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MCT8 transports thyroid hormone (TH) across the plasma membrane. Mutations in MCT8 result in the Allan-Herndon-Dudley syndrome (AHDS), comprising severe psychomotor retardation and elevated serum T3 levels. As the neurological symptoms are most likely caused by a lack of TH transport into the CNS, the administration of a TH analogue which does not require MCT8 for cellular uptake may represent a therapeutic strategy. Here, we investigated the therapeutic potential of the biologically active T3 metabolite Triac (TA3) by studying TA3 transport, metabolism and action both in vitro and in vivo. Incubation of SH-SY5Y neuroblastoma cells and MO3.13 oligodendrocytes with labeled substrates showed a time-dependent uptake of T3 and TA3. In intact SH-SY5Y cells, both T3 and TA3 were degraded by endogenous type 3 deiodinase, and they influenced gene expression to a similar extent. Fibroblasts from MCT8 patients showed an impaired T3 uptake compared to controls, whereas TA3 uptake was similar in patient and control fibroblasts. In transfected cells, TA3 did not show significant transport by MCT8. Most importantly, treatment of athyroid Pax8 knockout mice and Mct8/Oatp1c1 double knockout mice between postnatal day 1 and 12 with TA3 restored T3-dependent neural differentiation in the cerebral and cerebellar cortex indicating that TA3 can replace T3 in promoting brain development. In conclusion, we demonstrated uptake of TA3 in neuronal cells and in fibroblasts of MCT8 patients, and similar gene responses to T3 and TA3. This indicates that TA3 bypasses MCT8 and may be used to improve the neural status of MCT8 patients.

Background and objective: The reported incidence of persistent hypoparathyroidism varies widely, and consensus on a definition is lacking. The objective was to evaluate the real-life incidence of persistent hypoparathyroidism by investigating a new pragmatic definition. Methods: This retrospective multicenter cohort study evaluated the effect of different definitions for persistent hypoparathyroidism on the incidence of hypoparathyroidism. In addition, risk factors for hypoparathyroidism were analyzed. Results: In total, 749 patients were included. Using the new pragmatic definition, we report an incidence of 7.9% of persistent hypoparathyroidism. When applying other commonly used definitions, incidence varied between 11.8% and 22.1%. Risk factors were parathyroid autotransplantation, presence of another surgical complication, and low postoperative serum calcium. Conclusions: Our data show that the incidence of persistent hypoparathyroidism in the literature may vary through the use of different definitions. This study indicates that a new pragmatic definition of persistent hypoparathyroidism has the potential to enable unbiased comparison between studies.

IntroductionImmunoglobulins (Igs) play a pivotal role in host defense and prevention of pneumonia. Aging influences serum Ig levels, but the association between Igs and pneumonia in community-dwelling older individuals remains unknown. We evaluated the association of serum IgA, IgG, and IgM with pneumonia and lung function in middle-aged and older individuals.MethodsWe performed Cox and negative binomial regression analyses for the association of Igs with incident pneumonia and pneumonia-related mortality, and recurrent pneumonia respectively. We performed logistic regression analyses for the association between Igs and lung function values. Associations were adjusted for age, sex, smoking, comorbidities, and serum C-reactive protein.ResultsWe included 8,766 participants (median age 62.2 years, 57% women, median follow-up 9.8 years). Higher IgA (hazard ratio [HR]: 1.15; 95% confidence interval [95% CI]: 1.00-1.32) and IgG (HR: 1.13; 95% CI: 1.06-1.19) were associated with an increased pneumonia risk. Higher IgG was associated with an increased risk of pneumonia-related mortality (HR: 1.08; 95% CI: 1.01-1.16) and recurrent pneumonia (incidence rate ratio: 1.04; 95% CI: 1.00-1.09). Higher IgA and IgG were also associated with lower forced expiratory volume in one second (FEV1), lower forced vital capacity (FVC), and an increased odds of preserved ratio impaired spirometry (PRISm, i.e. FEV1 <80% and FEV1/FVC ratio ≥70%). No association was seen with an obstructive spirometry pattern.DiscussionHigher serum IgA and IgG levels were associated with pneumonia, pneumonia-related mortality, and PRISm in middle-aged and older individuals from the general population. Future studies should validate our findings and elucidate underlying pathophysiology.

Objective To perform a qualitative evaluation of the Thyroid Network, with a quantitative analysis of second opinion referrals for patients in the southwestern part of the Netherlands who have thyroid nodules and cancer. Methods This prospective observational study registered all patients with thyroid nodules and cancer who were referred to the academic hospital from 2 years before and 4 years after the foundation of the Thyroid Network. We implemented biweekly regional multidisciplinary tumor boards using video conference and a regional patient care pathway for patients with thyroid nodules and cancer. For qualitative evaluation, interviews were conducted with a broad selection of stakeholders via maximum variation sampling. The primary outcome was the change in second opinions after the foundation of the Thyroid Network. Results Second opinions from Thyroid Network hospitals to the academic hospital decreased from 10 (30%) to 2 (7%) two years after the start of the Thyroid Network ( P = .001), while patient referrals remained stable (n = 108 to 106). Qualitative evaluation indicated that the uniform care pathway and the regional multidisciplinary tumor board were valued high. Discussion Establishing a regional network, including multidisciplinary tumor boards and a care pathway for patients with thyroid nodules and cancer, resulted in a decrease in second opinions of in-network hospitals and high satisfaction of participating specialists. Implications for Practice The concept of the Thyroid Network could spread to other regions as well as to other specialties in health care. Future steps would be to assess the effect of regional collaboration on quality of care and patient satisfaction.