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Abstract Background Bardet–Biedl syndrome (BBS) is a rare autosomal-recessive ciliopathy with pathogenic variants in 26 BBS genes. It affects multiple organs, including the kidney and liver, with varying degrees regarding extent and time of first manifestation. Structural renal anomalies are an early feature and end-stage kidney disease (ESKD) cumulates to 25% in adulthood. Early-onset hyperphagia-associated obesity is another major symptom and contributes to liver pathology, presenting as steatosis/fibrosis. Aim of this study is the evaluation of high-end ultrasound (US) technologies in BBS patients regarding their potential to discriminate liver and kidney tissue pathology at an early stage. Materials and methods Patients with genetically proven BBS were recruited from the University Children’s Hospital of Essen and from BBS patient days hosted in Germany. Acute illness was an exclusion criterion. Clinical and laboratory data were extracted from patients’ digital records or medical letters. High-resolution ultrasound (US) imaging was utilized, including attenuation imaging (ATI), shear wave elastography (SWE) and dispersion (SWD) of liver tissue. Results 49 BBS patients (24/49 male; 1.1–51.0 years, mean 17.8 years) were included in the study. Mean body weight (SDS 2.13 ± 1.33) and BMI (SDS 2.64 ± 1.18) were increased. Structural kidney abnormalities (dysplasia, cysts) were present in 75% (36/48), and persistent fetal lobulation in 44% (21/48). Renal function was impaired in 27% (13/49) of whom 3 had ESKD (kidney transplantation (n = 2), hemodialysis (n = 1)). Elevation of liver enzymes was detected in 38% (16/42). In 51% (25/49) ATI of liver tissue was increased, indicating hepatic steatosis, and correlated with BMI SDS, liver size, and enzymes. SWE was elevated in 61% (30/49), suggesting hepatic fibrosis, and it correlated with BMI and GGT. Patients with pathogenic variants in BBS10 showed a tendency towards higher ATI, reduced GFR, and higher BMI SDS. Conclusions We detected kidney and liver abnormalities in a higher percentage of BBS patients than previously reported, indicating a high sensitivity and diagnostic yield of the evaluated high-end US applications. ATI detected liver pathology early (partially prior to liver enzymes) and revealed differences related to the affected genes. Evidence of tissue pathology at an early stage may improve diagnostics and the evaluation of therapeutic approaches.

Abstract Background The present study evaluates personality traits in adult patients with cystic fibrosis (CF) and correlates these results with health-related quality of life (HRQoL) and other clinical parameters indicative of disease severity. Methods Seventy adults completed the Cystic Fibrosis Questionnaire-Revised (CFQ-R 14+), a CF-specific measure of HRQoL, and a self-administered questionnaire about personality traits and disorders. Mean subscale scores and the prevalence of extreme personality traits on the `Persönlichkeits-Stil- und Störungs-Inventar (PSSI)´ were compared to the norming sample. Moreover, a cluster analysis was conducted to identify personality styles among people with cystic fibrosis (pwCF). The relationship between mean PSSI subscale scores and personality clusters with HRQoL and clinical outcomes, e.g., percent predicted forced expiratory volume in one second (ppFEV1), and body mass index (BMI), was studied by regression analysis considering important confounders. Results On several of the subscales of the personality questionnaire, people with cystic fibrosis (pwCF) showed either significantly higher or lower scores than the norm sample. In further analyses, two personality clusters could be identified. PwCF from the cluster with predominantly low scores on the subscales ‘negativistic’, ‘schizoid’, ‘borderline’, ‘depressed’, and ‘paranoid’ showed better HRQoL than pwCF from the other cluster with mainly high normal or elevated scores. The studied health outcomes proved to be independent of the respective personality clusters. Conclusions In pwCF, HRQoL is mainly determined by psychological factors, including personality. Since more recent personality theories assume that personality is modifiable, our findings imply that patients with accentuated personality traits may benefit from psychosocial support.

Abstract Background Cough suppression assessed by embarrassment about coughing has been shown in adolescents with cystic fibrosis (CF) and negatively affects health-related quality of life (HRQoL) and clinical indicators of disease severity in adolescent females. However, whether cough suppression exists in adults has been studied as little as its effects on clinical and psychological outcomes beyond adolescence. Methods Seventy-one subjects completed the self-reported 'Cystic Fibrosis Questionnaire-Revised (CFQ-R + 14)' and a self-report questionnaire about cough suppression, health-related perspectives, and therapy adherence. The status of CF disease was quantified in terms of the percentage of predicted forced expiratory volume in one second (ppFEV1), body mass index (BMI), Pseudomonas aeruginosa, pancreatic status, and CF-related diabetes (CFRD). Additional demographic data for sex, age, graduation, employment, and marital status were assessed. Results CS exists in adult CF and is associated with impaired HRQoL but not the overall CF disease status regarding BMI, ppFEV1, or health-related perspectives. Despite a higher prevalence of cough suppression in women, no effect of sex regarding either outcome measure was observed. Conclusion The results of this study suggest that mental health indicators have an impact on cough suppression.

Abstract There is preliminary evidence that adrenal steroids other than cortisol may be valuable biomarkers for major depressive disorder (MDD). So far, studies have been conducted in adults only, and conclusions are limited, mainly due to small sample sizes. Therefore, the present study assessed whether adrenal steroids serve as biomarkers for adolescent MDD. In 261 depressed adolescents (170 females) treated at a single psychiatric hospital, serum adrenal steroids (progesterone, 17-hydroxyprogesterone, 21-deoxycortisol, 11-deoxycortisol, cortisol, cortisone, deoxycorticosterone, corticosterone) were determined by liquid chromatography-tandem mass spectrometry. Findings were compared to that of an age- and sex-matched reference cohort (N = 255) by nonparametric analysis of variance. Nonparametric receiver operating characteristics (ROC) analyses were conducted to evaluate the diagnostic performance of single steroids and steroid ratios to classify depression status. Sensitivity analyses considered important confounders of adrenal functioning, and ROC results were verified by cross-validation. Compared to the reference cohort, levels of deoxycorticosterone and 21-deoxycortisol were decreased (P

Introduction: Recently, cystic fibrosis transmembrane regulator modulator therapy with elexacaftor/tezacaftor/ivacaftor has become available for children with cystic fibrosis (CF) carrying at least one F508del mutation.Objective: To assess the intermediate term effects of elexacaftor/tezacaftor/ivacaftor in children with cystic fibrosis in a real-world setting.Methods: We performed a retrospective analysis of records of children with cystic fibrosis, who started elexacaftor/tezacaftor/ivacaftor between 8/2020 and 10/2022. Pulmonary function tests, nutritional status, sweat chloride and laboratory data were assessed before, 3 and 6 months after the start of elexacaftor/tezacaftor/ivacaftor respectively.Results: Elexacaftor/tezacaftor/ivacaftor was started in 22 children 6–11 years and in 24 children 12–17 years. Twenty-seven (59%) patients were homozygous for F508del (F/F) and 23 (50%) patients were transitioned from ivacaftor/lumacaftor (IVA/LUM) or tezacaftor/ivacaftor (TEZ/IVA) to elexacaftor/tezacaftor/ivacaftor. Overall, mean sweat chloride concentration decreased by 59.3 mmol/L (95% confidence interval: −65.0 to −53.7 mmol/L, p < 0.0001) under elexacaftor/tezacaftor/ivacaftor. Sweat chloride concentration also decreased significantly after transition from IVA/LUM or TEZ/IVA to elexacaftor/tezacaftor/ivacaftor (−47.8 mmol/l; 95% confidence interval: −57.6 to −37.8 mmol/l, n = 14, p < 0.0001). Sweat chloride reduction was more marked in children with the F/F than in those with the F/MF genotype (69.4 vs 45.9 mmol/L, p < 0.0001). At 3 months follow-up, body-mass-index-z-score increased by 0.31 (95% CI, 0.2–0.42, p < 0.0001) with no further increase at 6 months. BMI-for-age-z-score was more markedly improved in the older group. Overall pulmonary function (percent predicted FEV1) at 3 months follow-up increased by 11.4% (95% CI: 8.0–14.9, p < 0.0001) with no further significant change after 6 months. No significant differences were noted between the age groups. Children with the F/MF genotype had a greater benefit regarding nutritional status and pulmonary function tests than those with the F/F genotype. Adverse events led to elexacaftor/tezacaftor/ivacaftor dose reduction in three cases and a temporary interruption of therapy in four cases.Conclusion: In a real-world setting, elexacaftor/tezacaftor/ivacaftor therapy had beneficial clinical effects and a good safety profile in eligible children with cystic fibrosis comparable to previously published data from controlled clinical trials. The positive impact on pulmonary function tests and nutritional status seen after 3 months of elexacaftor/tezacaftor/ivacaftor therapy was sustained at 6 months follow-up.

IntroductionThe number of children with acute and chronic liver disease is rising. Moreover, liver involvement may be limited to subtle changes in organ texture especially in early childhood and some syndromic conditions, such as ciliopathies. Attenuation imaging coefficient (ATI), shear wave elastography (SWE), and dispersion (SWD) are emerging ultrasound technologies providing data about attenuation, elasticity, and viscosity of liver tissue. This additional and qualitative information has been correlated with certain liver pathologies. However, limited data are available for healthy controls and have mainly been raised in adults.MethodsThis prospective monocentric study was conducted at a university hospital with a specialization in pediatric liver disease and transplantation. Between February and July 2021, 129 children aged 0-17.92 years were recruited. Study participants attended outpatient clinics due to minor illnesses excluding liver or cardiac diseases, acute (febrile) infections or other conditions affecting liver tissue and function. ATI, SWE, and SWD measurements were performed on an Aplio i800 (Canon Medical Systems) with an i8CX1 curved transducer by two different investigators with long-standing experience in pediatric ultrasound according to a standardized protocol.ResultsConsidering multiple potential covariates, we derived percentile charts for all 3 devices relying on the Lambda-Mu-Sigma (LMS) approach. 112 children were considered for further analysis, excluding those with abnormal liver function and under-/overweight (BMI SDS 1.96, respectively). Age range was 0-17.92 years (mean 6.89±0.50SD), 58% were male. The mean duration of the ultrasound examination (basic ultrasound plus SWE, SWD, and ATI) was 6.67±0.22 minutes and it was well tolerated in 83% (n=92) of cases. While ATI was related to age, SWD was found to depend on BMI SDS, and SWE on abdominal wall thickness and sex. ATI correlated with neither SWE nor SWD, but SWE was correlated with SWD.ConclusionsOur study provides norm values and reference charts for ATI, SWE, and SWD considering important covariates including age, sex and, BMI. This may help to implement these promising tools into imaging diagnostics of liver disease and to improve the diagnostic relevance of liver ultrasound. In addition, these noninvasive techniques proved to be time-effective and highly reliable, which make them ideal for application in children.

Increased thermogenesis in brown adipose tissue might have an obesity-reducing effect in humans. In transgenic mice, depletion of genes involved in creatine metabolism results in disrupted thermogenic capacity and altered effects of high-fat feeding on body weight. Data analyses of a sex-stratified genome-wide association study (GWAS) for body mass index (BMI) within the genomic regions of genes of this pathway (CKB, CKMT1B, and GATM) revealed one sex-dimorphic BMI-associated SNP in CKB (rs1136165). The effect size was larger in females than in males. A mutation screen of the coding regions of these three candidate genes in a screening group (192 children and adolescents with severe obesity, 192 female patients with anorexia nervosa, and 192 healthy-lean controls) identified five variants in each, CKB and GATM, and nine variants in the coding sequence of CKMT1B. Non-synonymous variants identified in CKB and CKMT1B were genotyped in an independent confirmation study group (781 families with severe obesity (trios), 320 children and adolescents with severe obesity, and 253 healthy-lean controls). In silico tools predicted mainly benign yet protein-destabilizing potentials. A transmission disequilibrium test in trios with severe obesity indicated an obesity-protective effect of the infrequent allele at rs149544188 located in CKMT1B. Subsequent correlation analyses in 1,479 individuals of the Leipzig Obesity BioBank revealed distinct correlations of CKB with the other two genes in omental visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue (SAT). Furthermore, between-subject comparisons of gene expression levels showed generally higher expressions of all three genes of interest in VAT than in SAT. Future in vitro analyses are needed to assess the functional implications of these findings.

A fair number of epidemiological studies suggest that age at menarche (AAM) is associated with depression, but the reported effect sizes are small, and there is evidence of residual confounding. Moreover, previous Mendelian randomization (MR) studies to avoid inferential problems inherent to epidemiological studies have provided mixed findings. To clarify the causal relationship between age at menarche and broadly defined depression risk, we used 360 genome-wide significantly AAM-related single-nucleotide polymorphisms (SNPs) as instrumental variable and data from the latest GWAS for the broadly defined depression risk on 807,553 individuals (246,363 cases and 561,190 controls). Multiple methods to account for heterogeneity of the instrumental variable (penalized weighted median, MR Lasso, and contamination mixture method), systematic and idiosyncratic pleiotropy (MR RAPS), and horizontal pleiotropy (MR PRESSO and multivariable MR using three methods) were used. Body mass index, education attainment, and total white blood count were considered pleiotropic phenotypes in the multivariable MR analysis. In the univariable [inverse-variance weighted (IVW): OR = 0.96, 95% confidence interval = 0.94–0.98, p = 0.0003] and multivariable MR analysis (IVW: OR = 0.96, 95% confidence interval = 0.94–0.99, p = 0.007), there was a significant causal effect of AAM on depression risk. Thus, the present study supports conclusions from previous epidemiological studies implicating AAM in depression without the pitfalls of residual confounding and reverse causation. Considering the adverse consequences of an earlier AAM on mental health, this finding should foster efforts to address risk factors that promote an earlier AAM.

There is a distinct increase in the prevalence of depression with the onset of puberty. The role of peripubertal testosterone levels in boys in this context is insufficiently understood and may be modulated by a functional polymorphism of the androgen receptor gene (AR), a variable number of CAG repeats. Moreover, there is preliminary evidence that the relationship between testosterone, CAG repeat length, and the severity of depressive symptoms may differ between subclinical and overt depression, but this has neither been studied in a clinical sample of adolescents with depression nor compared between subclinical and overt depression in an adequately powered study. To investigate the relationship between free testosterone, CAG repeat length of the AR, depression status (subclinical vs. overt), and the severity of depressive symptoms, 118 boys treated as in- or daycare patients at a single psychiatric hospital were studied. Of these, 73 boys had at least mild depressive symptoms according to the Beck Depression Inventory-II (BDI-II > 13). Higher-order moderation analysis in the multiple regression framework revealed a constant relationship between free testosterone and depression severity irrespective of the number of CAG repeats in adolescents with a BDI-II score ≤ 13. In adolescents with a BDI-II score > 13, however, there was a significant negative relationship between free testosterone and BDI-II score in patients with

In adults with major depressive disorder (MDD), a dysfunction between the hypothalamus-pituitary-adrenal (HPA) and the hypothalamus-pituitary-thyroid (HPT) axis has been shown, but the interaction of both axes has not yet been studied in adolescent major depressive disorder (MDD). Data from 273 adolescents diagnosed with MDD from two single center cross-sectional studies were used for analysis. Serum levels of thyrotropin (TSH), free levothyroxine (fT4), and cortisol were determined as indicators of basal HPT and HPA axis functioning and compared to that of adolescent controls by t-tests. Quantile regression was employed in the sample of adolescents with MDD to investigate the relationship between both axes in the normal as well as the pathological range of cortisol levels, considering confounders of both axes. In adolescent MDD, cortisol levels and TSH levels were significantly elevated in comparison to controls (p =

Background: In adults, a significant impact of thyroid dysfunction and autoimmunity on health-related quality of life (HRQoL) and mental health is described. However, studies in children and adolescents are sparse, underpowered, and findings are ambiguous.Methods: Data from 759 German children and adolescents affected by thyroid disease [subclinical hypothyroidism: 331; subclinical hyperthyroidism: 276; overt hypothyroidism: 20; overt hyperthyroidism: 28; Hashimoto's thyroiditis (HT): 68; thyroid-peroxidase antibody (TPO)-AB positivity without apparent thyroid dysfunction: 61] and 7,293 healthy controls from a nationwide cross-sectional study (“The German Health Interview and Examination Survey for Children and Adolescents”) were available. Self-assessed HRQoL (KINDL-R) and mental health (SDQ) were compared for each subgroup with healthy controls by analysis of covariance considering questionnaire-specific confounding factors. Thyroid parameters (TSH, fT4, fT3, TPO-AB levels, thyroid volume as well as urinary iodine excretion) were correlated with KINDL-R and SDQ scores employing multiple regression, likewise accounting for confounding factors.Results: The subsample of participants affected by overt hypothyroidism evidenced impaired mental health in comparison to healthy controls, but SDQ scores were within the normal range of normative data. Moreover, in no other subgroup, HRQoL or mental health were affected by thyroid disorders. Also, there was neither a significant relationship between any single biochemical parameter of thyroid function and HRQoL or mental health, nor did the combined thyroid parameters account for a significant proportion of variance in either outcome measure. Importantly, the present study was sufficiently powered to identify even small effects in children and adolescents affected by HT, subclinical hypothyroidism, and hyperthyroidism.Conclusions: In contrast to findings in adults, and especially in HT, there was no significant impairment of HRQoL or mental health in children and adolescents from the general pediatric population affected by thyroid disease. Moreover, mechanisms proposed to explain impaired mental health in thyroid dysfunction in adults do not pertain to children and adolescents in the present study.

Objective: The study was undertaken to determine the prevalence of subclinical and overt thyroid dysfunction as well as thyroid autoimmunity in depressed adolescents in comparison to the general pediatric population. Additionally, the relationship between parameters of thyroid function and Beck Depression Inventory-II (BDI-II) scores was examined., Methods: Parameters of thyroid function (thyrotropin, free thyroxine, thyroid peroxidase antibodies) and prevalence of thyroid dysfunction and autoimmunity were determined in 360 adolescents (11-19 years) with at least mild depression (BDI-II score > 13) between June 2016 and December 2019 and in a representative reference cohort without evidence of impaired mental health from a nationwide survey (German Health Interview and Examination Survey for Children and Adolescents [KiGGS], 2003-2006)., Results: There was a higher prevalence of thyroid peroxidase antibody positivity in depressed adolescents (mean ± SD BDI-II, 30.0 ± 10.4) compared to KiGGS participants (depressed adolescents: 5.8%, 95% CI [3.7-8.6]; odds ratio [OR] 1.9, P = .009, d = 0.36; KiGGS participants: 3.1%, 95% CI [2.5-3.9]). The prevalence of subclinical hypothyroidism was likewise higher in depressed adolescents (9.1%, 95% CI [6.3-12.4] vs KiGGS participants: 2.1%, 95% CI [1.6-2.7]; OR 4.7, P < .001, d = 0.85), but no other types of thyroid dysfunction had a higher prevalence. There was no significant relationship between parameters of thyroid function and BDI-II scores, as examined by multiple regression considering relevant covariates. The positive results were verified in a subsample of patients with a confirmed diagnosis of depression (N = 284)., Conclusions: The prevalence of subclinical hypothyroidism and of thyroid autoimmunity in depressed adolescents is increased. The etiology of these observations is not well understood, and further studies to examine the underlying relationship are required. Moreover, thyroid autoimmunity may constitute an additional risk factor for depression on its own., (© Copyright 2021 Physicians Postgraduate Press, Inc.)