bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Machine Learning Approach for Identifying Children at Risk of Suboptimal Adherence to Growth Hormone Therapy
Authors: Spataru Amalia , van Dommelen Paula , Arnaud Lilian , Masne Quentin Le , Quarteroni Silvia , Koledova Ekaterina B 
Published: May 2021

Abstract
Background: Suboptimal adherence to recombinant human growth hormone (r-hGH) treatment can lead to suboptimal clinical outcomes. Being able to identify children who are at risk of suboptimal adherence in the near future, and take adequate measures to support adherence, may maximize clinical outcomes. Our aim was to develop a model based on data from the first 3 months of treatment to identify potential indicators of suboptimal adherence and predict adherence over the following 9 months using a machine learning approach.
Methods: We assessed adherence to r-hGH treatment in children with growth disorders in their first 12 months of treatment using a connected autoinjector and e-device (easypod™), which automatically transmits adherence data via an online portal (easypod™ connect). We selected children who started the use of the device before 18 years of age and who transmitted their injection data for at least 12 months. Adherence (mg injected/mg prescribed) between 4-12 months (outcome) was categorized as optimal (≥85%) versus suboptimal (&lt;85%). In addition to adherence over the first 3 months, comfort settings (needle speed, injection depth, injection speed, injection time), number of transmissions, number of dose changes, age at start and sex were used as potential indicators of suboptimal adherence. Several machine learning models were optimized on a class-balanced training dataset using a 5-fold cross-validation scheme. On the best performing model, machine learning interpretation techniques and chi-squared statistical tests were applied to extract the statistically significant indicators of suboptimal and optimal adherence. Results: Anonymized data were available for 10,943 children. The optimal prediction performances were achieved with the random forest algorithm. The mean adherence and the adherence standard deviation over the first 3 months were the two most important features for predicting adherence in the following 9 months. Not using the system’s features (e.g. not transmitting data often and not changing some of the comfort settings, such as the needle speed setting), as well as starting treatment at an older age were significantly associated with an increased risk of suboptimal adherence (p&lt;0.001). When tested on first-time seen data following the same class distribution as the original data, the model achieved a sensitivity of 80% and a specificity of 81%.
Conclusions: We developed a model predicting whether a child’s adherence in the following 9 months will be below or above the optimal threshold (85%) based on early data from the first 3 months of treatment and we identified the indicators of suboptimal adherence. These results can be used to identify children needing additional medical or other support to reach optimal adherence and therefore optimal clinical outcomes.
Comparison of Quality of Life Responses From Caregiver and Children Aged ≥7 Years Using the Quality of Life in Short Stature Youth (QoLISSY) Questionnaire, Following 12 Months of Growth Hormone Treatment With Either a Weekly Somatrogon or a Daily Genotropin Injection Schedule
Authors: Loftus Jane , Quitmann Julia , Valluri Srinivas , Pastrak Aleksandra , Reiter Lawrence , Roland Carl 
Published: May 2021

Abstract
Objective: Paediatric growth hormone deficiency (pGHD) affects 1/4,000 children. Treatment with daily sub-cutaneous injections of recombinant human growth hormone (r-hGH) increase height velocity and quality of life (QoL). A recent randomised controlled clinical trial (NCT02968004) evaluated the efficacy/safety of weekly Somatrogon (hGH-CTP) and daily Genotropin in pGHD. QoL (an exploratory endpoint) was evaluated using the validated Quality of Life in Short Stature Youth (QoLISSY) questionnaire, which includes three subscales (physical, social, emotional) and total score.
Methods: The QoLISSY core module was administered to patients (aged 3-11 years [girls], 3-12 years [boys]) and parents in US, UK, Australia, New Zealand, Belarus, Russia, Ukraine and Spain, at Baseline (BL) and 12 months after treatment start. The QoLISSY-CHILD was completed by children aged ≥7 years; QoLISSY-PARENT was completed by the Caregiver for children &lt;7 years, and for some children aged ≥7 years. We report here only the QoLISSY results for children aged ≥7 years (reported from either child or parent).
Results: For Total QoLISSY-PARENT, for children aged ≥7 years in the Somatrogon group (N=26), mean scores are 53.65 (BL) and 65.52 (month 12) with mean change of 13.01 (95% Confidence Interval [CI]: 3.99, 22.02). In the Genotropin group (N=28), mean scores are 55.89 (BL) and 63.66 (month 12) with mean change of 6.60 (CI:-0.21, 13.40). For Total QoLISSY-CHILD in the Somatrogon group (N=35), mean scores are 61.48 (BL) and 74.69 (month 12) with mean change of 13.00 (CI: 5.81, 20.19). In the Genotropin group (N=35), these scores are 60.96 (BL) and 69.03 (Month 12) with mean change of 7.84 (CI: 2.71, 12.97). Scores of &gt;70 indicate a good QoL.
Conclusions: QoL in children aged ≥7 years improved, following 12 months of either treatment, whether this was reported by caregiver or child. However, these data show that the baseline scores and 12 month scores from the QoLISSY-PARENT in both treatment groups were numerically lower than those reported by the child. This is consistent with the literature¹, in which the caregivers generally report lower QoL scores on behalf of the child.
¹Explaining parent-child (dis)agreement in generic and short stature-specific health-related quality of life reports: do family and social relationships matter? Quitmann et al Health and Quality of Life Outcomes 2016 vol 14, Article 150
Factors Driving Patient Preferences for Growth Hormone Treatment in Japanese Children With Growth Hormone Deficiency
Authors: Tanaka Toshiaki , Sato Takahiro , Yuasa Akira , Akiyama Takeshi , Tawseef Adeeb 
Published: May 2021

Abstract
Background: There are no any clear evidence to date has evaluating patients and caregiver preferences for r-hGH (recombinant-human growth hormone) injection in children in Japan. This study quantitatively evaluated the factors driving preferences for daily r-hGH injection among Japanese children with Growth Hormone Deficiency (GHD) or their respective caregivers to determine the relative importance of treatment delivery attributes. This study was performed amongst Japanese children with GHD or their caregivers who visited a specialized clinic in Japan as part of their routine care between June and July 2020. Methods: The participants were asked to complete a web-based discrete choice experiment (DCE) questionnaire using a handheld tablet device during a routine clinical visit. DCE is a quantitative method widely used in healthcare to elicit preferences from participants in the absence of revealed preference data. Choice-based conjoint analysis was used to evaluate the relative importance of attributes as choice predictors and determine utilities for each attribute. Of the 47 respondents who participated in this study, 41 were caregivers who responded on behalf of the patients, and the remaining 6 were patients who completed the DCE themselves. All participants were screened by a clinician to ensure they met all eligibility criteria. Results: The injection schedule was found to be the most important attribute for both patients and caregivers (Relative importance: 43.6%); a once-weekly injection schedule was preferred over a daily injection schedule. For maintenance of injection devices, patients had a stronger preference for reusable pens which can be used by replacing cartridges, while caregivers preferred disposable pen devices. The storage and preparation attribute was deemed more important to patients than it was to caregivers, with patients preferring storage in room temperature even if it needed an additional mixing(reconstitution) step. Both patients and caregivers showed a clear preference for devices that offered a dose setting memory. Conclusion: The results of this study showed that patients prefer a once-weekly injection schedule over a daily injection schedule. A less frequent injection schedule should enhance adherence and compliance to r-hGH treatment over the long term and will also improve QoL in children with GHD. The benefits of a less frequent injection schedule can be further explored using real-world studies.
Long-Term Effect of Aromatase Inhibition in Aromatase Excess Syndrome
Authors: Binder Gerhard , Nakamura Akie , Schweizer Roland , Ogata Tsutomu , Fukami Maki , Nagasaki Keisuke 
Published: May 2021

Abstract
Aromatase excess syndrome (AEXS) is a very rare disorder characterized by prepubertal gynecomastia, bone age acceleration and early growth arrest. Heterozygote submicroscopic rearrangements within the promotor of CYP19A1 result in overexpression of aromatase and enhanced aromatization of androgens. Long-term treatment effects of aromatase inhibitors are unknown. Retrospectively we collected data from file records of 7 boys (three sibling pairs and one sporadic case) with AEXS. Genetic analysis revealed upstream of CYP19A1 a 165,901 bp deletion in 4 German cousins, a 198,662 bp deletion in 2 Japanese brothers and a 387,622 bp tandem duplication in a Japanese boy. All boys developed prepubertal gynecomastia, at 9.0 yr of age (median; range: 7.0 - 11.0). Height was +1.20 SDS (-0.24 - +1.98); predicted adult height was -1.29 (-3.29 - +1.09 SDS). Four boys were treated with anastrozole 1.0 mg daily, while three reached adult height untreated. Treatment with anastrozole was stopped after 5.6 yr (4.0 - 6.8). Three treated boys exceeded height prognosis by 2.4, 6.9 and 8.1 cm; while one untreated fell below prognosis by 8.6 cm. One treated with a low dose and two untreated reached their prognosis. Adult heights were -0.91 SDS with anastrozole (-2.86 - -0.29) and -0.15 SDS without (-2.31 - -0.03). Distance to target height was -0.22 SDS with anastrozole (-1.72 - +0.52) and +0.54 SDS without treatment (+0.23 - +1.30). Spontaneous growth in AEXS varied, even in the same family. Our data suggest that early started, long-term inhibition by aromatase inhibitor anastrozole (1 mg daily) promotes adult height in boys with AEXS.
Case Report: Primary Hypothyroidism Caused by Autoimmune Thyroiditis in Infancy Requires Early Intervention
Authors: McSweeney Zina C , Chang Christopher , Nemery Robin Lynne 
Published: May 2021

Abstract
Background: Primary hypothyroidism due to autoimmune thyroiditis is extremely rare in infants, especially under the age of 3 years. For infants, hypothyroidism is most commonly congenital, originating from thyroid dysgenesis with an absent, ectopic, or hypoplastic thyroid gland (1 in 4,000 live births). If left untreated, it can lead to permanent neurodevelopmental deficits. In this report, we describe a male infant who was diagnosed with Hashimoto thyroiditis at 18 months of life, providing a learning example to aid in recognition of this rare disease and enable timely intervention.
Clinical Case:Patient was a 2,765 gram, appropriate for gestational age, male born at term with hypospadias of the penis (surgical correction at 11 months). Patient passed meconium in the first 24 hours of life. During the first few months of life, patient developed constipation. Patient had amblyopia necessitating eye patching and began to wear eye glasses at 18 months of life. Patient’s linear and weight growth were within normal limits. Patient had normal motor development, however had language development delay. No known family history of thyroid disease. Screening labs performed at 17-months of age showed abnormal thyroid function: elevated TSH at 14.86 µIU/mL (ref: 0.45 - 4.50 µIU/mL) and normal free T4 level at 1.24 ng/dL (ref: 0.85-1.75 ng/dL). Repeat testing at 18 months of age continued to show elevated TSH at 6.18 µIU/mL (ref: 0.64 - 4.00 µIU/mL), normal free T4 at 1.07 ng/dL (ref: 0.88 - 2.03 ng/dL), and elevated thyroid peroxidase (TPO) antibodies at 163 IU/ml (ref: &lt;35 IU/ml). At 21 months of age, patient was initiated on L-thyroxine therapy for elevation of TSH (9.570 µIU/mL; ref: 0.64 - 4.00 µIU/mL) and free T4 was normal (1.03ng/dL; ref: 0.88 - 2.03 ng/dL). Notably, the newborn screen for hypothyroidism was within normal limits, suggesting chronic autoimmune thyroiditis instead of congenital thyroid dysgenesis.
Conclusions: This case report provides insights into autoimmune thyroiditis in infancy, which, although especially rare under age 3 years, should be considered in infants who present with autoimmunity or abnormal thyroid testing. In the neonatal period, infants’ immune systems are learning to discriminate requirements for self-tolerance versus protection against pathogens and may be more prone to infections. Although autoimmunity in this stage of development is uncommon, there can be breakthroughs in tolerance, as seen in this case. In addition to this patient, two other infants were seen with elevated TPO antibodies, diagnosed at 17 and 31 months old, with similar clinical trends. There remains a need for additional studies providing further insights into autoimmunity in infancy. Importantly, this case illustrates that, when infants have abnormal thyroid levels (with or without other autoimmune conditions), consideration should be made for anti-thyroid antibody testing.
Cortisol and Aldosterone Adrenocortical Mass in a Previously Healthy Pediatric Patient
Authors: Burdea Liliana , Jo Inha , Boucher-Berry Claudia Cheryl 
Published: May 2021

Abstract
Introduction: Adrenocortical tumors (ACTs) are rare in the pediatric population compared to the adults, with an incidence of 0.3-0.5 cases per million child-years. Most ACTs are sporadic, but some occur as a component of hereditary cancer syndrome. We report a case of a 16 year old male with single unilateral adrenocortical tumor that was found to secrete cortisol and aldosterone. Case Presentation: 16-year-old male previously healthy, presented to nephrology for elevated blood pressure (BP) and microscopic hematuria evaluation. He was otherwise asymptomatic. Manual BP was noted to be 156/84 mmHg and physical exam was within normal limits. Laboratory evaluation revealed a normal comprehensive metabolic panel. Echocardiography was notable for moderate left ventricular hypertrophy, and a renal ultrasound revealed a heterogeneous solid right adrenal mass which measured 5.6 x 4.5 cm. Adrenal MRI showed a well-defined round 5.7 x 5.0 x 5.2 cm right adrenal mass with heterogeneously T1 isointense and T2 hyperintensity, with no evidence of vascular invasion. The left adrenal gland was normal. Additional workup was notable for an aldosterone level of 18.4 ng/dL (4.0-31.0 ng/dL), plasma renin activity 0.2 ng/ml/h (&lt;6), and elevated aldosterone to renin ratio of 92. The morning cortisol level of 7.7 ug/dL (6.7-22.6), with a 24-urine cortisol level elevated at 70.2 ug/d (&lt;56.0). Low dose and high dose Dexamethasone suppression tests were performed, and the morning cortisol was not suppressed, pointing more towards hypercortisolism from the adrenal gland. ACTH levels were found to be suppressed as well. Due to concerns of possible adrenal crisis during or after surgery, the patient was started on stress dose steroids and then tapered off after several weeks. Patient underwent laparoscopic removal of the mass and right adrenal gland with uncomplicated postsurgey period. Pathology showed an adrenal cortical tumor 6 cm/68gm, indeterminate for malignancy versus benign. Extensive genetic studies revealed that patient was heterozygous for the p.N560(c/1679A&gt;T) variant of unknown significance in the MSH2 gene. His blood pressure continued to remain elevated after surgery, and he was started on lisinopril with minimal improvement. The patient is currently doing well, and his blood pressure is better controlled now with amlodipine. He is undergoing surveillance with laboratory evaluation and imagining every 3-6 months. Discussion: ACTs are extremely rare in pediatric patients. Their presentation might be variable, and even when they are found incidentally, it is crucial to assess for hormonal secretion. Although our patient had no signs of hypercortisolism on physical exam, his ACT was secreting both cortisol and aldosterone. In this case report, we demonstrated a rare case of unilateral ACT causing hyperaldosteronism and hypercortisolism with persistent hypertension following adrenalectomy.
Multiple Concomitant Episodes of Diabetic Ketoacidosis and Acute Pancreatitis in a Pediatric Patient With Type 1 Diabetes
Authors: Patel Aashka , Larsen Nicole , Burdea Liliana , Mantis Stelios , Minutti Carla 
Published: May 2021

Abstract
Introduction: Abdominal pain is a common presenting symptom in diabetic ketoacidosis (DKA). Correction of the acidosis usually leads to resolution of the abdominal pain. In some instances, the pain may persist due to additional etiologies presenting alongside DKA. Though uncommon, there has been shown to be an association between DKA and acute pancreatitis (AP). In these rare cases, AP was secondary to the hypertriglyceridemia (HTG) state induced by DKA. We report a 13-year-old female known with type 1 diabetes (T1D) who presented with multiple concomitant episodes of DKA and AP and normal triglyceride levels. Case Presentation: The patient is a 13-year-old female with T1D who presented with two days of hyperglycemia, nausea, and diffuse abdominal pain. Initial laboratory evaluation was remarkable for point-of-care glucose of &gt;500 mg/dL (60-99), venous pH of 7.006 (7.330-7.430), bicarbonate of &lt; 5 mmol/L (20-28), beta-hydroxybutyrate of 5.6 mmol/L (0.0-0.8); consistent with severe DKA. She received normal saline bolus fluids and then started on the DKA protocol with improvement of acidosis, though with the persistence of abdominal pain. Due to concern for other causes of her abdominal pain, additional workup was done, notable for elevated lipase of 624 U/L (10-52), amylase of 434 U/L (25-100), and triglyceride of 121 mg/dL (30-149). An abdominal ultrasound showed findings consistent with AP, lipase levels peaked at 1753 U/L before down-trending to 959 U/L, and amylase decreased to 389 U/L. After several days abdominal pain resolved, and the patient was discharged home. The patient was readmitted six weeks and again one year later for laboratory and symptoms, including abdominal pain consistent with DKA. Both lipase and amylase were elevated during both admissions with normal triglyceride levels. Magnetic resonance cholangiopancreatography was significant for findings compatible with acute pancreatitis with no evidence of cholelithiasis or choledocholithiasis. The patient underwent genetic testing, including normal PRSS1, SPINK1, CFTR, CPA1, and CTRC. A variant of unknown clinical significance was identified in the CTRC gene (c.550G&gt;A), which was not thought to be the cause of her recurrent pancreatitis. Interestingly, since her hemoglobin A1c has been in a better range for the past year, she did not have any recurrent episodes of pancreatitis. Conclusion: The insulin-deficient state associated with DKA can lead to moderate to severe HTG, which in turn can cause AP. Even though abdominal pain is a common symptom in patients presenting in DKA, one should think about other causes when the abdominal discomfort is out of proportion or not improving as acidosis resolves. Our patient had recurrent pancreatitis for unknown etiology; however, she has not had any pancreatitis episodes in the last year since her diabetes has been under better control.
Novel Heterozygous Calcium Sensing Receptor (CASR) Genetic Variant in Child with Unique Phenotype: Hypocalcemia, Mandibular Hypoplasia, Renal Cysts and Type E Brachydactyly
Authors: Legro Nicole , Kees-Folts Deborah , Ladda Roger , Huerta-Saenz Lina 
Published: May 2021

Abstract
Background: There are over 230 disease-causing variants in the calcium-sensing receptor gene (CaSR). Gain-of-function missense mutations in CaSR cause Autosomal Dominant Hypocalcemia (ADH) characterized by hypocalcemia (hCa), hypoparathyroidism (hPTH), and hypercalciuria. Patients with ADH are sensitive to fluctuations in serum calcium (Ca); and supplementation with Ca and vitamin D can cause inappropriate renal calcium retention leading to hypercalcemic events and long-term renal complications. Clinical Case: A 15-year-old adopted (at age 18 months) Korean female was initially diagnosed with hPTH and chronic hCa after presenting with hCa seizures. Laboratory values showed hCa (7.7 mg/dL), hyperphosphatemia (7.6 mg/dL) and hPTH (&lt; 3 pg/mL.) Initially, she was treated with Ca supplementation (20 mg/kg/day elemental Ca), and calcitriol (0.01 mcg/kg/day). She presented at age 4 with hematuria and was found to have obstructive nephrolithiasis requiring operative intervention. Renal ultrasound (US) showed bilateral medullary nephrocalcinosis. She continued treatment with Ca and calcitriol. At age 6, a thiazide diuretic and potassium citrate supplement were added due to hypercalciuria. She had recurrent nephrolithiasis and persistent nephrocalcinosis. Follow-up renal US also showed bilateral renal cysts. Biweekly laboratory evaluation demonstrated an exuberant response to calcium supplementation. Serum Ca levels oscillated between 7.0 -10 mg/dL, but she showed minimal symptoms of hCa. At age 14, she was also recognized to have submandibular hypoplasia and brachydactyly of the 4th and 5th metacarpals and metatarsals bilaterally and genetic testing for CaSR gene mutation was requested. Sshe developed acute kidney injury and hypercalcemia, possibly precipitated by viral illness. However, 3 weeks before, calcitriol dose was increased to 1.25 mcg twice a day (0.07 mcg/kg/day). At admission, serum Ca was 12.7 mg/dL, iPTH 5.2 mg/dL, phosphorus 4.5 mg/dL, BUN 36 mg/dL, creatinine 1.85 mg/dL. Symptoms included headache, muscle spasm and throat spasm. She received intravenous fluids and recovered, but had an extended hospital stay. Targeted genetic analysis of the CaSR gene was completed, and identified a heterozygous variant (c.2506G&gt;T, p.V836L) which is predicted to be likely pathogenic and cause ADH. After CaSR gene mutation identification, the calcitriol and also elemental Ca dosing were decreased to achieve a low Ca level (~7 mg/dL) with normal urine Ca/creatinine ratio. Patient remains asymptomatic. Conclusion: This is the first case of a novel mutation in the CaSR (c.2506G&gt;T, p.V836L) associated with ADH, brachydactyly, renal cysts, and mandibular hypoplasia. Timely genetic testing for ADH in patients with newly diagnosed hPTH can lead to changes in therapy and improved prognosis.