Changes In Growth Velocity Research Articles

Fetal Growth Velocity-A Breakthrough in Intrauterine Growth Assessment?

The pursuit of assessing fetal well-being in obstetrical practice remains a central tenet, propelling ongoing endeavors to explore innovative markers and diagnostic methodologies aimed at prognosing potential perinatal adversities. Deviations from standard patterns of intrauterine growth, whether exhibiting excessive or insufficient trajectories, stand as pivotal indices hinting at underlying pathophysiological processes or heightened concurrent medical conditions. Initiatives like the Delphi consensus and the INTERGROWTH-21st project strive to refine diagnostic criteria and establish international standards for fetal growth assessment. This article aims to present the current knowledge regarding the assessment of abnormal growth, including novel methods such as growth velocity. Integrating fetal growth velocity assessment into perinatal care protocols holds promise in enhancing diagnostic precision. Growth velocity, involving changes in fetal size over a given period, offers insights into distinguishing between constitutional and pathological growth abnormalities. Various methodologies and models have been proposed to evaluate growth velocity, with notable advancements in understanding fetal growth patterns across different trimesters. It is believed that accelerated and reduced growth velocity may be a sensible parameter in the detection of fetal growth restriction (FGR), small-for-gestational-age (SGA) fetuses, large-for-gestational-age (LGA) fetuses and macrosomic fetuses as well as appropriate-for-gestational age (AGA) fetuses that encounter problems with growth continuation. Recent studies found that changes in growth velocity reflect the risk of adverse perinatal outcomes (APOs). Future directions in fetal health research aim to elucidate the long-term consequences of abnormal fetal growth velocity on neurodevelopmental outcomes, highlighting the critical role of early assessment and intervention.

LGG-40. TYPE II RAF INHIBITOR TOVORAFENIB IN RELAPSED/REFRACTORY PEDIATRIC LOW-GRADE GLIOMA (PLGG): REVERSIBLE DECREASES IN GROWTH VELOCITY IN THE PHASE 2 FIREFLY-1 TRIAL

Abstract BACKGROUND: Tovorafenib is an investigational, selective, CNS-penetrant, type II RAF inhibitor. The ongoing FIREFLY-1 (NCT04775485) phase 2 study (Kilburn LK, et al. Nat Med. 2023) of tovorafenib in BRAF-altered pLGG resulted in antitumor activity and manageable safety. Decreased growth velocity (GV) was observed; this is an update on GV changes in skeletally immature children receiving tovorafenib. Methods A planned safety analysis was completed on August 8, 2023 on 137 patients (Arm 1: 77 & Arm 2: 60). Additional follow-up on all cases of decreased GV (an AESI) reported to the global safety database (GSDB) as of January 19, 2024 is provided. Results Overall, 29% had decreased GV from baseline (BL); 19% had ≥50% decrease. Of the 40 with this AESI, 75% had pre-existing neuromuscular or endocrine comorbidities potentially affecting normal growth, including 6 on GnRH-analogues for precocious puberty and 9 with BL heights 2 SDs above/below average for age and sex. Nineteen had on-treatment bone age assessments; none showed bone age advancement from BL or premature growth plate closure. No osteopenia or abnormal fractures reported. All 10 who discontinued or interrupted tovorafenib for ≥3 months for any reason (mean follow-up: 5.8 months), with off-treatment growth measurements available, showed post-treatment annualized GV (AGV) recovery (average AGV: on-treatment, 1.1 cm/y; off-treatment, 8 cm/y), with some exceeding expected average AGV for age. A 4-year-old boy with 1.2 cm/y AGV on-treatment had 12.3 cm/y AGV off-treatment (follow-up: 2 months). Five additional events of decreased GV in patients not on study FIREFLY-1 were reported to the GSDB; 4 of 5 had ≥3 months of off-treatment follow-up, all 4 recovered GV. Conclusions Decreased GV has been observed in patients on tovorafenib. Preliminary follow-up data in those who interrupted treatment show consistent evidence of GV recovery and preservation of growth potential on bone age studies.

Type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma (pLGG): Reversible decreases in growth velocity in the phase 2 FIREFLY-1 trial.

10036 Background: Tovorafenib is an investigational, selective, CNS-penetrant, type II RAF inhibitor. Results from the ongoing FIREFLY-1 (NCT04775485) phase 2 study (1) in BRAF-altered pLGG showed clinically meaningful tumor responses and a manageable safety profile with tovorafenib monotherapy. Decreased growth velocity (GV) was observed; this is an update on changes in GV in skeletally immature children receiving tovorafenib. Methods: A planned safety analysis was completed on August 8, 2023 and included 137 patients (Arm 1: 77 & Arm 2: 60) treated with ≥1 dose of tovorafenib in FIREFLY-1. This report provides additional follow-up on all cases of decreased growth velocity (GV), an adverse event of special interest (AESI), reported to the Sponsor’s global safety database (GSDB) as of January 19, 2024. Results: Decreased GV was reported in 40 (29.2%) of 137 patients; 26 (19%) had GV reduction ≥50% from baseline (BL). Of those with decreased GV, 30 (75.0%) had pre-existing neuromuscular or endocrine comorbidities that may affect normal growth, including 6 (15%) with precocious puberty being treated with a gonadotropin-releasing hormone analogue, and 9 (22.5%) with BL heights 2 standard deviations above or below average for age and sex. Nineteen of the 40 patients with this AESI had on-treatment bone age assessments; none showed advancement of bone age from BL or premature closure of growth plates. No osteopenia or abnormal fractures were reported. Of the 35 patients with growth hormone (GH) testing, only 2 had signs of GH deficiency (both had optic pathway tumors; 1 had GH deficiency at BL, the other, a new tumor-associated GH deficiency). Post-treatment heights ≥3 months off treatment were reported for 10 of 40 patients who had interrupted or discontinued treatment for any reason (mean follow up: 5.8 months), including 2 (1.5%) permanent discontinuations and 3 (2.2%) interruptions due to decreased GV. All 10 showed post-treatment recovery in annualized GV (AGV) (average on-treatment AGV 1.1 cm/y vs. average post-treatment AGV 8 cm/y), in some cases exceeding expected average AGV for age. One additional 4-year-old boy with on-treatment AGV of 1.2 cm/y had an off-treatment AGV of 12.3 cm/y after 2 months of off-treatment follow-up. Decreased GV was reported to the GSDB for 5 (11.4%) of 44 patients who received above the maximum dose of tovorafenib used in FIREFLY-1 in an ongoing investigator-initiated study. Four of the 5 patients from this study had ≥3 months of off-treatment follow-up reported; all 4 showed evidence of GV recovery. Conclusions: Decreased GV has been observed in patients treated with tovorafenib. Early follow-up data from patients whose treatment was interrupted show consistent evidence for GV recovery and preservation of growth potential on bone age studies. 1. Kilburn LK, et al. Nat Med.2023. Clinical trial information: NCT04775485 .

Associations between collagen X biomarker and linear growth velocity in a pediatric chronic kidney disease cohort.

Collagen X biomarker (CXM) is a novel biomarker of linear growth velocity. We investigated whether CXM correlated with measuredgrowth velocity in children with impaired kidney function. We used data from children aged 2 through 16years old enrolled in the Chronic Kidney Disease in Children (CKiD) study. We assessed the association between CXM level and growth velocity based on height measurements obtained at study visits using linear regression models constructed separately by sex, with and without adjustment for CKD covariates. Linear mixed-effects models were used to capture the between-individual and within-individual CXM changes over time associated with concomitant changes in growth velocity from baseline through follow-up. A total of 967 serum samples from 209 participants were assayed for CXM. CXM correlated more strongly in females compared to male participants. After adjustment for growth velocity and CKD covariates, only proteinuria in male participants affected CXM levels. Finally, we quantified the between- and within-participant associations between CXM level and growth velocity. A between-participant increase of 24% and 15% in CXM level in females and males, respectively, correlated with a 1cm/year higher growth velocity. Within an individual participant, on average, 28% and 13% increases in CXM values in females and males, respectively, correlated with a 1cm/year change in measured growth. CXM measurement is potentially a valuable aid for monitoring growth in pediatric CKD. However, future research, including studies of CXM metabolism, is needed to clarify whether CXM can be a surrogate of growth in children with CKD. A higher resolution version of the Graphical abstract is available as Supplementary information.

Corifollitropin Alfa Combined With Human Chorionic Gonadotropin in Adolescent Boys With Hypogonadotropic Hypogonadism.

Adolescent males with hypogonadotropic hypogonadism (HH) have traditionally been treated with exogenous testosterone (T) or human chorionic gonadotropin (hCG) to produce virilization; however, those modalities do not result in growth of the testes and may promote premature maturation and terminal differentiation of Sertoli cells prior to their proliferation, which may impact future fertility. Another option is to use gonadotropins in those individuals to induce testicular growth, proliferation and maturation of Sertoli cells, and production of endogenous T with consequent virilization. We examined the efficacy and safety of corifollitropin alfa (CFA) combined with hCG for the induction of testicular growth and pubertal development in adolescent boys with HH. This was a 64-week, multicenter, open-label, single-group study of CFA in adolescent boys, aged 14 to younger than 18 years, with HH. Seventeen participants initiated a 12-week priming period with CFA (100 μg if weight ≤ 60 kg, or 150 μg if weight > 60 kg) given subcutaneously once every 2 weeks, after which they entered a 52-week combined treatment period with CFA, once every 2 weeks, and subcutaneous hCG, twice-weekly (hCG dose adjusted between 500 IU and 5000 IU to keep total T and estradiol levels within protocol-specified ranges). The primary efficacy end point was change from baseline in testicular volume (TV), measured as the sum of volumes of left and right testes by ultrasound. After 64 weeks of therapy with CFA/CFA combined with hCG, geometric mean fold increase from baseline in TV was 9.43 (95% CI, 7.44-11.97) (arithmetic mean of change from baseline at week 64, 13.0 mL). Hormonal, Tanner stage, and growth velocity changes were consistent with initiation and progression of puberty. Treatment was generally well tolerated. No participant developed anti-CFA antibodies. Treatment of adolescent boys with HH with CFA alone for 12 weeks followed by CFA combined with hCG for 52 weeks induced testicular growth accompanied by pubertal progression, increased T, and a pubertal growth spurt (EudraCT: 2015-001878-18).

A Prospective Observational Multicenter Study on Deferiprone & Deferasirox in Clinical Practice of Pediatric Patients with Transfusion-Dependent B-Thalassemia

Background: Iron overload is inevitable but a manageable complication of frequent blood transfusion, the effectiveness and safety of two iron chelation therapy in young children with transfusion-dependent B thalassemia (TDB-T) using either deferiprone (DFP) or deferasirox (DFX) were well studied in clinical trials. The primary objectives were; reporting efficacy and frequency of all adverse events (AEs) as compared with published data. Secondary objective was reporting deviation from guidelines, The analysis of clinical data is the first step to design new strategies Methodology: An investigator initiated 2-year multicenter prospective study enrolling over 6 months period; 302 children with TDB-T from 11 centers; keeping pre-transfusion Hb >8gm/dl. When serum ferritin (SF) reached around 1000 ng/ml; they had received according to availability; either DFP liquid solution in a dose; 75 mg/kg/day (n=62) or DFX (n=240); (dispersed tablet; 25% or film-coated tablet 75% in a dose; 20-25 mg/kg/d or its equivalent). CBC was done biweekly in DFP and pre-transfusion in DFX group. Liver transaminases, serum creatinine and (SF) were done /3 months. Changes in growth velocity over time were documented. Results: 66% were males, age at enrolment was; (11-19 and 14-26 months) in DFP and DFX respectively; they had received (6-8) and (7-11) transfusions prior to chelation in both groups respectively in addition to (16-21) during the study. 20% of patients did not achieve the target pre-transfusion Hb level. At initiation of DFP; SF median; 960 (IQR; 122 ng/ml) while those on DFX had SF; median 1070 (IQR 138 ng/ml) both groups had comparable transfusion iron input during the study. At 24 months of regular transfusion-chelation; SF < 1000 ng/ml was noticed in 65% and 60% of the patients respectively with good growth velocity in children using either chelator. Unnecessary over-dosing of DFX > 40 mg/kg was observed in 5%, meanwhile 3.2% had received DFP in a dose >75-100 mg/kg while SF was <1500 ng/ml. Under-reporting of adverse events in both groups was observed; 5% GIT upset, neither arthralgia nor agranulocytosis, neutropenia (3.2%) in DFP group and CBC was not checked biweekly; but only prior to transfusion. 4-5 % had elevated transaminases in both chelators, while patients on DFX reported; GIT upset in 4.2% and rash in 1.6%. Elevated serum creatinine > 33% from baseline on 2 successive visits was observed in 5% in DFX without reducing the dose or re-check. No unexpected, serious severe adverse events were reported in both groups. Poorly controlled patients with SF > 1500 ng /ml at 12 or 24 months were 12, 8% in DFP group; in contrast to 15%, 10% in DFX group respectively; with no statistical difference; (compliance was comparable). The total DFP and DFX discontinuation ratio was 5% in each group. Conclusion: infants and young children with TDB-T naïve to chelation were put on mono-therapy at younger age than reported before. Both chelators were effective, well tolerated and with no severe safety concerns; however deviation from guidelines was observed as; unnecessary over-dosing of DFX and under-reporting of AEs in both groups in real life practice. DisclosuresHamdy: ApoPharma: Honoraria; Amgen: Honoraria; Bayer: Honoraria; Novartis: Honoraria; NovoNordisk: Honoraria; Roche: Honoraria; Takeda: Honoraria.

Ten-Year Outcomes of Children and Adolescents Who Underwent Sleeve Gastrectomy: Weight Loss, Comorbidity Resolution, Adverse Events, and Growth Velocity

To date, there are insufficient data on long-term outcomes of weight loss surgery in children and adolescents with obesity beyond 5 years of follow-up. This study aimed to analyze durability of weight loss and comorbidity resolution, growth velocity, and adverse events associated with laparoscopic sleeve gastrectomy (LSG) in children and adolescents with severe obesity. In this prospective cohort study, 2,504 children and adolescents with class II/III obesity who were enrolled in a multidisciplinary, family-based pediatric obesity management program underwent LSG between 2008 and 2021. Weight loss, growth, comorbidity resolution, and adverse event data during the first 10 years after LSG were analyzed. The cohort age was 5 to 21 years at the time of operation, and 55% were female. Mean ± SD percentage of excess weight lost during short- (1 to 3 years; n= 2,051), medium- (4 to 6 years; n= 1,268), and long-term (7 to 10 years; n= 632) follow-up was 82.3% ± 20.5%, 76.3% ± 29.1%, and 71.1% ± 26.9%, respectively. Complete comorbidity remission at long-term follow-up was observed in 74%, 59%, and 64% of type 2 diabetes, dyslipidemia, and hypertension cases, respectively. Mean ± SD height z-score change at short-, medium-, and long-term follow-up was 0.1 ± 0.5, 0.1 ± 1.2, and 0.0 ± 0.8, respectively, representing no significant change in growth velocity. There were 27 adverse events (1%) with no procedure-related mortality. Long-term follow-up after LSG in children and adolescents demonstrates durable weight loss, maintained comorbidity resolution, and unaltered growth.

Normal growth variance by Z scores should be considered when interpreting the growth inhibitory effect of inhaled corticosteroids.

Randomized clinical trials suggest that long-term inhaled corticosteroid (ICS) treatment significantly inhibits growth velocity (GV) assessed by centimeters/year (cm/year) in primarily prepubescent, mild asthmatics. However, several observational studies measuring normal growth variance by Z score suggest the absence of the ICS inhibitory effect. To demonstrate the generalizability of ICS growth inhibition in cm/year by establishing whether this measure exceeds the expected normal changes in GV by Z score for similar age and sex. This was a retrospective, observational study comparing height and GV across a 2 year period in asthmatics aged 2-10 years, receiving ICS therapy (Group 3) with non-asthmatics, and non-ICS asthmatics (Groups 1 and 2), respectively. Generalized linear model procedure compared GV measures after adjustment for age, gender, and dependence of group differences on the age of the child. Before initiation of ICS therapy at baseline, Group 3 patients (n = 22) were shorter than Groups 1 (n = 67) and 2 (n = 44) by mean height in cm, and height for age Z score in the adjusted model (p < .05). GV was also significantly reduced in Group 3 after initiation of ICS therapy versus Groups 1 and 2 by 1.0-1.5 cm/year, respectively, p < .05, but not significantly in comparison to expected normal GV variance determined by Z score, p ≥ .05. Our findings suggest the need to consider normal growth variance by Z scores in addition to absolute changes (cm/year) when interpreting the inhibitory effect of ICS on GV. Larger sample size studies will be necessary to confirm our findings.

Puberty and resultant increased bone turnover as a possible etiology of an increased lead concentration in a pre-adolescent girl

Introduction: We present a case in which puberty likely resulted in an increased lead concentration in a pre-adolescent girl.Case report: A 12-year-old girl was referred to the pediatric environmental health clinic (PEHC) after her blood lead level (BLL) was found to be elevated to 30 µg/dL (reference <5 µg/dL). She had been seen in the PEHC 6 years previously for management of a BLL as high as 36 µg/dL. Fifteen months prior to her repeat PEHC referral, her BLL had been 10 µg/dL. In those intervening 15 months, she grew 10.42 cm. Thyroid studies were normal. Four months after re-referral, her osteocalcin concentration, a marker of bone turnover, was 212 ng/mL (normal 9–42 ng/mL in adults >18 years); 10.5 months after the peak BLL of 32 mcg/dL, her BLL was 16 µg/dL, osteocalcin was 69 ng/mL, and her rate of growth had declined to 0.20 cm/30 days (peak: 1.07 cm/30 days). No external source of her exposure was found.Discussion: Osteocalcin concentrations and plotting the changes in growth velocity over time may assist clinicians in determining if pubertal growth is playing a role in unexpectedly increased BLL discovered in adolescents for whom no external source of lead exposure can be found.

Investigation of a Common Clinical Approach to Poor Growth in Preterm Infants.

This study aimed to determine the effect of elevated energy intake with medium-chain triglyceride (MCT) oil or formula powder on growth velocity and weight z-score in very low birth weight infants receiving human milk and human milk fortifier. This was a cohort study of infants exposed to MCT oil or formula powder for at least 7 days. Mean 7-day change in growth velocity and weight z-scores were compared pre- and postintervention. Forty-three infants received increased energy with either MCT oil or formula powder. Infants receiving MCT oil were more preterm and had a lower birth weight. When evaluating 7-day changes pre- and postintervention, growth velocity increased from 10.0 g/kg/day to 19.8 g/kg/day, and change in weight Z-score increased from -0.24 to 0.05. This clinical approach using MCT oil or formula powder for additional energy was associated with improved, at least short-term, growth velocity and weight z-score trajectory.

Impact of Growth Hormone Therapy on Adult Height in Patients with PTPN11 Mutations Related to Noonan Syndrome

Objectives: The aim of this study was to evaluate the response to recombinant human growth hormone (rhGH) treatment in patients with Noonan syndrome (NS). Materials and Methods: Forty-two patients (35 PTPN11+) were treated with rhGH, and 17 were followed-up until adult height. The outcomes were changes in growth velocity (GV) and height standard deviation scores (SDS) for normal (height-CDC SDS) and Noonan standards (height-NS SDS). Results: The pretreatment chronological age was 10.3 ± 3.5 years. Height-CDC SDS and height-NS SDS were –3.1 ± 0.7 and –0.5 ± 0.6, respectively. PTPN11+ patients had a better growth response than PTPN11– patients. GV SDS increased from –1.2 ± 1.8 to 3.1 ± 2.8 after the first year of therapy in PTPN11+ patients, and from –1.9 ± 2.6 to –0.1 ± 2.6 in PTPN11– patients. The gain in height-CDC SDS during the first year was higher in PTPN11+ than PTPN11– (0.6 ± 0.4 vs. 0.1 ± 0.2, p = 0.008). Similarly, the gain was observed in height-NS SDS (0.6 ± 0.3 vs. 0.2 ± 0.2, respectively, p < 0.001). Among the patients that reached adult height (n = 17), AH-CDC SDS and AH-NS SDS were –2.1 ± 0.7 and 0.7 ± 0.8, respectively. The total increase in height SDS was 1.3 ± 0.7 and 1.5 ± 0.6 for normal and NS standards, respectively. Conclusions: This study supports the advantage of rhGH therapy on adult height in PTPN11+ patients. In comparison, PTPN11– patients showed a poor response to rhGH. However, this PTPN11– group was small, preventing an adequate comparison among different genotypes and no guarantee of response to therapy in genes besides PTPN11.

The impact of bipedal mechanical loading history on longitudinal long bone growth.

Longitudinal bone growth is accomplished through a process where proliferating chondrocytes produce cartilage in the growth plate, which ultimately ossifies. Environmental influences, like mechanical loading, can moderate the growth of this cartilage, which can alter bone length. However, little is known about how specific behaviors like bipedalism, which is characterized by a shift in body mass (mechanical load), to the lower limbs, may impact bone growth. This study uses an experimental approach to induce bipedal behaviors in a rodent model (Rattus norvegicus) over a 12-week period using a treadmill-mounted harness system to test how rat hindlimbs respond to the following loading conditions: 1) fully loaded bipedal walking, 2) partially loaded bipedal walking, 3) standing, 4) quadrupedal walking, and 5) no exercise control. These experimental conditions test whether mechanical loading from 1) locomotor or postural behaviors, and 2) a change in the magnitude of load can moderate longitudinal bone growth in the femur and tibia, relative to controls. The results demonstrate that fully loaded bipedal walking and bipedal standing groups showed significant differences in the percentage change in length for the tibia and femur. When comparing the change from baseline, which control for body mass, all bipedal groups showed significant differences in tibia length compared to control groups. However, there were no absolute differences in bone length, which suggests that mechanical loads from bipedal behaviors may instead be moderating changes in growth velocity. Implications for the relationship between bipedal behaviors and longitudinal bone growth are discussed.

Leucine for the Treatment of Transfusion Dependence in Patients with Diamond Blackfan Anemia

▪Diamond Blackfan anemia (DBA) is a rare, inherited bone marrow failure syndrome characterized by anemia, congenital anomalies and a predisposition to cancer. The patients usually present during infancy or early childhood, but can also present in adulthood. In the majority of cases DBA is due to a mutation in a small or large ribosomal protein (RP) subunit leading to RP haploinsufficiency. The only treatments for the anemia of DBA are red cell transfusions (accompanied by iron chelation), oral corticosteroid therapy or stem cell transplantation. Pospisilova et al. (Haematologica 2007; 92(5):e66-67) reported one complete and two partial erythroid responses after the use of the branched chain amino acid L-leucine in 6 select patients. In skeletal muscle, leucine supplementation can upregulate components of the protein synthetic machinery, including ribosomal proteins, promoting protein translation. Mouse and fish models of DBA respond with amelioration of anemia to L-leucine. We therefore proposed to study the effect of L-leucine on transfusion dependence and growth in subjects with DBA.Methods: The primary objectives were to determine the feasibility of administering L-leucine in subjects with DBA who are red cell transfusion-dependent and to determine the efficacy of L-leucine to produce a hematologic and growth response. The secondary objective was to determine the safety profile of L-leucine. Twelve study sites were involved in this multi-center, Phase I/II study with an anticipated accrual of 50 subjects. A dose of 700 mg/M2 orally three times per day for 9 months was used. Inclusion criteria included age > 2 years, the diagnosis of DBA and transfusion dependence with adequate kidney and liver function. Response was evaluated at 9 months with Complete Response (CR) defined as no further transfusions required and Hb >9; Partial Response (PR): Hb < 9 gm/dL with an increase in reticulocyte count and transfusion interval; and No Response (NR): no change in transfusion needs, Hb or reticulocyte count . Growth percentiles were evaluated at baseline and at completion of 9 months of treatment and the growth velocity change was calculated.Results: The study opened July 2014 and closed February 2017; 55 subjects were consented; 12 were screen failures; 43 subjects were evaluable. There were 21 males; the median age was 9 years 1 month (2 years 5 months - 46 years 1 month). There were no untoward side effects experienced by any subject that were attributable to the L-leucine. Two subjects had an erythroid CR and 1 subject had a PR. The CRs occurred at 1 month and 3 months after start of L-leucine. The subject with PR had an elevated reticulocyte count but was not able to maintain a Hb >9 gm/dL without a transfusion and thus was not transfusion independent. Of the 30 subjects with growth potential who received L-leucine 10 experienced a positive growth velocity change at 9 months of therapy compared to baseline. At a median age of 7.5 years, the mean pre-leucine height percentile was 27 +/- 17.9 and the post-leucine height percentile was 35 +/- 19.9 (p <0.01). The mean weight percentile pre-leucine was 35.4 +/- 26.6 versus the post-Leucine weight percentile of 38.4 +/- 28.1.Conclusions: The administration of L-leucine is safe. L-leucine administration resulted in an erythroid response in 7% of subjects and an increased growth velocity in 33% of growing subjects. Based upon extrapolation from animal models, it is likely that this dose was suboptimal. We hypothesize that higher doses of L-leucine will lead to hematologic responses in more subjects who are transfusion dependent. The potential benefit of added growth in children with DBA may improve final adult height. DisclosuresGlader:Agios: Consultancy, Research Funding.

Mitotane (op'DDD) restores growth and puberty in nine children with Cushing's disease.

To investigate whether low-dose mitotane (up to 2 g/day) could be a temporary therapeutic alternative to transsphenoidal surgery (TSS) in pediatric Cushing’s disease (CD). Twenty-eight patients with CD aged 12.2 years (± 2.2) were referred to our center. We compared nine patients treated with mitotane alone for at least 6 months to 13 patients cured after surgery. Primary outcomes were changes in growth velocity, BMI and pubertal development. The following results were obtained: (1) Mitotane improved growth velocity z-scores (−3.8 (±0.3) vs −0.2 (±0.6)), BMI z-scores (2.1 (±0.5) vs 1.2 (±0.5) s.d.) and pubertal development. After 1 year on mitotane, the mean BMI z-score was not significantly different in both groups of patients. (2) Control of cortisol secretion was delayed and inconsistent with mitotane used as monotherapy. (3) Side effects were similar to those previously reported, reversible and dose dependent: unspecific digestive symptoms, concentration or memory problems, physical exhaustion, adrenal insufficiency and hepatitis. (4) In one patient, progressive growth of a pituitary adenoma was observed over 40 months of mitotane treatment, allowing selective adenomectomy by TSS. In conclusions, low-dose mitotane can restore growth velocity and pubertal development and decrease BMI in children with CD, even without optimal control of cortisol secretion. It may promote pituitary tumor growth thus facilitating second-line TSS. However, given its possibly life-threatening side effects (transient adrenal insufficiency and hepatitis), and in the absence of any reliable follow-up procedures, this therapy may be difficult to manage and should always be initiated and monitored by specialized teams.

Kinetic transition in the order-disorder transformation at a solid/liquid interface.

Phase-field analysis for the kinetic transition in an ordered crystal structure growing from an undercooled liquid is carried out. The results are interpreted on the basis of analytical and numerical solutions of equations describing the dynamics of the phase field, the long-range order parameter as well as the atomic diffusion within the crystal/liquid interface and in the bulk crystal. As an example, the growth of a binary A50B50 crystal is described, and critical undercoolings at characteristic changes of growth velocity and the long-range order parameter are defined. For rapidly growing crystals, analogies and qualitative differences are found in comparison with known non-equilibrium effects, particularly solute trapping and disorder trapping. The results and model predictions are compared qualitatively with results of the theory of kinetic phase transitions (Chernov 1968 Sov. Phys. JETP26, 1182-1190) and with experimental data obtained for rapid dendritic solidification of congruently melting alloy with order-disorder transition (Hartmann et al. 2009 Europhys. Lett.87, 40007 (doi:10.1209/0295-5075/87/40007)).This article is part of the theme issue 'From atomistic interfaces to dendritic patterns'.

Influence of growth velocity variations on the pattern formation during the directional solidification of ternary eutectic Al-Ag-Cu

In order to control the evolving microstructure in complex eutectics and other multi-phase systems, it is important to understand the adjustment mechanisms and the parameters that determine pattern evolution. Here, a combined experimental and simulation approach is taken to investigate the response of a three-phase eutectic system to changes in solidification velocity. Using Al-Ag-Cu as a model system, large scale three-dimensional phase-field simulations are compared to directionally solidified samples containing both, velocity increases and decreases. The experimental results are obtained by synchrotron tomography for detailed consideration of the microstructure directly before and after a targeted velocity change and by traditional SEM analysis of sample cross sections to capture effects over longer length scales. In addition to qualitative analysis of the images, the microstructures are statistically assessed using phase fractions, shape factor and nearest neighbor statistics. Both, simulation and experiment show an immediate change in phase fraction as a result of a change in growth velocity. Adjustment of the microstructural pattern occurs more slowly over a relatively long length scale, due to splitting, merging and overgrowing events. Novel quantification techniques emphasize that ternary eutectic phase arrangements are complex and continuously evolving structures which, even under ideal conditions, do not reach steady state growth as quickly as previously believed.

Disorders of Growth and Stature.

1. Laurie R. Braun, MD*,† 2. Rose Marino, MD* 1. *Pediatric Endocrine Unit and 2. †Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA * Abbreviations: ACTH: : adrenocorticotropic hormone CDC: : Centers for Disease Control and Prevention CDGP: : constitutional delay of growth and puberty CNS: : central nervous system FSS: : familial short stature GH: : growth hormone GnRH: : gonadotropin-releasing hormone IGF-BP3: : IGF-1 binding protein 3 IGF-1: : insulin-like growth factor 1 ISS: : idiopathic short stature NPR2 : : natriuretic peptide receptor B rhGH: : recombinant human GH SGA: : small for gestational age SHOX : : short stature homeobox TSH: : thyroid-stimulating hormone T4: : thyroxine It is often challenging to identify children with abnormal growth patterns and distinguish normal growth variants from pathologic variants. After completing this article, readers should be able to: 1. Perform growth measurements and interpret growth charts to be able to identify children with short or tall stature. 2. Differentiate among the common origins of short and tall stature and plan an appropriate diagnostic evaluation for a slowly or rapidly growing child. 3. Describe when treatment is indicated for children with short and tall stature. Growth parameters are routinely measured in general pediatrics, with the goal of identifying children with abnormalities in growth and stature. Short stature is defined as a height less than 2 standard deviations (SDs) below the mean of the “normal” population, while tall stature is defined as a height greater than 2 SDs above the mean of the normal population. Both single growth measurements and the pattern of growth over time (growth velocity) are useful in identifying children with abnormal stature. The growth velocity changes over time, with relatively rapid growth in infancy and early childhood, followed by slower growth (approximately 5 cm per year) in later childhood and then rapid growth again during puberty. There is a range of pubertal peak growth velocities of around 7 to 12 cm per year and 6 to 10.5 cm per year in boys and girls, respectively, representing approximately the 3rd to 97th percentiles. The timing of peak growth velocity varies with the age of puberty onset and frequently reflects familial pubertal and growth patterns. Overall, it is thought that …

Improving nutritional practices in premature infants can increase their growth velocity and the breastfeeding rates.

This study analysed the changes in growth velocity (GV) of preterm infants weighing <1500 g based on different nutritional practices over a 24-year period. A retrospective study with prospectively collected data was performed in a level three Spanish neonatal intensive care unit. Data on birthweight, gestational age (GA) and GV were collected from 1990 to 2013 and breastfeeding data were gathered from 2000. A generalised linear model corrected by GA and small for gestational age was applied. Multiple mean comparisons between the levels of the variables of interest were performed using the Tukey test. We included 1651 children in the study. The average GA in 1990-1991 was 30.48 ± 2.89 and the average GA in 2012-2013 was 28.79 ± 2.58 (p < 0.01). Significant differences were found when we compared the adjusted GV between the first and last study periods. The most important differences appeared between 1990 and 2013, when the GV increased by 3.27 ± 0.5 g/kg/day (p < 0.01). The breastfeeding rate in 2000-2001 was 47.95% and in 2012-2013 it was 73.58% (p = 0.0002). Introducing nutritional practices such as the increased use of breastmilk and the breastfeeding rate improved GV over the study period.

No Significant Growth Velocity Changes in Two Trials Evaluating the Potential Effects of Flunisolide HFA (AerospanTM) on Growth in Pediatric Patients with Mild-to-Moderate Asthma

No Significant Growth Velocity Changes in Two Trials Evaluating the Potential Effects of Flunisolide HFA (AerospanTM) on Growth in Pediatric Patients with Mild-to-Moderate Asthma

Phase-field modeling of microstructure evolution during solidification in presence of gas bubble

The microstructure evolution during solidification of pure Aluminum metal with gas bubble nucleation and growth is modeled and simulated by the phase-field method. Interface microstructure formation in the presence of gas bubble is simulated to investigate the interaction between gas bubble and microstructural evolution, and also a pressure correction equation is implemented to study the effect of pressure difference between the bubbles and melts. Results indicate that pressure difference between gas bubble and the liquid melt can significantly affect the gas atoms diffusion near the gas–liquid interface, which will lead to the bubble growth velocity change. These simulation results are in agreement with experimental observations.