Epigenetic activation of O-linked ß-N-acetylglucosamine transferase overrides the differentiation blockage in acute leukemia.

BACKGROUND: Overriding the differentiation blockage in acute myeloid leukemia (AML) is the most successful mode-of-action in leukemia therapy - now curing the vast majority of patients with acute promyelocytic leukemia (APL) using all-trans retinoic acid (ATRA)-based regimens. Similar approaches in other leukemia subtypes, such as IDH1/2-mutated AML, are under active investigation. We herein present successful release of the differentiation blockage upon treatment with the natural (-)-Δ9-Tetrahydrocannabinol isomer dronabinol in vitro and in vivo. METHODS: Cellular maturation and differentiation were followed in two patients employing whole genome methylation profiling, proteome analyses, NGS deep sequencing and multispectral imaging flow cytometry. For functional studies lentiviral OGT knock-down in vitro and ex vivo cell models were created to evaluate proliferative, apoptotic and differentiating effects of OGT in acute leukemia. FINDINGS: In here, we provide molecular evidence that dronbinol is capable to override the differentiation blockage of acute leukemia blasts at the state of the leukemia-initiating clone. We further identify the O-linked ß-N-acetyl glucosamine (O-GlcNAc) transferase (OGT) to be crucial in this process. OGT is a master regulator enzyme adding O-GlcNAc to serine or threonine residues in a multitude of target proteins. Aberrant O-GlcNAc modification is implicated in pathologies of metabolic, neurodegenerative and autoimme diseases as well as cancers. We provide evidence that dronabinol induces transcription of OGT via epigenetic hypomethylation of the transcription start site (TSS). A lentiviral OGT-knock out approach proves the central role of OGT exerting antileukemic efficacy via a dual-mechanism of action: High concentrations of dronabinol result in induction of apoptosis, whereas lower concentrations drive cellular maturation. Most intriguingly, overriding of the differentiation blockage of acute leukemia blasts is validated in vivo following two patients treated with dronabinol. INTERPRETATION: In conclusion, we provide evidence for overcoming the differentiation blockage in acute leukemia in subentities beyond promyelocytic and IDH1/2-mutated leukemia and thereby identify O-GlcNAcylation as a novel (drugable) field for future leukemia research. FUNDING: Unrestricted grant support by the IZKF Program of the Medical Faculty Tübingen (MMS) and Brigitte Schlieben-Lange Program as well as the Margarete von Wrangell Program of the Ministry of Science, Research and the Arts, Baden-Württemberg, Germany (KKS) and Athene Program of the excellence initiative University of Tübingen (KKS).

[Long-term experiences with corneal crosslinking in patients with progressive keratoconus at the University Eye Hospital in Tübingen, Germany]. / Langzeiterfahrungen des kornealen Crosslinkings bei Patienten mit progredientem Keratokonus an der Universitäts-Augenklinik Tübingen.

BACKGROUND AND PURPOSE: The corneal collagen crosslinking procedure has been clinically performed worldwide for approximately 20 years. The aim of the study was to analyze the long-term outcomes of corneal crosslinking at the University Eye Hospital in Tübingen. METHODS: In this retrospective study 136 consecutive eyes with progressive keratoconus from 107 patients were included. The observational period was from December 2008 to March 2018. The parameters analyzed were best corrected visual acuity (BCVA) and the keratometry values from elevation maps measured using a Scheimpflug camera. RESULTS: The study population of 107 patients included 96 (90%) male and 11 (10%) female subjects and the mean age was 23 ± 8 years. The mean observation time between corneal collagen crosslinking and the last follow-up examination was 42 ± 29 months. The mean postoperative BCVA showed a significant improvement from baseline at each point of postoperative measurement. The mean astigmatism and the mean Kmax showed a statistically significant reduction in the first 6 postoperative months. The mean thinnest point of the cornea showed a significant reduction in the first 6 months, after which the cornea thickness stabilized. No serious adverse events relating to the treatment were registered. CONCLUSION: Long-term outcomes after corneal collagen crosslinking showed a significant reduction of the keratometry values and the BCVA was significantly higher compared to the preoperative value at all times of observation. In conclusion, corneal collagen crosslinking was shown to be an effective and safe treatment for progressive keratoconus.

Preoperative breast MR Imaging in patients with primary breast cancer has the potential to decrease the rate of repeated surgeries.

PURPOSE: The impact of preoperative MRI on re-excisions and mastectomy rate is discussed controversially in the literature. Aim of this study was to evaluate the effect of preoperative breast MRI on the surgical procedure and rate of repeated surgeries. MATERIAL AND METHODS: A total of 991 consecutive patients in the years 2009 and 2010 with 1036 primary breast cancers were retrospectively analyzed. Sixty percent (599 patients with 626 cancers) received preoperative breast MRI. Planned surgical procedures before and after MRI and numbers of repeated surgeries in patients with (MR+ ) and without preoperative MRI (MR-) were compared. RESULTS: The result of preoperative MRI changed the surgical procedure in 25% (157/626) of the cases. In 81% (127/157), MRI was beneficial for the patients, as otherwise occult carcinomas were removed (n=122) or further biopsy could be prevented (n=5). Mastectomy rates did not differ between MR+ and MR- group (39% vs. 39%). On multiple regression analysis, the MR+ group had a lower chance for repeated surgery (p<0.05). CONCLUSION: Preoperative MRI could lower the chance for repeated surgery in patients with primary breast cancer. The rate of mastectomy did not differ between patients undergoing preoperative MRI and those who did not.

Aortic Elongation and Stanford B Dissection: The Tübingen Aortic Pathoanatomy (TAIPAN) Project.

OBJECTIVE/BACKGROUND: Aortic elongation has not yet been considered as a potential risk factor for Stanford type B dissection (TBD). The role of both aortic elongation and dilatation in patients with TBD was evaluated. METHODS: The aortic morphology of a healthy control group (n = 236) and patients with TBD (n = 96) was retrospectively examined using three dimensional computed tomography imaging. Curved multiplanar reformats were used to examine aortic diameters at defined landmarks and aortic segment lengths. RESULTS: Diameters at all landmarks were significantly larger in the TBD group. The greatest diameter difference (56%) was measured in dissected descending aortas (p < .001). The segment with the most considerable difference between the study groups with regard to elongation was the non-dissected aortic arch of patients with TBD (36%; p < .001). Elongation in the aortic arch was accompanied by a diameter increase of 21% (p < .001). In receiver-operating curve analysis, the area under the curve was .85 for the diameter and .86 for the length of the aortic arch. CONCLUSIONS: In addition to dilatation, aortic arch elongation is associated with the development of TBD. The diameter and length of the non-dissected aortic arch may be predictive for TBD and may possibly be used for risk assessment in the future. This study provides the basis for further prospective evaluation of these parameters.

Repeated surgeries in invasive lobular breast cancer with preoperative MRI: Role of additional carcinoma in situ and background parenchymal enhancement.

OBJECTIVES: Analysing the influence of additional carcinoma in situ (CIS) and background parenchymal enhancement (BPE) in preoperative MRI on repeated surgeries in patients with invasive lobular carcinoma (ILC) of the breast. METHODS: Retrospective analysis of 106 patients (mean age 58.6±9.9years) with 108 ILC. Preoperative tumour size as assessed by MRI, mammography and sonography was recorded and compared to histopathology. In contrast-enhanced MRI, the degree of BPE was categorised by two readers. The influence of additionally detected CIS and BPE on the rate of repeated surgeries was analysed. RESULTS: Additional CIS was present in 45.4% of the cases (49/108). The degree of BPE was minimal or mild in 80% of the cases and moderate or marked in 20% of the cases. In 17 cases (15.7%) at least one repeated surgery was performed. In n=15 of these cases, repeated surgery was performed after BCT (n=9 re-excisions, n=6 conversions to mastectomy), in n=2 cases after initial mastectomy. The initial surgical procedure (p=0.008) and additional CIS (p=0.046) significantly influenced the rate of repeated surgeries, while tumour size, patient age and BPE did not (p=ns). CONCLUSIONS: Additional CIS was associated with a higher rate of repeated surgeries, whereas BPE had no influence.

The potential of eHealth in otorhinolaryngology-head and neck surgery: patients' perspectives.

The use of modern information and communication technologies (ICT) in daily life has significantly increased during the last several years. These essential online technologies have also found their way into the healthcare system. The use of modern ICT for health reasons can be summarized by the term 'eHealth'. Despite the potential importance of eHealth in the field of otorhinolaryngology (ORL), there is little understanding of patients' attitudes towards the deeper integration of these technologies into intersectoral care. The aim of this study was to gain a better understanding of patients' attitudes towards the use of modern ICT for intersectoral communication and information transfer in the field of ORL. Therefore, a structured interview was developed by an interdisciplinary team of otorhinolaryngologists, public health researchers, and information technology (IT) specialists. Overall, 211 ORL patients were interviewed at the Department of Otorhinolaryngology-Head and Neck Surgery, Tuebingen University Hospital, Germany, and 203 of these patients completed the interview. This study revealed ORL patients' perspectives on the potential of eHealth, especially for appointment scheduling, appointment reminders, and intersectoral communication of personal medical information. Furthermore, this study provides evidence that data security and the impacts of eHealth on the physician-patient relationship and on treatment quality warrant special attention in future research.

Prevalence of type I sensitization to alpha-gal in forest service employees and hunters.

BACKGROUND: The production of IgE molecules specific to the carbohydrate galactose-α-1,3-galactose (alpha-gal) is known to induce delayed anaphylaxis against mammalian meat. Tick bites constitute the primary sensitization source, as ticks transfer alpha-gal in their saliva to a host during a bite. The reported prevalence of alpha-gal-specific IgE (alpha-gal-sIgE) positivity varies between different populations from diverse geographic regions. OBJECTIVE: To investigate the prevalence of alpha-gal-sIgE positivity in a population of forest service employees who are highly exposed to ticks in comparison with a residential population and a historic sample. METHODS: A cross-sectional study evaluating 300 forest service employees and hunters from southwest Germany was performed. Alpha-gal-sIgE levels were assessed by ImmunoCAP assay. The prevalence of alpha-gal-sIgE-positive individuals was compared with a matched cohort composed of a residential population and blood samples from forest service employees collected 15 years ago. RESULTS: In the study population, the prevalence of alpha-gal-sIgE-positive (≥0.10 kUA /L) individuals was 35.0%, whereas the prevalence of individuals with alpha-gal-sIgE levels ≥0.35 kUA /L was 19.3%. Alpha-gal-sIgE positivity was associated with total IgE levels and recent tick bites. Mammalian meat-induced delayed anaphylaxis was found in 8.6% of the participants with alpha-gal-sIgE levels ≥0.35 kUA /L. For forest service employees and hunters, the odds ratio for alpha-gal-sIgE positivity was 2.48 compared to the residential population. The prevalence of alpha-gal-sIgE positivity in the current and historic cohort was comparable. CONCLUSION: Forest service employees and hunters compose a population with a high prevalence of alpha-gal-sIgE positivity and carry a considerable risk of red meat allergy.

Undescended testis? How best to teach the physical examination.

BACKGROUND: Undescended testis in boys is common. Guidelines recommend surgical treatment between the ages of 6 months and 2 years; nevertheless, orchidopexy is frequently performed at later ages. One reason is the belated diagnosis due to a perceived difficulty in the physical examination (PE) and correct localization of the testis. OBJECTIVES: We aimed to find an effective method for teaching the physical examination of the testis in a child. STUDY DESIGN: An interdisciplinary team developed teaching sessions, including an educational video and a simulator. Medical students (n = 133) were randomized into three groups: self-study only, video, and video and simulator. The sessions were carried out and quantitative feedback was collected from the teachers and students. The learning achievements of the different groups were assessed with an objective structured clinical examination (OSCE). The differences in mean OSCE results between all three groups were tested using one-way analysis of variance (ANOVA). For multiple pairwise comparisons, a closed testing procedure was performed using unpaired t-tests. RESULTS: The self-study only group acquired the poorest results in the OSCE, with a mean score of 5.1 out of 10. The video-only-group reached a mean of 6.7, and the video-and-simulator group performed best with a mean score of 8.5. The differences between all three groups were found to be statistically significant, with P = 0.007. The attached figure illustrates this data. If analyzed in pairs, this difference was particularly apparent between the groups self-study only vs video and simulator, with P = 0.002. Qualitative feedback revealed doubtful effectiveness for educational videos, but positive reactions to training on a simulator. DISCUSSION: The poor results of the self-study-only group were in accordance with the literature, where textbook learning was found not to increase OSCE results. The effectiveness of video tutorials remains doubtful; studies focusing on this teaching method are divergent and the present students' feedback supports this data. The effective teaching with the simulator has been proven for other skills (i.e. ultrasound skills). The analyzed cohort for this study was small, and the study should be repeated at different institutions and with larger numbers of students to assure generalizability. CONCLUSIONS: Low-fidelity pediatric simulators with palpable testis are available and are able to improve examining skills in medical students. We hope the presented study inspires medical educators in their teaching of the PE of the pediatric testis.

[Treatment of proximal humeral fractures in Germany: Influence of the level of hospital care and the frequency of treatment]. / Behandlung proximaler Humerusfrakturen in Deutschland: Einfluss von Krankenhausversorgungsstufe und Behandlungsfrequenz.

BACKGROUND: Various treatment options exist for displaced proximal humeral fractures. The impact of the level of hospital care and frequency of treatment on current treatment regimens in Germany was analyzed. MATERIAL AND METHODS: A total of 576 hospitals were included. The survey covered questions on frequency, diagnostics, classification, therapy, complications, and clinical scenarios. RESULTS: In all, 48% of the hospitals returned the questionnaire: 73% treat more than 60% of the fractures surgically, mainly with angle-stable implants. The angle-stable plate is the treatment of choice for young patients, but older patients are treated using other treatment options. Problems and complications included malreduction, secondary displacement, screw perforation, avascular necrosis, and impingement. According to treatment indication, implant choice, and common complications, no significant differences between the level of hospital care and frequency of treatment were observed. CONCLUSION: Independent of the level of hospital care and frequency of treatment, there is a trend for head-preserving angular-stable surgery with a homogenous level of treatment in Germany.

Adult height and epigenotype in children with Silver-Russell syndrome treated with GH.

AIMS: To compare adult heights of GH-treated and GH-untreated patients with Silver-Russell syndrome (SRS) who were epigenotyped. METHODS: This was a nonrandomized retrospective study with matched controls at a single center. Molecular analysis of 32 out of 37 GH-treated patients (16 females) revealed IGF2-H19 epimutations in 12 and maternal uniparental disomy of chromosome 7 (matUPD7) in 5 patients; 15 were negative. At start of GH, mean age was 7.2 years and mean height -3.34 standard deviation score (SDS). Mean GH dose used was 51 µg/kg·day, mean duration of therapy was 5.6 years. Puberty was blocked by GnRH analogs in 16 patients. The untreated group comprised 13 individuals (5 females, mean age 6.8 years and mean height -3.34 SDS). End points were adult height and overall height gain. RESULTS: GH-treated patients reached an adult height of -2.12 ± 0.98 SDS gaining 1.22 SDS in comparison to baseline. Adult height SDS of the untreated was -3.13 ± 1.37 SDS. The matched treated patients were significantly taller than their untreated counterparts. Outcome was dependent on height at start of GH and duration of therapy. Height gain was highest in the shortest patients. CONCLUSIONS: GH improved adult height in SRS to a comparable degree as reported in nonsyndromic SGA children. A trend toward a better outcome in matUPD7 needs confirmation in larger cohorts.

Difference in dose area product between analog image intensifier and digital flat panel detector in peripheral angiography and the effect of BMI.

PURPOSE: Comparison of dose area products (DAP) in diagnostic angiography procedures between an image intensifier (II) and a flat panel detector (FPD) angiography system and the evaluation of DAP/body mass index (BMI) dependency. MATERIALS AND METHODS: An image intensifier system or a flat panel detector system was used to perform 571 diagnostic angiographies (n = 328 and n = 243, respectively) of 5 different types: peripheral arterial, venous, single leg, abdominal and upper extremity. The results were retrospectively analyzed. The DAP, fluoroscopy time (t) and the number of series of the respective interventions as calculated by the respective machines was compared for all interventions and for the respective subtypes and machines. The BMI dependency was calculated separately for both machines for all interventions by subdividing the patients into 6 BMI classes defined by the WHO. RESULTS: The average DAP for all diagnostic interventions was 1958.9 cGy×cm2 (t = 384.6 s, n = 7.85 series) for the II and 2927.4 cGy×cm2 (t = 267.4 s, n = 7.02 series) for the FPD. Group-dependent differences ranged between + 21 and + 252 % when using the FPD system. After time standardization, the respective increases were found to be 120 % for the FPD system. The DAPs increased considerably in patients with higher BMIs (766.7 cGy × cm2 - 6892.6 cGy × cm2, II machine, 950.5 cGy × cm2 - 12 487.7 cGy × cm2, FPD machine) with a greater DAP gain seen for the FPD. The average duration of the interventions was higher using the II machine. CONCLUSION: The use of an FPD system led to higher DAP values compared to the II system in diagnostic angiographic procedures. In addition, increased BMI values led to higher DAPs, especially for the FPD machine. However, the average fluoroscopy times were shorter.

Impact of New Shift Models for Doctors Working at a German University Hospital for Gynaecology and Obstetrics Four Years After Implementation. Can They Meet the European Working Time Directive Without Increasing Costs?

Background: The impact of the European Working Time Directive and subsequent collective wage agreements for doctors from 2006 onwards were substantial. So far, no systematic evaluation of their application in Germany has been performed. We evaluated the impact four years after implementation of new shift models in a University Hospital for Gynaecology and Obstetrics (UHGO). Methods: A new shift model was created together with doctors of Tübingen UHOG in 2007 and implemented in 2008. Documentation of working hours has hence been done electronically. Adherence to the average weekly working time limit (AWTL) and the maximum of 10 h daily working time (10 h-dwt) was evaluated, as well as staffing costs in relation to case-weight points gathered within the German DRG (diagnosis related groups) System. Results: Staff increased from a mean of 44.7 full time equivalent (FTE) doctors in 2007 to 52.5 FTE in 2009, 50.8 in 2010, and 54.5 in 2011. There was no statistically significant difference of the monthly staff expenditures per case-weight between the years 2009 or 2010 vs. 2007. 2011, however, was significantly more expensive than 2007 (p = 0.02). The internal control group (five other departments of the university hospital) did not show an increase during the same period. AWTL were respected by 90, 96, and 98 % in 2009, 2010, and 2011, respectively. Of all shifts 10 h-dwt was exceeded by 7.4 % in 2009, 1.3 % in 2010, and 2.6 % in 2011, with significant differences between 2009 and both, 2010 and 2011 (p < 0.001), and between 2010 and 2011 (p = 0.02). Discussion: AWTL and 10 h-dwt could be continuously respected quite well after implementation of the new shift model without increasing the cost/earnings ratio for the first two years. However, in 2011 the ratio increased significantly (p = 0.02).

[A new working shift model for anesthesiologists: an analysis 3 years after implementation]. / Neues Dienstzeitenmodell für Ärzte in der Anästhesie : Eine Analyse 3 Jahre nach Implementierung.

OBJECTIVE: The aim of this study was to assess the efficacy, appropriateness and cost-effectiveness of a new working shift model for anesthesiologists complying with the European working time directive (EWTD) at the University Hospital of Tübingen (UKT), Germany 3 years after implementation BACKGROUND: Applying the standards of the EWTD is challenging for university hospitals as doctors must comply with the challenge of combining patient care, research and teaching. So far there have been no data available for German university hospitals on how these requirements can be met. As the department of anesthesiology is also a service-providing department it is essential not to increase staffing costs with a new shift model. METHODS: In 2007 a new working shift model for the department of anesthesiology was designed and introduced in 2008. Shift planning and documentation of working hours were implemented electronically. The calculated number of doctors to run this model was 87.6 full time equivalents (FTE). For 2009 and 2010 the compliance with the EWTD parameters was checked for 1) average weekly working time limit (AWWTL) and 2) compliance to the maximum daily working time limit of 10 h (10 h DWTL). Furthermore, staffing costs for doctors in 2010 were compared to 2007. To check for the time spent in patient care the period of anesthetic attendance (PAA) was chosen, i.e. the total time of patient contact by anesthesiology staff. Data were analyzed descriptively for AWWTL and for 10 h DWTL. FTE, staff costs and PAA were evaluated by one-way ANOVA. RESULTS: The new shift model allowed 84.4 % of all doctors to comply with the individual AWWT limits of 54 h and 48 h in 2009 (81/96) and 76.0 % in 2010 (79/104). In 2009 61.5 % of anesthesiologists voted for opt-out (59/96) and 53.8 % did so in 2010 (56/104). The 10 h DWTL was respected by 84.0 % in 2009 and by 85.9 % in 2010. The mean number of anesthesiologists rose significantly from 78.4 FTE in 2007 to 82.5 FTE in 2009 and 84.6 FTE in 2010 (p < 0.001 for 2010 vs. 2007, p = 0.004 for 2009 vs. 2007 and was not significant for 2010 vs. 2009). Staff costs per FTE increased from 7,524.79 /month to 7,800.66 /month and 7,966.11 /month in 2007, 2009 and 2010, respectively with the differences being non-significant. The PAA increased significantly from a mean of 6,124 h/month in 2007 to 6,581 h/month in 2009 and 6,872 h/month in 2010 (p < 0.001 for 2010 vs. 2007, whereas 2009 vs. 2007 and 2010 vs. 2009 were not significant). Thus, labour costs increased from 96.59 /h PAA in 2007 to 98.53 /h in both 2009 and 2010, the differences being not significant. CONCLUSIONS: The newly designed shift model allowed a fair compliance with the EWTD in respect to AWTL and 10 h DWTL, although the calculated number of doctors to run the shift model could not be met in 2009 and 2010. Violations of the 10 h DWT limits were stable in 2009 and 2010; however the number of doctors exceeding the AWWT limits appeared to increase. The compliance with opt-out decreased from 2009 to 2010 and a high proportion of AWWTL violations resulted from the group of non-opt-out voters. The staff costs per hour PAA after implementation of the new shift model did not differ significantly from the year before although staffing costs increased by 7.2 % between 2007 and 2010. Costs increased by 162,454 /year for all PAA hours in 2010. Further evaluation of staff satisfaction with the new shift models is needed and already under way.

[Glaucoma screening by means of pupil campimetry]. / Glaukomerkennung mittels der Pupillenkampimetrie.

BACKGROUND: The aim of the study was to find out if pupillographic assessment of the visual field by means of pupil campimetry can identify glaucomatous visual field defects and as such be used for glaucoma screening purposes. PATIENTS AND METHODS: 20 patients with open angle glaucoma and 30 healthy persons were examined by means of pupil campimetry. All glaucoma patients had a glaucomatous visual field defect in at least one eye. The stimulus pattern consisted of 17 white-light stimuli which were presented within the 30° visual field, particularly in the Bjerrum region. The stimulus diameter was 6°. Each stimulus was presented for 200 ms and the interval between the stimuli was 1800 ms. Three stimulus intensities (16.4 cd/m2; 27.1 cd/m2 and 40.5 cd/m2) were tested. The individual pupil light reaction (PLR) amplitudes at all examined locations in the visual field, their sums and partial sums were compared between both groups by the two-sided two-sample t test. The diagnostic performance of the method in glaucoma diagnosis was evaluated by ROC curves (receiver operating characteristics). RESULTS: The average PLR at all locations in the visual field was reduced in glaucoma patients compared to healthy persons. The sums of the PLR were reduced in glaucoma patients as well. Significant differences in the PLR were found especially in the central and paracentral visual fields. The best AUC values (area under the curve) were reached with the highest stimulus intensity, the highest AUC value overall was 0.769. CONCLUSION: Although the difference in PLR between glaucoma patients and the control group was significant, the reached AUC values fell short of being ideal for screening purposes. A surprising finding was that the most central pupil response was reduced by the same amount as that in the Bjerrum region.

Variants of the FTO gene in obese children and their impact on body composition and metabolism before and after lifestyle intervention.

OBJECTIVE: To investigate the impact of variants of the FTO gene (rs1421085, rs17817449, rs9939609) in obese children before and after lifestyle intervention. DESIGN: Longitudinal, clinical intervention study with an increase in physical activity, and nutritional recommendations based on the 'Optimized Mixed Diet for German Children and Adolescents' (Research Institute of Child Nutrition, Germany). STUDY POPULATION: 75 overweight children (40 male, mean BMI 30.4±5.5 kg/m², mean age 12.6±2.6 years). MEASUREMENTS: Genotyping by means of a TaqMan SNP genotyping assay. Lean and fat mass were determined by means of DXA. RESULTS: For the whole study population, the 6-month lifestyle intervention resulted in a significant improvement (before intervention minus time point 6 months; mean±SD) in BMI-SDS (0.10±0.17, p<0.001), HOMA (1.41±3.19, p<0.001) and relative fat-mass-SDS (0.09±0.23, p=0.005). Before and after lifestyle intervention, there was no significant difference between heterozygote (n=52) and homozygote (n=21) carriers of the FTO gene in terms of BMI, body composition, and the metabolic profile (Insulin, HOMA, lipids, liver function tests). CONCLUSION: Variants in the FTO gene are common in obese children but have no impact on body composition and metabolism before and after lifestyle intervention.

[Stereometric parameters of the optic disc. Comparison between a simultaneous non-mydriatic stereoscopic fundus camera (KOWA WX 3D) and the Heidelberg scanning laser ophthalmoscope (HRT IIII)]. / Stereometrische Parameter der Papillentopographie. Vergleich einer simultan-stereoskopischen Non-Mydriasis-Funduskamera (KOWA WX 3D) mit dem Heidelberg Retina Tomograph (HRT III).

BACKGROUND: The Heidelberg retina tomograph (HRTIII, Heidelberg Engineering, Germany) in conjunction with the Moorfields regression analysis (MRA) allows monitoring for the progression of early damage to the optic nerve suspicious of early stage glaucoma. The confocal scanning laser ophthalmoscope provides clinicians with an objective and reproducible analysis of morphological parameters of the optic disc. Margins of the optic disc are approximated with a contour line to calculate the stereometric parameters leading to interobserver and intraobserver variability of the MRA. New devices enabling 3D fundus photography might be an alternative to the established HRT. It was the goal of this study to compare the methods by assessing the differences in the topographic parameters obtained by the HRT and the Kowa nonmyd WX 3D (2D/3D non-mydriatic retinal camera, Kowa, Japan) in a representative sample. METHODS: This retrospective study included 45 eyes of normal patients, 40 eyes of patients with macropapillae and 45 eyes of glaucoma patients. Each patient underwent an HRT examination and fundus photography with the Kowa nonmyd WX 3D on the same day. Excluded from the study were eyes with hazy media (cornea, lens, vitreous) or refractive anomalies higher than >4 dpt or astigmatisms >2 dpt. Eyes with previous refractive surgery history or other retinal diseases affecting the optic nerve were also excluded from the study. Bland-Altman plots were used for statistical evaluation. Distribution of parameters was described by 95% confidence intervals (CI). RESULTS: In normal eyes (n=45) a mean difference in the disc area of 0.33 mm(2) was found (95 % confidence interval CI: 0.22-0.43), in the cup-disc ratio (CDR) of 0.02 (95% CI: -0.06-0.14), in the cup volume of 0.03 mm(3) (95% CI: -0.04-0.01), in the rim volume of 0.04 mm(3) (95%-CI: -0.04-0.13) and in the maximum cup depth of 0.28 mm (95 %-CI: 0.34-0.23). All differences, except for the rim volume, were statistically significant (p<0.05). Patients exhibiting a macropapilla (n=40) displayed a mean difference of 0.03 mm(2) (95 % CI: -0.18-0.11) for the disc area, a difference in CDR of 0.09 (95% CI: -0.05-0.13), a difference in maximum cup depth of 0.28 mm (95% CI: 0.23-0.34) and a cup volume of 0.14 mm(3) (95%-CI: 0.10-0.18). In addition, there were no significant differences in rim volume (difference: -0.02 mm(3), 95% CI: -0.07-0.12) or in disc area. In glaucomatous eyes (n=45), the mean difference for cup area was 0.33 mm(2) (95% CI: 0.22-0.43), an area of 0.09 mm(2) (95% CI: 0.06-0.13) for the CDR, -0.03 mm(3) (95 % CI: -0.09-0.02) for the cup volume and 0.08 mm(3) (95% CI: 0.03-0.13) for the rim volume. Mean maximum cup depth difference was 0.25 mm (95% CI: 0.20-0.31). Mean differences in CDR, maximum cup depth and cup area were all statistically significant. The mean differences did not exceed the interobserver and intraobserver variability found in HRT measurements of other studies. CONCLUSIONS: To the best of our knowledge this study is the first comparing optic disc parameters of HRT and 3D photography. Mean differences in stereometric parameters did not exceed the known interobserver and intraobserver variability. The combination of non-mydriatic fundus photography and optic disc analysis is a very attractive and time-saving method. However, before progression of early glaucoma can be monitored or suspected glaucoma can be appraised over longer time periods, further studies are needed to clarify test and retest variability.

Auxology-based cut-off values for biochemical testing of GH secretion in childhood.

OBJECTIVE: The diagnosis of GH deficiency (GHD) in childhood requires GH tests with arbitrary cut-offs. We aimed to define GH cut-offs based on auxology. DESIGN: From a total of 349 children diagnosed with GHD between 1985 and 2005 at our hospital, we excluded all children who had additional characteristics likely to interfere with growth velocity. Age at start of therapy was defined as 4 to 8/9 years (girls/boys). Auxological inclusion criteria were pathological growth velocity, height at start of therapy >1.5 SD below the target, and efficient catch-up growth during GH therapy. Basal IGF-I/IGFBP-3, GH response to arginine and spontaneous GH secretion at night had been measured by the same polyclonal RIA. The reference was a group of 108 normally growing age-matched children with Turner syndrome or born small for gestational age tested during the same time period. RESULTS: We identified 52 children with GHD who fulfilled the inclusion criteria. ROC analysis showed the best diagnostic accuracy at a peak GH cut-off for arginine of 6.6 µg/L (sensitivity, 84.3%; specificity, 75.5%; AUC=0.83) and at a peak GH cut-off during spontaneous secretion at night of 7.3 µg/L (sensitivity, 96.8%; specificity, 82.4%; AUC=0.93). Our arbitrarily defined GH cut-offs had been higher. Children diagnosed with GHD in the past with GH test values above the new cut-offs were less responsive to GH therapy (P=0.007). CONCLUSIONS: Here we provide a new rational approach which allows the substitution of arbitrarily defined GH cut-offs by those based on auxology.

[Assessing the quality of quality indicators]. / Zur Qualität von Qualitätsindikatoren.

Quality in healthcare is not directly observable and measurable. Quality indicators serve as a tool for operationalizing quality of care. Different quality measures are required depending on the purpose, context, and audience concerned. The methodological quality of the indicators themselves has to be critically assessed. Various quality requirements for indicators have been published and can be described based on the steps of the developmental process. Importance, scientific acceptability, usability, and feasibility are reported as basic criteria for assessment. The QUALIFY instrument offers a standardized approach for assessing quality indicators and reflects best current practice. Measuring quality through indicators is no end in itself. The effect of measurement on motivating quality improvement must be evaluated in future studies.