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Olaf M Dekkers and Rolf H H Groenwold

The name of the study should properly reflect the actual conduct and analysis of the study. This short paper provides guidance on how to properly name the study design. The first distinction is between a trial (intervention given to patients to study its effect) and an observational study. For observational studies, it should further be decided whether it is cross-sectional or whether follow-up time is taken into account (cohort or case–control study). The distinction prospective-retrospective has two disadvantages: prospective is often seen as marker of higher quality, which is not necessarily true; there is no unifying definition that makes a proper distinction between retrospective and prospective possible.

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Juho Kärkinen, Päivi J Miettinen, Taneli Raivio, and Matti Hero

Objective:

To describe the etiology of severe short stature in the Helsinki University Hospital district covering a population of 1.2 million that is subject to frequent growth monitoring and screening rules during childhood.

Design:

Retrospective cohort study.

Methods:

We identified all subjects born 1990 or later with a height SD score <−3, after the age of 3 years, from the Helsinki University Hospital district growth database. A total of 785 subjects (376 females and 409 males) fulfilled our inclusion criteria; we reviewed their medical records and growth data and report their underlying diagnoses.

Results:

A pathological cause for short stature was diagnosed in 76% of the girls and 71% of the boys (P = NS). Syndromes were the most numerous pathological cause (n = 160; 20%), followed by organ disorders (n = 127; 16%), growth hormone deficiency (GHD, n = 94; 12%), SGA without catch-up growth (n = 73; 9%), and skeletal dysplasias (n = 57; 7%). Idiopathic short stature (ISS) was diagnosed in 210 (27%) subjects. The probability of growth-related pathology, particularly of a syndrome or skeletal dysplasia, increased with the shorter height SD score and the greater deviation from the target height. Sitting height to height SDS was increased in subjects with ISS, GHD, and SGA (all P < 0.01).

Conclusions:

Height <−3 SDS after 3 years of age usually results from a pathological cause and should be thoroughly investigated in specialized health care. The chance of finding a specific etiology increased with the severity of short stature, and the mismatch with target height.

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Athanasia Stoupa, Ghada Al Hage Chehade, Dulanjalee Kariyawasam, Celine Tohier, Christine Bole-Feysot, Patrick Nitschke, Helene Thibault, Marie-Laure Jullie, Michel Polak, and Aurore Carré

Background:

Among patients with congenital hypothyroidism, 35% have dyshormonogenesis (DH) with thyroid gland in situ with or without goiter. The majority of DH cases are due to mutations in genes involved in thyroid hormone production as TG, TPO, SLC5A5/NIS, SLC26A4/PDS, IYD/DEHAL1, DUOX2, and DUOXA2, and are usually inherited on an autosomal recessive basis. Most previously reported cases of fetal hypothyroidism and goiter were related to TG or TPO mutations and recently DUOXA2.

Patient:

In a male patient with antenatal goiter treated with intraamniotic levothyroxine injections, whose long-term follow-up is described in detail, two novel NIS mutations were detected. Mutations of NIS were located in exon 1 (c.52G>A, p.G18R) and exon 13 (c.1546C>T, p.R516X), each mutation was inherited from parents, who are healthy carriers. The p.G18R mutation affecting the first transmembrane domain of the protein can be responsible for deficient iodide uptake. However, the second is a nonsense mutation leading probably to mRNA degradation. In addition, the patient has undergone a thyroidectomy and we have studied the thyroid tissue. The thyroid histology showed heterogeneity with large follicles, epithelial hyperplasia and many areas of fibrosis. Immunohistochemistry with NIS specific antibody showed NIS staining at the basolateral plasma membrane of the thyrocytes.

Conclusions:

We report the first case of fetal goitrous hypothyroidism due to two novel NIS mutations with access to thyroid tissue of the patient, specific histology studies and long-term follow-up. This case expands our knowledge and provides further insights on molecular causes of fetal goiter in humans.

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C Berg, T E Wessendorf, F Mortsch, M Forsting, H Teschler, T Weischer, K Mann, B Saller, and B L Herrmann

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M Deandrea, P Trimboli, A Creanza, F Garino, A Mormile, S Bertolino, R Garberoglio, P P Limone, and M Zingrillo

Background and aim:

Cystic thyroid nodules (CNs), although generally benign, can cause compressive or aesthetic problems. Percutaneous ethanol injection (PEI) can represent an alternative to surgery. The present retrospective study evaluates: (i) the long-term outcome of CNs after PEI; (ii) the differences between two different PEI protocols; (iii) the CNs response according to the liquid component.

Materials and methods:

The study comprises 358 nodules post-PEI followed for at least 2 years. PEI was performed according to two different treatment protocols with a single (Foggia) or double (Turin) alcohol injection. CNs were divided according to their composition: cystic (CYS) >90%, mainly cystic (M-CYS) 75–90%, mixed (MIX) 50–75%, solid-mixed (S-MIX) 35-50%. The volume reduction rate (VRR) was defined as nodule volume (mL) after PEI/nodule volume (mL) before PEI x 100.

Results:

The 1-year VRR was significantly higher than that at 6 months (89.5% vs 72.9%, P = 0.0005), no differences were observed after 1 year. A significant difference between Turin and Foggia was observed only in VRR at early visit (79% vs 86%, respectively, P = 0.002) and recurrence rate (14% vs 24%, respectively, P = 0.001). Minor side-effects were infrequent. In 192 nodules with a 10-year follow-up CYS showed higher VRR than MIX and S-MIX nodules (P < 0.001).

Conclusion:

Our study reported that the long-term outcome of CNs treated with PEI is excellent regardless of the PEI technique utilized; the larger the cystic amount, the higher the VRR. Based on present results, PEI can be considered as the first-line choice for treating thyroid CNs.

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Kristen M Beavers, Katelyn A Greene, and Elaine W Yu

Despite well recognized improvements in obesity-related comorbidities, increasing evidence implicates bariatric surgery in the onset of adverse skeletal health outcomes. The purpose of this review is to provide a focused update in three critical areas: (i) emergent data on sleeve gastrectomy and bone loss, (ii) evidence linking bariatric surgery to incident fracture, and (iii) intervention strategies designed to mitigate surgical bone loss. Better understanding of these issues will inform our treatment of skeletal health for patients planning bariatric surgery.

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C Poitou, H Mosbah, and K Clément

Obesity, defined by an excess of body fat impacting on health, is a complex disease resulting from the interaction between many genetic/epigenetic factors and environmental triggers. For some clinical situations with severe obesity, it has been possible to classify these obesity forms according to the molecular alterations. These include: (i) syndromic obesity, which associates severe early-onset obesity with neurodevelopmental disorders and/or polymalformative syndrome and (ii) non-syndromic monogenic obesity, due to gene variants most often located in the leptin-melanocortin pathway. In addition to severe obesity, patients affected by these diseases display complex somatic conditions, eventually including obesity comorbidities, neuropsychological and psychiatric disorders. These conditions render the clinical management of these patients particularly challenging. Patients’ early diagnosis is critical to allow specialized and multidisciplinary care, with a necessary interaction between the health and social sectors. Up to now, the management of genetic obesity was only based, above all, on controlling the patient's environment, which involves limiting access to food, ensuring a reassuring daily eating environment that limits impulsiveness, and the practice of adapted, supported, and supervised physical activity. Bariatric surgery has also been undertaken in genetic obesity cases with uncertain outcomes. The context is rapidly changing, as new innovative therapies are currently being tested both for syndromic and monogenic forms of obesity. This review focuses on care management and new therapeutic opportunities in genetic obesity, including the use of the melanocortin 4 agonist, setmelanotide. The results from ongoing trials will hopefully pave the way to a future precision medicine approach for genetic obesity.

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John P Bilezikian, Daniel Bikle, Martin Hewison, Marise Lazaretti-Castro, Anna Maria Formenti, Aakriti Gupta, Mahesh V Madhavan, Nandini Nair, Varta Babalyan, Nicholas Hutchings, Nicola Napoli, Domenico Accili, Neil Binkley, Donald W Landry, and Andrea Giustina

The SARS-CoV-2 virus responsible for the COVID-19 pandemic has generated an explosion of interest both in the mechanisms of infection leading to dissemination and expression of this disease, and in potential risk factors that may have a mechanistic basis for disease propagation or control. Vitamin D has emerged as a factor that may be involved in these two areas. The focus of this article is to apply our current understanding of vitamin D as a facilitator of immunocompetence both with regard to innate and adaptive immunity and to consider how this may relate to COVID-19 disease. There are also intriguing potential links to vitamin D as a factor in the cytokine storm that portends some of the most serious consequences of SARS-CoV-2 infection, such as the acute respiratory distress syndrome. Moreover, cardiac and coagulopathic features of COVID-19 disease deserve attention as they may also be related to vitamin D. Finally, we review the current clinical data associating vitamin D with SARS-CoV-2 infection, a putative clinical link that at this time must still be considered hypothetical.

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Hyun-Wook Chae, Ji-Hoon Na, Ho-Seong Kim, and Young-Mock Lee

Objective:

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a very rare condition; it encompasses a diverse group of disorders including diabetes. Phenotypic variability can be attributed to heteroplasmy along with varying proportions of mutant and WT mitochondrial DNA (mtDNA). To examine the clinical relationship between mitochondrial diabetes and mutational load, we analyzed the mtDNA of children and young adolescents with MELAS syndrome using next generation sequencing (NGS).

Design and methods:

Of 57 subjects with suspected MELAS syndrome, 32 children and young adolescents were diagnosed as MELAS syndrome with mtDNA A-to-G transition at nucleotide 3243. Mutation load studies and NGS were performed for 25 subjects.

Results:

The mean mutation load was 60.4 ± 18.4% (range: 22.5‒100). Of the 25 subjects with NGS results, 15 (60%) were diagnosed with DM and 2 (8%) were diagnosed with impaired glucose tolerance (IGT). The mutational load of subjects inversely correlated with first symptom onset, age at diagnosis of MELAS syndrome, and DM (P < 0.001). However, mutational load did not correlate with the clinical severity or progression of DM/IGT. There was no significant difference in insulin resistance or sensitivity indices between the low- and high-mutation load groups. During the 3.7 years of follow-up, insulin resistance indices were not significantly different between baseline and follow-up.

Conclusions:

We can infer that the mutation load in the MELAS syndrome is significantly associated with the onset of symptoms and associated diseases, including mitochondrial diabetes. However, it may not influence disease progression.

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Flavia Magri, Spyridon Chytiris, Laura Croce, Martina Molteni, Giulia Bendotti, Giovanni Gruosso, Samuel Tata Ngnitejeu, Manuela Agozzino, Mario Rotondi, and Luca Chiovato

Objective:

The ultrasonographic scores EU TI-RADS and ACR TI-RADS were introduced to give the clinicians indications for fine needle aspiration cytology (FNAC). The predictive role of these scores was never evaluated and compared in a surgical series of patients. The aim of this study was to evaluate the ex post diagnostic accuracy of EU TI-RADS and ACR TI-RADS in a real-life series of thyroidectomized patients and to evaluate the ‘missing’ thyroid cancer following the operational indications of these scores.

Design:

Retrospective monocentric cohort study.

Methods:

In total, 255 patients (harboring 304 nodules) undergoing thyroidectomy for benign and malignant thyroid conditions were enrolled. The prevalence of thyroid malignancy for each class of ACR TI-RADS and EU TI-RADS, their diagnostic accuracy, the number of ‘unnecessary’ FNAC and the number of ‘missed’ cancers were evaluated.

Results:

ACR TI-RADS and EU TI-RADS score had similar and satisfactory accuracy values for predicting thyroid malignancy (AUC: 0.835 for ACR TI-RADS vs 0.827 for EU TI-RADS). The ACR TI-RADS and EU TI-RADS categories (suspicious vs non-suspicious), age, sex and presence of a single nodule significantly and independently predicted the presence of malignancy in a logistic regression model. An ex post analysis according to the indications for FNAC for each score indicated that 31 and 16 cases of cancer would have been missed by ACR TI-RADS and EU TI-RADS scores, respectively.

Conclusions:

ACR TI-RADS and EU TI-RADS display a good performance in predicting thyroid cancer when histology is taken as reference standard, but additional clinical judgement is required to decide the indication for FNAC.