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BackgroundNirmatrelvir-ritonavir (Paxlovid) has received emergency use authorization from the US Food and Drug Administration owing to its effectiveness and safety. However, data on the effectiveness and safety of Paxlovid use in COVID-19 patients with onset of more than 5 days are lacking.MethodsA real-world retrospective study was performed during the outbreak involving the SARS-CoV-2 BA.5.2 subvariant. Hospitalized COVID-19 patients (including mild, moderate, severe and critical cases) were divided into three groups: Paxlovid treatment within (Group A) or more than (Group B) 5 days of COVID-19 onset and no Paxlovid treatment during more than 5 days of COVID-19 onset with only basic symptomatic treatment (Group C). Endpoints were all-cause 28-day mortality, improvement in clinical classification, and a composite endpoint of disease progression, viral load and virus elimination time. Safety was assessed by comparing adverse events reported during treatment in each group.ResultsDuring the period, 248 hospitalized COVID-19 patients, including 55 in Group A, 170 in Group B, and 23 in Group C, were enrolled. There were no significant differences in the clinical classification improvement rate [80.0% (16/20) vs. 81.3% (52/64), p = 1.000; 60.0% (21/35) vs. 55.7% (59/106), p = 0.653, respectively] or all-cause 28-day mortality [0% (0/20) vs. 1.6% (1/64), p = 1.000; 11.4% (4/35) vs. 6.6% (7/106), p = 0.576, respectively] between Groups A and B for nonsevere and severe cases. However, the clinical classification improvement rate in Group B was markedly higher than that in Group C [81.3% (52/64) vs. 50.0% (6/12), p = 0.049] among nonsevere cases. Cycle threshold values of the N and ORF genes in Group B were significantly increased after Paxlovid treatment [31.14 (IQR 26.81–33.93) vs. 38.14 (IQR 36.92–40.00), p < 0.001; 31.33 (IQR 26.00–33.47) vs. 38.62 (IQR 35.62–40.00), p < 0.001, respectively]. No significant differences in reported adverse events of neurological disease (p = 0.571), liver injury (p = 0.960) or kidney injury (p = 0.193) between Group A and Group B were found.ConclusionPaxlovid treatment within 10 days of onset can shorten the disease course of COVID-19 by reducing the viral load. Paxlovid is effective and safe in treating COVID-19 with onset of more than five or even 10 days when patients have a high viral load.

BackgroundMicrovascular invasion (MVI) stands as a pivotal pathological hallmark of hepatocellular carcinoma (HCC), closely linked to unfavorable prognosis, early recurrence, and metastatic progression. However, the precise mechanistic underpinnings governing its onset and advancement remain elusive.MethodsIn this research, we downloaded bulk RNA-seq data from the TCGA and HCCDB repositories, single-cell RNA-seq data from the GEO database, and spatial transcriptomics data from the CNCB database. Leveraging the Scissor algorithm, we delineated prognosis-related cell subpopulations and discerned a distinct MVI-related malignant cell subtype. A comprehensive exploration of these malignant cell subpopulations was undertaken through pseudotime analysis and cell-cell communication scrutiny. Furthermore, we engineered a prognostic model grounded in MVI-related genes, employing 101 algorithm combinations integrated by 10 machine-learning algorithms on the TCGA training set. Rigorous evaluation ensued on internal testing sets and external validation sets, employing C-index, calibration curves, and decision curve analysis (DCA).ResultsPseudotime analysis indicated that malignant cells, showing a positive correlation with MVI, were primarily concentrated in the early to middle stages of differentiation, correlating with an unfavorable prognosis. Importantly, these cells showed significant enrichment in the MYC pathway and were involved in extensive interactions with diverse cell types via the MIF signaling pathway. The association of malignant cells with the MVI phenotype was corroborated through validation in spatial transcriptomics data. The prognostic model we devised demonstrated exceptional sensitivity and specificity, surpassing the performance of most previously published models. Calibration curves and DCA underscored the clinical utility of this model.ConclusionsThrough integrated multi-transcriptomics analysis, we delineated MVI-related malignant cells and elucidated their biological functions. This study provided novel insights for managing HCC, with the constructed prognostic model offering valuable support for clinical decision-making.

Abstract Background/Objective With the development of society, pulmonary fungal diseases, represented by pulmonary aspergillosis and pulmonary cryptococcosis, have become increasingly common. However, there is a lack of clear understanding regarding coinfection by these two types of fungi in immunocompetent individuals. Methods A retrospective study from 2014 to 2022 and a systematic literature review of original articles published in English were performed. Patients with pulmonary cryptococcosis complicated with pulmonary aspergillosis including 5 in the retrospective study and 6 in the systematic literature review. Result The diagnosis of concurrent pulmonary cryptococcosis and pulmonary aspergillosis in patients was confirmed through repeated biopsies or surgical resection. Pulmonary cryptococcosis is often diagnosed initially (6/11, 55%), while the diagnosis of pulmonary aspergillosis is established when the lesions become fixed or enlarged during treatment. Transbronchial lung biopsy (3/11, 27%), thoracoscopic lung biopsy (2/11, 18%), and percutaneous aspiration biopsy of the lung (1/11, 9%) were the main methods to confirm concurrent infection. Most patients were treated with voriconazole, resulting in a cure for the coinfection (6/11, 55%). Conclusion Pulmonary cryptococcosis complicated with pulmonary Aspergillus is an easily neglected mixed fungal infection. During the treatment of lesion enlargement in clinical cryptococcus, we need to watch out for Aspergillus infection.

BackgroundChronic obstructive pulmonary disease (COPD) is a prevalent condition that significantly impacts public health. Unfortunately, there are few effective treatment options available. Mendelian randomization (MR) has been utilized to repurpose existing drugs and identify new therapeutic targets. The objective of this study is to identify novel therapeutic targets for COPD.MethodsCis-expression quantitative trait loci (cis-eQTL) were extracted for 4,317 identified druggable genes from genomics and proteomics data of whole blood (eQTLGen) and lung tissue (GTEx Consortium). Genome-wide association studies (GWAS) data for doctor-diagnosed COPD, spirometry-defined COPD (Forced Expiratory Volume in one second [FEV1]/Forced Vital Capacity [FVC]

BackgroundThe prevalence of invasive pulmonary aspergillosis (IPA) among patients with chronic obstructive pulmonary disease (COPD) is steadily increasing, leading to high mortality. Although early diagnosis can significantly reduce mortality, the efficacy of current diagnostic methods is limited. Consequently, there is a need for novel approaches for early IPA detection.MethodsThis retrospective study involved 383 hospitalized COPD patients with GOLD stages III and IV. The IPA group (67 patients) and non-IPA group (316 patients) were identified at the First Affiliated Hospital of Guangzhou Medical University between January 2016 and February 2022. We analyzed common serological indicators in our hospital to identify predictive indicators for the early diagnosis of IPA in COPD patients.ResultsThe sensitivity and specificity of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), procalcitonin (PCT), lactate dehydrogenase (LDH), and ceruloplasmin (CER) for diagnosing IPA in COPD patients were as follows: CRP (91.2%, 57.7%), ESR (77.5%, 73.0%), PCT (60.5%, 71.4%), LDH (50.0%, 88.8%), and CER (60.7%, 74.3%). Combinations of biomarkers, such as CRP-ESR, CRP-LDH, ESR-LDH, ESR-CER, and LDH-CER, showed promising diagnostic potential, with larger area under the curve (AUC) values for IPA diagnosis in COPD patients. However, no statistically significant difference was observed between the diagnostic efficacy of single biomarkers and combined biomarkers. Notably, compared to those in the unassisted ventilation group, the patients in the assisted ventilation group (including noninvasive ventilation and tracheal intubation/incision-assisted ventilation group) exhibited significantly greater PCT and LDH levels, while the CER significantly decreased (p=0.021). There were no significant differences in biomarker levels between the ICU group and the non-ICU group. CRP (p

Objectives We assessed the efficacy of a 3-week primary or salvage caspofungin regimen in patients with chronic obstructive pulmonary disease (COPD) and concomitant proven or suspected invasive pulmonary aspergillosis (IPA). Methods Forty-four patients were treated with an initial loading caspofungin dose of 70 mg, followed by a daily dose of 50 mg for 20 days. The main efficacy endpoint was clinical effectiveness. Secondary endpoints included the clinical efficacy of caspofungin after 1 week, therapeutic efficacy based on the European Organization for Research and Treatment of Cancer and Mycoses Study Group Education and Research Consortium (EORTC/MSG) criteria, the sensitivity of different Aspergillus strains to caspofungin in vitro , and the safety of caspofungin. Results An assessment of 42 patients in the intention-to-treat group revealed efficacy rates of 33.33% within 1 week and 38.10% within 3 weeks. According to the EORTC/MSG criteria, the treatment success rate was 38.10%. The success rate of first-line treatment was 54.76%, whereas salvage treatment had a success rate of 45.24%. No adverse events were reported among the participants. Conclusions Caspofungin is effective and safe as an initial or salvage treatment for patients with IPA and COPD.

Abstract Objective Giant cervical disc herniation (GCDH) was defined as a herniated intervertebral disc that accounted for more than 50% of the spinal canal. The purpose of this study was to analyse the feasibility of anterior cervical discectomy and fusion (ACDF) for the treatment of GCDH. Methods Patient demographic and imaging data, clinical results, and perioperative complications were analysed retrospectively. Results A total of 23 patients were included in the study. Spinal cord recovery pulsation was observed under a microscope in all cases. Postoperative magnetic resonance imaging showed complete decompression of the spinal cord and no residual intervertebral disc. The patients were followed up for 12 to 18 months. The average visual analogue scale score and Neck Disability Index decreased from 8.6 ± 0.5 and 86.0 ± 2.7% to 2.2 ± 0.2 and 26.7 ± 2.0%, respectively, three days after surgery. The average Japanese Orthopedic Association score increased from 6.9 ± 2.1 to 13.9 ± 1.1. The cervical spinal cord function improvement rate was 69.3%. No neurological complications after surgery were observed. Conclusion This study shows that ACDF is feasible for the treatment of GCDH disease. The results indicate that this approach can be used to safely remove herniated disc fragments, effectively relieve compression of the spinal cord, and improve neurological function.

Intelligent Phytoprotection is an important direction for the modern development of plant protection related disciplines, and its essence is the innovative application of new generation information technology industry, high-end equipment manufacturing industry, and digital industry related technologies in the traditional plant protection field. This article first identifies 224 International Patent Classification (IPC) Main groups in the field of intelligent phytoprotection technology based on the International Patent Classification System. And then combines with China’s industrial policy practice, we explore the impact of industrial policy on the application number of invention patents in the field of intelligent phytoprotection technology using the Difference-in-difference (DID) method and the Synthetic DID method. The study results showed that the implementation of industrial policy can significantly promote the patent application activities in the intelligent phytoprotection treatment group, with an average increase of 517 invention patent applications compared to the control group that is not affected by the policy. The research conclusion of this article suggests that for countries and regions, industrial policies are an important tool for promoting the innovation and development of intelligent phytoprotection related technologies.

A previously unknown Nocardia species was isolated from the lung tissue and bronchoalveolar lavage fluid (BALF) of a 58-year-old woman with bronchiectasis and recurrent pneumonia. This Nocardia (GZ2020T), which grew readily in Columbia blood agar and could induce pneumonia in a mouse model, represents a novel Nocardia species, and its closest known relatives are Nocardia anaemiae NBRC 100462T, Nocardia pseudovaccinii NBRC 100343T and Nocardia vinacea NBRC 16497T. However, unlike all previously known species, GZ2020T is the first genus of Nocardia spp. that is not susceptible to multiple drugs but does show susceptibility to linezolid and moxifloxacin, and thus, GZ2020T potentially represents a substantial health threat to patients with bronchiectasis and immunocompromised individuals. Although the original pathogen source and method of spreading remain uncertain, a mode of transmission from the environment to humans could exist. Vigilance with respect to its spread in the population and the transmission of antibiotic resistance genes in the environment should be maintained.

Research on how thermal exposure affects the microstructure and mechanical properties of the Ti–48Al–3Nb–1.5Ta (at. %) alloy, which is prepared via powder hot isostatic pressing (P–HIP), is essential since this low-density alloy shows promise for use in high-temperature applications, particularly for aero-engines, which require long-term stable service. In this study, a P–HIP Ti–48Al–3Nb–1.5Ta (at. %) alloy was exposed to high temperatures for long durations. The phase, microstructure and mechanical properties of the P–HIP Ti–48Al–3Nb–1.5Ta alloy after thermal exposure under different conditions were analyzed using XRD, SEM, EBSD, EPMA, TEM, nanomechanical testing and tensile testing. The surface scale is composed of oxides and nitrides, primarily Al2O3, TiO2, and TiN, among which Al2O3 is preferentially generated and then covered by rapidly growing TiO2 as the thermal exposure duration increases. The nitrides appear later than the oxides and exist between the oxides and the substrate. With increasing exposure temperature and duration, the surface scale becomes more continuous, TiO2 particles grow larger, and the oxide layer thickens or even falls off. The addition of Ta and Nb can improve the oxidation resistance because Ta5+ and Nb5+ replace Ti4+ in the rutile lattice and weaken O diffusion. Compared with the P–HIP Ti–48Al–3Nb–1.5Ta alloy, after thermal exposure, the grain size does not increase significantly, and the γ phase increases slightly (by less than 3%) with the decomposition of the α2 phase. With increasing thermal exposure duration, the γ phase exhibits discontinuous coarsening (DC). Compared with the P–HIP Ti–48Al–3Nb–1.5Ta alloy, the hardness increases by about 2 GPa, the tensile strength increases by more than 50 MPa, and the fracture strain decreases by about 0.1% after thermal exposure. When the depth extends from the edge of the thermally exposed specimens, the hardness decreases overall.

In the process of oil and gas extraction and transportation, the aggregation and deposition of hydrate particles within oil and gas pipelines is a primary cause of pipeline blockage, with adhesion being the fundamental cause of hydrate particle aggregation. With the development of crude oil and natural gas transportation technology, the application of pipeline internal coating technology is becoming increasingly widespread. It is essential to compare the physical properties and practicality of various coating materials and conduct preliminary screening. Adhesion experiments on coating materials suitable for the conditions of oil and gas pipeline transport have been conducted. The experimental results indicate that the PTFE/PPS composite coating has advantages in reducing the adhesive force of hydrate particles under low temperatures and different degrees of subcooling. As the degree of subcooling increases, the adhesive force between the hydrate particles and the PTFE/PPS composite coating substrate gradually increases from 8.36 mN·m−1 to 10.26 mN·m−1. With a 3 °C increase in subcooling, the adhesion force increases by 1.92 mN·m−1, which is about 68% lower on average compared to an uncoated substrate. Epoxy resin E-51 coatings and polyurea coatings also demonstrate certain anti-hydrate adhesion properties, but their performance is slightly inferior compared to the PTFE/PPS composite coating. These research results can provide an important reference for hydrate prevention technology in oil and gas transportation pipelines.

Background: Rapid and reliable diagnostic methods for Aspergillus fumigatus infection are urgently needed. Clustered regularly interspaced short palindromic repeat (CRISPR)-associated protein 13a (Cas13a) has high sensitivity and specificity in the diagnosis of viral infection. However, its potential use in detecting A. fumigatus remains unexplored. A highly sensitive and specific method using the CRISPR/Cas13a system was developed for the reliable and rapid detection of A. fumigatus. Methods: The conserved internal transcribed spacer (ITS) region of A. fumigatus was used to design CRISPR-derived RNA (crRNA) and the corresponding recombinase polymerase amplification (RPA) primer sequence with the T7 promoter for the CRISPR assay. Twenty-five clinical isolates and 43 bronchoalveolar lavage fluid (BALF) remaining from routine examinations of patients with confirmed pulmonary aspergillosis were collected to further validate the CRISPR assay. Results: No amplification signal was observed when genomic DNA from closely clinically related Aspergillus species, such as Aspergillus flavus, Aspergillus niger, and Aspergillus terreus, as well as Monascus purpureus Went and Escherichia coli, was tested by this assay, and the detection limit for A. fumigatus was 3 copies in a single reaction system. Validation experiments using the 25 clinical isolates demonstrated 91.7% specificity for the A. fumigatus section, and the sensitivity was 100% when first-generation sequencing was used as the standard. There was no significant difference between the PCR and CRISPR methods (P = 1.0), and the diagnosis results of the two methods were consistent (Kappa = 0.459, P = 0.003). Conclusion: The study offers a new validated CRISPR/Cas13a technique for A. fumigatus detection, providing a simple, rapid and affordable test that is ready for application in the diagnosis of A. fumigatus infection.

Abstract Background Etiological diagnosis is a key step in the treatment of patients with rare pulmonary mycosis, and the lack of understanding of this disease and lack of specific markers for the detection of rare species, such as Exophiala dermatitidis, add to the difficulty in diagnosing the condition. Therefore, improving the diagnostic strategies for this disease is very important. Case presentation A 52-year-old man presented with cough, sputum production and hemoptysis; chest computed tomography (CT) revealed multiple bilateral lesions. The pathogen was unable to be identified after three biopsies. Subsequently, we performed combined tissue metagenomic next-generation sequencing (mNGS). The results of mNGS and a good therapeutic response helped to identify the causative pathogen as Exophiala dermatitidis. Finally, the patient was diagnosed with Exophiala dermatitidis pneumonia. Conclusions Combining molecular techniques, such as mNGS, with clinical microbiological tests will improve the rate of positivity in the diagnosis of rare fungal infections, and the importance of follow-up should be emphasized.

Background: We presented the performance of a Chinese-made cryptococcal glucuronoxylomannan (GXM) antigen test using serum and bronchoalveolar lavage fluid (BALF) samples in the HIV-negative Chinese population. Methods: Between February 2017 and January 2019, HIV-negative patients with pulmonary cryptococcosis were recruited and followed-up every three months, including completion of a chest CT examination and collection of serum and BALF samples. Results: Here, thirty-seven confirmed and ten clinically diagnosed patients were recruited. Furthermore, samples from 174 noncryptococcosis patients that may cause false positives were also collected. The sensitivity of a lateral flow assay (LFA) for detecting cryptococcal GXM antigen in serum and BALF samples from confirmed cases was 97% and 95%, respectively, and the specificity was 98.2% and 93%, respectively, and the differences in these values between the BALF and serum samples were not significant. The serum cryptococcal GXM antigen value showed a positive correlation (r: 0.581, p

ObjectivePulmonary aspergillosis is a rare but challenging pulmonary disease. The conditions of patients with chronic pulmonary aspergillosis (CPA) can be even more complicated. The mortality rate of CPA remains high, and the prognostic factors are not well established due to a high proportion of loss to follow-up. In this study, we aim to explore factors associated with loss to follow-up in CPA patients and their impact on the disease prognosis after withdrawing anti-fungal treatments.MethodsPatients with confirmed CPA, who were admitted to the Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Guangzhou Medical University from March 2017 to November 2019, were enrolled in this prospective study. The enrolled patients were followed up for 6 months after discharge. For loss to follow-up patients, the reasons for loss to follow-up and their prognosis after withdrawing anti-fungal treatments during loss to follow-up were recorded by telephone communication. Multivariate logistic regression analysis was performed to determine factors associated with loss to follow-up.ResultsThe 199 out of 298 screened patients were included in the study. Except for 67 cases with regular follow-up, the rest 132 cases were lost to follow-up. Factors, including age > 60 years (OR = 2.036, P = 0.03), monthly income ≤ $583 (OR = 5.568, P = 0.0001), education ≤ 6 years (OR = 7.474, P = 0.0001), and non-local residence (OR = 5.893, P = 0.0001) were associated with the loss to follow-up according to multivariate logistic regression analysis. The most common reasons for loss to follow-up were economic factors and clinic visit distance. The overall case fatality rate (CFR) within 180 days in patients with regular follow-up and patients who stopped anti-fungal treatment during the loss to follow-up was 0% and 19.65%, respectively.ConclusionThe proportion of loss to follow-up in CPA patients remained high. Age (>60 years), poor financial status, low education, and non-local residence were the key factors associated with the loss to follow-up in this study. Our study reveals the need to optimize the follow-up procedures and improve the patients understanding about the benefits and limitations of follow-up to reduce the CFR.

In this study, Ti-48Al-3Nb-1.5Ta powders were manufactured from cast bars by the supreme-speed plasma rotating electrode process (SS-PREP) and used to prepare hot isostatically pressed (HIPed) material at 1050–1260 °C with 150 MPa for 4 h. The phase, microstructure and mechanical performance were analyzed by XRD, SEM, electrical universal material testing machine and other methods. The results revealed that the phase constitution changed from γ phase to α2 phase and then to γ phase with the material changing from as-cast to powders and then to as-HIPed. Compared with the as-cast material, the grain size and element segregation were significantly reduced for both powders and as-HIPed. When the hot isostatic pressing (HIP) temperature was low, the genetic characteristics of the powder microstructure were evident. With the HIP temperature increasing, the homogeneity of the composition and microstructure increased, and the prior particle boundaries (PPBs) gradually disappeared. The elastic moduli of powder and as-HIPed were superior to those of as-cast, which increased with the HIP temperature increasing. The hardness of as-HIPed was lower than that of the powder. The compressive strength, compressive strain, bending strength, and tensile strength of as-HIPed were higher than those of as-cast. With an increase in the HIP temperature, the compressive strength decreased gradually, and the compressive strain first decreased and then increased.

Automatic milking systems (AMSs) for medium and large dairy farms in China require manual assistance to attach the teat cup, which greatly affects the milking efficiency and labor costs. In this regard, it is necessary to realize the automatic completion of cow teat attachment work. To address this issue, the authors developed a teat cup attachment robot for an AMS based on the theory of the solution of inventive problems (TRIZ). Specifically, we developed an enhanced algorithm for teat detection and designed a six-degree-of-freedom manipulator with integrated drive control. The design parameters were simulated and analyzed to validate their efficacy, while the rationality of the manipulator’s movement during teat cup attachment was verified. The maximum displacement and angle error of the cup was 1.625 mm and 1.216 mm, respectively, as verified by the teat cup attachment error test. A dynamic response test showed that the manipulator could follow the teat of the cow in real time. The attachment time for teat cups was 21 s per cow, with a success rate of 98%. The performance of the teat cup attachment robot was capable of meeting the automatic attachment teat cup needs for medium and large dairy farms during milking.

Background Serine protease inhibitor Kazal type I (SPINK1) is highly expressed and promotes tumor progress in different cancers. This study aimed to evaluate SPINK1’s prognostic value and its role in hepatocellular carcinoma (HCC) progress. Methods We use tissue micro-arrays containing 273 tumor and paired para-tumor tissues to evaluate SPINK1’s prognostic value in HCC. CCK8 cell proliferation assay, wound healing assays, transwell migration and invasion assays were performed to explore the effect of SPINIK1 on HCC cells. The Cancer Genome Atlas (TCGA) database and Gene set enrichment analysis (GSEA) were used to verify the prognosis value of SPINK1 in HCC and explore the underlying mechanisms. Results SPINK1 expression was significantly higher in tumor tissues than paired para-tumor tissues (P

BackgroundPneumocystis jirovecii can result in a serious pulmonary infection, Pneumocystis jirovecii pneumonia, in immunocompetent hosts. The diagnosis of Pneumocystis jirovecii pneumonia has long been a major clinical concern, and there are limitations with the currently utilized immunostaining and polymerase chain reaction diagnosis/detection technologies (e.g., insufficient sensitivity and accuracy). Hence, we sought to establish a rapid and RNA-specific transcription mediated amplification and CRISPR/Cas13a-based diagnostics targeted P. jirovecii-mitochondrial large subunit ribosomal RNA.MethodsThe procedure of the diagnostics included amplification of the extracted RNA samples by transcription mediated amplification, followed by CRISPR/Cas13 detection, and ultimately, the judgment of the results after 30 minutes of fluorescence signal. Later, the diagnostic performance of the CRISPR/Cas13-based diagnostics were tested on the 62 surplus clinical samples.ResultsThis CRISPR/Cas13-based diagnostics achieved limits of detection of approximately 2 copies/µL transcribed RNA templates, with no cross reaction to other respiratory pathogens, including bacteria and fungi. Similar to in-house quantitative real-time polymerase chain reaction, CRISPR/Cas13-based diagnostics was still positive in 243-fold diluted bronchial alveolar lavage fluid. A preliminary evaluation of 62 surplus bronchial alveolar lavage fluid samples from patients suspected of Pneumocystis jirovecii pneumonia showed that CRISPR/Cas13-based diagnostics achieved a 78.9% sensitivity and a 97.7% specificity in the diagnosis of Pneumocystis jirovecii pneumonia.ConclusionOur study demonstrates that the CRISPR/Cas13-based diagnostics technique has good performance for the accurate and specific diagnosis of Pneumocystis jirovecii pneumonia.

Abstract Background The aim to develop a highly stable near-infrared (NIR) photoinduced tumor therapy agent stems from its considerable potential for biological application. Due to its long wavelength, biological imaging exhibits a high signal-to-background ratio, deep tissue penetration and maximum permissible light power, which can minimize damage to an organism during photoinduced tumor therapy. Results A class of stable NIR-II fluorophores (NIR998, NIR1028, NIR980, NIR1030, and NIR1028-S) based on aza–boron–dipyrromethene (aza-BODIPY) dyes with donor–acceptor-donor structures have been rationally designed and synthesized by harnessing the steric relaxation effect and intramolecular photoinduced electron transfer (IPET). These fluorophores exhibit an intense range of NIR-II emission, large Stokes shift (≥ 100 nm), excellent photothermal conversion performance, and superior stability against photobleaching. Among the NIR-II fluorophores, NIR998 possesses better NIR-II emission and photothermal conversion performance. NIR998 nanoparticles (NIR998 NPs) can be encapsulated by liposomes. NIR998 NPs show superior stability in the presence of light, heat, and reactive oxygen nitrogen species than that of indocyanine green NPs, as well as a higher photothermal conversion ability (η = 50.5%) compared to other photothermal agents. Finally, under the guidance of photothermal imaging, NIR998 NPs have been proven to effectively eliminate tumors via their excellent photothermal conversion performance while presenting negligible cytotoxicity. Conclusions Utilizing IPET and the steric relaxation effect can effectively induce NIR-II emission of aza-BODIPY dyes. Stable NIR998 NPs have excellent photothermal conversion performance and negligible dark cytotoxicity, so they have the potential to act as photothermal agents in biological applications.

Recently, the prevalence trend of pulmonary fungal infection (PFI) has rapidly increased. Changes in the risk factors for, distributions of underlying diseases associated with and clinical characteristics of some individual PFIs have been reported in the past decade. However, data regarding PFIs remain uncertain. This study reports the epidemiological characteristics and trends of PFIs over time in recent years. We applied an automated natural language processing (NLP) system to extract clinically relevant information from the electronic health records (EHRs) of PFI patients at the First Affiliated Hospital of Guangzhou Medical University. Then, a trend analysis was performed. From January 1, 2013, to December 31, 2019, 40,504 inpatients and 219,414 outpatients with respiratory diseases were screened, in which 1368 inpatients and 1313 outpatients with PFI were identified. These patients were from throughout the country, but most patients were from southern China. Upward trends in PFIs were observed in both hospitalized patients and outpatients (P

ObjectiveThe limited information available on mixed mycosis involving the lungs makes the understanding of mixed fungal diseases insufficient and affects prognosis. Our study aims to improve understanding by exploring experience in the successful management of mixed fungal infections.MethodsPatients who had two types of mycosis involving the lung at the same disease course were retrospectively enrolled.ResultsBetween September 2011 and December 2019, 17 patients with proven mixed mycosis were enrolled. Four patients were immunocompromised, with one case each of lung transplantation, corticosteroid treatment, STAT3 hyper-IgE syndrome, and anti-IFN-γ autoantibody-associated immunodeficiency syndrome. Among 13 patients who were not immunocompromised, 9 had type 2 diabetes mellitus. Eight cases were coinfection with Mucor and Aspergillus, 4 cases were Cryptococcus and Aspergillus, 2 cases were Talaromyces marneffei and Cryptococcus, 2 cases were Talaromyces marneffei and Aspergillus, and 1 case was Candida and Aspergillus. Seven patients were diagnosed with mixed pulmonary mycosis at almost the same time. Among the remaining 10 patients, the initial treatment was ineffective in four cases, and six patients showed a partial response to the initial antifungal treatment, but the original fungal lesions became re-enlarged. Three patients were admitted to the intensive care unit during hospitalization, and one patient died. Another Mucor coinfection patient died due to treatment refusal.ConclusionMixed mycosis involving the lungs is not uncommon in patients without apparent immune deficiency diseases. During the management of mycosis, we recommend keeping mixed mycosis in mind for patients with a poor response to initial antifungal treatment, even in immunocompetent populations, and identifying the cause of illness through a rigorous procedure.

The features and significance of somatic mutation profiles in hepatocellular carcinoma (HCC) have not been completely elucidated to date. In this study, 39 tumor specimens from HCC patients were collected for gene variation analysis by next-generation sequencing (NGS), and a correlation analysis between mutated genes and clinical characteristics was also conducted. The results were compared with genome data from cBioPortal database. Our study found that T > G/A > C transversions (Tv) and C > T/G > A transitions (Ti) were dominant. The sequence variations of TP53, MUC16, MUC12, MUC4 and others, and the copy number variations (CNVs) of FGF3, TERT, and SOX2 were found to be more frequent in our cohort than in cBioPortal datasets, and they were highly enriched in pathways in cancer and participated in complex biological regulatory processes. The TP53 mutation was the key mutation (76.9%, 30/39), and the most common amino acid alteration and mutation types were p.R249S (23.5%) and missense mutation (82.3%) in the TP53 variation. Furthermore, TP53 had more co-mutations with MUC17, NBPF10, and AHNAK2. However, there were no significant differences in clinical characteristics between HCC patients with mutant TP53 and wild-type TP53, and the overall survival rate between treatment via precision medication guided by NGS and that via empirical medication (logrank p = 0.181). Therefore, the role of NGS in the guidance of personalized targeted therapy, solely based on NGS, may be limited. Multi-center, large sample, prospective studies are needed to further verify these results.

The formation and evolution of adiabatic shear behaviors, as well as the corresponding mechanical properties of a near-Ti-6Al-3Nb-2Zr-1Mo (Ti-6321) alloy during dynamic compression process, were systematically investigated by the split Hopkinson pressure bar (SHPB) compression tests in this paper. Ti-6321 samples containing three types of microstructures, i.e., equiaxed microstructure, duplex microstructure and Widmanstätten microstructure, were prepared to investigate the relationship between microstructures and dynamic mechanical behaviors under different strain rates in a range from 1000 s−1 to 3000 s−1. It was found by the dynamic strain–stress relation that the Ti-6321 alloys containing equiaxed microstructure, duplex microstructure and Widmanstätten microstructure all exhibited a strong strain-hardening effect. The samples containing equiaxed microstructure exhibited a larger flow stress than samples containing duplex microstructure and Widmanstätten microstructure. The adiabatic shearing behaviors in Ti-6321 alloy are significantly influenced by different types of microstructures. The formation of adiabatic shearing bands occurs in equiaxed microstructure when the strain rate is increased to 2000 s−1. The adiabatic shear bands are formed in duplex microstructure when the strain rate reaches 3000 s−1. However, the initiation of adiabatic shear bands is found in Widmanstätten microstructure under the strain rate of 1000 s−1. The Widmanstätten microstructure shows a larger sensitivity to adiabatic shearing than the equiaxed microstructure and duplex microstructure samples.

Hot workability and microstructural evolution of Ti-5.5Al-5Mo-5V-2Nb-1Fe-1Zr titanium alloy, which is also called Ti555211 titanium alloy, are investigated during compressive deformation at different temperatures and strain rates. It can be found that Ti555211 samples deformed at 750 and 850 °C comprised α and β phases, while Ti555211 samples deformed at 950 and 1050 °C consist of single β phase. When Ti555211 sample undergoes compressive deformation in the α + β phase region, microstructures of β phase vary more substantially than those of α phase, which means that plastic deformation of Ti555211 sample is governed by β phase. The process parameters are optimized by establishing processing maps based on dynamic material model. Ti555211 alloy generally possesses the better hot workability in the β phase zone. In the β phase zone of Ti555211 alloy, the best hot process area involves temperature range from 925 to 1025 °C and a strain rate range of 0.005 to 0.03 s−1.

Due to the complex and changing drilling conditions and the large scale of logging data, it is extremely difficult to process the data in real time and identify dangerous working conditions. Based on the multi-classification intelligent algorithm of Stacking model fusion, the 24 h actual working conditions of an XX well are classified and identified. The drilling conditions are divided into standpipe connection, tripping out, tripping in, Reaming, back Reaming, circulation, drilling, and other conditions. In the Stacking fusion model, the accuracy of the integrated model and the base learner is compared, and the confusion matrix of the drilling multi-condition recognition results is output, which verifies the effectiveness of the Stacking model fusion. Based on the variation in the parameter characteristics of different working conditions, a real-time working condition recognition diagram of the classification results is drawn, and the adaptation rules of the Stacking fusion model under different working conditions are summarized. The stacking model fusion method has a good recognition effect under the standpipe connection condition, tripping in condition, and drilling condition. These three conditions’ accuracy, recall rate, and F1 value are all above 90%. The stacking model fusion method has a relatively poor recognition effect on ‘other conditions‘, and the accuracy rate, recall rate, and F1 value reach less than 80%.

Pathological MVI diagnosis could help to determine the prognosis and need for adjuvant therapy in hepatocellular carcinoma (HCC). However, narrative reporting (NR) would miss relevant clinical information and non-standardized sampling would underestimate MVI detection. Our objective was to explore the impact of innovative synoptic reporting (SR) and seven-point sampling (SPRING) protocol on microvascular invasion (MVI) rate and patient outcomes. In retrospective cohort, we extracted MVI status from NR in three centers and re-reviewed specimen sections by SR recommended by the College of American Pathologists (CAP) in our center. In prospective cohort, our center implemented the SPRING protocol, and external centers remained traditional pathological examination. MVI rate was compared between our center and external centers in both cohorts. Recurrence-free survival (RFS) before and after implementation was calculated by Kaplan-Meier method and compared by the log-rank test. In retrospective study, we found there was no significant difference in MVI rate between our center and external centers [10.3% (115/1112) vs. 12.4% (35/282), P=0.316]. In our center, SR recommended by CAP improved the MVI detection rate from 10.3 to 38.6% (P

Clinical value of metagenomic next-generation sequencing (mNGS) in pneumonia management is still controversial. A prospective study was conducted to evaluate the clinical impact of PneumoSeq in 57 immunocompetent (ICO) and 75 immunocompromised (ICH) pneumonia patients. The value of PneumoSeq for both etiological and clinical impact investigation in pneumonia was assessed. Among the 276 potential pathogens detected with PneumoSeq in our cohort, 251 (90.9%) were cross-validated. Clinical diagnoses of the causative pathogens were obtained for 97 patients, 90.7% of which were supported by PneumoSeq. Compared to conventional testing, PneumoSeq suggested potentially missed diagnoses in 16.7% of cases (22/132), involving 48 additional pathogenic microorganisms. In 58 (43.9%) cases, PneumoSeq data led to antimicrobial treatment de-escalation (n = 12 in ICO, n = 18 in ICH) and targeted treatment initiation (n = 7 in ICO, n = 21 in ICH). The PneumoSeq assay benefited the diagnosis and clinical management of both ICH and ICO pneumonia patients in real-world settings.

Deep-water gas well testing is a key technology for obtaining reservoir production and physical property parameters. However, gas hydrates could easily form and cause blockage in the low-temperature and high-pressure environment on the seafloor. Therefore, it is extremely important to inhibit hydrate growth in deep-water operations. Ionic liquid is a type of hydrate inhibitor with both thermodynamic and kinetic effects. However, its intrinsic inhibiting mechanism is still unclear. By using molecular dynamics simulation, the growth process of methane hydrate in the 1-ethyl-3-methylimidazole chloride (EMIM-Cl)-containing system at the pressure of 15 MPa and temperature of 273.15 K was studied. The system energy and angular order parameters (AOP) were extracted as the evaluation indicators. It was found that the time for the complete growth of methane hydrate in the EMIM-Cl-containing system was about 10 ns, longer than that in the pure water, indicating that EMIM-Cl showed an obvious inhibition effect to hydrate growth. The results also implied that the joint action of hydrogen bond and steric hindrance might be the inhibition mechanism of EMIM-Cl. Some six-membered rings in hydrate crystal large cage structures evolved from five-membered rings under the effect of EMIM, which partly contributed to the delay of hydrate formation.

Ti555211 titanium alloy is subjected to plastic deformation in the dual-phase (α + β phase) zone and single-phase (β phase) zone at various deformation temperatures and strain rates. High-temperature constitutive equations of the alloy in the dual-phase zone and single-phase zone are established in order to describe deformation behavior of the alloy in the different phase zones. By comparing the constitutive equation of the alloy in the dual-phase zone with that of the alloy in the single-phase zone, the deformation activation energy of the former was found to be higher than that of the latter. It is obvious that the deformation activation energy of α phase is obviously greater than that of β phase. Furthermore, the microstructural evolution of the alloy is different in the dual-phase zone and single-phase zone. When the alloy was subjected to plastic deformation in the dual-phase zone, the size of the grains in the β phase increased with the decreasing strain rate. When the alloy was subjected to plastic deformation in the single-phase zone, the size of the grains in the β phase considerably increased with the increasing deformation temperature. In particular, in the microstructures of the alloy subjected to plastic deformation in the single-phase region, the elongated grains can be observed at higher strain rates. Furthermore, it is more difficult for the alloy to induce plastic deformation in the dual-phase region than in the single-phase region.

α-Linolenic acid (ALA) is a natural essential fatty acid widely found in plant seed oils and beans, which shows positive anti-inflammatory and antiallergic effects. In our previous study, ALA was proven to bind tightly to the seven protein targets closely associated with allergic rhinitis (AR) by molecular docking, which indicates that ALA may have a potential role in the treatment of AR. A mouse model of AR induced by ovalbumin (OVA) was adopted in this study to explore the therapeutical effect and potential mechanism of ALA in treating AR. Results demonstrated that ALA remarkably relieved the nasal symptoms, reduced the OVA-sIgE level in the serum, relieved the histopathological injuries, and downregulated the mRNA expression levels of IL-6 and IL-1β in the nasal mucosa. ALA also remarkably moderated the imbalance of Th1/Th2 cells, increased the mRNA expression levels of T-bet and STAT1, and reduced GATA3 and STAT6. ALA was proven to have a substantial therapeutic effect on mice with AR, and the underlying mechanism was likely to be the regulation of Th1/Th2 imbalance through the JAK/T-bet/STAT1 and JAK/GATA3/STAT6 pathways. This study provides a specific experimental basis for the clinical use and drug development of ALA in the treatment of AR.

Dysregulation of autophagy-related genes (ARGs) is related to the prognosis of cancers. However, the aberrant expression of ARGs signature in the prognosis of hepatocellular carcinoma (HCC) remain unclear. Using The Cancer Genome Atlas and the International Cancer Genome Consortium database, 188 common autophagy-related gene pairs (ARGPs) were identified. Through univariate, least absolute shrinkage and selection operator analysis, and multivariate Cox regression analysis, a prognostic signature of the training set was constructed on the basis of 6 ARGPs. Further analysis revealed that the ARGP based signature performed more accurately in overall survival (OS) prediction compared to other published gene signatures. In addition, a high risk of HCC was closely related to CTLA4 upregulation, LC3 downregulation, low-response to axitinib, rapamycin, temsirolimus, docetaxel, metformin, and high-response to bleomycin. Univariate Cox and multivariate Cox analysis revealed that the risk score was an independent prognostic factor for HCC. These results were internally validated in the test and TCGA sets and externally validated in the ICGC set. A nomogram, consisting of the risk score and the TNM stage, performed well when compared to an ideal nomogram. In conclusion, a 6-ARGP-based prognostic signature was identified and validated as an effective predictor of OS of patients with HCC. Furthermore, we recognized six small-molecule drugs, which may be potentially effective in treating HCC.

Abstract Background Limited effective intervention for advanced hepatocellular carcinoma (HCC) is available. This study aimed to investigate the potential clinical utility of apatinib, a highly selective inhibitor of the vascular endothelial growth factor receptor-2 (VEGFR2) tyrosine kinase, as a radiosensitizer in the treatment of HCC. Methods Four human HCC cell lines SMMC-7721, MHCC-97H, HCCLM3 and Hep-3B were treated with apatinib, irradiation or combination treatment. Colony formation assay, flow cytometry and nuclear γ-H2AX foci immunofluorescence staining were performed to evaluate the efficacy of combination treatment. RNA sequencing was conducted to explore the potential mechanism. The impact of combination treatment on tumor growth was assessed by xenograft mice models. Results Colony formation assay revealed that apatinib enhanced the radiosensitivity of HCC cell lines. Apatinib suppressed repair of radiation-induced DNA double-strand breaks. Flow cytometry analysis showed that apatinib increased radiation-induced apoptosis. Apatinib radiosensitized HCC via suppression of radiation-induced PI3K/AKT pathway. Moreover, an in vivo study indicated apatinib combined with irradiation significantly decreased xenograft tumor growth. Conclusions Our results indicate that apatinib has therapeutic potential as a radiosensitizer in HCC, and PI3K/AKT signaling pathway plays a critical role in mediating radiosensitization of apatinib.

Background: Epithelial-mesenchymal transition (EMT) is critical for cancer cell metastasis. Recently, EMT was reported to be associated with the inflammatory tumour microenvironment and, therefore, might be a predictive biomarker for immune checkpoint blockade agents. However, the underlying mechanism is still unclear. Methods: Patient survival data for our HCC cohort, TCGA and GEO datasets were determined by Kaplan-Meier analysis. The functional roles of ELMO1 in HCC were demonstrated by a series of in vitro and in vivo experiments. Gene microarray analysis was used to demonstrate potential mechanisms of ELMO1. Data retrieved from the TCGA datasets were used to determine the relationships of ELMO1, EMT and TMB. Findings: Here, we report an indispensable role for ELMO1 in linking EMT with tumour mutation burden (TMB), which is a promising biomarker for the immune checkpoint blockade agent response. Upregulated ELMO1 expression is associated with a poor prognosis in hepatocellular carcinoma (HCC), as well as increased cell growth, invasion, migration, angiogenesis and EMT in vitro and in vivo. Mechanistically, we provide evidence that ELMO1 regulates SOX10 expression and induces EMT through PI3K/Akt signalling. Moreover, ELMO1 is negatively associated with TMB, indicating a negative relationship between EMT and TMB. Interpretation: ELMO1 serves as a link between EMT and TMB, providing a mechanistic basis for the further development of ELMO1 as a therapeutic target against HCC and potentially a promising biomarker of the immune checkpoint blockade agent response. Fund: National Natural Science Foundation of China; Natural Science Foundation of Guangdong Province; Young Teacher Training Program of Sun Yat-sen University; Science and Technology Plan of Guangdong Province; Special Support Program of Guangdong Province, Science and Technology Innovation Youth Talent Support Program; the Pearl River Science and Technology New Talent of Guangzhou City; Medical Scientific Research Foundation of Guangdong Province. Keywords: ELMO1, Tumour mutation burden, Epithelial-mesenchymal transition, Hepatocellular carcinoma

In this study, high strain rate tension tests are conducted to determine and compare the dynamic mechanical behaviors and deformation mechanisms of different phase composition α-β metastable β-Ti alloys using a split Hopkinson tension bar. Two typical bimodal equiaxed αp + β and lamellar αs + β Ti-45551 alloy microstructures are formed through different hot working and thermal processing for investigating the effect of phase composition or microstructure on mechanical properties and strain rate sensitivity. It is demonstrated that dislocation nucleation and motion in the α/β phase and dislocation tangle or pile up at the α/β interface are typical deformation modes in both of the typical dual-phase Ti alloys at quasi-static loading conditions. Under dynamic loading, both the strength and ductility show a clearly positive strain rate dependence, which is directly related to dislocation activation in the α + β Ti-45551 alloy. Based on microstructure characterizations, it is shown that deformation twinning starts to become a major deformation mechanism in equiaxed αp + β microstructures under dynamic loading conditions. However, deformation twins are not favored in the lamellar αs + β Ti-45551 alloy due to its nano phase size. Finally, the mechanical behaviors and strain rate sensitivity are strongly dependent on the phase composition of metastable β-Ti alloys.

Objectives: Preoperative prediction of post-hepatectomy liver failure (PHLF) in patients with hepatocellular carcinoma (HCC) is significant for developing appropriate treatment strategies. We aimed to establish a radiomics-based clinical model for preoperative prediction of PHLF in HCC patients using gadolinium-ethoxybenzyl-diethylenetriamine (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI).Methods: A total of 144 HCC patients from two medical centers were included, with 111 patients as the training cohort and 33 patients as the test cohort, respectively. Radiomics features and clinical variables were selected to construct a radiomics model and a clinical model, respectively. A combined logistic regression model, the liver failure (LF) model that incorporated the developed radiomics signature and clinical risk factors was then constructed. The performance of these models was evaluated and compared by plotting the receiver operating characteristic (ROC) curve and calculating the area under the curve (AUC) with 95% confidence interval (CI).Results: The radiomics model showed a higher AUC than the clinical model in the training cohort and the test cohort for predicting PHLF in HCC patients. Moreover, the LF model had the highest AUCs in both cohorts [0.956 (95% CI: 0.955–0.962) and 0.844 (95% CI: 0.833–0.886), respectively], compared with the radiomics model and the clinical model.Conclusions: We evaluated quantitative radiomics features from MRI images and presented an externally validated radiomics-based clinical model, the LF model for the prediction of PHLF in HCC patients, which could assist clinicians in making treatment strategies before surgery.

The engine is one of the core components of aircraft, and the demand of mechanical properties of its raw materials is higher. The microstructure and properties of the raw materials could be improved by optimizing heat treatment systems. In this paper, the effects of annealing and solution aging on tensile properties of TC4 bar were compared, and the effect of solution temperature on microstructure and tensile properties of bar were studied. The results show that compared with annealing treatment, the tensile strength of bar is improved by 80MPa after solution aging treatment. And with the increase of solution temperature, the content of primary α phase is decreased, the content of secondary α phase is increased, the tensile strength is increased, and the maximum value reaches 1093MPa. Finally, it is determined that the heat treatment system of bar is ℃， ℃， 965 /1h WQ+720 /2h AC.

The effects of primary α phase volume fraction on the tensile properties at 400℃ of TC4 titanium alloy was studied by different solution temperature(Tβ-(10~80)℃). The effects of the thick of secondary α phase on the tensile properties at 400℃ of TC4 titanium alloy was studied by different cooling speed after solution treatment (water quench, air cooling, furnace cooling). The results show that with the decrease of primary α phase, the tensile and yield strength increase up, but the ductility has a little change. The thick of secondary α phase increases with the deceases of cooling speed after solution treatment, highest tensile and yield strength by water quench, the tensile strength of air cooling and furnace cooling were basically the same, but the yield strength of furnace cooling was 40MPa lower than air cooling. Therefore, the influence of the primary α phase volume fraction on the tensile strength at 400℃ was particularly obvious, we can control solution treatment and cooling way in combination with different requirements.

Halophytes are remarkable plants that can tolerate extremely high-salinity conditions, and have different salinity tolerance mechanisms from those of glycophytic plants. In this work, we investigated the mechanisms of salinity tolerance of an extreme halophyte, Kochia sieversiana (Pall.) C. A. M, using RNA sequencing and physiological tests. The results showed that moderate salinity stimulated the growth and water uptake of K. sieversiana and, even under 480-mM salinity condition, K. sieversiana maintained an extremely high water content. This high water content may be a specific adaptive strategy of K. sieversiana to high salinity. The physiological analysis indicated that increasing succulence and great accumulations of sodium, alanine, sucrose, and maltose may be favorable to the water uptake and osmotic regulation of K. sieversiana under high-salinity stress. Transcriptome data indicated that some aquaporin genes and potassium (K+) transporter genes may be important for water uptake and ion balance, respectively, while different members of those gene families were employed under low- and high-salinity stresses. In addition, several aquaporin genes were up-regulated in low- but not high-salinity stressed roots. The highly expressed aquaporin genes may allow low-salinity stressed K. sieversiana plants to uptake more water than control plants. The leaf K+/root K+ ratio was enhanced under low- but not high-salinity stress, which suggested that low salinity might promote K+ transport from the roots to the shoots. Hence, we speculated that low salinity might allow K. sieversiana to uptake more water and transport more K+ from roots to shoots, increasing the growth rate of K. sieversiana.