bluuebunny/crossref_metadata_2025 huggingface dataset:
SAT-LB115 Metformin-Use Is Associated With Slowed Cognitive Decline and Reduced Incident Dementia in Older Adults With Type 2 Diabetes Mellitus: The Sydney Memory and Ageing Study
Authors: Samaras Katherine , Makkar Steve , Crawford John D , Kochan Nicole A , Wen Wei , Brian Draper , Trollor Julia N , Brodaty Henry , Sachdev Perminder S
Published: May 2020

Background Metformin use in diabetes has been associated with both increased and decreased dementia rates in observational studies of people with diabetes.

Objective: To examine changes in global cognition and specific cognitive domains over 6 years in older adults with diabetes treated with metformin, compared to other glucose lowering medications, and to people without diabetes.

Methods Data were examined from the Sydney Memory and Ageing Study, a prospective observational study of 6 years duration of 1037 non-demented community-dwelling elderly aged 70-90 at baseline, derived from a compulsory electoral roll. Neuropsychological testing was performed every 2 years with domain measures of memory, executive function, language, visuospatial function, attention and processing speed and a composite of global cognition. Data were analysed by linear mixed modelling, including age, sex, education, body mass index, heart disease, diabetes, hypertension, stroke, smoking and apolipoprotein E ε4 carriage as covariates.

Results: At baseline, 123 participants had diabetes (DM) with 67 receiving metformin (DM+MF) who were similar in demographics to those not receiving metformin (DM-noMF) and those without diabetes (no-DM). Participants with diabetes had higher BMI, lower HDL- and LDL-cholesterol and more prevalent heart disease, hypertension and smoking, compared to no-DM.

Over 6-years, DM+MF participants had significantly slower rates of decline in global cognition and executive function, compared to DM-noMF, adjusted for covariates. The rate of decline for each cognitive domain was similar between DM+MF and controls. No impact was found in analyses examining interactions with sex, ApoEε4 carriage or hyperlipidemia. No difference was found in the rate of decline in brain volumes between the groups over 2 years.

Incident dementia was significantly higher in DM-noMF, compared to DM+MF (adjusted OR 5.29 [95% CI 1.17-23.88], p,0.05), whereas risk of incident dementia was similar between DM+MF and participants without diabetes.

Conclusions: In older people with diabetes receiving metformin, rates of cognitive decline and dementia were similar to that found in people without diabetes and significantly less than that found in people with diabetes not receiving metformin. Large randomized studies in people with and without diabetes are required to determine whether these associations can be attributed to metformin alone or if other factors explain these observations. Future studies will clarify if this cheap and safe medication can be repurposed for prevention of cognitive decline in older people.
SUN-LB102 Development of a Conceptual Model to Present the Impacts of Obesity on Physical Functioning
Authors: Poon Jiat Ling , Marshall Chris , Johnson Chloe , Pegram Hannah , Hunter Maile , Kan Hongjun , Ahmad Nadia
Published: May 2020

Background. Obesity is a chronic disease with a significant negative impact on health-related quality of life (HRQoL) and specifically, physical functioning, including the ability to complete activities of daily living (ADLs). Weight loss based on lifestyle management (e.g. diet, exercise), surgery, and pharmacotherapy can improve physical functioning; however, there is a need for further qualitative research to support the content validity of patient-reported outcome (PRO) measures for use in clinical studies of obesity and thus inform regulatory decision-making. Objective. To explore the impacts of obesity on physical functioning and develop a conceptual model (a visual representation of the concepts of importance and relevance to the experience of living with obesity) to ultimately support the content validity of PRO measures.Methods. Qualitative semi-structured interviews were conducted in the United States with individuals who have overweight and obesity (Body Mass Index [BMI] ≥ 27.0 kg/m2) with a history of at least one unsuccessful dietary effort to lose body weight. Recruitment quotas targeted a sample with diverse demographic and clinical characteristics, including participants with and without diabetes. Experienced qualitative interviewers used open-ended questions to elicit spontaneous reports of the impact of obesity on individuals’ daily lives, and specific probing questions to explore impacts on physical functioning. Interviews were audio-recorded, transcribed and analyzed using thematic techniques. Results. A total of 33 participants were interviewed (mean BMI of 37.6 kg/m2 [27.4 kg/m2 to 56.6 kg/m2]; mean age of 45 years [19 to 81 years]). The sample included a mix of races (Caucasian: n=12, 36%), education completed (high school: n=17, 51%) and split of gender (female: n=16, 48%). During development of the conceptual model, two separate domains were identified to group the reported impacts on physical functioning: ‘Mobility/Movement’ and ‘ADLs’. The most frequently reported impacts related to Mobility/Movement were ‘running’ (n=31/33, 94%), ‘bending’ (n=27/33, 82%), ‘walking’ (n=26/33, 79%), ‘difficulty standing for prolonged periods’ (n=22/33, 67%), and ‘lifting’ (n=19/33, 58%). All participants reported effects on some aspect of physical functioning, which were often characterized in terms of their direct impact on ADLs such as ‘household chores’ (n=21/33, 64%). Conclusions. The conceptual model will serve as a basis to identify fit-for-purpose PRO measures with strong content validity to evaluate the impact of anti-obesity therapies on physical functioning in future clinical studies. Obesity has a consistent and significant impact on physical functioning, leading to limitations in various aspects of mobility and affecting an individual’s ability to carry out specific daily activities.
MON-LB017 The Effectiveness of Computed Assessment Using GP and TW3 Hybrid System
Authors: Chung Lindsey Yoojin , Lee Kyu-chong , Ahn Kyung-Sik , Lee Jae Jun , Kang Chang Ho , Lee Kee-Hyoung
Published: May 2020

Background: Bone age assessments (BAAs) is an important clinical modality to investigate endocrine, genetic and growth disorders in children. It is generally performed by radiological examination of the left hand by using either the Greulich-Pyle (GP) or the Tanner-Whitehouse (TW) method. However, both clinical procedures show several limitations, from significant intra- and inter-operator variability to examination effort of clinicians. To address these problems, several automated approaches have been proposed; nevertheless, some disparity still exists between automated BAAs and manual BAAs to be employed in clinical practice. To overcome this disparity, deep learning-based bone age assess software using GP and TW3 hybrid method has been developed. In this study, we evaluate the accuracy and efficiency of the new automated hybrid software system for bone age assessment and validate its feasibility in clinical practice. Materials and Methods: Greulich-Pyle (GP) and Tanner-Whitehouse (TW3) hybrid method-based deep-learning technique was used to develop the automated software system for bone age assessment. Total 102 radiographs from children with the chronological age of 4.9-17.0 years (mean age 10.9±2.3, 51 cases for females and 51 cases for males) were selected and bone age was estimated with this software. For validation of the automated software system, three human experts have manually performed BAAs at expert’s discretion based on GP method for accuracy estimation and one naïve radiologist performed BAAs with automated software system assist and BAAs reading time was recorded in each session for efficiency evaluation. The performance of automated software system was assessed by comparing mean absolute difference (MAD) between the system estimates and the experts manual BAAs.Results: The results of bone age assessment by human experts and automated software system showed no significant difference between the two groups. Each assessed average of bone age were 11.39 ± 2.74 and 11.35 ± 2.76, respectively. MAD was 0.39 years between automated software system BAAs and experts manual BAAs. The 95% confidence interval of the MAD was 0.33 years and 0.45 years. BAAs reading time was reduced from 56.81 sec (95% confidence interval 52.81 - 60.81 sec) in naïve manual BAAs to 31.72 sec (95% confidence interval 29.74 - 33.69 sec) in automated software system assisted BAAs and statistically significant (p < 0.001). MAD showed 0.42 years between naïve manual BAAs and the software-assisted BAAs (95% confidence interval 0.31-0.47 years).Conclusion: The newly developed GP and TW3 hybrid automated software system were reliable for bone age assessments with equivalent accuracy to human experts. Also, the automated system appeared to enhance efficiency by reducing reading times without compromising diagnostic accuracy.
SUN-LB58 Repeated Once-Daily Administration of the Non-Hormonal Neurokinin 1,3 Receptor Antagonist NT-814 Reduces LH, Estradiol and Progesterone in Healthy Women
Authors: Dhillo Waljit Singh , Ballantyne Elizabeth , Donaldson Kirsteen , Kerr Mary , Trower Mike , Pawsey Steve
Published: May 2020

Introduction: Uterine fibroids (UF) affect up to 25% of women and endometriosis (EM) 10% of women worldwide. An ideal therapy would lower estradiol concentrations to reduce hormonal drive to the endometrium and myometrium, but not to the levels which cause the hot flashes and bone loss associated with current treatments. A target estradiol range of 110-180 pmol/L has been proposed1. GnRH secretion is modulated by neurokinin B (NKB) acting at the NK3 receptor via hypothalamic neurons expressing kisspeptin, NKB & dynorphin (KNDy neurons). In addition, Substance P acting at the NK1 receptor may also stimulate reproductive hormone release. We hypothesised that NT-814, a dual NK1,3 receptor antagonist, would reduce GnRH release and hence LH, estradiol and progesterone levels in women. This preliminary clinical study in healthy pre-menopausal women evaluated this hypothesis.

Methods: We undertook a randomized, single-blind, placebo-controlled study. 32 healthy women attended for 2 consecutive menstrual cycles. In each cycle blood samples were taken on days 3/4, 9/10, 15/16 and 21/22 to measure serum sex hormone concentrations. No treatment was given in cycle 1 (baseline). During cycle 2, participants received placebo or one of three doses of NT-814 once per day; 40mg, 80mg or 120mg (n=8 per group) for up to 21 days.

Results: Compared to placebo, NT-814 reduced LH, estradiol and progesterone concentrations in a dose-related manner. The median changes in average LH (IU/L) during cycle 2 compared to cycle 1 were: placebo, 0.16; 40mg, -0.13; 80mg, -0.46; 120mg, -0.58. Median change in average estradiol (pmol/L) in cycle 2 was: placebo, -16.5; 40mg, -9.3; 80mg, -92.1; 120mg, -141.4. The median changes in progesterone (nmol/L) on day 21/22 in cycle 2 compared to cycle 1 were: placebo, 3.2; 40mg, 8.0; 80mg, -5.7; 120mg, -19.4. The reductions in estradiol and progesterone with 120 mg NT-814 were significant (p=0.038 & p=0.046, respectively). There were no clear changes in FSH concentrations. Of note, in women treated with 120mg NT-814, the average estradiol level reduced from 310.8 pmol/L in cycle 1 to 179.8 pmol/L in cycle 2. Cycle length was extended by at least 6 days in 5 of 8 women receiving the 120 mg dose. NT-814 was well tolerated; no participant experienced hot flashes during treatment.

Conclusions: Once-daily administration of the non-hormonal NK1,3 receptor antagonist NT-814 reduced serum LH, estradiol and progesterone in healthy women in a dose-related manner without causing vasomotor symptoms. The 120 mg dose of NT-814 lowered estradiol levels to potentially ideal levels for UF and EM treatment. These preliminary data support further studies with NT-814 to establish its efficacy and safety in treating patients with these hormone driven disorders.

References: 1Barbieri RL Am J Obstet Gynaecol 1992 166 740-5.
SUN-LB136 A Comparison of Androgen Receptor Splice Variant, AR-V7, and Glucocorticoid Receptor Activity in Prostate Cancer
Authors: Dash Amit K , Paul Basil , Robertson Matthew J , Nagandla Harika , Rajapakshe Kimal Isira , Coarfa Cristian , Weigel Nancy Lynn
Published: May 2020

Prostate Cancer (PCa) is an androgen dependent disease and patients with metastatic PCa are treated with androgen deprivation therapy (ADT). Although most tumors respond initially, tumors become resistant and are termed castration resistant prostate cancer (CRPC). There is compelling evidence that most of these tumors retain androgen receptor (AR) dependence and some data to suggest that, in some cases, the glucocorticoid receptor (GR) substitutes for AR. AR, itself, is re-activated through a variety of mechanisms including the expression of constitutively active AR splice variants that lack the ligand binding domain (LBD) of AR. Expression of one variant, AR-V7, which contains the amino-terminal domain and DNA binding domain of AR and 16 unique amino-acids, has been correlated with resistance to second line ADT. Although there has been some debate regarding the role of AR-V7, whether it is only a partial substitute for AR or has unique activities, our studies of engineered cell lines treated to express levels of AR-V7 equivalent to AR, clearly show that while the AR isoforms have common targets, they each also have unique targets. Consistent with this, the cistromes of the two show many unique sites as well as common sites. AR-V7 binding is enriched near the transcription start site (TSS) and we have identified a novel de novo binding motif. These findings suggest the possibility of developing a gene signature unique to AR-V7.Because GR activity in PCa has also been suggested as an escape mechanism in response to ADT, and GR binds to the same consensus response elements, we sought to identify a GR signature in PCa, to compare it with the AR and AR-V7 signatures, and to ask whether the AR-V7 and/or GR signatures are enriched in CRPC. Because much of the gene signatures are cell line dependent, we sought to compare GR and AR-V7 action in cells that express both. LN-95 cells express both AR-V7 and GR. MDA-PCa-2b cells, a cell line derived from an African American patient, expresses GR, but not AR-V7. The parental line was infected with a lentivirus that expresses AR-V7 in response to doxycycline. Transcriptomes were determined for AR, GR, and AR-V7 in these lines using RNA-Seq. Overall the magnitude of regulation of gene expression was generally lower than in the LNCaP AR-V7 and VCaP-AR-V7 lines, but there was good overlap of the MDA-PCa-2b AR-V7 regulated with the LNCaP AR-V7 regulated genes. Genes induced by GR overlapped with AR and isoform common genes, but did not overlap with AR-V7 specific genes. A comparison of AR-V7 specific genes common to the LNCaP and VCaP models as well as to publicly available data sets for LN-95 and 22RV1 AR-V7 signatures, show a strong correlation with CRPC compared to primary tumors when analyzed in the Grasso data set.
SAT-LB113 Psychosocial Benefits of Using Basal-IQ® Predictive Low Glucose Suspend Technology in a Real-World Setting: Results From Pediatric Patients With Type 1 Diabetes
Authors: Singh Harsimran , Manning Michelle , McElwee-Malloy Molly , Habif Steph
Published: May 2020

Recent literature has highlighted remarkable clinical benefits of the Basal-IQ PredictiveLow Glucose Suspend (PLGS) technology for both pediatric and adult patients with type 1diabetes (PwT1D). Although less frequently acknowledged in the literature, psychosocial benefits and other patient-reported outcomes (PROs) related to this technology, are critical to its sustained and satisfactory use. For purposes of this study, we analyzed pediatric PwT1Ds (n=123) who had recently started using the t:slim X2 insulin pump with Basal-IQ technology (Tandem Diabetes Care). These pediatric users were part of a larger recruited sample that also included adults with T1D (not described here). Amongst other clinical and demographic measures, pediatric PwT1Ds completed the Diabetes Impact and Device Satisfaction (DIDS) scale at baseline and then again at 6 months post-assessment(PA). The DIDS is a brief, reliable, and validated measure to ascertain device-specific satisfaction as well as impact of diabetes management in PwT1D. Pre-Post differences on DIDS were analyzed using repeated measures analysis of variance. Mean age of the pediatric sample was 12.25 years, female=45%, mean HbA1c=7.62%. At baseline, 91%used CGM, 27% used multiple daily injections, and 73% used insulin pumps as their therapy method. Parents/caregivers completed the DIDS on behalf of their child in most cases (92%). At PA, pediatric PwT1Ds, demonstrated significant changes on both subscales of the DIDS. Significant improvements were observed for device-related satisfaction (DS) (p<.001) whereas significant reduction was noted for diabetes-related impact (DI) (p<.01) indicating reduced burden of diabetes on daily life. These findings were noted regardless of patients’ baseline insulin delivery methods (MDI or insulin pump). For DS, at PA, patients reported the most improvement on items relating to“satisfaction with insulin delivery device” (29% increase, p<.001) and “hassle to use” (58%decrease, p<.001). For DI, items indicating the most reduction of diabetes impact were“worry about going low” (36% decrease, p<.001) and “wake up at night to treat low BG”(27% decrease, p<.001). These findings highlighted robust real-world evidence for psychosocial benefits of Basal-IQ technology for pediatric patients and their parents/caregivers. Using psychosocial PROs while evaluating medical devices and technologies is critical as they improve our understanding of patients’ experiences with these systems and their impact on quality of life. These aspects may not always be reflected in patients’ clinical outcomes but are essential for determining long term use and acceptance of new treatments and management regimens.
SAT-LB67 Pseudohypoparathyroidism 1B Presenting in a Woman Aborting With Multiple Cerebral Calcifications
Authors: Garate Dioni , Villarreal Adriana , Chiu Erika , Salsavilca Elizabeth
Published: May 2020

Background. Pseudohypoparathyroidism is a heterogeneous condition characterized by hypocalcaemia and hyperphosphatemia as a result of the resistance of the target organ to parathyroid hormone (PTH) 1. It is classified into several different entities (1A, 1B, 1C AND 2) according to molecular and clinical causes. PHP1B has resistance to PTH, normal levels of Gsα activity and has no clear signs of hereditary Albright osteodystrophy (AHO) or other hormonal resistance. 2 Clinical case. A 26-year-old woman was admitted to the emergency service due to an abortion and severe hypocalcemia. Background: generalized tonic-clonic seizures and hypocalcemia for nine years without treatment. The physical exam showed Chvostek and Trousseau, and round face. Its height is 148 cm, weight 60 kg, BMI of 27 kg/m2, without clinical features of AHO. Analytics reported Calcium 4.6 mg / dl (8.5-10.5), βHCG 1795 mIU / ml (<10), PTH 206 pg / ml (15-65), phosphorus 7.35 mg / dl (2.5-4.9) Creatinine 0.57 mg / dl, magnesium 2.02 mg / dl, 25-OH-D3 29ng/ml (>30), TSH 4.2uUI /ml (0.27-4.20), Hb 10.6 mg/dl. A brain CT scan showed calcifications in the basal ganglia (thick annular), subcortical area (crescent) and cerebellar hemispheres. Renal and thyroid ultrasound without alterations. Radiographs of four limbs and skull found no radiological signs of AHO. Ophthalmologic evaluation revealed bilateral cataract.During hospitalization she underwent curettage, was treated with calcium gluconate, then calcium and calcitriol supplements. At follow-up, serum and urine calcium levels were monitored for optimal treatment. Conclusions. We report a patient with typical biochemical findings of PHP and in the absence of AHO it would be classified as 1B. The importance of early recognition and a mandatory multidisciplinary approach offer a better prognosis avoiding extensive brain calcifications, seizures and obstetric complications. The long-term treatment of hypocalcemia associated with resistance to PTH is similar but generally more aggressive than that of primary hypoparathyroidism. 1. Linglart A, Levine M, Juppner H. Pseudohypoparathyroidism. Endocrinol Metab Clin North Am 2018; 47: 865-888. 2. Mantovani G, Bastepe M, et al. Diagnosis and treatment of pseudohypoparathyroidism and related disorders: first declaration of international consensus. Nat Rev Endocrinol. 2018; 14 (8): 476-500.
SUN-LB85 Short-Term Outcomes of Radiofrequency Ablation of a Toxic and a Non-Toxic Benign Thyroid Nodule
Authors: Segkos Konstantinos , Gkeli Myrsini G
Published: May 2020

Background: Radiofrequency ablation (RFA) of benign thyroid nodules has been shown to be a safe and effective minimally invasive treatment for benign thyroid nodules, based on many years of international experience. Thyroid specific devices have recently become available in the US. Here, we present representative examples of our early experience with RFA for both non-toxic and toxic thyroid nodules in our outpatient center.

Clinical Cases: Case 1: A 39 year-old woman presented with subclinical hyperthyroidism, with a TSH of 0.013 uIU/mL (0.45-4.5 uIU/mL). Evaluation showed bilateral autonomously functioning thyroid nodules. Both nodules were predominantly solid with no suspicious features and grade 3 Doppler flow, and were benign (Bethesda II) on UG-FNA. She declined treatment with total thyroidectomy, radioactive iodine, or long-term thionamides, and decided to proceed with RFA, after pre-treatment with methimazole. We decided to target the right lobe nodule first, as it was larger, with a volume of 2.63 ml. The danger triange and vagus nerve were identified, and then we injected local anesthetic using the pericapsular lidocaine technique. We then performed ultrasound-guided RFA of this nodule, using an RF generator with an internally cooled 18-gauge electrode, with a length of 7 cm and an active tip of 7 mm. Power was set at 25 Watts. The trans-isthmic approach and moving shot technique were used. Total energy delivery was 3078 WS. At the end of the procedure, we visualized a transient hyperechoic zone and there was absence of Doppler flow throughout the nodule. She tolerated the procedure well without complications. Methimazole was stopped after the procedure. At the 3-month follow-up, the nodule had decreased in volume by 72.5% and had no internal Doppler flow; TSH normalized (1.37 uIU/mL), so we decided not to proceed with RFA of the left superior toxic adenoma. Case 2: A 49 year-old woman presented with a large right lobe thyroid nodule with a volume of 6.13 ml, which was causing dysphagia and dysphonia. It was predominantly solid with no suspicious features and grade 3 Doppler flow. TSH was normal. It was benign (Bethesda II) on UG-FNA on 2 occasions. She declined surgical therapy, and decided to proceed with RFA. We performed local anesthesia and then RFA in a similar fashion to case 1, with a power of 20-40 Watts. Total energy delivery was 11,491 WS. There were no complications. At the 3-month follow-up, TSH remained normal, and the volume of the ablated nodule had decreased by 59.9%. There was no intranodular Doppler flow. Her compressive symptoms completely resolved.

Conclusion: These cases are representative of our early experience with thyroid RFA in the USA, and showcase its safety, efficacy and feasibility in the outpatient setting, for patients with toxic or non-toxic symptomatic thyroid nodules.
SUN-LB16 Clitoromegaly in Premature Infants: Is It Truly Pathologic?
Authors: Gupta Meenal , Chambers Charis , O’Brien Katherine O’Flynn , Scheurer Michael , Adeyemi-Fowode Yemi , Karaviti Lefkothea P
Published: May 2020

Background: Normative data for clitoral size in premature infants are limited. Consequently, the potential for over-diagnosis is high; leading to unnecessary investigations, increased healthcare costs and parental stress. Several proposed mechanisms, e.g., persistence of fetal adrenal zone activity to term gestation, point to the transient physiologic nature of clitoromegaly in premature infants. Studies of normative data have shown a negative correlation between birth weight and clitoral size. We hypothesized that 1) the majority of clitoromegaly in premature infants is not associated with hormonal dysfunction and 2) lower birth weight and lower gestational age increase the likelihood of a formal consult in premature infants with perceived clitoromegaly. Methods: A retrospective chart review of female infants born at our institution from January 2012 to December 2018 with perceived clitoromegaly was conducted. Birth history, demographic and laboratory data were collected. Patients were divided into two groups: ‘formal consult’ and ‘no formal consult’ for clitoromegaly. True clitoromegaly was defined as clitoral length >9 mm or clitoral width >6 mm. Patients not meeting these criteria or those with clitoral edema, prominent clitoral hood were classified under false clitoromegaly. In the ‘no formal consult’ group, the documented discharge examination was used to assess persistence of clitoromegaly. Uni- and multi-variable logistic regression were used to determine factors that increased the likelihood of a formal consult. Results: 29 patients met inclusion criteria; 15 in the ‘formal consult’ group and 14 in the ‘no formal consult’ group. No significant differences were found between the groups in terms of birth weight, gestational age, race, ethnicity and maternal factors. History of IUGR (intrauterine growth restriction) was more common in the ‘formal consult’ group (60%) vs. ‘no formal consult’ group (21%) (p=0.04). Only 3/15 patients in the ‘formal consult’ group had true clitoromegaly; all 3 had normal 17-hydroxyprogesterone levels, and only 1 patient had transient elevation in androgen levels (androstenedione, deoxycortisol and testosterone). Of the ‘no formal consult’ group, only 3/14 patients had clitoromegaly noted on discharge; outcome was unknown for 1. Multi-variable logistic regression showed that lower gestational age (p=0.04) and history of IUGR (p=0.03), even after adjusting for birth weight, increased the likelihood of a formal consult. Conclusion: In summary, the majority of perceived clitoromegaly in premature infants is not associated with hormonal dysfunction. Lower gestational age and a history of IUGR increase the likelihood of a formal consult for clitoromegaly in these patients. Approximately half of the patients were noted to have false clitoromegaly indicating inconsistencies in examination technique and need for provider education.
SAT-LB100 Central and Peripheral Endocannabinoid Levels in Obese Versus Lean Women
Authors: Farage-Martins Mariana , Godoy-Matos Amelio , Carvalho Denise Pires , Harvey-White Judith , Silva Rosilene Taveira da
Published: May 2020

The endocannabinoid system (ECS) is thought to be involved in obesity because its activation increases appetite and weight gain (Pagotto et al 2006). The ECS is hyperactivated in the hypothalamus of obese mice, and peripheral overactivation has been observed in humans; circulating 2-arachidonoyl glycerol (2-AG) levels positively correlated with body fat, visceral fat and fasting glucose (Osei-Hyiaman et al 2005) (Bluher et al 2006) (Motaghedi and McGraw 2008) (Cavuoto et al 2007) (Artmann et al 2008) (Bermudez-Silva 2009). The aim of this study was to evaluate whether differential activation of the peripheral versus the central ECS occurred in humans and to test the hypothesis that the ECS is hyperactivated in the human central nervous system (CNS).Cerebral spinal fluid (CSF) and blood samples were collected from 13 obese and 11 lean control women to measure 2-AG and anandamide (AEA) levels.AEA levels were higher in the plasma of obese women (obese: 4.03 ± 0.91 pmol/mL, N=13; lean: 1.84 ± 0.21 pmol/mL, N=10; p<0.05) but were lower in the CSF of obese women. The plasma/CSF ratio was 41.58 ± 5.78 (N=10) in lean women and 103.0 ± 37.36 (N=6) in obese women (p=0.054). There were no correlations between plasma and CSF AEA levels or with any biochemical parameter. The 2-AG analysis was not possible because of technical problems.Our data suggested that in human obesity, the peripheral ECS may be more active than the central ECS. Indeed, the system appeared to be suppressed in the CNS of obese women. Therefore, the peripheral activation of the ECS may be more relevant for obesity. Keywords: Anandamide, 2-arachidonoyl glycerol, obesity, endocannabinoid, endocannabinoid system, cb1 receptor.
MON-LB53 Prior Injectable Somatostatin Receptor Ligand Dose Does Not Predict Oral Octreotide Response In The Treatment Of Acromegaly: Results From The Phase 3 OPTIMAL Study
Authors: Nachtigall Lisa B , Samson Susan Leanne , Fleseriu Maria , Bolanowski Marek , Ludlam William Henry , Patou Gary , Haviv Asi , Manning Patrick , Biermasz Nienke , Giustina Andrea , Strasburger Christian Joseph , Melmed Shlomo , Kennedy Laurence
Published: May 2020

Background: Injectable somatostatin receptor ligands (SRLs) are the most widely used therapy to control acromegaly. Oral octreotide capsules have been formulated as a potential therapy for this disorder and the efficacy and safety was evaluated in the CHIASMA OPTIMAL prospective phase 3 study in patients with acromegaly who were controlled on injectable SRL treatment of varying doses (Samson et al. ENDO 2020). Methods: Patients with confirmed acromegaly, who had been receiving a stable dose of injectable SRL (≥3 months) up until study entry, were randomized to receive octreotide capsules (40 mg/day) or placebo for 36 weeks. Patients were dose titrated to 60 or 80 mg of oral octreotide or equivalent placebo through week 24 at the investigator’s discretion based on increase of IGF-I levels or worsening of acromegaly signs and symptoms. The primary efficacy endpoint was the proportion of patients who maintained their biochemical response at the end of 36 weeks, defined as average IGF-I ≤1 x ULN between Weeks 34 and 36. An analysis evaluated maintenance of response based on prior dose of injectable SRL. Prior doses of injectable SRL were categorized based on the following classifications: octreotide 10 mg every 4 weeks or lanreotide 60 mg every 4 weeks or 120 mg every 8 weeks were stratified as low; octreotide 20 mg every 4 weeks or lanreotide 90 mg every 4 weeks or 120 mg every 6 weeks were stratified as medium; octreotide 30 mg or 40 mg or lanreotide 120 mg every 4 weeks were stratified as high. Randomization was stratified based on low dose vs med/high dose and efficacy results compared for these strata. The response rates reported for the primary end point are slightly adjusted for stratification differences as prespecified in the statistical analysis plan. Results: Six patients (21.4%) in the octreotide capsule group had received prior treatment with low doses of injectable SRLs while 22 (78.6%) had received prior treatment with medium-high doses of injectable SRLs. Maintenance of response was observed in 16 patients receiving oral octreotide. This included 66.7% of patients (n=4) previously receiving low doses of injected SRLs and 54.5% of patients (n=12) on medium-high injected doses. The treatment effect was consistent irrespective of prior dose of injectable SRL (odds ratio: 5.4 in low dose and 5.9 in medium-high dose). Conclusion: The CHIASMA OPTIMAL study recruited a population receiving predominantly medium-high doses of injectable SRLs and demonstrated maintenance of response in 58% of patients. Oral octreotide treatment effect was consistent irrespective of prior dose of injectable SRL.
MON-LB114 CGM in Cystic Fibrosis Patients to Predict Cystic Fibrosis-Related Diabetes Onset
Authors: Mei Hsia Pu Mariana Zorron , Ribeiro José D , Morcillo André M , Gonçalves Aline C , Ribeiro Antonio F , El Beck Mayra Souza
Published: May 2020

Background: Therapeutic progress and improvement on resources enabled the emergence of new comorbidities in cystic fibrosis (CF), such as cystic fibrosis-related diabetes (CFRD). About 20% of adolescents and 40-50% of adults are affected. CFRD and glucose intolerance reduce life expectancy in this population, highlighting the importance of early diagnosis and treatment. Up to 15% of CF patients have hypoglycemia during OGTT and its etiology remains unclear. Some authors associate hypoglycemia with CFRD onset, while others do not agree with this association. Objective: To determine whether abnormal CGM (hypo/hyperglycemia) can predict CFRD onset, pulmonary function and BMI decline in CF patients. Methods: Prospective single center study. All CF patients between 10-19yo from our outpatient clinic were screened for CFRD through OGTT following the World Health Organization (WHO) protocol. The enzymatic colorimetric method was used to classify them as per the ADA. Non-diabetic CF patients performed 3-day CGM, forced expiratory volume in the first second (FEV1), BMI and OGTT. All tests except for CGM were then reassessed after a long follow-up. The WHO’s 2006 curve was used to calculate the z scores for individuals ≤19yo and WHO cut-off values for >19yo. Oral corticoid use during data collection, pregnancy and solid organ transplantation were exclusion criteria. Results: Thirty-nine patients were recruited and 34 completed an average of 3.1 years (±0.51) follow-up. No clinical or laboratory variables could predict diabetes progression or hypoglycemic events. The cohort had an increase in mean BMI (17.80±3.65 vs 18.36±3.49; p=0.025) and a reduction in mean FEV1 (66.91±25.79% vs 56.32±29.57%; p=0.001) between the two evaluations. Patients who developed diabetes showed statistically significant worse FEV1 in the end of the follow-up (22.67±5 vs 59.58±28.9; p=0.041), and lower BMI at both start (14.37±1.23 vs 18.13±3.65; p=0.049) and end (14.81±0.66 vs 18.71±3.46; p=0.029) of follow-up. A logistic regression of the effect of time adjusted for independent variables for progression to CFRD was conducted. A higher possibility of evolution among participants with IGT (odds ratio [OR] 21.67; 95% confidence interval [CI] 7.03-67.36; p<0.01), and a lower possibility among participants with NGT (OR 1.84; 95% CI 1.06-3.19; p=0.031). Conclusion: CGM was not a useful tool to predict early diabetes onset in this population with the current cut-off values. However, the IGT group seems to be the riskiest group. The CF population has particular characteristics and may not have the same diagnostic criteria for DM as the non-CF population. More studies are necessary to determine the appropriate CGM cut-off values for CFRD.
SAT-LB106 Metabolic and Brown Adipose Tissue-Specific Effects of the Novel Non-Steroidal Mineralocorticoid Receptor Antagonist Finerenone in a Mouse Model of Diet-Induced Obesity
Authors: Marzolla Vincenzo , Feraco Alessandra , Gorini Stefania , Mammi Caterina , Marrese Carmen , Boitani Carla , Lombes Marc , Kolkhof Peter , Ciriolo Maria Rosa , Armani Andrea , Caprio Massimiliano
Published: May 2020

In this work we studied the metabolic effects of the novel non-steroidal MR antagonist Finerenone (FIN) in mice fed a high-fat diet (HFD, 60% kcal as fat). We also investigated the signaling pathways underlying the beneficial metabolic effects of MR antagonism. After 3 months of HFD, mice treated with FIN showed an improvement of glucose tolerance compared to control mice as shown by intraperitoneal glucose tolerance tests. Despite this metabolic improvement, FIN-treated mice did not show a reduction in body weight compared to control mice. In order to elucidate the favourable effect of FIN on glucose tolerance we performed histological and molecular analyses at level of different adipose depots. We did not observe significant differences in classical white adipose depots (subcutaneous and visceral) between control and FIN-treated mice. Interestingly, interscapular brown adipose tissue (iBAT) of FIN-treated mice showed an increased multilocularity and a reduced size of lipid droplets, suggesting an iBAT-specific effect of FIN. We than analyzed mRNA and protein expression of uncoupling protein 1 (UCP-1) and peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PCG1-alpha), showing a significant increase of both markers at iBAT level in FIN-treated mice. Furthermore, leptin and adenylate cyclase 5 (Adyc5) (specific white adipose tissue markers) mRNA expression was reduced at level of iBAT in FIN-treated mice. Finally, we demonstrated that FIN-induced MR antagonism determined an increased activation of AMP-activated protein kinase (AMPK) which, in turn, stimulated adipose triglyceride lipase (ATGL) activity, with subsequent up-regulation of genes involved in fatty acids oxidation, tricarboxylic acid cycle and thermogenesis, in iBAT. In summary, our study shows that FIN protects from iBAT dysfunction and improves glucose tolerance in HFD-fed mice. Importantly, FIN effects on iBAT are mediated by a MR-AMPK-ATGL-UCP-1 signaling cascade. Therefore, MR antagonism by FIN in clinical settings might offer metabolic advantages, on top of its anti-fibrotic action, in multi-morbid cardiorenal patients.
MON-LB308 Studying the Care and Social Pathway of Young Adults With Endocrine and Metabolic Diseases During Transition: The “Transend” Cohort
Authors: Roux Enora Le , Menesguen Florence , Tejedor Isabelle , Popelier Marc , Halbron Marine , Faucher Pauline , Malivoir Sabine , Polak Michel , Poitou Christine , Touraine Philippe
Published: May 2020

Context. The transition period between pediatric and adult medicine is associated with poor patient outcomes and an important number of patients lost to follow up. Intervention exist but the few published randomized trials do not allow to study long-term patient outcomes nor intervention sustainability in time. Objective. Describe the cohort of patients in adult care who benefit from a new transition program based on case management approach, its activity and follow-up outcomes. Methods. A longitudinal study was led since September 2016 in adult services of endocrinology, nutrition and diabetology of a French University Hospital. Patients with any endocrine disease diagnosed during childhood and transferred to adult care were included. The care pathway for these patients was built in three steps. Step 1 is dedicated in liaising with pediatric services and patient to facilitate its first visit in adult care. Step 2 defines the care pathway in adult service based on the needs assessment realized by the coordinator upon the patient’s arrival in adult service. Step 3 focuses in liaising with structures outside hospital (GP, educational and social sector). Thorough the follow-up, the coordinator is identified as the key contact by the patients. Attendance to medical appointments, clinical, and social data are collected throughout patient follow-up. Results. Since 3 years, 500 patients benefited from the case management mainly for their obesity (n=91, 18%), type 1 diabetes (n=54, 11%), malignant brain tumor (n=68, 14%) or congenital hypopituitarism (n=42, 8%). They were aged 19 in median at transfer in adult care, sex ratio: 0,5, A large majority live in the parental home (409, 82%), 169 (34%) are university students, 130 (26%) are in high school, 90 (18%) are in medico-social institution. Patients who required most of support from the coordinator usually combine one (or more) somatic disease and either a neuro-cognitive disorder or a psychiatric disorder, they all have social difficulties. In patients with more than 3 months of follow-up (median: 18 months), 22/418 (5%) are out of follow-up. Concerning the patients for whom the follow-up is 36 months or more, the percentage of out of lollow-up is the same: 5% Conclusions. The case manager addresses the complex needs of diverse patients. With time, the cohort will provide unprecedented long-term results of patients with various conditions who went through transition.
SAT-LB25 A Multi-Omics Analysis of Advanced Papillary Thyroid Cancer
Authors: Sanghi Akshay , Orloff Lisa , Snyder Michael
Published: May 2020

Molecular profiling of papillary thyroid carcinoma has largely been confined to exome sequencing of non-aggressive cancer.1,2 Canonical mutations in BRAF and RAS are significantly represented in thyroid tumors, but these mutations have not resulted in diagnostics and therapeutics for advanced disease. To broadly examine the molecular landscape of advanced disease, we conducted a multi-omic analysis of 34 cases of advanced papillary thyroid carcinoma, including patient-matched lymph node metastases, primary tumor, adjacent-normal thyroid and germline. Our genome-wide multi-omic analysis links the regions of activated chromatin with expressed transcripts and proteins, identifying regulatory elements at primary tumor and nodal metastases stages of thyroid cancer progression. Distal regulatory elements putatively upregulate expression of MAPK-pathway genes in both tumors and metastases (36 genes (p =0.0057) in tumors and 76 genes (p =0.0011) in metastases). Furthermore, tumors and metastases harbor accessible chromatin regions that appear to be bound by MAPK transcription factors, FOS and JUN (p-value <10-150 for tumors and metastases). This study identifies regulatory elements that mediate MAPK activity in tumors and metastases of advanced papillary thyroid carcinoma and may ultimately lead to diagnostics and therapeutics that utilize advanced-thyroid-cancer-specific epigenetic targets. References

• Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell. 2014

• Masoodi T, et al. Whole-Exome Sequencing of Matched Primary and Metastatic Papillary Thyroid Cancer. Thyroid. 2020
MON-LB84 Validation of TI-RADS (Thyroid Imaging, Reporting and Data System) Follow-Up Recommendations
Authors: Ravindra Sindhura , French Esra Karslioglu , Yip Linwah
Published: May 2020

Background:Thyroid nodules are exceedingly common, leading to costly interventions for many lesions that ultimately prove benign. Therefore, a reliable, noninvasive method to identify which nodules warrant fine needle aspiration and/or follow-up on the basis of a reasonable likelihood of malignancy is highly desirable. American College of Radiology (ACR) created a standard terminology (lexicon) to describe all thyroid nodules on sonography and standardized TI-RADS risk-stratification system to identify nodules that warrant biopsy and/or follow-up. Many healthcare institutions including UPMC adapted the TI-RADS scoring system in order to identify most clinically significant malignancies while reducing the number of biopsies and follow-up ultrasounds performed on benign nodules. According to ACR, TI-RADS category 3 nodules <1.5 cm and TI-RADS category 4 nodules <1 cm do not warrant follow-up imaging. There are no validation studies on TI-RADS follow-up recommendations.

Methods:We completed a retrospective chart review from UPMC endocrine surgery thyroid nodule database from 2002 to 2012. We identified 57 nodules that showed a change in size during follow-up and had surgical data. Patient demographics, nodule baseline TI-RADS category, size, follow-up volume change and histopathological data were recorded. We reviewed ultrasound images and calculated TI-RADS category at baseline and during follow-up.

Results:TI-RADS category 1-2 (TR1 and TR2) nodules(n=4) did not show any change in size over an average of 6.5 years confirming the recommendations that TR1 and TR2 nodules do not need follow-up.TI-RADS category (TR3) nodules (n=22) showed an average 225% change in volume over 4 years of follow-up. TR3 nodules <1.5 cm showed 397% volume change; 3 out of 15 (20%) nodules that showed a change in size proved to have thyroid cancer >1cm.

TI-RADS category (TR4) nodules(n=31) showed a 786% volume change over 2.6 years of follow-up. TR4 nodules <1 cm, 5/14(35%) proved to have thyroid cancer >1 cm in follow up.

Conclusions:TR1 and TR2 nodules did not show thyroid cancer during follow-up validating ACR recommendations not to follow these nodules. 3/15(26.5%) TR3 nodules <1.5 cm that showed a change in volume proved to have thyroid cancer. 5/14(35%) TR4 nodules <1cm that changed in volume were found to have thyroid cancer. Further studies are needed to identify nodules that require follow-up in order to decrease the misdiagnosis of thyroid cancer.
SUN-LB6 Characterization of PCOS Among Flo App Users Around the World
Authors: Galic Isabel , Brown Dannielle , Negris Olivia Ruth , Zhaunova Liudmila , Klepchukova Anna , Jain Tarun
Published: May 2020

Polycystic ovary syndrome (PCOS) is a common gynecological endocrine disorder associated with menstrual irregularity and androgen excess. The worldwide prevalence of PCOS among women of reproductive age ranges from 5-20%. Mobile menstrual cycle apps, such as Flo, provide an opportunity to gather data on the characteristics of PCOS in a globally representative and medically unbiased population. The objective of this study was to report PCOS symptomatology relative to country in order to better characterize PCOS and its differing phenotypes among users around the world. A questionnaire on PCOS related symptoms and previous PCOS diagnosis was available to Flo users during one month (2019). The geographical location of the user was estimated based on the IP address. Study inclusion criteria included women aged 18-44 years seeking to track their cycle or to conceive, who were not pregnant, on active contraception, or in stabilization mode after pregnancy and had Flo app running in English. All users in the study had agreed to the use of their de-identified and aggregated data for research purposes.The highest number of Flo app users who completed the PCOS questionnaire were coming from the following top 5 countries: United States (US) (n=240,732), United Kingdom (UK) (n=67,696), India (n=40,171), the Philippines (n=35,097), and Australia (n=28,946). The percentage of self-reported PCOS in these countries was 14.4% with higher percentages in India, the Philippines, and Australia (22.6%, 20.0%, 15.9, respectively) and lower in the US and UK (12.2% and 13.71%, respectively). In the US, UK, and Australia, the most common self-reported symptoms of PCOS positive women were bloating, hirsutism, and irregular cycles. In India and the Philippines, the most common symptoms of women with PCOS were bloating, baldness, and irregular cycles. Hirsutism, high glucose and high levels of both cholesterol and glucose are the three top symptoms increasing the probability of PCOS in all studied countries. The percentage of self-reported PCOS increases 3.04 times among users that reported hirsutism compared to all users that positively responded to the PCOS self-assessment question. Probability of PCOS among users that report hirsutism increases 3.85 times for Australia and 4.24 times for India. Australia and India had higher percentages of self-reported PCOS among those who reported experiencing nearly all PCOS related symptoms. Using Flo’s software, we are able to determine that geographic location has an effect on the phenotypic presentation of PCOS. Understanding the distribution of PCOS symptomology around the world will help to better characterize PCOS and improve diagnosis and treatment on both an individual and global scale.