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The secondary prevention trials of Alzheimer’s disease (AD) require an enrichment strategy to recruit individuals with imminent cognitive decline at the preclinical stage. Previously, we demonstrated a variant neural correlates of episodic memory (EM) function in apolipoprotein E (APOE) e4 carriers. Herein, we investigated whether this variation was associated with longitudinal EM performance. This 3-year longitudinal study included 88 normal elderly subjects with EM assessment and resting-state functional MRI data at baseline; 48 subjects (27 e3 homozygotes and 21 e4 carriers) underwent follow-up EM assessment. In the identified EM neural correlates, multivariable regression models examined the association between hippocampal functional connectivity (HFC) and longitudinal EM change. Independent validation was performed using the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset. At baseline, the EM neural correlates were characterized in the Papez circuit regions in the e3 homozygotes, but in the sensorimotor cortex and cuneus in the e4 carriers. Longitudinally, the e4 carriers exhibited a negative association of the baseline HFC strength in the EM neural correlates with annual rate of EM change (R2 = 0.25, p = 0.05). This association also showed a trend in the ADNI dataset (R2 = 0.42, p = 0.06). These results indicate that hippocampal hyperconnectivity in the variant EM neural correlates is associated with imminent EM decline in e4 carriers, which may serve as a promising enrichment strategy for secondary prevention trials of AD.

The occurrence of cardiac surgery-associated acute kidney injury (CSA-AKI) increases hospital stay and mortality. MicroRNAs has a crucial role in AKI. This objective of the current study is to explore the function of hsa-miR-494-3p in inflammatory response in human kidney tubular epithelial (HK2) cells with hypoxia/reoxygenation. According to KDIGO standard, patients after cardiac surgery with cardiopulmonary bypass were divided into two groups: AKI (n = 10) and non-AKI patients (n = 8). HK2 were raised in the normal and hypoxia/reoxygenation circumstances and mainly treated by overexpression ofmiR-494-3p and HtrA3. The relationship between miR-494-3p and HtrA3 was determined by dual-luciferase reporter assay. Our result showed that Hsa-miR-494-3p was elevated in the serum of patients with CSA-AKI, and also induced in hypoxic reoxygenated HK2 cells. Hsa-miR-494-3p also increased a hypoxia-reoxygenation induced inflammatory response in HK2 cells. Moreover, as a target gene of miR-494-3p, overexpression of HtrA3 downregulated the hypoxia-reoxygenation induced inflammatory response in HK2 cells. Overexpression of hsa-miR-494-3p-induced inflammatory response was inhibited by overexpression of HtrA3. Collectively, we identified that hsa-miR-494-3p, a miRNA induced in both circulation of AKI patients and hypoxia-reoxygenation-treated HK2 cells, enhanced renal inflammation by targeting HtrA3, which may suggest a possible role as a new therapeutic target for CSA-AKI.

Objective Acute grief, in an important minority of older adults, can become protracted, intense, and debilitating, leading to the development of complicated grief (CG). However, the neurobiologic mechanisms underlying a maladaptive grief response after an attachment loss are unknown. The current study aimed to examine the amygdala brain network features that cross-sectionally explain the symptom variance and longitudinally relate to grief symptom trajectories after an attachment loss. Methods Baseline amygdala functional connectivity (Fc) was assessed using a seed-based resting-state functional magnetic resonance imaging method in 35 adults who were within 1-year after death of a loved one and 21 healthy comparison (HC) participants. Magnetic resonance imaging scans were obtained at baseline, and clinical assessments, including the inventory of complicated grief (ICG) were completed at weeks 0, 8, 16, and 26 (endpoint). Results Relative to HC participants, grief participants showed increased amygdala Fc in the posterior default mode (bilateral medial temporal lobes and left precuneus) and thalamus. Amygdala Fc in the default mode and ventral affective regions positively correlated with ICG scores at baseline. Furthermore, increased baseline amygdala functional connections with the dorsal frontal executive control and salience network regions correlated with worsening ICG scores over time. These longitudinal findings persisted after controlling for covariates, including baseline depressive and anxiety symptoms. Conclusion These results provide novel preliminary evidence suggesting amygdala-based brain network measures to cross-sectionally explain symptom variance and longitudinally correlate with grief symptom trajectories in grievers. Amygdala brain network function measures may have the potential to serve as biomarkers of CG.

HCC is a common malignancy worldwide and surgery or reginal treatments are deemed insufficient for advanced-stage disease. Sorafenib is an inhibitor of many kinases and was shown to benefit advanced HCC patients. However, resistance emerges soon after initial treatment, limiting the clinical benefit of sorafenib, and the mechanisms still remain elusive. Thus, this study aims to investigate the mechanisms of sorafenib resistance and to provide possible targets for combination therapies. Through miRNA sequencing, we found that miR-486-3p was downregulated in sorafenib resistant HCC cell lines. Cell viability experiments showed increased miR-486-3p expression could induce cell apoptosis while miR-486-3p knockdown by CRISPR-CAS9 technique could reduce cell apoptosis in sorafenib treatment. Clinical data also indicated that miR-486-3p level was downregulated in tumor tissue compared with adjacent normal tissue in HCC patients. Mechanism dissections showed that FGFR4 and EGFR were the targets of miR-486-3p, which was verified by luciferase reporter assay. Importantly, FGFR4 or EGFR selective inhibitor could enhance sorafenib efficacy in the resistant cells. Moreover, in vivo sorafenib resistant model identified that over-expressing miR-486-3p by lentivirus injection could overcome sorafenib resistance by significantly suppressing tumor growth in combination with the treatment of sorafenib. In conclusion, we found miR-486-3p was an important mediator regulating sorafenib resistance by targeting FGFR4 and EGFR, thus offering a potential target for HCC treatment.

Purpose Retinitis pigmentosa (RP) is caused by mutations in more than 60 genes. Mutation-independent approaches to its treatment by exogeneous administration of neurotrophic factors that will preserve existing retinal anatomy and visual function are a rational strategy. Ciliary neurotrophic factor (CNTF) and oncostatin M (OSM) are two potent survival factors for neurons. However, growth factors degrade rapidly if administered directly. A sustained delivery of growth factors is required for translating their potential therapeutic benefit into patients. Methods Stable and biocompatible nanoparticles (NP) that incorporated with CNTF and OSM (CNTF- and OSM-NP) were formulated. Both NP-trophic factors were tested in vitro using photoreceptor progenitor cells (PPC) and retinal ganglion progenitor cells (RGPC) derived from induced pluripotent stem cells and in vivo using an optic nerve crush model for glaucoma and the Royal College of Surgeons rat, model of RP (n = 8/treatment) by intravitreal delivery. Efficacy was evaluated by electroretinography and optokinetic response. Retinal histology and a whole mount analysis were performed at the end of experiments. Results Significant prosurvival and pro-proliferation effects of both complexes were observed in both photoreceptor progenitor cells and RGPC in vitro. Importantly, significant RGC survival and preservation of vision and photoreceptors in both complex-treated animals were observed compared with control groups. Conclusions These results demonstrate that NP-trophic factors are neuroprotective both in vitro and in vivo. A single intravitreal delivery of both NP-trophic factors offered neuroprotection in animal models of retinal degeneration. Translational relevance Sustained nanoparticle delivery of neurotrophic factors may offer beneficial effects in slowing down progressive retinal degenerative conditions, including retinitis pigmentosa, age-related macular degeneration, and glaucoma.

Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Elucidating networks underlying conscious perception is important to understanding the mechanisms of anesthesia and consciousness. Previous studies have observed changes associated with loss of consciousness primarily using resting paradigms. The authors focused on the effects of sedation on specific cognitive systems using task-based functional magnetic resonance imaging. The authors hypothesized deepening sedation would degrade semantic more than perceptual discrimination. Methods Discrimination of pure tones and familiar names were studied in 13 volunteers during wakefulness and propofol sedation targeted to light and deep sedation. Contrasts highlighted specific cognitive systems: auditory/motor (tones vs. fixation), phonology (unfamiliar names vs. tones), and semantics (familiar vs. unfamiliar names), and were performed across sedation conditions, followed by region of interest analysis on representative regions. Results During light sedation, the spatial extent of auditory/motor activation was similar, becoming restricted to the superior temporal gyrus during deep sedation. Region of interest analysis revealed significant activation in the superior temporal gyrus during light (t [17] = 9.71, P < 0.001) and deep sedation (t [19] = 3.73, P = 0.001). Spatial extent of the phonologic contrast decreased progressively with sedation, with significant activation in the inferior frontal gyrus maintained during light sedation (t [35] = 5.17, P < 0.001), which didn’t meet criteria for significance in deep sedation (t [38] = 2.57, P = 0.014). The semantic contrast showed a similar pattern, with activation in the angular gyrus during light sedation (t [16] = 4.76, P = 0.002), which disappeared in deep sedation (t [18] = 0.35, P = 0.731). Conclusions Results illustrate broad impairment in cognitive cortex during sedation, with activation in primary sensory cortex beyond loss of consciousness. These results agree with clinical experience: a dose-dependent reduction of higher cognitive functions during light sedation, despite partial preservation of sensory processes through deep sedation.

This study aims to introduce an innovative adjustable prone positioning frame (APPF) and explore its feasibility and safety for treatment of severe kyphosis secondary to ankylosing spondylitis (AS) with two-level osteotomy.A retrospective, non-controlled study was conducted to illustrate the process where 13 patients diagnosed with severe kyphosis secondary to AS received operations on the APPF. Parameters of chin brow vertical angle (CBVA), global kyphosis (GK), thoracolumbar kyphosis (TLK), lumbar lordosis (LL) and sagittal vertical axis (SVA) were measured. Positioning time, operation time, intraoperative blood loss aḥd complications were also determined. The Scoliosis Research Society outcomes instrument (SRS-22) was applied for clinical assessment.All patients were placed on the APPF successfully with the positioning time of 2.92 ± 0.76 min, received operation with 457.00 ± 88.04 min and had blood loss of 2330.77 ± 1423.25 ml. Four cases experienced pain due to tensional skin of the abdomen and one case suffered cerebrospinal fluid leakage postoperatively, but these patients were all cured conservatively. No neurological complications were observed, although sagittal translation occurred in four patients. Significant improvements were detected in CBVA, GK, TLK, LL and SVA postoperatively (P 0.05), but no significant difference was observed between postoperation and the final follow-up (P 0.05). The SRS-22 scores at 2 years after operation were significantly higher than those before operation (P 0.05).The innovative APPF provided great convenience to place patients with severe kyphosis secondary to AS in a prone position. Performing two-level osteotomy with the aid of APPF is safe, feasible and effective.

Hepatocellular carcinoma (HCC) is a deadly tumor with high heterogeneity. Aerobic glycolysis is a common indicator of tumor growth and plays a key role in tumorigenesis. Heterogeneity in distinct metabolic pathways can be used to stratify HCC into clinically relevant subgroups, but these have not yet been well-established. In this study, we constructed a model called aerobic glycolysis index (AGI) as a marker of aerobic glycolysis using genomic data of hepatocellular carcinoma from The Cancer Genome Atlas (TCGA) project. Our results showed that this parameter inferred enhanced aerobic glycolysis activity in tumor tissues. Furthermore, high AGI is associated with poor tumor differentiation and advanced stages and could predict poor prognosis including reduced overall survival and disease-free survival. More importantly, the AGI could accurately predict tumor sensitivity to Sorafenib therapy. Therefore, the AGI may be a promising biomarker that can accurately stratify patients and improve their treatment efficacy.

Power sources play an important role in the characteristics and the applications of the electrothermal (ET) plasma as an edge localized mode (ELM) heat flux simulator. A repetitive high current ET plasma source with the capability of working at a 10 Hz repetition rate and peak current 7.5 kA is presented in this paper. By controlling the sequence of discharge of ten pulse power modules, a repetitive high heat flux plasma jet can be generated. A two-stage capillary structure is presented, and its repetitive trigger driving circuit based on surface flashover ignition is designed to achieve reliable and repetitive discharge. The topology of the inductive and capacitive (LC) series resonant circuit is applied to the charging system of the pulsed power source. The charging current is limited to 500 A with a charging time of 3.5 ms, and the ratio of the charging voltage to the operating voltage is 1.85. A diode and a power resistor in series are used to suppress the negative overvoltage, which is helpful to increase the thyristors’ operating reliability. Using the designed repetitive ET plasma source, the characteristics of the ET plasma jet are investigated by measuring the voltages and currents and by obtaining images of the discharges. Experimental results show that the repetitive ET plasma generator can be used as an appropriate way to simulate the ELM-like heat flux plasma.

Convergent studies have highlighted the amygdala-based and dorsal anterior cingulate cortex (dACC)-based circuit or network dysfunction in post-traumatic stress disorder (PTSD). However, previous studies are often complicated by various traumatic types, psychiatric comorbidities, chronic illness duration, and medication effect on brain function. Besides, little is known whether the functional integration with amygdala-dACC interaction disrupted or not in PTSD. Here, we investigated effective connectivity (EC) between the amygdala-dACC and rest of the cortex by applying psycho-physiological interaction (PPI) approach to resting-state functional magnetic resonance imaging data of 63 drug-naive PTSD patients and 74 matched trauma-exposed non-PTSD controls. Pearson correlation analysis was performed between EC values extracted from regions with between-group difference and clinical profiles in PTSD patients. We observed distinct amygdala-dACC interaction pattern between PTSD group and the control group, which is composed primarily by positive EC in the former and negative in the latter. In addition, compared with non-PTSD controls, PTSD patients showed increased EC between amygdala-dACC and the prefrontal cortex, left inferior parietal lobule, and bilateral ventral occipital cortex, and decreased EC between amygdala-dACC and the left fusiform gyrus. The EC increase between amygdala-dACC and the right middle frontal gyrus was negatively correlated with the clinician-administered PTSD scale scores in PTSD patients. Aberrent communication between amgydala-dACC and brain regions involved in central executive network and visual systems might be associated with the pathophysiology of PTSD. Further, these findings suggested that dysconnectivity of the amygdala and dACC could be adapted as a relatively early course diagnostic biomarker of PTSD.

Background Chronic pain has been associated with alterations in brain structure and function that appear dependent on pain phenotype. Functional connectivity (FC) data on chronic back pain (CBP) is limited and based on heterogeneous pain populations. We hypothesize that failed back surgery syndrome (FBSS) patients being considered for spinal cord stimulation (SCS) therapy have altered resting state (RS) FC cross-network patterns that 1) specifically involve emotion and reward/aversion functions and 2) are related to pain scores. Methods RS functional MRI (fMRI) scans were obtained for 10 FBSS patients who are being considered for but who have not yet undergone implantation of a permanent SCS device and 12 healthy age-matched controls. Seven RS networks were analyzed including the striatum (STM). The Wilcoxon signed-rank test evaluated differences in cross-network FC strength (FCS). Differences in periaqueductal grey (PAG) FC were assessed with seed-based analysis. Results Cross-network FCS was decreased (p

Purpose The aim is to measure and analyze the wave amplitudes and time intervals of differential graphs of reconstructed impedance cardiography (RICG). Methods 180 adults with normal cardiac function between the ages of 18–78 were included in the study. Six mingled impedance changes on chest surface were simultaneously detected for each subject. The differential graphs of five impedance change components of RICG were obtained through waveform separation and software differentiation. The amplitudes of C, X, O, b waves and time intervals of Q‐b and Q‐C were measured and statistically analyzed. Results The amplitudes of C and X waves in PL, PR, AO, and that of C, O, b waves in LV and RV, all decrease as age increases. Wave amplitudes of the female group were bigger than those of the male group (p

This paper is an attempt to study the mechanical behavior of square concrete-filled bimetallic tubular (CFBT) stub columns subjected to axial compression. The bimetallic tubes in the CFBT columns in this research comprised an outer layer made of stainless steel and an inner layer made of carbon steel. 200-mm square carbon steel tubes (wall thickness tsc = 3.30 mm) were manufactured first, then the bimetallic tubes were fabricated by cladding the carbon steel tubes with stainless steel sheets. In the experimental program, fourteen CFBT columns and two conventional concrete-filled steel tubular (CFST) counterparts were tested to failure under axial compressive loading. The test parameters included the stainless steel grade (Grade 316, 304, and 202), wall thickness of the stainless steel tube layer (tss = 0.84, 1.32, and 1.88 mm), and cube compressive strength of concrete (fcu = 54.5, 68.4, and 80.5 MPa). A finite element analysis (FEA) model was established and validated against the experimental measurements. The failure mode and mechanical behavior of the square CFBT stub columns were then investigated and compared with those of the conventional CFST columns. Finally, the ultimate loads obtained from the experiments were compared to those predicted by the available design codes.

Clinical patients in a vegetative state or unresponsive wakefulness syndrome (VS/UWS) demonstrate distinct arousal-awareness dissociation; the neuropathological mechanisms underlying such dissociation remain poorly understood. Here, we systematically examined how functional connectivity from the brainstem areas regulating arousal to the cortical networks supporting internal and external awareness is disrupted in minimally conscious state (MCS) and VS/UWS patients. Resting-state functional imaging was conducted in 23 MCS patients, 31 VS/UWS patients, and 20 age-matched healthy individuals. A hierarchical cluster analysis was conducted using all voxel-based signals in the brainstem to identify the specific areas for arousal. We found that the pontine tegmentum area (PTA) and caudal midbrain area persistently formed a distinct cluster that exclusively showed extensive connections with the cortical networks supporting internal and external awareness in healthy individuals, confirming their role in arousal. We show that functional connectivity from the PTA and caudal midbrain area to the cortical-awareness-supporting networks were significantly reduced in MCS and VS/UWS patients; importantly, as the clinical symptoms of consciousness disorders deepen from MCS to VS/UWS, functional connectivity strength became significantly reduced, changing from presenting no significant connections in MCS to widespread negative connections in VS/UWS. Additionally, we observed increased connectivity from the PTA and caudal midbrain area to limbic structures, the brainstem areas, and the cerebellum in MCS and VS/UWS patients, consistent with prior studies. These findings offer important insights into the neural network mechanisms underlying the long-observed arousal-awareness dissociation in VS/UWS patients and provide additional neuroimaging-based biomarkers for the clinical diagnosis of MCS and VS/UWS patients.

The level and richness of consciousness depend on information integration in the brain. Altered interregional functional interactions may indicate disrupted information integration during anesthetic-induced unconsciousness. How anesthetics modulate the amount of information in various brain regions has received less attention. Here, we propose a novel approach to quantify regional information content in the brain by the entropy of the principal components of regional blood oxygen-dependent imaging signals during graded propofol sedation. Fifteen healthy individuals underwent resting-state scans in wakeful baseline, light sedation (conscious), deep sedation (unconscious), and recovery (conscious). Light sedation characterized by lethargic behavioral responses was associated with global reduction of entropy in the brain. Deep sedation with completely suppressed overt responsiveness was associated with further reductions of entropy in sensory (primary and higher sensory plus orbital prefrontal cortices) but not high-order cognitive (dorsal and medial prefrontal, cingulate, parietotemporal cortices and hippocampal areas) systems. Upon recovery of responsiveness, entropy was restored in the sensory but not in high-order cognitive systems. These findings provide novel evidence for a reduction of information content of the brain as a potential systems-level mechanism of reduced consciousness during propofol anesthesia. The differential changes of entropy in the sensory and high-order cognitive systems associated with losing and regaining overt responsiveness are consistent with the notion of "disconnected consciousness", in which a complete sensory-motor disconnection from the environment occurs with preserved internal mentation.

Functional connectivity magnetic resonance imaging (fcMRI), a specific form of MRI imaging, quantitatively assesses connectivity between brain regions that share functional properties. Functional connectivity magnetic resonance imaging has already provided unique insights into changes in the brain in patients with conditions such as depression and pain and symptoms that have been reported by patients with psoriasis and are known to impact quality of life. To identify the central neurological impact of psoriasiform inflammation of the skin, we applied fcMRI analysis to mice that had been topically treated with the Toll-like receptor agonist, imiquimod (IMQ) to induce psoriasiform dermatitis. Brain insula regions, due to their suggested role in stress, were chosen as seed regions for fcMRI analysis. Mouse ear and head skin developed psoriasiform epidermal thickening (up to 4-fold, P < .05) and dermal inflammation after 4 days of topical treatment with IMQ. After fcMRI analysis, IMQ-treated mice showed significantly increased insula fc with wide areas throughout the brain, including, but not limited to, the somatosensory cortex, anterior cingulate cortex, and caudate putamen ( P < .005). This reflects a potential central neurological impact of IMQ-induced psoriasis-like skin inflammation. These data indicate that fcMRI may be valuable tool to quantitatively assess the neurological impact of skin inflammation in patients with psoriasis.

Objectives The study aimed to investigate and compare the effect of cognitive reserve (CR) on brain activation in healthy controls (HC) and amnestic mild cognitive impairment (aMCI) patients during 0-back and 1-back tasks measured by event-related potential (ERP). Methods The study recorded 85 subjects (39 aMCI patients and 46 their matched controls) with a 64-channel electroencephalogram (EEG). Subjects performed 0- and 1-back tasks. Results Compared to HC, aMCI patients showed reduced accuracy, delayed mean correct response time (RT) and decreased P300 amplitude at central-parietal and parietal electrodes. A mediation analysis indicated that higher CR reduced neural inefficiency, which might be associated with better task performance in HC. However, no correlation was detected between CR and neural inefficiency in aMCI patients, whereas higher CR was still related to enhanced accuracy and prolonged RT in aMCI patients. Conclusions The present study reported that higher CR could contribute to better task performance via down-regulating neural inefficiency in HC. In addition, higher CR might modulate attention processes in aMCI via a way distinct from that in HC, and eventually result in better task performance. Significance The study provided evidence for that improving CR might lower cognitive impairment of healthy elderly and aMCI patients.

Background and Aims: Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world. A recent randomized phase III trial of combined immunotherapy (atezolizumab) with antiangiogenesis (bevacizumab) versus the standard sorafenib monotherapy reported an unprecedented response rate of 27%, leading to FDA approval of this combination as the new standard treatment in May 2020. Yet, despite this undisputable progress, the majority of the HCC cases are likely to recur or develop resistance to both first line therapy. In this study, we aimed to identify novel, druggable candidate genes for patients with sorafenib resistant HCC. Method: CRISPR/Cas9 genome (GeCKO v2) library screening was used to identify loss of function mutations conferring sorafenib resistance upon HCC cells. CCK-8 and clonogenic assays were used to measure cell viability and cytotoxicity. Flow cytometry was performed to analyze cellular reactive oxidative species (ROS) and apoptosis level. Multiple animal models were used to study the synergistic efficacy of the combination of nuclear factor erythroid 2- related factor 2 (NRF2) inhibition and sorafenib. Results: In our study, we explored the mechanisms underlying sensitivity of HCC cells to sorafenib using genome-wide CRISPR-Cas9 screening. Kelch-like ECH- associated protein-1(KAEP1) was discovered as a previously unknown factor for determining the sensitivity of HCC cells to sorafenib. Using established sorafenib resistant HCC cell lines and the parental cell, we validated that KEAP1 mediates NRF2 degradation through the ubiquitin-proteasome pathway, thereby conferring sensitivity to sorafenib. Conversely, the loss of function of KEAP1 reduced degradation of NRF2 and conferred increased sorafenib resistance. Analysis of 55 patients with HCC, who had received hepatic resection followed by postoperative standard sorafenib treatment, revealed that high NRF2 expression shortened both overall survival (P Conclusion: Our results uncovered the potential of NRF2 as a drug target for patients with sorafenib resistant HCC. The impressive efficacy of NRF2 inhibitor and sorafenib suggests a potential combination therapy to supplement the existing standard of treatment for sorafenib resistant HCC. Citation Format: Jiang Chen, Shi Jiang, Bixia Li, Tong Ji, Staiculescu Daniel, Jiayan He, Junjie Xu, Xiujun Cai. Small molecule inhibitor of NRF2 selectively overcomes sorafenib resistance in KEAP1-deficient hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1419.

Concrete-filled bimetallic tubes (CFBTs) combine the mechanical advantages of concrete-filled steel tubes (CFSTs) and the functional features of bimetallic tubes. This paper presents the test results of fifteen circular short column specimens under eccentric compression. The bimetallic tube adopted in the current research was manufactured by combining an inner carbon steel tube and a cladding stainless steel layer, which can improve the corrosion resistance of the conventional carbon steel tube with economic efficiency. A total of fifteen specimens, including seven hollow bimetallic tubes and eight CFBT short columns, were fabricated and tested by considering the nominal load eccentricity (en/D = 0, 0.26, 0.53, or 0.79) as the main testing parameter. The test results indicated that all the CFBT short columns behaved in an improved ductile manner compared to the hollow bimetallic tubes, and the corresponding load-carrying capacity was significantly enhanced. The development of strain in the two tube layers demonstrated the inner and outer steel tube layers worked well together. The influences of load eccentricity on the mechanical behavior of CFBT short columns were discussed. Finally, an improved model was suggested for calculating the N/Nu-M/Mu interaction relationships of CFBT short columns subjected to eccentric compression.

The conventional treatment of onychomycosis, a common fungal infection, consists in the use of local and systemic drugs for 4-6 months. This long protocol is often ineffective due to patient compliance, and usually promotes important collateral effects such as liver and kidney failure. As the alternative, Photodynamic Therapy (PDT) has been used as a noninvasive alternative local treatment for onychomycosis due to the reduction of systemic side effects, fact indicates their use for patients undergoing other systemic treatments. In the present article, we evaluated the effectiveness, as well as the safety of PDT mediated by Aluminium-Phthalocyanine Chloride, entrapped in nanoemulsions, as a drug carrier, to treat onychomycosis in a proof of concept clinical trial. To the date, this is the first published clinical trial that uses PDT mediated by nanomedicines to treat onychomycosis. As main results, we can highlight the safety of the clinical protocol and the antifungal effectiveness similar to the conventional treatments. We observed the (1) clinical cure of 60% of treated lesions; (2) the absence of local and systemic adverse effects; (3) from these clinically healed lesions, 40% were negative for fungal infection in laboratorial exams; and (4) nails that presented negative fungal culture were kept without fungal infection for at least four weeks. The innovation of this approach is the absence of collateral effects, due to the local therapeutically treatment, and the possibility to repeat the treatment without inducing fungal resistance, a fact that indicates this approach as a possible alternative protocol for onychomycosis management.

The parahippocampal gyrus-orbitofrontal cortex (PHG-OFC) circuit in humans is homologous to the postrhinal cortex (POR)-ventral lateral orbitofrontal cortex (vlOFC) circuit in rodents. Both are associated with visuospatial malfunctions in Alzheimer's disease (AD). However, the underlying mechanisms remain to be elucidated. In this study, we explored the relationship between an impaired POR-vlOFC circuit and visuospatial memory deficits through retrograde tracing and in vivo local field potential recordings in 5XFAD mice, and investigated alterations of the PHG-OFC circuit by multi-domain magnetic resonance imaging (MRI) in patients on the AD spectrum. We demonstrated that an impaired glutamatergic POR-vlOFC circuit resulted in deficient visuospatial memory in 5XFAD mice. Moreover, MRI measurements of the PHG-OFC circuit had an accuracy of 77.33% for the classification of amnestic mild cognitive impairment converters versus non-converters. Thus, the PHG-OFC circuit explains the neuroanatomical basis of visuospatial memory deficits in AD, thereby providing a potential predictor for AD progression and a promising interventional approach for AD.

Objectives We aimed to evaluate the efficacy and safety of anterior column opening structural bone grafting with posterior column compression technique for the treatment of obsolete vertebral compression fractures with severe spinal kyphosis. Methods Fourteen patients with senile obsolete vertebral compression fractures and severe spinal kyphosis were admitted to our hospital. During the treatment processing, an "eggshell" osteotomy, anterior column opening structural bone grafting with posterior column compression, and pedicle screw internal fixation were performed in all patients. The Cobb angle, Visual Analogue Scale (VAS) score, Oswestry Disability Index (ODI) pre-operatively, post-operatively, and at the last follow-up were analyzed. Furthermore, the intra-operative blood loss and the operative time were also analyzed. Results The average osseous fusion time was 3.6 months (range from 3 to 5 months). The average operative time was 236 ± 20.1 min (range from 198 to 261 min). The average intra-operative blood loss was 1350.5 ± 70.2 ml (range from 809 to 2216 ml). The Cobb angle of localized kyphosis was 63.4 ± 12.4∘ pre-operatively, while 10.0 ± 2.1∘ post-operatively, and 12 ± 3.4∘ at the last follow-up evaluation, respectively. The average VAS score was decreased significantly from 8.7 ± 3.2 pre-operatively to 1.9 ± 0.4 post-operatively. The average ODI score was decreased from 78.3 ± 2.4% pre-operatively to 19.3 ± 5.3% post-operatively. Conclusions Anterior column opening structural bone grafting with posterior column compression technique is effective, can effectively restore the sagittal balance of the spine, ease pain, and improve the quality of life of the patients with obsolete vertebral compression fractures and spinal kyphosis.

The purposes of this study are to investigate whether the Characterizing Alzheimer's disease Risk Events (CARE) index can accurately predict progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD) on an individual subject basis, and to investigate whether this model can be generalized to an independent cohort. Using an event-based probabilistic model approach to integrate widely available biomarkers from behavioral data and brain structural and functional imaging, we calculated the CARE index. We then applied the CARE index to identify which MCI individuals from the ADNI dataset progressed to AD during a three-year follow-up period. Subsequently, the CARE index was generalized to the prediction of MCI individuals from an independent Nanjing Aging and Dementia Study (NADS) dataset during the same time period. The CARE index achieved high prediction performance with 80.4% accuracy, 75% sensitivity, 82% specificity, and 0.809 area under the receiver operating characteristic (ROC) curve (AUC) on MCI subjects from the ADNI dataset over three years, and a highly validated prediction performance with 87.5% accuracy, 81% sensitivity, 90% specificity, and 0.861 AUC on MCI subjects from the NADS dataset. In conclusion, the CARE index is highly accurate, sufficiently robust, and generalized for predicting which MCI individuals will develop AD over a three-year period. This suggests that the CARE index can be usefully applied to select individuals with MCI for clinical trials and to identify which individuals will convert from MCI to AD for administration of early disease-modifying treatment.

This study aims to develop a composite biomarker that can accurately measure the sequential biological stages of Alzheimer's disease (AD) on an individual level. We selected 144 subjects from the Alzheimer's Disease Neuroimaging Initiative 2 datasets. Ten biomarkers, from brain function and structure, cerebrospinal fluid, and cognitive performance, were integrated using the event-based probabilistic model to estimate their optimal temporal sequence (Soptimal). We identified the numerical order of the Soptimal as the characterizing Alzheimer's disease risk events (CARE) index to measure disease stage. The results show that, in the Soptimal, hippocampal and posterior cingulate cortex network biomarkers occur first, followed by aberrant cerebrospinal fluid amyloid-β and p-tau levels, then cognitive deficit, and finally regional gray matter loss and fusiform network abnormality. The CARE index significantly correlates with disease severity and exhibits high reliability. Our findings demonstrate that use of the CARE index would advance AD stage measurement across the whole AD continuum and facilitate personalized treatment of AD.

Objective To observe the protective effect of fasudil hydrochloride against acute renal injury in septicopyemia rats. Methods A total of 60 Wister rats were included in the study and divided into control group (n = 10), model group (n = 25) and treatment group (n = 25). Model group and treatment group received intraperitoneal injection of endotoxin (ET) to establish acute renal injury models while the control group only received daily intraperitoneal injection of normal saline 1 mL. Five rats were taken out of model group and treatment group respectively at 1 h (T1), 6 h (T2), 12 h (T3), 24 h (T4) and 48 h (T5), for intraperitoneal injection of ET 30 mg/kg. Treatment group received intraperitoneal injection of fasudil hydrochloride 30 mg/kg 1 h before injection of ET. For three groups, 5 mL blood samples were collected from postcava for determination of serum creatinine and urea nitrogen levels at different time points. Concentrations of serum tumor necrosis factor α and ET-1 were determined by using ELISA. The renal pathologic changes were observed under the microscope. Results Serum creatinine levels in both model group and treatment group were significantly higher than control group at T2–T5 (P

PURPOSE The aim of this study is to explore a calculated method used to measure the cardiac output using the aortic impedance change component of reconstructed impedance cardiography. METHODS Routine impedance cardiography was measured using Kubicek's method with four ring electrodes. The thoracic mixed impedance changes were measured by six leads, which consisted of 15 electrodes. The aortic impedance change component was separated from six thoracic mixed impedance changes through waveform reconstruction. The square root formula used to calculate the cardiac output was deduced based on the thoracic impedance change equation and the aortic volume change hypothesis during the systole period. The cardiac outputs of 180 normal adults and 72 patients with cardiac insufficiency who could still walk freely were contrastively computed with both Kubicek's formula and the square root formula. RESULTS For 180 normal adults, the cardiac index (CI) computed with the square root formula was 3.60 ± 0.45 L/min/m2 , with normal values ranging from 2.7 to 4.5 L/min/m2 . A total of 163 cases (90.6%) had a CI in the standard range (2.7-4.3 L/min/m2 ) adopted in clinical applications. The CI computed with Kubicek's formula was 3.61 ± 0.86 L/min/m2 , with normal values ranging from 1.9 to 5.3 L/min/m2 , and only 115 cases (63.9%) had a CI in the above standard range. Among the 72 patients with cardiac insufficiency, 20 (27.8%) patients had a CI < 2.0 L/min/m2 with Kubicek's formula. Of these 20 cases, 9 cases had a CI < 1.5 L/min/m2 , and 4 cases had a CI < 1.1 L/min/m2 . In contrast, none of the 72 patients had a CI < 2.0 L/min/m2 with the square root formula. In addition, the influence of the chest circumference on the CI was lower for the square root formula than for Kubicek's formula. CONCLUSIONS The CI calculated with the square root formula had a better normal value range, was more accurate for the patients with cardiac insufficiency, and was less affected by the chest circumference than the CI calculated with Kubicek's formula.

Aim: To develop a self-nanoemulsifying drug-delivery system (SNEDDS) able to improve oral absorption of epiisopiloturine (EPI), and test the antischistosomal activity in a mice model. Results: SNEDDS had a nanoscopic size and was able to enhance EPI bioavailability after oral administration, and SNEDDS-EPI (40 mg.kg-1) improved the in vivo antischistosomal activity of EPI, demonstrating that SNEDDS was able to improve the pharmacokinetics of EPI, and to maintain the pharmacodynamic activity against Schistosoma mansoni in vivo. Conclusion: Taken together, these results indicate that SNEDDS-EPI is efficient in reducing worm burden in comparison to treatment with the free version of EPI. [Formula: see text]

The hypothalamus plays a critical role in maintaining visceral homeostasis. Altered hypothalamus activation has been implicated in functional gastrointestinal disorders, including irritable bowel syndrome (IBS). One important aspect of homeostatic regulation is the cortical modulation of limbic and paralimbic subsystems, including the hypothalamus, which in turn affects the descending regulatory processes mediating visceral homeostasis. Using neuroimaging, we evaluated hypothalamus functional connectivity in adolescent patients with IBS and age-matched healthy controls who received rectal distension stimulations. More extensive hypothalamus connectivity was observed in liminal than subliminal condition in controls, but not in patients with IBS. Compared with controls, patients with IBS showed significantly reduced hypothalamus connectivity in the bilateral prefrontal cortices, supplementary motor and premotor areas, bilateral sensorimotor cortex, and limbic subareas, which are specifically involved in homeostatic regulation. The findings support the generalized homeostatic regulation model that reduced cortical and limbic modulations of hypothalamus functioning underlies disrupted visceral homeostasis in patients with IBS.

The present study was performed to investigate the therapeutic performance of polymer-lipid hybrid nanoparticles towards the delivery of lapatinib (LPT) in breast cancers. We have successfully developed the lapatinib-loaded polymer-lipid hybrid nanosystem and showed its therapeutic potential in in vitro and in vivo models of breast cancer. The nanoformulations consisted of a polymeric core (poly[lactide-co-glycolide]-D-a-tocopheryl polyethylene glycol 1000 succinate [PLGA–TPGS]), which was then enveloped by a PEGylated lipid layer (DSPE-PEG) (PLPT) to maintain the structural integrity. The PLPT formulation controlled the drug release in pH 7.4 conditions and accelerated the release at pH 5.5 conditions. The PLPT showed a remarkable cellular internalization and efficiently killed the MCF-7 cancer cells in a time- and concentration-dependent manner. Moreover, LPT-loaded nanoparticles effectively induced apoptosis of cancer cells than compared to free LPT. Pharmacokinetic data suggested that nanoparticles could significantly enhance the blood circulation time of LPT by reducing the uptake by a reticuloendothelial system (RES). The prolonged blood circulation of PLPT could allow the preferential accumulation of drug in the tumor tissues. Importantly, PLPT significantly reduced the tumor burden of cancerous mice and effectively controlled the tumor cell proliferation. TUNEL assay further showed a greater apoptosis of tumor tissues in the PLPT treated mice group. Our results suggest that the use of a hybrid system may allow a decrease in the dosage regimen without the loss of therapeutic effect. Overall, lapatinib-loaded hybrid nanoparticles hold great potential for achieving an optimal therapeutic effect in breast cancer treatment. The present anticancer drug delivery system could be potentially applied for the treatment of other cancers.

Background Antrodia camphorata, a traditional Chinese medicine, is widely used in the treatment of liver diseases and cancers. Anti-inflammatory properties have also been described. HSV infection represents one of the most serious public health concerns globally because of its devastating impact. Searching for new antiviral agents, especially those with different mechanisms of action, is a crucial goal and there is an unmet need for alternative and complementary therapy against HSV infection. In this study, anti-herpes screening was performed with extracts from A. camphorata mycelia. Methods MTT assay, fractional inhibitory concentration index and median-effect principle were used to evaluate antiviral activity and to calculate drug combination effect. Results Crude ethanol extracts and isolated constituents showed inhibition of HSV replication at a very low concentration. Fraction A and antrodin A showed viral inhibitory effect with reduction of viral cell-to-cell spread. In addition, neither fraction A nor antrodin A showed interaction in combination with acyclovir. Conclusions A. camphorata mycelia and antrodin A might have potential use as anti-HSV agents and are promising candidates for future antiviral drug design.

Objective Liver transplantation is an optimal radical therapy for selected patients with hepatocellular carcinoma. The stringent organ allocation system driven by the Milan criteria has been challenged by alternative sets of expanded criteria. Careful analysis is needed to prove that the Milan criteria can be expanded safely and effectively. Design This study collectively reviewed 6012 patients of hepatocellular carcinoma from the China Liver Transplant Registry. Expanded criteria were evaluated to characterise an optimised expansion with acceptable outcomes beyond the Milan criteria. Results Compared with the Milan criteria, Valencia, University of California, San Francisco, University Clinic of Navarra and Hangzhou criteria provided an expansion of 12.4%, 16.3%, 19.6%, and 51.5%, respectively. The post-transplant survivals of patients fulfilling the expanded criteria were comparable to that of the Milan criteria. The analysis of net reclassification improvement and area under the receiver operating characteristic curves showed an excellent efficiency in recurrence prediction for the expanded criteria compared with the Milan criteria. In patients exceeding Milan but fulfilling the Hangzhou criteria (N=1352), α-fetoprotein (AFP) >100 ng/mL and tumour burden>8 cm were the only two independent prognostic factors (p8 cm but AFP≤100 ng/mL) and type B (tumour burden >8 cm but AFP between 100 and 400 ng/mL). Type A showed significantly higher 5-year tumour-free survival rates compared with type B (p

Network analysis based on graph theory depicts the brain as a complex network that allows inspection of overall brain connectivity pattern and calculation of quantifiable network metrics. To date, large-scale network analysis has not been applied to resting-state functional networks in complete spinal cord injury (SCI) patients. To characterize modular reorganization of whole brain into constituent nodes and compare network metrics between SCI and control subjects, fifteen subjects with chronic complete cervical SCI and 15 neurologically intact controls were scanned. The data were preprocessed followed by parcellation of the brain into 116 regions of interest (ROI). Correlation analysis was performed between every ROI pair to construct connectivity matrices and ROIs were categorized into distinct modules. Subsequently, local efficiency (LE) and global efficiency (GE) network metrics were calculated at incremental cost thresholds. The application of a modularity algorithm organized the whole-brain resting-state functional network of the SCI and the control subjects into nine and seven modules, respectively. The individual modules differed across groups in terms of the number and the composition of constituent nodes. LE demonstrated statistically significant decrease at multiple cost levels in SCI subjects. GE did not differ significantly between the two groups. The demonstration of modular architecture in both groups highlights the applicability of large-scale network analysis in studying complex brain networks. Comparing modules across groups revealed differences in number and membership of constituent nodes, indicating modular reorganization due to neural plasticity.

Thoracic impedance graph is an impedance change curve measured on the surface of the human chest. It reflects indirectly the volume change of the heart and large vessels in the thorax, and it includes rich information about physiological activities and pathological changes. Thoracic impedance graph is measured using the four-electrode method in this article. Thoracic impedance change is transformed to the voltage change by means of the high frequency current Io, with a constant root-mean-square (rms) current. The voltage change which is directly proportional to thoracic impedance change can be obtained through the amplification, detection and calibration. The direct proportional relationship between the thoracic impedance change and volume change of the blood vessels is deduced by means of the thoracic parallel impedance model.

Background Rheumatic heart disease is an autoimmune disease caused by group A streptococci infection and frequently affects the aortic valve. Sex differences are common in the disease progression, treatment, and outcome. However, little is known about the sex differences in the pathology of aortic valves in rheumatic heart disease. Design We studied the end-stage calcific aortic valves from male versus female patients to reveal the sex-dependent pathology differences and molecular changes associated with requiring valve replacement. Methods Aortic valves from 39 patients with rheumatic heart disease (19 males and 20 females) were collected at the time of aortic valve replacement for comparative pathology, immunohistochemistry, and gene expression analyses. Clinical characteristics were also analyzed and compared between the two groups. Results Aortic valves from female patients exhibited increased expression of collagens, infiltration of monocytes/macrophages and neovascularization. Aortic valves from female patients also had increased expression of inflammatory genes involved in the NFKB pathway (phosphorylated NFKB p65 subunit, IL8, and NOS3) and Th1 cytokine genes (IFNA and IL12B). The severe valve pathology in female patients was correlated with a higher serum level of anti-streptolysin O antibodies. Conclusion Inflammation is more prominent in aortic valves of female patients with rheumatic heart disease. This sex difference may contribute to the severe valve pathology and worse outcome of female patients.

The purpose in this article is to investigate the measurement method and normal values of the total peripheral resistance (TPR) and total peripheral resistance index (TPRI) measured by the reconstructed impedance cardiogram (RICG). Methods The cardiac output and cardiac index of 180 normal adults is measured by means of the RICG. The computed formula of the TPR and TPRI are deduced, and the TPR and TPRI are calculated. The subjects are divided to the different groups according to the sex and age. The TPR and TPRI are calculated statistically. Results The TPR and TPRI are increased with the increase of the age, and there is significant difference between the young and elder groups (P0.05). The normal value of the TPR is less than 1650 dyn.s.cm-5, and that of the TPRI is less than 2650 dyn.s.cm-5.m2. Conclusion The TPR and TPRI measured by the RICG can reflect the hemodynamic changes of the normal or abnormal body.

Background Recent studies have suggested that cardiac surgery may affect sleep-disordered breathing (SDB) in chronic heart failure patients. However, the dynamic changes in sleep apnea and heart function after cardiac surgery and the mechanisms responsible for these changes remain unknown. Methods Patients with rheumatic valvular heart disease (RVHD) and SDB were enrolled and followed up at three, six and 12months after cardiac valve replacement (CVR). Baseline and follow-up clinical data consisting of NYHA classification, 6min walk distance (6-MWD), medications, echocardiography, electrocardiography, chest X-ray, arterial blood gas, lung-to-finger circulation time (LFCT), and sleep data were collected and evaluated. Results Twenty-four central sleep apnea (CSA) patients and 15 obstructive sleep apnea (OSA) patients completed three follow-up assessments. Comparison of the baseline parameters between OSA patients and CSA patients showed that CSA patients had a worse baseline cardiac function assessed by higher NYHA class, shorter 6-MWD, larger left atrial diameter, longer LFCT, and enhanced chemosensitivity (higher pH and lower arterial carbon dioxide tension (PaCO 2 )). A continuous significant elevation in 6-MWD and left ventricular ejection fraction and decrease in NYHA class, plasma BNP, and left atrial diameter were found in both CSA and OSA patients. When comparing CSA and OSA patients, the CSA indices were remarkably reduced at month 3 post CVR and sustained throughout the trial, whereas there were no significant decreases in OSA index and hypopnea index. pH values and LFCT were markedly decreased and PaCO 2 markedly increased in patients with CSA at the end of the third months following CVR. These changes were sustained until the end of the trial. Conclusions CSA patients with RVHD had a worse baseline cardiac function, enhanced chemosensitivity and disordered hemodynamic as compared with OSA patients with RVHD. CSA were eliminated after CVR; however, there were no changes in OSA. The elimination of CSA, post CVR, is associated with the combined efficacies of improvement of cardiac function, normalized chemosensitivity, and stabilized hemodynamic.

A shape optimization method based on strain energy is proposed for framed structures. This method combines free nodal shift, or restricted nodal shift on a specified line in the structural geometry. The optimization is based on nodal sensitivity information to amend the structural shape to achieve a structure with minimum strain energy. In this method, the design parameters, such as initial structure, supporting conditions, spatial constraints, etc, have significant influence on the final structural form; so various structural forms can be obtained by changing these design parameters in the project design phase. A numerical example is provided to illustrate the validity of this method and the mechanical behaviour of the structure. Results show that this can effectively reduce the structural bending moments and ensure sufficient structural stiffness.

Honeypot is a new type of active defense security technologies. This paper attempts to use of data mining methods to be mining and analysis of information collected on the honeypot system. Build a Windows system based on virtual machine technology research honeynet. Data collection be standardized and sequential pattern mining. Finding out the correlation between different data records and frequent with time-based sequence of audit data, which found that,select the law of value of the attack.

This paper presents a node shift method to find the optimal distribution of nodes in single-layer reticulated shells. The optimization process searches for the minimum strain energy configuration and this leads to reduced sensitivity in initial imperfections. Strain energy sensitivity numbers are derived for free shift and restricted shift where nodes can move freely in the 3D space or have to move within a predefined surface respectively. Numerical examples demonstrate the efficiency of the proposed approach. It was found that optimized structures achieve higher ultimate load and are less sensitive to imperfections than the initial structure. The configuration of the final structure is closely related to factors like the initial structural configuration, spatial conditions, etc. Based on different initial conditions, architects can be provided with diverse reasonable structures. Furthermore, by amending the defined shapes and nodal distributions, it is possible to improve the mechanical behavior of the structures.

Chronic pain affects 50% of adults with sickle cell disease (SCD). Although central sensitization is thought to contribute to the pathogenesis of this chronic pain, no studies have examined differences in functional connectivity of the brain between patients with SCD with and without chronic pain. We performed an observational cohort study using resting-state functional MRI (rsfMRI) of the brain on adults with SCD with and without chronic pain. We tested the hypothesis that, compared to those without chronic pain, those with chronic pain would have differences in functional connectivity between the periaqueductal grey (PAG) and other regions of the brain. Twenty-two adults with SCD, 15 with chronic pain and 7 without chronic pain, as well as 10 African-American controls, underwent rsfMRI of the brain. When SCD patients with chronic pain were compared to those without chronic pain, significant differences in connectivity were noted between the PAG and 9 regions of the brain, including several in the default mode network, a network involved in introspection that has been implicated in other chronic pain syndromes. Changes in functional connectivity between patients with SCD with and without chronic pain suggest a mechanism for chronic pain that involves neuro-plastic changes to the brain.

e15666 Background: Hepatocellular carcinoma (HCC) has a high mortality rate and is the fourth most common cancer in China. Immunotherapy of immune checkpoint inhibitors (ICI) is a promising novel treatment strategy, but the response rate is generally low and it is not clear which patients will benefit from ICI immunotherapy. Methods: Deep sequencing targeting 450 cancer genes was done on FFPE and matched blood samples from 601 Chinese HCC patients (pts). Genomic alterations including single nucleotide variations, short and long insertions/deletions, copy number variations (CNV), gene rearrangements and fusions were analyzed. Tumor mutation burden (TMB) was measured by an algorithm developed in-house, PD-L1 expression was done by immunohistochemistry staining and Hepatitis B Virus (HBV) by target capture. Results: Patients, median age 55 years old, had TMB values in a range of 0.7 to 69.6 Muts/Mb. The 1st Quartile, median and 3rd Quartile TMB values were 3.8, 5.4 and 7.8 Muts/Mb, respectively. Comparing 155 pts with TMB-H (≥3rd Quartile) to 181 TMB-L (≤1st Quartile) pts, the mutant frequencies of TERT (49% vs 38%, p= 0.044), CTNNB1 (32% vs 11%, p< 0.001), LRP1B (14% vs 5%, p= 0.004) and ARID1A (12% vs 5%, p= 0.014) were higher. The mutant frequency of TP53 was lower (57% vs 68%, p= 0.035). TMB-L had younger pts (median age 50y vs 60y, p< 0.001) and CNV (382 vs 232, p< 0.001). PD-L1 expression was detected seen in 222 pts, including 152 pts of Dako 28-8 Ab and 70 pts of Dako 22C3 Ab with no preference. The PD-L1 positive rate (TPS ≥1%) was 7% and 34% in 28-8 group and 22-C3 group, respectively. Eleven pts were both TMB-H and PD-L1 positive. HBV probe signal was detected in 285 pts, 262 of which were positive (≥10 reads). TMB, PD-L1 expression and HBV were not found to be significantly correlated. Conclusions: In our study, 37% of Chinese HCC pts with PD-L1 positive or TMB-H may benefit from immunotherapy. TMB-H HCC pts were older, had more common TERT, CTNNB1, LRP1B and ARID1A mutations, and fewer TP53 mutations and CNV. In our current cohort, TMB and PD-L1, TMB and HBV, and PD-L1 expression and HBV were not correlated significantly.

Aiming at the path sudden change and inconsistent turning of virtual vehicles in visual simulation system for bridge cranes, forklifts virtual paths are created by using path and navigator modules in Lynx interface based on the application principles of path and navigator in Vega software. Then, forklifts visual paths are edited to ensure the natural and fluent movements of forklifts by choosing spline navigator, setting smaller smoothing threshold and smaller spline tension parameters in Path Tool. Finally, combining working cycle requirements of loading and unloading goods for bridge cranes, continuous motions of several forklifts are realized by calling the path navigation library functions of Vega Software in VC++. Therefore, virtual vehicles complex paths are created and disadvantages of fixed path for virtual vehicles in visual simulation system are solved.

Collision detection is the key technology in the visual simulation system for bridge cranes. According to analyse the collision between hook and virtual objects in visual simulation system for bridge cranes, collision detection method of visual simulation system for bridge cranes is determined based on the collision detection principle. First of all, LOS intersection vector method is chosen based on the principle of collision detection in Vega. Hook is designed for the collision target using Isector module in Lynx and the same intersection vector masks in Isector Class are guaranteed. Then, the BUMP collision detection for hook is created by calling vgIsector functions in VC++ and BUMP detection method of hook is bounded with hook. Finally, conditional statements which ensure hook to move without collision are compiled. Therefore, the virtual scene around the hook is detected in real time. The results show that the phenomenon of passing through by mistake for the hook can be avoided applying the BUMP collision detection method in Vega software in visual simulation system for bridge cranes, and the accuracy for BUMP method detecting the goods is improved using LOS collision detection method.