diabetes onset or metabolic and inflammation parameters. This indicates that the clinical relevance of GR variants in patients with established type 2 diabetes is limited.

Microbiome-derived ethanol in nonalcoholic fatty liver disease.

To test the hypothesis that the gut microbiota of individuals with nonalcoholic fatty liver disease (NAFLD) produce enough ethanol to be a driving force in the development and progression of this complex disease, we performed one prospective clinical study and one intervention study. Ethanol was measured while fasting and 120 min after a mixed meal test (MMT) in 146 individuals. In a subset of 37 individuals and in an external validation cohort, ethanol was measured in portal vein blood. In an intervention study, ten individuals with NAFLD and ten overweight but otherwise healthy controls were infused with a selective alcohol dehydrogenase (ADH) inhibitor before an MMT. When compared to fasted peripheral blood, median portal vein ethanol concentrations were 187 (interquartile range (IQR), 17-516) times higher and increased with disease progression from 2.1 mM in individuals without steatosis to 8.0 mM in NAFL 21.0 mM in nonalcoholic steatohepatitis. Inhibition of ADH induced a 15-fold (IQR,1.6- to 20-fold) increase in peripheral blood ethanol concentrations in individuals with NAFLD, although this effect was abolished after antibiotic treatment. Specifically, Lactobacillaceae correlated with postprandial peripheral ethanol concentrations (Spearman's rho, 0.42; P < 10-5) in the prospective study. Our data show that the first-pass effect obscures the levels of endogenous ethanol production, suggesting that microbial ethanol could be considered in the pathogenesis of this highly prevalent liver disease.

Clinical practice of hepatitis B screening in patients starting with chemotherapy: A survey among Dutch oncologists.

OBJECTIVE: Screening for hepatitis B virus (HBV) before chemotherapy is recommended by international guidelines; still, the HBV screening rate is low, and patients remain at risk for HBV reactivation (HBVr). Because HBVr is a serious and preventable condition, we conducted a survey to evaluate the screening behaviour of oncologists in the Netherlands. METHODS: We conducted an anonymous digital survey by email to all practicing medical oncologists. The surveys were sent in two session, the first one in 2017 and the second one in 2019. Questions included HBV screening procedures, reasons for screening and experience with HBVr. RESULTS: Among the 110 respondents, 29 (27%) followed a standardised protocol. Overall, 13 (12%) oncologists screened all patients, 76 (70%) only screened patients they considered as high risk and 19 (18%) did not screen anyone. Fourteen percent of the respondents experienced a HBVr in one of their patients. CONCLUSION: This survey suggests that universal HBV screening is not common practice and usually patients considered as at risk for HBVr are screened, while this group is not always properly identified. Introduction of a national protocol for HBV screening and adjustment of the Dutch oncology guidelines might contribute to a reduction of HBVr during chemotherapy.

Smoking Behaviour and Beliefs About Smoking Cessation After Bariatric Surgery.

PURPOSE: Currently, bariatric surgery is the most effective intervention for treating morbid obesity and its complications. Smoking cessation is likely to improve smoking-related comorbidities and decrease postoperative complications. This study evaluated the smoking behaviour and thoughts about smoking cessation of patients more than 18 months after bariatric surgery. MATERIALS AND METHODS: A cross-sectional study was performed in patients who underwent bariatric surgery from July 2012 to December 2013. A questionnaire was used to evaluate smoking status, thoughts about the health benefits of cessation and characteristics of previous quit attempts in current and former smokers. Finally, actual bariatric surgery outcomes were evaluated in current, former and never smokers. RESULTS: Six hundred nine patients (response rate 52.0%) were included. Of them, 101 (16.6%) patients were current smokers, 239 (39.2%) former smokers and 269 (44.2%) patients were lifetime never smokers. Compared with former smokers, current smokers were less aware of the beneficial effects of smoking cessation on their general health; 66.4% of the former smokers thought smoking cessation would be much better for general health, compared with 20.6% of current smokers. Total weight loss was 2.8% higher in current smokers compared with former smokers. Actual long-term bariatric surgery outcomes were not significantly different between the groups. CONCLUSION: Despite advice to quit smoking and temporary quitting before surgery, a considerable group of bariatric surgery patients continues smoking after surgery. These patients were less aware of the beneficial effects of smoking cessation. This study emphasizes the need for better strategies to increase the number of successful cessations.

Self-Reported Smoking Compared to Serum Cotinine in Bariatric Surgery Patients: Smoking Is Underreported Before the Operation.

BACKGROUND: Smoking has been associated with postoperative complications and mortality in bariatric surgery. The evidence for smoking is based on self-report and medical charts, which can lead to misclassification and miscalculation of the associations. Determination of cotinine can objectively define nicotine exposure. We determined the accuracy of self-reported smoking compared to cotinine measurement in three phases of the bariatric surgery trajectory. METHODS: Patients in the phase of screening (screening), on the day of surgery (surgery), and more than 18 months after surgery (follow-up) were consecutively selected. Self-reported smoking was registered and serum cotinine was measured. We evaluated the accuracy of self-reported smoking compared to cotinine, and the level of agreement between self-report and cotinine for each phase. RESULTS: In total, 715 patients were included. In the screening, surgery, and follow-up group, 25.6%, 18.0%, and 15.5%, respectively, was smoking based on cotinine. The sensitivity of self-reported smoking was 72.5%, 31.0%, and 93.5% in the screening, surgery, and follow-up group, respectively (p < 0.001). The specificity of self-report was > 95% in all groups (p < 0.02). The level of agreement between self-report and cotinine was 0.778, 0.414, and 0.855 for the screening, surgery, and follow-up group, respectively. CONCLUSIONS: Underreporting of smoking occurs before bariatric surgery, mainly on the day of surgery. Future studies on effects of smoking and smoking cessation in bariatric surgery should include methods taking into account the issue of underreporting.

Absence of 18 F-fluorodeoxyglucose uptake using Positron Emission Tomography/Computed Tomography in Madelung's disease: A case report.

Madelung's disease is characterized by the manifestation of multiple ectopic lipomas, usually found in the cervical-thoracic region, however, clinical manifestation may vary among patients. It has been postulated that lipomas associated with Madelung's disease are linked to brown adipose tissue (BAT) due to the presence of uncoupling protein 1 (UCP1). Therefore, we here investigated whether BAT activity is present in a patient with Madelung's disease. 18 F-fluorodeoxyglucose (18 F-FDG) uptake using PET/CT after a cooling procedure was measured together with body temperature and energy expenditure. Finally, adipose tissue biopsies were taken from the lipomas for gene expression analysis and histology. 18 F-FDG uptake was not detected after the cooling procedure in the lipomas. Furthermore, adipose tissue biopsies derived from the lipomas did not express UCP1. We thus conclude that cold-stimulated BAT activity was not detected in lipomas associated with Madelung's disease. Additional research in other patients is needed to unravel the role of dysfunctional BAT in Madelung's disease.

Coagulation and fibrinolysis in hyperparathyroidism secondary to vitamin D deficiency.

INTRODUCTION: Abnormal coagulation tests have been observed in patients with primary hyperparathyroidism (HPT) suggesting a prothrombotic effect of parathyroid hormone (PTH). Vitamin D deficiency (VIDD) is the most frequent cause of secondary HPT. Aim of our study was to investigate the influence of HPT secondary to moderate-to-severe VIDD and vitamin D replacement on the coagulation and fibrinolysis system. SUBJECTS AND METHODS: Prospective cohort study of patients with vitamin D <25 nmol/L with and without HPT, and a control group of patients on vitamin D suppletion. At baseline and after 2 months of vitamin D suppletion (900,000 IU in 2 months), endocrine and coagulation markers were measured. RESULTS: 59 patients with VIDD of which 34 had secondary HPT and 36 controls were included. After 2 months of suppletion, vitamin D increased by 399% (VIDD with HPT), 442% (all patients with VIDD) and 6% (controls). PTH decreased by 34% (VIDD with HPT, P < 0.01 for decrease), 32% (all VIDD, P < 0.01) and increased by 8% in the controls (P-values: <0.01 for relative changes between VIDD with HPT or all VIDD patients vs controls). Relative changes in PT, aPTT, fibrinogen, Von Willebrand factor, factors VII, VIII and X, thrombin generation, TAFI, clot-lysis time and d-dimer were not different between patients with VIDD with HPT or all VIDD vs controls. DISCUSSION: Secondary HPT due to VIDD does not have a prothrombotic effect. In contrast with previous reports, PTH does not seem to influence coagulation or fibrinolysis, which is relevant because of the high prevalence of VIDD.

Dapagliflozin for prednisone-induced hyperglycaemia in acute exacerbation of chronic obstructive pulmonary disease.

The aim of the present study was to compare the effectiveness and safety of add-on treatment with dapagliflozin to placebo in patients with prednisone-induced hyperglycaemia during treatment for acute exacerbation of chronic obstructive pulmonary disease (AECOPD). We enrolled 46 patients hospitalized for an AECOPD in a multicentre double-blind randomized controlled study in which add-on treatment with dapagliflozin 10 mg was compared with placebo. Glycaemic control and incidence of hypoglycaemia were measured through a blinded subcutaneous continuous glucose monitoring device. Participants in the dapagliflozin group spent 54 ± 27.7% of the time in target range (3.9-10 mmol/L) and participants in the placebo group spent 53.6 ± 23.4% of the time in target range (P = .96). The mean glucose concentration was 10.1 mmol/L in the dapagliflozin group and 10.4 mmol/L in the placebo group (P = .66). One participant using dapagliflozin and 2 participants using placebo experienced symptomatic hypoglycaemia. Treatment with dapagliflozin was safe and there was no difference in risk of hypoglycaemia compared with placebo. Dapagliflozin did not result in better glycaemic control compared with placebo in participants with prednisone-induced hyperglycaemia during AECOPD.

Impact of hyperglycemia on the efficacy of chemotherapy-A systematic review of preclinical studies.

BACKGROUND: Antineoplastic agents can provoke hyperglycemia in cancer patients with and without diabetes mellitus. We systematically reviewed the impact of hyperglycemia on the efficacy of chemotherapy. METHODS: MEDLINE was searched for preclinical intervention studies which compared chemotherapy response in hyperglycemic and euglycemic conditions. RESULTS: Thirteen preclinical studies, including 23 cell lines and 2 animal experiments were identified. In 14 cell lines and 2 animal studies, chemotherapy response was lower in a hyperglycemic (>15mmol/L) compared to a euglycemic environment (5mmol/L). The response was similar in 4 cell lines. In the remaining 5 cell lines, the hyperglycemic environment potentiated chemotherapy efficacy. CONCLUSION: Hyperglycemia attenuated the antiproliferative effect of chemotherapy in preclinical experiments, but the results are inconsistent. Whether hyperglycemia influences efficacy of chemotherapy in patients needs to be explored.

Plasma Levels of Free Thyroxine and Risk of Major Bleeding in Bariatric Surgery.

BACKGROUND: In a recent study of patients using vitamin K antagonists, those with low free thyroxin (FT4) levels within the normal range had a 3- to 5-fold increased risk of major bleeding. We tested the hypothesis that low levels of preoperative FT4 within the reference range are associated with an increased risk of major bleeding during and after bariatric surgery. METHODS: The charts of 2,872 consecutive patients undergoing bariatric surgery were retrospectively screened for bleeding episodes. Patients with major bleeding until 1 month after surgery were compared to randomly selected control patients without bleeding, in a ratio of 1:4. We evaluated the association between preoperative FT4 levels and the risk of major bleeding by logistic regression. RESULTS: Seventy-two cases (2.5%) with major bleeding were identified and 288 controls were selected. The median plasma level of FT4 was 13 pmol/l (interquartile range: 12-14) in the cases as well as in the controls. No clear effect was observed of low levels of FT4 on the risk of major bleeding: odds ratio 1.48 (95% CI: 0.46-4.80) for patients with an FT4 level <11 pmol/l, 1.03 (0.49-2.18) for patients with an FT4 level <12 pmol/l, and 1.12 (0.65-1.94) for patients with an FT4 level <13 pmol/l as compared to patients with FT4 values greater than or equal to these cutoff levels. INTERPRETATION: We did not observe an increased risk of major bleeding with low levels of FT4 in patients undergoing bariatric surgery.

Impaired quality of life in treatment-seeking obese children of Dutch, Moroccan, Turkish and Surinamese descent.

OBJECTIVE: To determine the health-related quality of life (HRQOL) of overweight and obese multi-ethnic children compared with normal-weight children; and to investigate differences in HRQOL between self- and parent-proxy reports and ethnic groups. DESIGN: Prospective cross-sectional study. SETTING: Out-patient clinic where children and their parents filled out a validated HRQOL questionnaire (KIDSCREEN-52) and height, weight, waist circumference and fat percentage were measured. SUBJECTS: Overweight and obese children, aged 8-18 years (mean BMI Z-score 3·2 (sd 0·6)), from the obesity out-patient clinic. RESULTS: Three hundred and eight self- and 213 parent-proxy reported questionnaires were completed. Global HRQOL and the Physical Wellbeing, Moods & Emotions and Self-Perception subscales were markedly reduced in our multi-ethnic obese cohort, relative to the Dutch reference values. Parent proxies reported significantly lower on the global HRQOL and the Physical Wellbeing, Moods & Emotions and Bullying subscales. In Caucasian children, multivariate analyses showed that BMI was associated with the quality-of-life subscales Moods & Emotions, Self-Perception and Bullying. CONCLUSIONS: HRQOL was markedly reduced in our multi-ethnic overweight and obese out-patient clinic cohort, with significantly lower parent-proxy scores compared with self-reported scores. We believe intervention programmes aiming to improve HRQOL should be directed to both parents and children, while ethnic-specific programmes to enhance HRQOL seem of less importance.

Gastric bypass may promote weight loss in overweight partners.

INTRODUCTION: Following bariatric surgery, patients are expected to implement diet and lifestyle changes that may be imitated by cohabitating family members. We hypothesize that cohabitating family members will lose weight and improve their eating behavior within 1 year after surgery. METHODS: In this observational prospective study, family members of patients who had gastric bypass surgery (88 partners, 20 children ≥18 years old, and 25 children between 12 and 17 years old) were repeatedly assessed. Family members were asked to assess their weight and height before and 3, 6, and 12 months following bariatric surgery, and they filled out the Dutch Eating Behavior Questionnaire. RESULTS: Between baseline and 1 year following surgery, 49 partners of patients who underwent gastric bypass surgery (66.2%) lost weight, 6 (8.1%) remained stable, and 19 (25.7%) gained weight. Body mass index of partners (P = .002), particularly of overweight partners (P < .001)-but not children-showed a small, significant decrease over time. No significant changes in eating behavior among partners or children were found. CONCLUSION: The study indicates that gastric bypass surgery may have a ripple effect, with body weight in partners of patients decreasing over time. However, there is considerable variation in the postoperative weight loss of partners.

The development of a multidisciplinary, evidence-based guideline for "HIV and employment".

The objective of this study was to develop a multidisciplinary guideline that supports the care and vocational rehabilitation of HIV-infected people with employment-related problems. The guideline was developed according to the "evidence-based guideline development" method developed by the Dutch Institute for Health Care Improvement. This method consists of the following steps: forming a multidisciplinary core group and an expert panel, formulating key questions, searching and appraising the available literature, formulating considerations and recommendations, peer reviewing the draft guideline, and authorizing the final guideline. All relevant professional associations were represented in the core group that was assembled to develop the guideline, i.e., HIV doctors, HIV nurses, general practitioners, occupational health physicians, psychologists, social workers, occupational health nurses, vocational experts, and insurance physicians. Five key questions for the guideline were formulated with the following themes: determinants of employment, disclosure and stigma, self-management, interventions, and the organization of care. In the literature review on these topics, 45 studies met the inclusion criteria. The methodological quality of the included articles was poor. Factors such as patient preferences and medical/ethical issues were considered. The recommendations in the guideline are a weighting of the scientific evidence and the considerations of the core group. The guideline, as well as its summary for daily practice, clarifies the most important barriers and facilitators to people with HIV either staying at work or returning to work, and it constitutes a clinical, easy-to-use guideline for health-care providers and how they can support people with HIV who want to work.

Attachment anxiety predicts poor adherence to dietary recommendations: an indirect effect on weight change 1 year after gastric bypass surgery.

BACKGROUND: Weight loss after gastric bypass surgery depends on the adoption of healthy dietary recommendations, which may be influenced by psychological issues and patients' attachment representations (habitual states of mind with respect to interpersonal relations). The present study tests (1) whether attachment representations are associated with dietary adherence, (2) whether dietary adherence and weight loss are correlated and (3) whether dietary adherence mediates the relation of attachment representations with weight reduction after gastric bypass surgery. Besides attachment representations, psychological problems are examined. METHODS: This longitudinal study included 105 patients who had a laparoscopic Roux-en-Y gastric bypass operation. Current and past psychological problems and attachment representations were assessed before surgery. Dietary adherence was assessed 6 and 12 months postsurgery. Patients' weight and height were collected from medical records. Multiple linear and logistic regression analyses and mediation analyses using bootstrapping resampling procedures were conducted. RESULTS: Of all examined predictor variables, attachment anxiety, i.e., fear of social rejection and abandonment, was most strongly associated with low dietary adherence at both 6 months (p = 0.009) and 12 months (p = 0.006) postsurgery. Dietary adherence 6 months postsurgery was associated with weight loss 1 year after the operation (p = 0.003). Dietary adherence at 6 months (ß = 0.51; 95% confidence interval (CI) = 0.19-1.04) mediated the association between preoperative attachment anxiety and postoperative weight loss. CONCLUSIONS: The results suggest that more anxiously attached patients are less adherent to dietary recommendations 6 months after gastric bypass surgery, influencing weight loss in a negative way during the first year after surgery.

High prevalence of vitamin D insufficiency/deficiency in Dutch multi-ethnic obese children.

Vitamin D insufficiency/deficiency is common among non-white children; however, little is known about the prevalence of vitamin D insufficiency/deficiency in non-white obese children living in the Netherlands. Therefore, a retrospective analysis was performed on data from multi-ethnic Dutch children and adolescents 6­18 years who visited the obesity outpatient clinic in 2012­2013. We performed anthropometric measurements, oral glucose tolerance test, and measured 25(OH)D and lipid levels. Vitamin D insufficiency was defined as 25(OH)D levels 37.5- <50 nmol/L and vitamin D deficiency as 25(OH)D <37.5 nmol/L. In total, data from 387 children were obtained (mean age 11.6 years, 41.1 % boys, 10.3 % Dutch native, 25.6 % Turkish, 24.5 % Moroccan, 7.5 % African Surinamese, and 7.0 % West African). The median 25(OH)D level was 34 (range 12­105) nmol/L. In total, 17.8 % were vitamin D sufficient, 24.5 % with vitamin D insufficiency, and 57.6 % with vitamin D deficiency. Obese ethnic children showed the highest (87.5 %) and normal weight white children showed the lowest (20.0 %) prevalence of vitamin D insufficiency/deficiency . Conclusion: Vitamin D insufficiency and deficiency is extremely prevalent in treatment-seeking obese ethnic children. However, there was no evidence of an effect of vitamin D status on various components of the metabolic syndrome in our cohort.

Fixed-dose enoxaparin after bariatric surgery: the influence of body weight on peak anti-Xa levels.

INTRODUCTION: There is lack of data on the pharmacodynamics of low-molecular-weight heparins in obese patients. BACKGROUND: The aims of this study are to investigate the correlation between anti-factor Xa (anti-Xa) levels and body weight with fixed-dose enoxaparin after bariatric surgery and to investigate the percentage of patients that reach the desired prophylactic range for anti-Xa levels. METHODS: Blood for anti-Xa peak levels measurement was drawn 3-5 h after administration of enoxaparin at the planned visit 8-16 days after surgery. Patients were included in three categories: <110 kg (group 1), 110-150 kg (group 2), and >150 kg (group 3). RESULTS: Fifty-one patients were included (43.9 ± 9.9 years, 75% women). Mean anti-Xa level was 0.37 ± 0.14 IU/ml. This level was the highest in group 1 (0.47 ± 0.13 IU/ml) and lowest in group 3 (0.23 ± 0.07). No subprophylactic (<0.2 IU/ml) anti-Xa levels were detected in group 1, whereas this was observed in 38% in patients in group 3. Supraprophylactic levels (>0.5 IU/ml) were most often present in group 1 (36%). With multivariable regression analysis, body weight (ß -0.720 (95 % confidence interval -.717; -.993), p < 0.001) was an independent predictor of anti-Xa levels, whereas lean body was not independently associated. This was confirmed in a non-linear mixed effects analysis of the data. CONCLUSIONS: Patients with excessive body weight may not be adequately treated with fixed-dose enoxaparin thromboprophylaxis while patients with lower body weight may have an increased bleeding risk. Body weight is a better predictor of anti-Xa levels compared to lean body weight.

Efficacy and tolerability of a high loading dose (25,000 IU weekly) vitamin D3 supplementation in obese children with vitamin D insufficiency/deficiency.

BACKGROUND: The recommended dose of vitamin D supplementation of 400 IU/day might be inadequate to treat obese children with vitamin D insufficiency. Therefore, we tested the efficacy and tolerability of a high loading dose vitamin D3 supplementation of 25,000 IU weekly in multiethnic obese children, 8-18 years of age, with vitamin D insufficiency/deficiency. METHODS: Fasting blood samples were drawn for the assessment of vitamin D. Vitamin D-insufficient/-deficient children (<50 nmol/l) were supplemented, using a high loading dose of 25,000 IU weekly, and measured again 9 weeks later. Vitamin D supplementation was considered effective and tolerable when an increase to vitamin D sufficiency (25(OH)D >50 nmol/l) was reached in >75% without side effects nor reaching toxic levels. RESULTS: In total, 109 children (mean ± SD age 11.1 ± 3.0, 34.2% boys, 90.8% obese) received vitamin D supplementation. In 84.4% of the children, the vitamin D status improved from insufficiency/deficiency (<50 nmol/l) to sufficiency (≥50 nmol/l). The majority of children that did not reach vitamin D sufficiency reported non-compliance. No side effects were reported, and the highest level reached was far below the threshold for toxicity. CONCLUSION: A high loading dose vitamin D3 supplementation is effective and well-tolerated in our cohort of multiethnic obese children with vitamin D insufficiency/deficiency.

Coping style as a mediator between attachment and mental and physical health in patients suffering from morbid obesity.

OBJECTIVE: The presence of mental health problems and limitations in physical functioning is high in patients suffering from morbid obesity. The purpose of the current study was to examine the mediating role of coping style in the relationship between attachment representations and mental health and physical functioning in a morbidly obese population. METHOD: A total of 299 morbidly obese patients who were referred to the Slotervaart bariatric surgery unit in Amsterdam, the Netherlands, completed self-report questionnaires assessing adult attachment style (Experiences in Close Relationship-Revised Questionnaire), coping style (Utrecht Coping List), and patients physical functioning and mental health (Short Form-36). RESULTS: Attachment anxiety (beta = -.490, p < .001) and attachment avoidance (3 = -.387, p < .001) were both found to be related to mental health. In addition, attachment anxiety was also found to be related to physical functioning (beta = - .188,p < .001). Coping style partly mediated these associations. CONCLUSIONS: Findings suggest that coping mediates the association between attachment anxiety and attachment avoidance on the one hand and mental health and physical functioning in patients with morbid obesity on the other hand.