Long-term glucocorticoids in relation to the metabolic syndrome and cardiovascular disease: A systematic review and meta-analysis.

The striking link of Cushing's syndrome with the metabolic syndrome (MetS) and cardiovascular disease (CVD) suggests that long-term exposure to extremely high cortisol levels catalyzes cardiometabolic deterioration. However, it remained unclear whether the findings from the extreme glucocorticoid overabundance observed in Cushing's syndrome could be translated into more subtle variations in long-term glucocorticoid levels among the general population, for example, due to chronic stress. Here, we performed a systematic review (PROSPERO: CRD42023425541) of evidence regarding the role of subtle variations in long-term biological stress, measured as levels of scalp hair cortisol (HairF) and cortisone (HairE), in the context of MetS and CVD in adults. We also performed a meta-analysis on the cross-sectional difference in HairF levels between individuals with versus without CVD. Seven studies were included regarding MetS, sixteen regarding CVD, and one regarding both. Most articles indicated a strong, consistent cross-sectional association of higher HairF and HairE levels with CVD, which was confirmed by our meta-analysis for HairF (eight studies, SMD = 0.48, 95% confidence intervals [CIs]: 0.16-0.79, p = 0.0095). Moreover, these relationships appear largely independent of standard risk factors. Age seems relevant as the effect seems stronger in younger individuals. Results regarding the associations of HairF and HairE with MetS were inconsistent. Altogether, long-term biological stress, measured as HairF and HairE, is associated with the presence of CVD, and less consistently with MetS. Prospective studies need to evaluate the directionality of this relationship and determine whether HairF and HairE can be used in addition to standard risk factors in predicting future cardiometabolic deterioration.

Reversal of insulin resistance in people with obesity by lifestyle-induced weight loss does not impact the proportion of circulating 12α-hydroxylated bile acids.

AIM: Bile acids (BAs) are implicated in the pathogenesis of several metabolic syndrome-related diseases, including insulin resistance (IR) and type 2 diabetes (T2D). It has been reported that IR and T2D are associated with an increased ratio of 12α/non-12α-hydroxylated BAs in the circulating BA pool. It is, however, unknown whether the improvement of insulin sensitivity inversely affects BA composition in humans. Therefore, we assessed whether lifestyle-induced weight loss induces changes in BA metabolism in people with obesity, with or without T2D, and if these changes are associated with metabolic parameters. MATERIALS AND METHODS: Individual BAs and C4 were quantified by ultra-high-performance liquid chromatography-tandem mass spectrometry in plasma samples collected from two cohorts of people with obesity (OB) and with T2D and obesity (T2D), before and after a lifestyle intervention. RESULTS: Lifestyle-induced weight loss improved glycaemic control in both cohorts, with plasma BA concentrations not affected by the lifestyle interventions. The ratio of 12α/non-12α-hydroxylated BAs remained unchanged in OB (p = .178) and even slightly increased upon intervention in T2D (p = .0147). Plasma C4 levels were unaffected in OB participants (p = .20) but significantly reduced in T2D after intervention (p = .0003). There were no significant correlations between the ratio of 12α/non-12α-hydroxylated BAs and glucose, insulin, or homeostatic model assessment-IR, nor in plasma triglycerides, low-density lipoprotein cholesterol, lipoprotein (a) in the T2D cohort. CONCLUSIONS: Lifestyle-induced weight loss did improve glycaemic control but did not affect BA concentrations. Improvements in insulin sensitivity were not associated with changes in BA parameters in people with obesity, with or without T2D.

Determination of cortisone and cortisol in human scalp hair using an improved LC-MS/MS-based method.

OBJECTIVES: Human scalp hair is an easily available but complex matrix for determination of cortisone and cortisol, and has been shown to reflect long-term glucocorticoid exposure. Hair glucocorticoid analysis has been used to detect hypo- and hypercortisolism. In this study, we describe the development and validation of a LC-MS/MS method for quantification of cortisone and cortisol in human scalp hair, and provide a novel approach for analysis and interpretation of the results. METHODS: Improved sample preparation using pulverization and solid phase extraction allowed for low sample volumes (10 mg). Baseline chromatographic separation without matrix interference was achieved by reversed phase chromatography and MRM measurement in negative ion mode. Run-to-run time was 8 min. Mixed model analyses were performed to create individual patterns of cortisone and cortisol concentrations. RESULTS: Matrix matched calibration curves showed excellent linearity up to 100 pg (analyte)/mg (hair) for both cortisone and cortisol (R2>0.995). LLOQ was 1.5 and 1.0 pg/mg for cortisone and cortisol, respectively. Matrix effect was negligible for hair color (recoveries 95-105 %). Cortisone and cortisol concentrations decreased from proximal to distal hair segments, following a predictable, but subject-specific pattern, with less individual variation for cortisone than for cortisol. CONCLUSIONS: This improved LC-MS/MS method is able to accurately quantify cortisone and cortisol in human hair with minimum matrix interference. This new way of data analysis and interpretation including individual patterns of cortisone and cortisol will be of help with detection of pathological concentrations in both the high - and the low ranges of glucocorticoids.

Perceived weight stigma in healthcare settings among adults living with obesity: A cross-sectional investigation of the relationship with patient characteristics and person-centred care.

INTRODUCTION: Patients living with obesity often experience weight stigma in healthcare settings, which has worrying consequences for their healthcare experiences. This cross-sectional study aimed to: (1) provide an overview of stigmatising experiences in healthcare settings reported by adults living with varying classes of obesity, (2) identify associations among patient characteristics and perceived weight stigma and (3) investigate the association between perceived weight stigma and person-centred care (PCC). METHODS: Dutch adults living with obesity classes I (body mass index [BMI]: 30 to <35 kg/m2; n = 426), II (BMI: 35 to <40 kg/m2; n = 124) and III (BMI: ≥40 kg/m2; n = 40) completed measures of perceived weight stigma in healthcare settings and PCC. Descriptive, correlational and multivariate analyses were conducted. RESULTS: Of patients living with classes I, II and III obesity, 41%, 59% and 80%, respectively reported experiences of weight stigma in healthcare settings. Younger age, greater obesity severity and the presence of chronic illnesses were associated with greater perceived weight stigma. Greater perceived weight stigma was associated with lower PCC. CONCLUSION: The results of this study emphasise the significant role of weight stigma in the healthcare experiences of patients living with obesity. Reducing weight stigma is expected to improve PCC and the overall quality of care for these patients. Minimising weight stigma will require efforts across various healthcare domains, including increasing awareness among healthcare professionals about sensitive communication in weight-related discussions. PATIENT CONTRIBUTION: Our sample consisted of patients living with obesity. Additionally, patients were involved in the pilot testing and refinement of the PCC instrument.

The relationship between person-centred care and well-being and satisfaction with care of patients living with obesity.

BACKGROUND: Person-centred care (PCC) is associated with improved patient well-being and higher levels of satisfaction with care but its impact on individuals living with obesity is not well-established. The main aim of this study was to assess the relationship between PCC and the physical and social well-being of patients living with obesity, as well as their satisfaction with care. METHODS: This study is based on a cross-sectional, web-based survey administered among a representative panel of Dutch individuals living with obesity. The primary outcomes were physical and social well-being and satisfaction with care. The primary exposure was a rating of overall PCC, encompassing its eight dimensions. In addition, covariates considered in the analyses included sex, age, marital status, education level, BMI, and chronic illness. The data from a total of 590 participants were analysed using descriptive statistics, correlation analyses, and multiple regression analyses. RESULTS: Among PCC dimensions, participants rated 'access to care' the highest (M 4.1, SD 0.6), while 'coordination of care' (M 3.5, SD 0.8) was rated lower than all other dimensions. Participants' overall PCC ratings were positively correlated with their physical (r = 0.255, P<0.001) and social well-being (r = 0.289, P<0.001) and their satisfaction with care (r = 0.788, P<0.001), as were the separate dimension scores. After controlling for sex, age, marital status, education level, BMI, and chronic illness in the regression analyses, participants' overall PCC ratings were positively related to their physical (ß = 0.24, P<0.001) and social well-being (ß = 0.26, P<0.001), and satisfaction with care (ß = 0.79, P<0.001). CONCLUSION: PCC holds promise for improved outcomes among patients living with obesity, both in terms of physical and social well-being, as well as satisfaction with care. This is an important finding, particularly when considering the profound physical, social, and psychological consequences associated with obesity. In addition to highlighting the potential benefits of PCC in the healthcare of individuals living with obesity, the findings offer valuable insights into strategies for further refining the provision of PCC to meet the specific needs of these patients.

Genetic Obesity Disorders: Body Mass Index Trajectories and Age of Onset of Obesity Compared with Children with Obesity from the General Population.

OBJECTIVE: We sought to assess body mass index trajectories of children with genetic obesity to identify optimal early age of onset of obesity (AoO) cut-offs for genetic screening. STUDY DESIGN: This longitudinal, observational study included growth measurements from birth onward of children with nonsyndromic and syndromic genetic obesity and control children with obesity from a population-based cohort. Diagnostic performance of AoO was evaluated. RESULTS: We describe the body mass index trajectories of 62 children with genetic obesity (29 nonsyndromic, 33 syndromic) and 298 controls. Median AoO was 1.2 years in nonsyndromic genetic obesity (0.4 and 0.6 years in biallelic LEPR and MC4R; 1.7 in heterozygous MC4R); 2.0 years in syndromic genetic obesity (0.9, 2.3, 4.3, and 6.8 years in pseudohypoparathyroidism, Bardet-Biedl syndrome, 16p11.2del syndrome, and Temple syndrome, respectively); and 3.8 years in controls. The optimal AoO cut-off was ≤3.9 years (sensitivity, 0.83; specificity, 0.49; area under the curve, 0.79; P < .001) for nonsyndromic and ≤4.7 years (sensitivity, 0.82; specificity, 0.37; area under the curve, 0.68; P = .001) for syndromic genetic obesity. CONCLUSIONS: Optimal AoO cut-off as single parameter to determine which children should undergo genetic testing was ≤3.9 years. In case of older AoO, additional features indicative of genetic obesity should be present to warrant genetic testing. Optimal cut-offs might differ across different races and ethnicities.

Prenatal predictors of childhood anxiety disorders: An exploratory study of the role of attachment organization.

Childhood anxiety disorders (CAD) are a common childhood mental disorder and understanding early developmental pathways is key to prevention and early intervention. What is not understood is whether early life stress predictors of CAD might be both mediated by infant cortisol reactivity and moderated by infant attachment status. To address this question, this exploratory study draws on 190 women recruited in early pregnancy and followed together with their children until 4 years of age. Early life stress is operationalized as maternal depression measured using the Structured Clinical Interview for the DSM, Childhood Trauma Questionnaire, Parenting Stress Index, and antenatal maternal hair cortisol concentrations. Infant cortisol reactivity was measured at 12 months together with the Strange Situation Procedure and CAD assessed at 4 years of age using the Preschool Age Psychiatric Assessment. There was no direct association between attachment classification and CAD. Furthermore, infant cortisol reactivity neither mediated nor attachment moderated the association of early life stress predictors and CAD. However, only for infants with organized attachment classifications, higher maternal antenatal depression, and hair cortisol were associated with a higher risk of CAD.

The perinatal origins of childhood anxiety disorders and the role of early-life maternal predictors.

BACKGROUND: The development of childhood anxiety disorders (CADs) is likely to depend on pathways that can be programmed by early-life risk factors. We test the hypothesis that early-life maternal factors can predict this programming effect on CAD. METHODS: Data were obtained from 198 women and children from the Mercy Pregnancy and Emotional Wellbeing Study (MPEWS), a cohort study with data collected across pregnancy, postpartum and until 4 years of age. Maternal antenatal depression was measured using the Structured Clinical Interview for DSM-IV (SCID-IV), together with antenatal hair cortisol concentrations, maternal childhood trauma and parenting stress at 6 months postpartum. CAD was assessed with the Preschool Age Psychiatric Assessment and the Child Behaviour Checklist. RESULTS: Antenatal depression, a history of maternal childhood trauma and lower gestational age at birth were each associated with anxiety disorders at 4 years of age in their children. A multivariate binary logistic model with these early predictors explained approximately 9% of variance in CAD outcome at 4 years of age; however, only maternal trauma and gestational age were significant predictors in the model. The effect of early parenting stress on CAD was found to vary by the concentration of maternal antenatal hair cortisol, whereby postpartum parenting stress was associated with CAD only when there were higher maternal antenatal cortisol levels. CONCLUSIONS: This study suggests the importance of maternal factors pre-conception, pregnancy and in the postnatal period, which predict CADs and this is consistent with a developmental programming hypothesis for CAD.

Views of patients with obesity on person-centred care: A Q-methodology study.

INTRODUCTION: To better accommodate patients with obesity, the adoption of a person-centred approach to healthcare seems to be imperative. Eight dimensions are important for person-centred care (PCC): respect for patients' preferences, physical comfort, the coordination of care, emotional support, access to care, the continuity of care, the provision of information and education, and the involvement of family and friends. The aim of this study was to explore the views of patients with obesity on the relative importance of the dimensions of PCC. METHODS: Q methodology was used to study the viewpoints of 21 patients with obesity on PCC. Respondents were asked to rank 31 statements about the eight dimensions of PCC by level of personal significance. Using by-person factor analysis, distinct viewpoints were identified. Respondents' comments made while ranking were used to verify and refine the interpretation of the viewpoints. RESULTS: Five distinct viewpoints were identified: (1) 'someone who listens in an unbiased manner', (2) 'everything should run smoothly', (3) 'interpersonal communication is key', (4) 'I want my independence', and (5) 'support for myself and my loved ones'. Viewpoint 1 was supported by the largest number of respondents and explained the most variance in the data, followed by viewpoint 3 and the other viewpoints, respectively. CONCLUSION: Our findings highlight the need for tailored care in obesity treatment and shed light on aspects of care and support that are most important for patients with obesity. PATIENT CONTRIBUTION: Our sample consisted of patients. Patients were also involved in the development of the statement set through pilot testing.

STOP: an open label crossover trial to study ICS withdrawal in patients with a combination of obesity and low-inflammatory asthma and evaluate its effect on asthma control and quality of life.

BACKGROUND: Asthma patients with obesity often have a high disease burden, despite the use of high-dose inhaled corticosteroids (ICS). In contrast to asthmatics with normal weight, the efficacy of ICS in patients with obesity and asthma is often relatively low. Meanwhile, patients do suffer from side effects, such as weight gain, development of diabetes, cataract, or high blood pressure. The relatively poor response to ICS might be explained by the low prevalence of type 2 inflammatory patterns (T2-low) in patients with asthma and obesity. T2-low inflammation is characterized by low eosinophilic count, low Fractional exhaled NO (FeNO), no clinically allergy-driven asthma, and no need for maintenance oral corticosteroids (OCS). We aim to study whether ICS can be safely withdrawn in patients with T2-low asthma and obesity while maintaining an equal level of asthma control. Secondary outcomes focus on the prevalence of 'false-negative' T2-low phenotypes (i.e. T2-hidden) and the effect of ICS withdrawal on parameters of the metabolic syndrome. This study will lead to a better understanding of this poorly understood subgroup and might find new treatable traits. METHODS: The STOP trial is an investigator-initiated, multicenter, non-inferiority, open-label, crossover study aiming to assess whether ICS can be safely withdrawn in adults aged 17-75 years with T2-low asthma and obesity (body mass index (BMI) ≥ 30 kg/m2). Patients will be randomly divided into two arms (both n = 60). One arm will start with fixed-dose ICS (control group) and one arm will taper and subsequently stop ICS (intervention group). Patients in the intervention group will remain ICS naïve for ten weeks. After a washout of 4 weeks, patients will crossover to the other study arm. The crossover study takes 36 weeks to complete. Patients will be asked to participate in the extension study, to investigate the long-term metabolic benefits of ICS withdrawal. DISCUSSION: This study yields valuable data on ICS tapering in patients with T2-low asthma and obesity. It informs future guidelines and committees on corticosteroid-sparing algorithms in these patients. Trial registration Netherlands Trial Register, NL8759, registered 2020-07-06, https://www.trialregister.nl/trial/8759 . Protocol version and date: version 2.1, 20 November 2020.

Anthropometrics and Metabolic Syndrome in Relation to Glucocorticoid Receptor Polymorphisms in Corticosteroid Users.

INTRODUCTION: Corticosteroids are widely prescribed and their use has been linked to adverse cardiometabolic outcomes. A pivotal role in the action of corticosteroids is reserved for the glucocorticoid receptor (GR). Here, we assessed the relationship of glucocorticoid sensitivity-altering GR polymorphisms with anthropometrics and metabolic syndrome (MetS) in corticosteroid users. METHODS: In this population-based cohort study (Lifelines), we genotyped 10,621 adult participants for GR hypersensitive (1/2 copies BclI and/or N363S) and GR resistant (1/2 copies ER22/23EK and/or 9ß) variants. We assessed the relationship between functional GR polymorphisms with BMI, waist circumference (WC), and MetS in users of corticosteroids. RESULTS: Overall corticosteroid use was associated with a significantly higher BMI and WC in GR wild-type (WT) users (BMI, +0.63 kg/m2 [0.09-1.16], p = 0.022; WC, +2.03 cm [0.61-3.44], p = 0.005) and GR hypersensitive (BMI, +0.66 kg/m2 [95% CI, 0.31-1.01]; WC, +2.06 cm [1.13-2.98], both p < 0.001) but not in GR resistant users. Significantly higher WC in GR resistant carriers was observed only for inhaled corticosteroid users. With respect to MetS, again only GR WT users (odds ratio [OR] 1.44 [1.07-1.94], p = 0.017) and GR hypersensitives (OR 1.23 [95% CI, 1.00-1.50], p = 0.046) were more likely to have MetS; even more pronounced in only inhaled corticosteroid users (GR WT users, OR 1.64 [1.06-2.55], p = 0.027; GR hypersensitive users, OR 1.43 [1.08-1.91], p = 0.013). CONCLUSIONS: Polymorphisms associated with increased GR sensitivity and WT GR are related to increased BMI, WC, and an increased MetS presence in corticosteroid users, especially of the inhaled types, when compared to nonusers. The adverse effects of corticosteroid use are less pronounced in users harboring GR resistant polymorphisms.

Coping with stress before and after mild traumatic brain injury: a pilot hair cortisol study.

Background: Cortisol is a crucial hormone for adaptation to challenging and stressful situations. Hair cortisol measurement is used to determine chronic stress; the growth rate of hair allows to determine averaged cortisol levels for a longer period. Objective: Pre- and post-injury measures of hair cortisol were compared in patients with mild traumatic brain injury (mTBI), and related to their coping styles.Methods: For 46 patients with mTBI, 3 cm scalp hair samples were collected 4-6 weeks post-injury, resulting in two 1 cm segments, pre- and post-injury. Hair samples were also collected for 11 healthy controls. Hair cortisol was quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Complaints, anxiety, depression and coping style were measured two weeks post-injury and long term (six-twelve months), added with measures for post-traumatic stress and functional outcome.Results: There were no differences between patients' pre- and post-injury cortisol levels, nor between cortisol levels of patients and controls. However, pre- and post-injury cortisol levels of patients were negatively correlated with both passive and an avoidant coping style.Conclusions: Our findings suggest that mTBI has no separate impact on chronic long-term cortisol levels, possibility indicating that variability in cortisol levels reflects individuals' premorbid characteristics determining coping with stress in general.

Hair glucocorticoids in adults with intellectual disabilities and depressive symptoms pre- and post-bright light therapy: First explorations.

BACKGROUND: Depressive symptoms and stress are common in adults with intellectual disabilities. Our aim was to explore long-term biological stress levels, assessed by hair cortisol (HairF) and cortisone (HairE) concentrations, in adults with intellectual disabilities and depressive symptoms and to investigate the effects of bright light therapy (BLT) on hair glucocorticoids. METHOD: Scalp hair samples (n = 14) were retrospectively examined at baseline and post-BLT (10.000 and 300 lux). Liquid chromatography-tandem mass spectrometry was used to measure hair glucocorticoids. RESULTS: A significant correlation was found between baseline HairF and depression scores (r = .605, p = .028). Post-intervention HairE levels were significantly increased ([95% CI: 11.2-17.4 pg/mg], p = .003), in particular after dim light (300 lux) ([95% CI: 10.0-18.3 pg/mg], p = .020). CONCLUSIONS: This study showed that retrospectively examining biological levels of stress in adults with intellectual disabilities seems a potentially promising and objective method to gain insight in the stress level of adults with intellectual disabilities.

Depression and obesity: evidence of shared biological mechanisms.

Depression and obesity are common conditions with major public health implications that tend to co-occur within individuals. The relationship between these conditions is bidirectional: the presence of one increases the risk for developing the other. It has thus become crucial to gain a better understanding of the mechanisms responsible for the intertwined downward physiological spirals associated with both conditions. The present review focuses specifically on shared biological pathways that may mechanistically explain the depression-obesity link, including genetics, alterations in systems involved in homeostatic adjustments (HPA axis, immuno-inflammatory activation, neuroendocrine regulators of energy metabolism including leptin and insulin, and microbiome) and brain circuitries integrating homeostatic and mood regulatory responses. Furthermore, the review addresses interventional opportunities and questions to be answered by future research that will enable a comprehensive characterization and targeting of the biological links between depression and obesity.

Children's hair cortisol as a biomarker of stress at school: a follow-up study.

In a previous study, we examined hair cortisol concentrations (HCCs) in children when first entering elementary school (at 4 years). In this follow-up study, we examined their HCC when they entered third grade (at 6 years), where the more playful first grades proceed into a more formal learning setting. Participants were 30 6-year-old children (14 boys). Hair samples (≥5 cm) were collected 2 months after the summer holidays. Hair analysis was conducted using two 2-cm long segments, reflecting the first 2 months of school attendance in grade 3 (the scalp-near segment), and 2 months prior to the start in grade 3. Between these two sections, we left a gap of 1 cm to avoid overlap of periods (due to differences in hair growth rate). Children showed a significant increase in cortisol levels when they entered third grade. This increase was not associated with social fearfulness or academic achievement, but did show significant associations with inhibitory control: children with less inhibitory control had higher cortisol levels after entering third grade, and larger increases in cortisol than children with higher scores on inhibitory control. This suggests that the ability to inhibit or control impulsive responsivity is important for children's stress regulation when making the transition to a more formal school environment.

Systemic and Local Corticosteroid Use Is Associated with Reduced Executive Cognition, and Mood and Anxiety Disorders.

BACKGROUND: Use of local corticosteroids, especially the inhaled types, has increasingly been associated with systemic uptake and consequent adverse effects. In this study, we assessed the associations between the use of different corticosteroid types with cognitive and neuropsychiatric adverse effects related to high glucocorticoid exposure. METHODS: In 83,592 adults (mean age 44 years, 59% women) of the general population (Lifelines Cohort Study), we analyzed the relationship between corticosteroid use with executive cognitive functioning (Ruff Figural Fluency Test), and presence of mood and anxiety disorders (Mini-International Neuropsychiatric Interview survey). We performed additional exploration for effects of physical quality of life (QoL; RAND-36), and inflammation (high-sensitive C-reactive protein [CRP]). RESULTS: Cognitive scores were lower among corticosteroid users, in particular of systemic and inhaled types, when compared to nonusers. Users of inhaled types showed lower cognitive scores irrespective of physical QoL, psychiatric disorders, and high-sensitive CRP. Overall corticosteroid use was also associated with higher likelihood for mood and anxiety disorders. Users of inhaled corticosteroids were more likely to have mood disorders (OR 1.40 [95% CI 1.19-1.65], p < 0.001) and anxiety disorders (OR 1.19 [95% CI 1.06-1.33], p = 0.002). These findings were independent of physical QoL. A higher likelihood for mood disorders was also found for systemic users whereas nasal and dermal corticosteroid users were more likely to have anxiety disorders. CONCLUSIONS: Commonly used local corticosteroids, in particular inhaled types, and systemic corticosteroids are associated with reduced executive cognitive functioning and a higher likelihood of mood and anxiety disorders in the general adult population.

Hair cortisol-a method to detect chronic cortisol levels in patients with Prader-Willi syndrome.

BACKGROUND: Prader-Willi syndrome (PWS) is a multisymptomatic, rare, genetic, neurodevelopmental disorder in adults mainly characterized by hyperphagia, cognitive dysfunction, behavioral problems and risk of morbid obesity. Although endocrine insufficiencies are common, hypocortisolism is rare and knowledge on long-term cortisol concentrations is lacking. The aim of this study was to evaluate long-term cortisol levels in PWS by measurements of hair cortisol. METHODS: Twenty-nine adults with PWS, 15 men and 14 women, median age 29 years, median BMI 27 kg/m2, were included. Scalp hair samples were analyzed for cortisol content using liquid-chromatography tandem-mass spectrometry. In addition, a questionnaire on auxology, medication and stress were included. For comparison, 105 age- and sex-matched participants from the population-based Lifelines Cohort study were included as controls. The mean hair cortisol between the groups were compared and associations between BMI and stress were assessed by a generalized linear regression model. RESULTS: In the PWS group large variations in hair cortisol was seen. Mean hair cortisol was 12.8 ± 25.4 pg/mg compared to 3.8 ± 7.3 pg/mg in controls (p = 0.001). The linear regression model similarly showed higher cortisol levels in patients with PWS, which remained consistent after adjusting for BMI and stress (p = 0.023). Furthermore, hair cortisol increased with BMI (p = 0.012) and reported stress (p = 0.014). CONCLUSION: Long-term cortisol concentrations were higher in patients with PWS compared to controls and increased with BMI and stress, suggesting an adequate cortisol response to chronic stress. Hair cortisol demonstrate promising applications in the context of PWS treatment and disease management.

Gender-specific effects of raising Year-1 standards on medical students' academic performance and stress levels.

CONTEXT: Medical schools are challenged to create academic environments that stimulate students to improve their study progress without compromising their well-being. OBJECTIVES: This prospective comparative cohort study investigated the effects of raising Year-1 standards on academic performance and on students' chronic psychological and biological stress levels. METHODS: In a Dutch medical school, students within the last Bachelor's degree cohort (n = 410) exposed to the 40/60 (67%) credit Year-1 standard (67%-credit cohort) were compared with students within the first cohort (n = 413) exposed to a 60/60 (100%) credit standard (100%-credit cohort). Main outcome measures were Year-1 pass rate (academic performance), mean score on the Perceived Stress Scale (PSS, psychological stress) and hair cortisol concentration (HCC, biological stress). RESULTS: Year-1 pass rates were significantly higher in the 100%-credit cohort (odds ratio [OR] 4.65). Interestingly, there was a significant interaction effect (OR 0.46), indicating that raising the standard was more effective for male than for female students. PSS scores (n = 234 [response rate [RR]: 57%] and n = 244 [RR: 59%] in the 67%- and 100%-credit cohorts, respectively) were also significantly higher in the 100%-credit cohort (F(1,474)  = 15.08, P < .001). This applied specifically to female students in the 100%-credit cohort. Levels of HCC (n = 181 [RR: 44%] and n = 162 [RR: 39%] respectively) did not differ between cohorts, but were significantly higher in female students (F(1,332)  = 7.93, P < .01). In separate models including cohort and gender, both PSS score (OR 0.91) and HCC (OR 0.38) were significantly associated with Year-1 performance. Only students with both high PSS scores and high HCC values were significantly at risk of lower Year-1 pass rates (OR 0.27), particularly male students. CONCLUSIONS: Raising the Year-1 performance standard increased academic performance, most notably in male students. However, it also increased levels of perceived stress, especially in female students. In particular, the combination of high levels of perceived stress and biological stress, as measured by long-term cortisol, was related to poor academic performance. The study suggests a relationship between raising performance standards and student well-being, with differential effects in male and female students.

Clinical outcome in anti-neutrophil cytoplasmic antibody-associated vasculitis and gene variants of 11ß-hydroxysteroid dehydrogenase type 1 and the glucocorticoid receptor.

OBJECTIVES: We aimed to investigate whether five potential functional haplotypes of the glucocorticoid receptor (GR) gene and a single-nucleotide polymorphism of 11ß-hydroxysteroid dehydrogenase type 1 (HSD11B1) are associated with clinical outcome in ANCA-associated vasculitis. METHODS: Patients diagnosed with ANCA-associated vasculitis (n = 241) were genotyped for five polymorphisms of the GR gene and one polymorphism of the HSD11B1 gene. GR gene haplotypes were predicted based on genotyping results. Relapse-free survival, mortality, renal survival, metabolic adverse events and infections were compared between carriers and non-carriers of GR haplotypes and the HSD11B1 genotype. RESULTS: Carriers of haplotype 4 (ER22/23EK + 9ß+TthIII1) of GR had a significantly higher 5-year mortality risk [hazard ratio (HR) 4.5 (95% CI 1.6, 12.8)] and had a higher risk of developing end-stage renal disease [HR 7.4 (95% CI 1.9, 28.7)]. Carriers of a minor variant of HSD11B1 more frequently experienced relapse [HR 2.5 (95% CI 1.5, 4.1)] except if they also carried haplotype 1 (BclI) of GR. Homozygous carriers of haplotype 1 had a higher risk of developing dyslipidaemia [HR 4.1 (95% CI 1.8, 9.6)]. The occurrence of infections did not differ between GR haplotypes and HSD11B1 genotypes. CONCLUSION: Haplotypes 1 and 4 of GR and a polymorphism of the HSD11B1 gene were associated with clinically relevant inflammatory and metabolic outcomes in ANCA-associated vasculitis.

Hair Glucocorticoids as a Biomarker for Endogenous Cushing's Syndrome: Validation in Two Independent Cohorts.

BACKGROUND/AIMS: The current diagnostic workup of Cushing's syndrome (CS) requires various tests which only capture short-term cortisol exposure, whereas patients with endogenous CS generally have elevated cortisol levels over longer periods of time. Scalp hair assessment has emerged as a convenient test in capturing glucocorticoid concentrations over long periods of time. The aim of this multicenter, multinational, prospective, case-control study was to evaluate the diagnostic efficacy of scalp hair glucocorticoids in screening of endogenous CS. METHODS: We assessed the diagnostic performances of hair cortisol (HairF), hair cortisone (HairE), and the sum of both (sumHairF+E), as measured by a state-of-the-art LC-MS/MS technique, in untreated patients with confirmed endogenous CS (n = 89) as well as in community controls (n = 295) from the population-based Lifelines cohort study. RESULTS: Both glucocorticoids were significantly elevated in CS patients when compared to controls. A high diagnostic efficacy was found for HairF (area under the curve 0.87 [95% CI: 0.83-0.92]), HairE (0.93 [0.89-0.96]), and sumHairF+E (0.92 [0.88-0.96]) (all p < 0.001). The participants were accurately classified at the optimal cutoff threshold in 86% of the cases (81% sensitivity, 88% specificity, and 94% negative predictive value [NPV]) by HairF, in 90% of the cases (87% sensitivity, 90% specificity, and 96% NPV) by HairE, and in 87% of the cases (86% sensitivity, 88% specificity, and 95% NPV) by the sumHairF+E. HairE was shown to be the most accurate in differentiating CS patients from controls. CONCLUSION: Scalp hair glucocorticoids, especially hair cortisone, can be seen as a promising biomarker in screening for CS. Its convenience in collection and workup additionally makes it feasible for first-line screening.