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Background: Inflammatory bowel disease (IBD) is a chronic, inflammatory, and autoimmune disorder, and its incidence of comorbid with major depressive disorder (MDD) is significantly higher than the general population. However, many patients lack proper recognition and necessary psychological health treatments. We aimed to identify potential biomarkers and mechanisms involved in the development of IBD comorbid with MDD (IBD-MDD)., Methods: We utilized IBD and MDD-related datasets from the GEO database for differential gene expression analysis, protein-protein interaction (PPI) and pathway enrichment analysis, random forest algorithm, LASSO regression analysis, and construction of a disease prediction model. We assessed the accuracy of the model using ROC curve, explored potential mechanisms through immune infiltration analysis, and validated candidate biomarkers using peripheral blood samples from patients in our center's cohort., Results: We identified 484 IBD-related secreted proteins and 142 key module genes associated with MDD. PPI analysis revealed two crucial modules primarily involved in inflammation and immune regulation. We identified four diagnostic genes (HGF, SPARC, ADAM12, and MMP8) from the 21 shared genes between IBD-related secreted proteins and MDD key module genes, constructed a nomogram model and confirmed its accuracy using ROC curve from an external independent dataset. Immune infiltration analysis revealed significant associations between the four diagnostic genes, and cellular immune dysregulation in MDD. Finally, we validated the expression patterns of the four diagnostic genes in our cohort., Conclusions: Our study discovered four candidate biomarkers for IBD-MDD, providing new insights for the diagnosis and therapeutic intervention of serum-based IBD comorbid with MDD., (© 2024. The Author(s).)

Background: Lung cancer stands as the second most prevalent malignant neoplasm worldwide. Addressing the underlying mechanisms propelling the progression of non-small cell lung cancer is of paramount importance. In this study, we have elucidated the pivotal role of PHF12 in this context., Materials and Methods: We harnessed clinical lung cancer tissue samples and non-small cell lung cancer cell lines to discern the expression pattern of PHF12. In vitro assays probing cell proliferation were conducted to substantiate the functional impact of PHF12. Furthermore, an in vivo Xenograft model was employed to dissect the role of PHF12. Employing ChIP assays and qRT-PCR, we delved into the intricate binding dynamics between PHF12 and HDAC1. Mechanistic insights into the PHF12-HDAC1 axis in lung cancer progression were pursued via RNA-seq and GSEA analyses., Results: Notably, PHF12 exhibited a substantial upregulation within tumor tissue, concomitant with its correlation to HDAC1. The trilogy of cell proliferation assays, transwell assays, and the Xenograft model collectively underscored the promoting influence of PHF12 on lung cancer proliferation, both in vitro and in vivo. The ChIP assay unveiled the transcriptional regulatory role of PHF12 in governing HDAC1 expression. This correlation extended to both mRNA and protein levels. PHF12 promotes NSCLC progression through regulating HDCA1 expression. Intriguingly, the rescue of function within NSCLC cell lines post PHF12 knockdown was achievable through HDAC1 overexpression. Additionally, our findings unveiled the capacity of the PHF12-HDAC1 axis to activate the EGFR/AKT signaling pathway, thereby further corroborating its significance in lung cancer progression., Conclusion: Our study identified PHF12 as an oncogenic role in lung cancer proliferation and migration for the first time. PHF12 transcriptionally regulate HDAC1 and activate EGFR/AKT signaling pathway in NSCLC progression. PHF12 may serve as an important target in lung cancer therapy., (© 2024. The Author(s).)

Purpose: Assessing the clinical effectiveness of combining with the first dorsal (plantar) metatarsal artery pedicle free bilobed flap with a cell scaffold to repair mid-distal defects in adjacent fingers., Methods: From September 2012 to April 2022, 21 patients with 42 mid-distal defects of adjacent fingers underwent treatment using combined with the first dorsal (plantar) metatarsal artery pedicle free bilobed flap with a cell scaffold. The flaps size ranged from 2.1 cm * 1.6 to 4.9 cm * 3.2 cm. Follow-up evaluations included assessing function, sensation, and appearance, etc. of the injured fingers and donor areas., Results: All 42 flaps survived in 21 patients without any vascular crises, and the wounds healed in phase I. The mean follow-up time was 12.2 months (range 7-22 months). During follow-up, in injured fingers, according to the Michigan Hand Outcomes Questionnaire (MHOQ), the functional recovery and appearance were satisfactory; in Dargan Function Evaluation (DFE), the results were both "excellent" in fourteen patients, "excellent" and "good" in five patients, both "good" in one patient, "good" and "general" in one. In static two-point discrimination (2PD), the variation ranges from 4 to 9 mm in injured fingers and 6-10 mm in donor toes. Cold Intolerance Severity Score (CISS) is mild in all patients. The visual analogue score (VAS) showed no pain in the injured fingers and donor toes. No deformities or other complications were noted at the donor toes. According to Chinese Manchester Foot Pain and Disability Index (C-MFPDI), there was no morbidity on foot function in all donor areas., Conclusion: The surgical procedure of combined with the first dorsal (plantar) metatarsal artery pedicle free bilobed flap with a cell scaffold for the repair of mid-distal adjacent fingers defect is highly satisfactory. This approach helps the injured fingers to achieve good function, sensibility and appearance, while also achieving satisfactory results in the donor toes., (© 2024. The Author(s).)

Background: Quantitative determination of the correlation between cognitive ability and functional biomarkers in the older brain is essential. To identify biomarkers associated with cognitive performance in the older, this study combined an index model specific for resting-state functional connectivity (FC) with a supervised machine learning method., Methods: Performance scores on conventional cognitive test scores and resting-state functional MRI data were obtained for 98 healthy older individuals and 90 healthy youth from two public databases. Based on the test scores, the older cohort was categorized into two groups: excellent and poor. A resting-state FC scores model (rs-FCSM) was constructed for each older individual to determine the relative differences in FC among brain regions compared with that in the youth cohort. Brain areas sensitive to test scores could then be identified using this model. To suggest the effectiveness of constructed model, the scores of these brain areas were used as feature matrix inputs for training an extreme learning machine. classification accuracy (CA) was then tested in separate groups and validated by N-fold cross-validation., Results: This learning study could effectively classify the cognitive status of healthy older individuals according to the model scores of frontal lobe, temporal lobe, and parietal lobe with a mean accuracy of 86.67%, which is higher than that achieved using conventional correlation analysis., Conclusion: This classification study of the rs-FCSM may facilitate early detection of age-related cognitive decline as well as help reveal the underlying pathological mechanisms., (© 2024. The Author(s).)

Background: Dystrophinopathies are the most common X-linked inherited muscle diseases, and the disease-causing gene is DMD. Exonic duplications are a common type of pathogenic variants in the DMD gene, however, 5' end exonic duplications containing exon 1 are less common. When assessing the pathogenicity of exonic duplications in the DMD gene, consideration must be given to their impact on the reading frame. Traditional molecular methods, such as multiplex ligation-dependent probe amplification (MLPA) and next-generation sequencing (NGS), are commonly used in clinics. However, they cannot discriminate the precise physical locations of breakpoints and structural features of genomic rearrangement. Long-read sequencing (LRS) can effectively overcome this limitation., Results: We used LRS technology to perform whole genome sequencing on three families and analyze the structural variations of the DMD gene, which involves the duplications of exon 1 and/or exon 2. Two distinct variant types encompassing exon 1 in the DMD Dp427m isoform and/or Dp427c isoform are identified, which have been infrequently reported previously. In pedigree 1, the male individuals harboring duplication variant of consecutive exons 1-2 in the DMD canonical transcript (Dp427m) and exon 1 in the Dp427c transcript are normal, indicating the variant is likely benign. In pedigree 3, the patient carries complex SVs involving exon 1 of the DMD Dp427c transcript showing an obvious phenotype. The locations of the breakpoints and the characteristics of structural variants (SVs) are identified by LRS, enabling the classification of the variants' pathogenicity., Conclusions: Our research sheds light on the complexity of DMD variants encompassing Dp427c/Dp427m promoter regions and emphasizes the importance of cautious interpretation when assessing the pathogenicity of DMD 5' end exonic duplications, particularly in carrier screening scenarios without an affected proband., (© 2024. The Author(s).)

Background: The triglyceride-glucose (TyG) index, identified as a reliable indicator of insulin resistance (IR), was reported to be associated with stroke recurrence and morbidity in the general population and critically ill patients. However, the relationship in liver transplantation (LT) recipients remains unknown. This study aimed to investigate the correlation between the TyG index and post-LT stroke along with all-cause mortality and further assess the influence of IR on the LT recipients' prognosis., Methods: The retrospective cohort study enrolled 959 patients who underwent LT at a university-based medical centre between January 2015 and January 2021. The participants were divided into three groups according to their TyG index tertiles. The primary outcome was post-LT stroke. Multivariate logistic regression, COX proportional hazards regression, and restricted cubic spline RCS were used to examine the association between the TyG index and outcomes in LT recipients., Results: With a median TyG index of 8.23 (7.78-8.72), 780 (87.18% males) patients were eventually included. The incidence of post-LT stroke was 5.38%, and the in-hospital, 1-year, and 3-year mortality rates were 5.54%, 13.21%, and 15.77%, respectively. Multivariate regression analysis showed an independent association between the TyG index and an increased risk of post-LT stroke [adjusted odds ratio (aOR), 3.398 (95% confidence interval [CI]: 1.371-8.426) P = 0. 008], in-hospital mortality [adjusted hazard ratio (aHR), 2.326 (95% CI: 1.089-4.931) P = 0.025], 1-year mortality [aHR, 1.668 (95% CI: 1.024-2.717) P = 0.039], and 3-year mortality [aHR, 1.837 (95% CI: 1.445-2.950) P = 0.012]. Additional RCS analysis also suggested a linear increase in the risk of postoperative stroke with elevated TyG index (P for nonlinearity = 0.480)., Conclusions: The TyG index may be a valuable and reliable indicator for assessing stroke risk and all-cause mortality in patients undergoing LT, suggesting its potential relevance in improving risk stratification during the peri-LT period., (© 2024. The Author(s).)

Background: Wheat, a crucial food crop in China, is highly vulnerable to drought stress throughout its growth and development. WRKY transcription factors (TFs), being one of the largest families of TFs, play a vital role in responding to various abiotic stresses in plants., Results: Here, we cloned and characterized the TF TaWRKY31 isolated from wheat. This TF, belonging to the WRKY II family, contains a WRKYGQK amino acid sequence and a C 2 H 2 -type zinc finger structure. TaWRKY31 exhibits tissue-specific expression and demonstrates responsiveness to abiotic stresses in wheat. TaWRKY31 protein is localized in the nucleus and can function as a TF with transcription activating activity at the N-terminus. Results showed that the wheat plants with silenced strains (BSMV:TaWRKY31-1as and BSMV:TaWRKY31-2as) exhibited poor growth status and low relative water content when subjected to drought treatment. Moreover, the levels of O 2 · - , H 2 O 2 , and malondialdehyde (MDA) in the BSMV:TaWRKY31-induced wheat plants increased, while the activities of antioxidant enzymes (superoxide dismutase, peroxidase, and catalase) decreased. Compared to control plants, BSMV:TaWRKY31-induced wheat plants exhibited lower expression levels of TaSOD (Fe), TaPOD, TaCAT, TaDREB1, TaP5CS, TaNCED1, TaSnRK2, TaPP2C, and TaPYL5.Under stress or drought treatment conditions, the overexpression of TaWRKY31 in Arabidopsis resulted in decreased levels of H 2 O 2 and MDA, as well as reduced stomatal opening and water loss. Furthermore, an increase in resistance oxidase activity, germination rate, and root length in the TaWRKY31 transgenic Arabidopsis was observed. Lastly, overexpression of TaWRKY31 in Arabidopsis resulted in higher the expression levels of AtNCED3, AtABA2, AtSnRK2.2, AtABI1, AtABF3, AtP5CS1, AtSOD (Cu/Zn), AtPOD, AtCAT, AtRD29A, AtRD29B, and AtDREB2A than in control plants., Conclusions: Our findings indicate that TaWRKY31 enhances drought resistance in plants by promoting the scavenging of reactive oxygen species, reducing stomatal opening, and increasing the expression levels of stress-related genes., (© 2024. The Author(s).)

Using a magnetic resonance imaging (MRI) contrast agent, MRI has made substantial contributions to glioma diagnosis. Metal-free MRI agents, such as the nano free radical nitric oxide (NO · ) micelle, can overcome the inherent toxicity of metal-based agents in certain patient populations. However, the low spatial resolution of nano NO · micelle in MRI limits its clinical development. In this study, we pretreated platelets (PLTs) and loaded them with nano NO · micelles to synthesize NO · @PLT, which can overcome the low contrast and poor in vivo stability of nitroxide-based MRI contrast agents. The PLTs can serve as potential drug carriers for targeting and delivering nano NO · micelles to gliomas and thus increase the contrast in T1-weighted imaging (T1WI) of MRI. This drug carrier system uses the unique tumor-targeting ability of PLTs and takes advantage of the high signal presentation of steady nano NO · micelles in T1WI, thereby ultimately achieving signal amplification of glioma in T1WI. With the effect of PLTs-tumor cell adhesion, NO · @PLT has per-nitroxide transverse relativities of approximately 2-fold greater than those of free NO · particles. These features allow a sufficient NO · @PLT concentration to accumulate in murine subcutaneous glioma tumors up from 5 min to 2.5 h (optimum at 1.5 h) after systemic administration. This results in MRI contrast comparable to that of metal-based agents. This study established a promising metal-free MRI contrast agent, NO · @PLT, for glioma diagnosis, because it has superior spatial resolution owing to its high glioma-targeting ability and has significant translational implications in the clinic., (© 2023. The Author(s).)

In essence, the β 2 adrenergic receptor (β 2 AR) plays an antiproliferative role by increasing the intracellular cyclic 3',5'-adenosine monophosphate (cAMP) concentration through G αs coupling, but interestingly, β 2 AR antagonists are able to effectively inhibit fibroblast-like synoviocytes (FLSs) proliferation, thus ameliorating experimental RA, indicating that the β 2 AR signalling pathway is impaired in RA FLSs via unknown mechanisms. The local epinephrine (Epi) level was found to be much higher in inflammatory joints than in normal joints, and high-level stimulation with Epi or isoproterenol (ISO) directly promoted FLSs proliferation and migration due to impaired β 2 AR signalling and cAMP production. By applying inhibitor of receptor internalization, and small interfering RNA (siRNA) of G αs and G αi , and by using fluorescence resonance energy transfer and coimmunoprecipitation assays, a switch in G αs -G αi coupling to β 2 AR was observed in inflammatory FLSs as well as in FLSs with chronic ISO stimulation. This G αi coupling was then revealed to be initiated by G protein coupled receptor kinase 2 (GRK2) but not β-arrestin2 or protein kinase A-mediated phosphorylation of β 2 AR. Inhibiting the activity of GRK2 with the novel GRK2 inhibitor paeoniflorin-6'-O-benzene sulfonate (CP-25), a derivative of paeoniflorin, or the accepted GRK2 inhibitor paroxetine effectively reversed the switch in G αs -G αi coupling to β 2 AR during inflammation and restored the intracellular cAMP level in ISO-stimulated FLSs. As expected, CP-25 significantly inhibited the hyperplasia of FLSs in a collagen-induced arthritis (CIA) model (CIA FLSs) and normal FLSs stimulated with ISO and finally ameliorated CIA in rats. Together, our findings revealed the pathological changes in β 2 AR signalling in CIA FLSs, determined the underlying mechanisms and identified the pharmacological target of the GRK2 inhibitor CP-25 in treating CIA. Video Abstract., (© 2023. The Author(s).)

Background: The clinical application of coronary MR angiography (MRA) combining diastole and systole imaging has never been described comprehensively in coronary artery disease (CAD) patients. We aimed to design an optimal non-contrast coronary MRA scan protocol combining diastolic and systolic imaging and to (1) evaluate its diagnostic performance for detecting significant coronary stenosis; (2) evaluate the feasibility of this protocol to noninvasively measure the coronary distensibility index (CDI)., Methods: From June 2021 to May 2022, 33 healthy volunteers and 91 suspected CAD patients scheduled for X-ray coronary angiography (CAG) were prospectively enrolled. 3T non-contrast water-fat coronary MRA was carried out twice at diastole and systole. Significant coronary stenosis was defined as a luminal diameter reduction of ≥ 50% using CAG as the reference and was evaluated as follows: (1) by coronary MRA in diastole alone; (2) by coronary MRA in systole alone; (3) by combined coronary MRA in diastole and systole. According to CAG, the patients were divided into significant CAD patients and non-significant CAD patients. The difference in CDI among participants was evaluated., Results: Combined coronary MRA was completed in 31 volunteers and 76 patients. The per-patient sensitivity, specificity, and accuracy of combined coronary MRA were 97.5%, 83.3%, and 90.8%, respectively. Compared with single diastolic mode, combined coronary MRA showed equally high sensitivity but improved specificity on a per-patient basis (83.3% vs. 63.9%, adjusted P = 0.013). The CDI tested by coronary MRA decreased incrementally from healthy volunteers to non-significant and significant CAD patients., Conclusion: Compared with single-phase mode, 3 T non-contrast combined coronary MRA significantly improved specificity and may have potential to be a simple noninvasive method to measure CDI., (© 2023. The Author(s).)

Background: Depressive symptoms associated with schizophrenia are closely related to stigma and quality of life(QOL). There is, however, no thorough research on the connection between the three. This study sought to investigate the possible factors influencing depressive symptoms in people with schizophrenia (PWS) in rural Chaohu, China, and to further explore the role of depression severity in stigma and lifestyle quality., Methods: Eight hundred twenty-one schizophrenia patients accomplished the entire scale, including the 9-item Patient Health Questionnaire (PHQ-9), the Social Impact Scale (SIS), and the World Health Organization on Quality of Life Brief Scale(WHOQOL-BREF). A straightforward mediation model was employed to determine if the intensity of the depression could act as a mediator between stigma and QOL., Results: Two hundred seventy-nine schizophrenia patients (34%) had depressive symptoms (PHQ ≥ 10), and 542 patients (66%) did not (PHQ < 10). Logistic regression showed that marital status, job status, physical exercise, standard of living, and stigma contributed to the depressed symptoms of schizophrenia. Depression severity partially mediated the effect between stigma and QOL, with a mediating effect of 48.3%., Conclusions: This study discovered a significant incidence of depressed symptoms associated with schizophrenia, with depression severity serving as a mediator variable connecting stigma and QOL and partially moderating the association., (© 2023. The Author(s).)

Background: Previous studies have verified the dysfunction of mesenchymal stem cells (MSCs) for immunoregulation in acquired aplastic anemia (AA) patients. Exosomes derived from MSCs can partially substitute MSCs acting as immune regulator. Dysfunction of exosomes (Exos) derived from AA-MSC (AA-Exos) may play a key role in immunologic dissonance., Method: In this study, CD3 + T cells were collected and cocultured with AA-Exos and exosomes derived from HD-MSC (HD-Exos). The proliferation, differentiation and activation of CD3 + T cells were detected to compare the immunosuppressive effects between AA-Exos and HD-Exos. An immune-mediated murine model of AA was structured to compare the therapeutic effect of AA-Exos and HD-Exos. Furthermore, total RNA including miRNA from exosomes we purified and total RNA of CD3 + T cells were extracted for RNA-seq in order to construct the miRNA-mRNA network for interactions and functional analysis., Results: AA-Exos had impaired inhibition effects on CD3 + T cells in terms of cell proliferation, activation and differentiation compared with exosomes from HD-Exos. HD-Exos showed a more effective rescue of AA mice compared to AA-Exos. Importantly, we found some differentially expressed miRNA involved in immune response, such as miR-199, miR-128 and miR-486. The Gene Ontology analysis of differentially expressed genes (DEGs) revealed involvement of various cellular processes, such as lymphocyte chemotaxis, lymphocyte migration and response to interferon-gamma. The Kyoto Encyclopedia of Genes and Genomes analysis illustrated upregulation of critical pathways associated with T cell function after coculturing with AA-Exos compared with HD-Exos, such as graft-versus-host disease, Th17 cell differentiation and JAK-STAT signaling pathway. A miRNA-mRNA network was established to visualize the interaction between them., Conclusion: In summary, AA-Exos had impaired immunosuppressive effect on T cells, less ability to rescue AA mice and differently expressed miRNA profile, which might partly account for the pathogenesis of AA as well as provide a new target of AA treatment., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Most neurosurgery presentations in children present with a mass that may be scalp and skull lesions, including neoplastic and congenital malformed structural lesions, respectively. Clinicians should make early diagnoses and identify cases requiring surgical intervention promptly to help achieve a better prognosis., Method: This study retrospectively reviewed studies on children's scalp and skull lesions within a pediatric medical center's department of neurosurgery. The detailed clinical information and pathological types of these cases were scrutinized., Result: A total of 228 children's scalp and skull lesions with clinical information and identified histopathology types were summarized. The most common scalp and skull lesions were benign dermoid cysts; malignant types were rare but can occur in children., Conclusion: Based on the combined clinical symptoms and image information, children's scalp and skull lesions should be diagnosed early. Malignant scalp and skull lesions/other special cases should be treated seriously., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Stimulating ion channels targeting in neuromodulation by external signals with the help of functionalized nanoparticles, which integrates the pioneering achievements in the fields of neurosciences and nanomaterials, has involved into a novel interdisciplinary field. The emerging technique developed in this field enable simple, remote, non-invasive, and spatiotemporally precise nerve regulations and disease therapeutics, beyond traditional treatment methods. In this paper, we define this emerging field as nano-neuromodulation and summarize the most recent developments of non-genetic nano-neuromodulation (non-genetic NNM) over the past decade based on the innovative design concepts of neuromodulation nanoparticle systems. These nanosystems, which feature diverse compositions, structures and synthesis approaches, could absorb certain exogenous stimuli like light, sound, electric or magnetic signals, and subsequently mediate mutual transformations between above signals, or chemical reactions, to regulate stimuli-sensitive ion channels and ion migrations which play vital roles in the nervous system. We will also discuss the obstacles and challenges in the future development of non-genetic NNM, and propose its future developments, to add the further progress of this promising field., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Currently, the influenza epidemic in China is at a high level and mixed with other respiratory diseases. Current studies focus on regional influenza and the impact of environmental pollutants on time series, and lack of overall studies on the national influenza epidemic and the nonlinear correlation between environmental pollutants and influenza. The unclear spatial and temporal evolution patterns of influenza as well as the unclear correlation effect between environmental pollutants and influenza epidemic have greatly hindered the prevention and treatment of influenza epidemic by relevant departments, resulting in unnecessary economic and human losses., Method: This study used Chinese influenza incidence data for 2007-2017 released by the China CDC and air pollutant site monitoring data. Seasonal as well as inter monthly differences in influenza incidence across 31 provinces of China have been clarified through time series. Space-Time Cube model (STC) was used to investigate the spatio-temporal evolution of influenza incidence in 315 Chinese cities during 2007-2017. Then, based on the spatial heterogeneity of influenza incidence in China, Generalized additive model (GAM) was used to identify the correlation effect of environmental pollutants (PM 2.5 , PM 10 , CO, SO 2 , NO 2 , O 3 ) and influenza incidence., Result: The influenza incidence in China had obvious seasonal changes, with frequent outbreaks in winter and spring. The influenza incidence decreased significantly after March, with only sporadic outbreaks occurring in some areas. In the past 11 years, the influenza epidemic had gradually worsened, and the clustering of influenza had gradually expanded, which had become a serious public health problem. The correlation between environmental pollutants and influenza incidence was nonlinear. Generally, PM 2.5 , CO and NO 2 were positively correlated at high concentrations, while PM 10 and SO 2 were negatively correlated. O 3 was not strongly correlated with the influenza incidence., Conclusion: The study found that the influenza epidemic in China was in a rapidly rising stage, and several regions had a multi-year outbreak trend and the hot spots continue to expand outward. The association between environmental pollutants and influenza incidence was nonlinear and spatially heterogeneous. Relevant departments should improve the monitoring of influenza epidemic, optimize the allocation of resources, reduce environmental pollution, and strengthen vaccination to effectively prevent the aggravation and spread of influenza epidemic in the high incidence season and areas., (© 2023. BioMed Central Ltd., part of Springer Nature.)

The Anti-mullerian hormone (AMH) reference value is an important indicator of ovarian function. The main targets of this were to screen the geographical environmental factors that may influence the distribution of AMH reference values in Chinese females of childbearing age, and to further explore the geographical distribution differences of AMH reference values. We gathered the AMH data of 28,402 healthy Chinese females from 62 cities in China for this study in order to conduct a spearman regression analysis to determine the relationship between the AMH and 30 geography factors. The AMH reference value in different regions was forecasted by using a ridge regression model. The magnitude of influence from the geographical factor on different regions was analysed by geographically weighted regression. Ultimately, We were able to figure out the geographic distribution risk prediction of AMH reference values by utilizing the disjunctive Kriging method. The AMH reference value was significantly correlated with the 16 secondary indexes. The geographical distribution of AMH showed a trend of being higher in Qinghai-Tibet and Southern regions, and lower in the Northwest and Northern regions. This study lays the foundation for future investigations into the mechanism of different influencing factors on the reference value of AMH. It is suggested that such regional variations in AMH reference values be taken into account while diagnosing and treating individuals with reproductive medicine., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Anaplastic thyroid carcinoma (ATC) was a rare and extremely malignant endocrine cancer with the distinct hallmark of high proportion of cancer stem cell-like characteristics. Therapies aiming to cancer stem-like cells (CSCs) were emerging as a new direction in cancer treatment, but targeting ATC CSCs remained challenging, mainly due to incomplete insights of the regulatory mechanism of CSCs. Here, we unveiled a novel role of ISG15 in the modulation of ATC CSCs., Methods: The expression of ubiquitin-like proteins were detected by bioinformatics and immunohistochemistry. The correlation between ISG15 expression and tumor stem cells and malignant progression of ATC was analyzed by single-cell RNA sequence from the Gene Expression Omnibus. Flow cytometry combined with immunofluorescence were used to verify the enrichment of ISG15 and ISGyaltion in cancer stem cells. The effect and mechanism of ISG15 and KPNA2 on cancer stem cell-like characteristics of ATC cells were determined by molecular biology experiments. Mass spectrometry combined with immunoprecipitation to screen the substrates of ISG15 and validate its ISGylation modification. Nude mice and zebrafish xenograft models were utilized to demonstrate that ISG15 regulates stem cell characteristics and promotes malignant progression of ATC., Results: We found that among several ubiquitin proteins, only ISG15 was aberrantly expressed in ATC and enriched in CSCs. Single-cell sequencing analysis revealed that abnormal expression of ISG15 were intensely associated with stemness and malignant cells in ATC. Inhibition of ISG15 expression dramatically attenuated clone and sphere formation of ATC cells, and facilitated its sensitivity to doxorubicin. Notably, overexpression of ISGylation, but not the non-ISGylation mutant, effectively reinforced cancer stem cell-like characteristics. Mechanistically, ISG15 mediated the ISGylation of KPNA2 and impeded its ubiquitination to promote stability, further maintaining cancer stem cell-like characteristics. Finally, depletion of ISG15 inhibited ATC growth and metastasis in xenografted mouse and zebrafish models., Conclusion: Our studies not only provided new insights into potential intervention strategies targeting ATC CSCs, but also uncovered the novel biological functions and mechanisms of ISG15 and ISGylation for maintaining ATC cancer stem cell-like characteristics., (© 2023. The Author(s).)

Background: Acute gouty arthritis is inflammatory joint arthritis. Gouty arthritis (GA) involves multiple pathological processes. Deposition of joints by monosodium urate (MSU) crystals has been shown to play a critical role in the injury process. Due to the different effects of MSU stimulation on the joints, the exact changes in the synovial fluid are unknown. We want to explore the changes in proteins and metabolites in the joints of gouty arthritis. Regulating various functional substances in the joint can reduce inflammation and pain symptoms., Methods: 10 patients with gouty knee arthritis and 10 normal controls were selected from clinical, surgical cases. The biological function of the metabolome was assessed by co-expression network analysis. A molecular network based on metabolomic and proteomic data was constructed to study critical molecules. The fundamental molecular changes in the relevant pathways were then verified by western blot., Results: Proteomic analysis showed that the expressions of proteases Cathepsin B, Cathepsin D, Cathepsin G, and Cathepsin S in synovial fluid patients with gouty arthritis were significantly increased. Enrichment analysis showed a positive correlation between lysosomal and clinical inflammatory cell shape changes. Untargeted metabolomic analysis revealed that lipids and lipoids accumulate, inhibit autophagic flux, and modulate inflammation and immunity in gouty arthritis patients. It was determined that the accumulation of lipid substances such as phospholipase A2 led to the imbalanced state of the autophagy-lysosome complex, and the differentially expressed metabolites of Stearoylcarnitine, Tetradecanoylcarnitine, Palmitoylcarnitine were identified (|log2 fold change|> 1.5, adjusted P value < 0.05 and variable importance in prediction (VIP) > 1.5). The autophagy-lysosomal pathway was found to be associated with gouty knee arthritis. Essential molecular alterations of multi-omics networks in gouty knee arthritis patients compared with normal controls involve acute inflammatory response, exosomes, immune responses, lysosomes, linoleic acid metabolism, and synthesis., Conclusions: Comprehensive analysis of proteomic and untargeted metabolomics revealed protein and characteristic metabolite alterations in gouty arthritis, it mainly involves lipids and lipid like molecules, phospholipase A2 and autophagic lysosomes. This study describes the pathological characteristics, pathways, potential predictors and treatment goals of gouty knee arthritis., (© 2023. The Author(s).)

The development of head and neck squamous cell carcinoma (HNSCC) is a multi-step process, and its survival depends on a complex tumor ecosystem, which not only promotes tumor growth but also helps to protect tumor cells from immune surveillance. With the advances of existing technologies and emerging models for ecosystem research, the evidence for cell-cell interplay is increasing. Herein, we discuss the recent advances in understanding the interaction between tumor cells, the major components of the HNSCC tumor ecosystem, and summarize the mechanisms of how biological and abiotic factors affect the tumor ecosystem. In addition, we review the emerging ecological treatment strategy for HNSCC based on existing studies., (© 2023. The Author(s).)

Background: The trajectory of frailty and intrinsic capacity (IC) often overlap in older adults. Longitudinal analyses of transitions of frailty and IC, and their associations with incident functional decline are limited. The present study aimed to identify transitions of frailty status and IC, and explore associations between transitions of frailty and IC, and future disability among community-dwelling older adults., Methods: In the West China and Aging Trend Study, 808 participants aged ≥ 60 years completed baseline and three years follow-up (frailty, IC and disability assessments). Physical frailty was measured based on Fried phenotype. IC was evaluated by five domains (cognition, locomotion, sensory, psychological, and vitality). Disability was defined as a need for assistance in any items in activity of daily living (ADL) or the instrumental activity of daily living (IADL). Logistic regressions were performed to examine their relationships., Results: Four transitions of IC status (kept well: 27.4%, improved: 8.4%, worsened: 35.4%, and kept poor: 28.8%), and two transitions of frailty status (kept not-frail/improved: 93.2%, kept frail/worsened: 6.8%) were identified. Impaired locomotion and vitality at baseline were significantly associated with kept frail or worsened frail. However, impaired sensory and vitality at baseline not frailty status was significantly associated with transitions of IC. Adjusted for covariates and transitions of frailty, kept poor IC was associated with ADL (OR = 2.26, 95%CI = 1.17,4.34) and IADL disability (OR = 3.74, 95%CI = 1.79, 7.82)., Conclusions: Transitions of IC, but not frailty were associated with higher risk of incident disability. Baseline locomotion and vitality impairment were associated with worsened or kept frail. Our findings support the WHO's notion of monitoring and optimizing IC to delay deterioration of IC and preventing frailty and disability., Clinical Trial Number: ChiCTR1800018895., (© 2023. The Author(s).)

Background: Dyslipidemia is a key factor causing cardio cerebrovascular diseases, and the total cholesterol (TC) is an important lipid indicator among them. Studies have shown that environmental factors have a strong association with TC levels. Previous studies only focused on the seasonal variation of TC level and the short-term effects of some environmental factors on TC level over time, and few studies explored the geographical distribution of TC level and quantified the impact of environmental factors in space., Methods: Based on blood test data which was from China Health and Retirement Longitudinal Study (Charls) database, this study selected the TC level test data of middle-aged and elderly people in China in 2011 and 2015, and collected data from 665 meteorological stations and 1496 air pollutant monitoring stations in China. After pretreatment, the spatial distribution map of TC level was prepared and the regional statistics were made. GeoDetector and geographically weighted regression (GWR) were used to measure the relationship between environmental factors and TC level., Results: The TC level of middle-aged and elderly in China was higher in females than in males, and higher in urban areas than in rural areas, showing a clustered distribution. The high values were mainly in South China, Southwest China and North China. Temperature, humidity, PM 10 and PM 2.5 were significant environmental factors affecting TC level of middle-aged and elderly people. The impact of pollutants was more severe in northern China, and TC level in southern China was mainly affected by meteorological factors., Conclusions: There were gender and urban-rural differences in TC levels among the middle-aged and elderly population in China, showing aggregation in geographical distribution. Meteorological factors and air pollutants may be very important control factors, and their influencing mechanism needs further study., (© 2022. The Author(s).)

Background: The factors related to psychological sub-health (PSH) have been widely described, but the research on the mechanism behind the complex relationship between childhood trauma and PSH is limited. This study investigated the current situation and risk factors of PSH among Chinese adolescents. And further, explore whether Internet addiction (IA) plays a potential mediating effect in childhood trauma and PSH., Methods: The study was conducted in October 2020 in Anhui Province, China. The PSH state of 866 adolescents was investigated, including demographic information such as gender, age, and grade. Childhood trauma, IA, and PSH were measured by the Childhood Trauma Questionnaire Short Form (CTQ-SF), Young's Internet Addiction Test (IAT), and the Multidimensional Sub-health Questionnaire of Adolescents (MSQA). The mediating effect is further verified by the structural equation model (SEM)., Results: In this study, 866 adolescents were selected as subjects, and the proportion of male and female is roughly equal. The prevalence of PSH in adolescents was 25.8%, and left-behind children, boarding, or adolescents who have had non-suicidal self-injury (NSSI) are more likely to have PSH. Through the mediation test, the direct effect of childhood trauma on PSH was 0.23 (95% CI [4.91,9.00],p <0.001), and the mediating effect of IA on childhood trauma and PSH was 0.07 (95% CI [1.42, 3.32],p <0.001). and the proportion of them is 75.14% and 24.86% respectively., Conclusions: Childhood trauma has direct and indirect effects on PSH, and IA plays a mediating effect in the indirect effect. Therefore, clarifying these relationships helps formulate and implement effective interventions to improve psychological health (PH) in Chinese adolescents., (© 2022. The Author(s).)

Background: The relationship between vitamin D and sarcopenia was inconsistent between men and women. Physical activity (PA) may interact with vitamin D on sarcopenia. However, the sex-specific relationships of vitamin D, PA and sarcopenia have yet elucidated. We aimed to examine the sex differences in the relation between vitamin D status, PA levels, obesity and sarcopenia in community-dwelling middle-aged and older adults, as well as whether vitamin D status is a modifier in the relationship between PA and sarcopenia., Methods: The current study was a cross-sectional study based on the baseline survey of the West China Health and Aging Trend (WCHAT) study. A total of 3713 participants aged ≥ 50y were included in our study. Sarcopenia was defined according to the Asian Working Group for Sarcopenia (AWGS) 2019 consensus. Obesity was defined by body mass index (BMI) (≥ 28 kg/m2) and body fat mass percentage (≥ 60th percentile in each sex group). 25-hydroxyvitamin D was measured by chemiluminescent microparticle immunoassay and PA was evaluated by a validated China Leisure Time Physical Activity Questionnaire (CLTPAQ). Multinomial logistic regression was performed to examine the relationship between PA, vitamin D and sarcopenia and obesity., Results: Low PA was significantly associated with higher odds of sarcopenia in women only (OR = 1.70,95%CI:1.18,2.46, p < 0.01). Vitamin D deficiency was only associated with sarcopenia in men (OR = 1.85,95%CI: 1.27,2.69, p < 0.01). Low PA was significantly associated with obesity, sarcopenia, and sarcopenic obesity only in participants with serum 25(OH)D < 20 ng/ml., Conclusions: The role of vitamin D and PA in obesity and sarcopenia was different between men and women, and the relationship between PA and sarcopenia was modified by serum vitamin D status. These findings highlighted the need to supplement vitamin D in individuals with physical inactivity and provide different interventions strategies to sarcopenia in men and women., Trial Registration: Clinical trial number: ChiCTR1800018895., (© 2022. The Author(s).)

Objective: Uncertainties remain regarding the relationship between sarcopenic obesity and frailty. This study aimed to explore the association of these two common geriatric syndromes among community-dwelling older adults., Methods: Baseline data from the West China Health and Aging Trend (WCHAT) study was used. Sarcopenia was assessed based on the criteria established by the Asian working group for sarcopenia. Body fat percentages above the 60th percentile specified by sex were classified as obesity. Sarcopenic obesity was defined as the concurrence of obesity and sarcopenia. Frailty was assessed by Fried criteria. Multinomial logistic regression was adopted to explore associations of sarcopenic obesity with frailty., Results: Overall, 2372 older adults (mean age 67.6 ± 5.9) were involved in this study. The prevalence of frailty and sarcopenic obesity was 6.2 and 6.28%, respectively. After adjusting for covariates, sarcopenic obesity was significantly associated with prefrailty (OR = 1.74, 95% CI = 1.15-2.64, P = 0.009) and frailty (OR = 4.42, 95% CI = 2.19-8.93, P < 0.001) compared to nonsarcopenia and nonobesity., Conclusions: Sarcopenic obesity was significantly correlated with prefrailty and frailty among older adults. Intervention for sarcopenic obesity may contribute to the prevention of incident frailty., (© 2022. The Author(s).)

Background: Dual inhibition of PD-1/PD-L1 and TGF-β pathways is a rational therapeutic strategy for malignancies. SHR-1701 is a new bifunctional fusion protein composed of a monoclonal antibody against PD-L1 fused with the extracellular domain of TGF-β receptor II. This first-in-human trial aimed to assess SHR-1701 in pretreated advanced solid tumors and find the population who could benefit from SHR-1701., Methods: This was a dose-escalation, dose-expansion, and clinical-expansion phase 1 study. Dose escalation was initiated by accelerated titration (1 mg/kg q3w; intravenous infusion) and then switched to a 3+3 scheme (3, 10, 20, and 30 mg/kg q3w and 30 mg/kg q2w), followed by dose expansion at 10, 20, and 30 mg/kg q3w and 30 mg/kg q2w. The primary endpoints of the dose-escalation and dose-expansion parts were the maximum tolerated dose and recommended phase 2 dose. In the clinical-expansion part, selected tumors were enrolled to receive SHR-1701 at the recommended dose, with a primary endpoint of confirmed objective response rate (ORR)., Results: In total, 171 patients were enrolled (dose-escalation: n=17; dose-expansion, n=33; clinical-expansion, n=121). In the dose-escalation part, no dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. SHR-1701 showed a linear dose-exposure relationship and the highest ORR at 30 mg/kg every 3 weeks, without obviously aggravated toxicities across doses in the dose-escalation and dose-expansion parts. Combined, 30 mg/kg every 3 weeks was determined as the recommended phase 2 dose. In the clinical-expansion part, SHR-1701 showed the most favorable efficacy in the gastric cancer cohort, with an ORR of 20.0% (7/35; 95% CI, 8.4-36.9) and a 12-month overall survival rate of 54.5% (95% CI, 29.5-73.9). Grade ≥3 treatment-related adverse events occurred in 37 of 171 patients (22%), mainly including increased gamma-glutamyltransferase (4%), increased aspartate aminotransferase (3%), anemia (3%), hyponatremia (3%), and rash (2%). Generally, patients with PD-L1 CPS ≥1 or pSMAD2 histochemical score ≥235 had numerically higher ORR., Conclusions: SHR-1701 showed an acceptable safety profile and encouraging antitumor activity in pretreated advanced solid tumors, especially in gastric cancer, establishing the foundation for further exploration., Trial Registration: ClinicalTrials.gov , NCT03710265., (© 2022. The Author(s).)

Background: Pharmacy intravenous admixture service (PIVAS) center has emerged as an important department of hospital as it can improve occupational protection and ensure the safety and effectiveness of intravenous infusions. However, medication errors were considered to be a significant challenge in PIVAS, so information-intelligence technologies were introduced to optimize the management of PIVAS. Our article summarized the application of information-intelligence technologies in PIVAS of a large third-class A hospital in China, and provided an example for PIVAS in other hospitals at home and abroad., Methods: Prescription-reviewing rules containing intravenous medications and infusion solution guideline were recorded in the database of prescription-cheking system. Drugs information were recorded in the PIVAS management system with special identification and warning labels to reduce intravenous infusion errors. Automatic labeling device was used to label the infusion bags, and the quality control program database of intelligent compounding robot for cytotoxic drugs was established ingeniously. Automatic sorting devices were applied for the third batch of finished infusion admixtures, and intelligent logistics robots were used to transport the infusion to the ward., Results: After establishing and implementing of prescription-reviewing rules in the prescription-cheking system database, the number of prescriptions checked by pharmacists increased from 18 to 43 per minute. The success rate of intervention with irrational medical orders increased from 85.89% to 99.06% (P < 0.05). By introducing various intelligent devices, automatic labeling significantly enhanced work efficiency and reduced the error rate (P < 0.001). Furthermore, the use of intelligent intravenous compounding robots significantly reduced the risk of errors (P < 0.001)., Conclusions: The application of information-intelligence technologies in PIVAS can improve work efficiency and reduce error risk. However, some intelligent devices have failed to achieve the expected effect in practical use, and further improvements are needed to meet the demands of PIVAS in the future., (© 2022. The Author(s).)

Anaplastic thyroid carcinoma (ATC) is an extremely malignant type of endocrine cancer frequently accompanied by extrathyroidal extension or metastasis through mechanisms that remain elusive. We screened for the CREB3 transcription-factor family in a large cohort, consisting of four microarray datasets. This revealed that CREB3L1 was specifically up regulated in ATC tissues and negatively associated with overall survival of patients with thyroid cancer. Consistently, high expression of CREB3L1 was negatively correlated with progression-free survival in an independent cohort. CREB3L1 knockdown dramatically attenuated invasion of ATC cells, whereas overexpression of CREB3L1 facilitated the invasion of papillary thyroid carcinoma (PTC) cells. Loss of CREB3L1 inhibited metastasis and tumor growth of ATC xenografts in zebrafish and nude mouse model. Single-cell RNA-sequencing analysis revealed that CREB3L1 expression gradually increased during the neoplastic progression of a thyroid follicular epithelial cell to an ATC cell, accompanied by the activation of the extracellular matrix (ECM) signaling. CREB3L1 knockdown significantly decreased the expression of collagen subtypes in ATC cells and the fibrillar collagen in xenografts. Due to the loss of CREB3L1, ATC cells were unable to activate alpha-smooth muscle actin (α-SMA)-positive cancer-associated fibroblasts (CAFs). After CREB3L1 knockdown, the presence of CAFs inhibited the growth of ATC spheroids and the metastasis of ATC cells. Further cytokine array screening showed that ATC cells activated α-SMA-positive CAFs through CREB3L1-mediated IL-1α production. Moreover, KPNA2 mediated the nuclear translocation of CREB3L1, thus allowing it to activate downstream ECM signaling. These results demonstrate that CREB3L1 maintains the CAF-like property of ATC cells by activating the ECM signaling, which remodels the tumor stromal microenvironment and drives the malignancy of ATC., (© 2022. The Author(s).)

Background: Ticks (order Ixodida) are ectoparasites, vectors and reservoirs of many infectious agents affecting humans and domestic animals. However, the lack of information on tick genomic diversity leaves significant gaps in the understanding of the evolution of ticks and associated bacteria., Results: We collected > 20,000 contemporary and historical (up to 60 years of preservation) tick samples representing a wide range of tick biodiversity across diverse geographic regions in China. Metagenomic sequencing was performed on individual ticks to obtain the complete or near-complete mitochondrial (mt) genome sequences from 46 tick species, among which mitochondrial genomes of 23 species were recovered for the first time. These new mt genomes data greatly expanded the diversity of many tick groups and revealed five cryptic species. Utilizing the same metagenomic sequence data we identified divergent and abundant bacteria in Haemaphysalis, Ixodes, Dermacentor and Carios ticks, including nine species of pathogenetic bacteria and potentially new species within the genus Borrelia. We also used these data to explore the evolutionary relationship between ticks and their associated bacteria, revealing a pattern of long-term co-divergence relationship between ticks and Rickettsia and Coxiella bacteria., Conclusions: In sum, our study provides important new information on the genetic diversity of ticks based on an analysis of mitochondrial DNA as well as on the prevalence of tick-borne pathogens in China. It also sheds new light on the long-term evolutionary and ecological relationships between ticks and their associated bacteria., (© 2022. The Author(s).)

Background: Frailty is a geriatric syndrome characterized by a decline in physiological reserves, and multiple factors contribute to the occurrence and development of frailty. Growing evidence supports a strong link and overlap between frailty and cognitive impairment, but the mechanisms involved have not yet been fully elucidated., Aim: To identify associations between 12 plasma cognition-related biomarkers and frailty in community-dwelling older adults., Methods: A total of 375 participants (age 70.9 ± 5.8, 165 men and 210 women) were included in this study. Frailty was assessed using the modified Fried frailty phenotype. Participants were divided into not-frail group (n = 313) and frail group (n = 62). Twelve plasma cognitive biomarkers were detected by enzyme-linked immunosorbent assay (ELISA). Multinomial logistic regression was used to explore the association between different biomarkers and frailty status., Results: Among the 12 biomarkers, only pTau was higher in frail individuals than in their not-frail peers (471.3 ± 58.1 pg/mL vs. 451.9 ± 61.1 pg/mL, p = 0.022). No other biomarkers had any significant association with frailty, including total-Tau (tTau), neurofilament light (NFL), amyloid-β 40 (Aβ40), amyloid-β 40 (Aβ42), S100 calcium binding protein B (S100B), visinin-like protein 1 (VLP-1), Alzheimer-associated neuronal thread protein (AD7cNTP), β-amyloid precursor protein (βAPP), chitinase-3-like-1 (CHI3L1), soluble complement receptor 1 (sCR1) and heart-type fatty acid binding protein (hFABP). Furthermore, pTau was compared between negative and positive subject groups for each individual criterion of frailty. Significantly higher levels of pTau were observed in those who were positive for the criteria of low grip strength (451.2 ± 61.4 pg/mL vs. 469.1 ± 57.6 pg/mL, p = 0.019), exhaustion (451.2 ± 61.6 pg/mL vs. 466.4 ± 58.4 pg/mL, p = 0.035) and low physical activity (451.1 ± 60.7 pg/mL vs. 465.7 ± 60.7 pg/mL, p = 0.034) when compared to those who were negative for each corresponding criterion. Finally, in the multivariable-adjusted analysis, the association between pTau and frailty was statistically significantly associated (OR: 1.40, 95% CI: 1.04-1.89), even after adjusting., Conclusions: The present study found a potential association between pTau and frailty. Future works should monitor the longitudinal trajectory of changes of pTau concentrations in frailty older adults. A better understanding of the molecular mechanisms behind will contribute to biomarker research in frailty., (© 2022. The Author(s).)

Background: Although the World Health Organization reports that the incidence of tuberculosis in China is decreasing every year, the burden of tuberculosis in China is still very heavy. Understanding the spatial and temporal distribution pattern of tuberculosis in China and its influencing environmental factors will provide effective reference for the prevention and treatment of tuberculosis., Methods: Data of TB incidence from 2010 to 2017 were collected. Time series and global spatial autocorrelation were used to analyze the temporal and spatial distribution pattern of tuberculosis incidence in China, Geodetector and Geographically Weighted Regression model were used to analyze the environmental factors affecting the TB incidence., Results: In addition to 2007 and 2008, the TB incidence decreased in general. TB has a strong spatial aggregation. Cities in Northwest China have been showing a trend of high-value aggregation. In recent years, the center of gravity of high-value aggregation area in South China has moved further south. Temperature, humidity, precipitation, PM 10 , PM 2.5 , O 3 , NO 2 and SO 2 have impacts on TB incidence, and in different regions, the environmental factors show regional differences., Conclusions: Residents should pay more attention to the risk of developing TB caused by climate change and air pollutant exposure. Increased efforts should be placed on areas with high-value clustering in future public resource configurations., (© 2022. The Author(s).)

Background: Reconstruction of soft tissue defects following surgical tumor resection is important for quality of life in cancer patients with oral and oropharyngeal squamous cell carcinoma (SCC). This study presents a novel computer-aided reconstruction of soft tissue (CARST) technology employed with these patients., Methods: We first described the CARST technology in detail in a report of a 34-year-old male patient with locally invasive right-sided tongue SCC following a nearly total glossectomy and reported the postoperative outcomes. This digital technology was applied to construct a 3D model from CT images, which was used to delineate surgical resection boundaries and design a personalized reconstruction of the soft tissue defect. A nonuniform rational B-spline (NURBS) was generated and applied to transform the 3D model into a 2D flap-cutting guide printed out using a 3D printer. We then reported a case-series study on oral and oropharyngeal SCC patients who were randomly assigned to receive the CARST (n = 15) or a traditional soft tissue reconstruction (n = 15). Clinicopathological features and short- and long-term postoperative outcomes between the two groups were compared., Results: The patient with the tongue SCC had a successful CARST following surgical tumor resection without any complications. His speech and swallowing functions recovered well after surgery and he experienced no significant changes to his appearance following recovery. There was no recurrence within a 3-year follow-up period. Results of the case-series study showed that the CARST group had significantly shorter operative and post-operation hospital-stay time, a higher flap utilization rate, and a trend of less and milder postoperative complications, and they experienced no significant difference in intraoperative blood loss and long-term outcomes compared to the traditional group., Conclusion: CARST is a safer and more efficient personalized technology of soft tissue reconstruction following surgical tumor resection in patients with oral and oropharyngeal SCC., (© 2022. The Author(s).)

Background: Magnesium ion is one of the essential mineral elements for plant growth and development, which participates in a variety of physiological and biochemical processes. Since there is no report on the research of magnesium ion transporter in grape, the study of the structure and function of magnesium ion transporters (MGT) is helpful to understand the dynamic balance mechanism of intracellular magnesium ions and their inter- or intra-cellular activities., Result: In this study, we identified the members of MGT protein family in grape and performed the phylogenetic and expression analysis. We have identified nine VvMGT genes in grape genome, which are distributed on eight different chromosomes. Phylogenetic analysis showed that MGT family members of grapes were divided into five subfamilies and had obvious homology with Arabidopsis, maize, and pear. Based on transcriptome data from the web databases, we analyzed the expression patterns of VvMGTs at different development stages and in response to abiotic stresses including waterlogging, drought, salinity, and copper. Using qRT-PCR method, we tested the expression of grape VvMGTs under magnesium and aluminum treatments and found significant changes in VvMGTs expression. In addition, four of the MGT proteins in grape were located in the nucleus., Conclusion: Overall, in this study we investigated the structural characteristics, evolution pattern, and expression analysis of VvMGTs in depth, which laid the foundation for further revealing the function of VvMGT genes in grape., (© 2022. The Author(s).)

Background: Alexithymia, which is characterized by difficulty identifying and describing feelings, is a stable personality trait and it has been associated with early life experiences. Methamphetamine dependence patients with high level of alexithymia may be particularly vulnerable to engaging in more frequent methamphetamine use. Therefore, we aimed to evaluate whether alexithymia was associated with frequency of methamphetamine use. Additionally, the current study sought to examine early-life factors associated with the development of alexithymia, i.e., parental rearing styles., Method: Participants were 108 non-injecting methamphetamine dependent patients from a male compulsory detoxification center. The level of alexithymia was assessed by Toronto Alexithymia Scale-20(TAS-20). In addition, we applied Egna Minneu av. Bardndosnauppforstran (EMBU) to assess the parental rearing styles, including the dimensions of warmth, rejection, punishment/strictness, overinvolvement, overprotection, and favoring., Results: The total score of TAS-20 was positively correlated with frequency of methamphetamine use (r = 0.26, p < 0.01). Specifically, except for externally oriented thinking, difficulty identifying feelings (r = 0.23, p < 0.05) and difficulty describing feelings (r = 0.25, p < 0.05) were positively correlated with frequency of methamphetamine use. Multiple linear regression showed that more maternal rejection (B = 0.59, p = 0.002), or less maternal warmth (B = -0.22, p = 0.004) was associated with higher levels of alexithymia. Ordinal logistic regression showed that for every 1 score increase in the total score of TAS-20, there was a 1.06 times risk of a one level increase in the level of methamphetamine use frequency (OR = 1.06, p = 0.01)., Conclusions: These results have major implications for understanding the role of alexithymia in craving and addiction, while providing a further and explicit entry point for addiction treatment. Moreover, more attention should be focused on parenting in relation to early experiences., (© 2022. The Author(s).)

Osteosarcoma (OS) is one of the most common primary bone malignant tumors. Osteoclasts have been shown to have a valuable role in OS. In the present study, we analyzed the differentiation states of osteoclasts in OS and their prognostic significance based on integrated scRNA-seq and bulk RNA-seq data. Osteoclasts in distinct differentiation states were characterized, and 661 osteoclasts differentiation-related genes (ODRGs) were obtained. ORDGs in distinct differentiation states were enriched in distinct functions and pathways. TPM1, S100A13, LOXL1, PSMD10, ST3GAL4, PEF1, SERPINE2, TUBB, FAM207A, TUBA1A, and DCN were identified as the significant survival-predicting ODRGs. We successfully developed a risk score model based on these survival-predicting ODRGs. In addition, we generated a nomogram applicable for clinical with both ODRGs signatures and clinicopathological parameters, and validated in OS cohorts to predict OS patient outcome. This study proposed and verified the important roles of osteoclasts differentiation in the prognosis of patients with OS, suggesting promising therapeutic targets for OS., (© 2022. The Author(s).)

Background: Acute kidney injury (AKI) is a serious complication that often occurred after acute type A aortic dissection (ATAAD) surgery. Previous studies proved that the Kidney Disease Improving Global Outcomes (KDIGO) defined stage 3 AKI was associated with lower long-term survival rate. However, the risk factors for developing stage 3 AKI had not been identified. The aim of the study was to explore the risk factors for developing KDIGO stage 3 after ATAAD operation., Methods: This study included 993 patients who received ATAAD operation from 2014 to 2019 at the Nanjing Drum Tower Hospital. Postoperative AKI was diagnosed according to the KDIGO criteria. Multivariate logistic regression analyses were applied to identify risk factors for stage 3 AKI. Kaplan-Meier survival analyses and Cox proportional hazards regression model were conducted to explore the association between different AKI stages and postoperative survival rate., Results: The mean age of all enrolled patients was 53.0 ± 13.1 years. A total of 236 (23.8%) patients suffered postoperative stage 3 AKI including 165 patients who required renal replacement therapy. Advanced age (odds ratio [OR] 1.031; 95% confidence interval [CI] 1.005-1.057; P = 0.018), prolonged cardiopulmonary bypass (CPB) duration (OR 1.010; 95% CI 1.002-1.018; P = 0.013), and higher drainage volume 24 h after surgery (OR 1.000; 95% CI 1.000-1.001; P = 0.033) were identified as independent risk factors for developing stage 3 AKI. In addition, our result showed that the mortality rate was correlated significantly with the severity of AKI defined by KDIGO criteria and the Cox regression analysis showed that only stage 3 AKI, but not stage 1 and 2, was an independent risk factor for mortality (Hazard ratio 10.365, 95% CI 4.208 to 25.528; P < 0.001) after adjusting for important confounding factors., Conclusions: Our study suggested that stage 3 postoperative AKI was significantly associated with decreased postoperative survival rate after ATAAD surgery. Advanced age, increased CPB duration and drainage volume 24 h after surgery were identified as risk factors for developing stage 3 AKI., (© 2022. The Author(s).)

Background: Hyperlipidemia has become a common chronic disease worldwide in recent years. Studies have shown that hyperlipidemia patients, especially those with a high level of serum low-density lipoprotein cholesterol (LDL-C), have a significantly higher prevalence of atherosclerosis, leading to coronary heart disease. Previous basic experiments and clinical studies have shown that Qushi Huayu granules (QSHY) reduce blood lipids in patients with non-alcoholic fatty liver disease (NAFLD) accompanied by hyperlipidemia. However, the clinical efficacy of QSHY in patients with hyperlipidemia is still lacking. This study aims to investigate the effect and safety of QSHY for hyperlipidemia., Methods: This is a randomized, double-blind, placebo-controlled trial. A total of 210 participants will be enrolled and randomized into the QSHY or placebo granules groups in equal proportions, who will receive treatment for 24 weeks. The primary outcome will be the change in LDL-C from baseline to week 12. Secondary outcomes will be changes in other serum lipids markers, life quality measuring health surveys, and traditional Chinese medicine (TCM) pattern scale. All related tests will be measured at baseline, week 12, and week 24 after enrollment. Adverse events and the safety of intervention will be monitored and evaluated., Discussion: We designed a clinical trial of hyperlipidemia management with QSHY, a TCM prescription. The results of this trial will present the efficacy and safety of QSHY in patients with hyperlipidemia., Trial Registration: Chinese Clinical Trial Registry ChiCTR2000034125 . Registered on June 25, 2019., (© 2022. The Author(s).)

Background: Li-Fraumeni syndrome (LFS) is a rare autosomal dominant cancer predisposition syndrome caused by germline TP53 gene mutations. It is characterized by high risk of early-onset cancer, and has been confirmed as associated with multiple tumors clinically. So pediatricians should be more alert to LFS in children with tumors. Choroid plexus carcinoma (CPC) is a rare, malignant tumor which account for less than 1% of all central nervous system (CNS) tumors. However, when such tumorigenesis occurs, it is important to be vigilant for the presence of LFS., Case Presentation: The first patient is a 32-month-old boy admitted for convulsions and then was found intracranial space-occupying lesion. Underwent operation, he was diagnosis as choroid plexus carcinoma (WHO Grade III). After 5 months, his elder sister, a 13-year-old girl, was brought to emergency department for confusion and intermittent convulsions. Surgery was performed immediately after head CT examination found the lesion. The pathology result indicated glioblastoma. Because the siblings of the same family have successively suffered from malignant tumors, we performed genetic testing on this family. TP53 gene mutation occurred in both children of these two cases from their father, and their other brother was not spared either. So the two siblings both met the diagnostic criteria of LFS. Then they all received systematic anti-tumor therapy, and follow-up hitherto., Conclusion: Here we reported a rare LFS case that two siblings were inherited the same TP53 germline mutations from their father. They suffered from choroid plexus carcinoma and glioblastoma and were finally diagnosed with LFS. In this LFS family, the primary tumors of the two children were both central nervous system tumors, which were not reported in the previous literature. It is suggested that clinicians should be alert to LFS related tumors, which is helpful for early diagnosis. Timely detection of TP53 gene is an important way for early diagnosis of LFS, especially in children with tumor. The incidence of secondary tumor in LFS patients is significantly higher, and other family members of the LFS patient also have an increased risk of suffering from the tumors. Therefore, early diagnosis and timely tumor surveillance can obtain better therapeutic effect and prognosis for both proband and their family., (© 2021. The Author(s).)

Background: Papain-like cysteine proteases (PLCPs), a large group of cysteine proteases, are structurally related to papain. The members belonging to PLCPs family contribute to plant immunity, senescence, and defense responses in plants. The PLCP gene family has been identified in Arabidopsis, rice, soybean, and cotton. However, no systematic analysis of PLCP genes has been undertaken in grapevine. Since Plasmopara viticola as a destructive pathogen could affect immunity of grapes in the field, we considered that the members belonged to PLCPs family could play a crucial role in defensive mechanisms or programmed cell death. We aimed to evaluate the role of PLCPs in 2 different varieties of grapevines and compared the changes of their expressions with the transcriptional data in response to P. viticola., Results: In this study, 23 grapevine PLCP (VvPLCP) genes were identified by comprehensive bioinformatics analysis. Subsequently, the chromosomal localizations, gene structure, conserved domains, phylogenetic relationship, gene duplication, and cis-acting elements were analyzed. Numerous cis-acting elements related to plant development, hormone, and stress responses were identified in the promoter of the VvPLCP genes. Phylogenetic analysis grouped the VvPLCP genes into nine subgroups. The transcription of VvPLCP in different inoculation time points and varieties indicated that VvPLCP may have vital functions in grapevine defense against Plasmopara viticola. According to transcriptome data and qPCR analysis, we observed the increasing expression levels of VvRD21-1 at 72 h after inoculation in resistant variety, inferring that it was related to grape downy mildew resistance. Meanwhile, 3 genes including VvXBCP1, VvSAG12-1, and VvALP1 showed higher expression at 24 h after pathogen inoculation in the susceptible variety and might be related to the downy mildew phenotype. We nominated these four genes to function during hypersensitive response (HR) process, inferring that these genes could be associated with downy mildew resistance in grapes., Conclusions: Our results provide the reference for functional studies of PLCP gene family, and highlight its functions in grapevine defense against P. viticola. The results help us to better understand the complexity of the PLCP gene family in plant immunity and provide valuable information for future functional characterization of specific genes in grapevine., (© 2021. The Author(s).)

Objective: This study aimed to identify risk factors for 30-day mortality in patients who received DeBakey type I aortic dissection (AD) repair surgery., Methods: A total of 830 consecutive patients who received acute DeBakey type I AD surgery between 2014 and 2019 were included in the study. The associations between 30-day mortality and perioperative parameters were examined in order to identify risk factors., Results: Our data suggested that the overall 30-day mortality rate of all enrolled patients was 11.7%. Unsurprisingly, non-survivors were older and more frequently accompanied with histories of cardiovascular diseases. For intraoperative parameters, the prevalence of coronary artery bypass grafting and cardiopulmonary bypass times were increased in non-survivors. In addition, acute kidney injury (AKI), dialysis, stroke, and deep sternal wound infection were more commonly seen among non-survivors. The multivariate logistic regression analysis suggested that cardiovascular disease history, preoperative D-dimer level, drainage volume 24 h after surgery, and postoperative AKI were independent risk factors for 30-day mortality after DeBakey type I aortic dissection repair surgery., Conclusions: Our study demonstrated that cardiovascular disease history, preoperative D-dimer level, drainage volume 24 h after surgery as well as postoperative AKI were risk factors for 30-day mortality after DeBakey type I aortic dissection repair surgery., (© 2021. The Author(s).)

Objective: To investigate the association between sleep duration and cognitive frailty among older adults dwelling in western China., Methods: We used the baseline data from West China Health and Aging Trend (WCHAT) study. Sleep duration was classified as short sleep duration (< 6 h), normal sleep duration (6-8 h) and long sleep duration (≥ 9 h). Fried frailty criteria and Short Portable Mental Status Questionnaire were used to measure cognitive frailty. Multinomial logistic regression was conducted to estimate odds ratio (OR) and 95% confidence interval (CI)., Results: A total of 4093 older adults (age = 67.8 ± 5.9 years, 1708 males and 2385 females) were included in the analysis. The prevalence of cognitive frailty was 11.8% among older adults in western China. Approximately 11.9% participants had short sleep duration (< 6 h); 22.2% had a long sleep duration (≥ 9 h). After adjusting for covariates, only long sleep duration was significantly associated with high risk of cognitive frailty (OR = 2.07, 95%CI = 1.60-2.68, P <  0.001) in western China older adults compared to normal sleep duration., Conclusions: Long sleep duration was significantly related to cognitive frailty in older adults. Intervention for long sleep duration may be helpful to prevent cognitive frailty., Trial Registration: Chinese Clinical Trial Registry: ChiCTR1800018895 ., (© 2021. The Author(s).)

Background: Hepatic dysfunction (HD) increases the morbidity and mortality rates after cardiac surgery. However, few studies have investigated the association between HD and acute DeBakey type I aortic dissection (ADIAD) surgery. This retrospective study aimed to identify risk factors for developing HD in patients who received acute type I aortic dissection repair and its consequences., Methods: A total of 830 consecutive patients who received ADIAD surgery from January 2014 to December 2019 at our center were screened for this study. The End-Stage Liver Disease (MELD) score more than 14 was applied to identify postoperative HD. Logistic regression model was applied to identify risk factors for postoperative HD, Kaplan-Meier survival analysis and Cox proportional hazards regression assay were conducted to analyze the association between HD and postoperative long-term survival., Results: Among 634 patients who eventually enrolled in this study, 401 (63.2%) experienced postoperative HD with a 30-Day mortality of 15.5%. Preoperative plasma fibrinogen level (PFL) [odds ratio (OR): 0.581, 95% confidence interval (CI): 0.362-0.933, P = 0.025], serum creatinine (sCr) on admission (OR: 1.050, 95% CI 1.022-1.079, P < 0.001), cardiopulmonary bypass (CPB) time (OR: 1.017, 95% CI 1.010-1.033, P = 0.039), and postoperative mechanical ventilation (MV) duration (OR: 1.019, 95% CI 1.003-1.035, P = 0.020) were identified as independent risk factors for developing postoperative HD by multivariate analyses. In addition, the Kaplan-Meier analysis indicated that the long-term survival rate was significantly different between patients with or without postoperative HD. However, the hazard ratios of long-term survival for these two groups were not significantly different., Conclusions: HD was a common complication after ADIAD surgery and associated with an increasing 30-Day mortality rate. Decreased PFL, elevated sCr, prolonged CPB duration, and longer postoperative MV time were independent risk factors for postoperative HD., (© 2021. The Author(s).)

Backgrounds: Vitamin D deficiency and insufficiency in older adults seems to be common, but the prevalence estimates are lacking in West China. Previous studies suggested that low vitamin D status was associated with obesity. However, most of them evaluated obesity based on body mass index (BMI) and there are no studies at present exploring the association between vitamin D status and different obesity markers. The present study aims to investigate the prevalence of low vitamin D status and evaluate the association between the vitamin D status and different obesity markers among older adults in West China., Methods: Data was based on the baseline of West China Health and Aging Trends study (WCHAT). All of the participants were older than 60 years old in the present study. Vitamin D status was based on laboratory data, and obesity markers were assessed by bioelectrical impedance analysis (BIA) using the InBody 770 analyzer. Multiple linear regression was performed to find the association between the vitamin D status and various obesity markers., Results: The study included 2661 individuals (mean age: 67.7 ± 6.0 years; males: 41 %). The mean vitamin D level was 18.8 ± 6.3 ng/ml (range: 5 to 59 ng/ml); 5.2 % of participants had a sufficient level of vitamin D, 31.8 % had vitamin D insufficiency, and 63.0 % had vitamin D deficiency. Our results showed that vitamin D status was negatively associated with fat mass index (FMI), visceral fat area (VFA), and waist-hip ratio (WHR) in both sexes. Comparing to other obesity markers, WHR had the strongest correlation with vitamin D status in both sexes (β = -6.090, P = 0.046 in males; β = -11.253, P < 0.001 in females). No significant association was found between vitamin D status and BMI in males., Conclusion: The prevalence of vitamin D insufficiency and deficiency among older adults in West China was high. Among the older adults in west China, WHR showed stronger association with vitamin D status and was better for the prediction of vitamin D insufficiency or deficiency in both sexes, compared to BMI., Trial Registration: Chinese Clinical Trial Registry: ChiCTR1800018895 ., (© 2021. The Author(s).)

Background: Currently no optimal localization technique has been established for localization of ground glass opacity (GGO). We aimed to introduce a localization technique using geometric localization for peripheral GGO., Methods: We delineated the location of pulmonary GGO using geometric method which was similar with localization of a point in a spatial coordinate system. The localization technique was based on the anatomical landmarkers (ribs or intercostal spaces, capitulum costae and sternocostal joints). The geometric parameters were measured on preoperative CT images and the targeted GGO could be identified intraoperatively according to the parameters. We retrospectively collected the data of the patients with peripheral GGOs which were localized using this method and were wedge resected between June 2019 and July 2020. The efficacy and feasibility of the localization technique were assessed., Results: There were 93 patients (male 34, median = 55 years) with 108 peripheral GGOs in the study. All the targeted GGOs were successfully wedge resected in the operative field with negative surgical margin at the first attempt. For each GGO, the localization parameters could be measured in 2-4 min (median = 3 min) on CT images before operation, and surgical resection could be completed in 5-10 min (median = 7 min). A total of 106 (98.15%) GGOs achieved sufficient resection margin. No complications and deaths occurred related to the localization and surgical procedure., Conclusions: The localization technique can achieve satisfactory localization success rate and good safety profile. It can provide an easy-to-use alternative to localize peripheral GGO., (© 2021. The Author(s).)

Background: Recently, a variety of clinical trials have shown that apatinib, a small-molecule anti-angiogenic drug, exerts promising inhibitory effects on multiple solid tumors, including non-small cell lung cancer (NSCLC). However, the underlying molecular mechanism of apatinib on NSCLC remains unclear., Methods: MTT, EdU, AO/EB staining, TUNEL staining, flow cytometry, colony formation assays were performed to investigate the effects of apatinib on cell proliferation, cell cycle distribution, apoptosis and cancer stem like properties. Wound healing and transwell assays were conducted to explore the role of apatinib on migration and invasion. The regulation of apatinib on VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling were detected. Furthermore, we collected conditioned medium (CM) from A549 and H1299 cells to stimulate phorbol myristate acetate (PMA)-activated THP-1 cells, and examined the effect of apatinib on PD-L1 expression in macrophages. The Jurkat T cells and NSCLC cells co-culture model was used to assess the effect of apatinib on T cells activation. Subcutaneous tumor formation models were established to evaluate the effects of apatinib in vivo. Histochemical, immunohistochemical staining and ELISA assay were used to examine the levels of signaling molecules in tumors., Results: We showed that apatinib inhibited cell proliferation and promoted apoptosis in NSCLC cells in vitro. Apatinib induced cell cycle arrest at G1 phase and suppressed the expression of Cyclin D1 and CDK4. Moreover, apatinib upregulated Cleaved Caspase 3, Cleaved Caspase 9 and Bax, and downregulated Bcl-2 in NSCLC cells. The colony formation ability and the number of CD133 positive cells were significantly decreased by apatinib, suggesting that apatinib inhibited the malignant and stem-like features of NSCLC cells. Mechanistically, apatinib inhibited PD-L1 and c-Myc expression by targeting VEGFR2/STAT3 signaling. Apatinib also inhibited PD-L1 expression in THP-1 derived macrophages stimulated by CM from NSCLC cells. Furthermore, apatinib pretreatment increased CD69 expression and IFN-γ secretion in stimulated Jurkat T cells co-cultured with NSCLC cells. Apatinib also promoted ROS production and inhibited Nrf2 and p62 expression, leading to the autophagic and apoptotic cell death in NSCLC. Moreover, apatinib significantly inhibited tumor growth in vivo., Conclusion: Our data indicated that apatinib induced autophagy and apoptosis in NSCLC via regulating VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling., (© 2021. The Author(s).)

Background: Early prediction of acute kidney injury (AKI) after liver transplantation (LT) facilitates timely recognition and intervention. We aimed to build a risk predictor of post-LT AKI via supervised machine learning and visualize the mechanism driving within to assist clinical decision-making., Methods: Data of 894 cases that underwent liver transplantation from January 2015 to September 2019 were collected, covering demographics, donor characteristics, etiology, peri-operative laboratory results, co-morbidities and medications. The primary outcome was new-onset AKI after LT according to Kidney Disease Improving Global Outcomes guidelines. Predicting performance of five classifiers including logistic regression, support vector machine, random forest, gradient boosting machine (GBM) and adaptive boosting were respectively evaluated by the area under the receiver-operating characteristic curve (AUC), accuracy, F1-score, sensitivity and specificity. Model with the best performance was validated in an independent dataset involving 195 adult LT cases from October 2019 to March 2021. SHapley Additive exPlanations (SHAP) method was applied to evaluate feature importance and explain the predictions made by ML algorithms., Results: 430 AKI cases (55.1%) were diagnosed out of 780 included cases. The GBM model achieved the highest AUC (0.76, CI 0.70 to 0.82), F1-score (0.73, CI 0.66 to 0.79) and sensitivity (0.74, CI 0.66 to 0.8) in the internal validation set, and a comparable AUC (0.75, CI 0.67 to 0.81) in the external validation set. High preoperative indirect bilirubin, low intraoperative urine output, long anesthesia time, low preoperative platelets, and graft steatosis graded NASH CRN 1 and above were revealed by SHAP method the top 5 important variables contributing to the diagnosis of post-LT AKI made by GBM model., Conclusions: Our GBM-based predictor of post-LT AKI provides a highly interoperable tool across institutions to assist decision-making after LT., (© 2021. The Author(s).)

Background: X-linked sideroblastic anemia (XLSA) is the most common form of congenital sideroblastic anemia (CSA), and is associated with the mutations in the 5-aminolevulinate synthase 2 (ALAS2). The genetic basis of more than 40% of CSA cases remains unknown., Methods: A two-generation Chinese family with XLSA was studied by next-generation sequencing to identify the underlying CSA-related mutations., Results: In the study, we identified a missense ALAS2 R204Q mutation in a hemizygous Chinese Han man and in his heterozygous daughter. The male proband presented clinical manifestations at 38 years old and had a good response to pyridoxine., Conclusions: XLSA, as a hereditary disease, can present clinical manifestations later in lives, for adult male patients with ringed sideroblasts and hypochromic anemia, it should be evaluated with gene analyses to exclude CSA.