Background: Congenital hypothyroidism (CH) is the most common neonatal metabolic disorder. In patients with CH in China, thyroid dyshormonogenesis is more common than thyroid dysgenesis; however, the genetic causes of CH due to thyroid dyshormonogenesis remain largely unknown. Therefore, we aimed at identifying novel candidate causative genes for CH. Methods: To identify novel CH candidate genes, a total of 599 patients with CH were enrolled and next-generation sequencing was performed. The functions of the identified variants were confirmed using HEK293T and FTC-133 cell lines in vitro and in a mouse model organism in vivo . Results: Three pathogenic contactin 6 ( CNTN6 ) variants were identified in two patients with CH. Pedigree analysis showed that CH caused by CNTN6 variants was inherited in an autosomal recessive pattern. The CNTN6 gene was highly expressed in the thyroid in humans and mice. Cntn6 knockout mice presented with thyroid dyshormonogenesis and CH due to the decreased expression of crucial genes for thyroid hormone biosynthesis ( Slc5a5 , Tpo , and Duox2 ). All three CNTN6 variants resulted in the blocking of the release of the Notch intracellular domain, which could not translocate into the nucleus, impaired NOTCH1 transcriptional activity, and decreased expression of SLC5A5 , TPO , and DUOX2 . Further, we found that DTX1 was required for CNTN6 to promote thyroid hormone biosynthesis through Notch signaling. Conclusions: This study demonstrated that CNTN6 is a novel causative gene for CH through the mediation of thyroid hormone biosynthesis via Notch signaling, which provides new insights into the genetic background and mechanisms involved in CH and thyroid dyshormonogenesis.

The effectiveness of SARS-CoV-2 vaccines varies among individuals. During the COVID-19 global pandemic, SARS-CoV-2 infection showed significant Th1 characteristics, suggesting that the immune disorder and production of SARS-CoV-2 antibodies may be related to Th1/Th2 bias. However, the molecular mechanisms underlying Th1/Th2 bias effects on host immune responses to viruses remain unclear. In this study, the top three subjects with the highest and lowest changes in anti-SARS-CoV-2 antibodies after receiving three doses of SARS-CoV-2 vaccination were selected and defined as the elevated group (E) and the control group (C), respectively. Peripheral blood was collected, single-cell sequencing was performed before and after the third dose of the SARS-CoV-2 vaccine, and the changes in T cell clusters were analyzed. Compared with the C group, the Treg pre-vaccination proportion was lower in E, while the post-vaccination proportion was higher, suggesting that Tregs may be crucial in this process. Differential analysis results of Tregs between the two groups revealed that differentially expressed genes (DEGs) were significantly enriched in the IL4 pathway. Correlation analysis between DEGs and serum antibody showed that the expression of NR4A2, SOCS1, and SOCS3 in Tregs was significantly correlated with serum antibodies, suggesting that the immune response in E group changed to Th2 bias, thereby promoting host humoral immune responses. On the other hand, antibody-related genes SOCS1 and NR4A2, as well as lnc-RNA MALAT1 and NEAT1, were highly expressed in the CD4-MALAT1 subclusters. In summary, our study revealed that Th2 bias promotes humoral immune responses in humans by increasing SOCS1 in T cells after SARS-CoV-2 vaccination. Moreover, NR4A2, SOCS1, MALAT1, and NEAT1 were identified as the potential key biomarkers or treatment targets for enhanced SARS-CoV-2 antibody production by influencing the Th1/Th2 balance in T cells. Our findings have important implications for population stratification and tailored therapeutics for more effective SARS-CoV-2 vaccines.

Objective: Thermal ablation is an effective treatment for thyroid nodules; however, the range of complications associated with thermal ablation is unclear. In this study, we analyzed the complications of thyroid nodule thermal ablation in our hospital in combination with data from different countries for further analysis to determine the complications.Methods: 536 patients treated by thermal ablation at Shanghai Ninth People’s Hospital from Jan 2021 to Dec 2023 were enrolled in this retrospective study. The types and numbers of complications were recorded. Studies reporting complications of thermal ablation for thyroid nodules were identified in the PubMed database from Jan 2004 to Mar 2024. The incidence rate and types of complications were analyzed. Finally, we compared our data with those studies.Results: Twelve types of complications associated with thermal ablation occurred to patients in our hospital. The overall incidence was 10.82%. The top five complications were pain, edema, voice changes, hematoma, and vascular reactions. In addition, 21 kinds of complications were reported across 13 countries, and the average incidence rate was 12.61%. The top five complications were pain, vocal changes, edema, hematoma, and fever. The total incidence rate did not significantly differ between our hospital and other countries (P ≥ 0.05), though the incidences of specific complications, including tracheal injury, vasovagal reaction, dyspnea, scarring, infection and fever, were significantly different (P < 0.05).Conclusions: The incidence of complications associated with thermal ablation of thyroid nodules is similar across countries. However, the proportions and types of complications vary regionally.