Design, construction, and quality tests of the large Al-alloy mandrels for the CMS coil

The Compact Muon Solenoid (CMS) is one of the general-purpose detectors to be provided for the LHC project at CERN. The design field of the CMS superconducting magnet is 4 T, the magnetic length is 12.5 m and the free bore is 6 m. Almost all large indirectly cooled solenoids constructed to date (e.g., Zeus, Aleph, Delphi, Finuda, Babar) comprise Al-alloy mandrels fabricated by welding together plates bent to the correct radius. The external cylinder of CMS will consist of five modules having an inner diameter of 6.8 m, a thickness of 50 mm and an individual length of 2.5 m. It will be manufactured by bending and welding thick plates (75 mm) of the strain hardened aluminum alloy EN AW-5083-H321. The required high geometrical tolerances and mechanical strength (a yield strength of 209 MPa at 4.2 K) impose a critical appraisal of the design, the fabrication techniques, the welding procedures and the quality controls. The thick flanges at both ends of each module will be fabricated as seamless rolled rings, circumferentially welded to the body of the modules. The developed procedures and manufacturing methods will be validated by the construction of a prototype mandrel of full diameter and reduced length (670 mm). (7 refs)

Accuracy and limitations of the growth hormone (GH) releasing hormone-arginine retesting in young adults with childhood-onset GH deficiency

Background: Re-testing for GH secretion is needed to confirm the diagnosis of GH deficiency (GHD) after adult height achievement in childhood-onset GHD (COGHD). Aim: To define the cut-off of GH peak after retesting with GH-releasing hormone plus arginine (GHRHarg) in the diagnosis of permanent GHD in COGHD of different etiology. Patients and methods: Eighty-eight COGHD (median age 17.2 y), 29 idiopathic GHD (IGHD), 44 cancer survivors (TGHD) and 15 congenital GHD (CGHD) were enrolled in the study; 54 had isolated GHD (iGHD) and 34 had multiple pituitary hormone deficiencies (MPHD). All were tested with insulin tolerance test (ITT) and GHRHarg. IGHD with a GH response to ITT 656\ub5g/L were considered true negatives and served as the control group, and patients with a GH response <6\ub5g/L as true positives. Baseline IGF-I was also measured. The diagnostic accuracy of GHRHarg testing and of IGF-I SDS in patients with GHD of different etiologies was evaluated by ROC analysis. Results: Forty-six subjects with a GH peak to ITT 656\ub5g/L and 42 with GH peak <6 \ub5g/L showed a GH peak after GHRHarg between 8.8\u2013124\ub5g/L and 0.3\u201326.3\ub5g/L, respectively; 29 IGHD were true negatives, 42 were true positives and 17 with a high likelihood GHD showed a GH peak to ITT 656\ub5g/L. ROC analysis based on the etiology indicated the best diagnostic accuracy for peak GH cutoffs after GHRHarg of 25.3 \ub5g/L in CGHD, 15.7 in TGHD, and 13.8 in MPHD, and for IGF-1 SDS at 122.1 in CGHD, 121.5 in TGHD, and 121.9 in MPHD. Conclusions: Our findings indicate that the best cut-off for GH peak after retesting with GHRHarg changes according to the etiology of GHD during the transition age. Based on these results the diagnostic accuracy of GHRHarg remains questionable

Safety outcomes during pediatric GH therapy: final results from the prospective GeNeSIS observational program

CONTEXT: Safety concerns regarding premature mortality, diabetes, neoplasia and cerebrovascular disease in association with growth hormone (GH) therapy have been raised. OBJECTIVE: To assess incidence of key safety outcomes. DESIGN: Prospective, multinational, observational study (1999-2015). SETTING: 22,311 GH-treated children from 827 investigative sites in 30 countries. PATIENTS: Children with growth disorders. INTERVENTIONS: GH treatment. MAIN OUTCOME MEASURES: Standardized mortality (SMR) and incidence (SIR) ratios with 95% confidence intervals (CI) for mortality, diabetes, and primary cancer, using general population registries. RESULTS: Predominant short stature diagnoses were GH deficiency (63%), idiopathic short stature (13%), and Turner syndrome (8%), with mean±SD follow-up of 4.2±3.2 years (∼92,000 person-years [PY]). Forty-two deaths occurred in patients with follow-up, with SMR (95% CI) of 0.61 (0.44-0.82); the SMR was elevated for patients with cancer-related organic GH deficiency (5.87 [3.21-9.85]). Based on 18 cases, Type 2 diabetes (T2DM) risk was elevated (SIR 3.77 [2.24-5.96]), but 72% had risk factors. In patients without cancer history, 14 primary cancers were observed (SIR 0.71 [0.39-1.20]). Second neoplasms occurred in 31/622 (5.0%) cancer survivors (10.7 [7.5-15.2] cases/1000 PY), and intracranial tumor recurrences in 67/823 (8.1%) tumor survivors (16.9 [13.3-21.5] cases/1000 PY). All 3 hemorrhagic stroke cases had risk factors. CONCLUSIONS: GeNeSIS data support the favourable safety profile of pediatric GH treatment. Overall risk for death or primary cancer was not elevated in GH-treated children, and no hemorrhagic strokes occurred in patients without risk factors. T2DM incidence was elevated compared to the general population, but most cases had diabetes risk factors

Elevated blood pressure, cardiometabolic risk and target organ damage in youth with overweight and obesity

Background and aim: To compare cardiometabolic risk profile and preclinical signs of target organ damage in youth with normal and elevated blood pressure (BP), according to the American Academy of Pediatrics (AAP) guidelines. Methods and results: This cross-sectional multicenter study included 2739 youth (5-17 year-old; 170 normal-weight, 610 overweight and 1959 with obesity) defined non hypertensive by the AAP guidelines. Anthropometric, biochemical and liver ultrasound data were available in the whole population; carotid artery ultrasound and echocardiographic assessments were available respectively in 427 and 264 youth. Elevated BP was defined as BP 65 90th to <95th percentile for age, gender and height in children or BP 65 120/80 to <130/80 in adolescents. The overall prevalence of elevated BP was 18.3%, and significantly increased from normal-weight to obese youth. Young people with elevated BP showed higher levels of body mass index (BMI), insulin resistance and a higher prevalence of liver steatosis (45% vs 36%, p < 0.0001) than normotensive youth, whilst they did not differ for the other cardiometabolic risk factors, neither for carotid intima media thickness or left ventricular mass. Compared with normotensive youth, individuals with elevated BP had an odds ratio (95%Cl) of 3.60 (2.00\u20136.46) for overweight/obesity, 1.46 (1.19\u20131.78) for insulin-resistance and 1.45 (1.19\u20131.77) for liver steatosis, controlling for centers, age and prepubertal stage. The odds for insulin resistance and liver steatosis persisted elevated after correction for BMI-SDS. Conclusion: Compared to normotensive youth, elevated BP is associated with increased BMI, insulin resistance and liver steatosis, without significant target organ damage

Efficacy and safety of growth hormone treatment in children with short stature: the Italian cohort of the GeNeSIS clinical study

Purpose: We examined auxological changes in growth hormone (GH)-treated children in Italy using data from the Italian cohort of the multinational observational Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS) of pediatric patients requiring GH treatment. Methods: We studied 711 children (median baseline age 9.6&nbsp;years). Diagnosis associated with short stature was as determined by the investigator. Height standard deviation score (SDS) was evaluated yearly until final or near-final height (n&nbsp;=&nbsp;78). Adverse events were assessed in all GH-treated patients. Results: The diagnosis resulting in GH treatment was GH deficiency (GHD) in 85.5&nbsp;% of patients, followed by Turner syndrome (TS 6.6&nbsp;%). Median starting GH dose was higher in patients with TS (0.30&nbsp;mg/kg/week) than patients with GHD (0.23&nbsp;mg/kg/week). Median (interquartile range) GH treatment duration was 2.6 (0.6\u20133.7) years. Mean (95&nbsp;% confidence interval) final height SDS gain was 2.00 (1.27\u20132.73) for patients with organic GHD (n&nbsp;=&nbsp;18) and 1.19 (0.97\u20131.40) for patients with idiopathic GHD (n&nbsp;=&nbsp;41), but lower for patients with TS, 0.37 ( 120.03 to 0.77, n&nbsp;=&nbsp;13). Final height SDS was&nbsp;&gt; 122 for 94&nbsp;% of organic GHD, 88&nbsp;% of idiopathic GHD and 62&nbsp;% of TS patients. Mean age at GH start was lower for organic GHD patients, and treatment duration was longer than for other groups, resulting in greater mean final height gain. GH-related adverse events occurred mainly in patients diagnosed with idiopathic GHD. Conclusions: Data from the Italian cohort of GeNeSIS showed auxological changes and safety of GH therapy consistent with results from international surveillance databases