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Purpose: The Audiovisual-Assisted Therapeutic Ambience in Radiotherapy (AVATAR) trial was a prospective multicenter study (NCT03991156) examining the combination of video immersion with radiation therapy and was successfully conducted through the collaboration of pediatric radiation oncology teams at 10 institutions independent of any pre-existing consortium. We sought to analyze and report the methodology of trial conception and development, process map, and cost. Methods and Materials: The study enrolled patients aged 3 to 10 years preparing to undergo radiation therapy, integrated the combination of AVATAR-based video immersion with radiation therapy at each institution, and offered AVATAR use as an alternative to anesthesia, with rates of anesthesia use and outcomes of serial standardized anxiety and quality-of-life assessments assessed among the 81 children enrolled. A process map was created based on the trial timeline with the following components: study development time (time from conception of the trial to the accrual of the first patient, including design phase, agreement and approval phase, and site preparation phase), and accrual duration time (time from the first to last accrual). Costs and institutional success rates were calculated. Results: Time from inception of study to last accrual was 3.6 years (1313 days). The study development time was 417 days (31.7%), and accrual duration time was 896 days (68.3%), with the final 50% of accrual occurring in

Background: Periprosthetic femur fractures (PPFFs) following total hip arthroplasty (THA) have increased in the past decade as the demand for primary surgery continues to grow. Although there is now more evidence to describe the treatment of Vancouver B fractures, there is still limited knowledge regarding factors that cause surgeons to perform either an open reduction and internal fixation (ORIF) or revision THA (rTHA). The purpose of this study was to determine what type of surgeons treat Vancouver B PPFFs at 11 major academic institutions and if there are trends in treatment decision-making regarding the use of ORIF or rTHA based on surgical training or patient factors. Methods: This multicenter retrospective study evaluated patients surgically treated for Vancouver B PPFF after THA between 2014 and 2019. Patients from 11 academic centers located in the United States were included in this study. Surgical outcomes and patient demographics were evaluated based on surgeon training, surgical treatment type, and institution. Results: Presence of Vancouver B2 (odds ratio [OR]: 0.02, P < .001) or B3 (OR: 0.04, P < .001) fractures were independent risk factors for treatment with rTHA. Treatment by a trauma (OR: 12.49, P < .001) or other-specified surgeon (OR: 13.63, P < .001) were independent risk factors for ORIF repair of Vancouver B fractures. There were no differences in outcomes based on surgeon subspecialty training. Conclusions: This study showed the trends in surgeons who surgically manage Vancouver B fractures at 11 major academic institutions and highlighted that regardless of surgical training or surgical treatment type, postoperative outcomes following management of PPFF were similar.

Background: Conditional survival (CS) analyses provide an estimate of survival accounting for years already survived after treatment. We aim to evaluate the difference between actuarial and conditional survival in patients following lung resection for non–small cell lung cancer (NSCLC). In addition, CS analyses are used to examine whether prognosticators of survival change over time following surgery. Methods: Patients who underwent anatomic lung resection at a single institution for pathologic stage I-IIIA NSCLC between 2010 and 2021 were identified; those who underwent wedge resection for node-negative tumors ≤2 cm were also included. CS estimates were calculated as the probability of remaining disease-free after x years of nonrecurrence (CSx). Kaplan–Meier, log-rank, and Cox proportional hazard methods for examining CS were used for subgroup comparisons and assessing associations with baseline covariates. Results: Overall, 863 patients met the study inclusion criteria, with a median follow-up of 44.1 months. Conditional overall survival (OS) and disease-free survival (DFS) were greater than actuarial rates at all time points after surgery. At the time of resection, male sex (hazard ratio [HR], 1.33; 95% confidence interval [CI], 1.03 to 1.72; P = .032), tumor size >3 cm (HR, 1.17; 95% CI, 1.11-1.23; P

OBJECTIVES:. Examine the: 1) relative role of hemodynamic determinants of acute kidney injury (AKI) obtained in the immediate postcardiac surgery setting compared with established risk factors, 2) their predictive value, and 3) extent mediation via central venous pressure (CVP) and mean arterial pressure (MAP). DESIGN:. Retrospective observational study. The main outcome of the study was moderate to severe AKI, per kidney disease: improving global outcomes, within 14 days of surgery. SETTING:. U.S. academic medical center. PATIENTS:. Adult patients undergoing cardiac surgery between January 2000 and December 2019 (n = 40,426) in a single U.S.-based medical center. Pulmonary artery catheter measurements were performed at a median of 102 minutes (11, 132) following cardiopulmonary bypass discontinuation. INTERVENTIONS:. None. MEASUREMENTS AND RESULTS:. The median age of the cohort was 67 years (58, 75), and 33% were female; 70% had chronic hypertension, 29% had congestive heart failure, and 3% had chronic kidney disease. In a multivariable model, which included comorbidities and traditional intraoperative risk factors, CVP (p < 0.0001), heart rate (p < 0.0001), cardiac index (p < 0.0001), and MAP (p < 0.0001), were strong predictors of AKI, and superseded factors such as surgery type and cardiopulmonary bypass duration. The cardiac index had a significant interaction with heart rate (p = 0.026); a faster heart rate had a differentiating effect on the relationship of cardiac index with AKI, where a higher heart rate heightened the risk of AKI primarily in patients with low cardiac output. There was also significant interaction observed between CVP and MAP (p = 0.009); where the combination of elevated CVP and low MAP had a synergistic effect on AKI incidence. CONCLUSIONS:. Hemodynamic factors measured within a few hours of surgery showed a strong association with AKI. Furthermore, determinants of kidney perfusion, namely CVP and arterial pressure are interdependent; as are constituents of stroke volume, that is, cardiac output and heart rate.

Background: Current aspirin desensitization protocols for aspirin-exacerbated respiratory disease (AERD) require from 1 to 3 days to complete. Objective: Our aim was to assess the implementation of a 1-day versus 2-day aspirin desensitization protocol in patients with aspirin-exacerbated respiratory disease. Methods: We used a preintervention-postintervention quality improvement design to compare the completion rates, reaction rates, and estimated costs of a 2-day versus 1-day aspirin desensitization. The cost for each desensitization was estimated on the basis of 2017-2020 US Medicare standards. We included the predesensitization variables for FEV1 value, urinary leukotriene E4 level, absolute eosinophil count (AEC), and total IgE level for each group. Results: A total of 15 patients underwent a 2-day aspirin desensitization in the 4-year (2017-2020) preintervention period and were compared with 8 patients who underwent a 1-day aspirin desensitization in the 1-year (2021) postintervention period. The desensitization completion rate (93% vs 100% [P = 1]) and the mean number of reactions requiring intervention during the desensitization protocols (0.26 vs 0.8 [P = .14]) were similar between groups. The average time frame between last polypectomy and desensitization was longer in the 2-day group (1946 vs 39.2 days [P = .03]). The mean values for FEV1 level, urinary leukotriene E4 level, absolute eosinophil count, and total IgE level were 76% vs 83% (P = .6), 1084 vs 385 pg/mg (P = .2), 686 vs 306 cells/μL (P = .74), and 735 vs 278 kU/L (P = .5), respectively. The estimated direct cost reduction was $762 per aspirin desensitization for using 1-day vs 2-day aspirin desensitization. Conclusion: Compared with a 2-day protocol, the implementation of a 1-day aspirin desensitization was characterized by similar completion and reaction rates as well as lower costs.

ABSTRACT: Purpose: Children with leukemia who receive fractionated total body irradiation (fTBI) with 12 to 13.2 Gy as part of conditioning for hematopoietic stem cell transplant are frequently treated with an additional 4 Gy testicular boost to reduce the risk of testicular relapse. While institutional practices vary, limited data exists regarding whether the 4-Gy testicular boost reduces the risk of relapse and whether it causes toxicity beyond that imparted by TBI. This study compared the survival and endocrine outcomes among the patients who were treated with and without a testicular boost as part of fTBI from 1990 to 2019 at our center. Methods and Materials: We retrospectively reviewed charts of male children with leukemia treated with fTBI as part of a conditioning regimen for stem cell transplant from 1990 to 2019. Reported outcomes included progression-free survival, testicular relapse rate, and overall survival. Gonadal dysfunction and fertility were assessed by comparing the rate of abnormally low testosterone or high luteinizing hormone or follicular stimulating hormone, number of offspring, fertility service use, and abnormal sperm count in the subsequent follow-up period between the testicular boost and nonboost subset. Results: Ninety-three male patients (63 acute lymphoblastic leukemia, 30 acute myeloid leukemia) with a median age of 9 years (range, 1-22) and follow-up of 3.3 years were included. In addition to 12- to 13.2-Gy fTBI, 51 male patients (54%) received a testicular boost to 4 Gy. There was 1 testicular relapse in the boost subset and none in the nonboost subset. Five-year progression-free survival for the boost and nonboost subset was 74% and 66%, respectively (P = .31). On multivariable analysis, boost was not associated with improved relapse-free survival or overall survival. More patients in the boost subset (35 of 51, 69%) had abnormal serum gonadal blood work compared with the nonboost subset (18 of 42, 43%) (P = .03). Conclusions: Omission of testicular boost may be associated with comparable oncologic but improved gonadal endocrine outcomes and should be further studied.

Objective The uncinate process may play a role in the amount of irrigation penetrance. In this cadaver study, we aimed to investigate if the addition of partial uncinectomy provides better maxillary sinus irrigation penetrance than balloon sinuplasty (BSP) alone. Study Design Cadaveric study. Setting Simulation laboratory at the Mayo Clinic in Florida. Methods Five fresh-frozen human cadaveric heads (10 sides) were used to assess maxillary sinus irrigation penetration after 3 interventions performed sequentially: irrigation penetrance with no intervention, irrigation after BSP, and irrigation after BSP and partial removal of the uncinate. Penetrance was recorded with intrasinus endoscopy and scored by 4 blinded observers using a scale from 0 (no irrigation) to 5 (fully irrigated). The diameter of the maxillary ostium was measured before and after BSP. Internal consistency was evaluated with Cronbach’s alpha. Results Mean ostium size increased from 4.1 to 6.8 mm after BSP ( P = .013). Cronbach’s alpha was 0.93. The median scores of irrigation penetration after no intervention, BSP, and BSP and partial uncinectomy were 2.5, 3, and 4, respectively. We found a significantly higher penetrance following partial uncinectomy plus BSP versus BSP alone ( P = .008). Both interventions had a statistically significant difference in irrigation penetrance as compared with no intervention ( P = .0001). Conclusion Maxillary sinus irrigation penetration increased from baseline after BSP. The addition of a partial uncinectomy to the balloon dilation of the maxillary sinus was associated with a statistically significant increase in irrigation penetrance scores as compared with BSP alone.

This case report describes the clinical course of a heavily pretreated patient enrolled on the Phase II QUADRUPLE THREAT clinical trial (NCT02489903) with recurrent metastatic epithelial ovarian cancer that was previously treated with a platinum doublet and that benefited from another reintroduction of a platinum doublet after a brief priming period with RRx-001. Platinum-taxane combination is the initial treatment of choice in ovarian cancer and the “go-to regimen” for patients with recurrent, platinum-sensitive disease. However, platinum resistance is an inevitable and uniformly fatal development. One of the “Holy Grails” in ovarian cancer, besides early detection, is to reverse this resistance and retreat with a platinum doublet regimen. Because of the correlation between therapeutic resistance and poor clinical outcomes, this case, which potentially demonstrates a new avenue of anticancer development in epithelial ovarian cancer provided it is repeatable with other ovarian patients, was felt to merit a report.

Contemporary MOM bearings (large-diameter heads) offered the perceived benefits of much greater range of motion and greater stability with reduced risk of impingement and dislocation. A variety of design and Both positive [1-3] and negative reports [4-8] have now emerged with regard to total hip arthroplasty (THA) and resurfacing arthroplasty. As a result, there has been an avalanche of studies focused on critical issues such as: surgical positioning, shallow cups (face angles 144-170°) [9-11] and “edge loading”. [5,7,12-17] However, there are several, possibly synergistic, risk scenarios that could trigger adverse MOM wear and very little progress has been made in understanding such interacting parameters. In an effort to understand the role of metal ion analysis and how it relates to revision surgery and implant wear, selected MOM revised cases were reviewed [28]. Retrieval data was included in conjunction with metal ion analyses and intraoperative observations to determine various failure modes. We suggest MOM devices that are well fixed but fail after 2 years can be classified into one of six modes: (i) normal, (ii) allergic reaction, (iii) 3rd body wear, (iv) repetitive subluxation with metal impingement, (v) multi-directional subluxation with soft tissue impingement, and (vi) repetitive subluxation with soft tissue impingement.

Metal-on-polyethylene (MPE) bearings have been the gold standard in total hip arthroplasty (THA) for over 40 years. However, even for the improved polyethylenes steadily gathering a reputation of very high wear resistance, it also clear that there are additional issues to consider (Fig. 1). It is well documented that impingement of metal-on-polyethylene (MPE) is a serious risk that can damage the polyethylene liner, produce additional wear debris and also lead to 3rd-body abrasion and roughening of the femoral head.1-3 Adding to these risks is the contemporary use of larger femoral heads with the consequence of adjusting to thinner polyethylene liners once believed to be a contraindication in cup design.4 The superior surface finish of CoCr implants mated with polyethylene bearings is believed to be one factor in the longevity of metal-on-polyethylene bearings (MPE). However, it may be that under long-term conditions in vivo, these 3rd body-wear particles eventually degrade the MPE surfaces.2,5-7 The two-body and three-body wear mechanisms associated with MPE is an unavoidable risk given the nature of the hip mechanics. Studies of cup impingement have documented an incidence ranging 45-68%. However in MOM studies, impingement evidence has climbed to 96%.8 We therefore sought evidence of roughening damage to the femoral heads as a result of 3rd-body wear. A study of MPE retrievals with average 12-years follow-up (N = 35 cases)9 described CoCr roughness averaging 62nm (Ra= 41-80nm). A subsequent retrieval study (N=43: 6-years) with half the follow-up time described much lower roughness of 10nm (Ra), with roughness for non-worn surfaces reported as low as 3nm.10 The 1st goal of this study was determine if femoral heads became rougher or smoother in MPE bearings with time (10-20 years). The 2nd goal was to determine if CoCr roughness simulated in laboratory tests was an adequate representation of that occurring in-vivo.

Wear debris generated by a total hip arthroplasty (THA) bearing can cause considerable damage to the surrounding soft tissues and bone, compromising patient function and causing long-term pain. In the case of a traditional bearing, a metal (or ceramic) head articulates with an ultra high molecular weight polyethylene (UHMWPE) cup. The polyethylene debris generated is processed by the macrophage, and through a cascade of cytokines, results in an inflammatory response. The inflammatory response causes a surrounding toxic reactive synovitis7. Frequently an associated pronounced osteolysis phenomenon occurs, compromising implant fixation6. The significant bone loss makes subsequent revision THA very difficult and can affect long term implant survival. The severe osteolysis seen with UHMWPE bearings prompted many surgeons to utilize alternative bearing constructs such as metal-on-metal, metal-ceramic, and ceramic-ceramic bearings.

Worth mentioning that modern trends in “The Business of Medicine,” although carefully crafted by modern men to stay within legal boundaries, when viewed by many often morally and ethically test “tolerances” of same. This applies to the blunt consideration as to whether the modern orthopod who hopefully still wishes to behave appropriately as judged by his peers and colleagues, really should risk his reputation by getting involved in ownership of an implant distributorship where many critics may doubt his ability to practice without major conflict with his patients and their best considerations in care.

Background: Thyroid imaging is of proven help in establishing a diagnosis of congenital hypothyroidism in infants. US often shows tissue in the thyroid fossa when radionuclide scintigraphy reveals only ectopic uptake.Objective: Our hypothesis was that the use of US alone could lead to the mistaken diagnosis of normal or dysplastic thyroid in cases of scintigraphy-proven thyroid ectopia.Materials and Methods: We undertook a detailed retrospective review and analysis of imaging and concurrent biochemistry in infants with thyroid ectopia, confirmed by radionuclide scintigraphy.Results: Eighteen infants had thyroid ectopia; ten of the original US reports had suggested that cervical thyroid tissue was present. Review showed bilateral tissue in the thyroid fossa in all that was non-thyroidal in nature since, apart from showing no radionuclide uptake, it exhibited some or all of the following typical features: hyperechogenicity, heterogeneity, small size, poor vascularity, and anechoic and/or hypoechoic cysts. Also, extension of the tissue both around and behind the large cervical blood vessels was a universal finding.Conclusion: Considerable experience is required to interpret neonatal thyroid US. We caution against diagnosing a dysplastic/hypoplastic thyroid gland in situ on the basis of US alone, particularly if the tissue exhibits any of the non-thyroidal features described. [ABSTRACT FROM AUTHOR]

Fifteen per cent of children treated with growth hormone (GH) are receiving treatment for Turner syndrome, but few results are available on final height in the UK. In this study, data were obtained from the UK KIGS database for 485 girls with Turner syndrome who were treated from 1986, allowing an audit of practice and outcome over 10 years. Over the decade, the mean age of starting growth hormone treatment fell from 10.4 to 8.5 years and the starting dose increased from 0.55 to 0.95 IU/kg/week. The frequency of injections increased from three to six or seven/week. Some girls received suboptimal doses, which also differed depending on whether they were based on weight or surface area. To assess what height gain might be expected at final height, all 52 girls who were prepubertal at the start of treatment, which continued for four years or more, and who had reached final height or had a growth velocity < 2 cm/year were selected. Their mean gain in final height was 5.2 cm and the GH dose was 0.78 IU/kg/week over 5.8 years. Final height gain correlated significantly with duration of treatment, total dose received, and first year response, which itself related to starting dose. This audit shows a changing pattern of treatment over the past decade, which in many instances has been inadequate. When treatment starts before puberty and continues through to final height, with a dose of 30 IU/m2/week in six or seven injections, a mean increase in final height of 5 cm or more would be expected. [ABSTRACT FROM AUTHOR]

Primary adrenal insufficiency (PAI) is a potentially life-threatening condition that can present with nonspecific features and can be difficult to diagnose. We undertook next generation sequencing in a cohort of children and young adults with PAI of unknown etiology from around the world and identified a heterozygous missense variant (rs6161, c.940G>A, p.Glu314Lys) in CYP11A1 in 19 individuals from 13 different families (allele frequency within undiagnosed PAI in our cohort, 0.102 vs 0.0026 in the Genome Aggregation Database; P < 0.0001). Seventeen individuals harbored a second heterozygous rare disruptive variant in CYP11A1 and two had very rare synonymous changes in trans (c.990G>A, Thr330 = ; c.1173C>T, Ser391 =). Although p.Glu314Lys is predicted to be benign and showed no loss-of-function in an Escherichia coli assay system, in silico and in vitro studies revealed that the rs6161/c.940G>A variant, plus the c.990G>A and c.1173C>T changes, affected splicing and that p.Glu314Lys produces a nonfunctional protein in mammalian cells. Taken together, these findings show that compound heterozygosity involving a relatively common and predicted "benign" variant in CYP11A1 is a major contributor to PAI of unknown etiology, especially in European populations. These observations have implications for personalized management and demonstrate how variants that might be overlooked in standard analyses can be pathogenic when combined with other very rare disruptive changes.

Background: Congenital nasal pyriform aperture stenosis (CNPAS) is an increasingly recognised cause of upper airway obstruction associated with midline abnormalities. Studies have described pituitary dysfunction in 40% of patients. We aimed to develop guidelines for: (a) the early identification of pituitary insufficiency to minimise surgical risk and (b) to stratify patients for follow-up., Methods: Retrospective case note review of patients with CNPAS between 2000 and 2014 in a tertiary paediatric unit., Results: 20 patients (12 female:8 male) were analysed; 16 were diagnosed during the neonatal period while 4 were diagnosed later. There was no consistent approach in the evaluation of the pituitary axis at diagnosis. Pituitary dysfunction was identified in 3 (15%) patients, 2 of whom were found during evaluation of short stature in mid-late childhood. Hypoglycaemia and conjugated hyperbilirubinaemia, but not the degree of stenosis, were highly predictive of pituitary dysfunction (p < 0.05). Available height standard deviation score (SDS) data at 1 year of 70% of our patients identified both of the late-diagnosed growth hormone-deficient patients, with SDS of -2.6 and -3.6, respectively., Conclusion: All CNPAS patients should have MRI of the brain and baseline endocrine investigations at diagnosis. Growth monitoring for at least 1 year is recommended as low, or falling, height SDS at 1 year is a good predictor of pituitary dysfunction., (© 2015 S. Karger AG, Basel.)

Aim: Girls with Turner syndrome are prone to cholesteatoma, a serious suppurative middle ear disease. We aimed to confirm its high prevalence in Turner syndrome, identify risk factors and suggest possible strategies for earlier detection., Methods: We reviewed 179 girls with Turner syndrome between 1989 and 2012 to identify cases of cholesteatoma., Results: Seven girls (3.9%) had cholesteatoma (index girls) and each was compared with three age-matched girls without cholesteatoma (comparison girls). All the index girls had either the 45,X or 45,X/46X,i(Xq) karyotypes. Nine ears were initially affected, with three recurrences in two girls. Median age at first cholesteatoma presentation was 11.9 years (range: 7.5-15.2), with otorrhoea for three (range: one to seven) months in all 12 affected ears. Index girls had a significantly higher proportion of previous recurrent acute (p = 0.007) and chronic otitis media (p = 0.008), chronic perforation (p = 0.038) aural polyps (p < 0.0001) and tympanic membrane retraction (p = 0.0001) than comparison girls., Conclusion: Cholesteatoma has a high prevalence in Turner syndrome. Risk factors include 45,X and 46,XiXq karyotypes; a history of chronic otitis media, tympanic membrane retraction and persistent otorrhoea; and older age. Earlier recognition of ear disease is needed and otoscopy training for paediatricians caring for Turner syndrome patients may be beneficial., (©2014 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Background: A UK study showed final height in Turner syndrome (TS) girls receiving growth hormone is affected by age at pubertal induction and oxandrolone (Ox). Using data from that study, we analysed the effect of timing of oral ethinylestradiol (EE2) and Ox on height velocity (HV), bone maturation and pubertal progression, and compared growth response in EE2-treated versus spontaneous puberty., Methods: Analysis of HV, bone age and pubertal stage in 92 TS girls (7-13 years) randomised to Ox (0.05 mg/kg/day; max: 2.5 mg/day) or placebo from 9 years, and EE2 (year 1: 2 µg/day; year 2: 4 µg/day; year 3: 6/8/10 µg/day×4 months) or placebo at 12 years with EE2 at 14 years. Girls enrolled at >12.25 years received EE2 at 14 years ('late group')., Results: Fifty-six girls were randomised to EE2 at 12 years (n=28, 11 Ox) or 14 years (n=28, 13 Ox); there were 19 girls in the late group (9 Ox) and 17 girls with spontaneous puberty (10 Ox). Girls receiving EE2 at 12 versus 14 years had faster bone maturation, but neither group showed acceleration. Ox increased HV without altering bone maturation or pubertal progression. Girls with spontaneous puberty had greater pubertal growth (mean PHV 8.5 cm/year; p<0.001) and height gain (p<0.001) than EE2-treated girls despite similar mean enrolment height SD and dysmorphology scores., Conclusion: Pubertal induction with EE2 does not replicate the acceleration observed in unaffected girls or TS girls with spontaneous puberty., (© 2014 S. Karger AG, Basel.)

There has been no consensus regarding the efficacy and safety of oxandrolone (Ox) in addition to growth hormone (GH) in girls with Turner syndrome (TS), the optimal age of starting this treatment, or the optimal dose. This collaborative venture between Dutch, UK and US centers is intended to give a summary of the data from three recently published randomized, placebo-controlled, double-blind studies on the effects of Ox. The published papers from these studies were reviewed within the group of authors to reach consensus about the recommendations. The addition of Ox to GH treatment leads to an increase in adult height, on average 2.3–4.6 cm. If Ox dosages<0.06 mg/kg/day are used, side effects are modest. The most relevant safety concerns are virilization(including clitoromegaly and voice deepening) and a transient delay of breast development. We advise monitoring signs of virilization breast development and possibly blood lipids during Ox treatment, in addition to regular follow-up assessments for TS. In girls with TS who are severely short for age, in whom very short adult stature is anticipated,or in whom the growth rate is modest despite good compliance with GH, adjunctive treatment with Ox at a dosage of 0.03–0.05 mg/kg/day starting from the age of 8–10 years onward scan be considered., (© 2014 S. Karger AG, Basel.)

Objective: To examine the effect of oxandrolone and the timing of pubertal induction on final height in girls with Turner's syndrome receiving a standard dose of growth hormone., Design: Randomised, double blind, placebo controlled trial. Setting 36 paediatric endocrinology departments in UK hospitals., Participants: Girls with Turner's syndrome aged 7-13 years at recruitment, receiving recombinant growth hormone therapy (10 mg/m(2)/week)., Interventions: Participants were randomised to oxandrolone (0.05 mg/kg/day, maximum 2.5 mg/day) or placebo from 9 years of age. Those with evidence of ovarian failure at 12 years were further randomised to oral ethinylestradiol (year 1, 2 µg daily; year 2, 4 μg daily; year 3, 4 months each of 6, 8, and 10 μg daily) or placebo; participants who received placebo and those recruited after the age of 12.25 years started ethinylestradiol at age 14., Main Outcome Measure: Final height. Results 106 participants were recruited, of whom 14 withdrew and 82/92 reached final height. Both oxandrolone and late pubertal induction increased final height: by 4.6 (95% confidence interval 1.9 to 7.2) cm (P = 0.001, n = 82) for oxandrolone and 3.8 (0.0 to 7.5) cm (P = 0.05, n = 48) for late pubertal induction with ethinylestradiol. In the 48 children who were randomised twice, the effects on final height (compared with placebo and early induction of puberty) of oxandrolone alone, late induction alone, and oxandrolone plus late induction were similar, averaging 7.1 (3.4 to 10.8) cm (P < 0.001). No cases of virilisation were reported., Conclusion: Oxandrolone had a positive effect on final height in girls with Turner's syndrome treated with growth hormone, as did late pubertal induction with ethinylestradiol at age 14 years. However, these effects were not additive, so using both had no advantage. Oxandrolone could, therefore, be offered as an alternative to late pubertal induction for increasing final height in Turner's syndrome. Trial registration Current Controlled Trials ISRCTN50343149.

The study subject was a 13 day-old boy admitted to hospital, with weight loss since birth. He presented with the vomiting and hypotension that are classical features of congenital adrenal hyperplasia (CAH). The most common type of CAH is an autosomal recessive disorder caused by mutations in the 21-hydroxylase (CYP21A2) gene. To examine the CYP21A2 gene, gene-specific PCR was carried out, followed by sequencing. The baby was shown to be a compound heterozygote H365Y/R356W for two CYP21A2 gene mutations each inherited from a different parent. One of the mutations has not previously been functionally characterised. The mutations were reconstructed in an expression plasmid and characterised in vitro after transient transfection into human embryonic kidney (HEK293T) and hepatoblastoma (C3A) cell lines followed by measurement of enzyme activity. The CYP21A2 H365Y mutant exhibited minimal 21-hydroxylase activity to convert 17-hydroxyprogesterone to 11-deoxycortisol or progesterone to 11-deoxycorticosterone. Western immunoblotting indicated that the H365Y enzyme was produced in more variable amounts than wild type; in particular, the H365Y mutant protein may be unstable and/or subject to a more rapid degradation by the human proteosome as well as catalytically inefficient. The double mutant genotype with a severe mutation on each allele is compatible with the clinical presentation., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: Growth curve analysis is a statistical issue in life course epidemiology. Height in puberty involves a growth spurt, the timing and intensity of which varies between individuals. Such data can be summarized with individual Preece-Baines (PB) curves, and their five parameters then related to earlier exposures or later outcomes. But it involves fitting many curves., Methods: We present an alternative SuperImposition by Translation And Rotation (SITAR) model, a shape invariant model with a single fitted curve. Curves for individuals are matched to the mean curve by shifting their curve up-down (representing differences in mean size) and left-right (for differences in growth tempo), and the age scale is also shrunk or stretched to indicate how fast time passes in the individual (i.e. velocity). These three parameters per individual are estimated as random effects while fitting the curve. The outcome is a mean curve plus triplets of parameters per individual (size, tempo and velocity) that summarize the individual growth patterns. The data are heights for Christ's Hospital School (CHS) boys aged 9-19 years (N = 3245, n = 129,508), and girls with Turner syndrome (TS) aged 9-18 years from the UK Turner Study (N = 105, n = 1321)., Results: The SITAR model explained 99% of the variance in both datasets [residual standard deviation (RSD) 6-7 mm], matching the fit of individually-fitted PB curves. In CHS, growth tempo was associated with insulin-like growth factor-1 measured 50 years later (P = 0.01, N = 1009). For the girls with TS randomized to receive oxandrolone from 9 years, velocity was substantially increased compared with placebo (P = 10(-8))., Conclusions: The SITAR growth curve model is a useful epidemiological instrument for the analysis of height in puberty.