The Impact of Post-Thyroidectomy Neck Stretching Exercises on Neck Discomfort, Pressure Symptoms, Voice and Quality of Life: A Randomized Controlled Trial.

BACKGROUND: Following surgery for benign nodular goiter, patients may experience neck and shoulder pain, neck pressure and tightness, choking sensation, altered voice function, and dysphagia leading to decreased short-term quality of life (QoL). This single-blinded randomized controlled trial investigated the effect of post-thyroidectomy rehabilitative neck stretching and movement exercises on these variables including QoL. METHODS: Patients undergoing thyroid lobectomy or total thyroidectomy were randomized to perform neck stretching and movement exercises three times daily in four weeks following surgery (intervention group) or conventional follow-up without exercises (control group). Outcome measures were scores in the following questionnaires: Disease-specific Thyroid-Related Patient-Reported Outcome (ThyPRO-39) involving symptoms of "sense of fullness in the neck," "pressure in the throat," and "discomfort swallowing" combined in the multi-item Goiter Symptom Scale, the Voice Handicap-Index-10 (VHI-10), neck and shoulder pain measurement by a numeric rating scale (NRS), and General measure of health (EQ-5D-5L). All scores were assessed prior to surgery and one, two, four weeks, and three months after surgery. Data were analyzed using a linear mixed model. RESULTS: Eighty-nine patients were included and randomized to the control (n = 45) or the intervention group (n = 44). At three months after surgery, both the control and the intervention group experienced large to moderate improvements in the Goiter symptom and Hyperthyroid symptom scale of the ThyPRO questionnaire (p < 0.004). No significant between-group differences were found in any of the other applied scales. CONCLUSIONS: This study confirms that patients experience profound improvements in QoL after surgery for benign nodular goiter. However, early post-thyroidectomy neck stretching and movement exercises did not result in further QoL improvement, reduction in pain or less impacted subjective voice function for patients primarily undergoing thyroid lobectomy. Trial Registration Number NCT04645056 ( https://clinicaltrials.gov ).

Risk-stratification of thyroid nodules examined by 18FDG-PET/CT while ensuring congruity between imaging and histopathological localization.

PURPOSE: The risk of malignancy (ROM) in FDG-avid thyroid incidentalomas varies between studies, which may be contributed by discordance between the anatomical localization depicted on 18FDG-PET/CT and by histopathological examination. The purpose was to ensure anatomical congruity between the index tumour identified by 18FDG-PET/CT and the histopathological examination, in order to assess the risk of malignancy (ROM) in PET-positive and PET-negative thyroid nodules. Further, preoperative characteristics indicative of thyroid malignancy were identified. METHODS: Thirty-two patients referred to thyroid surgery were prospectively included. 18FDG-PET/CT, fine-needle aspiration biopsy and thyroid ultrasonography examination were performed in all participants. The exact anatomical localization of the index nodule was established by histopathological examination to ensure concordance with the 18FDG-PET/CT finding. RESULTS: Forty thyroid nodules were included. Malignancy was identified in 10 of 28 PET-positive nodules and in 1 of 12 PET-negative nodules, resulting in a ROM of 36% and 8%, respectively. A Hurtle cell neoplasm was found in 50% of patients with a benign nodule and a PET-positive scan. One PET-negative nodule represented a papillary microcarcinoma. In PET-positive nodules, hypoechogenicity, irregular margins, and pathological lymph nodes on thyroid ultrasonography were characteristics associated with malignancy. CONCLUSIONS: In this study-ensuring anatomical congruity between PET-findings and the histopathological examination-the risk of malignancy in PET-positive thyroid nodules was 36%. A low ROM was seen in thyroid nodules without suspicious ultrasonographic findings, independent of the 18FDG-PET/CT result. TRIAL REGISTRATION NUMBER: NCT02150772 registered 14th of April 2014.

Changes in Swallowing Symptoms and Esophageal Motility After Thyroid Surgery: A Prospective Cohort Study.

INTRODUCTION: Swallowing difficulties, the pathophysiology behind which is incompletely understood, have been reported in 47-83% of goiter patients referred for thyroidectomy. We aimed at examining the influence of thyroid surgery on swallowing symptoms and esophageal motility. METHODS: Thirty-three patients with benign nodular goiter undergoing thyroid surgery were included. All completed high-resolution esophageal manometry examinations and the goiter symptom scale score, assessed by the thyroid-specific patient-reported outcome measure. The evaluations were performed before and 6 months after surgery. RESULTS: Before surgery, the goiter symptom score was median 39 points (range 2-61), which improved to median five points (range 1-52) after surgery (p < 0.001). The motility parameters were within the limits of normal swallowing physiology, both before and after surgery. Only the upper esophageal sphincter (UES) pressure increased significantly from 70.6 ± 27.7 to 87.7 ± 43.2 mmHg after surgery (p = 0.04). Using regression analyses, there was no significant correlation between change in goiter symptoms and weight of the removed goiter, motility parameters, or motility disturbances. However, patients undergoing total thyroidectomy experienced a larger reduction in pressure in the area of the UES and former thyroid gland after surgery in comparison with patients undergoing less extensive surgery. CONCLUSIONS: Goiter symptoms improved significantly after thyroidectomy, but without correlation to esophageal motility disturbances. This information is essential when interpreting dysphagia in patients with nodular goiter, and when balancing patients' expectations to surgical goiter therapy. REGISTRATION NUMBER: NCT03100357 ( www.clinicaltrials.org ).

Conversion of standard retrospective patient-reported outcomes to momentary versions: cognitive interviewing reveals varying degrees of momentary compatibility.

PURPOSE: The purpose of this study was to adapt different domains of an existing retrospective questionnaire to momentary versions, to use and assess cognitive interviewing for evaluating the new versions, and to compare momentary compatibility (i.e. an item's potential to be validly converted to a momentary version) across different scales. METHODS: Initial momentary versions of retrospective patient-reported outcomes were produced by converting present perfect tense wording to present tense wording. Cognitive interviews were conducted iteratively with 21 patients to determine which reference period they actually employed, and to identify problems with new, revised versions. A think-aloud interview protocol was supplemented with non-specific concurrent and specific retrospective probing. The momentary compatibility of each item was evaluated by calculating the proportion of interviews wherein momentary reference periods were identified; problems were categorized according to cognitive aspects of survey methodology taxonomy. The efficiency of various cognitive interviewing techniques was determined by evaluating whether applied reference periods were identified by think-aloud alone or by supplementary probes. RESULTS: The momentary compatibility varied from 5 to 100% across items. Cognitive interviews revealed potential problems of various severities in the majority of items. Think-aloud alone was sufficient at determining the applied reference period in one-third of the cases, and the efficiency of additional concurrent and retrospective probing was 50 and 94%, respectively. CONCLUSIONS: Cognitive interviewing techniques proved useful for developing and evaluating momentary items. Researchers should be aware of the applied reference period and of emerging problems when evaluating adapted momentary items, since not all concepts are suitable. We recommend the proposed method in future adaptations of existing instruments.

The compensatory enlargement of the remaining thyroid lobe following hemithyroidectomy is small and without impact on symptom relief.

According to previous studies, hemithyroidectomy results in growth of the remaining thyroid lobe by up to 30% in first 12 months after surgery. However, this estimate is based on imprecise methods, high inter- and intra-observer variability, and lack of blinding of the measurements. Furthermore, it is unknown whether enlargement of the remaining hemi-thyroid interferes with the improvement in symptoms after surgery for goiter. We aimed to assess the impact of postoperative thyroid growth on goiter symptom relief following hemithyroidectomy in patients with benign nodular goiter. Outcomes were measured before and 6 months after hemithyroidectomy in 44 patients. Thyroid volumes were determined by two independent and blinded observers using magnetic resonance imaging (MRI). Inter- and intra-observer variability was visualized by Bland-Altman plots. Goiter symptoms were assessed by the Thyroid-Specific Patient-Reported-Outcome Questionnaire (ThyPRO) on a scale from 0 to 100 points. After hemithyroidectomy, the remaining thyroid lobe was 13.7 ± 6.4 mL, and enlarged by a mean of 1.8 mL over 6 months [95% confidence interval (CI) (1.6; 2.1), p < 0.001], corresponding to an increase of 17% [95% CI (12; 22)]. The Goiter Symptom score improved by 27 points [95% CI (21; 34), p < 0.0001] from median 39 points (range 2-86) at baseline, and was unaffected by the compensatory thyroid growth. Six months after hemithyroidectomy, using blinded MRI evaluations, we demonstrated a small but significant postoperative growth of the remaining hemi-thyroid, which did not significantly affect the considerable improvement in goiter symptoms.

Is the reproducibility of shear wave elastography of thyroid nodules high enough for clinical use? A methodological study.

OBJECTIVE: To systematically assess the reproducibility of thyroid ultrasonographic shear wave elastography (SWE). CONTEXT: SWE has been suggested as a potential tool for thyroid nodule evaluation, but assessment of its reproducibility has been insufficiently addressed. DESIGN: SWE examinations were performed prospectively by two investigators. PATIENTS: Seventy-two patients (male/female: 19/53; mean age: 53 ± 14 years; malignant/benign 17/55) undergoing thyroid surgery were enrolled in the study. MEASUREMENTS: Repeated and blinded measurements of elasticity index (EI) in predefined regions of interest (ROI) were collected. The inter- and intrarater agreement, along with the day-to-day agreement, was evaluated in terms of the 95% limits of agreement (LOA). Results are presented as a ratio, by which 1·0 indicates perfect agreement. RESULTS: The interrater, intrarater and day-to-day LOA showed ratios between repeated measurements of 1·7-3·6, 1·8-3·7 and 2·2-2·9, respectively. These values reflect a low to moderate degree of agreement for all EI outcomes. The interrater LOA was higher for malignant nodules compared with benign nodules for six of seven EI outcomes (P < 0·001-0·03). The proportion of agreement calculated from the optimum cutoff point for differentiating malignant from benign nodules was 63-88% for the investigated EI outcomes. CONCLUSIONS: In this methodological study, EI measured by thyroid SWE seems suboptimal for clinical use, due to a low inter- and intrarater agreement. That EI varies from day to day furthermore jeopardizes the validity of the method. Although the proportion of agreement was acceptable for some EI parameters, it is questionable whether EI assessments can reliably differentiate malignant from benign nodules in the individual patient.

Thyroid-specific questions on work ability showed known-groups validity among Danes with thyroid diseases.

PURPOSE: We aimed to identify the best approach to work ability assessment in patients with thyroid disease by evaluating the factor structure, measurement equivalence, known-groups validity, and predictive validity of a broad set of work ability items. METHODS: Based on the literature and interviews with thyroid patients, 24 work ability items were selected from previous questionnaires, revised, or developed anew. Items were tested among 632 patients with thyroid disease (non-toxic goiter, toxic nodular goiter, Graves' disease (with or without orbitopathy), autoimmune hypothyroidism, and other thyroid diseases), 391 of which had participated in a study 5 years previously. Responses to select items were compared to general population data. We used confirmatory factor analyses for categorical data, logistic regression analyses and tests of differential item function, and head-to-head comparisons of relative validity in distinguishing known groups. RESULTS: Although all work ability items loaded on a common factor, the optimal factor solution included five factors: role physical, role emotional, thyroid-specific limitations, work limitations (without disease attribution), and work performance. The scale on thyroid-specific limitations showed the most power in distinguishing clinical groups and time since diagnosis. A global single item proved useful for comparisons with the general population, and a thyroid-specific item predicted labor market exclusion within the next 5 years (OR 5.0, 95 % CI 2.7-9.1). CONCLUSIONS: Items on work limitations with attribution to thyroid disease were most effective in detecting impact on work ability and showed good predictive validity. Generic work ability items remain useful for general population comparisons.

Cross-cultural validity of the thyroid-specific quality-of-life patient-reported outcome measure, ThyPRO.

BACKGROUND AND PURPOSE: Thyroid diseases are common and often affect quality of life (QoL). No cross-culturally validated patient-reported outcome measuring thyroid-related QoL is available. The purpose of the present study was to test the cross-cultural validity of the newly developed thyroid-related patient-reported outcome ThyPRO, using tests for differential item functioning (DIF) according to language version. METHODS: The ThyPRO consists of 85 items summarized in 13 multi-item scales and one single item. Scales cover physical and mental symptoms, well-being and function as well as social and daily function and cosmetic concerns. Translation applied standard forward-backward methodology with subsequent cognitive interviews and reviews. Responses (N = 1,810) to the ThyPRO were collected in seven countries: UK (n = 166), The Netherlands (n = 147), Serbia (n = 150), Italy (n = 110), India (n = 148), Denmark (n = 902) and Sweden (n = 187). Translated versions were compared pairwise to the English version by examining uniform and nonuniform DIF, i.e., whether patients from different countries respond differently to a particular item, although they have identical level of the concept measured by the item. Analyses were controlled for thyroid diagnosis. DIF was investigated by ordinal logistic regression, testing for both statistical significance and magnitude (ΔR (2) > 0.02). Scale level was estimated by the sum score, after purification. RESULTS: For twelve of the 84 tested items, DIF was identified in more than one language. Eight of these were small, but four were indicative of possible low translatability. Twenty-one instances of DIF in single languages were identified, indicating potential problems with the particular translation. However, only seven were of a magnitude which could affect scale scores, most of which could be explained by sample differences not controlled for. CONCLUSION: The ThyPRO has good cross-cultural validity with only minor cross-cultural invariance and is recommended for use in international multicenter studies.

Confirmatory factor analysis of the thyroid-related quality of life questionnaire ThyPRO.

BACKGROUND AND AIM: Thyroid diseases are prevalent and chronic. With treatment, quality of life is restored in most, but not all patients. Construct validity of the thyroid-related quality of life questionnaire, ThyPRO, has been established by multi-trait scaling, but not evaluated with more elaborate methods. The purpose of the present study was to evaluate dimensionality of the ThyPRO scales and to attempt to understand possible item misfit through structural equation modeling for categorical data. METHODS: The current 85-item version of ThyPRO consists of 13 scales, covering domains of physical (4 scales) and mental (2 scales) symptoms, function and well-being (3 scales) and participation/social function (4 scales). The data were collected from a cross-sectional sample of 907 thyroid patients. One-factor confirmatory models were fitted to each scale, and evaluated by model fit statistics (comparative fit index >0.95, root mean square error of approximation <0.08), magnitude of factor loadings, model residual correlations and modification indices (MI). Indications of multi-dimensionality were tested in bi-factor models. Possible item misfit was evaluated in a combined, investigational model. RESULTS: Each ThyPRO scale was adequately represented by a unidimensional model after minor revisions. Eleven items were identified in the unidimensional models as potentially misfitting and were investigated further by multidimensional modeling. CONCLUSION: Elaborate psychometric modeling supported the construct validity of the ThyPRO. However, 11 potentially misfitting items and 18 items with local dependence to other items are candidates for removal in future item reduction processes.

Few items in the thyroid-related quality of life instrument ThyPRO exhibited differential item functioning.

OBJECTIVE: To evaluate the extent of differential item functioning (DIF) within the thyroid-specific quality of life patient-reported outcome measure, ThyPRO, according to sex, age, education and thyroid diagnosis. STUDY DESIGN AND SETTING: A total of 838 patients with benign thyroid diseases completed the ThyPRO questionnaire (84 five-point items, 13 scales). Uniform and nonuniform DIF were investigated using ordinal logistic regression, testing for both statistical significance and magnitude (∆R(2) > 0.02). Scale level was estimated by the sum score, after purification. RESULTS: Twenty instances of DIF in 17 of the 84 items were found. Eight according to diagnosis, where the goiter scale was the one most affected, possibly due to differing perceptions in patients with auto-immune thyroid diseases compared to patients with simple goiter. Eight DIFs according to age were found, of which 5 were in positively worded items, which younger patients were more likely to endorse; one according to gender: women were more likely to report crying, and three according to educational level. The vast majority of DIF had only minor influence on the scale scores (0.1-2.3 points on the 0-100 scales), but two DIF corresponded to a difference of 4.6 and 9.8, respectively. CONCLUSION: Ordinal logistic regression identified DIF in 17 of 84 items. The potential impact of this on the present scales was low, but items displaying DIF could be avoided when developing abbreviated scales, where the potential impact of DIF (due to fewer items) will be larger.

Development and implementation of PROgmatic: A clinical trial management system for pragmatic multi-centre trials, optimised for electronic data capture and patient-reported outcomes.

Background Many clinical trials are conducted as explanatory trials, but the applicability of results from explanatory trials to clinical practice may be questioned. Pragmatic trials elucidate both benefits and harms of an intervention under conditions close to daily clinical practice. We have planned a pragmatic multi-centre trial in patients with Graves' hyperthyroidism. However, trial management is a complicated task in pragmatic trials, due to limited interaction between participants and trial personnel. Purpose The aim of this project was to develop and implement PROgmatic, a fully integrated trial management system for pragmatic multi-centre trials, optimised for electronic data capture and patient-reported outcomes (PROs). Methods Necessary tasks and logistical challenges that should be handled by PROgmatic were identified, and the system was designed and developed to handle these tasks. A combination of generic applications and custom coding was applied to develop an integrated system that met the required needs. PROgmatic features include secure web-based data entry; electronic case report forms (eCRFs); central participant registration and randomisation; automated emails linking to electronic PROs; automated reminders to participants; automated notifications to trial personnel regarding booking of trial visits, safety and compliance alerts; and monitoring of trial progress. PROgmatic underwent rigorous pilot testing, including data verification and validation, before it was released for trial management. Results PROgmatic was successfully implemented in the GRAves' Selenium Supplementation (GRASS) trial (ClinicalTrials.gov: NCT01611896) December 2012. The feedback from trial personnel on usability and utility has been positive, and PROgmatic has handled all intended tasks properly. Limitations Implementation of PROgmatic in future studies requires adaptation of the custom coding. Not all email systems accept emails with active links, and participants who use these systems therefore need to complete paper surveys. Conclusions PROgmatic facilitated the complex task of conducting a pragmatic multi-centre trial. The automated electronic capture of PRO data is time saving and reduces the risk of erroneous data entry. Email notifications to trial personnel combined with serially activated eCRFs that logically lead patient flow through the trial have helped making the pragmatic trial feasible. PROgmatic provides a template for other pragmatic multi-centre trials with patient-reported measures as high-priority outcomes.

Potential Risks and Benefits of Desiccated Thyroid Extract for the Treatment of Hypothyroidism: A Systematic Review.

Background: Desiccated thyroid extract (DTE) is no longer recommended for the treatment of hypothyroidism but is still in use. This review aimed to summarize the available literature on treatment with DTE in adult patients with hypothyroidism. Methods: The search was conducted up until January 6, 2024, in six electronic databases. Two reviewers independently screened all the search results. The retrieved studies compared DTE treatment with levothyroxine or combination therapy with liothyronine and levothyroxine. The primary outcome was quality of life (QoL), and the secondary outcomes included symptoms, treatment preference, adverse effects, thyroid hormone levels, thyroid autoantibodies, cardiovascular measures, and gene polymorphisms in deiodinase enzymes. Results: In the qualitative synthesis, we included nine nonrandomized studies of interventions (NRSIs), two randomized clinical trials (RCTs), and three case reports. The overall quality of evidence was moderate to very low for the various outcomes. The RCTs found no difference between treatments regarding QoL and symptom score assessments. In the NRSIs, symptom and QoL assessments were in favor of DTE. The included studies indicated that DTE may cause an increase in heart rate, lower body weight, and lower high-density lipoprotein compared with other treatment regimens, but results were conflicting. Conclusions: Most studies of DTE treatment are hampered by an inferior design, and data on long-term effects and side effects are lacking. Two RCTs could not demonstrate any difference in QoL or symptom scores when comparing DTE with other thyroid hormone substitutions. Future trials of DTE in patients with hypothyroidism should be based on adequate study designs, validated measures of QoL, patients with reduced QoL, and the assessment of biomarkers reflecting long-term adverse effects.

Hyperthyroidism and the risk of non-thyroid cancer: a Danish register-based long-term follow-up study.

Objective: Cancer is the second most common cause of death worldwide. It is currently debated whether thyroid dysfunction is a modifiable cancer risk factor. Our aim was to evaluate the risk of cancer in patients with hyperthyroidism. Methods: This is a register-based nationwide cohort study of individuals with a diagnosis of hyperthyroidism. Each hyperthyroid case was matched with four reference individuals according to age and sex. Using Fine and Gray competing risk regression models, we studied the association of hyperthyroidism and subsequent all-cause cancer diagnoses, adjusted for preexisting morbidity. Sub-analyses were stratified for cause of hyperthyroidism (Graves' disease and toxic nodular goiter, age when diagnosed with hyperthyroidism, sex, and cancer localization (lung, prostate, breast, and colorectal cancer)). Results: The cohort consisted of 95,469 patients with hyperthyroidism (followed for a median of 10.9 years (range: 5.2-17.2)), and 364,494 reference individuals (followed for a median of 11.2 years (range: 5.4-17.4)). Hyperthyroidism was associated with increased all-cause cancer risk (sub-distribution hazard ratio (SHR): 1.12; 95% CI: 1.10-1.14), as well as an increased risk of breast (SHR: 1.07; 95% CI: 1.02-1.13), lung (SHR: 1.20; 95% CI: 1.16-1.26), and prostate cancer (SHR: 1.10; 95% CI: 1.02-1.19), but not colorectal cancer (SHR: 1.04; 95% CI: 0.99-1.09). Sub-analyses stratified for age when diagnosed with hyperthyroidism and cause of hyperthyroidism yielded similar results. Conclusion: In this register-based study, patients with hyperthyroidism had an increased risk of cancer, in particular lung, prostate, and breast cancer. Whether a causal link exists remains to be proven.

Validation of the Bethesda System for Reporting Thyroid Cytopathology in a Danish tertiary centre.

INTRODUCTION: The Bethesda System for Reporting Thyroid Cytopathology (BSRTC) is used to categorise thyroid fine-needle aspiration (FNA). The aim of this study was to validate the BSRTC in a consecutive cohort and to evaluate the derived management in terms of performing repeat FNA or thyroid surgery. METHODS: Results of thyroid FNAs assessed at the Department of Pathology, Aarhus University Hospital, in the period 2016-2019 were retrieved from The Danish Pathology Registry. FNA category according to the BSRTC along with the histological diagnosis (if available) were linked to the individual patient. RESULTS: In total, 3,669 biopsies were included from 2,873 thyroid nodules in 2,547 patients. Repeat FNA was performed in 23.6% of nodules. The majority of primary FNAs were Benign (BSRTC II; 52.4%). Non-diagnostic (ND) (BSRTC I) was found in 26.3% and BSRTC III-VI were found in 3.6-7.5%. Compared with the first with the last FNA, the frequency of Benign (BSRTC II) increased (61.3%), whereas the frequency of ND (BSRTC I) decreased (14.8%). Surgery was performed in 38.2% (n = 1,097) of nodules. The malignancy rate of 11.5% correlated positively with the BSRTC category, being 2.8% in Benign (BSRTC II) and 95.7% in Malignant (BSRTC VI). CONCLUSIONS: The malignancy rates in the BSRTC categories were in accordance with reports from other countries. Since the BSRTC ensures a standardised and concise communication of cytopathology assessments, application of the BSRTC for thyroid nodule management in a Danish setting is recommended. FUNDING: None. TRIAL REGISTRATION: Not relevant.

Maternal selenium deficiency during pregnancy in association with autism and ADHD traits in children: The Odense Child Cohort.

BACKGROUND: Selenoproteins regulate pathways controlling neurodevelopment, e.g., redox signaling and thyroid hormone metabolism. However, studies investigating maternal selenium in relation to child neurodevelopmental disorders are scarce. METHODS: 719 mother-child pairs from the prospective population-based Odense Child Cohort study in Denmark were included. Three selenium biomarkers, i.e. concentrations of serum selenium, selenoprotein P (SELENOP), and activity of glutathione peroxidase 3 (GPX3), along with serum copper, zinc and iron were measured in early third trimester (at 28.9+/-0.8 weeks of pregnancy). ADHD and ASD traits in children were assessed systematically using the established Child Behaviour Checklist at 5 years of age, based on a Danish reference cohort with cut-off at 90th percentile. Multivariable regression models adjusted for biologically relevant confounders were applied. RESULTS: 155 of 719 (21.6 %) children had ASD traits and 59 of 719 (8.2 %) children had traits of ADHD at 5 years of age. In crude and adjusted models, all three selenium biomarkers associated inversely with ADHD traits. For ADHD, fully adjusted OR for 10 µg/L increment in selenium was 0.76 (95 % CI 0.60, 0.94), for one mg/L increment in SELENOP was 0.73 (0.56, 0.95), and for 10 U/L increment in GPx3 was 0.93 (0.87,1.00). Maternal total selenium was inversely associated with child ASD traits, OR per 10 µg/L increment was 0.85 (0.74, 0,98). SELENOP and GPx3 were not associated with ASD traits. The associations were specific to selenium, as other trace elements such as copper, zinc, or iron were not associated with the outcomes. CONCLUSIONS: The results provide coherent evidence for selenium deficiency as a risk factor for ADHD and ASD traits in an environment with borderline supply, the causality of which should be elucidated in a randomized controlled trial.

Selenium supplementation and placebo are equally effective in improving quality of life in patients with hypothyroidism.

PURPOSE: We investigated whether selenium supplementation improves quality-of-life (QoL) in patients with autoimmune thyroiditis (ID:NCT02013479). METHODS: We included 412 patients ≥18 years with serum thyroid peroxidase antibody (TPOAb) level ≥100 IU/mL in a multicentre double-blinded randomised clinical trial. The patients were allocated 1:1 to daily supplementation with either 200 µg selenium as selenium-enriched yeast or matching placebo tablets for 12 months, as add-on to levothyroxine (LT4) treatment. QoL, assessed by the Thyroid-related Patient-Reported-Outcome questionnaire (ThyPRO-39), was measured at baseline, after six weeks, three, six, 12, and 18 months. RESULTS: In total, 332 patients (81%) completed the intervention period, of whom 82% were women. Although QoL improved during the trial, no difference in any of the ThyPRO-39 scales was found between the selenium group and the placebo group after 12 months of intervention. In addition, employing linear mixed model regression no difference between the two groups was observed in the ThyPRO-39 composite score (28.8 [95%CI:24.5-33.6] and 28.0 [24.5-33.1], respectively; P=0.602). Stratifying the patients according to duration of the disease at inclusion, ThyPRO-39 composite score, TPOAb level, or selenium status at baseline did not significantly change the results. TPOAb levels after 12 months of intervention were lower in the selenium group than in the placebo group (1995 [95%CI:1512-2512] vs. 2344 kIU/L [1862-2951]; P=0.016) but did not influence LT4 dosage or free triiodothyronine/free thyroxin ratio. CONCLUSION: In hypothyroid patients on LT4 therapy due to autoimmune thyroiditis, daily supplementation with 200 µg selenium or placebo for 12 months improved QoL to the same extent.

Evaluation of Surgeon-Performed Ultrasonography With or Without Contrast Enhancement vs Scintigraphy in Patients With Primary Hyperparathyroidism.

Importance: Scintigraphy and ultrasonography are common imaging modalities for the preoperative localization of enlarged parathyroid glands in primary hyperparathyroidism. When comparing the 2 modalities, the benefits of ultrasonography in terms of convenience, patient comfort, duration, cost, and lack of radiation should be taken into account. Objective: To investigate whether surgeon-performed ultrasonography, with or without contrast-enhanced ultrasonography (CEUS), is noninferior to scintigraphy for localizing pathological parathyroid glands in patients with primary hyperparathyroidism. Design, Setting, and Participants: Prospective, paired, noninferiority cohort study performed at a high-volume tertiary referral center for parathyroidectomy with blinded examiners and a 6-month follow-up. Participants were adults (age ≥18 years) referred for parathyroidectomy due to primary hyperparathyroidism. Of 207 eligible patients, 35 were excluded, leaving 172 enrolled in the study. Inclusion lasted from September 2019 until February 2021. Follow-up ended in December 2021. Exposures: 99mTechnetium-pertechnetate/99mtechnetium-sestamibi subtraction scintigraphy with 99mtechnetium-sestamibi single-photon emission computed tomography/computed tomography, followed by surgeon-performed ultrasonography and CEUS. Main Outcomes and Measures: The sensitivity of each imaging modality in localizing pathological parathyroid glands, calculated on a per-quadrant and a per-patient basis, respectively. The a priori noninferiority margin was a lower 95% confidence limit for the difference in sensitivity not falling below -10%. Results: Out of 172 participants, 139 (80.8%) were women, the median (range) age was 65 (24-87) years, and the median (IQR) follow-up was 200.5 (181-280.25) days. Quadrant sensitivity (95% CI) was 70.9% (63.2%-78.5%) for ultrasonography, 68.4% (60.4%-76.5%) for ultrasonography plus CEUS, and 67.0% (60.0%-74.0%) for scintigraphy. The sensitivity difference (95% CI) compared with scintigraphy was 3.9% (-4.1% to 11.8%) for ultrasonography and 1.5% (-6.4% to 9.3%) for ultrasonography plus CEUS, establishing noninferiority for both modalities. Per-patient sensitivity was 81.4% (74.8%-86.9%) for ultrasonography and 79.1% (72.2%-84.9%) for both scintigraphy and ultrasonography plus CEUS. The sensitivity difference compared with scintigraphy was 2.3% (-6.8% to 11.4%) for ultrasonography and 0.0% (-9.1% to 9.1%) for ultrasonography plus CEUS, establishing noninferiority for both modalities. Conclusions and Relevance: In this cohort study, conventional ultrasonography by an experienced parathyroid surgeon-sonographer was noninferior to scintigraphy and may constitute a valid first-line imaging modality in patients with primary hyperparathyroidism, even without the addition of CEUS. Further imaging should be reserved for cases that are equivocal or nonlocalizing on ultrasonography.

Severity of hypothyroidism is inversely associated with impaired quality of life in patients referred to an endocrine clinic.

PURPOSE: We investigated the association between health-related quality of life (HRQL) and the severity of hypothyroidism at diagnosis in patients referred to a secondary hospital clinic. METHODS: Sixty-seven adult patients referred from primary care were enrolled. All patients had newly diagnosed hypothyroidism due to autoimmune thyroiditis and were treated with levothyroxine (LT4). The dose was adjusted according to thyroid function tests aiming at a normal plasma thyrotropin. Patients were stratified according to the severity of hypothyroidism in two different ways: the conventional approach (subclinical or overt hypothyroidism) and a novel approach according to the change (decrease or increase) in plasma level of free triiodothyronine index (FT3I) following LT4 treatment. The ThyPRO-39 questionnaire was used for measurement of HRQL at referral to the Endocrine Outpatient Clinic (higher score corresponds to worse HRQL). RESULTS: Free thyroxine index (FT4I) at diagnosis correlated positively with the scores on the Hypothyroid Symptoms and Tiredness scales (p = 0.018 for both). In accordance, patients with subclinical hypothyroidism (n = 36) scored higher on Hypothyroid Symptoms (p = 0.029) than patients with overt hypothyroidism (n = 31). The difference in HRQL was more pronounced if patients were stratified according to the dynamics in FT3I following LT4 treatment. Thus, patients who showed a decrease in FT3I following treatment (n = 24) scored significantly worse for Anxiety (p = 0.032) and Emotional Susceptibility (p = 0.035) than patients with an increase in FT3I (n = 43). CONCLUSION: Patients referred to an endocrine clinic with mild hypothyroidism had an impaired HRQL, compared to patients with more severe hypothyroidism. The most likely explanation of this finding is a lower threshold for seeking medical consultation and secondary care referral if HRQL is deteriorated. The dynamics in plasma FT3I following treatment may be more sensitive for such a discrimination in HRQL than a stratification according to the thyroid function tests at diagnosis.

Serum selenium, selenoprotein P, and glutathione peroxidase 3 during early and late pregnancy in association with gestational diabetes mellitus: Prospective Odense Child Cohort.

BACKGROUND: Diet is an important modifiable risk factor for gestational diabetes mellitus (GDM) and its related complications; however, the role of essential micronutrients such as selenium (Se), particularly in populations with low Se intake, is inconclusive. OBJECTIVES: The aim was to investigate the association of 3 established biomarkers of Se status with GDM, gestational glucose metabolism, and large for gestational-age offspring. METHODS: This study included 1346 pregnant females with 2294 serum samples from the prospective, population-based Odense Child Cohort study, Denmark. Serum Se, selenoprotein P (SELENOP) concentrations, and glutathione peroxidase 3 (GPX3) activity were measured in early and late pregnancy, and fasting glucose and insulin assessments in late pregnancy. Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) was calculated, and the GDM definition was according to the WHO 2013 threshold of fasting venous plasma glucose of ≥5.1 mmol/L. A subcohort underwent an oral glucose tolerance test. Regression models adjusted for various confounders quantified dose-dependent associations. RESULTS: Se and SELENOP declined during pregnancy. There were dose-dependent inverse associations of early GPX3 with late pregnancy GDM (WHO 2013), fasting glucose, insulin, HOMA-IR, and 2 h glucose. The odds ratio (OR) of GDM was 0.33 (95% CI: 0.16, 0.65) for 1 log-scale-increment in early GPX3 activity. Late pregnancy GPX3 and SELENOP were inversely associated with GDM and HOMA-IR; the OR of GDM was 0.21 (95% CI: 0.12, 0.38) and 0.52 (95% CI: 0.35, 0.77), for 1 log-scale-increment of GPX3 and SELENOP, respectively. A decline in Se biomarkers during pregnancy was associated with a higher risk of GDM and higher HOMA-IR. Low GPX3 activity in late pregnancy was associated with a higher risk of large for gestational-age offspring, partly (∼20%) mediated by fasting glucose concentrations (P = 0.006). CONCLUSIONS: Low serum Se in pregnancy, particularly GPX3 activity, is independently associated with risk of GDM and large for gestational age. Offering Se status assessment in pregnancy identifies females at high risk for GDM who may benefit from Se substitution.