bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diagnosis of Childhood and Adolescent Growth Hormone Deficiency Using Transcriptomic Data
Authors: Garner Terence , Stevens Adam , Whatmore Andrew James , Clayton Peter Ellis , Murray Philip G 
Published: May 2021

Abstract
Background: We have shown that gene expression (GE) data have promise as a novel tool to aid in the diagnosis of childhood growth hormone deficiency (GHD)1. Our previous study compared GE data in children with GHD to healthy control children of normal stature. The aim of this study was to assess the utility of GE data in the diagnosis of GHD in childhood and adolescence using non-GHD short stature children as a control group.
Methods: GE data were obtained from patients undergoing growth hormone stimulation testing via a sample of blood taken at the start of the test. Arginine and glucagon stimulation tests with a cut-off for peak GH of &lt;7mcg/L (IDS iSYS assay) were used for the diagnosis of GHD. GE was assessed in peripheral blood mononuclear cells via RNA-seq using the Illumina HiSeq 4000 platform. Data were taken for the 271 genes whose expression was utilised in our previous study. The synthetic minority oversampling technique was used to balance the dataset and a random forest algorithm applied to predict GHD status. Boruta was used to assess which of the genes were contributing to the predictive capacity.
Results: Twenty-four patients were recruited to the study, with eight subsequently diagnosed with GHD. Of the eight patients diagnosed with GHD, three had two stimulation tests and five had one stimulation test with anterior pituitary hypoplasia (in addition one patient had an arachnoid cyst and another a thin stalk). Median (range) peak GH was 2.5 (0.1 - 5) mcg/L in the GHD group and 11.0 (7.4 - 31) mcg/L in the non-GHD group.
There were no significant differences in gender, age, auxology (height SDS, weight SDS, BMI SDS) or biochemistry (IGF-I or IGFBP-3 SDS) between the GHD and non-GHD subjects. 82 of the 271 genes used in our previous study were above the threshold of detection for RNA-seq in this study. A random forest algorithm using these 82 genes gave an AUC of 0.97 (95% CI 0.93 - 1.0) for the diagnosis of GHD. Boruta was able to identify 65/82 genes with predictive capacity greater than permuted data within the dataset. Using a gene ontology approach the top fifty biological processes generated 16 clusters by affinity propagation which included regulation of TORC1 signalling and inositol phosphate metabolism.
Conclusion: This study demonstrates highly accurate diagnosis of childhood GHD using a combination of GE data and random forest analysis and validates the findings of our original study.
1Murray etal (2018) JCI Insight 3(7): e93247
Long-Term Growth Hormone Therapy Does Not Advance Skeletal Maturation in Children and Adolescents
Authors: Nwosu Benjamin Udoka , Parajuli Sadichchha , Jasmin Gabrielle , Lee Austin F 
Published: May 2021

Abstract
Context: There is no consensus on the effect of recombinant human growth hormone (rhGH) therapy on skeletal maturation in children despite the current practice of annual monitoring of skeletal maturation with bone age in children on rhGH therapy. Aims: To investigate the effects of long-term rhGH therapy on skeletal age in children and explore the accuracy of bone age predicted adult height (BAPAH) at different ages based on 13 years of longitudinal data. Methods: A retrospective longitudinal study of 71 subjects aged 2-18 years, mean 9.9 ± 3.8y, treated with rhGH for non-syndromic short stature for a duration of 2-14y, mean, 5.5 ± 2.6y. Subjects with syndromic short stature and systemic illnesses such as renal failure were excluded. Results: Bone age minus chronological age (BA-CA) did not differ significantly between baseline and the end of rhGH therapy (-1.05 ± 1.42 vs -0.69 ± 1.63, p=0.09). Piece-wise regression however showed a quantifiable catch-up phenomenon in BA of 1.6 months per year of rhGH therapy in the first 6.5y, 95%CI 0.023 - 0.229, p=0.017, that plateaued thereafter, β=0.015, 95% CI -0.191-0.221, p=0.88. There was no relationship between BAPAH z score – height z score and the duration of rhGH therapy, p=0.68. BAPAH overestimated final adult height in younger subjects but became more precise in older subjects (p&lt;0.0001). Conclusion: Long-term rhGH therapy demonstrated an initial catch-up phenomenon in skeletal maturation in the first 6.5y that plateaued thereafter with no overall significant advancement in bone age. These findings are reassuring and do not support the practice of yearly monitoring of skeletal maturation with bone age in children on rhGH therapy, especially in younger subjects where BAPAH is imprecise.
Pharmacokinetics and Pharmacodynamics of Macimorelin Acetate (AEZS-130) in Paediatric Patients With Suspected Growth Hormone Deficiency (GHD)
Authors: Csákváry Violetta , Muzsnai Agota , Raduk Dmitri , Chaychenko Tetyana , Damholt Birgitte Bentz , Kelepouris Nicky , Teifel Michael , Ammer Nicola 
Published: May 2021

Abstract
Growth hormone deficiency (GHD) in children is a rare, aetiologically diverse condition that results in growth failure and short stature. Inadequate response to two different growth hormone stimulation tests (GHST) is required for the diagnosis of GHD. Macimorelin acetate, a potent, orally administered growth hormone (GH) secretagogue, is approved by the FDA and EMA for the diagnosis of adult GHD. Study AEZS-130-P01 is the first of two studies to investigate macimorelin acetate as a diagnostic test in children with suspected GHD.
This was an open-label, group comparison, dose escalation trial to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of single-dose 0.25, 0.5 and 1 mg/kg oral macimorelin acetate in paediatric subjects with suspected GHD. The macimorelin GHST was administered between two standard GHST, conducted as per local clinical practice, with a recovery period of 7-28 days between tests. Blood samples were collected pre-dose (±15 min) and 15, 30, 45, 60, 90, 120 and 360 minutes after macimorelin acetate intake.
Overall, 24 paediatric subjects (8 per cohort [C1, C2, C3]) were included in the pharmacokinetic/pharmacodynamic (PK/PD) analysis. Five males and 3 females were observed in C1 and C2, 7 males and 1 female in C3. In all three cohorts, at least 3 subjects represented Tanner stages I or II. All 24 subjects (100%) were white, with a median age of 9.8, 9.0 and 10.5 years (range 4-15 years) and a median body-mass index of 16.1 kg/m2 (12.4-21.4 kg/m2) at screening. Overall, 88 adverse events were reported, many related to the standard GHST; none were considered related to the macimorelin test. Maximum plasma concentrations for macimorelin were mainly observed between 30-45 min. The mean Cmax values were 3.46, 8.13 and 12.87 ng/ml for C1, C2, and C3, respectively. The AUCs increased with dose; the mean AUC0-6 values were 6.69, 18.02 and 30.92 h*ng/mL. The mean elimination half-lives were 1.22, 1.61 and 1.71 h, respectively. PK and PD profiles for all three cohorts were comparable, with peak GH levels mainly observed within 30-60 min following macimorelin intake.
Macimorelin acetate was safe and well tolerated in all dosing cohorts. A dose-dependent increase in macimorelin Cmax and AUC in children and adolescents correlated well with data from adult subjects. A robust dose-proportional GH response was also achieved. PD results showed that GH response was comparable in all dose groups, with a slight shift to earlier tmax at higher macimorelin doses.
Phase 3 Study Evaluating Once Weekly Somatrogon Compared to Daily Genotropin in Japanese Patients With Pediatric Growth Hormone Deficiency (pGHD)
Authors: Horikawa Reiko , Tanaka Toshiaki , Hasegawa Yukihiro , Yorifuji Tohru , Ng David , Rosenfeld Ron G , Hoshino Yuko , Okayama Akifumi , Shima Daisuke , Gomez Roy , Pastrak Aleksandra , Castellanos Orlando 
Published: May 2021

Abstract
Objectives: Somatrogon is a long-acting recombinant human growth hormone consisting of the amino acid sequence of human growth hormone and three copies of the carboxy-terminal peptide of human chorionic gonadotropin. Somatrogon is being developed as a once weekly treatment for children with pGHD. A Phase 3 trial was designed to compare the efficacy and safety of somatrogon administered once weekly with Genotropin administered once daily in Japanese patients with pGHD (ClinicalTrials. gov: NCT03874013).
Methods: 44 Japanese pGHD patients (age 3-11 years) were randomized in a 1:1 ratio to receive either once weekly somatrogon (0.66 mg/kg/week) or once daily Genotropin (0.025 mg/kg/day) subcutaneously for 12 months. Somatrogon-treated patients had a pharmacokinetic assessment in the first 6 weeks with dose escalation occurring in 3 steps, at 0.25, 0.48, and 0.66 mg/kg/week, for 2 weeks at each dose. For the remaining 46 weeks, patients in the somatrogon treatment group continued to receive somatrogon at a dose of 0.66 mg/kg/week. The primary endpoint of the study was annualized height velocity (HV) at 12 months.
Results: Baseline characteristics were balanced and comparable between the two treatment groups. The least square means of HV at month 12 were 9.65 cm/year in the somatrogon group (n=22) and 7.87 cm/year in the Genotropin group (n=22), with a point estimate treatment difference of 1.79 cm/year (95% confidence interval: 0.97, 2.60) in favour of somatrogon. The point estimate was greater than the pre-established mean treatment difference of -1.8 cm/year, which was the non-inferiority margin met in the global Phase 3 study (n=224) with somatrogon (0.66 mg/kg/week) and Genotropin (0.034mg/kg/day) (ClinicalTrials. gov: NCT02968004). Most of the adverse events were mild to moderate in severity and somatrogon was generally well-tolerated with no notable difference in safety between the two treatment groups. Injection site pain was more common in the somatrogon group (somatrogon: 72.7%, Genotropin: 13.6%).
Conclusions: The Japanese Phase 3 trial in patients with pGHD demonstrated that once weekly somatrogon was comparable to daily Genotropin. The annual HV after 12 months of treatment was higher in the somatrogon group than the Genotropin group. Somatrogon administration was generally well tolerated in patients with pGHD. The results of this Japanese Phase 3 study are consistent with the results previously reported from the global Phase 3 study that met its primary endpoint of noninferiority to daily Genotropin.
A Novel Case of Hyperinsulinemic Hypoglycemia in a Neonate With SARS-CoV-2 Infection
Authors: Paulo Remberto , Bowlby Deborah A , Matlock Kristal Anne 
Published: May 2021

Abstract
The Case: An 8 days old male, born at 40 wks, 2.8 kg (SGA) presented to local ED with lethargy, decreased PO intake and urine output, respiratory distress. No fever, URI sx, vomiting/diarrhea. His dad had URI symptoms and fever a week prior. He was found to have T=95.5F, glucose &lt;10 mg/dL, improved to 125 after D10 boluses x2; and required supplemental O2 due to desats/cyanosis. CXR showed bilateral hazy opacities. Sepsis rule out was initiated, patient admitted to the PICU, started on antibiotics and dextrose. Patient became more alert over the next 3 days, but could not be weaned off from IV dextrose/continuous feeds, GIR up to 15 mg/kg/min. He was transferred to our institution. Critical sample at BG of 45 mg/dl showed high insulin level (6.9 uU/ml) and C-peptide (1.25 ng/dl); low beta-OH butyrate &lt;0.2 mmol/L; and free fatty acids (0.25 mmol/L); all suggestive of hyerperinsulinemic hypoglycemia (HH). Cortisol and GH robust at 10.5 mcg/dl and 7.13 ng/ml. Nasopharyngeal swab for SARS-CoV-2 RT-PCR positive. Dad’s swab also positive. Mom was asymptomatic and not tested. ID was consulted, recommended supportive management and close observation. Pt was started on Diazoxide 10mg/kg/day divided q8h, and hydrochlorothiazide (HCT) 5mg/day. Patient’s status gradually improved - BG stabilized, feeds were compressed, IV fluids and O2 supplementation weaned off, and was discharged after 8 days with average BG in the 70-80’s range. Diazoxide and HCT were successfully weaned off in the following 3 mos. To this day patient remains well, no recurrence of hypoglycemia.
Discussion/Conclusion: There is a dearth of information on SARS-CoV-2 infection in newborns. The few studies available show favorable outcomes in this population, with typical mild-moderate respiratory symptoms and fever, while some newborns are asymptomatic. Our patient required oxygen tx and developed HH requiring Diazoxide therapy. To our knowledge, this is the first reported case of HH in the newborn with SARS-CoV-2 infection. Hyerperinsulinism is the most common cause of hypoglycemia in infants. These newborns are at risk of developing significant neurologic morbidity, which can be dose dependent. Prompt diagnosis and aggressive management are important to reduce such risk. Perinatal stress is likely the underlying mechanism leading to HH in newborns with SARS-CoV-2 infection. Patient is also SGA. Both perinatal stress and SGA can lead to inappropriately elevated insulin levels and resultant hypoglycemia. HH in both of these conditions is effectively managed by Diazoxide. Our case illustrates that although most newborns do well with SARS-CoV-2 infection, a high index of suspicion for HH should be maintained in such newborns, particularly in those with at least one other risk factor for HH such as SGA. More studies are needed to elucidate underlying pathology and tease out actual incidence of hypoglycemia in neonates with SARS-CoV-2 infection.
A Pediatric Patient With Noonan Syndrome and Late Onset Unilateral Lymphedema
Authors: Burdea Liliana , Aguirre Roxana L 
Published: May 2021

Abstract
Introduction: Noonan syndrome is a common autosomal dominant disorder with a prevalence of 1 in 1000-2500 births. The lymphatic disorders in Noonan syndrome are rare and usually bilateral. We present a 14-year-old male with Noonan syndrome and late-onset unilateral lower extremity lymphedema.
Case presentation: A 14-year-old male with Noonan syndrome due to a pathogenic mutation in the RIT1 gene (c.265T&gt;C p.Tyro89His) presented to emergency room due to progressive swelling of the right lower extremity. No history of recent trauma or injury. He had a history of small mid-muscular ventricular septal defect (VSD), chylothorax with right-sided pleural effusions during infancy, sensorineural hearing loss with bilateral hearing aids, and undescended testes status post-surgery. He had been on growth hormone (GH) therapy since age 12 years with good adherence and no reported side effects. In the emergency room, initial laboratory evaluation and Doppler ultrasound ruled out deep venous thrombosis. Physical exam was remarkable for edema of the right lower extremity, warm to touch, with erythema, not painful. Due to initial concerns for cellulitis, the patient was treated with antibiotics. Erythema improved but not the edema. Cardiac evaluation including echocardiogram with stable, unchanged VSD was unremarkable. Patient underwent additional workup notable for an albumin level of 4.4g/dl (3.4-5.0), Immunoglobulin (Ig) A 53 mg/dl (66-436), IgG 788 mg/dl (791-1643), IgM 82 mg/dl (43-279) and a stool alpha antitrypsin level of 0.65 mg/g (0.0-0.5) ruling out protein-losing enteropathy (PLE). Growth hormone was held initially and restarted after 2 months due to clinical improvement, but just for one week due to worsening swelling. Lymphoscintigraphy of lower extremities showed an asymmetry between the right and left leg in the transit, suggesting a mild lymphatic abnormality in the right leg. There was a significant improvement in terms of his lymphedema with physical therapy and compressive stocking after 6 months. He has been off growth hormone therapy since then. Discussion: Patients with Noonan syndrome may develop lymphedema and PLE, although findings are usually bilateral. Interestingly our patient has unilateral lymphedema that has been improving with compression stocks and physical therapy. Our patient was on GH therapy for 2 years before he developed lymphedema and although growth hormone causes water retention, we would not expect a selective involvement as in our patient. Based on his history of chylothorax we decided to perform a Lymphoscintigraphy that confirmed an abnormality in the lymphatic system of the right lower extremity. The effect of GH once restarting pointed it was a precipitating factor instead of the cause. Late-onset lymphedema is an uncommon presentation but should be a diagnosis that we have to keep in mind when patients with Noonan syndrome are presenting with edema.
A Pediatric Patient With Papillary Thyroid Carcinoma With Local and Distant Metastases
Authors: Burdea Liliana , Jo Inha , Mantis Stelios 
Published: May 2021

Abstract
Introduction: Thyroid cancer is less common among children than adults, but the incidence has been increasing, especially in adolescents. Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer in pediatric patients representing more than 90% of all cases. Children with PTC are likely to present with regional lymph node metastases, but distant metastases are rare. We present a 12-year-old female patient who presented with a neck mass found to be PTC with neck and pulmonary metastases. Case Presentation: A 12-year-old girl previously healthy presented to her primary doctor with a neck mass for several months. The patient had no other complaints, and the physical exam was notable for a palpable right anterior neck mass measuring 3x4cm. Thyroid studies were remarkable for a thyroid-stimulating hormone (TSH) of 2.13 uIU/mL (0.350-4.94) and negative antithyroid antibodies. Initial neck ultrasound (US) showed a multilobulated right thyroid nodule with macrocalcifications. Fine needle aspiration (FNA) of the nodule revealed PTC. Patient underwent neck and chest computed tomography (CT) preoperatively, notable for cervical lymph nodes involvement and multiple bilateral lung nodes less than 1cm each. She underwent neck exploration and total thyroidectomy and was started on thyroid hormone replacement therapy afterwards. Pathology of the specimen revealed PTC with extension into the perithyroidal soft tissue and two out of five lymph nodes with metastatic PTC. She underwent I-123 whole-body scan (WBS) eight weeks later, followed by I-131 therapy. Interestingly, the pulmonary nodes did not demonstrate any uptake on the WBS before or after receiving I-131 therapy. Patient continues with no pulmonary symptoms and her thyroglobulin (Tg) level continues to be low. She underwent extensive workup that ruled out infections and other malignancy causing the pulmonary nodes. The most recent chest CT, six months after I-131 therapy, showed a slight decrease in the pulmonary nodes. She underwent repeat WBS, 10 months after I-131, notable for minimal uptake in the lungs. The patient is currently euthyroid on thyroid hormone replacement therapy, and she is undergoing surveillance with laboratory studies every three months, neck US and chest CT every six months. Conclusion: In children with PTC, the pulmonary metastases usually demonstrate radioactive iodine uptake, making them responsive to I-131 treatment. Even though the pulmonary nodes were not iodine avid for our patient based on the WBS, it seems like they are responding to the first dose of I-131 as they have decreased in size. Pulmonary metastases in children have different behavior than in adults, and studies have shown that clinical response to I-131 therapy may take several years to show a reduction in the size of nodes. Therefore, careful consideration should be made before giving another dose of I-131 to this group of patients.
Approaching High-Metabolic Risk Youth During a Pandemic: Severe Presentations of New Onset Type 2 Diabetes
Authors: Long Nathaniel , Eichner Natalie Z M , Benavides-Vasquez Jorge , Saenz Lina Paola Huerta 
Published: May 2021

Abstract
Background: Delays in timely medical care due to the restrictions imposed by the COVID-19 pandemic have worsened patient outcomes with different disease conditions. Youth with obesity, insulin resistance, and dysglycemia are increasingly presenting with HHS and/or DKA, leading to increased morbidity and mortality. Case Descriptions:Case 1: A 17-year-old Hispanic female with history of obesity, insulin resistance, and hyperglycemia reported polyuria, polydipsia, and polyphagia for 2 months. The day of admission, EMS was called because patient was found unresponsive at home and required advanced CPR. At arrival to the ED, the patient was awake and responsive. She had acanthosis nigricans and abdominal striae. Initial labs showed elevated plasma glucose (1,256 mg/dL), sodium (153 mmol/L), bicarbonate (9 mmol/L), anion gap (35 mmol/L), phosphorus (7.5 mg/dL; N=3-4.8), lactate (4 mmol/L; N=0.5-2), BHB (11.4 mmol/L; N=0-0.3), venous pH (7.09), BUN (24 mg/dL), creatinine (1.63 mg/dL), and HbA1c (14.3%). She was admitted for DKA, hyperosmolarity, AKI, and metabolic encephalopathy. After IVF resuscitation, insulin drip at 0.05 U/kg/h was started. She recovered from DKA, AKI and hyperosmolarity after 5 days. T1D antibody tests were negative. C-peptide was low (0.7 ng/mL; N=0.8-3.5), and TSH was low (0.38 uIU/mL) with normal free T4 (0.88 mg/dL). Case 2: A 13-year-old Hispanic female with history of asthma, morbid obesity, premature adrenarche, and prediabetes started presenting polydipsia and polyuria 2 months before admission. One day before admission, she presented drowsiness, abdominal pain, and polyuria. Initial labs at the ED included glucose (792 mg/dL), bicarbonate (10.4 mmol/L), anion gap (28 mmol/L), venous CO2 (10.4 mmol/L; N=21-31), BHB (&gt;22.5 mmol/L), sodium (153 mmol/L), BUN (29 mg/dL), and creatinine (1.37 mg/dL), consistent with DKA, hyperosmolarity, and AKI. Physical exam showed severe obesity, acanthosis nigricans, and hypertension. IV fluids and insulin drip at 0.075 U/kg/h were started. DKA and AKI resolved after 4 days. Labs showed negative T1D antibodies, normal C-peptide (1.2 ng/mL), HgA1C (&gt;14%), microalbuminuria (16.22 mg/dL; N&lt;2 mg/dL), elevated total cholesterol (230 mg/dL) and triglycerides (550 mg/dL). Both youth were negative for SARS-CoV2 and had been engaging in unhealthy lifestyle choices, such as sedentarism and excessive sugary drink intake, exacerbated by COVID-19-related lockdowns and school closures. There were delays in seeking medical care associated to fear of COVID-19.
Conclusion: In the current context of a pandemic, it would be helpful to plan close evaluation and timely therapeutic interventions for youth with well-known high-metabolic risks to prevent hospitalizations, severe presentations of T2D and associated morbidity and/or mortality.