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Zusammenfassung. Genetische Varianten beeinflussen die Gewichtsregulation und die Entwicklung von Essstörungen. Zunächst haben familienbasierte, sogenannte formalgenetische Studien den erblichen Anteil an der Gewichtsregulation und an der Ätiologie von Essstörungen beleuchtet. In einer Vielzahl von Studien zeigten sich sowohl für die Varianz des Körpergewichts als auch für die Entstehung von Essstörungen Erblichkeitsschätzer (Heritabilitätsraten) von über 50 %. Mit diesem Wissen begab man sich in den 90er-Jahren des letzten Jahrhunderts auf die Suche nach den zugrundeliegenden Genen (genauer: genetischen Varianten), die das Körpergewicht, das Essverhalten oder beide Phänotypen auf Grundlage geteilter Mechanismen beeinflussen. Zunächst wurden Kandidatengenstudien durchgeführt. Dabei untersuchte man auf Grundlage unterschiedlicher, v. a. aber pathophysiologisch plausibler Überlegungen Gene mit hoher Relevanz für die untersuchten Phänotypen. Dieser Ansatz war für Essstörungen nicht sehr erfolgreich, für die Gewichtsregulation konnte eine Handvoll Gene identifiziert werden. Verbunden mit großen methodischen Fortschritten in der genetischen Forschung und v. a. der Etablierung sogenannter genomweiter Assoziationsstudien (GWAS) Anfang der 2000er-Jahre konnten bislang über 1000 Varianten/Genorte detektiert werden, die das Körpergewicht beeinflussen. Für die Essstörung Anorexia nervosa (AN) sind aktuell acht solcher Genorte beschrieben. Diese Ergebnisse, aber auch aktuelle Ansätze zu phänotypübergreifenden Analysen lassen Einblicke in die komplexe Regulation des Körpergewichtes zu und haben zudem unerwartete Pathomechanismen für AN aufgezeigt.

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.

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.

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.

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.

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.

Purpose While observational studies revealed inverse associations between serum vitamin D levels [25(OH)D] and depression, randomized controlled trials (RCT) in children and adolescents are lacking. This RCT examined the effect of an untreated vitamin D deficiency compared to an immediate vitamin D3 supplementation on depression scores in children and adolescents during standard day and in-patient psychiatric treatment. Methods Patients with vitamin D deficiency [25(OH)D ≤ 30 nmol/l] and at least mild depression [Beck Depression Inventory II (BDI-II) > 13] (n = 113) were 1:1 randomized into verum (VG; 2640 IU vitamin D3/d) or placebo group (PG) in a double-blind manner. During the intervention period of 28 days, both groups additionally received treatment as usual. BDI-II scores were assessed as primary outcome, DISYPS-II (Diagnostic System for Mental Disorders in Childhood and Adolescence, Self- and Parent Rating) and serum total 25(OH)D were secondary outcomes. Results At admission, 49.3% of the screened patients (n = 280) had vitamin D deficiency. Although the intervention led to a higher increase of 25(OH)D levels in the VG than in the PG (treatment difference: + 14 ng/ml; 95% CI 4.86–23.77; p = 0.003), the change in BDI-II scores did not differ (+ 1.3; 95% CI − 2.22 to 4.81; p = 0.466). In contrast, DISYPS parental ratings revealed pronounced improvements of depressive symptoms in the VG (− 0.68; 95% CI − 1.23 to − 0.13; p = 0.016). Conclusion Whereas this study failed to show a vitamin D supplementation effect on self-rated depression in adolescent in- or daycare patients, parents reported less depressive symptoms in VG at the end of our study. Future trials should consider clinician-rated depressive symptoms as primary outcome. Trial registration “German Clinical Trials Register” (https://www.drks.de), registration number: DRKS00009758

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 P

OBJECTIVE The aim of this study was to investigate the frequency of newly diagnosed type 1 diabetes without evidence of autoimmunity and the respective frequencies of ketoacidosis in children, adolescents, and young adults during the coronavirus disease 2019 (COVID-19) pandemic in Germany compared with the previous decade. RESEARCH DESIGN AND METHODS Based on data from the German Diabetes Prospective Follow-up Registry (DPV), we compared data from 715 children, adolescents, and young adults, newly diagnosed with type 1 diabetes during the COVID-19 pandemic in Germany between 1 March and 30 June 2020, with data from 5,428 children, adolescents, and young adults of the same periods from 2011 to 2019. Adjusted differences and relative risks (RRs) of negative β-cell autoantibody test results and diabetic ketoacidosis were estimated using multivariable log-binomial regression analysis. An upper noninferiority test (margin 1%) was applied to evaluate whether the autoantibody-negativity rate in 2020 was not higher than that in 2011 to 2019. RESULTS The estimated frequencies of autoantibody negativity in 2020 and 2011–2019 were 6.6% (95% CI 5.1–8.4) and 7.2% (95% CI 6.5–8.0), respectively, with an absolute difference of −0.68% (90% CI −2.07 to 0.71; Pupper noninferiority = 0.023). The increase of the estimated frequency of diabetic ketoacidosis during the COVID-19 pandemic was similar between autoantibody-negative and -positive type 1 diabetes (adjusted RRs 1.28 [95% CI 0.80–2.05] and 1.57 [1.41–1.75], respectively). CONCLUSIONS This study found no evidence that the COVID-19 pandemic leads to a significantly increased number of new cases with autoantibody-negative type 1 diabetes in children, adolescents, and young adults. In addition, autoantibody-negative type 1 diabetes showed no particular susceptibility to ketoacidosis, neither before nor during the pandemic.

Objective To examine the effect of intrathecal application of nusinersen on the respiratory function in terms of vital capacity in pediatric patients with spinal muscular atrophy (SMA). SMA is characterized by on-going muscular atrophy and weakness that lead to respiratory insufficiency. In recent years therapy with nusinersen has been shown to improve motor function in patients with SMA. Methods We retrospectively analyzed data from 12 pediatric patients (aged 4–12 years) with SMA II or III (7 walkers, 5 sitters) treated with nusinersen. We examined forced vital capacity (FVC) at baseline (i.e., before treatment) and 180 and 300 days after initiation of treatment. Results No significant difference in the ranks of FVC of patients with SMA at baseline and day 300 was found and, thus, stable FVCs are implied (n = 6; Z = - 0.105, pexact = 1.000; Medianbaseline = 96.0%, 95%-CI [86.5, 110.5]; Medianday300 = 96.0%, 95%-CI [92.0, 109.5]; s. Table 1). This also applied to the comparison between baseline and day 180 (n = 7; Z = 0.00, pexact = 1.00; Medianbaseline = 93.0%, 95%-CI [85.0, 110.0]; Medianday180 = 91.0%, 95%-CI [72.0, 118.0]) and day 180 and 300 (n = 9; Z = - 0.533, pexact = .652; Medianday180 = 95.0%, 95%-CI [72.0, 118.0]; Medianday300 = 90.0%, 95%-CI [74.0, 105.0]). Conclusion Nusinersen therapy alone may not improve lung function of pediatric patients with SMA type II or III.

While there is a growing body of evidence regarding the behavioral and neurofunctional changes in response to the longitudinal delivery of transcranial direct current stimulation (tDCS), there is limited evidence regarding its structural effects. Therefore, the present study was intended to investigate the effect of repeatedly applied anodal tDCS over the primary somatosensory cortex on the gray matter (GM) and white matter (WM) compartment of the brain. Structural tDCS effects were, moreover, related to effects evidenced by functional imaging and behavioral assessment. tDCS was applied over the course of 5 days in 25 subjects with concomitant assessment of tactile acuity of the right and left index finger as well as imaging at baseline, after the last delivery of tDCS and at follow-up 4 weeks thereafter. Irrespective of the stimulation condition (anodal vs. sham), voxel-based morphometry revealed a behaviorally relevant decrease of GM in the precuneus co-localized with a functional change of its activity. Moreover, there was a decrease in GM of the bilateral lingual gyrus and the right cerebellum. Diffusion tensor imaging analysis showed an increase of fractional anisotropy exclusively in the tDCSanodal condition in the left frontal cortex affecting the final stretch of a somatosensory decision making network comprising the middle and superior frontal gyrus as well as regions adjacent to the genu of the corpus callosum. Thus, this is the first study in humans to identify structural plasticity in the GM compartment and tDCS-specific changes in the WM compartment in response to somatosensory learning.

Transfer learning is an immanent feature of perceptual learning. Yet, despite the increasingly widespread application of transcranial direct current stimulation (tDCS) to study learning, transfer effects in response to tDCS have not been studied. Therefore, the present study investigated the transfer of tactile acuity evoked by repeatedly applied anodal tDCS over the left primary somatosensory cortex (S1) over the course of five days from the dominant (right) to the non-dominant (left) index finger (IF). There was a complete transfer of improvement of the right IF to its contralateral homologue by follow-up four weeks later. Changes in tactile acuity of the left IF in the tDCSanodal condition were accompanied by a significant longitudinal change in functional connectivity between the left S1 and the right secondary somatosensory cortex (S2) assessed at day five of tDCS delivery and four week later. Moreover, we observed a close link between tactile acuity and (changes of) functional connectivity of the right S2 in the tDCSanodal condition identifying the S2 as neural correlate to mediate the transfer of tDCS effects in the somatosensory domain. These findings provide unprecedented evidence of transfer effects evoked by tDCS, implicate the S2 in somatosensory transfer learning and provide evidence in support of models of perceptual learning allocating learning to the reweighting of connections between different levels of processing.