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This paper investigates least squares spectral analysis as a tool to analyze non-stationary signals from pass-by noise measurements in water. The spectral analysis involves successive least squares fitting of a finite Fourier series to approximate the observation in a piecewise manner. The least squares spectral analysis is used to search the signals for first- and second-order periodicity as well as the presence of fundamental periodicity. A first-order analysis reveals line components in the signals, whereas a second-order analysis reveals periodic amplitude modulations. Analysis with a higher-order finite Fourier series reveals harmonic structures in the signals. The main contribution of this paper is the model of a magnitude-squared cosine wave which can be used to analyze second-order periodicity. The developed short-time least squares spectral analysis is illustrated on noise radiated from a rigid inflatable boat in shallow water.

BackgroundDiagnosing growth hormone deficiency (GHD) can be challenging; hence, prediction models on growth outcome from growth hormone (GH) treatment have shown to be useful. We aim to compare the accuracy of the more readily available KIGS (Pfizer International Growth Study) prediction model to the previously clinically validated Gothenburg model.MethodsPrepubertal children with GHD who started GH treatment at Queen Silvia Children’s Hospital between 2004 and 2016 were considered for the study. Exclusion criteria were short stature due to syndrome, chronic disease, oncology disease, or known bad adherence. Growth predictions were made according to the Gothenburg model and the KIGS model. Growth data from birth until one year after start of GH treatment were collected from medical charts. Predicted height and observed height were then compared. ResultsA total of 123 children, 47 girls (38%) and 76 boys (62%) were included, with a mean age of 5.71 (±1.81 SD) years at start of GH treatment. The Pearson correlation of predicted first-year growth versus growth outcome were r = 0.990 for the Gothenburg model and r = 0.991 for the KIGS model. Studentized residuals were 0.10 ± 0.81 SD and 0.03 ± 0.96 SD, respectively, for the models. The comparison between the two models showed r = 0.995.ConclusionThe Gothenburg model and the KIGS model are equally accurate at predicting height outcome from GH treatment for our study cohort. We therefore promote the use of either model in clinical settings.

Context Children born prematurely have been treated with growth hormone (GH), and a significant improvement in height during the first years of treatment has been described. Objective To evaluate the influence of prematurity on near-adult height (NAH) after GH treatment. Design KIGS (Pfizer International Growth Database) was queried for children born preterm treated with GH. Setting KIGS database. Patients A total of 586 children short in stature born preterm with various GH status and with available gestational age (GA), birth weight, and NAH, all treated with GH. Intervention GH treatment. Main Outcome Measure NAH. Results Values were expressed as median. From the 586 children included, 482 born appropriate for GA (AGA; median age 8.26 years) and 104 born small for gestational age (SGA) (median age 8.54 years); 66.6% of preterm AGA had GH peak Conclusion GH treatment resulted in significant improvement in height in children born preterm, particularly during prepubertal years and for those with GH deficiency. The degree of prematurity did not influence the growth response.

Background/Aims: To compare racial/ethnic proportions of subjects receiving growth hormone (GH) treatment to the expected proportions, and secondarily, to assess racial/ethnic differences in subject characteristics at GH treatment initiation. Methods: Race/ethnicity-based expected frequencies of height 2 test. Characteristics of white and black subjects at GH treatment initiation were presented as medians and compared by the Wilcoxon rank sum test (significant p < 0.01). Results: White subjects exceeded the expected frequency (63%) for all indications (83%) and each separately, ranging from 73% for congenital GH deficiency (GHD) to 85% for idiopathic short stature (p < 0.001). Compared to white subjects, black subjects treated for idiopathic GHD had greater height deficits relative both to the population (–2.97 vs. –2.56 SD) and to their mid-parental heights (–2.47 vs. –1.89 SD), lower stimulated GH peak levels (4.9 vs. 6.0 ng/mL), and lower birth weights (–0.86 vs. –0.48 SD). Black subjects with congenital GHD had lower stimulated GH peaks (2.1 vs. 3.2 ng/mL) and started GH treatment at younger ages (2.9 vs. 4.8 years), while those with acquired GHD had lower birth weights (–1.12 vs. –0.08 SD). Male predominance did not differ by race for any or all indications. Conclusion: Overrepresentation of white children among those receiving GH treatment in the US KIGS registry reflects racial/ethnic treatment biases, not just differences in growth rates.

__Abstract__ This is the fifth thesis of our research group in the field of Prader-Willi syndrome (PWS) and encompasses 6 new studies embedded in the Dutch PWS Cohort study in children and adolescents with PWS. In 1887, sir Langdon Down described an adolescent girl with short stature, obesity, hypogonadism and cognitive impairment. Almost a century later, in 1956, 3 endocrinologists Prader, Labhart and Willi described the most characteristic features as “Ein Syndrom von Adipositas, Kleinwuchs, Kryptorchidismus und Oligophrenie nach myotoniertigem Zustand im Neugeborenenalter”. A detailed description of the syndrome was given several years later. The clinical features which were considered characteristic were floppy at birth, obesity, mental retardation, hypogonadism, hypotonia, shortness of stature, prominent forehead, almond-shaped eyes, retrousse nose, small fish-like mouth, short hands and feet and some of them showed a diabetic type of glucose tolerance test. First research topics were predominantly describing the syndrome, at that time also known as syndrome of Hypotonia-Hypomentia-Hypogonadism-Obesity (HHHO), and focused on the relations with diabetes and the cause of hypotonia. In the 70s studies reported on low growth hormone (GH) levels9-11 and the first clinical trial with GH treatment was published in the 80s. Since 2002, our research group has been investigating the effects of GH treatment in children with PWS in the Dutch PWS Cohort study. Knowledge about different aspects of PWS has vastly increased over the past 50 years, although new questions and dilemmas are met and need further investigations. This chapter describes the clinical manifestations in different stages of life, the genetic background, the hypothalamic – pituitary axis in children with PWS. In the scope of this thesis, characteristics of children with PWS are described in combination with the longterm effects of GH treatment. Finally, the aims of the studies described in the following chapters are presented.

PurposeTo explore the effects of pegvisomant (PEGV) on glucose metabolism in patients with acromegaly within ACROSTUDY, an international, observational, prospective safety surveillance study.MethodsPatients were retrospectively divided into two cohorts, with (DM group) or without diabetes mellitus (no-DM). Parameters of glucose metabolism and IGF-I values were analyzed yearly both cross-sectionally for 4 years (yrs) and longitudinally at 1 and 4-5yrs of PEGV treatment.ResultsAmong 1762 patients, 510 (28.9%) had DM before PEGV start. At cross-sectional analyses, in the DM group mean blood glucose was 140.058.7mg/dl at baseline, 116.4 +/- 44.8mg/dl at year 1 and 120.0 +/- 44.3mg/dl at yr 4. Mean HbA1c was 6.6 +/- 1.2 % at yr 1 vs. 7.0 +/- 1.4 % at baseline. HbA1c was above 6.5% in 61.9% at baseline and ranged from 45.4 to 53.8% at subsequent yearly time points. At the 4-yr longitudinal analysis, in the DM group (n=109), mean blood glucose decreased by 20.2mg/dl at yr 4, mean HbA1c was 7.0 +/- 1.5% at baseline vs. 6.8 +/- 1.4%. Patients achieved IGF-I normalization in 52.1% and 57.4% of cases in the DM and no-DM groups, respectively at 1 year. The mean daily PEGV dose (mg/day) was higher in the DM group (18.2 vs. 15.3) while the absolute change of IGF-I values from baseline was similar in both groups. PEGV was well tolerated in both groups without any unexpected AEs.Conclusions p id=Par4 Patients with DM had a moderate decrease in mean fasting glucose values during PEGV treatment.

Objective The aim of this study was to identify targets predicting allergic sensitization to laboratory animals using shift in skin prick test to laboratory animals as primary outcome variable. Methods In a prospective longitudinal study, personnel who were employed to work with laboratory animals at a medical university were investigated before and 6, 12 and 24 month after the start of employment. Lung function, bronchial challenges, exhaled NO and nasal lavage were performed and blood samples were drawn at all visits. Results Seventy subjects attended all four visits and 13 (19%) became sensitized to laboratory animals during the two years of follow up. Lung function (VC and FEV 1 ) deteriorated and blood levels of eosinophils and IL-2 producing lymphocytes increased after 24 months. An increased risk of developing laboratory animal allergy was significantly associated with female sex, atopy, symptoms associated with exposure to laboratory animals, low proportion of blood CD4+ cells, specific IgE to rat and mouse and high total IgE when starting to work with laboratory animals. Conclusions A sensitization rate of 19% in 2 years, were demonstrated in laboratory animal workers. Atopy, increased total and specific IgE levels (rat and mouse) were the strongest predictors for laboratory animal sensitization. The progressive lung function impairment over time, observed in the whole study population may indicate that exposure in animal facilities induces harmful effects, irrespective to allergic sensitization.

Sound radiation by a driver set in a rigid closed cabinet is modeled analytically using the principle of wave superposition. The driver-cabinet assembly is replaced by an array of volumeless substitute sources-monopoles-confined within its surface. The role of substitute sources is to reproduce the sound field exterior to the surface as close to the original field as possible. The frequency dependent positions and strengths of substitute monopoles are optimized by an iterative search procedure aimed at matching the prescribed surface boundary conditions of the original source. The time-consuming optimization of monopole positions is carried out at narrowband center frequencies reducing the computational cost without significant loss of accuracy. The consistency of computed results is verified by checking the power output through the cabinet surface. Modeling is done for anechoic and semi-anechoic conditions. The model has been validated experimentally in a semi-anechoic room with satisfactory results using a mid-range driver set in a closed-box baffle.

BACKGROUND: Whether children with chromosomal disorders of growth and puberty are affected by secular trends (STs) as observed in the general population remains unanswered, but this question has relevance for expectations of spontaneous development and treatment responses. OBJECTIVES: The aim of the study was to evaluate STs in birth parameters, growth, and pubertal development in girls with Turner syndrome (TS). STUDY DESIGN: Retrospective analysis of KIGS data (Pfizer International Growth Database). We included all TS patients who entered KIGS between 1987 and 2012 and were born from 1975 to 2004, who were prepubertal and growth treatment naïve at first entry (total number: 7,219). Pretreatment height and ages at the start of treatment were compared across 5-year birth year groups, with subgroup analyses stratified by induced or spontaneous puberty start. RESULTS: We observed significant STs across the birth year groups for birth weight [+0.18 SD score (SDS), p < 0.001], pretreatment height at mean age 8 years (+0.73 SDS, p < 0.001), height at the start of growth hormone (GH) therapy (+0.38 SDS, p < 0.001) and start of puberty (+0.42 SDS, p < 0.001). Spontaneous puberty onset increased from 15 to 30% (p < 0.001). Mean age at the start of GH treatment decreased from 10.8 to 7.4 years (-3.4 years; p < 0.001), and substantial declines were seen in ages at onset of spontaneous and induced puberty (-2.0 years; p < 0.001) and menarche (-2.1 years; p < 0.001). CONCLUSION: Environmental changes leading to increased height and earlier and also more common, spontaneous puberty are applicable in TS as in normal girls. In addition, greater awareness for TS may underlie trends to earlier start of GH therapy and induction of puberty at a more physiological age.

Additive manufacturing (3D printing) enables the designing and producing of complex geometries in a layer-by-layer approach. The layered structure leads to anisotropic behaviour in the material. To accommodate anisotropic behaviour, geometrical optimization is needed so that the 3D printed object meets the pre-set strength and quality requirements. In this article a material description for polymer powder bed fused also or selective laser sintered (SLS) PA12 (Nylon-12), which is a common 3D printing plastic, was investigated, using the Finite Element Method (FEM). The Material Model parameters were obtained by matching them to the test results of multipurpose test specimens (dumb-bells or dog bones) and the model was then used to simulate/predict the mechanical performance of the SLS printed lower-leg prosthesis components, pylon and support. For verification purposes, two FEM designs for a support were SLS printed together with additional test specimens in order to validate the used Material Model. The SLS printed prosthesis pieces were tested according to ISO 10328 Standard. The FEM simulations, together with the Material Model, was found to give good estimations for the location of a failure and its load. It was also noted that there were significant variations among individual SLS printed test specimens, which impacted on the material parameters and the FEM simulations. Hence, to enable reliable FEM simulations for the designing of 3D printed products, better control of the SLS process with regards to porosity, pore morphology and pore distribution is needed.

Children born small for gestational age (SGA) with poor growth during the first years of life may remain short in stature during childhood and as adults.To evaluate the 3-year growth response to GH treatment in very young short children born SGA, and to test the existing predictions models for growth response developed for older SGA children.KIGS (The Pfizer International Growth Database).A total of 620 SGA children (birth length and/or weight below -2 SD score [SDS]) on GH treatment, 156 in the 2- to 4-year-old group (100 boys; median age, 3.3 y), and 464 in the 4- to 6-year-old group (284 boys; median age, 4.9 y).Median values and 10th-90th percentiles are presented. Both groups presented a significant increase in height velocity during GH treatment. Median height SDS increased from -3.9 (-5.4 to -2.9) at the start to -2.2 (-3.8 to -1.0) at 3 years in the 2- to 4-year-old group (P.01) and from -3.4 (-4.5 to -2.6) to -2.0 (-3.3 to -0.9) in the 4- to 6-year-old group (P.01). Median weight SDS increased from -3.8 (-5.9 to -2.4) to -2.1 (-4.1 to -0.5) in the 2- to 4-year-old group (P.01). Respective values for the 4- to 6-year-old group were -3.1 (-4.8 to -1.8) to -1.6 (-3.1 to -0.1) SDS (P.01). First- and second-year growth response could be estimated by the SGA model.Very young children born SGA without spontaneous catch-up growth presented a significant improvement in height and weight during the 3 years of GH treatment. Growth response could be estimated by the SGA model.

Background Response to growth hormone (GH) therapy may vary between individual patients. Therefore the use of GH in children should be closely monitored to avoid over, under, or ineffective treatment regimens. The treatment response can be evaluated using growth prediction models. In an effort to improve the accuracy of these prediction models, Ranke et al. (J Clin Endocrinol Metab 95(3):1229–37) proposed a novel ‘data-driven’ approach based on a quantitative analysis of a large cohort of patients from the Pfizer International Growth Database (KIGS) treated with Genotropin (human growth hormone). This model allows physicians to predict and evaluate the level of growth response and responsiveness for their patients so they can adapt treatment accordingly. By comparing the actually observed and the predicted growth response the ability of an individual to respond to GH (responsiveness) can be estimated and further treatment can be adapted accordingly Objective To determine the potential population level reduction in the amount of GH used and impact on height outcome of using this data-driven approach to guide treatment decisions, compared to conventional, ‘experience-based’ GH treatment in prepubertal patients with growth hormone deficiency (GHD) or Turner syndrome (TS). Methods A model was developed to study the height outcome and the total amount of GH used in the presence or absence of data-driven treatment decisions. The proportion of patients for whom height outcome could be improved or GH use could be reduced (i.e. for low compliance, high or low responder) was estimated using the KIGS cohort. The analysis assumed that this segmentation allows physicians to tailor dosage to the individual patient’s needs or even to discontinue therapy when it is not effective. The analysis used a 4-year time horizon, with Germany as an example country, but results are extendable to other countries. Only the total amount of GH used was included, and effects were defined as the height outcome after 4 years. Results The analysis estimated that an evidence-driven approach may reduce the total amount of GH utilized by 7.0 % over 4 years for the treatment of short stature in prepubertal patients with GHD and TS in Germany. Despite the reduction in drug use the average growth outcomes remained unaffected with the new treatment approach. Univariate and probabilistic sensitivity analyses showed that the results are robust. Conclusions Our analysis showed that using a data-driven approach to guide treatment decisions for children with GHD or TS is estimated to result in efficiencies in the amount of GH used, without reducing the average growth in the population.

Treatment with growth hormone (GH) has become standard practice for replacement in GH-deficient children or pharmacotherapy in a variety of disorders with short stature. However, even today, the reported adult heights achieved often remain below the normal range. In addition, the treatment is expensive and may be associated with long-term risks. Thus, a discussion of the factors relevant for achieving an optimal individual outcome in terms of growth, costs, and risks is required. In the present review, the heterogenous approaches of treatment with GH are discussed, considering the parameters available for an evaluation of the short- and long-term outcomes at different stages of treatment. This discourse introduces the potential of the newly emerging prediction algorithms in comparison to other more conventional approaches for the planning and evaluation of the response to GH. In rare disorders such as those with short stature, treatment decisions cannot easily be deduced from personal experience. An interactive approach utilizing the derived experience from large cohorts for the evaluation of the individual patient and the required decision-making may facilitate the use of GH. Such an approach should also lead to avoiding unnecessary long-term treatment in unresponsive individuals.

Information about the expected growth response of children to GH therapy is currently inadequate.The aim of the study was to compare observed and expected growth in response to GH in prepubertal children and to propose how these parameters can be used to optimize GH therapy. Indices considered were observed growth, observed growth relative to reference data [height sd score (Ht SDS), change in (Delta) Ht SDS, height velocity (HV)], and observed growth relative to growth predicted from prediction models [Studentized residual (SR)]. Design/Setting/Patients/Intervention: Growth data from KIGS-Pfizer International Growth Database-on prepubertal children aged 1-13 yr with severe GH deficiency (GHD; maxGH5 microg/liter; n = 2129), with less-severe GHD (maxGH of 5-10 microg/liter; n = 3075), and with Turner syndrome (n = 2350), and short children born small for gestational age (n = 993) were analyzed before and during 2 yr of GH treatment.For each patient group, growth responses during the first 2 yr of GH treatment were established. The relationships of HV and DeltaHt SDS with SR were determined.Reference data were generated for assessing adequate individual responses. Responses to GH in terms of HV and DeltaHt SDS were greatest in children with severe GHD. HV and DeltaHt SDS were highly correlated with SR during only the first year of GH treatment (R approximately 0.7; P0.001).Decisions on GH therapy regimens should be made using both traditional (HV or DeltaHt SDS) and prediction model-derived (SR) indices of growth response.

Context: GH therapy is an accepted measure to increase adult height in young prepubertal patients suffering from growth failure related to chronic kidney disease (CKD). The impact of GH therapy on final height (FH) in CKD patients of pubertal age is unclear.Objective: This study set out to analyze near-FH in a cohort of GH-treated CKD patients.Design, Settings, and Patients: Of 240 evaluable patients in the Pfizer International Growth Database (KIGS) with CKD, 39% were prepubertal and 61% were pubertal at baseline; 45% were on conservative treatment for CKD, 28% were on dialysis, and 27% were in the period after renal transplantation.Main Outcome Measures: Near-FH, relation to pubertal stage, and factors predictive of growth response were the main outcome measures.Results: Mean height sd scores increased continuously during GH treatment until near-FH by 1.2 and 1.6 in boys and girls, respectively. Mean near-FH differed significantly from prepubertal patients showing severely delayed puberty (−3.6), late pubertal patients (−2.9), early pubertal patients (−2.2), and prepubertal patients with normal onset of puberty (−2.0). The initial degree of stunting, degree of bone age retardation, duration of GH therapy, time spent on conservative treatment/dialysis, pubertal delay (>2 sd), gender, and age at start of GH treatment were significant predictors of growth response to GH therapy, explaining between 33 and 61% of the overall variability.Conclusions: Long-term GH therapy of CKD patients in prepubertal and pubertal age results in an increased adult height, but response is diminished in patients on dialysis and/or with severely delayed puberty.

Little is known about factors determining height outcome during GH treatment in Turner syndrome (TS). We investigated 987 TS children within the Kabi International Growth Study (KIGS) who had reached near adult height (NAH) after >4 y GH treatment (including >1 y before puberty). Through multiple regression analysis we developed a model for NAH and total gain. Our results were as follows (median): 1) At start, age 9.7 yrs, height (HT) 118.0 cm (0.0 TS SDS), projected adult height 146.1 cm, GH dose 0.27 mg/kg wk; 2) NAH HT 151.0 cm (1.5 TS SDS); 3) Prepubertal gain 21.2 cm (1.6 TS SDS); 4) Pubertal gain 9.4 cm (0.0 TS SDS). NAH correlated (r = 0.67) with (ranked) HT at GH start (+), 1 year responsiveness to GH (+), MPH (+), age at puberty onset (+), age at GH start (-), and dose (+). The same factors explained (R = 0.90) the total HT gain. However, HT at GH start correlated negatively. Karyotype had no influence on outcome. Evidently, height at GH start (the taller, the better), age at GH start (the younger, the better), the responsiveness to GH (the higher, the better) and age at puberty (the later, the better) determine NAH.

Growth hormone (GH) deficiency is normally diagnosed when the affected child is between 6 and 8 years of age and a lack of normal growth first becomes noticeable. Some patients, however, are diagnosed as being GH deficient at a relatively young age (

OBJECTIVES: We aimed to evaluate the factors influencing true adult height (HT) after long-term (from 1987 to 2000) GH treatment in Ullrich-Turner syndrome (UTS) based on modalities conceived in the 1980s. DESIGN: Out of 347 near-adult (>16 Years) patients from 96 German centres, whose longitudinal growth was documented within KIGS (Pharmacia International Growth Database), 188 (45, X=59%; bone age >15 Years) were available for further anthropometric measurements. RESULTS: At a median GH dose of 0.88 (10th/90th percentiles: 0.47/1.06) IU/kg per week, a gain of 6.0 (-1.3/+13) cm above the projected adult height was recorded. Variables were recorded at GH start, after 1 Year GH, puberty onset, and last visit on GH therapy. At these visits, the median ages were 11.7, 12.7, 14.2, 16.6 and 18.7 Years; and median heights, 0.4, 1.1, 1.7, 1.7 and 1.3 SDS (UTS) respectively. Height gain (DeltaHT) after GH discontinuation was 1.5 cm. Total DeltaHT correlated (P

Item does not contain fulltext The aim of this meta-analysis, based on individual participant data from several studies, was to investigate the influence of patient-, materials-, and tooth-related variables on the survival of posterior resin composite restorations. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a search resulting in 12 longitudinal studies of direct posterior resin composite restorations with at least 5 years' follow-up. Original datasets were still available, including placement/failure/censoring of restorations, restored surfaces, materials used, reasons for clinical failure, and caries-risk status. A database including all restorations was constructed, and a multivariate Cox regression method was used to analyze variables of interest [patient (age; gender; caries-risk status), jaw (upper; lower), number of restored surfaces, resin composite and adhesive materials, and use of glass-ionomer cement as base/liner (present or absent)]. The hazard ratios with respective 95% confidence intervals were determined, and annual failure rates were calculated for subgroups. Of all restorations, 2,816 (2,585 Class II and 231 Class I) were included in the analysis, of which 569 failed during the observation period. Main reasons for failure were caries and fracture. The regression analyses showed a significantly higher risk of failure for restorations in high-caries-risk individuals and those with a higher number of restored surfaces.

It has become common practice to apply GH treatment in short Turner syndrome patients with the objective of promoting growth. The variability in response and the high costs of this treatment demand the individualization and optimization of therapy. Based on 686 prepubertal Turner patients from the Kabi International Growth Study (KIGS; Pharmacia & Upjohn, Inc. International Growth Database), we undertook a multiple regression analysis of height velocity (centimeters per yr) by using various parameters of potential relevance. Derived prediction models for the first 4 yr of GH treatment were validated with 76 additional KIGS patients and 81 patients from Tuebingen, Germany. Among the 6 predictors identified, the most influential variable for first year growth response was the natural log (ln) of the weekly GH dose. The first year growth response was also correlated with age and distance between height and target height (SD score; both negative) and body weight SD, number of GH injections per week, and oxandrolone treatment given additionally (positive). The first year model explains 46% of the variability, with 1 SD of 1.26 cm. For the second to fourth years, 5 predictors were identified: height velocity during previous years, weekly GH dose (ln), weight SD, oxandrolone therapy (all positive), and age (negative). These models explained 32%, 29%, and 30% of the variability, respectively, with SD scores of 1.1, 1.0, and 1.0 cm, respectively. When the models were applied to the other cohorts, no significant difference was noted between observed and predicted responses. Although the parameters used in our models do not entirely explain the variability in the growth response in Turner syndrome, the parameters themselves were clinically relevant to our present understanding and proved to be of high precision. Some of the tested markers, such as karyotype, do not contribute to the growth response. These variables make the models practical and suitable for planning beneficial and cost-effective therapy.

Postmarketing surveillance studies of recombinant human GH therapy, such as the Kabi Pharmacia International Growth Study (KIGS; Pharmacia & Upjohn, Inc., International Growth Database), have accumulated extensive data concerning the characteristics and growth outcomes of children with various causes of short stature. These data provide an opportunity to analyze the factors that determine responsiveness to GH and allow the development of disease-specific growth prediction models. We undertook a multiple regression analysis of height velocity (centimeter per yr) with various patient parameters of potential relevance using data from a cohort of 593 prepubertal children with idiopathic GH deficiency (GHD) from the KIGS database. Our aim was to produce models that would have practical utility for predicting prepubertal growth during each of the first 4 yr of GH replacement therapy. These models were validated by a prospective comparison of predicted and observed growth outcomes in an additional 3 cohorts of prepubertal children with idiopathic GHD: 237 additional KIGS patients, 29 patients from the Australian OZGROW study, and 33 patients from Tubingen, Germany. The most influential variable for first year growth response was the natural log (ln) of the maximum GH response during provocation testing, which was inversely correlated with height velocity. The first year growth response was also inversely correlated with chronological age and height SD score minus midparental height SD score. First year growth was positively correlated with body weight SD score, weekly GH dose (ln), and birth weight SD score. Two first year models were developed using these parameters, 1 including and 1 excluding the maximum GH response to provocative testing. The former model explained 61% of the response variability, with a SD of 1.46 cm; the latter model explained 45% of the variability, with a SD of 1.72 cm. The two models gave similar predictions, although the model excluding the maximum GH response to testing tended to underpredict the growth response in patients with very low GH secretory capacity. For the second, third, and fourth year growth responses, 4 predictors were identified: height velocity during the previous year (positively correlated), body weight SD score (positively correlated), chronological age (negatively correlated), and weekly GH dose (ln; positively correlated). The models for the second, third, and fourth year responses explained 40%, 37%, and 30% of the variability, respectively, with SDs of 1.19, 1.05, and 0.95 cm, respectively. When the models were applied prospectively to the other cohorts, there were no significant differences between observed and predicted responses in any of the cohorts in any year of treatment. The fourth year response model gave accurate prospective growth predictions for the fifth to the eighth prepubertal years of GH treatment in a subset of 48 KIGS patients. Analyses of Studentized residuals provided further validation of the models. The parameters used in our models do not explain all of the variability in growth response, but they have a high degree of precision (low error SDs). Moreover, the parameters used are robust and easily accessible. These properties give the models' practical utility as growth prediction tools. The availability of longitudinal, disease-specific models will be helpful in the future for enabling growth-promoting therapy to be planned at the outset, optimized for efficacy and economy, and individualized to meet treatment goals based on realistic expectations.

ObjectivesNeuroimaging has become an essential part of the diagnostic process in children with GH deficiency (GHD). The aim of the study was to document the frequency of neuroanatomical abnormalities in a very large cohort of children with GHD and to relate these findings to patient clinical characteristics.Design and methodsResults of magnetic resonance imaging (MRI) were reported in 15 043 of 43 725 children with non-acquired GHD (idiopathic, neurosecretory dysfunction (NSD) and known congenital cause) who were enrolled in KIGS (Pfizer International Growth Database) between 1987 and 2011. Clinical characteristics of patients before GH treatment with normal MRI (idiopathic GHD (IGHD) and NSD) were compared with those of patients with abnormal pituitaries (hypoplasia, empty sella (ES), HME (hypoplastic anterior pituitary, missing pituitary stalk and ectopic posterior pituitary)).ResultsAbnormal MRIs were found in 4032 (26.8%) children, within which ES (n=1178 (7.8%)) and HME (n=1019 (6.8%)) were the most frequent findings. In 2361 children diagnosed as IGHD or NSD before MRI examination, anatomical abnormalities ((pituitary hypoplasia:n=974); (HME:n=459)) were documented. Patients with anatomical abnormalities had more severe characteristics of GHD: normal MRI < pituitary hypoplasia < ES < HME.ConclusionsGHD is associated with a great variety of neuroanatomical abnormalities as identified by MRI. The investigation and evaluation of MRI need to be conducted in a structured mode. There is an association between anatomical and functional abnormalities of the pituitary.

Short stature in children with chronic kidney disease (CKD) is due to various underlying congenital or acquired renal disorders resulting in variable impairment of renal function and variable response to GH treatment.It was the aim to develop a mathematical model that allows the prediction of the individual growth response and to identify nonresponders.Data from 208 prepubertal children on conservative or dialysis treatment in a large pharmaco-epidemiological survey, the KIGS (Pfizer International Growth Database), were used for the model and data from 67 similar CKD patients registered at the Dutch Growth Research Foundation for validation.Annualized height velocity (centimeters per year) during the first year of GH treatment was best predicted by age at start, weight sd score, underlying renal disorder (hereditary kidney disorder), glomerular filtration rate (at baseline), and GH dosage. Using these parameters, the final model explained 37% of the overall variability of growth response. Standard error of the estimates was 1.6 cm. Age was the most important predictor of growth response (20.3% of variability) followed by weight sd score at start, and 27.2% of the variability of the second-year response could be predicted by the first-year response and glomerular filtration rate. Nonresponders of the validation group could be correctly identified.Based on simple clinical variables, a robust prediction model was developed that provides realistic expectations of individual growth response to GH in short children with CKD. The model will help in identifying nonresponders and to tailor treatment strategies.

Background/Aims: We investigated whether genetic or maternal/environmental risk factors for being born small for gestational age (SGA), e.g. Silver-Russell syndrome, congenital heart defects, infections of mothers or smoking during pregnancy, explain the variation in the first-year growth response to GH therapy. Methods: Secondary analysis was made of growth response in 135 short prepubertal German children (66% males) enrolled in a SGA phase III trial. Initial mean patient age was 6.8 ± 2.6 years; mean patient height SDS –3.8 ± 1.2, and GH treatment dose was 0.066 mg/kg body weight per day. Results: Growth velocity increased by 4.5 ± 2.0 cm/year and height SDS by 1.0 ± 0.5 SDS. Although patient number was limited and variation was high, both growth response (cm/year) and change in height SDS did not appear to differ between subgroups which also did not differ in terms of Studentized residuals set up in the KIGS growth prediction model for SGA. Likewise, in a step-forward multivariate analysis, the variables Silver-Russell syndrome, congenital heart defects, infections of mothers and smoking were not identified as independent factors influencing growth velocity. Conclusion: The retrospectively analyzed genetic and maternal/environmental risk factors for SGA do not appear to explain the observed patient variance in response to GH. Larger prospective studies are needed, however, to substantiate these preliminary findings.

An outbreak of enterohaemorrhagic Escherichia coli O157 VT2 infections is known to have affected 120 people on the west coast of Sweden (Halland and Västra Götaland counties) between 16 August and 10 September 2005

Background: Medulloblastoma is the most frequent primary solid central nervous system tumour in children. The 5-year survival rate is at present at about 60%. Height in general is severely compromised in survivors. The present study is an extension of the investigation by the author’s group of the effect of exogenous growth hormone (GH) among medulloblastoma patients. Methods: A total of 113 patients with medulloblastoma (out of 682 cases documented in KIGS, Pfizer International Growth Database) were treated with GH till final height was achieved. At the start of GH therapy (median dose 0.18 mg/kg/week), patients were 8.9 years old and had a median height SDS of –1.6. Results: After 6.8 years of GH, final height SDS was –1.9, reflecting an overall loss in height of 0.3 SDS. This contrasted with an age-matched group of patients with idiopathic growth hormone deficiency (iGHD, n = 1,986), whose gain in height was 1.6 SDS on the same dose. The index of responsiveness averaged –0.9 during the first prepubertal year and –2.0 during total pubertal growth, thus indicating a major impairment in responsiveness to GH as compared to iGHD. Height at GH start, which correlated positively with the age at disease onset, was found to be the major determinant of final height. Conclusions: Our findings show that attempts to improve the height outcome in medulloblastoma must involve earlier recognition and treatment with higher-than-replacement doses of GH; additionally, modifications in cancer treatment programs need to be considered, such as lowering the dose of craniospinal irradiation or avoiding it as far as possible.

In children, GH secretion and sensitivity to GH are influenced by developmental changes. It is not clear whether the response to GH in very young children with GH deficiency (GHD) is the same as that in older, prepubertal children. A cohort of 265 children (180 males and 85 females) with idiopathic GHD from KIGS (Pfizer International Growth Database), with treatment started at less than 3 yr of age (mean age, 1.9 yr; group I) was compared with a cohort of 509 children (331 males and 178 females; group II) with treatment started at 7-8 yr of age (mean age, 7.5 yr). The following differences (P < 0.01) were found (given in mean values) between groups I and II at the start of GH treatment: 9% vs. 5% breech delivery, 38% vs. 14% multiple pituitary hormone deficiency, 4.2 vs. 5.9 ng/ml maximum GH in response to tests, -0.1 vs. -0.8 midparental height (MPH) sd score (SDS), -3.1 vs. -2.5 height SDS, 0.83 vs. 0.66 IU/kg.wk GH dose. After the first year of GH, the results were: 13.3 vs. 8.6 cm/yr height velocity, and 1.7 vs. 0.6 maximum change in height SDS. Using the previously developed growth prediction models for prepubertal children with idiopathic GHD more than 2 yr of age, our analysis revealed differences in the indexes of responsiveness in prediction models (Studentized residuals SDS, 0.7 vs.-0.3) and strikingly higher responsiveness to treatment among the young cohort, but with large scatter. Thus, new prediction models of height velocity (centimeters per year) were derived by means of multiple regression analysis for the young cohort, either involving (model A) or excluding (model B) the GH peak in tests. Model A explained 54% of the total variability with an error sd of 2.1 cm. Height velocity correlated with (parameters in order of importance) age (-), maximum GH (-), GH dose (+), weight SDS (+), height SDS minus MPH SDS (-), and birth weight SDS (+). Model B explained 45% of the total variability with an error sd of 2.3 cm. Height velocity correlated with (parameters in order of importance) age (-), GH dose (+), birth weight SDS (+), height SDS minus MPH SDS (-), and weight SDS (+). The predictors were qualitatively the same as those in the total prepubertal model involving all children more than 2 yr of age, but their quantitative impact in terms of partial contribution and the order of their importance were different for the young cohort. In particular, the partial contribution of the GH dose was higher, suggesting a greater gain in height per GH dose unit in the very young than in the older children. However, the rank order of the GH dose in the new models was lower, which suggests a slightly low sensitivity to GH in toddlers after the phase of severe GH insensitivity during early infancy. The early detection and GH treatment of congenital GHD is advantageous as a cost-effective strategy for achieving greater improvement of absolute height and growth velocity.

The role of GH treatment during total pubertal growth (TPG) is still unclear. We developed a prediction model for TPG (centimeters) through a multiple regression analysis of various prepubertal parameters in 303 adolescents with idiopathic GH deficiency from the KIGS database. Prepubertal catch-up growth and near-adult height were achieved, and GH dose was kept constant at approximately 30 micro g/kg.d. The model was validated on a cohort of 36 patients from one center. Four TPG predictors explained 70% of the variability with an error SD of 4.2 cm: gender (TPG in males was >11.3 cm vs. that in females), age at onset of puberty (negative), height SD score minus midparental height SD score at puberty onset (negative), and mean GH dose during puberty (positive). Our analysis suggests that TPG in idiopathic GH deficiency is only moderately dependent on GH dose. The use of a higher GH dosage at the onset of puberty should thus depend on the individual's height development. The TPG model aids in the planning of individually optimized and cost-effective GH treatment.

Although recombinant techniques have enabled the production of limitless amounts of human growth hormone (GH), and clinical methods for diagnosis and treatment have been greatly enhanced, the mean final heights of children with idiopathic GH deficiency (IGHD) treated with GH remain in the range of –1.3 standard deviation scores (SDS) below normal height. One of the methods used to increase height outcomes is to delay the onset and progression of puberty to allow for a longer ‘pre-pubertal’ growth phase. We reviewed the KIGS (Pharmacia International Growth Database) data of patients with IGHD who had been treated with gonadotropin-releasing hormone agonists (GnRHa) in order to see if a greater gain in height could be achieved by altering the tempo of pubertal maturation. Near-final height data were analysed in 39 adolescents (out of a total of 249) who had received GH + GnRHa therapy and were compared with similar data from 1,893 patients with IGHD treated with GH alone. The total change in height SDS in boys who received GH alone was +1.6, in contrast to +1.1 in GH + GnRHa-treated boys; the total change in height SDS in girls who received GH alone was +1.4 in contrast to +1.1 in girls treated with GH + GnRHa. The near final height SDS in girls treated with GH + GnRHa was 1.0 below the mid-parental target height (MPH), whereas there was only a –0.5 SDS difference in girls treated with GH. Approximation to the MPH did not differ in boys between the two treatment groups. These data suggest that the attainment of a substantial height SDS by manipulating the tempo of puberty is limited, but that optimizing growth during the pre-pubertal phase is a more important factor.

A model was developed that allows physicians to individualize GH treatment in children born short for gestational age (SGA) who fail to show spontaneous catch-up growth. Data from children (n = 613) in a large pharmacoepidemiological survey, the KIGS (Pharmacia International Growth Database), or who had participated in clinical trials were used to develop the model. Another group of similar children (n = 68) from KIGS was used for validation. In the first year of GH treatment, the growth response correlated positively with GH dose, weight at the start of GH treatment, and midparental height SD score and negatively with age at treatment start. Using this model, 52% of the variability of the growth response could be explained, with a mean error SD of 1.3 cm. GH dose was the most important response predictor (35% of variability), followed by age at treatment start. The second year growth response was best predicted by a three-parameter model (height velocity in yr 1 of treatment, age at start of treatment, and GH dose), which accounted for 34% of the variability, with an error SD of 1.1 cm. The first year response to GH treatment was the most important predictor of the second year response, accounting for 29% of the variability. No statistically significant differences between the predicted and observed growth responses were found when the models were applied to the validation groups. In conclusion, using simple variables, we have developed a model that can be used in clinical practice to adjust the GH dose to achieve the desired growth response in patients born SGA. Furthermore, this model can be used to provide patients with a realistic expectation of treatment and may help to identify compliance problems or other underlying causes of treatment failure.

Accessible online at: www.karger.com/hre When discussing total pubertal growth, it is essential that the times of onset and completion of puberty are defined accurately. For example, Gasser and colleagues [1] studied growth curves from boys and girls and defined the onset of puberty as the nadir of growth velocity (i.e. zero growth acceleration). The end of puberty was defined as the point of minimum growth acceleration. This is in contrast to Marshall and Tanner’s definition of puberty, which is based on clinical signs such as genital and breast development [2]. Marshall and Tanner found that the onset of puberty was at 11.6 years in boys and 11.2 years in girls, with a total pubertal duration of about 3 years [2], whereas Gasser et al., using growth data, showed that the onset of puberty was at 10.9 years in boys and 9.7 years in girls, with a pubertal duration of 4 years [1]. Total pubertal growth was therefore greater when assessed using the methods of Gasser et al. with a difference of 3.7 cm in boys and 9.4 cm in girls [1]. We studied 303 children from KIGS (Pharmacia International Growth Database) who had idiopathic growth hormone (GH) deficiency and a GH level of less than 10 ng/ml in response to provocative testing. Patients had received at least 5 years of GH replacement, with at least 2 years of pre-pubertal and 2 years of post-pubertal therapy. For this study, the age at onset of puberty had to be between 10 and 17 years in boys and between 9 and 16 years in girls. The age at the end of puberty was over 16 years in boys and over 14 years in girls. Height velocity at the time of the analysis needed to be less than 2 cm/year and patients were receiving a constant dose of GH, administered as six or more injections per week. The results are summarized in table 1. Final height was reached at about 18 years in boys and 16 years in girls. Final height in boys was 0.7 standard deviations (SD) with a total pubertal growth of 25.3 cm. In girls, the final height was –1.7 SD, with a total pubertal growth of only 16 cm. Similar results were seen in an analysis of 36 patients (24 boys, 12 girls) from the University Children’s Hospital, Tubingen, Germany. When simple linear correlations were performed on the KIGS data, total pubertal growth correlated positively with both the age at onset of puberty and with the distance from target height, expressed as SD. Total pubertal growth also correlated positively with GH dose. Thus, a prediction model was developed with four variables: distance to target height (the greater the distance to target height, the greater the growth when receiving GH); mean GH dose; age at onset of puberty (the younger the age at

Background Mathematical models can be developed to predict growth in short children treated with growth hormone (GH). These models can serve to optimize and individualize treatment in terms of height outcomes and costs. The aims of this study were to compile existing prediction models for short children born SGA (SGA), to develop new models and to validate the algorithms. Methods Existing models to predict height velocity (HV) for the first two and the fourth prepubertal years and during total pubertal growth (TPG) on GH were applied to SGA children from the KIGS (Pfizer International Growth Database) - 1st year: N = 2340; 2nd year: N = 1358; 4th year: N = 182; TPG: N = 59. A new prediction model was developed for the 3rd prepubertal year based upon 317 children by means of the all-possible regression approach, using Mallow's C(p) criterion. Results The comparison between the observed and predicted height velocity showed no significant difference when the existing prediction models were applied to new cohorts. A model for predicting HV during the 3rd year explained 33% of the variability with an error SD of 1.0 cm/year. The predictors were (in order of importance): HV previous year; chronological age; weight SDS; mid-parent height SDS and GH dose. Conclusions Models to predict growth to GH from prepubertal years to adult height are available for short children born SGA. The models utilize easily accessible predictors and are accurate. The overall explained variability in SGA is relatively low, due to the heterogeneity of the disorder. The models can be used to provide patients with a realistic expectation of treatment, and may help to identify compliance problems or other underlying causes of treatment failure.

α-Methylation de l'alaninate de [chloro-4 α,α-dimethyl] phenethyle (alaproclate) via la protection du groupe amino par reaction avec le bis-[chloro dimethyl silyl]-1,2 ethane en presence de triethylamine