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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.

Aim Children treated with a growth hormone (GH) for idiopathic growth hormone deficiency (IGHD) may be monitored with the first-year prediction model from the Pfizer International Growth Database (KIGS) using auxology, age, GH dose and the maximum GH concentration from a stimulation test (GHmaxstim). We tested the hypothesis that using a 12-hour spontaneous profile (GHmax12h) would be as accurate. Methods We studied 98 prepubertal Swedish children (78 boys) aged 2-12 years enrolled in KIGS. The first-year growth was predicted using the GHmax from the GH profile and a stimulation test and both of these were compared separately with the observed growth response. Results The increased height observed in the first year was 0.74 standard deviation scores (SDS) and the studentised residuals for the predicted and observed growth with GHmaxstim (-0.16 SDS) and GHmax12h (-0.22) were similar. Individual predictions calculated with stimulated or spontaneous GHmax showed a significant correlation (r=0.80). Conclusion We validated the KIGS IGHD prediction model and found that the stimulated GHmax peak can be reliably replaced by the GHmax 12h with similar accuracy. This makes the model more accessible for clinicians, who can then provide realistic expectations for the growth response during the first year of treatment. This article is protected by copyright. All rights reserved.

__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.

Background/Aims: There is little information how rhGH treatment affects height in NS. This study aims to analyze data from the NS patients assembled in KIGS over 25 years. Patients/Methods: Of 613 (389 m/224 f) NS patients documented, 476 (302 m/174 f) were treated for 1 year, 237 (160 m/77 f) of which served to develop a 1st year height velocity (HV) prediction algorithm. One-hundred and forty (74 m/66 f) had reached near adult height (NAH). Factors affecting NAH on rhGH were determined. Results: At the start of rhGH, the NAH groups were (median, m, f) 11.0 and 10.3 years, with a height SDS of –3.2 and –3.8 SDS (Prader), respectively. The total gain after 6.3 and 5.6 years on rhGH (0.27 and 0.30 mg/kg/week) was 1.2 and 1.3 SDS. Age at the start of rhGH (negative), height at the start of rhGH, rhGH dose, number of rhGH injections/wk and birth weight (all positive) explained 36% of the variability of 1st year HV. Height at the start of rhGH, 1st year growth on rhGH, birth weight, and gender explained 74% of the variability of NAH. Causes for rhGH treatment discontinuation and adverse events were also analyzed. Conclusion: rhGH treatment increases NAH in NS. Prediction algorithms may optimize treatment in the future.

Objective To understand whether spontaneous vs induced puberty and the type and route of estrogen influence the height of girls with Turner syndrome on growth hormone (GH). Study design Search of an international database of children treated with GH revealed 772 girls with Turner syndrome followed from GH initiation to near adult height. Data from girls with sustained spontaneous puberty (n = 145) were compared with those requiring estrogens for induction or maintenance of puberty (n = 627). Results At GH start, mean age (7.5 vs 7.9 years), weight (−1.7 vs −1.7 SDS), and body mass index (0.2 SDS vs 0.1 SDS) were similar for girls with spontaneous puberty and with induced puberty. Although those girls with spontaneous puberty were shorter than those with induced puberty, when midparental height was taken into consideration, starting heights in both groups averaged −2.8 SDS. Both groups received approximately 0.3 mg/kg/week of GH. Girls with spontaneous puberty initiated puberty and reached near adult height earlier than girls with induced puberty (12.6 ± 1.8 years vs 13.4 ± 1.4 years and 16.0 ± 1.3 years vs 16.9 ± 1.4 years, respectively). Although girls with spontaneous puberty grew more in the first year of GH therapy and between the onset of puberty and near adult height (11.0 cm vs 9.3 cm), height SDS at near adult height and the length of time in puberty before reaching near adult height were comparable. A 45,X karyotype was detected in 22.1% of girls with spontaneous puberty and in 58.4% of girls with induced puberty. Patients receiving transdermal estrogens did not grow better than those on oral estrogens. Adverse event reporting was comparable between groups. Conclusions Girls with Turner syndrome with spontaneous puberty tended to grow better in response to GH than girls with induced puberty, but not enough to produce a difference in height SDS at near adult height.

SummaryContext Girls with Turner Syndrome (TS) treated or not treated with growth hormone (GH) are prone to overweight. Therefore, we hypothesize that puberty induction in TS is associated with weight gain. Methods We analyzed weight changes (BMI-SDS) between onset of GH treatment and near adult height (NAH) in 887 girls with TS enrolled in KIGS (Pfizer International Growth Database). Puberty was induced with estrogens in 646 (72·8%) girls with TS. Results Weight status did not change significantly between GH treatment start and 1 year later (mean difference −0·02 BMI-SDS), but increased significantly (P < 0·001) until NAH (+0·40 BMI-SDS). The BMI-SDS increased +0·21 until start of puberty (P < 0·001). Girls with spontaneous and induced puberty showed similar BMI-SDS changes. Puberty induction at ≥12 years was associated with a significant (P < 0·001) less increase of BMI-SDS (+0·7 BMI-SDS) between baseline and NAH compared to puberty induction at

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.

Objectives The aim of this randomized controlled study was to evaluate the long term effectiveness of a reduced shrinkage stress resin composite in Class II restorations. The material was compared intra-individually with a microhybrid resin composite. Materials and methods Each of 50 patients with at least one pair of two similar sized Class II cavities participated (22 female, 28 male, mean age 43 years, range 18–64). Each participant received in each pair, in a randomized way, one Class II restoration performed with a reduced shrinkage stress resin composite (InTen-S) and the other restoration with a microhybrid resin composite restoration (Point 4). Both restorations were placed with an etch-and-rinse bonding system and an oblique layering technique. A total of 106 restorations, 33 premolar and 73 molars, were placed. The restorations were evaluated blindly each year using modified USPHS criteria. The overall performance of the experimental restorations was tested after intra-individual comparison using the Friedmans two-way analysis of variance test. The hypothesis was rejected at the 5% level. Results At 15 years, 91 restorations were evaluated. The drop out frequency was 15 restorations (5 male, 3 female participants; 2 premolar and 13 molar restorations). Except for 2 participants, who reported slight symptoms during a few weeks after placement, no post-operative sensitivity was observed at the recalls. The overall success rate at 15 years was 77%. Twenty-one non acceptable restorations were observed during the 15 years follow up, 10 InTen-S (21.7%) and 11 Point 4 (24.4%) restorations (p > 0.05). Annual failure rates for the resin composites were 1.5% and 1.6%, respectively. The main reasons for failure were secondary caries (8) and resin composite fracture (7). The differences between premolar vs. molar restorations and between restorations in male vs. female participants were not significant. Significant differences were observed between 2-surface vs. 3-surface restorations. Significance During the 15-year follow up, the reduced shrinkage stress resin composite showed a good clinical durability in Class II cavities, but not significantly better than the control microhybrid resin composite. Secondary caries and material fracture were the main reasons of failure.

Aim: The aim of this study was to evaluate the response to recombinant growth hormone (GH) treatment in short children with CHARGE syndrome. Patients: We identified 51 children (28 boys and 23 girls) in KIGS (Pfizer International Growth Database). The median chronological age was 7.6 years at the start of GH therapy and 13.2 years at the latest visit. Evaluation for GH deficiency (n = 33) was based on the following: peak GH level 7.3 μg/l and IGF-I level -2.01 standard deviation score (SDS). Sixteen subjects (9 boys) were followed longitudinally for 2 years. Results: Birth length (median SDS, -0.47) and weight (-0.97) were slightly reduced. At the start of GH therapy, height was -3.6 SDS, BMI -0.7 SDS, and the GH dose was 0.26 mg/kg/week. At the latest visit after 2.7 years of GH therapy, height had increased to -2.2 SDS and BMI to -0.5 SDS. In the longitudinal group, height increased from -3.72 SDS at the start of GH therapy to -2.92 SDS after 1 year to -2.37 SDS after 2 years of therapy (start - 2 years: p < 0.05), height velocity increased from -1.69 to 2.98 to 0.95 SDS, and BMI and GH dose (mg/kg/week) remained almost unchanged. Conclusions: Our data show a positive effect of conventional doses of GH on short-term growth velocity for the longitudinal as well as for the total group, without any safety issues.

Objective To analyze first-year treatment growth response and growth hormone (GH) dosage in prepubertal patients with the combination of type 1 diabetes mellitus (T1DM) and growth hormone deficiency (GHD). Study design A total of 69 patients with T1DM and GHD treated with GH have been enrolled in KIGS (Pfizer International Growth Database). Of these, 24 prepubertal patients had developed T1DM before GHD and were included in this analysis. Of 30 570 patients with GHD without T1DM, 15 024 were prepubertal and served as controls. Values are expressed as mean ± SD. Results Patients with T1DM and GHD had similar characteristics compared with the GHD-alone group. Neither age (10.2 ± 3.13 vs 8.42 ± 3.46 years, P = .14), height SDS corrected for midparental height SDS at start of treatment (−1.62 ± 1.38 vs −1.61 ± 1.51, P = .80), nor GH dosage (0.24 ± 0.08 mg/kg/wk vs 0.20 ± 0.04 mg/kg/wk, P = .09) were different between those with and without T1DM. First-year catch-up growth was comparable between the 2 patient groups (first treatment year height velocity 7.54 ± 3.11 cm/year compared with 8.35 ± 2.54 cm/year in control patients, P = .38). Height SDS of children with T1DM and GHD improved from −2.62 ± 1.04 to −1.88 ± 1.11 over 1 year of GH treatment. Conclusion Short-term response to GH therapy appeared similar in subjects with T1DM who then developed GHD and in those with GHD alone. Thus, T1DM does not appear to compromise GH response in children with GHD and should not exclude GH treatment in these children. GH treatment was safe in both subgroups of patients.

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: Children receiving stimulants for attention deficit hyperactivity disorder (ADHD) frequently present to pediatric endocrinology clinics for evaluation and treatment of growth disorders. The worldwide prevalence of stimulant use in children with ADHD also receiving recombinant human growth hormone (rhGH) and the impact on response to rhGH are unknown. Methods: Data on children enrolled in the KIGS® (Pfizer International Growth Study) registry were evaluated for the associated diagnosis of ADHD prior to initiation of Genotropin® rhGH. Concomitant stimulant medications and auxological information were captured. Response to rhGH was evaluated using established growth prediction models. Results: The prevalence of ADHD in KIGS was 2.3% (1,748/75,251), with stimulants used in 1.8% (1,326/75,251). Children with idiopathic growth hormone deficiency (IGHD) who received stimulants grew significantly less (1.1 cm) in the first year of rhGH therapy than expected for rhGH-treated non-ADHD IGHD children. After one year of rhGH, idiopathic short stature (ISS) children with ADHD were significantly shorter [0.74 cm (with stimulants) and 0.69 cm (without stimulants)] than non-ADHD ISS children. Conclusions: We demonstrated an impaired response to rhGH in IGHD and ISS children with ADHD. Our findings suggest that the ADHD phenotype, alone or in conjunction with stimulant therapy, may impair the short-term growth response to rhGH.

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.

Background:Growth prediction models (GPMs) exist to support clinical management of children treated with growth hormone (GH) for growth hormone deficiency (GHD), Turner syndrome (TS) and for short children born small for gestational age (SGA). Currently, no prediction system has been widely adopted.Content:The objective was to develop a stand-alone web-based system to enable the widespread use of an ‘individualised growth response optimisation’ (iGRO) tool across European endocrinology clinics. A modern platform was developed to ensure compatibility with IT systems and web browsers. Seventeen GPMs derived from the KIGS database were included and tested for accuracy.Summary:The iGRO system demonstrated prediction accuracy and IT compatibility. The observed discrepancies between actual and predicted height may support clinicians in investigating the reasons for deviations around the expected growth and optimise treatment.Conclusions:This system has the potential for wide access in endocrinology clinics to support the clinical management of children treated with GH for these three indications.

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.

Background: Information about disease-specific and gender-associated differences over longer time of short children treated with recombinant human growth hormone is missing. Methods: We analyzed data at growth hormone (GH) start in prepubertal children diagnosed with idiopathic GH deficiency (IGHD), congenital GHD, acquired GHD, idiopathic short stature (ISS), and born small for gestational age (SGA) enrolled (1987-2012) in the Pfizer International Growth Study (KIGS®) from Europe, USA, and Japan. Results: The demographic characteristics of patients in the three regions were similar. There was a diagnosis-specific pattern for age and height, and a universal pattern showing that girls were younger and smaller at GH start. There was a predominance of males with IGHD (n = 25,703; 70.1%), congenital GHD (n = 2,860; 63.9%), acquired GHD (n = 3,280; 63.9%), ISS (n = 4,327; 71.4%), and SGA (n = 5,848; 58.0%). Male prevalence in the USA population was more pronounced in IGHD, ISS, and SGA, but less so in congenital and acquired GHD. In IGHD (Europe and Japan) and ISS (Europe), there was a trend toward decreasing male prevalence. Conclusions: The male prevalence in prepubertal children treated with GH varies according to geographical region and is not explained by the underlying diagnoses. A global appreciation of gender biases is required for the proper care of short girls.

Background/Aims: The study aim was to develop and validate models for long-term prediction of growth in prepubertal children with idiopathic growth hormone deficiency (GHD) or Turner syndrome (TS) for optimal, cost-effective growth hormone (GH) therapy. Methods: Height was predicted by sequential application of annual prediction algorithms for height velocity in cohorts of GHD (n = 664) and TS (n = 607) as documented within KIGS (Pfizer International Growth Database). As height prediction models also require an estimate of weight, new algorithms for weight increase during the first to fourth prepubertal years on GH were developed. Results: When height was predicted from the start of GH treatment, the predicted and observed mean (SD) gain over 4 years was 30.4 (3.4) cm and 30.1 (4.9) cm, respectively, in GHD patients, and 27.2 (2.2) cm and 26.6 (3.5) cm, respectively, in TS patients. For all 4 years, gains of weight SD scores (SDS) were accurately described as a function of weight SDS and observed gain in height SDS (R2 > 0.89). Conclusion: In GHD and TS patients treated with GH, an accurate prepubertal long-term prediction of height development in groups is possible. Based on this, an optimal individual height outcome could be simulated.

Background/Aims: The aim was to describe the factors determining total pubertal growth (TPG) in adolescents with growth hormone deficiency (GHD), Turner syndrome (TS), who were small for gestational age (SGA) or had idiopathic short stature (ISS). Methods: The patients were documented within KIGS (Pfizer International Growth Database). TPG was defined as growth from puberty onset – spontaneous (>B1 or testes >3 ml) or induced with sex steroids to adult height in idiopathic GHD (n = 639; males 399), TS (n = 463), SGA (n = 59; males 35), and ISS (n = 130; males 87). Algorithms to predict TPG at puberty onset were developed by multiple linear regression analysis. Results: In GHD (males, females) and TS TPG could be explained with the same four predictors: (1) age (years) at puberty onset (neg.), (2) age – bone age at puberty onset (pos.), (3) height – midparental height (SDS) at puberty onset (neg.), and (4) mean dose of growth hormone (GH) during puberty (pos.). The algorithms explained 66, 65 and 68%, respectively, of the variability with total errors of 4.5, 3.8 and 2.9 cm, in spontaneous and induced TPG. Conclusions: TPG is determined by the same factors at puberty onset in adolescents with GHD, TS, SGA or ISS treated with GH. Thus, TPG depends mostly on the outcomes achieved at the end of prepubertal growth and less so on the dose of GH.

Background: Growth hormone (GH) therapy successfully increases height prognosis in children with GH deficiency (GHD); however, adult height data are still limited. Aim: This study investigated near-adult height (NAH) in patients with idiopathic GHD (i.e. those with a GH peak Methods: All patients were registered in the Pfizer International Growth Study Database (KIGS). Median (10th to 90th percentile) values are given and measurements were expressed as standard deviation scores (SDS). Parental-adjusted height was determined. Results: GH therapy was started at a median age of 9.2 (range 4.9–12) years in patients with isolated GHD (n = 1,619, 60% males) and at 7.7 (range 2.8–12.2) years in those with MPHD (n = 554, 65% males; p < 0.001) at a median dose of 0.20 mg/kg/week. Height SDS at onset of therapy was –3.1 (range –4.5 to –2.1) and –3.8 (range –5.7 to –2.3), respectively (p < 0.001). The maximum GH peak and insulin-like growth factor I SDS were significantly (p < 0.05) lower in patients with MPHD than in those with isolated GHD. Both groups showed a significant (p < 0.05) increase in height SDS at 1 year that continued until the onset of puberty. Parental-adjusted height at the start of puberty was –0.1 (range –1.6 to 1.1) in patients with isolated GHD and –0.4 (range –1.9 to 1.2) in those with MPHD. Parental-adjusted NAH SDS in patients with isolated GHD was 0.0 (range –1.5 to 1.2) and slightly, but significantly, higher than NAH (–0.3, range –2.1 to 1.2; p < 0.001) in patients with MPHD. In patients with isolated GHD, total change in height SDS while receiving GH therapy was 1.6 (range 0.5–3.2), and the change in height SDS at puberty was 0.1 (range –0.7 to 1). The respective values were 2.6 (range 0.9–4.6) and 0.2 (range –1 to 1.3) in patients with MPHD. Parental-adjusted NAH was slightly lower in girls than in boys with isolated GHD, but no gender difference was observed in patients with MPHD. Multivariate analysis in patients with GHD and MPHD showed that higher birth weight, taller parents, greater height at onset, first-year responsiveness, and predicted height velocity were the most important predictors of NAH. Conclusions: 89% of patients with isolated GHD and 81% of those with MPHD reached an NAH within their genetic potential while receiving GH therapy. Most of the height gain occurred during prepubertal years.

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.

Background/Aims: There is limited information about adult height (AH) outcomes and the factors influencing outcomes of growth hormone (GH) therapy in short children born small for gestational age (SGA). Methods: AH (SDS) and Δheight (SDS) from GH start to AH were analyzed in 161 SGA children who had reached AH (55 with Silver-Russell syndrome, SRS). Results: SGA patients treated to AH were started on GH (median) 0.25 mg/kg/week at an age of 7.8 years with a height of –3.8 SDS. AH after 7.7 years was –2.2 SDS and –1.1 SDS below mid-parental height (MPH). AH (SDS) was explained by: height (SDS) at GH start (+), Δheight (SDS) 1st year on GH (+), years on GH (+), maternal height (SDS) (+), length (SDS) at birth (+), and the diagnosis of SRS (–) (explained variability 70%; error 0.6 SD). Gain in height (SDS) was explained by: Δheight (SDS) 1st year on GH (+), years on GH (+), height – MPH (SDS) at GH start (–) (explained variability 60%; error 0.7 SD). Conclusions: Algorithms for AH outcomes provides useful information about the potential of long-term growth on GH in short children born SGA.

Aim: To assess final height in children with growth hormone deficiency (GHD) treated with human recombinant growth hormone (GH). Methods: Final height data for 401 Swedish children with idiopathic GHD and treated with GH, included in KIGS (Pfizer International Growth Database) between 1987 and spring 2006, were analysed retrospectively. Data were grouped according to sex, age and severity of GHD. Height at entry into KIGS, at the onset of puberty and near final height were analysed between groups. Results: Groups were heterogeneous for GHD, which ranged from partial to severe. For all groups, mean final height corrected for mid-parental height was within the normal Swedish height range. In patients with severe GHD, mean final height was almost identical to mean normal Swedish height. About 16% of patients showed disproportionality (short legs) at final height and were significantly shorter than other patients. The parents of these children also demonstrated short stature. Conclusion: Children with idiopathic GHD receiving GH replacement therapy can achieve a final height that as a group is within the normal range and all achieve a height within their genetic potential.

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.

The aim of this study was to evaluate in an intraindividual comparison the durability of a polyacid-modified resin composite/resin composite open sandwich restoration in a 9 years follow-up. A polyacid-modified resin composite (PMRC; compomer, Dyract) was placed as an intermediate layer and covered with resin composite (RC, Prisma TPH). A direct RC restoration was used as control.Each of 57 patients, received at least one pair of Class II restorations, one open sandwich and one resin composite control. In total 75 pairs of Class II restorations, 68 premolars and 82 molars, all in occlusion, were placed by two dentists. Most of the cavities were surrounded by enamel. The restorations were evaluated at baseline, 6, 12, 24, 36 months and 9 years by slightly modified USPHS criteria. Survival of restorations grouped on the two different techniques was determined using Kaplan-Meier survival curves.After 9 years, 14 of 135 evaluated restorations were estimated as unacceptable, 6 in the sandwich group and 8 in the control group. Over all annual failure rate during the 9-year period was 1.1%. The survival rate was not significant different between the two techniques (p=0.604). Reasons of failure were: secondary caries (8), fracture of tooth (1), fracture of restoration (2), endodontic treatment (3).Both restorative techniques showed good durability during the 9-year period. No clinical advantage was observed for the sandwich technique.

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.

Background: Recently, growth hormone (GH) therapy for children with short stature born small for gestational age (SGA) has been approved in the USA and Europe. There have been few reports examining adverse events during GH treatment of these children. Aims: (i) To examine glucose tolerance and insulin sensitivity during GH treatment of children born SGA in a US trial. (ii) To determine and compare adverse events reported in children born SGA with those reported in children with idiopathic short stature (ISS) enrolled in KIGS – Pfizer International Growth Database. Methods: In the US SGA trial, an oral glucose tolerance test was performed and fasting plasma glucose, insulin and glycosylated haemoglobin (HbA1C) concentrations were measured at baseline and after 12 months of GH therapy. Insulin sensitivity was calculated using the homeostasis model assessment (HOMA) and the quantitative insulin sensitivity check index (QUICKI). In the KIGS analysis, a retrospective audit of spontaneously logged cumulative adverse events in children born SGA and those with ISS was undertaken. Adverse events are reported per 1,000 patients. Values are expressed as mean with 10th–90th percentiles. Results: In the US trial, 84 patients had complete data sets for analysis. Median birth weight was 1.78 kg (SDS, –2.5) and birth length 43 cm (SDS, –2.2) at a median gestational age of 36.5 weeks; 79% were Caucasian. At entry, median age of the patients analysed was 6.6 years, and 65% were male. Median height was 104.3 cm (SDS, –2.97), median weight 15.95 kg (SDS, –2.21) and body mass index 14.66 kg/m2 (SDS, –0.67). No patients developed impaired glucose tolerance or overt diabetes mellitus. The 0-min glucose concentration was 81 mg/dl at baseline and 86 mg/dl at 1 year, while the 120-min glucose concentration was 90 mg/dl at baseline and 96 mg/dl at 1 year. The 0-min insulin concentrations were 2.9 mU/l at baseline and 5.3 mU/l at 1 year, while the 120-min insulin levels were 7.7 mU/l at baseline and 11 mU/l at 1 year. The proportions of HbA1C were 5.2 and 5.4% at baseline and 1 year, respectively. HOMA and QUICKI values were 0.59 and 0.42, respectively, at baseline, and 1.13 and 0.38 at 1 year. In KIGS, there were 1909 children born SGA aged 9.1 (3.9–13.3) years with a birth weight SDS of –2.6 (–4.0 to –1.5), birth length SDS of –2.7 (–4.3 to –1.3) and height SDS of –2.71 (–3.9 to –1.8) prior to treatment. GH doses ranged from 0.032 to 0.037 in the USA and from 0.022 to 0.023 mg/kg/day in the remaining countries in KIGS. Neither total (187 vs. 183) nor serious (14 vs. 10) adverse events occurred more commonly in the SGA group than in the ISS group. Although respiratory adverse events occurred more commonly in children born SGA (34.3 vs. 16.8; p < 0.05), endocrine (12.0 vs. 2.7; p < 0.05) and hepatobiliary (6.2 vs. 1.1; p < 0.05) adverse events occurred more commonly in children with ISS. Conclusions: As expected, a reduction in insulin sensitivity occurred during GH treatment of children born SGA; however, glucose tolerance remained normal. No adverse events were reported more commonly in children born SGA than in those with ISS. Minor differences in adverse events reporting within organ systems between children born SGA and those with ISS are probably due to variable under-reporting of adverse events. GH appears to be a safe drug to use at current doses as a growth-promoting agent in short children born SGA.

The aim of this study was to evaluate in vivo the interfacial adaptation of class II resin composite restorations with and without a flowable liner. In 24 premolars scheduled to be extracted after 1 month, 48 box-shaped, enamel-bordered class II cavities were prepared and restored with a flowable liner (FRC, Tetric Flow/Tetric Ceram/Syntac Single-Component) or without (TRC), cured with three different curing modes: soft start and 500- or 700-mW/cm2 continuous irradiation. Interfacial adaptation was evaluated by quantitative scanning electron microscopic analysis using replica method. Gap-free adaptation in the cervical enamel (CE) was observed for FRC and TRC in 96.2 and 90.2%, for the dentin (D) in 63.6 and 64.9%, and for occlusal enamel (OE) in 99.7 and 99.5%, respectively. The difference between the two restorations was not statistically significant (ns). Significant better adaptation was observed for OE than CE and D (p

This in vitro study evaluated curing depths of a universal hybrid resin composite with two viscosities (Tetric Ceram and Tetric Flow) after curing with 6 different quartz tungsten halogen and light-emitting diode curing units. Irradiance (light intensity) of the curing units varied between 200 and 700 mW/cm2. The curing units were used for standard, soft-start, or pulse curing. Curing times were 20 and 40 s for standard curing, 3 + 10 s and 3 + 30 s for pulse curing, and 40 s for soft-start. Resin composite specimens, 5 in each group, with a diameter of 4 mm and a height of 6 mm, were made in brass molds and cured from one side at a distance of 6 mm. After 2 weeks, the specimens were ground longitudinally half through the specimen. Curing depth was then determined by measurement of Wallace hardness for each half millimeter starting at 0.5 mm from the top surface. For all curing units and for both resin composites an increased curing time led to statistically significantly higher depth of cure (P < 0.0005). Tetric Flow showed a statistically significantly higher depth of cure than Tetric Ceram (P < 0.0005). All curing units cured more than 2.0 mm of both composites from a distance of 6 mm at 20 s curing time. The value for 40 s was 3.0 mm. The composite closer to the surface than the depth of cure value was equally well cured with all curing units investigated. There was a significant linear correlation between the determined irradiance of the curing units and the depths of cure obtained (20s: r = 0.89, P < 0.025; 40 s: r = 0.91, P < 0.01).

The aim of this in vivo study was to evaluate the interfacial marginal adaptation of a calcium aluminate cement, Doxadent (DD), and to compare it intra-individually with a resin composite, Tetric Ceram/Syntac Single-Component (TC/SS), in Class II cavities. Sixteen Class II box-shaped, enamel-bordered cavities were prepared in eight premolars scheduled to be extracted after 1 month's service for orthodontic reasons. The interfacial marginal adaptation (internal surfaces) of the restorations was evaluated by a quantitative scanning electron microscope analysis using a replica method. DD showed a statistically significant, lower degree of gap-free adaptation to enamel compared with TC/SS: 84% vs. 93%. To dentin, DD showed a significantly better adaptation than TC/SS: 72% vs. 49%. A high frequency of enamel fractures perpendicular to the margins was observed for the DD restorations, which may be explained by an expansion of the calcium-aluminate cement. It can be concluded that DD showed a better adaptation to dentin while TC/SS showed a better adaptation to enamel. The dimensional changes of DD have to be investigated before clinical use can be recommended.

The introduction of the 2 neuraminidase inhibitors (NAIs) zanamivir and oseltamivir has offered new options for the prevention and treatment of influenza. This article summarizes a Swedish consensus guidance document on the rational use of antiviral drugs in the management of influenza virus infections. Vaccination remains the cornerstone for influenza prophylaxis. Target groups for the annual vaccination programme are the 'at-risk' individuals, i.e. elderly patients ( > or = 65 y) and patients with chronic pulmonary disease or cardiovascular disease or other chronic diseases predisposing for a complicated course of influenza. Antiviral drugs are not a substitute for influenza vaccination, but could be used as adjuncts. Currently, 3 drugs have been approved for the treatment of influenza, including zanamivir and oseltamivir and the M2 inhibitor amantadin. Amantadin has come to very limited use, has recently been withdrawn from the Swedish market and is available only on a named patient basis. Compared with amantadin, the NAIs have clear advantages because of their broader anti-influenza activity against both type A and B, improved safety profiles and low potential for inducing drug resistance. The NAls are therefore recommended as first options in the treatment of influenza. Oseltamivir can be taken orally, whereas zanamivir is for oral inhalation. Limited in vitro and in vivo data suggest that oseltamivir is less potent against influenza B, whereas zanamivir seems equally effective against influenza A and B. In influenza-positive healthy adults and children, treated within 48 h after symptom onset, the NAIs shorten the duration of illness by about 1 d. No significant effect on the duration of symptoms has been documented in treated at-risk patients with influenza. Owing to their limited therapeutic benefit, general use of the NAIs in the treatment of influenza is not recommended, but they can be advocated on an individualized basis for patients with severe influenza who can start therapy within 48 h of the onset of symptoms. Zanamivir is the preferred choice in a confirmed influenza B epidemic. For prevention of influenza, 2 drugs are approved, oseltamivir in adults above 12 y old and amantadin in people above 10 y old. The 70-90% protective efficacy of oseltamivir for household postexposure prophylaxis and for seasonal prophylaxis is comparable to that reported for amantadin. Oseltamivir is the preferred drug for prophylactic use. Chemoprophylaxis is targeted at high-risk groups and should be considered on a case-by-case basis depending on the circumstances and the population requiring protection. A broader preventive use of oseltamivir can be advocated in at-risk groups during seasons when there is a poor antigenic match between the epidemic strains and the vaccine strains. Oseltamivir prophylaxis is otherwise recommended for patients unable to be vaccinated and for families exposed to influenza which include a member of the at-risk groups. In high-risk hospital units and in institutions caring for the elderly, oseltamivir prophylaxis, in combination with vaccination, can be recommended as measures to control an influenza outbreak.

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 (

Recombinant human (rh) growth hormone (GH) raises the glomerular filtration rate (GFR) in healthy individuals. Concern has been raised that long-term rhGH treatment in short children with chronic kidney disease (CKD) may accelerate the progression of CKD via induction of glomerular hyperfiltration. We compared the decline in GFR in children with CKD enrolled in two large clinical studies with (KIGS registry) and without (ESCAPE trial) concomitant rhGH treatment and followed for up to 10 years. Estimated GFR (eGFR) was determined at yearly intervals. The annual decline in eGFR was analyzed cross-sectionally for up to 10 years and longitudinally for 5 years. In the KIGS registry 367 patients with CKD stages II–IV (mean age 8.0 years; 72 % boys; mean eGFR 38.4 ml/min/1.73 m2) were treated with 0.33 mg rhGH/kg per week for at least 1 year. In the ESCAPE trial 274 non-rhGH-treated patients with CKD stages II–IV (mean age 11.6 years; 61 % boys; mean GFR 47.3 ml/min/1.73 m2) were followed for at least 1 year. At the 5-year follow-up, the mean loss of eGFR in the KIGS children receiving continuous rhGH treatment (n = 97) did not differ significantly from that in the controls (n = 113) in the ESCAPE trial (−5.8 vs. −8.6 ml/5 years, respectively; p = 0.17). Absolute height and eGFR at baseline were significant correlates of the annual eGFR loss (model R 2 =0.121). Long-term rhGH-treatment does not accelerate the decline in GFR in short children with CKD. Height and baseline eGFR are significant predictors of the loss of GFR in CKD patients.

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

Many children with idiopathic short stature (ISS) remain short as adults. Height can be improved permanently by growth hormone (GH) treatment, as in children with Turner syndrome or born small for gestational age. Although GH treatment for ISS is an approved indication in the United States, there is ongoing controversy in Europe about approving GH treatment for this indication as well as determining the optimal mode of treatment. In addition to data from randomized controlled trials, data from pharmacoepidemiological surveys such as the Pfizer International Growth Study Database (KIGS) have provided substantial information about the short-term and long-term effects of GH on growth and adult height in children with ISS. Based on published articles and a recent survey from KIGS on 454 patients who have reached adult height, we attempted to categorize those children with ISS who have the greatest chances of achieving a normal adult height, or at least gain the most height following GH treatment. This analysis provides a rational basis for discussion about the most efficacious and cost-effective uses of GH treatment in children with ISS.

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.

Data collected from 102 neurofibromatosis (NF) children with growth hormone (GH) deficiency (GHD) who were receiving GH replacement therapy were reviewed to assess the efficacy and safety of GH therapy in this condition. GH was administered at a mean dose of 0.18 mg/kg/week. During the 1st year the median height velocity increased significantly from 4.2 cm/year before treatment to 7.1 cm/year, and the median height standard deviation score increased from –2.4 to –1.9. The response to therapy, however, was not as good as that observed in patients with idiopathic GHD. GH therapy did not influence the progression of any of the features of NF, including intracranial tumours, and was not associated with an excess of other adverse events. We conclude that GH treatment of NF patients with GHD is beneficial in terms of improved growth rate and is well tolerated.

Objective: To assess the efficacy and safety of growth hormone (GH) therapy in children with GH deficiency in association with neurofibromatosis. Methods: Retrospective analysis of data from the Pharmacia and Upjohn International Growth Database (KIGS) in a total of 102 GH-deficient children with neurofibromatosis treated with recombinant GH. Results: Median pretreatment height velocity was 4.2 cm/yr (1.7 to 6.4 cm/yr), increased to 7.1 cm/yr (4.6 to 10.0 cm/yr) in the first year of GH therapy, and remained significantly greater than pretreatment at 5.7 cm/yr (2.9 to 8.3 cm/yr) and 5.7 cm/yr (2.6 to 7.9 cm/yr) in the second and third years, respectively. The median height SD score increased from –2.4 to –1.8 by the end of 3 years of treatment. Five patients had either a recurrence of an intracranial tumor or a second intracranial tumor; this incidence of tumor occurrence is comparable to that reported previously in similar patients with neurofibromatosis. Other adverse events were relatively minor and unlikely to be attributable to GH therapy. Conclusions: The data indicate that GH replacement therapy, per se, for patients with neurofibromatosis and GH deficiency is likely to be beneficial and unassociated with excessive malignant risk. (J Pediatr 1998;133:201-5)

Objective Growth hormone (GH) increases lean body mass and reduces fat mass. However, the long-term changes in weight status during growth hormone treatment, according to age and weight status at onset of treatment, have not previously been reported in large data sets. Methods Changes in BMI-SDS between starting GH treatment and attaining near adult height (NAH) were analysed in 2643 children with idiopathic GH deficiency (IGHD), 281 children small for gestational age (SGA), 1661 girls with Turner syndrome (TS), and 142 children with Prader-Willi syndrome (PWS) in the KIGS database. Results BMI-SDS increased significantly between onset of GH treatment and NAH (IGHD:+0·29, SGA:+0·69, TS:+0·48) except in PWS (-0·02). These increases were greater in children with younger age at onset of GH treatment (significant in all indications) and with lower doses of GH treatment (significant in IGHD & TS) in multiple linear regression analyses also including gender, duration of GH treatment, BMI-SDS and height-SDS at onset of treatment, and birth weight-SDS. Obese children at onset of GH treatment decreased their BMI-SDS, while underweight and normal weight children at onset of GH treatment increased their BMI-SDS independently of GH treatment indication. Conclusions Long-term GH treatment was associated with changes in weight status, which were beneficial for underweight and obese children independent of the indication for GH. However, the increase in BMI-SDS in normal weight children treated with GH needs to be investigated in future prospective longitudinal studies to analyse whether this represents an increase of fat mass, lean body mass or both.

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.

To study the durability of a recently developed low-shrinkage resin composite, suggested to counter the stress formation in direct resin composite restorations.Each of 50 patients received one or two pair(s) of Class II restorations. The first restoration in the pair was a low-shrinkage resin composite (InTen-S) and the second a hybrid resin composite restoration (Point 4). Both restorations were placed with an etch-and-rinse bonding system and an oblique layering technique. A total of 106 restorations, 33 premolar and 73 molars, were placed. The restorations were evaluated annually.At 5 years, 97 restorations were evaluated. Two participants reported slight postoperative sensitivity symptoms for a few weeks after placement. Twelve non acceptable restorations were observed during the 5 years, five InTen-S (10.4%) and 7 Point 4 (14.3%) (not significant). Secondary caries was the main reason for failure (8) followed by composite fracture (2) and tooth fracture (2).The low-shrinkage resin composite showed good durability, but not significantly better than the control resin composite in Class II cavities. Most failures occurred at the last part of the study. Secondary caries was the main reason for failure.

To investigate the selection of direct restorative materials and longevity of replaced restorations in relation to operator and patients characteristics.A cross-sectional study of treatment in practice, recording all new placements and replacements of direct restorations was performed during 2 weeks comprising all dentists within the Public Dental Health clinics in the county council of Västerbotten.A total of 2834 data collection sheets, one for each placed restoration, were received with a dropout of 10%. Restorations analyzed in the study were placed in permanent teeth in patients older than 15 years. First restorations placed due to primary caries were 671 and replacements 1536. Class II was the most frequently treated cavity followed by class I. The median longevity of replaced restorations was for amalgam, resin based composite and glass ionomer 16, 6 and 11 years, respectively. High caries risk patients showed shorter longevity for resin based composite restorations than low or moderate risk patients. Secondary caries as reason for failure for class II resin based composite restorations occurred significantly later than loss or fracture. Significantly longer longevity was observed for replaced restorations executed by more experienced dentists.The use of amalgam was negligible and the material was predominantly replaced by resin based composites in first and replaced restorations. Class II was the most frequent placed and replaced restorations. Caries risk and experience of operator influenced longevity of replacements.

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.

The use of growth hormone (GH) to treat children who have disturbances of growth is complicated by variability both within and across diagnostic groups, and at the start of and throughout treatment. Growth prediction models are important tools in the effort to account for these sources of variability and tailor GH treatment to each patient's needs. This review considers the methodological approach taken to the development of models from data in large databases such as the Pfizer International Growth Database (KIGS); it also assesses the limitations of these models and their data sources, and the potential for improvements. While all aspects of model development bear continued scrutiny and improvement, the incorporation of more predictors is key if treatment outcomes are to be optimized in terms of efficacy, safety and cost.

Aim: To develop methods to identify factors associated with a favorable outcome in GH-treated children with idiopathic short stature (ISS). Methods: From 4,685 children listed as having ISS within KIGS (Pfizer International Growth Database), we studied (a) the prediction model group (n = 657) to develop the first-year prediction model, and (b) the near adult height group (NAH; n = 256) which received GH for >4 years to develop descriptive models for adult height and overall height gain. Results: NAH group at GH start: age was 10.0 years, height –2.5 SD score (SDS), weight –2.3 SDS, height minus mid-parental height (MPH) –1.5 SDS; GH dose 0.19 mg/kg/week. Height gain was 1.1 SDS at a median age of 17.2 years. Growth response correlated positively with GH dose and weight at the start of GH treatment, and negatively with age and height SDS minus MPH SDS. The model explains 39% (error SD 1.2 cm) of the variability. Adult height correlated (R2 = 0.64) positively with height at GH start, MPH and the first-year responsiveness to GH, and negatively with age. Conclusions: Prepubertal children with ISS who show an appropriate first-year response to GH are likely to benefit from long-term treatment, even on low GH dosages.