Proteostatic reactivation of the developmental transcription factor TBX3 drives BRAF/MAPK-mediated tumorigenesis.

MAPK pathway-driven tumorigenesis, often induced by BRAFV600E, relies on epithelial dedifferentiation. However, how lineage differentiation events are reprogrammed remains unexplored. Here, we demonstrate that proteostatic reactivation of developmental factor, TBX3, accounts for BRAF/MAPK-mediated dedifferentiation and tumorigenesis. During embryonic development, BRAF/MAPK upregulates USP15 to stabilize TBX3, which orchestrates organogenesis by restraining differentiation. The USP15-TBX3 axis is reactivated during tumorigenesis, and Usp15 knockout prohibits BRAFV600E-driven tumor development in a Tbx3-dependent manner. Deleting Tbx3 or Usp15 leads to tumor redifferentiation, which parallels their overdifferentiation tendency during development, exemplified by disrupted thyroid folliculogenesis and elevated differentiation factors such as Tpo, Nis, Tg. The clinical relevance is highlighted in that both USP15 and TBX3 highly correlates with BRAFV600E signature and poor tumor prognosis. Thus, USP15 stabilized TBX3 represents a critical proteostatic mechanism downstream of BRAF/MAPK-directed developmental homeostasis and pathological transformation, supporting that tumorigenesis largely relies on epithelial dedifferentiation achieved via embryonic regulatory program reinitiation.

Evaluating the progression to abnormal thyrotropin in euthyroid preconception women: a population-based study.

BACKGROUND: Abnormal preconception thyrotropin levels were associated with fecundability and adverse fetomaternal outcomes, however, little is known regarding the natural change of serum thyrotropin in euthyroid preconception women. Thus, we performed a population-based study to evaluate the progression to abnormal thyrotropin in euthyroid preconception women. METHODS: This retrospective cohort study used data from the National Free Prepregnancy Checkups Project (NFPCP) collected between 2010 and 2020. Female Han Chinese participants aged 20-49 years who had two repeated NFPCP participations with a time interval of 1.5-3.0 years, confirmed non-pregnant status within this duration, and normal thyrotropin levels during their first participation were included for the analysis of thyrotropin abnormalities during the second NFPCP examination. Data were analyzed between June 1 and October 1, 2023. RESULTS: This study included 186,095 euthyroid women of reproductive age (mean ± SD, 26.72 ± 4.70 years) whose preconception thyrotropin levels were between 0.37 and 4.87 mIU/L. The median follow-up time was 2.13 (IQR, 1.85-2.54) years. A total of 8,497 (4.57%) women developed abnormal thyrotropin, including 4,118 (2.21%) subnormal thyrotropin and 4,379 (2.35%) supranormal thyrotropin. Compared with the reference group (thyrotropin 1.01-2.00 mIU/L), the lower baseline thyrotropin group had greater risk of developing subnormal thyrotropin, and the higher baseline thyrotropin group had greater risk of developing supranormal thyrotropin. Moreover, the restricted cubic spline analysis revealed a U-shaped dose-response association of baseline thyrotropin levels or thyrotropin multiples of the median (MOM) levels against risk of subnormal thyrotropin in the follow-up, and a J-shaped dose-response association against risk of supranormal thyrotropin levels in the follow-up. We further found that baseline thyrotropin outside of 1.43-1.93 mIU/L or baseline thyrotropin MOM outside 0.59-1.36 would hava a higher risk of developing of abnormal thyrotropin. CONCLUSIONS: Both low and high baseline thyrotropin were associated with a significantly increased risk of developing abnormal thyrotropin outcomes. The optimal preconception baseline thyrotropin levels may be between 1.43 mIU/L and 1.93 mIU/L or baseline thyrotropin MoM between 0.59 and 1.36 to minimize progression toward abnormal thyrotropin after 1.5-3.0 years. These findings may help with counseling of preconception thyroid function monitoring.

Evaluating the effect of recombinant human growth hormone treatment on sleep-related breathing disorders in toddlers with Prader-Willi syndrome: a one-year retrospective cohort study.

BACKGROUND: Recombinant human growth hormone (rhGH) therapy is beneficial for children with Prader-Willi syndrome (PWS) in improving short stature and metabolism, but the effect of early rhGH treatment on respiratory and sleep parameters for PWS children under three years old remains elusive. Thus, this study aimed to investigate the impact of rhGH treatment on sleep-related breathing disorders (SRBDs) for toddlers with PWS. METHODS: A total of 17 age-matched PWS patients receiving rhGH treatment (rhGH group) and 17 control individuals not receiving rhGH treatment (non-rhGH group) were recruited for this study between October 2018 and January 2023. Data related to polysomnography-polygraphy (PSG) and serum levels of insulin-like growth factor (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3) were collected. RESULTS: The mean age in the rhGH group was 20.76 ± 9.22 months, which was comparable to that of the non-rhGH group (25.23 ± 13.81 months). The demographic and anthropometric parameters were similar across the two groups after 52 weeks of treatment. Administration of rhGH to toddlers did not exert adverse effects on the obstructive apnea-hypopnea index (OAHI), central apnea index (CAI), oxygen desaturation index (ODI), mean percutaneous oxygen saturation (SpO2), lowest SpO2, duration when SpO2 is lower than 90%, or proportion of the patients with SpO2 lower than 90%. Furthermore, the increased IGF-1 z-score and IGFBP-3 level did not worsen SRBDs. CONCLUSION: Treatment with rhGH for 52 weeks on young toddlers with PWS showed no deleterious effects on SRBDs. This shed more light on the importance of initiating rhGH therapy early in PWS patients.

RNA m6A methylation modulates airway inflammation in allergic asthma via PTX3-dependent macrophage homeostasis.

N6-methyladenosine (m6A), the most prevalent mRNA modification, has an important function in diverse biological processes. However, the involvement of m6A in allergic asthma and macrophage homeostasis remains largely unknown. Here we show that m6A methyltransferases METTL3 is expressed at a low level in monocyte-derived macrophages from childhood allergic asthma patients. Conditional knockout of Mettl3 in myeloid cells enhances Th2 cell response and aggravates allergic airway inflammation by facilitating M2 macrophage activation. Loss and gain functional studies confirm that METTL3 suppresses M2 macrophage activation partly through PI3K/AKT and JAK/STAT6 signaling. Mechanistically, m6A-sequencing shows that loss of METTL3 impairs the m6A-YTHDF3-dependent degradation of PTX3 mRNA, while higher PTX3 expression positively correlates with asthma severity through promoting M2 macrophage activation. Furthermore, the METTL3/YTHDF3-m6A/PTX3 interactions contribute to autophagy maturation in macrophages by modulating STX17 expression. Collectively, this study highlights the function of m6A in regulating macrophage homeostasis and identifies potential targets in controlling allergic asthma.

The nuclear cytokine IL-37a controls lethal cytokine storms primarily via IL-1R8-independent transcriptional upregulation of PPARγ.

Cytokine storms are crucial in the development of various inflammatory diseases, including sepsis and autoimmune disorders. The immunosuppressive cytokine INTERLEUKIN (IL)-37 consists of five isoforms (IL-37a-e). We identified IL-37a as a nuclear cytokine for the first time. Compared to IL-37b, IL-37a demonstrated greater efficacy in protecting against Toll-like receptor-induced cytokine hypersecretion and lethal endotoxic shock. The full-length (FL) form of IL-37a and the N-terminal fragment, which is processed by elastase, could translocate into cell nuclei through a distinctive nuclear localization sequence (NLS)/importin nuclear transport pathway. These forms exerted their regulatory effects independent of the IL-1R8 receptor by transcriptionally upregulating the nuclear receptor peroxisome proliferator-activated receptor (PPARγ). This process involved the recruitment of the H3K4 methyltransferase complex WDR5/MLL4/C/EBPß and H3K4me1/2 to the enhancer/promoter of Pparg. The receptor-independent regulatory pathway of the nuclear IL-37a-PPARγ axis and receptor-dependent signaling by secreted IL-37a maintain homeostasis and are potential therapeutic targets for various inflammatory diseases, including sepsis.

Circadian clock disruption in autoimmune thyroiditis.

Objective: A vicious cycle between circadian disruption and escalating immune responses has been described in diverse inflammatory disease. The current study aimed to explore the role of circadian clock disruption in autoimmune thyroiditis (AIT). Methods: Thirty AIT patients and 30 controls were enrolled and biopsied for thyroid tissues. Alterations of core clock genes expression in AIT thyroid tissues, and its association with serum and tissue inflammatory biomarkers were assessed. For animal studies, C57BL/6J mice administered with porcine thyroglobulin or PBS (as control) combined with adjuvants were sacrificed at four time points to investigate the circadian characteristic of experimental autoimmune thyroiditis (EAT). Light shift (LS) conditions were used to explore the influence of external circadian disturbance on EAT. Results: The expression of clock genes BMAL1 and PER2 was significantly reduced in thyroid tissues from AIT patients and was negatively correlated to levels of thyroid peroxidase antibodies. In mouse models, diurnal fluctuations of proinflammatory cytokines were demonstrated, and further exposing mice to LS led to overproduction of TNF-α, IFN-γ, and anti-thyroglobulin antibodies. Circadian analysis revealed significant oscillations of Bmal1, Clock, Per2, Cry1, Ror, and Rev-erb, which was broadly disturbed in EAT, LS, and EAT + LS groups. Conclusions: This study demonstrates that expression pattern of clock genes was disrupted in AIT thyroid, and chronic circadian disruption may aggravate the inflammatory responses in AIT. Whether maintaining a regular circadian rhythm can alleviate autoimmune thyroid diseases warrants further research.

Comparing the performance of machine learning and conventional models for predicting atherosclerotic cardiovascular disease in a general Chinese population.

BACKGROUND: Accurately predicting the risk of atherosclerotic cardiovascular disease (ASCVD) is crucial for implementing individualized prevention strategies and improving patient outcomes. Our objective is to develop machine learning (ML)-based models for predicting ASCVD risk in a prospective Chinese population and compare their performance with conventional regression models. METHODS: A hybrid dataset consisting of 551 features was used, including 98 demographic, behavioral, and psychological features, 444 Electrocardiograph (ECG) features, and 9 Echocardiography (Echo) features. Seven machine learning (ML)-based models were trained, validated, and tested after selecting the 30 most informative features. We compared the discrimination, calibration, net benefit, and net reclassification improvement (NRI) of the ML models with those of conventional ASCVD risk calculators, such as the Pooled Cohort Equations (PCE) and Prediction for ASCVD Risk in China (China-PAR). RESULTS: The study included 9,609 participants (mean age 53.4 ± 10.4 years, 53.7% female), and during a median follow-up of 4.7 years, 431 (4.5%) participants developed ASCVD. In the testing set, the final ML-based ANN model outperformed PCE, China-PAR, recalibrated PCE, and recalibrated China-PAR in predicting ASCVD. This was demonstrated by the model's higher area under the curve (AUC) of 0.800, compared to 0.777, 0.780, 0.779, and 0.779 for the other models, respectively. Additionally, the model had a lower Hosmer-Lemeshow χ2 of 9.1, compared to 37.3, 67.6, 126.6, and 18.6 for the other models. The net benefit at a threshold of 5% was also higher for the ML-based ANN model at 0.017, compared to 0.016, 0.013, 0.017, and 0.016 for the other models, respectively. Furthermore, the NRI was 0.089 for the ML-based ANN model, while it was 0.355, 0.098, and 0.088 for PCE, China-PAR, and recalibrated PCE, respectively. CONCLUSIONS: Compared to conventional regression ASCVD risk calculators, such as PCE and China-PAR, the ANN prediction model may help optimize identification of individuals at heightened cardiovascular risk by flexibly incorporating a wider range of potential predictors. The findings may help guide clinical decision-making and ultimately contribute to ASCVD prevention and management.

Multidimensional Analysis of Lung Lymph Nodes in a Mouse Model of Allergic Lung Inflammation following PM2.5 and Indeno[1,2,3-cd]pyrene Exposure.

BACKGROUND: Ambient particulate matter with an aerodynamic diameter of ≤2.5 µm (PM2.5) is suggested to act as an adjuvant for allergen-mediated sensitization and recent evidence suggests the importance of T follicular helper (Tfh) cells in allergic diseases. However, the impact of PM2.5 exposure and its absorbed polycyclic aromatic hydrocarbon (PAHs) on Tfh cells and humoral immunity remains unknown. OBJECTIVES: We aimed to explore the impact of environmental PM2.5 and indeno[1,2,3-cd]pyrene (IP), a prominent PAH, as a model, on Tfh cells and the subsequent pulmonary allergic responses. METHODS: PM2.5- or IP-mediated remodeling of cellular composition in lung lymph nodes (LNs) was determined by mass cytometry in a house dust mite (HDM)-induced mouse allergic lung inflammation model. The differentiation and function of Tfh cells in vitro were analyzed by flow cytometry, quantitative reverse transcription polymerase chain reaction, enzyme-linked immunosorbent assay, chromatin immunoprecipitation, immunoprecipitation, and western blot analyses. RESULTS: Mice exposed to PM2.5 during the HDM sensitization period demonstrated immune cell population shifts in lung LNs as compared with those sensitized with HDM alone, with a greater number of differentiated Tfh2 cells, enhanced allergen-induced immunoglobulin E (IgE) response and pulmonary inflammation. Similarly enhanced phenotypes were also found in mice exposed to IP and sensitized with HDM. Further, IP administration was found to induce interleukin-21 (Il21) and Il4 expression and enhance Tfh2 cell differentiation in vitro, a finding which was abrogated in aryl hydrocarbon receptor (AhR)-deficient CD4+ T cells. Moreover, we showed that IP exposure increased the interaction of AhR and cellular musculoaponeurotic fibrosarcoma (c-Maf) and its occupancy on the Il21 and Il4 promoters in differentiated Tfh2 cells. DISCUSSION: These findings suggest that the PM2.5 (IP)-AhR-c-Maf axis in Tfh2 cells was important in allergen sensitization and lung inflammation, thus adding a new dimension in the understanding of Tfh2 cell differentiation and function and providing a basis for establishing the environment-disease causal relationship. https://doi.org/10.1289/EHP11580.

circS100A11 enhances M2a macrophage activation and lung inflammation in children with asthma.

BACKGROUND: Dysregulation of circRNAs is associated with a variety of human diseases; however, its role in childhood asthma is undefined. METHODS: The differential expression profiles of circRNAs were analyzed by microarray. The effects and mechanisms by which circRNAs influence macrophage activation were detected by quantitative real-time PCR, RNA immunoprecipitation assay, and chromatin immunoprecipitation assay, among others. The roles of circRNA and its host gene in asthma were tested in a cockroach allergen extract (CRE)-induced murine asthma model. RESULTS: We identified 372 circRNAs that were differentially expressed in PBMCs of children with asthma as compared with healthy controls. A circRNA with unknown function, circS100A11, was dominantly expressed in monocytes and significantly upregulated in children with asthma. circS100A11 facilitated M2a macrophage activation by enhancing translation of its host gene, S100A11, and exacerbated lung inflammation in a CRE-induced murine asthma model with macrophage-specific overexpression of circS100A11. Mechanistically, circS100A11 promoted S100A11 translation by competitively binding to CAPRIN1 to decrease the suppression of CAPRIN1 upon S100A11 translation. Then, S100A11 liberated SP3 from nucleolin and promoted SP3 binding to the STAT6 promoter to enhance STAT6 expression and M2a macrophage activation. Macrophage-specific knockdown of S100A11 could alleviate lung inflammation in a CRE-induced murine asthma model in vivo. CONCLUSIONS: circS100A11 and S100A11 promote M2a macrophage activation and lung inflammation in asthma model and may serve as potential therapeutic and diagnostic targets in children with asthma.

Association of Preconception Thyrotropin Levels With Fecundability and Risk of Spontaneous Abortion in China.

Importance: Abundant evidence suggests thyroid dysfunction is associated with adverse pregnancy outcomes. However, associations of preconception thyrotropin levels outside of reference range with reproductive health outcomes are not well characterized. Objective: To evaluate the associations of preconception thyrotropin levels with time to pregnancy (TTP) and risk of spontaneous abortion (SA). Design, Setting, and Participants: This population-based cohort study used data from the Chinese National Free Prepregnancy Checkups Project. Female participants aged 20 to 49 years who were trying to conceive were enrolled between January 1, 2013, and December 31, 2016, for the analysis of TTP or SA. Data were analyzed between August 1, 2020, and July 5, 2021. Exposures: Levels of thyrotropin within 1 year prior to pregnancy. Main Outcomes and Measures: The main outcomes were TTP, assessed using hazard ratios (HRs), and SA, assessed using odds ratios (ORs), according to preconception thyrotropin levels. Thyrotropin dose-response associations were assessed using restricted cubic spline regression. Results: Among 11 194 002 female participants (mean [SD] age, 27.56 [5.10] years) in the TTP cohort, 4 739 421 (42.34%) participants became pregnant within 1 year. Both low and high preconception thyrotropin levels were associated with delayed TTP compared with thyrotropin levels of 0.37 to 2.49 mIU/L (thyrotropin <0.10 mIU/L: HR, 0.90; 95% CI, 0.89-0.92; thyrotropin 4.88-9.99 mIU/L: HR, 0.86; 95% CI, 0.86-0.87; thyrotropin ≥10.00 mIU/L: HR, 0.78; 95% CI, 0.77-0.79). In the SA analysis cohort including 4 678 679 pregnancies, 108 064 SA events (2.31%) were documented. High thyrotropin groups showed an increased risk of SA compared with the group with thyrotropin levels of 0.37 to 2.49 mIU/L (thyrotropin 4.88-9.99 mIU/L: OR, 1.33; 95% CI, 1.28-1.38; thyrotropin ≥10.00 mIU/L: OR, 1.25; 95% CI, 1.14-1.36). Preconception thyrotropin levels showed an inverted J-shaped dose-response association with TTP (χ2 = 311.29; nonlinear P < .001) and a J-shaped dose-response association with SA (χ2 = 58.29; nonlinear P < .001). Conclusions and Relevance: In this cohort study, preconception thyrotropin levels outside of reference range were associated with increased risk of reduced fecundity and SA. These findings may provide insights for the implementation of preconception thyroid function screening and the design of future levothyroxine supplementation trials.

Thyroid Feedback Quantile-Based Index Is Associated With Blood Pressure and Other Hemodynamic Measures: A Cross-sectional Study.

OBJECTIVE: Previous studies have reported inconsistent relationships between thyroid function and blood pressure (BP) levels. We aimed to explore the associations between thyroid hormone sensitivity and BP parameters. METHODS: This retrospective study included 6272 participants who underwent a health examination at the First Hospital of China Medical University between January 2017 and December 2018. The Thyroid Feedback Quantile-based Index (TFQI), Parametric TFQI, thyroid-stimulating hormone index, and thyrotroph thyroxine resistance index were calculated to reflect thyroid hormone sensitivity. Mean arterial pressure, pulse pressure, and rate-pressure product were used to indirectly represent arterial stiffness. RESULTS: The TFQI was positively associated with systolic BP (ß = 3.22), diastolic BP (ß =2.32), and mean arterial pressure (ß = 2.62) (P < .001, for all). Analyses of the Parametric TFQI, thyroid-stimulating hormone index, and thyrotroph thyroxine resistance index yielded similar results. The TFQI was positively related to pulse pressure and rate-pressure product. With a 1 SD increase in the TFQI, the adjusted odds ratio for hypertension was 1.11 (95% CI 1.04-1.18). When comparing the fourth quartile of the TFQI with the first, the odds ratio for hypertension was 1.27 (95% CI 1.07-1.51, Pfor trend = .006). These relationships remained significant when stratified by age, sex, and body mass index. Similar results were observed in a euthyroid or normotensive population. CONCLUSION: The TFQI was positively associated with BP and markers of arterial stiffness. Impaired thyroid hormone sensitivity was related to increased risk for hypertension.

Exosomal miR-101-3p and miR-423-5p inhibit medulloblastoma tumorigenesis through targeting FOXP4 and EZH2.

Exosomal microRNAs (miRNAs) have been implicated in the development and progression of a variety of tumors; however, whether they contribute to medulloblastoma (MB) tumorigenesis remains to be elucidated. To address this, we first characterized the miRNA profiles of circulating exosomes by miRNA sequencing to identify miRNAs differentially expressed between children with MB and healthy controls. Then, we conducted in vitro and in vivo functional assays with the identified miRNAs and their predicted targets. We found that, compared with healthy controls, 35 miRNAs were upregulated and 5 downregulated in exosomes isolated from the plasma of MB patients. We further found that the expression of miR-101-3p and miR-423-5p was significantly higher in plasma exosomes from MB patients than in healthy controls in an expanded cohort and these exosomal miRNAs could be delivered to tumor cells via exosomes. An in vitro functional analysis of miR-101-3p and miR-423-5p showed that treating MB cells with the corresponding mimics significantly inhibited the proliferation, colony-forming ability, migratory ability, and invasive capacity of tumor cells, and promoted cell apoptosis. Additionally, miR-101-3p and miR-423-5p were found to act as tumor suppressors by directly targeting a common gene, FOXP4, which encodes a transcription factor with a vital role in embryonic development and tumorigenesis. Moreover, miR-101-3p also targeted EZH2, a histone methyltransferase, to reinforce its tumor inhibitory effects. Using a xenograft nude mouse model of MB, we further identified that the overexpression of miR-101-3p and miR-423-5p inhibited tumorigenesis in vivo. Our findings provide novel insights into the functions of exosomal miRNAs in mediating MB progression and suggest a potential therapeutic approach for the treatment of children with MB.

Hsa_circ_0004287 inhibits macrophage-mediated inflammation in an N6-methyladenosine-dependent manner in atopic dermatitis and psoriasis.

BACKGROUND: Circular RNA (circRNA) has been implicated in various diseases; however, its role in atopic dermatitis (AD) or psoriasis remains unclear. OBJECTIVE: We sought to determine the differential expression profiles of circRNAs in peripheral blood mononuclear cells between healthy controls and AD patients, and explore the mechanisms underlying the effects of circRNAs on the pathogenesis of AD. METHODS: The differential expression profiles of circRNAs were analyzed by circRNA microarray. In vitro function and mechanisms by which circRNAs regulate macrophage-mediated inflammation were detected by reverse transcription quantitative PCR, Western blot analysis, RNA stability assay, immunoprecipitation, ELISA, and methylated RNA immunoprecipitation assay. In vivo roles of circRNAs were determined in 2,4-dinitrochlorobenzene (DNCB)-induced dermatitis and imiquimod (IMQ)-induced psoriasis mouse model. RESULTS: We identified a functional unknown circRNA hsa_circ_0004287 from 88750 circRNAs, which was upregulated in peripheral blood mononuclear cells of both AD and psoriasis patients, and was mainly expressed by macrophages under inflammatory conditions. Hsa_circ_0004287 inhibited M1 macrophage activation in vitro, and macrophage-specific overexpression of hsa_circ_0004287 alleviated skin inflammation in both AD- and psoriasis-like mice. Mechanistically, hsa_circ_0004287 reduced the stability of its host gene metastasis associated lung adenocarcinoma transcript 1 (MALAT1) by competitively binding to IGF2BP3 with MALAT1 in an N6-methyladenosine (m6A)-dependent manner. Lower levels of MALAT1 promoted the ubiquitination degradation of S100A8/S100A9, thereby impeding p38/mitogen-activated protein kinase phosphorylation and macrophage-mediated inflammation. CONCLUSION: hsa_circ_0004287 inhibits M1 macrophage activation in an m6A-dependent manner in AD and psoriasis, and may serve as a general therapeutic candidate for AD and psoriasis.

Adolescent suicide attempts in three diverse island nations: patterns, contextual differences and demographic associations.

OBJECTIVE: Most epidemiological studies on suicidal behavior have been focused on high-income country settings. This study examine factors associated with suicidal behaviors among school-attending adolescents in three island nations. In this secondary analysis of the publicly available 2015 nationally representative GSHS data, we tested demographic, social, and behavioral attributes using multivariable logistic regression to association with suicide attempts. RESULTS: Within the recall period, 13.6% of participants reported having attempted suicide one or more times in the Cook Islands, 10.8% in Curaçao, and 9.8% in East Timor. In the Cook Islands, suicide ideation (AOR = 19.42, 95% CI = 9.11-41.41), anxiety (AOR = 2.51, 95% CI = 1.08-5.82), physical bullying (AOR = 3.3, 95% CI = 1.10-9.91), and cigarette smoking (AOR = 3.82, 95% CI = 1.38-10.54) were associated with suicide attempts. For Curaçaoo, suicide ideation (AOR = 7.88, 95% CI = 5.20-11.95) and suicide planning (AOR = 7.01, 95% CI = 4.24-11.60) were statistically significant. While for East Timor, suicide ideation (AOR = 4.59, 95% CI = 2.14-9.88), suicide planning (AOR = 3.36, 95% CI = 1.76-6.29), bullying victimization (AOR = 2.69, 95% CI = 1.02-7.12), and serious injuries (AOR = 2.22, 95% CI = 1.31-3.74) were statistically significant. Suicide attempt is relatively common in each of the three island nations. The socioeconomic context of adolescents might play a significant role in moderating suicidal behavior. Therefore, prevention efforts should be grounded in view of geographic, demographic, and socioeconomic contexts of the populations at risk.

Seasonal Changes of Thyroid Function Parameters in Women of Reproductive Age Between 2012 and 2018: A Retrospective, Observational, Single-Center Study.

Background: Thyroid function can be influenced by external stimuli such as light and temperature. However, it is currently unknown whether there is seasonal variation of thyroid function in women of reproductive age. Adequate thyroid function in reproductive-aged women is necessary for optimal fetal-maternal outcomes. Therefore, this study aims to evaluate the seasonal changes in levels of thyrotropin (TSH), free triiodothyronine (FT3), free thyroxine (FT4), and TSH index (TSHI) in women of reproductive age. Methods: A large retrospective study was conducted that included women aged 20-49 years who visited our outpatient or checkup center between 2012 and 2018. Thyroid function was measured using the automated immunochemiluminescent assay kit. Subjects with overt thyroid dysfunction, pregnancy, thyroid disease, cancer, and severe infectious or psychological disease were excluded. Seasonal differences of thyroid function were analyzed using the Kruskal-Wallis test or the analysis of means with transformed ranks. Spearman's correlation was performed to evaluate the association between thyroid function parameters and age. A subset of 181 subjects was included in the longitudinal analyses. Differences in thyroid function between summer and winter were analyzed using the Wilcoxon signed-rank test. Results: A total of 48,990 women with a median age of 39 years were included. The prevalence of subclinical hypothyroidism was lower in summer but higher in winter (5.6% vs. 7.0%, p < 0.05). The TSH, FT3, and FT4 levels and TSHI reached a peak in winter, while they declined to trough in summer. The TSH concentrations (r = 0.044, p < 0.001) and TSHI (r = 0.025, p < 0.001) were positively correlated with age, whereas FT3 (r = -0.073, p < 0.001) and FT4 (r = -0.059, p < 0.001) were negatively correlated with age. The associations of thyroid parameters with age were similar between subjects with positive thyroid peroxidase antibody (TPOAb) and those with negative TPOAb. In the matched longitudinal analysis of 181 subjects, no differences were detected in the thyroid parameters between summer and winter. Conclusions: This retrospective single-center study showed that thyroid hormone levels and central sensitivity to thyroid hormones are influenced by age and seasonal fluctuations among women of reproductive age, while their impact on reproductive health remains to be elucidated in future studies.

The signal pathways and treatment of cytokine storm in COVID-19.

The Coronavirus Disease 2019 (COVID-19) pandemic has become a global crisis and is more devastating than any other previous infectious disease. It has affected a significant proportion of the global population both physically and mentally, and destroyed businesses and societies. Current evidence suggested that immunopathology may be responsible for COVID-19 pathogenesis, including lymphopenia, neutrophilia, dysregulation of monocytes and macrophages, reduced or delayed type I interferon (IFN-I) response, antibody-dependent enhancement, and especially, cytokine storm (CS). The CS is characterized by hyperproduction of an array of pro-inflammatory cytokines and is closely associated with poor prognosis. These excessively secreted pro-inflammatory cytokines initiate different inflammatory signaling pathways via their receptors on immune and tissue cells, resulting in complicated medical symptoms including fever, capillary leak syndrome, disseminated intravascular coagulation, acute respiratory distress syndrome, and multiorgan failure, ultimately leading to death in the most severe cases. Therefore, it is clinically important to understand the initiation and signaling pathways of CS to develop more effective treatment strategies for COVID-19. Herein, we discuss the latest developments in the immunopathological characteristics of COVID-19 and focus on CS including the current research status of the different cytokines involved. We also discuss the induction, function, downstream signaling, and existing and potential interventions for targeting these cytokines or related signal pathways. We believe that a comprehensive understanding of CS in COVID-19 will help to develop better strategies to effectively control immunopathology in this disease and other infectious and inflammatory diseases.

Sensitivity to Thyroid Hormones and Risk of Prediabetes: A Cross-Sectional Study.

Context: Thyroid hormone influences glucose homeostasis through central and peripheral regulations. To date, the link between sensitivity to thyroid hormones and prediabetes remains unknown. We aimed to investigate the association between thyroid hormones sensitivity and risk of prediabetes in both general and euthyroid populations. Methods: Participants with serum free triiodothyronine (FT3), free thyroxine (FT4), and thyrotropin (TSH) measurements from the health checkup programs of the First Hospital of China Medical University were collected. We measured the parameters representing central and peripheral sensitivities to thyroid hormones (central sensitivity, assessed by calculating Thyroid Feedback Quantile-based Index (TFQI), TSH Index (TSHI), and Thyrotroph Thyroxine Resistance Index (TT4RI); peripheral sensitivity, evaluated by FT3/FT4 ratio). Associations between thyroid hormones sensitivities and risk of prediabetes were assessed with logistic regression. Results: A total of 4378 participants (mean age ± SD, 49 ± 11 years) were included, with 1457 (33%) subjects had prediabetes. The risk of prediabetes was negatively associated with levels of TSHI (odds ratio [OR] 0.91; 95% confidence interval [CI], 0.85-0.97), TT4RI (OR 0.91; 95% CI, 0.84-0.99) and Parametric TFQI (PTFQI) (OR 0.89; 95% CI, 0.83-0.95) among all subjects. The association remained significant in euthyroid subjects and euthyroid subjects with negative thyroid autoimmunity. Higher FT3/FT4 ratio was associated with a mild increased risk of prediabetes (95% CI 1.09; 1.02-1.16). Compared with subjects in the lowest quartile of PTFQI, those in the highest quartile had lower risk of prediabetes (0.70; 95% CI, 0.58-0.84). Conclusions: Decreased central sensitivity to thyroid hormones is associated with lower risk of prediabetes. This demonstrates the complex interaction between thyroid system and glucose metabolism. Future studies are warranted to confirm our findings and underlying mechanisms.