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BackgroundNew drugs targeting antimicrobial resistant pathogens, including Pseudomonas aeruginosa, have been challenging to evaluate in clinical trials, particularly for the non-ventilated hospital-acquired pneumonia and ventilator-associated pneumonia indications. Development of new antibacterial drugs is facilitated by preclinical animal models that could predict clinical efficacy in patients with these infections.MethodsWe report here an FDA-funded study to develop a rabbit model of non-ventilated pneumonia with Pseudomonas aeruginosa by determining the extent to which the natural history of animal disease reproduced human pathophysiology and conducting validation studies to evaluate whether humanized dosing regimens of two antibiotics, meropenem and tobramycin, can halt or reverse disease progression.ResultsIn a rabbit model of non-ventilated pneumonia, endobronchial challenge with live P. aeruginosa strain 6206, but not with UV-killed Pa6206, caused acute respiratory distress syndrome, as evidenced by acute lung inflammation, pulmonary edema, hemorrhage, severe hypoxemia, hyperlactatemia, neutropenia, thrombocytopenia, and hypoglycemia, which preceded respiratory failure and death. Pa6206 increased >100-fold in the lungs and then disseminated from there to infect distal organs, including spleen and kidneys. At 5 h post-infection, 67% of Pa6206-challenged rabbits had PaO2 MIC, resulting in 75% microbiological clearance rate of Pa6206 from the lungs. For tobramycin which exhibits concentration-dependent killing, rabbits treated with a humanized tobramycin dosing regimen of 8 mg/kg q8h for 24 h achieved Cmax/MIC of 9.8 ± 1.4 at 60 min post-dose, resulting in 50% lung microbiological clearance rate. In contrast, rabbits treated with a single tobramycin dose of 2.5 mg/kg had Cmax/MIC of 7.8 ± 0.8 and 8% (1/12) microbiological clearance rate, indicating that this rabbit model can detect dose-response effects.ConclusionThe rabbit model may be used to help predict clinical efficacy of new antibacterial drugs for the treatment of non-ventilated P. aeruginosa pneumonia.

The plume–surface interaction (PSI) is a common phenomenon that describes the environment surrounding the landers resulting from the impingement of hot rocket exhaust on the regolith of planetary bodies. The PSI will cause obscuration, erosion of the planetary surface, and high-speed spreading of dust or high-energy ejecta streams, which will induce risks to a safe landing and cause damage to payloads on the landers or to nearby assets. Safe landings and the subsequent scientific goals of deep-space exploration in China call for a comprehensive understanding of the PSI process, including the plume flow mechanics, erosion mechanism, and ejecta dynamics. In addition, the landing crater caused by the plume provides a unique and insightful perspective on the understanding of PSI. In particular, the PSI can be used directly to constrain the composition, structure, and mechanical properties of the surface and subsurface soil. In this study, we conducted a systematic review of the phenomenology and terrestrial tests of PSI: we analyzed the critical factors in the PSI process and compared the differences in PSI phenomena between lunar and Martian conditions; we also reviewed the main erosion mechanisms and the evolution and development of terrestrial tests on PSI. We discuss the problems with PSI, challenges of terrestrial tests, and prospects of PSI, and we show the preliminary results obtained from the landing crater caused by the PSI of Tianwen-1. From analysis of the camera images and digital elevation model reconstructions, we concluded that the landing of Tianwen-1 caused the deepest crater (depth > 40 cm) on a planetary surface reported to date and revealed stratigraphic layers in the subsurface of Martian soil. We further constrained the lower bounds of the mechanical properties of Martian soil by a slope stability analysis of the Tianwen-1 landing crater. The PSI may offer promising opportunities to obtain greater insights into planetary science, including the subsurface structure, mineral composition, and properties of soil.

Abstract Backgroud The role of epigenetic modifications in tumorigenesis has been widely reported. However, the role and mechanism of H3K4me3 modification in lung adenocarcinoma (LUAD) are rarely reported systematically. We, therefore, sought to analyze the characteristics of LUAD associated with H3K4me3 modification, build an H3K4me3-lncRNAs score model to predict the prognosis of patients with LUAD and clarify the potential value of H3K4me3 in immunotherapy of LUAD. Methods We evaluated H3K4me3-lncRNA patterns and H3K4me3-lncRNA scores of 477 LUAD samples based on 53 lncRNAs closely correlated to H3K4me3 regulators and comprehensive analyzed the role of these patterns in tumorigenesis and tumor immunity. Using Gene set variation analysis (GSVA), we systematically evaluated the H3K4me3 level of every sample and deeply analyzed the effect of H3K4me3 on the prognosis of LUAD. In addition, we included two independent immunotherapy cohorts to study the impact of high H3K4me3 score on the prognosis of patients. We also used an independent cohort with 52 matched paraffin specimens of LUAD to verify the impact of high H3K3me3 expression on the prognosis of patients. Results We identified three H3K4me3-lncRNA patterns that exhibited specific immune characteristics. Characterized by immunosuppressive and increased TGFβ-mediated epithelial-mesenchymal transition (EMT), patients with high H3K4me3-lncRNA score had a poor overall survival and decreased H3K4me3 score. H3K4me3 score was significantly positively correlated with CD4+T-cell and CD8+T-cell activation, programmed cell death and immune checkpoints (ICs) expression, and was negatively correlated with MYC pathway, TP53 pathway, and cell proliferation. Patients with high H3K4me3 score showed elevated expression of ICs, potentiated CD4 T-cell and CD8 T-cell activation, increased programmed cell death, and suppressed cell proliferation and TGFβ-mediated EMT. Patients with high H3K4me3 score and high expression of CTLA4, ICOS, TIGIT, PDCD1LG2, IDO1, CD274, PDCD1, LAG3, or HAVCR2 had the best survival advantage. Two independent immunotherapy cohorts verified that patients with high H3K4me3 score showed an increased inflamed tumor microenvironment (TME) phenotype and enhanced anti-PD-1/L1 immunotherapy response. Immunohistochemistry (IHC) data from 52 matched paraffin specimens of LUAD confirmed that the protein level of H3K4me3 in tumor was significantly lower than that of paracancerous tissues and H3K4me3 brought significant survival benefits to patients with LUAD. Conclusions We build an H3K4me3-lncRNAs score model to predict the prognosis of patients with LUAD. More importantly, this study revealed characteristics of H3K4me3 modification in LUAD and clarified the important potential role of H3K4me3 on tumor immunotherapy and patients’ survival.

Abstract Background From March to June 2022, an Omicron BA.2 epidemic occurred in Shanghai. We aimed to better understand the transmission dynamics and identify age-specific transmission characteristics for the epidemic. Methods Data on COVID-19 cases were collected from the Shanghai Municipal Health Commission during the period from 20th February to 1st June. The effective reproductive number (Rt) and transmission distance between cases were calculated. An age-structured SEIR model with social contact patterns was developed to reconstruct the transmission dynamics and evaluate age-specific transmission characteristics. Least square method was used to calibrate the model. Basic reproduction number (R0) was estimated with next generation matrix. Results R0 of Omicron variant was 7.9 (95% CI: 7.4 to 8.4). With strict interventions, Rt had dropped quickly from 3.6 (95% CI: 2.7 to 4.7) on 4th March to below 1 on 18th April. The mean transmission distance of the Omicron epidemic in Shanghai was 13.4 km (95% CI: 11.1 to 15.8 km), which was threefold longer compared with that of epidemic caused by the wild-type virus in Wuhan, China. The model estimated that there would have been a total 870,845 (95% CI: 815,400 to 926,289) cases for the epidemic from 20th February to 15th June, and 27.7% (95% CI: 24.4% to 30.9%) cases would have been unascertained. People aged 50–59 years had the highest transmission risk 0.216 (95% CI: 0.210 to 0.222), and the highest secondary attack rate (47.62%, 95% CI: 38.71% to 56.53%). Conclusions The Omicron variant spread more quickly and widely than other variants and resulted in about one third cases unascertained for the recent outbreak in Shanghai. Prioritizing isolation and screening of people aged 40–59 might suppress the epidemic more effectively. Routine surveillance among people aged 40–59 years could also provide insight into the stage of the epidemic and the timely detection of new variants. Trial registration We did not involve clinical trial.

Background: Vancomycin-resistant Enterococcus (VRE) can be carried in the gut for a long period and its carriage status is associated with subsequent infections. This study aimed to investigate the frequency of intestinal VRE carriage in intensive care patients in Beijing. Methods: A multicenter, retrospective cross-sectional study was conducted at six hospitals in Beijing, China. All patients admitted to intensive care units (ICUs) between April 2 and May 1, 2017, were enrolled, and their clinical data were gathered by reviewing electronic medical records. Rectal swabs collected from patients were stored at −80 °C in the Institute of Clinical Pharmacology, Peking University First Hospital, and they were selectively cultured for VRE, then the identified strains were analyzed by polymerase chain reaction (PCR) to detect the glycopeptide resistance gene and were characterized by multilocus sequence typing (MLST). Results: Of 148 patients recruited, 46 (31.1%) carried VRE, with the majority (n = 42) being Enterococcus faecium. In total, 78.3% of the VRE were vanA positive and 15.2% vanM positive, while 6.5% undetected glycopeptide resistance gene. The predominant ST was ST78 (47.6%) followed by ST192 (14.3%), ST555 (9.5%), and ST789 (9.5%). Multivariate analysis showed that factors associated VRE carriage were patients aged >65 years (odds ratio [OR], 3.786; 95% confidence interval [CI], 1.402–10.222) and recent third-generation cephalosporins use (OR, 6.360; 95% CI, 1.873–21.601). Conclusions: The overall proportion of VRE carriage in patients admitted to ICUs was markedly high in Beijing, China. The vanM gene has been spread widely but vanA gene was the dominant resistance determinant in VRE in Beijing.

Fluorescence-guided surgery (FGS) with tumor-targeted imaging agents, particularly those using the near-infrared wavelength, has emerged as a real-time technique to highlight the tumor location and margins during a surgical procedure. For accurate visualization of prostate cancer (PCa) boundary and lymphatic metastasis, we developed a new approach involving an efficient self-quenched near-infrared fluorescence probe, Cy-KUE-OA, with dual PCa-membrane affinity. Cy-KUE-OA specifically targeted the prostate-specific membrane antigen (PSMA), anchored into the phospholipids of the cell membrane of PCa cells and consequently showed a strong Cy7-de-quenching effect. This dual–membrane-targeting probe allowed us to detect PSMA-expressing PCa cells both in vitro and in vivo and enabled clear visualization of the tumor boundary during fluorescence-guided laparoscopic surgery in PCa mouse models. Furthermore, the high PCa preference of Cy-KUE-OA was confirmed on surgically resected patient specimens of healthy tissues, PCa, and lymph node metastases. Taken together, our results serve as a bridge between preclinical and clinical research in FGS of PCa and lay a solid foundation for further clinical research.

Background: The question of whether extending embryo culture can provide more benefits for clinical outcomes has been raised. It is important to explore whether the fourth day morulae could be a widely used alternative transplantation option to replace the fifth day blastocysts. Methods: This study involved 1167 patients undergoing their first in in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycles. They were divided into two groups: those undergoing embryo transfer on the fourth day (D4 ET, n = 974 patients) and those undergoing embryo transfer on the fifth day (D5 ET, n = 193 patients). The time of the study was between January 2018 and June 2021. We used logistic regression to calculate propensity scores based on several variables such as female age, female body mass index (BMI), infertility duration, basal follicle-stimulating hormone (FSH), basal luteinizing hormone (LH), antral follicle count (AFC), follicular output rate (FORT), number of embryos transferred, number of transferable embryos, and number of high-quality embryos on day 3. The nearest neighbor random match algorithm was employed to determine the matches for each individual in the study population. The propensity score matching (PSM) was performed with a ratio of 1:1, ensuring equal representation of treated and control groups in the analysis. After PSM, 198 patients were included in the two groups. Results: Before matching, patients in the D4 ET group had lower AFC (16 [13, 20] vs. 17 [14, 22], p = 0.027). Estradiol on the human chorionic gonadotropin (hCG) day, FORT, number of oocytes retrieved, number of normal fertilization, number of transferable embryos, and number of high-quality embryos on day 3 were lower in the D4 ET group. After PSM, these characteristics were similar in the two groups, except for the number of high-quality embryos on day 3, which was lower in the D4 ET group (3 [2, 3.5] vs. 4 [2, 4], p = 0.035). The D4 ET group showed a higher live birth rate (54.21% vs. 44.88%, p = 0.015), with a lower rate of 1 embryo transferred (21.36% vs. 43.01%, p < 0 .001) before PSM. D4 ET increased live birth rate in fresh cycles relative to D5 ET before PSM (odds ratio (OR) = 1.552, 95% confidence interval (95% CI): 1.036~2.323, p = 0.033). No significant differences were observed in blastocyst formation rate (33.57 vs. 34.05, p = 0.618; 35.10 vs. 33.80, p = 0.468) and cumulative live birth rate (70.02 vs. 73.58, p = 0.322; 69.70 vs. 72.73, p = 0.638) between the two groups before and after PSM in the fresh cycles. There was no significant difference in endometrial thickness (8.8 [8, 10] vs. 8.9 [8, 9.6], p = 0.689; 8.6 [8, 10] vs. 8.9 [8, 9.7], p = 0.993), one embryo transferred rate (28.35 vs. 25.84, p = 0.639; 22.86 vs. 24.44, p = 0.724), clinical pregnancy rate (54.88 vs. 61.80, p = 0.243; 57.14 vs. 73.33, p = 0.129), live birth rate (43.90 vs. 50.56, p = 0.263; 45.71 vs. 55.56, p = 0.382) between the two groups before and after PSM in the first frozen ET cycle after fresh ET. Conclusions: D4 ET did not have a significant adverse impact on clinical outcome in fresh cycles and first frozen ET cycles relative to D5 ET.

Oil shale, as a vast potential resource, is considered an important alternative energy source, and its effective development and economic utilization are of significant importance in alleviating the contradiction between energy supply and demand. Presently, the in situ conversion technology for oil shale has gained significant global attention, with numerous extraction methods undergoing active research and development. One of these methods is the in situ conversion of oil shale based on the hydration reaction of calcium-oxide-based composite material (CaO-CM). This approach harnesses the heat produced by the reaction between CaO-CM and water as a heat source for the pyrolysis of oil shale. This paper conducted experiments to assess the feasibility of temperature associated with this method. The feasibility study mainly includes two aspects: First, it is necessary to investigate whether the temperature generated by the hydration reaction of CaO-CM can meet the temperature requirements for the pyrolysis of oil shale. Through pyrolysis experiments of Xinjiang oil shale, the minimum temperature required for oil shale pyrolysis was determined to be 330 °C. High-temperature and high-pressure reaction vessels were employed to explore the temperature generated by the hydration reaction of CaO-CM. The results show that with the increase in environment pressure, environment temperature, and reaction mass, the maximum temperature generated by the hydration reaction of CaO-CM also increases (reach 455.5 °C), meeting the temperature requirements for the pyrolysis of oil shale. Second, the study evaluates whether the hydration reaction of CaO-CM can induce pyrolysis hydrocarbons of the oil shale. Through the pyrolysis experiments of oil shale based on the hydration reaction of CaO-CM, the changes in the content of pyrolysis hydrocarbons (S2) in oil shale before and after pyrolysis are measured. The results show that under 10 MPa pressure, the content of pyrolysis hydrocarbons in the oil shale decreased from 40.96 mg/g to 0.08 mg/g after pyrolysis. This confirms the feasibility of the temperature conditions for the in situ conversion of oil shale based on the hydration reaction of CaO-CM.

As vital equipment in modern industry, the health state of rotating machinery influences the production process and equipment safety. However, rotating machinery generally operates in a normal state most of the time, which results in limited fault data, thus greatly constraining the performance of intelligent fault diagnosis methods. To solve this problem, this paper proposes a novel fault diagnosis method for rotating machinery with limited multisensor fusion samples based on the fused attention-guided Wasserstein generative adversarial network (WGAN). Firstly, the dimensionality of collected multisensor data is reduced to three channels by principal component analysis, and then the one-dimensional data of each channel are converted into a two-dimensional pixel matrix, of which the RGB images are obtained by fusing the three-channel two-dimensional images. Subsequently, the limited RGB samples are augmented to obtain sufficient samples utilizing the fused attention-guided WGAN combined with the gradient penalty (FAWGAN-GP) method. Lastly, the augmented samples are applied to train a residual convolutional neural network for fault diagnosis. The effectiveness of the proposed method is demonstrated by two case studies. When training samples per class are 50, 35, 25, and 15 on the KAT-bearing dataset, the average classification accuracy is 99.9%, 99.65%, 99.6%, and 98.7%, respectively. Meanwhile, the methods of multisensor fusion and the fused attention mechanism have an average improvement of 1.51% and 1.09%, respectively, by ablation experiments on the WT gearbox dataset.

Abstract Background This study aims to assess and compare the functional outcomes of patients with acute ischemic stroke (AIS) eligible for tissue plasminogen activator (t‐PA) treatment who received care from either a fifth‐generation(5G) mobile stroke unit (MSU) or traditional emergency medical service (EMS). Method The study recruited patients between February 2020 and January 2022, with the final 90‐day follow‐up concluded in April 2022. Prior to enrollment, patients were assigned to either EMS or MSU care based on predetermined rules. The primary outcome measure was the Modified Rankin Scale (mRS) score at 90 days, with secondary outcome measures including time metrics, mRS and National Institutes of Health Stroke Scale scores at 7‐day follow‐up, and hospitalization costs. Results Of the 2281 enrolled patients, 207 were eligible for t‐PA treatment, with 101 allocated to MSU care and 106 to EMS care. The percentage of patients achieving a favorable mRS score (0–2) at 90 days was 82.2% in the MSU group compared to 72.6% in the EMS group (p < .05). Median times from symptom onset to thrombolysis were 146 min in the MSU group and 204 min in the EMS group, while median times from ambulance alert to computed tomography (CT) completion were 53 and 128 min, respectively. Hospitalization charges averaged approximately $3592 in the MSU group and $4800 in the EMS group. Conclusions Our findings indicate that 5G MSU care significantly reduces the time from symptom onset to stroke diagnosis and intravenous thrombolysis in patients with AIS, resulting in improved functional outcomes compared to EMS care. As China continues its deployment of 5G technology and other digital infrastructures, the adoption of 5G MSU care on a broader scale may eventually supplant traditional stroke treatment approaches.

It is well recognized that carbon dioxide and air pollutants share similar emission sources so that synergetic policies on climate change mitigation and air pollution control can lead to remarkable co-benefits on greenhouse gas reduction, air quality improvement, and improved health. In the context of carbon peak, carbon neutrality, and clean air policies, this perspective tracks and analyzes the process of the synergetic governance of air pollution and climate change in China by developing and monitoring 18 indicators. The 18 indicators cover the following five aspects: air pollution and associated weather-climate conditions, progress in structural transition, sources, inks, and mitigation pathway of atmospheric composition, health impacts and benefits of coordinated control, and synergetic governance system and practices. By tracking the progress in each indicator, this perspective presents the major accomplishment of coordinated control, identifies the emerging challenges toward the synergetic governance, and provides policy recommendations for designing a synergetic roadmap of Carbon Neutrality and Clean Air for China.

Objective The primary objective of this study is to investigate the prevalence and risk factors of stroke in high-altitude areas through a comprehensive systematic review and meta-analysis.Design This study adopts a systematic review and meta-analysis design.Data sources A thorough search was conducted on databases including PubMed, Web of Science, Embase, Cochrane Library, MEDLINE and SCOPUS, covering the period up to June 2023.Eligibility criteria Studies reporting the prevalence of stroke in high-altitude areas and exploring related risk factors were included, regardless of whether they involved clinical samples or the general population. Studies with incomplete, outdated or duplicate data were excluded.Data extraction and synthesis We performed eligibility screening, data extraction and quality evaluation of the retrieved articles. Meta-analysis was employed to estimate the prevalence and risk factors of stroke in high-altitude areas. The Newcastle-Ottawa Scale was used to assess the risk of bias.Results A total of 17 studies encompassing 8 566 042 participants from four continents were included, with altitudes ranging from 1500 m to nearly 5000 m. The pooled prevalence of stroke in high-altitude areas was found to be 0.5% (95% CI 0.3%–7%). Notably, the prevalence was higher in clinical samples (1.2%; 0.4%–2.5%) compared with the general population (0.3%; 95% CI 0.1%–0.6%). When considering geographic regions, the aggregated data indicated that stroke prevalence in the Eurasia plate was 0.3% (0.2%–0.4%), while in the American region, it was 0.8% (0.4%–1.3%). Age (OR, 14.891), gender (OR, 1.289), hypertension (OR, 3.158) and obesity (OR, 1.502) were identified as significant risk factors for stroke in high-altitude areas.Conclusions The findings of this study provide insights into the pooled prevalence of stroke in high-altitude areas, highlighting variations based on geographic regions and sampling type. Moreover, age, gender, hypertension and obesity were found to be associated with the occurrence of stroke.PROSPERO registration number CRD42022381541.

Purpose: Recently, the proportion of patients with high myopia has shown a continuous growing trend, more toward the younger age groups. This study aimed to predict the changes in spherical equivalent refraction (SER) and axial length (AL) in children using machine learning methods. Methods: This study is a retrospective study. The cooperative ophthalmology hospital of this study collected data on 179 sets of childhood myopia examinations. The data collected included AL and SER from grades 1 to 6. This study used the six machine learning models to predict AL and SER based on the data. Six evaluation indicators were used to evaluate the prediction results of the models. Results: For predicting SER in grade 6, grade 5, grade 4, grade 3, and grade 2, the best results were obtained through the multilayer perceptron (MLP) algorithm, MLP algorithm, orthogonal matching pursuit (OMP) algorithm, OMP algorithm, and OMP algorithm, respectively. The R2 of the five models were 0.8997, 0.7839, 0.7177, 0.5118, and 0.1758, respectively. For predicting AL in grade 6, grade 5, grade 4, grade 3, and grade 2, the best results were obtained through the Extra Tree (ET) algorithm, MLP algorithm, kernel ridge (KR) algorithm, KR algorithm, and MLP algorithm, respectively. The R2 of the five models were 0.7546, 0.5456, 0.8755, 0.9072, and 0.8534, respectively. Conclusion: Therefore, in predicting SER, the OMP model performed better than the other models in most experiments. In predicting AL, the KR and MLP models were better than the other models in most experiments.

Abstract. Background:. Breast cancer patients who are positive for hormone receptor typically exhibit a favorable prognosis. It is controversial whether chemotherapy is necessary for them after surgery. Our study aimed to establish a multigene model to predict the relapse of hormone receptor-positive early-stage Chinese breast cancer after surgery and direct individualized application of chemotherapy in breast cancer patients after surgery. Methods:. In this study, differentially expressed genes (DEGs) were identified between relapse and nonrelapse breast cancer groups based on RNA sequencing. Gene set enrichment analysis (GSEA) was performed to identify potential relapse-relevant pathways. CIBERSORT and Microenvironment Cell Populations-counter algorithms were used to analyze immune infiltration. The least absolute shrinkage and selection operator (LASSO) regression, log-rank tests, and multiple Cox regression were performed to identify prognostic signatures. A predictive model was developed and validated based on Kaplan–Meier analysis, receiver operating characteristic curve (ROC). Results:. A total of 234 out of 487 patients were enrolled in this study, and 1588 DEGs were identified between the relapse and nonrelapse groups. GSEA results showed that immune-related pathways were enriched in the nonrelapse group, whereas cell cycle- and metabolism-relevant pathways were enriched in the relapse group. A predictive model was developed using three genes (CKMT1B, SMR3B, and OR11M1P) generated from the LASSO regression. The model stratified breast cancer patients into high- and low-risk subgroups with significantly different prognostic statuses, and our model was independent of other clinical factors. Time-dependent ROC showed high predictive performance of the model. Conclusions:. A multigene model was established from RNA-sequencing data to direct risk classification and predict relapse of hormone receptor-positive breast cancer in Chinese patients. Utilization of the model could provide individualized evaluation of chemotherapy after surgery for breast cancer patients.

Abstract Background Hepatocellular carcinoma (HCC) generally arises from a background of liver cirrhosis (LC). Patients with cirrhosis and suspected HCC are recommended to undergo serum biomarker tests and imaging diagnostic evaluation. However, the performance of routine diagnostic methods in detecting early HCC remains unpromising. Methods Here, we conducted a large-scale, multicenter study of 1675 participants including 490 healthy controls, 577 LC patients, and 608 HCC patients from nine clinical centers across nine provinces of China, profiled gene mutation signatures of cell-free DNA (cfDNA) using Circulating Single-Molecule Amplification and Resequencing Technology (cSMART) through detecting 931 mutation sites across 21 genes. Results An integrated diagnostic model called “Combined method” was developed by combining three mutation sites and three serum biomarkers. Combined method outperformed AFP in the diagnosis of HCC, especially early HCC, with sensitivities of 81.25% for all stages and 66.67% for early HCC, respectively. Importantly, the integrated model exhibited high accuracy in differentiating AFP-negative, AFP-L3-negative, and PIVKA-II-negative HCCs from LCs.

Objective To analyze the influencing factors of clinical efficacy of autologous platelet-rich plasma in the treatment of androgenetic alopecia. Methods From January, 2019 to December, 2021, 151 outpatients with androgenetic alopecia were treated in our hospital. All patients were treated with autologous PRP injection once a month and planned to received injection for 4-6 occasions. According to the hair growth before and after treatment, the treatment results were evaluated. The influencing factors in the treatment results were grouped and analyzed, including the treatment numbers (divided into 1-6 occasions), the grade of alopecia(three grades: mild, moderate and severe alopecia) and the Plt concentration in PRP[five grades(×109/L): extremely low concentration (1 501)]. Results The correlation coefficient between the number of treatments and the effective rate was pearson=0.986, P1, the effective rate increased by 2.619 times and 2.033 times, respectively, as treatment numbers and Plt concentration increased. When the OR value of the grade of alopecia was 0.338 (0

Abstract Pulse wave velocity (PWV) is the most widely used measurement of arterial stiffness in clinical practice. This study aimed to evaluate and compare the relationships between carotid‐femoral pulse wave velocity (cfPWV) and brachial‐ankle PWV (baPWV) and the presence of carotid plaque. This study was designed cross‐sectionally and included 6027 participants from a community‐based cohort in Beijing. Logistic regression analyses were performed to evaluate and compare the associations of cfPWV and baPWV with the presence of carotid plaque. The mean (SD) cfPWV and baPWV were 8.55 ± 1.83 and 16.79 ± 3.36, respectively. The prevalence of carotid plaque was 45.26% (n = 2728). Both cfPWV (per 1 m/s increase: OR = 1.11, 95% CI: 1.07–1.16) and baPWV (OR = 1.04, 95% CI: 1.02–1.06) were independently associated with carotid plaque after adjusting for various confounders. Compared with bottom quartile (cfPWV ≤7.31 m/s and baPWV ≤14.44 m/s), the top quartile of cfPWV and baPWV had a significantly higher prevalence of carotid plaque (for cfPWV: OR = 1.59, 95% CI: 1.32–1.92; for baPWV: OR = 1.53, 95% CI: 1.26–1.86). However, the relationship of baPWV and carotid plaque was nonlinear, with a positive trend only when baPWV

Introduction Virtual home visits may improve chronic disease management. However, whether they are suitable for peritoneal dialysis (PD) patients has not yet been fully investigated. This study aimed to compare the agreement and acceptance of virtual home visits and in-person home visits in PD patients.Methods This was a paired, single center, noninferiority trial. Participants received a virtual home visit and an in-person home visit simultaneously. A home visit checklist was built for standardization visits. The content was divided into three parts: domestic habits (57 items), bag exchange procedures (56 items), and exit site care (53 items). Satisfaction questionnaires for both patients and nurses were designed to assess attitudes toward home visits and socioeconomic effects.Results A total of 30 PD patients were enrolled in a single center. The information collected from virtual home visits and in-person home visits was found to be highly consistent. The perfect agreement was found in 52/57, 49/56, and 44/53 items (Cohen's kappa 0.81–1.00), substantial agreement in 4/57, 7/56, and 8/53 items (Cohen's kappa 0.61–0.80). Patients reported almost identical satisfaction for virtual home visits and in-person home visits (Z = 0.39, p = 0.70). PD nurses reported similar feasibility and patient cooperation for the two visit types (Z = 0.99, p = 0.33; Z = 1.65, p = 0.10, respectively). In addition, virtual home visits were found to be more cost-effective than in-person home visits.Conclusions Virtual home visits information collection was similar to in-person home visits in PD. There were no differences in participant satisfaction and feasibility between the two visit types.

ABSTRACT: Objectives: XNW4107 is a novel β-lactamase inhibitor that possesses broad activity against serine-β-lactamases. XNW4107 in combination with imipenem exhibited potent in vitro activity against carbapenem-resistant bacteria and particularly against carbapenem-resistant Acinetobacter baumannii. This study aimed to evaluate the in vitro and in vivo antibacterial activities of imipenem/XNW4107. Methods: The minimum inhibitory concentrations, minimum bactericidal concentrations, time-kill curves, post-antibiotic effects, and spontaneous frequency of resistance were used to investigate the imipenem/XNW4107 in vitro activity. A mouse systemic infection model was used to evaluate the imipenem/XNW4107 in vivo efficacy. Results: MIC90 of imipenem/XNW4107 against imipenem-nonsusceptible A. baumannii (n = 106) was 8 mg/L, which was 16-fold lower than the MIC90 of imipenem; the resistance rate decreased from 90% to 20% applying the CLSI imipenem breakpoint. MIC90 of imipenem/XNW4107 against imipenem-resistant Klebsiella pneumoniae (n = 54) was 2 mg/L, which was 128-fold lower than the MIC90 of imipenem; 80% imipenem-nonsusceptible Pseudomonas aeruginosa (n = 101) exhibited MICs of imipenem/XNW4107 from 2 to 8 mg/L, which were 4- to 8-fold lower than the MICs of imipenem. Imipenem/XNW4107 was bactericidal against A. baumannii, K. pneumoniae, and Escherichia coli. The time-kill curves showed that increasing concentrations did not result in progressively increased killing at concentrations >4 × MIC. Imipenem/XNW4107 has a low potential for resistance development in tested strains except for K. pneumoniae. Imipenem/XNW4107 provided good protection against imipenem-resistant A. baumannii and K. pneumoniae in vivo. Conclusions: The broad-spectrum profile and potent in vitro and in vivo antibacterial activities support imipenem/XNW4107 as a promising investigational candidate.

Aspergillus luchuensis, an industrially important member of Aspergillus species belonging to section Nigri used in fermentation in East Asia, was isolated from an immunocompromised patient with probable invasive pulmonary aspergillosis who failed voriconazole therapy in China. This isolate showed non-wild-type susceptibility to itraconazole, voriconazole, isavuconazole, and posaconazole. A G1378A mutation in cyp51A, resulting in the G441S amino acid substitution, which is the homolog to G448S conferring triazole-resistance in A. fumigatus, was detected in the A. luchuensis isolate.

Abstract Background From 20 July to 26 August 2021, local outbreaks of COVID-19 occurred in Nanjing City and Yangzhou City (Jiangsu Province, China). We analyzed the characteristics of these outbreaks in an effort to develop specific and effective intervention strategies. Methods Publicly available data on the characteristics of the COVID-19 outbreaks in Jiangsu Province were collected. Logistic regression was used to assess the association of age and sex with clinical severity. Analysis of onset dates, generation time distributions, and locations were used to estimate the mean transmission distance. A branching process model was used to evaluate different management strategies. Results From 20 July to 26 August 2021, 820 patients were diagnosed with COVID-19 in Jiangsu Province, with 235 patients (28.7%) from Nanjing, 570 (69.5%) from Yangzhou, and 15 (1.8%) from other cities. Overall, 57.9% of the patients were female, 13.7% were under 20 years-old, and 58.3% had moderate disease status. The mean transmission distance was 4.12 km, and closed-loop management of the area within 2.23 km of cases seemed sufficient to control an outbreak. The model predicted that the cumulative cases in Yangzhou would increase from 311 to 642 if the interval between rounds of nucleic acid amplification testing (NAAT) increased from 1 to 6 days. It also predicted there would be 44.7% more patients if the NAAT started 10 days (rather than 0 days) after diagnosis of the first case. The proportion of cases detected by NAAT would increase from 11.16 to 44.12% when the rounds of NAAT increased from 1 to 7 within 17 days. When the effective vaccine coverage was 50%, the outbreak would be controlled even when using the most relaxed non-pharmaceutical interventions. Conclusions The model predicted that a timely closed-loop management of a 2.23 km area around positive COVID-19 cases was sufficient to control the outbreak. Prompt serial NAAT is likely to contain an outbreak quickly, and our model results indicated that three rounds of NAAT sufficiently controlled local transmission. Trial registration We did not involve clinical trial.

Abstract Small-cell lung cancer (SCLC) is the most aggressive and lethal subtype of lung cancer, for which, better understandings of its biology are urgently needed. Single-cell sequencing technologies provide an opportunity to profile individual cells within the tumor microenvironment (TME) and investigate their roles in tumorigenic processes. Here, we performed high-precision single-cell transcriptomic analysis of ~5000 individual cells from primary tumors (PTs) and matched normal adjacent tissues (NATs) from 11 SCLC patients, including one patient with both PT and relapsed tumor (RT). The comparison revealed an immunosuppressive landscape of human SCLC. Malignant cells in SCLC tumors exhibited diverse states mainly related to the cell cycle, immune, and hypoxic properties. Our data also revealed the intratumor heterogeneity (ITH) of key transcription factors (TFs) in SCLC and related gene expression patterns and functions. The non-neuroendocrine (non-NE) tumors were correlated with increased inflammatory gene signatures and immune cell infiltrates in SCLC, which contributed to better responses to immune checkpoint inhibitors. These findings indicate a significant heterogeneity of human SCLC, and intensive crosstalk between cancer cells and the TME at single-cell resolution, and thus, set the stage for a better understanding of the biology of SCLC as well as for developing new therapeutics for SCLC.

Abstract CSL112 (apolipoprotein A‐I [apoA‐I, human]) is a novel drug in development to reduce the risk of recurrent cardiovascular events following acute myocardial infarction by increasing cholesterol efflux capacity (CEC). This phase I study aimed to compare the pharmacokinetics (PKs), pharmacodynamics (PDs), and safety of CSL112 in Japanese and White subjects. A total of 34 Japanese subjects were randomized to receive a single infusion of CSL112 (2, 4, or 6 g) or placebo and 18 White subjects were randomized to receive a single dose of 6 g CSL112 or placebo, followed by PK/PD assessment and adverse events monitoring. In addition, PK/PD parameters were compared across the CSL112 clinical development program. Plasma exposure of apoA‐I increased in a dose‐dependent but nonlinear manner in Japanese subjects receiving a single dose of CSL112. Mean baseline‐corrected area under the curve from 0 to 72 h (AUC0–72) increased from 840 to 6490 mg h/dl, in the 2 and 6 g cohorts, respectively, followed by dose‐dependent increase of CEC. The plasma PK profile of apoA‐I and increases in total and ATP binding cassette transporter A1 dependent CEC were comparable in Japanese and White subjects. The geometric mean ratio (Japanese:White) for plasma apoA‐I AUC0–72 and maximum plasma concentration (Cmax) was 1.08 and 0.945, respectively. Cross‐study comparison analysis demonstrated similar CSL112 exposure and CEC enhancement in Japanese and non‐Japanese subjects (including patients with cardiovascular disease) and further confirmed consistent PKs/PDs of CSL112. This study suggests CSL112 acutely enhances CEC and is well‐tolerated with no differences between Japanese and White subjects.

ABSTRACT: Objectives: This study aimed to investigate the synergistic activity of eravacycline combined with other antimicrobial agents against carbapenem-resistant Enterobacteriaceae and Acinetobacter baumannii collected from China. Methods: Sixty carbapenem-resistant strains, including 20 Escherichia coli, 20 Klebsiella pneumoniae, and 20 Acinetobacter baumannii were investigated for the synergy analysis. Imipenem, ceftazidime, cefoperazone-sulbactam, ciprofloxacin, amikacin, and polymyxin B were selected to investigate their efficacy in combination with eravacycline against 60 carbapenem-resistant strains. Minimum inhibitory concentrations (MICs) of the drugs were determined by broth microdilution method. The efficacy of eravacycline in combination with these agents was determined by the chequerboard method. Results: Antimicrobial susceptibility testing revealed that polymyxin B was most effective against all carbapenem-resistant strains, with resistance rates between 0% and 15%. Eravacycline showed potent activity against E. coli with an 85% susceptibility rate, and may also have activity against K. pneumoniae and A. baumannii with low MIC90 values. The chequerboard method showed that eravacycline-polymyxin B was the most effective combination against E. coli and K. pneumoniae, with more than 30% synergy. The most active combination against A. baumannii was eravacycline-ceftazidime and eravacycline-imipenem, which showed synergy in more than 50% of isolates. Conclusion: Eravacycline combined with β-lactams or polymyxin B can lead to synergistic effects against clinically common carbapenem-resistant Gram-negative bacteria. The synergistic effects of eravacycline-based combinations varied in different species. A combination of eravacycline and polymyxin B may be considered for the treatment of carbapenem-resistant E. coli and K. pneumoniae; eravacycline in combination with ceftazidime or a carbapenem antimicrobial may be considered for the treatment of carbapenem-resistant A. baumannii.

Backgrounds Immune checkpoint blockade has revolutionized cancer treatment and has improved the survival of a subset of patients with cancer. However, numerous patients do not benefit from immunotherapy, and treatment resistance is a major challenge. Krüppel-like factor 12 (KLF12) is a transcriptional inhibitor whose role in tumor immunity is unclear.Methods We demonstrated a relationship between KLF12 and CD8+ T cells in vivo and in vitro by flow cytometry. The role and underlying mechanism that KLF12 regulates CD8+ T cells were investigated using reverse transcription and quantitative PCR, western blot FACS, chromatin immunoprecipitation-PCR and Dual-Luciferase reporter assays, etc, and employing small interfering RNA (siRNA) and inhibitors. In vivo efficacy studies were conducted with multiple mouse tumor models, employing anti-programmed cell death protein 1 combined with KLF12 or galectin-1 (Gal-1) inhibitor.Results Here, we found that the expression of tumor KLF12 correlates with immunotherapy resistance. KLF12 suppresses CD8+ T cells infiltration and function in vitro and in vivo. Mechanistically, KLF12 inhibits the expression of Gal-1 by binding with its promoter, thereby improving the infiltration and function of CD8+ T cells, which plays a vital role in cancer immunotherapy.Conclusions This work identifies a novel pathway regulating CD8+ T-cell intratumoral infiltration, and targeting the KLF12/Gal-1 axis may serve as a novel therapeutic target for patients with immunotherapy resistance.

During spermatogenesis, mitochondria extend along the whole length of spermatid tail and offer a structural platform for microtubule reorganization and synchronized spermatid individualization, that eventually helps to generate mature sperm in Drosophila. However, the regulatory mechanism of spermatid mitochondria during elongation remains largely unknown. Herein, we demonstrated that NADH dehydrogenase (ubiquinone) 42 kDa subunit (ND-42) was essential for male fertility and spermatid elongation in Drosophila. Moreover, ND-42 depletion led to mitochondrial disorders in Drosophila testes. Based on single-cell RNA-sequencing (scRNA-seq), we identified 15 distinct cell clusters, including several unanticipated transitional subpopulations or differentiative stages for testicular germ cell complexity in Drosophila testes. Enrichments of the transcriptional regulatory network in the late-stage cell populations revealed key roles of ND-42 in mitochondria and its related biological processes during spermatid elongation. Notably, we demonstrated that ND-42 depletion led to maintenance defects of the major mitochondrial derivative and the minor mitochondrial derivative by affecting mitochondrial membrane potential and mitochondrial-encoded genes. Our study proposes a novel regulatory mechanism of ND-42 for spermatid mitochondrial derivative maintenance, contributing to a better understanding of spermatid elongation.

Extracellular vesicles (EVs), especially exosomes, have shown great therapeutic potential in the treatment of diseases, as they can target cells or tissues. However, the therapeutic effect of EVs is limited due to the susceptibility of EVs to immune system clearance during transport in vivo. Hydrogels have become an ideal delivery platform for EVs due to their good biocompatibility and porous structure. This article reviews the preparation and application of EVs-loaded hydrogels as a cell-free therapy strategy in the treatment of diseases. The article also discusses the challenges and future outlook of EVs-loaded hydrogels.

Background: The impact of polycystic ovary syndrome (PCOS) on endometrial receptivity and embryo quality is a subject of debate. Different PCOS patient types may exhibit different effects on these factors. This study aimed to identify causes for low live birth rate by comparing endometrial receptivity and embryo quality among different PCOS types. Methods: Overall, a total of 767 PCOS patients with first in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatment classified into phenotype A (n = 167 patients) and phenotype D (n = 600 patients) were eligible for analysis. Patients with single polycystic ovary (n = 406 patients) served as a control group to exclude the advantages of clinical outcome from higher number of oocytes retrieved in women with PCOS. Results: In phenotype A and D, Anti-Müllerian hormone (AMH), antral follicle count (AFC) and basic estradiol were significantly higher compared to single polycystic ovary. However, estradiol, progestin and endometrial thickness on the human chorionic gonadotropin (hCG) day were significantly decreased. In fresh cycles, phenotype A had a significant statistical decrease in the live birth rate compared with single polycystic ovary (35/78 [44.87%] vs. 135/233 [57.94%], p < 0.05), although there was no significant difference in the number of embryo transplants and clinical pregnancy rate among the three groups. It might be associated with the significant reduction of total gonadotropin (Gn) dose, Gn duration, and follicular output rate (FORT) in all the typed PCOS groups. In the first frozen embryo transfer (ET) cycles, no significant difference was observed for estrogen, progestin, or endometrial thickness on the day of ovulation and live birth rate. Women with live birth had a higher estradiol on the hCG day in the phenotype A (3763 [3121, 4752] vs. 2954 [2112, 4036] ng/mL) while a lower estradiol in the single polycystic ovary (3312 [2341, 4465] vs. 3417 [2350, 4638] ng/mL). In multivariate logistic regression analysis, estradiol on the hCG day was a significant independent factor predicting live birth for women with phenotype A (odds ratio (OR) >1.000, 95% confidence interval (95% CI): 1.000–1.001), p = 0.034) and single polycystic ovary (OR

The ΔCO/ΔCO _2 ratio is a good indicator of the combustion efficiency of carbon-containing fuels, and can be useful to assess the combustion efficiency on a regional scale. In this study, we analyzed in-situ observations of CO _2 and CO concentrations from 2011 to 2021 at the Station for Observing Regional Processes of the Earth System (SORPES), in the Yangtze River Delta (YRD) region of eastern China, and calculated the ΔCO/ΔCO _2 ratio to investigate the combustion efficiency in the YRD region. Furthermore, we used a Lagrangian particle dispersion model WRF-FLEXPART to evaluate the contribution of each emission sources to the observed ΔCO/ΔCO _2 ratio. We found that the observed ΔCO/ΔCO _2 ratio showed a persistent decreasing trend of 1.0 ppb/ppm per year and decreased ∼47.9% during this period, illustrating an evident improvement in the combustion efficiency in the YRD region. The improvement of the combustion efficiency is a result of China’s Air Pollution Prevention and Control Action Plan announced in 2013. However, the decrease of ΔCO/ΔCO _2 ratio slowed down from 1.3 ppb ppm ^−1 per year during 2011–2016 to 0.6 ppb ppm ^−1 per year during 2017–2021. The simulation results reveal that the slowdown of the decrease in the ΔCO/ΔCO _2 ratios can be explained by the slowing improvement of combustion efficiency in steel source in the industry sector. Our results verify the effectiveness of emission reduction efforts in the YRD region and highlight the necessity of long-term observations of CO _2 and CO.

There is scarce evidence to demonstrate the pattern of antibiotic use in children in China. We aimed to describe antibiotic prescribing practices among children in primary healthcare institutions (PHIs) in China. We described outpatient antibiotic prescriptions for children in PHIs from January 2017 to December 2019 at both the national and diagnostic levels, utilizing the antibiotic prescribing rate (APR), multi-antibiotic prescribing rate (MAPR), and broad-spectrum prescribing rate (BAPR). Generalized estimating equations were adopted to analyze the factors associated with antibiotic use. Among the total 155,262.2 weighted prescriptions for children, the APR, MAPR, and BAPR were 43.5%, 9.9%, and 84.8%. At the national level, J01DC second-generation cephalosporins were the most prescribed antibiotic category (21.0%, N = 15,313.0), followed by J01DD third-generation cephalosporins (17.4%, N = 12,695.8). Watch group antibiotics accounted for 55.0% of the total antibiotic prescriptions (N = 52,056.3). At the diagnostic level, respiratory tract infections accounted for 67.4% of antibiotic prescriptions, among which prescriptions with diagnoses classified as potentially bacterial RTIs occupied the highest APR (55.0%). For each diagnostic category, the MAPR and BAPR varied. Age, region, and diagnostic categories were associated with antibiotic use. Concerns were raised regarding the appropriateness of antibiotic use, especially for broad-spectrum antibiotics.

Gonorrhea, a sexually transmitted disease caused by Neisseria gonorrhoeae, poses a significant global public health threat. Infection in women can be asymptomatic and may result in severe reproductive complications. Escalating antibiotic resistance underscores the need for an effective vaccine. Approaches being explored include subunit vaccines and outer membrane vesicles (OMVs), but an ideal candidate remains elusive. Meningococcal OMV-based vaccines have been associated with reduced rates of gonorrhea in retrospective epidemiologic studies, and with accelerated gonococcal clearance in mouse vaginal colonization models. Cross-protection is attributed to shared antigens and possibly cross-reactive, bactericidal antibodies. Using a Candidate Antigen Selection Strategy (CASS) based on the gonococcal transcriptome during human mucosal infection, we identified new potential vaccine targets that, when used to immunize mice, induced the production of antibodies with bactericidal activity against N. gonorrhoeae strains. The current study determined antigen recognition by human sera from N. gonorrhoeae-infected subjects, evaluated their potential as a multi-antigen (combination) vaccine in mice and examined the impact of different adjuvants (Alum or Alum+MPLA) on functional antibody responses to N. gonorrhoeae. Our results indicated that a stronger Th1 immune response component induced by Alum+MPLA led to antibodies with improved bactericidal activity. In conclusion, a combination of CASS-derived antigens may be promising for developing effective gonococcal vaccines.

China’s clean air action stimulated a net accumulative reduction of 2.43 Gt CO2 emission from 2013-2020. Phase-out and upgrades of outdated, polluting, and inefficient combustion facilities have promoted the transition of the country’s energy system.

Abstract. End-stage liver disease (ESLD) is a life-threatening clinical syndrome that markedly increases mortality in patients with infections. In patients with ESLD, infections can induce or aggravate the occurrence of liver decompensation. Consequently, infections are among the most common complications of disease progression. There is a lack of working procedure for early diagnosis and appropriate management for patients with ESLD complicated by infections as well as local and international guidelines or consensus. This consensus assembled up-to-date knowledge and experience across Chinese colleagues, providing data on principles as well as working procedures for the diagnosis and treatment of patients with ESLD complicated by infections.

Abstract Background Stem cell niche maintains stem cell population identity and is essential for the homeostasis of self-renewal and differentiation in Drosophila testes. However, the mechanisms of CySC lineage signals-mediated soma–germline communications in response to external stimuli are unclear. Methods Pre-initiation complex functions were evaluated by UAS-Gal4-mediated cell effects. RNA sequencing was conducted in NC and eIF5 siRNA-treated cells. Genetic interaction analysis was used to indicate the relationships between eIF5 and eIF1A/eIF2γ in Drosophila testes. Results Here, we demonstrated that in CySCs, translation initiation factor eIF5 mediates cyst cell differentiation and the non-autonomously affected germ cell differentiation process. CySCs lacking eIF5 displayed unbalanced cell proliferation and apoptosis, forming testicular germ cell tumors (TGCTs) during spermatogenesis. eIF5 transcriptional regulation network analysis identified multiple metabolic processes and several key factors that might be involved in germ cell differentiation and TGCT formation. Importantly, knockdown of eIF1A and eIF2γ, key components of pre-initiation complex, mimicked the phenotype of knocking down eIF5 in the stem cell niche of Drosophila testes. Genetic interaction analysis indicated that eIF5 was sufficient to rescue the phenotype of tumorlike structures induced by down-regulating eIF1A or eIF2γ in CySCs. Conclusions These findings demonstrated that CySC lineage eIF5, together with eIF1A or eIF2γ, mediates soma–germline communications for the stem cell niche homeostasis in Drosophila testes, providing new insights for the prevention of TGCTs.

Abstract Background Except for B7-CD28 family members, more novel immune checkpoints are being discovered. They are closely associated with tumor immune microenvironment and regulate the function of many immune cells. Various cancer therapeutic studies targeting these novel immune checkpoints are currently in full swing. However, studies concerning novel immune checkpoints phenotypes and clinical significance in lung adenocarcinoma (LUAD) are still limited. Methods We enrolled 1883 LUAD cases from nine different cohorts. The samples from The Cancer Genome Atlas (TCGA) were used as a training set, whereas seven microarray data cohorts and an independent cohort with 102 qPCR data were used for validation. The immune profiles and potential mechanism of the system were also explored. Results After univariate Cox proportional hazards regression and stepwise multivariable Cox analysis, a novel immune checkpoints-based system (LTA, CD160, and CD40LG) were identified from the training set, which significantly stratified patients into high- and low-risk groups with different survivals. Furthermore, this system has been well validated in different clinical subgroups and multiple validation cohorts. It also acted as an independent prognostic factor for patients with LAUD in different cohorts. Further exploration suggested that high-risk patients exhibited distinctive immune cells infiltration and suffered an immunosuppressive state. Additionally, this system is closely linked to various classical immunotherapy biomarkers. Conclusion we constructed a novel immune checkpoints-based system for LUAD, which predicts prognosis and immunotherapeutic implications. We believe that these findings will not only aid in clinical management but will also shed some light on screening appropriate patients for immunotherapy.

Abstract Background PolyC-RNA-binding protein 1 (PCBP1) functions as a tumour suppressor and RNA regulator that is downregulated in human cancers. Here, we aimed to reveal the biological function of PCBP1 in lung adenocarcinoma (LUAD). Methods First, PCBP1 was identified as an important biomarker that maintains LUAD through The Cancer Genome Atlas (TCGA) project screening and confirmed by immunohistochemistry and qPCR. Via colony formation, CCK8, IncuCyte cell proliferation, wound healing and Transwell assays, we confirmed that PCBP1 was closely related to the proliferation and migration of LUAD cells. The downstream gene DKK1 was discovered by RNA sequencing of PCBP1 knockdown cells. The underlying mechanisms were further investigated using western blot, qPCR, RIP, RNA pulldown and mRNA stability assays. Results We demonstrate that PCBP1 is downregulated in LUAD tumour tissues. The reduction in PCBP1 promotes the proliferation, migration and invasion of LUAD in vitro and in vivo. Mechanistically, the RNA-binding protein PCBP1 represses LUAD by stabilizing DKK1 mRNA. Subsequently, decreased expression of the DKK1 protein relieves the inhibitory effect on the Wnt/β-catenin signalling pathway. Taken together, these results show that PCBP1 acts as a tumour suppressor gene, inhibiting the tumorigenesis of LUAD. Conclusions We found that PCBP1 inhibits LUAD development by upregulating DKK1 to inactivate the Wnt/β-catenin pathway. Our findings highlight the potential of PCBP1 as a promising therapeutic target.

Abstract Background The pandemic of coronavirus disease 2019 (COVID-19) has changed human behavior in areas such as contact patterns and mask-wearing frequency. Exploring human–human contact patterns and mask-wearing habits in high-risk groups is an essential step in fully understanding the transmission of respiratory infection-based diseases. This study had aims to quantify local human–human (H–H) contacts in high-risk groups in representative provinces of China and to explore the occupation-specific assortativity and heterogeneity of social contacts. Methods Delivery workers, medical workers, preschoolers, and students from Qinghai, Shanghai, and Zhejiang were recruited to complete an online questionnaire that queried general information, logged contacts, and assessed the willingness to wear a mask in different settings. The “group contact” was defined as contact with a group at least 20 individuals. The numbers of contacts across different characteristics were assessed and age-specific contact matrices were established. A generalized additive mixed model was used to analyze the associations between the number of individual contacts and several characteristics. The factors influencing the frequency of mask wearing were evaluated with a logistic regression model. Results A total of 611,287 contacts were reported by 15,635 participants. The frequency of daily individual contacts averaged 3.14 (95% confidence interval: 3.13–3.15) people per day, while that of group contacts was 37.90 (95% CI: 37.20–38.70). Skin-to-skin contact and long-duration contact were more likely to occur at home or among family members. Contact matrices of students were the most assortative (all contacts q-index = 0.899, 95% CI: 0.894–0.904). Participants with larger household sizes reported having more contacts. Higher household income per capita was significantly associated with a greater number of contacts among preschoolers (P 50,000–99,999 = 0.033) and students (P 10,000–29,999 = 0.017). In each of the public places, the frequency of mask wearing was highest for delivery workers. For preschoolers and students with more contacts, the proportion of those who reported always wearing masks was lower (P

AIM: To study the precise segmentation of pterygium lesions using the convolutional neural networks from artificial intelligence.METHODS: The network structure of Phase-fusion PSPNet for the segmentation of pterygium lesions is proposed based on the PSPNet model structure. In our network, the up-sampling module is connected behind the pyramid pooling module, which gradually increase the sampling based on the principle of phased increase. Therefore, the information loss is reduced, it is suitable for segmentation tasks with fuzzy edges. The experiments conducted on the dataset provided by the Affiliated Eye Hospital of Nanjing Medical University, which includes 517 ocular surface photographic images of pterygium were divided into training set(330 images), validation set(37 images)and test set(150 images), which the training set and the validation set images are used for training, and the test set images are only used for testing. Comparing results of intelligent segmentation and expert annotation of pterygium lesions.RESULTS: Phase-fusion PSPNet network structure for pterygium mean intersection over union(MIOU)and mean average precision(MPA)were 86.31% and 91.91%, respectively, and pterygium intersection over union(IOU)and average precision(PA)were 77.64% and 86.10%, respectively.CONCLUSION: Convolutional neural networks can segment pterygium lesions with high precision, which is helpful to provide an important reference for doctors' further diagnosis of disease and surgical recommendations, and can also visualize the pterygium intelligent diagnosis.

The magnetically hardened shells constructed by the spontaneous core–shell structure due to the enrichment of Y in the core region of (Y/RE)-Fe-B facilitate the enhancement of coercivity. In this work, we systematically compared the metallurgical behaviors of Y in R2Fe14B (RE = Nd, Tb) to investigate the modulation effect of Y on the distribution of REs in the matrix phase. During the strip casting, Y was depleted in the RE-rich phase in Y1/3Nd2/3-Fe-B while enriched in Y1/3Tb2/3-Fe-B. Under the sintering and annealing, Y was simultaneously enriched in the core of matrix phase grain, resulting in the spontaneously formation of Y-rich core and Nd-rich shell structure as well as the Y-rich core and Tb-rich shell structure. Further statistics on the concentration distribution of Y in the matrix phase indicated that the degree of aggregation for Y in Y1/3Nd2/3-Fe-B is higher than that of Y1/3Tb2/3-Fe-B, due to the different formation energy of Re2Fe14B phases. Notably, the spontaneous Y-rich core and Tb-rich shell structure demonstrates the modulation effect of Y on the distribution of Tb, inspiring an innovative scheme for construction of magnetically hardened shells.

Recent studies have shown that microtransplant (MST) could improve outcome of patients with elderly acute myeloid leukemia (EAML). To further standardize the MST therapy and improve outcomes in EAML patients, based on analysis of the literature on MST, especially MST with EAML from January 1st, 2011 to November 30th, 2022, the International Microtransplant Interest Group provides recommendations and considerations for MST in the treatment of EAML. Four major issues related to MST for treating EAML were addressed: therapeutic principle of MST (1), candidates for MST (2), induction chemotherapy regimens (3), and post-remission therapy based on MST (4). Others included donor screening, infusion of donor cells, laboratory examinations, and complications of treatment.

Despite the rapidly growing interest in nanoparticle-mediated controllable male contraception and recovery of male fertility, novel applications of nanoparticles in these processes are limited by a knowledge gap regarding their transport and distribution in the testes. Here, we investigated the fate of gold nanoparticles in the mouse testes using two injection methods, namely, interstitial testicular injection (IT-AuNPs, AuNPs exposure in the interstitial compartment of the testes) and rete testis injection (RT-AuNPs, AuNPs exposure in the adluminal compartment of the seminiferous tubules). In this study, we used 100 nm spherical AuNPs and microinjected with 5 μL AuNPs (30 mg/mL) for the experiments. For IT-AuNP injection, we found that AuNPs could not penetrate through the Sertoli cell-mediated blood–testis barrier (BTB) of the seminiferous tubules, and no male reproductive toxicity was observed. For RT-AuNP injection, AuNPs could be retrogradely transported from the adluminal compartment to the interstitial compartment of the testes via Sertoli cell-mediated endocytosis/exocytosis, resulting in damage and the release of inflammatory cytokines in the mouse testis. Our results highlight a retrograde nanoparticle transport function of Sertoli cells, thereby providing a mechanistic overview of the development and use of nanobiotechnology in male reproduction. Synopsis: This study provides new insights into male reproductive immunotoxicity for AuNPs exposure and elucidates a mechanism via Sertoli cell-mediated endocytosis/exocytosis.

Telomere wear and dysfunction may lead to aging-related diseases. Moreover, increasing evidence show that the occurrence, development, and prognosis of some pediatric diseases are also related to telomere dysfunction. In this review, we systematically analyzed the relationship between telomere biology and some pediatric congenital and growth-related diseases and proposed new theoretical basis and therapeutic targets for the treatment of these diseases.

BackgroundRapid profiling of the EGFR mutations is crucial to help clinicians choose the optimal treatment for patients with advanced/metastatic Non-Small Cell Lung Cancer (NSCLC). Unfortunately, current diagnostic techniques, including ARMS-PCR and NGS, generally require several days to deliver final results. This diagnostic delay may lead to treatment delays for patients who are worsening rapidly.MethodsThis study introduced the ultra-rapid Idylla™ system for rapid, sensitive and specific identification of the EGFR mutations among Chinese NSCLC patients. Idylla™ EGFR Assay, an integrated cartridge running on the Idylla™ system, which can detect 51 EGFR mutations directly from Formalin-Fixed, Paraffin-Embedded (FFPE) samples within 2.5 hours, was used in this study. The sensitivity and specificity of the Idylla™ system were evaluated in comparison with ARMS-PCR or NGS using 95 clinical samples.ResultsThe Idylla™ system achieved a sensitivity of 97.6%, a specificity of 100%, and an overall concordance of 97.9% for 95 retrospective samples. When compared to ARMS-PCR, the Idylla™ system demonstrated high accuracy with an overall agreement of 97.1% (34/35), a sensitivity of 95.2% (20/21) (95% CI, 76.2% - 99.9%), and an estimated specificity of 100% (12/12) (95% CI, 76.8% - 100%) for 35 prospective samples.ConclusionsThis Idylla system provides a rapid, accurate and simple approach for screening EGFR mutations, which can guide Tyrosine Kinase Inhibitors (TKI) treatment for NSCLC patients in a timely manner.

AIM: To evaluate the application value of the automatic classification and diagnosis system of pterygium based on deep learning.METHODS: A total of 750 images of normal, observational and operative anterior sections of pterygium were collected from the Affiliated Eye Hospital of Nanjing Medical University between May 2020 and April 2021. Seven triclassification models were respectively trained with original data set and enhanced data set. Totally 470 clinical images were tested, and the generalization ability of the model before and after data enhancement was compared to determine the best model for the automatic classification system of pterygium.RESULTS:The average sensitivity, specificity and AUC of the best model trained on the original data set were 92.55%, 96.86% and 94.70% respectively. After data was enhanced, the sensitivity, specificity and AUC of different models were increased by 3.7%, 1.9% and 2.7% on average. The sensitivity, specificity and AUC of the EfficientNetB7 model trained on the enhanced data set were 93.63%, 97.34% and 95.47% respectively.CONDLUSION: The EfficientNetB7 model, which was trained on the enhanced data set, achieves the best classification result and can be used in the automatic classification system of pterygium.This automatic classification system can diagnose diseases about pterygium better, and it is expected to be an effective screening tool for primary medical care. It also provides reference for the research on the refinement and grading of pterygium.

Abstract Background Clinical data repositories (CDR) including electronic health record (EHR) data have great potential for outcome prediction and risk modeling. We built a prediction tool integrated with CDR based on pattern discovery and demonstrated a case study on contrast related acute kidney injury (AKI). Methods Patients undergoing cardiac catheterization from January 2015 to April 2017 were included. AKI was identified based on Acute Kidney Injury Network definition. Predictive model including 16 variables covered in existing AKI models was built. A visual analytics tool based on pattern discovery was trained on 70% data up to August 2016 with three interactive knowledge incorporation modes to develop 3 models: (1) pure data-driven, (2) domain knowledge, and (3) clinician-interactive, which were tested and compared on 30% consecutive cases dated afterwards. Results Among 2560 patients in the final dataset, 189 (7.3%) had AKI. We measured 4 existing models, whose areas under curves (AUCs) of receiver operating characteristics curve for the test dataset were 0.70 (Mehran's), 0.72 (Chen's), 0.67 (Gao's) and 0.62 (AGEF), respectively. A pure data-driven machine learning method achieves AUC of 0.72 (Easy Ensemble). The AUCs of our 3 models are 0.77, 0.80, 0.82, respectively, with the last being top where physician knowledge is incorporated. Conclusions We developed a novel pattern-discovery-based outcome prediction tool integrated with CDR and purely using EHR data. On the case of predicting contrast related AKI, the tool showed user-friendliness by physicians, and demonstrated a competitive performance in comparison with the state-of-the-art models.

Abstract We report a feasibility study of pure leptonic decay $$D_s^+\rightarrow \mu ^+\nu _\mu $$ D s + → μ + ν μ by using a fast simulation software package at STCF. With an expected luminosity of $$1~\mathrm {ab}^{-1}$$ 1 ab - 1 collected at STCF at a center-of-mass energy of 4.009 GeV, the statistical sensitivity of the branching fraction is determined to be 0.3%. Combining this result with the $$c \rightarrow s$$ c → s quark mixing matrix element $$|V_{cs}|$$ | V cs | determined from the current global Standard Model fit, the statistical sensitivity of $$D_s^+$$ D s + decay constant, $$f_{D_s^+}$$ f D s + , is estimated to be 0.2%. Alternatively, combining the current results of $$f_{D_s^+}$$ f D s + calculated by lattice QCD, the statistical sensitivity of $$|V_{cs}|$$ | V cs | is determined to be 0.2%, which helps probe possible new physics beyond Standard Model. The unprecedented precision to be achieved at STCF will provide a precise calibration of QCD and rigorous test of Standard Model.

Growing emissions from Pacific Northwest wildfires have increased atmospheric carbon monoxide in August, raising questions about potential health impacts as the seasonal pattern of air quality changes for large regions of North America.

Releasing Wolbachia-infected mosquitoes to replace wild mosquito vectors has been proved to be a promising way to control mosquito-borne diseases. To guarantee the success of population replacement, the existing theoretical results show that the reproductive advantage from Wolbachia-causing cytoplasmic incompatibility and fecundity cost produce an unstable equilibrium frequency that must be surpassed for the infection frequency to tend to increase. Motivated by lab experiments which manifest that redundant release of infected males can speed up population replacement by suppressing effective matings between uninfected mosquitoes, we develop an ordinary differential equation model to study the dynamics of Wolbachia infection frequency with supplementary releases of infected males. Under the assumption that infected males are released at a ratio $ r $ to the total population size during each release period $ T $, we find two thresholds $ r^* $ and $ T^* $, and prove that when $ 0 < r < r^* $, or $ r\ge r^* $ and $ T > T^* $, an unstable $ T $-periodic solution exists which serves as a new infection frequency threshold. Increasing the release ratio to $ r > r^* $ and shortening the waiting period to $ T\leq T^* $, the unstable $ T $-periodic solution disappears and population replacement is always guaranteed.

Abstract Background Osteosarcoma (OS) is the most common malignant tumor of bone, and the clinical efficacy of current treatments and associated survival rates need to be further improved by employing novel therapeutic strategies. Although various studies have shown that BMI1 protein is universally upregulated in OS cells and tissues, its specific role and underlying mechanism have not yet been fully explored. Methods Expression of BMI1 protein in OS cells was detected by western blot. The effect of BMI1 on proliferation and migration of OS cells (143B and U-2OS cell lines) was investigated in vitro using CCK-8, colony formation and transwell assays, and in vivo using subcutaneous tumorigenesis and lung metastasis assays in xenograft nude mice. Expression of epithelial–mesenchymal transition (EMT)-associated proteins was detected by immunofluorescence imaging. Bioinformatic analysis was performed using ENCODE databases to predict downstream targets of BMI1. SIK1 mRNA expression in osteosarcoma cells was detected by quantitative real-time reverse transcription PCR (qPCR). Chromatin immunoprecipitation-qPCR (ChIP-qPCR) was used to investigate expression of BMI1-associated, RING1B-associated, H2AK119ub-associated and H3K4me3-associated DNA at the putative binding region of BMI1 on the SIK1 promoter in OS cells. Results Using both in vitro and in vivo experimental approaches, we found that BMI1 promotes OS cell proliferation and metastasis. The tumor suppressor SIK1 was identified as the direct target gene of BMI1 in OS cells. In vitro experiments demonstrated that SIK1 could inhibit proliferation and migration of OS cells. Inhibition of SIK1 largely rescued the altered phenotypes of BMI1-deficient OS cells. Mechanistically, we demonstrated that BMI1 directly binds to the promoter region of SIK1 in a complex with RING1B to promote monoubiquitination of histone H2A at lysine 119 (H2AK119ub) and inhibit H3K4 trimethylation (H3K4me3), resulting in inhibition of SIK1 transcription. We therefore suggest that BMI1 promotes OS cell proliferation and metastasis by inhibiting SIK1. Conclusions Our results reveal a novel molecular mechanism of OS development promoted by BMI1 and provides a new potential target for OS treatment.

This paper reports the first discovery of basic igneous rocks in Bairin Right Banner in southeastern Inner Mongolia, China. To understand the genesis and tectonic evolution of these rocks, we have carried out geochronology and geochemistry research on them. The results show that LA-ICP-MS zircon U-Pb concordant mean ages of massive basalt, diabase, and pillow basalt are 272.0 ± 2.8 Ma, 261.5 ± 3.2 Ma, and 256.5 ± 2.5 Ma, respectively, suggesting their formation during the Late Permian. The massive basalt, diabase, and pillow basalt are tholeiitic with low Mg# values in the ranges of 46.2–66.8, 54.4–71.0, and 53.5–58.2, respectively. They have similar chondrite-normalized rare earth element (REE) patterns. The intensity of REE differentiation is similar to that of typical enriched mid-ocean ridge basalts (E-MORB). The pillow basalts are relatively enriched in Ba and U, while slightly depleted in Rb and Th, and show geochemical affinity to E-MORB. The massive basalts and diabases have the same primitive mantle-normalized patterns and are relatively enriched in Rb, Ba, and U, while depleted in Nb and Ta, similar to the typical island arc magmas. Our new findings indicate that the intra-oceanic subduction of the Paleo-Asian Oceanic slab was still ongoing during the late Permian in the Bairin Right Banner area and, combined with previous studies, it might have been closed during the Late Permian to Early Triassic along the Xar Moron suture zone.