bluuebunny/crossref_metadata_2025_split huggingface dataset:
Body Composition, Insulin Resistance and Mediators of Appetite and Energy Homeostasis in Hyperthyroidism
Authors: Patil Avinash , Vaikkakara Suresh , Sachan Alok , Buddharaju P Varma 
Published: May 2021

Abstract
Background: Hyperthyroidism is associated with reduced body weight despite an increase in appetite; due mainly to an increase in energy production. While appetite is regulated by the balance of orexogenic and anorexogenic peripheral signals like Ghrelin and Leptin respectively, energy expenditure is profoundly influenced by thyroxine itself as well as mediators like FGF 21 and Leptin. Hyperthyroidism offers a good model to study the impact of thyroid hormones on the above mediators. Materials & Methods: 35 adult patients with overt hyperthyroidism were evaluated for leptin, ghrelin, adiponectin, FGF21 levels & insulin resistance as well as the body composition by DEXA both at baseline and a minimum of two months following normalization of serum thyroxin on carbimazole treatment. Results: Correction of hyperthyroidism was associated with an increase in body weight including both the lean body (p&lt;0.001) and the fat mass (p&lt;0.001), but with no change in percentage of total body fat (p=0.516). Accompanying the weight gain, there was no change in adiponectin (p=0.98), while a paradoxical decrease in insulin resistance was observed (p&lt;0.001). Correction of hyperthyroidism was also associated with a decrease in FGF21 (p&lt;0.001) and leptin levels (p=0.03) and an increase in ghrelin (p=0.05).
Conclusion: Thyrotoxic state is associated with high leptin & FGF21 levels - both known to be thermogenic. Despite a lower weight and fat mass, thyrotoxicosis is associated with insulin resistance- possibly a direct effect of thyroxine. Ghrelin levels are low in thyrotoxicosis; which together with raised leptin is an unexpected finding, given the increased appetite observed in this condition.
CDC Clinical Standardization Programs (CSP) for Free Thyroxine (FT4) to Improve the Accuracy and Reliability of FT4 Measurements in Patient Care and Clinical Research
Authors: Ribera Ashley , Dabbs-Brown Amonae , Poynter Krista , Sugahara Otoe , Zhang Li , Danilenko Uliana , Vesper Hubert W 
Published: May 2021

Abstract
Reliable FT4 measurement is critical to assess thyroid function and diagnose and treat thyroid disorders. The Partnership for the Accurate Testing of Hormones (PATH) categorizes FT4 as a biomarker in high need for standardization, and currently high inter-assay variability restricts the interpretation of FT4 results in patient care to assay-specific reference intervals. The CDC CSP has partnered with the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) and PATH to create a standardization program for FT4 to improve accuracy, reliability, and comparability of current methods and thus to improve diagnosis, treatment and prevention of thyroidal illnesses. Currently, there are no serum FT4 reference materials available to assess the accuracy and reliability of FT4 assays. CDC has developed an accurate and sensitive reference measurement procedure (RMP) to create commutable serum reference materials with FT4 target values. Assay manufacturers, research and clinical laboratories can use these reference materials to assess their calibration, certify the analytical performance of their measurements, and monitor performance over time by collaborating with CDC CSP. The CDC FT4 RMP uses equilibrium dialysis (ED) with LC-MS/MS based on an internationally recognized ED procedure[1] followed by solid-phase and solvent extractions. Certified primary reference material IRMM468 was used to prepare calibrators. Chromatographic separation is achieved with a gradient of methanol and water with 0.1% formic acid. FT4 is quantified using positive electrospray ionization in positive mode. The intra- and inter-day imprecision of the CDC RMP are 3.0% and 1.1%. A comparison among FT4 RMPs resulted in a +2.5% bias for the CDC RMP to the mean for all labs. The CDC RMP measurement range was 3.02-258 pmol/L and thus suitable for analysis of hypo- and hyperthyroid patients. The CDC FT4 RMP demonstrates good accuracy and precision, and can be used as a viable accuracy base to which routine methods can be compared. An initial comparison study of a commercially available FT4 immunoassay (IA) and the CDC RMP with 24 samples (7.98-109 pmol/L) indicated a mean bias of -37.7%, further indicating a need for standardization. Findings from an IFCC study suggest that alignment of IA measurements to a FT4 RMP can improve comparability and would allow for a uniform reference interval for FT4.[2] CDC CSP established a new standardization program for FT4 to address the needs of the community and assist with improving test comparability and reliability.1. Clin. Chem. Lab. Med. 2011, 49: 1275-81. 2. Clin. Chem. 2017, 63: 1642-52.
Development of High-Throughput Measurement of Free Thyroxine in Serum Using Equilibrium Dialysis in Couple With Liquid Chromatography-Tandem Mass Spectrometry
Authors: Zhang Li , Amonae Dabbs-Brown , Ribera Ashley , Krista Poynter , Sugahara Otoe , Danilenko Uliana , Vesper Hubert W 
Published: May 2021

Abstract
Free thyroxine (FT4) measurements are critical in the diagnosis, classification, and treatment of thyroid diseases. It is estimated that about 18 million FT4 tests are requested in the USA per year annually. In clinical laboratories, most of FT4 assays are performed by using immunoassays (I As). However, the significant bias of IAs and large variation between laboratories have been reported. The reference measurement procedures (RMPs) of FT4based on equilibrium dialysis (ED) - liquid chromatography-tandem mass spectrometry (LC-MS/MS) have been established and recognized by the clinical chemistry community. However, the FT4 RMP is relatively low throughput and labor-intensive. Also, an aliquot of 1 mL sample is required for an RMP. A routine FT4 assay high-throughput procedure that is based on ED LC-MS/MS and utilized less sample volume will allow to conduct large biomonitoring studies and establish FT4 levels in US population. In the described method, FT4 in 150 uL of serum was separated from protein-bound T4 at 37.0 oC in 96-well Micro-ED Teflon devices from HTDialysis. The ED conditions suggested by CLSI C45-A guideline were followed. A volume of 150 uL dialysate samples with FT4 was obtained after the ED step. FT4 in the dialysate was purified by extractions before LC-MS/MS analysis. Chromatographic separation of T4 from the sample matrix is achieved on a C18 UPLC column with a gradient of methanol and water with 0.1% formic acid. Quantification of FT4 was performed by using selective reaction monitoring in positive electrospray ionization mode. The IRMM-468 certified primary reference material (JRC, Belgium) of T4 is used for the calibration curves. FT4 concentrations reached equilibrium after 4 hours under current dialysis conditions, which was also observed in the RMP setting. The developed routine FT4 assay 96-well ED system is within 5% bias from the FT4 RMP based on preliminary method comparison study using human serum. The studies to further characterize the FT4 routine method performance are ongoing. In summary, we are developing an analytical method based on a 96-well ED-LC-MS/MS system for the measurements of FT4 in serum. By comparison with RMP, the described method significantly improve throughput and reduce sample volume, which will fulfill the requirement of FT4 routine assay in clinical laboratories and allow for its use in the large biomonitoring studies and other activities in the research and public health settings.
Development of Intranasal Levothyroxine Powder Delivery for Hypothyroidism
Authors: Imran Syed Ali , Esomchukwu Obinna , Agu Remigius 
Published: May 2021

Abstract
Background: Hypothyroidism affects 3-5% of the general population with oral levothyroxine (LT4) being the predominant replacement therapy. However, significant proportion of hypothyroid patients are unable to absorb oral replacement leading to therapeutic failure and may require injectable thyroxine. Objectives: To develop non-invasive, less costly, and patient-friendly LT4 nasal delivery alternative using mucoadhesive polymers: chitosan and hydroxypropylmethylcellulose (HPMC). Methods: Six nasal LT4 formulations were developed with either chitosan or hydroxypropyl methylcellulose as mucoadhesive. The formulations were prepared through freeze-drying by varying the drug to polymer ratio (1:1, 1:3, and 1:5). The percentage drug yield was calculated by analyzing the weight of the formulation pre- and post-freeze drying. HPLC analysis was conducted to determine the amount of LT4 loaded in each formulation. Furthermore, the surface morphology, particle size, zeta potential, differential scanning calorimetry, X-ray diffraction as well as the in vitro release were assessed to determine the physicochemical properties and release characteristics of the formulations, respectively. Results: Both percentage drug loading and yield were &gt; 70% for all the formulations. The freeze-dried formulations displayed a compact needle-like surface morphology. LT4-chitosan formulations, 1:1, 1:3, and 1:5 had mean particle size of 2.45 ± 0.88 µm, 2.76 ± 1.38 µm, and 1.59 ± 0.27 µm, respectively. Mean particle sizes for 1:1, 1:3, and 1:5 LT4-HPMC formulations were 0.56 ± 0.02 µm, 0.22 ± 0.06 µm, and 0.46 ± 0.04 µm. Zeta potential for LT4-chitosan formulation 1:1, 1:3, and 1:5 were -18.7 ± 1.00 mV, -16.2 ± 0.79 mV, and -19.17 ± 1.01 mV, respectively. LT4-HPMC 1:1, 1:3, and 1:5 formulations had zeta charges of -11.66 ± 3.16 mV, -6.06 ± 3.92 mV, and -9.53 ± 1.68 mV, respectively. Differential calorimetric analysis confirmed drug-polymer integration in all formulations, and X-ray powder diffraction showed both chitosan and HPMC formulations as crystalline configuration. The formulations with the highest in vitro release were LT4-HPMC 1:3 and LT4-chitosan 1:5. Conclusions: Results of this study suggest that both chitosan and HPMC can be used as sustained release polymers for the intranasal delivery of LT4.
Goiter at Diagnosis Might Be Predicting Factor for Early Onset Intractable Graves’ Disease
Authors: Kim Sungeun , Nam Goong Ho , Lee Nayeong , Kim Seulki , Ahn Moon Bae , Kim Shin-Hee , Won-Kyoung Cho , Cho Kyoung Soon , Jung Min-Ho , Suh Byung-Kyu 
Published: May 2021

Abstract
Introduction: The clinical course of Graves’ disease (GD) treated with anti-thyroid drug (ATD) treatment were reviewed with the aim of establishing criteria able to predict intractable GD. Methods: The clinical course of 116 patients with GD who agreed to participate in this study between March 2009 and August 2019 in the pediatric endocrine clinic at Seoul St. Mary’s and St. Vincent’s Hospitals were reviewed. We defined an intractable as hyperthyroidism persistent over 2 years of ATD or relapsed after ATD withdrawal or had been treated ATD for at least 5 years [1-3]. Result: Of 116 patients diagnosed with GD, 37 patients (31.8%) had remission and 79 (68.2%) had intractable GD. Between intractable and remission GD group, there were no significant difference of female percentage, age at diagnosis, thyroid associated ophthalmopathy, serum levels of triiodothyronine (T3), free tetraiodothyronine (T4), Thyroid stimulating hormone (TSH) and positive rate of thyroid autoantibody (Thyroid peroxidase (TPO), Thyroglobulin (Tg), Thyroid stimulating hormone receptor (TSHR)). In intractable GD patients, the frequency of goiter at diagnosis is higher than remission group (89.9% [71/79] and 70.3% [26/37], P-value = 0.014). In correlation analysis, intractable GD showed positive correlation with goiter (R=0.247, P-value = 0.008). In multivariate logistic analyses, goiter is showed strong relationship with intractable GD (odds ratio, 3.793; 95% confidence interval, 1.367-10.524) after adjusting age and sex. Conclusion: Our study supported that goiter at initial presentation might be predicting factor for early onset intractable GD.
Serum TSH Levels Normalisation in Patients Affected by Autoimmune Atrophic Gastritis, After the Switch From Oral L-T4 in Tablet Form to L-T4 in Liquid Formulation
Authors: Fallahi Poupak , Ferrari Silvia Martina , Elia Giusy , Ragusa Francesca , Paparo Sabrina Rosaria , Ruffilli Ilaria , Antonelli Alessandro 
Published: May 2021

Abstract
Patients affected by autoimmune atrophic gastritis could have some issues in L-thyroxine (L-T4) absorption, due to drug malabsorption, induced by the increased gastric pH. Different factors influence L-T4 absorption, such as dietary habits, interference with other drugs, absorption kinetics, age of the patient, adherence to therapy, and others. We enrolled 36 patients affected by autoimmune atrophic gastritis with high serum thyrotropin (TSH) levels under therapy with L-T4 in the tablet formulation. L-T4 tablets were changed to an oral liquid L-T4 preparation, maintaining the same dose. The switch from L-T4 in tablet formulation to the liquid one, at the same L-T4 dosage, led to the normalisation/reduction of circulating TSH levels. Then 14 patients, who were switched back again to receive L-T4 in tablets (with the same dose), had a worsening of TSH values, falling in the hypothyroid range. In conclusion, our findings led to hypothesize that the pH alteration issue caused by autoimmune atrophic gastritis could be overcome by the oral L-T4 liquid formulation administration.
What Matters Most to Patients With Thyroid Dysfunction in Malaysia: A Preliminary Qualitative Analysis
Authors: Ooi Cheow Peng , Yusof Khan Abdul Hanif , Manaf Rosliza Abdul , Adulazeem Hebatullah M , Sukor Norlela , Mustafa Norlaila , Kamaruddin Nor Azmi 
Published: May 2021

Abstract
Background: Relatively little is known on the aspects of research that matter most to patients with thyroid dysfunction (TD). We aimed to explore the patients’ experience when they were diagnosed and treated for TD, as well as what they needed to improve their care: Methods: Qualitative data were obtained online using the Malay language version of the semi-structured qualitative survey in Malaysia, part of the larger research: A CORE OUTCOME SET FOR THYROID DYSFUNCTION. The questionnaires were developed from interactive discussions with patients who have thyroid dysfunction. The responses were analyzed using Braun and Clark’s thematic analysis framework guided by the question: What are the perceptions and experiences of thyroid care that matter most to patients with TD? Results: Responses from 38 participants, in the 18-60 age range, with TD, were analyzed. Most patients across the spectrum of thyroid dysfunctions experienced emotional disturbances. These negative emotions were related to the whole spectrum of disease state, the associated treatments, pre-treatment, post-treatment care, and personal aspects of daily life. Uncertainties in medical outcomes were associated with the personal need for further information. Functional psychosocial impairments and socioeconomic disruptions have a strong ability to arouse the anxiety of outcome uncertainties further. Getting treatment and independence in routine daily activities were prioritized while acknowledging treatments may differ in modality and risk of complications. Physician-patient interactions were valued in alleviating concerns and fear. Four salient themes emerged suggesting emotional security, functional ability, self-care (including psychosocial and socioeconomic well-being), and quality of physician-patient relationships were what matters to these participants. Conclusion: This insight into the problems of patients with TD underlined the need for quality patient-centered thyroid care and may be enhanced, personalized, and improved through outcomes that mattered most to patients in clinical research/trials, routine clinical practice, and the health system.
Association Study of the Thyroid Peroxidase Gene in Autoimmune Thyroid Diseases
Authors: Ban Yoshiyuki , Tozaki Teruaki , Iwai Shinichi 
Published: May 2021

Abstract
Introduction: The etiology of autoimmune thyroid diseases (AITDs), such as Graves’ disease (GD) and Hashimoto’s thyroiditis (HT), is largely unknown. However, genetic susceptibility is believed to play a major role. Recently, a case-control association study performed in Croatia showed a significant association of the single nucleotide polymorphism (SNP) rs11675434 near thyroid peroxidase (TPO) with HT, and also with thyroid autoantibodies against TPO (TPOAb) levels. High TPOAb levels are present in 90% of patients with HT and serve as a clinical marker for the detection of early AITD/HT. Therefore, we conducted a case-control study to determine the genetic association of the rs11675434 near TPO with AITD in a cohort of the Japanese population. Methods: We genotyped the rs11675434 near TPO in 457 Japanese patients with AITD (286 with GD, 171 with HT) and 242 matched Japanese control subjects. The SNP was analyzed using TaqMan probe method, and association study was performed using the χ 2 and Fisher’s exact tests with Yates correction. Results: Both GD and HT showed no significant associations. Moreover, when patients with GD were stratified according to Graves’ ophthalmopathy (GO) (n=96), there were no allelic associations with GO, although there were weak associations between GO and controls (P=0.0494, Odds ratios (ORs)=0.3102). Conclusions: Our finding suggest that the rs11675434 near TPO may not contribute to the risk of AITD in the Japanese population, although the study was in insufficient and underpowered sample size.
At Last the Explanation for Increased Spontaneous Miscarriages in Thyroid Autoantibody Positive Pregnant Women
Authors: Behringer-Massera Stephanie , Morshed Syed A , Davies Terry F 
Published: May 2021

Abstract
In women who are pregnant, the presence of thyroid autoantibodies is associated with an increased rate of miscarriage in the first trimester, with multiple reports averaging ~17% compared with ~8% in autoantibody negative women. During pregnancy immune tolerance is altered to allow implantation of the semi-allogeneic fetus and T-regulatory cells (Tregs), which play a major role in such tolerance, have been shown to increase during pregnancy, reaching a peak in the second trimester. A deficiency in this Treg response has been widely associated with spontaneous miscarriages. While it is known that the number of Tregs in patients with autoimmune thyroid disease (AITD) is decreased there are no data on pregnant women with AITD. In this study, we examined both the number and function of Tregs in pregnant women with (n=26) and without (n=41) thyroid autoantibodies (anti-Tg and/or anti-TPO) as well as healthy non pregnant women (n=25). Tregs were measured by flow cytometry of isolated CD4+, CD25+ and FoxP3+ T-cells. We found that the total number of CD4+CD25+FoxP3+ high Tregs was significantly increased in pregnancy consistent with previous reports (from 11% to 22%, p&lt;0.024). Furthermore, this increase in Tregs was less in pregnant women with thyroid autoantibodies (mean of 12%). In addition, studies of phosphorylated signal transducer and activator of transcription-5a (pStat-5a) as a marker of Treg function, showed that while Tregs were activated in pregnancy, their activity per cell was diminished in the pregnant antibody positive women with a frequency:MFI ratio of 201 compared to 316 in the negative group. These data demonstrate that pregnant women with thyroid antibodies have a reduced Treg response to pregnancy, both in number and function, and offer a likely explanation for the increased miscarriage rate in such patients.
Comparison of Block and Replace Regime and Titration Regime in Graves’ Disease
Authors: Mar Cho 
Published: May 2021

Abstract
In Graves’ disease (GD), medical treatment is still the cornerstone in its management and there were some studies done on comparison of the block and replace regime and titration regime of the antithyroid drugs (ATDs). In Myanmar, titration regime is mostly practiced for management of GD. In daily clinical practice, frequent hospital visits are needed in titration regime and loss of follow-up is an obstacle in patients treated with titration regime. A hospital based randomized clinical trial was conducted and aimed to compare the proportion of attainment of euthyroid status between block and replace regime and titration regime in patients with recently diagnosed GD. A total of 117 patients; 58 patients in block and replace regime and 59 patients in titration regime, who met the inclusion criteria were included. The results showed that euthyroid status was observed in increasing trend during the study period for both regimes but there was no significant difference of achieving euthyroid status between the regimes at the end of 12 months. Regarding side effects of ATDs, skin rash and pruritus were more frequently occurred during the first 3 months of ATDs but no significant difference was noted between the regimes at the end of study. There was also no case of serious side effects such as agranulocytosis and hepatotoxicity up to the end of 12 months. The results of the study pointed out that block and replace regime was comparable to dose titration regime in attaining euthyroid status. As a conclusion, block and replace regime can be applied as an alternative option where titration regime is not feasible. Reference: (1) Abraham et al., 2005; A systematic review of drug therapy for Graves’ hyperthyroidism. Eur J Endocrinol. 153: 489-98. (2) Vaidya et al., 2014; Block & replace regime versus titration regime of antithyroid drugs for the treatment of Graves’ disease: a retrospective observational study. Clinical Endocrinology. 81: 610–613.