bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of TRAb and TSI Leves and Thyroid Function in Pregnant Women With Graves’ Disease and Newborn: Preliminary Data
Authors: Negri Maurício Massucati , Araujo Paula Bruna Mattos Coelho , Gomes Dalva Margareth Valente , Pinheiro Maria Fernanda Miguens Castelar , Schrank Yolanda , Perozo Andrea Faria Dutra Fragoso , Marui Suemi , Fontes Rosita 
Published: May 2021

Abstract
Introduction: GD, mediated by TSH receptor-stimulating immunoglobulins (Igs) (rTSH), can lead to fetal thyroid dysfunction through the passage of Igs through the placenta during pregnancy. TRAb levels, used for prognostic evaluation, measure rTSH-stimulating and blocking Igs while TSI evaluates only as stimulating Igs. Objective: To prospectively evaluate pregnant women with DG and newborns (NB) by measuring TRAb and TSI and their correlation with thyroid function and postpartum complications. Methods: The patients were evaluated during pregnancy and the puerperium and the respective newborns. TSH, thyroid hormones and TRAb were evaluated by electrochemiluminescent method (Roche) and TSI by chemiluminescent assay (Siemens). TRAb&lt;1.75IU/L and TSI&lt;0.55IU/L were considered negative. Results: Nine patients were evaluated, with a mean age of 27.4±5.7 years: 6 had TRAb and TSI positive in the 1st trimester (1st-tri), when they maintained or started DAT; one with both negative (without DAT) and one with weakly positive TSI, when DAT was suspended. These last two remained euthyroid during pregnancy and puerperium. Of the first 6, 4 were evaluated in the 3rd-tri: three negative for TRAb and maintained positive TSI, 2 in low leves and one for high titles, when DAT was suspended or reduced; one kept both at very high levels. A patient with post-DT hypothyroidism, performed 3 years ago, using levothyroxine, evaluated in the 3rd-tri, had a negative TRAb and a highly positive TSI and remained so after pregnancy. The two patients who presented weakly positive TSI in the 3rd-tri evolved with their negative results and without DAT in the puerperium. The patient with TSI in high titers evolved with elevated levels as well as positive TRAb titers and postpartum decompensation. The patient with positive antibodies remained compensated for stable doses of DAT. Four NB were evaluated: all healthy, with normal thyroid function and negative TRAb. TSI was positive in 2 in the postpartum period; TSI was negative afterwards, while in the other 2 both antibodies were negative. Conclusions: TSI was not associated with thyroid dysfunction in NB, although it was associated with worsening hyperthyroidism in pregnant women, when at high titers. Positive TSI at low levels were not associated with worsening of the condition, which requires further studies to determine the cutoff point for assessing treatment suspension.
Meta-Analysis of Proptosis Response in Thyroid Eye Disease: Efficacy of EUGOGO Recommended Treatment Regimen With IV Methylprednisolone
Authors: Douglas Raymond S , Batten Ryan , Qadeer Rana A , Cameron Chris 
Published: May 2021

Abstract
Background: The European Group on Graves’ Orbitopathy (EUGOGO) recommends intravenous methylprednisolone (IVMP) as the first line treatment for moderate-to-severe active thyroid eye disease (TED). While many studies with varying doses of IVMP have reported improvements in inflammation, via clinical activity score (CAS) reduction, the reported improvements in the major progressive outcome of TED, proptosis, vary widely. A reduction in proptosis of ≥2 millimeter (mm) is considered by clinicians and EUGOGO as clinically meaningful. A meta-analysis of existing literature on use of IVMP in TED management, specifically proptosis response, was conducted.
Methods: PubMed and Embase were searched for relevant randomized controlled trials (RCTs) and observational studies that included patients with moderate-to-severe active TED receiving treatment with the EUGOGO recommended dose of IVMP (4.5-5g over 12 weeks) from the inception of the databases to date of search (October 2020); regular alerts were established to capture any recent studies. The outcome of interest was change from baseline to week 12 in proptosis in mms. Single-arm meta-analyses were conducted for IVMP using the DerSimonian-Laird random-effects models and forest plots were generated. Pooled means and corresponding 95% confidence intervals (CIs) were calculated. The primary analysis included all identified studies. Sensitivity analyses were conducted based on study design, study characteristics (smoking status), and methodologies (weighted Bayesian meta-analyses based on study design).
Results: The search retrieved 12 studies (10 single-center, 8 RCTs, 4 observational studies: 7 from China, 4 from EU, 1 from Turkey), reporting proptosis for 498 patients that were used for the meta-analysis. No placebo-controlled study with the EUGOGO recommended dose of IVMP was found. All studies included patients who were 18 years or older with moderate-to-severe TED and most (n=11) studies included patients with CAS of ≥3. For studies that reported this data, the mean or median (if mean not reported) age ranged from 35 to 52 years and duration of TED symptoms ranged from 4 to 13.6 months. Treatment with IVMP resulted in a reduction of 0.94 mm (95% CI: -1.57 to -0.32) in proptosis from baseline to week 12. The results from the sensitivity analyses were aligned with those from the primary analysis.
Conclusions: Among patients with moderate-to-severe TED, this meta-analysis found the EUGOGO-recommended dose of IVMP may result in modest, but not clinically meaningful, improvements in proptosis. However, these results should be interpreted with caution given the paucity of published data and the lack of risk/benefit analyses with glucocorticoid use as compared to the recently FDA-approved therapy, teprotumumab, for the treatment of TED.
Severe Thyroid Eye Disease in the US: A National Perspective
Authors: Singh Gurkirpal , Sehgal Maanek , Mithal Alka , Alabiad Chris , Kossler Andrea 
Published: May 2021

Abstract
Background: Thyroid eye disease (TED) is an unpredictable autoimmune inflammatory disease which can be sight-threatening, debilitating, and disfiguring. The majority of patients have mild, self-limited TED, 20-30% of patients experience moderate/severe disease, and 3-5% may develop sight-threatening disease, such as CON or exposure keratopathy. Surgical intervention is commonly necessary for patients with moderate/severe stable disease or sight-threatening disease, however, there is little data on the prevalence of TED requiring surgical interventions. Objective: To document the number of surgical procedures for thyroid eye disease in the US and evaluate the associated costs of these interventions. Methods: National Ambulatory Surgery Sample (NASS) is the largest ambulatory surgery database, representing approximately 14 million ambulatory surgeries performed annually in a hospital setting in the US. Data from 2,699 hospital-owned facilities located in 31 States and the District of Columbia, approximating a 63-percent stratified sample of U.S. hospital-owned facilities performing selected ambulatory surgeries are available for analyses. Data on clinical procedures and diagnoses, disposition of the patient, expected source of payment, and total charges, as well as geographic, hospital-owned facility, and patient characteristics are collected. For the purposes of this study, TED was identified by concomitantly occurring ICD 10 codes of thyroid disease and ICD-10 codes for eye manifestations of thyroid eye disease. CPT codes were used to identify eye surgeries performed in these patients. The coding algorithms were developed by consensus of three ophthalmic surgeons. Results: In 2018, a total of 1,991 patients with TED required eye surgery, with a national prevalence of 0.6 per 100,000 population. Mean age at surgery was 56.2 years (95% Confidence Interval (CI) 55.3-57.2). Women comprised 73% (1455 women and 536 men) of TED patients who underwent surgery. The average charges for each surgical encounter were $21,875 (95% CI $19,066-$24,684). Total charges for TED surgery in the US totaled over 43.5 million annually. While many patients had private insurance (49.7%), Medicare (31%) and Medicaid (13%) were also significant sources of reimbursement. Of all TED-related surgeries, 93% were conducted in teaching hospitals. Only 0.2% of surgeries were conducted in non-urban rural settings. Conclusion: In the US, severe TED requiring surgery, although uncommon, has significant economic impact. Further research is warranted to better understand the natural history of TED that may inform treatment pathways which may prevent complications needing surgery.
The Synergistic Effect of Corticosteroids and Mycophenolic Acid on Chemokines in Orbital Cells From Patients With Graves’ Ophthalmopathy
Authors: Fallahi Poupak , Ferrari Silvia Martina , Ragusa Francesca , Elia Giusy , Ruffilli Ilaria , Paparo Sabrina Rosaria , Patrizio Armando , Benvenga Salvatore , Antonelli Alessandro 
Published: May 2021

Abstract
In recent studies, an improvement of the response rate to therapy has been reported with corticosteroids and mycophenolic acid in patients with Graves’ ophthalmopathy (GO). In GO, retro-orbital cells (fibroblasts, preadipocytes, and extraocular muscle cells) secrete Th1 and Th2 chemokines stimulated by cytokines. Until now, no studies are present in literature regarding the effect of corticosteroids and mycophenolic acid on the secretion of chemokines in GO orbital cells. For this reason, the effect of increasing concentrations of mycophenolic acid or corticosteroids on the secretion of either the Th1 (CXCL10) and Th2 (CCL2) chemokines was tested in primary cultures of myoblasts, preadipocytes and fibroblasts obtained from GO patients. CXCL10 was undetectable in the supernatants of the retro-orbital cells in primary cultures; its release was induced dose-dependently by IFNγ, while TNFα alone had no effect. On the contrary CCL2 release (that was produced in low amounts basally) was dose-dependently induced by TNFα, while IFNγ alone had no effect. In both cases the combination of TNFα and IFNγ had a significant synergistic effect on CXCL10 and CCL2 secretion. The release of these chemokines was dose-dependently inhibited by increasing concentrations of mycophenolic acid, or corticosteroids (in a pharmacological range), in presence of IFNγ and TNFα stimulation. Moreover, the association of corticosteroids and mycophenolic acid (in presence of IFNγ and TNFα) had a stronger inhibitory effect on the chemokines release. In conclusion, in GO orbital cells, mycophenolic acid and/or corticosteroids (in a pharmacological range) have an inhibitory role on the secretion of both Th1 (CXCL10) and Th2 (CCL2) chemokines. This suggests a possible therapeutic role of these drugs.
Alert for TSH Measurement in High-Risk Pregnancies in Brazil
Authors: Santos Lívia Marcela , Marietto Déborah Buso Piccinalli , Miura Juliana Miyuki , Megale Luisa Lacaz Martins , Ganadjian Gabriela Terzian , Alvares Leonardo Azevedo , Oyama Priscila Rodrigues Leite , Bueno Thiago Limoli , Boas Roberta Frota Villas 
Published: May 2021

Abstract
Introduction: The hypothyroidism during pregnancy can lead to alterations in fetal neurological formation and has metabolic impact on pregnant women. If not diagnosed and treated it can cause complications during pregnancy and childbirth, besides causing changes in fetal formation. The TSH test is not part of routine examinations of the pregnancy monitoring care in Brazilian public health system (SUS). The test is not requested in low-risk pregnant women like those at high risk. The Overt Hypothyroidism (no subclinical) is prevalent in 0.3% to 0.5% of pregnant women and is asymptomatic in 70% of these patients. Thus, in order to avoid risks to the mother and fetus health due absence of early diagnosis, it would be ideal for pregnancy monitoring care examinations in the public health system to request a TSH test, especially in high-risk pregnancies. Method: A cross-sectional observational study was approved by the Ethics Committee (CAAE 22906619.2.0000.0062) to review 83 medical records of high-risk pregnant women in a Brazilian public hospital, State of São Paulo, Brazil in 2020. Inclusion criteria: All patients who are being followed up in high-risk childbirth or are hospitalized in the high-risk sector on the maternity during the year 2020. Complete medical records containing the data proposed to be researched and results of exams to be analyzed in the research. Results: The study included the review of 83 medical records of high-risk pregnant women with average age of 30 years old, average gestational age of 31 weeks and average weight of 84 kg. From these 11.4% (n = 10) declared that they had hypothyroidism and 2.4% (n = 2) hyperthyroidism in the first consultation. The 47% (n = 39) had their TSH measured during pregnancy, of which TSH had changed 30.8% (n = 12), 5.1% (n = 2) with suppressed TSH and 25.6% (n = 10) with TSH above the limit for pregnancy. Of the pregnant women who had a diagnosis prior to the pregnancy of hypothyroidism, only 1 did not have their TSH collected during pregnancy. Of the pregnant women who had hyperthyroidism, all had TSH collected during pregnancy, but kept TSH suppressed and free T4 at the upper limit throughout the pregnancy. 10% (n = 8) had gestational bleeding, of which only 25% (n = 2) had TSH measured at some point during pregnancy, of these, one had an altered TSH, but no medication was prescribed or the test repeated. Conclusion: Recognizing that the evolution of pregnancy depends on the normal thyroid eixo, we believe that for high-risk pregnant women they should have their thyroid eixo evaluated in the first trimester.
Generation and Transplantation of HiPSC-Derived Thyroid Follicular Cells
Authors: Undeutsch Hendrik Julian , Posabella Alberto , Kurmann Anita A , Kotton Darrell N , Hollenberg Anthony Neil 
Published: May 2021

Abstract
Despite the availability of synthetic thyroid hormone (TH) for therapeutic use, many patients with hypothyroidism do not feel well on replacement doses of TH. Indeed, hypothyroid children may develop various behavioral issues if under- or overtreated for hypothyroidism, suggesting the need of better individualized therapy. The development of stem cell-based models of thyroid replacement would greatly facilitate the treatment of post-surgical and congenital hypothyroidism and our understanding of the causes of congenital hypothyroidism. To generate thyroid follicular cells from human induced pluripotent stem cells (hiPSCs), we utilize a directed differentiation approach by activating endogenous signaling pathways we have previously identified in the mouse. We are employing a hiPSC-line with a GFP reporter targeted to the NKX2-1 locus allowing us to identify and purify cells positive for the transcription factor NKX2-1. Using these cells, we confirmed that BMP4 and FGF2 led to the induction of thyroid progenitors from foregut endoderm, expressing the four transcription factors in thyroid development NKX2-1, PAX8, HHEX and FOXE1. Subsequent differentiation of the purified, NKX2-1-positive progenitors led to follicular cell maturation, expressing genes related to TH synthesis, such as TG, TSHR, NIS (SLC5A5) and TPO. To assess the in vivo function of these hiPSC-derived thyroid follicular cells, we grafted the cells under the kidney capsule of radioablated, immunocompromised mice. First, hypothyroidism was confirmed 4 weeks post-ablation by increased TSH and low T4 levels. Next, mice received matured hiPSC-derived follicular cells, undifferentiated hiPSCs or sham surgery and were monitored for 8 weeks. In this preliminary test, no difference in TH levels was detected between the three groups. However, the grafted follicular cells formed a distinct cell population with thyroid-like histology. In order to optimize our directed differentiation protocol further and obtain a purer thyroid progenitor population, we generated a hiPSC line carrying a tdTomato reporter targeted to the PAX8 locus in addition to the NKX2-1-GFP-reporter. After directed differentiation cells sorted for NKX2-1-GFP and PAX8-tdTomato showed high induction of NKX2-1, PAX8, HHEX and FOXE1 expression, as well as expression of TG and TPO. Utilizing this double-reporter hiPSC line will enhance our ability to generate mature follicular cells for transplantation.
Generation of Adult Stem Cell Derived Organoid Cultures From Thyroid Follicular Cells
Authors: van der Vaart Jelte , Bosmans Lynn , van Santen Hanneke Margo , Vriens Menno R , Clevers Hans 
Published: May 2021

Abstract
The thyroid is essential for maintaining systemic homeostasis by regulating thyroid hormone concentrations in the bloodstream. Due to the limited number of representative model systems, there is limited understanding of fundamental thyroid biology as well as thyroid carcinogenesis. To fill the caveats in the understanding of thyroid cell biology, we aimed to develop an adult stem cell-derived three-dimensional (3D) organoid culture system using murine and human thyroid follicular cells (TFCs). We have succeeded to grow such an organoid culture system that harbours the complete machinery of hormone production visualised by the presence of colloid in the lumen and essential transporters and enzymes in a polarised cell layer. Both the established murine as human thyroid organoids express canonical thyroid markers PAX8 and NKX2.1/TTF1. Moreover, the thyroid hormone precursor thyroglobulin is expressed in both cultures to similar levels as in tissue. Extensive characterisation furthermore identifies known and new biological insights in TFC subclassification, subcellular organisation and hormone production using state-of-the art techniques like single cell RNA sequencing, transmission electron microscopy and genome editing. These 3D in vitro cultures allow for a variety of thyroid-related studies including the progression of wild type cells towards cancer. Additionally, due to the success of generating patient-specific tumour organoids of primary differentiated thyroid carcinoma and metastasis, insights in drug resistance and metastases can be identified. In short, this newly developed organoid culture of murine and human wild type TFCs as well as tumour tissue opens up an extensive area of research that will help understand the drivers for growth and development of thyroid (cancer) cells and enable studies upon drug responsiveness.
Thyroid Function in Adults With Prader-Willi Syndrome
Authors: Pellikaan Karlijn , Snijders Fleur , Wilhelmina Rosenberg Anna Gerarda , Van der Lely Aart Jan , de Graaff Laura 
Published: May 2021

Abstract
Introduction: Prader-Willi syndrome (PWS) is a complex genetic syndrome in which hypothalamic dysfunction leads to extreme appetite (hyperphagia) and pituitary hormone deficiencies (PHD), among others. Compared with the ‘general endocrine population’, the population of adults with PWS is characterized by a high prevalence of intellectual disability (ID) and frequent use of psychotropic drugs. Due to hypotonia and the low muscle mass associated with the syndrome, adults with PWS have a low basal metabolic rate (BMR) and a high risk of developing obesity. Therefore, exercising is extremely important. However, PHD like hypothyroidism can cause fatigue and exercise intolerance. If left untreated, hypothyroidism can lead to a further decrease in BMR, an increase in Body Mass Index (BMI) and increased cardiovascular risk. As mortality in PWS is high (3% yearly) and often related to cardiovascular problems and obesity, it is of utmost importance to optimize thyroid function and other factors affecting BMR.
Methods: In 122 adults with PWS (median age 29 y [IQR 21-39], median BMI 29 kg/m2 [IQR 26-36]), we measured TSH, free T4 and T3 (the active form of thyroid hormone) and searched the medical history for use of medication and any pre-existing diagnosis of hypothyroidism. Moreover, we performed an extensive literature search and summarized the current literature on hypothyroidism, T3 and T4 levels in adults with PWS.
Results: Hypothyroidism was present in 17% and more prevalent in females (23%) than in males (10%), even though this was not statistically significant (P=0.06). Although within the reference range, serum T3 levels were relatively high compared to free T4 levels. T3 levels were significantly lower in patients that used psychotropic medication (n=45) than in patients that did not (median 1.7 [IQR 1.5-2.0] vs 2.1 [IQR 1.7-2.3], P=0.013).
Conclusion: We found a prevalence of hypothyroidism of 17% (compared to 3% in the non-PWS population). T3 levels were relatively high, which might be explained by increased peripheral conversion of T4 to T3 by deiodinase type 2. Levels of the active thyroid hormone T3 were significantly lower in patients using psychotropic medication. Based on our findings, we recommend 1) yearly screening of thyroid hormone levels in adults with PWS to avoid negative effects of untreated hypothyroidism on BMR, BMI and cardiovascular risk and 2) extra monitoring of the active thyroid hormone T3 in patients using psychotropic drugs.
TRH Stimulation Testing in Older Individuals with Persistent Subclinical Hypothyroidism: A Randomized, Double-Blind, Cross-Over Study of Levothyroxine and Liothyronine Administration
Authors: Meizlik Paige , Cucchiara Andrew , Kannan Lakshmi , Scattergood Theresa , Cappola Anne Rentoumis 
Published: May 2021

Abstract
Background: Subclinical hypothyroidism is common in older individuals. To better understand the underlying physiology, we examined the pituitary-thyroid axis using thyrotropin releasing hormone (TRH) stimulation testing both at baseline and after levothyroxine (LT4) and liothyronine (LT3) supplementation. Methods: We conducted a randomized, double-blind, cross-over study in men and women aged 70 years and over without anti-thyroid peroxidase antibodies with persistent subclinical hypothyroidism, defined as having a TSH level between 4.5 and 19.9 µIU/mL with a normal free thyroxine (FT4) level at two consecutive time points. The primary outcome measures were TSH serum concentration area under the curve (AUC), maximum TSH serum concentration (Cmax), and change in free thyroxine (∆FT4) and total triiodothyronine (∆TT3) levels following TRH stimulation, each measured at three time points: once at baseline and once each after achieving euthyroid TSH levels with the two thyroid preparations. The maximal change in TSH (∆TSH); FT4 and TT3 AUCs; and time to maximal TSH, FT4, and TT3 (Tmax) were also analyzed. Results: Thirteen participants [mean (SD) age 77 (5) years], 4 women and 9 men, completed TRH stimulation testing at baseline and after achieving a TSH level of 0.5-1.5 µIU/mL with each therapy. Baseline mean TSH was 4.84 (1.29) µIU/mL. The mean LT4 dose was 105 (36) µg/day and LT4 dose was 34 (9) µg/day. After TRH stimulation, the mean TSH AUC (0-180) at baseline was 3099.5 (1424.4) µIU*min/mL, and significantly decreased after both LT4 [631.4 (315.2), p&lt;0.001] and LT3 [631.5 (317.3), p&lt;0.001]. There was no difference in TSH AUC (0-180) between LT4 and LT3 treatment arms. Baseline mean TSH Cmax was 27.2 (14.5) µIU/mL and significantly decreased after LT4 [5.5 (3.0), p&lt;0.001] and LT3 [5.4 (2.9), p&lt;0.001], with no difference between the LT4 and LT3 treatment arms. The ∆FT4 was 0.11 (0.07) ng/dL at baseline and decreased significantly on LT3. The ∆TT3 was 0.32 (0.09) ng/mL at baseline and significantly decreased on both LT4 and LT3, with no difference between treatment arms. Conclusions: Older individuals with antibody-negative persistent subclinical hypothyroidism have a heterogeneous TSH response to TRH stimulation. Our data show a significantly diminished response to TRH stimulation after thyroid hormone replacement, and they support the pharmacodynamic equivalence of LT4 and LT3 treatment.