Clinical phenotypes of adults with monogenic and syndromic genetic obesity.

OBJECTIVE: Considering limited evidence on diagnostics of genetic obesity in adults, we evaluated phenotypes of adults with genetic obesity. Additionally, we assessed the applicability of Endocrine Society (ES) recommendations for genetic testing in pediatric obesity. METHODS: We compared clinical features, including age of onset of obesity and appetite, between adults with non-syndromic monogenic obesity (MO), adults with syndromic obesity (SO), and adults with common obesity (CO) as control patients. RESULTS: A total of 79 adults with genetic obesity (32 with MO, 47 with SO) were compared with 186 control patients with CO. Median BMI was similar among the groups: 41.2, 39.5, and 38.7 kg/m2 for patients with MO, SO, and CO, respectively. Median age of onset of obesity was 3 (IQR: 1-6) years in patients with MO, 9 (IQR: 4-13) years in patients with SO, and 21 (IQR: 13-33) years in patients with CO (p < 0.001). Patients with genetic obesity more often reported increased appetite: 65.6%, 68.1%, and 33.9% in patients with MO, SO, and CO, respectively (p < 0.001). Intellectual deficit and autism spectrum disorder were more prevalent in patients with SO (53.2% and 21.3%) compared with those with MO (3.1% and 6.3%) and CO (both 0.0%). The ES recommendations were fulfilled in 56.3%, 29.8%, and 2.7% of patients with MO, SO, and CO, respectively (p < 0.001). CONCLUSIONS: We found distinct phenotypes in adult genetic obesity. Additionally, we demonstrated low sensitivity for detecting genetic obesity in adults using pediatric ES recommendations, necessitating specific genetic testing recommendations in adult obesity care.

Long-term glucocorticoid exposure and incident cardiovascular diseases - the Lifelines cohort.

CONTEXT: Long-term glucocorticoid levels in scalp hair (HairGCs), including cortisol and the inactive form cortisone, represent the cumulative systemic exposure to glucocorticoids over months. HairGCs have repeatedly shown associations with cardiometabolic and immune parameters, but longitudinal data are lacking. DESIGN: We investigated 6341 hair samples of participants from the Lifelines cohort study for cortisol and cortisone levels, and associated these to incident cardiovascular diseases (CVD) during 5-7 years of follow-up. We computed the odds ratio (OR) of HairGC levels for incident CVD via logistic regression, adjusting for classical cardiovascular risk factors, and performed a sensitivity analysis in subcohorts of participants <60 years and >= 60 years. Also, we associated HairGC levels to immune parameters (total leukocytes and subtypes). RESULTS: Hair cortisone levels (available in n = 4701) were independently associated with incident CVD (p < 0.001), particularly in younger individuals (multivariate-adjusted OR 4.21, 95% confidence interval (CI) 1.91-9.07 per point increase in 10-log cortisone concentration (pg/mg), p < 0.001). All immune parameters except eosinophils were associated with hair cortisone (all multivariate-adjusted p < 0.05). CONCLUSIONS: In this large, prospective cohort study, we found that long-term cortisone levels, measured in scalp hair, represent a relevant and significant predictor for future cardiovascular diseases in younger individuals. These results highlight glucocorticoid action as possible treatment target for CVD prevention, where hair glucocorticoid measurements could help identify individuals that may benefit from such treatments.

Improved Physical and Mental Health After a Combined Lifestyle Intervention with Cognitive Behavioural Therapy for Obesity.

Background: Obesity is a multifactorial, chronic, progressive disease associated with decreased health-related quality of life, comorbidities, and increased mortality risk. Lifestyle interventions, focusing on dietetics, physical exercise, and behavioral therapy, are a cornerstone of therapy. Despite this very multidisciplinary treatment approach, the definition of treatment success is often based only on a weight loss of ≥ 5%. However, the heterogeneous nature of obesity may necessitate a more comprehensive approach to assessing treatment effects. Objectives: Here, we describe changes in physiological, psychological, and behavioral health after a multidisciplinary combined lifestyle intervention (CLI). Additionally, we investigated whether these changes were related to weight loss. Methods: This prospective observational longitudinal study comprised 96 adults with obesity (73 women, 81 Caucasian) participating in a CLI at the Obesity Center CGG, Erasmus University Medical Center, Rotterdam, the Netherlands. The 1.5-year intervention comprised multidisciplinary professional guidance towards a healthy diet, increased physical activity, and included cognitive behavioral therapy. Physiological health outcomes, psychological well-being, eating behavior, and physical activity were assessed after ten weeks and 1.5 years and compared to baseline. Results: An average of 5.2% weight loss (-6.0 kg) was accompanied by a mean 9.8% decrease in fat mass (-5.9 kg; both P < 0.001) and significant improvements in metabolism, hormonal status, and immune parameters (all P < 0.05). Moreover, we observed decreased psychopathology, increased quality of life, and decreased disordered eating (all P < 0.05). Weight loss correlated with most metabolic changes (all P < 0.05) but not with most psychological/behavioral changes. Conclusions: Combined lifestyle intervention in patients with obesity was accompanied by significant improvements in body weight and body composition along with cardiometabolic, endocrine, immunological, psychological, and behavioral improvements. Interestingly, most changes in psychological and behavioral health occurred independently of weight loss. Obesity treatment success should be evaluated based on a combination of physical and patient-reported outcomes rather than weight loss alone.

Successful naltrexone-bupropion treatment after several treatment failures in a patient with severe monogenic obesity.

We describe the therapeutic journey of a 33-year-old patient with early-onset obesity (BMI 56.7 kg/m2) and hyperphagia due to a likely pathogenic heterozygous melanocortin-4 receptor (MC4R) gene variant. She was unsuccessfully treated with several intensive lifestyle interventions, gastric bypass surgery (-40 kg weight loss, followed by +39.8 kg weight regain), liraglutide 3 mg (-3.8% weight loss with sustained hyperphagia), and metformin treatment. However, naltrexone-bupropion treatment led to -48.9 kg (-26.7%) weight loss, of which -39.9 kg (-38.3%) was fat mass, in 17 months of treatment. Importantly, she reported improved hyperphagia and quality of life. We describe the potential beneficial effects of naltrexone-bupropion on weight, hyperphagia, and quality of life in a patient with genetic obesity. This extensive journey shows that various anti-obesity agents can be initiated, subsequently terminated when ineffective and substituted with other anti-obesity agents to identify the most efficient anti-obesity treatment.

Levels of hormones regulating appetite and energy homeostasis in response to a 1.5-Year combined lifestyle intervention for obesity.

Background: Weight loss can induce changes in appetite-regulating hormone levels, possibly linked to increases in appetite and weight regain. However, hormonal changes vary across interventions. Here, we studied levels of appetite-regulating hormones during a combined lifestyle intervention (CLI: healthy diet, exercise and cognitive behavioral therapy). Methods: We measured levels of long-term adiposity-related hormones (leptin, insulin, high-molecular-weight (HMW) adiponectin) and short-term appetite hormones (PYY, cholecystokinin, gastric-inhibitory polypeptide, pancreatic polypeptide, FGF21, AgRP) in overnight-fasted serum of 39 patients with obesity. Hormone levels were compared between T0 (baseline), T1 (after 10 weeks) and T2 (end of treatment, 1.5 years). T0-T1 hormone changes were correlated with T1-T2 anthropometric changes. Results: Initial weight loss at T1 was maintained at T2 (-5.0%, p < 0.001), and accompanied by decreased leptin and insulin levels at T1 and T2 (all p < 0.05) compared to T0. Most short-term signals were not affected. Only PP levels were decreased at T2 compared to T0 (p < 0.05). Most changes in hormone levels during initial weight loss did not predict subsequent changes in anthropometrics, except for T0-T1 decreases in FGF21 levels and T0-T1 increases in HMW adiponectin levels tended to be associated with larger T1-T2 increases in BMI (p < 0.05 and p = 0.05, respectively). Conclusion: CLI-induced weight loss was associated with changes in levels of long-term adiposity-related hormones towards healthy levels, but not with orexigenic changes in most short-term appetite signals. Our data indicates that the clinical impact of alterations in appetite-regulating hormones during modest weight loss remains questionable. Future studies should investigate potential associations of weight-loss-induced changes in FGF21 and adiponectin levels with weight regain.

Analysis of Serious Weight Gain in Patients Using Alectinib for ALK-Positive Lung Cancer.

INTRODUCTION: Alectinib is a standard-of-care treatment for metastatic ALK+ NSCLC. Weight gain is an unexplored side effect reported in approximately 10%. To prevent or intervene alectinib-induced weight gain, more insight in its extent and etiology is needed. METHODS: Change in body composition was analyzed in a prospective series of 46 patients with ALK+ NSCLC, treated with alectinib. Waist circumference, visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and skeletal muscle were quantified using sliceOmatic software on computed tomography images at baseline, 3 months (3M), and 1 year (1Y). To investigate an exposure-toxicity relationship, alectinib plasma concentrations were quantified. Four patients with more than 10 kg weight gain were referred to Erasmus MC Obesity Center CGG for in-depth analysis (e.g., assessments of appetite, dietary habits, other lifestyle, medical and psychosocial factors, and extensive metabolic and endocrine assessments, including resting energy expenditure). RESULTS: Mean increase in waist circumference was 9 cm (9.7%, p < 0.001) in 1Y with a 40% increase in abdominal obesity (p = 0.014). VAT increased to 10.8 cm2 (15.0%, p = 0.003) in 3M and 35.7 cm2 (39.0%, p < 0.001) in 1Y. SAT increased to 18.8 cm2 (12.4%, p < 0.001) in 3M and 45.4 cm2 (33.3%, p < 0.001) in 1Y. The incidence of sarcopenic obesity increased from 23.7% to 47.4% during 1Y of treatment. Baseline waist circumference was a positive predictor of increase in VAT (p = 0.037). No exposure-toxicity relationship was found. In-depth analysis (n = 4) revealed increased appetite in two patients and metabolic syndrome in all four patients. CONCLUSIONS: Alectinib may cause relevant increased sarcopenic abdominal obesity, with increases of both VAT and SAT, quickly after initiation. This may lead to many serious metabolic, physical, and mental disturbances in long-surviving patients.

Cross-sectional relation of long-term glucocorticoids in hair with anthropometric measurements and their possible determinants: A systematic review and meta-analysis.

BACKGROUND: Long-term glucocorticoids (HairGC) measured in scalp hair have been associated with body mass index (BMI), waist circumference (WC), and waist-hip-ratio (WHR) in several cross-sectional studies. We aimed to investigate the magnitude, strength, and clinical relevance of these relations across all ages. METHODS: We performed a systematic review and meta-analysis (PROSPERO registration CRD42020205187) searching for articles relating HairGC to measures of obesity. Main outcomes were bivariate correlation coefficients and unadjusted simple linear regression coefficients relating hair cortisol (HairF) and hair cortisone (HairE) to BMI, WC, and WHR. RESULTS: We included k = 146 cohorts (n = 34,342 individuals). HairGC were positively related to all anthropometric measurements. The strongest correlation and largest effect size were seen for HairE-WC: pooled correlation 0.18 (95%CI 0.11-0.24; k = 7; n = 3,158; I2  = 45.7%) and pooled regression coefficient 11.0 cm increase in WC per point increase in 10-log-transformed HairE (pg/mg) on liquid-chromatography-(tandem) mass spectrometry (LC-MS) (95%CI 10.1-11.9 cm; k = 6; n = 3,102). Pooled correlation for HairF-BMI was 0.10 (95%CI 0.08-0.13; k = 122; n = 26,527; I2  = 51.2%) and pooled regression coefficient 0.049 kg/m2 per point increase in 10-log-transformed HairF (pg/mg) on LC-MS (95%CI 0.045-0.054 kg/m2 ; k = 26; n = 11,635). DISCUSSION: There is a consistent positive association between HairGC and BMI, WC, and WHR, most prominently and clinically relevant for HairE-WC. These findings overall suggest an altered setpoint of the hypothalamic-pituitary-adrenal axis with increasing central adiposity.

Hair cortisol, obesity and the immune system: Results from a 3 year longitudinal study.

OBJECTIVES: Higher long-term glucocorticoid levels, measured in scalp hair (HairGC), are associated with obesity. This may represent the state of obesity (perhaps interrelated with chronic immune activation), but could also promote further weight gain. We studied whether hair cortisol (HairF) and hair cortisone (HairE) predict changes in body mass index (BMI) and waist circumference (WC) over time, and assessed the association between HairGC and common immune parameters. METHODS: We measured HairGC in 1604 participants of the Netherlands Study of Depression and Anxiety (NESDA), and investigated their associations to BMI, WC, and immune parameters (interleukin-6 (IL-6), C-reactive protein (CRP), and leukocyte subsets). Also, we assessed whether baseline HairGC predict changes in BMI and WC at follow-up (three years later). RESULTS: In cross-sectional analyses, HairF and HairE were positively associated to BMI (ß = 2.06 kg/m2, 95% confidence interval (CI)= 1.22-2.90 kg/m2) and ß = 2.84 kg/m2 (95%CI 1.75-3.93 kg/m2) respectively) and WC (ß = 5.36 cm (95%CI 3.09-7.62 cm) and ß = 8.54 cm (95%CI 5.60-11.48 cm) respectively, all p < 0.001). HairF was also positively associated to IL-6 (ß = 0.15 (95%CI 0.003-0.292) p < 0.05) and leukocyte count (ß = 0.57 (95%CI 0.234-0.909), p < 0.01), and HairE to IL-6 (ß = 0.21 (95%CI 0.016-0.399), p < 0.05). In the longitudinal analyses, higher HairF was associated with yearly increases in BMI (ß = 0.58% BMI change per year (95%CI 0.14-1.01%), p = 0.009) and higher HairE with increases in WC (ß = 0.84% WC change per year (95%CI 0.02-1.69%), p = 0.049). Adjusting for baseline IL-6 or leukocytes did not change the found associations between HairGC and WC or BMI change. CONCLUSIONS: HairGC levels are positively associated to BMI, WC, IL-6 and leukocyte numbers in cross-sectional analyses, and to increases in BMI and WC in longitudinal analyses. Although causality is yet to be proven, higher long-term glucocorticoid levels could represent a relevant risk factor for the development of obesity.

A methodological quality assessment of systematic reviews and meta-analyses of antidepressants effect on low back pain using updated AMSTAR.

BACKGROUND: Antidepressants are prescribed widely to manage low back pain. There are a number of systematic reviews and meta-analyses which have investigated the efficacy of the treatments, while the methodological quality of them has not been assessed yet. This study aims to evaluate the methodological quality of the systematic reviews and meta-analyses investigating the effect of antidepressants on low back pain. METHODS: A systematic search was conducted in PubMed, EMBASE, Medline, and Cochrane Library databases up to November 2018. The 16-item Assessment of Multiple Systematic Reviews (AMSTAR2) scale was used to assess the methodological quality of the studies. Systematic reviews and meta-analyses of the Antidepressants treatment effects on low back pain published in English language were included. There was no limitation on the type of Antidepressants drugs, clinical setting, and study population, while non-systematical reviews and qualitative and narrative reviews were excluded. RESULTS: A total of 25 systematic reviews and meta-analyses were evaluated; the studies were reported between 1992 and 2017. Obtained results from AMSTAR2 showed that 11 (44%), 9 (36%) and 5 (20%) of the included studies had high, moderate and low qualities, respectively. 13(52%) of studies assessed risk of bias and 2(20%) of meta analyses considered publication bias. Also, 16 (64%) of the included reviews provided a satisfactory explanation for any heterogeneity observed in the results. CONCLUSIONS: Although the trend of publishing high quality papers in ADs effect on LBP increased recently, performing more high-quality SRs and MAs in this field with precise subgroups of the type of pains, the class of drugs and their dosages may give clear and more reliable evidence to help clinicians and policymakers.

The intensive care infection score - a novel marker for the prediction of infection and its severity.

BACKGROUND: The prediction of infection and its severity remains difficult in the critically ill. A novel, simple biomarker derived from five blood-cell derived parameters that characterize the innate immune response in routine blood samples, the intensive care infection score (ICIS), could be helpful in this respect. We therefore compared the predictive value of the ICIS with that of the white blood cell count (WBC), C-reactive protein (CRP) and procalcitonin (PCT) for infection and its severity in critically ill patients. METHODS: We performed a multicenter, cluster-randomized, crossover study in critically ill patients between January 2013 and September 2014. Patients with a suspected infection for which blood cultures were taken by the attending intensivist were included. Blood was taken at the same time for WBC, ICIS, CRP and PCT measurements in the control study periods. Results of imaging and cultures were collected. Patients were divided into groups of increasing likelihood of infection and invasiveness: group 1 without infection or with possible infection irrespective of cultures, group 2 with probable or microbiologically proven local infection without blood stream infection (BSI) and group 3 with BSI irrespective of local infection. Septic shock was assessed. RESULTS: In total, 301 patients were enrolled. CRP, PCT and ICIS were higher in groups 2 and 3 than group 1. The area under the receiver operating characteristic curve (AUROC) for the prediction of infection was 0.70 for CRP, 0.71 for PCT and 0.73 for ICIS (P < 0.001). For the prediction of septic shock the AUROC was 0.73 for CRP, 0.85 for PCT and 0.76 for ICIS. These AUROC did not differ from each other. CONCLUSION: The data suggest that the ICIS is potentially useful for the prediction of infection and its severity in critically ill patients, non-inferiorly to CRP and PCT. In contrast to CRP and PCT, the ICIS can be determined routinely without extra blood sampling and lower costs, yielding results within 15 minutes. TRIAL REGISTRATION: ClinicalTrials.gov identifier: ID NCT01847079 . Registered on 24 April 2013.

Immature granulocytes predict microbial infection and its adverse sequelae in the intensive care unit.

BACKGROUND: We evaluated the predictive value of immature granulocyte (IG) percentage in comparison with white blood cell counts (WBC) and C-reactive protein (CRP), for infection, its invasiveness, and severity in critically ill patients. METHODS: In 46 consecutive patients, blood samples were collected at the day (0) of a clinical suspicion of microbial infection and at days 1 and 3 thereafter. We defined infections, bloodstream infection, and septic shock within 7 days after enrollment. RESULTS: Of the 46 patients, 31 patients had infection, 15 patients developed bloodstream infection, and 13 patients septic shock. C-reactive protein and IG percentage increased with increasing invasiveness and severity of infection, from day 0 onwards. Receiver operating characteristic analysis to predict infection showed an area under the curve of 0.66 (P=.10) for WBC vs 0.74 (P=.01) for CRP and 0.73 (P=.02) for IG percentage on day 0. Comparing WBC and CRP to WBC and IG percentage results in comparable prediction of microbial infection. Comparing WBC and CRP with WBC, CRP, and IG percentage suggests an additional early value of IG percentage, when not elevated, in ruling out infection. CONCLUSION: Immature granulocyte percentage is a useful marker, as CRP, to predict infection, its invasiveness, and severity, in critically ill patients. However, the IG percentage adds to WBC and CRP in the early exclusion of infection and can be obtained routinely without extra blood sampling or costs.

Diffusion tensor tractography in the presurgical assessment of cerebral gliomas.

Glioma is the most common intra-axial brain tumor characterized by invasion into the surrounding white matter (WM) tracts. These tumors are usually diagnosed by conventional MRI, but this method is unable to describe the relationship between tumor and neighboring WM tracts. Diffusion tensor tractography (DTT) is a new imaging modality which can solve this problem. The current study evaluated the application of DTT imaging in the presurgical assessment of gliomas, and introduces this new modality and its importance to physicians and imaging centers in Iran. Ten patients with intra-axial brain tumor and suspicion of glioma underwent conventional brain MRI pulse sequences and DTT imaging between December 2011 and February 2013 with a 1.5 Tesla system using 64 independent diffusion encoding directions. Acquired images were assessed by the neuroradiologist and neurosurgeon. The treatment strategies were recognized and compared using data before and after the tractography. On the basis of DTT data, the treatment strategy changed from radiotherapy to the craniotomy in seven patients, and in one patient, the neurosurgeon preferred to avoid surgery. In one patient, the treatment technique did not change, and in the last one radiosurgery was replaced by craniotomy. As we can infer from this study, based on the tractography results, the treatment strategy may be changed, and the treatment technique could be devised more accurately and may lead to fewer postoperative neurological deficits and better outcomes.