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Abstract Older adults’ functional and intrinsic abilities may decline with increasing age. The positive effects of comprehensive community-based rehabilitation services to maintain physical, mental, and social function are essential. Nevertheless, few tools are available to assess the community-based rehabilitation needs of older adults. Therefore, we aimed to construct a list for the comprehensive evaluation of community-based rehabilitation needs of older adults. The International Classification of Functioning, Disability, and Health (ICF) was used to construct a first draft of the assessment list. From September to November 2023, 18 experts from five provinces and nine tertiary hospitals and institutions of higher education in China participated in this Delphi study. The older adult community-based rehabilitation needs evaluation list included six dimensions and 29 items. The weights of the six dimensions, from high to low, included mental function rehabilitation need (0.30), body function rehabilitation need (0.24), social participation need (0.18), individual activity rehabilitation need (0.14), environmental rehabilitation need (0.09) and rehabilitation information need (0.05). Using the Delphi method, an assessment list of older adult community-based rehabilitation needs based on ICF was developed. Future work should evaluate the list’s reliability and validity and its application in managing community-based rehabilitation for older adults.

Summary: Breast cancer is the second leading cause of carcinoma-linked death in women. We developed a multi-modal deep-learning model (BreNet) to differentiate breast cancer from benign lesions. BreNet was constructed and trained on 10,108 images from one center and tested on 3,762 images from two centers in three steps. The diagnostic ability of BreNet was first compared with that of six radiologists; a BreNet-aided scheme was constructed to improve the diagnostic ability of the radiologists; and the diagnosis of real-world radiologists’ scheme was then compared with the BreNet-aided scheme. The diagnostic performance of BreNet was superior to that of the radiologists (area under the curve [AUC]: 0.996 vs. 0.841). BreNet-aided scheme increased the pooled AUC of the radiologists from 0.841 to 0.934 for reviewing images, and from 0.892 to 0.934 in the real-world test. The use of BreNet significantly enhances the diagnostic ability of radiologists in the detection of breast cancer.

Summary: The high heritability of amyotrophic lateral sclerosis (ALS) contrasts with its low molecular diagnosis rate post-genetic testing, pointing to potential undiscovered genetic factors. To aid the exploration of these factors, we introduced EpiOut, an algorithm to identify chromatin accessibility outliers that are regions exhibiting divergent accessibility from the population baseline in a single or few samples. Annotation of accessible regions with histone chromatin immunoprecipitation sequencing and Hi-C indicates that outliers are concentrated in functional loci, especially among promoters interacting with active enhancers. Across different omics levels, outliers are robustly replicated, and chromatin accessibility outliers are reliable predictors of gene expression outliers and aberrant protein levels. When promoter accessibility does not align with gene expression, our results indicate that molecular aberrations are more likely to be linked to post-transcriptional regulation rather than transcriptional regulation. Our findings demonstrate that the outlier detection paradigm can uncover dysregulated regions in rare diseases. EpiOut is available at github.com/uci-cbcl/EpiOut.

Abstract Background In HIV-1 infection, more than 95% of CD4+T cells die of caspase-1 mediated pyroptosis. What governs the increased susceptibility of CD4+T cells to pyroptosis is poorly understood. Methods Blood samples were obtained from 31 untreated HIV-infected patients (UNT), 29 antiretroviral therapy treated HIV-infected patients (ART), and 21 healthy control donors (HD). Plasma levels of IL-18 and IL-1β, caspase-1 expression, mitochondrial mass (MM) and mitochondrial fusion/fisson genes of CD4+T subsets were measured. Results A significantly higher IL-18 level in plasma and MM level of CD4+T cells were found in HIV-infected patients (UNT and ART) compared to HD, and the MMhigh phenotype was manifested, related to increased caspase-1 expression. Moreover, the increased MM was more pronounced in the early differentiated and inactivated CD4+T cells. However, higher MM was not intrinsically linked to T cell differentiation disorder or excessive activation of the CD4+T cells. Mechanistically, the increased MM was significantly correlated with an elevated level of expression of the mitochondrial fusion gene mitofusin1. Conclusion An increase in MM was associated with heightened sensitivity of CD4+T cells to pyroptosis, even in early differentiated and inactivated CD4+T cells, in patients with HIV-1 infection, regardless of whether patients were on antiretroviral therapy or not. These new revelations have uncovered a previously unappreciated challenge to immune reconstitution with antiretroviral therapy.

Objective The escalating global aging population underscores the need to effectively manage geriatric diseases, constituting a significant public health concern. Community-based rehabilitation has emerged as a crucial and accessible paradigm for the rehabilitation of older adults. In China, however, the practical implementation of community-based rehabilitation faces formidable challenges, including a dearth of specialized rehabilitation therapists, substantial disparities between demand and supply, and suboptimal satisfaction rates. We aimed to develop a community-based rehabilitation management platform for older adults centered around digital health technology, with the plan to conduct a cluster randomized controlled trial to gather more evidence to explore the best practices and service models of community-based rehabilitation based on digital health technology. Methods This cluster randomized controlled trial will be conducted in Zunyi City, China. We will recruit 286 adults aged ≥60 years and randomly allocate 20 subdistricts in a 1:1 ratio into either the intervention group, which will use the Rehabilitation Journey application, or the control group, which will be given a Rehabilitation Information Booklet for Older Adults. Both groups will undergo a 12-month rehabilitation management program, encompassing six months of guidance and an additional six months of follow-up through online and offline methods. The evaluation indicators will be assessed at enrollment and at 3 rd , 6 th , and 12 th month. Discussion This study endeavors to furnish novel insights to develop a tailored community-based rehabilitation management program for older adults, delivering customized, intelligent, and precise rehabilitation services.

BackgroundGeriatric diseases (e.g., chronic diseases and geriatric syndromes) may result in impaired physical performance and a decline in the quality of life. The results of previous studies reported the positive effects of comprehensive community-based rehabilitation (CBR) services on physical and social functioning and psychosocial wellbeing. However, to provide adequate and personalised rehabilitation services, it is essential to understand the needs of the older adults population. There have been no studies on the need for CBR in older adults populations that consider their heterogeneity. Therefore, high-quality studies are required to recognise the heterogeneity and latent classes of CBR needs in older adults population groups. This study aims to identify the heterogeneity of the rehabilitation needs of older adults in the community and explore whether older adults with similar characteristics have similar needs through a cross-sectional survey and latent class analysis (LCA) to provide support for personalised rehabilitation services.MethodsThe study is structured into four phases. The first phase will focus on constructing a comprehensive questionnaire to assess rehabilitation needs. In the second phase, a pilot study will be conducted to evaluate the reliability and validity of the completed questionnaire. This step ensures the robustness of the instrument for data collection. The third phase will involve cross-sectional surveys using the finalised questionnaires to collect the necessary data from the targeted population. The fourth phase will focus on conducting LCA to determine the CBR needs of the older adult population.DiscussionThe results of this study will provide novel and critical information for a better understanding of the rehabilitation needs, potential categories, and influencing factors of older adults in the community. The study will be conducted in Guizhou Province in western China, where economic and social development is relatively low, and the results will inform and benefit other regions and developing countries facing similar challenges. However, because of the complete social security and rehabilitation service systems in developed areas, our research results may not fully reflect the situation in these areas. Future studies may need to be conducted in places with different levels of social development.Clinical trial registrationhttps://www.chictr.org.cn/showproj.html?proj=191398, ChiCTR2300071478.

To comprehend the etiology and pathogenesis of many illnesses, it is essential to identify disease-associated microRNAs (miRNAs). However, there are a number of challenges with current computational approaches, such as the lack of "negative samples", that is, confirmed irrelevant miRNA-disease pairs, and the poor performance in terms of predicting miRNAs related with "isolated diseases", i.e. illnesses with no known associated miRNAs, which presents the need for novel computational methods. In this study, for the purpose of predicting the connection between disease and miRNA, an inductive matrix completion model was designed, referred to as IMC-MDA. In the model of IMC-MDA, for each miRNA-disease pair, the predicted marks are calculated by combining the known miRNA-disease connection with the integrated disease similarities and miRNA similarities. Based on LOOCV, IMC-MDA had an AUC of 0.8034, which shows better performance than previous methods. Furthermore, experiments have validated the prediction of disease-related miRNAs for three major human diseases: colon cancer, kidney cancer, and lung cancer.

Background: Inflammation is essential in cardiorenal syndrome, however there is still a lack of evidence proving the interaction between cardiac injury, renal dysfunction and the inflammatory response. This study aimed to illustrate the association between renal dysfunction and cardiac injury with a specific focus on the role of inflammation. Methods: A single-center, retrospective study included patients with heart failure admitted to the cardiovascular department from September 2019 to April 2022. Patients received cardiovascular magnetic resonance (CMR) imaging (T1 mapping and late gadolinium enhancement (LGE)). Demographic, creatinine and native T1 were analyzed using pearson correlation, linear regression and adjusted for confounders. Interaction and subgroup analysis were performed. Results: Finally, 50 validated heart failure (HF) patients (age 58.5 ± 14.8 years; 78.0% men) were included. Cardiac global native T1 for the high estimated glomeruar filtration rate (eGFR) group was 1117.0 ± 56.6 ms, and for the low eGFR group was 1096.5 ± 61.8 ms. Univariate analysis identified global native T1 (β = 0.16, 95% confidence interval (CI): 0.04–0.28, p = 0.014) and C-reactive protein (CRP) (β = 0.30, 95% CI: 0.15–0.45, p < 0.001) as determinants of creatinine. Multivariable linear regression analysis identified global native T1 (β = 0.12, 95% CI: 0.01–0.123, p = 0.040) as a determinant of creatinine while age and diabetes were adjusted. Significant interactions between CRP and global native T1 in relation to creatinine level (p for interaction = 0.005) were identified. Conclusions: Kidney dysfunction was associated with cardiac injury and inflammation, respectively. The interaction between myocardial injury and kidney dysfunction is contingent on the severity of the inflammatory response. Further studies were needed to identify the mechanisms of the inflammatory response in cardiorenal syndrome.

Abstract The incidence of chronic obstructive pulmonary disease (COPD) is related to the interaction between environmental exposure and genetic factors. Far more than 15% of smokers eventually develop COPD. In addition to smoking, genetic susceptibility may be another factor in the development of COPD. IL‐22 and its receptors are increased in human and experimental COPD and contribute to pathogenesis. Here, we conducted a case–control study to evaluate the association between IL‐22 tag‐single nucleotide polymorphisms (SNPs) and COPD risk. Four tag‐SNPs (rs2227478, rs2227481, rs2227484 and rs2227485) were identified according to linkage disequilibrium (LD) analysis in 30 healthy controls. A total of 513 COPD cases and 504 controls were recruited to perform an association study between these four tag‐SNPs and COPD risk. We found that the “C” allele of rs2227478T>C and the “T” allele of rs2227481C>T were obviously related to decreased COPD susceptibility. Genetic model analysis showed that rs2227478T>C and rs2227481C>T were significantly associated with a decreased risk of COPD under dominant models after adjusting for the above factors. In the recessive model, rs2227485T>C was obviously associated with decreased COPD risk. Our data showed that only rs2227485T>C was associated with a decreased COPD risk after Bonferroni correction. The eQTL analysis showed that rs2227485T>C was significantly associated with IL‐22 expression. The pGL4‐rs2227485‐C gene reporter had a higher promoter activity than pGL4‐rs2227485‐T. In our study, rs2227485T>C, located in the promoter region of IL‐22, was associated with a decreased risk of COPD and increased IL‐22 promoter activity, suggesting that this variant might modulate COPD susceptibility.

Abstract Mooring data collected at a flat‐topped seamount suggest the generation of pure inertial waves (PIWs; waves with a dominant frequency equal to the local inertial frequency f) by low‐frequency flows over large‐scale topography. Energetic PIWs were observed within a narrow depth range (∼100 m) near the seafloor at the edge of the summit. These waves could be associated with low‐frequency flows. A two‐dimensional nonhydrostatic model was used to show that the observed PIWs are most likely internal wave beams generated by low‐frequency flows over the seamount. Two types of PIWs were identified via observation and model. The first is a PIW that can only travel horizontally. The other propagates upward, with super‐inertial intrinsic frequency that is Doppler‐shifted by the flows to f. Nonlinear triadic interactions among waves with the frequencies [0, f, f] may transfer energy from mean flows to PIWs, promoting energy decay of geostrophic flows over large‐scale topography.

Recent mooring observations on the continental slope on the east side of the Dongsha Island in the northeastern South China Sea (SCS) showed that an along-slope bottom current can be generated when internal tides obliquely incident to the slope are dissipated near the seafloor. In this study, new mooring data collected on the south side of the Dongsha Island are used to explore the universality of internal wave driven the bottom currents and test the ability of the previous theory in estimating the along-slope current. The data show strong near-bottom energy dissipation due to the critical reflection of diurnal internal tides on the continental slope, with a time-mean depth-integrated dissipation rate of ~4.8×10-3 W/m2. Because of the obliquely incident of diurnal internal tides to the slope, near-bottom dissipation of internal tides generates a southwestward along-slope current, with the maximum velocity exceeding 6 cm/s. By comparing the observations, the previous theory for internal wave induced mean flows developed by Thorpe (1999) shows a good ability to estimate the along-slope bottom current velocity. Based on the theory, as well as modelled energy dissipation on the entire continental slope in the northeastern SCS, a map is obtained to quantitatively describe the along-slope bottom flow caused by internal tide breaking on the slope.

ObjectiveThis study aimed to investigate the effect of posterior circulation ischemia (PCI) on attention network function and to determine whether PCI is holistic or selective attention network deficit and which attention network is affected.MethodsThirty-six PCI patients aged 30 to 75 were assessed using the Attention Network Test and the Mini-Mental State Examination (MMSE). There were no significant differences in age, sex, and education between PCI group and the control group (n = 32). All data were statistically analyzed by SPSS 23.0 software.ResultThere were no significant difference in the MMSE scores between the two groups. Compared with the control group, the PCI group had significantly shorter response time for alerting and orienting network. The executive control network response time was significantly longer in PCI group than in the control group. The overall mean response time was also significantly longer in PCI group than in normal control group. There was no significant difference in mean accuracy between the two groups.ConclusionThe alerting, orienting, and executive control networks were significantly less efficient in PCI group than in the control group (P < 0.01). This indicates impaired attention network in PCI patients. Since transient nerve seizures caused by vertebrobasilar ischemia may precede posterior circulation stroke, early assessment of cognitive function in patients with PCI is particularly important, and ANT is an excellent tool for this assessment.

Abstract Background In our previous study, we found that formyl peptide receptor 2 (FPR2) promoted the invasion and metastasis of epithelial ovarian cancer (EOC) and could be a prognostic marker for EOC. In this study, we aimed to study the possible mechanism of FPR2 in promoting EOC progression. Methods EOC cell lines with ectopic FPR2 expression and knockdown as well as their control cell lines were established, and the expression change of RhoA in each cell line was evaluated by real time quantitative polymerase chain reaction (RT-qPCR) and Western blot. Wound healing and Transwell assays were performed to detect the migratory ability of EOCs affected by FPR2 and RhoA. The supernatant of each EOC cell line was used to coculture with macrophages, and then we tested M1 and M2 macrophage biomarkers in the supernatants by flow cytometry. The THP-1 cell line was also induced to differentiate into M1 and M2 macrophages, and FPR2 and RhoA expression in each macrophage cell line was detected by RT-qPCR and Western blot. A tumour xenograft model was established with SKOV3 and SKOV3−shFPR2 cell lines, and tumour volumes and weights were recorded. Results RhoA expression was significantly increased in EOCs along with the overexpression of FPR2, which showed a positive correlation by Pearson correlation analysis. Ectopic FPR2 expression contributes to the migratory ability of EOCs, and a RhoA inhibitor (C3 transferase) impairs EOC migration. Furthermore, FPR2 stimulated the secretion of Th2 cytokines by EOCs, which induced macrophages to differentiate to the M2 phenotype, while a RhoA inhibitor stimulated the secretion of Th1 cytokines and induced macrophages to differentiate to the M1 phenotype. Moreover, compared with M1 macrophages and THP-1 cells, FPR2 and RhoA expression was significantly upregulated in M2 macrophages. Conclusion FPR2 stimulated M2 macrophage polarization and promoted invasion and metastasis of ovarian cancer cells through RhoA.

Abstract Background Peritoneal dialysis (PD) is a form of dialysis to replace the function of kidney, that uses the peritoneum as a dialysis membrane to remove metabolites and water retained in the body. Vitamin D deficiency is prevalent in patients treated with PD. This research investigated the correlation between serum 25-hydroxyvitamin D [25(OH)D] concentration and anemia, microinflammation, and oxidative stress in PD patients. Methods 62 PD patients and 56 healthy volunteers were recruited in this research. Serum concentrations of 25(OH)D and basic parameters of anemia were detected. The correlation between serum 25(OH)D concentration with anemia, oxidative stress, and microinflammatory state were analyzed. Results In the PD group, the concentration of 25(OH)D was lower than the healthy control (HC) group (p

Abstract Aims There is paucity of clinical data comparing continuous infusion (CI) with bolus injection (BI) of intravenous loop diuretics in patients with acute decompensated heart failure (ADHF) and chronic renal dysfunction. This study aimed to compare the efficacy and safety of CI versus BI intravenous furosemide administration in patients with ADHF and moderate chronic renal insufficiency. Methods and results Acute decompensated heart failure and moderate chronic renal insufficiency [with estimated glomerular filtration rate (eGFR) 15.0–44.9 mL/min/1.73 m2] were randomized to start intravenous furosemide by BI or by a 6 h CI. End points included freedom from congestion at 72 h, the degree of dyspnoea assessed using the 0–10 Borg's category ratio scale, net daily urine output, weight loss during the study, length of hospital stay, total urinary sodium excretion, and development of acute kidney injury or electrolyte disturbance. After 72 h of treatment, the rate of the primary endpoint of freedom from congestion in the CI group was significantly higher than that in the BI group (69.05% vs. 43.59%, P = 0.02). The modified Borg scale indicated patients in the CI group had lower dyspnoea score than those in the BI group at 48 h (4.29 ± 1.23 vs. 5.97 ± 1.56; P = 0.02) and 72 h (1.15 ± 0.35 vs. 2.66 ± 0.83; P = 0.003). There were other significant differences favouring the CI group with regard to net urine output at 72 h (5145.98 ± 621.37 mL vs. 3755.95 ± 456.93 mL; P = 0.007), the mean body weight loss (4.72 ± 1.01 kg vs. 3.53 ± 0.73 kg; P = 0.02) and the total urinary sodium excretion (385.05 ± 38.15 vs. 320.33 ± 37.67; P = 0.02). The length of hospitalization in the CI group was significantly shorter than that in the BI group (10.36 ± 4.20 days vs. 15.68 ± 6.15 days; P = 0.02). No significant differences were observed between groups in the frequency of acute kidney injury, tinnitus, electrolyte disturbance or mortality. Conclusions Continuous intravenous infusion of furosemide resulted in significantly greater diuresis than bolus administration of an equal dose in patients with moderate chronic renal insufficiency and ADHF, while no differences emerged in terms of side effects or mortality.

Cardiovascular diseases remain the leading cause of death worldwide, particularly ischemic heart disease (IHD). It is also classified as incurable given the irreversible damage it causes to cardiomyocytes. Thus, myocardial tissue rejuvenation following ischemia is one of the global primary research concerns for scientists. Interestingly, the mammalian heart thrives after an injury during the embryonic or neonatal period; however, this ability disappears with increasing age. Previous studies have found that specific non-coding (nc) RNAs play a pivotal role in this process. Hence, the review herein summarizes the research on cardiomyocyte regenerative medicine in recent years and sets forth the biological functions and mechanisms of the micro (mi)RNA, long non-coding (lnc)RNA, and circular (circ)RNA in the posttranscriptional regulation of cardiomyocytes. In addition, this review summarizes the roles of ncRNAs in specific species while enumerating potential therapeutic strategies for myocardial infarction.

Fibroblasts, in particular myofibroblasts, are the critical effector cells in idiopathic pulmonary fibrosis (IPF), a deadly lung disease characterized by abnormal lung remodeling and the formation of “fibroblastic foci”. Aberrant activation of TGF-β1 is frequently encountered and promotes fibroblast proliferation, activation, and differentiation in pulmonary fibrosis. Hence, the inhibition of TGF-β1-induced lung fibroblast activation holds promise as a therapeutic strategy for IPF. The present study aimed to investigate the potential effect and underlying mechanisms of bone morphogenetic protein 4 (BMP4) on TGF-β1-induced proliferation, apoptosis, activation and myofibroblast differentiation of adult lung fibroblasts. Here, we demonstrated that BMP4 expression was significantly decreased in TGF-β1-stimulated mouse primary lung fibroblasts (PLFs). BMP4 inhibited proliferation and apoptosis resistance of TGF-β1-stimulated mouse PLFs. BMP4 suppressed TGF-β1-induced fibroblast activation and differentiation in mouse PLFs. We also found that BMP4 inhibited TGF-β1-induced ERK and p38 MAPK phosphorylation. Our findings indicate that BMP4 exerts its anti-fibrotic effects by regulating fibroblast proliferation, apoptosis, activation and differentiation via the inhibition of the ERK/p38 MAPK signaling pathway, and thus has a potential for the treatment of pulmonary fibrosis.

Background The use of gastric acid suppressants (GASs) has an influence on the exposure of some epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and therefore may affect the effectiveness and safety of EGFR-TKIs. The impact of GASs, including proton pump inhibitors (PPIs) and histamine type 2 receptor antagonists (H2RAs), on the effectiveness and safety of EGFR-TKIs remains unclear. We conducted a meta-analysis to explore the impact of GASs on the effectiveness and safety of EGFR-TKIs in non–small cell lung cancer (NSCLC) patients.Method We searched the PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, and Wanfang databases thoroughly from inception to 2nd February 2021, including the studies for NSCLC patients who used GASs, offering the adjusted hazard ratio (HR) of effectiveness outcomes such as overall survival (OS) and progression-free survival (PFS) or adjusted odds ratio (OR) of the adverse drug reaction (ADRs), and the results were calculated with a random effect. Two researchers independently screened the literature, extracted data, and evaluated the quality. Stata 15.0 was used for meta-analysis.Result Twelve studies were finally included. Nine of them were cohort studies, and three of them were case–control studies. For effectiveness outcomes, the use of GASs was associated with shorter PFS (HR 1.66 [1.40, 1.98]) and OS (HR 1.50 [1.31, 1.72]), and the use of PPIs was associated with shorter OS (HR 1.56 [1.21, 2.02]), regardless of the overlap time and type of EGFR-TKIs. For safety outcomes, the use of GASs (OR 1.98 [1.19, 3.31]) or PPIs (OR 1.91 [1.17, 3.12]) were both associated with an increased risk of hepatotoxicity.Conclusion The concomitant use of GASs is associated with shorter PFS and OS for NSCLC patients taking EGFR-TKIs and is also associated with a higher risk of hepatotoxicity. The co-administration of GASs should be avoided; if they cannot be avoided, H2RAs is a better choice.Systematic Review Registration: (https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021235018), identifier (PROSPERO 2021 CRD42021235018)

Background: The most common type of primary liver cancer is hepatocellular carcinoma (HCC), and hepatitis B virus (HBV)-related HCC accounts for many HCC cases and has a high mortality rate. The goal of our study was to investigate the efficacy and safety of lenvatinib plus sintilimab therapy in real-world practice and identify factors affecting long-term prognosis. Methods: A retrospective study was conducted with 139 consecutive patients with unresectable HCC treated with lenvatinib or lenvatinib plus sintilimab at the Fifth Medical Center of PLA General Hospital from June 2018 to June 2021. The 139 patients were divided into the control group (85 patients) and the combined treatment group (54 patients) according to the antitumour drugs used for treatment. Efficacy was determined using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and the HCC-specific modified RECIST (mRECIST) for 139 patients who completed the 1st and second tumour assessments. Safety was evaluated in 60 patients in the combined treatment group and 90 patients in the control group using the Common Terminology Criteria for Adverse Events version 5.0. Results: A total of 139 male Chinese patients (49.6% ≥ 55 years old) were included in the efficacy analysis. The median overall survival in the combined treatment group was 21.7 months, and the median progression-free survival was 11.3 months. According to the mRECIST criteria, the objective response rate was 38.9%, and the disease control rate was 92.6%. The median overall survival (mOS), median progression-free survival (mPFS), overall response rate (ORR) and disease control rate (DCR) in the lenvatinib monotherapy group were 12.8 months, 6.6 months, 24.7%, and 74.1%, respectively. Hypertension was the most common adverse event in both groups. Some immune-related adverse events, such as hypothyroidism (n = 5), elevated blood creatinine (n = 3), elevated cardiac enzymes (n = 1), elevated amylase (n = 1) and increased fasting glucose (n = 1), occurred only in the combined therapy group. Five patients in the lenvatinib monotherapy group and six patients in the lenvatinib plus sintilimab group discontinued therapy due to severe adverse events (AEs) (grade 3). No ≥ 4-grade AEs occurred in any patients. Conclusion: The TKI lenvatinib combined with PD-1-targeted immunotherapy sintilimab is efficacious and safe in real-world practice and may lead to better long-term outcomes than lenvatinib alone.

Abstract Background Schizotypal traits are considered as inheritable traits and the endophenotype for schizophrenia. A common variant in the NOTCH4 gene, rs204993, has been linked with schizophrenia, but the neural underpinnings are largely unknown. Methods In present study, we compared the differences of brain functions between different genotypes of rs204993 and its relationship with schizotypal traits among 402 Chinese Han healthy volunteers. The brain function was evaluated with functional connectivity strength (FCS) using the resting-state functional magnetic resonance image(rs-fMRI). The schizotypal traits were measured by the schizotypal personality questionnaire (SPQ). Results Our results showed that carriers with the AA genotype showed reduced FCS in the left occipital cortex when compared with carriers with the AG and GG genotypes, and the carriers with the AG genotype showed reduced FCS in the left occipital cortex when compared with carriers with the GG genotype. The FCS values in the left occipital lobe were negatively associated with the SPQ scores and its subscale scores within the carriers with the GG genotype, but not within the carriers with AA or AG genotype. Conclusion Our results suggested that the common variant in the NOTCH4 gene, rs204993, modulates the function of the occipital cortex, which may contribute to schizotypal traits. These findings provide insight for genetic effects on schizotypal traits and its potential neural substrate.

Background: The Duke Anticoagulation Satisfaction Scale (DASS) offers a method to measure the quality of life and satisfaction of patients taking oral anticoagulants. The study aimed to validate the Chinese version of the DASS in Chinese patients on anticoagulation therapy.Methods: The DASS was translated, back-translated, and transculturally adapted into the Chinese version and then administered to participants taking oral anticoagulants in a physician–pharmacist collaborative anticoagulation clinic at a tertiary teaching hospital from October 2019 to December 2020. Reliability was analyzed through Cronbach’s alpha (α) and split-half reliability. Confirmatory factor analysis was performed to test the structural validity of the scale. Exploratory factor analysis was performed for items in the scales using the varimax rotation method.Results: A total of 189 patients completed the Chinese version of the DASS. Four dimensions and 23 items were included, with Cronbach’s α values of 0.89, 0.81, 0.89, and 0.74 for limitations on physical activities, diet restrictions, hassles and burdens, and positive psychological effect, respectively. Cronbach’s α coefficient of whole scale was 0.91. The split-half reliability of this scale is 0.747 (>0.7).Conclusion: The Chinese version of the DASS indicated excellent reliability and validity, compared to the original version. It could provide a practical instrument for healthcare practitioners to evaluate satisfaction and quality of life for anticoagulated patients in China. The difference in quality of life between patients taking warfarin and novel oral anticoagulants (NOACs) needs to be further explored in future studies.

Two sets of more than 850 days of mooring records and satellite altimeter data are used to explore the features and spatiotemporal evolution of near-inertial waves (NIWs) near Nansha Island in the southern South China Sea (SCS). The observed NIWs are dominated by clockwise (downward energy propagation) motions and show a clear blue shift with a distinct peak frequency of 1.09 f during two large NIW events. The near-inertial kinetic energy (NIKE) is primarily concentrated in the upper layer and radiated downward. The largest value of depth-integrated NIKE reaches 3.5 KJ/m2. Besides, the NIWs are dominated by the first three modes, which account for 80% of the total NIKE. Moreover, the depth-integrated NIKE exhibits an apparent seasonal variation, with the largest NIKE in winter, which is almost three times larger than that in other seasons. Every large NIKE event is attributed to the passage of storms and is dominated by mode-2 NIWs. The dominance of the mode-2 NIWs is likely caused by the interaction between NIWs and mesoscale eddies.

One of the main responses of the ocean to typhoons is the generation of near-inertial waves (NIWs), whose intrinsic frequency is close to the local inertial frequency. Based on the mooring observations, we carefully investigated the spatial–temporal variations in NIWs in the northern South China Sea (SCS) after Typhoon “Haima,” which passed through the northern SCS from October 20 to 21, 2016, with its track parallel to the mooring array on its northeast side. Moorings in different locations responded differently to this typhoon, with stronger NIWs found on the continental slope to the shelf break and relatively weak NIWs found on the shallow continental shelf. Strong NIWs appeared twice within a short period and showed different characteristics and frequencies. The first NIWs were generated locally with blue-shifted (super-inertial) frequencies. These initial NIWs were dominated by the first three baroclinic modes and rapidly weakened due to their propagation away and local dissipation. However, the second NIWs mainly consisted of higher baroclinic modes with red-shifted (sub-inertial) frequencies. The analysis of the mean background flow revealed that these red-shifted NIWs were excited at low latitudes, and subsequently advected by the poleward background flow to moorings whose latitudes were higher than their critical latitudes. Higher-mode (n > 3) NIWs were more easily carried away by mean background flow, and, at the same time, high-mode NIWs propagated downward to the subsurface layer, leading to the significant elevation of velocity shear therein. Given these findings, the mean background flow may provide an important route to redistributing the energy of the upper ocean imported from typhoons.

The effect of target phosphorus (P) content on the precipitates, microstructure, texture, magnetic properties, and mechanical properties of low-carbon (C) and low-silicon (Si) non-oriented electrical steel (NOES) was investigated and the influence mechanism was clarified. The results indicate that the precipitates in the steels are mainly aluminum (Al)-manganese (Mn)-Si-bearing complex nitrides ((Al,Si,Mn)xNy) and P-bearing complex nitrides ((Al,Si,Mn)xNy-P). Increasing target phosphorus content in the steels decreases (Al,Si,Mn)xNy, and increases (Al,Si,Mn)xNy-P. The number density of the precipitates is the lowest, and the average size of the precipitates and grain size of the finished steel is the largest in the samples with target P content at the 0.14% level (0.14%P-targeted). The average grain size and microstructure homogeneity of the steels are influenced by the addition of phosphorus. The content of the {111} component decreases, and the favorable texture increases after phosphorus is added to the steel. The magnetic induction of the steel is improved. Grain refinement and microstructure inhomogeneity lead to an iron loss increase after target phosphorus content increases in the steel. The best magnetic induction B50 is 1.765 T in the 0.14%P-targeted samples. The tensile strength and yield strength are improved owing to solid solution strengthening and the grain refinement effect of phosphorus added to the steels.

Background: Trastuzumab is associated with the risk of cardiotoxicity. Here, we aim to explore interventions for preventing trastuzumab-related cardiotoxic effects in breast cancer patients.Methods: A systematic review was performed including trials of breast cancer patients with intervention to prevent cardiotoxicity of trastuzumab. Trials were searched through databases including PubMed, Embase, and Cochrane Library.Results: Eight RCTs were included. Five trials reported the outcomes of short-duration interventions, including 6-month and 9-week durations, and only 9-week treatment has a significant difference from the 12-month group (OR 0.38; 95% CI 0.18–0.83) using cardiotoxicity as the outcome. However, 6-month treatment turned out to yield less occurrence of trastuzumab discontinuation (OR 0.32; 95% CI 0.24–0.42). Three trials reported interventions of cardioprotective drugs, and there is no significant difference shown in any cardioprotective group compared with placebo (cardiotoxicity outcome: angiotensin-converting enzyme inhibitor: OR 0.48; 95% CI 0.057–2.3; angiotensin receptor blocker: OR 1.3; 95% CI 0.12–14; β-blocker: OR 0.48; 95% CI 0.057–2.3; trastuzumab interruption outcome: angiotensin-converting enzyme inhibitor: OR 0.45; 95% CI 0.12–1.3; angiotensin receptor blocker: OR 0.87; 95% CI 0.15–4.8; β-blocker: OR 0.41; 95% CI 0.11–1.2).Conclusion: Only the 9-week group has a significant difference from the 12-month group using cardiotoxicity as the outcome. And 6-month treatment turned out to yield less occurrence of trastuzumab discontinuation. The use of cardioprotective drugs failed to prevent trastuzumab-related cardiotoxic effects in breast cancer patients.

High-frequency motions in the southeastern South China Sea (SCS) have rarely been investigated due to sparse field observations. The vertical distribution and temporal variation of internal tides (ITs) and near-inertial waves (NIWs) near the Nansha area in the southeastern SCS were studied using a mooring current dataset from December 2018 to June 2019 in this study. Results showed that ITs were mainly dominated by O1, K1, and M2. Tidal energy analysis indicates that the diurnal ITs were the most energetic components, followed by the semidiurnal ITs. Modal decomposition reveals that diurnal ITs were dominated by mode-3, rather than mode-1, as reported by previous studies. The horizontal kinetic energy (HKE) of diurnal ITs fluctuated within a limited range, almost unaffected by the background field. However, the HKE of semidiurnal ITs was dominated by mode-1 and more affected by the background field, especially at the end of March. Most observations showed the phase of the NIWs propagating upward and the energy propagating downward. During the northeast monsoon period, the near-inertial energy had a large magnitude due to strong wind forcing. In addition, the near-inertial energy peaked from the middle of March to the beginning of April because of the input of NIWs from afar. Overall, near-inertial energy was found concentrated above a 500–600 m depth in the southeastern SCS.

Abstract Herein, a magnetic graphene field-effect transistor biosensor was prepared through the transfer of a chemical vapor deposition graphene film onto a glass substrate to produce a sensing film and conductive channel. By fixing 1-pyrenebutanoic acid succinimidyl ester onto graphene film as an anchor, a probe aptamer was immobilized on the graphene film in order to capture magnetically labeled complementary single-stranded DNA. Our experiments showed that, within a periodic magnetic field, the biosensor impedance exhibited a periodic oscillation, the amplitude of which was correlated to the complementary DNA concentration. Based on this principle, the magnetic graphene field-effect transistor was utilized to detect single-stranded DNA with detection limition of 1 pM. The results were rationalized using a model wherein the magnetic force causes the DNA strand to bend, thereby resulting in magnetic nanobeads/DNA modulation of the double conductive layer of graphene transistors. Furthermore, since a periodic magnetic field could be introduced to produce a periodic impedance changes of MGFETs, sampling integration could be used to improve the signal-to-noise ratio efficiently by increasing the number of periods of the external magnetic field. Therefore, a novel biosensor for DNA detection with high sensitivity has been presented in this work. Based on the detection principle, this system may also be a potential tool for detecting other bio-molecules, cells, etc.

Linguistic deficits are frequent symptoms among stroke survivors. The neural mechanism of post-stroke aphasia (PSA) was incompletely understood. Recently, resting-state functional magnetic resonance imaging (rs-fMRI) was widely used among several neuropsychological disorders. However, previous rs-fMRI studies of PSA were limited to very small sample size and the absence of reproducibility with different neuroimaging indexes. The present study performed comparisons with static and dynamic amplitude of low-frequency fluctuations (ALFF) and functional connectivity (FC) based on modest sample size (40 PSA and 37 healthy controls). Compared with controls, PSA showed significantly increased static ALFF predominantly in the bilateral supplementary motor area (SMA) and right hippocampus-parahippocampus (R HIP-ParaHip) and decreased static ALFF in right cerebellum. The increased dynamic ALFF in SMA and decreased dynamic ALFF in right cerebellum were also found in PSA. The static and dynamic ALFF in right cerebellum was positively correlated with spontaneous speech. The FC between the SMA and R HIP-ParaHip was significantly stronger in patients than controls and positively correlated with ALFF in bilateral SMA. In addition, the FC between the R HIP-ParaHip and the right temporal was also enhanced in patients and negatively correlated with repetition, naming, and comprehension score. These findings revealed consistently abnormal intrinsic neural activity in SMA and cerebellum, which may underlie linguistic deficits in PSA.

A scheme of a gas–liquid mixed jet is designed by installing gas distributor at the bottom of a stirred tank reactor to generate Taylor vortex. The eddy flow characteristics and mass transfer mechanism in the reactor are analyzed by numerical simulation and experiment. The results show that the evolution law of Taylor vortex in a stirred tank reactor with a rotating Reynolds number is similar to that in a conventional Taylor reactor. The Taylor vortex generated in the stirred tank reactor creates a partial plug flow region in the original complete mixing flow pattern, which reduces back mixing, the plug flow area expands with the increase of rotating Reynolds number. Under the condition of a critical rotating Reynolds number (Recr), the gas phase homogeneity of the reactor is increased by 28% and the dissolved oxygen rate is increased by about 5 times, which effectively improves the flow condition in the reactor and strengthens the mass transfer efficiency between the gas and liquid. The research results provide a theoretical basis for breaking through the limitation of small reaction space of conventional Taylor flow reactor and expanding production scale. The refit of kettle reactor is universal and easy to operate.

BACKGROUND:Several anti-D immunoglobulin strategies exist for preventing Rh hemolytic disease of the fetus and newborn. This study systematically assessed the clinical value of those therapeutic strategies. METHODS:The Web of Science, PubMed, EMBASE, China National Knowledge Infrastructure (CNKI) and Wanfang databases were searched for eligible studies that evaluated the value of different anti-D immunoglobulin strategies in preventing maternal anti-D antibody sensitization. Combined odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated. The network meta-analysis was conducted using Stata 14.2 and WinBUGS 1.4.3 software. RESULTS:Twenty-four original studies involving 64860 patients were included. Among all therapeutic measures, injecting 300 μg anti-D immunoglobulin at 28 and 34 gestational weeks (antenatal 5/E) appeared to be the most effective measure for preventing maternal antibody sensitization (surface under the cumulative ranking curve [SUCRA] = 96.8%), while a single injection at 28 gestational weeks (SUCRA = 89.2%) was the second most effective. Administering no injection or a placebo (SUCRA = 0.0%) was the least effective intervention measure. CONCLUSION:Among the therapeutic measures, antenatal 5/E appeared to be the best method for reducing the positive incidence of anti-D antibodies in the maternal serum; thus, it may be the most effective treatment for preventing fetal hemolytic disease.

BackgroundThe rapid spread of coronavirus disease 2019 (COVID-19) revealed significant constraints in critical care capacity. In anticipation of subsequent waves, reliable prediction of disease severity is essential for critical care capacity management and may enable earlier targeted interventions to improve patient outcomes. The purpose of this study is to develop and externally validate a prognostic model/clinical tool for predicting COVID-19 critical disease at presentation to medical care.MethodsThis is a retrospective study of a prognostic model for the prediction of COVID-19 critical disease where critical disease was defined as ICU admission, ventilation, and/or death. The derivation cohort was used to develop a multivariable logistic regression model. Covariates included patient comorbidities, presenting vital signs, and laboratory values. Model performance was assessed on the validation cohort by concordance statistics. The model was developed with consecutive patients with COVID-19 who presented to University of California Irvine Medical Center in Orange County, California. External validation was performed with a random sample of patients with COVID-19 at Emory Healthcare in Atlanta, Georgia.ResultsOf a total 3208 patients tested in the derivation cohort, 9% (299/3028) were positive for COVID-19. Clinical data including past medical history and presenting laboratory values were available for 29% (87/299) of patients (median age, 48 years [range, 21-88 years]; 64% [36/55] male). The most common comorbidities included obesity (37%, 31/87), hypertension (37%, 32/87), and diabetes (24%, 24/87). Critical disease was present in 24% (21/87). After backward stepwise selection, the following factors were associated with greatest increased risk of critical disease: number of comorbidities, body mass index, respiratory rate, white blood cell count, % lymphocytes, serum creatinine, lactate dehydrogenase, high sensitivity troponin I, ferritin, procalcitonin, and C-reactive protein. Of a total of 40 patients in the validation cohort (median age, 60 years [range, 27-88 years]; 55% [22/40] male), critical disease was present in 65% (26/40). Model discrimination in the validation cohort was high (concordance statistic: 0.94, 95% confidence interval 0.87-1.01). A web-based tool was developed to enable clinicians to input patient data and view likelihood of critical disease.Conclusions and relevanceWe present a model which accurately predicted COVID-19 critical disease risk using comorbidities and presenting vital signs and laboratory values, on derivation and validation cohorts from two different institutions. If further validated on additional cohorts of patients, this model/clinical tool may provide useful prognostication of critical care needs.

Abstract Background Cornelia de Lange syndrome (CdLS) is a multisystem developmental disorder frequently associated with heterozygous loss-of-function mutations of Nipped-B-like (NIPBL), the human homolog of Drosophila Nipped-B. NIPBL loads cohesin onto chromatin. Cohesin mediates sister chromatid cohesion important for mitosis but is also increasingly recognized as a regulator of gene expression. In CdLS patient cells and animal models, expression changes of multiple genes with little or no sister chromatid cohesion defect suggests that disruption of gene regulation underlies this disorder. However, the effect of NIPBL haploinsufficiency on cohesin binding, and how this relates to the clinical presentation of CdLS, has not been fully investigated. Nipbl haploinsufficiency causes CdLS-like phenotype in mice. We examined genome-wide cohesin binding and its relationship to gene expression using mouse embryonic fibroblasts (MEFs) from Nipbl+/− mice that recapitulate the CdLS phenotype. Results We found a global decrease in cohesin binding, including at CCCTC-binding factor (CTCF) binding sites and repeat regions. Cohesin-bound genes were found to be enriched for histone H3 lysine 4 trimethylation (H3K4me3) at their promoters; were disproportionately downregulated in Nipbl mutant MEFs; and displayed evidence of reduced promoter-enhancer interaction. The results suggest that gene activation is the primary cohesin function sensitive to Nipbl reduction. Over 50% of significantly dysregulated transcripts in mutant MEFs come from cohesin target genes, including genes involved in adipogenesis that have been implicated in contributing to the CdLS phenotype. Conclusions Decreased cohesin binding at the gene regions is directly linked to disease-specific expression changes. Taken together, our Nipbl haploinsufficiency model allows us to analyze the dosage effect of cohesin loading on CdLS development.

Early-stage ovarian serous carcinoma is usually difficult to detect in clinical practice. The profiling of protein expression in high-grade serous carcinoma (HGSC) and low-grade serous carcinoma (LGSC) would provide important information for diagnoses and chemotherapy. Here, we performed proteomic profiling of specimens from 13 HGSC and 7 LGSC patients by iTRAQ. A total of 323 proteins that were differentially expressed were identified. After immunohistochemical confirmation of expressed proteins in 166 clinical tissues, asparagine synthetase (ASNS) and filamin A (FLNA) were selected for further functional study. Cisplatin-sensitive (CS; ASNShigh and FLNAlow) and cisplatin-resistant (CR; ASNSlow and FLNAhigh) SKOV3 and OVCAR3 ovarian cancer cell lines were used for subsequent in vitro and in vivo experiments. Notably, ASNS overexpression (ASNS+) or FLNA knockdown (shFLNA) enabled cisplatin-induced apoptosis and autophagy in CR cells. However, ASNS+ and shFLNA promoted and attenuated tumor growth, respectively. In CS cells, ASNS knockdown (shASNS) attenuated clonogenicity, cell proliferation, and the epithelial–mesenchymal transition, whereas FLNA overexpression (FLNA+) protected cells from cisplatin. In vivo, cisplatin resistance was attenuated in mice xenografted with ASNS+, shFLNA, or ASNS+-shFLNA CR cells, whereas xenografts of shASNS or FLNA+ CS cells exhibited resistance to cisplatin. Clinically, all HGSC patients (83/83) responded to cisplatin, while 6 in 41 LGSC patients exhibited cisplatin resistance. These findings identify ASNS and FLNA as distinct biomarkers for HGSC and LGSC, which may have potential value in the prognosis and clinical treatment of serous carcinoma.

A kind of graphene foam chemical sensor (GFCS) system based on the principal component analysis (PCA) and backpropagation neural network (BPNN) was presented in this paper. Compared with conventional chemical sensors, the GFCS could discriminate various chemical molecules with selectivity without surface modification. The GFCS system consisted of an unmodified graphene foam chemical sensor, an electrical resistance time domain detection system (ERTDS), and a pattern recognition module. The GFCS has been validated via several chemical molecules discrimination including chloroform, acetone, and ether. The experimental results showed that the discrimination accuracy for each molecule exceeded 97% and a single measurement can be achieved in ten minutes. This work may have presented a new strategy for research and application for graphene chemical sensors.

Tropical cyclones (TCs) are natural disasters for coastal regions. TCs with maximum wind speeds higher than 32.7 m/s in the north-western Pacific are referred to as typhoons. Typhoons Sarika and Haima successively passed our moored observation array in the northern South China Sea in 2016. Based on the satellite data, the winds (clouds and rainfall) biased to the right (left) sides of the typhoon tracks. Sarika and Haima cooled the sea surface ~4 and ~2 °C and increased the salinity ~1.2 and ~0.6 psu, respectively. The maximum sea surface cooling occurred nearly one day after the two typhoons. Station 2 (S2) was on left side of Sarika’s track and right side of Haima’s track, which is studied because its data was complete. Strong near-inertial currents from the ocean surface toward the bottom were generated at S2, with a maximum mixed-layer speed of ~80 cm/s. The current spectrum also shows weak signal at twice the inertial frequency (2f). Sarika deepened the mixed layer, cooled the sea surface, but warmed the subsurface by ~1 °C. Haima subsequently pushed the subsurface warming anomaly into deeper ocean, causing a temperature increase of ~1.8 °C therein. Sarika and Haima successively increased the heat content anomaly upper than 160 m at S2 to ~50 and ~100 m°C, respectively. Model simulation of the two typhoons shows that mixing and horizontal advection caused surface ocean cooling, mixing and downwelling caused subsurface warming, while downwelling warmed the deeper ocean. It indicates that Sarika and Haima sequentially modulated warm water into deeper ocean and influenced internal ocean heat budget. Upper ocean salinity response was similar to temperature, except that rainfall refreshed sea surface and caused a successive salinity decrease of ~0.03 and ~0.1 psu during the two typhoons, changing the positive subsurface salinity anomaly to negative

Deregulation of canonical Wnt/CTNNB1 (beta-catenin) pathway is one of the earliest events in the pathogenesis of colon cancer. Mutations in APC or CTNNB1 are highly frequent in colon cancer and cause aberrant stabilization of CTNNB1, which activates the transcription of Wnt target genes by binding to chromatin via the TCF/LEF transcription factors. Here we report an integrative analysis of genome-wide chromatin occupancy of CTNNB1 by chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) and gene expression profiling by microarray analysis upon RNAi-mediated knockdown of CTNNB1 in colon cancer cells.We observed 3629 CTNNB1 binding peaks across the genome and a significant correlation between CTNNB1 binding and knockdown-induced gene expression change. Our integrative analysis led to the discovery of a direct Wnt target signature composed of 162 genes. Gene ontology analysis of this signature revealed a significant enrichment of Wnt pathway genes, suggesting multiple feedback regulations of the pathway. We provide evidence that this gene signature partially overlaps with the Lgr5+ intestinal stem cell signature, and is significantly enriched in normal intestinal stem cells as well as in clinical colorectal cancer samples. Interestingly, while the expression of the CTNNB1 target gene set does not correlate with survival, elevated expression of negative feedback regulators within the signature predicts better prognosis.Our data provide a genome-wide view of chromatin occupancy and gene regulation of Wnt/CTNNB1 signaling in colon cancer cells.