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ObjectivesThis research aims to assess the effectiveness and cost-effectiveness of pre-pregnancy deafness screening policies.MethodsMarried couples from Shanghai, Beijing, and Suzhou in China were enrolled. We conducted high-throughput, pre-pregnancy genetic screenings for deafness in women and their partners. We compared the cost-effectiveness of deafness genetic screening with the status quo. The two-step screening (wife then partner) and following treatments and interventions were included in the decision tree model. We conducted a cost-effectiveness analysis based on the decrease in deaf newborns, healthy newborn births, and cost-utility analysis of pre-pregnancy deafness genetic screening separately. Cost, utility, and probability data used in the three models were collected from a survey combined with literature and expert consultants. A 5% discount rate and a series of one-way sensitivity analyses along with a Monte Carlo simulation were used to test the reliability of this research.ResultsBetween Jan 1, 2019, and Dec 31, 2021, we recruited 6,200 females and 540 male spouses from community health service centers in Shanghai, Beijing, and Suzhou. The incremental cost-effectiveness ratio (ICER) for reducing deaf newborn births was USD 32,656 per case and USD 1,203,926 per case for increasing one healthy newborn birth. This gap exists because of the overall decrease of newborn births. From the perspective of the whole society, deafness genetic screening is not cost-effective for reducing the overall quality-adjusted life years (QALY) in the population.DiscussionPre-pregnancy genetic testing is effective in decreasing the occurrence of congenital deafness. It is a cost-saving measure when compared with the costs of future medical expenditure and income loss for the affected families. However, such screening and preventive avoidance of pregnancy will decrease the population size and QALY. Only post-screening ART with PGT was shown to increase the birth of healthy newborns. Focusing on key groups such as premature births or consanguineous couples may improve the societal effects of screening.

Introduction: Asthma is the most common chronic condition in children, with allergic asthma being the most common phenotype, accounting for approximately 80% of cases. Growing evidence suggests that disruption of iron homeostasis and iron regulatory molecules may be associated with childhood allergic asthma. However, the underlying molecular mechanism remains unclear.Methods: Three childhood asthma gene expression datasets were analyzed to detect aberrant expression profiles of iron metabolism-related genes in the airways of children with allergic asthma. Common iron metabolism-related differentially expressed genes (DEGs) across the three datasets were identified and were subjected to functional enrichment analysis. Possible correlations between key iron metabolism-related DEGs and type 2 airway inflammatory genes were investigated. Single-cell transcriptome analysis further identified major airway cell subpopulations driving key gene expression. Key iron metabolism-related gene SLC40A1 was validated in bronchoalveolar lavage (BAL) cells from childhood asthmatics with control individuals by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunofluorescence. The intracellular iron content in BAL cells was assessed by Perls iron staining and the iron levels in BAL supernatant was measured by iron assay to assess airway iron metabolism status in childhood asthmatics.Results: Five common iron metabolism-related DEGs were identified, which were functionally related to iron homeostasis. Among these genes, downregulated SLC40A1 was strongly correlated with type 2 airway inflammatory markers and the gene signature of SLC40A1 could potentially be used to determine type 2-high and type 2-low subsets in childhood allergic asthmatics. Further single-cell transcriptomic analysis identified airway macrophages driving SLC40A1 expression. Immunofluorescence staining revealed colocalization of FPN (encoded by SLC40A1) and macrophage marker CD68. Down-regulation of SLC40A1 (FPN) was validated by qRT-PCR and immunofluorescence analysis. Results further indicated reduced iron levels in the BAL fluid, but increased iron accumulation in BAL cells in childhood allergic asthma patients. Furthermore, decreased expression of SLC40A1 was closely correlated with reduced iron levels in the airways of children with allergic asthma.Discussion: Overall, these findings reveal the potential role of the iron metabolism-related gene SLC40A1 in the pathogenesis of childhood allergic asthma.

BackgroundPredicting which preschool children with recurrent wheezing (RW) will develop school-age asthma (SA) is difficult, highlighting the critical need to clarify the pathogenesis of RW and the mechanistic relationship between RW and SA. Despite shared environmental exposures and genetic determinants, RW and SA are usually studied in isolation. Based on network analysis of nasal and tracheal transcriptomes, we aimed to identify convergent transcriptomic mechanisms in RW and SA.MethodsRNA-sequencing data from nasal and tracheal brushing samples were acquired from the Gene Expression Omnibus. Combined with single-cell transcriptome data, cell deconvolution was used to infer the composition of 18 cellular components within the airway. Consensus weighted gene co-expression network analysis was performed to identify consensus modules closely related to both RW and SA. Shared pathways underlying consensus modules between RW and SA were explored by enrichment analysis. Hub genes between RW and SA were identified using machine learning strategies and validated using external datasets and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Finally, the potential value of hub genes in defining RW subsets was determined using nasal and tracheal transcriptome data.ResultsCo-expression network analysis revealed similarities in the transcriptional networks of RW and SA in the upper and lower airways. Cell deconvolution analysis revealed an increase in mast cell fraction but decrease in club cell fraction in both RW and SA airways compared to controls. Consensus network analysis identified two consensus modules highly associated with both RW and SA. Enrichment analysis of the two consensus modules indicated that fatty acid metabolism-related pathways were shared key signals between RW and SA. Furthermore, machine learning strategies identified five hub genes, i.e., CST1, CST2, CST4, POSTN, and NRTK2, with the up-regulated hub genes in RW and SA validated using three independent external datasets and qRT-PCR. The gene signatures of the five hub genes could potentially be used to determine type 2 (T2)-high and T2-low subsets in preschoolers with RW.ConclusionsThese findings improve our understanding of the molecular pathogenesis of RW and provide a rationale for future exploration of the mechanistic relationship between RW and SA.

Asthma is the most common chronic condition among children; however, the underlying molecular mechanism remains unclear. Dysregulated immune response and different infiltration states of immune cells are critical for asthma pathogenesis. Here, three childhood asthma gene expression datasets were used to detect key genes, immune cells, and pathways involved in childhood asthma. From these datasets, 33 common differentially expressed genes (DEGs) were identified, which showed enrichment in the T helper 1 (Th1) and T helper 2 (Th2) cell differentiation pathway and the T helper 17 (Th17) cell differentiation pathway. Using the weighted gene co-expression network analysis (WGCNA), CD3D and CD3G were identified as key genes closely correlated with childhood asthma. Upregulation of CD3D and CD3G was further validated in bronchoalveolar lavage cells from childhood asthmatics with control individuals by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The immune cell infiltration analysis indicated that CD3D and CD3G were negatively correlated with increased resting mast cells and eosinophils, and highly correlated with several cell markers of Th1, Th2, and Th17 cells. In addition, we found that CD3D and CD3G were closely related to the Th1 and Th2 cell differentiation pathway and the Th17 cell differentiation pathway. Our results reveal the important roles of two key genes and immune infiltration in the pathogenesis of childhood asthma. Thus, this study provides a new perspective for exploring potential molecular targets for childhood asthma treatment.

The water-sediment regulation scheme (WSRS) imposed on dams throughout the Yellow River not only alleviates siltation in the downstream section but also alters the nutrient characteristics, which indirectly affects the enrichment of nutrients in the estuary. Nevertheless, the long-term changes in the nutrient contents and their causes in the lower Yellow River (LYR) remain unclear, and the nutrients characteristics during the years with and without WSRS have yet to be compared. Therefore, the purpose of this study was to explore the variations in the nutrient contents and limitations at the Lijin station on the LYR over the past decade, especially during the annual WSRS period, and to compare the water quality characteristics at Lijin between the years with and without WSRS. The results reveal that WSRS significantly changed the seasonal nutrient concentrations (nitrogen, phosphorus and silicon) at the Lijin station. The fluxes of these nutrients during WSRS (excluding 2016 and 2017) accounted for 11.64–40.63% of the total annual fluxes. The N concentration in the LYR was higher than that in some global rivers, while the concentrations of dissolved inorganic phosphorus (DIP) and dissolved silica (DSi) were lower than the average levels in other rivers. In addition, higher values of dissolved inorganic nitrogen (DIN), DSi and the Redfield ratio indicated that the growth of phytoplankton at the Lijin station was strongly restricted by P. However, during the 2 years without WSRS (2016 and 2017), the proportions of the nutrient fluxes in June were less than 66% of those in the WSRS period in other years. Additionally, there was a potential Si limitation in June in these 2 years. Furthermore, due to the occurrence of floods upstream of the Yellow River and the low-level operation of the Xiaolangdi Reservoir, the fluxes of nutrients during WSRS in 2018 were approximately 0.90–4.20 times those during the same period in 2009–2015 and 6.30–35.76 times those in June 2016 and June 2017. This study shows that WSRS effectively changes the nutrient balance in the LYR and provides a reference for the multi-objective collaborative optimization of WSRS to improve siltation and control flood in the LYR.

Respiratory syncytial virus (RSV) a leading cause of pediatric and adult morbidity and mortality worldwide. It can cause complications in multiple organs, thus increasing hospital stays and costs. However, RSV-based studies have primarily focused on effects in the lungs and blood, thereby potentially neglecting critical genes and pathways. Hence, studying RSV infection via a novel multi-organ approach is important. In this study, lung, intestine, brain, and spleen tissues from six BALB/c mice (6–8 weeks old; three in control group and three in RSV-infected group) were subjected to RNA sequencing. Differentially expressed genes (DEGs) in each organ were obtained and functional enrichment analysis was performed. We first used CIBERSORT to evaluate the immune-infiltration landscape. Subsequently, common DEGs (co-DEGs) among the four organs were analyzed to identify key genes and pathways. After quantitative reverse transcription-polymerase chain reaction, western blotting, and external validation analysis of key hub genes, their correlation with immune cells and potential functions were explored. We found that the host response to RSV infection varied among the four organs regarding gene expression profiles and immune cell infiltration. Analysis of the 16 co-DEGs indicated enrichment in the platelet and neutrophil degranulation pathways. Importantly, the key gene hemopexin (Hpx) was strongly correlated with the immune cell fraction in the lungs and may participate in the regulation of platelet activation and immune response.

Circulating tumor cells (CTCs) have been well-established as promising biomarkers that can be leveraged to gauge the prognosis of patients with cancers and to guide patient treatment efforts. Although the scarcity of CTCs within peripheral circulation and the associated phenotypic changes that they exhibit owing to the epithelial-mesenchymal transition (EMT) process make the reliable isolation of these cells very challenging. Recently, several studies have discussed platforms capable of mediating the efficient and sensitive isolation of CTCs, but these approaches are nonetheless subject to certain limitations that preclude their clinical application. For example, these platforms are poorly-suited to minimizing damage in the context of cellular capture and release or the in vitro culture of captured cells for subsequent molecular analyses, which would better enable clinicians to select appropriate precision treatments on an individualized basis. In this study, we report the layer-by-layer assembly approach to synthesize a novel composite nanomaterial consisting of modified zirconium-based metal-organic-frameworks (MOFs) on the surface of magnetic beads with dual antibody surface modifications capable of capturing CTCs without being hampered by the state of cellular EMT process. Our analyses indicated that these dual antibody-modified nanomaterials exhibited greater capture efficiency than that observed for single antibody. Importantly, captured cells can be gradually released following capture and undergo subsequent in vitro proliferation following water molecule-induced MOF structural collapse. This release mechanism, which does not require operator intervention, may be effective as a means of minimizing damage and preserving cellular viability such that cells can be more reliably utilized for downstream molecular analyses and associated treatment planning. To further confirm the potential clinical applicability of the developed nanomaterial, it was successfully utilized for capturing CTCs from peripheral blood samples collected from cases diagnosed with gastrointestinal tumors.

Background: Multiple non-invasive ventilation (NIV) modalities have been identified that may improve the prognosis of pediatric patients with acute lower respiratory infection (ALRI). However, the effect of NIV in children with ALRI remains inconclusive. Hence, this study aimed to evaluate the efficacy of various NIV strategies including continuous positive airway pressure (CPAP), high flow nasal cannula (HFNC), bilevel positive airway pressure (BIPAP), and standard oxygen therapy in children with ALRI and the need for supplemental oxygen.Methods: Embase, PubMed, Cochrane Library, and Web of Science databases were searched from inception to July 2021. Randomized controlled trials (RCTs) that compared different NIV modalities for children with ALRI and the need for supplemental oxygen were included. Data were independently extracted by two reviewers. Primary outcomes were intubation and treatment failure rates. Secondary outcome was in-hospital mortality. Pairwise and Bayesian network meta-analyses within the random-effects model were used to synthesize data. The certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation framework.Results: A total of 21 RCTs involving 5,342 children were included. Compared with standard oxygen therapy, CPAP (OR: 0.40, 95% CrI: 0.16–0.90, moderate quality) was associated with a lower risk of intubation. Furthermore, both CPAP (OR: 0.42, 95% CrI: 0.19–0.81, low quality) and HFNC (OR: 0.51, 95% CrI: 0.29–0.81, low quality) reduced treatment failure compared with standard oxygen therapy. There were no significant differences among all interventions for in-hospital mortality. Network meta-regression showed that there were no statistically significant subgroup effects.Conclusion: Among children with ALRI and the need for supplemental oxygen, CPAP reduced the risk of intubation when compared to standard oxygen therapy. Both CPAP and HFNC were associated with a lower risk of treatment failure than standard oxygen therapy. However, evidence is still lacking to show benefits concerning mortality between different interventions. Further large-scale, multicenter studies are needed to confirm our results.Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=172156, identifier: CRD42020172156.

Plant acyl-CoA-binding proteins (ACBPs) form a highly conserved protein family that binds to acyl-CoA esters as well as other lipid and protein interactors to function in developmental and stress responses. This protein family had been extensively studied in non-leguminous species such as Arabidopsis thaliana (thale cress), Oryza sativa (rice), and Brassica napus (oilseed rape). However, the characterization of soybean (Glycine max) ACBPs, designated GmACBPs, has remained unreported although this legume is a globally important crop cultivated for its high oil and protein content, and plays a significant role in the food and chemical industries. In this study, 11 members of the GmACBP family from four classes, comprising Class I (small), Class II (ankyrin repeats), Class III (large), and Class IV (kelch motif), were identified. For each class, more than one copy occurred and their domain architecture including the acyl-CoA-binding domain was compared with Arabidopsis and rice. The expression profile, tertiary structure and subcellular localization of each GmACBP were predicted, and the similarities and differences between GmACBPs and other plant ACBPs were deduced. A potential role for some Class III GmACBPs in nodulation, not previously encountered in non-leguminous ACBPs, has emerged. Interestingly, the sole member of Class III ACBP in each of non-leguminous Arabidopsis and rice had been previously identified in plant-pathogen interactions. As plant ACBPs are known to play important roles in development and responses to abiotic and biotic stresses, the in silico expression profiles on GmACBPs, gathered from data mining of RNA-sequencing and microarray analyses, will lay the foundation for future studies in their applications in biotechnology.

Salinity is a major environmental factor that constrains soybean yield and grain quality. Given our past observations using the salt-sensitive soybean (Glycine max [L.] Merr.) accession C08 on its early responses to salinity and salt-induced transcriptomic modifications, the aim of this study was to assess the lipid profile changes in this cultivar before and after short-term salt stress, and to explore the adaptive mechanisms underpinning lipid homeostasis. To this end, lipid profiling and proteomic analyses were performed on the leaves of soybean seedlings subjected to salt treatment for 0, 0.5, 1, and 2 h. Our results revealed that short-term salt stress caused dynamic lipid alterations resulting in recycling for both galactolipids and phospholipids. A comprehensive understanding of membrane lipid adaption following salt treatment was achieved by combining time-dependent lipidomic and proteomic data. Proteins involved in phosphoinositide synthesis and turnover were upregulated at the onset of salt treatment. Salinity-induced lipid recycling was shown to enhance jasmonic acid and phosphatidylinositol biosyntheses. Our study demonstrated that salt stress resulted in a remodeling of membrane lipid composition and an alteration in membrane lipids associated with lipid signaling and metabolism in C08 leaves.

Hirschsprung Disease (HSCR) and/or hypoganglionosis are common pediatric disorders that arise from developmental deficiencies of enteric neural crest cells (ENCCs). Retinoid acid (RA) signaling has been shown to affect neural crest (NC) development. However, the mechanisms underlying RA deficiency-induced HSCR or hypoganglionosis are not well-defined. In this report, we found that in HSCR patient bowels, the RA nuclear receptor RARα and its interacting coregulator CREB-binding protein (CBP) were expressed in enteric neural plexuses in the normal ganglionic segment. However, the expression of these two genes was significantly inhibited in the pathological aganglionic segment. In a Xenopus laevis animal model, endogenous RARα interacted with CBP and was expressed in NC territory. Morpholino-mediated knockdown of RARα blocked expression of the NC marker genes Sox10 and FoxD3 and inhibited NC induction. The morphant embryos exhibited reduced nervous cells in the gastrointestinal anlage, a typical enteric nervous deficiency-associated phenotype. Injection of CBP mRNA rescued NC induction and reduced enteric nervous deficiency-associated phenotypes. Our work demonstrates that RARα regulates Sox10 expression via CBP during NC induction, and alteration of the RA-CBP signaling pathway may contribute to the development of enteric nervous system disorders.

Objective: To evaluate the frequency and clinical features of restless legs syndrome (RLS) in a group of Chinese patients with amyotrophic lateral sclerosis (ALS).Methods: 109 Patients included in this study fulfilled the revised El Escorial diagnostic criteria for clinically definite, probable and lab-supported probable ALS, and a group of 109 control subjects was matched for age and sex to the ALS group. Disease severity was assessed by the revised ALS functional rating scale (ALSFRS-R). The diagnosis of RLS was made according to the criteria of the International RLS Study Group. Other characteristics including sleep quality, excessive daytime sleepiness (EDS), REM sleep behavior disorder (RBD), depression and anxiety were also evaluated in ALS patients.Results: RLS was significantly more frequent in ALS patients than in control subjects (14.6 vs. 0.9%; P < 0.05). Compared to those without RLS, ALS patients with RLS reported a higher frequency of anxiety and EDS. ALS patients with RLS showed more severe legs dysfunction. EDS and legs function scores of the ALSFRS-R were independent factors significantly associated with RLS in ALS patients.Conclusions: Our findings suggest that Chinese ALS patients exhibit a high frequency of RLS symptoms and that these patients may benefit from recognition of the condition and optimized management of its symptoms. Moreover, ALS patients might cause circadian rhythms disturbance and our study further supports that ALS is a heterogeneous disorder involving multiple systems; further studies are needed to confirm these preliminary findings.