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Abstract Background For patients with steroid-refractory acute graft-versus-host disease (SR-aGVHD), effective second-line regimens are urgently needed. Mesenchymal stromal cells (MSCs) have been used as salvage regimens for SR-aGVHD in the past. However, clinical trials and an overall understanding of the molecular mechanisms of MSCs combined with basiliximab for SR-aGVHD are limited, especially in haploidentical haemopoietic stem cell transplantation (HID HSCT). Methods The primary endpoint of this multicentre, randomized, controlled trial was the 4-week complete response (CR) rate of SR-aGVHD. A total of 130 patients with SR-aGVHD were assigned in a 1:1 randomization schedule to the MSC group (receiving basiliximab plus MSCs) or control group (receiving basiliximab alone) (NCT04738981). Results Most enrolled patients (96.2%) received HID HSCT. The 4-week CR rate of SR-aGVHD in the MSC group was obviously better than that in the control group (83.1% vs. 55.4%, P = 0.001). However, for the overall response rates at week 4, the two groups were comparable. More patients in the control group used ≥ 6 doses of basiliximab (4.6% vs. 20%, P = 0.008). We collected blood samples from 19 consecutive patients and evaluated MSC-derived immunosuppressive cytokines, including HO1, GAL1, GAL9, TNFIA6, PGE2, PDL1, TGF-β and HGF. Compared to the levels before MSC infusion, the HO1 (P = 0.0072) and TGF-β (P = 0.0243) levels increased significantly 1 day after MSC infusion. At 7 days after MSC infusion, the levels of HO1, GAL1, TNFIA6 and TGF-β tended to increase; however, the differences were not statistically significant. Although the 52-week cumulative incidence of cGVHD in the MSC group was comparable to that in the control group, fewer patients in the MSC group developed cGVHD involving ≥3 organs (14.3% vs. 43.6%, P = 0.006). MSCs were well tolerated, no infusion-related adverse events (AEs) occurred and other AEs were also comparable between the two groups. However, patients with malignant haematological diseases in the MSC group had a higher 52-week disease-free survival rate than those in the control group (84.8% vs. 65.9%, P = 0.031). Conclusions For SR-aGVHD after allo-HSCT, especially HID HSCT, the combination of MSCs and basiliximab as the second-line therapy led to significantly better 4-week CR rates than basiliximab alone. The addition of MSCs not only did not increase toxicity but also provided a survival benefit.

ABSTRACT The upper and lower respiratory tract may share microbiome because they are directly continuous, and the nasal microbiome contributes partially to the composition of the lung microbiome. But little is known about the upper and lower airway microbiome of early postoperative lung transplant recipients (LTRs). Using 16S rRNA gene sequencing, we compared paired nasal swab (NS) and bronchoalveolar lavage fluid (BALF) microbiome from 17 early postoperative LTRs. The microbiome between the two compartments were significantly different in Shannon diversity and beta diversity. Four and eight core NS‐associated and BALF‐associated microbiome were identified, respectively. NS samples harbored more Corynebacterium, Acinetobacter, and Pseudomonas, while BALF contained more Ralstonia, Stenotrophomonas, Enterococcus, and Pedobacter. The within-subject dissimilarity was higher than the between-subject dissimilarity, indicating a greater impact of sampling sites than sampling individuals on microbial difference. There were both difference and homogeneity between NS and BALF microbiome in early postoperative LTRs. High levels of pathogens were detected in both samples, suggesting that both of them can reflect the diseases characteristics of transplanted lung. The differences between upper and lower airway microbiome mainly come from sampling sites instead of sampling individuals.IMPORTANCELung transplantation is the only therapeutic option for patients with end-stage lung disease, but its outcome is much worse than other solid organ transplants. Little is known about the NS and BALF microbiome of early postoperative LTRs. Here, we compared paired samples of the nasal and lung microbiome from 17 early postoperative LTRs and showed both difference and homogeneity between the two samples. Most of the “core” microbiome in both NS and BALF samples were recognized respiratory pathogens, suggesting that both samples can reflect the diseases characteristics of transplanted lung. We also found that the differences between upper and lower airway microbiome in early postoperative LTRs mainly come from sampling sites instead of sampling individuals.

Introduction Postoperative pulmonary complications (PPCs) occur frequently in patients undergoing lung surgery under general anaesthesia and are strongly associated with longer postoperative hospital stays and increased mortality. The existing literature has shown that a higher level of preoperative physical activity (PA) plays a positive role in the low incidence of postoperative complications and the quality of life in patients undergoing lung surgery. However, the association between preoperative PA levels and the incidence of PPCs has rarely been studied, particularly in thoracoscopic lung surgery. This study aims to evaluate PA levels in patients undergoing thoracoscopic lung surgery using the International Physical Activity Questionnaire and to investigate the association between PA levels and the incidence of PPCs.Methods and analysis A total of 204 participants aged 18–80 years undergoing thoracoscopic lung surgery (thoracoscopic wedge resection, thoracoscopic segmentectomy and thoracoscopic lobectomy) will be included in the study. The primary outcome is the incidence of PPCs within the first 5 postoperative days. The secondary outcomes include the number of PPCs, the incidence of PPCs 1 month postoperatively, the arterial blood levels of inflammatory markers, the incidence of postoperative adverse events within the first 5 postoperative days, extubation time, unplanned admission to the intensive care unit, postoperative length of stay and mortality 1 month postoperatively.Ethics and dissemination The study was reviewed and approved by the Research Ethics Committee of the First Affiliated Hospital of Shandong First Medical University on 31 March 2022 (YXLL-KY-2022(014)) and is registered at ClinicalTrials.gov. We plan to disseminate the data and findings of this study in international and peer-reviewed journals.Trial registration number The trial has been prospectively registered at the clinicaltrials.gov registry (NCT05401253).

This study aimed to dynamically track the priorities and potential research hotspots in the field of heart failure with sarcopenia. Using CiteSpace, we analyzed the literature on heart failure with sarcopenia from the Web of Science database from 1995 to 2022. The analysis encompassed 507 records, revealing an overall upward trend in annual publication volume. Europe and the United States emerged as the primary regions for publishing, particularly driven by contributions from developed countries such as the United States, Germany, and Italy. Productive institutions included the Charite Universitatsmedizin Berlin, University Medical Center Gottingen, the German Center for Cardiovascular Research (DZHK), Universita Cattolica del Sacro Cuore, and the National Institute on Aging (NIA). Noteworthy academic groups have formed around these institutions; von Haehling S, Anker Stefan D, Springer J, and Doehner W frequently collaborated. The core journals that frequently published articles in this area included Circulation, European Heart Journal, and The Journals of Gerontology Series A-Biological Sciences and Medical Sciences.Based on the keyword analysis, we identified three key research areas. First, the diagnosis and definition of sarcopenia emerged as significant themes. Second, researchers have focused on exploring the mechanisms underlying heart failure with sarcopenia, including inflammation, insulin resistance, and oxidative stress. Finally, treatment strategies, such as physical activity and nutritional support, constitute another critical research theme. Furthermore, potential research hotspots within this field include clinical randomized controlled trials, investigations into inflammatory mechanisms, cardiac rehabilitation, studies on physical activity, androgen receptor modulators, and investigations into clinical outcomes such as cognitive impairment.

This case report presents a 72-year-old male patient who presented with exertional dyspnea for over 10 years, which had progressively worsened over the past 4 months. Transthoracic echocardiography revealed severe aortic and mitral regurgitation, with a left ventricular ejection fraction of 37% and a left ventricular end-diastolic diameter of 64 mm. Despite receiving long-term optimal medical management, there was no improvement in symptoms or severity of valvular regurgitation. Given the relatively high surgical risk associated with double valve replacement in this elderly patient and his preference for minimally invasive procedures, a one-stage transapical aortic valve replacement and transcatheter mitral valve repair using the edge-to-edge technique were planned. The patient was discharged 8 days post-procedure without any complications. At 1-month follow-up, the patient's New York Heart Association (NYHA) functional class had improved to grade II.

Apple trees face various challenges during cultivation. Apple leaves, as the key part of the apple tree for photosynthesis, occupy most of the area of the tree. Diseases of the leaves can hinder the healthy growth of trees and cause huge economic losses to fruit growers. The prerequisite for precise control of apple leaf diseases is the timely and accurate detection of different diseases on apple leaves. Traditional methods relying on manual detection have problems such as limited accuracy and slow speed. In this study, both the attention mechanism and the module containing the transformer encoder were innovatively introduced into YOLOV5, resulting in YOLOV5-CBAM-C3TR for apple leaf disease detection. The datasets used in this experiment were uniformly RGB images. To better evaluate the effectiveness of YOLOV5-CBAM-C3TR, the model was compared with different target detection models such as SSD, YOLOV3, YOLOV4, and YOLOV5. The results showed that YOLOV5-CBAM-C3TR achieved mAP@0.5, precision, and recall of 73.4%, 70.9%, and 69.5% for three apple leaf diseases including Alternaria blotch, Grey spot, and Rust. Compared with the original model YOLOV5, the mAP 0.5increased by 8.25% with a small change in the number of parameters. In addition, YOLOV5-CBAM-C3TR can achieve an average accuracy of 92.4% in detecting 208 randomly selected apple leaf disease samples. Notably, YOLOV5-CBAM-C3TR achieved 93.1% and 89.6% accuracy in detecting two very similar diseases including Alternaria Blotch and Grey Spot, respectively. The YOLOV5-CBAM-C3TR model proposed in this paper has been applied to the detection of apple leaf diseases for the first time, and also showed strong recognition ability in identifying similar diseases, which is expected to promote the further development of disease detection technology.

BackgroundThe vasoplegic syndrome is one of the major consequences of cardiac surgery. If pulmonary hypertension is additionally involved with vasoplegic syndrome, circulation management becomes much more complicated. According to previous studies, pituitrin (a substitute for vasopressin, which contains vasopressin and oxytocin) not only constricts systemic circulation vessels and increases systemic circulation pressure but also likely decreases pulmonary artery pressure and pulmonary vascular resistance. The aim of this study is to investigate whether pituitrin is beneficial for the postoperative outcomes in patients with pulmonary hypertension undergoing cardiac surgery.Methods and analysisThe randomized controlled trial will include an intervention group continuously infused with 0.04 U/(kg h) of pituitrin and a control group. Adult patients with pulmonary hypertension undergoing elective cardiac surgery will be included in this study. Patients who meet the conditions and give their consent will be randomly assigned to the intervention group or the control group. The primary outcome is the composite endpoint of all-cause mortality within 30 days after surgery or common complications after cardiac surgery. Secondary outcomes include the incidence of other postoperative complications, length of hospital stay, and so on.DiscussionPituitrin constricts systemic circulation vessels, increases systemic circulation pressure, and may reduce pulmonary artery pressure and pulmonary vascular resistance, which makes it a potentially promising vasopressor during the perioperative period in patients with pulmonary hypertension. Therefore, evidence from randomized controlled trials is necessary to elucidate whether pituitrin influences outcomes in patients with pulmonary hypertension following cardiac surgery.

Choosing a suitable bioaerosol sampler for atmospheric microbial monitoring has been a challenge to researchers interested in environmental microbiology, especially during a pandemic. However, a comprehensive and integrated evaluation method to fully assess bioaerosol sampler performance is still lacking. Herein, we constructed a customized wind tunnel operated at 2–20 km/h wind speed to systematically and efficiently evaluate the performance of six frequently used samplers, where various aerosols, including Arizona test dust, bacterial spores, gram-positive and gram-negative bacteria, phages, and viruses, were generated. After 10 or 60 min of sampling, the physical and biological sampling efficiency and short or long-term sampling capabilities were determined by performing aerodynamic particle size analysis, live microbial culturing, and a qPCR assay. The results showed that AGI-30 and BioSampler impingers have good physical and biological sampling efficiencies for short-term sampling. However, their ability to capture aerosols at low concentrations is restricted. SASS 2300 and BSA-350 wet-wall cyclones had excellent enrichment ratios and high microbial cultivability in both short-term and long-term sampling; however, they were not suitable for quantitative studies of aerosols. Polycarbonate filter samplers showed outstanding performance in physical and long-term sampling but lacked the ability to maintain microbial activity, which can be improved by gelatin filter samplers. However, limitations remain for some fragile microorganisms, such as E. coli phage PhiX174 and coronavirus GX_P2V. In addition, the effects of wind speed and direction should be considered when sampling particles larger than 4 µm. This study provides an improved strategy and guidance for the characterization and selection of a bioaerosol sampler for better measurement and interpretation of collected ambient bioaerosols.

ABSTRACTAtherosclerosis (AS) is the main underlying cause of cardiovascular disease, and B cells are considered a key immune cell type to regulate AS. So far, there is no bibliometric study on B cell and AS. This study aims to comprehensively analyze the scientific output about B cell and AS, summarize the literature characteristics, explore research hotspots, and point out emerging trends. We searched the literature from 2003 to 2022 from the Web of Science Core Collection (WoSCC) database. CiteSpace, VOSviewer, and the R package “Bibliometrix” were used for literature analysis and visualization. A total of 1,062 articles and reviews were identified. The number of annual publications generally showed an upward trend. The United States and China were the most productive countries. Medical University of Vienna was the most productive research institution, and Binder Christoph J. was the most productive author, who was also from Medical University of Vienna. “Arteriosclerosis Thrombosis and Vascular Biology” was the most published journal and the most frequently cited journal. The most cited reference was written by Caligiuri G (2002) in “Journal of Clinical Investigation.” The most frequent keywords were “inflammation,” “macrophages,” “cardiovascular disease,” “T cells,” “apoptosis,” “immunity,” “cytokines,” “lymphocytes,” etc. The trend topics were mainly focused on “immune infiltration,” “immunoglobulins,” and “biomarkers.” The complex role of B cell subtypes and a variety of B cell mediators is the main research direction at present. In-depth analysis of B cell-specific targets can provide new ideas and methods for the prevention and treatment of AS.

BackgroundChina had its first wave of COVID-19 in 2020 and second wave of COVID-19 Omicron in 2022. The number of RSV cases decreased sharply in 2020 and 2022. Investigation of the resurge of RSV infections after the first wave of COVID-19 will guide us to take preventive actions before the resurge of RSV infections after the second wave of COVID-19 Omicron.MethodsWe analysed epidemiological and clinical data of 59934 patients with lower respiratory tract infections (LRTI) from a prospective long-term cohort surveillance programme in Suzhou, China, collected from February 2016 to January 2022. The annual incidence of RSV infection in children aged

BackgroundImperforate anus (IA) has a life-long impact on patients and their families. The caregivers of children with IA (CoCIA) might experience distress, which could be detrimental to them physically and mentally. However, there are limitations in the related studies. This study aimed to investigate the prevalence of IA and the associated factors contributing to the distress experienced by CoCIA.MethodsA cross-sectional study was conducted in three tertiary children's hospitals from November 2018 to February 2019. Distress was assessed using the Chinese version of the Kessler Psychological Distress Scale, and possible determinants were assessed by the Caregiver Reaction Assessment, the Parent Stigma Scale, the Parent Perception of Uncertainty Scale, and the Social Support Scale. Demographic and clinical information was also collected. Multiple regression analysis was performed to explore the association between variables.ResultsOut of 229 CoCIA, 52.9% reported experiencing a high level of distress or above. The data analysis revealed that health problems associated with caregiving, stigma, uncertainty, social support, and children who underwent anal reconstruction surgery 1 year before or earlier could significantly predicate caregivers' distress, and these factors could explain 50.1% of the variance.ConclusionsThe majority of the caregivers of children with IA experience high levels of distress, particularly when their children undergo anal reconstruction surgery 1 year before or earlier. Additionally, health problems related to caregiving, stigma, uncertainty, and low social support could significantly predicate caregivers' distress. It is important for clinical staff to be aware of the prevalent situation of caregivers' distress and to make targeted interventions focused on addressing modifiable factors that should be carried out in family-based care.

ABSTRACTPulmonary anthrax is the most fatal clinical form of anthrax and currently available injectable vaccines do not provide adequate protection against it. Hence, next-generation vaccines that effectively induce immunity against pulmonary anthrax are urgently needed. In the present study, we prepared an attenuated and low protease activity Bacillus anthracis strain A16R-5.1 by deleting five of its extracellular protease activity-associated genes and its lef gene through the CRISPR-Cas9 genome editing system. This mutant strain was then used to formulate a lethal toxin (LeTx)-free culture supernatant extract (CSE) anthrax vaccine, of which half was protective antigen (PA). We generated liquid, powder, and powder reconstituted formulations that could be delivered by aerosolized intratracheal inoculation. All of them induced strong humoral, cellular, and mucosal immune responses. The vaccines also produced LeTx neutralizing antibodies and conferred full protection against the lethal aerosol challenges of B. anthracis Pasteur II spores in mice. Compared to the recombinant PA vaccine, the CSE anthrax vaccine with equal PA content provided superior immunoprotection against pulmonary anthrax. The preceding results suggest that the CSE anthrax vaccine developed herein is suitable and scalable for use in inhalational immunization against pulmonary anthrax.

Abstract Aim To investigate paediatric surgical nurses' knowledge, attitudes and practices (KAP) regarding enhanced recovery after surgery (ERAS). Design A cross‐sectional study. Methods A 34‐question survey was developed. An electronic version of the questionnaire was distributed to nurses working in paediatric surgical departments of 22 tertiary hospitals from 14 provinces of China by means of convenience sampling from February to April 2021. A total of 855 nurses' data was used as the final sample. The statistical analysis included nonparametric test, Spearman′s correlation and multiple linear regression. Results There is still room for improvement regarding the KAP of paediatric surgical nurses, especially in the knowledge of “postoperative recovery” and “preoperative preparation”. The influencing factors of KAP were educational level, geographical region (South, Central, North, Northwest), years of work experience, hospital category (general hospital, women and children′s hospital), and familiarity with ERAS.

Ectomycorrhizal (EM) fungi play a vital role in ensuring plant health, plant diversity, and ecosystem function. However, the study on fungal diversity and community assembly of EM fungi associated with herbaceous plants remains poorly understood. Thus, in our study, Carex pediformis and Polygonum divaricatum in the subalpine meadow of central Inner Mongolia, China were selected for exploring EM fungal diversity and community assembly mechanisms by using llumina MiSeq sequencing of the fungal internal transcribed spacer 2 region (ITS2). We evaluated the impact of soil, climatic, and spatial variables on EM fungal diversity and community turnover. Deterministic vs. stochastic processes for EM fungal community assembly were quantified using β-Nearest taxon index scores. The results showed that a total of 70 EM fungal OTUs belonging to 21 lineages were identified, of which Tomentella-Thelephora, Helotiales1, Tricholoma, Inocybe, Wilcoxina were the most dominant EM fungal lineages. EM fungal communities were significantly different between the two herbaceous plants and among the two sampling sites, and this difference was mainly influenced by soil organic matter (OM) content and mean annual precipitation (MAP). The neutral community model (NCM) explained 45.7% of the variations in EM fungi community assembly. A total of 99.27% of the β-Nearest Taxa Index (βNTI) value was between −2 and 2. These results suggest that the dominant role of stochastic processes in shaping EM fungal community assembly. In addition, RCbray values showed that ecological drift in stochastic processes dominantly determined community assembly of EM fungi. Overall, our study shed light on the EM fungal diversity and community assembly associated with herbaceous plants in the subalpine region of central Inner Mongolia for the first time, which provided a better understanding of the role of herbaceous EM fungi.

Abstract Merocyanine dyes are of great interest amongst researchers due to their nonlinear optical (NLO) properties and solvatochromism. Molecular structure of these dyes constitutes conjugated pathway between the donor and acceptor substituents, with lowest energy transition of $$\mathrm \pi$$ π – $$\mathrm \pi$$ π * character. To rationalize the design of these dyes and deduce structure-property relationship, it is eminent to unravel the excited state dynamics in these complex molecular structures in different solvents. Here we have studied excited state dynamics of a merocyanine dye known as HB194, which has shown commendable efficiency in small molecule based bulk heterojuction solar cells. We have employed femtosecond transient absorption in combination with the quantum chemistry calculations to unravel the solvent dependent charge transfer dynamics of HB194. The excited state decays of the HB194 in different solvents show multi-exponential components. The analysis of the time-resolved data reveals that the polar solvents induce conformationally relaxed intramolecular charge transfer state. In non-polar solvent cyclohexane, only solvent-stabilized ICT state is observed. Additionally, we observe an anomalously red-shifted emission in ethylene glycol centred at $$\sim$$ ∼ 750 nm. Our computational calculations suggest the presence of molecular dimers resulting into observed red-shifted emission band. Our work therefore underscores the importance of gathering molecular-level insight into the system-bath interactions for designing next generation merocynanine-based solvatochromic dyes.

Abstract Background Postoperative delirium in elderly patients is a common and costly complication after surgery. Propofol and sevoflurane are commonly used anesthetics during general anesthesia, and the sedative and anti-inflammatory mechanisms of the two medications are different. The aim of this trial is to compare the impact of propofol with sevoflurane on the incidence of postoperative delirium in elderly patients after spine surgery. Methods A single-center randomized controlled trial will be performed at First Affiliated Hospital of Shandong First Medical University, China. A total of 298 participants will be enrolled in the study and randomized to propofol infusion or sevoflurane inhalation groups. The primary outcome is the incidence of delirium within 7 days after surgery. Secondary outcomes include the day of postoperative delirium onset, duration (time from first to last delirium-positive day), and total delirium-positive days among patients who developed delirium; tracheal intubation time in PACU; the length of stay in PACU; the rate of postoperative shivering; the rate of postoperative nausea and vomiting; the rate of emergence agitation; pain severity; QoR40 at the first day after surgery; the length of stay in hospital after surgery; and the incidence of non-delirium complications within 30 days after surgery. Discussion The primary objective of this study is to compare the impact of propofol and sevoflurane on the incidence of postoperative delirium for elderly patients undergoing spine surgery. The results may help inform strategies to the optimal selection of maintenance drugs for general anesthesia in elderly patients undergoing spine surgery. Trial registration ClinicalTrials.gov NCT05158998 . Registered on 14 December 2021

Abstract Background The "Law on Doctors of the People's Republic of China," which was officially implemented on March 1, 2022, emphasizes the requirements for rational drug use and the necessity for appropriate management of off-label drug use. The safety and ethical considerations related to off-label drug use are different in children than in adults. There is so far no management guideline for pediatric off-label use of drugs in China, and the applicability of foreign guidelines is limited. Establishing a localized evidence-based management guideline for pediatric off-label use of drugs to support the national legislation and clinical practice is of critical importance. Methods We established a guideline working group, including experts from a broad range of disciplines and developed recommendations following the guidance of the World Health Organization Handbook and the Chinese Medical Association. The following themes were identified by questionnaires and expert interviews to be of great concern in the management of off-label drug use in children: general principles and characteristics of management of pediatric off-label drug use; establishment of expert committees; evidence evaluation; risk–benefit assessment; informed consent; monitoring and assessment of the risk; and monitoring and patient education. Two rounds of Delphi surveys were organized to determine the final recommendations of this guideline. We graded the recommendations based on the body of evidence, referring to the evaluation tool of the Evidence-based management (EBMgt) and the Oxford Center for Evidence-Based Medicine: Level of Evidence (March 2009). Results We developed the first guideline for the management of pediatric off-label use of drugs in China. Conclusions The guideline is to offer guidance for pediatricians, pharmacists, medical managers, policymakers, and primary care physicians on how to manage off-label drug use in pediatrics and to provide recommendations for Chinese healthcare policy in the future.

IntroductionAllogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a major strategy to cure patients with acute lymphoblastic leukemia (ALL). The aim of this study was to evaluate whether isolated flow cytometry (FCM)-positive central nervous system (CNS) involvement before allo-HSCT is clinically significant.MethodsThe effects of isolated FCM-positive CNS involvement prior to transplantation on the outcomes of 1406 ALL patients with complete remission (CR) were retrospectively investigated.ResultsPatients were classified into isolated FCM-positive CNS involvement (n=31), cytology-positive CNS involvement (n = 43), and negative CNS involvement (n = 1332) groups. Among the three groups, the 5-year cumulative incidence of relapse (CIR) values were 42.3%, 48.8%, and 23.4%, respectively (P

ObjectiveTo investigate the ability of preoperative neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) to predict postoperative nausea and vomiting (PONV) after total knee arthroplasty (TKA).MethodsThe clinical data of 108 male patients with hemophilia A who underwent TKA an our institution were collected and analyzed. Confounding factors were adjusted by propensity score matching. The best cutoffs of the NLR and PLR were determined by the area under the receiver operating characteristic curve (ROC). The predictive ability of these indexes was assessed by measuring the sensitivity, specificity, and positive and negative likelihood ratios.ResultsThere were significant differences in the use of antiemetics (p = 0.036) and the incidence of nausea (p

BackgroundOwing to the emergence of drugs targeting human epidermal growth factor receptor 2 (HER2), remarkable prognostic enhancement has been seen for patients with HER2-positive breast carcinoma. However, anti-HER2 medicines are applicable merely to individuals with HER2-positive tumors, and the benefit for those with low HER2 expression is unclear. The DESTINY-Breast04 phase III and RC48 clinical trial results showed the benefit of antibody-drug couples for low HER2-expressing individuals with breast carcinoma, challenging the traditional dichotomy between HER2-negative and -positive tumors. Hence, the purposes of the present work are to explore the clinicopathological traits and prognostic differences in the HER2-low expression Chinese population with early-stage breast carcinoma.MethodsData from the database of the Breast Center of the Affiliated Hospital of Qingdao University were collected from January 2008 to December 2017. We screened a total of 4,598 patients, of which 2,837 had HER2-0 tumors and 1,761 had HER2-low tumors. Additionally, clinicopathological characteristics, survival, and prognostic information were obtained. Difference comparisons were made between HER2-0 and HER2-low groups regarding the clinical traits and outcomes.ResultsWe enrolled 4598 patients, with the HR-positive subjects suffering from HER2-low breast carcinoma higher in proportion than the HR-negative patients. In contrast to HER2-0 tumors, the HER2-low tumors were linked to an older median age at diagnosis, T1 tumors, N1 stage, a higher Ki-67 index, as well as inferior histological grade. Insignificant inter-group difference was noted regarding overall survival (OS), although the HER2–0 group exhibited better disease-free survival (DFS) than the HER2-low group for the entire (P = 0.003), lymph node-negative (P = 0.009) and HR-positive (P = 0.007) populations. According to the multivariate regression finding, low HER2 expression was an inferior DFS prognostic factor in the HER2-negative population with early-stage breast cancer (HR,1.33;95% CI, 1.06-1.66; P = 0.013).ConclusionThe clinical traits of the HER2-low carcinomas differed from those of HER2–0 tumors. Despite the insignificant inter-group difference in OS, the differences in DFS were found for the overall, lymph node-negative and HR-positive subjects, suggesting the possibility of HER2-low as an inferior prognostic factor for disease progression in early-stage breast cancer.

Response surface methodology was used to determine the optimum ratio of rice husk dietary fiber, soybean hull dietary fiber, and inulin as 1.40, 1.42, and 3.24%. The effects of compound and single dietary fiber on water holding capacity, gel strength, secondary structure, rheological properties, chemical action force, and microstructure of myofibrillar proteins (MP) gel were investigated. The application of composite dietary fiber significantly (P < 0.05) improved the gel strength, water holding capacity and storage modulus (G′) of MP gel. Fourier transform infrared spectrum analysis shows that the addition of compound dietary fiber can make the gel structure more stable. The effect of dietary fiber complex on the chemical action of MP gel was further studied, and it was found that hydrophobic interaction and disulfide bond could promote the formation of compound gel. By comparing the microstructure of the MP gel with and without dietary fiber, the results showed that the MP gel with compound dietary fiber had smaller pores and stronger structure. Therefore, the rice hull dietary fiber, the soybean hull dietary fiber and the inulin are compounded and added into the low-fat recombinant meat product in a proper proportion, so that the quality characteristics and the nutritional value of the low-fat recombinant meat product can be effectively improved, the rice hull dietary fiber has the potential of being used as a fat substitute, and a theoretical basis is provided for the development of the functional meat product.

There is uncertainty regarding the usefulness of CDK4/6-inhibitor-based therapy for hormone receptor positive (HR+), human epidermal grow factor receptor 2 negative (HER2−), metastatic breast cancer (MBC), when CDK4/6 inhibitor treatment had previously failed. Furthermore, a biomarker for abemaciclib resistance has not been identified. Herein, we reported outcomes for an HR+/HER2− MBC patient diagnosed with multiple myeloma and treated with abemaciclib and exemestane, who had cancer progression after treatment with palbociclib and fulvestrant. Thalidomide was used in conjunction with all treatments. The patient had a good response to abemaciclib and exemestane, with progression-free survival much longer than previously reported. PIK3CA and TP53 mutations were identified after cancer progression following abemaciclib treatment. It is unclear whether thalidomide increased the effectiveness of abemaciclib. Whether benefit can be derived by the use of PI3K inhibitors, after cancer progression, requires further investigation, and this may be best accomplished by the use of next-generation sequencing.

Abstract Aerosol samplers are critical tools for studying indoor and outdoor aerosols. Development and evaluation of samplers is often labor-intensive and time-consuming due to the need to use monodisperse aerosols spanning a range of sizes. This study develops a rapid experimental methodology using polydisperse solid aerosols to evaluate size-resolved aerosol-to-aerosol (AtoA) and aerosol-to-hydrosol (AtoH) sampling efficiencies. Arizona Test Dust (diameter 0.5–20 µm) was generated and dispersed into an aerosol test chamber and two candidate samplers were tested. For the AtoA test, aerosols upstream and downstream of a sampler were measured using an online aerodynamic particle sizer. For the AtoH test, aerosols collected in sampling medium were mixed with a reference sample and then measured by the laser diffraction method. The experimental methodology were validated as an impressive time-saving procedure, with reasonable spatial uniformity and time stability of aerosols in the test chamber and an acceptable accuracy of absolute mass quantification of collected particles. Evaluation results showed that the AGI-30 and the BioSampler sampler had similar size-resolved sampling efficiencies and that efficiencies decreased with decreasing sampling flow rate. The combined evaluation of AtoA and AtoH efficiency provided more comprehensive performance indicators than either test alone. The experimental methodology presented here can facilitate the design and choice of aerosol sampler.

Abstract Background Myelodysplastic syndromes (MDS) are a group of heterogeneous myeloid clonal disorders characterized by ineffective haematopoiesis and immune deregulation. Emerging evidence has shown the effect of bone marrow (BM) endothelial progenitor cells (EPCs) in regulating haematopoiesis and immune balance. However, the number and functions of BM EPCs in patients with different stages of MDS remain largely unknown. Methods Patients with MDS (N = 30), de novo acute myeloid leukaemia (AML) (N = 15), and healthy donors (HDs) (N = 15) were enrolled. MDS patients were divided into lower-risk MDS (N = 15) and higher-risk MDS (N = 15) groups according to the dichotomization of the Revised International Prognostic Scoring System. Flow cytometry was performed to analyse the number of BM EPCs. Tube formation and migration assays were performed to evaluate the functions of BM EPCs. In order to assess the gene expression profiles of BM EPCs, RNA sequencing (RNA-seq) were performed. BM EPC supporting abilities of haematopoietic stem cells (HSCs), leukaemia cells and T cells were assessed by in vitro coculture experiments. Results Increased but dysfunctional BM EPCs were found in MDS patients compared with HDs, especially in patients with higher-risk MDS. RNA-seq indicated the progressive change and differences of haematopoiesis- and immune-related pathways and genes in MDS BM EPCs. In vitro coculture experiments verified that BM EPCs from HDs, lower-risk MDS, and higher-risk MDS to AML exhibited a progressively decreased ability to support HSCs, manifested as elevated apoptosis rates and intracellular reactive oxygen species (ROS) levels and decreased colony-forming unit plating efficiencies of HSCs. Moreover, BM EPCs from higher-risk MDS patients demonstrated an increased ability to support leukaemia cells, characterized by increased proliferation, leukaemia colony-forming unit plating efficiencies, decreased apoptosis rates and apoptosis-related genes. Furthermore, BM EPCs induced T cell differentiation towards more immune-tolerant cells in higher-risk MDS patients in vitro. In addition, the levels of intracellular ROS and the apoptosis ratios were increased in BM EPCs from MDS patients, especially in higher-risk MDS patients, which may be therapeutic candidates for MDS patients. Conclusion Our results suggest that dysfunctional BM EPCs are involved in MDS patients, which indicates that improving haematopoiesis supporting ability and immuneregulation ability of BM EPCs may represent a promising therapeutic approach for MDS patients.

Abstract Background Despite extensive investigations on photothermal therapy, the clinical application is restricted due to poor stability, low therapeutic efficacy of photothermal therapy agents and its affinity loss in the multistep synthesis of delivery carriers. To address this, we designed an IR792-MCN@ZIF-8-PD-L1 siRNA (IM@ZP) nanoparticle drug delivery system. IM@ZP was prepared by in situ synthesis and physical adsorption, followed by characterization. Photothermal conversion ability of IM@ZP was assessed by irradiation of near-infrared (NIR) laser, followed by analysis of its effect on 4T1 cell viability, maturation of dendritic cells (DCs) and the secretion of related cytokines in vitro, and the changes of tumor infiltrating T cells and natural killer (NK) cells in vivo. Subcutaneous 4T1 tumor-bearing mouse and lung metastasis models were established to investigate the role of IM@ZP in killing tumor and inhibiting metastasis in vivo. Results IM@ZP was uniform nanoparticles of 81.67 nm with the characteristic UV absorption peak of IR792, and could effectively adsorb PD-L1 siRNA. Under the irradiation of 808 nm laser, IM@ZP exhibited excellent photothermal performance. IM@ZP could be efficiently uptaken by 4T1 cells, and had high transfection efficiency of PD-L1 siRNA. Upon NIR laser irradiation, IM@ZP effectively killed 4T1 cells, upregulated HSP70 expression, induced DC maturation and increased secretion of TNF-α and IL-6 in vitro. Moreover, in vivo experimental results revealed that IM@ZP enhanced photothermal immunotherapy as shown by promoted tumor infiltrating CD8 + and CD4 + T cells and NK cells, and inhibited tumor growth and lung metastasis. Conclusion Together, biocompatible IM@ZP nanoparticles result in high photothermal immunotherapy efficiency and may have a great potential as a delivery system for sustained cancer therapy. Graphical Abstract

Fermented sausage is popular with consumers because of its unique flavor, rich nutrition and long shelf life. In recent years, It has become a hot topic to endow the fermented sausage with functional characteristics under the premise of ensuring safety. The application of functional starter culture in fermented sausages can effectively inhibit the reproduction of harmful microorganisms, reduce the generation of biological amines and N-nitrosamines, promote the formation of good flavor, inhibit excessive oxidation, reduce blood pressure, and reduce cholesterol content. This paper reviews the research progress of functional starter cultureand functional characteristics of functional starter culture in fermented sausages, and looks forward to its future research trend.

The persistence of spin-polarized fuels is a crucial problem for polarized magnetic and inertial confinement fusion (ICF). The depolarizations of polarized deuterium-tritium (DT) fuels in indirectly driven ICF implosions are investigated with three-dimensional spin transport hydrodynamics simulations. The spin transport equations for deuterons and tritons are derived with the density matrix formalism, which are used to investigate the evolutions of spin eigenstate distributions of DT fuel. The depolarization of DT ions by strong self-generated magnetic fields and the mixings of DT ions with different spin states can be captured by the spin transport equation. The simulation results show that triton polarizations are sensitive to large scale magnetic fields generated by polar mode asymmetries. It is also found that the depolarization of tritons can be reduced by an optimized spin alignment of the polarized fuel. The methods and results can be used to optimize the design of polarized fusion targets and interpret polarized fusion experiments.

Finding field management techniques that increase crop output while protecting soil sustainability is essential for maintaining a long-term food supply in a changing environment. However, comprehensive evaluation of the effects of nitrogen (N) reduction combined with organic fertilizer on grain yield, N use efficiency (NUE), water use efficiency (WUE), and soil organic carbon (SOC) and total N (TN) contents of winter wheat–summer maize double cropping systems in drought-prone areas remains limited. Therefore, a 3-year field experiment (2018–2021) was conducted in a winter wheat–summer maize double cropping system with five treatments: no N fertilizer (CK), conventional farmer fertilization (CF), recommended fertilization (R), organic N substitution of 20% of the recommended synthetic N (R20), and organic N substitution of 40% of the recommended synthetic N (R40). When results were averaged from 2018 to 2021, R20 had the highest annual grain yield, which increased by 42.15%, 7.69%, 7.58%, and 12.50% compared with CK, CF, R, and R40, respectively. Compared with CF, R20 increased winter wheat and summer maize NAE, NPFP, NUE, and WUE. In addition, the soil organic carbon content of R20 and R40 treatment increased with the increase in years. In conclusion, R20 was considered ideal for improving crop yield, promoting soil fertility, and increasing the fertilizer utilization rate in a semiarid winter wheat–summer maize rotation.

BackgroundPatients scheduled for cardiac surgery are often accompanied by cardiac dysfunction and hemodynamic instability. However, the conventional induction strategy for anesthesia using high-dose intravenous anesthetics is often associated with persistent and recurrent hypotension after tracheal intubation. The purpose of this study is to investigate the effects of topical airway anesthesia on the hemodynamic profile of patients undergoing cardiac surgery during the induction period.MethodsThis is a superiority, single-blind, randomized controlled study with two parallel groups. Participants scheduled to undergo elective cardiac surgery will be allocated into two blocks according to the New York Heart Association (NYHA) classification and then randomly assigned to the following two groups at a 1:1 ratio: the conventional induction group and the combined topical airway anesthesia induction group. The combined topical airway anesthesia induction strategy includes aerosol inhalation airway anesthesia, subglottic airway anesthesia, and general anesthesia induction using low-dose intravenous anesthetics. The primary outcome is the area under the curve (AUC) of blood pressure below baseline mean arterial pressure (MAP) from 3 to 15 min after endotracheal intubation. Secondary outcomes include the AUC above baseline MAP and below baseline MAP at other time points, the highest and lowest arterial blood pressure values during the induction period, type and dose of vasoactive drugs, incidence of arrhythmias, cardiac function, and the incidence of postoperative hoarseness and sore throat.DiscussionThe study will explore whether aerosol inhalation airway anesthesia and subglottic airway anesthesia could reduce the incidence and duration of hypotension during the induction period in patients undergoing cardiac surgery.Clinical Trial RegistrationThis trial was registered on www.ClinicalTrials.gov (NCT05323786).

BackgroundIt is controversial whether the short-axis out-of-plane or long-axis in-plane approach is a better needling technique for ultrasound-guidance radial artery cannulation. We aimed to compare the efficacy and safety of the two approaches for ultrasound-guided radial artery cannulation.MethodsA systematic search of Medline, Embase, the Cochrane Library, and Web of Science for relevant articles published until 1 May 2021 was conducted. Randomised controlled trials comparing the long-axis in-plane with short-axis out-of-plane approaches were included. Review Manager software version 5.4, STATA version 14.2, and trial sequential analysis (TSA) version 0.9.5.10 Beta were used for statistical analysis. Risk of bias and methodological quality of all studies included in this review were assessed according to the Cochrane Collaboration tool for the risk of bias. Subgroup analyses and meta-regression were performed to explore sources of heterogeneity.ResultsThe rate of cannula insertion success on the first attempt was similar between the short-axis out-of-plane and long-axis in-plane approaches (RR = 1.03; 95% CI: 0.83 to 1.28; P = 0.79; I2 = 83.0%). No significant differences were observed in total time to successful cannulation between the two approaches (MD = –3.9; 95% CI:-18.30 to 10.49; P = 0.6; I2 = 97%). However, the required information size for the success rate of the first attempt and total time to successful cannulation was not reached.ConclusionIt remains inconclusive whether short-axis out-of-plane is a better choice for radial arterial cannulation than the long-axis in-plane approach. Inexperienced operators may need more attempts and longer ultrasound location time with the short-axis out-of-plane technique.Systematic review registration[https://www.crd.york.ac.uk/prospero/], identifier [CRD42021236098].

BackgroundEnoyl-CoA hydratase domain containing 3 (ECHDC3) increased in CD34+ progenitor cells of acute myeloid leukemia (AML) cells after chemotherapy. However, the prognostic significance and function of ECHDC3 in AML remain to be clarified.MethodsIn the training cohort, 24 AML (non-acute promyelocytic leukemia, APL) patients were enrolled in Peking University People’s Hospital and tested for ECHDC3 in enriched CD34+ cells at diagnosis. In the validation set, 351 bone marrow RNA-seq data of non-APL AML were obtained by two independent online datasets (TCGA-LAML and BEAT-AML). LASSO regression model was conducted to a new prediction model of ECHDC3-related genes. In addition, the ECHDC3 signature was further explored by GO, KEGG, GSEA, and immuno-infiltration analysis. By RNA interference, the function of ECHDC3 in mitochondrial DNA (mt-DNA) transcriptome and chemoresistance was further explored, and the GSE52919 database re-verified the ECHDC3 chemoresistance feature.ResultsBy Kaplan-Meier analysis, patients with ECHDC3high demonstrated inferior overall survival (OS) compared to those with ECHDC3low both in the training (2-year OS, 55.6% vs. 100%, p = 0.011) and validation cohorts (5-year OS, 9.6% vs. 24.3%, p = 0.002). In addition, ECHDC3high predicted inferior OS in the subgroup of patients with ELN 2017 intermediated (int) risk (5-year OS, 9.5% vs. 26.3%, p = 0.039) or FLT3+NPM1− adverse (adv) risk (4-year OS, 6.4% vs. 31.8%, p = 0.003). In multivariate analysis, ECHDC3 was an independent risk factor of inferior OS (HR 1.159, 95% CI 1.013–1.326, p = 0.032). In the prediction model combining ECHDC3 and nine selected genes (RPS6KL1, RELL2, FAM64A, SPATS2L, MEIS3P1, CDCP1, CD276, IL1R2, and OLFML2A) by Lasso regression, patients with high risk showed inferior 5-year OS (9.3% vs. 23.5%, p < 0.001). Bioinformatic analysis suggested that ECHDC3 alters the bone marrow microenvironment by inducing NK, resting mast cell, and monocyte differentiation. Knocking down ECHDC3 in AML cells by RNAi promoted the death of leukemia cells with cytarabine and doxorubicin.ConclusionThese bioinformatic analyses and experimental verification indicated that high ECHDC3 expression might be a poor prognostic biomarker for non-APL AML, which might be a potential target for reverting chemoresistance.

BackgroundNowadays, immunotherapy targeting immune checkpoint receptors is one of the cornerstones of systemic treatment in melanoma. Homologous recombination repair (HRR) is one of the DNA damage response (DDR) pathways, which has been proved to correlate with the efficacy of platinum-based chemotherapy, PARP inhibitor therapy, and immunotherapy in a variety of cancers. However, their predictive value of HRR remained unknown in patients with advanced melanoma.MethodsData of advanced melanoma patients from an independent cohort (Samstein2018) were used to analyze the correlation with immunogenic markers and the prognostic effect of HRR on immunotherapy, and another four cohorts (pooled cohort: Miao2018, Allen 2015, Hugo2016, and Synder2014) were used for validation. Immune infiltration cell scores analyzed by TCGA-SKCM cohort were used to explore potential mechanisms related to the immune microenvironment.ResultsCompared to patients with an HRR wild type (HRRwt), those with HRR mutations (HRRmut) in anti-CTLA-4-treated patients of the Samstein2018 cohort had higher tumor mutation burden (TMB; P = 0.0041) and longer median overall survival (mOS; P = 0.0094). In terms of results validation, it was also confirmed that the mOS (P = 0.0014) of HRRmut patients receiving anti-CTLA-4 therapy was significantly better than that of HRRwt patients in the pooled cohort, and objective response rates (ORR; P = 0.0053) were also found to be significant. However, there was no significant difference in mOS between HRRmut patients who received anti-PD-1/L1 therapy and HRRwt patients in either the discovery (Samstein2018 cohort, P = 0.94) or validation (pooled cohort, P = 0.96) set. Exploratory analysis found that although HRRmut patients showed no significant difference in mOS between anti-CTLA-4 and anti-PD-1/L1 therapy (P = 0.79), the mOS value of the anti-CTLA-4 therapy group (31.7 months) in HRRmut patients was numerically superior to the anti-PD-1/L1 therapy group (27.5 months). In contrast, the mOS of the anti-CTLA-4 therapy group was significantly lower than that of the anti-PD-1/L1 therapy group (12.4 vs. 32.0 months) in HRRwt patients. In addition, transcriptome profiling analysis revealed that the 29 (65.9%)-gene mutation of the HRR pathway associated with reshaping of the immunological microenvironment in melanoma.ConclusionsHRR mutations were associated with a higher TMB level, and better anti-CTLA-4 therapy outcomes. HRR may serve as an independent predictor of anti-CTLA-4 therapy efficacy in patients with advanced melanoma and their clinical value warrants further investigation.

BackgroundTranscatheter occlusion of patent foramen ovale (PFO) has become a recognized treatment option for high-risk PFO-related diseases. However, traditional metal occluders have some disadvantages, such as permanent retention in the body, abrasion of tissues, and obstruction of access to the left side of the heart for interventional procedures. With biodegradable occluders that release non-toxic degradation products and are absorbable by the body, the risk of long-term complications could be greatly reduced. The experimental results of using a PFO-degradable occluder in beagle dogs in early stages, independently developed by Shanghai Mallow Medical Instrument Co., Ltd., showed that the occluding umbrella disc network was degraded 6 months after occlusion. The occluder also showed good memory, biocompatibility, and mechanical properties.MethodsAs one of the multi-center research units, this prospective Phase III clinical trial study included 16 patients with PFO-related complications who were treated with a degradable occluder. The follow-up period lasted for 12 months to analyze the echocardiographic characteristics and procedural feasibility.ResultsThe immediate success rate of the procedure was 100% with no serious complications. Postoperative color Doppler transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) at 12 months showed that one patient with atrial septal aneurysm (ASA) had a residual shunt at the edge of the occluder, and contrast transcranial Doppler (cTCD) showed that all patients were grade I or 0 right-to-left shunts (RLS), indicating that the occlusion success rate was 100%. The occluder gradually degraded after the procedure, particularly when the umbrella disc structure became vague, and the size of the occluder decreased significantly 6 months after occlusion.ConclusionsPFO closure with a Mallow degradable occluder has a high plugging success rate, is safe and effective, and has no serious complications. However, for PFO closure with special anatomical features, further research with a larger sample size is required. TTE can dynamically, conveniently, and accurately observe the entire degradation process of the occluder.Clinical Trial RegistrationChiCTR1900024036.

This paper briefly analyzes the current development of lightweight design and applications for hydraulic support in the coal mines. Specifically, the comparative investigations of lightweight design demonstrate the potential application for carbon fiber reinforced composites (CFRP) in the production and manufacturing process of hydraulic support. After analyzing the major industrial applications of CFRP in the three main parts, hydraulic structure, cylinder and special frames, it demonstrated the feasibility of the potential CFRP exploitations in the future research of hydraulic support for coal mining sites.

In highland pastures, grazing is a common method for managing sheep due to the abundance of grassland resources. However, it is easy for sheep to encounter situations such as stray, deviation and attacks from natural enemies; therefore, the remote monitoring of sheep in the highland pastures is an urgent problem to be solved. This paper proposes a mid-infrared sheep segmentation method based on the multi-level region fusion maximum between-class variance algorithm, i.e., OTSU algorithm, for sheep surveillance. First, a mean adjustment OTSU algorithm is designed to better distinguish the interference areas in the background. Second, the Butterworth high-pass filter is combined with the mean adjustment OTSU segmentation algorithm to remove the high-brightness interference areas in the background with slow gray intensity changes. Finally, after filtering out the large area background and small stray point, the two processed results above are fused with the AND logical operation to obtain a final segmentation result. Our algorithm is evaluated using three objective evaluation indicators: the root mean square error (RMSE), structural similarity index metric (SSIM), and peak signal to noise ratio (PSNR). The RMSE, SSIM, PSNR of highland wetland image are 0.43187, 0.99526, and 29.16353. The RMSE, SSIM, PSNR of sandy land image are 0.87472, 0.98388, and 23.87430. The RMSE, SSIM, PSNR of grassland image are 0.65307, 0.99437, and 30.33159. The results show that our algorithm can meet the requirements for the mid-infrared sheep segmentation in highland pastures.

Abstract Dysfunctional megakaryopoiesis hampers platelet production, which is closely associated with thrombocytopenia (PT). Macrophages (MФs) are crucial cellular components in the bone marrow (BM) microenvironment. However, the specific effects of M1 MФs or M2 MФs on regulating megakaryocytes (MKs) are largely unknown. In the current study, aberrant BM-M1/M2 MФ polarization, characterized by increased M1 MФs and decreased M2 MФs and accompanied by impaired megakaryopoiesis-supporting abilities, was found in patients with PT post-allotransplant. RNA-seq and western blot analysis showed that the PI3K-AKT pathway was downregulated in the BM MФs of PT patients. Moreover, in vitro treatment with PI3K-AKT activators restored the impaired megakaryopoiesis-supporting ability of MФs from PT patients. Furthermore, we found M1 MФs suppress, whereas M2 MФs support MK maturation and platelet formation in humans. Chemical inhibition of PI3K-AKT pathway reduced megakaryopoiesis-supporting ability of M2 MФs, as indicated by decreased MK count, colony-forming unit number, high-ploidy distribution, and platelet count. Importantly, genetic knockdown of the PI3K-AKT pathway impaired the megakaryopoiesis-supporting ability of MФs both in vitro and in a MФ-specific PI3K-knockdown murine model, indicating a critical role of PI3K-AKT pathway in regulating the megakaryopoiesis-supporting ability of M2 MФs. Furthermore, our preliminary data indicated that TGF-β released by M2 MФs may facilitate megakaryopoiesis through upregulation of the JAK2/STAT5 and MAPK/ERK pathways in MKs. Taken together, our data reveal that M1 and M2 MФs have opposing effects on MKs in a PI3K-AKT pathway-dependent manner, which may lead to new insights into the pathogenesis of thrombocytopenia and provide a potential therapeutic strategy to promote megakaryopoiesis.

BackgroundUveal melanoma (UM) is the most frequent primary intraocular tumor in adults. This study aims to develop a nomogram and an individualized web-based calculator to predict the overall survival (OS) of elderly patients with UM.MethodsPatients aged more than 60 years and diagnosed with UM were derived from the Surveillance, Epidemiology, and End Results (SEER) database during 2004–2015. The selected patients were randomly divided into training and validation cohorts. In the training cohort, the univariate and multivariate Cox analyses were carried out to determine the independent prognostic factors, and the predictors were integrated to establish a nomogram for predicting the 1-, 2-, and 3-year OS of elderly patients with UM. The discrimination of the nomogram was validated by receiver operating characteristic (ROC) curves and the area under the curve (AUC). The clinical practicability and accuracy of the nomogram were evaluated by the calibration curves and decision curve analysis (DCA). A web-based survival calculator was then constructed using a fitted survival prediction model (https://yuexinupup.shinyapps.io/DynNomapp/).ResultsA total of 1,427 patients with UM were included in this study. Age, T stage, N stage, M stage, marital status, sex, and radiotherapy (RT) were identified as independent prognostic factors. Based on the abovementioned factors, the nomogram was then constructed. The AUC values of the nomogram predicting 1-, 2-, and 3-year OS were 0.841, 0.801, and 0.768 in the training cohort, and 0.745, 0.717, and 0.710 in the validation cohort, respectively. The calibration curves and DCA also indicated the good performance of the predictive model.ConclusionThis study established and validated a novel nomogram risk stratification model and a web-based survival rate calculator that can dynamically predict the long-term OS for elderly patients with UM.

Pediatric acute lymphoblastic leukemia (ALL) is the most common subtype of childhood leukemia, which is characterized by the abnormal proliferation and accumulation of immature lymphoid cell in the bone marrow. Although the long-term survival rate for pediatric ALL has made significant progress over years with the development of contemporary therapeutic regimens, patients are still suffered from relapse, leading to an unsatisfactory outcome. Since the immune system played an important role in the progression and relapse of ALL, immunotherapy including bispecific T-cell engagers and chimeric antigen receptor T cells has been demonstrated to be capable of enhancing the immune response in pediatric patients with refractory or relapsed B-cell ALL, and improving the cure rate of the disease and patients’ quality of life, thus receiving the authorization for market. Nevertheless, the resistance and toxicities associated with the current immunotherapy remains a huge challenge. Novel therapeutic options to overcome the above disadvantages should be further explored. In this review, we will thoroughly discuss the emerging immunotherapeutics for the treatment of pediatric ALL, as well as side-effects and new development.

Hypervirulent Klebsiella pneumoniae (hvKp) can cause life-threatening community-acquired infections among healthy young individuals and is thus of concern for global dissemination. In this study, a mouse model of acute primary hvKp pneumonia was established via aerosolized intratracheal (i.t.) inoculation, laying the foundation for conducting extensive studies related to hvKp. Subsequently, a time-course transcriptional profile was created of the lungs from the mouse model at 0, 12, 24, 48 and 60 hours post-infection (hpi) using RNA Sequencing (RNA-Seq). RNA-Seq data were analyzed with the use of Mfuzz time clustering, weighted gene co-expression network analysis (WGCNA) and Immune Cell Abundance Identifier for mouse (ImmuCellAI-mouse). A gradual change in the transcriptional profile of the lungs was observed that reflected expected disease progression. At 12 hpi, genes related to acute phase inflammatory response increased in expression and lipid metabolism appeared to have a pro-inflammatory effect. At 24 hpi, exacerbation of inflammation was observed and active IFN-γ suggested that signaling promoted activation and recruitment of macrophages occurred. Genes related to maintaining the structural integrity of lung tissues showed a sustained decrease in expression after infection and the decrease was especially marked at 48 hpi. TNF, IL-17, MAPK and NF-kB signaling pathways may play key roles in the immunopathogenesis mechanism at all stages of infection. Natural killer (NK) cells consistently decreased in abundance after infection, which has rarely been reported in hvKp infection and could provide a new target for treatment. Genes Saa1 and Slpi were significantly upregulated during infection. Both Saa1, which is associated with lipopolysaccharide (LPS) that elicits host inflammatory response, and Slpi, which encodes an antimicrobial protein, have not previously been reported in hvKp infections and could be important targets for subsequent studies. To t our knowledge, this paper represents the first study to investigate the pulmonary transcriptional response to hvKp infection. The results provide new insights into the molecular mechanisms underlying the pathogenesis of hvKp pulmonary infection that can contribute to the development of therapies to reduce hvKp pneumonia.

Spin-triplet energy transfer in molecular systems underlies important applications for chemistry and devices. Here, the authors investigate the triplet energy transfer in CdSe quantum dots with varying ZnS shell thicknesses to surface-anchored anthracene molecules and identify a stepwise mechanism mediated by endothermic charge-transfer states.

USA300, a dominant clone of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA), is circulating globally and can cause necrotizing pneumonia with high morbidity and mortality. To further reveal the host anti-MRSA infection immune response, we established a mouse model of acute primary MRSA pneumonia challenged with aerosols of the USA300 clone. A time-course transcriptome analysis of the lungs collected at 0, 12, 24, 48 and 96 h post-infection (hpi) was conducted using RNA sequencing (RNA-seq) and multiple bioinformatic analysis methods. The change trend of histopathology and five innate immune cell (neutrophils, mononuclear cells, eosinophils, macrophages, DC cells) proportions in the lungs after infection was also examined. We observed a distinct acute pulmonary recovery process. A rapid initiation period of inflammation was present at 12 hpi, during which the IL-17 pathway dominantly mediated inflammation and immune defense. The main stages of host inflammatory response occurred at 24 and 48 hpi, and the regulation of interferon activation and macrophage polarization played an important role in the control of inflammatory balance at this stage. At 96 hpi, cellular proliferation processes associated with host repair were observed, as well as adaptive immunity and complement system responses involving C1q molecules. More importantly, the data provide new insight into and identify potential functional genes involved in the checks and balances occurring between host anti-inflammatory and proinflammatory responses. To the best of our knowledge, this is the first study to investigate transcriptional responses throughout the inflammatory recovery process in the lungs after MRSA infection. Our study uncovers valuable research targets for key regulatory mechanisms underlying the pathogenesis of MRSA lung infections, which may help to develop novel treatment strategies for MRSA pneumonia.

Bone marrow (BM) endothelial progenitor cell (EPC) damage of unknown mechanism delays the repair of endothelial cells (EC) and recovery of hematopoiesis after chemo-radiotherapy. We found increased levels of the glycolytic enzyme PFKFB3 in the damaged BM EPC of patients with poor graft function, a clinical model of EPC damage-associated poor hematopoiesis after allogeneic hematopoietic stem cell transplantation. Moreover, in vitro the glycolysis inhibitor 3-(3-pyridinyl)- 1-(4-pyridinyl)-2-propen-1-one (3PO) alleviated the damaged BM EPC from patients with poor graft function. Consistently, PFKFB3 overexpression triggered BM EPC damage after 5-fluorouracil treatment and impaired hematopoiesis-supporting ability in vitro. Mechanistically, PFKFB3 facilitated pro-apoptotic transcription factor FOXO3A and expression of its downstream genes, including p21, p27, and FAS, after 5-fluorouracil treatment in vitro. Moreover, PFKFB3 induced activation of NF-κB and expression of its downstream adhesion molecule E-selectin, while it reduced hematopoietic factor SDF-1 expression, which could be rescued by FOXO3A silencing. High expression of PFKFB3 was found in damaged BM EC of murine models of chemo-radiotherapy-induced myelosuppression. Furthermore, a murine model of BM EC-specific PFKFB3 overexpression demonstrated that PFKFB3 aggravated BM EC damage, and impaired the recovery of hematopoiesis after chemotherapy in vivo, effects which could be mitigated by 3PO, indicating a critical role of PFKFB3 in regulating BM EC damage. Clinically, PFKFB3-induced FOXO3A expression and NF-κB activation were confirmed to contribute to the damaged BM EPC of patients with acute leukemia after chemotherapy. 3PO repaired the damaged BM EPC by reducing FOXO3A expression and phospho-NF-κB p65 in patients after chemotherapy. In summary, our results reveal a critical role of PFKFB3 in triggering BM EPC damage and indicate that endothelial-PFKFB3 may be a potential therapeutic target for myelosuppressive injury.

Abstract The leaf angle (LA), plant height (PH), and ear height (EH) are key plant architectural traits influencing maize (Zea mays L.) yield. However, their genetic determinants have not yet been well‐characterized. Here, we developed a maize advanced backcross‐nested association mapping population in Henan Agricultural University (HNAU‐NAM1) comprised of 1,625 BC1F4/BC2F4 lines. These were obtained by crossing a diverse set of 12 representative inbred lines with the common GEMS41 line, which were then genotyped using the MaizeSNP9.4K array. Genetic diversity and phenotypic distribution analyses showed considerable levels of genetic variation. We obtained 18–88 quantitative trait loci (QTLs) associated with LA, PH, and EH by using three complementary mapping methods, named as separate linkage mapping, joint linkage mapping, and genome‐wide association studies. Our analyses enabled the identification of ten QTL hot‐spot regions associated with the three traits, which were distributed on nine different chromosomes. We further selected 13 major QTLs that were simultaneously detected by three methods and deduced the candidate genes, of which eight were not reported before. The newly constructed HNAU‐NAM1 population in this study will further broaden our insights into understanding of genetic regulation of plant architecture, thus will help to improve maize yield and provide an invaluable resource for maize functional genomics and breeding research.

CMV infection remains an important cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Several investigators have reported that adaptive NKG2C+ NK cells persistently expand during CMV reactivation. In our study, 2 cohorts were enrolled to explore the relationships among the NKG2C genotype, NKG2C+ NK cell reconstitution, and CMV infection. Multivariate analysis showed that donor NKG2C gene deletion was an independent prognostic factor for CMV reactivation and refractory CMV reactivation. Furthermore, adaptive NKG2C+ NK cells’ quantitative and qualitative reconstitution, along with their anti-CMV function after transplantation, was significantly lower in patients grafted with NKG2Cwt/del donor cells than in those grafted with NKG2Cwt/wt donor cells. At day 30 after transplantation, quantitative reconstitution of NKG2C+ NK cells was significantly lower in patients with treatment-refractory CMV reactivation than in patients without CMV reactivation and those with nonrefractory CMV reactivation. In humanized CMV-infected mice, we found that, compared with those from NKG2Cwt/del donors, adaptive NKG2C+ NK cells from NKG2Cwt/wt donors induced earlier and stronger expansion of NKG2C+ NK cells as well as earlier and stronger CMV clearance in vivo. In conclusion, donor NKG2C homozygosity contributes to CMV clearance by promoting the quantitative and qualitative reconstruction of adaptive NKG2C+ NK cells after haploidentical allo-HSCT.