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Abstract Background Macrophages are key inflammatory immune cells that orchestrate the initiation and progression of autoimmune diseases. The characters of macrophage in diseases are determined by its phenotype in response to the local microenvironment. Ficolins have been confirmed as crucial contributors to autoimmune diseases, with Ficolin-2 being particularly elevated in patients with autoimmune diseases. However, whether Ficolin-A stimulates macrophage polarization is still poorly understood. Methods We investigated the transcriptomic expression profile of murine bone marrow-derived macrophages (BMDMs) stimulated with Ficolin-A using RNA-sequencing. To further confirm a distinct phenotype activated by Ficolin-A, quantitative RT-PCR and Luminex assay were performed in this study. Additionally, we assessed the activation of underlying cell signaling pathways triggered by Ficolin-A. Finally, the impact of Ficolin-A on macrophages were investigated in vivo through building Collagen-induced arthritis (CIA) and Dextran Sulfate Sodium Salt (DSS)-induced colitis mouse models with Fcna-/- mice. Results Ficolin-A activated macrophages into a pro-inflammatory phenotype distinct to LPS-, IFN-γ- and IFN-γ + LPS-induced phenotypes. The transcriptomic profile induced by Ficolin-A was primarily characterized by upregulation of interleukins, chemokines, iNOS, and Arginase 1, along with downregulation of CD86 and CD206, setting it apart from the M1 and M2 phenotypes. The activation effect of Ficolin-A on macrophages deteriorated the symptoms of CIA and DSS mouse models, and the deletion of Fcna significantly alleviated the severity of diseases in mice. Conclusion Our work used transcriptomic analysis by RNA-Seq to investigate the impact of Ficolin-A on macrophage polarization. Our findings demonstrate that Ficolin-A induces a novel pro-inflammatory phenotype distinct to the phenotypes activated by LPS, IFN-γ and IFN-γ + LPS on macrophages.

Obstructive sleep apnea hypopnea syndrome (OSAHS) in adults is a common sleep-breathing disorder closely associated with hypertension, diabetes, cardiovascular diseases, and other health concerns. Despite its widespread impact on global health, the screening and diagnosis of OSAHS is still not widely available in clinical practice. In this context, the U.S. Preventive Services Task Force (USPSTF) has recently released updated recommendations for adult OSAHS screening to help more people identify and treat potential sleep-breathing disorders. This article interprets the latest recommendations and consider the practical situation in China, providing reference for OSAHS screening of adults in China.

Background Observational studies show that patients with chronic obstructive pulmonary disease (COPD) tend to be sedentary during leisure time. Physical activity (PA) may reduce the risk of COPD, but the causal relationship is unclear. We used a Mendelian randomisation (MR) method to elucidate the association of leisure sedentary behaviours (LSB) and PA with lung function and COPD.Methods Data on LSB (n=422 218), PA (n=608 595), COPD (n=299 929) and lung function (n=79 055) were obtained from the large-scale genome-wide association study. Causal inference used inverse variance-weighted, MR-Egger and weighted median. Sensitivity analysis was performed to assess heterogeneity and pleiotropy, and radial MR was used to distinguish outliers. The primary outcome was analysed by multifactorial MR adjusted for daily smoking.Results The inverse variance weighted analysis indicated that increased moderate-to-vigorous PA (MVPA) is associated with higher levels of forced vital capacity (FVC) (beta=0.27, 95% CI 0.12 to 0.42; p=3.51×10–4). For each increment of 2.8 hours in television watching, the odds of COPD were 2.25 times greater (OR=2.25; 95% CI 1.84 to 2.75; p=2.38×10–15). For early-onset COPD, the odds were 2.11 times greater (OR=2.11; 95% CI 1.56 to 2.85; p=1.06×10–6), and for late-onset COPD, the odds were 2.16 times greater (OR=2.16; 95% CI 1.64 to 2.84; p=3.12×10–8). Similarly, the odds of hospitalisation for COPD were 2.02 times greater with increased television watching (OR=2.02; 95% CI 1.59 to 2.55; p=4.68×10–9). Television watching was associated with lower FVC (beta=−0.19, 95% CI −0.28 to −0.10; p=1.54×10–5) and forced expiratory volume in the 1 s (FEV1) (beta=−0.16, 95% CI −0.25 to −0.08; p=1.21×10–4) levels. The results remained significant after adjustment for smoking.Conclusions Our study suggests a potential association with LSB, particularly television watching, is associated with higher odds of COPD and lower indices of lung function as measured continuously, including FEV1 and FVC. Conversely, an increase in MVPA is associated with higher indices of lung function, particularly reflected in increased FVC levels.

Abstract Background Patients with Alzheimer’s disease (AD) are often co-morbid with unprovoked seizures, making clinical diagnosis and management difficult. Although it has an important role in both AD and epilepsy, abnormal γ-aminobutyric acid (GABA)ergic transmission is recognized only as a compensative change for glutamatergic damage. Neuregulin 1 (NRG1)-ErbB4 signaling can promote GABA release and suppress epileptogenesis, but its effects on cognition in AD are still controversial. Methods Four-month-old APPswe/PS1dE9 mice (APP mice) were used as animal models in the early stage of AD in this study. Acute/chronic chemical-kindling epilepsy models were established with pentylenetetrazol. Electroencephalogram and Racine scores were performed to assess seizures. Behavioral tests were used to assess cognition and emotion. Electrophysiology, western blot and immunofluorescence were performed to detect the alterations in synapses, GABAergic system components and NRG1-ErbB4 signaling. Furthermore, NRG1 was administrated intracerebroventricularly into APP mice and then its antiepileptic and cognitive effects were evaluated. Results APP mice had increased susceptibility to epilepsy and resulting hippocampal synaptic damage and cognitive impairment. Electrophysiological analysis revealed decreased GABAergic transmission in the hippocampus. This abnormal GABAergic transmission involved a reduction in the number of parvalbumin interneurons (PV+ Ins) and decreased levels of GABA synthesis and transport. We also found impaired NRG1-ErbB4 signaling which mediated by PV+ Ins loss. And NRG1 administration could effectively reduce seizures and improve cognition in four-month-old APP mice. Conclusion Our results indicated that abnormal GABAergic transmission mediated hippocampal hyperexcitability, further excitation/inhibition imbalance, and promoted epileptogenesis in the early stage of AD. Appropriate NRG1 administration could down-regulate seizure susceptibility and rescue cognitive function. Our study provided a potential direction for intervening in the co-morbidity of AD and epilepsy.

Abstract Objective To develop a clinical learning environment scale for Chinese nursing students and test its reliability and validity. Methods Based on Moos social environment theory, qualitative interviews and expert consultations were used to develop a pretest version of the Chinese Nursing Students’ Clinical Learning Environment Scale. With a convenience sampling method, 255 and 1582 Chinese nursing students were selected as the prediction and validation samples, respectively, from December 2022 to March 2023. Exploratory and confirmatory factor analyses were conducted to determine the construct validity. Results The scale consisted of 19 items. Exploratory factor analysis revealed three sub-scales, named goal orientation, interpersonal relation, and learning support, which explained 71.500% of the total variance. The results of the confirmatory factor analysis showed that the GFI was 0.848, the AGFI was 0.806, the RMSEA was 0.090, the RMR was 0.041, the NFI was 0.910, the IFI was 0.916, the CFI was 0.916, the PCFI was 0.798, and the PNFI was 0.793. The reliability values of the three dimensions were 0.870, 0.858, and 0.943, respectively, and the convergent validity values were 0.574, 0.603, and 0.625, respectively. Conclusion The reliability and validity of the dimensions of the Chinese Nursing Students’ Clinical Learning Environment Scale are acceptable, and the scale can be used as a useful tool for measuring the clinical learning environment of Chinese nursing students.

Abstract HBV-miR-3 is encoded by HBV and takes part in pathogenesis of HBV-related liver disease. Whether HBV-miR-3 has a relationship with HBV replication and is predictive of PegIFN-α treatment response is still unknown. HBV-miR-3 quantification is based on qRT-PCR. The relationship of HBV-miR-3 and HBV replication, and predictive value of HBV-miR-3 were evaluated in a cohort of 650 HBeAg positive patients from a multi-center, randomized phase III clinical trial for the study of PegIFN-a2b. HBV-miR-3 is significantly positively related to HBVDNA, HBVpgRNA, HBeAg and HBsAg at baseline and at all the different time points during PegIFN-α treatment. Both univariate regression analyses and multivariate logistic regression analyses showed HBV-miR-3 is a predictor of HBeAg seroconversion in the patients treated with PegIFN-α at weeks of 0, 12, and 24. 70.0% of patients with HBV-miR-3 6log at week 12 no patient obtained HBeAg seroconversion. Conbination of HBV-miR-3 and HBeAg is more strongly predictive of HBeAg seroconversion (83.64%) at week 12. HBV-miR-3 is new biomarker for HBV replication and positively correlated to HBV replication. HBV-miR-3 is also an early predictor of HBeAg seroconversion in the patients treated with PegIFN-α.

Summary: Background: Both defects in mismatch repair (dMMR) and high microsatellite instability (MSI-H) have been recognised as crucial biomarkers that guide treatment strategies and disease management in colorectal cancer (CRC). As MMR and MSI tests are being widely conducted, an increasing number of MSI-H tumours have been identified in CRCs with mismatch repair proficiency (pMMR). The objective of this study was to assess the clinical features of patients with pMMR/MSI-H CRC and elucidate the underlying molecular mechanism in these cases. Methods: From January 2015 to December 2018, 1684 cases of pMMR and 401 dMMR CRCs were enrolled. Of those patients, 93 pMMR/MSI-H were identified. The clinical phenotypes and prognosis were analysed. Frozen and paraffin-embedded tissue were available in 35 patients with pMMR/MSI-H, for which comprehensive genomic and transcriptomic analyses were performed. Findings: In comparison to pMMR/MSS CRCs, pMMR/MSI-H CRCs exhibited significantly less tumour progression and better long-term prognosis. The pMMR/MSI-H cohorts displayed a higher presence of CD8+ T cells and NK cells when compared to the pMMR/MSS group. Mutational signature analysis revealed that nearly all samples exhibited deficiencies in MMR genes, and we also identified deleterious mutations in MSH3-K383fs. Interpretation: This study revealed pMMR/MSI-H CRC as a distinct subgroup within CRC, which manifests diverse clinicopathological features and long-term prognostic outcomes. Distinct features in the tumour immune-microenvironment were observed in pMMR/MSI-H CRCs. Pathogenic deleterious mutations in MSH3-K383fs were frequently detected, suggesting another potential biomarker for identifying MSI-H. Funding: This work was supported by the Science and Technology Commission of Shanghai Municipality (20DZ1100101).

Abstract Background Damage in the ischemic core and penumbra after stroke affects patient prognosis. Microglia immediately respond to ischemic insult and initiate immune inflammation, playing an important role in the cellular injury after stroke. However, the microglial heterogeneity and the mechanisms involved remain unclear. Methods We first performed single-cell RNA-sequencing (scRNA-seq) and spatial transcriptomics (ST) on middle cerebral artery occlusion (MCAO) mice from three time points to determine stroke-associated microglial subclusters and their spatial distributions. Furthermore, the expression of microglial subcluster-specific marker genes and the localization of different microglial subclusters were verified on MCAO mice through RNAscope and immunofluorescence. Gene set variation analysis (GSVA) was performed to reveal functional characteristics of microglia sub-clusters. Additionally, ingenuity pathway analysis (IPA) was used to explore upstream regulators of microglial subclusters, which was confirmed by immunofluorescence, RT-qPCR, shRNA-mediated knockdown, and targeted metabolomics. Finally, the infarct size, neurological deficits, and neuronal apoptosis were evaluated in MCAO mice after manipulation of specific microglial subcluster. Results We discovered stroke-associated microglial subclusters in the brains of MCAO mice. We also identified novel marker genes of these microglial subclusters and defined these cells as ischemic core-associated (ICAM) and ischemic penumbra-associated (IPAM) microglia, according to their spatial distribution. ICAM, induced by damage-associated molecular patterns, are probably fueled by glycolysis, and exhibit increased pro-inflammatory cytokines and chemokines production. BACH1 is a key transcription factor driving ICAM generation. In contrast, glucocorticoids, which are enriched in the penumbra, likely trigger IPAM formation, which are presumably powered by the citrate cycle and oxidative phosphorylation and are characterized by moderate pro-inflammatory responses, inflammation-alleviating metabolic features, and myelinotrophic properties. Conclusions ICAM could induce excessive neuroinflammation, aggravating brain injury, whereas IPAM probably exhibit neuroprotective features, which could be essential for the homeostasis and survival of cells in the penumbra. Our findings provide a biological basis for targeting specific microglial subclusters as a potential therapeutic strategy for ischemic stroke.

Profiling gene expression while preserving cell locations aids in the comprehensive understanding of cell fates in multicellular organisms. However, simple and flexible isolation of microregions of interest (mROIs) for spatial transcriptomics is still challenging. We present a laser-induced forward transfer (LIFT)-based method combined with a full-length mRNA-sequencing protocol (LIFT-seq) for profiling region-specific tissues. LIFT-seq demonstrated that mROIs from two adjacent sections could reliably and sensitively detect and display gene expression. In addition, LIFT-seq can identify region-specific mROIs in the mouse cortex and hippocampus. Finally, LIFT-seq identified marker genes in different layers of the cortex with very similar expression patterns. These genes were then validated using in situ hybridization (ISH) results. Therefore, LIFT-seq will be a valuable and efficient technique for profiling the spatial transcriptome in various tissues.

Abstract The visceral hybrid procedure combining retrograde visceral bypass grafting and completion endovascular stent grafting is a feasible alternative to conventional open surgical or wholly endovascular repairs of thoracoabdominal aneurysms (TAAA). However, the wide variability in visceral hybrid configurations means that a priori prediction of surgical outcome based on haemodynamic flow profiles such as velocity pattern and wall shear stress post repair remain challenging. We sought to appraise the clinical relevance of computational fluid dynamics (CFD) analyses in the setting of visceral hybrid TAAA repairs. Two patients, one with a type III and the other with a type V TAAA, underwent successful elective and emergency visceral hybrid repairs, respectively. Flow patterns and haemodynamic parameters were analysed using reconstructed pre- and post-operative CT scans. Both type III and type V TAAAs showed highly disturbed flow patterns with varying helicity values preoperatively within their respective aneurysms. Low time-averaged wall shear stress (TAWSS) and high endothelial cell action potential (ECAP) and relative residence time (RRT) associated with thrombogenic susceptibility was observed in the posterior aspect of both TAAAs preoperatively. Despite differing bypass configurations in the elective and emergency repairs, both treatment options appear to improve haemodynamic performance compared to preoperative study. However, we observed reduced TAWSS in the right iliac artery (portending a theoretical risk of future graft and possibly limb thrombosis), after the elective type III visceral hybrid repair, but not the emergency type V repair. We surmise that this difference may be attributed to the higher neo-bifurcation of the aortic stent graft in the type III as compared to the type V repair. Our results demonstrate that CFD can be used in complicated visceral hybrid repair to yield potentially actionable predictive insights with implications on surveillance and enhanced post-operative management, even in patients with complicated geometrical bypass configurations.

Abstract Stent graft-induced new entry tear (SINE) is a serious complication in aortic dissection patients caused by the stent-graft itself after thoracic endovascular aortic repair (TEVAR). The stability of SINE is a key indicator for the need and timing of reinterventions. This study aimed to understand the role of hemodynamics in SINE stability by means of computational fluid dynamics (CFD) analysis based on patient-specific anatomical information. Four patients treated with TEVAR who developed a distal SINE (dSINE) were included; two patients had a stable dSINE and two patients experienced expansion of the dSINE upon follow-up examinations. CFD simulations were performed on geometries reconstructed from computed tomography scans acquired upon early detection of dSINE in these patients. Computational results showed that stable dSINEs presented larger regions with low time-averaged wall shear stress (TAWSS) and high relative residence time (RRT), and partial thrombosis was observed at subsequent follow-ups. Furthermore, significant systolic antegrade flow was observed in the unstable dSINE which also had a larger retrograde flow fraction (RFF) on the SINE plane. In conclusion, this pilot study suggested that high RRT and low TAWSS may indicate stable dSINE by promoting thrombosis, whereas larger RFF and antegrade flows inside dSINE might be associated with its expansion.

Abstract Stroke usually causes prolonged or lifelong disability, owing to the permanent loss of infarcted tissue. Although a variety of stem cell transplantation has been explored to improve neuronal defect behavior by enhancing neuroplasticity, it remains unknown whether the infarcted tissue can be reconstructed. We here cultured human cerebral organoids derived from human pluripotent stem cells (hPSCs) and transplanted them into the junction of the infarct core and the peri-infarct zone of NOD-SCID mice subjected to stroke. Months later, we found that the grafted organoids survived well in the infarcted core, differentiated into target neurons, repaired infarcted tissue, sent axons to distant brain targets, and integrated into the host neural circuit and thereby eliminated sensorimotor defect behaviors of stroke mice, whereas transplantation of dissociated single cells from organoids failed to repair the infarcted tissue. Our study offers a new strategy for reconstructing infarcted tissue via organoids transplantation thereby reversing stroke-induced disability.

Objectives This work aimed to analyse the risk factors for poor outcomes and mortality among patients with anterior large vessel occlusion (LVO) ischaemic stroke, despite successful recanalisation.Setting and participants This study conducted a secondary analysis among patients who underwent successful recanalisation in the CAPTURE trial. The trial took place between March 2018 and September 2020 at 21 sites in China. The CAPTURE trial enrolled patients who had an acute ischaemic stroke aged 18–80 years with LVO in anterior circulation.Interventions Thrombectomy was immediately performed using Neurohawk or the Solitaire FR after randomisation in CAPTURE trial. Rescue treatment was available for patients with severe residual stenosis caused by atherosclerosis.Primary and secondary outcome measures The primary goal was to predict poor 90-day survival or mortality within 90 days post-thrombectomy. Univariate analysis, using the χ2 test or Fisher’s exact test, was conducted for each selected factor. Subsequently, a multivariable analysis was performed on significant factors (p≤0.10) identified through univariate analysis using the backward selection logistic regression approach.Results Among the 207 recruited patients, 79 (38.2%) exhibited poor clinical outcomes, and 26 (12.6%) died within 90 days post-thrombectomy. Multivariate analysis revealed that the following factors were significantly associated with poor 90-day survival: age ≥67 years, internal carotid artery (ICA) occlusion (compared with middle cerebral artery (MCA) occlusion), initial National Institutes of Health Stroke Scale (NIHSS) score ≥17 and final modified Thrombolysis in Cerebral Infarction (mTICI) score 2b (compared with mTICI 3). Additionally, the following factors were significantly associated with mortality 90 days post-thrombectomy: initial NIHSS score ≥17, ICA occlusion (compared with MCA occlusion) and recanalisation with more than one pass.Conclusions Age, NIHSS score, occlusion site, mTICI score and the number of passes can be independently used to predict poor 90-day survival or mortality within 90 days post-thrombectomy.Trial registration number NCT04995757.

Abstract Ductal carcinoma in situ with microinvasion (DCIS-MI) is a subtype of breast cancer with a good prognosis, for which both breast conserving surgery plus radiotherapy (BCS + RT) and mastectomy are feasible surgical methods, but no clear conclusion has been made on the choice of these treatments. We used the Surveillance, Epidemiology and End Results database to extract 5432 DCIS-MI patients. Participants were divided into the BCS + RT group and the mastectomy group. We compared the overall survival (OS) and breast cancer-specific survival (BCSS) of the two groups using the Kaplan–Meier method and Cox regressions before and after propensity score matching (PSM). Before PSM, both univariate and multivariate analyses showed that BCS + RT group had significantly higher OS and BCSS compared with patients in the mastectomy group (P

The protein encoded by dynein axonemal heavy chain 1 (DNAH1) is a part of dynein, which regulates the function of cilia and sperm flagella. The mutant of DNAH1 causes the deletion of inner dynein arm 3 in the flagellum, leading to multiple morphological abnormalities of the sperm flagella (MMAF) and severe asthenozoospermia. However, instead of asthenozoospermia and MMAF, the result caused by the mutation of DNAH1 remains unknown. Here we report a male infertility patient with severe asthenozoospermia and teratozoospermia. We found two heterozygous mutations in DNAH1 (c.6912C>A and c.7076G>T) and which were reported to be associated with MMAF for the first time. We next collected and analyzed 65 cases of DNAH1 mutation and found that the proportion of short flagella is the largest, while the bent flagella account for the smallest, and the incidence of head deformity is not high in the sperm of these patients. Finally, we also analyzed 31 DNAH1 mutation patients who were treated with intracytoplasmic sperm injection (ICSI) and achieved beneficial outcomes. We hope our research will be helpful in the diagnosis and treatment of male infertility caused by DNAH1 mutation.

Synaptic plasticity impairment plays a critical role in the pathogenesis of Alzheimer’s disease (AD), and emerging evidence has shown that microRNAs (miRs) are alternative biomarkers and therapeutic targets for synaptic dysfunctions in AD. In this study, we found that the level of miR-431 was downregulated in the plasma of patients with amnestic mild cognitive impairment and AD. In addition, it was decreased in the hippocampus and plasma of APPswe/PS1dE9 (APP/PS1) mice. Lentivirus-mediated miR-431 overexpression in the hippocampus CA1 ameliorated synaptic plasticity and memory deficits of APP/PS1 mice, while it did not affect amyloid-β levels. Smad4 was identified as a target of miR-431, and Smad4 knockdown modulated the expression of synaptic proteins, including SAP102, and protected against synaptic plasticity and memory dysfunctions in APP/PS1 mice. Furthermore, Smad4 overexpression reversed the protective effects of miR-431, indicating that miR-431 attenuated synaptic impairment at least partially by Smad4 inhibition. Thus, these results indicated that miR-431/Smad4 might be a potential therapeutic target for AD treatment.

Objective To investigate the effects of down-regulation of long non-coding RNA-H19 (lncRNA-H19) expression on apoptosis and autophagy of human keloid fibroblast cell line and to explore potential mechanism. Methods Human scar fibroblasts cell line (KFs) and normal human dermal fibroblasts cell line (HDFs) were collected and KFs cells were infected with lncRNA-H19F low-expressing adenovirus (si-lncRNA-H19) and empty virus vector without si-lncRNA-H19 (si-eGFP). They were divided into HDFs group, KFs group, si-lncRNA-H19+KFs group and si-eGFP+KFs group. KFs cells were co-transfected with si-lncRNA, mTOR over-expressing adenovirus (Ad-mTOR) and empty vector (Ad-eGFP-m), then divided into KFs group, si-lncRNA-H19+Ad-mTOR group,si-eGFP+Ad-mTOR group, si-lncRNA-H19+Ad-eGFP group and si-eGFP+Ad-eGFP group. RT-qPCR was used to detect the expression of lncRNA-H19; flow cytometry was used to detect the cell apoptosis ; autophagy was examined by EM microscopy with fluorescence (acridine orange,AO) staining; immuno-histochemical method was used to detect the positive expression of autophagy pathway-mammalian target of rapamycin (mTOR); Western blot was used to detect the expression of apoptosis and autophagy-related proteins. Results Compared with the HDFs group, the expression of lncRNA-H19 and mTOR activity in the KFs group increased and the number of autophagic vesicles and the expression of apoptosis and autophagy-related proteins decreased (P＜0.05); after down-regulating lncRNA-H19 in KFs cells, the activity of mTOR in KFs cells decreased and apoptosis/autophagy increased (P＜0.05). Up-regulating mTOR while down-regulating lncRNA-H19 lead to more autophagy and apoptotic in KFs cells as compared to that resulted from down-regulation of lncRNA-H19 alone (P＜0.05). Conclusions Down-regulation of lncRNA-H19 expression may promote the autophagy and apoptosis of KFs cells through inhibiting activation of mTOR pathway.

Objectives The aims of the study were to assess the management of low-density lipoprotein cholesterol (LDL-C) and the goal achievement, as well as to investigate the association between baseline LDL-C level, lipid-lowering treatment (LLT), and stroke recurrence in patients with ischaemic stroke or transient ischaemic attack (TIA).Design Our study was a post hoc analysis of the Third China National Stroke Registry (CNSR-III).Setting We derived data from the CNSR-III - a nationwide clinical registry of ischaemic stroke and TIA based on 201 participating hospitals in mainland China.Participants 15,166 patients were included in this study with demographic characteristics, etiology, imaging, and biological markers from August 2015 to March 2018.Primary and secondary outcome measures The primary outcome was a new stroke, LDL-C goal (LDL-C

Background. Lung cancer (LC) has the highest mortality rate all over the world. It is necessary to search for novel potential biomarkers that are easily accessible and inexpensive in identifying patients with LC at early stage. Methods. A total of 195 patients with advanced LC who have received first-line chemotherapy were involved in this study. The optimized cut-off values of AGR and SIRI (AGR = albumin/globulin; SIRI = neutrophil ∗ monocyte/lymphocyte) were determined by survival function analysis based on R software. COX regression analysis was performed to obtain the independent factors for establishing the nomogram model. A nomogram model comprising these independent prognostic parameters was built for the TNI (tumor-nutrition-inflammation index) score calculation. The predictive accuracy was demonstrated through ROC curve and calibration curves after index concordance. Results. The optimized cut-off values of AGR and SIRI were 1.22 and 1.60, respectively. It was revealed that liver metastasis, SCC, AGR, and SIRI were independent prognostic factors in advanced lung cancer by Cox analysis. Afterwards, the nomogram model comprised of these independent prognostic parameters was built for TNI scores calculation. Based on the TNI quartile values, patients were divided into four groups. And it was indicated that higher TNI had worse OS (P

Objective: Advanced endovascular options for acute and chronic pathology of the ascending aorta are emerging; however, several problems with stent grafts placed in the ascending aorta have been identified in patients unsuitable for surgical repair, such as migration and erosion at aorta interface. Method: Among the six cases analysed in this report, three were treated with a stent graft in the ascending aorta to manage chronic dissection in the proximal aorta; dimensions of those stent grafts varied between 34 and 45 mm in diameter, and from 77 to 100 mm in length. Three patients, matched by age, sex and their nature of pathology, were subjected to the focal closure of a single communicating entry by the use of an occluding device (Amplatzer ASD and PFO occluders between 14 and 18 mm disc diameter) with similar Charlson comorbidity score. Results: Both conceptually different nonsurgical management strategies were technically feasible; however, with stent grafts, an early or delayed erosion to full re-dissection was documented with stent grafts, in contrast to complete seal, with an induced remodelling and a long-term survival after the successful placing of coils and occluder devices. Moreover, aortic root motion was not impaired by the focal occlusion of a communication with an occluder, while free motion was impeded after stent graft placement. Conclusions: The intriguing observation in our small series was that stent grafts placed in the ascending aorta portends the risk of an either early (post-procedural) or delayed migration and erosion of aortic tissues at the landing site or biological interface between 12 and 16 months after the procedure, a phenomenon not seen with the use of focal occluding devices up to 5 years of follow-up. Obviously, the focal approach avoids the erosion of the aortic wall as the result of minimal interaction with the biological interface, such as a diseased aortic wall. Potential explanations may be related to a reduced motion of the aortic root after the placement of stent graft in the ascending aorta, whereas the free motion of aortic root was preserved with an occluder. The causality of erosion may however not be fully understood, as besides the stiffness and radial force of the stent graft, other factors such as the induced inflammatory reactions of aortic tissue and local adhesions within the chest may also play a role. With stent grafts failing to portend long-term success, they may still have a role as a temporizing solution for elective surgical conversion. Larger datasets from registries are needed to further explore this evolving field of interventions to the ascending aorta.

Abstract Type A aortic dissection (TAAD) involves the ascending aorta or the arch. Acute TAAD usually requires urgent replacement of the ascending aorta. However, a subset of these patients develops aortic rupture due to further dilatation of the residual dissected aorta. There is currently no reliable means to predict the risk of dilatation following TAAD repair. In this study, we performed a comprehensive morphological and hemodynamic analysis for patients with and without progressive aortic dilatation following surgical replacement of the ascending aorta. Patient-specific models of repaired TAAD were reconstructed from post-surgery computed tomography images for detailed computational fluid dynamic analysis. Geometric and hemodynamic parameters were evaluated and compared between patients with stable aortic diameters (N = 9) and those with aortic dilatation (N = 8). Our results showed that the number of re-entry tears and true/false lumen pressure difference were significantly different between the two groups. Patients with progressive aortic dilatation had higher luminal pressure difference (6.7 [4.6, 10.9] vs. 0.9 [0.5, 2.3] mmHg; P = 0.001) and fewer re-entry tears (1.5 [1, 2.8] vs. 5 [3.3, 7.5]; P = 0.02) compared to patients with stable aortic diameters, suggesting that these factors may serve as potential predictors of aneurysmal dilatation following surgical repair of TAAD.

Introduction The present study aimed to investigate the differences in the proteomic expression between uncomplicated parapneumonic pleural effusion (UPPE) and complicated parapneumonic pleural effusion (CPPE). Material and methods There were 10 patients with UPPE and 10 patients with CPPE. These patients were combined due to the complication of pleural effusion and further divided into group A and group B. An LC-MS analysis was conducted with the extraction of high-abundance proteins, and proteins with 1.5-fold or higher difference multiples were identified as differential proteins. Then, gene ontology (GO) and KEGG analyses were conducted on the differential proteins between the groups. Results Compared with the UPPE group, there were 38 upregulated proteins and 29 downregulated proteins in the CPPE group. The GO analysis revealed that the CPPE group had enhanced expressions in monosaccharide biosynthesis, glucose catabolism, fructose-6-phosphate glycolysis, glucose-6-phosphate glycolysis, and NADH regeneration as well as reduced expressions in fibrinogen complexes, protein polymerization, and coagulation. Moreover, the KEGG analysis showed that the CPPE group had enhanced expressions in amino acid synthesis, the HIF-1 signalling pathway, and glycolysis/glyco-isogenesis and decreased expressions in platelet activation and complement activation. Conclusions In pleural effusion in patients with CPPE, there are enhanced expressions of proteins concerning glucose and amino acid metabolism, NADH regeneration, and HIF-1 signalling pathways together with decreased expressions of proteins concerning protein polymerization, blood coagulation, platelet activation, and complement activation.

Objective To study the effect of bone marrow mesenchymal stem cells(BM-MSCs) combined with chitosan composite hydrogel loaded with transforming growth factor beta 3 (TGF-β3) to repair meniscus defects. Methods A full-thickness defect model of the anterior horn of the meniscus was developed in 60 New Zealand white rabbits. They were randomly divided into: the control group which did not implant any materials. The repair group Ⅰ in which chitosan composite hydrogel and bone marrow mesenchymal stem cells composite were injected into the defect group, and in group Ⅱ,the chitosan composite hydrogel loaded with TGF-beta 3 and bone marrow mesenchymal stem cells complex were repaired. After 12 weeks of operation, the samples were taken for radiology, gross and histological observation. Western blot was used to detect type Ⅱ collagen and proteoglycan protein. Results In the control group, the full-thickness defect of the meniscus anterior horn was not obviously repaired; in the repair group Ⅰ,most of the defects were filled with repaired tissue; in the repair group Ⅱ, the defects were completely filled with repaired tissue. The expression level of type Ⅱ collagen and proteoglycan protein in repair group Ⅱ was higher than that in control group (P＜0.05). Conclusions Bone marrow mesenchymal stem cells combined with chitosan hydrogel loaded with TGF-beta 3 can promote the repair of meniscus defects in rabbits.

Introduction The pathology of Alzheimer’s disease (AD) includes β-amy�loid (Aβ) (plaques) and neurofibrillary tangles (NFTs). This study aimed to explore the efficacy of Huatuo Zaizao pill (HTZP) in an AD mouse model in�duced by injecting Aβ 1-42 , and the neuroprotective mechanism of HTZP in Material and methods C57BL/6 (B6) mice were randomly divided into 4 groups (n = 10, per group): control group, AD model group, and 2 differ�ent doses of HTZP treated groups. The Morris water maze test was carried out on AD mice to assess the learning ability after treatment with HTZP for 15 day. The levels of inflammatory factors and the nuclear factor-κB (NF-κB) pathway were examined by western blot and real-time polymerase chain reac�tion (PCR). The content of microglia was investigated by immunofluorescence. Results This study revealed that a cognitive disorder could be mitigated when the AD mice were treated with HTZP, which might be associated with the decreased level of pro-inflammatory factors, and the inhibitory activities of microglia. Additionally, phosphorylation of IκB and NF-κB p65 could be reduced by prohibiting the neuroinflammation of NF-κB activation in the hippocampus of AD mice. Conclusions These results showed that HTZP could mitigate a cognitive disorder, diminish the activation of microglia, and inhibit the content of inflammatory factors through the NF-κB pathway in Aβ 1-42 -induced AD mice. HTZP may be an appropriate agent for AD treatment in the future.

BackgroundThe effect of postmastectomy radiotherapy (PMRT) on T1-2N1M0 triple-negative breast cancers (TNBC) remains unclear. The population-based study aimed to investigate the survival outcomes of T1-2N1M0 TNBC patients who underwent PMRT or not.MethodsWe selected 1743 patients with T1-2N1M0 TNBC who underwent mastectomy between 2010 and 2015 through the Surveillance, Epidemiology and End Results (SEER) database. After propensity score matching (PSM), the PMRT and no-PMRT groups consisted of 586 matched patients, respectively. The Kaplan-Meier method was applied to calculate breast cancer-specific survival (BCSS) and cox proportional hazard model was used to determine the prognostic factors of T1-2N1M0 TNBC.ResultsThe 5-year BCSS for the PMRT and no-PMRT groups was 79.1% and 74.7%, respectively. Analysis showed that in patients with three nodes positive, radiotherapy could significantly improve BCSS (HR = 0.396, 95% CI = 0.175-0.900, P = 0.027), but it brought no significant advantage in BCSS in patients with one or two nodes positive (HR = 1.061, 95% CI = 0.725-1.552, P = 0.761; HR = 0.657, 95% CI = 0.405-1.065, P = 0.088). In addition, PMRT improves the BCSS in TNBC patients with T2 tumor concomitant with three positive lymph nodes (HR = 0.343, 95% CI = 0.132-0.890, P = 0.028).ConclusionTNBC patients with T2 tumor concomitant with three positive lymph nodes can benefit from PMRT.

A service can be an intangible commodity in which no physical goods are transferred from the seller to the buyer. However, traditional trading platforms have many limitations in trading services due to dishonest buyers and brokers. In this paper, we propose a service trading ecosystem based on blockchain, named STEB, which combines blockchain, smart contract, encryption, and digital authentication techniques for service trading. In addition, a dual-chain architecture, which contains two types of blockchains, namely TraChain and SerChain, and a hierarchical encryption scheme of the data on the chain, are proposed to ensure the integrity of transaction data and fine-grained privacy protection of users. Furthermore, we describe a new set of smart contracts to ensure safe transactions for the entire service trading. Security analysis and simulation results confirm that the proposed STEB can achieve more efficient contract execution and enhance service transaction privacy.

To analyze the results of HIV screening and the HIV-positive rate based on different HIV detection strategies in Zhejiang Province, China. Data were downloaded from the AIDS Prevention and Control Information System on May 1, 2019. HIV screening, prevalence, and incidence data were analyzed from 2008 to 2018. The incidence of HIV was calculated from the results of BED testing. SPSS software (ver. 19.0) was used for the analysis. The number of people screened for HIV increased by 229.7% from 2008 to 2018, while the incidence of HIV increased from 1.14‱ (2010) to 1.67‱ (2018), peak by 2015 (2.28‱). The proportion of people screened for HIV in medical institutions increased from 62.0% in 2008 to 67.1% in 2018, while of all positive tests, 47.9% were conducted at medical institutions in 2008, which increased to 63.2% in 2018. VCT and STD clinic attendees, who had only 4.5% of all those undergoing HIV tests, accounted for 23.7% of all HIV positive in 2018. The rate of HIV-positive people and incidence of HIV both increased in Zhejiang Province between 2008 and 2015. The most effective strategy for detecting HIV new cases is screening visitors to VCT and STD clinics.

BackgroundMetaplastic breast cancer (MBC) are rare. The survival outcomes of MBC patients after breast conserving surgery plus radiotherapy (BCS+RT) or mastectomy have not been established. The study aimed to compare survival outcomes of MBC patients subjected to BCS+RT or mastectomy therapeutic options.MethodsPatients who were subjected to BCS+RT or mastectomy between 2004 and 2014 were enrolled in this study through the Surveillance, Epidemiology and End Results (SEER) database. Breast cancer-specific survival (BCSS) and the overall survival (OS) of the participants were determined. Cox proportional hazard model and the Kaplan Meier method were used to determine the correlation between the two surgical methods and survival outcomes.ResultsA total of 1197 patients were enrolled in this study. Among them, 439 patients were subjected to BCS+RT, while 758 patients were subjected to mastectomy. After propensity score matching (PSM), the BCS+RT and mastectomy groups consisted of 321 patients, respectively. The univariate and multivariate analysis with a 6-month landmark all indicate that patients receiving BCS+RT has higher OS than patients receiving mastectomy (HR = 0.701,95% CI = 0.496-0.990, P = 0.044; HR = 0.684,95% CI = 0.479-0.977, P = 0.037) while the BCSS was no difference between the two groups (HR = 0.739,95% CI = 0.474-1.153, P = 0.183; HR = 0.741,95% CI = 0.468-1.173, P = 0.200).ConclusionThe BCS+RT therapeutic option exhibits a higher OS in MBC patients compared to the mastectomy approach.

Profiling skin microbiome and metabolome has been utilised to gain further insight into wound healing processes. The aims of this multi-part temporal study in 11 volunteers were to analytically profile the dynamic wound tissue and headspace metabolome and sequence microbial communities in acute wound healing at days 0, 7, 14, 21 and 28, and to investigate their relationship to wound healing, using non-invasive quantitative devices. Metabolites were obtained using tissue extraction, sorbent and polydimethylsiloxane patches and analysed using GCMS. PCA of wound tissue metabolome clearly separated time points with 10 metabolites of 346 being involved in separation. Analysis of variance-simultaneous component analysis identified a statistical difference between the wound headspace metabolome, sites (P = 0.0024) and time points (P

Background: White matter lesions (WMLs) are common findings in brain magnetic resonance imaging (MRI) and are strongly associated with stroke incidence, recurrence, and prognosis. However, the relationship between WMLs and transient ischemic attacks (TIAs) is not well established. This study aimed to determine the clinical significance of WMLs in patients with TIA. Methods: A total of 181 consecutive inpatients with first-ever TIA were enrolled. Brain MRIs within 2 days of symptom onset were used to measure WML volumes. Recurrent vascular events within 1 year of TIA onset were assessed. The relationship between WMLs and recurrent risk of vascular events was determined by a multivariate logistic regression. Results: WMLs were identified in 104 patients (57.5%). Age and ratio of hypertension were significantly different between patients with and without WMLs. The incidence of vascular events in patients with WMLs significantly increased in comparison to those without WMLs (21.15% vs. 5.19%, 95% confidence interval [CI]: 1.18–15.20, P = 0.027) after controlling for confounders. Furthermore, distributions of WML loads were found to be different between patients who developed vascular events and those who did not. WML volumes were demonstrated to be correlated with recurrent risks, and the fourth quartile of WML volumes led to an 8.5-fold elevation of recurrent risk of vascular events compared with the first quartile (95% CI: 1.52–47.65, P = 0.015) after adjusting for hyperlipidemia. Conclusion: WMLs occur frequently in patients with TIA and are associated with the high risk of recurrent vascular events, suggesting a predictive neuroimaging marker for TIA outcomes.

Abstract Immuno-inflammation has been shown to play a pivotal role in the pathogenesis of moyamoya disease (MMD). However, how did circulating Treg/Th17 cells involve in MMD patients remains unclear. 26 MMD, 21 atherothrombotic stroke, and 32 healthy controls were enrolled in this study. MMD patients have a significantly higher percentage of circulating Treg and Th17 cells as well as their dominantly secreting cytokines than other groups (P

Abstract Acute myeloid leukaemia (AML) is a life threatening cancer for which there is an urgent clinical need for novel therapeutic approaches. A redeployed drug combination of bezafibrate and medroxyprogesterone acetate (BaP) has shown anti-leukaemic activity in vitro and in vivo. Elucidation of the BaP mechanism of action is required in order to understand how to maximise the clinical benefit. Attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy, Synchrotron radiation FTIR (S-FTIR) and Raman microspectroscopy are powerful complementary techniques which were employed to probe the biochemical composition of two AML cell lines in the presence and absence of BaP. Analysis was performed on single living cells along with dehydrated and fixed cells to provide a large and detailed data set. A consideration of the main spectral differences in conjunction with multivariate statistical analysis reveals a significant change to the cellular lipid composition with drug treatment; furthermore, this response is not caused by cell apoptosis. No change to the DNA of either cell line was observed suggesting this combination therapy primarily targets lipid biosynthesis or effects bioactive lipids that activate specific signalling pathways.

Background: High expressions of galectin-3 were identified recently in the end stage of amyotrophic lateral sclerosis (ALS) patients, which suggested that immune reactivity and inflammatory mechanisms might play an important role in the pathogenesis of ALS. The purpose of this study was to investigate plasma galectin-3 levels in different groups and stages of ALS patients and the association with related clinical characteristics. Methods: A total of 51 patients with ALS and 60 normal controls (NCs) were recruited in this study. Plasma galectin-3 levels were determined using the enzyme-linked immunosorbent assay. Patients with ALS were divided into several groups according to their clinical characteristics: gender, type of disease onset, duration of disease, and clinical conditions of disease. Statistical analyses of the differences of galectin-3 levels between groups and the association with the clinical characteristics of disease were performed. Results: As compared with the NCs (201.64 [22.35–401.63] ng/ml), plasma galectin-3 levels were significantly elevated in the patients with duration >12 months (341.17 [69.12–859.22] ng/ml, P< 0.05), and the patients with limb onset of disease (254.14 [69.12–859.22] ng/ml, P< 0.05); however, no difference was found in the patients with duration ≤12 months (250.62 [109.77–334.92] ng/ml, P > 0.05), and the patients with bulbar onset of disease (251.79 [109.20–404.76] ng/ml, P > 0.05). In addition, galectin-3 levels were significantly increased in the female patients (263.27 [123.32–859.22] ng/ml, P< 0.05) while no difference was found in the male patients (220.39 [69.12–748.73] ng/ml, P > 0.05). The further statistical analyses showed that plasma galectin-3 levels were positively correlated with the duration of disease (r = 0.293, P = 0.037). Conclusions: Plasma galectin-3 levels were significantly increased in ALS patients with limb onset of disease, especially in ALS female patients, and positively correlated with the duration of disease, which suggested that plasma galectin-3 might be an interesting and useful factor associated with ALS.

Metabolomics-based approaches were applied to understand interactions of trimethoprim with Escherichia coli K-12 at sub-minimum inhibitory concentrations (MIC≈0.2, 0.03 and 0.003 mg L-1). Trimethoprim inhibits dihydrofolate reductase and thereby is an indirect inhibitor of nucleic acid synthesis. Due to the basicity of trimethoprim, two pH levels (5 and 7) were selected which mimicked healthy urine pH. This also allowed investigation of the effect on bacterial metabolism when trimethoprim exists in different ionization states. UHPLC-MS was employed to detect trimethoprim molecules inside the bacterial cell and this showed that at pH 7 more of the drug was recovered compared to pH 5; this correlated with classical growth curve measurements. FT-IR spectroscopy was used to establish recovery of reproducible phenotypes under all 8 conditions (3 drug levels and control in 2 pH levels) and GC-MS was used to generate global metabolic profiles. In addition to finding direct mode-of-action effects where nucleotides were decreased at pH 7 with increasing trimethoprim levels, off-target pH-related effects were observed for many amino acids. Additionally, stress-related effects were observed where the osmoprotectant trehalose was higher at increased antibiotic levels at pH 7. This correlated with glucose and fructose consumption and increase in pyruvate-related products as well as lactate and alanine. Alanine is a known regulator of sugar metabolism and this increase may be to enhance sugar consumption and thus trehalose production. These results provide a wider view of the action of trimethoprim. Metabolomics indicated alternative metabolism areas to be investigated to further understand the off-target effects of trimethoprim.