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[Display omitted] • PFAS levels in infants at age 3 months predict levels at age 2 years. • 2–3 fold higher levels in exclusive breastfed compared to formula fed infants. • Longer total duration of breastfeeding increases PFAS levels at age 2 years. • Trans-placental transmission is another important determinant of infant PFAS levels. • PFAS exposure in early life has potentially lasting effects, further research needed. Per- and polyfluoroalkyl substances (PFAS) are a potential hazard for public health. These man-made-chemicals are non-degradable with an elimination half-life of multiple years, causing accumulation in the environment and humans. Rodent studies demonstrated that PFAS are harmful, especially when present during the critical window in the first months of life. Because longitudinal data during infancy are limited, we investigated longitudinal plasma levels in infants aged 3 months and 2 years and its most important determinants. In 369 healthy term-born Dutch infants, we determined plasma PFOS, PFOA, PFHxS, PFNA and PFDA levels at age 3 months and 2 years, using liquid chromatography-electrospray-ionization-tandem-mass-spectrometry (LC-ESI-MS/MS). We studied the associations with maternal and child characteristics by multiple regression models. At age 3 months, median plasma levels of PFOS, PFOA, PFHxS, PFNA and PFDA were 1.48, 2.40, 0.43, 0.23 and 0.07 ng/mL, resp. Levels decreased slightly until age 2 years to 1.30, 1.81, 0.40, 0.21 and 0.08 ng/mL, resp. Maternal age, first born, Caucasian ethnicity and exclusive breastfeeding were associated with higher infant's plasma levels at age 3 months. Levels at 3 months were the most important predictor for PFAS levels at age 2 years. Infants with exclusive breastfeeding during the first 3 months of life (EBF) had 2–3 fold higher levels throughout infancy compared to infants with exclusive formula feeding (EFF), with PFOA levels at 3 months 3.72 ng/mL versus 1.26 ng/mL and at 2 years 3.15 ng/mL versus 1.22 ng/mL, respectively. Plasma PFAS levels decreased only slightly during infancy. Higher levels at age 3 months were found in Caucasian, first-born infants from older mothers and throughout infancy in EBF-infants. Our findings indicate that trans-placental transmission and breastfeeding are the most important determinants of PFAS exposure in early life. [ABSTRACT FROM AUTHOR]

Background: In contrast to the thyroid hormones (TH) 3,3′,5-triiodothyronine (T3) and thyroxine (T4), current literature on thyroid hormone metabolite concentrations in the hypothyroid and hyperthyroid states is inconclusive. It is unknown how thyroidectomy affects thyroid hormone metabolite concentrations and if levothyroxine (LT4) replacement therapy after thyroidectomy restores thyroid hormone metabolite concentrations in those without a thyroid gland. The treatment of patients with differentiated thyroid cancer (DTC) covers the euthyroid, hypothyroid, and (subclinical) hyperthyroid states and therefore provides a unique model to answer this. Here, we prospectively studied nine TH and its metabolites (THM) across different thyroid states in a cohort of patients treated for DTC. Also, three potentially important determinants for THM concentrations were studied. Methods: We prospectively included patients aged 18 to 80 years who were scheduled for DTC treatment at the Erasmus MC. Peripheral blood samples were obtained before surgery (euthyroid, endogenous TH production), after surgery just before radioactive iodine therapy (hypothyroid), and six months later on LT4 therapy ([subclinically] hyperthyroid, exogenous T4 supplementation). Nine THMs were quantified in serum with an established liquid chromatography/tandem mass spectrometry method. Repeated measurement analysis was used to compare the three different thyroid states with each other for each THM, while linear regression was used to determine the association between THM concentrations and age, sex, and kidney function. Results: In total, 77 patients (mean age 49 years; 65% women) were eligible for the study. 3,5-diiodothyronine and 3,3′,5-triiodothyroacetic acids were below the lower limit of detection. Compared with the euthyroid state, all THMs were significantly decreased in the hypothyroid state and significantly increased in the (subclinically) hyperthyroid state, with T3 concentrations remaining within the reference interval. Higher age was associated with higher 3-monoiodothyronine (3-T1) concentrations (p < 0.001). Women had higher L-thyronine concentrations than men (p = 0.003). A better kidney function was associated with lower 3-T1 concentrations (p < 0.001). Conclusions: All THMs decrease after a thyroidectomy and increase under thyrotropin (TSH)-suppressive LT4-therapy, suggesting that formation of thyroid hormone metabolites is dependent on peripheral extrathyroidal metabolism of T4. This is also reflected by T3 concentrations that remained within the reference interval in patients receiving TSH-suppressive LT4-therapy as T3 has some thyroidal origin. [ABSTRACT FROM AUTHOR]

BACKGROUND: Individuals with type 2 diabetes mellitus (T2DM) have increased fracture risk with high bone mineral density, possibly related to advanced glycation end products (AGEs) accumulation in bone. Flavanol supplementation in postmenopausal women reduced AGEs formation and decreased bone resorption markers. However, to date, these effects have not been investigated in T2DM. OBJECTIVE: We used a post hoc secondary analysis to determine the effect of monomeric and oligomeric flavanols supplementation on bone turnover markers (BTMs) in individuals with T2DM. METHODS: Eighty-three individuals with T2DM, aged 40–85 years, with microalbuminuria were enrolled from 4 trial centers in Rotterdam, the Netherlands, into a randomized, double-blind, placebo-controlled trial with renal vascular health as the primary outcome. Participants were randomized (1:1) to receive either a placebo or 200 mg of monomeric and oligomeric flavanols as intervention for three months. Serum alkaline phosphatase (ALP), type I collagen crosslinked beta C-telopeptide (β-CTx), and type I procollagen-N-propeptide (P1NP) were measured at baseline and three months. ANCOVA was performed on rank transformed BTMs at three months as the outcome, adjusting for baseline BTMs, group, age, sex, and BMI. RESULTS: Baseline characteristics did not differ between the two arms. The adjusted mean change in BTMs at three months was not different between the placebo vs. intervention arm: ALP –0.059 (–0.262–0.145) vs. 0.060 (–0.135–0.356), p = 0.41; β-CTx 0.013 (–0.205–0.231) vs. 0.100 (–0.109–0.310), p = 0.53 and P1NP 0.091 (–0.080–0.262) vs. 0.030 (–0.134–0.195), p = 0.61. There was no significant within-group change in BTMs after three months in both study arms. CONCLUSION: Supplementation with daily 200 mg of flavanols during three months, on top of usual care in individuals with T2DM, did not result in changes in BTMs compared to placebo. Future studies are needed to show whether long-term supplementation in higher dosages may positively affect BTMs in individuals with T2DM. [ABSTRACT FROM AUTHOR]

Current perioperative patient care aims to maintain homeostasis by attenuation of the stress response to surgery, as a more vigorous stress response can have detrimental effects on postoperative recovery. This systematic review and meta-analysis aims to assess the effect of perioperative music on the physiological stress response to surgery. The Embase, Medline Ovid, Cochrane Central, Web of Science, and Google Scholar databases were searched from inception date until February 5, 2019, using a systematic literature search following the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines for randomized controlled trials investigating the effect of music before, during, and/or after surgery in adult surgical patients on the stress response to surgery. Meta-analysis was performed using a random effects model and pooled standardized mean differences were calculated with 95% confidence intervals. This study was registered in the PROSPERO database (CRD42018097060). The literature search identified 1076 articles. Eighteen studies (1301 patients) were included in the systematic review, of which eight were included in the meta-analysis. Perioperative music attenuated the neuroendocrine cortisol stress response to surgery (pooled standardized mean difference −0.30, [95% confidence interval −0.53 to −0.07], P = 0.01, I2 = 0). Perioperative music can attenuate the neuroendocrine stress response to surgery. [ABSTRACT FROM AUTHOR]

Background: Measurement of adequate glucose concentrations is complicated by in vitro breakdown of glucose due to glycolysis. Unlike the commonly used NaF-EDTA and NaF-oxalate phlebotomy tubes, citrated NaF-EDTA tubes are reported to directly and thereby completely inhibit glycolysis. Recently, Greiner introduced the Vacuette ® FC-Mix NaF-EDTA-citrate tube, currently the only NaF-citrate tube without volume-disturbing liquid additions available on the European market. Here we present its potential as alternative for the laborious and therefore unfeasible conditions for glucose sampling as recommended by the World Health Organization (WHO). Methods: The FC-Mix tube was tested against the WHO recommended method of optimal laboratory conditions, both in healthy volunteers and pregnant woman undergoing oral glucose tolerance test (oGTT) for screening of gestational diabetes mellitus (GDM). Glucose concentrations were measured after different incubation times (0-48 h) and temperatures (room temperature, 37 °C), both in uncentrifuged whole blood and centrifuged material. Results: Deming regression analysis shows that glucose concentrations measured in the FC-Mix tube correlate to the WHO recommended method. Stability is maintained at room temperature for 48 h and at least 24 h at 37 °C. The use of the FC-Mix tube was also validated in screening for GDM and proved comparable to the WHO recommended method in diagnostic outcome. Conclusions: The new Greiner FC-Mix tube combines the easy handling of a routine tube with dry additive with the ability to immediately inhibit glycolysis as in the WHO method for optimal pre-analytical and analytical conditions and performs equally to those conditions when screening for GDM. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitor (ICI) associated diabetes is a harmful adverse event (AE) in patients with cancer following anti-programmed (cell) death protein-1 (PD-1) treatment. There are no available biomarkers able to predict this AE. The primary aim of this study was to investigate C-peptide levels as potential predictor for the occurrence of ICI-related diabetes. The secondary aim was to describe the presence of islet autoantibodies and course of pancreatic enzymes in patients with and without ICI-related diabetes. From a total of 1318 patients with cancer who started anti-PD-1 treatment 8 cases and 16 controls were studied in this nested case-control study. C-peptide levels, islet autoantibodies, and pancreatic enzymes were measured in prospectively collected blood serum. In cases versus controls, median C-peptide levels were comparable at baseline and before toxicity or at the corresponding time point in controls. No patient had C-peptide levels below reference range before toxicity onset. Two out of eight patients in the ICI-related diabetes group had positive islet autoantibodies, whereas one out of 16 patients in the control group had positive islet autoantibodies. Pancreatic enzymes were elevated before diabetes onset in one patient (13%) and in one control (6%) at the corresponding time point. In patients developing ICI-related diabetes, changes in C-peptide levels, islet autoantibody positivity, and pancreatic enzymes before ICI-related diabetes onset seem comparable to patients without ICI-related diabetes. (NTR: NL6828) [Display omitted] • Diabetes is a potentially life-threatening adverse event of ICI treatment. • There was no decline in C-peptide levels prior to onset of ICI-related diabetes. • Islet autoantibodies did not differ between ICI-related diabetes cases and controls. • Pancreatic enzymes did not differ between ICI-related diabetes cases and controls. [ABSTRACT FROM AUTHOR]

Although cold exposure is commonly believed to be causally related to acute viral respiratory infections, its effect on the immune system is largely unexplored. In this study, we determined transcript levels of a large panel of immune genes in blood before and after cold exposure. We included both Dutch Europid and Dutch South Asian men to address whether the immune system is differently regulated in the metabolically vulnerable South Asian population. Fasted blood samples were obtained from nonobese Dutch Europid (n = 11; mean age 26 ± 3 y) and Dutch South Asian (n = 12; mean age 28 ± 3 y) men before and directly after short-term (∼2.5 h) mild cold exposure. Transcript levels of 144 immune genes were measured using a dual-color reverse transcriptase multiplex ligation-dependent probe amplification (dcRT-MLPA) assay. Cold exposure acutely upregulated mRNA levels of GNLY (+35%, P < 0.001) and PRF1 (+45%, P < 0.001), which encode cytotoxic proteins, and CCL4 (+8%, P < 0.01) and CCL5 (+5%, P < 0.05), both pro-inflammatory chemokines. At thermoneutrality, mRNA levels of four markers of the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR)-family, involved in inflammasomes, were lower in Dutch South Asians compared to Dutch Europids, namely NLRP2 (−57%, P < 0.05), NLRP7 (−17%, P < 0.05), NLRP10 (−21%, P < 0.05), and NLRC4 (−23%, P < 0.05). Mild cold exposure acutely increases mRNA levels of genes involved in cytotoxicity of immune cells in blood. In addition, Dutch South Asians display lower circulating mRNA levels of inflammasome genes compared to Dutch Europids. • Cold exposure modulates circulating mRNA levels of immune genes in Dutch Europids and Dutch South Asians. • Cold exposure acutely increases circulating mRNA levels of genes involved in cytotoxic T cells and NK cells. • Circulating mRNA levels of inflammasome components are lower in Dutch South Asians compared to Dutch Europids. [ABSTRACT FROM AUTHOR]

The article reports on the normalisation issues of glucose measurements using phlebotomy tubes with liquid additives. It informs about the preanalytical procedures recognised by the National Academy of Clinical Biochemistry. It further informs about the Glucomedics tube from Greiner which contains a buffered citrate/sodium fluoride additive.

The immune system plays an instrumental role in obesity and insulin resistance. Here, we unravel the role of the costimulatory molecule CD40 and its signaling intermediates, TNF receptor-associated factors (TRAFs), in diet-induced obesity (DIO). Although not exhibiting increased weight gain, male CD4G-/- mice in DIO displayed worsened insulin resistance, compared with wild-type mice. This worsening was associated with excessive inflammation of adipose tissue (AT), characterized by increased accumulation of CD8+ T cells and Ml macrophages, and enhanced hepatosteatosis. Mice with deficient CD40-TRAF2/3/5 signaling in MHCir cells exhibited a similar phenotype in DIO as CD40-/- mice. In contrast, mice with deficient CD40-TRAF6 signaling in MHCi+ cells displayed no insulin resistance and showed a reduction in both AT inflammation and hepatosteatosis in DIO. To prove the therapeutic potential of inhibition of CD40-TRAF6 in obesity, DIO mice were treated with a small-molecule inhibitor that we designed to specifically block CD40-TRAF6 interactions; this compound improved insulin sensitivity, reduced AT inflammation, and decreased hepatosteatosis. Our study reveals that the CD40-TRAF2/ 3/5 signaling pathway in MHCII+ cells protects against AT inflammation and metabolic complications associated with obesity whereas CD40-TRAF6 interactions in MHCII+ cells aggravate these complications. Inhibition of CD40-TRAF6 signaling by our compound may provide a therapeutic option in obesity-associated insulin resistance. [ABSTRACT FROM AUTHOR]

[Display omitted] • Human milk contains measurable amounts of PFOA and PFOS. • Daily PFAS intake is highest in exclusively breastfed infants of older mothers. • Daily PFAS intake is highly correlated with PFAS plasma levels throughout infancy. • Breastfeeding is an important exposure pathway of PFOA and PFOS in early life. • Knowing the important health benefits of breastfeeding, our findings warrant more research. Per- and polyfluoroalkyl substances (PFAS) are non-degradable, man-made-chemicals with an elimination half-life of multiple years, causing accumulation in the environment and humans with potential harmful effects. However, longitudinal PFAS levels in human milk, daily PFAS intake and the association with infant plasma PFAS levels have never been reported. We investigated longitudinal PFOA and PFOS levels in human milk and the daily PFAS intake through infant feeding in the first 3 months of life, the most important determinants and the correlation with PFAS plasma levels at age 3 months and 2 years. In 372 healthy term-born Dutch infants, we determined PFOA and PFOS levels in human milk given at age 1 and 3 months, in 6 infant formula brands and in infant plasma at 3 months and 2 years, using liquid-chromatography-electrospray-ionization-tandem-mass-spectrometry(LC-ESI-MS/MS). We studied the associations between daily PFAS intake and predictive characteristics by multiple regression models. PFOA and PFOS levels in human milk decreased between 1 and 3 months after delivery, regardless whether breastfeeding was given exclusively(EBF) or in combination with formula feeding. PFOA and PFOS could not be detected in any formula feeding. Daily PFAS intake(ng/kg) was highest in EBF-infants. Higher amount of human milk, older maternal age, lower parity and first-time breastfeeding were associated with higher daily intake. Daily PFAS intake in early life was strongly correlated with PFAS plasma levels at age 3 months and 2 years(R = 0.642–0.875, p < 0.001). Human milk contains PFOA and PFOS, in contrast to formula feeding. Daily PFOA and PFOS intake in early life is highest in exclusively breastfed infants and it is highly correlated with infant's plasma levels throughout infancy. Our findings show that breastfeeding is an important PFAS exposure pathway in the first months of life, with unknown but potential adverse effects. Knowing the important health benefits of breastfeeding, our findings warrant more research about the health outcomes in later life. [ABSTRACT FROM AUTHOR]

In children with Prader–Willi syndrome (PWS), the standard growth hormone (GH) dose often results in high immunoreactive IGF-I levels. These high immunoreactive IGF-I levels lead to concern because their long-term effects are unknown. As a result, clinicians have to lower the GH dose, which worsens body composition and quality of life. As clinical features do not seem to correspond to immunoreactive IGF-I values, it is questionable whether immunoreactive IGF-I is a suitable marker for GH dosing, or whether another parameter better reflects IGF-I bioavailability and bioactivity. We, therefore, investigate serum immunoreactive IGF-I, free IGF-I and IGFBP-3 levels in 70 GH-treated children with PWS. Our study showed that, although immunoreactive IGF-I levels were high (>2 SDS) in the vast majority of prepubertal and pubertal children, free IGF-I SDS levels were <0 SDS in most and <1 SDS in all. Free IGF-I correlated with the immunoreactive IGF-I, IGFBP-3 and IGF-I/IGFBP-3 ratio. We conclude that there is a major discrepancy between immunoreactive and free IGF-I levels. While in the majority of GH-treated children with PWS, immunoreactive IGF-I levels were high, free IGF-I levels were <0 SDS in most. Our data appear to be very reassuring and suggest that free IGF-I levels should also be taken into consideration when the immunoreactive IGF-I levels are >2 SDS in GH-treated children with PWS. [ABSTRACT FROM AUTHOR]

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. 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). In cross-sectional analyses, HairF and HairE were positively associated to BMI (β = 2.06 kg/m2, 95% confidence interval (CI)= 1.22–2.90 kg/m2) and β = 2.84 kg/m2 (95%CI 1.75–3.93 kg/m2) respectively) and WC (β = 5.36 cm (95%CI 3.09–7.62 cm) and β = 8.54 cm (95%CI 5.60–11.48 cm) respectively, all p < 0.001). HairF was also positively associated to IL-6 (β = 0.15 (95%CI 0.003–0.292) p < 0.05) and leukocyte count (β = 0.57 (95%CI 0.234–0.909), p < 0.01), and HairE to IL-6 (β = 0.21 (95%CI 0.016–0.399), p < 0.05). In the longitudinal analyses, higher HairF was associated with yearly increases in BMI (β = 0.58% BMI change per year (95%CI 0.14–1.01%), p = 0.009) and higher HairE with increases in WC (β = 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. 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. • Long-term glucocorticoid levels in scalp hair (HairGC), are positively associated to obesity parameters on a cross-sectional level. • Similarly, HairGC are positively associated to interleukin-6 levels and absolute leukocyte counts. • Higher HairGC at baseline are associated with greater increases in BMI (for hair cortisol) and waist circumference (for hair cortisone) at follow-up. [ABSTRACT FROM AUTHOR]

Study Question: Is the degree of maternal vulnerability positively associated with stress biomarkers (stress hormones, C-reactive protein, tryptophan metabolites, and one-carbon metabolites), and does long-term exposure to stress hormones reduce first-trimester growth?, Summary Answer: The maternal vulnerability risk score is positively associated with concentrations of hair cortisol and cortisone and negatively with tryptophan, while higher hair cortisol concentrations are associated with reduced first-trimester growth without mediation of tryptophan., What Is Known Already: A high degree of maternal vulnerability during the periconception period is associated with impaired first-trimester growth and pregnancy complications, with consequences for long-term health of the child and future life course. However, due to the challenges of early identification of vulnerable women, the uptake of periconception care is low in this target group., Study Design, Size, Duration: Between June 2022 and June 2023, this study was conducted in a sub-cohort of 160 pregnant women participating in the Rotterdam Periconceptional Cohort (Predict Study), an ongoing prospective tertiary hospital-based cohort., Participants/materials, Setting, Methods: One hundred and thirty-two women with ongoing pregnancies and available stress biomarker data were included in the analysis. Data on periconceptional social, lifestyle, and medical risk factors were collected via self-administered questionnaires, and these factors were used for the development of a composite maternal vulnerability risk score. Stress biomarkers, including stress hormones (hair cortisol and cortisone) and inflammatory and oxidative stress biomarkers (C-reactive protein, total homocysteine, and tryptophan metabolites) were determined in the first trimester of pregnancy. First-trimester growth was assessed by crown-rump length (CRL) and embryonic volume (EV) measurements at 7, 9, and 11 weeks gestation by making use of an artificial intelligence algorithm and virtual reality techniques using 3D ultrasound data sets. The associations between the maternal vulnerability risk score and stress biomarkers were identified using linear regression models, and between stress hormones and CRL- and EV-trajectories using mixed models. A mediation analysis was performed to assess the contribution of tryptophan. All associations were adjusted for potential confounders, which were identified using a data-driven approach. Several sensitivity analyses were performed to check the robustness of the findings., Main Results and the Role of Chance: The maternal vulnerability risk score was positively associated with concentrations of hair cortisol and cortisone (pg/mg) (β = 0.366, 95% CI = 0.010-0.722; β = 0.897, 95% CI = 0.102-1.691, respectively), and negatively with tryptophan concentrations (µmol/L) (β = -1.637, 95% CI = -2.693 to -0.582). No associations revealed for C-reactive protein and total homocysteine. Higher hair cortisol concentrations were associated with reduced EV-trajectories (3√EV: β = -0.010, 95% CI = -0.017 to -0.002), while no associations were found with CRL-trajectories. Mediation by tryptophan was not shown., Limitations, Reasons for Caution: Residual confounding cannot be ruled out, and the external validity may be limited due to the study's single-center observational design in a tertiary hospital., Wider Implications of the Findings: There is mounting evidence that a high degree of maternal vulnerability negatively affects maternal and perinatal health, and that of the future life course. The results of our study emphasize the need to identify highly vulnerable women as early as possible, at least before conception. Our findings suggest that the chronic stress response and alterations of the maternal tryptophan metabolism are involved in maternal vulnerability, affecting first-trimester growth, with potential impact on the long-term health of the offspring., Study Funding/competing Interest(s): This study was funded by the Departments of Obstetrics and Gynecology and Clinical Chemistry of the Erasmus MC, University Medical Center, Rotterdam, the Netherlands, and the Junior Award granted by the De Snoo-van 't Hoogerhuijs Foundation in March 2022. There are no conflicts of interest., Trial Registration Number: N/A., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Background: In patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), momentary cortisol concentrations in blood, urine, and saliva are lower compared to healthy controls. Long-term cortisol concentration can be assessed through hair, but it is unclear whether these concentrations are also lower. Additionally, it is unknown if lower cortisol extends to other patients suffering from persistent fatigue and how hair cortisol concentration (HCC) relates to fatigue levels. Therefore, this study examines HCC in fatigued patients with ME/CFS, Q fever Fatigue Syndrome (QFS), Post-COVID-19 condition (PCC), and Juvenile Idiopathic Arthritis (JIA)., Methods: Adolescent and young adult patients with ME/CFS (n=12), QFS (n=20), PCC (n=8), JIA (n=19), and controls (n=57) were included. Patients participated in a randomized cross-over trial (RCT) targeting fatigue through lifestyle and dietary self-management strategies. HCC was measured pre-post RCT in patients and once in controls, quantified using a LC-MS/MS-based method. Fatigue severity was measured with the Checklist Individual Strength-8. HCC was compared between groups with ANOVAs. Relations between HCC, fatigue severity, and other variables were investigated using linear regression analyses., Results: The ME/CFS (p=.009) and QFS (p=.047) groups had lower HCC compared to controls. Overall, HCC was negatively associated with the presence of symptoms related to chronic fatigue syndromes (e.g., sleeping issues, often feeling tired, trouble thinking clearly; β=-0.018, p=.035), except in the QFS group (β=.063, p<.001). Baseline HCC did not predict fatigue improvement during the RCT (p=.449), and HCC increased during the trial (M dif =.076, p=.021) regardless of clinically relevant fatigue improvement (p=.658)., Conclusion: Lower cortisol concentration can also be observed in the long-term. Lower HCC is not limited to ME/CFS, as it was also observed in QFS. The role of cortisol may differ between these diagnoses and appears to be unrelated to fatigue levels., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to report., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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 to 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 of age. We also 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 < .001), particularly in younger individuals (multivariate-adjusted OR 4.21, 95% CI 1.91-9.07 per point increase in 10-log cortisone concentration [pg/mg], P < .001). All immune parameters except eosinophils were associated with hair cortisone (all multivariate-adjusted P < .05)., Conclusion: 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 CVD 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., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Importance: Poly- and perfluoroalkyl substances (PFASs) are nondegradable, man-made chemicals. They accumulate in humans with potential harmful effects, especially in susceptible periods of human development, such as the first months of life. We found that, in our cohort, exclusively breastfed (EBF) infants had 3 times higher PFAS plasma levels compared with exclusively formula-fed (EFF) infants at the age of 3 months. Thus, PFASs could potentially reduce the health benefits of breastfeeding., Objective: We investigated the associations between PFAS levels at the age of 3 months and accelerated gain in fat mass during the first 6 months of life, body composition at 2 years, and whether these associations differ between EBF and EFF infants., Setting: In 372 healthy term-born infants, we longitudinally assessed anthropometrics, body composition (by air-displacement plethysmography and dual-energy X-ray absorptiometry), and visceral and subcutaneous fat (by abdominal ultrasound) until the age of 2 years., Measures: The plasma levels of 5 individual PFASs were determined by liquid chromatography-electrospray ionization-tandem mass spectrometry at the age of 3 months., Main Outcomes: We studied associations between PFAS levels and outcomes using multiple regression analyses., Results: Higher early life plasma perfluorooctanoic acid and total PFAS levels were associated with an accelerated gain in fat mass percentage [FM%; >0.67 SD score (SDS)] during the first 6 months of life. Higher early life PFAS levels were associated with lower fat-free mass (FFM) SDS at the age of 2 years, but not with total FM% SDS at 2 years. Furthermore, we found opposite effects of PFAS levels (negative) and exclusive breastfeeding (positive) at the age of 3 months on FFM SDS at 2 years., Conclusion: Higher PFAS levels in early life are associated with accelerated gains in FM% during the first 6 months of life and with lower FFM SDS at the age of 2 years, which have been associated with an unfavorable body composition and metabolic profile later in life. Our findings warrant further research with longer follow-up times., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology.)

Context: During treatment, children with acute lymphoblastic leukemia (ALL) receive high doses dexamethasone, which induce acute side effects., Objective: To determine the influence of a 5-day dexamethasone course on changes in leptin, fat mass, BMI, hunger, sleep, and fatigue and to explore associations between these changes., Methods: Pediatric ALL patients were included during maintenance treatment. Data were collected before (T1) and after (T2) a 5-day dexamethasone course (6 mg/m2/day). At both time points, BMI, fat mass (bioelectrical impedance analysis), and leptin were assessed, as well as parent-reported questionnaires regarding hunger, fatigue, and sleep problems. Changes between T1 and T2 were assessed using paired tests. Correlation coefficients were calculated to assess associations between these changes (Delta scores: T2-T1). Univariable regression models were estimated to study associations between covariates and elevated leptin., Results: We included 105 children, with median age 5.4 years (range, 3.0-18.8). Leptin and fat mass, as well as hunger scores, fatigue, and sleep deteriorated after 5 days of dexamethasone (P < .001), in contrast to BMI (P = .12). No correlations between delta leptin and delta fat mass, BMI, hunger, fatigue, or sleep were found. Elevated leptin on T1 was associated with older age (odds ratio [OR] 1.51; 95% CI, 1.28-1.77), higher fat mass (OR 1.19; 95% CI, 1.07-1.33), and earlier maintenance week (OR 0.96; 95% CI, 0.92-0.99)., Conclusion: Five days of high-dose dexamethasone treatment led to direct and significant changes in leptin, hunger scores, and fat mass. Since children with ALL are at increased risk for metabolic adverse events, understanding underlying mechanisms is important, and a dexamethasone-induced state of acute leptin resistance might play a role., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Objectives: Interference from isomeric steroids is a potential cause of disparity between mass spectrometry-based 17-hydroxyprogesterone (17OHP) results. We aimed to assess the proficiency of mass spectrometry laboratories to report 17OHP in the presence of known isomeric steroids., Methods: A series of five samples were prepared using a previously demonstrated commutable approach. These samples included a control (spiked to 15.0 nmol/L 17OHP) and four challenge samples further enriched with equimolar concentrations of 17OHP isomers (11α-hydroxyprogesterone, 11β-hydroxyprogesterone, 16α-hydroxyprogesterone or 21-hydroxyprogesterone). These samples were distributed to 38 participating laboratories that reported serum 17OHP results using mass spectrometry in two external quality assurance programs. The result for each challenge sample was compared to the control sample submitted by each participant., Results: Twenty-six laboratories (68 % of distribution) across three continents returned results. Twenty-five laboratories used liquid chromatography-tandem mass spectrometry (LC-MS/MS), and one used gas chromatography-tandem mass spectrometry to measure 17OHP. The all-method median of the control sample was 14.3 nmol/L, ranging from 12.4 to 17.6 nmol/L. One laboratory had results that approached the lower limit of tolerance (minus 17.7 % of the control sample), suggesting the isomeric steroid caused an irregular result., Conclusions: Most participating laboratories demonstrated their ability to reliably measure 17OHP in the presence of the four clinically relevant isomeric steroids. The performance of the 12 (32 %) laboratories that did not engage in this activity remains unclear. We recommend that all laboratories offering LC-MS/MS analysis of 17OHP in serum, plasma, or dried bloodspots determine that the isomeric steroids are appropriately separated., (© 2023 the author(s), published by De Gruyter, Berlin/Boston.)

Objectives: Predicting the patients' tolerance to enteral nutrition (EN) would help clinicians optimize individual nutritional intake. This study investigated the course of several gastrointestinal (GI) biomarkers and their association with EN advancement (ENA) longitudinally during pediatric intensive care unit (PICU) admission., Methods: This is a secondary analysis of the Early versus Late Parenteral Nutrition in the Pediatric Intensive Care Unit randomized controlled trial. EN was started early and increased gradually. The cholecystokinin (CCK), leptin, glucagon, intestinal fatty acid-binding protein 2 (I-FABP2), and citrulline plasma concentrations were measured upon PICU admission, day 3 and day 5. ENA was defined as kcal EN provided as % of predicted resting energy expenditure. The course of the biomarkers and ENA was examined in patients with samples on all time points using Friedman and Wilcoxon signed-rank tests. The association of ENA with the biomarkers was examined using a 2-part mixed-effects model with data of the complete population, adjusted for possible confounders., Results: For 172 patients, median age 8.6 years (first quartile; third quartile: 4.2; 13.4), samples were available, of which 55 had samples on all time points. The median ENA was 0 (0; 0) on admission, 14.5 (0.0; 43.8) on day 3, and 28.0 (7.6; 94.8) on day 5. During PICU stay, CCK and I-FABP2 concentrations decreased significantly, whereas glucagon concentrations increased significantly, and leptin and citrulline remained stable. None of the biomarkers was longitudinally associated with ENA., Conclusions: Based on the current evidence, CCK, leptin, glucagon, I-FABP2, and citrulline appear to have no added value in predicting ENA in the first 5 days of pediatric critical illness., Competing Interests: Dr Hulst has received speaker fees from Abbott Nutrition and Nutricia Canada. Drs Vanhorebeek and Van den Berghe were granted funding by the Methusalem programme of the Flemish Government (METH14/06). Dr Gunst holds a postdoctoral research fellowship granted by the Clinical Research and Education Council of the University Hospitals Leuven, and Dr Casaer by the Research-Foundation Flanders Belgium (Fundamental Clinical Research Fellowship 1700111N). Dr Van den Berghe was supported by ERC Advanced Grants from the Ideas Program of the European Union 7th framework program (AdvG-2012-321670 and AdvG-2017-785809), and by the Agency for Innovation through Science and Technology, Flanders, Belgium (IWT/110685/TBM). Dr Verbruggen holds an unrestricted research agreement funded by Danone Nutricia Research, The Netherlands, and has received grants from the Sophia Research Foundation (S19-33), the Stichting Agis Zorginnovatie, and the Erasmus Trustfonds. The remaining authors report no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer on behalf of European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Purpose: The aim of this study is to design a population pharmacokinetic study to gain a deeper understanding of the pharmacokinetics of dexamethasone in critically ill COVID-19 patients in order to identify relevant covariates that can be used to personalize dosing regimens., Methods: Blood samples from critically ill patients receiving fixed-dose intravenous dexamethasone (6 mg/day) for the treatment of COVID-19 were sampled in a retrospective pilot study. The data were analyzed using Nonlinear Mixed Effects Modeling (NONMEM) software for population pharmacokinetic analysis and clinically relevant covariates were selected and evaluated., Results: A total of 51 dexamethasone samples from 18 patients were analyzed and a two-compartment model fit the data best. The mean population estimates were 2.85 L/h (inter-individual-variability 62.9%) for clearance, 15.4 L for the central volume of distribution, 12.3 L for the peripheral volume of distribution and 2.1 L/h for the inter-compartmental distribution clearance. The covariate analysis showed a significant negative correlation between dexamethasone clearance and CRP., Conclusions: Dexamethasone PK parameters in ICU COVID patients were substantially different from those from non-ICU non-COVID patients, and inflammation may play an important role in dexamethasone exposure. This finding suggests that fixed-dose dexamethasone over several days may not be appropriate for ICU COVID patients., Competing Interests: Declaration of Competing Interest The authors declared no competing interests for this work., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The ACTH (adrenocorticotropic hormone) stimulation test is the gold standard for the diagnosis of adrenal insufficiency (AI), performed with ACTH high dose (HDT) or low dose (LDT). As salivary cortisol has been proposed as an alternative to serum cortisol, our aim was to evaluate the reliability of salivary cortisol compared to serum cortisol for diagnosing AI in children. Data were collected retrospectively. Salivary and serum cortisol values derived by 80 ACTH stimulation tests were obtained (39 F, 36 M; median age 11.5 years, IQR 6.9). Sampling was performed at baseline and after 30 and 60 min from ACTH administration during the HDT, and at baseline and 10, 20, 30, 40 and 60 min after the stimulation for the LDT. A serum cortisol level > 420 nmol/L ruled out AI. The correlation coefficients between serum and salivary cortisol for the HDT ( n = 24) were 0.80 at t0, 0.48 at t30 and 0.75 at t60. All patients were adrenal sufficient. In 41% of the LDT, peak serum cortisol indicated insufficient adrenal function. The correlation coefficients between serum and salivary cortisol were 0.59 at t0 and 0.33 at the peak. For a cut-off of salivary cortisol < 15 nmol/L, sensitivity was 73.9% and specificity 69.6%. Our data do not support salivary cortisol as a valid alternative to serum cortisol during LDT. Regarding the HDT, results are more encouraging, however, further studies are needed.

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 (R 2 >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., (© 2023 the author(s), published by De Gruyter, Berlin/Boston.)

Background: Prader-Willi syndrome (PWS) is a rare, complex, genetic disorder characterized by hyperphagia, hypotonia, delayed psychomotor development, low muscle mass and hypothalamic dysfunction. Adults with PWS often have obesity, hypertension and type 2 diabetes mellitus (DM2), known risk factors for cardiovascular disease (CVD) and chronic kidney disease (CKD). Early symptoms of CVD and CKD may be masked by intellectual disability and inability to express physical complaints. Furthermore, kidney diseases are often asymptomatic. Therefore, renal and cardiovascular disease might be missed in patients with PWS. Microalbuminuria is an early sign of microvascular damage in the kidneys and other vascular beds. Therefore, we screened our adult PWS cohort for the presence of elevated urinary albumin and (micro)albuminuria., Methods: We retrospectively collected anthropometric measurements, blood pressure, medical history, medication use, urine dipstick and biochemical measurements form electronic patient files. In addition, we performed a systematic literature review on kidney disease in PWS., Results: We included 162 adults with genetically confirmed PWS (56% male, median age 28 years), of whom 44 (27%) had DM2. None had known CVD. All subjects had normal estimated glomerular filtration rate (eGFR) according to non-PWS reference intervals. Elevated urinary albumin or (micro)albuminuria was present in 28 (18%); 19 out of 75 (25%) had an increased urinary albumin-to-creatinine ratio (UACR) and 10 out of 57 (18%) had an increased urinary protein-to-creatinine ratio. Elevated urinary albumin was present at a young age (median age 26 (IQR 24-32) years) and was associated with an significantly higher BMI and LDL-cholesterol levels and higher prevalence of DM2, hypertension and dyslipidemia than those with normal UACR ( p =0.027, p =0.019, p <0.001, p <0.001, p =0.011 and respectively)., Conclusion: Upon screening, one in every five adults with PWS had increased urinary albumin or (micro)albuminuria, early signs of microvascular disease. All had normal eGFR, according to non-PWS reference intervals, and none had a formal diagnosis of CVD. As muscle mass is low in PWS, creatinine levels and eGFR may be spuriously normal. Urinalysis in this patient group can be used as a screening tool for microvascular (kidney) disease. We propose an algorithm for the detection and management of microvascular disease in adults with PWS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 van Abswoude, Pellikaan, Nguyen, Rosenberg, Davidse, Hoekstra, Rood, Poitou, Grugni, Høybye, Markovic, Caixàs, Crinò, van den Berg, van der Lely and de Graaff.)

Background: Childhood cancer survivors appear to be at increased risk of frailty and sarcopenia, but evidence on the occurrence of and high-risk groups for these aging phenotypes is scarce, especially in European survivors. The aim of this cross-sectional study was to assess the prevalence of and explore risk factors for pre-frailty, frailty, and sarcopenia in a national cohort of Dutch childhood cancer survivors diagnosed between 1963 and 2001., Methods: Eligible individuals (alive at the time of study, living in the Netherlands, age 18-45 years, and had not previously declined to participate in a late-effects study) from the Dutch Childhood Cancer Survivor Study (DCCSS-LATER) cohort were invited to take part in this cross-sectional study. We defined pre-frailty and frailty according to modified Fried criteria, and sarcopenia according to the European Working Group on Sarcopenia in Older People 2 definition. Associations between these conditions and demographic and treatment-related as well as endocrine and lifestyle-related factors were estimated with two separate multivariable logistic regression models in survivors with any frailty measurement or complete sarcopenia measurements., Findings: 3996 adult survivors of the DCCSS-LATER cohort were invited to participate in this cross-sectional study. 1993 non-participants were excluded due to lack of response or a decline to participate and 2003 (50·1%) childhood cancer survivors aged 18-45 years were included. 1114 (55·6%) participants had complete frailty measurements and 1472 (73·5%) participants had complete sarcopenia measurements. Mean age at participation was 33·1 years (SD  7·2). 1037 (51·8%) participants were male, 966 (48·2%) were female, and none were transgender. In survivors with complete frailty measurements or complete sarcopenia measurements, the percentage of pre-frailty was 20·3% (95% CI 18·0-22·7), frailty was 7·4% (6·0-9·0), and sarcopenia was 4·4% (3·5-5·6). In the models for pre-frailty, underweight (odds ratio [OR] 3·38 [95% CI 1·92-5·95]) and obesity (OR 1·67 [1·14-2·43]), cranial irradiation (OR 2·07 [1·47-2·93]), total body irradiation (OR 3·17 [1·77-5·70]), cisplatin dose of at least 600 mg/m 2 (OR 3·75 [1·82-7·74]), growth hormone deficiency (OR 2·25 [1·23-4·09]), hyperthyroidism (OR 3·72 [1·63-8·47]), bone mineral density (Z score ≤-1 and >-2, OR 1·80 [95% CI 1·31-2·47]; Z score ≤-2, OR 3·37 [2·20-5·15]), and folic acid deficiency (OR 1·87 [1·31-2·68]) were considered significant. For frailty, associated factors included age at diagnosis between 10-18 years (OR 1·94 [95% CI 1·19-3·16]), underweight (OR 3·09 [1·42-6·69]), cranial irradiation (OR 2·65 [1·59-4·34]), total body irradiation (OR 3·28 [1·48-7·28]), cisplatin dose of at least 600 mg/m 2 (OR 3·93 [1·45-10·67]), higher carboplatin doses (per g/m 2 ; OR 1·15 [1·02-1·31]), cyclophosphamide equivalent dose of at least 20 g/m 2 (OR 3·90 [1·65-9·24]), hyperthyroidism (OR 2·87 [1·06-7·76]), bone mineral density Z score ≤-2 (OR 2·85 [1·54-5·29]), and folic acid deficiency (OR 2·04 [1·20-3·46]). Male sex (OR 4·56 [95%CI 2·26-9·17]), lower BMI (continuous, OR 0·52 [0·45-0·60]), cranial irradiation (OR 3·87 [1·80-8·31]), total body irradiation (OR 4·52 [1·67-12·20]), hypogonadism (OR 3·96 [1·40-11·18]), growth hormone deficiency (OR 4·66 [1·44-15·15]), and vitamin B12 deficiency (OR 6·26 [2·17-1·81]) were significantly associated with sarcopenia., Interpretation: Our findings show that frailty and sarcopenia occur already at a mean age of 33 years in childhood cancer survivors. Early recognition and interventions for endocrine disorders and dietary deficiencies could be important in minimising the risk of pre-frailty, frailty, and sarcopenia in this population., Funding: Children Cancer-free Foundation, KiKaRoW, Dutch Cancer Society, ODAS Foundation., Competing Interests: Declaration of interests IH has institutional contracts with Abbott, Siemens Healthineers, and Beckman Coulter. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kuckuck, van der Valk, Scheurink, Lengton, Mohseni, Visser, Iyer, van den Berg and van Rossum.)

Background: Alterations in stress regulation and function of the hypothalamic-pituitary-adrenal (HPA) axis during infancy may be a risk factor for the development of psychopathology later in life. Maternal childhood trauma, depression, anxiety and stressful life events are individually associated with HPA axis dysregulation. Less is known about their interdependent influence on maternal and infant stress regulation in at risk populations. In a sample of mothers with a history of depressive-, and/or anxiety disorders and their infants we explored if a history of maternal childhood trauma, current depressive and anxiety symptomatology, and recent life events were associated with maternal and infant long-term cortisol levels three months postpartum., Methods: Data were available of 89 mothers and 49 infants. All mothers fulfilled criteria for a lifetime depressive or anxiety disorder. Diagnosis was established with a diagnostic interview. Current depressive symptomatology was assessed with the Edinburgh Postnatal Depression Scale (EPDS), current anxiety with the State-Trait Anxiety Inventory (STAI), maternal childhood trauma with the Childhood Trauma Questionnaire (CTQ) and recent life events with the Everyday Problem Checklist (EPC). Maternal and infant hair cortisol concentrations (HCC) were quantified with liquid chromatography with tandem mass spectrometry (LC-MS/MS) three months after birth. Total scores of the CTQ and subscales, EPDS, STAI, and EPC were regressed on maternal and infant HCC using regression analyses. Differences in HCC regarding trauma history were tested with t-tests. Potential confounders were identified and adjusted for., Results: In regression analyses, a positive curvilinear relationship was found between CTQ total score and maternal HCC (n = 83, B = 0.076, SE 0.033, p = .021), but not for current depression (n = 88, B = -0.001, SE 0.011, p = .931), current anxiety (n = 88, B = 0.002, SE 0.004, p = .650) or recent life events (n = 89, B = 0.018, SE 0.032, p = .568). Analyses were adjusted for confounders. A negative linear relationship was found between maternal CTQ score and infant HCC (n = 49, β = -0.264, B = -0.006, SE 0.003, p = .052), but not for current maternal depression (n = 45, β = -0.182, B = -0.011, SE 0.008, p = .164), current maternal anxiety (n = 45, β = -0.209, B = -0.005, SE 0.003, p = .113) or recent life events (n = 46, β = -0.128, B = -0.022, SE 0.023, p = .325). Analyses were adjusted for relevant infant hair characteristics. Specifically, maternal emotional and physical neglect were related to HCC in both mothers and infants., Conclusions: Results suggest that maternal childhood trauma is more prominent in altering maternal and infant long-term cortisol levels than perinatal depressive and anxiety symptomatology or recent life stressors in mothers with a history of depressive and/or anxiety disorders, and their infants. As infants of mothers with psychopathology are at increased risk for later psychiatric disease, future studies should investigate the interplay of possible risk factors for transgenerational transmission, intra-uterine programming of the HPA axis, including (epi-)genetic phenomena, of the HPA axis, and the influence of parenting impairment., Competing Interests: None., (© 2023 The Author(s).)

Background: Childhood cancer survivors are at risk of developing skeletal comorbidities later in life. We aimed to assess risk factors for low and very low bone mineral density (BMD), and the risk of and risk factors for any fractures and vertebral fractures in a national cohort of Dutch adult childhood cancer survivors., Methods: In this cross-sectional study, we used data from the DCCSS LATER cohort, which comprised individuals who were alive for at least 5 years after diagnosis of childhood cancer (ie, histologically confirmed malignancies or Langerhans cell histiocytosis), were diagnosed before the age of 19 years, and who had been treated at one of seven Dutch paediatric oncology centres between 1963 and 2002 (hereafter referred to as survivors). For this study, we invited survivors aged 18-45 years, who were alive as of Oct 10, 2016, living in the Netherlands, and who were deemed eligible by their treating physician to participate. We assessed BMD using dual-energy x-ray absorptiometry (DXA). Self-reported fractures that occurred at least 5 years after cancer diagnosis were assessed using available medical history and compared with population-level data from the Swedish national registry. We assessed vertebral fractures in a subset of participants using a vertebral fracture assessment. We assessed associations between the occurrence of low (Z-score of ≤-1) or very low (Z-score of ≤-2) BMD, fractures, and vertebral fractures and demographic, treatment-related, endocrine, and lifestyle-related factors using logistic regression analysis., Findings: Between April 29, 2016, and Jan 22, 2020, 3996 (64·8%) of 6165 individuals from the DCCSS LATER cohort were invited to participate, of whom 2003 (50·1%) were enrolled (mean age at participation was 33·1 years [SD 7·2], 966 [48·2%] were female, and 1037 [51·8%] were male [data on ethnicity and race were not available due to national policies]). 1548 (77·3%) had evaluable DXA scans for assessment of BMD, 1892 (94·5%) provided medical history of fractures, and 249 (12·4%) were assessed for vertebral fractures. 559 (36·1%) of 1548 had low BMD at any site, and 149 (9·6%) had very low BMD at any site. The standardised incidence ratio of any first fracture was 3·53 (95% CI 3·06-4·06) for male participants and 5·35 (4·46-6·52) for female participants. 33 (13·3%) of 249 participants had vertebral fractures. Male sex, underweight, high carboplatin dose, any dose of cranial radiotherapy, hypogonadism, hyperthyroidism, low physical activity, and severe vitamin D deficiency were associated with low BMD at any site and male sex, underweight, cranial radiotherapy, growth hormone deficiency, and severe vitamin D deficiency were associated with very low BMD at any site. Additionally, male sex, former and current smoking, and very low lumbar spine BMD were associated with any fractures, whereas older age at follow-up, previous treatment with platinum compounds, growth hormone deficiency, and low physical activity were specifically associated with vertebral fractures., Interpretation: Survivors of childhood cancer are at increased risk of any first fracture. Very low lumbar spine BMD was associated with fractures, highlighting the importance of active BMD surveillance in high-risk survivors (ie, those treated with cranial, craniospinal, or total body irradiation). Moreover, our results indicate that intensive surveillance and timely interventions for endocrine disorders and vitamin deficiencies might improve bone health in childhood cancer survivors, but this needs to be assessed in future studies., Funding: Children Cancer-free Foundation (KiKa), KiKaRoW, and ODAS foundation., Competing Interests: Declaration of interests IH declares institutional contracts from Abbott, Siemens Healthineers, and Beckman Coulter. CMR declares a non-commercial charity grant funding, and a personal grant for Jr Group Leaders 2013–2018 (Dutch Cancer Society). All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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., Competing Interests: Conflict of Interests: All authors are employed by ErasmusMC Medical Center, Rotterdam, the Netherlands, (Copyright © 2022, International Journal of Endocrinology and Metabolism.)

Purpose: Measurement of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) is important for assessing thyroid dysfunction. After changing assay manufacturer, high FT4 versus TSH levels were reported at Ente Ospedaliero Cantonale (EOC; Bellinzona, Switzerland)., Methods: Exploratory analysis used existing TSH and FT4 measurements taken at EOC during routine clinical practice (February 2018-April 2020) using Elecsys® TSH and Elecsys FT4 III immunoassays on cobas® 6000 and cobas 8000 analyzers (Roche Diagnostics). Reference intervals (RIs) were estimated using both direct and indirect (refineR algorithm) methods., Results: In samples with normal TSH levels, 90.9% of FT4 measurements were within the normal range provided by Roche (12-22 pmol/L). For FT4 measurements, confidence intervals (CIs) for the lower end of the RI obtained using direct and indirect methods were lower than estimated values in the method sheet; the estimated value of the upper end of the RI (UEoRI) in the method sheet was within the CI for the UEoRI using the direct method but not the indirect method. CIs for the direct and indirect methods overlapped at both ends of the RI. The most common cause of increased FT4 with normal TSH was identified in a subset of patients as use of thyroxine therapy (72.6%)., Conclusions: It is important to verify RIs for FT4 in the laboratory population when changing testing platforms; indirect methods may constitute a convenient tool for this. Applying specific RIs for selected subpopulations should be considered to avoid misinterpretations and inappropriate clinical actions., (© 2022. The Author(s).)

Competing Interests: There is no conflict of interest.

Background: Low sFlt-1 (soluble Fms-like tyrosine kinase-1) and ET-1 (endothelin-1) levels have been reported in preeclamptic women using proton pump inhibitors., Methods: Here, we examined whether the proton pump inhibitor omeprazole could acutely reduce sFlt-1 and ET-1 (measured as CT-proET-1 [C-terminal pro-endothelin-1]), or increase free PlGF (placental growth factor) in 20 women with confirmed preeclampsia. Primary outcome was specified as the difference in sFlt-1, PlGF, or CT-proET-1 after 4 days of omeprazole versus 20 preeclamptic women not receiving omeprazole., Results: Mean maternal age was 30 years, and median gestational age was 30 +3 weeks. Baseline sFlt-1 levels were identical in both groups, and the same was true for PlGF or CT-proET-1. After 4 days, sFlt-1 levels remained similar in women not receiving omeprazole compared with women receiving omeprazole, while the levels of PlGF and CT-proET-1 also did not differ between groups. Women receiving omeprazole had a similar prolongation of pregnancy after inclusion compared with those in the nonomeprazole group (median 15 versus 14 days). Except for a higher neonatal intubation rate in the nonomeprazole group (31% versus 4%, P =0.02), there were no differences in maternal/perinatal complications. Finally, making use of the placenta perfusion model, we established that both omeprazole and its S-isomer, esomeprazole, when maternally applied, reached the fetal compartment (fetal-to-maternal ratio's 0.43-0.59), while only esomeprazole inhibited placental sFlt-1 release., Conclusions: Administration of omeprazole to women with confirmed preeclampsia does not alter their circulating levels of sFlt-1, PlGF, or ET-1, arguing against a role of this drug as a treatment for this syndrome.

Prolonged niacin treatment elicits beneficial effects on the plasma lipid and lipoprotein profile that is associated with a protective CVD risk profile. Acute niacin treatment inhibits nonesterified fatty acid release from adipocytes and stimulates prostaglandin release from skin Langerhans cells, but the acute effects diminish upon prolonged treatment, while the beneficial effects remain. To gain insight in the prolonged effects of niacin on lipid metabolism in adipocytes, we used a mouse model with a human-like lipoprotein metabolism and drug response [female APOE*3-Leiden.CETP (apoE3 Leiden cholesteryl ester transfer protein) mice] treated with and without niacin for 15 weeks. The gene expression profile of gonadal white adipose tissue (gWAT) from niacin-treated mice showed an upregulation of the "biosynthesis of unsaturated fatty acids" pathway, which was corroborated by quantitative PCR and analysis of the FA ratios in gWAT. Also, adipocytes from niacin-treated mice secreted more of the PUFA DHA ex vivo. This resulted in an increased DHA/arachidonic acid (AA) ratio in the adipocyte FA secretion profile and in plasma of niacin-treated mice. Interestingly, the DHA metabolite 19,20-dihydroxy docosapentaenoic acid (19,20-diHDPA) was increased in plasma of niacin-treated mice. Both an increased DHA/AA ratio and increased 19,20-diHDPA are indicative for an anti-inflammatory profile and may indirectly contribute to the atheroprotective lipid and lipoprotein profile associated with prolonged niacin treatment., (Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.)

The lipid-lowering effect of niacin has been attributed to the inhibition of cAMP production in adipocytes, thereby inhibiting intracellular lipolysis and release of nonesterified fatty acids (NEFA) to the circulation. However, long-term niacin treatment leads to a normalization of plasma NEFA levels and induces insulin resistance, for which the underlying mechanisms are poorly understood. The current study addressed the effects of long-term niacin treatment on insulin-mediated inhibition of adipocyte lipolysis and focused on the regulation of cAMP levels. APOE*3-Leiden.CETP transgenic mice treated with niacin for 15 wk were subjected to an insulin tolerance test and showed whole body insulin resistance. Similarly, adipocytes isolated from niacin-treated mice were insulin resistant and, interestingly, exhibited an increased response to cAMP stimulation by 8Br-cAMP, β1- and β2-adrenergic stimulation. Gene expression analysis of the insulin and β-adrenergic pathways in adipose tissue indicated that all genes were downregulated, including the gene encoding the cAMP-degrading enzyme phosphodiesterase 3B (PDE3B). In line with this, we showed that insulin induced a lower PDE3B response in adipocytes isolated from niacin-treated mice. Inhibiting PDE3B with cilostazol increased lipolytic responsiveness to cAMP stimulation in adipocytes. These data show that long-term niacin treatment leads to a downregulation of PDE3B in adipocytes, which could explain part of the observed insulin resistance and the increased responsiveness to cAMP stimulation.

Objective: The scavenger receptor CD36 facilitates the cellular uptake of long-chain fatty acids. As CD36-deficiency attenuates the development of high fat diet (HFD)-induced obesity, the role of CD36-deficiency in preadipocyte recruitment and adipocyte function was set out to characterize., Design and Methods: Fat cell size and number were determined in gonadal, visceral, and subcutaneous adipose tissue of CD36(-/-) and WT mice after 6 weeks on HFD. Basal lipolysis and insulin-inhibited lipolysis were investigated in gonadal adipose tissue., Results: CD36(-/-) mice showed a reduction in adipocyte size in all fat pads. Gonadal adipose tissue also showed a lower total number of adipocytes because of a lower number of very small adipocytes (diameter <50 μm). This was accompanied by an increased pool of preadipocytes, which suggests that CD36-deficiency reduces the capacity of preadipocytes to become adipocytes. Regarding lipolysis, in adipose tissue from CD36(-/-) mice, cAMP levels were increased and both basal and 8-bromo-cAMP stimulated lipolysis were higher. However, insulin-mediated inhibition of lipolysis was more potent in CD36(-/-) mice., Conclusions: These results indicate that during fat depot expansion, CD36-deficiency negatively affects preadipocyte recruitment and that in mature adipocytes, CD36-deficiency is associated with increased basal lipolysis and insulin responsiveness., (Copyright © 2013 The Obesity Society.)

Caspase-1 is known to activate the proinflammatory cytokines IL-1β and IL-18. Additionally, it can cleave other substrates, including proteins involved in metabolism. Recently, we showed that caspase-1 deficiency in mice strongly reduces high-fat diet-induced weight gain, at least partly caused by an increased energy production. Increased feces secretion by caspase-1-deficient mice suggests that lipid malabsorption possibly further reduces adipose tissue mass. In this study we investigated whether caspase-1 plays a role in triglyceride-(TG)-rich lipoprotein metabolism using caspase-1-deficient and wild-type mice. Caspase-1 deficiency reduced the postprandial TG response to an oral lipid load, whereas TG-derived fatty acid (FA) uptake by peripheral tissues was not affected, demonstrated by unaltered kinetics of [(3)H]TG-labeled very low-density lipoprotein (VLDL)-like emulsion particles. An oral gavage of [(3)H]TG-containing olive oil revealed that caspase-1 deficiency reduced TG absorption and subsequent uptake of TG-derived FA in liver, muscle, and adipose tissue. Similarly, despite an elevated hepatic TG content, caspase-1 deficiency reduced hepatic VLDL-TG production. Intestinal and hepatic gene expression analysis revealed that caspase-1 deficiency did not affect FA oxidation or FA uptake but rather reduced intracellular FA transport, thereby limiting lipid availability for the assembly and secretion of TG-rich lipoproteins. The current study reveals a novel function for caspase-1, or caspase-1-cleaved substrates, in controlling intestinal TG absorption and hepatic TG secretion.

Objective: We investigated whether a reduced iso-α acid derived from an extract of Humulus lupulus L., META060, had an effect on weight gain, body composition, and metabolism in a high-fat-diet (HFD) fed mouse model., Methods: Weight gain was monitored for up to 20 wk in mice receiving a low-fat diet, an HFD, or an HFD supplemented with META060 or rosiglitazone. Body composition was determined using dual-energy x-ray absorptiometric analysis. Indirect calorimetric measurements were performed to investigate the energy balance in the mice, and oral glucose tolerance tests were administered to examine the effect of META060 on the glycemic response., Results: The HFD-fed mice administered META060 for 14 wk had a significantly lower mean weight than HFD-fed mice (30.58 ± 0.5 versus 37.88 ± 0.7 g, P < 0.05). Indirect calorimetric measurements showed an increased metabolic flexibility in mice supplemented with META060. In addition, glucose tolerance was improved, comparable to the effects of rosiglitazone treatment., Conclusions: META060 has potential therapeutic value for managing obesity and insulin resistance, and further research into the mechanism of action is warranted., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Obesity and its associated conditions such as type 2 diabetes mellitus are major causes of morbidity and mortality. The iminosugar N-(5-adamantane-1-yl-methoxy-pentyl)-deoxynojirimycin (AMP-DNM) improves insulin sensitivity in rodent models of insulin resistance and type 2 diabetes mellitus. In the current study, we characterized the impact of AMP-DNM on substrate oxidation patterns, food intake, and body weight gain in obese mice. Eight ob/ob mice treated with 100 mg/(kg d) AMP-DNM mixed in the food and 8 control ob/ob mice were placed in metabolic cages during the first, third, and fifth week of the experiment for measurement of substrate oxidation rates, energy expenditure, activity, and food intake. Mice were killed after 6 weeks of treatment. Initiation of treatment with AMP-DNM resulted in a rapid increase in fat oxidation by 129% (P = .05), a decrease in carbohydrate oxidation by 35% (P = .01), and a reduction in food intake by approximately 26% (P < .01) compared with control mice. Treatment with AMP-DNM decreased hepatic triglyceride content by 66% (P < .01) and, in line with the elevated fat oxidation rates, increased hepatic carnitine palmitoyl transferase 1a expression. Treatment with AMP-DNM increased plasma levels of the appetite-regulating peptide YY compared with control mice. Treatment with AMP-DNM rapidly reduces food intake and increases fat oxidation, resulting in improvement of the obese phenotype. These features of AMP-DNM, together with its insulin-sensitizing capacity, make it an attractive candidate drug for the treatment of obesity and its associated metabolic derangements., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Excess dietary long-chain fatty acid (LCFA) intake results in ectopic lipid accumulation and insulin resistance. Since medium-chain fatty acids (MCFA) are preferentially oxidized over LCFA, we hypothesized that diets rich in MCFA result in a lower ectopic lipid accumulation and insulin resistance compared to diets rich in LCFA. Feeding mice high-fat (HF) (45% kcal fat) diets for 8 weeks rich in triacylglycerols composed of MCFA (HFMCT) or LCFA (HFLCT) revealed a lower body weight gain in the HFMCT-fed mice. Indirect calorimetry revealed higher fat oxidation on HFMCT compared to HFLCT (0.011.0±0.0007 vs. 0.0096±0.0015 kcal/g body weight per hour, P<.05). In line with this, neutral lipid immunohistochemistry revealed significantly lower lipid storage in skeletal muscle (0.05±0.08 vs. 0.30±0.23 area%, P <.05) and in liver (0.9±0.4 vs. 6.4±0.8 area%, P<.05) after HFMCT vs. HFLCT, while ectopic fat storage in low fat (LF) was very low. Hyperinsulinemic euglycemic clamps revealed that the HFMCT and HFLCT resulted in severe whole body insulin resistance (glucose infusion rate: 53.1±6.8, 50.8±15.3 vs. 124.6±25.4 μmol min(-1) kg(-1), P<.001 in HFMCT, HFLCT and LF-fed mice, respectively). However, under hyperinsulinemic conditions, HFMCT revealed a lower endogenous glucose output (22.6±8.0 vs. 34.7±8.5 μmol min(-1) kg(-1), P<.05) and a lower peripheral glucose disappearance (75.7±7.8 vs. 93.4±12.4 μmol min(-1) kg(-1), P<.03) compared to HFLCT-fed mice. In conclusion, both HF diets induced whole body insulin resistance compared to LF. However, the HFMCT gained less weight, had less ectopic lipid accumulation, while peripheral insulin resistance was more pronounced compared to HFLCT. This suggests that HF-diets rich in medium- versus long-chain triacylglycerols induce insulin resistance via distinct mechanisms., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Skeletal muscle is responsible for most of the insulin-stimulated glucose uptake and metabolism. Therefore, it plays an important role in the development of insulin resistance, one of the characteristics of the metabolic syndrome (MS). As the prevalence of the MS is increasing, there is an urgent need for more effective intervention strategies., Methods: C57BL/6J mice were fed an 8-week low-fat diet (10 kcal%; LFD) or high-fat diet (45 kcal%; HFD). Microarray analysis was performed by using two comparisons: (1) 8-week HFD transcriptome versus 8-week LFD transcriptome and (2) transcriptome of mice sacrificed at the start of the intervention versus 8-week LFD transcriptome and 8-week HFD transcriptome, respectively., Results: Although an 8-week HFD induced obesity and impaired insulin sensitivity, HFD-responsive changes in the muscle transcriptome were relatively small (<1.3-fold). In fact, 8-weeks of aging induced more pronounced changes than an HFD. One comparison revealed the transcriptional downregulation of the mito- gen-activated protein kinase cascade, whereas both comparisons showed the upregulation of fatty acid oxidation, demonstrating that the two comparison strategies are confirmative as well as complementary., Conclusion: We suggest using complementary analysis strategies in the genome-wide search for gene expression changes induced by mild interventions, such as an HFD., (Copyright © 2010 S. Karger AG, Basel.)