Search

Abstract Background and objectives Congenital heart defect (CHD) is one of the most common birth defects. The aim of this cohort study was to evaluate the prevalence of chromosomal abnormalities and the clinical utility of chromosomal microarray analysis (CMA) in fetuses with different types of CHD, aiming to assist genetic counseling and clinical decision-making. Methods In this study, 642 fetuses with CHD were enrolled from a single center over a six-year period (2017–2022). Both conventional karyotyping and CMA were performed simultaneously on these fetuses. Results The diagnostic yield of CMA in fetuses with CHD in our study was 15.3% (98/642). Our findings revealed a significant increase in the diagnostic yield of CMA compared to karyotyping in fetuses with CHD. Among CHD subgroups, the diagnostic yields were high in complex CHD (34.9%), conotruncal defects (28.6%), right ventricular outflow tract obstructive defects (RVOTO) (25.9%), atrioventricular septal defects (AVSD) (25.0%) and left ventricular outflow tract obstructive defects (LVOTO) (24.1%), while those in other CHD (10.6%) and septal defects (10.9%) were relatively low. The overall detection rate of clinically significant chromosomal abnormalities was significantly higher in the non-isolated CHD group compared to the isolated CHD group (33.1% vs. 9.9%, P

A highly pH-responsive gelatin film incorporating purple cabbage anthocyanin (PCA) and chondroitin sulphate (CS)/tannic acid (TA) was developed. Co-pigmentation of PCA via CS/TA improved its photothermal stability and visibility of color change in gelatin film. The morphological and structural properties of CS-PCA and TA-PCA films revealed that a more stable network was formed as new hydrogen bonds were generated by the co-pigmentation. Meanwhile, the co-pigmentation improved film's mechanical and hydrophobic properties, expressed as higher tensile strength (16.65 and 17.97 Mpa) and lower water vapor permeability (1.45 and 1.41) in CS-PCA and TA-PCA films, compared to PCA film. CS-PCA and TA-PCA films showed distinct color transitions for chilled fish fillets during storage. Total color difference (ΔE) of CS-PCA and TA-PCA films correlated well with the deterioration indexes of total volatile base nitrogen (TVB-N). All the results provided a novel pH-sensitive intelligent packaging strategy by co-pigmenting CS/TA with PCA for freshness monitoring.

PurposeThis meta-analysis aimed to evaluate the diagnostic efficacy of dual-energy computed tomography (DECT) in detecting cervical lymph node metastasis among papillary thyroid cancer (PTC) patients.MethodsA comprehensive search across PubMed, Embase, and Web of Science databases was conducted to identify pertinent publications up to May 2024. This search focused on studies examining the diagnostic accuracy of DECT in detecting cervical lymph node metastases in PTC patients. We employed a bivariate random-effects model to calculate pooled sensitivity and specificity of DECT. The degree of heterogeneity in the studies was quantified using the I2 statistic. Furthermore, the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool was utilized to evaluate the methodological quality of the included studies.ResultsThis meta-analysis encompassed 14 articles, collectively involving 1,615 patients. The pooled sensitivity, specificity, and AUC for DECT in detecting cervical lymph node metastases in PTC patients were 0.81 (95% CI: 0.76–0.85), 0.86 (95% CI: 0.80–0.91), and 0.89 (95% CI: 0.86–0.92), respectively. According to Fagan’s nomogram, for DECT, with a pre-test probability of 50%, the post-test probability was calculated as 85% for a positive result and 18% for a negative result. Deeks’ funnel plot asymmetry test showed no significant publication bias was observed for DECT (p = 0.28).ConclusionOur meta-analysis indicates that DECT demonstrates superior sensitivity and specificity in cervical lymph node metastasis among PTC patients. To corroborate these findings and evaluate their clinical applicability, further prospective studies are necessary.

This study presents the first column-averaged dry-air mole fractions of carbon dioxide (XCO2), methane (XCH4) and carbon monoxide (XCO) in the coal mine aggregation area in Shanxi, China, using two portable Fourier transform infrared spectrometers (EM27/SUNs), in the framework of the Collaborative Carbon Column Observing Network (COCCON). The measurements, collected over two months, were analyzed. Significant daily variations were observed, particularly in XCH4, which highlight the impact of coal mining emissions as a major CH4 source in the region. This study also compares COCCON XCO with measurements from the TROPOspheric Monitoring Instrument (TROPOMI) onboard the Sentinel-5P satellite, revealing good agreement, with a mean bias of 7.15 ± 9.49 ppb. Additionally, comparisons were made between COCCON XCO2 and XCH4 data and analytical data from the Copernicus Atmosphere Monitoring Service (CAMS). The mean biases between COCCON and CAMS were −6.43 ± 1.75 ppm for XCO2 and 15.40 ± 31.60 ppb for XCH4. The findings affirm the stability and accuracy of the COCCON instruments for validating satellite observations and detecting local greenhouse gas sources. Operating COCCON spectrometers in coal mining areas offers valuable insights into emissions from these high-impact sources.

IntroductionInterleukin 15 (IL-15) is a potential anticancer agent and numerous engineered IL-15 agonists are currently under clinical investigation. Selective targeting of IL-15 to specific lymphocytes may enhance therapeutic effects while helping to minimize toxicities.MethodsWe designed and built a heterodimeric targeted cytokine (TaCk) that consists of an anti-programmed cell death 1 receptor antibody (anti-PD-1) and an engineered IL-15. This “PD1/IL15” selectively delivers IL-15 signaling to lymphocytes expressing PD-1. We then investigated the pharmacokinetic (PK) and pharmacodynamic (PD) effects of PD1/IL15 TaCk on immune cell subsets in cynomolgus monkeys after single and repeat intravenous dose administrations. We used these results to determine the first-in-human (FIH) dose and dosing frequency for early clinical trials.ResultsThe PD1/IL15 TaCk exhibited a nonlinear multiphasic PK profile, while the untargeted isotype control TaCk, containing an anti-respiratory syncytial virus antibody (RSV/IL15), showed linear and dose proportional PK. The PD1/IL15 TaCk also displayed a considerably prolonged PK (half-life range ∼1.0–4.1 days) compared to wild-type IL-15 (half-life ∼1.1 h), which led to an enhanced cell expansion PD response. The PD was dose-dependent, durable, and selective for PD-1+ lymphocytes. Notably, the dose- and time-dependent PK was attributed to dynamic TMDD resulting from test article-induced lymphocyte expansion upon repeat administration. The recommended first-in-human (FIH) dose of PD1/IL15 TaCk is 0.003 mg/kg, determined based on a minimum anticipated biological effect level (MABEL) approach utilizing a combination of in vitro and preclinical in vivo data.ConclusionThis work provides insight into the complex PK/PD relationship of PD1/IL15 TaCk in monkeys and informs the recommended starting dose and dosing frequency selection to support clinical evaluation of this novel targeted cytokine.

Objective To evaluate the safety and preliminary efficacy of YSCH-01 (Recombinant L-IFN adenovirus) in subjects with advanced solid tumors.Methods In this single-center, open-label, investigator-initiated trial of YSCH-01, 14 patients with advanced solid tumors were enrolled. The study consisted of two distinct phases: (1) the dose escalation phase and (2) the dose expansion phase; with three dose groups in the dose escalation phase based on dose levels (5.0×109 viral particles (VP)/subject, 5.0×1010 VP/subject, and 5.0×1011 VP/subject). Subjects were administered YSCH-01 injection via intratumoral injections. The safety was assessed using National Cancer Institute Common Terminology Criteria for Adverse Events V.5.0, and the efficacy evaluation was performed using Response Evaluation Criteria in Solid Tumor V.1.1.Results 14 subjects were enrolled in the study, including 9 subjects in the dose escalation phase and 5 subjects in the dose expansion phase. Of the 13 subjects included in the full analysis set, 4 (30.8%) were men and 9 (69.2%) were women. The most common tumor type was lung cancer (38.5%, 5 subjects), followed by breast cancer (23.1%, 3 subjects) and melanoma (23.1%, 3 subjects). During the dose escalation phase, no subject experienced dose-limiting toxicities. The content of recombinant L-IFN adenovirus genome and recombinant L-IFN protein in blood showed no trend of significant intergroup changes. No significant change was observed in interleukin-6 and interferon-gamma. For 11 subjects evaluated for efficacy, the overall response rate with its 95% CI was 27.3% (6.02% to 60.97%) and the disease control rate with its 95% CI was 81.8% (48.22% to 97.72%). The median progression-free survival was 4.97 months, and the median overall survival was 8.62 months. In addition, a tendency of decrease in the sum of the diameters of target lesions was observed. For 13 subjects evaluated for safety, the overall incidence of adverse events (AEs) was 92.3%, the overall incidence of adverse drug reactions (ADRs) was 84.6%, and the overall incidence of >Grade 3 AEs was 7.7%, while no AEs/ADRs leading to death occurred. The most common AEs were fever (69.2%), nausea (30.8%), vomiting (30.8%), and hypophagia (23.1%).Conclusions The study shows that YSCH-01 injections were safe and well tolerated and exhibited preliminary efficacy in patients with advanced solid tumors, supporting further investigation to evaluate its efficacy and safety.Trial registration number NCT05180851.

Abstract Background Individuals with X chromosomal translocations, variable phenotypes, and a high risk of live birth defects are of interest for scientific study. These characteristics are related to differential breakpoints and various types of chromosomal abnormalities. To investigate the effects of X chromosome translocation on clinical phenotype, a retrospective analysis of clinical data for patients with X chromosome translocation was conducted. Karyotype analysis plus endocrine evaluation was utilized for all the patients. Additional semen analysis and Y chromosome microdeletions were assessed in male patients. Results X chromosome translocations were detected in ten cases, including seven females and three males. Infantile uterus and no ovaries were detected in case 1 (FSH: 114 IU/L, LH: 30.90 mIU/mL, E2:

Abstract Argonaute proteins (Agos) bind short nucleic acids as guides and are directed by them to recognize target complementary nucleic acids. Diverse prokaryotic Agos (pAgos) play potential functions in microbial defense. The functions and mechanisms of a group of full-length yet catalytically inactive pAgos, long-B pAgos, remain unclear. Here, we show that most long-B pAgos are functionally connected with distinct associated proteins, including nucleases, Sir2-domain-containing proteins and trans-membrane proteins, respectively. The long-B pAgo-nuclease system (BPAN) is activated by guide RNA-directed target DNA recognition and performs collateral DNA degradation in vitro. In vivo, the system mediates genomic DNA degradation after sensing invading plasmid, which kills the infected cells and results in the depletion of the invader from the cell population. Together, the BPAN system provides immunoprotection via abortive infection. Our data also suggest that the defense strategy is employed by other long-B pAgos equipped with distinct associated proteins.

Abstract Background Low-pass genome sequencing (LP GS) has shown distinct advantages over traditional methods for the detection of mosaicism. However, no study has systematically evaluated the accuracy of LP GS in the detection of mosaic aneuploidies and copy number variants (CNVs) in prenatal diagnosis. Moreover, the influence of sequencing depth on mosaicism detection of LP GS has not been fully evaluated. Methods To evaluate the accuracy of LP GS in the detection of mosaic aneuploidies and mosaic CNVs, 27 samples with known aneuploidies and CNVs and 1 negative female sample were used to generate 6 simulated samples and 21 virtual samples, each sample contained 9 different mosaic levels. Mosaic levels were simulated by pooling reads or DNA from each positive sample and the negative sample according to a series of percentages (ranging from 3 to 40%). Then, the influence of sequencing depth on LP GS in the detection of mosaic aneuploidies and CNVs was evaluated by downsampling. Results To evaluate the accuracy of LP GS in the detection of mosaic aneuploidies and CNVs, a comparative analysis of mosaic levels was performed using 6 simulated samples and 21 virtual samples with 35 M million (M) uniquely aligned high-quality reads (UAHRs). For mosaic levels > 30%, the average difference (detected mosaic levels vs. theoretical mosaic levels) of 6 mosaic CNVs in simulated samples was 4.0%, and the average difference (detected mosaic levels vs. mosaic levels of Y chromosome) of 6 mosaic aneuploidies and 15 mosaic CNVs in virtual samples was 2.7%. Furthermore, LP GS had a higher detection rate and accuracy for the detection of mosaic aneuploidies and CNVs of larger sizes, especially mosaic aneuploidies. For depth evaluation, the results of LP GS in downsampling samples were compared with those of LP GS using 35 M UAHRs. The detection sensitivity of LP GS for 6 mosaic aneuploidies and 15 mosaic CNVs in virtual samples increased with UAHR. For mosaic levels > 30%, the total detection sensitivity reached a plateau at 30 M UAHRs. With 30 M UAHRs, the total detection sensitivity was 99.2% for virtual samples. Conclusions We demonstrated the accuracy of LP GS in mosaicism detection using simulated data and virtual samples, respectively. Thirty M UAHRs (single-end 35 bp) were optimal for LP GS in the detection of mosaic aneuploidies and most mosaic CNVs larger than 1.48 Mb (Megabases) with mosaic levels > 30%. These results could provide a reference for laboratories that perform clinical LP GS in the detection of mosaic aneuploidies and CNVs.

Abstract Background Thalassemia is an extremely prevalent monogenic inherited blood disorder in southern China. It is important to comprehensively understand the molecular spectrum of thalassemia in an area with such a high prevalence of thalassemia before taking appropriate actions for the prevention and treatment of this disorder. Herein, we explored the clinical feasibility of using next-generation sequencing (NGS) for large-scale population screening to illustrate the prevalence and spectrum of thalassemia in Southern Jiangxi. Methods Blood samples collected from 136,312 residents of reproductive age in Southern Jiangxi were characterized for thalassemia by NGS. A retrospective analysis was then conducted on blood samples determined to be positive for thalassemia. Results In total, 19,827 (14.545%) subjects were diagnosed as thalassemia carriers, and the thalassemia prevalence rate significantly varied by geographical region (p T accounting for 35.257% of these β-thalassemia genotypes. Furthermore, 74 genotypes were identified among 608 individuals with combined α- and β-thalassemia. Notably, most individuals with rare thalassemia mutations had mildly abnormal hematologic parameters including microcytic hypochromia. Conclusions Our findings demonstrate the great heterogeneity and diverse spectrum of thalassemia in Southern Jiangxi, emphasizing the importance and necessity of persistent prevention and control of thalassemia in this region. Additionally, our findings further suggest that NGS can effectively identify rare mutations and reduce the misdiagnosis rate of thalassemia.

Background: Preconception or prenatal carrier screening plays an important role in reproductive decision-making, but current research on hereditary deafness is limited. This study aimed to investigate the carrier frequencies of common deafness genes in the Chinese population who underwent carrier screening and to follow up on pregnancy outcomes in high-chance couples.Methods: Individual females or couples in preconception or early pregnancy were recruited from two hospitals in China. Carrier screening for common deafness genes in the Chinese population, including the GJB2 and SLC26A4 genes, was performed using next-generation sequencing technology. Genetic counseling was provided to subjects before and after testing.Results: Of the 9,993 subjects screened, the carrier rate was 2.86% for the GJB2 gene and 2.63% for the SLC26A4 gene. The variant with the highest carrier frequency in GJB2 was c.235delC (1.89%), and c.919–2A>G (1.08%) in SLC26A4. Of the six high-chance couples, four made alternative reproductive decisions (three with prenatal diagnosis and one with preimplantation genetic testing), with consequent termination of the birth of two affected fetuses.Conclusion: These findings confirmed the clinical utility of preconception or prenatal carrier screening for hereditary deafness.

Abstract Most variations in the human genome refer to single-nucleotide variation (SNV), small fragment insertions and deletions, and genomic copy number variation (CNV). Many human diseases including genetic disorders are associated with variations in the genome. These disorders are often difficult to be diagnosed because of their complex clinical conditions, therefore, an effective detection method is needed to facilitate clinical diagnosis and prevent birth defects. With the development of high-throughput sequencing technology, the method of targeted sequence capture chip has been extensively used owing to its high throughput, high accuracy, fast speed, and low cost. In this study, we designed a chip that potentially captured the coding region of 3043 genes associated with 4013 monogenic diseases, with an addition of 148 chromosomal abnormalities that can be identified by targeting specific regions. To assess the efficiency, a strategy of combining the BGISEQ500 sequencing platform with the designed chip was utilized to screen variants in 63 patients. Eventually, 67 disease-associated variants were found, 31 of which were novel. The results of the evaluation test also show that this combined strategy complies with the requirements of clinical testing and has proper clinical application value.

In this study, we propose a novel method for detecting cyberattack behaviors by leveraging the combined strengths of large language models and a synchronized attention mechanism. Extensive experiments conducted on diverse datasets, including server logs, financial behaviors, and comment data, demonstrate the significant advantages of this method over existing models such as Transformer, BERT, OPT-175B, LLaMa, and ChatGLM3-6B in key performance metrics such as precision, recall, and accuracy. For instance, on the server log dataset, the method achieved a precision of 93%, a recall of 91%, and an accuracy of 92%; on the financial behavior dataset, it reached a precision of 90%, a recall of 87%, and an accuracy of 89%; and on the comment data dataset, it excelled with a precision of 95%, a recall of 93%, and an accuracy of 94%. The introduction of a synchronized attention mechanism and a newly designed synchronized loss function proved especially effective, enhancing the method’s ability to process multi-source data and providing superior performance in identifying complex cyberattack patterns. Ablation experiments further validated the crucial roles of these innovations in boosting model performance: the synchronous attention mechanism substantially improved the model’s precision, recall, and accuracy to 93%, 89%, and 91% respectively, far exceeding other attention mechanisms. Similarly, the synchronized loss showcased a significant advantage, achieving the best performance across all tested metrics compared to traditional cross-entropy loss, focal loss, and MSE. These results underscore the method’s ability to deeply mine and analyze semantic information and contextual relationships within text data as well as to effectively integrate and process multimodal data, thereby offering strong technical support for the accurate and efficient detection of cyberattack behaviors.

Background and purpose: Intellectual disability-7 (MRD7) is a subtype disorder of intellectual disability (MRD) involving feeding difficulties, hypoactivity, and febrile seizures at an age of early onset, then progressive intellectual and physical development deterioration. We purposed to identify the underlying causative genetic factors of three individuals in each Chinese family who presented with symptoms of intellectual disability and facial dysmorphic features. We provided prenatal diagnosis for the three families and genetic counseling for the prevention of this disease.Methods: We collected retrospective clinical diagnostic evidence for the three probands in our study, which included magnetic resonance imaging (MRI), computerized tomography (CT), electroencephalogram (EEG), and intelligence tests for the three probands in our study. Genetic investigation of the probands and their next of kin was performed by Trio-whole exome sequencing (WES). Sanger sequencing or quantitative PCR technologies were then used as the next step to verify the variants confirmed with Trio-WES for the three families. Moreover, we performed amniocentesis to explore the state of the three pathogenic variants in the fetuses by prenatal molecular genetic diagnosis at an appropriate gestational period for the three families.Results: The three probands and one fetus were clinically diagnosed with microcephaly and exhibited intellectual developmental disability, postnatal feeding difficulties, and facial dysmorphic features. Combining probands’ clinical manifestations, Trio-WES uncovered the three heterozygous variants in DYRK1A: a novel variant exon3_exon4del p.(Gly4_Asn109del), a novel variant c.1159C>T p.(Gln387*), and a previously presented but rare pathogenic variant c.1309C>T p.(Arg437*) (NM_001396.5) in three families, respectively. In light of the updated American College of Medical Genetic and Genomics (ACMG) criterion, the variant of exon3_exon4del and c.1159C>T were both classified as likely pathogenic (PSV1+PM6), while c1309C>T was identified as pathogenic (PVS1+PS2_Moderate+PM2). Considering clinical features and molecular testimony, the three probands were confirmed diagnosed with MRD7. These three discovered variants were considered as the three causal mutations for MRD7. Prenatal diagnosis detected the heterozygous dominant variant of c.1159C>T p.(Gln387*) in one of the fetuses, indicating a significant probability of MRD7, subsequently the gestation was intervened by the parents’ determination and professional obstetrical operation. On the other side, prenatal molecular genetic testing revealed wild-type alleles in the other two fetuses, and their parents both decided to sustain the gestation.Conclusion: We identified two novel and one rare mutation in DYRK1A which has broadened the spectrum of DYRK1A and provided evidence for the diagnosis of MRD7 at the molecular level. Besides, this study has supported the three families with MRD7 to determine the causative genetic factors efficiently and provide concise genetic counseling for the three families by using Trio-WES technology.

Background Thyroid-associated orbitopathy (TAO) is a disease associated with autoimmune thyroid disorders and it can lead to proptosis, diplopia, and vision-threatening compressive optic neuropathy. To comprehensively understand the molecular mechanisms underlying orbital adipogenesis in TAO, we characterize the intrinsic molecular properties of orbital adipose/connective tissue from patients with TAO and control individuals. Methods RNA sequencing analysis (RNA-seq) was performed to measure the gene expression of orbital adipose/connective tissues of TAO patients. Differentially expressed genes (DEGs) were detected and analyzed through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and Gene Set Enrichment Analysis (GSEA). The protein–protein interaction (PPI) network was constructed using the STRING database, and hub genes were identified by the Cytoscape plug-in, cytoHubba. We validated several top DEGs through quantitative real-time polymerase chain reaction (qRT–PCR). Results We identified 183 DEGs in adipose tissue between TAO patients (n = 3) and control patients (n = 3) through RNA sequencing, including 114 upregulated genes and 69 downregulated genes. The PPI network of these DEGs had 202 nodes and 743 edges. PCR-based validation results of orbital adipose tissue showed multiple top-ranked genes in TAO patients (n = 4) are immune and inflammatory response genes compared with the control individual (n = 4). They include ceruloplasmin isoform x3 (CP), alkaline tissue-nonspecific isozyme isoform x1 (ALPL), and angiotensinogen (AGT), which were overrepresented by 2.27- to 6.40-fold. Meanwhile, protein mab-21-like 1 (MAB21L1), phosphoinositide 3-kinase gamma-subunit (PIK3C2G), and clavesin-2 (CLVS2) decreased by 2.6% to 32.8%. R-spondin 1 (RSPO1), which is related to oogonia differentiation and developmental angiogenesis, was significantly downregulated in the orbital muscle tissues of patients with TAO compared with the control groups (P = 0.024). Conclusions Our results suggest that there are genetic differences in orbital adipose-connective tissues derived from TAO patients. The upregulation of the inflammatory response in orbital fat of TAO may be consistent with the clinical phenotype like eyelid edema, exophthalmos, and excess tearing. Downregulation of MAB21L1, PIK3C2G, and CLVS2 in TAO tissue demonstrates dysregulation of differentiation, oxidative stress, and developmental pathways.

Background Initiation of dialysis encompasses new cardiovascular challenges on patients with end-stage renal disease (ESRD). This study used two-dimensional speckle-tracking echocardiography (2D-STE) to investigate the change of left ventricular (LV) myocardial function undergoing peritoneal dialysis (PD) within 1–3 months.Methods A total of 56 patients with ESRD and 27 healthy controls were enrolled in this prospective study. Mean duration of PD was 44.41 ± 16.44 days. We evaluated LV myocardial function of patients with ESRD in baseline and within 1–3 months after PD by 2D-STE with global longitudinal strains (GLS) and myocardial work (MW). Based on the level of serum phosphate before PD, patients were divided into two groups: the group with normal serum phosphate or hyperphosphatemia.Results Compared with healthy controls, patients with ESRD had impaired GLS (p .05) and no significant improvement was observed in GLS (p = .387). GLS of basal segments worsened in the hyperphosphatemia group (p = .005) and GWW reduced remarkably in the group with normal serum phosphate after PD treatment (p = .008). The change of left ventricular internal diameter in diastole (LVIDd) was the only parameter influenced GWI in post-dialysis patients (β = 0.324, p = .013).Conclusions Short-term PD treatment improved LV MW in ESRD patients. They benefited more when receiving treatment before the increase of serum phosphorus.

BackgroundEpilepsy is characterized by recurrent unprovoked seizures. Mutations in the voltage-gated sodium channel alpha subunit 1 (SCN1A) gene are the main monogenic cause of epilepsy. Type and location of variants make a huge difference in the severity of SCN1A disorder, ranging from the mild phenotype (genetic epilepsy with febrile seizures plus, GEFS+) to the severe phenotype (developmental and epileptic encephalopathies, DEEs). Dravet Syndrome (DS) is an infantile-onset DEE, characterized by drug-resistant epilepsy and temperature sensitivity or febrile seizures. Genetic test results reveal SCN1A variants are positive in 80% DS patients and DS is mainly caused by de novo variants.MethodsTrio-whole exome sequencing (WES) was used to detect variants which were associated with clinical phenotype of five probands with epilepsy or twitching. Then, Sanger sequencing was performed to validate the five novel SCN1A variants and segregation analysis. After analyzing the location of five SCN1A variants, the pathogenic potential was assessed.ResultsIn this study, we identified five novel SCN1A variants (c.4224G > C, c.3744_3752del, c.209del, c.5727_5734delTTTAAAACinsCTTAAAAAG and c.5776delT) as the causative variants. In the five novel SCN1A variants, four were de novo and the remaining one was inherited. All novel variants would be classified as “pathogenic” or “likely pathogenic.”ConclusionThe five novel SCN1A variants will enrich the SCN1A mutations database and provide the corresponding reference data for the further genetic counseling.

Abstract Objective Connexin 43 (Cx43) is a critical gene for maintaining myocardial homeostasis. Interestingly, Cx43 and stress‐induced phosphoprotein 1 (STIP1) were recorded to be lowly expressed in ischemia/reperfusion (I/R). However, their impacts on reperfusion arrhythmia (RA) remain to be explored. Our study aimed to find out the related underlying mechanisms. Methods After the establishment of an isolated heart model through Langendorff perfusion, the heart rate, conduction activation time, conduction velocity, and conduction direction of the left ventricle were evaluated, along with the apoptotic rate detection in the collected myocardial tissues. After the construction of a hypoxia/reoxygenation (H/R)‐induced cellular model, cell apoptosis, intercellular communication, cell viability, and the content of reactive oxygen species, superoxide dismutase, malondialdehyde, and lactic dehydrogenase were measured. The expression of Cx43 and STIP1 was determined in both rat heart and cell models. The bindings of STIP3 and Cx43 to heat shock protein 90 (HSP90) and heat shock protein 70 (HSP70) were verified. Results Relative to the corresponding controls, Cx43 and STIP1 were decreased in myocardial tissues of RA rats and H/R‐stimulated H9C2 cells, where Cx43‐binding HSP70 and HSP90 were respectively increased and decreased, and ubiquitination level of Cx43 was enhanced. STIP1 overexpression promoted protein expression of Cx43, intercellular communication, and cell viability, and reduced cell apoptosis and oxidative stress in H/R‐stimulated H9C2 cells. Conclusion STIP1 promoted Cx43 expression to improve intercellular communication and reduce oxidative stress in H/R‐stimulated H9C2 cells.

In the face of uncertainty in customer demand and dynamic traffic conditions, determining the optimal logistics distribution route under deterministic conditions becomes challenging. To address this issue, we propose a novel approach by adopting Robust Optimization Models for Electric Vehicle Path Optimization. Our robust optimization model incorporates two uncertainty sets, namely the convex set and the box set, to tackle variations in demand and speed. By introducing deviation coefficients, we compare the objective function values of the robust optimization model with those of the deterministic model. This enables us to understand the trade-offs between robustness and optimality. To find solutions for various instance sizes, we apply an improved genetic algorithm to solve the constructed model efficiently. Our case study results demonstrate that while the optimal objective function value of the robust optimization model may be higher than that of the deterministic model, it ensures the feasibility of the path even amidst demand fluctuations and dynamic traffic conditions. Moreover, we analyze the economic returns of velocity and demand under both uncertainty sets with different data sizes, using the deviation coefficients. These discoveries provide valuable perspectives for pertinent departments, assisting them in rendering well-informed choices and attaining practical significance in real-world scenarios. To recapitulate, our study introduces an innovative methodology for addressing the challenges of optimizing electric vehicle routes in the face of unpredictable demand fluctuations and time-dependent speed variations. By demonstrating the effectiveness of our proposed robust optimization model, we contribute to the advancement of logistics and transportation systems in a volatile and uncertain environment.

An improved road impedance function in conformity with Chinese city road traffic is designed for calculating the actual transportation time based on real-time traffic information and the complex road environment in the city. The objective function minimizes the total distribution cost, including fixed cost, transportation cost, damage cost, energy cost, penalty cost, and carbon emission cost. A mathematical model is constructed for cold-chain logistics distribution path optimization considering the influence of road impedance. The model is solved using three particle swarm optimization algorithms with improved weights. The experimental results show that the self-adaptive weighted particle swarm optimization algorithm is more efficient in solving this model. Experimental results obtained from the cold-chain logistics path optimization model considering road impedance compared to those of the model without road impedance indicate that the former are closer to the actual situation. Based on the changes in carbon emission and total cost under different carbon taxes, we analyze the critical carbon tax value and the optimal carbon tax value range to improve the economic and environmental benefits in the distribution process. This study should prove to be of great practical significance and application value for logistics enterprises to conduct rational planning of path problems.

Background and aims: Certain chromosomal structural variations (SVs) in biological parents can lead to recurrent spontaneous abortions (RSAs). Unequal crossing over during meiosis can result in the unbalanced rearrangement of gamete chromosomes such as duplication or deletion. Unfortunately, routine techniques such as karyotyping, fluorescence in situ hybridization (FISH), chromosomal microarray analysis (CMA), and copy number variation sequencing (CNV-seq) cannot detect all types of SVs. In this study, we show that optical genome mapping (OGM) quickly and accurately detects SVs for RSA patients with a high resolution and provides more information about the breakpoint regions at gene level.Methods: Seven couples who had suffered RSA with unbalanced chromosomal rearrangements of aborted embryos were recruited, and ultra-high molecular weight (UHMW) DNA was isolated from their peripheral blood. The consensus genome map was created by de novo assembly on the Bionano Solve data analysis software. SVs and breakpoints were identified via alignments of the reference genome GRCh38/hg38. The exact breakpoint sequences were verified using either Oxford Nanopore sequencing or Sanger sequencing.Results: Various SVs in the recruited couples were successfully detected by OGM. Also, additional complex chromosomal rearrangement (CCRs) and four cryptic balanced reciprocal translocations (BRTs) were revealed, further refining the underlying genetic causes of RSA. Two of the disrupted genes identified in this study, FOXK2 [46,XY,t(7; 17)(q31.3; q25)] and PLXDC2 [46,XX,t(10; 16)(p12.31; q23.1)], had been previously shown to be associated with male fertility and embryo transit.Conclusion: OGM accurately detects chromosomal SVs, especially cryptic BRTs and CCRs. It is a useful complement to routine human genetic diagnostics, such as karyotyping, and detects cryptic BRTs and CCRs more accurately than routine genetic diagnostics.

As a new delivery mode, the collaborative delivery of packages using trucks and drones has been proven to reduce delivery costs and delivery time. To cope with the huge cost challenges brought by strict time constraints and ever-changing customer orders in the actual delivery process, we established a two-stage optimization model based on different demand response strategies with the goal of minimizing delivery costs. To solve this problem, we designed a simulated annealing chimp optimization algorithm with a sine–cosine operator. The performance of this algorithm is improved by designing a variable-dimensional matrix encode to generate an initial solution, incorporating a sine–cosine operator and a simulated annealing mechanism to avoid falling into a local optimum. Numerical experiments verify the effectiveness of the proposed algorithm and strategy. Finally, we analyze the impact of dynamic degree on delivery cost. The proposed model and algorithm extend the theory of the vehicle routing problem with drones and also provide a feasible solution for route planning, taking into account dynamic demands and time windows.

Changes in cerebral blood flow (CBF) and regulation of cerebral circulation occur at high altitude (HA). However, the changes in CBF and their associations with neurological syndrome sequelae and blood pressure after subjects return to the lowlands remain unclear. In this study, the subjects were 23 college students who were teaching at an altitude of 4300 m for 30 days. These subjects were studied before reaching the HA (Test 1), one week after returning to the lowlands (Test 2), and three months after returning to the lowlands (Test 3). Symptom scores for de-acclimatization syndrome were evaluated. Changes in CBF were measured using the magnetic resonance imaging arterial spin labeling (ASL) technique. Additionally, the velocity of CBF in the cerebral arteries was measured using a transcranial doppler (TCD). In Test 2 vs. Test 1, the peak systolic velocity and mean velocity in the basilar artery were significantly decreased. CBF exhibited significant decreases in the left putamen/cerebellum crus1/vermis and right thalamus/inferior temporal gyrus, while significant increases were observed in the left postcentral gyrus/precuneus and right middle cingulate gyrus/superior frontal gyrus. In Test 3 vs. Test 1, the basilar artery velocity returned to the baseline level, while CBF continued to decrease. The mean global CBF showed a decreasing trend from Test 1 to Test 3. Furthermore, the mean global CBF had a negative correlation with the systolic pressure, pulse pressure, and mean arterial pressure. The decrease in CBF after reoxygenation may underlie the neurological symptoms in subjects returning to the lowlands. Increased blood pressure could serve as a predictor of a decrease in CBF.

In this paper, the image sensor compensation frameworks are established based on the correlation of pixel response characteristics; The pixel response model is established, and a method to measure the crosstalk of adjacent pixels of color image sensor under flat field light is proposed; at the same time, an artificial neural network training set is constructed by using the measured values and theoretical values of pixel response generated by combined exposures; a compensation method of using neural network compensation framework to replace high-dimensional neural network to traverse the image is proposed, which reduces the scale and training complexity of neural network; Finally, the corresponding spatial arrangement data of pixels are transformed into the frequency domain through the Fourier expansion algorithm, and the compensation effect is evaluated according to the change of high-frequency components. According to the experimental results, this method can effectively suppress color aliasing and crosstalk noise of the color image sensor. This paper provides a new method to compensate color aliasing and crosstalk noise.

BackgroundMore than half of the cases of fetal structural anomalies have no known cause with standard investigations like karyotype testing and chromosomal microarray. The differential metabolic profiles of amniotic fluid (AF) and maternal blood may reveal valuable information about the physiological processes of fetal development, which may provide valuable biomarkers for fetal health diagnostics.MethodsThis cohort study of singleton-pregnant women had indications for amniocentesis, including structural anomalies and a positive result from maternal serum screening or non-invasive prenatal testing, but did not have any positive abnormal karyotype or chromosomal microarray analysis results. A total of 1580 participants were enrolled between June 2021 and March 2022. Of the 1580 pregnant women who underwent amniocentesis, 294 were included in the analysis. There were 137 pregnant women in the discovery cohort and 157 in the validation cohort.ResultsHigh-coverage untargeted metabolomic analysis of AF revealed distinct metabolic signatures with 321 of the 602 metabolites measured (53%) (false discovery rate, q < 0.005), among which amino acids predominantly changed in structural anomalies. Targeted metabolomics identified glutamate and glutamine as novel predictive markers for structural anomalies, their vital role was also confirmed in the validation cohort with great predictive ability, and the area under the receiver operating characteristic curves (AUCs) were 0.862 and 0.894 respectively. And AUCs for glutamine/glutamate were 0.913 and 0.903 among the two cohorts.ConclusionsOur results suggested that the aberrant glutamine/glutamate metabolism in AF is associated with nonchromosomal modificantions fetal structural anomalies. Based on our findings, a novel screening method could be established for the nonchromosomal modificantions fetal structural anomalies. And the results also indicate that monitoring fetal metabolic conditions (especially glutamine and glutamine metabolism) may be helpful for antenatal diagnosis and therapy.

Background: Phenylalanine hydroxylase deficiency (PAHD) is an autosomal recessive disorder of amino acid metabolism and caused by mutations in the phenylalanine hydroxylase (PAH) gene. Without timely and appropriate dietary management, the disturbance of amino acid metabolism may impair cognitive development and neurophysiological function. Newborn screening (NBS) can aid the early diagnosis of PAHD, which can give accurate therapy to PAHD patients in time. In China, the PAHD incidence and PAH mutation spectrum vary enormously across the provinces. A total of 5,541,627 newborns from Jiangxi province were screened by NBS between 1997 and 2021.Method: One seventy one newborns from Jiangxi province were diagnosed with PAHD. By Sanger sequencing and the multiplex ligation-dependent probe amplification (MLPA) analysis, mutation analysis was performed in 123 PAHD patients. Using an arbitrary values (AV)-based model, we compared the observed phenotype with the predicted phenotype based on the genotype.Results: In this study, we speculated the PAHD incidence of Jiangxi province was about 30.9 per 1,000,000 live births (171/5,541,627). We summarized the PAH mutation spectrum in Jiangxi province for the first time. Two novel variants (c.433G > C, c.706 + 2T > A) were found. The most prevalent variant was c.728G > A (14.1%). The overall prediction rate of the genotype-phenotype was 77.4%.Conclusion: This mutation spectrum is very meaningful to improve the diagnostic rate of PAHD and to increase the accuracy genetic counseling. This study offers data for the genotype-phenotype prediction suitable for Chinese population.

Prenatal exposure to nicotine that are mainly produced from tobacco smoke has been reported to affect infants. Therefore, nicotine exposure is one of important health concerns for newborn screening. Detecting nicotine and its metabolites such as cotinine in meconium were widely used to evaluate the tobacco exposure of pregnancy. In this study, disposable wooden tips were applied for touch sampling of meconium from newborn infants, and then were directly mounted on mass spectrometer (MS) to perform rapid screening of nicotine and cotinine. Choice of extraction/spray solvents was optimized. The limits of detection, reproducibility, linear response for direct analysis of meconium were also investigated. It is found the limits of detection (S/N = 3) to be as low as 0.36 ng/mg and 1.18 ng/mg for nicotine and cotinine, respectively, while the limits of quantitation (S/N = 10) to be 1.19 ng/mg and 3.94 ng/mg for nicotine and cotinine, respectively. The relative standard deviations (RSD) were found to be at 8.4%–19.8% (n = 6) for nicotine and cotinine, a good linear range from 5–500 ng/mL (R2 > 0.99). These analytical performances are well-accepted levels for ambient mass spectrometer analysis. In this study, evaluation of nicotine and cotinine in 22 puerpera volunteers were conducted by the established wooden-tip spray mass spectrometry (WTS-MS). These results showed that wooden-tip spray mass spectrometry would be useful for newborn screening of nicotine and cotinine in meconium with high reproducibility, speed, sensitivity, and specificity. Owing to the use of disposable wooden tips that involves no sample preparation and no chromatographic separation, our results show that wooden-tip spray mass spectrometry is a powerful tool for determination of nicotine in newborn meconium.

To evaluate the performance of expanded non-invasive prenatal testing (expanded noninvasive prenatal testing, NIPT-Plus) in screening for fetal chromosomal abnormalities includes aneuploidies and copy number variations, a total of 23,116 pregnant women with a singleton pregnancy were recruited for NIPT-Plus. Screening positive results were verified by karyotype analysis and chromosomal microarray analysis after amniocentesis. A total of 264 pregnancies (1.14%) were positive results as predicted by NIPT-Plus, including 233 aneuploidies and 31 copy number variations. Following genetic counseling, 233 (88.26%) pregnant women underwent invasive prenatal diagnosis and 136 were verified as true positives, comprising 72 common trisomies (T21, T18, T13), 47 sex chromosomal abnormalities two rare autosomal aneuploidies (RATs) and 15 copy number variations The positive predictive value for common trisomies, SCAs, RATs and CNVs were 68.57%, 68.12%, 6.67% and 51.72%, respectively. Pregnant women with screen-positive results for common trisomies have higher rates of invasive prenatal diagnosis and pregnancy termination than those with positive results for SCAs, RATs, and CNVs. NIPT-Plus showed a good performance in detecting common trisomies, SCAs and also contributed to detecting pathogenic CNVs, but higher accuracy was required in the detection of RATs. In summary, this study provides a reference for the clinical application of NIPT-Plus for screening fetal chromosomal abnormalities in this region. Therefore, we suggest that NIPT-Plus could be widely used in clinical screening for fetal chromosomal abnormalities in combination with prenatal diagnosis and genetic counseling.

Alzheimer’s disease (AD) is a neurodegenerative disease dominated by progressive cognitive dysfunction causing significant social, economic, and medical crises. Cell therapy has demonstrated favorable effects for AD. This pilot study examined the safety and neurorestorative effects of the olfactory ensheathing cell (OEC), olfactory neuron (ON), and Schwann cell (SC) on patients with AD. Seven patients with AD were enrolled in this two-center, randomized, double-blind, and placebo- controlled cell therapy study with a subsequent 12-month follow-up. We randomly assigned one or two participants in OEC, ON, and SC therapy or OEC combined with ON and placebo control. All enrolled patients were injected cells or medium into the olfactory sub-mucosa. They got an assessment of Mini-Mental State Examination, Montreal Cognitive Assessment, and Clinical Dementia Rating before treatment and 1, 3, 6, 12 months after treatment. We performed MRI or CT scans before treatment and 12 months after treatment. After integrating the results from the three evaluation methods, all cell types showed better results than a placebo control. ON and SC seem to exhibit more vital potential neurorestorative ability to enhance or convert the neurological functions of patients with AD, and OEC may help AD patients keep neurological functions stable. In this pilot study, there was no adverse or side-effect event. The results of this study strongly suggest conducting a phase II clinical trial of ON, SC, and OEC therapy to prove their neurorestorative effect on patients with AD.

Background: Hyperphenylalaninemia (HPA) is the most common inborn error in amino acid metabolism. It can be primarily classified into phenylalanine hydroxylase (PAH) deficiency and tetrahydrobiopterin (BH4) deficiency. BH4 deficiency (BH4D) is caused by genetic defects in enzymes involved in the biosynthesis and regeneration of BH4. 6-pyruvoyl-tetrahydropterin synthase (PTPS/PTS), which is encoded by the PTS gene, participates in the biosynthesis of BH4. PTPS deficiency (PTPSD) is the major cause of BH4D. In this study, we investigated that the prevalence of BH4D in Jiangxi province was approximately 12.5 per 1,000,000 live births (69/5,541,627). Furthermore, the frequency of BH4D was estimated to be 28.8% (69/240) in the HPA population of Jiangxi. In this study, we aimed to characterize the mutational spectrum of the PTS gene in patients with PTPSD from Jiangxi province.Method: Newborn screening data of Jiangxi province from 1997 to 2021 were analyzed and 53 families with PTPSD were enrolled for the analysis of the PTS gene variants by Sanger sequencing.Results: 106 variants were identified in 106 alleles of 53 patients with PTPSD, including 13 types of variants reported previously, and two novel variants (c.164-36A>G and c.146_147insTG). The predominant variant was c.259C>T (47.2%), followed by c.84-291A>G (19.8%), c.155A>G (8.5%), c.286G>A (6.6%) and c.379C>T (4.7%).Conclusion: The results of this study can not only provide guidance for the molecular diagnosis and genetic counseling in cases of PTPS deficiency but also enrich the PTS mutation database.

Although there is a large volume of literature on executive compensation, few of these studies have focused on executive pay comparisons and even fewer on the antecedents of executive pay comparisons. This paper fills this gap in executive pay comparison literature by beginning with executive pay comparison behaviors, and then the elements that influence executive pay comparison behaviors are discussed. A questionnaire survey found that executive pay comparison behaviors exist in both China and Poland. Furthermore, the findings show that the factors influencing executive pay comparison behaviors are different in the two countries. In China, there is a significant relationship between executive pay comparison behaviors and the dysfunctional agent market, herd mentality. And in Poland, there is a significant relationship between executive pay comparison behaviors and the ineffectiveness of government intervention, herd mentality. The implications of the study are also discussed.

Background and aimsConcurrent hearing and genetic screening of newborns have been widely adopted as an effective strategy in early diagnosis and intervention for hearing loss in many cities in China. Here, we aimed to firstly explore the efficacy of combining conventional hearing screening with genetic screening among the large-scale newborns in Jiangxi Province.MethodsA total of 24,349 newborns from Jiangxi Maternal and Child Health Hospital were enrolled in our study from April 2021 to June 2022. Newborn hearing screening was conducted using otoacoustic emission (OAE) and automated auditory brainstem response (AABR). Meanwhile, newborn dried blood spots were collected and twenty common variants in four genes, including GJB2, SLC26A4, MT-RNR1(12SrRNA), and GJB3, were screened using a BGISEQ-500 next generation sequencing platform. Whole coding regions sequencing of GJB2 and SLC26A4 were performed by Sanger sequencing and NGS, respectively. Following up of hearing for the newborns was undertaken by phone interviews.ResultsAmong the 24,349 newborns, 7.00% (1,704/24,349) were bilaterally or unilaterally referred in their initial hearing screening, whereas 1.30% (316/24,349) exhibited bilateral or unilateral hearing loss in the repeated screening. Genetic screening revealed that 4.813% (1,172/24,349) of the screened newborns were positive for at least one mutant allele (heterozygote, homozygote, or compound heterozygote in one gene, mtDNA homoplasmy or heteroplasmy and combined variants in different genes). A total of 1,146 individuals were identified with mutant allele in one gene, including 525 of GJB2, 371 of SLC26A4, 189 as homoplasmic or heteroplasmic of MT-RNR1, and 61 of GJB3, indicating that GJB2 and SLC26A4 are the most common endemic deafness-associated genes among newborns in Jiangxi Province. Nineteen newborns were detected with combined heterozygous variants in different genes, with “c.235delC heterozygous and c.919-2A > G heterozygous” as the most prevalent genotype. Additionally, seven newborns were screened as homozygotes or compound heterozygotes responsible for congenital or late-onset prelingual hearing loss, including three cases with GJB2 c.235delC homozygous and one with SLC26A4 c.919-2A > G homozygous variant, one case with compound heterozygous variants for GJB2 and two with compound heterozygous variants for SLC26A4. Coding regions sequencing of GJB2 or SLC26A4 for overall 265 infants revealed that 14 individuals were identified as compound heterozygote with a second pathogenic variant not screened by our genetic panel.ConclusionsHerein our study firstly investigated the efficacy of concurrent hearing screening and genetic screening of common hearing impairment variants among large-scale newborns in Jiangxi Province. Concurrent screening provides a more comprehensive approach for management of congenital or delayed onset prelingual hearing loss and prevention of drug-induced hearing impairment for newborns at risk as well as their maternal relatives. An insight into the molecular epidemiology for hearing loss genes among Jiangxi population will also be beneficial to the genetic counseling and birth defect prevention.

Background and aims: Hemoglobinopathy associated with the HBB gene, with its two general subtypes as thalassemia and abnormal hemoglobin (Hb) variants, is one of the most prevalent hereditary Hb disorders worldwide. Herein we aimed to elucidate the prevalence of ß-thalassemia and abnormal hemoglobin variants and the prenatal diagnosis of the HBB gene in Jiangxi Province, southern central China.Methods: Hematological indices and capillary Hb electrophoresis were conducted for 136,149 subjects who were admitted to Jiangxi Maternal and Child Health Hospital and requested for hemoglobinopathy investigation. Routine α- and ß-globin genotyping were performed by gap-polymerase chain reaction (Gap-PCR) and reverse dot-blot (RDB) hybridization for the 11,549 individuals suspected to be thalassemia carriers. For participants whose genotypes could not explain their hematological indices, further Sanger sequencing and Gap-PCR were conducted for the detection of rare or novel variants in related globin genes. Prenatal diagnosis was performed for 77 pregnant couples both carrying ß-thalassemia trait at appropriate gestational ages.Results: Among the 11,549 subjects, 2,548 individuals were identified with HBB-associated hemoglobinopathy based on molecular analysis. A total of 2,358 subjects were identified as ß-thalassemia heterozygous carriers and nine cases were diagnosed as compound heterozygous ß-thalassemia. Additionally, 125 cases were detected with composite α- and ß-thalassemia and the remaining 56 individuals with abnormal Hb variants in the HBB. A total of 35 types of variants were identified in the HBB gene, including 26 types of ß-thalassemia and nine types of abnormal Hb variants. Four novel variants were firstly reported, including one variant in HBA2 and three variants in HBB. Overall, 77 prenatal samples underwent ß-thalassemia molecular diagnosis; 20 fetuses were identified with normal ß-thalassemia genotypes, 30 fetuses as ß-thalassemia heterozygotes, 11 as homozygotes, and 16 as compound heterozygotes in HBB.Conclusion: We have demonstrated a relatively high prevalence rate at 1.872% of ß-hemoglobinopathies including common and rare ß-thalassemia as well as abnormal Hb variants among large child-bearing population in the Jiangxi area of southern central China for the first time. Our data presents that prenatal diagnosis is an effective way to prevent and control birth defects of ß-thalassemia.

Background and PurposeInfantile neuroaxonal dystrophy (INAD) is a subtype of PLA2G6-Associated Neurodegeneration (PLAN) with an age of early onset and severe clinical phenotypes of neurodegeneration. Individuals affected with INAD are characterized by rapid progressive psychomotor deterioration, neuroregression, and hypotonia followed by generalized spasticity, optic atrophy, and dementia. In this case, we aimed to identify the underlying causative genetic factors of a Chinese family with two siblings who presented with walking difficulty and inability to speak. We provided a prenatal diagnosis for the family and information for the prevention of this genetic disease.MethodsRetrospective clinical information and magnetic resonance imaging (MRI) findings of the proband were collected. Trio-whole exome sequencing (WES) including the proband and his parents was performed to explore the genetic causes, while Sanger sequencing was subsequently used to validate the variants identified by Trio-WES in the pedigree. Furthermore, prenatal molecular genetic diagnosis was carried out through amniocentesis to investigate the status of pathogenic mutations in the fetus by Sanger sequencing at an appropriate gestational age.ResultsThe two siblings were both clinically diagnosed with rapid regression in psychomotor development milestones. Brain MRI showed cerebellar atrophy and typical bilaterally symmetrical T2/FLAIR hyperintense signal changes in periventricular areas, indicating periventricular leukomalacia, and myelin sheath dysplasia. Trio-WES revealed two heterozygous variants in PlA2G6 associated with clinical manifestations in the proband: a novel maternally inherited variant c.217C>T (p.Gln73*) and a previously reported paternally inherited recurrent pathogenic variant c.1894C>T (p.Arg632Trp). These two heterozygous mutations were also detected in the younger brother who had similar clinical features as the proband. The novel variant c.217C>T was classified as “pathogenic (PVS1 + PM2 + PP3),” while the variant c.1894C>T was “pathogenic” (PS1 + PM1 + PM2 + PM3 + PP3) based on the latest American College of Medical Genetics and Genomics (ACMG) guidelines on sequence variants. Combining the molecular evidence and clinical phenotypes, the diagnosis of INAD was established for the two affected siblings. The two variants that were identified were considered the causative mutations for INAD in this family. Prenatal diagnosis suggested compound heterozygous mutations of c.217C>T and c.1894C>T in the fetus, indicating a high risk of INAD, and the parents chose to terminate the pregnancy.ConclusionWe identified a novel pathogenic mutation that broadens the mutation spectrum of PLA2G6 and will provide clues for the molecular diagnosis of INAD. Furthermore, our study has helped to elucidate the causative genetic factors of this Chinese family with INAD effectively and efficiently by using the emerging Trio-WES strategy and providing precise genetic counseling for this family.

Background:Vascular dementia (VD) is a series of clinical and neurophysiological manifestations caused by cerebrovascular disease. As the human lifespan increases, the number of people affected by age-related dementia is growing at an alarming pace, but no proved therapeutic methods can stop it from getting worse.Objective:To investigate the neurorestorative effects of injecting olfactory ensheathing cells (OECs), Schwann cells (SCs), and olfactory receptor neurons (ORNs) into olfactory sub-mucosa in VD patients.Methods:A pilot study of double-blind randomized controlled cell therapies was conducted in VD patients (n = 5). Cells were injected into the patients’ olfactory sub-mucosa. Two patients received OEC treatment, one received SC treatment, one ORN treatment, and one OEC combined with ORN. Mental state and cognitive function were observed before treatment and 1, 3, 6, and 12 months after treatment. magnetic resonance imaging (MRI) or computed tomography (CT) was performed before treatment and 12 months after treatment.Results:The directional function score on the Mini-Mental Status Examination (MMSE) in the patient who received SC treatment had increased slightly 1 and 3 months after treatment. The scores for orientation, attention, delayed verbal recall, and repetition increased in the ORN group patient 1 month after treatment. The orientation and repetition scores of the ORN group patient continued to increase 3 months after treatment. The scores for attention, delayed verbal recall, and phase 3 command decreased in the OEC and the OEC + ORN group patients after treatment assessment Scores on the Montreal Cognitive Assessment (MoCA) and Clinical Dementia Rating (CDR) scale also improved in the ORN group patient. Clinical and MRI or CT examinations did not find any side effects from the cell therapy or transplanting procedure.Conclusion:All of the cell transplantations were found to be safe. ORN was shown to be a promising therapy for VD patients. Phase II clinical trials of ORN, SC, and OEC therapy are required to verify their effects on VD symptoms, especially ORNs.

Epidermal growth factor receptor (EGFR) is often overexpressed in head and neck squamous cell carcinoma (HNSCC) and represents a top candidate for targeted HNSCC therapy. However, the clinical effectiveness of current Food and Drug Administration (FDA)‐approved drugs targeting EGFR is moderate, and the overall survival rate for HNSCC patients remains low. Therefore, more effective treatments are urgently needed. In this study, we generated a novel diphtheria toxin‐based bivalent human epidermal growth factor fusion toxin (bi‐EGF‐IT) to treat EGFR‐expressing HNSCC. Bi‐EGF‐IT was tested for in vitro binding affinity, cytotoxicity, and specificity using 14 human EGFR‐expressing HNSCC cell lines and three human EGFR‐negative cancer cell lines. Bi‐EGF‐IT had increased binding affinity for EGFR‐expressing HNSCC compared with the monovalent version (mono‐EGF‐IT), and both versions specifically depleted EGFR‐positive HNSCC, but not EGFR‐negative cell lines, in vitro. Bi‐EGF‐IT exhibited a comparable potency to that of the FDA‐approved EGFR inhibitor, erlotinib, for inhibiting HNSCC tumor growth in vivo using both subcutaneous and orthotopic HNSCC xenograft mouse models. When tested in an experimental metastasis model, survival was significantly longer in the bi‐EGF‐IT treatment group than the erlotinib treatment group, with a significantly reduced number of metastases compared with mono‐EGF‐IT. In addition, in vivo off‐target toxicities were significantly reduced in the bi‐EGF‐IT treatment group compared with the mono‐EGF‐IT group. These results demonstrate that bi‐EGF‐IT is more effective and markedly less toxic at inhibiting primary HNSCC tumor growth and metastasis than mono‐EGF‐IT and erlotinib. Thus, the novel bi‐EGF‐IT is a promising drug candidate for further development.

The large-scale and precise intelligent breeding mode for dairy cows is the main direction for the development of the dairy industry. Machine vision has become an important technological means for the intelligent breeding of dairy cows due to its non-invasive, low-cost, and multi-behavior recognition capabilities. This review summarizes the recent application of machine vision technology, machine learning, and deep learning in the main behavior recognition of dairy cows. The authors summarized identity recognition technology based on facial features, muzzle prints, and body features of dairy cows; motion behavior recognition technology such as lying, standing, walking, drinking, eating, rumination, estrus; and the recognition of common diseases such as lameness and mastitis. Based on current research results, machine vision technology will become one of the important technological means for the intelligent breeding of dairy cows. Finally, the author also summarized the advantages of this technology in intelligent dairy farming, as well as the problems and challenges faced in the next development.

Overview: Idiopathic pulmonary fibrosis (IPF) is a disease caused by many factors, eventually resulting in lung function failure. Jinbei oral liquid (JBOL) is a traditional Chinese clinical medicine used to treat pulmonary diseases. However, the pharmacological effects and mechanism of the action of JBOL on IPF remain unclear. This study investigated the protective effects and mechanism of the action of JBOL on IPF using network pharmacology analysis, followed by in vivo and in vitro experimental validation.Methods: The components of JBOL and their targets were screened using the TCMSP database. IPF-associated genes were obtained using DisGeNET and Drugbank. The common targets of JBOL and IPF were identified with the STRING database, and a protein–protein interaction (PPI) network was constructed. GO and KEGG analyses were performed. Sprague–Dawley rats were injected with bleomycin (BLM) to establish an IPF model and treated orally with JBOL at doses of 5.4, 10.8, and 21.6 ml/kg. A dose of 54 mg/kg of pirfenidone was used as a control. All rats were treated for 28 successive days. Dynamic pulmonary compliance (Cdyn), minute ventilation volume (MVV), vital capacity (VC), and lung resistance (LR) were used to evaluate the efficacy of JBOL. TGF-β–treated A549 cells were exposed to JBOL, and epithelial-to-mesenchymal transition (EMT) changes were assessed. Western blots were performed.Results: Two hundred seventy-eight compounds and 374 targets were screened, and 103 targets related to IPF were identified. Core targets, including MAPK1 (ERK2), MAPK14 (p38), JUN, IL-6, AKT, and others, were identified by constructing a PPI network. Several pathways were involved, including the MAPK pathway. Experimentally, JBOL increased the levels of the pulmonary function indices (Cdyn, MVV, and VC) in a dose-dependent manner and reduced the RL level in the BLM-treated rats. JBOL increased the epithelial marker E-cadherin and suppressed the mesenchymal marker vimentin expression in the TGF-β–treated A549 cells. The suppression of ERK1/2, JNK, and p38 phosphorylation by JBOL was validated.Conclusion: JBOL had therapeutic effects against IPF by regulating pulmonary function and EMT through a systemic network mechanism, thus supporting the need for future clinical trials of JBOL.

ObjectiveTo investigate iodine status among pregnant women in an iodine-sufficient region in China after the implementation of revised universal salt iodization (USI) standards in 2012 and assess the association between urinary iodine concentrations (UIC) in early pregnancy and the incidence of subclinical hypothyroidism (SCH) in euthyroid women negative for antithyroid Ab during different trimesters.MethodsWe measured the iodine status of 1,264 pregnant women, and performed follow-up assessment of thyroid function at 20 and 30 weeks of gestation among a cohort of 250 euthyroid women. We assessed the association of UIC in the 1st trimester with the incidence of SCH in subsequent trimesters. UIC and serum free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH), thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb) were measured.ResultsThe median UIC was 135.95 μg/L among 1,264 women. Serum FT4 level was significantly higher in the group of UIC 150 to 249 μg/L compared with other UIC groups (P < 0.001). TSH was significantly higher in the UIC more than or equal to 250 μg/L group than the UIC 150 to 249 g/L group (P = 0.043). Of the 250 euthyroid women negative for antithyroid Ab (TSH value of 2.5–3.55 mU/L) in the 1st trimester, pregnant women with UIC lower than 100 μg/L in the 1st trimester exhibited a significantly increased risk of SCH (odds ratio [OR] = 2.47; 95% confidence interval [CI] = 1.22–5.71; P = 0.012, according to the Chinese Medical Association criteria; OR = 5.22, 95% CI = 1.73–6.09, P = 0.004, according to ATA criteria) during the latter half of pregnancy compared with the UIC 150 to 249 μg/L group.ConclusionModerate-to-severe iodine deficiency (UIC lower than 100 μg/L) in the 1st trimester was associated with a significantly higher risk of SCH during the 2nd or 3rd trimesters among euthyroid pregnant women who had negative for antithyroid Ab. Women with SCH during pregnancy require regular UIC tests to maintain appropriate iodine status.

Olfactory ensheathing cells (OECs) have shown promising results for patients with neurologic diseases in non-double-blind, placebo control studies. Thirty patients with a unilateral ischemic stroke of more than a year were enrolled in a phase 2, multicenter, randomized, double-blind, and placebo-controlled cell therapy trial with a subsequent 12-month follow-up. The primary therapeutic objective has shown that after 12 months, there were significant differences in National Institutes of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS) and Barthel Index (BI) assessment scores among the OEC group, Schwann cell group and placebo medium group at one-year follow-up. The second therapeutic objective found that there were significant differences in NIHSS, mRS, and BI assessment scores when comparing the endpoint data with the baseline data in the OEC group. There was neither hypersensitivity reaction nor adverse event. The results of this multicenter, randomized, double-blind, and placebo-controlled study indicate that injecting OECs into the olfactory sub-mucosa have neurorestorative effects, which can improve the quality of life for patients with chronic ischemic strokes without serious side effects.

Aim: Protein-energy malnutrition and cardiovascular (CV) disease predisposes patients with end-stage renal disease (ESRD) on dialysis to a high risk of early death, but the prognostic value of prealbumin (PAB) and echocardiographic indices in ESRD patients treated with maintenance peritoneal dialysis (PD) remains unclear. Methods: A total of 211 PD patients (mean age 49.2 ± 15.4 years, 51.7% male) were prospectively studied. PAB and echocardiography parameters were recorded at baseline. Follow-up (mean ± SD: 33.7 ± 17.3 months) was conducted based on hospital records, clinic visits, and telephone reviews, to record death events and their causes. Results: In the Cox proportional hazards model, PAB and the echocardiographic parameters listed below were found to be optimal predictors of all-cause mortality: PAB (p = 0.003), aortic root diameter (ARD) (p = 0.004), interventricular septum end-diastolic thickness (IVSd) (p = 0.046), and left ventricular end-diastolic diameter index (LVEDDI) (p = 0.029). Of the above-mentioned factors, PAB (p = 0.018), ARD (p = 0.031), and IVSd (p = 0.037) were independent predictors of CV mortality in PD patients. Of note, malnutrition, degradation of the aorta, and myocardial hypertrophy are also known death risk factors in the general population. The all-cause mortality and CV death rate significantly increased as the number of risk factors increased, reaching values as high as 40 and 22% in patients who had all of the risk factors, i.e., abnormal PAB, ARD, and IVSd (p < 0.001 and p = 0.011). Conclusion: In PD patients, low serum PAB and abnormal echocardiographic parameters together were significantly associated with all-cause mortality and CV death, independently of other risk factors. These risk factors for death in PD are similar to those in the general population. Noticeably, the combination of echocardiographic parameters and PAB could provide additional predictive value for mortality in PD patients. In light of these findings, more studies in an optimal model containing PAB and echocardiographic parameters for the prediction of outcomes in ESRD are required.

Abstract Background Hypothermic ischemia-reperfusion arrhythmia remains the main factor affecting cardiac resuscitation under cardiopulmonary bypass. Existing research shows that certain miRNAs exhibit significantly different expressions and effects in arrhythmias, however, the effect of miRNAs on the progression of hypothermic ischemic–reperfusion arrhythmias (RA) and its potential mechanism remain to be further explored. Methods Sprague-Dawley (SD) rats were randomly divided into two groups (n = 8): a normal control group (Group C) and a hypothermic ischemia-reperfusion group (Group IR), which were used to establish a Langendorff isolated cardiac perfusion model. According to the arrhythmia scoring system, rats in group IR were divided into a high-risk group (IR-H) and a low-risk group (IR-L). miRNAs expression profiles of ventricular myocardium with global hypothermic ischemia–reperfusion and those of ventricular myocardium with hypothermic ischemia–RA were established through high-throughput sequencing. Furthermore, the aberrantly expressed miRNAs in myocardium with and without hypothermic ischemia–RA were screened and verified. The target genes of these aberrantly expressed miRNAs were predicted using RNAhybrid and MiRanda software. Based on Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) databases, we determined the mRNA targets associated with these miRNAs and studied the miRNA–mRNA interaction during the cardiovascular disease progression. The aberrantly expressed miRNAs related to hypothermic ischemia–RA were validated by Real-time Quantitative polymerase chain reaction (RT-qPCR). Results Eight significantly aberrantly expressed miRNAs (rno-miR-122-5p, rno-miR-429, novel_miR-1, novel_miR-16, novel_miR-17, novel_miR-19, novel_miR-30, and novel_miR-43) were identified, among which six were up-regulated and two were down-regulated. Moreover, target genes and signaling pathways associated with these aberrantly expressed miRNAs were predicted and analyzed. The miRNA–mRNA interaction network graph showed that GJA1 gene was considered as the target of novel_miR-17. Conclusions Aberrantly expressed miRNAs were possibly associated with the formation mechanism of hypothermic ischemia–RA. Specific miRNAs, such as novel_miR-17 and rno-miR-429 are probably new potential targets for further functional studies of hypothermic ischemia–RA.

Abstract Background TAB2 is an activator of MAP 3 K7/TAK1, which is required for the IL-1 induced signal pathway. Microdeletions encompassing TAB2 have been detected in various patients with congenital heart defects (CHD), indicating that haploinsufficiency of TAB2 causes CHD. To date, seven variants within TAB2 were reported associated with CHD, only two of them are nonsense mutations. Case presentation Here we describe a three-generation Chinese family that included five CHD patients with heart valvular defects, such as mitral or tricuspid valves prolapse or regurgitation, and aortic valve stenosis or regurgitation. Our proband was a pregnant woman presenting with mitral, tricuspid, and aortic defects; her first child experienced sudden cardiac death at the age of 2 years. Whole-exome sequencing of the proband revealed a novel nonsense variant in TAB2 (c.C446G, p.S149X), which results in the elimination of the majority of C-terminal amino acids of TAB2, including the critical TAK1-binding domain. The variant was identified in five affected patients but not in the eight unaffected family members using Sanger sequencing and was classified as “pathogenic” according to the latest recommendation on sequence variants laid out by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Conclusion We described a family with CHD caused by a novel TAB2 nonsense mutation. Our study broadens the mutation spectrum of TAB2; to the best of our knowledge, this is the first report of a pathogenic mutation within TAB2 in a Chinese population.

Recurrence and metastasis are the major causes of mortality in head and neck squamous cell carcinoma (HNSCC). It is suggested that cancer stem cells (CSCs) play pivotal roles in recurrence and metastasis. Thus, a greater understanding of the mechanisms of CSC regulation may provide opportunities to develop novel therapies for improving survival by controlling recurrence or metastasis. Here, we report that overexpression of the gene encoding the catalytic subunit of PI3K (PIK3CA), the most frequently amplified oncogene in HNSCC, promotes epithelial‐to‐mesenchymal transition and enriches the CSC population. However, PIK3CA is not required to maintain these traits and inhibition of the phosphatidylinositol 3‐kinase (PI3K) signaling pathway paradoxically promotes CSC population. Molecular analysis revealed that overexpression of PIK3CA activates multiple receptor tyrosine kinases (RTKs), in which ephrin receptors (Ephs), tropomyosin receptor kinases (TRK) and mast/stem cell growth factor receptor (c‐Kit) contribute to maintain CSC population. Accordingly, simultaneous inhibition of these RTKs using a multi‐kinase inhibitor ponatinib has a superior effect at eliminating the CSC population and reduces metastasis of PIK3CA‐overexpressing HNSCC cells. Our result suggests that co‐targeting of Ephs, TRKs and the c‐Kit pathway may be effective at eliminating the PI3K‐independent CSC population, thereby providing potential targets for future development of a novel anti‐CSC therapeutic approach for HNSCC patients, particularly for patients with PIK3CA amplification.

Bioluminescence tomography (BLT) is a promising in vivo molecular imaging tool that allows non-invasive monitoring of physiological and pathological processes at the cellular and molecular levels. However, the accuracy of the BLT reconstruction is significantly affected by the forward modeling errors in the simplified photon propagation model, the measurement noise in data acquisition, and the inherent ill-posedness of the inverse problem. In this paper, we present a new multispectral differential strategy (MDS) on the basis of analyzing the errors generated from the simplification from radiative transfer equation (RTE) to diffusion approximation and data acquisition of the imaging system. Through rigorous theoretical analysis, we learn that spectral differential not only can eliminate the errors caused by the approximation of RTE and imaging system measurement noise but also can further increase the constraint condition and decrease the condition number of system matrix for reconstruction compared with traditional multispectral (TM) reconstruction strategy. In forward simulations, energy differences and cosine similarity of the measured surface light energy calculated by Monte Carlo (MC) and diffusion equation (DE) showed that MDS can reduce the systematic errors in the process of light transmission. In addition, in inverse simulations and in vivo experiments, the results demonstrated that MDS was able to alleviate the ill-posedness of the inverse problem of BLT. Thus, the MDS method had superior location accuracy, morphology recovery capability, and image contrast capability in the source reconstruction as compared with the TM method and spectral derivative (SD) method. In vivo experiments verified the practicability and effectiveness of the proposed method.

X-ray luminescence computed tomography (XLCT) is an emerging hybrid imaging modality in optical molecular imaging, which has attracted more attention and has been widely studied. In XLCT, the accuracy and operational efficiency of an optical transmission model play a decisive role in the rapid and accurate reconstruction of light sources. For simulation of optical transmission characteristics in XLCT, considering the limitations of the diffusion equation (DE) and the time and memory costs of simplified spherical harmonic approximation equation (SPN), a hybrid light transport model needs to be built. DE and SPN models are first-order and higher-order approximations of RTE, respectively. Due to the discontinuity of the regions using the DE and SPN models and the inconsistencies of the system matrix dimensions constructed by the two models in the solving process, the system matrix construction of a hybrid light transmission model is a problem to be solved. We provided a new finite element mesh regrouping strategy-based hybrid light transport model for XLCT. Firstly, based on the finite element mesh regrouping strategy, two separate meshes can be obtained. Thus, for DE and SPN models, the system matrixes and source weight matrixes can be calculated separately in two respective mesh systems. Meanwhile, some parallel computation strategy can be combined with finite element mesh regrouping strategy to further save the system matrix calculation time. Then, the two system matrixes with different dimensions were coupled though repeated nodes were processed according to the hybrid boundary conditions, the two meshes were combined into a regrouping mesh, and the hybrid optical transmission model was established. In addition, the proposed method can reduce the computational memory consumption than the previously proposed hybrid light transport model achieving good balance between computational accuracy and efficiency. The forward numerical simulation results showed that the proposed method had better transmission accuracy and achieved a balance between efficiency and accuracy. The reverse simulation results showed that the proposed method had superior location accuracy, morphological recovery capability, and image contrast capability in source reconstruction. In-vivo experiments verified the practicability and effectiveness of the proposed method.

Objective. The aim of this study was to investigate the changes of syndecan-4 (SDC-4) during the hypertensive period in two kidney-two clip (2K2C) hypertension rats and compare them to brain natriuretic peptide (BNP) and the echocardiographic parameters for diastolic function evaluation in the rat model of 2K2C hypertension. Methods. A total of 36 Sprague–Dawley (SD) rats were used in this study. Hypertension was induced in 21 by 2K2C surgery, and 15 were sham-operated. Both the 2K2C hypertension group (n = 21) and the sham-operated group (n = 15) were equally divided into 3 subgroups according to the schedules (week 4, week 8, and week 12). Serum SDC-4 and BNP were detected by ELISA, and echocardiography indexes were acquired. Results. The level of SDC-4 and cardiac fibrosis increased gradually as the experiment was processed, and BNP, Tei index, and E/E′ followed to be raised as high blood pressure was maintained after four weeks in the 2K2C hypertension rats. In the earlier 4 weeks, only SDC-4 and cardiac fibrosis were significantly increased in 2K2C hypertensive rats in comparison with normotensive rats. And it was shown that SDC-4 was positively correlated with BNP level during the entire study (r = 0.762, p

In recent years, traditional farming methods have been increasingly replaced by more modern, intelligent farming techniques. This shift towards information and intelligence in farming is becoming a trend. When they are bitten by dinoflagellates, cows display stress behaviors, including tail wagging, head tossing, leg kicking, ear flapping, and skin fluttering. The study of cow protective behavior can indirectly reveal the health status of cows and their living patterns under different environmental conditions, allowing for the evaluation of the breeding environment and animal welfare status. In this study, we generated key point feature marker information using the DeepLabCut target detection algorithm and constructed the spatial relationship of cow feature marker points to detect the cow’s protective behavior based on the change in key elements of the cow’s head swinging and walking performance. The algorithm can detect the protective behavior of cows, with the detection accuracy reaching the level of manual detection. The next step in the research focuses on analyzing the differences in protective behaviors of cows in different environments, which can help in cow breed selection. It is an important guide for diagnosing the health status of cows and improving milk production in a practical setting.

Purpose: Dry eye disease (DED) is projected to have increasing public health burden in China with the aging population. No published studies on the epidemiology of DED have been found in grasslands. We estimated DED prevalence among older adults living in grasslands of northern China and investigated its associated factors and impact on vision-related quality of life (VR-QoL).Methods: A multistage cluster random sampling technique was used to select Mongolian and Han participants aged over 40 from November 2020 to May 2021 in this area. An assessment of DED was performed with Ocular Surface Disease Index (OSDI) questionnaire, Schirmer's I test (ST), and Tear film break up time (TBUT). All the participants completed the Chinese version of National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) assessing VR-QoL.Results: Of the 1,400 enumerated residents, 1,287 were examined. The overall age and gender standardized prevalence of DED was 34.5%, of which, 32.6% of Mongolian and 35.4% of Han had DED. In a multivariate model, statistically significant associations were found with advancing age [odds ratio (OR) 1.03, 95% confidence interval (CI) 1.02–1.04], female gender (OR 1.32, 95% CI 1.04–1.68), smoking (OR 0.7, 95% CI 0.5–0.98), anti-fatigue eye-drop use (OR 0.56, 95% CI 0.41–0.77), milk product intake (OR 0.55, 95% CI 0.39–0.77), number of household members (OR 0.8, 95% CI 0.72–0.88). DED was associated with lower scores on VR-QoL (β= −0.14, P < 0.01). Similar results were observed when analyses were stratified by ethnicity.Conclusions: The novelty-associated factors for DED in the grasslands area were anti-fatigue eye drop use, milk product intake, and number of household members. DED and its components were associated with VR-QoL. Further prospective studies are needed to confirm these findings.