Dissection of a Down syndrome-associated trisomy to separate the gene dosage-dependent and -independent effects of an extra chromosome.

As an aneuploidy, trisomy is associated with mammalian embryonic and postnatal abnormalities. Understanding the underlying mechanisms involved in mutant phenotypes is broadly important and may lead to new strategies to treat clinical manifestations in individuals with trisomies, such as trisomy 21 [Down syndrome (DS)]. Although increased gene dosage effects because of a trisomy may account for the mutant phenotypes, there is also the possibility that phenotypic consequences of a trisomy can arise because of the presence of a freely segregating extra chromosome with its own centromere, i.e. a 'free trisomy' independent of gene dosage effects. Presently, there are no reports of attempts to functionally separate these two types of effects in mammals. To fill this gap, here we describe a strategy that employed two new mouse models of DS, Ts65Dn;Df(17)2Yey/+ and Dp(16)1Yey/Df(16)8Yey. Both models carry triplications of the same 103 human chromosome 21 gene orthologs; however, only Ts65Dn;Df(17)2Yey/+ mice carry a free trisomy. Comparison of these models revealed the gene dosage-independent impacts of an extra chromosome at the phenotypic and molecular levels for the first time. They are reflected by impairments of Ts65Dn;Df(17)2Yey/+ males in T-maze tests when compared with Dp(16)1Yey/Df(16)8Yey males. Results from the transcriptomic analysis suggest the extra chromosome plays a major role in trisomy-associated expression alterations of disomic genes beyond gene dosage effects. This model system can now be used to deepen our mechanistic understanding of this common human aneuploidy and obtain new insights into the effects of free trisomies in other human diseases such as cancers.

Detection and characterization of novel luchacoviruses, genus Alphacoronavirus, in saliva and feces of meso-carnivores in the northeastern United States.

IMPORTANCE: Several coronaviruses (CoVs) have been detected in domesticated, farmed, and wild meso-carnivores, causing a wide range of diseases and infecting diverse species, highlighting their important but understudied role in the epidemiology of these viruses. Assessing the viral diversity hosted in wildlife species is essential to understand their significance in the cross-species transmission of CoVs. Our focus here was on CoV discovery in meso-carnivores in the Northeast United States as a potential "hotspot" area with high density of humans and urban wildlife. This study identifies novel alphacoronaviruses circulating in multiple free-ranging wild and domestic species in this area and explores their potential epidemiological importance based on regions of the Spike gene, which are relevant for virus-host interactions.

Preoperative diagnostic value of coronary CT angiography in acute Stanford type A aortic dissection involving the coronary arteries.

AIM: To assess the diagnostic value of coronary computed tomography angiography (CCTA) in acute type A aortic dissection (ATAAD) with coronary artery involvement and to evaluate whether CCTA could provide potentially useful information for selecting the surgical method. MATERIALS AND METHODS: Patients with ATAAD treated from January 2019 to December 2020 were reviewed retrospectively. Involvement of the coronary arteries based on CCTA findings were grouped into three major types and five subtypes. Interobserver and intraobserver diagnostic agreement for five subtypes were determined. The patients were divided into the coronary artery bypass grafting (CABG) and non-CABG groups, and the proportions of the five subtypes between the two groups were compared. RESULTS: A total of 95 patients were enrolled in this study. Interobserver and intraobserver diagnostic agreement were both substantial in the left and right coronary arteries. Overall, the proportions of the five subtypes of coronary artery involvement were significantly different between the two groups (p<0.001). The proportion of Type A was elevated in the non-CABG group compared with the CABG group (22.6% versus 71.9%); by contrast, the proportions of Type B1 (35.5% versus 14.1%), Type B2 (19.4% versus 10.9%), Type C1 (6.5% versus 0%), and Type C2 (16.1% versus 3.1%) were elevated in the CABG group. CONCLUSION: CCTA is reliable in evaluating coronary artery involvement by ATAAD. The present retrospective study indicated that CABG may be considered if the intimal flap disrupts the coronary orifice and causes luminal stenosis >50%, particularly Type B, or if an intimal tear occurs in the coronary orifice (Type C), which deserve further validation through prospective studies.

The value of T2-weighted MRI contrast ratio combined with DWI in evaluating the pathological grade of solid lung adenocarcinoma.

AIM: To assess the predictive value of T2-weighted (T2W) magnetic resonance imaging (MRI) in combination with diffusion-weighted imaging (DWI) for determining the pathological grading of solid lung adenocarcinoma. MATERIALS AND METHODS: The clinical and imaging data from 153 cases of solid lung adenocarcinoma (82 men, 71 women, mean age 63.2 years) confirmed at histopathology in The First Affiliated Hospital of Xi'an Jiaotong University from January 2017 to May 2022 were analysed retrospectively. Adenocarcinomas were classified into low-grade (G1 and G2) and high-grade (G3) groups following the 2020 pathological grading system proposed by the International Association for the Study of Lung Cancer. The T2-weighted contrast ratio (T2CR), calculated as the T2 signal intensity of the lung mass/nodule divided by the T2 signal intensity of the right rhomboid muscle was utilised. Two experienced radiologists reviewed the MRI images independently, measured the T2CR, and obtained apparent diffusion coefficient (ADC) values. The Mann-Whitney U-test was used to compare general characteristics (sex, age, maximum diameter), T2CR, and ADC values between the low-grade and high-grade groups. The non-parametric Kruskal-Wallis test determined differences in T2CR and ADC values among the five adenocarcinoma subtypes. Receiver characteristic curve (ROC) analysis, along with area under the curve (AUC) calculation, assessed the effectiveness of each parameter in distinguishing the pathological grade of lung adenocarcinoma. A Z-test was used to compare the AUC values. RESULTS: Among the 153 patients with adenocarcinoma, 103 had low-grade adenocarcinoma, and 50 had high-grade adenocarcinoma. The agreement between T2CR and ADC observers was good (0.948 and 0.929, respectively). None of the parameters followed a normal distribution (p<0.05). The ADC value was lower in the high-grade adenocarcinoma group compared to the low-grade adenocarcinoma group (p=0.004), while the T2CR value was higher in the high-grade group (p=0.011). Statistically significant differences were observed in maximum diameter and gender between the two groups (p<0.001 and p=0.005, respectively), while no significant differences were noted in age (p=0.980). Among the five adenocarcinoma subtypes, only the lepidic and micropapillary subtypes displayed statistical differences in ADC values (p=0.047), with the remaining subtypes showing no statistical differences (p>0.05). The AUC values for distinguishing high-grade adenocarcinoma from low-grade adenocarcinoma were 0.645 for ADC and 0.627 for T2CR. Combining T2CR, ADC, sex, and maximum diameter resulted in an AUC of 0.778, sensitivity of 70%, and specificity of 75%. This combination significantly improved diagnostic efficiency compared to T2CR and ADC alone (p=0.008, z = 2.624; p=0.007, z = 2.679). CONCLUSION: The MRI quantitative parameters are useful for distinguishing the pathological grades of solid lung adenocarcinoma, offering valuable insights for precise lung cancer treatment.

Predictive value of spectral computed tomography parameters for EGFR gene mutation in non-small-cell lung cancer.

AIM: To explore the predictive value of morphological signs and quantitative parameters from spectral CT for EGFR gene mutations in intermediate and advanced non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: This retrospective observational study included patients with intermediate or advanced NSCLC at Xinjiang Medical University Affiliated Tumor Hospital between January 2017 and December 2019. The patients were divided into the EGFR gene mutation-positive and -negative groups. RESULTS: Seventy-nine patients aged 60.75 ± 9.66 years old were included: 32 were EGFR mutation-positive, and 47 were negative. There were significant differences in pathological stage (P<0.001), tumor diameter (P=0.019), lobulation sign, intrapulmonary metastasis, mediastinal lymph node metastasis, distant metastasis (P<0.001), bone metastasis (P<0.001), arterial phase normalized iodine concentration (NIC) (P=0.001), venous phase NIC (P=0.001), slope of the energy spectrum curve (λ) (P<0.001), and CT value at 70 keV in arterial phase (P=0.004) and venous phase (P=0.003) between the EGFR mutation-positive and -negative patients. The multivariable logistic regression analysis showed that intrapulmonary metastasis, distant metastasis, venous phase NIC, venous phase λ, and pathological stage were independent factors predicting EGFR gene mutations, with high diagnostic power (AUC = 0.975, 91.5% sensitivity, and 90.6% specificity). CONCLUSION: The pathological stage and the spectral CT parameters of intrapulmonary metastasis, distant metastasis, venous phase NIC, and venous phase λ might pre-operatively predict EGFR gene mutations in intermediate and advanced NSCLC.

Changes in brain susceptibility in Wilson's disease patients: a quantitative susceptibility mapping study.

AIM: To assess changes in the susceptibility of the caudate nucleus (CN), putamen, and globus pallidus (GP) in patients with neurological and hepatic Wilson's disease (WD) by quantitative susceptibility mapping (QSM). MATERIAL AND METHODS: The brain MRI images of 33 patients diagnosed with WD and 20 age-matched controls were analysed retrospectively. All participants underwent brain T1-weighted, T2-weighted, and QSM imaging using a 1.5 T magnetic resonance imaging (MRI) machine. QSM maps were evaluated with the STISuite toolbox. The quantitative susceptibility levels of the CN, putamen, and GP were analysed using region of interest analysis on QSM maps. Differences among neurological WD patients, hepatic patients, and controls were determined. RESULTS: Susceptibility levels were significantly higher for all examined structures (CN, putamen and GP) in patients with neurological WD compared with controls (all p<0.05) and hepatic WD patients (all p<0.05). No statistically significant differences were found in susceptibility levels between patients with hepatic WD and controls (all p>0.05). CONCLUSION: The QSM technique is a valuable tool for detecting changes in brain susceptibility in WD patients, indicating abnormal metal deposition. Notably, the current findings suggest that neurological WD patients exhibit more severe susceptibility changes compared with hepatic WD patients. Therefore, QSM can be utilised as a complementary method to detect brain injury in WD patients.

Long-term prognostic value of CT-based high-risk coronary lesion attributes and radiomic features of pericoronary adipose tissue in diabetic patients.

AIMS: To investigate the long-term prognostic value of coronary computed tomography angiography (CCTA)-derived high-risk attributes and radiomic features of pericoronary adipose tissue (PCAT) in diabetic patients for predicting major adverse cardiac event (MACE). METHODS AND RESULTS: Diabetic patients with intermediate pre-test probability of coronary artery disease were prospectively enrolled and referred for CCTA. Three models (model-1 with clinical parameters; model-2 with clinical factors + CCTA imaging parameters; model-3 with the above parameters and PCAT radiomic features) were developed in the training cohort (835 patients) and tested in the independent validation cohort (557 patients). 1392 patients were included and MACEs occurred in 108 patients (7.8%). Multivariable Cox regression analysis revealed that HbA1c, coronary calcium Agatston score, significant stenosis and high-risk plaque were independent predictors for MACE whereas none of PCAT radiomic features showed predictive value. In the training cohort, model-2 demonstrated higher predictive performance over model-1 (C-index = 0.79 vs. 0.68, p < 0.001) whereas model-3 did not show incremental value over model-2(C-index = 0.79 vs. 0.80, p = 0.408). Similar findings were found in the validation cohort. CONCLUSIONS: The combined model (clinical and CCTA high-risk anatomical features) demonstrated high efficacy in predicting MACE in diabetes. PCAT radiomic features failed to show incremental value for risk stratification.

Acromegaly presented with acne vulgaris: a retrospective study with 123 cases.

BACKGROUND: Acne vulgaris is a prevalent skin condition. We have found that some acromegaly patients have acne. However, no study has examined the relationship between acromegaly and acne. OBJECTIVE: To explore prevalence and correlation of adult acne in patients with acromegaly. METHODS: For this cross-sectional study, we collected questionnaires, clinical information, and laboratory test results of acromegaly patients from January 2022 to December 2022 at Huashan Hospital. Of the 133 questionnaires returned, 123 had valid responses. RESULTS: Of the 123 patients with acromegaly enrolled in this study, 54.5% had adult acne. No statistically significant difference was found in prevalence between male and female patients. 61.2% of adult acne patients reported late-onset acne. Late-onset acne patients first developed acne years before acromegaly diagnosis (mean of 5.6 years for male and 4.5 years for female patients). Some acne patients have received traditional anti-acne treatment. Moreover, 31% of the patients reported no improvement, and only 3.5% of patients claimed complete resolution of acne after treatment. Before acromegaly treatment, the prevalence of adult acne was 51.2%, with mild acne accounting for 73.0%, moderate acne accounting for 23.8%, and severe acne accounting for 3.2%. After acromegaly treatment, the prevalence of adult acne was significantly decreased to 37.4% (P = 0.007). An overall decrease in acne severity was noted, with 93.5%, 6.5%, and 0% having mild, moderate, and severe acne, respectively. A total of 83.6% of the patients had self-assessed acne remission, and 33.3% of the patients reported complete acne resolution. However, 9.0% of patients reported that their condition had worsened after acromegaly treatment. After treatment, GH, IGF-1, IGF-1 index, insulin levels, and HOMA-IR decreased significantly in all patients with acromegaly (P < 0.05). Acne remission correlated positively with IGF-1 levels, but not with GH levels. The relationship between acromegaly and acne remains to be elucidated. CONCLUSIONS: Our findings provide preliminary evidence of the high prevalence of adult acne in acromegaly patients, and a high rate of late-onset acne as well. Traditional anti-acne treatments are less effective. Acne could be considerably relieved by treating acromegaly. Acne remission positively correlated with IGF-1 decline as well, which revealed the correlation between acne and IGF-1.

Remnant cholesterol is associated with hip BMD and low bone mass in young and middle-aged men: a cross-sectional study.

PURPOSE: Remnant cholesterol (RC) is a contributor to cardiovascular diseases, obesity, diabetes, and metabolic syndrome. However, the specific relationship between RC and bone metabolism remains unexplored. Therefore, we aimed to investigate the relationships of RC with hip bone mineral density (BMD) and the risk of low bone mass. METHODS: Physical examination data was collected from men aged < 60 years as part of the Kailuan Study between 2014 and 2018. The characteristics of the participants were compared between RC quartile groups. A generalized linear regression model was used to evaluate the relationship between RC and hip BMD and a logistic regression model was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for low bone mass. Additional analyses were performed after stratification by body mass index (BMI) (≥ or < 24 kg/m2). Sensitivity analyses were performed by excluding individuals who were taking lipid-lowering therapy or had cancer, cardiovascular diseases, or diabetes. RESULTS: Data from a total of 7,053 participants were included in the analysis. After adjustment for confounding factors, RC negatively correlated with hip BMD (ß = - 0.0079, 95% CI: - 0.0133, - 0.0025). The risk of low bone mass increased from the lowest to the highest RC quartile, with ORs of 1 (reference), 1.09 (95% CI: (0.82, 1.44), 1.35 (95%CI: 1.02, 1.77), and 1.43 (95% CI: 1.09, 1.89) for Q1, Q2, Q3, and Q4, respectively (P for trend = 0.004) in the fully adjusted model. Compared to RC < 0.80 mmol/l group, the risk of low bone mass increased 39% in RC ≥ 0.80 mmol/l group (P < 0.001). The correlation between RC and hip BMD was stronger in participants with BMI ≥ 24 kg/m2 group (ß = - 0.0159, 95% CI: - 0.0289, - 0.0029). The results of sensitivity analyses were consistent with the main results. CONCLUSION: We have identified a negative correlation between serum RC and hip BMD, and a higher RC concentration was found to be associated with a greater risk of low bone mass in young and middle-aged men.

[Analysis of a family with 11ß-hydroxylase deficiency due to a mutation in the CYP11B1 gene].

This study reports a family of patients with 11ß-hydroxylase deficiency (11ß-OHD) caused by a novel mutation in the CYP11B1 gene, and analyzes its clinical and genetic characteristics. The clinical data of a patient with intractable hypertension at Air Force Medical Center on May 16, 2014 were retrospectively analyzed. The patient was clinically diagnosed with congenital adrenal cortical hyperplasia. The clinical data of the patient were further collected and the peripheral blood samples of the patient, his parents and his sister were collected for CYP11B1(NM_000497) gene sequencing, suggesting that the patient had compound heterozygous mutations in exon 1:c.199delG, p.Glu67Lysfs*9 and exon 5:c.905_907 delATGinsTT, p.Asp302Valfs*23, both of which were pathogenic variants. The patient's father and sister carried heterozygous mutations in exon 1:c.199delG, p.Glu67Lysfs*9, and the mother carried heterozygous mutations in exon 5:c.905_907delATGinsTT, p.Asp302Valfs*23. This study is the first to report a new compound heterozygous mutation in exon 1:c.199delG and exon 5 c.905_907 delATGinsTT of CYP11B1 gene, enriching the database of 11ß-OHD mutations and providing information to further understand the genetic mechanism of the disease.