Background: Our studies over recent years have focused on some new ideas concerning the pathogenesis for the orbital reaction that characterizes Graves’ ophthalmopathy namely, that there are antigens expressed by thyroid tissue and orbital tissue where they are targeted by autoantibodies and/or sensitized T cells, leading to orbital inflammation. While this has been well studied for the thyroid stimulating hormone-receptor, the possible role of another major thyroid antigen, Thyroglobulin (TG), has been largely ignored. Methods: We identified novel variant 1623 A/G single nucleotide polymorphism (SNP) (rs180195) in the promoter of TG gene associated with autoimmune thyroid disorders. We genotyped the TG SNPs rs2069566, rs2076739, rs121912646, rs121912647, rs121912648, rs121912649, rs121912650, rs137854433, rs137854434, and rs180195 by MassARRAY SNP analysis using iPLEX technology in a cohort of 529 patients with thyroid autoimmunity with and without ophthalmopathy, and controls. Results: We showed that variant 1623 A/G SNP (rs180195) in the promoter of TG gene is a marker for thyroid autoimmunity, but not for ophthalmopathy. We showed that there was a significant difference in the distribution of the major allele (G) vs minor allele (A) in patients with Hashimoto’s thyroiditis (HT). In HT the wild-type (GG) genotype was less common. We showed that the genotypes homozygous AA and heterozygous GA rs180195 SNP in the promoter of TG gene were more closely associated with thyroid autoimmunity than the wild-type (GG) polymorphism, and are thus, markers of autoimmunity. Conclusion: rs180195 SNP was previously identified by Stefan et al independently of us, who showed that this TG SNP predisposed to autoimmune thyroid diseases. However, this is the first study to explore the association between TG SNPs and HT. Our findings support the notion that the thyroid and orbital disorders are not part of the same disease, ie, “Graves’ disease” or “Hashimoto’s disease”, but separate autoimmune disorders.

Novel single-nucleotide polymorphisms in the calsequestrin-1 gene are associated with Graves’ ophthalmopathy and Hashimoto’s thyroiditis Hooshang Lahooti,1,2 Daniele Cultrone,1,2 Senarath Edirimanne,1,2 John P Walsh,3,4 Leigh Delbridge,5,6 Patrick Cregan,1,2 Bernard Champion,1,2 Jack R Wall1,21Thyroid Research Laboratory, Sydney Medical School – Nepean Clinical School, The University of Sydney, 2Nepean Blue Mountains Local Health District, Nepean Hospital, Kingswood, NSW, 3Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, 4School of Medicine and Pharmacology, The University of Western Australia, Crawley, WA, 5Department of Surgery, Royal North Shore Hospital, 6Sydney Medical School – Northern Clinical School, The University of Sydney, St Leonards, NSW, AustraliaBackground: The eye disorder associated with Graves’ disease, called Graves’ ophthalmopathy (GO), greatly reduces the quality of life in affected patients. Expression of the calsequestrin (CASQ1) protein in thyroid tissue may be the trigger for the development of eye muscle damage in patients with GO. We determined the prevalence of rs74123279, rs3747673, and rs2275703 single-nucleotide polymorphism (SNPs) in patients with autoimmune thyroid disorders, GO, Graves’ hyperthyroidism (GH), or Hashimoto’s thyroiditis (HT) and control subjects with no personal or family history of autoimmune thyroid disorders. Furthermore, we measured the concentration of the CASQ1 protein in normal and Graves’ thyroid tissue, correlating levels with parameters of the eye signs, CASQ1 antibody levels, and the CASQ1 gene polymorphism rs74123279 and rs2275703.Methods: High-quality genomic DNA was isolated from fresh blood samples, assayed for identification of rs74123279, rs3747673, and rs2275703 SNPs in CASQ1 gene by MassARRAY SNP analysis using iPLEX technology of SEQUENOM.Results: DNA samples from 300 patients and 106 control subjects (100 males, 306 females) with GO (n=74), GH (n=130), HT (n=96) and control subjects (n=106) were genotyped for the SNPs rs74123279, rs3747673 (n=405), and rs2275703 (n=407). The SNP rs74123279, rs3747673, and rs2275703 were identified as 1) common homozygous or wild type, 2) heterozygote, and 3) rare homozygous. Minor allele frequency for rs74123279, rs3747763, and rs2275703 were 21%, 40%, and 44%, respectively. Multiple comparisons of genotype frequency for rs74123279, rs3747763, and rs2275703 in the GO, GH, HT, and control groups showed P=0.06, 0.641, and 0.189, respectively. These results were substantiated by multiple comparison of alleles frequency for rs74123279, rs3838216, rs3747763, and rs2275703 in the GO, GH, HT, and control groups showed, P=0.36, 0.008, 0.66, and 0.05, respectively. Pairwise analysis of alleles frequency distribution in patients with GO showed significant probability for rs2275703, P=0.008.Conclusion: Based on their evolutionary conservation and their significant prevalence, we suggest that CASQ1 gene SNPs rs74123279, rs3838216, and rs2275703 may be considered as genetic markers for GO.Keywords: thyroid eye disease, autoimmune thyroiditis, ophthalmology, orbitopathy, eye muscles antibodies, wild-type, homozygous, heterozygous, genotyping

When it comes to COVID-19, access to reliable data is vital. It is crucial for the scientific community to use data reported by independent territories worldwide. This study evaluates the reliability of the pandemic data disclosed by 182 countries worldwide. We collected and assessed conformity of COVID-19 daily infections, deaths, tests, and vaccinations with Benford’s law since the beginning of the coronavirus pandemic. It is commonly accepted that the frequency of leading digits of the pandemic data shall conform to Benford’s law. Our analysis of Benfordness elicits that most countries partially distributed reliable data over the past eighteen months. Notably, the UK, Australia, Spain, Israel, and Germany, followed by 22 different nations, provided the most reliable COVID-19 data within the same period. In contrast, twenty-six nations, including Tajikistan, Belarus, Bangladesh, and Myanmar, published less reliable data on the coronavirus spread. In this context, over 31% of countries worldwide seem to have improved reliability. Our measurement of Benfordness moderately correlates with Johns Hopkin’s Global Health Security Index, suggesting that the quality of data may depend on national healthcare policies and systems. We conclude that economically or politically distressed societies have declined in conformity to the law over time. Our results are particularly relevant for policymakers worldwide.

The availability of accurate information has proved fundamental to managing health crises. This research examined pandemic data provided by 198 countries worldwide two years after the outbreak of the deadly Coronavirus in Wuhan, China. We compiled and reevaluated the consistency of daily COVID-19 infections with Benford’s Law. It is commonly accepted that the distribution of the leading digits of pandemic data should conform to Newcomb-Benford’s expected frequencies. Consistency with the law of leading digits might be an indicator of data reliability. Our analysis shows that most countries have disseminated partially reliable data over 24 months. The United States, Israel, and Spain spread the most consistent COVID-19 data with the law. In line with previous findings, Belarus, Iraq, Iran, Russia, Pakistan, and Chile published questionable epidemic data. Against this trend, 45 percent of countries worldwide appeared to demonstrate significant BL conformity. Our measures of Benfordness were moderately correlated with the Johns Hopkins Global Health Security Index, suggesting that the conformity to Benford’s law may also depend on national health care policies and practices. Our findings might be of particular importance to policymakers and researchers around the world.

Background: Ophthalmopathy is a common manifestation of Graves’ disease (GD) occurring in up to 50% of patients. Mild eye signs are also common in patients with Hashimoto’s thyroiditis. Whilst a genetic predisposition to GD has been demonstrated this is not the case for the ophthalmopathy which often runs a separate course. Objective: We determined the prevalences of eye and eyelid signs and positive thyroid and orbital antibody tests in first and second degree relatives from a single family with multiple cases of Graves’ disease, ophthalmopathy and Hashimoto’s thyroiditis. Design: The study cohort comprised 16 subjects from the same family, 4 probands namely, 3 with GD and one with Hashimoto’s thyroiditis and hypothyroidism and 12 of their euthyroid first or second degree relatives. We measured antibodies against calsequestrin (CASQ1) and collagen XIII in an enzyme-linked-immunosorbent assays and TSH-Receptor (TSH-R) antibodies as i) TSH-R binding inhibiting immunoglobulin (TBII) and ii) thyroid stimulating immunoglobulin (TSI). Eye signs were classified and quantified using the clinical activity score (CAS), NOSPECS classes, Nunery types 1 and 2 and the margin-reflex-distance (MRD) as a measure of upper eyelid retraction (UER). Main outcomes: Whilst significant ophthalmopathy was uncommon in the relatives, mild eye signs, in particular UER, were demonstrated in about a third of them. The presence of eye signs was moderately, but not significantly, associated with the detection of CASQ1 and collagen XIII antibodies, but not TSH-R antibodies. Conclusion: Our study demonstrates a significant prevalence of positive orbital antibody tests and ophthalmopathy in probands with thyroid autoimmunity and their euthyroid relatives, favouring a role of genetic factors in the development of ophthalmopathy in patients with thyroid autoimmunity.

The Editor-in-Chief has retracted this paper because the authors did not seek informed consent from participants prior to conducting the telephone interviews. Concerns have also been raised about the accuracy of some of the demographic information reported in this study. The authors do not have access to the original data, and were unable to confirm the accuracy of the information reported. The Editor-in-Chief therefore no longer has confidence in the reliability of the data. Jack R Wall agrees with this retraction. The remaining authors did not respond to correspondence from the publisher about this retraction. The online version of this article contains the full text of the retracted article as Supplementary Information.