bluuebunny/crossref_metadata_2025_split huggingface dataset:
THU239 Tolvaptan For SIADH Management In Children
Authors: Igarashi Mizuho , Kashima Takemoto , Doi Hibiki , Yoshii Keisuke , Naiki Yasuhiro , Horikawa Reiko 
Published: October 2023

Abstract
Disclosure: M. Igarashi: None. T. Kashima: None. H. Doi: None. K. Yoshii: None. Y. Naiki: None. R. Horikawa: None.
[Background] Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is common after brain surgery and its’ management is difficult. In Japan, tolvaptan was approved for SIADH management in adults, but there are limited reports on the use of tolvaptan for SIADH in children.We presented two cases which showed triphasic response after neurosurgery and was treated with tolvaptan for SIADH phase. We will also summarize other cases which were treated with tolvaptan for SIADH phase after neurosurgery in discussion. [Case] Case1 is a 5-month-old boy with choroid plexus papilloma.A tumor resection was performed after chemotherapy. After tumor resection, serum sodium level went up to 171 mEq/L with diluted polyuria. So he was diagnosed as diabetes insipidus and treated with vasopressin. The dose of vasopressin was decreased and it was stopped on postoperative day (POD) 6, but serum sodium level further decreased and he was diagnosed as SIADH. Water restriction and hypertonic saline administration were performed. Tolvaptan at a dose of 0.1mg/kg was administered and sodium level improved from 123 mEq/L to 137 mEq/L.However, urine volume was decreased again and sodium level went down to 132 mEq/L, so tolvaptan was administered again. After second administration of tolvaptan, polyuria lasted and sodium level went up to 145 mEq/L, which was managed with temporary use of vasopressin. Case 2 is a 6-year-old girl with craniopharyngioma. After tumor resection, polyuria was observed and she was diagnosed as diabetes insipidus, which was treated with vasopressin.On POD 4, she was diagnosed as SIADH. Since water restriction was not effective, tolvaptan was administered twice (0.1mg/kg and 0.4mg/kg respectively). After second administration of tolvaptan, due to polyuria and diluted urine sodium level went up to 161 mEq/L, which was treated with vasopressin. Diluted urine and polyuria lasted, so finally she was diagnosed as diabetes insipidus. [Discussion] Tolvaptan was used for the management of SIADH that was resistant to water restriction or salt supplementation and it was useful for improving or maintaining sodium level. However, in some case, hypernatremia due to excessive free water excretion was caused after the dose of tolvaptan was increased. The appropriate dosage of tolvaptan has not yet been established. The risk of rapid sodium elevation should be considered and monitoring of water balance and sodium level was needed after using tolvaptan. [Conclusion] Tolvaptan could be an effective option for the management of SIADH, but frequent monitoring of sodium level is needed.
Presentation: Thursday, June 15, 2023
FRI590 Predictors Of Metabolically (Un)Healthy Obesity In Children
Authors: der Veken Lotte Van , Chestermann Xavier , Casteels Kristina , Helsen Jan , Rochtus Anne Maria 
Published: October 2023

Abstract
Disclosure: L. Van der Veken: None. X. Chestermann: None. K. Casteels: None. J. Helsen: None. A.M. Rochtus: None.
Childhood obesity is a growing problem worldwide and can lead to type 2 diabetes, hypertension, dyslipidemia, and carotid-artery atherosclerosis. This is known as “metabolically unhealthy obesity” (MUO). However, a subgroup of children who are obese have been described as “metabolically healthy” (MHO) due to the absence of these cardiometabolic risk factors. The current definition of MHO only includes cardiometabolic criteria (MHO-CR) such as systolic blood pressure, diastolic blood pressure, triglycerides, HDL-cholesterol and a measure of fasting plasma glucose. The aim of this review is to compare the current definition based on cardiometabolic risk factors with a definition that includes insulin resistance (MHO-IR). We investigated the differences between these definitions in terms of prevalence, characteristics, predictors, and the recommended way of measuring insulin and its respective cut-off value. We searched Pubmed, Embase, Web of Science and Cochrane Library for studies on prevalence and predictors of insulin resistance in pediatric MHO. The prevalence of MHO-CR, MHO-IR, MUO-CR, MUO-IR and MHO, based on combined criteria from both MHO-CR and MHO-IR, were compared and the mean-values for each group were calculated. A meta-analysis study was designed to investigate the characteristics of MHO-CR and MHO-IR. Summary effects were calculated using random effects models. The standardized mean differences (SMD) are presented together with their confidence intervals (5% significance level). The recommended way of measuring insulin resistance was investigated by a frequency-based representation of used units and cut-off values in the included studies. Eight full text articles met the eligibility criteria for inclusion. Out of 4036 participants, the mean prevalence of different groups was MHO-CR (35%), MHO-IR (44%), MUO-CR (61%) and MUO-IR (56%). After combining the cardiometabolic criteria with the factor insulin resistance, prevalence of MHO and MUO were respectively 11% and 54%. The characteristics found to be significantly different between MHO-CR and MHO-IR were fasting insulin [SMD 1.7406; CI (0.0198-3.4614); P=0.0481] and HOMA-IR [SMD 0.7202; CI (0.4414-0.9989); P=0.0007]. HOMA-IR was also significantly higher in MUO-IR than MUO-CR [SMD -0.3940; CI (-0.7471- -0.0409); P=0.0342]. Several predictors for MHO-CR and MHO-IR were defined. The most frequently used unit and cut-off value of MHO was HOMA-IR&lt;3.16.The implementation of insulin resistance in the definition of pediatric MHO could provide a stricter way of categorizing patients as MHO and MUO, and allow earlier treatment interventions.
Presentation: Friday, June 16, 2023
FRI592 Pediatric Diabetes Mellitus And The COVID-19 Pandemic
Authors: Cooper Felicia Ilyssa , Thokalath Adrien , Chalise Sweta , Vyas Neha , Gurnurkar Shilpa 
Published: October 2023

Abstract
Disclosure: F.I. Cooper: None. A. Thokalath: None. S. Chalise: None. N. Vyas: None. S. Gurnurkar: None.
Introduction: Evidence suggests that during the COVID-19 pandemic, adults had delayed detection of diabetes mellitus (DM) and its complications as well as an increase in the severity of DM symptoms. Our retrospective study aimed to determine the difference in prevalence of new onset DM and to compare the severity of diabetic ketoacidosis (DKA) in these children prior to and during the COVID-19 pandemic at Nemours Children’s Health in Orlando, FL. Methods: Chart review was performed on children with new onset DM (type 1 and 2) pre-pandemic and during the pandemic (9/1/2017-9/1/2022). 509 participants met inclusion criteria. Demographic information and laboratory data were collected. One sample proportions test was used to compare the proportion of new onset DM diagnoses and severity of presentation. Chi square test was used to test association of demographics with DM onset and DKA status. Statistical significance was set at p&lt;0.05 and all analyses were run on IBM SPSS 28.0. Results: A greater number of pediatric DM diagnoses were made during the COVID-19 pandemic when compared to pre-pandemic [295 vs 214 (p&lt;0.001)]. More patients presented in DKA at initial diagnosis during the pandemic compared to pre-pandemic (52% vs 48%, p=0.046). There was no significant difference in DKA severity between the pre-pandemic and pandemic groups (p=0.179). There was a significant difference in the average Hemoglobin A1C at diagnosis between COVID-19 unknown and COVID-19 negative group (12% vs. 10.6%, p&lt;0.05). Conclusion: Our study found that more children were diagnosed with DM during the COVID-19 pandemic compared to an equal length of time pre-pandemic. We also found that the prevalence of DKA among those with new-onset DM was higher during the pandemic period. It is speculated that SARS-CoV-2 can disturb self-tolerance and trigger autoimmune responses through cross-reactivity with host cells. Additional studies are needed to investigate this mechanism specifically among children with new onset DM.
Presentation: Friday, June 16, 2023
OR04-02 KANK1 Deficiencies Underlie A Subset of Male Congenital Genitourinary Anomalies
Authors: Lamb Dolores J , O'Neill Marisol Ann 
Published: October 2023

Abstract
Disclosure: D.J. Lamb: Advisory Board Member; Self; Roman Health, American Board of Bioanalysts, American Association of Bioanalysts, Northeastern Region. Consulting Fee; Self; Roman Health. Stock Owner; Self; Fellow Health. M.A. O'Neill: None.
Development of the genitourinary (GU) system involves several complex processes directed both by genetic and hormonal signals essential for proper sexual differentiation. Studying genetic and genomic variants can provide insight into genes which drive GU development. Using array comparative genomic hybridization (aCGH), 9p24 was identified as a putative hotspot for copy number variants (CNVs) in patients with non-syndromic GU anomalies. Analysis of genes in the minimal overlap region of these CNVs revealed KANK1 as a candidate for GU development. KANK1, an anchor protein, which has been studied in kidney cancer and cerebral palsy, is an important regulator of cytoskeletal formation through the polymerization of f-actin. Using DECIPHER, ICSA, ClinVar, and published datasets a total of 43 CNVs (30 duplications, 13 deletions) encompassing KANK1, variants were identified in patients with GU anomalies including both upper tract and lower tract anomalies. The incidence of KANK1 CNVs was further established by screening non-syndromic patients with GU anomalies from Texas Children’s Hospital by Taqman CNV qPCR and 2.2% of patients screened have KANK1 CNVs. Since the majority of KANK1 CNVs identified encompassed of more than one gene, KANK1 was further analyzed as a causative gene for GU anomalies through an analysis of exome sequencing variants in the University of Washington Center for Mendelian Genomics (Geno2MP). Through Geno2MP, 46 KANK1 missense variants were identified in patients with GU anomalies including hypospadias, cryptorchidism, and nephrotic syndrome. Of these variants, 31 were predicted to be deleterious or probably deleterious by Polyphen2. A mouse model of Kank1 loss was generated by CRISPR/Cas9 deletion to further analyze Kank1’s role in GU development and function. Kank1 deficient males were found to have decreased penile length, abnormal development of the urethral opening, and renal dysfunction. These phenotypes are consistent with those found in patients with Kank1 CNVs and SNPS supporting the hypothesis that KANK1 regulates GU development and function.
Presentation: Thursday, June 15, 2023
FRI129 Adrenal Insufficiency In Olmsted County, MN, USA: A Population-Based Study
Authors: Moazzami Mitra , Achenbach Sara , (Beth) Atkinson Elizabeth J , Bancos Irina 
Published: October 2023

Abstract
Disclosure: M. Moazzami: Grant Recipient; Self; Rochester Epidemiology Project. S. Achenbach: None. E. Atkinson: None. I. Bancos: None.
Background: Epidemiology of adrenal insufficiency (AI) is incompletely characterized with most data originating from referral centers and registries. We aimed to determine the incidence, morbidity index, risk of hospitalizations, and mortality in patients with AI living in Olmsted County, Minnesota. Methods: We assessed the standardized incidence rate, morbidity index, risk of hospitalizations and mortality of AI in residents (aged 18+) in Olmsted County, MN, USA, from Jan 1, 2005, to December 31, 2021. The data was collected using the Rochester Epidemiology Project (REP), a database of medical records for all Olmsted County residents since 1966. Incidence rates were standardized for age and sex according to the 2020 US white population. Sex- and age- matched referent subjects were selected from the REP. AI was defined based on presence of oral chronic glucocorticoid therapy (hydrocortisone, prednisone, prednisolone, or dexamethasone) defined as (1) any hydrocortisone use or (2) 6 months of consecutive use of prednisone, prednisolone, or dexamethasone or (3) two AI diagnosis codes 6+ months apart plus at least one glucocorticoid prescription within 1 year of the second diagnosis. Elixhauser morbidity index was used. Findings: Between 2005 and 2021, 5419 patients were diagnosed with AI (median age of 62 years, range 18-103), 56% women). Overall standardized incidence rates for AI increased from 206 (95% CI 174-238) in 2005 to 252 (223-280) per 100 000 person-years in 2021. At baseline, patients with AI had a higher morbidity index (median 3 vs median 1, p &lt;0.001) and a higher history of hospitalizations within 5 years prior to baseline (57% vs 30%; p&lt;0.001) when compared to referent subjects. When comparing patients with AI to referent subjects, and after adjusting for age, sex, morbidity index and prior history of hospitalizations, patients with AI were more likely to be hospitalized during follow-up (aHR 1.4, 95% CI 1.3-1.5). When comparing patients with AI to referent subjects, and after adjusting age, sex, and morbidity index, patients with AI had higher mortality (aHR 1.7, 95% CI 1.6-1.9). Patients with AI demonstrated a higher risk of dying from musculoskeletal disorders (aHR 4.9, 95% CI 2.2-10.8), respiratory disorders (aHR 4.7, 95% CI 3.3-6.6), neoplasms (aHR 2.4, 95% CI 2.0-2.9), and infectious disorders (aHR 2.3, 95% CI 1.2-4.3) than referent subjects. Interpretation: We demonstrate an increase in AI incidence between 2005 and 2021. Surprisingly, even after controlling for morbidity and prior hospitalizations, patients with AI were more likely to be hospitalized. In comparison to referent subjects, mortality was higher in patients with AI, even after adjustment for morbidity index.
Presentation: Friday, June 16, 2023
FRI419 Progesterone Regulation Of The GnRH Pulse Generator
Authors: Wall Ellen Gabrielle 
Published: October 2023

Abstract
Disclosure: E.G. Wall: None.
A group of kisspeptin neurons located in the arcuate nucleus (ARN) of the hypothalamus represent the GnRH pulse generator and their activity is thought to be controlled primarily by the feedback actions of estradiol and progesterone (P4). In a healthy menstruating woman, following the mid-cycle ovulation, P4 levels dramatically increase and exert a negative feedback action onto the hypothalamus to slow pulsatile LH secretion. However, the exact mechanism by which P4 negatively feeds back to the hypothalamus remains unknown. The ARN kisspeptin neurons display synchronized episodes (SEs) of activity approximately every hour for most of the cycle but these dramatically reduce in number following the LH surge. As these ARN kisspeptin neurons express the progesterone receptor (PR) it is hypothesized that they may be the site at which P4 negative feedback occurs. Given the lack of detailed information in the mouse, we first assessed the profile of circulating P4 levels in mice at 8-hr intervals throughout the estrous cycle. Terminal blood samples were taken from individual mice along the 4 stages of the estrous cycle at 3-time points 8 hrs apart and the gonadal hormones were analyzed using LC-MS. The concentration of P4 was found to peak around the time of the LH surge at 6 pm on proestrus (21.94 ± 3.78 ng/ml) and was at its lowest at diestrus 10 am (0.42 ± 0.11 ng/ml). We next assessed the impact of circulating P4 on the activity of the ARN kisspeptin pulse generator using GCaMP fibre photometry in freely behaving mice. A prior study found that IP administration of 8 mg/kg P4 resulted in circulating P4 concentrations reaching 34 ng/ml (Wong et al., J Pharm Pharmacol 64, 2012). Hence, in this study, diestrus mice equipped for monitoring the activity of the kisspeptin pulse generator were injected with either 8 or 4 mg/kg P4 at 10 am and SEs monitored for 24 hrs. Both doses resulted in a significantly decreased frequency of SEs compared to the vehicle (p&lt;0.05), which persisted for 6 hrs. To next examine whether P4 may be acting directly on the ARN kisspeptin neurons to slow pulse generation, P4 (25 ng/ml) was infused directly into the ARN while the activity of the pulse generator was monitored. Again, this resulted in a decreased frequency of SEs compared to the vehicle with the effects lasting approximately 5 hrs (p&lt;0.05).These results indicate that P4 exerts powerful inhibitory control over the activity of the kisspeptin pulse generator and that these effects may be direct. Elucidating the mechanisms of P4 negative feedback may provide a platform for the development of new therapeutic strategies in the infertility clinic.
Presentation: Friday, June 16, 2023
FRI421 Immunomodulatory Therapy Can Improve Fertility In Women With Autoimmune Premature Ovarian Insufficiency - A Proof Of Concept Study
Authors: Hirschberg Angelica Linden , Björnsdottir Sigridur , Gunnarsson Iva , Sergouniotis Fotios , Vogt Elinor , Øksnes Marianne , Husebye Eystein Sverre , Bensing Sophie , Kämpe Olle 
Published: October 2023

Abstract
Disclosure: A.L. Hirschberg: None. S. Björnsdottir: None. I. Gunnarsson: None. F. Sergouniotis: None. E. Vogt: None. M. Øksnes: None. E.S. Husebye: None. S. Bensing: None. O. Kämpe: None.
Introduction: Autoimmune disorders are associated with increased risk of premature ovarian insufficiency (POI), leading to early menopause and infertility. The etiology of autoimmune POI remains unknown, but measurable levels of anti-Mullerian hormone indicate that some follicles may be intact. We asked if rituximab, a B cell specific anti-CD20 monoclonal drug could improve the ovarian response to gonadotropin stimulation and restore fertility.
Methodology: In this open label pilot study, nine women aged 18-35 years, BMI 19-30 kg/m2 with autoimmune POI (S- FSH &gt; 40 IE/L), of which six had Addison’s disease, were included. The procedure comprised controlled ovarian hyperstimulation according to a standard high dose protocol with daily subcutaneous injections of follitropin alpha, prior to, and 4 months after, two infusions of 1-gram rituximab 2 weeks apart, and a follow-up period of 12 months. If positive response to ovarian stimulation was obtained, GnRH antagonist was given to prevent premature ovulation and choriogonadotropin alpha to induce ovulation. When possible, oocytes were retrieved for cryopreservation and later fertilization.
Results: None of the nine patients responded to ovarian stimulation prior to rituximab treatment (mean stimulation days 15.7 ± 1.6 days). After rituximab therapy, five of seven responded with follicular development, and in four women mature eggs were harvested (oocyte yield 3-13 oocytes) for preservation. Four of these five women experienced spontaneous menstrual bleedings and decreased vasomotor symptoms. All responders had autoimmune Addison’s disease, whereas two women with no response had Myasthenia gravis and Hashimoto thyroiditis, respectively. We observed no serious drug reactions or other complications.
Conclusions: We have shown for the first time that rituximab can restore menstrual bleedings and enable egg retrieval with the potential to restore fertility in patients with autoimmune POI. This could become an alternative fertility treatment to egg donation, which is the only option today.
Presentation: Friday, June 16, 2023
FRI429 Association Between Nonalcoholic Fatty Liver Disease And Fib-4 In Patients With Hypogonadism
Authors: Godar Cassandra M , Brown Kevin F , Spiro Andrew J , Vietor Nicole O , Hoang Thanh D , Shakir Mohamed K M 
Published: October 2023

Abstract
Disclosure: C.M. Godar: None. K.F. Brown: None. A.J. Spiro: None. N.O. Vietor: None. T.D. Hoang: None. M.K. Shakir: None.
Introduction: Recent studies have reported a strong bidirectional association between non-alcoholic fatty liver disease (NAFLD) and hypogonadism in both genders. Men with hypogonadism may have higher noninvasive indices of NAFLD via hepatic steatosis index (HSI, reference range &lt;36) and hepatic fibrosis via FIB-4 (reference range &lt;1.3). However, there is limited clinical data on the association between serum testosterone concentrations and NAFLD in men. We report here HSI and FIB-4 in 3 men with hypogonadism.
Case #1: 56-year-old male with a 20-year history of idiopathic hypogonadism, hypertension on telmisartan and amlodipine, and obstructive sleep apnea with regular CPAP use. Pituitary MRI is normal. He uses 3 pumps of topical testosterone gel daily. Vital signs: BP 139/83mmHg, HR 59bpm and BMI 36.2. Examination of heart and lungs is normal, testes are 15cc bilaterally. Serum testosterone is 400-500 ng/dL, alanine aminotransferase (ALT) 88 U/L (0-50), aspartate aminotransferase (AST) 71 U/L (17-59), alkaline phosphatase (ALP) 78 U/L (38-126), iron saturation 43.1% (20-55), ferritin 452 ng/mL (30-400). Calculated FIB-4: 2.3, HSI: 46.
Case #2: 71-year-old male with 46XX phenotype with hypogonadism and gynecomastia on 2 pumps of transdermal testosterone gel daily. Vital signs: BP 150/79 mmHg, HR 67/min, BMI 36.8. Examination of heart and lungs is normal, and testes are 5cc bilaterally. Serum testosterone is 416 ng/dL, ferritin 509 ng/mL, iron saturation 41.3%, ALT 19 U/L, AST 22 U/L, ALP 136 U/L. Liver ultrasound demonstrated diffuse hepatic steatosis with borderline hepatomegaly. Calculated FIB-4: 1.38, HSI: 48.4.
Case #3: 48-year-old male with central hypogonadism currently taking testosterone 100 mg IM every week. Evaluation for central hypogonadism was unrevealing for pituitary lesion. Vital signs of BP 130/91, HR 76/min, BMI 27.2. Examination of heart and lungs is normal, and testes are 20cc bilaterally. ALT 201U/L, AST 80U/L, ALP 136U/L, serum testosterone 241 ng/dL. Liver ultrasound is consistent with hepatic steatosis. Calculated FIB-4: 1.22, HSI 59.2.
Conclusion: Patients with a combination of hypogonadism, high BMI, mild or moderate elevations of AST/ALT/ALP, elevated serum ferritin or transferrin saturation should undergo screening for NAFLD. In this series, all 3 patients had high HSI, an early indicator of fibrosis although only 1 patient had a high FIB-4 level. As fibrosis is the strongest predictor for long-term clinical outcomes among patients with NAFLD there is growing interest in employing non-invasive methods such as HSI, FIB-4, NFS and APRI for risk stratification. In conclusion, it is recommended that high risk patients with hypogonadism need to be screened for NAFLD and hepatic fibrosis with these simple tools.
Presentation: Friday, June 16, 2023