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Next-generation sequencing (NGS) is of great benefit to clinical practice in terms of identifying genetic alterations. This study aims to clarify the gene background and its influence on thyroid tumor in Chinese population. NGS data and corresponding clinicopathological features (sex, age, tumor size, extrathyroidal invasion, metastasis, multifocality and TNM stage) were collected and analyzed retrospectively from 2844 individual thyroid tumor samples during July 2021 to August 2022. 2337 (82%) of the cohort possess genetic alterations including BRAF (71%), RAS (4%), RET/PTC (4%), TERT (3%), RET (2.2%) and TP53 (1.4%). Diagnostic sensitivity before surgery can be significantly increased from 0.76 to 0.91 when cytology is supplemented by NGS. Our results show that BRAF positive papillary thyroid cancer (PTC) patients tend to have elder age, smaller tumor size, less vascular invasion, more frequent tumor multifocality and significantly higher cervical lymph node metastatic rate. Mutation at RET gene codon 918 and 634 is strongly correlated with medullary thyroid cancer (MTC), However it did not display more invasive clinical characteristics. TERT positive patients are more likely to have elder age, larger tumor size, more tumor invasiveness, and more advanced TNM stage, indicating poor prognosis. Patients with TERT, RET/PTC1 and CHEK2 mutation are more susceptible to lateral lymph node metastasis. In conclusion. NGS can be a useful tool which provides practical gene evidence in the process of diagnosis and treatment in thyroid tumors.
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Fanconi anemia (FA), dyskeratosis congenita-related telomere biology disorders (DC/TBD), and Diamond–Blackfan anemia (DBA) are inherited bone marrow failure syndromes (IBMFS) with high risks of bone marrow failure, leukemia, and solid tumors. Individuals with FA have reduced fertility. Previously, we showed low levels of anti-Müllerian hormone (AMH), a circulating marker of ovarian reserve, in females with IBMFS. In males, AMH may be a direct marker of Sertoli cell function and an indirect marker of spermatogenesis. In this study, we assessed serum AMH levels in pubertal and postpubertal males with FA, DC/TBD, or DBA and compared this with their unaffected male relatives and unrelated healthy male volunteers. Males with FA had significantly lower levels of AMH (median: 5 ng/mL, range: 1.18–6.75) compared with unaffected male relatives (median: 7.31 ng/mL, range: 3.46–18.82, P = 0.03) or healthy male volunteers (median: 7.66 ng/mL, range: 3.3–14.67, P = 0.008). Males with DC/TBD had lower levels of AMH (median: 3.76 ng/mL, range: 0–8.9) compared with unaffected relatives (median: 5.31 ng/mL, range: 1.2–17.77, P = 0.01) or healthy volunteers (median: 5.995 ng/mL, range: 1.57–14.67, P < 0.001). Males with DBA had similar levels of AMH (median: 3.46 ng/mL, range: 2.32–11.85) as unaffected relatives (median: 4.66 ng/mL, range: 0.09–13.51, P = 0.56) and healthy volunteers (median: 5.81 ng/mL, range: 1.57–14.67, P = 0.10). Our findings suggest a defect in the production of AMH in postpubertal males with FA and DC/TBD, similar to that observed in females. These findings warrant confirmation in larger prospective studies.
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Background
Reproductive hormones may be a risk factor for cardiovascular disease (CVD), but their influence is often underestimated. Obesity can exacerbate the progression of CVD. Arterial stiffness (AS) is correlated with the risk of CVD. Brachial-ankle pulse wave velocity (baPWV) has served as a practical tool for assessing AS with broad clinical applications. This study aimed to investigate the association between reproductive hormones and baPWV in obese male and female subjects.
Methods
A retrospective case–control design was designed. AS was assessed using baPWV, with a baPWV ≥ 1400 cm/s indicating increased AS. Between September 2018 and October 2022, 241 obese subjects with increased AS were recruited from Ningbo Yinzhou No. 2 Hospital. The control group consisted of 241 obese subjects without increased AS. A 1:1 propensity score matching was performed to correct potential confounders by age and sex. We additionally performed a sex-based sub-analysis.
Results
Correlation analysis demonstrated that luteinizing hormone (LH) (r = 0.214, P = 0.001) and follicle-stimulating hormone (FSH) (r = 0.328, P < 0.001) were positively correlated with baPWV in obese male subjects. In the multivariate conditional logistic regression analysis, FSH (OR = 1.407, 95% CI = 1.040–1.902, P = 0.027) rather than LH (OR = 1.210, 95% CI = 0.908–1.612, P = 0.194) was independently and positively associated with increased AS in obese male subjects. However, there was no significant correlation between reproductive hormones and baPWV in women.
Conclusions
Our study identified FSH as a potential risk factor for arteriosclerosis in obese male subjects. This provides a novel and intriguing perspective on the pathogenesis of CVD in obese subjects.
Division of Endocrinology, Mid and South Essex NHS Trust, Broomfield, UK
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Objective
We studied the temporal course of hypothalamic–pituitary–adrenal (HPA) dysfunction in patients with coronavirus disease 2019 (COVID-19).
Methods
Three hundred and two patients (median age 54 years (interquartile range (IQR) 42–64), 76% males) were recruited. The HPA axis was evaluated by morning cortisol and adrenocorticotrophic hormone (ACTH) at admission (n = 232). Adrenal insufficiency (AI) during acute illness was defined using a morning cortisol <83 nmol/L. AI at 12 months follow-up was defined using a peak cortisol <406 nmol/L in the ACTH stimulation test (APST) (n = 90). Those with AI at 12 months were further assessed by APST every 6 months for recovery of hypoadrenalism.
Results
The median morning cortisol and ACTH levels during COVID-19 were 295 (IQR 133–460) nmol/L and 3.9 (0.8–6.9) pmol/L, respectively. AI was present in 33 (14%) patients; ACTH was elevated in three and low or inappropriately normal in the rest 30 patients. At 12 months, AI was seen in 13% (12/90) patients, with all cases being hypothalamic–pituitary in origin; five (42%) of them had not met the diagnostic criteria for AI during COVID-19. AI diagnosed at admission persisted at 12 months in seven patients and recovered in seven; the remaining 19 patients were lost to follow-up. The presence of AI at 12 months was independent of severity and steroid use during COVID-19. A morning cortisol <138 nmol/L during COVID-19 predicted the presence of AI at 12 months. All patients showed recovery of the HPA axis in the ensuing 12 months.
Conclusion
Central AI was common during acute COVID-19 and at 12 months of follow-up. AI can be late onset, developing after recovery from COVID-19, and was transient in nature.
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Glucose-like peptide-1 (GLP-1) is a vital hormone in the intestines that regulates glucose metabolism. Although pancreatic derived factor (PANDER) overexpression is known to suppress GLP-1, the underlying mechanisms are unclear. Our study aims to uncover how PANDER influences GLP-1 synthesis and secretion. We established a PANDER overexpression model in STC-1 intestinal cells, confirming its inhibitory effect on GLP-1 secretion. This effect was reversed in PANDER-knockout cells. Additionally, a negative correlation between PANDER and GLP-1 was observed in patients with gestational diabetes history. Subsequently, through whole transcriptome gene sequencing in PANDER-overexpressed STC-1 cells, we discovered that the activation of IL-6 and its related STAT3 signaling pathway was significantly inhibited, and this finding was validated by WB and QPCR. Finally, rescue experiments confirmed that the IL-6-related STAT3/Akt/GSK3β/β-catenin signaling pathway mediates the negative regulatory effect of PANDER on GLP-1. Taken together, our data identify IL-6 as a bridge connecting PANDER and GLP-1 in the STC-1 cells, demonstrating the potential therapeutic targets for diabetes treatment by targeting PANDER-IL-6-GLP-1 axis.
School of Public Health, Ningxia Medical University, Yinchuan, Ningxia, China
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Key Laboratory of Environmental Factors and Chronic Disease Control, Ningxia Medical University, Yinchuan, Ningxia, China
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Key Laboratory of Environmental Factors and Chronic Disease Control, Ningxia Medical University, Yinchuan, Ningxia, China
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Key Laboratory of Environmental Factors and Chronic Disease Control, Ningxia Medical University, Yinchuan, Ningxia, China
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In the last 40 years, there has been a notable rise in the occurrence of diabetes within China, leading to the country now having the highest number of individuals affected by this condition globally. This prospective observational study examined the effect of different baseline relative leukocyte telomere length (RTL) and the combined effect of baseline RTL and plasma phospholipid fatty acid (PPFA) on the risk of developing diabetes. Adults from Ningxia Province who underwent baseline and follow-up surveys were included in the study. The correlation between the baseline RTL and PPFA was investigated using a multiple linear regression model. The combined effects of baseline RTL and PPFA levels on the risk of developing type 2 diabetes mellitus (T2DM) were investigated using a Cox regression model with time as the covariate. A total of 1461 study subjects were included in this study. According to the diagnostic criteria of the Chinese Diabetes Society, 141 subjects developed T2DM during the follow-up period. The baseline age was negatively correlated with RTL. After adjustment for age, C16:0, C18:1 n-9, C20:4 n-6, C20:3 n-3, and monounsaturated fatty acid (MUFA) concentrations were negatively correlated with RTL. Multiple linear regression analysis showed that C16:0 and MUFA concentrations influenced RTL. Subjects with shorter RTL at baseline had a higher risk of developing diabetes than those with longer RTL. Subjects with shorter RTL and higher C16:0 and MUFA concentrations at baseline had a higher risk of developing T2DM than those with longer RTL and lower C16:0 and MUFA concentrations. Our findings indicated that PPFA affects changes in RTL. In addition, RTL and PPFA are associated with the occurrence of T2DM.
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Department of Gynecology and Obstetrics, Copenhagen University Hospital (Hvidovre Hospital), Hvidovre, Denmark
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Carelink Nærhospital, Roskilde, Denmark
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Institute of Clinical Medicine, Faculty of Health and Clinical Research, Copenhagen University, Copenhagen, Denmark
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Université Libre de Bruxelles (ULB), Brussels, Belgium
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Background
Thyroid autoimmunity (TAI) may be present in 1–17% of pregnant women. Monitoring of thyroid function in euthyroid pregnant women positive for anti-thyroperoxidase antibodies (TPOAb+) is recommended.
Objective
To determine the prevalence and possible clinical and biological risk factors of biochemical progression (rise in serum thyroid-stimulating hormone (TSH) > 2.5 mU/L) at second blood sampling during pregnancy, in euthyroid women (TSH ≤ 2.5 mU/L) according to their TPOAb status.
Methods
This study included demographic and biological data from two previously published cohorts (n = 274 women from August 1996 to May 1997 Copenhagen cohort, and n = 66 women from January 2013 to December 2014 Brussels cohort) having at least two measurements of TSH and free thyroxine (FT4) and at least one of TPOAb during spontaneously achieved singleton pregnancies.
Results
The majority of women studied did not show biochemical progression. Only 4.2% progressed, significantly more frequently among TPOAb+ women, as compared to TPOAb− group (9.4 vs 2.7%, P = 0.015). No rise in serum TSH > 4 mU/L at 2nd sampling was observed. Higher baseline TSH levels were associated with biochemical progression in both TPOAb+ (P = 0.05) and TPOAb− women (P < 0.001), whereas maternal age, BMI, multiparity, smoking, FT4, and TPOAb concentrations were not significantly different between women with and without progression.
Conclusions
Only a minority of euthyroid women with thyroid autoimmunity presented biochemical progression and none with a TSH > 4 mU/L. Larger studies are needed to better target the subset of women who would benefit most from repeated thyroid function monitoring during pregnancy.
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Background: Fatty acid-binding protein 4 (FABP4) is an adipokine that plays significant roles in the development of insulin resistance and atherosclerosis. High levels of soluble tumor necrosis factor receptors (TNFRs) including TNFR1 and TNFR2 are associated with renal dysfunction and increased mortality in patients with diabetes mellitus (DM). However, the association between circulating levels of FABP4 and TNFRs remains unclear.
Methods: We investigated the associations of FABP4 with TNFRs and metabolic markers in Japanese patients with type 1 DM (T1DM, n=76, men/women: 31/45) and type 2 DM (T2DM, n=575, men/women: 312/263).
Results: FABP4 concentration was positively correlated with levels of TNFR1 and TNFR2 in both patients with T1DM and those with T2DM. Multivariable regression analyses showed that there were independent associations of FABP4 concentration with body mass index (BMI) and estimated glomerular filtration rate (eGFR) after adjustment of age and sex in both patients with T1DM and those with T2DM. FABP4 concentration was independently associated with circulating levels of TNFR1 and TNFR2 after adjustment of the confounders in patients with T2DM but not in those with T1DM. Similarly, levels of TNFR1 and TNFR2 were independently associated with FABP4 concentration after adjustment of age, sex, systolic blood pressure, duration of DM and levels of eGFR, high-density lipoprotein cholesterol and C-reactive protein in patients with T2DM but not in those with T1DM.
Conclusion: FABP4 concentration is independently associated with levels of TNFRs in patients with DM, but the association is more evident in patients with T2DM than in those with T1DM.
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Objective: Children with a supratentorial midline low grade glioma (LGG) may be at risk for impaired bone health due to hypothalamic-pituitary dysfunction, obesity, exposure to multiple treatment modalities, and/or decreased mobility. The presence of impaired bone health and/or its severity in this population has been understudied. We aimed to identify the prevalence and risk factors for bone problems in children with supratentorial midline LGG.
Design and Methods: A retrospective study was performed in children with supratentorial midline (suprasellar or thalamic) LGG between 1-1-2003 and 1-1-2022, visiting the Princess Máxima Center for Pediatric Oncology. Impaired bone health was defined as presence of vertebral fractures and/or very low bone mineral density (BMD).
Results: In total, 161 children were included, with a median age at tumor diagnosis of 4.7 years (range 0.1 – 17.9) and a median follow-up of 6.1 years (range 0.1 – 19.9). Five patients (3.1 %) had vertebral fractures. In 99 patients BMD was assessed either by Dual Energy X ray Absorptiometry (n=12) or Bone Health Index (n=95); 34 patients (34.3%) had a low BMD (≤ -2.0). Impaired visual capacity was associated with bone problems in multivariable analysis (OR 6.63, 95% CI 1.83 – 24.00, p = 0.004).
Conclusions: In this retrospective evaluation, decreased BMD was prevalent in 34.3% of children with supratentorial midline LGG. For the risk to develop bone problems visual capacity seems highly relevant. Surveillance of bone health must be an aspect for awareness in the care and follow-up of children with a supratentorial midline LGG.
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Background
Prednisolone and prednisone are recommended treatment options for adults with congenital adrenal hyperplasia (CAH); however, there is no randomised comparison of prednis(ol)one with hydrocortisone.
Design
Six-month open-label randomised phase 3 study and interim analysis of a single-arm extension study was the design of the study.
Methods
The method of the study was hydrocortisone dose equivalent and 09:00-h 17-hydroxyprogesterone (17OHP) from 48 patients taking prednis(ol)one at baseline.
Results
At baseline, the median hydrocortisone dose equivalent was 30 mg/day and 17OHP was < 36 nmol/L (3× upper limit of normal) in 56% of patients. Patients were randomised to continue prednis(ol)one or switch to modified-release hydrocortisone capsule (MRHC) at the same hydrocortisone-equivalent dose. At 4 weeks, 94% on MRHC and 71% on prednis(ol)one had 17OHP < 36 nmol/L. At 18 months in the extension study of MRHC, the median MRHC dose was 20 mg/day and 82% had 17OHP < 36 nmol/L. The per cent of patients with 17OHP < 36 nmol/L on a hydrocortisone dose equivalent ≤ 25 mg/day was greater at 18 months in the extension study on MRHC than while on prednis(ol)one at baseline: 57% vs 27%, P = 0.04. In the randomised study, no patients had an adrenal crisis on MRHC and one on prednisolone. In the extension study (221 patient years), there were 12 adrenal crises in 5 patients (5.4/100 patient years).
Conclusion
MRHC reduces 17OHP at 09:00 h compared to prednis(ol)one and the dose of MRHC can be down-titrated over time in the majority of patients.