bluuebunny/crossref_metadata_2025_split huggingface dataset:
Measurement of Steroid Fatty Acyl Esters in Blood and Brain
Authors: Gray Sofia L , Jalabert Cecilia , Ma Chunqi , Soma Kiran K 
Published: May 2021

Abstract
Steroid fatty acyl esters (FAEs) are a class of steroid conjugates that are abundant in circulation, have long half-lives, and are stored in lipid-rich tissues. Steroid-FAEs are present in many species, but their functions are poorly understood. They can be metabolized to active, unconjugated steroids and therefore may act as a reservoir of steroids. Dehydroepiandrosterone (DHEA) is an androgen precursor that can be conjugated to various fatty acids. DHEA also modulates aggression in several species, including songbirds, rodents and humans. Recent studies suggest that DHEA-FAEs might be present in songbird blood and/or brain, in part, to regulate aggression. Here, we (1) investigated the abundance of multiple fatty acids in songbird blood and (2) developed an indirect method to measure DHEA-FAEs in songbird blood and brain. First, preliminary work demonstrated high circulating levels of total (esterified and non-esterified) fatty acids, especially oleic, linoleic, and palmitic acids. These data, in conjunction with previous research, suggest that these fatty acids might be conjugated to steroids, including DHEA. Second, we successfully developed a saponification technique to indirectly measure DHEA-FAEs. Saponification cleaves the bond between the steroid molecule and the fatty acid, and we then measure the unconjugated steroid. DHEA-FAEs were incubated in 0.5M potassium hydroxide in ethanol for 30 min at room temperature, and steroids were subsequently extracted twice with dichloromethane. Unconjugated DHEA was quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS), the gold standard in steroid measurement. DHEA recovery was 88% using reference standards in neat solution. We validated this method with song sparrow plasma and chicken serum and obtained recoveries of 94-105% with intra-assay variation of 2.6%. Future research will directly measure specific DHEA-FAEs (e.g. DHEA-oleate) in blood and brain using LC-MS/MS. This research will elucidate the possible roles of steroid-FAEs in brain function and the regulation of steroid-dependent behavior. This work may also clarify the identities, levels and functions of steroid-FAEs in other species, including rodent models and humans. These data have implications for basic and clinical neuroendocrinology, offering insights into a possible storage system for steroids that may influence social behaviour.
Structural Insights of Transcriptionally Active, Full-Length Androgen Receptor Coactivator Complexes
Authors: Yu Xinzhe , Yi Ping 
Published: May 2021

Abstract
Steroid hormone receptors activate gene transcription by binding specific DNA sequences and recruiting coactivators to initiate transcription of their target genes. For most nuclear hormone receptors (NRs), the ligand-dependent activation function domain-2 (AF-2), residing in the C-terminal ligand binding domain (LBD), is a primary contributor to the NR transcriptional activity. In contrast to other steroid receptors such as estrogen receptor-α (ERα), the transcriptional activation function of androgen receptor (AR) is thought to be largely dependent on its ligand-independent activation function domain-1 (AF-1) located in its N-terminal domain (NTD). It remains unclear why AR utilizes a different activation function domain from other steroid receptors despite the fact that NRs share similar domain organizations and have a highly conserved DNA binding domain (DBD) and LBD. Here we present cryo-electron microscopic structures of DNA-bound full-length AR and its functional complex structure with its key coactivators, steroid receptor coactivator-3 (SRC-3) and the histone acetyltransferase p300. The structures reveal that androgen-bound full-length AR dimerization follows a unique head-to-head and tail-to-tail manner with all of the domains involved. The DBD and LBD are located at the center of the dimer interface. The NTDs wrap around the LBDs through their unique intra- and inter-molecular N- and C-terminal interactions and connect to each other. We observe that unlike ERα, AR binds a single SRC-3 molecule along with a single p300 molecule. The AR NTD appears to be the primary site for recruitment of both coactivators. The N-terminal region of SRC-3, rather than its receptor interaction domain, is important for this interaction. The structures presented here highlight the importance of the AR NTD for its transcriptional functions and provide a structural basis for understanding the assembly of the AR:coactivator complex and its domain contributions to transcriptional regulation.
A Randomised, Controlled Trial of Adjunctive Cholestyramine or Prednisolone Compared to Standard Therapy for the Treatment of Uncontrolled Graves’ Disease (the Chops Study)
Authors: Kim Khoo Serena Sert , Hussein Zanariah , Krishnan Gayathri Devi , Tee Hwee Ching , Chan Pei Lin , Alias Siti Aribah , Nor Lisa Mohamed , Badarudin Nurul Zaidah , Valayatham Vijiya Mala , Fung Yin Khet 
Published: May 2021

Abstract
Introduction: Antithyroid drugs (ATDs) are recommended effective treatment for uncontrolled Graves’ disease but achieves maximal antithyroid effects between 6 to 12 weeks. Cholestyramine sequesters thyroid hormones in the intestine and enhances its fecal excretion. Steroids inhibits the conversion of thyroxine to triiodothyronine peripherally and blocks thyroid hormone production. We hypothesize that adjunctive cholestyramine or prednisolone to ATDs may reduce circulating thyroid hormones and improve biochemical control.
Methods: In this multicenter, open labelled, parallel-group trial, we randomly assigned in a 1:1:1 ratio, adult Graves’ disease patients with moderate to severe hyperthyroidism (FT4 levels &gt; 40 pmol/L) to receive either adjunctive cholestyramine 4g twice daily or prednisolone 30 mg daily in tapering down doses in addition to standard treatment or standard treatment alone for 4 weeks. Standard treatment was carbimazole 30mg daily and propanolol 40mg BD for 4 weeks. The primary endpoint was change from baseline for FT4 and FT3 levels at the end of 2 and 4 weeks of intervention. Safety endpoints including gastrointestinal adverse events, hypokalemia, hypothyroid and hyperglycemia were recorded.
Results: A total of 107 patients were screened and 97 patients randomised. Baseline demographics, clinical and biochemical characteristics were similar between the
groups. The baseline median FT4 levels were 51.6 pmol/L (42.2-71.1) and FT3 levels 22.5 pmol/L (5.7-30.8). Both FT4 and FT3 declined at two and four weeks from baseline but were no different between the three groups. At week 2, median FT4 levels declined by 43.3% (25.8-53.3), 39.8% (19.1-55.1) and 33.4% (20.1-62.0) (p=0.988) and at 4 weeks, 50.9% (33.3-63.8), 57.8% (39-70.9), 55.8% (36.2-72.0) (p =0.362) in the cholestyramine, prednisolone and standard treatment group respectively. Median FT3 levels reduced by 51.2% (22.8- 58.9), 59.9% (38.9-69.3) and 50.9% (26.9-63.9) (p=0.084) at week 2 and 60% (39.2-67.9), 67.5% (38.4-78.4), 63.1% (45.7-69.3) (p=0.387) in the corresponding cholestyramine, prednisolone and standard treatment only group. A higher number of gastrointestinal adverse events: constipation, bloating, diarrhea, abdominal pain and vomiting were observed in the cholestyramine group in the first 2 weeks of treatment and no difference in the incidence of hypokalemia between groups.
Conclusion: Adjunctive cholestyramine or prednisolone did not improve the biochemical control of uncontrolled moderate to severe Graves’ disease when added to ATDs. The additional use of cholestyramine resulted in a higher number of gastrointestinal adverse events but were mild and self-limiting.
Genetic Alterations and Clinical Features in Brazilian Patients With Pheochromocytomas and Paragangliomas
Authors: Lin Wo Julia Mey , Botelho Mariana Coelho , Carvallo Mirna Sánchez , de Sousa Rafaela Marchon , Nascimento João Bosco , Lima Vinicius , Macedo Ana Sofia , Carvalho Denise Pires , Coelho Araujo Paula Bruna Mattos , Lima Jorge , Soares Paula , de Oliveira Naliato Erika Cesar , Violante Alice H D 
Published: May 2021

Abstract
Pheochromocytomas and paragangliomas are tumors derived from chromaffin cells which result from mutations of at least six different genes as autosomal dominant disorders. We evaluated the existence of correlations between genetic alterations and clinical data in 16 patients with pheochromocytomas and/or paragangliomas. From 2007 to 2019, 13 patients with pheochromocytoma [3 men, medium age 39 years (14–61)] and 3 with paraganglioma [1 men, medium age 33 years (22–35)] were evaluated regarding the presence of genetic mutations and possible correlations between the latter and some clinical features. Besides the mutations, tumor size, symptoms and signs present by the time of the diagnosis were studied. Four patients had pathogenic mutations (SDHB deletion encompassing the promoter and exon 1, C98Y in the SDHB gene, N78S in the VHL gene, and C634R in the RET gene) and one subject had a V90M variant in the TMEM127 gene. Two patients did not present mutations and nine had nonpathogenic mutations. Regarding the presence of clinical features before treatment, there was a predominance of arterial hypertension (75.0%), while the prevalence of tachycardia, abdominal pain and headaches was respectively 12.5%, 12.5% and 6.25%. There was no significant difference between the age of patients with pathogenic mutations and that of the other patients (31.2 vs. 38.6 years, p= 0.3952). Moreover, there were no differences regarding the prevalence of pheochromocytoma (p= 0.2143) or clinical features (p: hypertension= 0.6346, tachycardia= 0.4583, abdominal pain= 0.5417, headaches= 0.6875), or tumor dimensions (p= 0.4578) when the two groups were compared. However, the prevalence of paragangliomas was higher in patients with pathogenic mutations (p= 0.0179). In patients with pheochromocytoma and paraganglioma, the absence of correlations between pathogenic mutations and clinical features increases the importance of the genetic studies in the determination of treatment and prognosis of these tumors. Furthermore, subjects with germline mutations associated with pheochromocytoma and paraganglioma should undergo lifelong clinical, biochemical and imaging surveillance and their families should receive genetic counseling.
Interfering Medications in Older Adults on Thyroid Hormone Replacement: Who Is at Risk?
Authors: Beeson Rachel , Coe Antoinette B , Reyes-Gastelum David , Haymart Megan R , Papaleontiou Maria 
Published: May 2021

Abstract
Background: Thyroid hormone prescriptions have steadily increased in the past few years with levothyroxine being one of the most frequently prescribed medications in the United States. Population-based studies have shown that older age is a significant predictor for thyroid hormone initiation, with use continuing long-term. Thyroid hormone management in older adults is complicated by the presence of comorbidities and polypharmacy, particularly due to medications that can interfere with thyroid function tests. However, the prevalence of concurrent use of thyroid hormone and interfering medications in older adults and patient characteristics associated with this practice remain unknown. Methods: We conducted a population-based, retrospective cohort study of 538,137 thyroid hormone users aged ≥65 years from the Corporate Data Warehouse of the Veterans Health Administration (2004-2017). First, we described the prevalence of concurrent use of thyroid hormone and medications that commonly interfere with thyroid function tests (i.e., prednisone, prednisolone, carbamazepine, phenytoin, phenobarbital, amiodarone, lithium, interferon-alpha, tamoxifen). Then, we performed a multivariable logistic regression analysis to determine patient characteristics associated with concurrent use of thyroid hormone and at least one interfering medication during the study period. Covariates included in the model were patient age, sex, race, ethnicity and number of comorbidities. Results: Overall, 170,261 (31.6%) of patients were on at least one interfering medication while on thyroid hormone during the study period (median follow up 56 months). Non-white race [odds ratio (OR) 1.18, 95% confidence interval (CI) 1.15-1.21], compared to white race), Hispanic ethnicity (OR 1.11, 95% CI 1.08-1.14, compared to non-Hispanic), female sex (OR 1.12, 95% CI 1.08-1.15, compared to male sex), and presence of comorbidities (e.g. Charlson-Deyo Comorbidity Score ≥2, OR 2.47, 95% CI 2.43-2.52, compared to zero) were more likely to be associated with concurrent use of thyroid hormone and interfering medications. Older age (e.g., ≥85 years, OR 0.47, 95% CI 0.46 - 0.48, compared to age 65-74 years) was less likely to be associated with concurrent use of thyroid hormone and interfering medications. Conclusions: Almost one-third of older adults on thyroid hormone were taking medications that have been known to interfere with thyroid function tests. Our study highlights the complexity of managing thyroid hormone replacement in older patients, many of whom are at risk for adverse effects in the context of polypharmacy and comorbidities.
Does Primary BCG Vaccination Prevent Autoimmune Hypothyroid Disease?
Authors: Agrawal Kanhaiya , Basak Preetam , Dutta Pinaki , Walia Rama , Bhansali Anil , Sachdeva Naresh 
Published: May 2021

Abstract
Autoimmune thyroid disease (AITD) involves autoimmune destruction of thyrocytes marked by the presence of anti-TPO and/or anti-TG antibodies. In autoimmune diseases, an immunomodulatory role of BCG vaccination has been reported with decreased autoantibody production and induction of regulatory T cells (Tregs). We hypothesize that the loss of efficacy of BCG vaccine in adulthood might be associated with the appearance of AITD. To evaluate the protective efficacy of primary BCG vaccination, we assessed the anti-mycobacterial responses, thyroid function, and anti-thyroid autoimmune responses in autoimmune subclinical hypothyroid (SCH) (n=39) and non-autoimmune SCH (n=25) subjects. The anti-mycobacterial responses were determined by the Mantoux test and by BCG induced in-vitro proliferation of peripheral blood mononuclear cells in terms of proliferation index (PI). The immunophenotyping of autoreactive CD8+ T cells recognizing TPO derived epitopes was performed by flow cytometry using APC labelled dextramers by flow cytometry in patients with HLA-A*02 and HLA-A*24 alleles. We observed that the autoimmune SCH group had more subjects with a negative Mantoux reaction (less than 5mm) (61.5% vs 33.3%, p= 0.01). The PI with BCG stimulation was similar in both groups (2.55±0.31 vs 2.51±0.41, p = 0.667). The correlations (r) between Mantoux test and PI in autoimmune SCH and non-autoimmune SCH were, insignificant. The autoimmune SCH group had more subjects with diffused thyroiditis (43% vs 13%, p= 0.02). The SCH subjects with the presence of a BCG scar (n=11) had lower TSH (µIU/ml) (7.94±1.67 vs 6.75±1.56, p= 0.026) levels and lower frequencies of TPO-reactive CD8+ T cells (3.35±0.72% vs 1.77±0.98%, p= 0.061), as compared to subjects with the absence of a BCG scar (n = 53). The SCH subjects with positive Mantoux test (more than 10mm) demonstrated similar titres of anti-TG antibody (IU/ml) [(230 (56.71-508.90) vs 85.5 (15-345.9), p= 0.055] and anti-TPO antibody (IU/ml) [29.9 (5-135) vs 12 (5-83), p= 0.665)] as compared to those with a negative Mantoux test. The TPO-reactive CD8+ T cells and anti-TG antibody titres had a negative correlation in autoimmune SCH (r= -0.695, p=0.038) and non-autoimmune SCH (r= -0.642, p=0.024) subjects. Next, we observed a similar frequency of TPO-reactive CD8+ T cells in non-autoimmune and autoimmune SCH subjects (8.40±3.74% vs 9.02±4.17% p= 0.937). The absence of anti-TPO or anti-TG antibody did not rule out the presence of any underlying autoimmunity. The persistence of the protective effects of either BCG vaccination or exposure to Mycobacterium species might be involved in modulating autoimmune responses towards the thyroid gland. Our study warrants further research on the immunomodulatory role of BCG in adult subjects with a family history of autoimmune diseases including AITD.
Management of Thyrotoxicosis Induced by PD1 or PD-L1 Blockade
Authors: Brancatella Alessandro , Lupi Isabella , Montanelli Lucia , Ricci Debora , Viola Nicola , Sgrò Daniele , Antonangeli Lucia , Sardella Chiara , Brogioni Sandra , Piaggi Paolo , Molinaro Eleonora , Bianchi Francesca , Aragona Michele , Antonuzzo Andrea , Sbrana Andrea , Lucchesi Maurizio , Chella Antonio , Alfredo Falcone , Del Prato Stefano , Elisei Rossella , Marcocci Claudio , Caturegli Patrizio , Santini Ferruccio , Latrofa Francesco 
Published: May 2021

Abstract
Context: Thyrotoxicosis is a common immune-related adverse event in patients treated with PD1 or PD-L1 checkpoint inhibitors. A detailed endocrinological assessment, including thyroid ultrasound and scintigraphy is missing, as are data on response to treatment and follow-up. Objectives: To better characterize the thyrotoxicosis secondary to immune checkpoint inhibitors, gaining insights into pathogenesis and informing management. Methods: We conducted a prospective cohort study of 20 consecutive patients who had normal thyroid function before starting immunotherapy and then experienced thyrotoxicosis upon PD1 or PD-L1 blockade. Clinical assessment was combined with thyroid ultrasound, scintigraphy, and longitudinal thyroid function tests. Results: Five patients had normal scintigraphic uptake (Sci+), no serum antibodies against the TSH receptor, and remained hyperthyroid throughout follow-up. The other 15 patients had no scintigraphic uptake (Sci-) and experienced destructive thyrotoxicosis followed by hypothyroidism (N= 9) or euthyroidism (N= 6). Hypothyroidism was more readily seen in those with normal thyroid volume than in those with goiter (P= 0.04). Among Sci- subjects, a larger thyroid volume was associated to a longer time to remission (P&lt;0.05). Methimazole (MMI) was effective only in Sci+ subjects (P&lt;0.05). Conclusions: Administration of PD1 or PD-L1 blocking antibodies may induce two different forms of thyrotoxicosis that appear similar in clinical severity at onset: a type 1 characterized by persistent hyperthyroidism that requires treatment with MMI, and a type 2 characterized by destructive and transient thyrotoxicosis that evolves to hypo- or eu-thyroidism. Thyroid scintigraphy and ultrasound help differentiating and managing these two forms of iatrogenic thyrotoxicosis
The Potential Impact of the COVID-19 Pandemic on Clinical Management of Thyroid Disorders in Japan
Authors: Inoue Kosuke , Noh Jaeduk Yoshimura , Yoshihara Ai , Watanabe Natsuko , Watanabe Masako , Fukushita Miho , Suzuki Nami , Hoshiyama Ayako , Mitsumatsu Takako , Suzuki Ai , Kinoshita Aya , Mikura Kentaro , Yoshimura Ran , Sugino Kiminori , Ito Koichi 
Published: May 2021

Abstract
Background: The indirect influence of the coronavirus disease 2019 (COVID-19) pandemic on clinical practice has received great attention. However, the evidence about how the pandemic has affected clinical management of hypothyroidism and hyperthyroidism, two common diseases worldwide, is lacking. We therefore aimed to examine the trends in the number of outpatients with thyroid disorders and their thyrotropin (TSH) levels before and during the pandemic in Japan. Methods: This cohort study included all patients aged ≥20 years who visited Ito Hospital, one of the largest hospitals that specialize in thyroid disorders in Japan, during 2019/1-2020/6. Our outcomes of interest were 1) trends in the aggregated number of visits at the clinic and 2) trends in average TSH levels from January 2019 to June 2020. The trends in TSH according to the clinic visit in early 2020 were assessed utilizing difference-in-difference models controlling for age, sex, and city of residence, stratified by each medication use (i.e., levothyroxine [LT4], antithyroid drug [ATD], potassium iodine [KI], or no medication). Results: During 2019/1-2020/6, we observed 517,412 visits at Ito Hospital for thyroid disorders, and the average number of visits per month was significantly decreased for both the first visits (1,995 in 2019 vs. 1,268 in 2020; reduction rate, 36%; p&lt;0.001) and the follow-up visits (29,509 in 2019 vs. 21,959 in 2020; reduction rate, 26%; p&lt;0.001). Among 15,455 patients who had been followed in 2019, we found a higher TSH at the follow-up visits during 2020/4-2020/6 among patients with LT4 who did not visit the clinic during 2020/1-2020/3 than those who did (difference-in-difference [95%CI]=+1.77 [1.25-2.29], p&lt;0.001). We also found decreased trends in TSH among patients with ATD or KI who visited the clinic during 2020/1-2020/3 (p&lt;0.001 for both categories), but not among patients with no medications (p=0.29). Conclusions: In this large cohort in Japan, we found the decreased number of outpatients with thyroid disorders since 2020/1 with a nadir in 2020/4. Using individual-level data, we also found the association between visiting the clinic in early 2020 and TSH control at the following visit among patients with medications. These findings highlight the importance of careful monitoring of patients with medications for thyroid disorders during the COVID-19 pandemic.
Thyroid Function Before, During and After COVID-19
Authors: Eu Khoo Bernard Chong , Tan Tricia , Mills Edouard , Clarke Sophie A , Patel Bijal , Modi Manish , Phylactou Maria , Eng Pei Chia , Thurston Layla , Alexander Emma C , Meeran Karim , Comninos Alexander N , Abbara Ali , Dhillo Waljit Singh 
Published: May 2021

Abstract
Context: The effects of COVID-19 on the thyroid axis remain uncertain. Recent evidence has been conflicting, with both thyrotoxicosis and suppression of thyroid function reported. Objective: We aimed to detail the acute effects of COVID-19 on thyroid function and determine if these effects persisted upon recovery from COVID-19. Design: Cohort observational study. Participants and Setting: Adult patients admitted to Imperial College Healthcare National Health Service Trust, London, UK with suspected COVID-19 between March 9 to April 22, 2020 were included, excluding those with pre-existing thyroid disease and those missing either free thyroxine (FT4) or TSH measurements. Of 456 patients, 334 had COVID-19 and 122 did not. Main Outcome Measures: TSH and FT4 measurements at admission, and where available, those taken in 2019 and at COVID-19 follow-up. Results: Most patients (86·6%) presenting with COVID-19 were euthyroid, with none presenting with overt thyrotoxicosis. Patients with COVID-19 had a lower admission TSH and FT4 compared to those without COVID-19. In the COVID-19 patients with matching baseline thyroid function tests from 2019 (n=185 for TSH and 104 for FT4), both TSH and FT4 were reduced at admission compared to baseline. In a complete cases analysis of COVID-19 patients with TSH measurements at follow-up, admission and baseline (n=55), TSH was seen to recover to baseline at follow-up. Conclusions: Most patients with COVID-19 present with euthyroidism. We observed mild reductions in TSH and FT4 in keeping with a non-thyroidal illness syndrome. Furthermore, in survivors of COVID-19, thyroid function tests at follow-up returned to baseline.