Exploring the impact of interleukins on sarcopenia development: A systematic review and meta-analysis.

BACKGROUND: The role of interleukins in sarcopenia development has been acknowledged, yet the specifics of their involvement remain to be fully understood. This study aimed to explore alterations in interleukin levels among sarcopenia patients. METHODS: Searches were conducted in Embase, Medline, and the Cochrane Library for literature published up to May 2023. Eligible observational studies with a diagnosis of sarcopenia were included. The Newcastle-Ottawa Scale was utilized for quality assessment. For data synthesis, a random-effects model was used, and the Mantel-Haenszel method was used for pooled estimates. RESULTS: Of the 7685 articles screened, 37 met the inclusion criteria. Statistically significant differences in the levels of IL-1ß, IL-6 and IL-10 were detected in sarcopenia patients. Specifically, IL-1ß (95 % CI: 0.33 [0.12, 0.54], P < 0.05), IL-6 (95 % CI: 0.91 [0.59, 1.24], P < 0.05), and IL-10 (95 % CI: 0.11 [0.07,0.15], P < 0.05) were detected. However, no significant associations were found between serum IL-4 (95 % CI: 0.36 [-0.18, 0.42], P = 0.44), IL-8 (95 % CI: -1.05 [-3.06, 0.95], P = 0.3), IL-12 (95 % CI: -3.92 [-8.32,0.48], P = 0.08) or IL-17 (95 % CI: 0.22 [-2.43, 2.88], P = 0.87) and sarcopenia. Subgroup analysis showed no significant difference in IL-6 (95 % CI: -0.03 [-0.72, 0.66], P = 0.93) and IL-10 (95 % CI: 0.1 [-0.44, 0.64], P = 0.72) among patients with European standard sarcopenia. CONCLUSIONS: Inflammation plays a role in sarcopenia, and the serum levels of IL-1ß, IL-6, and IL-10 are associated with sarcopenia. Further research is needed to clarify these associations. CLINICAL TRIALS REGISTRATION NUMBER: CRD42024506656.

Functional Validation of Doxorubicin-Induced Cardiotoxicity-Related Genes.

Background: Genome-wide association studies and candidate gene association studies have identified more than 180 genetic variants statistically associated with anthracycline-induced cardiotoxicity (AIC). However, the lack of functional validation has hindered the clinical translation of these findings. Objectives: The aim of this study was to functionally validate all genes associated with AIC using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Methods: Through a systemic literature search, 80 genes containing variants significantly associated with AIC were identified. Additionally, 3 more genes with potential roles in AIC (GSTM1, CBR1, and ERBB2) were included. Of these, 38 genes exhibited expression in human fetal heart, adult heart, and hiPSC-CMs. Using clustered regularly interspaced short palindromic repeats/Cas9-based genome editing, each of these 38 genes was systematically knocked out in control hiPSC-CMs, and the resulting doxorubicin-induced cardiotoxicity (DIC) phenotype was assessed using hiPSC-CMs. Subsequently, functional assays were conducted for each gene knockout on the basis of hypothesized mechanistic implications in DIC. Results: Knockout of 26 genes increased the susceptibility of hiPSC-CMs to DIC. Notable genes included efflux transporters (ABCC10, ABCC2, ABCB4, ABCC5, and ABCC9), well-established DIC-associated genes (CBR1, CBR3, and RAC2), and genome-wide association study-discovered genes (RARG and CELF4). Conversely, knockout of ATP2B1, HNMT, POR, CYBA, WDR4, and COL1A2 had no significant effect on the in vitro DIC phenotype of hiPSC-CMs. Furthermore, knockout of the uptake transporters (SLC28A3, SLC22A17, and SLC28A1) demonstrated a protective effect against DIC. Conclusions: The present findings establish a comprehensive platform for the functional validation of DIC-associated genes, providing insights for future studies in DIC variant associations and potential mechanistic targets for the development of cardioprotective drugs.

Sarcopenia in systemic sclerosis: prevalence and impact-a systematic review and meta-analysis.

OBJECTIVE: This review aims to provide an estimate of sarcopenia prevalence and its impact on clinical characteristics in patients with systemic sclerosis (SSc). DESIGN: Systematic review and meta-analysis. DATA SOURCES: Embase, Medline, Web of Science and the Cochrane Central Register of Controlled Trials were systemically searched from inception to 24 May 2023. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: We included observational studies that reported the prevalence of sarcopenia in patients with SSc. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently performed study selection and data extraction using standardised methods. Risk of bias was assessed using the Agency for Healthcare Research and Quality Scale and the Newcastle-Ottawa Scale. Meta-analysis was conducted using random effects models. RESULTS: A total of 4583 articles were screened and 9 studies with data from 815 patients were included in the analysis (8 cross-sectional studies and 1 retrospective cohort study). The overall prevalence of sarcopenia in patients with SSc was 22% (95% CI 17% to 28%). Patients with SSc with sarcopenia had a poorer quality of life (mean difference -12.02; 95% CI -19.11 to -4.93) and higher C reactive protein (CRP) levels (standardised mean difference 0.67; 95% CI 0.35 to 1.00). CONCLUSIONS: Sarcopenia is common in patients with SSc. Patients with SSc with sarcopenia had a worse quality of life and higher CRP levels, based on our findings. Given the detrimental impact of sarcopenia on quality of life, future efforts aimed at early identification of sarcopenia in the clinical assessment of patients with SSc may have significance. PROSPERO REGISTRATION NUMBER: CRD42022368326.

Programming memristor arrays with arbitrarily high precision for analog computing.

In-memory computing represents an effective method for modeling complex physical systems that are typically challenging for conventional computing architectures but has been hindered by issues such as reading noise and writing variability that restrict scalability, accuracy, and precision in high-performance computations. We propose and demonstrate a circuit architecture and programming protocol that converts the analog computing result to digital at the last step and enables low-precision analog devices to perform high-precision computing. We use a weighted sum of multiple devices to represent one number, in which subsequently programmed devices are used to compensate for preceding programming errors. With a memristor system-on-chip, we experimentally demonstrate high-precision solutions for multiple scientific computing tasks while maintaining a substantial power efficiency advantage over conventional digital approaches.

Association between sarcopenia grade and fall history among older adults in West China: A retrospective study.

OBJECTIVES: The association between sarcopenia severity and fall history remains under-researched at present. Accordingly, this study was developed to evaluate the relationship between sarcopenic status and prior fall events in a multiethnic group of older community-dwelling adults in Western China. DESIGN: A retrospective survey study, the data comes from the West China Health and Aging Trend study. SETTING: The study was based in Western China. PARTICIPANTS: In total, this retrospective analysis incorporated data from 2719 older adults (59.2% women). PRIMARY AND SECONDARY OUTCOME MEASURES: Grip strength, gait speed and skeletal muscle mass index values were analysed for all participants, and the Asian Working Group for Sarcopenia (AWGS) 2014 and 2019 consensus criteria were leveraged to assess sarcopenia status in these individuals. Prior fall history was defined by any incidents in which an individual unintentionally came to rest on the floor within the past year. The association between sarcopenia status and fall history was examined through a binary logistic regression approach, with p<0.05 as the threshold for significance. RESULTS: Using the AWGS2014 and AWGS2019 diagnostic criteria, of the individuals included in this study cohort 1851 (68.1%) were free of sarcopenia, 160 (5.9%) and 56 (2.1%) showed only muscle-mass loss, 322 (11.8%) and 267 (9.8%) exhibited non-severe sarcopenia and the remaining 386 (14.2%) and 545 (20.0%) exhibited severe sarcopenia, respectively. Previous fall events were reported for 14.8% of study cohort members. After full adjustment for potential confounders, a significant link between severe sarcopenia diagnosed by the AWGS2014 diagnostic criteria and fall history was observed (OR 1.397, 95% CI 1.029 to 1.896, p=0.032), while the AWGS2019 diagnostic criteria did not (OR 1.29, 95% CI 0.982 to 1.694, p=0.068). CONCLUSIONS: Severe sarcopenia, as defined per the AWGS2014 criteria, was associated with a significantly higher risk of falls in this multiethnic cohort of older adults from Western China, while the AWGS2019 diagnostic criteria did not. However, this relationship was not observed for individuals who experienced muscle mass loss or had non-severe sarcopenia, according to both the AWGS2014 and AWGS2019 diagnostic criteria.

[Forkhead Box M1 Regulates the Proliferation,Invasion,and Drug Resistance of Gastric Cancer Cells via circ_NOTCH1].

Objective To investigate the impacts of forkhead box M1(FOXM1)on the proliferation,invasion,and drug resistance of gastric cancer cells by regulating the circular RNA circ_NOTCH1.Methods Western blotting and real-time quantitative PCR were performed to determine the expression of FOXM1 protein and circ_NOTCH1,respectively,in the gastric cancer tissue,para-carcinoma tissue,human normal gastric mucosa epithelial cell line GES-1 and gastric cancer cell lines MGC-803,HGC-27,and BGC-823.BGC-823 cells were classified into the following groups:control,short hairpin RNA FOXM1(sh-FOXM1)and negative control(sh-NC),small interfering RNA circ_NOTCH1(si-circ_NOTCH1)and negative control(si-NC),and sh-FOXM1+circ_NOTCH1 overexpression plasmid(sh-FOXM1+pcDNA-circ_NOTCH1)and sh-FOXM1+negative control(sh-FOXM1+pcDNA).CCK-8 assay and clone formation assay were employed to measure the cell proliferation,and Transwell assay to measure cell invasion.After treatment with 1.0 mg/L adriamycin for 48 h,the cell resistance in each group was analyzed.Western blotting was employed to determine the expression levels of FOXM1,proliferating cell nuclear antigen(PCNA),Bax,multi-drug resistance-associated protein 1(MRP1),and multi-drug resistance gene 1(MDR1).RNA pull-down and RNA immunoprecipitation were employed to examine the binding of circ_NOTCH1 to FOXM1 protein.Results Compared with those in the para-carcinoma tissue,the expression levels of FOXM1 protein and circ_NOTCH1 in the gastric cancer tissue were up-regulated(all P<0.001).Compared with GES-1 cells,MGC-803,HGC-27,and BGC-823 cells showed up-regulated expression levels of FOXM1 protein and circ_NOTCH1(all P<0.001).Compared with the control group and sh-NC group,the sh-FOXM1 group with down-regulated expression of FOXM1 protein and circ_NOTCH1 showed decreased optical density value,clone formation rate,cell invasion number,and cell viability,down-regulated expression of PCNA,MRP1,and MDR1,and up-regulated expression of Bax protein in BGC-823 cells(all P<0.001).Compared with the control group and the si-NC group,the si-circ_NOTCH1 group with down-regulated expression of circ_NOTCH1 showed decreased optical density value,clone formation rate,cell invasion number,and cell viability,down-regulated expression of PCNA,MRP1,and MDR1,and up-regulated expression of Bax protein in BGC-823 cells(all P<0.001).Compared with sh-FOXM1 group and sh-FOXM1+pcDNA group,the sh-FOXM1+pcDNA-circ_NOTCH1 group with up-regulated expression of circ_NOTCH1 showed increased optical density value,clone formation rate,cell invasion number,and cell viability,up-regulated expression of PCNA,MRP1,and MDR1,and down-regulated expression of Bax protein(all P<0.001).FOXM1 protein was able to interact with circ_NOTCH1.Conclusion Interference with FOXM1 may inhibit the proliferation,invasion,and drug resistance of gastric cancer cells by silencing circ_NOTCH1 expression.

Using Ribonucleoprotein-based CRISPR/Cas9 to Edit Single Nucleotide on Human Induced Pluripotent Stem Cells to Model Type 3 Long QT Syndrome (SCN5A±).

Human induced pluripotent stem cells (hiPSCs) have been widely used in cardiac disease modelling, drug discovery, and regenerative medicine as they can be differentiated into patient-specific cardiomyocytes. Long QT syndrome type 3 (LQT3) is one of the more malignant congenital long QT syndrome (LQTS) variants with an SCN5A gain-of-function effect on the gated sodium channel. Moreover, the predominant pathogenic variants in LQTS genes are single nucleotide substitutions (missense) and small insertion/deletions (INDEL). CRISPR/Cas9 genome editing has been utilised to create isogenic hiPSCs to control for an identical genetic background and to isolate the pathogenicity of a single nucleotide change. In this study, we described an optimized and rapid protocol to introduce a heterozygous LQT3-specific variant into healthy control hiPSCs using ribonucleoprotein (RNP) and single-stranded oligonucleotide (ssODN). Based on this protocol, we successfully screened hiPSCs carrying a heterozygous LQT3 pathogenic variant (SCN5A±) with high efficiency (6 out of 69) and confirmed no off-target effect, normal karyotype, high alkaline phosphatase activity, unaffected pluripotency, and in vitro embryonic body formation capacity within 2 weeks. In addition, we also provide protocols to robustly differentiate hiPSCs into cardiomyocytes and evaluate the electrophysiological characteristics using Multi-electrode Array. This protocol is also applicable to introduce and/or correct other disease-specific variants into hiPSCs for future pharmacological screening and gene therapeutic development.

The accuracy of screening instruments for sarcopenia: a diagnostic systematic review and meta-analysis.

OBJECTIVE: This review aimed to summarise the diagnostic accuracy of screening tools for sarcopenia. METHODS: We conducted a systematic review along with a critical appraisal of published studies on screening tools for sarcopenia. We assessed the measurement properties of screening instruments using the consensus-based standards for selecting health measurement instruments (COSMIN) checklist. We evaluated the risk bias of the included studies using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. The diagnostic test accuracy of instruments for sarcopenia was reported using sensitivity, specificity, positive likelihood ratio (PLR) and negative likelihood ratio (NLR). RESULTS: We screened 7,120 titles and abstracts; 42 studies including five screening tools for sarcopenia were included. The overall study quality assessed by the QUADAS-2 tool was moderate to good. Of the five screening tools, three instruments had specificities ≥85%: 92% [95% confidence interval (CI): 63-99%] for the SARC-F modified version, 87% (95% CI: 82-90%) for the SARC-F and 85% (95% CI: 77-90%) for the Ishii score. Three tools had sensitivity ≥75%, namely, MSRA 82% (95% CI: 69-90%), Ishii score 79% (95% CI: 62-89%) and U-TEST 76%. PLR higher than 5.0 were present for the Ishii score and SARC-F modified versions; the Ishii score also had the best NLR of 0.25 of all scales. CONCLUSION: The MSRA and Ishii score had excellent sensitivity for sarcopenia screening at an early stage; SARC-F modified versions and Ishii score had superior specificity for sarcopenia diagnosis.

Is waist-calf circumference ratio associated with frailty in older adults? Findings from a cohort study.

BACKGROUND: The waist-calf circumference ratio (WCR) has been suggested as a potential indicator of visceral adiposity. Nevertheless, the relationship between WCR and the risk of frailty remains unclear. Therefore, our study aimed to investigate the association between WCR and longitudinal changes in WCR with frailty risk in older adults. METHODS: We included 2359 participants aged ≥ 65 years without frailty (frailty index [FI] ≤ 0.21) from the Chinese Longitudinal Healthy Longevity Survey in the 2014 wave. The follow-up was conducted in 2018. We investigated the relationship of WCR, waist circumference (WC), and calf circumference (CC) with frailty using both the Cox proportional hazards model and the generalized estimating equation (GEE). RESULTS: During a median follow-up of 4.0 years, 668 (28.2%) frailty occurred. Those with higher WCR and WC had a significantly increased risk of frailty (fifth quintile compared with first quintile: hazard ratio [HR] = 1.59, 95% confidence interval [CI] 1.24-2.04 for WCR; HR = 1.69, 95% CI 1.27-2.24 for WC), whereas those in the fourth quintile of CC had a lower likelihood of developing frailty compared to those in the first quintile (HR = 0.67, 95% CI 0.50-0.89). Interaction analyses showed that the effects of WCR on frailty were more pronounced in females (P-interaction = 0.016). GEE analyses revealed that increased WCR and WC were associated with a higher risk of frailty (odds ratio [OR] = 1.74, 95% CI 1.43-2.12 for WCR; OR = 1.03, 95% CI 1.02-1.04 for WC), while CC showed opposite results (OR = 0.95, 95% CI 0.93-0.97). CONCLUSIONS: A higher WCR and WC, as well as a lower CC, were significantly associated with higher frailty. Of these measures, WCR demonstrated the strongest association with frailty, suggesting that having a combination of high central fat and low lean body mass may increase the risk of developing frailty.

SMAD4 regulates the progression of cholangiocarcinoma by modulating the expression of STING1.

SMAD4 is a tumour suppressor and an important regulator of tumour immune scape which is downregulated in cholangiocarcinoma (CCA). STING1 is a vital sensing factor of abnormal DNA; however, the correlation between SMAD4 and STING1 and the role of the SMAD4-STING1 interaction in the progression of CCA have not yet been evaluated. Public database was analysed to reveal the expression of SMAD4 and STING1. A cohort comprising 50 iCCA, 113 pCCA and 119 dCCA patients was assembled for the study. Immunohistochemistry was employed to evaluate the expression levels of STING1 and SMAD4. In vitro transwell and CCK8 assays, along with luciferase reporter assay, were conducted to analyse the potential regulatory mechanisms of SMAD4 on the expression of STING1. Expression of SMAD4 and STING1 were downregulated in CCA tumours and STING1 expression correlated with SMAD4 expression. The overexpression of SMAD4 was found to suppress the migration, invasion and proliferation capabilities of CCA cells; whereas, the knockdown of SMAD4 enhanced these abilities. Furthermore, it was observed that SMAD4 translocated into the nucleus following TGF-ß1 stimulation. Knockdown of SMAD4 resulted in the inhibition of STING1 transcriptional activity, whereas the overexpression of SMAD4 promoted the transcriptional activity of STING1. Clinically, low STING1 and SMAD4 expression indicated poor prognosis in CCA, and simultaneously low expression of STING1 and SMAD4 predicts poorer patient survival. SMAD4 regulates the expression of STING1 through its transcription regulating function. Dual low expression of STING1 and SMAD4 had more power in predicting patient survival. These results indicate that SMAD4-silenced CCA may downregulate its STING1 expression to adapt to the immune system.

Combined associations of vitamin D and cognitive function with all-cause mortality among older adults in Chinese longevity areas: A prospective cohort study.

Objectives: While both vitamin D deficiency and cognitive impairment have individually been linked to a greater risk of all-cause mortality, the combined effects of these two different conditions have not previously been explored in this context. We aimed to investigate the combined impact of vitamin D concentration and cognitive impairment on all-cause mortality in older adults. Methods: The analyzed data were collected from community-dwelling adults ≥65 years of age that were enrolled in the Chinese Longitudinal Healthy Longevity Survey (n = 1,673). The Mini-Mental Status Examination (MMSE) was used to assess cognitive function, while the plasma 25-hydroxyvitamin D [25(OH)D] test was used to assess vitamin D status. The associations between vitamin D concentration, cognitive function, and all-cause mortality were assessed with Cox proportional hazards models. We used restricted cubic splines to examine the dose-response relationship between vitamin D and the risk of all-cause mortality and used joint effect testing to explore interactions between vitamin D concentration and cognitive function. Results: During a mean (SD) follow-up of 3.8 (1.9) years, 899 (53.7%) deaths occurred. A negative dose-response relationship was observed between 25(OH)D concentration and cognition impairment at baseline, as well as the odds of all-cause mortality during follow-up. Similarly, cognitive impairment was significantly related to all-cause mortality risk (HR 1.81, 95% CI: 1.54 to 2.12). The combined analyses showed positive associations, with the highest mortality risk observed in older adults with both low vitamin D and cognitive impairment (HR 3.04, 95% CI: 2.40 to 3.86). Moreover, the interaction between 25(OH)D concentration and cognitive function was found to be significant in relation to the risk of mortality (p for interaction <0.001). Conclusion: Lower plasma 25(OH)D and cognitive impairment were, respectively, associated with increased all-cause mortality risks. The 25(OH)D concentration and cognitive impairment exhibited a combined additive effect on all-cause mortality among older Chinese adults.

Radiographic and α-fetoprotein response predict pathologic complete response to immunotherapy plus a TKI in hepatocellular carcinoma: a multicenter study.

BACKGROUND: Pathologic complete response (pCR) following preoperative systemic therapy is associated with improved outcomes after subsequent liver transplant/resection in hepatocellular carcinoma (HCC). However, the relationship between radiographic and histopathological response remains unclear. METHODS: We retrospectively examined patients with initially unresectable HCC who received tyrosine kinase inhibitor (TKI) plus anti-programmed death 1 (PD-1) therapy before undergoing liver resection between March 2019 and September 2021 across 7 hospitals in China. Radiographic response was evaluated using mRECIST. A pCR was defined as no viable tumor cells in resected samples. RESULTS: We included 35 eligible patients, of whom 15 (42.9%) achieved pCR after systemic therapy. After a median follow-up of 13.2 months, tumors recurred in 8 non-pCR and 1 pCR patient. Before resection, there were 6 complete responses, 24 partial responses, 4 stable disease cases, and 1 progressive disease case, per mRECIST. Predicting pCR by radiographic response yielded an area under the receiver operating characteristic curve (AUC) of 0.727 (95% CI: 0.558-0.902), with an optimal cutoff value of 80% reduction in the enhanced area in MRI (called major radiographic response), which had a 66.7% sensitivity, 85.0% specificity, and a 77.1% diagnostic accuracy. When radiographic response was combined with α-fetoprotein response, the AUC was 0.926 (95% CI: 0.785-0.999); the optimal cutoff value was 0.446, which had a 91.7% sensitivity, 84.6%, specificity, and an 88.0% diagnostic accuracy. CONCLUSIONS: In patients with unresectable HCC receiving combined TKI/anti-PD 1 therapy, major radiographic response alone or combined with α-fetoprotein response may predict pCR.

Detecting delirium: a systematic review of ultrabrief identification instruments for hospital patients.

Objective: Early identification of delirium, which often occurs in older patients, can effectively reduce adverse prognoses. One way to increase the detection rate of delirium is to use an effective ultrabrief instrument for higher-frequency screening. The purpose of this review is to evaluate the diagnostic accuracy of ultrabrief screening tools for delirium. Methods: The Cochrane Library, PubMed and EMBASE were searched from January 1, 1974, to November 31, 2022. We assessed the measurement properties of screening instruments using the consensus-based standards for selecting health measurement instruments (COSMIN) checklist and evaluated the risk bias of the included studies using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. The diagnostic test accuracy of instruments for delirium was reported using sensitivity, specificity, positive likelihood ratio (PLR) and negative likelihood ratio (NLR). Result: Of the 4,914 items identified, 26 met the eligibility criteria, resulting in 5 different delirium identification tools. The overall study quality assessed by the QUADAS-2 tool was moderate to good. Of the five screening tools, two instruments had sensitivity ≥80% and specificities ≥80%: 4AT and UB-2. The most comprehensive is the 4AT scale, which has a sensitivity of 0.80 [95% confidence interval (CI):0.68, 0.88] and a specificity of 0.89 (95%CI: 0.83, 0.93) and contains 4 items. UB-2 has a sensitivity of 0.88 (95%CI: 0.72, 0.96) and a specificity of 0.64 (95%CI: 0.56, 0.70). Conclusion: UB-2 and MOTYB had excellent sensitivity for delirium screening at an early stage. In terms of sensitivity and intentionality, the 4AT is the best recommended scale.

Toripalimab combined with lenvatinib and GEMOX is a promising regimen as first-line treatment for advanced intrahepatic cholangiocarcinoma: a single-center, single-arm, phase 2 study.

Advanced intrahepatic cholangiocarcinoma (ICC) has a dismal prognosis. Here, we report the efficacy and safety of combining toripalimab, lenvatinib, and gemcitabine plus oxaliplatin (GEMOX) as first-line therapy for advanced ICC. Thirty patients with pathologically confirmed advanced ICC received intravenous gemcitabine (1 g/m2) on Days 1 and 8 and oxaliplatin (85 mg/m2) Q3W for six cycles along with intravenous toripalimab (240 mg) Q3W and oral lenvatinib (8 mg) once daily for one year. The expression of programmed death-ligand 1 (PD-L1) and genetic status was investigated in paraffin-embedded tissues using immunohistochemistry and whole-exome sequencing (WES) analysis. The primary endpoint was the objective response rate (ORR). Secondary outcomes included safety, overall survival (OS), progression-free survival (PFS), disease control rate (DCR) and duration of response (DoR). As of July 1, 2022, the median follow-up time was 23.5 months, and the ORR was 80%. Twenty-three patients achieved partial response, and one achieved complete response. Patients (21/30) with DNA damage response (DDR)-related gene mutations showed a higher ORR, while patients (14/30) with tumor area positivity ≥1 (PD-L1 staining) showed a trend of high ORR, but without significant difference. The median OS, PFS, and DoR were 22.5, 10.2, and 11.0 months, respectively. The DCR was 93.3%. Further, 56.7% of patients experienced manageable grade ≥3 adverse events (AEs), commonly neutropenia (40.0%) and leukocytopenia (23.3%). In conclusion, toripalimab plus lenvatinib and GEMOX are promising first-line regimens for the treatment of advanced ICC. A phase-III, multicenter, double-blinded, randomized study to validate our findings was approved by the National Medical Products Administration (NMPA, No. 2021LP01825).Trial registration Clinical trials: NCT03951597.

Thousands of conductance levels in memristors integrated on CMOS.

Neural networks based on memristive devices1-3 have the ability to improve throughput and energy efficiency for machine learning4,5 and artificial intelligence6, especially in edge applications7-21. Because training a neural network model from scratch is costly in terms of hardware resources, time and energy, it is impractical to do it individually on billions of memristive neural networks distributed at the edge. A practical approach would be to download the synaptic weights obtained from the cloud training and program them directly into memristors for the commercialization of edge applications. Some post-tuning in memristor conductance could be done afterwards or during applications to adapt to specific situations. Therefore, in neural network applications, memristors require high-precision programmability to guarantee uniform and accurate performance across a large number of memristive networks22-28. This requires many distinguishable conductance levels on each memristive device, not only laboratory-made devices but also devices fabricated in factories. Analog memristors with many conductance states also benefit other applications, such as neural network training, scientific computing and even 'mortal computing'25,29,30. Here we report 2,048 conductance levels achieved with memristors in fully integrated chips with 256 × 256 memristor arrays monolithically integrated on complementary metal-oxide-semiconductor (CMOS) circuits in a commercial foundry. We have identified the underlying physics that previously limited the number of conductance levels that could be achieved in memristors and developed electrical operation protocols to avoid such limitations. These results provide insights into the fundamental understanding of the microscopic picture of memristive switching as well as approaches to enable high-precision memristors for various applications. Fig. 1 HIGH-PRECISION MEMRISTOR FOR NEUROMORPHIC COMPUTING.: a, Proposed scheme of the large-scale application of memristive neural networks for edge computing. Neural network training is performed in the cloud. The obtained weights are downloaded and accurately programmed into a massive number of memristor arrays distributed at the edge, which imposes high-precision requirements on memristive devices. b, An eight-inch wafer with memristors fabricated by a commercial semiconductor manufacturer. c, High-resolution transmission electron microscopy image of the cross-section view of a memristor. Pt and Ta serve as the bottom electrode (BE) and top electrode (TE), respectively. Scale bars, 1 µm and 100 nm (inset). d, Magnification of the memristor material stack. Scale bar, 5 nm. e, As-programmed (blue) and after-denoising (red) currents of a memristor are read by a constant voltage (0.2 V). The denoising process eliminated the large-amplitude RTN observed in the as-programmed state (see Methods). f, Magnification of three nearest-neighbour states after denoising. The current of each state was read by a constant voltage (0.2 V). No large-amplitude RTN was observed, and all of the states can be clearly distinguished. g, An individual memristor on the chip was tuned into 2,048 resistance levels by high-resolution off-chip driving circuitry, and each resistance level was read by a d.c. voltage sweeping from 0 to 0.2 V. The target resistance was set from 50 µS to 4,144 µS with a 2-µS interval between neighbouring levels. All readings at 0.2 V are less than 1 µS from the target conductance. Bottom inset, magnification of the resistance levels. Top inset, experimental results of an entire 256 × 256 array programmed by its 6-bit on-chip circuitry into 64 32 × 32 blocks, and each block is programmed into one of the 64 conductance levels. Each of the 256 × 256 memristors has been previously switched over one million cycles, demonstrating the high endurance and robustness of the devices.

Hepatectomy After Conversion Therapy Using Tyrosine Kinase Inhibitors Plus Anti-PD-1 Antibody Therapy for Patients with Unresectable Hepatocellular Carcinoma.

BACKGROUND: Combined treatment with tyrosine kinase inhibitors (TKI) plus anti-PD-1 antibodies showed high anti-tumor efficacy and made conversion resection possible for patients with unresectable hepatocellular carcinoma (HCC). However, long-term survival has not been reported. METHODS: A cohort of consecutive patients who received combined TKI/anti-PD-1 antibodies as first-line treatment for initially unresectable HCC at the authors' hospital between August 2018 and September 2020 was eligible for this study. Patients who were responding to systemic therapy and met the criteria for hepatectomy underwent liver resection with curative intention. The study also investigated the association of clinical factors with successful conversion resection and postoperative recurrence. RESULTS: The study enrolled 101 patients including 24 patients (23.8 %) who underwent R0 resection a median of 3.9 months (interquartile range: 2.5-5.9 months) after initiation of systemic therapy. Patients with an Eastern cooperative oncology group performance status of 0, fewer intrahepatic tumors, or a radiographic response to systemic therapy were more likely to be able to receive curative resection. After a median follow-up period of 21.5 months, hepatectomy was independently associated with a favorable overall survival (hazard ratio [HR], 0.050; 95 % confidence interval [CI], 0.007-0.365; P = 0.003). For the 24 patients who underwent surgery, the 12-month recurrence-free survival and overall survival rates were respectively 75% and 95.8%. Achieving a pathologic complete response (n = 10) to systemic therapy was associated with a favorable recurrence-free survival after resection, with a trend toward significance (HR, 0.345; 95% CI, 0.067-1.785; P = 0.187). CONCLUSIONS: Selected patients with initially unresectable HCC can undergo hepatectomy after systemic therapy with combined TKI/anti-PD-1 antibodies. In this study, conversion resection was associated with a favorable prognosis.

Effect of Local Pressurization on Microstructure and Mechanical Properties of Aluminum Alloy Flywheel Housing with Complex Shape.

In this work, squeeze casting experiments of flywheel housing components with a large wall thickness difference and a complex shape were carried out with AlSi9Mg aluminum alloy. The defects, microstructures, and mechanical properties under different process parameters were investigated. Furthermore, the local pressurization process was applied to the thick-walled positions to force-feed the cast defects. The mechanical properties and microstructures at these positions were analyzed. The results showed that the surface quality of formed components was good and that local pressurization could effectively reduce the shrinkage cavity and shrinkage porosity in thick walls, but the scope and effect of forced feeding were limited. The optimum process parameters were a pouring temperature of 650 °C, a specific pressure of 48 MPa, a mold temperature of 220 °C, a local pressurization of 800 MPa, and pressure delay times of 15 s (side A) and 17 s (side B). The ultimate tensile strength, yield strength, and elongation of the formed component under validation experiments of the optimum process parameters were 201 MPa, 103 MPa, and 5.1%. Meanwhile, the fine grains of primary α-Al were mainly rosette and equiaxed grains, and the average grain size was about 40 µm. The microstructure of the eutectic silicon was acicular and was prone to segregation under pressure. According to profile morphology, the positions after pressurization were divided into a deformation zone, a direct action zone, and an indirect action zone. The coexistence of as-cast and plastic deformation microstructures was observed. The effect of local pressurization mainly involved a change in the solidification process, plastic deformation, and forced feeding.

Pregnancy complicated with aortic dissection: Two cases report.

RATIONALE: This study aims to investigate the characteristics of pregnancy complicated with aortic dissection (AD), diagnosis and treatment plan, and maternal and infant outcomes. PATIENT CONCERNS: Two pregnant women suffered persistent back pain were admitted to Hubei Maternal and Child Health Hospital from December 2019 to December 2020. DIAGNOSIS: Pregnant women with chest and back pain and especially hypertension should be highly suspected of AD. However, to confirm diagnosis results, laboratory tests such as D-dimer, fibrinogen and white blood cells, and even some Special examination, cardiac ultrasound, computed tomographic angiography (CTA), magnetic resonance angiography (MRA), are required. Early diagnosis and intervention can improve maternal and infant outcomes. INTERVENTIONS: Cesarean sections were performed in both patients. Case 1 underwent thoracic aortic stent implantation one day after the onset of AD symptoms. Case 2 received endovascular repair of AD 4 days after the onset of AD symptoms. OUTCOMES: In these two cases, good maternal and infant outcomes were obtained through effective early identification and treatment. LESSONS: AD is characterized with an acute onset, and the rates of misdiagnosis and missed diagnosis are high, which seriously endangers the life of mother and child. Hypertension is one of the high-risk factors causing AD. Good maternal and infant outcomes can be achieved by early identification, multidisciplinary collaboration and timely cardiac surgical intervention.

Adjuvant treatment for patients with incidentally resected limited disease small cell lung cancer-a retrospective study.

Background: With the exception of very early-stage small cell lung cancer (SCLC), surgery is not typically recommended for this disease; however, incidental resection still occurs. After incidental resection, adjuvant salvage therapy is widely offered, but the evidence supporting its use is limited. This study aimed to explore proper adjuvant therapy for these incidentally resected SCLC cases. Methods: Patients incidentally diagnosed with SCLC after surgery at the Shanghai Pulmonary Hospital in China from January 2005 to December 2014 were included in this study. The primary outcome was overall survival. Patients were classified into different group according to the type of adjuvant therapy they received and stratified by their pathological lymph node status. Patients' survival was analyzed using a Kaplan-Meier analysis and Cox regression analysis. Results: A total of 161 patients were included in this study. Overall 5-year survival rate was 36.5%. For pathological N0 (pN0) cases (n=70), multivariable analysis revealed that adjuvant chemotherapy (ad-chemo) was associated with reduced risk of death [hazard ratio (HR): 0.373; 95% confidence interval (CI): 0.141-0.985, P=0.047] compared to omission of adjuvant therapy. For pathological N1 or N2 (pN1/2) cases (n=91), taking no adjuvant therapy cases as a reference, the multivariable analysis showed that ad-chemo was not associated with a lower risk of death (HR: 0.869; 95% CI: 0.459-1.645, P=0.666), while adjuvant chemo-radiotherapy (ad-CRT) was associated with a lower risk of death (HR: 0.279; 95% CI: 0.102-0.761, P=0.013). Conclusions: Patients who incidentally receive surgical resection and are diagnosed with limited disease SCLC after resection should be offered adjuvant therapy as a salvage treatment. For incidentally resected pN0 cases, ad-chemo should be considered and for pN1/2 cases, ad-CRT should be received.