bluuebunny/crossref_metadata_2025 huggingface dataset:
FRI570 Repatha Induced Thyroid Storm
Authors: Sepulveda-Garcia Luis Ruben , Madera Marin Luis Norberto , Musa Penna Laurianne El , Medina-Torres Wilnelia , Ortiz-Rivera Monica Alexandra , Rosado-Burgos Alexandra , Alvarado Milliette , Ramirez Margarita , Alejandra Gonzalez-Rodriguez Loida
Published: October 2023

Disclosure: L.R. Sepulveda-Garcia: None. L.N. Madera Marin: None. L. El Musa Penna: None. W. Medina-Torres: None. M.A. Ortiz-Rivera: None. A. Rosado-Burgos: None. M. Alvarado: None. M. Ramirez: None. L.A. Gonzalez-Rodriguez: None.

Introduction: Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors are an effective medical therapy for lowering plasma LDL-cholesterol and enhancing the LDL-cholesterol ability of statins. In 2020, a case of transient hyperthyroidism secondary to evolocumab was reported. We present a case of impending thyroid storm after a patient received evolocumab. Patient description: 60 y/o female patient with medical history remarkable for hyperlipidemia, anti-TPO positive non-toxic multinodular goiter, hypertension, fibromyalgia, and coronary artery disease who presented with heat intolerance, palpitations, tremors, and insomnia after second dose of evolocumab. At physical exam found with tachycardia, hypertension, anxious mood, tremors, leg pitting edema +1 bilateral, and deep tendon reflexes +3 in lower extremities, although no palpable or painful goiter. Laboratories compatible with hyperthyroidism [TSH < 0.008 uIU/mL (0.3 – 3.0 uIU/mL), Free T4 4.29 ng/dL (0.89 – 1.76 ng/dL), Total T4 20.03 ug/dL (4.5-12 ug/dL)] and clinically with severe thyrotoxicosis. Patient was sent to ED for further evaluation and management. Case outcomes: Upon admission patient presented with a tonic-clonic seizure with short post ictal state. Burch-Wartofsky scale Point Scale 35, consistent with impending thyroid storm. Thyrotoxicosis management given requiring high doses of PTU, hydrocortisone and propranolol, including the need to add cholestyramine to the regime. By day 9 of therapy, patient was transitioned to methimazole 30mg daily with discontinuation of hydrocortisone and cholestyramine. Upon discharge, 2 weeks later, thyroid function tests had normalized to a FT4 of 1.39 ng/dL and a Total T4 of 9.6 ug/dL. Case discussion: A case of transient hyperthyroidism with PCSK9 inhibitor was previously reported requiring only symptomatic treatment. In this case a patient presented with severe thyrotoxicosis after she received her second dose of evolocumab. PCSK9 inhibitor therapy immunological influence on thyroid remains unknown. This case shows the importance of thyroid function test follow up in patients on PCSK9 inhibitor therapy and the possibility of immunological influence on the thyroid.

Presentation: Friday, June 16, 2023
SAT550 Warthin-like Variant of Papillary Thyroid Carcinoma: An Even Rarer Presentation
Authors: Kunadia Jessica , Chablani Sumedha
Published: October 2023

Disclosure: J. Kunadia: None. S. Chablani: None.

Introduction: We present a rare case of Warthin-like variant of papillary thyroid carcinoma (WLPTC) with later development of a second primary malignancy. Clinical Case: A 56 year old female with hypertension, hyperlipidemia, ulcerative colitis, asthma, and a strong family history of cancer presented in 2017 for evaluation of an enlarged thyroid gland noted by her primary care provider. Patient was asymptomatic and denied prior thyroid disease and head or neck radiation. Labs demonstrated normal TSH and free T4 levels. TPO antibodies were elevated to 1,155 IU/mL (reference range 0.0 – 5.5 IU/mL). Thyroid US was notable for a diffusely enlarged thyroid gland containing a 1.4 x 0.6 x 1.0 cm solid, hypoechoic nodule without calcifications in the upper pole of the right lobe. Shared decision-making resulted in a plan for continued surveillance. Repeat thyroid US in 2018 demonstrated that this nodule had increased in volume by 56.25%, now measuring 1.4 x 0.75 x 1.25 cm. Fine needle aspiration (FNA) biopsy was performed and positive for papillary thyroid carcinoma (PTC). Patient underwent total thyroidectomy; pathology revealed a 1.2 x 1 x 0.9 cm WLPTC and 0.2 cm papillary thyroid microcarcinoma. There was no evidence of extrathyroidal extension, angioinvasion, or lymph node involvement. Follow-up neck US in 2020 demonstrated a 0.4 cm hypoechoic ovoid structure in the left thyroid bed and an enlarged but morphologically normal-appearing right level II lymph node. Repeat neck US in 2021 showed the appearance of a new 2.8 cm right level II lymph node; FNA was positive for malignancy with negative thyroid transcription factor-1 staining and undetectable thyroglobulin. Patient underwent an excision biopsy of the lymph node, and pathology was consistent with metastatic adenoid cystic carcinoma (ACC). A right submandibular gland lesion detected on subsequent MRI head and neck was resected and confirmed to be the primary source of ACC. Patient was treated with adjuvant radiation therapy with adequate response to therapy. Conclusion: WLPTC is a rare subtype of PTC that accounts for 0.2-1.9% of cases and carries a strong association with Hashimoto’s thyroiditis. It is histologically characterized by papillary architecture, oncocytic changes, nuclear features of PTC, and dense lymphoplasmacytic infiltration of the papillary cores. WLPTC is considered to have a favorable prognosis given its low frequency of lymphovascular invasion and low recurrence risk. This case also highlights the importance of keeping a broad differential when evaluating new findings on neck US in patients with a history of thyroid cancer. Metastases to cervical lymph nodes most commonly occur from head and neck tumors. However, to date, only one other case of PTC with second primary malignancy of salivary ACC has been reported.

Presentation Date: Saturday, June 17, 2023
SAT551 Significantly Elevated Thyroglobulin Levels with Negative Whole-Body Scan and PET/CT After Treatment of Thyroid Cancer: A Case Report
Authors: Bassatne Aya , Chaiban Joumana T
Published: October 2023

Disclosure: A. Bassatne: None. J.T. Chaiban: None.

Background: Thyroglobulin (Tg) levels are used to monitor recurrence or persistence of disease after treatment of differentiated thyroid cancer. Some cases may have persistently elevated Tg and negative whole-body scans (WBS). We present a case of substantially elevated Tg levels despite negative WBS and PET/CT after thyroidectomy and radioactive iodine (RAI) treatment in a patient with papillary thyroid carcinoma (PTC). Clinical Case: A 66 years old lady was referred to the endocrinology clinic almost 5 years ago after incidental findings of calcified thyroid nodules on CT. Thyroid US confirmed 2cm aggregate calcified nodules. FNA revealed PTC for which she underwent thyroidectomy. Pathology showed a unifocal 3.5 cm left lobe conventional PTC without angioinvasion nor extrathyroidal extension, 3/13 positive lymph nodes (LN) on the lateral dissection of the left neck as well as multiple small LN on the central dissection. 6 days postop, her Tg was still significantly high at 40.5ng/mL (Ref 1.2-35 ng/mL) and then increased to 397ng/mL after thyrogen preparation for RAI ablation, antithyroglobulin antibodies were negative. WBS post RAI was negative except for the physiologic neck uptake. Almost a year later, a diagnostic WBS after thyrogen stimulation was still negative but the stimulated Tg increased again to 235 ng/mL with negative thyroglobulin antibodies. Tg result were confirmed by LC-MS method. Heterophile Antibodies were negative. Patient confirmed that every single time she followed at least 2 weeks of low iodine diet in preparation for the WBS. Unfortunately, we were not able to get a 24 hour urine collection for iodine. A PET/CT was reassuring. CT neck/chest did not show any suspicious metastases. TSH was maintained at an adequately suppressed level all through and Tg levels were ranging around 6-8 ng/mL. After another year, a stimulated Tg was 302.4 ng/mL with a TSH of 198 mcU/mL (Ref 0.35-5.0 mcU/mL). At that time, a repeat WBS was negative and a repeat PET/CT demonstrated an interval development of a small thyroid focus thought to be consistent with recurrence of malignancy. However, a CT of neck/chest did not reveal any abnormal thyroid findings or metastases. Patient received 100 mCi of RAI after thyroid hormone withdrawal. Subsequent WBS was negative. Currently her Tg levels are stable at around 8-9ng/mL for the past 6 months with a suppressed TSH. Patient had another PET/CT through her breast surgeon to follow on a previous breast lesion and no thyroid abnormality was noted. Conclusion: Elevated Tg levels despite negative imaging may be seen in patients with PTC as illustrated in this case. We are reporting it due to the extent of elevation of Tg levels seen on more than one occasion in the absence of structural recurrence. Evaluation and treatment of such patients remain controversial.

Presentation Date: Saturday, June 17, 2023
FRI209 Psychiatric Illness Masking Autoimmune Polyglandular Syndrome In A Middle-aged Woman
Authors: Esper Layal , Ibrahim Amira , Sen Sabyasachi
Published: October 2023

Disclosure: L. Esper: None. A. Ibrahim: None. S. Sen: None.

Introduction: Autoimmune polyglandular syndrome type 2 (APS-2) or Schmidt's syndrome, is a rare disorder characterized by the coexistence of autoimmune adrenal and thyroid disease and/or type 1 diabetes mellitus. Clinical case: A 51-year-old woman with past medical history of depression and bipolar disorder presented to the hospital with weakness and dizziness. The patient reported increased dizziness and weakness over several months that progressed and limited her level of daily activities. She had been experiencing decreased energy, poor appetite and occasional nausea but denied vomiting or abdominal pain. She also denied any changes in her weight. She suffered from constipation but that was her baseline for many years. She was diagnosed with bipolar disorder with depression in her 20s and required multiple admissions for severe depression. She had been following up with her psychiatrist and assumed to have worsening depression. Her mood stabilizers and antidepressant medications were adjusted over several months without improvement. In the Emergency Department, her blood pressure was 98/58. Her heart rate was 57. Labs revealed Na: 115, K: 5.3 and Cr:0.87. The patient was admitted to the general medical floor for treatment of symptomatic hyponatremia. Hyponatremia was initially thought to be due to depression and decreased oral intake. She was started on fluid with slight improvement in sodium levels without significant improvement in symptoms. Further work up for the etiology of her hyponatremia and weakness elicited 2 endocrinopathies. She had a morning cortisol of 4. Cosyntropin stimulation test did not elicit a proper response. At baseline, cortisol was 4.2 and then 4.5 and 4.3 at 30 and 60 minutes, respectively. She was also found to have hypothyroidism (TSH 10, FT4: 0.4). Patient was started on hydrocortisone and fludrocortisone initially and subsequently thyroid hormone replacement was added with resolution of symptoms and hyponatremia. She reported being postmenopausal since age 41. Given that the patient had at least two endocrinopathies, 21 hydroxylase antibody testing was ordered and found to be positive. Addison's disease diagnosis is often delayed. A cross-sectional study in 2013 showed that less than 50% of patients with adrenal insufficiency were correctly diagnosed within the first half year after symptoms appeared. It however took more than 5 years until the condition was diagnosed for 20% patients. (1) The delay was primarily attributed to concomitant presence of psychiatric and gastroenterological conditions. Conclusion: Poly endocrinopathies often present with vague symptoms that need to be worked up to prevent the life-threatening effects of APS2 including adrenal crisis. We present an uncommon case of middle-aged woman with Tri-glandular syndrome with delayed diagnosis due to underlying psychiatric disease.

(1) Meyer et al. Horm Metab 2013; 45:92-95

Presentation: Friday, June 16, 2023
SAT308 An Assessment Of Prognostic Markers To Predict Metastatic Pheochromocytoma/Paraganglioma
Authors: Lundholm Michelle D , Berber Eren , Rao Pratibha P R
Published: October 2023

Disclosure: M.D. Lundholm: None. E. Berber: None. P.P. Rao: None.

Introduction: Pheochromocytoma/paraganglioma (PCC/PGL, or PPGL) are rare neuroendocrine tumors arising from chromaffin cells. Early identification of PPGL with metastatic potential is a diagnostic challenge. More data are needed on features and scoring markers used to predict PPGL metastasis. Methods: A single-center, retrospective observational study was performed of consecutive patients with pathology-confirmed PPGL from 2005 to 2022. Features associated with metastasis were identified and Pheochromocytoma of the Adrenal gland Scaled Score (PASS), Age, Size, Extra-adrenal location and Secretory type (ASES) score, and Size, Genetic, Age, and PASS (SGAP) score were calculated. Results: We identified 371 patients with PPGL (251 PCC, 120 PGL), age 52.2±15.4yrs, 60.6% female, 69.8% incidental. Metastatic disease was reported in 13.2% (N=49; 30 PCC, 19 PGL) associated with younger age (47.3 vs 53.0yrs, p=0.029), larger tumor size (6.3 vs 4.0cm, p<0.001), histologic findings of necrosis (26% vs 2.5%, p<0.001) and vascular invasion (42.1% vs 19.6% p=0.038), hyperadrenergic symptoms at diagnosis (38.8% vs 22.0%, p=0.038), norepinephrine-only secreting tumors (59.6% vs 30.1%, p<0.001), extra-adrenal location (51.0% vs 32.0%, p=0.009), presence of genetic mutations (72.4% vs 38.5%, p<0.001), particularly SDHx (31.0% vs 12.2%, p=0.020) and VHL mutations (24.1% vs 3.8%, p=0.001). There were no significant differences by gender, race, other histologic criteria from PASS, or other mutations such as RET or NF-1. ASES was positive (≥2) in 27.2% (N=100/371) with sensitivity (SN) 79.6%, specificity (SP) 81.1%, positive predictive value (PPV) 39.0%, and negative predictive value (NPV) 96.3% for predicting metastatic disease. PASS and SGAP could only be applied to patients with PCC: PASS was positive (≥4) in 29.7% (N=55/185) with SN 60.0%, SP 73.9%, PPV 21.8%, and NPV 93.8%. SGAP was positive (≥5) in 27.6% (N=32/116) with SN 56.3%, SP 77.0%, PPV 28.1%, and NPV 91.7%. Discussion: Metastatic PPGL is associated with age, tumor size and location, select histologic findings, symptomatic presentation, hormone-secreting pattern, and select genetic mutations. PPGL scoring markers ASES, PASS, and SGAP were all effective at identifying cases with low likelihood of metastasis, but had poor PPV. ASES outperformed PASS and SGAP in test metrics and practicality as the only clinically-derived marker which could be applied to all cases of PPGL. ASES can also be used pre-operatively. Most histologic features and genetic mutations included in PASS and SGAP were not strongly correlated with metastasis, though limited by lower prevalence in the study population. Conclusion: Our data supports the use of ASES alongside data on necrosis, vascular invasion, SDHx and VHL mutations where available to fine-tune our prediction of metastatic potential for PPGL.

Presentation: Saturday, June 17, 2023
SAT337 Maternal Cell free DNA Testing Reveals Incidental Finding Of Adrenocortical Carcinoma
Authors: Akanbi Folake , Raja Sobia , Else Tobias
Published: October 2023

Disclosure: F. Akanbi: None. S. Raja: None. T. Else: None.

Maternal Cell-free DNA Testing Reveals Incidental Adrenocortical Carcinoma IntroductionAdrenocortical carcinoma (ACC) is rare; with 1 to 2 cases per million. It is unclear if ACC in pregnancy represents a specific association though 150 cases have been reported. We report a case of ACC detected during fetal sex determination using cell free DNA (cfDNA).

Case Report: A 30 year old G1P0 woman presented at GA of 25 weeks with results of non-invasive prenatal screening (NIPS) done for fetal sex determination, which noted atypical findings concerning for possible maternal neoplasm. Pregnancy had been uncomplicated; she had no significant past medical history or features of hypercortisolism. Family history was positive for lung and prostate cancer. Physical examination revealed healthy looking female with no Cushingoid facies, abdomen matched stated GA. Full body MRI revealed 5.5 cm right adrenal mass with lymph nodes metastases. CT-guided retroperitoneal lymph node biopsy showed ACC.She was asymptomatic with significantly elevated urine free cortisol 3648 (3.5-45 mcg/24 hour), serum cortisol 67.5 (5-25 ug/dl), 11-deoxycortisol 3910 (10-79 ng/dl), and suppressed ACTH <5 (5-52 pg/ml). Electrolytes were normal, DHEAS 342 (35-430 ug/dl), aldosterone < 3 (4-31 ng/dl), renin mass 5 (4-44pg/ml), urinary free normetanephrine 0.23 (< 0.9 nmol/l), urinary free metanephrine < 0.2 (< 0.5 nmol/l). MRI of the chest and brain did not show metastases. She developed at GA 29 weeks, hypertension, proteinuria, and transaminitis. Cesarean section was done at GA 30 weeks followed the next day by right adrenalectomy, IVC repair and retroperitoneal lymph node resection. Pathology showed high-grade adrenal cortical carcinoma (12 cm size) with negative margins, vascular invasion and lymph node involvement (T3, N1, M0), no caval involvement, stage III ACC. During chemotherapy planning, metastases were noted, mitotane and pembrolizumab were initiated, but discontinued after 2 cycles on account of generalized rash and elevated liver enzymes. The tumor progressed on etoposide, doxorubicin and cisplatin (EDP), and second line therapy (gemcitabine and capecitabine) was initiated. Conclusion: Physiologic changes of pregnancy mimic clinical features of ACC and pregnancy associated changes in the HPA axis also make ACC diagnosis challenging. Short fragments of DNA (cfDNA) released into the maternal bloodstream can be detected after 7 weeks of gestation. Approximately 2-20% of total cfDNA is placental, it is used for sex determination and detection of congenital genetic abnormalities, cfDNA can also originate from maternal neoplasms and has been shown to detect lung, breast and colon while case series in patients with ACC showed detection of only 1 out of 3 cases. Surgery remains first line therapy for ACC, but adjuvant therapy, surveillance and hormone replacement are also vital in ACC management.

Presentation: Saturday, June 17, 2023
THU298 Effect Of SGLT2 Inhibition On Metabolic, Cardiac And Renal Outcomes In Heart Transplant Recipients (EMPA-HTx study): Protocol And Study Design
Authors: Raven Lisa M , Muir Christopher A , Kessler Iglesias Cassia , Kotlyar Eugene , Muthiah Kavitha , Bart Nicole K , Macdonald Peter S , Hayward Christopher S , Jabbour Andrew , Greenfield Jerry R
Published: October 2023

Disclosure: L.M. Raven: None. C.A. Muir: None. C. Kessler Iglesias: None. E. Kotlyar: None. K. Muthiah: None. N.K. Bart: Advisory Board Member; Self; Bristol-Myers Squibb. Grant Recipient; Self; Pfizer, Inc. Speaker; Self; Pfizer, Inc. P.S. Macdonald: Speaker; Self; Boehringer Ingelheim, AstraZeneca. C.S. Hayward: None. A. Jabbour: None. J.R. Greenfield: Speaker; Self; Boehringer Ingelheim, AstraZeneca.

Background: Heart transplantation (HTx) is standard of care for treatment of end-stage heart failure. Immunosuppression medication, required to prevent rejection, can result in adverse metabolic and renal effects. Clinically significant post-transplant complications include metabolic (diabetes, weight gain), renal impairment and cardiac disease, such as allograft vasculopathy and myocardial fibrosis. Sodium glucose co-transporter 2 inhibitors (SGLT2i) may have positive effects on all of these post-transplant complications. SGLT2i have been observed to improve metabolic parameters in patients with type 2 diabetes following cardiac and renal transplantation, but their benefit and safety in HTx has not been evaluated in randomised prospective studies. Aims: The overall aim of this project is to study the safety and efficacy of empagliflozin in HTx recipients. The primary end point will be improvement in glycaemic control assessed by change in glycosylated hemoglobin (HbA1c) and/or fructosamine, with secondary endpoints of cardiac fibrosis assessed by cardiac magnetic resonance, and renal function assessed by serum creatinine. Methods: Randomised, placebo-controlled trial of empagliflozin 10 mg daily versus placebo in recent HTx recipients. One hundred participants will be randomised 1:1. They will commence the study medication within 6-8 weeks of transplantation. Follow up will be 12 months after transplantation. Results from routine pre-HTx assessment will be reviewed to assess for pre-HTx diagnosis of diabetes. Routine laboratory tests, including full blood count, biochemistry, glucose, lipids and liver function as well as HbA1c, fructosamine, beta-hydroxybutyrate and urine albumin creatinine ratio, will be measured at baseline prior to receipt of study drug or placebo. Patients will be reviewed monthly during the study until 12 months post-HTx and data will be collected for each patient at each study visit. Cardiovascular magnetic resonance will be measured at baseline and 12 months after HTx. This study has been approved by St Vincent’s Hospital Human Research Ethics Committee (2021/ETH12184). Trial registration: ACTRN12622000978763. Discussion: This study will, for the first time, determine the efficacy and safety of SGLT2i in HTx recipients.

Presentation: Thursday, June 15, 2023
OR12-03 The Pancreatic Islet Alpha Cell Arginine Transporter SLC7A2 Regulates Arginine-induced Glucagon Secretion and Glycemia
Authors: Stanley Jade E , Reuter Austin , Sellick Katelyn , Attie Alan D , Keller Mark P , Dean E Danielle
Published: October 2023

Disclosure: J.E. Stanley: None. A. Reuter: None. K. Sellick: None. A.D. Attie: None. M.P. Keller: None. E. Dean: None.

Glucagon secreted from pancreatic islet α cells stimulates both hepatic glycogenolysis and gluconeogenesis resulting in the fractional extraction of amino acids from the blood. Thus, glucagon stimulates hepatic glucose output and raises blood glucose. When liver glucagon signaling is impaired, amino acid accumulation (hyperaminoacidemia) promotes subsequent α cell hyperplasia and hyperglucagonemia via this liver-α-cell axis, an endocrine feedback loop. We show that high levels of both glutamine and recently arginine are required to stimulate α cells to proliferate. Arginine also potently stimulates glucagon secretion, but the mechanisms behind this are not well defined. We find that the cationic amino acid transporter, SLC7A2/CAT2 is the most highly expressed amino acid transporter in human pancreatic α cells and three-fold higher in α cells than it is in β-cells in both mouse and human islets. We also find two SNPs in the human SLC7A2 locus are strongly associated with HbA1c (rs142010226 (A/G) - chr8: 17,367,112; p=9.11e-18; β=0.0113 and rs2517232 - chr8: 17,367,421; p=2.553e-14; β=-0.0283). Both SNPs are in the first intron of SLC7A2 but appear to exert opposite effect on HbA1c and associated with distinct haplotype blocks. ATAC-Seq analyses of human islets show that these SNPs are within 1 kb of binding sites for MAFB and FOXA2 transcription factors, both critical for α cell gene expression. To test if α cell expression of SLC7A2 plays a role in both glycemia and arginine-stimulated glucagon secretion, we generated α cell-specific Slc7a2-/- (α7A2KO) mice. Blood glucose and glucagon levels were not significantly different after a 6-hour fast in α7A2KO and 7A2WTCre+ mice. After a 6-hour fast, mice were administered an arginine bolus (2g/kg) via intraperitoneal injections and their blood glucose and glucagon levels were measured 15 minutes post-injection. α7A2KO mice had a significantly higher blood glucose level than 7A2WTcre+ mice after stimulation with arginine (arginine-stimulated blood glucose - 7A2WTCre+ 124.3 ± 26.7 mg/dl vs. α7A2KO 159.6 ± 32.1 mg/dl n=23-25 p=0.0019). However, glucagon secretion was significantly lower after stimulation with arginine in the α7A2KO mice compared to the 7A2WTCre+ mice (arginine-stimulated glucagon - 7A2WTCre+ 321.8 ± 171.9 pM vs. α7A2KO 74.6 ± 22.8 pM n=4-6; p<0.0001). Together, these data indicate that SLC7A2 mediates arginine’s effects in α cells and plays an important role in regulating glycemia.

Presentation: Friday, June 16, 2023
OR12-05 Blunting Of Sympathetic Activation Of Pancreas As A Cause For Hypoglycemic Unawareness In Hypoglycemia Associated Autonomic Failure
Authors: Thakkar Keya , Hampton Rollie , Jimenez Gonzalez Maria , Espinoza Diego , Stanley Sarah
Published: October 2023

Disclosure: K. Thakkar: None. R. Hampton: None. M. Jimenez Gonzalez: None. D. Espinoza: None. S. Stanley: None.

Introduction: Hypoglycemia activates the autonomic nervous system to suppress pancreatic insulin and increase glucagon release, restoring blood glucose levels to normal. These effects occur partly via sympathetic innervation of pancreatic islets. Recurrent hypoglycemia leads to a blunted autonomic response known as Hypoglycemia Associated Autonomic Failure (HAAF), which further exacerbates hypoglycemia. The mechanisms underlying HAAF are not well-understood, but changes in pancreatic innervation may contribute. Hypothesis: Decreased activity and remodeling of sympathetic innervation to the pancreas contribute to autonomic dysfunction with repeated hypoglycemia. Methods: To examine pancreatic sympathetic innervation with repeated hypoglycemia, C57Bl6 mice were treated with 0, 1, or 5 episodes (0, 1x, or 5x) of insulin-induced hypoglycemia. Pancreata, sympathetic celiac ganglia, and brains were harvested. Pancreatic tissue was immunostained for insulin, glucagon, and tyrosine hydroxylase (TH), a marker for sympathetic innervation. Samples were then cleared using iDISCO+, imaged, and analyzed using Imaris to examine the 3D distribution of innervation and islets. To determine if pancreatic sympathetic nerve function is altered in HAAF, we used viral delivery to express activating chemogenetic constructs specifically in pancreas-projecting sympathetic nerves. We assessed the effects of chemogenetic activation of pancreatic sympathetic innervation during insulin tolerance testing (ITT) in C57Bl6 mice with or without previous recurrent hypoglycemia. Results: 3D image analyses suggest acute hypoglycemia (1x) upregulates islet glucagon staining intensity. By comparison, recurrent hypoglycemia (5x) ​decreases pancreatic TH+ innervation and may blunt hypoglycemia-induced increases in islet glucagon staining intensity. Chemogenetic activation of pancreas sympathetic nerves in mice with repeated hypoglycemia increased blood glucose during an ITT while activation in mice without previous hypoglycemia did not significantly alter blood glucose. These data suggest reduced activity in pancreatic sympathetic innervation with recurrent hypoglycemia that can be restored by chemogenetic activation. Conclusions: Our data suggest repeated episodes of hypoglycemia may remodel the structure and function of peripheral pancreatic sympathetic innervation as compared to one episode of hypoglycemia. Restoring activity in pancreatic sympathetic innervation may partially reverse the severity of hypoglycemia in HAAF. Staining and analysis of celiac ganglia and sympathetic outflow circuits in the CNS will allow determination of the level at which blunting of sympathetic activation and/or remodeling of innervation occurs.

Presentation: Friday, June 16, 2023
OR18-02 Mammary Insulin Sensitivity Increases At The Onset Of Lactation And Promotes Metabolic Pathways Supporting Breast Milk Synthesis
Authors: Meng Xin , Rostom Hussam , Fry Alexandria , Elajnaf Taha , Hannan Fadil
Published: October 2023

Disclosure: X. Meng: None. H. Rostom: None. A. Fry: None. T. Elajnaf: None. F. Hannan: None.

The initiation of lactation during postpartum days 1-4 is hormonally regulated and critical for successful breastfeeding. Insulin represents a key lactogenic hormone as evidenced by women with diabetes mellitus who have delayed lactation onset. However, the role of insulin in lactation and its influence on mammary cells are unclear. We utilised clinical and cellular approaches to investigate this, and recruited n=38 healthy pregnant women (age range 26-42 years) following informed consent and measured serum insulin at 36 weeks’ gestation and during post-partum days 1-4 (1). Serum insulin progressively decreased from 36 weeks’ gestation to day 4 post-partum (244±33pmol/L vs 37±4pmol/L, p<0.0001). Moreover, reverse transcription-quantitative PCR (RT-qPCR) of lactating human mammary epithelial cells (HMECs) isolated from breast milk showed a >20-fold increase in insulin receptor expression compared to non-lactating HMECs (p<0.01, n=4). These findings indicated an increase in both systemic and mammary insulin sensitivity at lactation onset. We hypothesised that insulin promotes lactation by influencing mammary metabolism and used cultured HMECs to evaluate this. Stimulation of HMECs with 10nM insulin caused a >7-fold increase (p=0.001, n=5) in the phosphorylation of Akt, a signalling protein required for initiating lactation. Akt influences oxidative phosphorylation and glycolysis, and we assessed these processes by measuring oxygen consumption rate (OCR) and extracellular acidification rate (ECAR), respectively. Cultured HMECs treated with 10nM insulin for ≤18hrs showed increased OCR (22±0.9 vs. 17±0.4pmol O2/min/106 cells for control HMECs, p<0.05, n=4) and ECAR (0.23±0.003 vs. 0.18±0.002mpH/min/106 cells for control HMECs, p<0.001, n=4), consistent with increased oxidative phosphorylation and glycolysis. HMECs treated with 10nM insulin for 8hrs had significant upregulation of genes encoding glycolytic enzymes, namely hexokinase 2 (>4-fold increase, p<0.0001, n=4) and pyruvate kinase M1/2 (1.4-fold increase, p<0.05, n=4). However, RT-qPCR analysis of HMECs showed that insulin did not increase expression of genes mediating oxidative phosphorylation, suggesting an Akt-mediated post-transcriptional mechanism. In summary, increased mammary insulin sensitivity together with insulin-stimulated oxidative phosphorylation and glycolysis may support mammary function and milk component synthesis at the onset of lactation.

Reference: (1) Rostom, H. et al. Protocol for an observational study investigating hormones triggering the onset of sustained lactation: the INSIGHT study. BMJ Open 12, e062478.

Presentation: Saturday, June 17, 2023
SAT043 Chronically High Cerebrospinal Fluid Glucose Levels Impair Memory In Male Mice
Authors: Raza Muhammad U , Chhabra Kavaljit H
Published: October 2023

Disclosure: M.U. Raza: None. K.H. Chhabra: None.

Diabetes doubles the risk of cognitive decline and Alzheimer’s disease (AD). Whether this is mediated by an increase in blood glucose or cerebrospinal fluid (CSF) glucose levels, or by other metabolic factors such as changes in plasma insulin levels is unclear. To clarify the contribution of high blood glucose versus high CSF glucose levels toward increasing the risk of cognitive decline in mice, we have developed a method through which glucose concentration can be increased selectively in CSF. We implanted 8 weeks old male mice (n= 7-8 / group) with cannula attached to osmotic minipumps to directly infuse either artificial CSF (aCSF/sham group) or 50% glucose solution (treatment group) into the right lateral ventricle for eight weeks at a flow rate of 0.25ul/hr. CSF glucose was measured two and eight weeks after initiating the infusion in these mice. We also performed oral glucose tolerance tests (OGTT) in these mice to assess their peripheral glucose metabolism and uptake. Moreover, these mice were tested through the Morris water maze (MWM) to investigate the effects of high CSF glucose on learning and memory. Mice in the treatment group showed a significant increase (p<0.0001, unpaired t-test) in CSF glucose levels (mean=328±30.15 and 358±15.03mg/dl post-2, and 8 weeks of implantation, respectively) as compared to the sham group (mean=56±2.63 and 73±8.61mg/dl post-2, and 8 weeks of implantation, respectively). There was no significant change in body weight and food intake during the study. In OGTT, the treatment group showed significantly lower blood glucose levels (p<0.05, two-way ANOVA repeated measures design, Bonferroni’s multiple comparisons) at 15 minutes post-gavage (mean=336.3±24.41mg/dl) as compared to the sham group (mean=478.6±30.06 mg/dl). Mice in the treatment group made significantly fewer entries to the correct quadrant (i.e. the quadrant where the hidden platform was placed during training) (mean=12.43±1.55 entries, p<0.05, unpaired t-test) in the MWM test, as compared to the sham group (mean=18.4±1.84 entries). Additionally, mice in the treatment group were significantly less likely to revisit the correct quadrant (mean=10.7±1.50 revisits, p<0.05, unpaired t-test) than the mice in the sham group (mean=16.8±1.78 revisits). Importantly, there was no significant difference in the overall locomotor activity between the groups as measured through the open field test. To summarize, we have developed a method to test the effects of high CSF glucose levels on learning and memory in mice. Our results show that high CSF glucose levels for up to two months cause memory deficits in mice. This mouse model of chronically high CSF glucose presents a useful tool to investigate how diabetes-associated dysregulation of glucose homeostasis in the brain may contribute to AD and other neurodegenerative disorders.

Presentation: Saturday, June 17, 2023
Population Pharmacokinetics of Single Bolus Dose Fentanyl in Obese Children
Authors: Okada Carol R. , Henthorn Thomas K. , Zuk Jeannie , Sempio Cristina , Roosevelt Genie , Ruiz Amanda G. , Cohen Mindy N. , Chatterjee Debnath , Galinkin Jeffrey L.
Published: October 2023

BACKGROUND:

Childhood obesity is a significant problem. Obesity may alter the pharmacokinetics (PKs) of medications. Fentanyl is commonly used for procedural sedation, but there is a paucity of bolus dose fentanyl PK data in obese children. Better understanding of fentanyl PK in obese children would facilitate dosing recommendations. We conducted a study involving children with and without obesity to assess the potential differences in bolus dose fentanyl PK between the 2 groups.

METHODS:

We enrolled children 2 to 12 years of age with and without obesity, defined as >95th percentile body mass index (BMI) for age and sex, undergoing elective tonsillectomy ± adenoidectomy. After induction, subjects had 2 intravenous (IV) lines placed in 2 different extremities: 1 for medications and IV fluids and 1 for obtaining blood aliquots for fentanyl concentration analysis. After administration of 1 mcg/kg of fentanyl based on total body weight (TBW), blood sample collections for fentanyl concentration analysis were attempted at 5, 15, 30, 60, 90, and 120 minutes. Five-minute fentanyl concentrations were compared between obese and nonobese cohorts. Population PK analysis to examine the differences between obese and nonobese children was performed and included various body size descriptors, such as TBW, BMI, and fat-free mass (FFM), to examine their influence on model parameters.

RESULTS:

Half of the 30 subjects were obese. Mean fentanyl concentrations at 5 minutes were 0.53 ng/mL for the nonobese group and 0.88 ng/mL for the obese group, difference 0.35 ng/mL (95% CI, 0.08–0.61 ng/mL; P = .01). Population PK analysis showed that FFM was a significant covariate for the central volume of distribution. The potential clinical effect of an IV bolus dose of fentanyl based on TBW versus FFM in an obese child was assessed in a simulation using our model. 1 mcg/kg fentanyl dose based on TBW resulted in an approximately 60% higher peak fentanyl effect site concentration than dosing based on FFM.

CONCLUSIONS:

Our data demonstrated higher peak plasma fentanyl concentrations in obese compared to nonobese subjects. Population PK analysis found that FFM was a significant covariate for the central volume of distribution. Model simulation showed dosing of fentanyl in obese children based on TBW resulted in significantly higher peak concentrations than dosing based on FFM. Based on this modeling and the known concentration-effect relationship between fentanyl and adverse effects, our results suggest that bolus dosing of fentanyl in obese children should be based on FFM rather than TBW, particularly for procedures of short duration.
Autopsy, Patrimony, and a Christianized Reforma: Manuel Ramírez Aparicio's Mexican Conventual History, 1861–1862
Authors: Mächler Alejandro Quintero
Published: October 2023

The article offers a contextualized introduction to one of the most interesting and understudied Spanish American responses to mid-nineteenth-century anticlericalism: Manuel Ramírez Aparicio's Los conventos suprimidos en México (1861–62), a unique assessment of the Reforma's aftermath and a pioneering historiographical effort eluding any facile categorization. Penned by a moderate Liberal who did not endorse the obliteration of the Catholic legacy, it inaugurated the conventual history genre in Mexico, the first of many textual and visual efforts to preserve the receding religious memory in print. The article highlights the first-person autopsy regime that determined the work's methodology, uncovers the assumptions that underlay Ramírez Aparicio's conception of inevitable historical change, and showcases how the notion of national material patrimony, paired with the idea of a Christianized Reforma, aimed at guaranteeing the permanence of all that was noble, admirable, and beneficial in conventual life while reconciling it with the Liberal Party's main tenets.
Astronomy and Politics in Chile: The Role of Friedrich Ristenpart, Director of the National Astronomical Observatory, in the Dissemination and Popularization of Science, 1909–1911
Authors: Ramírez Errázuriz Verónica , Leyton Alvarado Patricio
Published: October 2023

This article examines Friedrich Ristenpart's role in popularizing scientific knowledge as director of the National Astronomical Observatory in Santiago, Chile, from 1909 to 1911. Our analysis centers on four scientific texts that he published with the aim of reaching a wider reading public; we also draw on press releases and administrative documents, among other sources. We posit that Ristenpart's role in popularizing scientific knowledge was closely aligned with Chilean president Pedro Montt's political agenda to modernize the nation by establishing new scientific institutions, restoring old ones, and using the 1910 centennial of Chilean independence to showcase these institutional advances. This essay also explores why Ristenpart's communicative strategy, which was dependent on the incumbent government's power, made it difficult for him to cultivate local buy-in and ultimately realize his goal of popularizing scientific knowledge.
A New Treatment Strategy for Spinal Metastasis: The “Systemic Conditions, Effectiveness of Systemic Treatment, Neurology, and Oncology” Decision Framework System
Authors: Cao Xuyong , Jiang Weihao , Zhang Bin , Zhao Xiongwei , Yu Haikuan , Lei Mingxing , Cao Yuncen , Su Xiuyun , Liu Yaosheng
Published: October 2023

BACKGROUND AND OBJECTIVES:

Treating metastatic spinal tumors poses a significant challenge because there are currently no universally applied guidelines for managing spinal metastases. This study aims to propose a new decision framework for the 12-point epidural spinal cord compression grading system to treat patients with metastatic spinal tumors and investigate its clinical effectiveness in a multicenter analysis.

METHODS:

This study analyzed 940 patients with metastatic spinal tumors between December 2017 and March 2023. The study provided the clinical evidence for the systemic conditions, effectiveness of systemic treatment, neurology, and oncology (SENO) decision framework among spine metastases. The SENO decision framework was launched in January 2021 in our hospitals, classifying patients into 2 groups: The non-SENO group (n = 489) consisted of patients treated between December 2017 and January 2021, while the SENO group (n = 451) comprised patients treated from January 2021 to March 2023.

RESULTS:

Patients in the SENO group were more likely to receive minimally invasive surgery (67.85% vs 58.69%) and less chance of receiving spinal cord circular decompression surgery (14.41% vs 24.74%) than patients in the non-SENO group (P < .001). Furthermore, patients in the SENO group experienced fewer perioperative complications (9.09% vs 15.34%, P = .004), incurred lower hospitalization costs (P < .001), had shorter length of hospitalization (P < .001), and received systematic treatments for tumors earlier (P < .001). As a result, patients in the SENO group (329.00 [95% CI: 292.06-365.94] days) demonstrated significantly improved survival outcomes compared with those in the non-SENO group (279.00 [95% CI: 256.91-301.09], days) (P < .001). At 3 months postdischarge, patients in the SENO group reported greater improvements in their quality of life, encompassing physical, social, emotional, and functional well-being, when compared with patients in the non-SENO group.

CONCLUSION:

The SENO decision framework is a promising approach for treating patients with metastatic spinal tumors.
Φύλο και φυσικές επιστήμες
Authors: Μποταΐτη Αρετή
Published: October 2023

Η παρούσα διδακτορική διατριβή ενσωματώνει την οπτική του φύλου στη διδακτική των φυσικών επιστημών. Εστιάζει στην ανάδειξη του έργου των επιστημονισσών στο πλαίσιο σειράς δραστηριοτήτων για νηπιαγωγούς και νήπια, οι οποίες ενσωματώνουν το ιστορικό, κοινωνικό και φιλοσοφικό περιβάλλον της επιστήμης και αξιοποιούν τις ψηφιακές αφηγήσεις ως βασικό εκπαιδευτικό υλικό. Συγκεκριμένα, αναζητά την απάντηση στα ερευνητικά ερωτήματα: α) Πώς να διδάξουμε για τις επιστημόνισσες των φυσικών επιστημών και το έργο τους σε εν ενεργεία εκπαιδευτικούς και σε μικρά παιδιά; β) Το δημιουργικό μαθησιακό περιβάλλον κατασκευής ψηφιακών αφηγήσεων βοηθάει τους εν ενεργεία εκπαιδευτικούς και τα μικρά παιδιά να μάθουν για το φύλο στις φυσικές επιστήμες; Στο πρώτο μέρος της διδακτορικής διατριβής παρουσιάζεται πώς ασκείται η έμφυλη εξουσία στον χώρο των φυσικών επιστημών διαχρονικά, που οδηγεί στον περιορισμό της γυναικείας παρουσίας, καθώς και ποια είναι η σύγχρονη άποψη για τη διδασκαλία και μάθηση των φυσικών επιστημών. Δίνεται έμφαση στα πλεονεκτήματα της διδασκαλίας με ψηφιακές αφηγήσεις που προβάλλουν τη ζωή και το έργο επιστημονισσών, των «κρυμμένων μορφών» της επιστήμης, ώστε αφενός οι εκπαιδευτικοί να βελτιώσουν τις διδακτικές τους δεξιότητες και να δημιουργούν φιλικό μαθησιακό περιβάλλον, αφετέρου τα παιδιά (και κυρίως τα κορίτσια) να αυξήσουν το ενδιαφέρον τους για τις φυσικές επιστήμες, να μπορούν να εμπνέονται για να τολμούν στο πεδίο των φυσικών επιστημών. Στο δεύτερο μέρος της διδακτορικής διατριβής σχεδιάζεται, εφαρμόζεται και αξιολογείται έρευνα σε δύο πληθυσμούς: α) σε εν ενεργεία νηπιαγωγούς ως μελέτη περίπτωσης και β) σε νήπια ως έρευνα δράσης. Στην πρώτη περίπτωση εφαρμογής, 52 νηπιαγωγοί από την περιοχή της Θεσσαλονίκης συμμετέχουν και δημιουργούν ομαδικά 11 ψηφιακές αφηγήσεις για τη ζωή και το έργο 9 επιστημονισσών. Στην δεύτερη περίπτωση εφαρμογής, σε ένα τμήμα νηπιαγωγείου αξιοποιείται μία από τις ψηφιακές αφηγήσεις που αναπτύχθηκαν ως βασικό εκπαιδευτικό υλικό, παρουσιάζεται μια πρότυπη ιστορία–παραβολή ως γέφυρα για την αναπλαισίωση επιστημονικού φαινομένου που σχετίζεται με το έργο μιας επιστημόνισσας και τα νήπια δημιουργούν τη δική τους ψηφιακή αφήγηση. Τα βιντεοσκοπημένα διδακτικά επεισόδια από τις δύο περιπτώσεις εφαρμογής αναλύονται με τα μοντέλα GNOSIS και VISUAL GNOSIS. Η ανάλυση των αποτελεσμάτων δείχνει ότι κατά την εφαρμογή σε νηπιαγωγούς και νήπια συμβαίνει μια διπλή αναπλαισίωση που ενισχύει τη μάθηση: μία αναπλαισίωση στο ιστορικό, φιλοσοφικό, κοινωνικό πλαίσιο γύρω από τη ζωή και το έργο επιστημόνισσας και μία αναπλαισίωση στο δημιουργικό μαθησιακό περιβάλλον των ψηφιακών αφηγήσεων. Επίσης, τόσο οι νηπιαγωγοί, όσο και τα νήπια αναγνωρίζουν και εκτιμούν το έργο των επιστημονισσών και επιθυμούν να το αναδείξουν και να αποκαταστήσουν την προσφορά και τη συμβολή τους στην επιστήμη και στην κοινωνία. Επιπλέον, στέκονται κριτικά απέναντι σε παράγοντες που έχουν εμποδίσει την παρουσία των γυναικών στον χώρο των φυσικών επιστημών, ενώ εντοπίζουν και αναδεικνύουν τους περιοριστικούς αυτούς παράγοντες μέσα από τις δικές τους ψηφιακές αφηγήσεις.
Ολοκληρωμένη και βιώσιμη χωροθέτηση των αιολικών και ηλιακών ενεργειακών έργων
Authors: Σπυριδωνίδου Σοφία
Published: October 2023

Η αιολική και ηλιακή ενέργεια είναι σήμερα από τις κυρίαρχες ανανεώσιμες πηγές ενέργειας σε όρους συνολικής εγκατεστημένης ισχύς σε παγκόσμιο επίπεδο. Η επιστημονική έρευνα στις διαδικασίες χωροθέτησης των αιολικών και ηλιακών έργων είναι υψηλής σημασίας, καθώς εστιάζει στον εντοπισμό περιοχών χωροθέτησης που συμβάλλουν σημαντικά στην τεχνική, οικονομική, κοινωνική και περιβαλλοντική βιωσιμότητα των ανανεώσιμων ενεργειακών έργων. Η παρούσα διδακτορική διατριβή πραγματοποιεί μία απευθείας ανάλυση και αξιολόγηση των υφιστάμενων διαδικασιών χωροθέτησης των αιολικών και ηλιακών έργων και δημιουργεί εργαλεία και μεθοδολογίες που θα μπορέσουν να βελτιώσουν τις υφιστάμενες διαδικασίες και να καλύψουν δυνητικά ερευνητικά κενά. Πιο συγκεκριμένα, η διδακτορική διατριβή αποτελείται από τα ακόλουθα έξι βασικά μεθοδολογικά στάδια: (1) βιβλιογραφική έρευνα και συστηματική ανασκόπηση των υφιστάμενων διαδικασιών χωροθέτησης των αιολικών (χερσαίων και υπεράκτιων) και ηλιακών (φωτοβολταϊκών και συστημάτων συγκεντρωτικής ηλιακής ενέργειας) έργων (συνολικά 205 σχετικές επιστημονικές μελέτες διερευνήθηκαν ενδελεχώς), (2) ανάπτυξη και εφαρμογή εργαλείου υποστήριξης λήψης αποφάσεων για τον προσδιορισμό των καταλληλότερων περιοχών μελέτης της Ελλάδας με σκοπό την εκπόνηση λεπτομερών ερευνών χωροθέτησης αιολικών και ηλιακών έργων σε αυτές τις περιοχές, (3) συλλογή, επεξεργασία και ανάλυση πρωτογενών δεδομένων και πληροφοριών μέσω της δημιουργίας συστηματικών ερευνών ερωτηματολογίου (συμμετοχικά εργαλεία), για την ενσωμάτωση των προτιμήσεων και απαιτήσεων των πολιτών και της γνώμης και γνώσης των εμπειρογνωμόνων σε αρχικά ή/και προχωρημένα στάδια της διαδικασίας της χωροθέτησης, (4) ανάπτυξη και εφαρμογή καινοτόμων εργαλείων αποκλεισμού (ανάπτυξη αλγορίθμων γεώ-επεξεργασίας σε κώδικα Python για την ορθή διαχείριση και επεξεργασία των γεωγραφικών πληροφοριακών δεδομένων) για τη βιώσιμη χωροθέτηση των αιολικών και ηλιακών έργων, επιβεβαίωση της αξιοπιστίας των εργαλείων αποκλεισμού και ανάλυση του αντίκτυπου της συμμετοχής των πολιτών και των εμπειρογνωμόνων στη διαδικασία της χωροθέτησης, (5) ανάπτυξη και εφαρμογή ολοκληρωμένων εργαλείων βελτιστοποίησης (σχηματισμός μαθηματικών εξισώσεων και προσδιορισμός βέλτιστων κατά Pareto λύσεων χωροθέτησης μέσω εφαρμογής σχετικού αλγορίθμου) για τη βέλτιστη χωροθέτηση των αιολικών και των ηλιακών έργων, και (6) τελική διαμόρφωση των εργαλείων που αναπτύχθηκαν, των μελετών χωροθέτησης που εκπονήθηκαν και των αποτελεσμάτων και των πορισμάτων που εξάχθηκαν από την παρούσα διδακτορική έρευνα. Χρήσιμα εργαλεία και καινοτόμες μεθοδολογίες παράχθηκαν από την παρούσα διατριβή, τα οποία μπορούν να ενισχύσουν τις παγκόσμιες εφαρμογές χωροθέτησης και να βελτιώσουν περαιτέρω ποίκιλες και σημαντικές θεματικές ενότητες του ζητήματος της χωροθέτησης. Σημαντικά αποτελέσματα και ευρήματα εξάχθηκαν από την διδακτορική διατριβή, τα οποία μπορούν να βελτιώσουν και να ενισχύσουν με χρήσιμες πληροφορίες και γνώση τις μελλοντικές μελέτες χωροθέτησης.
Όψεις της ζωής των επαναστατών κατά το 1821
Authors: Λούκος Χρήστος
Published: October 2023

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