Design of the Growth hormone deficiency and Efficacy of Treatment (GET) score and non-interventional proof of concept study.

BACKGROUND: The adverse effects of growth hormone (GH) deficiency (GHD) in adults (AGHD) on metabolism and health-related quality of life (HRQoL) can be improved with GH substitution. This investigation aimed to design a score summarising the features of GHD and evaluate its ability to measure the effect of GH substitution in AGHD. METHODS: The Growth hormone deficiency and Efficacy of Treatment (GET) score (0-100 points) assessed (weighting): HRQoL (40%), disease-related days off work (10%), bone mineral density (20%), waist circumference (10%), low-density lipoprotein cholesterol (10%) and body fat mass (10%). A prospective, non-interventional, multicentre proof-of-concept study investigated whether the score could distinguish between untreated and GH-treated patients with AGHD. A 10-point difference in GET score during a 2-year study period was expected based on pre-existing knowledge of the effect of GH substitution in AGHD. RESULTS: Of 106 patients eligible for analysis, 22 were untreated GHD controls (9 females, mean ± SD age 52 ± 17 years; 13 males, 57 ± 13 years) and 84 were GH-treated (31 females, age 45 ± 13 years, GH dose 0.30 ± 0.16 mg/day; 53 males, age 49 ± 15 years, GH dose 0.25 ± 0.10 mg/day). Follow-up was 706 ± 258 days in females and 653 ± 242 days in males. The GET score differed between the untreated control and treated groups with a least squares mean difference of + 10.01 ± 4.01 (p = 0.0145). CONCLUSIONS: The GET score appeared to be a suitable integrative instrument to summarise the clinical features of GHD and measure the effects of GH substitution in adults. Exercise capacity and muscle strength/body muscle mass could be included in the GET score. TRIAL REGISTRATION: NCT number: NCT00934063 . Date of registration: 02 July 2009.

Gender-, age- and time-dependent dosing of growth hormone in adults - real-world data from a decade of clinical practice in Germany.

We evaluated treatment patterns and gender-dependent dosing of growth hormone (GH) substitution in adults with GH deficiency (AGHD). Data on GH dose were collected (2003-2013) from 509 GH-treated patients (mean age: 48.9 years; 47% female) enroled in the observational German NordiWin study (NCT01543880). The impact of gender, age, treatment duration and calendar year on GH treatment patterns was evaluated by multiple regression analysis. Mean (SD) baseline GH dose (mg/day) was similar between females (0.25 [0.19] and males (0.24 [0.15]), but increased with treatment duration (at year 10, 0.55 [0.48] and 0.31 [0.09] in females and males, respectively), reflecting patient dose titration. GH dose increased more in females than males during treatment; this was statistically significant in years 2-6 (p < 0.05). Over the 10-year study period, a time trend of an overall estimated GH dose increase by 0.06 mg/day (females) and decrease by 0.07 mg/day (males) was shown; this interaction of gender and calendar year was significant (p < 0.0001). In both genders, overall GH dose decreased with increasing age (p < 0.0001). Our study confirms that females and younger patients require higher GH doses compared with males and older patients.

Development and Psychometric Evaluation of an Instrument Assessing Barriers to Growth Hormone Treatment (BAR-GHT).

Purpose: This paper presents development and validation of a new patient reported outcome measure (PRO), the Barriers to Growth Hormone Therapy (BAR-GHT) in a patient (child/adolescent) and a parent version. The BAR-GHT was developed to measure problems and potential barriers to GHT. Methods: The development and validation of the BAR-GHT was conducted according to the Food and Drug Administration (FDA) Guidance on the development of PROs. Concept elicitation included a literature review and open-ended interviews with young patients, parents, and clinical experts. Qualitative data were analyzed based on grounded theory principles and draft items were rated in terms of their importance and clarity. The instruments underwent psychometric validation in a German clinic-based patient population of children and adolescents who inject themselves and in a parent sample who inject their child. The statistical analysis plan included exploratory factor analysis, reliability, and validity. Results: 29 patients, 22 parents, and 4 clinical experts participated in the concept elicitation, 156 children and adolescents aged 8-18 years and 146 parents completed the validation study. Exploratory factor analysis resulted in six domains: Fear, Public Embarrassment, Annoyance, Daily Routine, Supplies, and Travel. Internal consistencies and test-retest reliabilities of the total score of both the patient version and the parent version were >0.8. Convergent and discriminant validity was demonstrated. Conclusions: The final 19-item BAR-GHT for patients aged 8-18 years and the 16-item version for parents can be considered reliable and valid PROs of barriers to GHT. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03672617. Universal Trial Number (UTN) of the International Clinical Trials Registry Platform (ICTRP, www.who.int): U1111-1210-1036.

European Stroke Facilities Survey: the German and Austrian perspective.

BACKGROUND: The aim of this nested analysis was to identify the major components of stroke centers and other facilities actually available for acute stroke patients in hospitals of Germany and Austria. METHODS: This analysis is part of a much larger European Stroke Facility Survey of 886 hospitals treating stroke patients all over Europe initiated by the European Stroke Initiative. Three levels of stroke care were predefined: comprehensive stroke centers (CSC), primary stroke centers (PSC) and a minimum level required for any hospital ward (AHW) admitting stroke patients. Hospitals providing even less than that were indicated in the 'none' category. RESULTS: The present survey was conducted in 178 (166 and 12) German and Austrian hospitals which returned the questionnaire (41% response rate). They treated a total of 54,257 acute stroke patients per year (25% of all strokes in Germany and Austria), with a mean of 376 patients per year per hospital. 2,168 patients were given recombinant tissue plasminogen activator (4.7%), a proportion much higher than the pan-European average, but strongly dependent on the level of the facility considered (range 7.5-1.3%). Criteria for CSC were met in 13 hospitals (7.3%), for PSC in 15 (8.4%) and for AHW in 85 (47.7%). The minimum level required for AHW was not met in 65 hospitals (36.5%). 15.7% of German and Austrian hospitals provide stroke center facilities at the CSC or PSC level, as compared with 8.5% in Europe. A 24-hour availability of a stroke-trained physician was met by 100% of CSC, 73% of PSC, 85% of AHW and by 62% at the 'none' level of care. At the levels of CSC and PSC, a 100% availability was achieved for multidisciplinary stroke team, stroke-trained nurses, in-house emergency department, physiotherapy and speech therapy within 2 days, 24-hour brain CT and CT or MR angiography, as well as for transesophageal echocardiography and automated 24-hour monitoring of vital parameters. Nearly all these hospitals had training programs, stroke pathways, thrombolysis protocols and prevention procedures in place for the acute care of stroke patients. CONCLUSIONS: This survey shows that the minimum level of care is met in Germany and Austria in 63% of hospitals treating stroke patients, whereas the European average is 48.6%. However, the lack of stroke center coverage should encourage health policy decision makers to further improve the infrastructure for acute stroke care in order to make stroke centers available to every stroke victim.

EEG dipole source localisation of interictal spikes acquired during routine clinical video-EEG monitoring.

OBJECTIVE: We investigated the feasibility of electroencephalography (EEG) dipole source localisation of interictal epileptiform discharges from data acquired during routine clinical inpatient video-EEG monitoring (VEM) and compared a 19-channel 'routine montage' with a 29-channel 'surgical montage' that includes an additional row of 10 inferior temporal electrodes. METHODS: Twenty consecutive patients who had VEM for the presurgical evaluation of medically refractory partial epilepsy were screened. Thirteen of the patients had focal interictal spikes recorded, and in 11 (85%) these were technically satisfactory for source localisation. Fourteen spike foci were analysed as 3 patients had bilateral independent spikes. EEG data was acquired with 29 electrodes including an inferior temporal row (surgical montage). For comparison, the 10 additional electrodes were excluded from analysis (routine montage). Using NEUROSCAN Source 2.0 software, a computed dipole source localisation of averaged spikes was performed utilising a magnetic resonance imaging-based finite element model. Dipole localisation was compared with that of the Comprehensive Epilepsy Program (CEP) evaluation. RESULTS: Using the surgical montage dipole source localisation was consistent with the CEP spike localisation for 13/14 spikes (93%, P<0.005), compared with only 5/14 spikes (36%) using the routine montage. CONCLUSIONS: Data derived from routine clinical inpatient VEM using a routine montage can yield accurate EEG dipole source localisation, but significantly more accurate localisation is obtained using the surgical montage.

EEG dipole source localization of interictal spikes in non-lesional TLE with and without hippocampal sclerosis.

PURPOSE: A subgroup of patients with non-lesional temporal lobe epilepsy (NLTLE) have no evidence of hippocampal sclerosis (HS) on MRI or on histopathology. It is controversial whether this represents a different clinicopathological syndrome from NLTLE with HS, or whether both subgroups represent different ends of the spectrum of mesial TLE. Here the EEG source localization dipoles were compared between NLTLE patients with HS (HS+) and without HS (HS-), and the relationship with post-surgical outcome was investigated. METHODS: EEG dipole source localization of interictal epileptiform spikes recorded during prolonged video-EEG monitoring was performed from 22 consecutive HS+ and 12 HS- NLTLE patients. EEG was acquired using 29 scalp electrodes, including an inferior temporal row. Up to 13 spikes per patient were averaged and sources localized using a boundary element model based on the patients volumetric MRI. RESULTS: 21/34 patients (62%) had dipoles for the interictal spikes localized to the epileptogenic temporal lobe. The site of the intratemporal localization did not differ significantly between the HS+ and HS- patients, with the dipoles localizing to the mesial temporal region in 27% of HS+ and 25% of HS- patients. There was no significant relationship between the localization and orientation of the dipoles and the surgical outcome. CONCLUSION: The dipoles for interictal spikes do not differ between HS+ and HS- patients, suggesting that these subgroups of NLTLE patients do not have distinct cerebral generators.