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Due to cross-linked structures, thermoset polymers cannot provide sufficient free volume for nanofillers to maneuver. Related composites are therefore governed by phase separation where filler-deficit regions become mechanical weakness. This work discovers that carbon nanotubes can be redispersed in thermoset polymer through heat treatments, thus, enhancing strength, thermal, and electrical conductivity of composites. Experiments carried out on a different thermoset matrix gives a similar trend where heating induced tube displacement is also verified by molecular dynamic simulations and piezo-resistivity tests.

Resistance to glucocorticoids (GCs), the common agents for remission induction in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL), poses a significant therapeutic hurdle. Therefore, dissecting the mechanisms shaping GC resistance could lead to new treatment modalities. Here, we showed that CD9- BCP-ALL cells were preferentially resistant to prednisone and dexamethasone over other standard cytotoxic agents. Concordantly, we identified significantly more poor responders to the prednisone prephase among BCP-ALL patients with a CD9- phenotype, especially for those with adverse presenting features including older age, higher white cell count and BCR-ABL1. Furthermore, gain- and loss-of-function experiments dictated a definitive functional linkage between CD9 expression and GC susceptibility, as demonstrated by the reversal and acquisition of relative GC resistance in CD9low and CD9high BCP-ALL cells, respectively. Despite physical binding to the GC receptor NR3C1, CD9 did not alter its expression, phosphorylation or nuclear translocation but potentiated the induction of GC-responsive genes in GCresistant cells. Importantly, the MEK inhibitor trametinib exhibited higher synergy with GCs against CD9- than CD9+ lymphoblasts to reverse drug resistance in vitro and in vivo. Collectively, our results elucidate a previously unrecognized regulatory function of CD9 in GC sensitivity, and inform new strategies for management of children with resistant BCP-ALL.

Abstract Southeastern South America (SESA) is a highly productive agricultural region and a hot spot for land‐atmosphere interactions. To evaluate the impact of dry soil moisture anomalies (SMAs) on SESA climate and the sensitivity of the regional climate response to the location of SMAs, we perform three experimental simulations using the Community Earth System Model (CESM) with prescribed dry SMAs over (a) SESA, (b) western SESA, and (c) eastern SESA. The dry SESA and eastern SESA simulations show widespread negative precipitation anomalies. In contrast, the dry western SESA simulation shows positive precipitation anomalies over northeastern Argentina, which are associated with the enhanced southward moisture flux co‐located with the South American low‐level jet exit region. A composite analysis of extremely dry cases over western SESA using reanalysis data agrees with the findings from our CESM experiment. These findings have potential implications for subseasonal forecasting in this region.

This article presents a benchmark study of symbolic piano music classification using the masked language modelling approach of the Bidirectional Encoder Representations from Transformers (BERT). Specifically, we consider two types of MIDI data: MIDI scores, which are musical scores rendered directly into MIDI with no dynamics and precisely aligned with the metrical grids notated by their composers and MIDI performances, which are MIDI encodings of human performances of musical scoresheets. With five public-domain datasets of single-track piano MIDI files, we pre-train two 12-layer Transformer models using the BERT approach, one for MIDI scores and the other for MIDI performances, and fine-tune them for four downstream classification tasks. These include two note-level classification tasks (melody extraction and velocity prediction) and two sequence-level classification tasks (style classification and emotion classification). Our evaluation shows that the BERT approach leads to higher classification accuracy than recurrent neural network (RNN)-based baselines.

BackgroundPost-thrombectomy intraparenchymal hyperdensity (PTIH) in patients with acute anterior circulation large vessel occlusion is a common CT sign associated with a higher incidence of futile reperfusion (FR). We aimed to develop a nomogram to predict FR specifically in patients with PTIH.MethodsWe retrospectively collected information on patients with acute ischemic stroke who underwent endovascular thrombectomy (EVT) at two stroke centers. A total of 398 patients with PTIH were included to develop and validate the nomogram, including 214 patients in the development cohort, 92 patients in the internal validation cohort and 92 patients in the external validation cohort. The nomogram was developed according to the independent predictors obtained from multivariate logistic regression analysis, including clinical factors and CT texture features extracted from hyperdense areas on CT images within half an hour after EVT. The performance of the nomogram was evaluated with integrated discrimination improvement (IDI), category-free net reclassification improvement (NRI), the area under the receiver operating characteristic curve (AUC-ROC), calibration plots, and decision curve analyses for discrimination, calibration ability, and clinical net benefits, respectively.ResultsOur nomogram was constructed based on three clinical factors (age, NIHSS score and ASPECT score) and two CT texture features (entropy and kurtosis), with AUC-ROC of 0.900, 0.897, and 0.870 in the development, internal validation, and external validation cohorts, respectively. NRI and IDI further validated the superior predictive ability of the nomogram compared to the clinical model. The calibration plot revealed good consistency between the predicted and the actual outcome. The decision curve indicated good positive net benefit and clinical validity of the nomogram.ConclusionThe nomogram enables clinicians to accurately predict FR specifically in patients with PTIH within half an hour after EVT and helps to formulate more appropriate treatment plans in the early post-EVT period.

Abstract Background This study aimed to examine the clinical characteristics of bone metastasis (BoM) in patients with non‐small cell lung cancer (NSCLC) who have an epidermal growth factor receptor (EGFR) mutation and to identify the most effective treatment strategy using EGFR–tyrosine kinase inhibitors (TKIs). Methods The study included patients with stage IV EGFR‐mutated NSCLC who were receiving first‐line treatment with EGFR–TKIs between January 2014 and December 2020. These patients were divided into two groups based on the presence or absence of BoM at the time of initial diagnosis. The BoM group was further subdivided based on whether they received denosumab or not. Results The final analysis included 247 patients. Those with BoM at initial diagnosis had shorter progression‐free survival (12.6 vs. 10.5 months, p = 0.002) and overall survival (OS) (49.7 vs. 30.9 months, p = 0.002) compared to those without BoM. There was a difference in the location of metastatic sites between the two groups, with a higher incidence of extrathoracic metastasis in the BoM group (p

Nonaqueous Li metal batteries (LMBs) and aqueous Zn metal batteries (ZMBs) are promising next-generation secondary batteries owing to their high energy density. Selecting an appropriate electrolyte is critical for addressing the safety issues nonaqueous and aqueous metal batteries can encounter. Ionic liquids (ILs) have been widely used in secondary metal batteries because they are non-flammable, present good thermal stability, and have wide electrochemical windows. This review highlights the research progress on IL-based electrolytes for stable Li/Zn metal anodes. We focus particularly on these electrolytes' electrochemistry and functionalities at the electrolyte/anode interface for inhibiting dendrite growth, preventing side reactions, and enhancing electrochemical performance. It is expected that this review will shed some light on the development of ILs for next-generation metal batteries.

The limited osteointegration often leads to the failure of implant, which can be improved by fixing bioactive molecules onto the surface, such as arginyl-glycyl-aspartic acid (RGD): a cell adhesion motif. Metal-Phenolic Networks (MPNs) have garnered increasing attention from different disciplines in recent years due to their simple and rapid process for depositing on various substrates or particles with different shapes. However, the lack of cellular binding sites on MPNs greatly blocks its application in tissue engineering. In this study, we present a facile and efficient approach for producing PC/Fe@c(RGDfc) composite coatings through the conjugation of c(RGDfc) peptides onto the surface of PC/Fe-MPNs utilizing thiol-click reaction. By combined various techniques (ellipsometry, X-ray photoelectron spectroscopy, Liquid Chromatography-Mass Spectrometry, water contact angle, scanning electronic microscopy, atomic force microscopy) the physicochemical properties (composition, coating mechanism and process, modulus and hydrophilicity) of PC/Fe@c(RGDfc) surface were characterized in detail. In addition, the PC/Fe@c(RGDfc) coating exhibits the remarkable ability to positively modulate cellular attachment, proliferation, migration and promoted bone-implant integration in vivo, maintaining the inherent features of MPNs: anti-inflammatory, anti-oxidative properties, as well as multiple substrate deposition. This work contributes to engineering MPNs-based coatings with bioactive molecules by a facile and efficient thiol-click reaction, as an innovative perspective for future development of surface modification of implant materials.

We present a case involving a 60-year-old man with subacute delirium characterized by challenging attention shifts and obstinate behavior, contrasting with his usual mild-mannered personality. The patient developed pneumonia and a urinary tract infection following the onset of subacute delirium. Despite exhaustive investigations, the cause remained elusive until cerebrospinal fluid analysis revealed Tau positivity. Our overview suggests neurodegenerative diseases as the primary cause, rather than infectious or autoimmune factors. The case underscores a significant association between Tau and delirium superimposed on dementia, offering guidance to clinicians managing such patients.

IntroductionThe aim of this study is to investigate changes in TNF-related apoptosis-inducing ligand (TRAIL) and gamma interferon-induced protein 10 (IP-10) after COVID-19 vaccination in pregnant women and to explore their association with neutralizing antibody (Nab) inhibition.MethodsThe study evaluated 93 pregnant women who had previously received two (n=21), three (n=55) or four (n=17) doses of COVID-19 vaccine. Also we evaluated maternal blood samples that were collected during childbirth. The levels of TRAIL, IP-10 and Nab inhibition were measured using enzyme-linked immunosorbent assays (ELISA).Results and discussionOur study revealed four-dose group resulted in lower TRAIL levels when compared to the two-dose and three-dose groups (4.78 vs. 16.07 vs. 21.61 pg/ml, p = 0.014). The two-dose group had reduced IP-10 levels than the three-dose cohort (111.49 vs. 147.89 pg/ml, p=0.013), with no significant variation compared to the four-dose group. In addition, the four-dose group showed stronger Nab inhibition against specific strains (BA.2 and BA.5) than the three-dose group. A positive correlation was observed between TRAIL and IP-10 in the two-dose group, while this relationship was not found in other dose groups or between TRAIL/IP-10 and Nab inhibition. As the doses of the COVID-19 vaccine increase, the levels of TRAIL and IP-10 generally increase, only by the fourth dose, the group previously vaccinated with AZD1222 showed lower TRAIL but higher IP-10. Despite these changes, more doses of the vaccine consistently reinforced Nab inhibition, apparently without any relation to TRAIL and IP-10 levels. The variation may indicate the induction of immunological memory in vaccinated mothers, which justifies further research in the future.

Paphiopedilum Clair de Lune ‘Edgard Van Belle’, an excellent Maudiae-type hybrid that has been propagated by artificial division for a long time. We studied its flower bud initiation, development of floral organs, and flowering habits with a view to providing information for flowering control and efficient commercial production. According to our research, the flower bud initiation phase of this cultivar begins in February every year, and 80% of the plants completed sepal primordium differentiation in March, The flower bud differentiation lasts for 6 to 7 months, until flowering in August. Within 1 to 3 months after flower bud differentiation, all tested plants differentiated lateral buds. After 5 to 6 months, the new, aboveground vegetative shoots reached their maximum growth, with an average plant height of 20 cm, five leaves, and a shoot dry weight of more than 3 g. From February to April of the following year, a new cycle of flower development and vegetative growth began. In addition, this cultivar was notably sensitivity to high ambient temperature during the late phase of flower development, with a flower bud drop rate as high as 33.3% under average day/night temperatures of 29.0/26.5 °C.

Objectives This study measures the differences in inpatient performance after a points-counting payment policy based on diagnosis-related group (DRG) was implemented. The point value is dynamic; its change depends on the annual DRGs’ cost settlements and points of the current year, which are calculated at the beginning of the following year.Design A longitudinal study using a robust multiple interrupted time series model to evaluate service performance following policy implementation.Setting Twenty-two public general hospitals (8 tertiary institutions and 14 secondary institutions) in Wenzhou, China.Intervention The intervention was implemented in January 2020.Outcome measures The indicators were case mix index (CMI), cost per hospitalisation (CPH), average length of stay (ALOS), cost efficiency index (CEI) and time efficiency index (TEI). The study employed the means of these indicators.Results The impact of COVID-19, which reached Zhejiang Province at the end of January 2020, was temporary given rapid containment following strict control measures. After the intervention, except for the ALOS mean, the change-points for the other outcomes (p0.05), the uptrend of the CEI mean in tertiary institutions alleviated (p0.05).Conclusions This study showed a positive effect of the DRG policy in Wenzhou, even during COVID-19. The policy can motivate public general hospitals to improve their comprehensive capacity and mitigate discrepancies in treatment expenses efficiency for similar diseases. Policymakers are interested in whether the reform successfully motivates hospitals to strengthen their internal impetus and improve their performance, and this is supported by this study.

Deficiency in regulatory T cells (Tregs) is an important mechanism underlying the pathogenesis of pediatric aplastic anemia, but its specific mechanism is unclear. In our study, we aimed to investigate whether IL-2/STAT5 can regulate the proliferation of Tregs in aplastic anemia (AA) by regulating their expression of B lymphocyte-induced mature protein-1 (BLIMP-1) or interferon regulatory factor 4 (IRF4). Through clinical research and animal experiments, we found that poor activation of the IL-2/STAT5 signaling pathway may leads to low expression of BLIMP-1 in Tregs of children with AA, which leads to defects in the differentiation and proliferation of Tregs in AA. In AA model mice, treatment with IL-2c reversed the decrease in Treg proportions and reduction in Blimp-1 expression in Tregs by increasing the phosphorylation of Stat5 in Tregs. In AA, deficiency of IRF4 expression in Tregs is closely related to the deficiency of Tregs, but is not regulated by the IL-2/STAT5 pathway.

Ginger-infused sesame oil enriches the nutrition and provides enhanced flavor for the foods. An original processing procedure and module for evaluation were established in this study, using different raw materials (Guangdong and Chu ginger) and treatments (ginger powder, extract, and both). The quality, functionality, and flavor of the infused oils were evaluated. Ginger-infused sesame oil contained 0.58–3.22 µg/g of 6-gingerol, 0.21–0.88 µg/g of 6-shogaol. The number range of volatile compounds from 48 to 55 identified by gas chromatography-mass spectrometry varies depending on different process procedures. Agglomerative hierarchical clustering analysis revealed the flavor profiles were clustered by different varieties, while gingerol and phytosterol was by different treatments. In conclusion, sesame oil was an appropriate carrier for gingerol and phytosterol, which are characterized by higher antioxidant capacities (p

Artificial sweeteners (AS) are extensively utilized as sugar substitutes and have been recognized as emerging environmental contaminants. While the effect of AS on aquatic organisms has garnered recent attention, their effects on soil invertebrates and gut microbial communities remain unclear. To address this knowledge gap, we exposed springtails (Folsomia candida) to both single and combined treatments of four typical AS (sucralose [SUC], saccharin [SAC], cyclamate [CYC], and acesulfame [ACE]) at environmentally relevant concentrations of 0.01, 0.1 and 1 mg kg−1 in soil. Following the first-generational exposure, the reproduction of juveniles showed a significant increase under all the AS treatments of 0.1 mg kg−1. The transcriptomic analysis revealed significant enrichment of several Kyoto Encyclopedia of Gene and Genome pathways (e.g., glycolysis/gluconeogenesis, pentose and glucuronate interconversions, amino sugar, and nucleotide sugar metabolism, ribosome, and lysosome) in springtails under all AS treatments. Analysis of gut bacterial microbiota indicated that three AS (SUC, CYC, and ACE) significantly decreased alpha diversity, and all AS treatments increased the abundance of the genus Achromobacter. After the sixth-generational exposure to CYC, weight increased, but reproduction was inhibited. The pathways that changed significantly (e.g., extracellular matrix-receptor interaction, amino sugar and nucleotide sugar metabolism, lysosome) were generally similar to those altered in first-generational exposure, but with opposite regulation directions. Furthermore, the effect on the alpha diversity of gut microbiota was contrary to that after first-generational exposure, and more noticeable disturbances in microbiota composition were observed. These findings underscore the ecological risk of AS in soils and improve our understanding of the toxicity effects of AS on living organisms.

Mutations in the master hematopoietic transcription factor GATA1 are often associated with functional defects in erythropoiesis and megakaryopoiesis. In this study, we identified a novel GATA1 germline mutation (c.1162delGG, p.Leu387Leufs*62) in a patient with congenital anemia and occasional thrombocytopenia. The C-terminal GATA1, a rarely studied mutational region, undergoes frameshifting translation as a consequence of this double-base deletion mutation. To investigate the specific function and pathogenic mechanism of this mutant, in vitro mutant models of stable re-expression cells were generated. The mutation was subsequently validated to cause diminished transcriptional activity of GATA1 and defective differentiation of erythroid and megakaryocytes. Using proximity labeling and mass spectrometry, we identified selective alterations in the proximal protein networks of the mutant, revealing decreased binding to a set of normal GATA1-interaction proteins, including the essential co-factor FOG1. Notably, our findings further demonstrated enhanced recruitment of the protein arginine methyltransferase PRMT6, which mediates histone modification at H3R2me2a and represses transcription activity. We also found an enhanced binding of this mutant GATA1/PRMT6 complex to the transcriptional regulatory elements of GATA1’s target genes. Moreover, treatment of the PRMT6 inhibitor MS023 could partially rescue the inhibited transcriptional and impaired erythroid differentiation caused by the GATA1 mutation. Taken together, our results provide molecular insights into erythropoiesis in which mutation leads to partial loss of GATA1 function and the broader role of PRMT6 and its inhibitor MS023 in congenital anemia, highlighting PRMT6 binding as a negative factor of GATA1 transcriptional activity in aberrant hematopoiesis.

Introduction Oesophageal cancer (OC) has higher morbidity and mortality rate than most other malignancies. The standard treatment for unresectable locally advanced oesophageal squamous cell carcinoma (OSCC) is concurrent chemoradiotherapy, with tumour regression observed in a proportion of patients after treatment, but prognostic improvement remains limited. Immunotherapy in combination with chemotherapy (CT) has been shown to be efficacious as the first-line treatment of advanced OC and neoadjuvant therapy. Therefore, we conducted a prospective, two-arm, randomised, unblinded phase II study to explore the efficacy of camrelizumab in combination with CT versus chemoradiotherapy for the conversion of unresectable advanced OSCC.Methods and analysis All participants meeting the inclusion criteria will be enrolled after signing an informed consent form. Patients with clinically cT4b or spread to at least one group of lymph nodes with possible invasion of surrounding organs and unresectable locally advanced squamous carcinoma of the thoracic segment of the oesophagus will be included in the study. Patients with suspected distant metastases on the preoperative examination will be excluded from this study. Patients eligible for enrolment will be grouped by centre randomisation according to the study plan. Patients will undergo radical surgery after completion of two cycles of chemotherapy (CT) combined with camrelizumab induction therapy or concurrent chemoradiotherapy if assessed to be operable. Patients evaluated as inoperable will be scheduled for a multidisciplinary consultation to determine the next treatment option. The primary endpoint is the R0 resection rate in patients undergoing surgery after treatment. Secondary endpoints are the rate of major pathological remission, pathological complete response rate, overall survival, progression-free survival and adverse events for all patients.Ethics and dissemination Ethical approval was obtained from the ethics committees of Fujian Medical University Union Hospital (No. 2022YF039-02). The findings will be disseminated in peer-reviewed publications.Trial registration number NCT05821452.

Purpose: To assess the potential of ultraviolet-visible near-infrared spectroscopy to provide quantitative information on the cartilage surface at early osteoarthritis. Methods: We used a similar source and optical path to a standard arthroscope and constraining input to the range available to a standard detector/camera, further capturing and analyzing spectral information quantitatively in terms of specific electronic absorbance bands and scattering from the cartilage surface, with a focus on the early stages of degradation. Results: The ratio of the 320-nm and longer than 500-nm absorbances produced a distinct change from the normal to diseased states. The slopes between the wavelengths of 600 and 980 nm may show the transition of the single fibril to fibril bundles that occurs during early stages disease. Conclusions: Ultraviolet-visible near-infrared spectroscopy has good potential for use in integrated arthroscopic assessment. Clinical Relevance: This raises the possibility of advancing arthroscopy from a qualitative to a quantitative tool, without requiring modification of either the radiation (the light source and path) or instrumentation (the arthroscope itself) delivered to the patient, thus allowing a low-cost yet potentially high-value technology.

Utilizing complementary bioactive peptides is a promising surface engineering strategy for bone regeneration on osteogenesis. In this study, we designed block peptides, (Lysine)6-capped RGD (K6-(linker-RGD)3) and OGP (K6-linker-(YGFGG)2), which were mildly grafted onto PC/Fe-MPNs through supramolecular interactions between K6 and PC residues on the MPNs surface to form a dual peptide coating, named PC/Fe@K6-RGD/OGP. The properties of the block peptides coating, including mechanics, hydrophilicity, chemical composition, etc., were detailly characterized by various techniques (ellipsometry, quartz crystal microbalance, X-ray photoelectron spectroscopy, water contact angle, scanning electronic microscopy and atomic force microscopy). Importantly, the RGD/OGP ratio can be well adjusted, which allowed optimizing the RGD/OGP ratio to endow significantly enhanced osteogenic activity of MC3T3-E1 cells through the Wnt/β-catenin pathway, while also promoting cell adhesion, immune regulation, inhibiting osteoclast differentiation and oxidative stress reduction. In vivo, the optimized RGD/OGP coatings promoted bone regeneration and osseointegration around implants in rats with bone defects. In conclusion, rationally designed PC/Fe@K6-RGD/OGP coating integrated RGD and OGP bioactivities, providing a convenient approach to enhance bioinert implant surfaces for bone regeneration.

Dementia is a leading cause of disability and dependence in older adults worldwide. The aim of this pilot study was to explore the effect of using a kazoo instrument to improve pulmonary function and cognitive reserve in middle-aged and older adults in rural areas. This quasi-experimental study was conducted at two community care stations selected using cluster sampling from a rural district in southern Taiwan. We enrolled 85 middle-aged and older adults who were randomly assigned into self-learner and in-class groups. Both groups received a 6-month kazoo program. Cognitive and pulmonary function were compared before and after the intervention between the two groups. Significantly improved pulmonary function with regards to forced vital capacity ( p

Reducing the secondary inflammatory response, which is partly mediated by microglia, is a key focus in the treatment of spinal cord injury. Src homology 2-containing protein tyrosine phosphatase 2 (SHP2), encoded by PTPN11, is widely expressed in the human body and plays a role in inflammation through various mechanisms. Therefore, SHP2 is considered a potential target for the treatment of inflammation-related diseases. However, its role in secondary inflammation after spinal cord injury remains unclear. In this study, SHP2 was found to be abundantly expressed in microglia at the site of spinal cord injury. Inhibition of SHP2 expression using siRNA and SHP2 inhibitors attenuated the microglial inflammatory response in an in vitro lipopolysaccharide-induced model of inflammation. Notably, after treatment with SHP2 inhibitors, mice with spinal cord injury exhibited significantly improved hind limb locomotor function and reduced residual urine volume in the bladder. Subsequent in vitro experiments showed that, in microglia stimulated with lipopolysaccharide, inhibiting SHP2 expression promoted M2 polarization and inhibited M1 polarization. Finally, a co-culture experiment was conducted to assess the effect of microglia treated with SHP2 inhibitors on neuronal cells. The results demonstrated that inflammatory factors produced by microglia promoted neuronal apoptosis, while inhibiting SHP2 expression mitigated these effects. Collectively, our findings suggest that SHP2 enhances secondary inflammation and neuronal damage subsequent to spinal cord injury by modulating microglial phenotype. Therefore, inhibiting SHP2 alleviates the inflammatory response in mice with spinal cord injury and promotes functional recovery postinjury.

Abstract Objectives The incidence of multiple primary lung cancer (MPLC) has increased in recent years. The risk factors of MPLC are not well studied, especially in the Asian population. This case-control study investigated the association between a family history of cancer and MPLC risk. Methods We used data from people who surgically confirmed MPLC with at least 2 nodes of Fujian Medical University Union Hospital and matched 1:2 normal individuals as controls between 2016 and 2017. Information on age, sex, lifestyle, personal history, and family history of cancer was collected using a self-administered questionnaire, and odds ratios (OR) were estimated using unconditional logistic regression. Results We included 2 104 patients. In total, 321 patients with histologically confirmed MPLC and 642 healthy controls were studied. The significantly higher ratio of current smokers was observed for the cases than the controls (54.1% vs. 30.0%). A family history of LC in first-degree relatives of the cases reported a significantly higher proportion than in the controls (15.3% vs. 8.6%). Family history of all cancers and LC significantly increased the risk of MPLC (OR = 1.64, P = 0.009 and OR = 2.59, P = 0.000, respectively). The multivariate analysis identified a significantly increased risk of MPLC (OR = 2.45, P = 0.000) associated with parents and siblings influenced by LC history. The younger age (aged

Background Allergic bronchopulmonary aspergillosis (ABPA) is a lung disease caused by aspergillus sensitization, which is often misdiagnosed or missed diagnosis due to low prevalence, few case reports, and controversial diagnostic criteria, leading to inappropriate treatment and exacerbation of the disease. Previous studies have shown that ABPA is one of the etiologies of bronchiectasis, but its prevalence and clinical characteristics still remain to be studied. Objective To analyze the prevalence and clinical characteristics of ABPA in patients with bronchiectasis. Methods Outpatients or inpatients diagnosed with bronchiectasis and received examinations for peripheral blood eosinophilcount, serum total IgE and aspergillus-specific IgE at Peking University Third Hospital from January 2012 to September 2021 were retrospectively selected. The data including gender, age, smoking history, asthma/wheezing symptoma, laboratory indicators (peripheral blood eosinophil count, serum total IgE, aspergillus-specific IgE and IgG), chest CT (types of bronchiectasis, number oflobes involved), and pulmonary function indexes〔the first forced expiratory volume as a percentage of the predicted value (FEV1%pred), ratio of the first forced expiratory volume and forced vital capacity in percentage (FEV1/FVC) 〕was collected. The Smith score and the Bhalla score was used to evaluate the extent and the severity of bronchiectasis lesions, respectively. The included patients were divided into the ABPA group (n=10) and non-ABPA group (n=149) according to the combination of ABPA and analyzed for the cases with total serum IgE>60 U/mL, total serum IgE>500 U/mL, total serum IgE>1 000 U/mL, aspergillus-specific IgE>0.35 U/mL, and peripheral blood eosinophil count >0.5×109/L. Results In 159 patients with bronchiectasis, 10 cases met the diagnostic criteria of ABPA (6.29%, 10/159) with elevated aspergillus-specific IgE level (>0.35 U/mL), including 9 cases with aspergillus-specific IgE>1 000 U/mL and 1 case with aspergillus-specific IgE0.5×109/L, radiological bronchiectasis, positive serum aspergillus-specific IgG), of whom 7 cases had episodic wheezingsymptom and 9 cases with absolute peripheral blood eosinophil count>0.5×109/L. Aspergillus-specific IgG was detected in 5 of the 10 cases with ABPA, 4 of whom were positive. Chest CT findings showed central bronchiectasis and peripheral bronchiectasis in 6 and 4 of the 10 cases with ABPA, and cystic bronchiectasis were shown in all 10 cases. Compared with the non-ABPA group, the ABPA group showed a higher number of lung lobesinvolved, Smith score and Bhalla score (P

Abstract Background Esophageal cancer (ESCA) is one of the most aggressive and lethal human malignant cancers. MicroRNA‐1301‐3p (miR‐1301‐3p) plays vital roles in a majority of malignancies. The aim of this study was to investigate the role of miR‐1301‐3p/NBL1 axis on ESCA cell invasion, migration, epithelial‐mesenchymal transition (EMT) process, as well as its association with prognosis of ESCA patients. Methods The expression levels of miR‐1301‐3p and NBL1 were predicted by bioinformatics and further verified by RT‐qPCR assays. Kaplan–Meier (K–M) plotter analysis and univariate and multivariate Cox analyses were used to evaluate the relationship between miR‐1301‐3p and clinicopathological variables and prognosis. The role of miR‐1301‐3p on cell invasion, migration was detected by transwell invasion, and wound healing assays, respectively. The EMT‐related proteins were detected by western blot. The target genes and the target binding sites were predicted by bioinformatics and further determined by RT‐qPCR assay. Results MiR‐1301‐3p was remarkably upregulated in ESCA tissues and cells, and its high expression was associated with poor prognosis of ESCA. Overexpression of miR‐1301‐3p promoted ESCA cell invasion, migration and mediated EMT process in vitro, whereas knockdown of miR‐1301‐3p showed the opposite effects. Moreover, NBL1 was predicted as a target gene of miR‐1301‐3p. NBL1 was lowly expressed in ESCA cells and significantly decreased after upregulation of miR‐1301‐3p. Meanwhile, we found that low expression of NBL1 was significantly associated with poor prognosis of ESCA patients. Conclusion MiR‐1301‐3p is a potential biomarker for predicting the prognosis of ESCA patients. It may promote ESCA invasion, migration and EMT progression by regulating NBL1 expression.

Abstract Background Immune checkpoint inhibitors have revolutionized the treatment of malignancies. However, disproportionate enrollment among races and ethnicities places the generalizability of global trial results in doubt. Methods In this systematic review, phase 3 randomized controlled trials investigating pembrolizumab in advanced cancers and providing subgroup analyses of Asian and non‐Asian participants were included. The primary and secondary effect measures were the mean differences (MDs) in the natural logarithms of the hazard ratios (HRs) for overall survival (OS) and progression‐free survival (PFS) between these two subgroups, respectively. We used random‐effects meta‐analysis to calculate the pooled ratios of HRs (i.e., exp(MD)) and implemented a meta‐regression analysis to identify significant covariates. Results A total of 17 and 11 trials were included in the meta‐analyses of OS and PFS, respectively. These trials included 2732 (25.49%) Asian and 7000 (65.32%) non‐Asian participants in the OS analysis and 1438 (22.5%) Asian and 4129 (64.61%) non‐Asian participants in the PFS analysis. The pooled ratio of HRs for OS was 0.87 (95% CI: 0.76–0.99; p = 0.0391), favoring Asian participants, but no significant difference was found in PFS (pooled ratio of HRs: 0.93; 95% CI: 0.82–1.07; p = 0.2391). Both linear meta‐regression analyses revealed an open‐label design as a crucial covariate, which indicated more benefits for non‐Asian participants. Conclusions Compared with non‐Asian patients, Asian patients with advanced cancers may derive superior OS benefits from pembrolizumab. Although the results warrant further exploration, this meta‐analysis provides insight into clinical research design.

Abstract Background Indeterminate pulmonary nodules (IPNs) are common after surgery for esophageal cancer. The paucity of data on postoperative IPNs for esophageal cancer causes a clinical dilemma. Objective The aim of this study was to identify the characteristics and clinical significance of IPNs after radical esophagectomy for metastatic esophageal cancer, determine the risk factors for pulmonary metastasis, and construct a risk score model to standardize the appropriate time to either follow up or treat the patient. Methods All consecutive patients with esophageal squamous cell carcinoma (ESCC) who underwent radical surgery between 2013 and 2016 were included in this retrospective study. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors and develop risk score models. Results A total of 816 patients were enrolled in the study. During a median follow-up period of 45 months, IPNs were detected in 221 (27.1%) patients, of whom 66 (29.9%) were diagnosed with pulmonary metastases. The following five variables maintained prognostic significance after multivariate analyses: the pathologic N category, number of IPNs, shape of IPNs, time of detection of IPNs, and size of IPNs. The Pulmonary Metastasis Prediction Model (PMPM) scale ranges from 0 to 15 points, and patients with higher scores have a higher probability of pulmonary metastases. The Hosmer–Lemeshow test showed a good calibration performance of the clinical prediction model (χ 2 = 8.573, P = 0.380). After validation, the PMPM scale showed good discrimination with an AUC of 0.939. Conclusion A PMPM scale for IPNs in patients who underwent esophagectomy for ESCC may be clinically useful for diagnostic and therapeutic decision-making.

Abstract Objectives The proper procedure for inferior pulmonary ligament (IPL) during upper lobectomy remains a topic of debate. To address this matter, we carried out a trial comparing the clinical outcomes of IPL preservation versus IPL dissection during thoracoscopic upper lobectomy (TUL). Methods Patients undergoing thoracoscopic left/right upper lobectomy (TLUL/TRUL) were assigned to either the dissection group (Group D) or the preservation group (Group P). Our primary objective was to quantify and compare the alterations in postoperative residual bronchial angle and lung volume changes between the two groups. Our secondary objective encompassed the assessment of various other intraoperative and postoperative outcomes. Results Following adherence to the inclusion and exclusion criteria, we enrolled 100 patients (41 left and 59 right) in Group P and 108 patients (41 left and 67 right) in Group D for the study. Our findings revealed that in TLUL, Group P was able to reduce the degree of postoperative residual bronchial angle change (P 0.05) with regard to alterations in lung volume or the occurrence of postoperative complications—except for the duration of postoperative hospital stay (P

Abstract Background We conducted a retrospective observational study to explore the potential application of impulse oscillometry (IOS) as an alternative to high-resolution computed tomography (HRCT) for detecting pulmonary involvement in patients with rheumatoid arthritis (RA) because clinically evident interstitial lung disease (ILD) and airway involvement are common in this population. Methods We enrolled 72 patients with RA who underwent pulmonary function tests (PFTs) and IOS between September 2021 and September 2022. We aimed to identify the PFT and IOS variables associated with lung diseases shown on HRCT images. Results In our cohort of 72 patients, 48 underwent HRCT; of these, 35 had airway disease or ILD and 13 showed no obvious abnormalities on HRCT. Abnormal IOS and PFT parameters were observed in 34 and 23 patients, respectively, with abnormal HRCT images. The predicted percentages for forced vital capacity, the ratio of forced expiratory volume in the first one second to forced vital capacity, and forced mid-expiratory flow value were significantly lower in patients with abnormal HRCT. Lung resistance at 5 Hz, difference in resistance between 5 and 20 Hz, resonant frequency (Fres), and reactance area were higher in these patients and reactance at 5 Hz was lower. Compared to other parameters, Fres > 14.14 was significantly associated with alterations in HRCT and may be used as an indicator for monitoring disease. Conclusion Fres > 14.14 is significantly associated with lung involvement in RA patients. Performance of spirometry with IOS is more beneficial than spirometry alone for evaluating lung involvement in RA patients.

Abstract The strategies of the extrapolation adjusted by model prediction (ExAMP) blending scheme, which trusts the field pattern predicted by extrapolation and allows the field intensity to be adjusted by numerical weather prediction (NWP), for rainfall nowcasting are analyzed in this study. The McGill algorithm for precipitation nowcasting by Lagrangian extrapolation (MAPLE) and the Weather Research and Forecasting (WRF) model serve as the extrapolation and NWP models, respectively. Seven 150-min rainfall nowcasting experiments with different strategies are carried out for 37 sampled periods from seven heavy rainfall events in Taiwan in 2019. The results of the overall statistics indicate that, for the extrapolation component, extrapolating the current rainfall rate estimated from the lowest dual-polarimetric radar observations is a superior strategy. The ExAMP scheme that blends the MAPLE and WRF forecasts can surpass both components in 150-min rainfall nowcasting, and an empirical limitation on the innovation of intensity during the blending procedure is found unnecessary in this study. Moreover, the spatial performance for two contrasting events reveals the ability of ExAMP in grasping the rainfall strengthening and weakening in different areas. The skill statistics separately at rainfall strengthening gauges and weakening gauges further prove the effectiveness of ExAMP even though it is effective in intensity correction instead of pattern correction.

Background: In Taiwan, the prevalence of COVID-19 was low before April 2022. The low SARS-CoV-2 seroprevalence in the population of Taiwan provides an opportunity for comparison with fewer confounding factors than other populations globally. Cycle threshold (Ct) value is an easily accessible method for modeling SARS-CoV-2 dynamics. In this study, we used clinical samples collected from hospitalized patients to explore the Ct value dynamics of the Omicron variant infection. Methods: From Jan 2022 to May 2022, we retrospectively included hospitalized patients tested positive by nasopharyngeal SARS-CoV-2 PCR. We categorized the test-positive subjects into different groups according to age, vaccination status, and use of antiviral agents. To investigate the nonlinear relationship between symptom onset days and Ct value, a fractional polynomial model was applied to draw a regression line. Results: We collected 1718 SARS-CoV-2 viral samples from 812 individuals. The Ct values of unvaccinated individuals were lower than those of vaccinated persons from Day 4 to Day 10 after symptom onset. The Ct value increased more rapidly in those individuals with antiviral drug treatment from Day 2 to Day 7. In elderly individuals, the Ct values increased slowly from Day 5 to Day 10, and the increasing trend was unique compared with that in children and adults. Conclusion: Our study demonstrated the primary viral infection dynamics of the Omicron variant in hospitalized patients. Vaccination significantly affected viral dynamics, and antiviral agents modified viral dynamics irrespective of vaccination status. In elderly individuals, viral clearance is slower than that in adults and children.

Abstract Electrical impulses from cardiac pacemaker cardiomyocytes initiate cardiac contraction and blood pumping and maintain life. Abnormal electrical impulses bring patients with low heart rates to cardiac arrest. The current therapy is to implant electronic devices to generate backup electricity. However, complications inherent to electronic devices remain unbearable suffering. Therefore, cardiac biological pacing has been developed as a hardware-free alternative. The approaches to generating biological pacing have evolved recently using cell reprogramming technology to generate pacemaker cardiomyocytes in-vivo or in-vitro. Different from conventional methods by electrical re-engineering, reprogramming-based biological pacing recapitulates various phenotypes of de novo pacemaker cardiomyocytes and is more physiological, efficient, and easy for clinical implementation. This article reviews the present state of the art in reprogramming-based biological pacing. We begin with the rationale for this new approach and review its advances in creating a biological pacemaker to treat bradyarrhythmia.

Abstract Background Neoadjuvant chemoradiotherapy followed by esophagectomy is the standard of care for locally advanced esophageal squamous cell carcinoma (ESCC). However, approximately 30% of patients still develop distant metastases and have a high incidence of treatment-related adverse events. Immunotherapy, as a new modality for anti-cancer treatment, has shown promising clinical benefits for patients with ESCC. The synergistic effects of immunotherapy and radiotherapy make their combination promising as neoadjuvant treatment for locally advanced ESCC. Methods All participants who meet the inclusion criteria will be enrolled after signing the informed consent form. Patients with thoracic segment esophageal cancer with clinical stage T2–3 N0 M0 or T2–3 N + M0 will be included. A total of 25 patients are to be recruited for the study. Twelve patients will be recruited in phase I, with at least two achieving major pathological response (MPR) before entering phase II. They will be treated with radical surgery within 4–8 weeks after the completion of two cycles of neoadjuvant radiotherapy in combination with camrelizumab according to the study schedule. The primary endpoint is the major pathological remission rate of all per-protocol patients. The secondary endpoints are the R0 resection rate, pathological complete remission rate, and adverse events. The interim analysis will be conducted after 12 patients have been enrolled. The trials will be terminated when more than two treatment-related deaths occur or fewer than five patients have major pathological remission. Discussion We designed this prospective single-arm phase II clinical study to evaluate the combination of camrelizumab and standard radiotherapy as preoperative neoadjuvant therapy for patients with resectable ESCC as part of the quest for better treatment options for patients with locally advanced ESCC. Trial registration This trial protocol has been registered on the NIH Clinical Trials database ( www.clinicaltrials.gov/ , NCT05176002. Registered on 2022/01/04). The posted information will be updated as needed to reflect protocol amendments and study progress.

Abstract Background Osteoarthritis is a very common clinical disease in middle-aged and elderly individuals, and with the advent of ageing, the incidence of this disease is gradually increasing. There are few studies on the role of basement membrane (BM)-related genes in OA. Method We used bioinformatics and machine learning methods to identify important genes related to BMs in OA patients and performed immune infiltration analysis, lncRNA‒miRNA-mRNA network prediction, ROC analysis, and qRT‒PCR. Result Based on the results of machine learning, we determined that LAMA2 and NID2 were the key diagnostic genes of OA, which were confirmed by ROC and qRT‒PCR analyses. Immune analysis showed that LAMA2 and NID2 were closely related to resting memory CD4 T cells, mast cells and plasma cells. Two lncRNAs, XIST and TTTY15, were simultaneously identified, and lncRNA‒miRNA‒mRNA network prediction was performed. Conclusion LAMA2 and NID2 are important potential targets for the diagnosis and treatment of OA.

Abstract Background Prenatal infection has been implicated in the development of neuropsychiatric disorders in children. We hypothesised that exposure to lipopolysaccharide during prenatal development could induce anxiety-like behaviour and sensorineural hearing loss in offspring, as well as disrupt neural differentiation during embryonic neural development. Methods We simulated prenatal infection in FVB mice and mouse embryonic stem cell (ESC) lines, specifically 46C and E14Tg2a, through lipopolysaccharide treatment. Gene expression profiling analyses and behavioural tests were utilized to study the effects of lipopolysaccharide on the offspring and alterations in toll-like receptor (TLR) 2-positive and TLR4-positive cells during neural differentiation in the ESCs. Results Exposure to lipopolysaccharide (25 µg/kg) on gestation day 9 resulted in anxiety-like behaviour specifically in male offspring, while no effects were detected in female offspring. We also found significant increases in the expression of GFAP and CNPase, as well as higher numbers of GFAP + astrocytes and O4+ oligodendrocytes in the prefrontal cortex of male offspring. Furthermore, increased scores for genes related to oligodendrocyte and lipid metabolism, particularly ApoE, were observed in the prefrontal cortex regions. Upon exposure to lipopolysaccharide during the ESC-to-neural stem cell (NSC) transition, Tuj1, Map2, Gfap, O4, and Oligo2 mRNA levels increased in the differentiated neural cells on day 14. In vitro experiments demonstrated that lipopolysaccharide exposure induced inflammatory responses, as evidenced by increased expression of IL1b and ApoB mRNA. Conclusions Our findings suggest that prenatal infection at different stages of neural differentiation may result in distinct disturbances in neural differentiation during ESC—NSC transitions. Furthermore, early prenatal challenges with lipopolysaccharide selectively induce anxiety-like behaviour in male offspring. This behaviour may be attributed to the abnormal differentiation of astrocytes and oligodendrocytes in the brain, potentially mediated by ApoB/E signalling pathways in response to inflammatory stimuli.

Abstract Background Several observational cohorts and meta-analytical studies on humans have shown that users of sodium-glucose cotransporter-2 inhibitors (SGLT2is) have a lower risk for new-onset acute coronary syndrome (ACS) than nonusers. However, some studies, including randomized clinical trials, reported the opposite results. This study aimed to investigate the impacts of a SGLT2i on new-onset ACS in a population. Methods We conducted a retrospective population-based cohort study involving 56,356 subjects who received SGLT2i therapy and 112,712 patients who did not receive SGLT2i therapy between May 1, 2016 and December 31, 2019. The outcome was the risk of new-onset ACS. Multivariable Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals for associations between SGLT2i use and ACS risk. Results A total of 670 and 1408 ACS events occurred in SGLT2i users and nonusers, respectively, during a follow-up of 3.7 years. SGLT2i use was associated with a nonsignificantly lower risk of ACS (adjusted HR 0.95, 95%confidence intervals (CI 0.87–1.04, P = 0.3218). We confirmed the robustness of these results through a propensity score 1:1 matching analysis. The results of the subgroup analysis of the subtype of the SGLT2i treatments were consistent with the main findings. An increased risk for the incidence of ACS in male and older (> 70 years) patients were also found. Conclusions In this population-based cohort study, we found that SGLT2i use is associated with a nonsignificantly decreased risk of ACS. No difference in the SGLT2i subtype was observed in subgroup analyses. However, the results of this study indicated an increased risk for the incidence of ACS in male and older (> 70 years) patients.

Abstract Mitochondrial dysfunction has been suggested to contribute to Parkinson’s disease pathogenesis, though an understanding of the extent or exact mechanism of this contribution remains elusive. This has been complicated by challenging nature of pathway-based analysis and an inability simultaneously study multiple related proteins within human brain tissue. We used imaging mass cytometry (IMC) to overcome these challenges, measuring multiple protein targets, whilst retaining the spatial relationship between targets in post-mortem midbrain sections. We used IMC to simultaneously interrogate subunits of the mitochondrial oxidative phosphorylation complexes, and several key signalling pathways important for mitochondrial homoeostasis, in a large cohort of PD patient and control cases. We revealed a generalised and synergistic reduction in mitochondrial quality control proteins in dopaminergic neurons from Parkinson’s patients. Further, protein-protein abundance relationships appeared significantly different between PD and disease control tissue. Our data showed a significant reduction in the abundance of PINK1, Parkin and phosphorylated ubiquitinSer65, integral to the mitophagy machinery; two mitochondrial chaperones, HSP60 and PHB1; and regulators of mitochondrial protein synthesis and the unfolded protein response, SIRT3 and TFAM. Further, SIRT3 and PINK1 did not show an adaptive response to an ATP synthase defect in the Parkinson’s neurons. We also observed intraneuronal aggregates of phosphorylated ubiquitinSer65, alongside increased abundance of mitochondrial proteases, LONP1 and HTRA2, within the Parkinson’s neurons with Lewy body pathology, compared to those without. Taken together, these findings suggest an inability to turnover mitochondria and maintain mitochondrial proteostasis in Parkinson’s neurons. This may exacerbate the impact of oxidative phosphorylation defects and ageing related oxidative stress, leading to neuronal degeneration. Our data also suggest that that Lewy pathology may affect mitochondrial quality control regulation through the disturbance of mitophagy and intramitochondrial proteostasis.

Background: Patients recovering from COVID-19 may need vaccination against SARS-CoV-2 because acquired immunity from primary infection may wane, given the emergence of new SARS-CoV-2 variants. Understanding the trends of anti-spike IgG and neutralizing antibody titers in patients recovering from COVID-19 may inform the decision made on the appropriate interval between recovery and vaccination. Methods: Participants aged 20 years or older and diagnosed with COVID-19 between January and December, 2020 were enrolled. Serum specimens were collected every three months from 10 days to 12 months after the onset of symptom for determinations of anti-spike IgG and neutralizing antibody titers against SARS-CoV-2 Wuhan strain with D614G mutation, alpha, gamma and delta variants. Results: Of 19 participants, we found a decreasing trend of geometric mean titers of anti-spike IgG from 560.9 to 217 and 92 BAU/mL after a 4-month and a 7-month follow-up, respectively. The anti-spike IgG titers declined more quickly in the ten participants with severe or critical disease than the nine participants with only mild to moderate disease between one month and seven months after SARS-CoV-2 infection (−8.49 vs - 2.34-fold, p

Background: COVID-19 rebound is usually reported among patients experiencing concurrent symptomatic and viral rebound. But longitudinal viral RT-PCR results from early stage to rebound of COVID-19 was less characterized. Further, identifying the factors associated with viral rebound after nirmatrelvir-ritonavir (NMV/r) and molnupiravir may expand understanding of COVID-19 rebound. Methods: We retrospectively analyzed clinical data and sequential viral RT-PCR results from COVID-19 patients receiving oral antivirals between April and May, 2022. Viral rebound was defined by the degree of viral load increase (ΔCt ≥ 5 units). Results: A total of 58 and 27 COVID-19 patients taking NMV/r and molnupiravir, respectively, were enrolled. Patients receiving NMV/r were younger, had fewer risk factors for disease progression and faster viral clearance rate compared to those receiving molnupiravr (All P

To address challenges in locating high-impedance grounding faults (HIGFs) and isolating fault areas in resonant grounding systems, this paper proposes a novel fault identification method based on coordinating a Peterson coil and a resistance grounding system. This method ensures power supply reliability by extinguishing the fault arc during transient faults with the Peterson coil. When a fault is determined to be permanent, the neutral point switches to a resistance grounding mode, ensuring regular distribution of zero-sequence currents in the network, thereby addressing the challenges of HIGF localization and fault area isolation. Fault calibration and nature determination rely on recognizing neutral point displacement voltage waveforms and dynamic characteristics, eliminating interference from asymmetric phase voltage variations. Fault area identification involves assessing the polarity of zero-sequence current waveforms attenuation during grounding mode switching, preventing misjudgments in grounding protection due to random initial fault angles and Peterson coil compensation states. Field experiments validate the feasibility of this fault location method and its control strategy.