bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sphingosine 1- Phosphate Lyase Insufficiency Syndrome (SPLIS); A Role in Multiple Endocrinopathies
Authors: Wai Kwong Ruth Ming , Maharaj Avinaash Vickram , Metherell Louise , Prasad Rathi 
Published: May 2021

Abstract
Sphingosine 1-phosphate lyase insufficiency syndrome (SPLIS) was described in 2017 as a novel condition affecting sphingolipid metabolism. There is a multisystemic phenotype including nephrotic syndrome and primary adrenal insufficiency (PAI) and to a lesser extent ichthyosis, neurological disease and lymphopenia. A proportion of patients also presented with hypothyroidism and hypogonadism. To interrogate the endocrine aspect of the syndrome we reviewed clinical data within our patient cohort with SPLIS and those within the wider literature. To date there have been 45 patients identified with SPLIS with significant associated mortality (n=23/45, 51%; 4 of these in utero). There is no clear genotype-phenotype correlation. Whilst nephrotic syndrome is most prevalent (n=34/45; 76%), a significant proportion of patients (n=27/45, 60%) also presented with glucocorticoid deficiency, some with additional mineralocorticoid deficiency (n=7/27). Five further patients were noted to have adrenal calcifications though biochemistry was not undertaken. Most patients presented with PAI in the first 2 years of life (n=21/27), with the oldest presentation being 11 years of age. Adrenal calcifications are a common finding in those who had documented imaging (n=13/15, 87%). Primary gonadal failure has been reported in 8 male cases, all with concomitant PAI. Presenting features included microphallus (n=7/8) and cryptorchidism (n=8/8), indicating reduced in utero androgen exposure. All who had biochemical evaluation demonstrated raised basal LH and FSH/ exaggerated response to LHRH stimulation, a lack of testosterone response to HCG stimulation and low antimullerian hormone (AMH) levels. To date there are no reports of pubertal delay in female patients, and those of age within our cohort have normal ovarian reserve as evidenced by AMH levels (n=2). Primary hypothyroidism, with mildly raised TSH and low Free T4 is reported in 12 patients. Most did not have goiters and had concomitant PAI and nephrotic syndrome (n=11/12). SPLIS is unique amongst sphingolipid disorders in presenting with significant endocrinopathy. This may be the consequence of the particular sphingolipid signature of the disease and the pathogenic mechanisms need to be explored further. It is clear that endocrine dysfunction needs to be considered at diagnosis and surveillance undertaken to detect evolving disease which could have a significant impact on morbidity and mortality.
Trends in HbA1c Change Among Youth Referred to a Pediatric Type 2 Diabetes Prevention Clinic
Authors: Paprocki Emily , Yan Yun , Lee Brian R , Barnes Mitchell , De Luca Francesco , Halpin Kelsee 
Published: May 2021

Abstract
Background: Pediatric type 2 diabetes (T2D) has increased in prevalence as childhood obesity rates climb. More youth are being referred to pediatric endocrinology due to the concern for developing T2D, yet prediction of which children will progress to overt T2D is challenging. We describe a single center experience with pediatric prediabetes referrals and trends in HbA1c change.
Methods: Retrospective review of new patients seen at a Type 2 Diabetes Prevention (T2DP) Clinic July 2015 - December 2019. All children referred to T2DP Clinic have an elevated BMI and findings of insulin resistance/prediabetes/early T2D. They are evaluated by pediatric endocrinology providers and dieticians at each visit.
The outcome of interest was categorical HbA1c change between patients’ initial and most recent T2DP Clinic visit. Only HbA1c measurements conducted at the study site were included to address inconsistencies in lab assays. HbA1c at the initial visit was categorized into 3 groups: 1) &lt; 5.7%; 2) 5.7 to &lt;6.5%; 3) 6.5% to &lt;8.5%. Final HbA1c was categorized similarly with the option to progress to a 4th HbA1c group of ≥8.5%. Patients were categorized as progressors, regressors, or stable depending on change in group (e.g., group 1 --&gt; group 2) between initial and most recent HbA1c. Comparisons between groups were made using ANOVA and Fisher’s exact tests.
Results: Among 297 patients seen for an initial visit, mean BMI z-score was 2.3 and body fat percentage was 44%. High blood pressure occurred in 47%, high ALT in 24%, low HDL in 14%. Prevalence of initial HbA1c &lt; 5.7%, 5.7 to &lt; 6.5%, and 6.5% to &lt; 8.5% was 46%, 42%, and 12%, respectively. One-third (31%) were prescribed metformin at their initial visit.
Only 63 patients (21%) had 2 or more visits in the T2DP Clinic with study site HbA1c data available. Of those 63 patients, mean age at initial visit was 12.5 years, BMI z-score 2.0, and body fat 46%. Most patients were female (68%) with public insurance (70%). Race/ethnicity was 35% black, 29% white, 30% Hispanic. Mean time between initial and most recent HbA1c was 11.9 months. Assessment of categorical HbA1c change showed 14% of patients with progression (n=9), 65% stable (n=41), and 21% with regression (n=13). Female sex, ALT elevation, HbA1c, fasting glucose were found to be statistically different between the groups at baseline (p &lt; 0.05). Age, race/ethnicity, BMI, body fat percentage, elevated blood pressure, lipid profile, 120-minute glucose on OGTT, and metformin use were not different between the groups.
Conclusions. Only 14% of children who presented for follow up in our T2DP clinic demonstrated progression in HbA1c. Risk factors for those who progress include female sex and ALT elevation. Further development of predictive models to identify this high-risk population who will progress is necessary. Retaining consistent follow up in pediatric prediabetes clinics presents a challenge.
Trends of Diabetes and Prediabetes Prevalence Among Korean Adolescents From 2007 to 2018
Authors: Kim Jihyun , Lim Jungsub 
Published: May 2021

Abstract
Background: To provide updated prevalence data and to estimate changes in the prevalence of diabetes among Korean adolescents by sex and age between 2007 and 2018. Methods: We used the data of children and adolescents (8,718 subjects aged 10 to 18 years) from the Korea National Health and Nutrition Examination Survey IV-VII (KNHANES 2007-2018). The recent prevalence of diabetes and pre-diabetes estimated by using the latest KNHANES VII. The linear trends were estimated by comparing 3-year KNHANES cycles according to sex and by using logistic regression. Results: The prevalence of diabetes and pre-diabetes was 0.298% (95% CI, 0.289-0.308) and 7.914% (95%CI, 0.43-0.49). The prevalence of diabetes was a significant increase from 0.189 to 0.430 during KNHANE IV and VII. A positive linear trend is significant for diabetes (p trends=0.006) in only male subjects. The prevalence of pre-diabetes was a significant increase from 5.86 to 12.08 in both sexes. During KNHANES IV and VII, the prevalence of obesity increased significantly. Conclusion: Between 2007 and 2018, the prevalence of diabetes among Korean adolescents increased. Further studies are required to determine the causes of these increases.
Economic Burden of Growth Hormone Deficiency in a US Pediatric Population
Authors: Kaplowitz Paul B , Manjelievskaia Janna , Lopez-Gonzalez Lorena , Marrow Cynthia D , Pitukcheewanont Pisit , Smith Alden 
Published: May 2021

Abstract
Pediatric GHD is a rare disorder of short stature that is currently treated with daily injections of GH. In addition to short stature, GHD is associated with other comorbidities such as impaired musculoskeletal development, cardiovascular disease, and decreased quality of life. The objective of this study was to analyze GH utilization, adherence, and healthcare costs among children with GHD who had either Medicaid or commercial health insurance. Children (age &lt;18 years) with a diagnosis of GHD between January 1, 2007, and December 31, 2017 were identified in the IBM Marketscan Commercial and Medicaid Databases. Children with GHD were direct matched (1:3) to controls without GHD (or other short stature-related disorder) on age, gender, plan type, region, and race (Medicaid only). The index date was set as the date of the first GHD diagnosis during the selection window for GHD patients and using random assignment for controls. Patients were followed for the 12 months prior to the index date until the end of continuous database enrollment or December 31, 2018. Baseline comorbidities and medications were measured during the 12 months pre-index. Treatment patterns and all-cause and GHD-related healthcare costs were measured during the variable follow-up period. Multivariable modeling was used to compare costs between GHD patients and controls and between GH treated and untreated GHD patients while adjusting for baseline characteristics. There were 6,820 Medicaid and 14,070 commercial patients with GHD who met the study inclusion criteria. Mean (SD) age at index was 9.5 (4.5) years for Medicaid patients and 11.1 (3.7) years for commercial patients. A majority of patients were male (&gt;65%) and followed for at least 3.7 years. Overall, 63.2% of Medicaid and 68.4% of commercial patients were treated with GH during follow-up. Among Medicaid patients, the treatment rate was highest among white males and lowest among black females. Adherence, as measured by proportion of days covered, was low, with 18.4% of Medicaid patients and 32.3% of commercial patients considered “adherent” (PDC ≥ 0.8). Nearly half (49.1%) of treated Medicaid patients and 24.3% of commercial patients discontinued GH therapy before age 13. After adjusting for baseline characteristics, all-cause non-GH costs were 5.7times higher (Δ$19,309) for Medicaid patients and 5.5 times higher (Δ$12,305) for commercial patients than matched non-GHD controls. Adjusted all-cause non-GH costs were 0.6 times lower (Δ$14,416) for treated Medicaid patients and 0.7 times lower (Δ$7,650) for treated commercial patients than for untreated patients. Pediatric GHD presents a significant healthcare burden, and many patients remain untreated or undertreated. Untreated GHD was associated with higher non-GH healthcare costs than treated GHD. Strategies to improve adherence may reduce the healthcare burden faced by these patients.
LUM-201 Elicits Greater GH Response than Standard GH Secretagogues in Pediatric Growth Hormone Deficiency
Authors: Bright George , Smith Roy , Thorner Michael O 
Published: May 2021

Abstract
Presentation Type: OralScience Type and Topic: Clinical Trial Introduction: LUM-201 (ibutamoren, formerly MK-0677) is an orally administered GH-secretagogue that stimulates the GH secretagogue receptor (GHSR1a) in the hypothalamus and pituitary. LUM-201 is in development for long-term use in a subset of PGHD patients with moderate growth deficiencies. A diagnosis of PGHD is confirmed by low GH responses to standard GH secretagogues (clonidine, arginine, L-dopa, glucagon, insulin) so it is somewhat counter-intuitive to suggest that children who cannot respond to one GH secretagogue might have favorable responses to LUM-201. Objective: To determine if LUM-201 stimulates GH responses differently than standard GH secretagogues. Methods: 68 naïve-to-treatment, prepubertal children with GHD received two standard GH stimulation tests and a test with a single 0.8 mg/kg dose of LUM-201. The 68 subjects included 20 girls and 48 boys. The median (interquartile range) age was 9.2 years (7.2,10.8), bone age 6.0 years (4.5, 7.9), height SDS -3.3 (-4.5, -2.5), pretreatment height velocity 4.0 cm/y (3.2, 4.6), and baseline IGF-1 51 ng/mL (24,111). Results: The median (interquartile range) of maximal GH response to single dose LUM-201 was 15.0 ng/mL (3.5, 49) and to various pairs of standard stimuli was 5.4 ng/mL (1.8-7.6) (p&lt; 0.00001). The median (IQR) for the difference between GH responses to LUM-201 and standard stimuli was 9.6 ng/ml (1.9, 42). In a multivariate analysis (r2 =0.73) differential GH increased with higher values of baseline IGF-I (p &lt; 0.00001) and standard GH stimulation test (p = 0.047) but was not influenced by age (p = 0.16), sex (p = 0.28), baseline HV (p = 0.24), age-bone age differences (p = 0.33) or height-SDS (p = 0.75). Conclusion: In GHD children, the GH response to single dose LUM-201 greatly exceeds that observed with standard GH testing agents. The difference is greatest among patients with higher baseline values of IGF-I and higher GH responses to standard stimuli. The synergistic actions of LUM-201 on the physiological mechanisms regulating GH release explain why GH responses are greater in response to LUM-201 compared to traditional tests used to diagnose PGHD. Key words: LUM-201, GH deficiency, GH secretagogues, pediatrics, stimulation tests, short stature, pituitary, hypothalamus
Persistence of Use in Children Receiving Growth Hormone Therapy
Authors: Spataru Amalia , van Dommelen Paula , Arnaud Lilian , Masne Quentin Le , Quarteroni Silvia , Koledova Ekaterina B 
Published: May 2021

Abstract
Background: Long-term persistence of use and starting at the earliest possible age are associated with attainment of near-normal adult or final height in children who are treated with growth hormone therapy. However, there are many factors associated with a lack of persistence. Our aim was to study persistence of use in children with growth disorders using the easypod™ connected autoinjector e-device, which automatically records adherence data and can transmit them via an online portal (easypod™ connect). We investigated persistence of use, defined indicators of a long persistence of use, and developed a model to predict and identify children at risk of discontinuing treatment in the following 6 months. Data and Methods: Anonymized data from children transmitting over 10 injections between January 2007 and April 2020 were analyzed. A child was considered to discontinue the use if they had no injection in the last 6 months (before April 2020) or had an injection pause of at least 6 consecutive months. Persistence was estimated by Kaplan-Meier analyses and Weibull accelerated failure time modeling. To predict the individual risk of discontinuing the use in the following 6 months, individual survival probabilities curves were estimated for each patient still using the system, and the survival probabilities were then recalculated such that they were conditional on the fact that a child had already used the device for a certain time. The Harrell’s c-index was used to assess the algorithm performance. Results: Data were available for 17,651 children of whom 11,056 discontinued the use and 6,595 were still persistent in April 2020. Median persistence of use for all patients using the device was 2.1 years. There was a highly significant difference in median persistence of use between the regions: 1.0, 1.5 and 2.8 years in the available countries in the Asia-Pacific, America and Europe regions, respectively. Other indicators that had a significant positive impact on persistence of use were: at least one dose change a year, having auxological measurements recorded in the system (and if ‘Yes’, height standard deviation &lt; -2 at start of use had an additional effect), starting treatment at an early age, adherence ≥85%, customized injection speed setting and being male. For the individual prediction, random survival forests showed the best performance (Harrell’s c-index=0.72). Conclusions: Data from the connected autoinjector e-device showed that the persistence of use was approximately 2 years in children with growth disorders. We were able to define 8 indicators that had a positive impact on persistence of use of which several indicators were related to patient management. Our prediction model can be used to identify children needing support to reach longer persistence of use and subsequently optimal clinical outcomes.
Human Adrenal Cortical Zone Changes With Aging
Authors: Tezuka Yuta , Atsumi Nanako , Blinder Amy , Rege Juilee , Giordano Thomas J , Rainey William E , Turcu Adina 
Published: May 2021

Abstract
Background: Previous adrenal morphological studies have shown that the zona reticularis (ZR) and the zona glomerulosa (ZG) decrease in size with aging. Although several lines of evidence indicate that the hypothalamic-pituitary-adrenal axis becomes hyperactive in elderly, little is known about age-related transformations of the adrenal zona fasciculata (ZF). Objectives: To investigate the morphological and functional changes of the adrenal cortex across the adult life span, with emphasis on: 1) the understudied ZF, and 2) potential sexual dimorphisms. Methods: We used immunohistochemistry to evaluate the expression of several cortical proteins: aldosterone synthase (CYP11B2), visinin-like protein 1 (VSNL1), 3β-hydroxysteroid dehydrogenase type II (HSD3B2), 11β-hydroxylase (CYP11B1) and cytochrome b5 type A (CYB5A). The ZF area was estimated by subtracting the VSNL1-positive (a ZG marker) area from the HSD3B2-expressing area (ZG and ZF). All captured images were quantitated by ImageJ. In addition, we employed liquid chromatography-tandem mass spectrometry to quantify the morning serum concentrations of 6 steroids: cortisol, 11-deoxycortisol (11dF), 17α-hydroxyprogesterone (17OHP4), 11-deoxycorticosterone (DOC), corticosterone, and androstenedione (A4). The Mann-Whitney U test and Spearman’s rank correlation coefficients were used for statistical analysis, as appropriate. Results: We included 60 adrenal glands from 30 men and 30 women, with ages between 18–86 years. The total cortical area was positively correlated with age (r=0.34, p=0.008), and this association was significant only in men (p=0.02). Both the total (VSNL1-positive) and functional ZG (CYP11B2-positive) areas declined abruptly with aging in men (r=-0.57 and -0.76, p=0.001 and p&lt;0.0001, respectively), but not women (p=0.06 and 0.27, respectively). The CYB5A-positive area, marking the ZR, correlated negatively with age (r=-0.76, p&lt;0.0001) in both sexes. In contrast, the estimated ZF area showed a strong positive correlation with age both in men (r=0.59, p=0.0006) and women (r=0.49, p=0.007), while CYP11B1-positive area remained stable across ages (p=0.86). Finally, we measured morning levels of 6 steroids in 149 men and 149 women, with ages between 21–95 years, matched for age and body mass index. Serum cortisol, corticosterone, and DOC levels remained relatively stable across ages (p=0.38, 0.64 and 0.25, respectively), while 11dF levels increased slightly with age (r=0.16 and p=0.007), particularly so in men (p=0.005). Expectedly, 17OHP4 and A4 declined with aging (r=-0.37 and -0.37, p&lt;0.0001 for both). Conclusions: In contrast with the ZG and ZR, the ZF and the total adrenal cortex area enlarge with aging. An abrupt decline of the ZG occurs with age in men, but not in women, possibly contributing to sexual dimorphism in cardiovascular risk.
Intracellular Cholesterol Metabolism in Aldosterone-Producing Adenoma.~A Possible Association With Cellular Morphometry and Genotype~
Authors: Harashima Shogo , Yamazaki Yuto , Ono Yoshikiyo , Omata Kei , Tezuka Yuta , Morimoto Ryo , Nakamura Yasuhiro , Satoh Fumitoshi , Suzuki Hiroyoshi , Sasano Hironobu 
Published: May 2021

Abstract
Introduction: Primary aldosteronism (PA) is the most common cause of secondary hypertension. More than 70% of APAs have been reported to have KCNJ5 somatic mutation in Asian countiries. Patients with KCNJ5 mutated APAs generally harbor high plasma aldosterone concentration (PAC), and are mainly composed of clear tumor cells containing abundant lipid droplets. However, an association among intracellular cholesterol metabolism, morphological features and genotypes in tumor cells has remained virtually unknown.[Materials and methods]Three cholesterol receptors (SR-B1, LDL-R, VLDL-R) were immunolocakized in 25 APA cases (KCNJ5 mt: n= 15, WT: n=10) who underwent adrenalectomy at Tohoku University Hospital. Image analysis software (HALO, India Labs) was used to quantitatively analyze the intracellular localization and immunoreactivity and expored their correlation with genotype and clinical factors.[Results]LDL-R immunoreactivity was significantly lower in KCNJ5 mt group than WT group (P = 0.0369). In KCNJ5 mt group, a significant correlation was detected between LDL-R immunoreactivity and CYP11B2 (Aldosterone synthase), (P = 0.0271, ρ = 0.5684) but not in WT group. In addition, LDL-R immunoreactivity was significantly inversely correlated with tumor size (P = 0.0142, ρ = -0.6176) and PAC (P = &lt;0.001, ρ = -0.7179) in mt group as well as in whole APA cases.[Discussion]This is the first study to compare cholesterol receptor expression profiles with morphological tumor cell subtype, genotype, and clinical data in APAs. Results indicated that KCNJ5 mt APAabundantly stored cholesterol ester in their cytoplasm and cholesterol uptake was less activated, resulting In rather efficient aldosterone biosynthesis in tumor cells. In addition, a significant correlation was detected between LDL-R and CYP11B2 with the abundant localization of LDL-R in tumor cells. Therefore, LDL-R could be a predominant resource of plasma lipoprotein uptake in aldosterone-producing tumor cells, especially for KCNJ5mt APAs.
A Case of Definitive Therapy in Persistent Congenital Hyperthyroidism Secondary to an Activating Variant of the TSHR Gene
Authors: Reynolds Sarah M , Shimy Kim J , Merchant Nadia 
Published: May 2021

Abstract
Background: Sporadic congenital non-autoimmune hyperthyroidism (SCNAH) causes permanent hyperthyroidism secondary to activating mutations in the TSHR gene. SCNAH usually presents during infancy and can be difficult to treat with antithyroid drugs or subtotal thyroidectomy.1 When adequate therapy is delayed, irreversible sequela such as craniosynostosis, growth failure, and cognitive delays may develop. Definitive therapy for children with SCNAH is recommended with no consensus on timing or type of intervention. Our case highlights the importance of early total thyroidectomy to optimize clinical outcomes in patients with SCNAH.
Clinical case: A now 3-year-old male was born small for gestational age (SGA) at 34 weeks gestation with biochemical and clinical signs of hyperthyroidism in the neonatal period. On day of life 6, his TSH was 0.02 mcU/mL (reference range 0.34-5.6 mcU/mL) and free thyroxine (T4) was 5.42 ng/dL (reference range 0.58-1.64 ng/dL). Methimazole (MMI) 0.3 mg/kg/day was started at that time, and the dose was titrated over 6 weeks of life to 0.8 mg/kg/day due to continued elevation of free T4 levels. Negative thyroid autoantibodies and normal maternal thyroid studies prompted genetic testing at 3 months of age. This testing revealed a heterozygous variant in the TSHR gene [c.842G-&gt;A (p.G116R)] that was determined to be pathologic. Despite frequent MMI dose changes and confirmation of medication adherence, high-dose MMI was not effective in consistently normalizing his TSH and free T4 levels in the first two years of life. Concerns for poor growth and hyperactive behavior were also present. A “block and replace” strategy was not feasible since the patient remained hyperthyroid even at MMI doses up to 0.8 mg/kg/day. Despite normal insulin-like growth factor 1 and insulin-like growth factor binding protein 3 levels, poor linear growth persisted with a height Z-score of -3.61 by age 3 years. While he was SGA at birth, his recurrent hyperthyroidism impeded catch-up growth potential, so treatment with growth hormone (rhGH) was initiated. His height Z-score improved to -2.39 after 9 months on rhGH dosed at 0.18 mg/kg/week. Due to the difficulty in consistently managing him medically with MMI, he underwent total thyroidectomy at age three.
Conclusion: There is currently no consensus on the timing of definitive therapy for children with SCNAH. This case highlights the importance of considering total thyroidectomy at an early age to avoid long-term sequela of persistent hyperthyroidism.
1. Gozu HI, Lublinghoff J, Bircan R, Paschke R. Genetics and phenomics of inherited and sporadic non-autoimmune hyperthyroidism. Mol Cell Endocrinol. 2010;322:125–34.