Induction-concurrent chemoradiotherapy with or without sintilimab in patients with locoregionally advanced nasopharyngeal carcinoma in China (CONTINUUM): a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.

BACKGROUND: Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains unknown in patients with locoregionally advanced nasopharyngeal carcinoma. We assessed the addition of sintilimab, a PD-1 inhibitor, to standard chemoradiotherapy in this patient population. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was conducted at nine hospitals in China. Adults aged 18-65 years with newly diagnosed high-risk non-metastatic stage III-IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3-4N0 and T3N1) were eligible. Patients were randomly assigned (1:1) using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles (comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy; sintilimab group). The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events. This trial is registered with ClinicalTrials.gov (NCT03700476) and is now completed; follow-up is ongoing. FINDINGS: Between Dec 21, 2018, and March 31, 2020, 425 patients were enrolled and randomly assigned to the sintilimab (n=210) or standard therapy groups (n=215). At median follow-up of 41·9 months (IQR 38·0-44·8; 389 alive at primary data cutoff [Feb 28, 2023] and 366 [94%] had at least 36 months of follow-up), event-free survival was higher in the sintilimab group compared with the standard therapy group (36-month rates 86% [95% CI 81-90] vs 76% [70-81]; stratified hazard ratio 0·59 [0·38-0·92]; p=0·019). Grade 3-4 adverse events occurred in 155 (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (68 [33%] vs 64 [30%]), leukopenia (54 [26%] vs 48 [22%]), and neutropenia (50 [24%] vs 46 [21%]). Two (1%) patients died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3-4 immune-related adverse events occurred in 20 (10%) patients in the sintilimab group. INTERPRETATION: Addition of sintilimab to chemoradiotherapy improved event-free survival, albeit with higher but manageable adverse events. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with high-risk locoregionally advanced nasopharyngeal carcinoma. FUNDING: National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

A bright red fluorescent genetically encoded sensor for lactate imaging.

Lactate plays a crucial role in energy metabolism and greatly impacts protein activities, exerting diverse physiological and pathological effects. Therefore, convenient lactate assays for tracking spatiotemporal dynamics in living cells are desirable. In this paper, we engineered and optimized a red fluorescent protein sensor for l-lactate named FiLa-Red. This indicator exhibited a maximal fluorescence change of 730 % and an apparent dissociation constant (Kd) of approximately 460 µM. By utilizing FiLa-Red and other sensors, we monitored energy metabolism in a multiplex manner by simultaneously tracking lactate and NAD+/NADH abundance in the cytoplasm, nucleus, and mitochondria. The FiLa-Red sensor is expected to be a useful tool for performing metabolic analysis in vitro, in living cells and in vivo.

Constructing Cyclic Hydrogen Bonding to Suppress Side Reactions and Dendrite Formation on Zinc Anodes.

The high electrochemical reactivity of H2O molecules and zinc metal results in severe side reactions and dendrite formation on zinc anodes. Here we demonstrate that these issues can be addressed by using N-hydroxymethylacetamide (NHA) as additives in 2 M ZnSO4 electrolytes. The addition of NHA molecules, acting as both a hydrogen bond donor and acceptor, enables the formation of cyclic hydrogen bonding with H2O molecules. This interaction disrupts the existing hydrogen bonding networks between H2O molecules, hindering proton transport, and containing H2O molecules within the cyclic hydrogen bonding structure to prevent deprotonation. Additionally, NHA molecules show a preference for adsorption on the (101) crystal surface of zinc metal. This preferential adsorption reduces the surface energy of the (101) plane, facilitating the homogeneous Zn deposition along the (101) direction. Thus, the NHA enables Zn||Zn symmetric cell with a cycle lifespan of 1100 hours at 5 mA cm-2 and Zn||Cu asymmetric cell with a high Coulombic efficiency over 99.5%. Moreover, the NHA-modified Zn||AC zinc ion hybrid capacitor is capable of sustaining 15000 cycles at 2 A g-1. This electrolyte additive engineering presents a promising strategy to enhance the performance and broaden the application potential of zinc metal-based energy storage devices.

The link between gut microbiome and Alzheimer's disease: From the perspective of new revised criteria for diagnosis and staging of Alzheimer's disease.

Over the past decades, accumulating evidence suggests that the gut microbiome exerts a key role in Alzheimer's disease (AD). The Alzheimer's Association Workgroup is updating the diagnostic criteria for AD, which changed the profiles and categorization of biomarkers from "AT(N)" to "ATNIVS." Previously, most of studies focus on the correlation between the gut microbiome and amyloid beta deposition ("A"), the initial AD pathological feature triggering the "downstream" tauopathy and neurodegeneration. However, limited research investigated the interactions between the gut microbiome and other AD pathogenesis ("TNIVS"). In this review, we summarize current findings of the gut microbial characteristics in the whole spectrum of AD. Then, we describe the association of the gut microbiome with updated biomarker categories of AD pathogenesis. In addition, we outline the gut microbiome-related therapeutic strategies for AD. Finally, we discuss current key issues of the gut microbiome research in the AD field and future research directions. HIGHLIGHTS: The new revised criteria for Alzheimer's disease (AD) proposed by the Alzheimer's Association Workgroup have updated the profiles and categorization of biomarkers from "AT(N)" to "ATNIVS." The associations of the gut microbiome with updated biomarker categories of AD pathogenesis are described. Current findings of the gut microbial characteristics in the whole spectrum of AD are summarized. Therapeutic strategies for AD based on the gut microbiome are proposed.

Urine Metabolites Changes in Acute Myocardial Infarction Rats via Metabolomic Analysis.

OBJECTIVES: To screen biomarkers for forensic identification of acute myocardial infarction (AMI) by non-targeted metabolomic studies on changes of urine metabolites in rats with AMI. METHODS: The rat models of the sham surgery group, AMI group and hyperlipidemia + acute myocardial infarction (HAMI) group were established. Ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) was used to analyze the changes of urine metabolic spectrometry in AMI rats. Principal component analysis, partial least squares-discriminant analysis, and orthogonal partial least squares-discriminant analysis were used to screen differential metabolites. The MetaboAnalyst database was used to analyze the metabolic pathway enrichment and access the predictive ability of differential metabolites. RESULTS: A total of 40 and 61 differential metabolites associated with AMI and HAMI were screened, respectively. Among them, 22 metabolites were common in both rat models. These small metabolites were mainly concentrated in the niacin and nicotinamide metabolic pathways. Within the 95% confidence interval, the area under the curve (AUC) values of receiver operator characteristic curve for N8-acetylspermidine, 3-methylhistamine, and thymine were greater than 0.95. CONCLUSIONS: N8-acetylspermidine, 3-methylhistamine, and thymine can be used as potential biomarkers for AMI diagnosis, and abnormal metabolism in niacin and nicotinamide may be the main causes of AMI. This study can provide reference for the mechanism and causes of AMI identification.

Visualization Analysis of Artificial Intelligence Literature in Forensic Research.

OBJECTIVES: To analyze the literature on artificial intelligence in forensic research from 2012 to 2022 in the Web of Science Core Collection Database, to explore research hotspots and developmental trends. METHODS: A total of 736 articles on artificial intelligence in forensic medicine in the Web of Science Core Collection Database from 2012 to 2022 were visualized and analyzed through the literature measuring tool CiteSpace. The authors, institution, country (region), title, journal, keywords, cited references and other information of relevant literatures were analyzed. RESULTS: A total of 736 articles published in 220 journals by 355 authors from 289 institutions in 69 countries (regions) were identified, with the number of articles published showing an increasing trend year by year. Among them, the United States had the highest number of publications and China ranked the second. Academy of Forensic Science had the highest number of publications among the institutions. Forensic Science International, Journal of Forensic Sciences, International Journal of Legal Medicine ranked high in publication and citation frequency. Through the analysis of keywords, it was found that the research hotspots of artificial intelligence in the forensic field mainly focused on the use of artificial intelligence technology for sex and age estimation, cause of death analysis, postmortem interval estimation, individual identification and so on. CONCLUSIONS: It is necessary to pay attention to international and institutional cooperation and to strengthen the cross-disciplinary research. Exploring the combination of advanced artificial intelligence technologies with forensic research will be a hotspot and direction for future research.

Iodine-Promoted Oxidative Cyclization of Acylated and Alkylated Derivatives from Epoxides toward the Synthesis of Aza Heterocycles.

A new method for directly synthesizing acylated and alkylated quinazoline derivatives by the epoxide ring-opening reaction in the presence of I2/DMSO with 2-aminobenzamide is described herein. The developed mild protocol is efficient and displays a wide variety of functional group tolerance and substrate-controlled high selectivity, and the application of a continuous flow technique allows for faster reaction time and higher yields. Moreover, the robustness of the method is applicable in gram-scale synthesis.

Resistive switching mechanism of MoS2based atomristor.

The non-volatile resistive switching process of a MoS2based atomristor with a vertical structure is investigated by first-principles calculations. It is found that the monolayer MoS2with a S vacancy defect (VS) could maintain an insulation characteristic and a high resistance state (HRS) is remained. As an electrode metal atom is adsorbed on the MoS2monolayer, the semi-conductive filament is formed with the assistance ofVS. Under this condition, the atomristor presents a low resistance state (LRS). The ON state current of this semi-filament is increased close to two orders of magnitude larger than that without the filament. The energy barrier for an Au-atom to penetrate the monolayer MoS2viaVSis as high as 6.991 eV. When it comes to a double S vacancy (VS2), the energy barrier is still amounted to 3.554 eV, which manifests the bridge-like full conductive filament cannot form in monolayer MoS2based atomristor. The investigation here promotes the atomic level understanding of the resistive switching properties about the monolayer MoS2based memristor. The physics behind should also work in atomristors based on other monolayer transition-metal dichalcogenides, like WSe2and MoTe2. The investigation will be a reference for atomristor-device design or optimization.

Mesenchymal stem cell-derived exosomes and skin photoaging: From basic research to practical application.

BACKGROUND: Skin photoaging is a condition caused by long-term exposure to ultraviolet irradiation, resulting in a variety of changes in the skin, such as capillary dilation, increased or absent pigmentation, dryness, sagging, and wrinkles. Stem cells possess a remarkable antioxidant capacity and the ability to proliferate, differentiate, and migrate, and their main mode of action is through paracrine secretion, with exosomes being the primary form of secretion. Stem cell-derived exosomes contain a variety of growth factors and cytokines and may have great potential to promote skin repair and delay skin ageing. METHODS: This review focuses on the mechanisms of UV-induced skin photoaging, the research progress of stem cell exosomes against skin photoaging, emerging application approaches and limitations in the application of exosome therapy. RESULT: Exosomes derived from various stem cells have the potential to prevent skin photoaging. CONCLUSION: The combination with novel materials may be a key step for their practical application, which could be an important direction for future basic research and practical applications.

Combined Efficacy of Modified Yangxin Anshen Decoction and Western Medicine Treatment in Elderly Patients with Schizophrenia and Sleep Disorders.

Objective: To explore the combined efficacy of modified Yangxin Anshen decoction and Western medicine treatment in elderly patients with schizophrenia and sleep disorders. Methods: A total of 144 elderly patients with schizophrenia and sleep disorders in Wuhan Wudong Hospital were enrolled as participants in this study from April 2021 to April 2022. The participants were randomly and equally divided into a control group (receiving conventional Western medicine treatment) and two study groups: study group 1 received modified Yangxin Anshen decoction, and study group 2 receive modified Yangxin Anshen decoction in addition to Western medicine treatment. TCM syndrome scores, sleep quality, polysomnography, serum levels of 5-HT, DA, and MT were compared between the two groups. Moreover, the efficacy and adverse reactions were recorded. Results: After four weeks of treatment, the efficacy of study group 2 was significantly better than that of the control group and Study Group 1 (P < .05). There was no statistically significant difference between the three groups in secondary and main symptoms before treatment (P >.05), while the secondary and main symptoms of study group 2 were significantly lower than those of the control group and study group 1 after four weeks of treatment (P < .05). Before treatment, no statistically significant difference was found in sleep quality score between the three groups (P > .05), whereas the index of the study group 2 was evidently lower than that of the control group and study group 1 after four weeks of treatment (P < .05). Before treatment, there was no significant difference in terms of total recording time, total sleep time, sleep onset latency, sleep efficiency, and four stages (N1, N2, N3, and REM) between the three groups (P > .05). After four weeks of treatment, although no statistically significant difference was shown in total recording time between the three groups (P > .05), the total sleep time, sleep onset latency, sleep efficiency, and four stages (N1, N2, N3, and REM) of the study group 2 were significantly improved than those of the control group and the study group 1 (P < .05). Before treatment, there was no significant difference in serum levels of 5-HT, DA, and MT between the three groups (P > .05), while the three indexes were evidently lower than the control group and the study group 1 after four weeks of treatment (P < .05). During the treatment process, 1 case of mild dry mouth occurred in the study group who did not receive special treatment, and the incidence of adverse reactions was 1/48. In the control group, there were 3 cases of dry mouth, 1 case of constipation, 1 case of diarrhea, 1 case of decreased appetite, and 1 case of nausea, whose symptoms were not specially treated, with the incidence of adverse reactions of 7/48. Hence the incidence of adverse reactions in the study group was significantly lower than that in the control group (P < .05). Conclusion: Combined treatment with modified Yangxin Anshen decoction and Western medicine improved sleep quality in elderly patients with schizophrenia and sleep disorders, which is available for wide clinical application.

[Dihydromyricetin improves Parkinson's disease-like lesions in T2DM rats by activating AMPK/ULK1 pathway].

The purpose of this study was to explore the effect and mechanism of dihydromyricetin (DHM) on Parkinson's disease (PD)-like lesions in type 2 diabetes mellitus (T2DM) rats. The T2DM model was established by feeding Sprague Dawley (SD) rats with high-fat diet and intraperitoneal injection of streptozocin (STZ). The rats were intragastrically administered with DHM (125 or 250 mg/kg per day) for 24 weeks. The motor ability of the rats was measured by balance beam experiment, the changes of dopaminergic (DA) neurons and the expression of autophagy initiation related protein ULK1 in the midbrains of the rats were detected by immunohistochemistry, and the protein expression levels of α-synuclein (α-syn), tyrosine hydroxylase (TH), as well as AMPK activation level, in the midbrains of the rats were detected by Western blot. The results showed that, compared with normal control, the rats with long-term T2DM exhibited motor dysfunction, increased α-syn aggregation, down-regulated TH protein expression, decreased number of DA neurons, declined activation level of AMPK, and significantly down-regulated ULK1 expression in the midbrain. DHM (250 mg/kg per day) treatment for 24 weeks significantly improved the above PD-like lesions, increased AMPK activity, and up-regulated ULK1 protein expression in T2DM rats. These results suggest that DHM may improve PD-like lesions in T2DM rats by activating AMPK/ULK1 pathway.

Temporal and spatial characteristics of tumor evolution in a mouse model of oral squamous cell carcinoma.

OBJECTIVES: We aimed to elucidate the temporal and spatial characteristics of tumor evolution in an oral squamous cell carcinoma (OSCC) mouse model with higher burden of lymphatic metastasis through high-throughput sequencing. METHODS: The OSCC model was established in 9 mice. DNA was extracted from the tumors of primary tongue lesions and disseminated tumor cells (DTCs) of submandibular gland lymph nodes and bone marrow, and then whole genome sequencing was performed. After bioinformatics analysis, somatic single-nucleotide variants (SSNVs) and copy number variations (CNVs) data were obtained. Based on SSNVs, clonal architecture and ancestor-descendant relationships among tumor cell subclones were elucidated. RESULTS: A total of 238 tumor-related SSNVs with 120 high-frequency mutated genes were obtained from 36 samples of 9 mice by whole-genome sequencing. The number of unique SSNVs in the primary lesion, submandibular lymph node and bone marrow was greater than the number of shared SSNVs. Furthermore, the primary lesion-originated subclones, which were identified by SSNVs, were also detected in submandibular lymph nodes in the early stage of oral carcinogenesis. Moreover, at different histopathological stages, unique subclones were also identified in DTCs isolated from lymph nodes. CONCLUSION: Tumor heterogeneity is significant in primary tumor cells and disseminated tumor cells. OSCC cells probably disseminate to lymph nodes in the early stage of oral carcinogenesis. OSCC is characterized by polyclonal dissemination, and the evolutionary trajectory of DTCs is potentially dominated by the tumor microenvironment.

Metal-Free N-H/C-H Carbonylation by Phenyl Isocyanate: Divergent Synthesis of Six-Membered N-Heterocycles.

We disclose a method using phenyl isocyanate to synthesize carbonyl-containing N-heterocycles. The metal-free novel approach for both N-H and C-H carbonylation processes was successfully refined, delivering a range of synthetically valuable derivatives of quinazoline-2,4(1H,3H)-dione, 2H-benzo[e] [1,2,4] thiadiazin-3(4H)-one 1,1-dioxide, and pyrrolo[1,2-a] quinoxalin-4(5H)-one. The protocol features broad substrates with diverse reactions suitable for excellent yields, mild conditions, and good functional group compatibility. Moreover, the applicability of the reaction was characterized by gram-scale synthesis and synthetic transformations for drug molecules.

Bacillus subtilis WB800N alleviates diabetic wounds in mice by regulating gut microbiota homeostasis and TLR2.

OBJECTIVE: This study aims to investigate the effect of Bacillus subtilis WB800N on diabetic wounds. METHODS: Haematoxylin & eosin (H&E) staining was used to observe the healing of skin wounds. Collagen deposition was assessed by Masson staining. Western blotting and qRT-PCR were used to detect vascular endothelial-related factors (VWF), CD31, TLR2, NLRP3, ASC and Caspase-1 expression. 16S rDNA sequencing detected microbiota distribution. The concentrations of IL-1ß and IL-37 were measured by ELISA. Apoptosis was measured by the TUNEL assay. RESULTS: Compared with the control group, wound healing was delayed in diabetic mice. The wound area in the Bacillus subtilis group decreased more significantly than the diabetic wound group. H&E staining showed that Bacillus subtilis WB800N promoted wound healing and increased re-epithelialization. Masson staining showed that Bacillus subtilis WB800N increased collagen deposition in mice with diabetic wounds. Bacillus subtilis WB800N upregulated VWF and CD31 protein expression in diabetic wounds mice. The 16S rDNA results showed that Bacillus subtilis WB800N reduced the diversity of the gut microbiota of diabetic wounds mice and regulated the microbial composition. At the genus level, Bacillus subtilis WB800N reduced the relative abundance of Muribaculaceae and CG - 005 in diabetic wounds mice, whilst increasing the relative abundance of Lactobacillus. Bacillus subtilis WB800N increased the expression of TLR2, NLRP3, ASC and Caspase-1. Bacillus subtilis WB800N increased the concentrations of IL-1ß and IL-37 in serum. Bacillus subtilis WB800N upregulated cell apoptosis. The TLR2 antagonist Sparstolonin B (SsnB) reduced the expression of TLR2, NLRP3, ASC, Caspase-1, IL-1ß and IL-37 and the apoptosis in diabetic wounds mice, whilst the combined intervention of Bacillus subtilis and SsnB reversed the effect of SsnB treatment alone. CONCLUSION: Bacillus subtilis WB800N alleviated diabetic wound healing by regulating gut microbiota homeostasis and TLR2. SIGNIFICANCE AND IMPACT OF RESEARCH: Our findings might provide potential therapeutic targets for diabetic wounds.

Effect of Stromal Vascular Fractions on Angiogenesis of Injected Diced Cartilage.

OBJECTIVES: This study explored the effect of adipose-derived stromal vascular fractions (SVFs) on angiogenesis in injected autologous diced cartilage. METHODS: Stromal vascular fractions were extracted by enzymatic digestion. Cartilage grafts were harvested from 1 side of the auricular cartilage of New Zealand rabbit and then diced to a size of 1.0 mm3. The grafts were divided into 2 groups. The control group was diced cartilage mixed with culture medium, and the experimental group was diced cartilage mixed with SVFs. The 2 groups of composite grafts were subcutaneously implanted on both sides of the back of each rabbit. After 4, 12 and 24 weeks, the tissue structure, number of blood vessels, and angiogenic factors in the grafts were observed. RESULTS: The SVFs conformed to the current standard of the biological evaluation. Under an inverted microscope, the number of layers of chondrocytes in the experimental group was higher than that in the control group at 4 weeks. A small number of inflammatory cells and blood vessels were observed around the cartilage grafts. At 12 and 24 weeks, the volume of tissue was increased gradually by general observation. And a large number of chondrocytes were observed microscopically, whereas the number of inflammatory cells decreased. And meanwhile additional new blood vessels were observed. Immunohistochemical analysis of CD31 showed that the number of capillaries in the control group was significantly lower than that in the experimental group at 4, 12 and 24 weeks. Further, the expression of Hypoxia inducible factor-1 (HIF-1) and vascular endothelial growth factor (VEGF) mRNA and protein were measured by RT-PCR and Western bloting, respectively. The results showed that the mRNA expression of VEGF and HIF-1α in the experimental group was increased. The mRNA level remained higher than that of the control group at 24 weeks (P < 0.05). And the relative expression levels of VEGF and HIF-1α protein in the experimental group were higher than those in the control group at 4, 12 and 24 weeks (P < 0.05). CONCLUSION: Autologous diced cartilage mixed with adipose-derived SVFs can promote angiogenesis when transplanted by injection. Further research showed that SVFs could increase the expression levels of VEGF and HIF-1α in the grafts, which may be part of the mechanism that SVFs promoted the angiogenesis of diced cartilage.

Screening Biomarkers of Sudden Coronary Death Based on mRNA Expression Profile of Rat Myocardial Tissues.

OBJECTIVES: To explore the differential expression of messenger RNA (mRNA) in myocardial tissues of rats with sudden coronary death (SCD), and to provide ideas for the forensic identification of SCD. METHODS: The rat SCD model was established, and the transcriptome sequencing was performed by next-generation sequencing technology. Differentially expressed genes (DEGs) in myocardial tissues of SCD rats were screened by using the R package limma. A protein-protein interaction (PPI) network was constructed by using the STRING database and Cytoscape 3.8.2 on DEG, and hub genes were screened based on cytoHubba plug-in. Finally, the R package clusterProfiler was used to analyze the biological function and signal pathway enrichment of the selected DEG. RESULTS: A total of 177 DEGs were associated with SCD and were mainly involved in the renin-angiotensin system and PI3K-Akt signaling pathway. The genes including angiotensinogen (AGT), complement component 4a (C4a), Fos proto-oncogene (FOS) and others played key roles in the development of SCD. CONCLUSIONS: Genes such as AGT, C4a, FOS and other genes are expected to be potential biomarkers for forensic identification of SCD. The study based on mRNA expression profile can provide a reference for forensic identification of SCD.

Gravity determines the direction of nerve roots sedimentation in the lumbar spinal canal.

OBJECTIVES: To investigate the role of gravity in the sedimentation of lumbar spine nerve roots using magnetic resonance (MR) imaging of various body positions. METHODS: A total of 56 patients, who suffered from back pain and underwent conventional supine lumbar spine MR imaging, were selected from sanmen hospital database. All the patients were called back to our hospital to perform MR imaging in prone position or lateral position. Furthermore, the sedimentation sign (SedSign) was determined based on the suspension of the nerve roots in the dural sac on cross-sectional MR images, and 31 cases were rated as positive and another 25 cases were negative. RESULTS: The mean age of negative SedSign group was significantly younger than that of positive SedSign group (51.7 ± 8.7 vs 68.4 ± 10.5, P < 0.05). The constitutions of clinical diagnosis were significantly different between patients with a positive SedSign and those with a negative SedSign (P < 0.001). Overall, nerve roots of the vast majority of patients (48/56, 85.7%) subsided to the ventral side of the dural sac on the prone MR images, although that of 8 (14.3%) patients remain stay in the dorsal side of dural sac. Nerve roots of only one patient with negative SedSign did not settle to the ventral dural sac, while this phenomenon occurred in 7 patients in positive SedSign group (4% vs 22.6%, P < 0.001). In addition, the nerve roots of all the five patients subsided to the left side of dural sac on lateral position MR images. CONCLUSIONS: The nerve roots sedimentation followed the direction of gravity. Positive SedSign may be a MR sign of lumbar pathology involved the spinal canal.

Creating a Scoring System with an Armband Wearable Device for Table Tennis Forehand Loop Training: Combined Use of the Principal Component Analysis and Artificial Neural Network.

BACKGROUND: This study presents an intelligent table tennis e-training system based on a neural network (NN) model that recognizes data from sensors built into an armband device, with the component values (performances scores) estimated through principal component analysis (PCA). METHODS: Six expert male table tennis players on the National Youth Team (mean age 17.8 ± 1.2 years) and seven novice male players (mean age 20.5 ± 1.5 years) with less than 1 year of experience were recruited into the study. Three-axis peak forearm angular velocity, acceleration, and eight-channel integrated electromyographic data were used to classify both player level and stroke phase. Data were preprocessed through PCA extraction from forehand loop signals. The model was trained using 160 datasets from five experts and five novices and validated using 48 new datasets from one expert and two novices. RESULTS: The overall model's recognition accuracy was 89.84%, and its prediction accuracies for testing and new data were 93.75% and 85.42%, respectively. Principal components corresponding to the skills "explosive force of the forearm" and "wrist muscle control" were extracted, and their factor scores were standardized (0-100) to score the skills of the players. Assessment results indicated that expert scores generally fell between 60 and 100, whereas novice scores were less than 70. CONCLUSION: The developed system can provide useful information to quantify expert-novice differences in fore-hand loop skills.

Concurrent chemoradiotherapy with/without induction chemotherapy in locoregionally advanced nasopharyngeal carcinoma: Long-term results of phase 3 randomized controlled trial.

To report long-term results of a randomized controlled trial that compared cisplatin/fluorouracil/docetaxel (TPF) induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT) with CCRT alone in locoregionally advanced nasopharyngeal carcinoma (NPC). Patients with stage III-IVB (except T3-4 N0) NPC were randomly assigned to receive IC plus CCRT (n = 241) or CCRT alone (n = 239). IC included three cycles of docetaxel (60 mg/m2 d1), cisplatin (60 mg/m2 d1), and fluorouracil (600 mg/m2 /d civ d1-5) every 3 weeks. Patients from both groups received intensity-modulated radiotherapy concurrently with three cycles of 100 mg/m2 cisplatin every 3 weeks. After a median follow-up of 71.5 months, the IC plus CCRT group showed significantly better 5-year failure-free survival (FFS, 77.4% vs. 66.4%, p = 0.019), overall survival (OS, 85.6% vs. 77.7%, p = 0.042), distant failure-free survival (88% vs. 79.8%, p = 0.030), and locoregional failure-free survival (90.7% vs. 83.8%, p = 0.044) compared to the CCRT alone group. Post hoc subgroup analyses revealed that beneficial effects on FFS were primarily observed in patients with N1, stage IVA, pretreatment lactate dehydrogenase ≥170 U/l, or pretreatment plasma Epstein-Barr virus DNA ≥6000 copies/mL. Two nomograms were further developed to predict the potential FFS and OS benefit of TPF IC. The incidence of grade 3 or 4 late toxicities was 8.8% (21/239) in the IC plus CCRT group and 9.2% (22/238) in the CCRT alone group. Long-term follow-up confirmed that TPF IC plus CCRT significantly improved survival in locoregionally advanced NPC with no marked increase in late toxicities and could be an option of treatment for these patients.

Carbamazepine promotes specific stimuli-induced NLRP3 inflammasome activation and causes idiosyncratic liver injury in mice.

The occurrence of idiosyncratic drug-induced liver injury (IDILI) is a leading cause of post-marketing safety warnings and withdrawals of drugs. Carbamazepine (CBZ), widely used as an antiepileptic agent, could cause rare but severe idiosyncratic liver injury in humans. Although recent studies have shown that inflammasome is implicated in CBZ-induced hepatocellular injury in vitro, the precise pathogenesis of hepatotoxicity remains largely unexplored. Here we report that CBZ causes idiosyncratic liver injury through promoting specific stimuli-induced NLRP3 inflammasome activation. CBZ (40 µM) enhances NLRP3 inflammasome activation triggered by adenosine triphosphate (ATP) or nigericin, rather than SiO2, monosodium urate crystal or intracellular lipopolysaccharide (LPS). In addition, CBZ has no effect on NLRC4 or AIM2 inflammasome activation. Mechanistically, synergistic induction of mitochondrial reactive oxygen species (mtROS) is a crucial event in the enhancement effect of CBZ on ATP- or nigericin-induced NLRP3 inflammasome activation. Moreover, the "C=C" on the seven-membered ring and "C=O" on the nitrogen of CBZ may be contribute to NLRP3 inflammasome hyperactivation and hepatotoxicity. Notably, in vivo data indicate that CBZ (50 mg/kg) causes liver injury in an LPS (2 mg/kg)-mediated susceptibility mouse model of IDILI, accompanied by an increase in caspase-1 activity and IL-1ß production, whereas the combination of CBZ and LPS does not exhibit the effect in NLRP3-knockout mice. In conclusion, CBZ specifically promotes ATP- or nigericin-induced NLRP3 inflammasome activation and causes idiosyncratic liver injury. Our findings also suggest that CBZ may be avoided in patients with NLRP3 inflammasome activation-related diseases that are triggered by ATP or nigericin, which may be risk factors for IDILI.