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Abstract Background The gut microbiota plays a pivotal role in ulcerative colitis (UC) development. This study explores the impact of latent tuberculosis infection (LTBI) on the gut microbiota in UC and assesses changes during vedolizumab treatment, investigating prophylactic anti-tuberculosis therapy. Results This cohort study included adult patients with UC receiving vedolizumab treatment at Jinhua Hospital, Zhejiang University from April 2021 to December 2022. Patients were divided into LTBI (n = 24) and non-LTBI (n = 21) groups. Patients in the LTBI group were further subdivided into prophylactic (n = 13) and non-prophylactic (n = 11) groups. Clinical and fecal samples were collected pre- and post-vedolizumab treatment for the LTBI groups and pre-treatment for the non-LTBI group. The gut microbiota was analyzed using 16 S rRNA sequencing. Patients in the non-LTBI group exhibited higher diversity indices. Vedolizumab demonstrated efficacy in the LTBI group, with clinical response and remission rates of 83.3% and 75.0%, respectively. The gut microbiota diversity in the LTBI group increased post-vedolizumab treatment, and receiving prophylactic isoniazid showed no significant difference in vedolizumab treatment response compared to not receiving prophylactic isoniazid. Microbiota changes were similar between groups, with an increase in [Ruminococcus] expression after vedolizumab treatment. Conclusions This cohort study, conducted at a single center, highlights that LTBI can reduce gut microbiota diversity among adult patient with UC. The observed efficacy of vedolizumab treatment in the LTBI group indicates a potential association with microbiota changes. However, mono-isoniazid exhibited limited impact, underscoring the potential of vedolizumab as a promising candidate for prophylactic anti-tuberculosis treatment in the context of UC.

Abstract Depression is a prevalent mental disorder characterized by unknown pathogenesis and challenging treatment. Recent meta-analyses reveal an association between cardiovascular risk factors and an elevated risk of depression. Despite this, the precise role of vascular injury in depression development remains unclear. In this investigation, we assess vascular system function in three established animal models of depression— chronic unpredictable mild stress (CUMS), chronic social defeat stress (CSDS) and maternal separation (MS)—utilizing ultrasonography and laser Doppler measurement. All three model animals exhibit anhedonia and despair-like behavior. However, significant microvascular dysfunction (not macrovascular) is observed in animals subjected to CUMS and CSDS models, while such dysfunction is absent in the MS model. Statistical analysis further indicates that microcirculation dysfunction is not only associated with depression-like behavior but is also intricately involved in the development of depression in the CUMS and CSDS models. Furthermore, our study has proved for the first time that endothelial nitric oxide synthase-deficient (eNOS +/− ) mice, which is a classic model of vascular endothelial injury, showed depression-like behavior which occurred two months later than microvascular dysfunction. Notably, the mitigation of microvascular dysfunction successfully reverses depression-like behavior in eNOS +/− mice by enhancing nitric oxide production. In conclusion, this study unveils the pivotal role of microvascular dysfunction in the onset of depression induced by chronic stress in adulthood and proposes that modulating microvascular function may serve as a potential intervention in the treatment of depression.

Background The importance of integrating humanities into medical education has been recognized. However, the medical humanities curriculum is usually lacking during standardized training for residents in China. This study aims to determine the feasibility and effectiveness of pilot-specific courses in medical humanities in standardized residency training. Methods We designed specific courses in medical humanities, composed of 3 courses: Identifying and Managing Common Psychological Disorders of Patients, Patient-Clinician Communication, and Medical Dispute Cases Analysis and Resolution. The courses were scheduled monthly throughout the one semester, and a total of 118 residents participated in the curriculum. Participants completed the evaluation containing ethic-legal knowledge and humanistic competencies related to course content before and after the curriculum. Results Most participant residents had a bachelor's degree (85.6%) and were in the first year of standardized residency training (61.0%). Their disciplinary backgrounds are diverse, encompassing 18 different clinical medical specialties. The residents’ average scores of postcourse self-assessments keep a steady increase in humanistic competencies compared with precourse average scores. All postcourse self-assessments showed significant improvement compared to precourse ( P

Abstract Pleural empyema can lead to significant morbidity and mortality despite chest drainage and antibiotic treatment, necessitating novel and minimally invasive interventions. Fusobacterium nucleatum is an obligate anaerobe found in the human oral and gut microbiota. Advances in sequencing and puncture techniques have made it common to detect anaerobic bacteria in empyema cases. In this report, we describe the case of a 65-year-old man with hypertension who presented with a left-sided encapsulated pleural effusion. Initial fluid analysis using metagenomic next-generation sequencing (mNGS) revealed the presence of Fusobacterium nucleatum and Aspergillus chevalieri. Unfortunately, the patient experienced worsening pleural effusion despite drainage and antimicrobial therapy. Ultimately, successful treatment was achieved through intrapleural metronidazole therapy in conjunction with systemic antibiotics. The present case showed that intrapleural antibiotic therapy is a promising measure for pleural empyema.

Abstract Objective This study aims to investigate the role of the triglyceride glucose (TyG) index in differentiating cardiogenic stroke (CE) from large atherosclerotic stroke (LAA). Method In this retrospective study, patients with acute ischemic stroke were recruited from the First Affiliated Hospital of Soochow University, Lianyungang Second People’s Hospital and Lianyungang First People’s Hospital. Their general data, medical history and laboratory indicators were collected and TyG index was calculated. Groups were classified by the TyG index quartile to compare the differences between groups. Logistic regression was utilized to assess the relationship between the TyG index and LAA. The receiver operating characteristic curve (ROC) curve was used to evaluate the diagnostic efficiency of the TyG index in differentiating LAA from CE. Result The study recruited 1149 patients. After adjusting for several identified risk factors, groups TyG-Q2, TyG-Q3, and TyG-Q4 had a higher risk of developing LAA compared to group TyG-Q1(odds ratio (OR) = 1.63,95% confidence interval (CI) = 1.11–2.39, OR = 1.72,95%CI = 1.16–2.55, OR = 2.06,95%CI = 1.36–3.09). TyG has certain diagnostic value in distinguishing LAA from CE(AUC = 0.595, 95%CI0.566–0.623;P

Background/Aims: There is a lack of effective and safe methods for preventing esophageal stricture after large endoscopic submucosal dissection (ESD) in patients with superficial esophageal cancer. We aimed to compare the effectiveness of oral prednisolone alone versus a combination of oral prednisolone and nasogastric tube in preventing esophageal stricture following extensive ESD. Materials and Methods: We retrospectively gathered clinical data from a single center on patients with early esophageal cancer who underwent ESD. Patients were categorized into 2 groups: the steroid group (receiving only oral prednisolone) and the steroid+nasogastric tube retention (NGT) group. We analyzed the incidence of esophageal stricture and identified risk factors for its development. Results: The study included 79 patients, with 30 in the steroid group and 49 in the steroid+NGT group. The incidence of stricture was significantly higher in the steroid group (9/30, 30.0%) compared to the steroid+NGT group (3/49, 6.1%) (P = .004). Notably, we observed a significant difference in the stricture rates between the 2 groups, particularly in patients with a complete circumferential defect (100% and 16.7%) (P = .015). Multivariate logistic regression analysis revealed that a full circumferential defect of the esophageal mucosa (OR 12.501; 95% CI 1.907, 81.047; P = .008), invasion depth beyond the lamina propria (OR 5.635; 95% CI 1.039, 30.559; P = .045), and the absence of NGT retention (OR 12.896; 95% CI 2.099, 79.219; P = .006) were independent risk factors predicting the development of a stricture. Conclusion: The combination of steroids with NGT retention is more effective than using oral steroids alone in preventing esophageal stricture after extensive ESD.

IntroductionEpidemiological studies have assessed the correlation between daily dietary branch chain amino acid (BCAA) intakes and the risk of obesity, however, the findings from these studies were inconsistent and investigations among GDM women were few.ObjectiveThe present study was to investigate the associations of daily BCAA intakes with the risks of overweight and abdominal obesity among women with prior gestational diabetes mellitus (GDM) postpartum.MethodWe performed a cross-sectional study of 1,263 women with prior GDM at 1–5 years post-delivery. Logistic regression models were used to estimate the associations of daily dietary intakes of BCAAs with the risks of overweight and abdominal obesity.ResultsThe multivariable-adjusted odds ratios (ORs) across quartiles of daily BCAA intakes postpartum were 1.42 (95% confidence interval [CI] 1.02–1.97), 1.00 (reference), 1.21 (95% CI 0.88–1.68), and 1.31 (95% CI 0.95–1.81) for general overweight, and 1.38 (95% CI 0.99–1.90), 1.00, 1.19 (95% CI 0.86–1.64), and 1.43 (95% CI 1.04–1.98) for abdominal obesity, respectively. Women with the lowest quartile of daily BCAA intakes significantly increased the risks of general overweight (OR 1.49; 95 %CI 1.06–2.09) and abdominal obesity (OR 1.50; 95 %CI 1.08–2.11) compared with women at quartile 2 of daily BCAA intakes after further adjustment of daily energy intake.ConclusionThe present study indicated that daily lower BCAA intakes were associated with increased risks of general overweight and abdominal obesity among women with prior GDM.

Accurate estimation of unknown parameters of complex photovoltaic models is crucial to whether photovoltaic generators can efficiently convert energy. When a photovoltaic model has multiple diode branches, its complexity increases geometrically. To address the problems of high complexity and difficulty in estimation, this paper proposes an effective improved algorithm based on success-history adaptation differential evolution with linear population size reduction (L-SHADE)—Bi-parameter coordinated updating L-SHADE with parameter decomposition method (CSpL-SHADED). First in CSpL-SHADED, dynamic crossover rate ranking technology is developed to bridge the relationship between individuals and crossover rates, thereby improving effective mutation capabilities. In addition, a dynamic sub-population mechanism is also proposed to divide the entire population into multiple sub-populations so that they are evenly distributed in the search space, so the search ability of individuals in local areas is improved. Secondly, the unknown parameters of solar photovoltaic models of different complexity are effectively decomposed into linear and nonlinear parameters by the decomposition method. The nonlinear parameters are accurately estimated by CSpL-SHADED, and the linear parameters are calculated based on the constructed matrix equation. Through experiments on four solar photovoltaic models of different complexity, CSpL-SHADED showed strong competitiveness to varying degrees compared to the comparative algorithms.

The determination of unknown parameters of photovoltaic models has always been a difficult problem in the field of nonlinear optimization, which is inseparable from the energy conversion efficiency of photovoltaic power generation systems. Due to the high degree of nonlinearity and difficulty in parameter identification of photovoltaic models with multiple diode branches, this paper proposes a novel and efficient evolutionary algorithm based on success-history adaptation differential evolution with linear population size reduction (L-SHADE)—Dynamic L-SHADE with parameter decomposition method (DaL-SHADE) to identify unknown parameters of photovoltaic models. In DaL-SHADE, a dynamic crossover rate sorting technology is introduced, which establishes the relationship between the population and its crossover rate that is ignored in L-SHADE, and thereby the optimization ability of the algorithm to identify unknown parameters is improved. Secondly, the unknown parameters of different types of photovoltaic models are decomposed into linear parameters and nonlinear parameters, so that the dimensionality of the photovoltaic model is reduced. Therefore, DaL-SHADE not only has efficient optimization capabilities but also reduces the dimensionality of different types of photovoltaic models. Through the examination of four photovoltaic models with different degrees of nonlinearization, root mean square error obtained by DaL-SHADE is better than that of the comparison algorithms.

Abstract Introduction Transforming growth factor beta (TGFβ) cytokines (TGFβ1, TGFβ2, and TGFβ3) play critical roles in tissue fibrosis. However, treatment with systemic pan-TGFβ inhibitors have demonstrated unacceptable toxicities. In this study, we evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of RO7303509, a high-affinity, TGFβ3-specific, humanized immunoglobulin G1 monoclonal antibody, in healthy adult volunteers (HVs). Methods This phase 1a, randomized, double-blind trial included six cohorts for evaluation, with each cohort receiving single doses of placebo or RO7303509, administered intravenously (IV; 50 mg, 150 mg, 240 mg) or subcutaneously (SC; 240 mg, 675 mg, 1200 mg). The frequency and severity of adverse events (AEs) and RO7303509 serum concentrations were monitored throughout the study. We also measured serum periostin and cartilage oligomeric matrix protein (COMP) by immunoassay and developed a population pharmacokinetics model to characterize RO7303509 serum concentrations. Results The study enrolled 49 HVs, with a median age of 39 (range 18–73) years. Ten (27.8%) RO7303509-treated subjects reported 24 AEs, and six (30.8%) placebo-treated subjects reported six AEs. The most frequent AEs related to the study drug were injection site reactions and infusion-related reactions. Maximum serum concentrations (C max) and area under the concentration–time curve from time 0 to infinity (AUC0–inf) values for RO7303509 appeared to increase dose-proportionally across all doses tested. Serum concentrations across cohorts were best characterized by a two-compartment model plus a depot compartment with first-order SC absorption kinetics. No subjects tested positive for anti-drug antibodies (ADAs) at baseline; one subject (2.8%; 50 mg IV) tested positive for ADAs at a single time point (day 15). No clear pharmacodynamic effects were observed for periostin or COMP upon TGFβ3 inhibition. Conclusion RO7303509 was well tolerated at single SC doses up to 1200 mg in HVs with favorable pharmacokinetic data that appeared to increase dose-proportionally. TGFβ3-specific inhibition may be suitable for development as a chronic antifibrotic therapy. Trial Registration ISRCTN13175485.

Abstract It is increasingly clear that longitudinal risk factor levels and trajectories are related to risk for atherosclerotic cardiovascular disease (ASCVD) above and beyond single measures. Currently used in clinical care, the Pooled Cohort Equations (PCE) are based on regression methods that predict ASCVD risk based on cross-sectional risk factor levels. Deep learning (DL) models have been developed to incorporate longitudinal data for risk prediction but its benefit for ASCVD risk prediction relative to the traditional Pooled Cohort Equations (PCE) remain unknown. Our study included 15,565 participants from four cardiovascular disease cohorts free of baseline ASCVD who were followed for adjudicated ASCVD. Ten-year ASCVD risk was calculated in the training set using our benchmark, the PCE, and a longitudinal DL model, Dynamic-DeepHit. Predictors included those incorporated in the PCE: sex, race, age, total cholesterol, high density lipid cholesterol, systolic and diastolic blood pressure, diabetes, hypertension treatment and smoking. The discrimination and calibration performance of the two models were evaluated in an overall hold-out testing dataset. Of the 15,565 participants in our dataset, 2170 (13.9%) developed ASCVD. The performance of the longitudinal DL model that incorporated 8 years of longitudinal risk factor data improved upon that of the PCE [AUROC: 0.815 (CI 0.782–0.844) vs 0.792 (CI 0.760–0.825)] and the net reclassification index was 0.385. The brier score for the DL model was 0.0514 compared with 0.0542 in the PCE. Incorporating longitudinal risk factors in ASCVD risk prediction using DL can improve model discrimination and calibration.

BackgroundLung cancer, characterized by its high morbidity and lethality, necessitates thorough research to enhance our understanding of its pathogenesis and discover novel therapeutic approaches. Recent studies increasingly demonstrate that lung cancer cells can modulate the tumor microenvironment, promoting tumor growth, and metastasis through the release of exosomes. Exosomes are small vesicles secreted by cells and contain a variety of bioactive molecules such as proteins, nucleic acids, and metabolites. This paper presents a comprehensive review of exosome research in lung cancer and its progress through bibliometric analysis.MethodsPublications related to exosomes in lung cancer patients were systematically searched on the Web of Science Core Collection (WoSCC) database. Bibliometric analysis was performed using VOSviwers, CiteSpace, and the R package “Bibliometrics”. Publications were quantitatively analyzed using Microsoft Office Excel 2019. The language of publication was restricted to “English” and the search strategy employed TS=(exosomes or exosomes or exosomes) and TS=(lung cancer). The search period commenced on January 1, 2004, and concluded on November 12, 2023, at noon. The selected literature types included Articles and Reviews.ResultsThe study encompassed 1699 papers from 521 journals across 71 countries and 2105 institutions. Analysis revealed a consistent upward trend in lung cancer exosome research over the years, with a notable surge in recent times. This surge indicates a growing interest and depth of inquiry into lung cancer exosomes. Major research institutions in China and the United States, including Nanjing Medical University, Shanghai Jiao Tong University, Chinese Academy Of Sciences, and Utmd Anderson Cancer Center, emerged as crucial research hubs. The annual publication count in this field witnessed a continuous rise, particularly in recent years. Key terms such as lung cancer, non-small cell lung cancer (NSCLC), microvesicles, intercellular communication, exosomal miRNAs, and oncology dominated the research landscape. Fields like cell biology, biochemistry, biotechnology, and oncology exhibited close relation with this research. Clotilde Théry emerged as the most cited author in the field, underlining her significant contributions. These results demonstrate the broad impact of exosome research in lung cancer, with key terms covering not only disease-specific aspects such as lung cancer and NSCLC but also basic biological concepts like microvesicles and intercellular communication. Explorations into exosomal microRNAs and oncology have opened new avenues for lung cancer exosome research. In summary, lung cancer exosome research is poised to continue receiving attention, potentially leading to breakthroughs in treatment and prevention.ConclusionPublications on lung cancer exosomes show a rising trend year by year, with China and the United States ranking first and second in terms of the number of publications. However, there is insufficient academic learning cooperation and exchanges between the two sides, and Chinese universities account for a large proportion of research institutions in this field. Jing Li is the most productive author, Clotilde Théry is the most co-cited author, and Cancers is the journal with the highest number of publications. The current focus in the field of lung cancer exosomes is on biomarkers, liquid biopsies, immunotherapy, and tumor microenvironment.

ObjectivePrevious studies reported possible connections between inflammatory bowel disease (IBD) and several neurodegenerative disorders. However, the comprehensive relationships between IBD and various neurodegenerative disorders were not summarized. We executed a meta-analysis of longitudinal studies to provide an estimate of the strength of the two-directional prospective association between IBD and neurodegenerative disorders.MethodsWe accomplished a thorough bibliographic search of PubMed, Web of Science, Embase, PsycINFO, and Cochrane Library databases until June 2023 to locate relevant longitudinal studies. The extracted data were then analyzed via meta-analysis using either a fixed or random effects model.ResultsThe final analysis encompassed 27 studies. Individuals with IBD faced an increased risk of developing four neurodegenerative disorders than the general public, namely, Alzheimer’s disease (hazard ratio[HR] = 1.35, 95% confidence interval [CI]: 1.03–1.77, P=0.031), dementia (HR =1.24, 95% CI: 1.13–1.36, P

Abstract Antimicrobial peptides (AMPs) are important mediators of intestinal immune surveillance. However, the regional heterogeneity of AMPs and its regulatory mechanisms remain obscure. Here, we clarified the regional heterogeneity of intestinal AMPs at the single-cell level, and revealed a cross-lineages AMP regulation mechanism that bile acid dependent transcription factors (BATFs), NR1H4, NR1H3 and VDR, regulate AMPs through a ligand-independent manner. Bile acids regulate AMPs by perturbing cell differentiation rather than activating BATFs signaling. Chromatin accessibility determines the potential of BATFs to regulate AMPs at the pre-transcriptional level, thus shaping the regional heterogeneity of AMPs. The BATFs-AMPs axis also participates in the establishment of intestinal antimicrobial barriers of fetuses and the defects of antibacterial ability during Crohn’s disease. Overall, BATFs and chromatin accessibility play essential roles in shaping the regional heterogeneity of AMPs at pre- and postnatal stages, as well as in maintenance of antimicrobial immunity during homeostasis and disease.

IntroductionMemory T (Tm) cells are a subpopulation of immune cells with great heterogeneity. Part of this diversity came from T cells that were primed with different viruses. Understanding the differences among different viral-specific Tms will help develop new therapeutic strategies for viral infections.MethodsIn this study, we compared the transcriptome of Tm cells that primed with CMV, EBV and SARS-CoV-2 with single-cell sequencing and studied the similarities and differences in terms of subpopulation composition, activation, metabolism and transcriptional regulation.ResultsWe found that CMV is marked by plentiful cytotoxic Temra cells, while EBV is more abundant in functional Tem cells. More importantly, we found that CD28 and CTLA4 can be used as continuous indicators to interrogate the antiviral ability of T cells. Furthermore, we proposed that REL is a main regulatory factor for CMV-specific T cells producing cytokines and plays an antiviral role.DiscussionOur data gives deep insight into molecular characteristics of Tm subsets from different viral infection, which is important to understand T cell immunization. Furthermore, our results provide basic background knowledges for T cell based vaccine development in future.

The implementation of green finance is crucial in achieving a reduction in regional emissions. As such, understanding how green finance affects regional emission reduction is essential. Using provincial panel data from 2008 to 2019, we employed the fixed effects model to examine the impact of green finance on regional emission reduction. The empirical results reveal the following: (1) Green finance has a negative effect on sulfur dioxide intensity, and the development of green finance can significantly reduce the emission of regional pollutants. (2) Among the different instruments of green finance, green credit and green investment exhibit more substantial emission reduction effects than green securities and green insurance. (3) The mechanism by which green finance affects regional emission reduction is mainly through the advanced industrial structure and green technology innovation. (4) The development of green finance shows geographical discrepancies: The eastern region of China is more effective in reducing emissions than the central and western regions. To fully maximize the role of green finance in emission reduction, this paper offers pertinent suggestions for strengthening the green financial system, improving the advanced industrial process, increasing investment in green energy technology, and formulating specific development tactics that consider the prominent characteristics of distinct regions.

This study aimed to evaluate the efficacy and safety of olaparib for the treatment of advanced ovarian cancer. All studies that assessed the efficacy and safety of olaparib in advanced ovarian cancer were searched in PubMed, Embase, and Web of Science from their inception to 20 September 2022. The analysis included six studies and 2016 patients. Olaparib could significantly prolong the progression-free survival (PFS) of patients compared to that of the control group (HR = 0.49, 95% CI = 0.36 − 0.68). However, no statistically significant differences were detected in overall survival (OS) and objective response rate (ORR) between the olaparib and control groups. Olaparib treatment increased the number of grade ≥3 adverse events (AEs) in patients with advanced ovarian cancer compared with that in the control group. Olaparib significantly prolonged PFS in patients with advanced ovarian cancer; however, no statistically significant differences were detected in OS and ORR. In terms of safety, olaparib has manageable adverse effects.

Abstract Background The Pooled Cohort Equations (PCEs) are race- and sex-specific Cox proportional hazards (PH)-based models used for 10-year atherosclerotic cardiovascular disease (ASCVD) risk prediction with acceptable discrimination. In recent years, neural network models have gained increasing popularity with their success in image recognition and text classification. Various survival neural network models have been proposed by combining survival analysis and neural network architecture to take advantage of the strengths from both. However, the performance of these survival neural network models compared to each other and to PCEs in ASCVD prediction is unknown. Methods In this study, we used 6 cohorts from the Lifetime Risk Pooling Project (with 5 cohorts as training/internal validation and one cohort as external validation) and compared the performance of the PCEs in 10-year ASCVD risk prediction with an all two-way interactions Cox PH model (Cox PH-TWI) and three state-of-the-art neural network survival models including Nnet-survival, Deepsurv, and Cox-nnet. For all the models, we used the same 7 covariates as used in the PCEs. We fitted each of the aforementioned models in white females, white males, black females, and black males, respectively. We evaluated models’ internal and external discrimination power and calibration. Results The training/internal validation sample comprised 23216 individuals. The average age at baseline was 57.8 years old (SD = 9.6); 16% developed ASCVD during average follow-up of 10.50 (SD = 3.02) years. Based on 10 × 10 cross-validation, the method that had the highest C-statistics was Deepsurv (0.7371) for white males, Deepsurv and Cox PH-TWI (0.7972) for white females, PCE (0.6981) for black males, and Deepsurv (0.7886) for black females. In the external validation dataset, Deepsurv (0.7032), Cox-nnet (0.7282), PCE (0.6811), and Deepsurv (0.7316) had the highest C-statistics for white male, white female, black male, and black female population, respectively. Calibration plots showed that in 10 × 10 validation, all models had good calibration in all race and sex groups. In external validation, all models overestimated the risk for 10-year ASCVD. Conclusions We demonstrated the use of the state-of-the-art neural network survival models in ASCVD risk prediction. Neural network survival models had similar if not superior discrimination and calibration compared to PCEs.

Waned vaccine-induced immunity and emerging severe acute respiratory syndrome coronavirus 2 variants with potential for immune escape pose a major threat to the coronavirus disease (COVID-19) pandemic. Here, we showed that humoral immunity components, including anti-S + N, anti-RBD IgG, and neutralizing antibodies (NAbs), gradually waned and decreased the neutralizing capacity against emerging Omicron variants at 3 and 6 months after two inactivated COVID-19 vaccinations. We evaluated two boosting strategies with either a third dose of inactivated vaccine (homologous, I-I-I) or a recombinant subunit vaccine (heterologous, I-I-S). Both strategies induced the production of high levels of NAbs with a broad neutralizing capacity and longer retention. Interestingly, I-I-S induced 3.5-fold to 6.8-fold higher NAb titres than I-I-I, with a broader neutralizing capacity against six variants of concern, including Omicron. Further immunological analysis revealed that the two immunization strategies differ considerably, not only in the magnitude of total NAbs produced, but also in the composite pattern of NAbs and the population of virus-specific CD4+ T cells produced. Additionally, in some cases, heterologous boosted immunity induced the production of more effective epitopes than natural infection. The level of I-I-S-induced NAbs decreased to 48% and 18% at 1 and 3 months after booster vaccination, respectively. Overall, our data provide important evidence for vaccination strategies based on available vaccines and may help guide future global vaccination plans.

BackgroundPatients with atrial septal defect (ASD) exhibit distinctive electrocardiogram (ECG) patterns. However, ASD cannot be diagnosed solely based on these differences. Artificial intelligence (AI) has been widely used for specifically diagnosing cardiovascular diseases other than arrhythmia. Our study aimed to develop an artificial intelligence-enabled 8-lead ECG to detect ASD among adults.MethodIn this study, our AI model was trained and validated using 526 ECGs from patients with ASD and 2,124 ECGs from a control group with a normal cardiac structure in our hospital. External testing was conducted at Wuhan Central Hospital, involving 50 ECGs from the ASD group and 46 ECGs from the normal group. The model was based on a convolutional neural network (CNN) with a residual network to classify 8-lead ECG data into either the ASD or normal group. We employed a 10-fold cross-validation approach.ResultsStatistically significant differences (p

Summary: Background: Heterologous vaccine schedules have been recommended to provide superior immunity and protection against emergent SARS-CoV-2 variants of concern. We aimed to evaluate the safety, immunogenicity, and efficacy of an mRNA COVID-19 vaccine RQ3013 compared with adenoviral vectored vaccine Ad5-nCoV and protein subunit vaccine ZF2001 as the fourth dose in adults primed with three doses of inactivated vaccines in China. Methods: We conducted a double-blinded, randomised, controlled, phase 3b trial among healthy Chinese adults at Lancang County, Yunnan, China. Adults who had received three doses of inactivated COVID-19 vaccines at least 6 months prior were randomly allocated (3:1:1) to receive heterologous boosters with RQ3013, Ad5-nCoV, or ZF2001. We assessed safety within 28 days post boost and the serum geometric mean titres (GMTs) of neutralising antibodies (NAbs) against the live SARS-CoV-2 omicron variant BA.5 on day 14 post-boost. We used Poisson regression to assess the vaccine efficacy against the first episode of virologically confirmed symptomatic COVID-19 occurring at least 7 days post boost. Subgroup analyses categorized by age and sex were also performed for safety and immunogenicity outcomes. This trial has been registered with the Chinese Clinical Trial Registry (ChiCTR2200065281) and is now complete. Findings: Between December 12 and December 18, 2022, a total of 1382 adults were screened, and 1250 were enrolled and randomly assigned to receive one dose of RQ3013 (n = 750), Ad5-nCoV (n = 250), or ZF2001 (n = 250). Although solicited adverse reactions within 28 days post boost were more frequent in the RQ3013 group (175 [23.3%]) compared to the control groups (24 [9.6%] in both the Ad5-nCOV and ZF2001 groups, P 0.05). On day 14 post-boost, RQ3013 (GMT 69.14, 95% CI 47.90–99.81) elicited 4.8-fold and 5.6-fold higher concentrations of NAbs against BA.5 than did Ad5-nCoV (14.37, 7.78–26.56) and ZF2001 (12.21, 5.13–29.06), respectively. On day 28 post-boost, RQ3013 demonstrated a relative efficacy of 62.2% (95% CI 13.7–83.1, P = 0.02) compared to Ad5-nCoV, and of 69.0% (33.5–85.7, P = 0.002) compared to ZF2001. Interpretation: The administrations of all the three heterologous boosters were well tolerated. The heterologous prime-boost regimen with RQ3013 elicited superior immune responses and demonstrated better protection against symptomatic SARS-CoV-2 infections compared with Ad5-nCoV or ZF2001, supporting the use of RQ3013 as a booster vaccination in adults. Funding: Yunnan Province Science and Technology Department (grant no.202302AA310047).

PldA, a phospholipase D (PLD) effector, catalyzes hydrolysis of the phosphodiester bonds of glycerophospholipids—the main component of cell membranes—and assists the invasion of the opportunistic pathogen Pseudomonas aeruginosa. In this work, the authors report three intermediate structures of PldA by employing an integrated approach combining structural biology and biochemistry. Structural analysis reveals that the significant conformational changes in the “lid” region and the peripheral helical domain trigger the switch of the active pocket of PldA to regulate the enzymatic activity. The structure-based mutational experiments identified a series of key residues responsible for substrate hydrolysis activity and the interactions between PldA and PA3488. In summary, this work provides the structural basis for understanding the PldA-mediated invasion of P. aeruginosa and can aid the future drug development targeting PldA.

An unstable influenza genome leads to the virus resistance to antiviral drugs that target viral proteins. Thus, identification of host factors essential for virus replication may pave the way to develop novel antiviral therapies. In this study, we investigated the roles of the poly(ADP-ribose) polymerase enzyme, tankyrase1 (TNKS1) and the endogenous small noncoding RNA, miR-9-1 in influenza A virus (IAV) infection. Increased expression of TNKS1 was observed in IAV-infected human lung epithelial cells and mouse lungs. TNKS1 knock-down by RNA interference repressed influenza viral replication. A screen using TNKS1 3’-untranslation region (3’-UTR) reporter assays and predicted microRNAs identified that miR-9-1 targeted TNKS1. Overexpression of miR-9-1 reduced influenza viral replication in lung epithelial cells as measured by viral mRNA and protein levels as well as virus production. miR-9-1 induced type I interferon production and enhanced the phosphorylation of STAT1 in cell culture. The ectopic expression of miR-9-1 in the lungs of mice by using an adenoviral viral vector enhanced type I interferon response, inhibited viral replication and reduced susceptibility to IAV infection. Our results indicate that miR-9-1 is an antiinfluenza microRNA that targeting TNKS1 and enhanced cellular antiviral state.

Objective The COVID-19 pandemic has had a significant impact on the burnout and mental health of medical staff. This meta-analysis aims to provide additional (and updated) evidence related to burnout and mental health problems among medical staff using a broader data pool.Design Systematic review and meta-analysis.Data sources PubMed, Embase, Cochrane Library, CNKI, Wanfang data and three preprint databases (SSRN, bioRxiv and medRxiv) were searched from 1 January 2020 to 17 May 2021.Eligibility criteria We included observational studies investigating the prevalence of burnout and mental health problems among medical staff during the COVID-19 pandemic, including cross-sectional study, cohort study and case–control study.Data extraction and synthesis Two independent reviewers used a self-designed form to extract the primary data. The Joanna Briggs Institute quality appraisal tool was used to assess the quality of selected studies. Heterogeneity among studies was assessed by I2 statistic. A random-effects model was used to pool the prevalence. Subgroup analysis was performed to explore between-group differences.Results 250 studies were included, with a sample of 292 230 participants from 46 countries. The pooled prevalence of burnout, anxiety, depression, insomnia, stress, post-traumatic stress disorder symptoms and somatic symptoms was 43.6% (95% CI 36.3% to 51.2%), 37.1% (95% CI 34.7% to 39.7%), 37.6% (95% CI 35.0% to 40.4%), 43.7% (95% CI 39.1% to 48.5%), 41.3% (95% CI 35.1% to 47.9%), 30.6% (95% CI 23.6% to 38.5%) and 25.0% (95% CI 16.7% to 35.6%), respectively. Subgroup analysis showed a higher prevalence of anxiety, depression and insomnia in frontline workers than in non-frontline workers, and a higher prevalence of anxiety in females than males. Mild cases accounted for the most significant proportion of the outcomes except for stress.Conclusions This study highlights that identifying the risks of burnout and mental health problems and adopting preventive interventions are priorities for policymakers and medical staff to avoid long-term occupational, health and social impacts.PROSPERO registration number CRD42021254425.

Abstract Aim To examine the demographic and work characteristics of mental health workers associated with burnout during the COVID‐19 epidemic and to examine the relationship between burnout and humanistic care ability. Design Online cross‐sectional design. Methods 270 mental health workers in Chongqing, China, were recruited via WeChat from 1 to 31 December 2020. Online self‐administered questionnaires were used to collect data. Data were analyzed by t‐tests and one‐way analyses of variance, Pearson's correlation analysis, and multiple linear regression analysis. Results During the COVID‐19 pandemic, mental health workers had a high prevalence of burnout and a low level of humanistic care ability. Work factors including profession, work shift, work pressure, work‐family conflict, practice environment satisfaction, salary satisfaction, and humanistic care ability were significantly associated with burnout and its subdimension.

Abstract Acute lymphoblastic leukemia (ALL) is the most common malignant hematological diseases in children. An immunosuppressive microenvironment, particularly regulatory T cell (Treg) infiltration, has been documented to be highly associated with childhood ALL. This present study, based on genetic factors, was aimed at investigating the mutations potentially involved in the immunosuppressive microenvironment in childhood ALL. After whole-exome sequencing was used on DNA extracted from the T cells of ALL bone marrow samples, we found the FOXC1 H446HG induced a increased Treg while decreased cytotoxic T lymphocyte (CTL) in bone marrow. The mutation of FOXC1 in T cell promoted the proliferation of leukemia cells in vitro and in vivo. CpG islands formed by insertion mutation led to an abnormal increase in exon methylation and were associated with the suppression of FOXC1. Decreased FOXC1 attenuated the transcription of HDAC1, thus resulting in the activation of KLF10 through increasing H3K27 acetylation in the promoter region. In conclusion, the de novo insertion mutation in FOXC1 induced suppression of FOXC1, thereby promoting a Treg/CTL shift in the ALL immune microenvironment. The FOXC1 H446HG mutation might be a potential therapeutic target for ALL in the future.

Abstract Understanding the decay and maintenance of long-term SARS-CoV-2 neutralizing antibodies in infected or vaccinated people and how vaccines protect against other SARS-CoV-2 variants is critical for assessing public vaccination plans. Here, we measured different plasm antibody levels 2 and 12 months after disease onset, including anti-RBD, anti-N, total neutralizing antibodies, and two neutralizing-antibody clusters. We found that total neutralizing antibodies declined more slowly than total anti-RBD and anti-N IgG, and the two neutralizing-antibody clusters decayed even more slowly than total neutralizing antibodies. Interestingly, the level of neutralizing antibodies at 12 months after disease onset was significantly lower than that at 2 months but more broadly neutralized SARS-CoV-2 variants, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Lambda (C.37). Significant immune escape by the Omicron variant (B.1.1.529) was also observed 2 months post-recovery. Furthermore, we revealed that a high percentage of virus-specific CD4+ T cells and cTfh1 were associated with a slower decline in humoral immunity, accompanied by higher levels of CXCR3 ligands such as CXCL9 and CXCL10, higher frequency of cTfh1, and lower levels of cTfh2 and cTfh17. Our data highlight the importance of coordinating T-cell and humoral immunity to achieve long-term protective immunity.

Abstract. Background:. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused a global pandemic that has resulted in millions of casualties. Although researchers have reported the existence of neutralizing antibodies and viral T cell immunity against SARS-CoV-2, little is known about the presence of antibody-dependent cellular cytotoxicity (ADCC) and its role in combating SARS-CoV-2 infection. Methods:. Nineteen acute COVID-19 patients at the First Affiliated Hospital of Guangzhou Medical University from January to February, 2020 and 55 recovery COVID-19 patients at the Second Peoples Hospital of Changde City from February, 2020 to February, 2021 were recruited in this study. Longitudinal plasma samples were collected. A virus-specific ADCC assay was performed to study the COVID-19 plasma samples. The correlations between ADCC and total IgG titer, including anti-RBD, anti-N, and neutralizing antibody titer were analyzed. Results:. A high level of ADCC with 0.86% of IFN-γ+CD107a+ NK cells induced by anti RBD antibodies and with 0.54% of IFN-γ+CD107a+ NK cells induced by anti N antibodies was observed. This activity peaked at 3 weeks after disease onset with 1.16% and 0.63% of IFN-γ+CD107a+ NK cells induced by anti RBD and anti N antibodies respectively, declined to 0.32% and 0.32% of IFN-γ+CD107a+ NK cells respectively after more than 2 months, and persisted for 12 months after disease onset. The ADCC did not aggravate the severity of COVID-19 in terms of sequential organ failure assessment, although ADCC decreased with the age of COVID-19 patients. Interestingly, ADCC response is not correlated with neutralizing antibody titer or total IgG titers against S protein RBD and N protein in acute patients. ADCC in recovered patients showed a significant correlation with anti RBD IgG titer (R2 = 0.33, P

232Th/233U fuel cycle is an alternate candidate for future nuclear energy. Neutron-induced fission cross section of 232Th is one of the important nuclear data if using thorium as the fuel in the future. 232Th(n, f) cross sections from 1 to 300 MeV were measured at China Spallation Neutron Source (CSNS) Back-streaming neutron facility (Back-n) relative to 235U(n, f) and n-p scattering. A fast ionization chamber for fission cross section measurement (FIXM) and a proton recoil telescope (PRT) were used to perform the measurement. The neutron energy in this measurement reaches up to 300 MeV which is supposed to be the highest among the current Experimental Nuclear Reaction Data (EXFOR) library. It stands as the only experimental data in the region of 200-300 MeV in EXFOR as well. The experimental and evaluated data of 232Th(n, f) cross section above 60 MeV are scarce, the measurement data of this work will be valuable references for future evaluation in high energy. For the data below 60 MeV, most of our data are more consistent with ENDF/B-VIII.0, excepting in the region of 1-2 MeV where our data are more in favor of CENDL-3.2.

The devastating COVID-19 pandemic caused by SARS-CoV-2 and multiple variants or subvariants remains an ongoing global challenge. SARS-CoV-2-specific T cell responses play a critical role in early virus clearance, disease severity control, limiting the viral transmission and underpinning COVID-19 vaccine efficacy. Studies estimated broad and robust T cell responses in each individual recognized at least 30 to 40 SARS-CoV-2 antigen epitopes and associated with COVID-19 clinical outcome. Several key immunodominant viral proteome epitopes, including S protein- and non-S protein-derived epitopes, may primarily induce potent and long-lasting antiviral protective effects. In this review, we summarized the immune response features of immunodominant epitope-specific T cells targeting different SRAS-CoV-2 proteome structures after infection and vaccination, including abundance, magnitude, frequency, phenotypic features and response kinetics. Further, we analyzed the epitopes immunodominance hierarchy in combination with multiple epitope-specific T cell attributes and TCR repertoires characteristics, and discussed the significant implications of cross-reactive T cells toward HCoVs, SRAS-CoV-2 and variants of concern, especially Omicron. This review may be essential for mapping the landscape of T cell responses toward SARS-CoV-2 and optimizing the current vaccine strategy.

Objective: Drug repurposing, the application of existing therapeutics to new indications, holds promise in achieving rapid clinical effects at a much lower cost than that of de novo drug development. The aim of our study was to perform a more comprehensive drug repurposing prediction of diseases, particularly cancers. Methods: Here, by targeting 4,096 human diseases, including 384 cancers, we propose a greedy computational model based on a heterogeneous multilayer network for the repurposing of 1,419 existing drugs in DrugBank. We performed additional experimental validation for the dominant repurposed drugs in cancer. Results: The overall performance of the model was well supported by cross-validation and literature mining. Focusing on the top-ranked repurposed drugs in cancers, we verified the anticancer effects of 5 repurposed drugs widely used clinically in drug sensitivity experiments. Because of the distinctive antitumor effects of nifedipine (an antihypertensive agent) and nortriptyline (an antidepressant drug) in prostate cancer, we further explored their underlying mechanisms by using quantitative proteomics. Our analysis revealed that both nifedipine and nortriptyline affected the cancer-related pathways of DNA replication, the cell cycle, and RNA transport. Moreover, in vivo experiments demonstrated that nifedipine and nortriptyline significantly inhibited the growth of prostate tumors in a xenograft model. Conclusions: Our predicted results, which have been released in a public database named The Predictive Database for Drug Repurposing (PAD), provide an informative resource for discovering and ranking drugs that may potentially be repurposed for cancer treatment and determining new therapeutic effects of existing drugs.

Abstract Background Geographic heterogeneity in COVID-19 outcomes in the United States is well-documented and has been linked with factors at the county level, including sociodemographic and health factors. Whether an integrated measure of place-based risk can classify counties at high risk for COVID-19 outcomes is not known. Methods We conducted an ecological nationwide analysis of 2,701 US counties from 1/21/20 to 2/17/21. County-level characteristics across multiple domains, including demographic, socioeconomic, healthcare access, physical environment, and health factor prevalence were harmonized and linked from a variety of sources. We performed latent class analysis to identify distinct groups of counties based on multiple sociodemographic, health, and environmental domains and examined the association with COVID-19 cases and deaths per 100,000 population. Results Analysis of 25.9 million COVID-19 cases and 481,238 COVID-19 deaths revealed large between-county differences with widespread geographic dispersion, with the gap in cumulative cases and death rates between counties in the 90th and 10th percentile of 6,581 and 291 per 100,000, respectively. Counties from rural areas tended to cluster together compared with urban areas and were further stratified by social determinants of health factors that reflected high and low social vulnerability. Highest rates of cumulative COVID-19 cases (9,557 [2,520]) and deaths (210 [97]) per 100,000 occurred in the cluster comprised of rural disadvantaged counties. Conclusions County-level COVID-19 cases and deaths had substantial disparities with heterogeneous geographic spread across the US. The approach to county-level risk characterization used in this study has the potential to provide novel insights into communicable disease patterns and disparities at the local level.

Objective: Hepatitis B virus (HBV) infection is a major public health problem worldwide. However, the regulatory mechanisms underlying HBV replication remain unclear. Cullin 4B-RING ubiquitin E3 ligase (CRL4B) is involved in regulating diverse physiological and pathophysiological processes. In our study, we aimed to explain the role of CUL4B in HBV infection. Methods: Cul4b transgenic mice or conditional knockout mice, as well as liver cell lines with CUL4B overexpression or knockdown, were used to assess the role of CUL4B in HBV replication. Immunoprecipitation assays and immunofluorescence staining were performed to study the interaction between CUL4B and HBx. Cycloheximide chase assays and in vivo ubiquitination assays were performed to evaluate the half-life and the ubiquitination status of HBx. Results: The hydrodynamics-based hepatitis B model in Cul4b transgenic or conditional knockout mice indicated that CUL4B promoted HBV replication (P < 0.05). Moreover, the overexpression or knockdown system in human liver cell lines validated that CUL4B increased HBV replication in an HBx-dependent manner. Importantly, immunoprecipitation assays and immunofluorescence staining showed an interaction between CUL4B and HBx. Furthermore, CUL4B upregulated HBx protein levels by inhibiting HBx ubiquitination and proteasomal degradation (P < 0.05). Finally, a positive correlation between CUL4B expression and HBV pgRNA level was observed in liver tissues from HBV-positive patients and HBV transgenic mice. Conclusions: CUL4B enhances HBV replication by interacting with HBx and disrupting its ubiquitin-dependent proteasomal degradation. CUL4B may therefore be a potential target for anti-HBV therapy.

Purpose: We aim to present effective and computer aided diagnostics in the field of ophthalmology and improve eye health. This study aims to create an automated deep learning based system for categorizing fundus images into three classes: normal, macular degeneration and tessellated fundus for the timely recognition and treatment of diabetic retinopathy and other diseases.Methods: A total of 1,032 fundus images were collected from 516 patients using fundus camera from Health Management Center, Shenzhen University General Hospital Shenzhen University, Shenzhen 518055, Guangdong, China. Then, Inception V3 and ResNet-50 deep learning models are used to classify fundus images into three classes, Normal, Macular degeneration and tessellated fundus for the timely recognition and treatment of fundus diseases.Results: The experimental results show that the effect of model recognition is the best when the Adam is used as optimizer method, the number of iterations is 150, and 0.00 as the learning rate. According to our proposed approach we, achieved the highest accuracy of 93.81% and 91.76% by using ResNet-50 and Inception V3 after fine-tuned and adjusted hyper parameters according to our classification problem.Conclusion: Our research provides a reference to the clinical diagnosis or screening for diabetic retinopathy and other eye diseases. Our suggested computer aided diagnostics framework will prevent incorrect diagnoses caused by the low image quality and individual experience, and other factors. In future implementations, the ophthalmologists can implement more advanced learning algorithms to improve the accuracy of diagnosis.

Hepatocellular carcinoma (HCC) is one of the most fatal malignant tumors worldwide. Circular RNAs (circRNAs) are a special type of RNA that lacks the 5′ and 3’ ends. The functional roles of circRNAs in HCC remain largely unknown. Using high-throughput sequencing, we found several differentially expressed circRNAs in HCC tissues compared with nearby normal tissues. Among them, circRNA derived from the LIFR gene, named circLIFR, was significantly downregulated in HCC. Intriguingly, circLIFR overexpression in SK-Hep-1 cells promoted cell growth and invasion. RNA pull-down and mass spectrometry detection revealed circLIFR interacting with TANK binding kinase 1 (TBK1). Anti-TBK1 RIP confirmed the interaction between circLIFR and TBK1. TBK1 is a serine/threonine kinase that regulates several signaling pathways, including the NF-κB pathway. TBK1 inhibitors inhibit NF-κB activation. Overexpression of circLIFR overcame the in-hibitory function of TBK1, resulting in the upregulation of several genes, including MMP13, MMP3, VEGF, and MAPK. This study shows that the downregulation of circLIFR in HCC has a can-cer-promoting effect by interacting with TBK1 to promote the activation of downstream NF-κB pathway genes related to cell proliferation, migration, and invasion. This novel finding reveals the diversity of circRNA functions in HCC and provides novel insights into the role of circRNAs.

BackgroundElectrocardiography (ECG) plays a very important role in various cardiovascular diseases and elevated D-dimer in serum associated with thrombosis. In patients with coronavirus disease 2019 (COVID-19), immense pieces of evidence showed that ECG abnormalities or elevated D-dimer in serum occurred frequently. However, it remains unclear whether ECG abnormalities combined with elevated D-dimer could be a new risk predictor in patients with COVID-19.Methods and resultsThis retrospective cohort study enrolled 416 patients with COVID-19 at Wuhan Tongji Hospital from 1 February to 20 March 2020. ECG manifestations, D-dimer levels, and in-hospital deaths were recorded for all patients. Logistic regression analysis was performed to examine the association between ECG manifestations and in-hospital mortality in patients with elevated D-dimer levels. In patients hospitalized for COVID-19, ST-T abnormalities (34.3%) were the most frequent ECG manifestations, whereas sinus tachycardia (ST) (13.3%) and atrial arrhythmias with rapid rhythms (8.5%) were the two most common cardiac arrhythmias. Compared to severely ill patients with COVID-19, ST-T abnormalities, ST and atrial arrhythmias (p

BackgroundPatients with apical hypertrophic cardiomyopathy (ApHCM) have marked inverted T-waves that vary over several years. Inverted T-waves in ApHCM are unstable, but it is unclear whether this change is due to coronary artery disease (CAD) or if it is a characteristic of ApHCM itself. We aimed to study the characteristics of inverted T-waves in patients with ApHCM over the course of 24 h to improve the diagnostic indices of ApHCM.MethodsWe examined 83 patients with ApHCM and 89 patients with CAD (who served as the control group). All patients underwent a 24-h dynamic electrocardiogram (ECG). We analyzed the average depth of inverted T-waves per minute and sorted them from shallow to deep; the sorted ECG segments at the 10th, 50th, and 90th positions of the T-wave were subsequently analyzed.ResultsThe amplitudes of inverted T-waves in ApHCM corresponding to the 10th, 50th, and 90th percentiles were −5.13 ± 4.11, −8.10 ± 4.55, and −10.9 ± 5.04 mm, respectively. Changes in the degree of inverted T-waves were greater in ApHCM than in CAD. T-wave amplitudes in ApHCM were strongly associated with heart rate and circadian rhythm and only weakly associated with CAD and posture. Maximum T-wave amplitudes in the CAD group were 10 mm, and all patients with ApHCM aged 10 mm.ConclusionNotable variations in the T-waves of patients with ApHCM were observed over 24 h. ECG examinations during states of inactivity (comparable to sleep) improved the sensitivity of the diagnosis of ApHCM. Inverted T-wave amplitudes correlated with heart rate and circadian rhythm, where T-wave changes in ApHCM may be due to the normalization of abnormal T-waves effect. Identifying T-wave amplitudes >10 mm can effectively improve the diagnostic rate of ApHCM, especially in patients aged

Influenza A virus (IAV) is an eight-segment negative-sense RNA virus and is subjected to gene recombination between strains to form novel strains, which may lead to influenza pandemics. Seasonal influenza occurs annually and causes great losses in public healthcare. In this study, we examined the role of interferon-induced protein with tetratricopeptide repeats 1 and 2 (IFIT1 and IFIT2) in influenza virus infection. Knockdown of IFIT1 or IFIT2 using a lentiviral shRNA increased viral nucleoprotein (NP) and nonstructural protein 1 (NS1) protein levels, as well as progeny virus production in A/Puerto Rico/8/34 H1N1 (PR/8)-infected lung epithelial A549 cells. Overexpression of IFIT1 or IFIT2 reduced viral NP and NS1 RNA and protein levels in PR/8-infected HEK293 cells. Overexpression of IFIT1 or IFIT2 also inhibited influenza virus infection of various H1N1 strains, including PR/8, A/WSN/1933, A/California/07/2009 and A/Oklahoma/3052/2009, as determined by a viral reporter luciferase assay. Furthermore, knockdown of IFIT1 or IFIT2 increased while overexpression of IFIT1 or IFIT2 decreased viral RNA, complementary RNA, and mRNA levels of NP and NS1, as well as viral polymerase activities. Taken together, our results support that both IFIT1 and -2 have anti-influenza virus activities by inhibiting viral RNA synthesis.

Abstract Background Epitope prediction is a useful approach in cancer immunology and immunotherapy. Many computational methods, including machine learning and network analysis, have been developed quickly for such purposes. However, regarding clinical applications, the existing tools are insufficient because few of the predicted binding molecules are immunogenic. Hence, to develop more potent and effective vaccines, it is important to understand binding and immunogenic potential. Here, we observed that the interactive association constituted by human leukocyte antigen (HLA)-peptide pairs can be regarded as a network in which each HLA and peptide is taken as a node. We speculated whether this network could detect the essential interactive propensities embedded in HLA-peptide pairs. Thus, we developed a network-based deep learning method called DeepNetBim by harnessing binding and immunogenic information to predict HLA-peptide interactions. Results Quantitative class I HLA-peptide binding data and qualitative immunogenic data (including data generated from T cell activation assays, major histocompatibility complex (MHC) binding assays and MHC ligand elution assays) were retrieved from the Immune Epitope Database database. The weighted HLA-peptide binding network and immunogenic network were integrated into a network-based deep learning algorithm constituted by a convolutional neural network and an attention mechanism. The results showed that the integration of network centrality metrics increased the power of both binding and immunogenicity predictions, while the new model significantly outperformed those that did not include network features and those with shuffled networks. Applied on benchmark and independent datasets, DeepNetBim achieved an AUC score of 93.74% in HLA-peptide binding prediction, outperforming 11 state-of-the-art relevant models. Furthermore, the performance enhancement of the combined model, which filtered out negative immunogenic predictions, was confirmed on neoantigen identification by an increase in both positive predictive value (PPV) and the proportion of neoantigen recognition. Conclusions We developed a network-based deep learning method called DeepNetBim as a pan-specific epitope prediction tool. It extracted the attributes of the network as new features from HLA-peptide binding and immunogenic models. We observed that not only did DeepNetBim binding model outperform other updated methods but the combination of our two models showed better performance. This indicates further applications in clinical practice.

T cells compose a critical component of the immune response to coronavirus infection with SARS-CoV-2. Here the authors characterise the T cell response to SARS CoV-2 in patients and their close contacts, and show the presence of SARS-CoV-2 specific T cells in the absence of detectable virus infection.

BackgroundExtramedullary plasmacytoma (EMP) is an extremely rare kind of soft tissue plasma cell neoplasm without bone marrow involvement or other systemic characteristics of multiple myeloma. Primary pulmonary plasmacytoma (PPP), with no specific clinical manifestations, is an exceedingly rare type of EMP. Because of its complexity, PPP is often difficult to diagnose. Computed tomography-guided percutaneous core needle biopsy (CT-guided PCNB) has been shown to have high sensitivity, specificity and accuracy for characterization of pulmonary lesion, particularly if malignancy is suspected. Here we presented a rare case of PPP diagnosed with CT-guided PCNB.Case presentationA 78-year-old female smoker who visited our outpatient clinic for a mass in the left lower lobe of the lung. Pathological based on CT-guided PCNB yielded a PPP with no lymph node or other distant metastasis.ConclusionsExtramedullary plasmacytoma should be considered in the differential diagnosis of a pulmonary mass.

BackgroundUnderstanding the epidemiological characteristics of various cancers can optimize the prevention and control strategies in the national cancer control plan. This study aimed to report the burden differences, pattern trend, and potential risk factors of all neoplasm types in China in recent 30 years, and further compared with top economies in the world.MethodsThe disability-adjusted life-years (DALYs) and age-standardized DALY rate (ASDR) of all neoplasms with the attributable risk factors from 1990 to 2019 in China, Japan, European Union, USA, and the world were extracted from the Global Burden of Disease Study 2019. The temporal trend analysis was estimated using the joinpoint regression model.ResultsIn 2019, about 251.4 million DALYs worldwide were caused by all neoplasms, and nearly 26.9% (67.5 million DALYs) occurred in China with the ASDR in 2019 of 342.09/10 000, which was higher than European Union (334.25/10 000), USA (322.94/10 000), and Japan (250.36/10 000). Although the cancer burden of the colorectum, non-Hodgkin lymphoma, oral cavity, ovary, and kidney in China was lower than in Japan, European Union and USA, the corresponding ASDR gradually increased in China over the past 30 years, but declined in the three developed areas. Around 46.29% of overall neoplasms DALYs in China in 2019 were attributed to 22 identified risk factors, and the specific risk attributable-fraction for several neoplasm types varied greatly in these regions.ConclusionThe ASDR of cancers of the lung, colorectum, pancreas, non-Hodgkin lymphoma, oral cavity, ovary, kidney, and chronic lymphoid leukemia increased in China compared to 30 years ago. With the population aging and the social transformation in China, the increasing burden of neoplasms and the changing spectrum of neoplasms suggest that effective comprehensive prevention and treatment measures should be adopted to reduce the burden, including public health education, strict tobacco-control policy, healthier lifestyles, along with expanding vaccination programs and early cancer screening.

Background and objective: Idiopathic pulmonary fibrosis (IPF) is an aggressive fibrotic pulmonary disease with spatially and temporally heterogeneous alveolar lesions. There are no early diagnostic biomarkers, limiting our understanding of IPF pathogenesis.Methods: Lung tissue from surgical lung biopsy of patients with early-stage IPF (n = 7), transplant-stage IPF (n = 2), and healthy controls (n = 6) were subjected to mRNA sequencing and verified by real-time quantitative PCR (RT-qPCR), immunohistochemistry, Western blot, and single-cell RNA sequencing (scRNA-Seq).Results: Three hundred eighty differentially expressed transcripts (DETs) were identified in IPF that were principally involved in extracellular matrix (ECM) remodeling, lipid metabolism, and immune effect. Of these DETs, 21 (DMD, MMP7, POSTN, ECM2, MMP13, FASN, FADS1, SDR16C5, ACAT2, ACSL1, CYP1A1, UGT1A6, CXCL13, CXCL5, CXCL14, IL5RA, TNFRSF19, CSF3R, S100A9, S100A8, and S100A12) were selected and verified by RT-qPCR. Differences in DMD, FASN, and MMP7 were also confirmed at a protein level. Analysis of scRNA-Seq was used to trace their cellular origin to determine which lung cells regulated them. The principal cell sources of DMD were ciliated cells, alveolar type I/II epithelial cells (AT cells), club cells, and alveolar macrophages (AMs); MMP7 derives from AT cells, club cells, and AMs, while FASN originates from AT cells, ciliated cells, and AMs.Conclusion: Our data revealed a comprehensive transcriptional mRNA profile of IPF and demonstrated that ECM remodeling, lipid metabolism, and immune effect were collaboratively involved in the early development of IPF.

Abstract “Double fire” is generally characterized by 1:2 atrioventricular conduction of sinus beats traveling down fast and slow pathways that result in double ventricular response. When this phenomenon repeats rapidly, dual atrioventricular nodal nonreentrant tachycardia (DAVNNT) occurs. We report a case of an irregular tachycardia with a comprehensive record that includes an electrocardiogram, a transesophageal electrophysiology study, and an intracardiac electrophysiology study. This is the first report of transesophageal electrophysiology study in the diagnosis of DAVNNT. A diagnosis of DAVNNT was deduced, and the patient was successfully treated with radiofrequency ablation of the slow pathway.

Abstract Background In the past decade, miR‐100, miR‐146a, and miR‐210 were reported to be dysregulated in childhood acute lymphoblastic leukemia (ALL). However, effects of genetic variants in these three microRNAs have not been investigated in Chinese population. Methods In this study, we conducted a case‐control study to evaluate the relationship between genetic variants in miR‐100, miR‐146a, and miR‐210 and the risk of childhood ALL in Chinese population. Subsequently, plasma expression level of miR‐100 was also detected. Result We found that subjects carrying mutant homozygous TT genotype of miR‐100 rs543412 had a statistically significantly decreased risk of childhood ALL (adjusted odds ratio [OR] = 0.73, 95% confidence interval [CI] = 0.55‐0.97, P = 0.029). This protective effect was also observed among subjects whose parents were ever drinkers (adjusted OR = 0.53, 95% CI = 0.29‐0.94), or whose living house were ever painted (adjusted OR = 0.57, 95% CI = 0.34‐0.94). Besides, rs543412 variant homozygous TT had a significantly protective role in patients with childhood B‐ALL. Finally, we found that expression level of miR‐100 in plasma of childhood ALL cases was significantly higher than that of noncancer controls. Conclusion Our study suggested that there was significant association between the polymorphisms in miR‐100 (rs543412) and decreased susceptibility to childhood ALL.

Polygonatum cyrtonema rhizome (PCR), the dried sweet rhizome of Polygonatum cyrtonema Hua, is commonly used as a tonic remedy and a functional food in Asia, Europe, and North America. Multiple components, including secondary metabolites, monosaccharides, oligosaccharides, and polysaccharides, collectively contribute to the therapeutic effects of PCR. Processing time exerts a significant influence on the quality of PCR, but the various processing stages have not been comprehensively chemically profiled. It is urgent to study processing-induced chemical variations in PCR to control the processing degree. In this study, multiple chromatographic and mass spectrometric techniques were used in combination with multivariate statistical analysis to perform qualitative and quantitative research on secondary metabolites and carbohydrates in PCR during processing. The results demonstrated that PCR processing can be divided into three stages, namely the raw stage (0 h), the middle stage (1–6 h), and the late stage (8–18 h). Twenty differential compounds were screened from secondary metabolites and oligosaccharides to distinguish PCR in different processing stages. Furthermore, the chemical variations of Polygonatum cyrtonema polysaccharides (PCP) also entered a new stage after processing for 6 h. Multiple chemical mechanisms, including hydrolysis, oxidative decomposition, dehydration, Maillard reaction, and polymerization were involved in the processing. This work provides a scientific basis to reveal the relationship between processing stage and chemical variations.

BackgroundControlling blood glucose, blood pressure, and blood lipid is of great importance for patients with type 2 diabetes, not only for cardiovascular disease, but also for other complications. Previous studies mainly focused on the control rate of outpatients, and the results were suboptimal, but few studies aimed at the inpatients.MethodThe present study involved 3,245 hospitalized patients with type 2 diabetes from 2013 to 2017 in the Department of Endocrinology and Metabolism of Tianjin Medical University General Hospital. The percentages of inpatients who attained the goals of the China Diabetes Society and the American Diabetes Association were calculated for major cardiovascular risk factors (HbA1c, blood pressure, and blood lipid). The prevalence of microvascular and macrovascular complications was also assessed.ResultThe percentages of patients who met the Chinese Diabetes Society goals—HbA1c

Retinoic acid-inducible gene I (RIG-I) serves as an essential viral RNA sensor for innate immune. The activation of the RIG-I-like receptors (RLRs) pathway triggers many regulations for the outcome of type I interferon, including ubiquitination, dephosphorylation, ISGylation, and autophagy. However, the autophagy-related regulation of RIG-I is still not fully understood. To investigate the potentially unknown genes related to autophagy-related regulation of RIG-I, we firstly confirm the induction of autophagy derived by overexpression of RIG-I. Furthermore, the autophagy inducer and inhibitor drugs were used in different assays. The results showed autophagy could control the activation of RLRs pathway and expression of exogenous RIG-I. In addition, we carried out the transcriptome analysis of overexpression of RIG-I in vitro. Differentially expressed genes (DEGs) in GO and KEGG signaling pathways enrichment provided a newly complex network. Finally, the validation of qPCR indicated that the DEGs PTPN22, PRKN, OTUD7B, and SIRT2 were correlated to the negative regulation of excessive expression of RIG-I. Taken together, our study contributed new insights into a more comprehensive understanding of the regulation of excessive expression of RIG-I. It provided the potential candidate genes for autophagy-related negative regulation for further investigation.

Aims. We investigated the changes of retinal structure in normal glucose tolerance (NGT), impaired glucose tolerance (IGT), diabetes mellitus (DM), and diabetic kidney disease (DKD) stages in Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Methods. We assigned OLETF rats to four groups based on their OGTT results and 24 h urinary microalbumin (24 h UMA) levels: NGT, IGT, DM, and DKD groups. We observed the structural and the corresponding pathological changes and quantified the expression of HIF-1α, iNOS, NF-κB, VEGF, ICAM-1, and occludin in the retina. Results. Significant damage to the retinal structure, especially in retinal ganglion cells (RGCs), was observed in the IGT stage. The expression of HIF-1α, iNOS, NF-κB, VEGF, and ICAM-1 was significantly upregulated, while that of occludin was downregulated. Conclusion. Significant retinal neuropathy occurs in the IGT stage. Inflammation and hypoxia may damage the blood retina barrier (BRB), leading to diabetic retinopathy.