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Human immunodeficiency Virus (HIV) and Mycobacterium tuberculosis (Mtb) co-infection presents a significant public health challenge worldwide. Comprehensive assessment of the immune response in HIV/Mtb co-infection is complex and challenging. CD8+T cells play a pivotal role in the adaptive immune response to both HIV and Mtb. The differentiation of CD8+T cells follow a hierarchical pattern, with varying degrees of exhaustion throughout the process. Memory stem T cells (TSCM cells) is at the apex of the memory T lymphocyte system, which has recently emerged as a promising target in immunotherapy. In this context, we discuss the alterations of CD8+TSCM cells in HIV/Mtb mono- and co-infection, their implications and clinical significance, and potential for improving immunotherapy.

BackgroundDevelopment of anti-drug antibodies (ADAs) and neutralizing antibodies (NAbs) to monoclonal antibodies may adversely impact pharmacokinetics, efficacy, and/or safety.ObjectiveTo describe incidence, titer, and persistence of dupilumab ADAs and NAbs, and their effects on pharmacokinetics, efficacy, and safety in patients with atopic dermatitis (AD).MethodsThis analysis included seven phase 3 randomized, placebo-controlled (N=2,992) and two long-term open-label extension (N=2,287) trials of subcutaneous dupilumab in adults and pediatric patients with moderate-to-severe AD. ADA, NAb, and dupilumab concentration in serum were assessed using validated immunoassays. ADA impacts on efficacy (EASI) and safety were assessed.ResultsTreatment-emergent ADAs were observed in up to 8.6% (aged ≥18 years), 16.0% (12-17 years), 5.3% (6-11 years), and 2.0% (6 months to 5 years) dupilumab-treated patients. Among dupilumab-treated patients, ≤3.7% had persistent responses,

In patients with rheumatoid arthritis (RA), intestinal flora imbalance and butyrate metabolism disorders precede clinical arthritis and are associated with the pathogenesis of RA. This imbalance can alter the immunology and intestinal permeability of the intestinal mucosa, leading to damage to the intestinal barrier. In this context, bacteria and their metabolites can enter the bloodstream and reach the distant target tissues of the host, resulting in local inflammation and aggravating arthritis. Additionally, arthritis is also exacerbated by bone destruction and immune tolerance due to disturbed differentiation of osteoclasts and adaptive immune cells. Of note, butyrate is a metabolite of intestinal flora, which not only locally inhibits intestinal immunity and targets zonulin and tight junction proteins to alleviate intestinal barrier-mediated arthritis but also inhibits osteoclasts and autoantibodies and balances the immune responses of T and B lymphocytes throughout the body to repress bone erosion and inflammation. Therefore, butyrate is a key intermediate linking intestinal flora to the host. As a result, restoring the butyrate-producing capacity of intestinal flora and using exogenous butyrate are potential therapeutic strategies for RA in the future.

IntroductionAcquired vulvar lymphangioma (AVL), a rare disease caused by the dilation of superficial lymphatic vessels secondary to deep lymphatic vessel injury, is characterized by a wide range of morphological diversity and massive exudate. This morphological heterogeneity has often led to misdiagnosis or non-diagnosis. The management of AVL presents a therapeutic challenge due to the absence of a standardized treatment protocol.Case presentationA 53-year-old female patient, previously received surgical treatments for stage IIb cervical squamous cell carcinoma, presented with vulvar enlargement and copious amount of yellow exudate seven years post-treatment. Clinically, the patient exhibited chronic vulvar swelling, with easily-exudated nodules. The vulvar biopsy revealed lymphatic vessel dilation with lymphocyte infiltration, consistent with AVL. Due to the extensive lesions and severe exudate, staged excisions of bilateral vulvar lesions were performed at one-month intervals. Follow-up examinations of this patient for one-year post-surgery showed no evidence of recurrence.ConclusionIn this instance, AVL manifest secondary to cervical cancer surgery, as a result of damage to the deep lymphatic vessels of the vulva, with characteristic symptoms of copious amounts of exudate and vulvar lesions with diverse morphologies, which provides a cautionary note for physicians. Besides, the staged resection strategy in this case may offer insights into surgical treatment protocol for extensive AVL.

BackgroundThis study aimed to identify the predictive factors for prolonged length of stay (LOS) in elderly type 2 diabetes mellitus (T2DM) patients suffering from cerebral infarction (CI) and construct a predictive model to effectively utilize hospital resources.MethodsClinical data were retrospectively collected from T2DM patients suffering from CI aged ≥65 years who were admitted to five tertiary hospitals in Southwest China. The least absolute shrinkage and selection operator (LASSO) regression model and multivariable logistic regression analysis were conducted to identify the independent predictors of prolonged LOS. A nomogram was constructed to visualize the model. The discrimination, calibration, and clinical practicality of the model were evaluated according to the area under the receiver operating characteristic curve (AUROC), calibration curve, decision curve analysis (DCA), and clinical impact curve (CIC).ResultsA total of 13,361 patients were included, comprising 6,023, 2,582, and 4,756 patients in the training, internal validation, and external validation sets, respectively. The results revealed that the ACCI score, OP, PI, analgesics use, antibiotics use, psychotropic drug use, insurance type, and ALB were independent predictors for prolonged LOS. The eight-predictor LASSO logistic regression displayed high prediction ability, with an AUROC of 0.725 (95% confidence interval [CI]: 0.710–0.739), a sensitivity of 0.662 (95% CI: 0.639–0.686), and a specificity of 0.675 (95% CI: 0.661–0.689). The calibration curve (bootstraps = 1,000) showed good calibration. In addition, the DCA and CIC also indicated good clinical practicality. An operation interface on a web page (https://xxmyyz.shinyapps.io/prolonged_los1/) was also established to facilitate clinical use.ConclusionThe developed model can predict the risk of prolonged LOS in elderly T2DM patients diagnosed with CI, enabling clinicians to optimize bed management.

Rheumatoid arthritis (RA) is a chronic autoimmune disease with a complex etiology. Neutrophil extracellular traps (NETs are NETwork protein structures activated by neutrophils to induce the cleavage and release of DNA-protein complexes). Current studies have shown the critical involvement of NETs in the progression of autoimmune diseases, Neutrophils mostly gather in the inflammatory sites of patients and participate in the pathogenesis of autoimmune diseases in various ways. NETs, as the activated state of neutrophils, have attracted much attention in immune diseases. Many molecules released in NETs are targeted autoantigens in autoimmune diseases, such as histones, citrulline peptides, and myeloperoxidase. All of these suggest that NETs have a direct causal relationship between the production of autoantigens and autoimmune diseases. For RA in particular, as a disorder of the innate and adaptive immune response, the pathogenesis of RA is inseparable from the generation of RA. In this article, we investigate the emerging role of NETs in the pathogenesis of RA and suggest that NETs may be an important target for the treatment of inflammatory autoimmune diseases.

Background: Qingdu Fang (QDF) is a traditional Chinese herbal formula with remarkable clinical effect in the treatment of HR-HPV, but its mechanism remains unclear. In this study, UPLC-QTOF-MS was used to detect its components, network pharmacology was used to explore the traditional Chinese medicine monomers and their related targets for the treatment of HR-HPV in QDF. Molecular docking and in vitro experiments were performed to verify the results.Methods: QDF constituents and active compounds were identified using UPLC-QTOF-MS analysis. TCMSP and GeneCard databases were used to identify active components, targets, and potential therapeutic targets in HR-HPV. PPI network was constructed using the String database to analyze protein-protein interactions. Cytoscape3.7.2 was used to construct PPI networks, while GO enrichment and KEGG pathway analyses with R. The effect of QDF on H8 cell proliferation was measured using the CCK-8 method, and apoptosis and cell cycle was assessed with flow cytometry. The effects of QDF on PI3K/AKT pathway were detected by Western blotting.Results: A total of 27 compounds were identified on QDF by UPLC-QTOF-MS. Base on Network pharmacology,a total of 254 target genes are involved in the action of QDF on cervical HR-HPV. PPI analysis suggested that TP53, JUN, AKT1, STAT3, TNF and IL6 were potential targets for QDF treatment of HR-HPV. Molecular docking shows that two compounds have strong binding activity with AKT1. CCK-8 and morphological observation have shown that QDF inhibits H8 cell proliferation in a dose-dependent manner. Flow cytometry experiments suggest that QDF induces apoptosis and cell cycle arrest in H8 cells. Western blotting experiments reveal that QDF inhibits the PI3K/AKT signaling pathway.Conclusion: QDF has a multi-faceted therapeutic approach for HR-HPV, targeting inflammation, oxidation, and apoptosis. It induces apoptosis in H8 cells by inhibiting the PI3K/AKT pathway.

BackgroundSputum immunoglobulin G (Sp-IgG) has been discovered to induce cytolytic extracellular trap cell death in eosinophils, suggesting a potential autoimmune mechanism contributing to asthma. This study aimed to explore the potential origin of Sp-IgG and identify clinically relevant subtypes of Sp-IgG that may indicate autoimmune events in asthma.MethodsThis study included 165 asthmatic patients and 38 healthy volunteers. We measured Sp-IgG and its five subtypes against eosinophil inflammatory proteins (Sp-IgGEPs), including eosinophil peroxidase, eosinophil major basic protein, eosinophil-derived neurotoxin, eosinophil cationic protein, and Charcot-Leyden Crystal protein in varying asthma severity. Clinical and Mendelian randomization (MR) analyses were conducted. A positive Sp-IgGEPs signature (Sp-IgGEPs+) was defined when any of the five Sp-IgGEPs values exceeded the predefined cutoff thresholds, calculated as the mean values of healthy controls plus twice the standard deviation.ResultsThe levels of Sp-IgG and Sp-IgGEPs were significantly elevated in moderate/severe asthma than those in mild asthma/healthy groups (all p < 0.05). Sp-IgG levels were positively correlated with airway eosinophil and Sp-IgGEPs. MR analysis showed causality between eosinophil and IgG (OR = 1.02, 95%CI = 1.00-1.04, p = 0.020), and elevated IgG was a risk factor for asthma (OR = 2.05, 95%CI = 1.00-4.17, p = 0.049). Subjects with Sp-IgGEPs+ exhibited worse disease severity and served as an independent risk factor contributing to severe asthma (adjusted-OR = 5.818, adjusted-95% CI = 2.193-15.431, adjusted-p < 0.001). Receiver operating characteristic curve analysis demonstrated that the combination of Sp-IgGEPs+ with non-allergic status, an ACT score < 15, and age ≥ 45 years, effectively predicted severe asthma (AUC = 0.84, sensitivity = 86.20%, specificity = 67.80%).ConclusionThis study identifies a significant association between airway eosinophilic inflammation, Sp-IgG, and asthma severity. The Sp-IgGEPs panel potentially serves as the specific biomarker reflecting airway autoimmune events in asthma.

There are lasting concerns on calvarial development because cranium not only accommodates the growing brain, but also safeguards it from exogenous strikes. In the past decades, most studies attributed the dynamic expansion and remodeling of cranium to the proliferation of osteoprecursors in cranial primordium, and the proliferation of osteoprogenitors at the osteogenic front of cranial suture mesenchyme. Further investigations identified series genes expressed in suture mesenchymal cells as the markers of the progenitors, precursors and postnatal stem cells in cranium. However, similar to many other organs, it is suggested that the reciprocal interactions among different tissues also play essential roles in calvarial development. Actually, there are increasing evidence indicating that dura mater (DM) is indispensable for the calvarial morphogenesis and osteogenesis by secreting multiple growth factors, cytokines and extracellular matrix (ECM). Thus, in this review, we first briefly introduce the development of cranium, suture and DM, and then, comprehensively summarize the latest studies exploring the involvement of ECM in DM and cranium development. Eventually, we discussed the reciprocal interactions between calvarium and DM in calvarial development. Actually, our review provides a novel perspective for cranium development by integrating previous classical researches with a spotlight on the mutual interplay between the developing DM and cranium.

Objectives: Multi-Criteria Decision Analysis (MCDA) has gained increasing attention in supporting drug risk-benefit assessment, pricing and reimbursement, as well as optimization of clinical interventions. The objective of this study was to systematically collect and categorize evaluation criteria and techniques of weighting and scoring of MCDA for drug value assessment.Methods: A systematic review of the literature was conducted across seven databases to identify articles utilizing the MCDA frameworks for the evaluation of drug value. Evaluation criteria mentioned in the included studies were extracted and assigned to 5 dimensions including clinical, economic, innovative, societal and humanistic value. A descriptive statistical analysis was performed on the identified drug value evaluation criteria, as well as the weighting and scoring techniques employed. The more a criterion or technique were mentioned in articles, the more important we consider it.Results: Out of the 82 articles included, 111 unique criteria were identified to evaluate the value of drug. Among the 56 unique criteria (448 times) used to measure clinical value, the most frequently mentioned were “comparative safety/tolerability” (58 times), “comparative effectiveness/efficacy” (56 times), “comparative patient-perceived health/patient reported outcomes” (37 times), “disease severity” (34 times), and “unmet needs” (25 times). Regarding economic value measurement, out of the 20 unique criteria (124 times), the most frequently utilized criteria were “cost of intervention” (17 times), “comparative other medical costs” (16 times), and “comparative non-medical costs” (18 times). Out of the 10 criteria (18 times) for assessing innovative value, “a novel pharmacological mechanism” was the most frequently mentioned criterion (5 times). Among the 22 criteria (73 times) used to measure societal value, “system capacity and appropriate use of intervention” was the most frequently cited criterion (14 times). Out of the 3 criteria (15 times) utilized to measure humanistic value, “political/historical/cultural context” was the most frequently mentioned criterion (9 times). Furthermore, 11 scoring and 11 weighting techniques were found from various MCDA frameworks. “Swing weighting” and “a direct rating scale” were the most frequently used techniques in included articles.Conclusion: This study comprehensively presented the current evaluation dimensions, criteria, and techniques for scoring and weighting in drug-oriented MCDA articles. By highlighting the frequently cited evaluation criteria and techniques for scoring and weighting, this analysis will provide a foundation to reasonably select appropriate evaluation criteria and technique in constructing the MCDA framework that aligns with research objectives.

In this paper, a novel fusion network for automatic modulation classification (AMC) is proposed in underwater acoustic communication, which consists of a Transformer and depth-wise convolution (DWC) network. Transformer breaks the limitation of sequential signal input and establishes the connection between different modulations in a parallel manner. Its attention mechanism can improve the modulation recognition ability by focusing on the key information. DWC is regularly inserted in the Transformer network to constitute a spatial–temporal structure, which can enhance the classification results at lower signal-to-noise ratios (SNRs). The proposed method can obtain more deep features of underwater acoustic signals. The experiment results achieve an average of 92.1% at −4 dB ≤ SNR ≤ 0 dB, which exceed other state-of-the-art neural networks.

Salmonella, especially antimicrobial resistant strains, remains one of the leading causes of foodborne bacterial disease. Retail chicken is a major source of human salmonellosis. Here, we investigated the prevalence, antimicrobial resistance (AMR), and genomic characteristics of Salmonella in 88 out of 360 (24.4%) chilled chicken carcasses, together with 86 Salmonella from humans with diarrhea in Qingdao, China in 2020. The most common serotypes were Enteritidis and Typhimurium (including the serotype I 4,[5],12:i:-) among Salmonella from both chicken and humans. The sequence types were consistent with serotypes, with ST11, ST34 and ST19 the most dominantly identified. Resistance to nalidixic acid, ampicillin, tetracycline and chloramphenicol were the top four detected in Salmonella from both chicken and human sources. High multi-drug resistance (MDR) and resistance to third-generation cephalosporins resistance were found in Salmonella from chicken (53.4%) and humans (75.6%). In total, 149 of 174 (85.6%) Salmonella isolates could be categorized into 60 known SNP clusters, with 8 SNP clusters detected in both sources. Furthermore, high prevalence of plasmid replicons and prophages were observed among the studied isolates. A total of 79 antimicrobial resistant genes (ARGs) were found, with aac(6′)-Iaa, blaTEM-1B, tet(A), aph(6)-Id, aph(3″)-Ib, sul2, floR and qnrS1 being the dominant ARGs. Moreover, nine CTX-M-type ESBL genes and the genes blaNMD-1, mcr-1.1, and mcr-9.1 were detected. The high incidence of MDR Salmonella, especially possessing lots of mobile genetic elements (MGEs) in this study posed a severe risk to food safety and public health, highlighting the importance of improving food hygiene measures to reduce the contamination and transmission of this bacterium. Overall, it is essential to continue monitoring the Salmonella serotypes, implement the necessary prevention and strategic control plans, and conduct an epidemiological surveillance system based on whole-genome sequencing.

Glass fiber reinforced plastic (GFRP) composites have been applied to the manufacture of missile shields and unmanned aerial vehicle (UAV) shells. It is of great significance to explore the ablation characteristics of different lasers for these composites. Currently, most existing studies on the ablation characteristics of lasers for Glass fiber reinforced plastic composites are conducted under a single laser output mode, such as continuous wave (CW) laser or pulsed laser. However, the ablation characteristics of combined lasers for Glass fiber reinforced plastic composites have not been clarified. Therefore, the ablation characteristics of single lasers (continuous wave, millisecond (ms) pulsed, or nanosecond (ns) pulsed laser) and combined laser (CW/ms or CW/ns combined pulsed lasers) were investigated by experimental and simulation methods in this study. Additionally, the ablation mechanisms of Glass fiber reinforced plastic under different laser irradiation conditions were compared and analyzed. The results demonstrated that the ablation rates of single lasers for Glass fiber reinforced plastic composites were all within an order of magnitude of 10 μg/J, which was not significantly correlated with the light source system. The ablation efficiency of the single laser was determined by the incident laser energy. The continuous wave laser was found to be the optimal light source for the ablation and destruction of Glass fiber reinforced plastic composites. Nevertheless, there were some obstacles in the ablation process of continuous wave lasers. Applying pulsed lasers during the irradiation of the continuous wave laser may generate a synergistic effect. Under the conditions in this study, the CW/ns pulsed combined laser increased the ablation efficiency by 53.8%.

Since the onset of the COVID-19 pandemic in 2020, global efforts towards tuberculosis (TB) control have encountered unprecedented challenges. There is an urgent demand for efficient and cost-effective diagnostic technologies for TB. Recent advancements in CRISPR–Cas technologies have improved our capacity to detect pathogens. The present study established a CRISPR–Cas12a-based multiplex detection (designated as MCMD) that simultaneously targets two conserved insertion sequences (IS6110 and IS1081) to detect Mycobacterium tuberculosis complex (MTBC). The MCMD integrated a graphene oxide-assisted multiplex recombinase polymerase amplification (RPA) assay with a Cas12a-based trans-cleavage assay identified with fluorescent or lateral flow biosensor (LFB). The process can be performed at a constant temperature of around 37°C and completed within 1 h. The limit of detection (LoD) was 4 copies μL−1, and no cross-reaction was observed with non-MTBC bacteria strains. This MCMD showed 74.8% sensitivity and 100% specificity in clinical samples from 107 patients with pulmonary TB and 40 non-TB patients compared to Xpert MTB/RIF assay (63.6%, 100%). In this study, we have developed a straightforward, rapid, highly sensitive, specific, and cost-effective assay for the multiplex detection of MTBC. Our assay showed superior diagnostic performance when compared to the widely used Xpert assay. The novel approach employed in this study makes a substantial contribution to the detection of strains with low or no copies of IS6110 and facilitates point-of-care (POC) testing for MTBC in resource-limited countries.

Since the first 70 years of reporting cancer chemotherapy, malignant tumors have been the second most common cause of death in children and adults. Currently, the commonly used anti-cancer methods include surgery, chemotherapy, radiotherapy, and immunotherapy. Although these treatment methods could alleviate cancer, they lead to different forms of side effects and have no particularly significant effect on prolonging the patients’ life span. Glycyrrhizic acid (GL), a native Chinese herbal extract, has a wide range of pharmacological effects, such as anti-cancer, anti-inflammatory, antioxidant, and immune regulation. In this review, the anti-cancer effects and mechanisms of GL are summarized in various cancers. The inhibition of GL on chemotherapy-induced side effects, including hepatotoxicity, nephrotoxicity, genotoxicity, neurotoxicity and pulmonary toxicity, is highlighted. Therefore, GL may be a promising and ideal drug for cancer therapy.

Background: Methamphetamine use disorder (MUD) has become a global problem due to the highly addictive nature of methamphetamine. Earlier research have demonstrated that PROK2 functions as a compensatory and protective response against neurotoxic stress by stimulating astrocyte reactivity. The aim of our study was to evaluate the correlation between the PROK2 gene and both MUD risk susceptibility and craving scale in the Chinese Han population.Methods: A total of 5,282 participants (1,796 MUD patients and 3,486 controls) were recruited. Seven tag SNPs of the PROK2 gene were chosen and genotyped in the samples. Genetic association analyses were performed to capture the significant SNPs. To investigate the relationship between PROK2 levels and craving scores with the associated-SNP genotypes, we conducted a linear model.Results: SNP rs75433452 was significantly linked with MUD risk (p-value = 1.54 × 10−8), with the A allele being positively correlated with an increased risk of MUD. Moreover, the average serum level of PROK2 decreased when more copies of the A allele were presented in both MUD patients (p-value = 4.57 × 10−6) and controls (p-value = 1.13 × 10−5). Furthermore, the genotypes of SNP rs75433452 were strongly correlated with the craving scores in MUD patients (p-value = 4.05 × 10−4).Conclusion: Our study identified a significant association signal of the PROK2 gene with MUD risk susceptibility and methamphetamine craving scores in the Chinese Han population, providing potential valuable insights into the underlying mechanisms of METH dependence.

BackgroundThe outbreak of the COVID-19 pandemic has had a tremendous impact on people’s health and well-being. The crisis also threw into sharp relief the fact that police officers faced an increased risk of developing mental health problems. The main purpose of this study was to explore the effects of work stress and risk perception on the mental health of police officers during the epidemic.MethodsWe conducted a cross-sectional online survey among police officers in Wuhan city, China, and data were collected from 11 March to 12 May 2022. A total of 358 questionnaires were received, of which 302 were considered valid. The questionnaires included demographic information, work stress scale, Symptom Checklist 90 (SCL-90) and epidemic risk perception scale. Descriptive analyses, one-way analysis of variance and linear regression were used to analyze the data.ResultsThe prevalence of mental health problems was 38.74% among the surveyed police officers. The results indicated that the total score of SCL-90 and its subdimensions were positively correlated with work stress and risk perception. Moreover, we found that three factors were relevant to the police’s mental health: age, marital status, and education.ConclusionFront-line police officers tend to show a higher prevalence of symptoms of mental disorders during the COVID-19 pandemic. We found that increased work stress and risk perception may adversely affect police officers’ mental health. Consequently, policy-makers and police organizations should establish an internal mental health problem coping team to improve police officers’ mental health resilience.

ObjectiveWe aimed to compare QuantiFERON-TB Gold In-Tube (QFT-GIT) and X.DOT-TB for screening latent tuberculosis infection (LTBI) in kawasaki patients, and to identify the risk factors associated with indeterminate IGRA results.MethodsWe conducted a retrospective study on children with KD, who were screened for mycobacterium tuberculosis (Mtb) infection by either ELISA-based QFT-GIT or ELISPOT-based X.DOT-TB tests, admitted in Department of Cardiology, Beijing Children's Hospital from July 2019 to April 2022.ResultsA total of 1327 cases were included. Among them, 932 cases were tested by QFT-GIT and 395 cases by X.DOT-TB. The positive rate of children was 0.1% and 0.2%, and the indeterminate rate was 68.2% and 6.1% for QFT-GIT and X.DOT-TB, respectively. Patients with hypoproteinemia had a higher risk of indeterminate X.DOT-TB result. Female, critical ill, shock or hypoproteinemia presented statistically significant associations with an increased risk of indeterminate QFT-GIT result. High-dose of IVIG inhibited the release of IFN-γ by more than 90%, which might account for the high indeterminate incidence.ConclusionIt is recommended to perform X.DOT-TB rather than QFT-GIT to screen LTBI in patients with high level of the mitogen that can inhibit IFN-γ release. For KD children with positive IGRA results, it has a higher risk of activation TB infection when treated with immunosuppressive therapy in the future. Children with KD aged

IntroductionIntensive and long-lasting office work is a common cause of muscular and mental disorders due to workplace stressors. Mindful and slow breathing exercises decrease psychological stress and improve mental health, whereas fast breathing increases neuronal excitability. This study aimed to explore the influence of 5 min of mindful breathing (MINDFUL), slow breathing (SLOW), fast breathing (FAST), and listening to music (MUSIC) on muscle tension and executive function during an intensive psychological task.MethodsForty-eight participants (24 men and 24 women) were enrolled. Muscle tension was recorded using surface electromyography, and executive function was assessed using the Stroop Color and Word Test (Stroop Test). The respiration rate (RR), oxygen saturation (SpO2), end-tidal carbon dioxide (EtCO2), and the subjects' preferred method were also recorded. During the experiment, participants performed a one-time baseline test (watching a neutral video for 5 min) and then completed 5 min of MUSIC, MINDFUL, SLOW, and FAST in a random sequence. The Stroop Test was performed after each intervention, including the baseline test, and was followed by a 5 min rest before performing the next intervention.ResultsNone of the methods significantly influenced muscular activity and performance of the Stroop Test in both men and women, based on the average 5 min values. However, at the fifth minute, men's accuracy rate in the Stroop Test was significantly higher after SLOW than after MUSIC and FAST, and the reaction time after the SLOW was the shortest. SpO2 was significantly higher during SLOW than during MUSIC, and RR was relatively lower after SLOW than after MUSIC. Most men preferred SLOW, and most women preferred MUSIC, whereas FAST was the most unfavorable method for both men and women.ConclusionBrief breathing exercises did not substantially affect muscle tension under psychological stress. SLOW demonstrated greater potential for sustaining executive function in men, possibly via its superior respiration efficiency on SpO2 and inhibition of RR.

Rubinstein-Taybi syndrome (RSTS) is a rare autosomal dominantly inherited disease characterized by slow mental and physical growth, skeletal abnormalities (broad thumbs and big toes), and dysmorphic facial features. RSTS is associated with de novo variants of the epigenetic-associated gene CREBBP. RSTS is primarily diagnosed based on clinical manifestations and genetic testing. Cutis marmorata telangiectatica congenita (CMTC) is a rare, congenital, and typically benign vascular anomaly of unknown etiology; it is described as persistent reticulated marbled erythema. The diagnosis of CMTC is largely based on clinical features, and GNA11 mutations are associated with CMTC. In this case report, we describe the case of a preterm infant (boy) with RSTS and CMTC who had a novel frameshift mutation leading to a premature stop codon in the CREBBP gene. This study adds the novel mutation c.5837dupC to the known molecular spectrum of disease-causing CREBBP gene mutations.

Metabolic syndrome (MS) is a complex group of metabolic disorders syndrome with hypertension, hyperuricemia and disorders of glucose or lipid metabolism. As an important organ involved in metabolism, the kidney is inevitably attacked by various metabolic disorders, leading to abnormalities in kidney structure and function. Recently, an increasing number of studies have shown that mitochondrial dysfunction is actively involved in the development of metabolic-associated kidney diseases. Mitochondrial dysfunction can be used as a potential therapeutic strategy for the treatment of metabolic-associated kidney diseases. Many natural products have been widely used to improve the treatment of metabolic-associated kidney diseases by inhibiting mitochondrial dysfunction. In this paper, by searching several authoritative databases such as PubMed, Web of Science, Wiley Online Library, and Springer Link. We summarize the Natural Products Protect Against Metabolic-Associated Kidney Diseases by Regulating Mitochondrial Dysfunction. In this review, we sought to provide an overview of the mechanisms by which mitochondrial dysfunction impaired metabolic-associated kidney diseases, with particular attention to the role of mitochondrial dysfunction in diabetic nephropathy, gouty nephropathy, hypertensive kidney disease, and obesity-related nephropathy, and then the protective role of natural products in the kidney through inhibition of mitochondrial disorders, thus providing a systematic understanding of the targets of mitochondrial dysfunction in metabolic-associated kidney diseases, and finally a review of promising therapeutic targets and herbal candidates for metabolic-associated kidney diseases through inhibition of mitochondrial dysfunction.

ObjectiveDiabetic kidney disease (DKD) is one of the most prevalent complications of diabetes mellitus (DM) and is associated with gut microbial dysbiosis. We aim to build a diagnostic model to aid clinical practice and uncover a crucial harmful microbial community that contributes to DKD pathogenesis and exacerbation.DesignA total of 528 fecal samples from 180 DKD patients and 348 non-DKD populations (138 DM and 210 healthy volunteers) from the First Affiliated Hospital of Zhengzhou University were recruited and randomly divided into a discovery phase and a validation phase. The gut microbial composition was compared using 16S rRNA sequencing. Then, the 180 DKD patients were stratified into four groups based on clinical stages and underwent gut microbiota analysis. We established DKD mouse models and a healthy fecal microbiota transplantation (FMT) model to validate the effects of gut microbiota on DKD and select the potential harmful microbial community. Untargeted metabolome–microbiome combined analysis of mouse models helps decipher the pathogenetic mechanism from a metabolic perspective.ResultsThe diversity of the gut microbiome was significantly decreased in DKD patients when compared with that of the non-DKD population and was increased in the patients with more advanced DKD stages. The DKD severity in mice was relieved after healthy gut microbiota reconstruction. The common harmful microbial community was accumulated in the subjects with more severe DKD phenotypes (i.e., DKD and DKD5 patients and DKD mice). The harmful microbial community was positively associated with the serum injurious metabolites (e.g., cholic acid and hippuric acid).ConclusionThe fecal microbial community was altered markedly in DKD. Combining the fecal analysis of both human and animal models selected the accumulated harmful pathogens. Partially recovering healthy gut microbiota can relieve DKD phenotypes via influencing pathogens’ effect on DKD mice’s metabolism.

Hepatocellular carcinoma (HCC) is one of the most malignant cancers worldwide, with high mortality. However, the molecular regulatory mechanisms of liver cancer, especially transcriptional and post-transcriptional mechanisms, should be further studied. Here we used chromatin and cross-linking immunoprecipitation with high throughput sequencing methods (ChIP-seq and CLIP-seq) to capture the global binding profiles on RNAs and DNAs of Enhancer of zeste homolog 2 (EZH2) and its partner Jumonji And AT-Rich Interaction Domain Containing 2 (JARID2) in liver carcinoma cell lines (HepG2) and normal liver cell line (THLE-2), respectively. We also integrated HCC transcriptome data from the TCGA to analyze the expression pattern of bound genes. We found that EZH2 and JARID2 both showed distinct binding profiles between HepG2 and THLE-2 cells. By binding to the primary RNAs, bound transcripts of EZH2 and JARID2 in HepG2 showed significantly increased transcriptional levels in HCC patients. By performing gene set enrichment analysis (GSEA), the bound transcripts were also highly related to HCC development. We also found EZH2 and JARID2 could specifically bind to several long noncoding RNAs (lncRNAs), including H19. By exploring the DNA binding profile, we detected a dramatically repressed DNA binding ability of EZH2 in HepG2 cells. We also found that the EZH2-bound genes showed slightly increased transcriptional levels in HepG2 cells. Integrating analysis of the RNA and DNA binding profiles suggests EZH2 and JARID2 shift their binding ability from DNA to RNA in HepG2 cells to promote cancer development in HCC. Our study provided a comprehensive and distinct binding profile on RNAs and DNAs of EZH2 and JARID2 in liver cancer cell lines, suggesting their potential novel functional manners to promote HCC development.

Phytoplankton cell size is well known as an essential functional trait, but its control factors are still unclear. Considering light provides the necessary energy for phytoplankton survival, we hypothesized that photosynthetic light energy utilization could influence phytoplankton cell size control. Several scenarios were conducted to understand the relationship between Fv/Fm and cell size for phytoplankton interspecies, and metatranscriptome in the field and transcriptome in the laboratory were used to understand relevant molecular mechanisms. The results indicated that there was a universal significant positive relationship between Fv/Fm and cell volume in general. The molecular evidence demonstrated that light utilization by phytoplankton regulates their cell size by harmonizing the generation and allocation of chemical energy and fixed carbon in the cell. Phytoplankton cell size would cease to enlarge once the increased light energy conversion and subsequent fixed carbon could no longer satisfy the increasing demand of size enlargement. This unity of energy and matter in shaping phytoplankton size results in cell size being an important functional trait. This study is the first to discover the above molecular mechanisms and is helpful to deepen the understanding on the cell size control of phytoplankton.

Chloroquine was once thought to be a promising treatment for COVID-19 but it quickly failed due to its inefficiency and association with increased mortality. Further, comorbidities such as hypertension may have contributed this failure. The safety and toxicity of chloroquine at doses required for treating SARS-CoV-2 infection in hypertensive patients remain unknown. Herein, to investigate these effects, we performed a safety evaluation of chloroquine at the approved dose (63 mg/kg) and at a high dose (126 mg/kg) in hypertensive rats. We found that chloroquine increased the mortality of hypertensive rats to 18.2% and 100%, respectively, after 7 days. During the chloroquine exposure period, the bodyweight, feed, and water consumption of hypertensive rats were decreased significantly. In addition, we show that chloroquine induces prolongation of QTc interval, elevation of LDH and CK, and histopathological damage of the myocardium in hypertensive rats. Ocular toxicity was observed in hypertensive rats in the form of hemorrhage in the eyes and retinal damage. Furthermore, we also observed intestinal toxicity in hypertensive rats, which presented as thinning intestinal walls with hemorrhagic contents, and histopathological changes of the jejunum. Hepatotoxicity was also evidenced by elevated ALT, and vacuolization of hepatocytes was also observed. Nephrotoxicity was observed only in high dose chloroquine-treated hypertensive rats, presenting as alterations of urinalysis and renal function. Immune alterations were also found in high-dose chloroquine-treated hypertensive rats with elevation of serum IL-10, IL-1β and GRO, and moderate damage to the spleen. In summary, this study partially explains the reason for the failure of chloroquine as a COVID-19 therapy, and underlines the importance of safety evaluation and medical supervision of chloroquine to avoid patient harm, especially to those with hypertension.

Xylanase, a glycoside hydrolase, is widely used in the food, papermaking, and textile industries; however, most xylanases are inactive at high temperatures. In this study, a xylanase gene, CFXyl3, was cloned from Cellulomonas flavigena and expressed in Escherichia coli BL21 (DE3). To improve the thermostability of xylanase, four hybrid xylanases with enhanced thermostability (designated EcsXyl1–4) were engineered from CFXyl3, guided by primary and 3D structure analyses. The optimal temperature of CFXyl3 was improved by replacing its N-terminus with the corresponding area of SyXyn11P, a xylanase that belongs to the hyperthermostable GH11 family. The optimal temperatures of the hybrid xylanases EcsXyl1–4 were 60, 60, 65, and 85°C, respectively. The optimal temperature of EcsXyl4 was 30 C higher than that of CFXyl3 (55°C) and its melting temperature was 34.5°C higher than that of CFXyl3. After the hydrolysis of beechwood xylan, the main hydrolysates were xylotetraose, xylotriose, and xylobiose; thus, these hybrid xylanases could be applied to prebiotic xylooligosaccharide manufacturing.

Objective: The decision of vancomycin dosage for central nervous system (CNS) infections is still a challenge because its bactericidal nature in cerebrospinal fluid (CSF) has not been confirmed by human studies. This study systematically reviewed the literatures on vancomycin in patients with meningitis, ventriculitis, and CNS device-associated infections, to assess efficacy, safety, and pharmacokinetics to better serve as a practical reference.Methods: Medline, Embase, and Cochrane Library were searched using terms vancomycin, Glycopeptides, meningitis, and central nervous system infections. Data were extracted including characteristics of participants, causative organism(s), administration, dosage, etc., The clinical response, microbiological response, adverse events and pharmacokinetic parameters were analyzed.Results: Nineteen articles were included. Indications for vancomycin included meningitis, ventriculitis, and intracranial device infections. No serious adverse effects of intravenous (IV) and intraventricular (IVT) vancomycin have been reported. Dosages of IV and IVT vancomycin ranged from 1000–3000 mg/day and 2–20 mg/day. Duration of IV and IVT vancomycin therapy most commonly ranged from 3–27 days and 2–21 days. Therapeutic drug monitoring was conducted in 14 studies. Vancomycin levels in CSF in patients using IV and IVT vancomycin were varied widely from 0.06 to 22.3 mg/L and 2.5–292.9 mg/L. No clear relationships were found between vancomycin CSF levels and efficacy or toxicity.Conclusion: Using vancomycin to treat CNS infections appears effective and safe based on current evidence. However, the optimal regimens are still unclear. Higher quality clinical trials are required to explore the vancomycin disposition within CNS.

AimTo compare the clinical efficacy of ultrasound-assisted thrombolysis (USAT) vs. standard catheter-directed thrombolysis (SCDT) in patients with acute pulmonary embolism (aPE).MethodsThis study analyzed the clinical outcomes of patients with non-low-risk aPE who received USAT or SCDT. The primary outcomes were all-cause death, total bleeding, and major bleeding. Secondary outcomes included pulmonary thrombotic load score (Miller), improvement in right ventricular-to-left ventricular ratio (RV/LV), dose and duration of the thrombolytic drug tissue plasminogen activator (tPA), length of stay (LOS) in the ICU, and total LOS in the hospital.ResultsA total of seven articles and 451 patients were included in this study. 241 patients were in the USAT group and 210 patients were in the SCDT group. There were no significant differences in all-cause mortality, total bleeding, and major bleeding between the two groups. Miller scores for pulmonary thrombus also showed no difference between the two groups, but pulmonary artery systolic pressure (PASP) was lower in the SCDT group after-treatment. The reduction of RV/LV from baseline was more pronounced in the SCDT group than in the USAT group (OR: −0.14, 95%CI: −0.20 to 0.07, P < 0.0001, I2 = 0%). Total dose of tPA and duration of infusion in the USAT group were lower than those in the SCDT group, but there was no significant statistical difference. LOS in the ICU was similar between the two groups, while LOS in the hospital was lower in the SCDT group.ConclusionThis study did not detect any differences in all-cause mortality, total bleeding, and major bleeding between non-low-risk aPE patients treated with USAT or SCDT. Improvement in right ventricular function was better in the SCDT group, and hospital LOS was lower in the SCDT group.

With the emerging wide bandgap (WBG) semiconductor development, the increasing power density and efficiency of power electronic converters may cause more switching oscillation, electromagnetic interference noise, and additional power loss, further increasing the probability of device failure. Therefore, determining and quantifying the failure of a metal-oxide-semiconductor-field-effect transistor (MOSFET), which assembled using WBG semiconductor in some applications, is crucial to improving the reliability of a power converter. This study proposes a novel failure quantitative assessment approach based on MOSFET parasitic parameters. According to the two-port network theory, MOSFET is equivalent to some second-order RLC circuits composed of independent inductances, capacitances, and resistances in series. Then, the frequency-domain impedance associated with the physical failure of MOSFET is identified through frequency domain reflectometry. Accelerated aging and bond wires cut-off experiments are employed to obtain various quality states of the MOSFET device. Result shows that the MOSFET quality level and its number of bond wire lift-offs can be quantified effectively. Drain-to-source on-resistance (RDS(on)) that normally represents the MOSFET quality shows a positive linear function relationship on drain-to-source parasitic resistance (RD + RS) during the quality degradation proceeding. This finding matches with the correlation established between RDS (on) and RD + RS in theory. Meanwhile, source parasitic inductance (LS) increases with the severity of bond wires faults, and even the slight fault shows a high sensitivity. The proposed approach would be an effective quality screening technology for power semiconductor devices without power on treatment, which can effectively avoid the impact of junction temperature and test conditions (current and voltage) on test results, and does not need to design additional test circuits. The test frequency range we used in this approach was 10–300 MHz, which to some extent is suitable for providing an on-line quality monitoring technology for high-frequency WBG power devices manufacturing.

The increasing mass loss from the Greenland ice sheet is becoming growingly important to present-day global sea level rise. Meltwater export to the ocean may be amplified by near-surface ice layers in firn (i.e., snow that has survived at least one melt season) which prevent infiltration. Such ice layers have been documented at various sites in southwest Greenland, but little is known about the local-scale (less than 1 km) variability in firn and ice properties. Here we investigate the local variability in firn density and ice content (ice layer thickness fraction) by analyzing 45 shallow firn cores retrieved from 15 sites in southwest Greenland between 2012 and 2019. The core dataset contains groups of cores that were collected at the same site (1–632 m apart from each other) and in the same year (here referred to as same site/year cores). The two-sided Mann-Whitney U-tests suggest that most same site/year cores do not have statistically significant differences in median density or ice content over the upper 0–4.5, 4.5–9, and 9–13.5 m sections below the winter snow layer. That said, the same site/year cores still exhibit substantial density and ice content differences as well as variable ice layer stratigraphy (especially the distribution of centimeters-thick ice lenses) not explainable by measurement uncertainties. The local-scale variability in density and ice content (calculated from the same site/year cores) over the three 4.5-m sections is 4% and 19–29%, respectively. The variability is comparable to the regional gradient in our study area within an elevation difference of up to ∼200 m. The local variability is non-negligible particularly at mid- to high-elevation sites (>2,000 m a.s.l.), where firn structure changes such as ice layer formation are more recent phenomena compared to lower elevations. This study confirms that single cores can provide representative bulk statistics such as mean density and ice content of one site. However, these mean values mask substantial local variability which can compromise regional comparisons. Therefore, collection of same site/year cores and consideration of local variability are necessary for an in-depth analysis of regional variability.

The H2S concentration in exhaled breath increases marginally with the progress of periodontal disease, and H2S is considered to be one of the most important gases related to meat and seafood decomposition; however, the concentration of H2S is low and difficult to detect in such scenarios. In this study, Au–PrFeO3 nanocrystalline powders with high specific surface areas and porosities were prepared using an electrospinning method. Our experimental results show that loading Au on the material provides an effective way to increase its gas sensitivity. Au doping can decrease the material’s resistance by adjusting its energy band, allowing more oxygen ions to be adsorbed onto the material’s surface due to a spillover effect. Compared with pure PrFeO3, the response of 3 wt% Au–PrFeO3 is improved by more than 10 times, and the response time is more than 10 s shorter. In addition, the concentration of H2S due to the decomposition of shrimp was detected using the designed gas sensor, where the error was less than 15%, compared with that obtained using a GC-MS method. This study fully demonstrates the potential of Au–PrFeO3 for H2S concentration detection.

BackgroundLarge fluctuations in blood glucose levels greatly impact the health and life span of elderly individuals. This study describes the characteristics of variability in glycemic indices in centenarians with the aim of emphasizing the importance of glycemic variability in elderly people.MethodsWe recruited individuals from Rugao City, Jiangsu Province, China from April 2020 to May 2021. The study cohort included 60 centenarians and 60 first-generation offspring, as well as 20 randomly selected non-cohabitant control individuals aged 60–80 years. A FreeStyle Libre H (hospital version) continuous glucose monitoring (CGM) device (Abbott Ireland UK) was used to measure glycemic variability. The indices measured included the time in target glucose range (TIR), time below target glucose range (TBR), time above target glucose range (TAR), mean amplitude of glycemic excursions (MAGE), mean of daily differences (MODD), coefficient of variation (CV), standard deviation of blood glucose (SDBG), continuous overlapping net glycemic action (CONGA), glucose management indicator (GMI) and estimated glycated hemoglobin (eHbA1c). Logistic regression was used to analyze the association between glycemic variability and longevity.ResultsMean blood glucose (MBG), eHbA1c, GMI, mean fasting plasma glucose (M-FPG) and CONGA were lower in the centenarian group (p all < 0.05). PPGE-2 was higher in the control group than that measured in the centenarian and first-generation offspring groups (p < 0.05). There were no differences between the groups in MAGE, MODD, MAG, or TIR (p > 0.05). The risk of not achieving longevity increased with each one unit increase in MBG by 126% [2.26 (1.05–4.91)], eHbA1c by 67% [1.67 (1.03–2.72)], GMI by 568% [6.68 (1.11–40.30)], M-FPG by 365% [4.65 (1.57–13.75)], M-PPG1h by 98% [1.98 (1.18–3.31)], CONGA1 by 102% [2.02 (1.01–4.06)], Li by 200% [3.00 (1.04–8.61)], and PPGE-2 by 150% [2.50 (1.39–4.50)]. However, the risk of achieving longevity decreased with each unit increase of LBGI by 53% [0.47 (0.28–0.80)], ADRR by 60% [0.40 (0.18–0.86)], and TBR by 11% [0.89 (0.80–0.98)].ConclusionFluctuation in blood glucose levels in centenarians is relatively small. Maintaining an average blood glucose level and keeping blood glucose fluctuations in the normal range is conducive to longevity.

Chronic subdural hematoma, a common neurosurgical disease, is mostly caused by craniocerebral trauma. Chronic subdural hematoma caused by acute myeloblastic leukemia is rarely reported, and its pathogenesis and strategies for clinical treatment remain controversial. Here, we report a rare case of chronic subdural hematoma caused by acute myeloblastic leukemia. The patient's condition deteriorated quickly after admission, and emergency trepanation and drainage of the chronic subdural hematoma was performed, followed by oral administration of atorvastatin. The platelet levels continued to decrease during neurosurgical treatment. Bone marrow cytology, flow cytology, and karyotype analysis suggested acute myelocytic leukemia (AML). Then, the patient was transferred to the hematology department for chemotherapy treatment, during which there was no recurrence of hematoma. Chronic subdural hematoma caused by acute myeloblastic leukemia is a very rare disease. Surgery should be performed when the intracranial hematoma is more than 10 mm thick and the midline structures are displaced by more than 5 mm, and postoperative treatment should be supplemented with atorvastatin to prevent recurrence. Chemotherapy should be given promptly to treat leukemia after stabilization of neurological conditions.

BackgroundEosinophilic granulomatosis with polyangiitis (EGPA) is characterized by asthma-like attacks in its early stage, which is easily misdiagnosed as severe asthma. Therefore, new biomarkers for the early diagnosis of EGPA are needed, especially for differentiating the diagnosis of asthma.ObjectivesTo identify serum biomarkers that can be used for early diagnosis of EGPA and to distinguish EGPA from severe asthma.MethodData-independent acquisition (DIA) analysis was performed to identify 45 healthy controls (HC), severe asthma (S-A), and EGPA patients in a cohort to screen biomarkers for early diagnosis of EGPA and to differentiate asthma diagnosis. Subsequently, parallel reaction monitoring (PRM) analysis was applied to a validation cohort of 71 HC, S-A, and EGPA patients.ResultFour candidate biomarkers were identified from DIA and PRM analysis—i.e., serum amyloid A1 (SAA1), fibrinogen-α (FGA), and serum amyloid P component (SAP)—and were upregulated in the EGPA group, while cholesteryl ester transfer protein (CETP) was downregulated in the EGPA group compared with the S-A group. Receiver operating characteristics analysis shows that, as biomarkers for early diagnosis of EGPA, the combination of SAA1, FGA, and SAP has an area under the curve (AUC) of 0.947, a sensitivity of 82.35%, and a specificity of 100%. The combination of SAA1, FGA, SAP, and CETP as biomarkers for differential diagnosis of asthma had an AUC of 0.921, a sensitivity of 78.13%, and a specificity of 100%, which were all larger than single markers. Moreover, SAA1, FGA, and SAP were positively and CETP was negatively correlated with eosinophil count.ConclusionDIA-PRM combined analysis screened and validated four previously unexplored but potentially useful biomarkers for early diagnosis of EGPA and differential diagnosis of asthma.

Background: The immune checkpoint blockade (ICB) with anti-programmed cell death protein 1(PD-1) on HNSCC is not as effective as on other tumors. In this study, we try to find out the key factors in the heterogeneous tumor-associated monocyte/macrophage (TAMM) that could regulate immune responses and predict the validity of ICB on HNSCC.Experimental Design: To explore the correlation of the TAMM heterogeneity with the immune properties and prognosis of HNSCC, we established the differentiation trajectory of TAMM by analyzing the single-cell RNA-seq data of HNSCC, by which the HNSCC patients were divided into different sub-populations. Then, we exploited the topology of the network to screen out the genes critical for immune hot phenotype of HNSCC, as well as their roles in TAMM differentiation, tumor immune cycle, and progression. Finally, these key genes were used to construct a neural net model via deep-learning framework to predict the validity of treatment with anti-PD-1/PDL-1Results: According to the differentiation trajectory, the genes involved in TAMM differentiation were categorized into early and later groups. Then, the early group genes divided the HNSCC patients into sub-populations with more detailed immune properties. Through network topology, CXCL9, 10, 11, and CLL5 related to TAMM differentiation in the TME were identified as the key genes initiating and maintaining the immune hot phenotype in HNSCC by remarkably strengthening immune responses and infiltration. Genome wide, CASP8 mutations were found to be key to triggering immune responses in the immune hot phenotype. On the other hand, in the immune cold phenotype, the evident changes in CNV resulted in immune evasion by disrupting immune balance. Finally, based on the framework of CXCL9-11, CLL5, CD8+, CD4+ T cells, and Macrophage M1, the neural network model could predict the validity of PD-1/PDL-1 therapy with 75% of AUC in the test cohort.Conclusion: We concluded that the CXCL9, 10,11, and CCL5 mediated TAMM differentiation and constructed immune hot phenotype of HNSCC. Since they positively regulated immune cells and immune cycle in HNSCC, the CXCL9-11 and CCL5 could be used to predict the effects of anti-PD-1/PDL-1 therapy on HNSCC.

ObjectivesMethamphetamine (METH) is a central nervous psychostimulant and one of the most frequently used illicit drugs. Numerous genetic loci that influence complex traits, including alcohol abuse, have been discovered; however, genetic analyses for METH dependence remain limited. An increased histone deacetylase 3 (HDAC3) expression has been detected in Fos-positive neurons in the dorsomedial striatum following withdrawal after METH self-administration. Herein, we aimed to systematically investigate the contribution of HDAC3 to the vulnerability to METH dependence in a Han Chinese population.MethodsIn total, we recruited 1,221 patients with METH dependence and 2,328 age- and gender-matched controls. For genotyping, we selected 14 single nucleotide polymorphisms (SNPs) located within ± 3 kb regions of HDAC3. The associations between genotyped genetic polymorphisms and the vulnerability to METH dependence were examined by single marker- and haplotype-based methods using PLINK. The effects of expression quantitative trait loci (eQTLs) on targeted gene expressions were investigated using the Genotype-Tissue Expression (GTEx) database.ResultsThe SNP rs14251 was identified as a significant association signal (χ2 = 9.84, P = 0.0017). An increased risk of METH dependence was associated with the A allele (minor allele) of rs14251 [odds ratio (95% CI) = 1.25 (1.09–1.43)]. The results of in silico analyses suggested that SNP rs14251 could be a potential eQTL signal for FCHSD1, PCDHGB6, and RELL2, but not for HDAC3, in various human tissues.ConclusionWe demonstrated that genetic polymorphism rs14251 located at 5q31.3 was significantly associated with the vulnerability to METH dependence in Han Chinese population.

Lung cancer has the highest tumor incidence in China. Lung squamous cell carcinoma (LUSC) is the most common type, accounting for 40–51% of primary lung cancers. LUSC is slow in growth and late in metastasis. Immune-related genes (IRGs) and immune infiltrating cells play a vital role in the clinical outcomes of LUSC. It is important to systematically study its immune gene map to help the prognosis of cancer patients. In this study, we combined the prognostic landscape and expression status of IRGs downloaded from the TCGA and InnatedDB databases and systematically analyzed the prognostic information of LUSC patients to obtain IRGs. After systematically exploring the survival analysis, prognosis-related genes were found, and the PPI network revealed that a total of 11 genes were hub genes. A two-gene prognosis risk model was established by multivariate Cox analysis. Two IRGs were closely correlated with the prognosis of LUSC. Based on these two genes, a new independent prognostic risk model was established, and this model was further verified in the GEO database. Moreover, the risk score of the model was correlated with sex, survival status, and lymphatic metastasis in LUSC patients, and the predictive risk of the prognostic risk model was significantly positively correlated with five kinds of immune cells (CD4 T cells, CD8 T cells, neutrophils, macrophages, and dendritic cells). This study comprehensively analyzed immunogenomics and presented immune-related prognostic biomarkers for LUSC.

ObjectiveTo investigate whether first-trimester fasting plasma glucose (FPG), blood coagulation function and lipid metabolism could predict gestational diabetes mellitus (GDM) risk.MethodsFrom October 2020 to May 2021, a total of 584 pregnant women who took prenatal care in Shanghai Jiaotong University Affiliated Sixth People's Hospital were chosen as the observation subjects. The clinical information and serum samples of all pregnant women were collected at 10–13 weeks of gestation and the blood coagulation function, fasting blood glucose and lipid profiles of the pregnant women were detected. A 75 g oral glucose tolerance test was performed up to 24–28 weeks of gestation. One hundred forty-two pregnant women with GDM and 442 pregnant women without GDM were detected. Data were expressed by x ± s or median (interquartile range) and were analyzed using student's t-test, Wilcoxon rank sum test and Logistic regression analysis. The area under the curve (AUC) was calculated by receiver operating characteristic curve (ROC) to analyze the predictive values.ResultsCompared with non-GDM group, age, pre-pregnancy BMI, FPG, FIB, D-Dimer, FDP, FPG, TC, TG, LDL-C, sdLDL-C, APOB and APOE in GDM group were significantly higher than those in non-GDM group, while PT, INR, APTT and TT were significantly lower than those in non-GDM group. Univariate logistic regression analysis was used to explore the risk factors of GDM. Gestational age, pre-pregnancy BMI, FPG, PT, INR, APTT, FIB, TT, D-Dimer, TC, TG, LDL-C, sdLDL-C, APOB and APOE were all independent predictors of GDM. Multivariatelogistic regression showed that pre-pregnancy BMI, FPG, APTT, TT, TG, LDL-C, sdLDL-C and APOB were risk factors for GDM. The AUC of the established GDM risk prediction model was 0.892 (0.858–0.927), and the sensitivity and specificity were 80.71 and 86.85%, respectively; which were greater than that of pre-pregnancy BMI, FPG, APTT, TT,TG, LDL-C, sdLDL-C, APOB alone, and the difffference was statistically signifificant (P < 0.05).ConclusionsFPG, APTT, TT, TG, LDL-C, sdLDL-C, APOB and pre-pregnancy BMI in early pregnancy has important clinical value for the prediction of GDM, We combined these laboratory indicators and established a GDM risk prediction model, which is conducive to the early identification, intervention and treatment of GDM, so as to reduce the morbidity of maternal and infant complications.

Electrocardiogram (ECG), as a product that can most directly reflect the electrical activity of the heart, has become the most common clinical technique used for the analysis of cardiac abnormalities. However, it is a heavy and tedious burden for doctors to analyze a large amount of ECG data from the long-term monitoring system. The realization of automatic ECG analysis is of great significance. This work proposes a beat-level interpretation method based on the automatic annotation algorithm and object detector, which abandons the previous mode of separate R peak detection and heartbeat classification. The ground truth of the QRS complex is automatically annotated and also regarded as the object the model can learn like category information. The object detector unifies the localization and classification tasks, achieving an end-to-end optimization as well as decoupling the high dependence on the R peak. Compared with most advanced methods, this work shows superior performance. For the interpretation of 12 heartbeat types in the MIT-BIH dataset, the average accuracy is 99.60%, the average sensitivity is 97.56%, and the average specificity is 99.78%. This method can be used as a clinical auxiliary tool to help doctors diagnose arrhythmia after receiving large-scale database training.

Mycoplasma pneumoniae (MP) is a one of most common pathogen in causing respiratory infection in children and adolescents. Rapid and efficient diagnostic methods are crucial for control and treatment of MP infections. Herein, we present an operationally simple, rapid and efficient molecular method for MP identification, which eliminates expensive instruments and specialized personnel. The method combines recombinase polymerase amplification (RPA) with clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated proteins (Cas) 12a-based detection, with an optimal procedure less than 1 h from sample to result including DNA extraction (25 min), RPA reaction (39°C for 15-20 min), CRISPR/Cas12a detection (37°C for 10 min) and visual detection by naked eyes (2 min). This diagnostic method shows high sensitivity (two copies per reaction) and no cross-reactivity against other common pathogenic bacteria. Preliminary evaluation using 201 clinical samples shows sensitivity of 99.1% (107/108), specificity of 100% (93/93) and consistency of 99.5% (200/201), compared with real-time PCR method. The above data demonstrate that our developed method is reliable for rapid diagnosis of MP. In conclusion, the RPA-CRISPR/Cas12a has a great potential to be as a useful tool for reliable and quick diagnosis of MP infection, especially in primary hospitals with limited conditions.

Diabetes mellitus is a metabolic disease closely related to a disordered gut microbiome. Diabetic patients usually suffer from various metabolic disorders, such as increased serum uric acid levels. Although serum uric acid levels depend partially on intestine excretion, the relationship between uric acid and gut microbiome in diabetic patients remains unknown. We collected a total of 126 fecal samples from diabetic patients for 16S ribosomal RNA gene amplicon sequencing and recorded clinical data. We analyzed the correlation between clinical indicators and gut microbiota of diabetic patients using Spearman analysis. Since uric acid was the most prominent one, we classified diabetic patients based on their uric acid levels to find the microbiome associated with uric acid disturbance. We constructed Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway profiles using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) to identify variations between the different groups. Among all the clinical indicators, uric acid had the strongest correlation with gut microbiota. First, we divided the patients into three groups according to their uric acid levels. The two low uric acid groups were similar, while the elevated uric acid group had significant differences in gut microbiota and metabolic pathways. The elevated uric acid group had a significantly lower gut microbiota diversity. At the genus level, this group had remarkably higher Escherichia–Shigella amounts and notably lower Faecalibacterium, Oscillospiraceae_UCG−002, and Oscillospiraceae_UCG−005 amounts. The gut microbiota of the high uric acid group was predicted to be enriched in metabolism, human diseases, and lipopolysaccharide biosynthesis. Since the two low uric acid groups were similar, we regrouped and matched the abnormal uric acid patients with normal uric acid patients. The differences in gut microbiota and metabolic pathways related to nucleotide metabolism became more significant. The serum uric acid levels were associated with gut microbiome changes. This might be related to uric acid metabolism by gut microbes. Our study indicates that targeting the gut microbiome could help manage elevated uric acid levels.

BackgroundThe current clinical workflow for esophageal gross tumor volume (GTV) contouring relies on manual delineation with high labor costs and inter-user variability.PurposeTo validate the clinical applicability of a deep learning multimodality esophageal GTV contouring model, developed at one institution whereas tested at multiple institutions.Materials and MethodsWe collected 606 patients with esophageal cancer retrospectively from four institutions. Among them, 252 patients from institution 1 contained both a treatment planning CT (pCT) and a pair of diagnostic FDG-PET/CT; 354 patients from three other institutions had only pCT scans under different staging protocols or lacking PET scanners. A two-streamed deep learning model for GTV segmentation was developed using pCT and PET/CT scans of a subset (148 patients) from institution 1. This built model had the flexibility of segmenting GTVs via only pCT or pCT+PET/CT combined when available. For independent evaluation, the remaining 104 patients from institution 1 behaved as an unseen internal testing, and 354 patients from the other three institutions were used for external testing. Degrees of manual revision were further evaluated by human experts to assess the contour-editing effort. Furthermore, the deep model’s performance was compared against four radiation oncologists in a multi-user study using 20 randomly chosen external patients. Contouring accuracy and time were recorded for the pre- and post-deep learning-assisted delineation process.

In this study, we evaluated the diagnostic accuracy of multiple cross displacement amplification (MCDA) combined with real-time PCR platform in pulmonary tuberculosis (PTB) patients. Total 228 PTB patients and 141 non-TB cases were enrolled. Based on the analysis of the first available sample of all participants, MCDA assay showed a higher overall sensitivity (64.0%), with a difference of more than 10% compared with Xpert MTB/RIF (Xpert) assay (51.8%, P < 0.05) and combined liquid and solid culture (47.8%, P < 0.001) for PTB diagnosis. In particular, MCDA assay detected 31 probable TB patients, which notably increased the percentage of confirmed TB from 57.9% (132/228) to 71.5% (163/228). The specificities of microscopy, culture, Xpert and MCDA assay were 100% (141/141), 100% (141/141), 100% (141/141), and 98.6% (139/141), respectively. Among the patients with multiple samples, per patient sensitivity of MCDA assay was 60.5% (52/86) when only the first available sputum sample was taken into account, and the sensitivity increased to 75.6% (65/86) when all samples tested by MCDA assay were included into the analysis. Therefore, MCDA assay established in this study is rapid, accurate and affordable, which has the potential in assisting the accurate and rapid diagnosis of PTB and speed up initiation of TB treatment in settings equipped with real-time PCR platform.

Non-invasive early prediction of septic acute kidney injury (S-AKI) is still urgent and challenging. Increased Doppler-based renal resistive index (RRI) has been shown to be associated with S-AKI, but its clinical use is limited, which may be explained by the complex effects of systemic circulation. Echocardiogram allows non-invasive assessment of systemic circulation, which may provide an effective supplement to RRI. To find the value of RRI combined with echocardiographic parameters in the non-invasive early prediction of S-AKI, we designed this experiment with repeated measurements of ultrasonographic parameters in the early stage of sepsis (3, 6, 12, and 24 h) in cecum ligation and puncture (CLP) rats (divided into AKI and non-AKI groups at 24 h based on serum creatinine), with sham-operated group serving as controls. Our results found that RRI alone could not effectively predict S-AKI, but when combined with echocardiographic parameters (heart rate, left ventricular end-diastolic internal diameter, and left ventricular end-systolic internal diameter), the predictive value was significantly improved, especially in the early stage of sepsis (3 h, AUC: 0.948, 95% CI 0.839–0.992, P < 0.001), and far earlier than the conventional renal function indicators (serum creatinine and blood urea nitrogen), which only significantly elevated at 24 h. Our method showed novel advances and potential in the early detection of S-AKI.

Many methods used in multi-locus genome-wide association studies (GWAS) have been developed to improve statistical power. However, most existing multi-locus methods are not quicker than single-locus methods. To address this concern, we proposed a fast score test integrated with Empirical Bayes (ScoreEB) for multi-locus GWAS. Firstly, a score test was conducted for each single nucleotide polymorphism (SNP) under a linear mixed model (LMM) framework, taking into account the genetic relatedness and population structure. Then, all of the potentially associated SNPs were selected with a less stringent criterion. Finally, Empirical Bayes in a multi-locus model was performed for all of the selected SNPs to identify the true quantitative trait nucleotide (QTN). Our new method ScoreEB adopts the similar strategy of multi-locus random-SNP-effect mixed linear model (mrMLM) and fast multi-locus random-SNP-effect EMMA (FASTmrEMMA), and the only difference is that we use the score test to select all the potentially associated markers. Monte Carlo simulation studies demonstrate that ScoreEB significantly improved the computational efficiency compared with the popular methods mrMLM, FASTmrEMMA, iterative modified-sure independence screening EM-Bayesian lasso (ISIS EM-BLASSO), hybrid of restricted and penalized maximum likelihood (HRePML) and genome-wide efficient mixed model association (GEMMA). In addition, ScoreEB remained accurate in QTN effect estimation and effectively controlled false positive rate. Subsequently, ScoreEB was applied to re-analyze quantitative traits in plants and animals. The results show that ScoreEB not only can detect previously reported genes, but also can mine new genes.

The roles of bone morphogenetic protein (BMP) signaling in palatogenesis were well documented in the developing hard palate; however, little is known about how BMP signaling regulates the development of soft palate. In this study, we overexpressed Noggin transgene via Osr2-creKI allele to suppress BMP signaling in the developing soft palate. We found that BMP-Smad signaling was detected in the palatal muscles and surrounding mesenchyme. When BMP-Smad signaling was suppressed by the overexpressed Noggin, the soft palatal shelves were reduced in size with the hypoplastic muscles and the extroversive hypophosphatasia (HPP). The downregulated cell proliferation and survival in the Osr2-creKI;pMes-Noggin soft palates were suggested to result from the repressed Shh transcription and Gli1 activity, implicating that the BMP-Shh-Gli1 network played a similar role in soft palate development as in the hard palate. The downregulated Sox9, Tenascin-C (TnC), and Col1 expression in Osr2-creKI;pMes-Noggin soft palate indicated the impaired differentiation of the aponeurosis and tendons, which was suggested to result in the hypoplasia of palatal muscles. Intriguingly, in the Myf5-creKI;pMes-Noggin and the Myf5-creKI;Rosa26R-DTA soft palates, the hypoplastic or abrogated muscles affected little the fusion of soft palate. Although the Scx, Tnc, and Co1 transcription was significantly repressed in the tenogenic mesenchyme of the Myf5-creKI;pMes-Noggin soft palate, the Sox9 expression, and the Tnc and Col1 transcription in aponeurosis mesenchyme were almost unaffected. It implicated that the fusion of soft palate was controlled by the mesenchymal clues at the tensor veli palatini (TVP) and levator veli palatini (LVP) levels, but by the myogenic components at the palatopharyngeus (PLP) level.

ObjectiveThe purpose of our study was to evaluate the effectiveness of thermal ablation (TA) for Bethesda IV thyroid nodules, and to compare TA and surgery in terms of treatment outcomes, complications, and costs.MethodThis study was approved by the local ethics committee. From January 2017 to December 2019, 30 patients elected TA and 31 patients elected surgery for treatment of Bethesda IV thyroid nodules. Demographics information and conventional ultrasound before treatment for each patient was obtained. For the TA group, the ablation extent was 3 mm beyond the edge of the tumor to prevent marginal residual and recurrence. Patients were followed up at 1, 3, and 6 months after intervention, and every 6 months thereafter. Postoperative complications, operation time, hospitalization time, blood loss, and incision length were recorded.ResultsIn the TA group, the volume reduction ratio (VRR) was 94.63 ± 8.99% (range:76%-100%) at the final follow-up. The mean follow-up time was 16.4 ± 5.2months (range:12–24 months). No recurrences, no metastatic lymph node, and no distant metastases were detected during follow-up. The TA group had fewer complications, shorter operation time, smaller incision length, less blood loss, shorter hospitalization time, and lower treatment costs compared to the surgery group (all P

ObjectiveThe cytochrome c oxidase assembly factor 7 (COA7) gene encodes a protein localized to mitochondria that is involved in the assembly of mitochondrial respiratory chain complex IV. Here, we report the clinical, genetic and biochemical analysis of a female patient with suspected mitochondrial disorder and novel variants in COA7, that presented with a considerably different phenotype and age of onset than the five COA7 patients reported to date.MethodsWe performed trio-exome sequencing in the affected patient and both parents. To verify the pathogenicity of the detected variants in COA7, mitochondrial enzyme activities and oxygen consumption rate were investigated in fibroblasts of the patient and her parents.ResultsA Chinese girl was referred at 9 months of age with a history of developmental delay and regression since 3 months of age. In the following months, she lost previously acquired skills and developed progressive spasticity of the lower extremities. Trio-exome sequencing revealed compound heterzygous variants in COA7 (c.511G > A/p.Ala171Thr and c.566A > G/p.Asn189Ser). Functional validation experiments revealed isolated complex IV deficiency and a significantly reduced mitochondrial respiration rate in patient-derived fibroblasts.InterpretationHitherto, characteristic features of COA7 patients were described as slowly progressing neuropathy and spinocerebellar ataxia, starting at the toddler age and progressing into adulthood. In contrast, our patient was reported to show developmental delay from 3 months of age, which was found to be due to a rapidly progressive encephalopathy and brain atrophy seen at 9 months of age. Unexpectedly, the genetic investigation revealed a COA7-associated mitochondrial disease, which was confirmed functionally. Thus, this report broadens the genetic and clinical spectrum of this heterogeneous mitochondriopathy and highlights the value of the presented unbiased approach.

Purpose: Computed tomography (CT) characteristics associated with critical outcomes of patients with coronavirus disease 2019 (COVID-19) have been reported. However, CT risk factors for mortality have not been directly reported. We aim to determine the CT-based quantitative predictors for COVID-19 mortality.Methods: In this retrospective study, laboratory-confirmed COVID-19 patients at Wuhan Central Hospital between December 9, 2019, and March 19, 2020, were included. A novel prognostic biomarker, V-HU score, depicting the volume (V) of total pneumonia infection and the average Hounsfield unit (HU) of consolidation areas was automatically quantified from CT by an artificial intelligence (AI) system. Cox proportional hazards models were used to investigate risk factors for mortality.Results: The study included 238 patients (women 136/238, 57%; median age, 65 years, IQR 51–74 years), 126 of whom were survivors. The V-HU score was an independent predictor (hazard ratio [HR] 2.78, 95% confidence interval [CI] 1.50–5.17; p = 0.001) after adjusting for several COVID-19 prognostic indicators significant in univariable analysis. The prognostic performance of the model containing clinical and outpatient laboratory factors was improved by integrating the V-HU score (c-index: 0.695 vs. 0.728; p < 0.001). Older patients (age ≥ 65 years; HR 3.56, 95% CI 1.64–7.71; p < 0.001) and younger patients (age < 65 years; HR 4.60, 95% CI 1.92–10.99; p < 0.001) could be further risk-stratified by the V-HU score.Conclusions: A combination of an increased volume of total pneumonia infection and high HU value of consolidation areas showed a strong correlation to COVID-19 mortality, as determined by AI quantified CT.