Hydrocortisone dosing in children with classic congenital adrenal hyperplasia: results of the German/Austrian registry.

OBJECTIVE: Treatment of classic congenital adrenal hyperplasia (CAH) is necessary to compensate for glucocorticoid/mineralocorticoid deficiencies and to suppress androgen excess. Hydrocortisone (HC) is preferred in growing children with classic CAH but recommendations regarding dosage/administration are inconsistent. The aim of this study was to evaluate HC dosing in children with CAH in relation to chronological age, sex, and phenotype based on a multicenter CAH registry. DESIGN: The CAH registry was initiated in 1997 by the AQUAPE in Germany. On December 31st 2018, data from 1571 patients were included. METHODS: A custom-made electronic health record software is used at the participating centers. Pseudonymized data are transferred for central analysis. Parameters were selected based on current guidelines. Descriptive analyses and linear regression models were implemented with SAS 9.4. RESULTS: We identified 1288 patients on exclusive treatment with hydrocortisone three times daily (604 boys; median age 7.2 years; 817 salt-wasting phenotype, 471 simple-virilizing phenotype). The mean (lower-upper quartiles) daily HC dose (mg/m² body surface area) was 19.4 (18.9-19.8) for patients <3 months (n = 329), 15.0 (14.6-15.3) for age ≥3-12 months (n = 463), 14.0 (13.7-14.3) for age 1-5.9 years (n = 745), 14.2 (14.0-14.5) for age 6 years to puberty entry (n = 669), and 14.9 (14.6-15.2) during puberty to 18 years (n = 801). Fludrocortisone was administered in 74.1% of patients with a median daily dosage of 88.8 µg. CONCLUSION: Our analyses showed that still a high proportion of children are treated with HC doses higher than recommended. This evaluation provides comprehensive information on nationwide hydrocortisone substitution dosages in children with CAH underlining the benefit of systematic data within a registry to assess daily practice.

Population-based cross-sectional study to assess newborn hearing screening program in central Germany.

OBJECTIVES: Early diagnosis of congenital hearing loss is fundamental to minimize the negative consequences on the speech development. To lower the age at diagnosis and at intervention in hearing impaired children, not only universal newborn hearing screening (NHS) but also tracking is considered essential. The aim of the study was to evaluate the first six years after implementation of the population based newborn hearing screening program in Saxony-Anhalt, one German Federal State. METHODS: The cross-sectional cohort study consisted of three cohort samples. Overall 102,301 infants born between January 2010 and December 2015 were included. NHS protocol was developed as dual target group protocol with two sub-protocols. The screening technique included Transient Evoked Otoacoustic Emissions (TEOAE) and Automated Auditory Brainstem Response (AABR) test. Newborns were assigned to the sub-protocols according to their audiological risk factors. Additionally, to evaluate the quality of NHS and tracking (false-negative screening) we were analysing data from a cohort of hearing impaired children diagnosed up to the age of three years. We calculated quality indicators and compared them with international guidelines. RESULTS: 101,102 (98.8%) infants were screened. The prevalence of bilateral neonatal hearing loss was 2.32 per 1000 newborns. The median age was two days at first screening, three month at diagnostic testing, and four month at intervention onset. 2.6% infants were lost to follow-up. 56.3% had a final diagnosis of bilateral sensorineural hearing loss. The sensitivity of 0.85 (KI 95%: 0.76­0.91) and a specificity of 0.84 (KI 95%: 0.84­0.85) was calculated for the NHS program. CONCLUSIONS: The analysis of benchmarks and outcomes of NHS demonstrated that the program reaches its main goal to identify the hearing impaired newborns in a timely manner.

Outcome after Hypospadias Repair: Evaluation Using the Hypospadias Objective Penile Evaluation Score.

INTRODUCTION: The Hypospadias Objective Penile Evaluation Score (HOPE-Score) is a concise and reproducible way to describe hypospadias severity. We classified boys undergoing primary hypospadias repair to determine the correlation between the HOPE-Score and the severity of hypospadias first and the outcome after surgery second. MATERIALS AND METHODS: Patients who underwent primary hypospadias repair from 2005 to 2014 were identified. An independent physician assessed retrospectively the HOPE-Score, using photographies of the patients before, after primary surgery, and after all necessary surgeries. The correlation between the HOPE-Score and the severity of hypospadias, on the one hand, and the outcome after surgery, on the other hand, were analyzed. RESULTS: The HOPE-Score was assessed preoperatively for 79 boys, postoperatively for 66, and after all necessary surgeries for 21 patients. Mean HOPE-Score reached 30.2 ± 5.9 before surgery, 42.2 ± 6.1 after primary surgery, and 43.7 ± 3.4 after all necessary surgeries. A significant correlation between the HOPE-Score and the severity of hypospadias before surgery was observed. The boys with glanular hypospadias scored significantly higher (36.3 ± 5.4) than those with distal (29.6 ± 4.4) and proximal hypospadias (21.1 ± 3.5). Furthermore, a significant correlation between the HOPE-Score and the outcome after hypospadias repair was observed. Patients who needed no reintervention after primary hypospadias repair scored significantly higher postoperatively (45.1 ± 5.4) than those who needed a second (40.8 ± 4.2) or more than two surgeries (36.9 ± 7.4). CONCLUSION: The HOPE-Score is a good system to assess the severity of hypospadias and the cosmetic outcome after hypospadias repair.

Inactivation of JNK2 as carcinogenic factor in colitis-associated and sporadic colorectal carcinogenesis.

We recently reported that dysregulated c-Jun N-terminal kinases (JNK) activity causes defective cell cycle checkpoint control, inducing neoplastic transformation in a cellular ulcerative colitis (UC) model. In the quiescent chronic phase of UC, p-p54 JNK was down-regulated and p-p46 JNK was up-regulated. Both were up-regulated in the acute phase. Consequently, increased p21WAF1 and γ-H2AX, two JNK-regulated proteins, induced cell cycle arrest. Their down-regulation led to checkpoint override, causing increased proliferation and undetected DNA damage in quiescent chronic phase, all characteristics of tumorigenesis. We investigated expression of p-JNK2, p-JNK1-3, p21WAF1, γ-H2AX and Ki67 by immunohistochemistry in cases of quiescent UC (QUC), active UC (AUC), UC-dysplasia and UC-related colorectal carcinoma (UC-CRC). Comparison was made to normal healthy colorectal mucosa, sporadic adenoma and colorectal carcinoma (CRC), diverticulitis and Crohns disease (CD). We found p-JNK2 up-regulation in AUC and its early down-regulation in UC-CRC and CRC carcinogenesis. With down-regulated p-JNK2, p21WAF1 was also decreased. Ki67 was inversely expressed, showing increased proliferation early in UC-CRC and CRC carcinogenesis. p-JNK1-3 was increased in AUC and QUC. Less increased γ-H2AX in UC-CRC compared to CRC gave evidence that colitis-triggered inflammation masks DNA damage, thus contributing to neoplastic transformation. We hypothesize that JNK-dependent cell cycle arrest is important in AUC, while chronic inflammation causes dysregulated JNK activity in quiescent phase that may contribute to checkpoint override, promoting UC carcinogenesis. We suggest restoring p-JNK2 expression as a novel therapeutic strategy to early prevent the development of UC-related cancer.

Prevalence of uterine myomas in women in Germany: data of an epidemiological study.

PURPOSE: Currently, no reliable data are available concerning the prevalence of uterine myomas in Germany. In this prospective study, we examined the prevalence of myomas in women older than 30 years by means of vaginal ultrasound. METHODS: 2296 women, who consented to the procedure, were examined by means of vaginal ultrasound for the presence of myomas in seven gynaecological outpatient departments in Germany. PREVALENCE: myomas were detected in 41.6 % of all women. Age dependence: With increasing age, the prevalence of uterine myomas rose from 21.3 % (30-35 years) to 62.8 % (46-50 years). Later, the number of myomas decreased again from 56.1 % (51-55 years) to 29.4 % in women older than 55 years. Menarche/BMI: no correlation could be found between the age at first menstrual period or the body mass index and the occurrence of myomas. Parity: since the group of nulliparous women and the group of women with more than four deliveries stand out by increased occurrence of myomas, a non-linear correlation seems to exist, necessitating more in-depth discussion with regard to age dependency. CONCLUSIONS: The results of this study suggest that more than 40 % of women over 30 years of age suffered from myomas and more than 50 % of all women in Germany may develop uterine myomas at some time in their life.

Blood Pressure in a Large Cohort of Children and Adolescents With Classic Adrenal Hyperplasia (CAH) Due to 21-Hydroxylase Deficiency.

BACKGROUND: Data on blood pressure (BP) in children and adolescents with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency are conflicting in the literature. PATIENTS AND METHODS: BP data of n = 716 children and adolescents (aged 3-18 years) from a national CAH database were analyzed. BP data were adjusted for height and compared to contemporary national reference data. A systolic and diastolic BP above the 95th centile was defined as hypertensive. RESULTS: Overall prevalence of hypertension was 12.5%. Prevalence of hypertension was higher in younger children than in adolescents (18.5% vs. 4.9%). Until 8 years of age, fludrocortisone dose/m(2)/day correlated significantly with BP in regression analysis (P < 0.0001). BP correlated significantly with body mass index standard deviation score (BMI-SDS) (P < 0.0001), but not with hydrocortisone dose. In patients with salt-wasting CAH, BMI-SDS and BP were significantly higher compared to patients with simple virilising CAH, P < 0.01. CONCLUSION: Especially young CAH children seem to be at risk for-most likely transient-hypertension, since the prevalence of hypertension decreases with age. In children up to 8 years of age, the used fludrocortisone dose is a significant risk factor for hypertension. Therefore we recommend accurate measurement of BP and careful fludrocortisone dosing in children with CAH.

Therapy monitoring in congenital adrenal hyperplasia by dried blood samples.

Careful monitoring of the therapy is crucial for patients with congenital adrenal hyperplasia (CAH) in order to prevent the effects of increased androgen production as well as life-threatening salt-wasting crisis. The key metabolite, 17α-hydroxyprogesterone (17-OHP) can be detected in serum, saliva or dried blood. In clinical practice there are challenges due to discomfort of venous blood sampling and complicated retrieval of saliva during infancy. Furthermore, the immunoassay method is limited in its specificity due to cross-reactions. In this observational study we prospectively examined over a period of 5 years, 20 patients with CAH due to 21-hydroxylase deficiency using standard immunoassays for serum samples (radioimmunoassay and enzyme immunoassay) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) in dried blood spots. Bland-Altman plots show goodness of agreement between both the methods for the desirable therapeutic concentration range of 17-OHP. LC-MS/MS is characterized by a high accuracy in the therapeutic concentration range of 17-OHP <100 nmol/L (r=0.91). Dried blood samples are convenient and reliable specimen for 17-OHP measured by LC-MS/MS. This method could be used for home monitoring of hydrocortisone replacement therapy both in salt-waster and simple virilizer CAH.

Portable flat-panel detector for low-dose imaging in a pediatric intensive care unit: comparison with an asymmetric film-screen system.

OBJECTIVE: We sought to evaluate the diagnostic performance of a portable indirect flat-panel detector for low-dose imaging as compared with an asymmetric film-screen system in a pediatric intensive care unit. MATERIALS AND METHODS: A total of 120 neonates underwent chest radiographs using a portable flat-panel detector (digital speed 800) and an asymmetric film-screen system (400 speed). Four readers evaluated the detection of 11 anatomic and 5 pathologic landmarks and 4 support devices. Statistical analysis was performed using repeated analysis of variance. The level of statistical significance was P = 0.05. RESULTS: The detection of 4 anatomic/4 pathologic landmarks and 2 support devices was significantly better using the flat-panel detector as compared with the asymmetric film-screen system (P < 0.05). Another 8 anatomic and one pathologic landmarks were detected equally well or slightly better with the flat-panel detector (P > 0.05). CONCLUSIONS: The portable flat-panel detector offers the potential of a 50% dose reduction with equal or significantly better detection of clinically important structures.

The Magdeburg Clinical Studies' Network for pediatric diseases.

New pharmaceutical technologies had created either enthusiastic hope for major improvements in the medical treatment or major doubts on the use of research data and wrongdoing in clinical trials. Clinical investigators have to consider methodological and scientific principles, to stick to ethical rules, national law and international guidelines. With the invention of General Clinical Research Centres the necessary infrastructure in hospitals with well-trained personnel and the availability of laboratory, clinical and supporting service has been created in the US. Taking GCRC as a model to improve the clinical research in pediatrics, a formal collaboration between the Department of Pediatrics and the Institute for Biometry and Medical Informatics was established at the Otto-von-Guericke-University Magdeburg in 2001. Both nation-wide quality assurance programmes in Pediatric Endocrinology and clinical trials according to the principles of good clinical practice ('GCP') were planned and currently performed. Thus with the resources of the Medical faculty and additional project bound finances the necessary infrastructure has been developed.