Search

Abstract Objective The purpose of this study was to compare the analgesic effects of intercostal nerve block (ICNB) and local anesthetic infiltration (LAI) on postoperative pain and recovery following thoracoscopic resection of pulmonary bullae. Methods A total of 160 patients undergoing thoracoscopic pulmonary bullae resection were randomly assigned to receive either ICNB (n = 80) or LAI (n = 80). An experienced anesthesiologist administered ultrasound guided ICNB at the T4 and T7 levels with 5 mL of 0.375% ropivacaine hydrochloride for the ICNB group. Instead, the LAI group received 10 mL of the same concentration of ropivacaine hydrochloride at the same concentration used for ICNB for infiltration anesthesia at the incision sites. Out of the initial cohort, 146 patients completed the study (ICNB group, n = 71; LAI group, n = 75). The collected data included preoperative clinical characteristics, visual analog scale (VAS) scores for pain at various time points post-surgery (6, 12, 24, 48, and 72 h). Additionally, the Quality of Recovery-15 (QoR-15) questionnaire was administered 24 h after surgery, and sleep quality was evaluated using the Pittsburgh Sleep Quality Index (PSQI). Results No significant differences were found in drainage volume, use of additional analgesics, duration of chest tube placement, or hospital stay between the two groups. However, the ICNB group had significantly lower VAS scores and QoR-15 scores 24 h postoperatively (p

Abstract Methionine, an indispensable amino acid crucial for dietary balance, intricately governs metabolic pathways. Disruption in its equilibrium has the potential to heighten homocysteine levels in both plasma and tissues, posing a conceivable risk of inducing inflammation and detriment to the integrity of vascular endothelial cells. The intricate interplay between methionine metabolism, with a specific focus on S-adenosyl-L-methionine (SAM), and the onset of thoracic aortic dissection (TAD) remains enigmatic despite acknowledging the pivotal role of inflammation in this vascular condition. In an established murine model induced by β-aminopropionitrile monofumarate (BAPN), we delved into the repercussions of supplementing with S-adenosyl-L-methionine (SAM) on the progression of TAD. Our observations uncovered a noteworthy improvement in aortic dissection and rupture rates, accompanied by a marked reduction in mortality upon SAM supplementation. Notably, SAM supplementation exhibited a considerable protective effect against BAPN-induced degradation of elastin and the extracellular matrix. Furthermore, SAM supplementation demonstrated a robust inhibitory influence on the infiltration of immune cells, particularly neutrophils and macrophages. It also manifested a notable reduction in the inflammatory polarization of macrophages, evident through diminished accumulation of MHC-IIhigh macrophages and reduced expression of inflammatory cytokines such as IL1β and TNFα in macrophages. Simultaneously, SAM supplementation exerted a suppressive effect on the activation of CD4 + and CD8 + T cells within the aorta. This was evidenced by an elevated proportion of CD44- CD62L + naïve T cells and a concurrent decrease in CD44 + CD62L- effector T cells. In summary, our findings strongly suggest that the supplementation of SAM exhibits remarkable efficacy in alleviating BAPN-induced aortic inflammation, consequently impeding the progression of thoracic aortic dissection.

Abstract Multi‐agent reinforcement learning relies on reward signals to guide the policy networks of individual agents. However, in high‐dimensional continuous spaces, the non‐stationary environment can provide outdated experiences that hinder convergence, resulting in ineffective training performance for multi‐agent systems. To tackle this issue, a novel reinforcement learning scheme, Mutual Information Oriented Deep Skill Chaining (MioDSC), is proposed that generates an optimised cooperative policy by incorporating intrinsic rewards based on mutual information to improve exploration efficiency. These rewards encourage agents to diversify their learning process by engaging in actions that increase the mutual information between their actions and the environment state. In addition, MioDSC can generate cooperative policies using the options framework, allowing agents to learn and reuse complex action sequences and accelerating the convergence speed of multi‐agent learning. MioDSC was evaluated in the multi‐agent particle environment and the StarCraft multi‐agent challenge at varying difficulty levels. The experimental results demonstrate that MioDSC outperforms state‐of‐the‐art methods and is robust across various multi‐agent system tasks with high stability.

Abstract Sepsis is a critical global health concern linked to high mortality rates, often due to acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). While the gut-lung axis involvement in ALI is recognized, direct migration of gut immune cells to the lung remains unclear. Our study reveals sepsis-induced migration of γδ T17 cells from the small intestine to the lung, triggering an IL-17A-dominated inflammatory response in mice. Wnt signaling activation in alveolar macrophages drives CCL1 upregulation, facilitating γδ T17 cell migration. CD44+ Ly6C– IL-7Rhigh CD8low cells are the primary migratory subtype exacerbating ALI. Esketamine attenuates ALI by inhibiting pulmonary Wnt/β-catenin signaling-mediated migration. This work underscores the pivotal role of direct gut-to-lung memory γδ T17 cell migration in septic ALI and clarifies the importance of localized IL-17A elevation in the lung.

Objective Surgical site infection (SSI) after spinal surgery is still a persistent worldwide health concern as it is a worrying and devastating complication. The number of samples in previous studies is limited and the role of conservative antibiotic therapy has not been established. This study aims to evaluate the clinical efficacy and feasibility of empirical antibiotic treatment for suspected early‐onset deep spinal SSI. Methods We conducted a retrospective study to identify all cases with suspected early‐onset deep SSI after lumbar instrumented surgery between January 2009 and December 2018. We evaluated the potential risks for antibiotic treatment, examined the antibiotic treatment failure rate, and applied logistic regression analysis to assess the risk factors for empirical antibiotic treatment failure. Results Over the past 10 years, 45 patients matched the inclusion criteria. The success rate of antibiotic treatment was 62.2% (28/45). Of the 17 patients who failed antibiotic treatment, 16 were cured after a debridement intervention and the remaining one required removal of the internal fixation before recovery. On univariate analysis, risk factors for antibiotic treatment failure included age, increasing or persisting back pain, wound dehiscence, localized swelling, and time to SSI (cut‐off: 10 days). Multivariate analysis revealed that infection occurring 10 days after primary surgery and wound dehiscence were independent risk factors for antibiotic treatment failure. Conclusion Appropriate antibiotic treatment is an alternative strategy for suspected early‐onset deep SSI after lumbar instrumented surgery. Antibiotic treatment for suspected SSI occurring within 10 days after primary surgery may improve the success rate of antibiotic intervention. Patients with wound dehiscence have a significantly higher likelihood of requiring surgical intervention.

Abstract Background The research aims to explore the characteristics of intestinal flora, nutritional status and immune function in patients with different types of obese colon cancer. Methods A retrospective analysis is conducted on 64 cases of obese colon cancer diagnosed from June 2018 to January 2020. According to the histological staging of the cancer, they are classified into adenocarcinoma, adenosquamous carcinoma and undifferentiated carcinoma, with corresponding cases of 24, 22 and 18, respectively. The intestinal flora (Bifidobacterium, Lactobacillus, Enterococcus faecalis, Escherichia coli, and yeast), nutritional status (Hb, Alb, PA, TFN, and PNI), immune function (IgG, IgM, IgA, CD4 +, CD8 +, and CD4 +/CD8 +) are analyzed in the different groups of patients. Survival curves are evaluated by Kaplan-Meier method and log-rank test for tumour death, local recurrence, and distant metastasis. Results There were no statistically significant differences in intestinal flora (Bifidobacterium, Lactobacillus, Enterococcus faecalis, Escherichia coli, and yeast), nutritional status (Hb, Alb, PA, TFN, and PNI) and immune function (IgG, IgM, IgA, CD4 +, CD8 +, and CD4 +/CD8 +) between different groups. There was a significant correlation between intestinal flora, nutritional status and immune function for all three. The survival curves of tumour death, local recurrence and distant metastasis in different groups of obese colon cancer patients were statistically significant. The tumor mortality rate, local recurrence, and distant metastasis rate in adenocarcinoma were 78.65%, 54.25% and 48.26% respectively. Conclusion There are differences in intestinal flora, nutritional status and immune function among different types of obese colon cancer patients, but adenocarcinoma has the least benefit in intestinal flora, poor nutritional status, and weakest immune function.

The fracture behaviours of pearlite structures in several typical carbon steels were investigated by scanning electron microscopy (SEM). Microstructural analysis indicated that the fracture of pearlite is a mixed ductile-brittle fracture, and brittle fracture has cleavage fracture characteristics, which often occur inside the pearlite structure. The fracture surface can exhibit any orientation relationship with the ferrite/cementite interface plane in the pearlite structure. The two phases in the pearlite structure (ferrite (α-Fe) and cementite (θ-Fe3C)) are fine grains rather than single-crystal platelets. The cleavage fracture mechanism in any direction of pearlite structure occurs due to the fine grain substructure.

BackgroundPrevious studies have demonstrated that the Naples Prognostic Score (NPS) provides strategic direction in the prognosis of malignant illness. Nevertheless, its relationship with chronic obstructive pulmonary disease (COPD) remains underexplored. Therefore, additional research specifically focusing on the relationship between the Naples Prognostic Score and COPD is necessary to determine its widespread applicability.ObjectivesThe objective was to explore the relationship between the NPS and the susceptibility to developing COPD.MethodsA total of 15,184 participants were included in our research, and statistical analyses were performed after weighting. We used weighted logistic regression to assess whether the NPS and COPD had a relationship, as well as its association with lung function. Subgroup analysis was used to detect the interaction. In addition, Kaplan–Meier survival curves were generated, and adjusted hazard ratios of different causes of death were calculated using Cox regression.ResultsOur investigation examined 15,184 participants’ data and then revealed a significant positive link between the NPS and COPD risk, while smoking has an interactive effect on it. A trend toward a decreasing prevalence of lung function indicators such as FEV1 [OR (95%CI), −339.70 (−456.53, −222.87)], FVC [OR (95%CI), −296.70 (−435.34, −158.06)], FEV1/FVC [OR (95%CI), −0.03 (−0.04, −0.02)], predicted FEV1 [OR (95%CI), −0.09 (−0.14, −0.04)], and predicted FVC [OR (95%CI), −0.08 (−0.15, −0.01)] was observed with increased NPS levels. Survival curves were drawn, and Cox regression analysis was conducted by dividing participants into group 0, group 1, and group 2 with NPS values of 0, 1–2, and 3–4, respectively. After assigning participants to groups 0, 1, and 2, with NPS values of 0, 1–2, and 3–4, respectively, the survival curves were created, and the Cox regression analysis was carried out. All-cause mortality [HR (95%CI), 1.68 (1.39–2.85)] and hypertension-related mortality [HR (95%CI), 67.64 (8.88–515.07)] of group 2 were significantly elevated.ConclusionThe findings of this study suggested that the NPS serves as a robust prognostic indicator of COPD.

Forest fuels are the material basis of forest fires and the main factor in the spread of fires. The current global warming has led to an increase in the effective fuel load in the global boreal forests, and the long-term implementation of the fire suppression policy will lead to a continuous accumulation of fuels in the forests, which will further increase the likelihood of the occurrence of mega-forest fires and the risk of such fires. This challenge has prompted different countries and regions to shift away from monolithic fire suppression policies to practising effective fuel regulation measures in order to strike a balance between reducing the risk of wildfires and protecting ecosystems. This study utilises the LANDIS PRO model to investigate the effects of fire management policies and fuel regulation measures on fire risk in high-latitude boreal forest region of China over 100 years using a 10-year time step. The results show that (1) Fire suppression policies accelerate the accumulation of coarse and fine fuels (by 19.05 % and 9.28 %, respectively) and increase the potential average fire intensity of the area (by 58.81 %) compared to no fire suppression policies; (2) Implementation of mechanical removal, prescribed burning and mechanical removal plus prescribed burning under the fire suppression policy reduces the area of high-intensity fires in the region and thus significantly reduces the forest fire risk (by 17.37 %, 13.37 %, and 21.18 %, respectively); (3) Implementing a fire suppression policy and mechanical removal plus prescribed burning on 3.0 % of the area every 15 years are supposed to be the optimal fuel treatment program for the region, which resulted in significant reductions in total area burned, and low, medium, and high-intensity area burned by 23.34, 26.23, 23.73, and 22.87 %, respectively, when compared to no fuel treatment. This study found that fire management policies have a greater impact on fire risk than fuel regulation measures and that reasonable fuel control can help reduce the area of high-intensity fires in the region. This study aids to provide a scientific basis and data support for formulating forest fire management policies and selecting fuel control methods in high-latitude boreal forests of China.

AbstractCholangiocarcinoma (CCA) is a malignant tumor originating in the bile duct and its branching epithelium. Due to its high heterogeneity, there are no specific clinical indications at the early stage, the diagnosis is often in advanced CCA. With surgical resection, the 5-year postoperative survival rate (long-term survival rate) is very poor. The regimen of gemcitabine combined with platinum has been used as the first-line chemotherapy for advanced patients. In recent years, targeted therapy for a variety of malignant tumors has made great progress, showing good efficacy and safety in advanced CCA. However, the current targeted therapy of CCA still has many challenges, such as adverse reactions, drug resistance, and individual differences. Therefore, the researches need to further explore the targeted therapy mechanism of CCA malignancies in depth, develop more effective and safe drugs, and accurately formulate plans based on patient characteristics to further improve patient prognosis in the future. This article reviews the recent progress of targeted therapy for CCA, aiming to provide a strategy for the research and clinical work of targeted therapy for CCA.

AbstractA new series of 1H-pyrrolo[3,2-c]pyridine derivatives were designed and synthesised as colchicine-binding site inhibitors. Preliminary biological evaluations showed that most of the target compounds displayed moderate to excellent antitumor activities against three cancer cell lines (HeLa, SGC-7901, and MCF-7) in vitro. Among them, 10t exhibited the most potent activities against three cancer cell lines with IC50 values ranging from 0.12 to 0.21 μM. Tubulin polymerisation experiments indicated that 10t potently inhibited tubulin polymerisation at concentrations of 3 μM and 5 μM, and immunostaining assays revealed that 10t remarkably disrupted tubulin microtubule dynamics at a concentration of 0.12 μM. Furthermore, cell cycle studies and cell apoptosis analyses demonstrated that 10t at concentrations of 0.12 μM, 0.24 μM, and 0.36 μM significantly caused G2/M phase cell cycle arrest and apoptosis. The results of molecular modelling studies suggested that 10t interacts with tubulin by forming hydrogen bonds with colchicine sites Thrα179 and Asnβ349. In addition, the prediction of physicochemical properties disclosed that 10t conformed well to the Lipinski’s rule of five.

AbstractA series of cis-restricted 3-aryl-4-(3,4,5-trimethoxyphenyl)pyridines as novel tubulin polymerisation inhibitors was designed based on molecular docking. Compound 9p, exhibited potent antiproliferative activity against HeLa, MCF-7, and A549 cell lines. Mechanism studies indicated that 9p potently inhibited tubulin polymerisation and disrupted the microtubule dynamics of tubulin in HeLa cells. Moreover, 9p could cause G2/M phase cell cycle arrest and apoptosis in HeLa cells. In addition, the prediction of physicochemical properties disclosed that 9p conformed well to the Lipinski’s rule of five. The initial results suggest that the 3-aryl-4-(3,4,5-trimethoxyphenyl)pyridines could serve as a promising scaffold for the development of novel anticancer drugs.

Objective In the digital age, eHealth is vital in modern healthcare, impacting medical services and public health. Despite its potential in disease management, a comprehensive bibliometric analysis is lacking. This study utilizes bibliometric methods to explore the evolution of eHealth in disease management from 1999 to 2023, aiming to discern the research status and trends. Methods A literature search was conducted using the Web of Science Core Collection (WOSCC) database. Publications and journals were quantitatively analyzed using Microsoft Office Excel 2023. Country/institution/author collaborations and keyword co-occurrences were analyzed using VOSviewer. CiteSpace was employed to analyze the citation bursts of reference. A global distribution network of publications was constructed and thematic trends were analyzed using R package “bibliometrix.” Results The study identified 1763 articles on eHealth in disease management. Since 2011, there has been a notable increase in publications, with the United States (n = 391, 22.08%) and the University of Sydney (n = 60, 3.40%) as leading contributors. High-quality journals primarily publish this research. Globally, 9631 authors contributed, with Chavannes, Niels H being the most prolific (n = 23). Author co-citation analysis indicated Eysenbach, G as the most cited (n = 336). Research currently focuses on developing a comprehensive eHealth framework, optimizing mHealth for chronic diseases, improving eHealth intervention trial reporting, assessing social factors in eHealth literacy, and examining telemedicine's role during the Covid-19 pandemic. Conclusion This study offers a comprehensive overview of eHealth research in disease management. eHealth's potential in disease prevention and treatment is significant. To enhance eHealth's impact, international collaboration, technological innovation, tailored intervention trials, addressing the digital divide, and solving legal and ethical issues are crucial. This study will guide future research endeavors, with the goal of enhancing eHealth's benefits and expanding its accessibility to a wider patient base.

IntroductionThe extent to which sinks are contaminated by carbapenem-resistant Acinetobacter baumannii (CRAB) in intensive care units (ICUs) and the association between these contaminated sinks and hospital-acquired CRAB infections during the non-cluster period remains largely unknown. Here, we performed a prospective multicenter study in 16 ICUs at 11 tertiary hospitals in Chengdu, China.MethodsWe sampled sinks, collected CRAB clinical isolates, and conducted whole-genome sequencing and analysis.ResultsA total of 789 swabs were collected from 158 sinks, and 16 CRAB isolates were recovered from 16 sinks, resulting in a contamination rate of 10.16%. Twenty-seven clinical isolates were collected during the study period. The majority (97.67%, 42/43) of the CRAB isolates belonged to ST2, and 36 (83.72%) of them had both blaOXA-23 and blaOXA-66. The 43 strains belonged to 12 clones. One certain clone caused multiple contaminations of seven sinks in one GICU. Two clones of ST2 blaOXA-23 and blaOXA-66-carrying sink strains were likely the sources of the two clusters in the two GICUs, respectively. Five ST2 blaOXA-23-carrying isolates were found to be common clones but were recovered from two hospitals.ConclusionThe contamination rate of CRAB in handwashing sinks is high in some local ICUs, and the contaminated sinks can serve as environmental reservoirs for CRAB clusters.

Abstract Proteolysis-targeting chimeras (PROTACs) technology has garnered significant attention over the last 10 years, representing a burgeoning therapeutic approach with the potential to address pathogenic proteins that have historically posed challenges for traditional small-molecule inhibitors. PROTACs exploit the endogenous E3 ubiquitin ligases to facilitate degradation of the proteins of interest (POIs) through the ubiquitin–proteasome system (UPS) in a cyclic catalytic manner. Despite recent endeavors to advance the utilization of PROTACs in clinical settings, the majority of PROTACs fail to progress beyond the preclinical phase of drug development. There are multiple factors impeding the market entry of PROTACs, with the insufficiently precise degradation of favorable POIs standing out as one of the most formidable obstacles. Recently, there has been exploration of new-generation advanced PROTACs, including small-molecule PROTAC prodrugs, biomacromolecule-PROTAC conjugates, and nano-PROTACs, to improve the in vivo efficacy of PROTACs. These improved PROTACs possess the capability to mitigate undesirable physicochemical characteristics inherent in traditional PROTACs, thereby enhancing their targetability and reducing off-target side effects. The new-generation of advanced PROTACs will mark a pivotal turning point in the realm of targeted protein degradation. In this comprehensive review, we have meticulously summarized the state-of-the-art advancements achieved by these cutting-edge PROTACs, elucidated their underlying design principles, deliberated upon the prevailing challenges encountered, and provided an insightful outlook on future prospects within this burgeoning field.

Highlights The frequency and intensity of multi-magnetic resonance are freely regulated by co-doping La3+ and Zr4+ ions. Zr4+ occupation is elaborately modified for promoting the portion of polarization/conduction loss to increase profoundly. The optimized electromagnetic characteristics lead to an ultra-wide bandwidth of 12.5+ GHz around millimeter-wave atmospheric window.

In this work, a series of new diarylpyrimidine derivatives as microtubule destabilizers were designed, synthesized, and evaluated for anticancer activities. Based on restriction configuration strategy, we introduced the pyrimidine moiety containing the hydrogen-bond acceptors as cis-olefin bond of CA-4 analogs to improve structural stability. Compounds 11a-t exerted antiproliferative activities against three human cancer cell lines (SGC-7901, HeLa, and MCF-7), due to tubulin polymerization inhibition, showing high selectivity toward cancer cells in comparison with non-tumoral HSF cells, as evidenced by MTT assays. In mechanistic investigations, compound 11s remarkably inhibited tubulin polymerization and disorganized microtubule in SGC-7901 cells by binding to tubulin. Moreover, 11s caused G2/M phase cell cycle arrest in SGC-7901 cells in a concentration-dependent manner. Furthermore, molecular modeling analysis revealed that 11s interacts with tubulin through binding to the colchicine site. In addition, the prediction of physicochemical properties disclosed that 11s conformed well to the Lipinski’s rule of five. This work offered a fresh viewpoint for the discovery of new tubulin-targeting anticancer drugs.

Sepsis is described as a life-threatening organ dysfunction and a heterogeneous syndrome that is a leading cause of morbidity and mortality in intensive care settings. Severe sepsis could incite an uncontrollable surge of inflammatory cytokines, and the host immune system's immunosuppression could respond to counter excessive inflammatory responses, characterized by the accumulated anti-inflammatory cytokines, impaired function of immune cells, over-proliferation of myeloid-derived suppressor cells and regulatory T cells, depletion of immune effector cells by different means of death, etc. In this review, we delve into the underlying pathological mechanisms of sepsis, emphasizing both the hyperinflammatory phase and the associated immunosuppression. We offer an in-depth exploration of the critical mechanisms underlying sepsis, spanning from individual immune cells to a holistic organ perspective, and further down to the epigenetic and metabolic reprogramming. Furthermore, we outline the strengths of artificial intelligence in analyzing extensive datasets pertaining to septic patients, showcasing how classifiers trained on various clinical data sources can identify distinct sepsis phenotypes and thus to guide personalized therapy strategies for the management of sepsis. Additionally, we provide a comprehensive summary of recent, reliable biomarkers for hyperinflammatory and immunosuppressive states, facilitating more precise and expedited diagnosis of sepsis.

Background: Approximately 10%–30% of patients with Hodgkin's lymphoma (HL) experience relapse or refractory (R/R) disease after first-line standard therapy. Brentuximab vedotin (BV) and immune checkpoint inhibitors (ICIs) have important roles in the salvage treatment of R/R HL. However, subsequent treatment for HL refractory to BV and/or ICI treatment is challenging. Methods: We retrospectively analyzed patients in two institutions who had R/R HL, experienced BV or ICI treatment failure, and received radiotherapy (RT) thereafter. The overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were analyzed. Results: Overall, 19 patients were enrolled. First-line systemic therapy comprised doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD, 84.2%); AVD plus ICIs (10.5%); and bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP, 5.3%). After first-line therapy, 15 (78.9%) and four patients (21.1%) had refractory disease and relapsed, respectively. After R/R HL diagnosis, six (31.6%), two (10.5%), and 11 (57.9%) patients received BV and ICIs concurrently, BV monotherapy, and ICI monotherapy, respectively. All patients received intensity-modulated RT (n = 12, 63.2%) or volumetric modulated arc therapy (VMAT; n = 7, 36.8%). The ORR as well as the complete response (CR) rate was 100%; the median DOR to RT was 17.2 months (range, 7.9–46.7 months). Two patients showed progression outside the radiation field; one patient had extensive in-field, out-of-field, nodal, and extranodal relapse. With a median follow-up time of 16.2 months (range, 9.2–23.2 months), the 1-year PFS and OS were 84.4% and 100%, respectively. PFS was associated with extranodal involvement (P = 0.019) and gross tumor volume (P = 0.044). All patients tolerated RT well without adverse events of grade ≥ 3. Conclusion: RT is effective and safe for treating HL refractory to BV or ICIs and has the potential to be part of a comprehensive strategy for HL.

Abstract Stress tolerance plays a vital role in ensuring the effectiveness of piezoresistive sensing films used in flexible pressure sensors. However, existing methods for enhancing stress tolerance employ dome-shaped, wrinkle-shaped, and pyramidal-shaped microstructures in intricate molding and demolding processes, which introduce significant fabrication challenges and limit the sensing performance. To address these shortcomings, this paper presents periodic microslits in a sensing film made of multiwalled carbon nanotubes and polydimethylsiloxane to realize ultrahigh stress tolerance with a theoretical maximum of 2.477 MPa and a sensitivity of 18.092 kPa−1. The periodic microslits permit extensive deformation under high pressure (e.g., 400 kPa) to widen the detection range. Moreover, the periodic microslits also enhance the sensitivity based on simultaneously exhibiting multiple synapses within the sensing interface and between the periodic sensing cells. The proposed solution is verified by experiments using sensors based on the microslit strategy for wind direction detection, robot movement sensing, and human health monitoring. In these experiments, vehicle load detection is achieved for ultrahigh pressure sensing under an ultrahigh pressure of over 400 kPa and a ratio of the contact area to the total area of 32.74%. The results indicate that the proposed microslit strategy can achieve ultrahigh stress tolerance while simplifying the fabrication complexity of preparing microstructure sensing films.

This paper introduces a novel deep-learning assisted video list decoding method for error-prone video transmission systems. Unlike traditional list decoding techniques, our proposed system uses a Transformer-based no-reference image quality assessment method to select the highest-scoring reconstructed video candidate after reception. Three new components are defined and used in the Transformer-assisted image quality evaluation metric: neighborhood-based patch fidelity aggregation, discriminant color texture transformation and ranking-constrained penalty loss function. We have also created our own database of non-uniformly distorted images, similar to those that might result from transmission errors, in a High Efficiency Video Coding (HEVC) context. In our specific testing context, our improved Transformer-assisted method has a decision accuracy of 100% for intra-coded image, while, for errors occurring in an inter image, it is 96%. Notably, in the few cases where a wrong choice is made, the selected candidate’s quality remains similar to the intact frame. Code: https://github.com/Yujing0926/Robust-Video-List-Decoding-Using-a-Deep-Learning-Approach.

Prior to clinical application, reliability of percutaneous ventricular assist devices(pVAD) requires to be tested systematically. Currently, there's a lack of dedicated reliability testing equipment and methodologies for pVAD. Considering the structural and functional aspects of percutaneous ventricular assist devices, this study conducts research on pVAD reliability test engineering. Test setups, clinical conditions, failure modes, effects analysis, and evaluation models have been investigated. A highly feasible methodological approach for percutaneous ventricular assist device reliability assessment has been formed. This study offers valuable insights into standardizing their reliability evaluation in clinical settings.

Magnetic metals have attracted extensive attention in microwave absorption for comprehensive merits of high magnetic loss and suitability for mass productions. Nevertheless, the applications have been limited by shortcomings of high conductivity and inadequate impedance matching. In this study, we have successfully synthesized a biphasic magnetic Sm2O3@Co composite through a facile one-step precipitation method. The resultant features a well-designed structure with spherical cores and flaky shells, exhibiting highly-tunable absorption performance over 2–18 GHz. Particularly, under 20 wt% filling ratio with paraffin, the Sm2O3@Co composite achieved minimum reflection loss (RLmin) of −30.1 dB and effective absorbing bandwidth (EAB) of 6.22 GHz at only 1.7 mm. The dielectric and magnetic losses could be easily modulated by simply changing the induced Co ratios. Through a systematic study, the microwave absorption mechanisms of the Sm2O3@Co magnetic composite have been comprehensively elucidated. This research offers a fresh perspective on developing highly efficient electromagnetic wave absorbents based on traditional magnetic metals.

The diversity of the microbial community structure plays a crucial role in the flavor and nutritional value of Shanxi aged vinegar in fermentation. Illumina Miseq high-throughput sequencing identified thirteen bacterial genera, with Lactobacillales (44.89%) and Acetobacter (21.04%) being the predominant species. Meanwhile, the fermentation characteristics of selected lactic acid bacteria strains isolated from Shanxi aged vinegar were studied in different media. The results showed that the biomass, and physical and chemical indices, as well as flavor compounds of the four strains of lactic acid bacteria in the simulated vinegar fermented grains medium were superior to those in barley and pea medium and sorghum juice medium. The bacterial interaction was conducted to investigate the effects on growth, the physicochemical indices, and flavor substances in order to determine the optimal combination. Furthermore, the interaction between pure cultures and co-cultures of lactic acid bacteria in a simulated vinegar culture medium was investigated, with a focus on the impact of this interaction on strain growth, fermentation characteristics, and flavor compound production. Compared with the pure culture, when strains L7 and L729 were co-inoculated, the reducing sugar content was 0.31 ± 0.01 g/100 g, total acid content was 3.02 ± 0.06 g/100 g, acetoin content was 2.41 ± 0.07 g/100 g, and total organic acid content was 3.77 ± 0.17 g/100 g. In terms of flavor compounds, the combined culture system exhibited higher levels of esters, aldehydes, and acids compared to pure cultures or other co-culture systems. This study revealed the fermentation characteristics of selected lactic acid strains in Shanxi aged vinegar under different conditions and their interaction in simulated vinegar fermentation media, which could provide theoretical support for the safety and health evaluation of aged vinegar.

Abstract Background Recent state-of-the-art sequencing technologies enable the investigation of challenging regions in the human genome and expand the scope of variant benchmarking datasets. Herein, we sequence a Chinese Quartet, comprising two monozygotic twin daughters and their biological parents, using four short and long sequencing platforms (Illumina, BGI, PacBio, and Oxford Nanopore Technology). Results The long reads from the monozygotic twin daughters are phased into paternal and maternal haplotypes using the parent–child genetic map and for each haplotype. We also use long reads to generate haplotype-resolved whole-genome assemblies with completeness and continuity exceeding that of GRCh38. Using this Quartet, we comprehensively catalogue the human variant landscape, generating a dataset of 3,962,453 SNVs, 886,648 indels (

Abstract The expansion of available information in location-based social networks (LBSNs) has led to information overload, making it urgent to discover users’ next point-of-interest (POI). Some existing works only consider certain modal information in LBSNs and do not transform them into high-dimensional structures, which hinders the alleviation of the data sparsity problem. Moreover, many approaches rely solely on social relationships, making it difficult to recommend POIs to new users without association information. To tackle these challenges, we propose a social- and spatial–temporal-aware next point-of-Interest (SSTP) recommendation model. SSTP uses two feature encoders based on self-attention mechanism and gate recurrent unit to model users’ check-in enhancement sequence hierarchically. We also design a random neighborhood sampling approach to mine user social relationships, thus alleviating the user cold start problem. Finally, we propose a geographical-aware graph attention network to learn the sensitivity of users to distance. Extensive experiments on two real-world datasets show that SSTP outperforms state-of-the-art models, improving Hit@k by 2.26–6.55 $$\%$$ % and MAP@k by 3.49–6.55 $$\%$$ % . Moreover, SSTP has better performance on sparse data, with an average improvement of 6.09 $$\%$$ % on the Hit@k. The code can be downloaded at https://github.com/Rih0/sstp .

Abstract Background Hepatocellular carcinoma (HCC) is one of the most common human cancers with poor prognosis in the world. HCC has become the second leading cause of cancer-related death in China. It is urgent to identify novel biomarker and valid target to effectively diagnose, treat or predict the prognosis of HCC. It has been reported that S100A family is closely related to cell proliferation and migration of different cancers. However, the values of S100As in HCC remain to be further analyzed. Methods We investigated the transcriptional and translational expression of S100As, as well as the value of this family in HCC patients from the various databases. Results S100A10 was most relevant to HCC. Conclusions The results from HCC patients’ tissues and different cells also confirmed the role of S100A10 in HCC. Furthermore, we proved that S100A10 could influenced the cell proliferation of HCC cells via ANXA2/Akt/mTOR pathway. However, it would appear that the relationship between S100A10 and HCC is complex and requires more research.

IntroductionHypoxic-ischemic encephalopathy (HIE) is one of severe neonatal brain injuries, resulting from inflammation and the immune response after perinatal hypoxia and ischemia. IgG N-glycosylation plays a crucial role in various inflammatory diseases through mediating the balance between anti-inflammatory and pro-inflammatory responses. This study aimed to explore the effect of IgG N-glycosylation on the development of HIE.MethodsThis case-control study included 53 HIE patients and 57 control neonates. An ultrahigh-performance liquid chromatography (UPLC) method was used to determine the features of the plasma IgG N-glycans, by which 24 initial glycan peaks (GPs) were quantified. Multivariate logistic regression was used to examine the association between initial glycans and HIE, by which the significant parameters were used to develop a diagnostic model. Though receiver operating characteristic (ROC) curves, area under the curve (AUC) and 95% confidence interval (CI) were calculated to assess the performance of the diagnostic model.ResultsThere were significant differences in 11 initial glycans between the patient and control groups. The levels of fucosylated and galactosylated glycans were significantly lower in HIE patients than in control individuals, while sialylated glycans were higher in HIE patients (p < 0.05). A prediction model was developed using three initial IgG N-glycans and fetal distress, low birth weight, and globulin. The ROC analysis showed that this model was able to discriminate between HIE patients and healthy individuals [AUC = 0.798, 95% CI: (0.716–0.880)].DiscussionIgG N-glycosylation may play a role in the pathogenesis of HIE. Plasma IgG N-glycans are potential noninvasive biomarkers for screening individuals at high risk of HIE.

The intricate relationship between resistant starch (RS) and the gut microbiome presents a dynamic frontier in nutrition science. This review synthesizes current understandings of how RS, an indigestible form of starch found naturally in certain foods and also enhanced through various modification methods, interacts with the gut microbiome. We particularly focus on how RS fermentation in the colon contributes to the production of beneficial volatile fatty acids (VFAs) such as butyrate, acetate, and propionate. These VFAs have been recognized for their vital roles in maintaining gut barrier integrity, modulating inflammation, and potentially influencing systemic health. Additionally, we discuss the dietary implications of consuming foods rich in RS, both in terms of gut health and broader metabolic outcomes. By consolidating these insights, we emphasize the significance of RS in the context of dietary strategies aimed at harnessing the gut microbiome's potential to impact human health.

Background: This study aimed to retrospectively investigate the early predictive value of inflammation-related parameters in-hospital mortality of septic patients. Methods: We retrospectively recruited 606 patients from Wuhan Union Hospital from January 2009 to October 2022. The inflammation-related parameters including neutrophil-to-lymphocyte ratio (NLR), neutrophil percentage (NE%), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) in survivals and non-survivals on day 1, 2, 3 and 7 after hospitalization were collected and analyzed. Results: NLR and NE% in non-survivals (n = 185) were significantly higher than those in survivals (n = 421). The area under the receiver operating characteristic curve (AUC) of NLR or NE% was 0.880 or 0.852 on day 1, 0.770 or 0.790 on day 2, 0.784 or 0.777 on day 3, and 0.732 or 0.741 on day 7. The optimal cut-off values of NLR or NE% for predicting in-hospital mortality were 10.769 or 87.70% on day 1, 17.544 or 90.69% on day 2, 14.395 or 85.00% on day 3, and 9.105 or 83.93% on day 7. The day 1, 2 and 3 NLR and NE% were significant predictors of in-hospital mortality in the Cox proportional hazards models. Conclusions: NLR ≥10.769 and NE% ≥ 87.70% could be used early biomarkers for predicting in-hospital mortality of septic patients.

Frank’s sign (FS) refers to a diagonal skin fold between the tragus and the outer edge of the earlobe. FS has been identified as an independent variable in coronary artery disease (CAD). Young patients with FS and previous myocardial infarction are still rarely reported in clinical studies. We report the case of a 49-year-old male smoker and diabetic, with a history of myocardial infarction, who presented to the emergency department due to 2 h typical cardiac chest pain. His urgent electrocardiography (ECG) showed ST elevation, and cardiac biomarkers were elevated after admission. A diagonal earlobe crease (DELC) was observed in physical tests. The preliminary diagnosis considered acute coronary syndrome (ACS). Subsequently, acute coronary artery angiography demonstrated a slit-like contrast defect in the proximal right coronary artery (RCA), with stenosis and occlusion in the distal segment. The percutaneous coronary intervention (PCI) was performed immediately. The patient’s chest pain symptoms were relieved significantly after intervention. Our case indicates that FS should be highly regarded as a routine cardiovascular clinical examination, which can be effortlessly applied and be easily interpreted for screening to suspect the presence of ischemic heart disease. This may set strategies for primary screening in a younger population and prompt early diagnosis and treatment.

Single-screw extruders and injection molding machines are essential equipment in polymer processing. It is of great importance for the optimization of operating parameters and the design of extrusion screw to predict the throughput of an extruder and the metering time of an injection molding machine according to the geometric parameters of the screw, operating parameters, and the rheological behavior of materials. Most polymer melts exhibit non-Newtonian behavior. The lattice Boltzmann method has many advantages in simulating the flow of non-Newtonian fluids. Herein, the dimensionless velocity profiles and dimensionless volumetric flow rate of generalized Newtonian fluids in a screw channel have been studied using the two-relaxation-time lattice Boltzmann method (TRT–LBM). The numerical results of power-law fluids are in good agreement with the analytical solutions, which verifies the validity of TRT–LBM. Through research, the change rule of the dimensionless volumetric flow rate of Bingham fluids with dimensionless pressure gradient has been obtained. It was found that the rheological properties of polymer melts and the dimensionless pressure gradient significantly affect the dimensionless velocity profiles and dimensionless volumetric flow rate. The dimensionless volume flow rate has some unexpected changes with the increase of the dimensionless pressure gradient. This study can provide theoretical guidance for the optimization of operating parameters and the design of extrusion screws.

Cytokine release syndrome (CRS) can be induced by immune checkpoint inhibitors (ICIs). Although the incidence of CRS is low, it is often underreported. Here, we report two severe CRS cases and summarize and review 51 patients with ICI-induced CRS to explore the possible contributing factors to the disease prognosis and provide assistance for therapy. Our analysis found that the population with ICI-induced CRS consists mainly of male patients with an average age of 61.74 years. The primary malignant tumor type was lung cancer, and the clinical stage of most patients was stage IV. Notably, patients who experience a longer time to CRS onset, higher IL-6 levels, and lower platelet counts may be more likely to develop severe CRS. Cardiovascular, respiratory, neurological, and coagulation toxicities are more common in higher-grade CRS and may serve as markers for patient experiencing ICU admission, oxygen supplementation, hypotension, high-dose vasopressors usage, and intubation.

Abstract Acute pancreatitis (AP) is a common and potentially life-threatening inflammatory disease of the pancreas. Reactive oxygen species (ROS) play a key role in the occurrence and development of AP. With increasing ROS levels, the degree of oxidative stress and the severity of AP increase. However, diagnosing AP still has many drawbacks, including difficulties with early diagnosis and undesirable sensitivity and accuracy. Herein, we synthesized a semiconducting polymer nanoplatform (SPN) that can emit ROS-correlated chemiluminescence (CL) signals. The CL intensity increased in solution after optimization of the SPN. The biosafety of the SPN was verified in vitro and in vivo. The mechanism and sensitivity of the SPN for AP early diagnosis and severity assessment were evaluated in three groups of mice using CL intensity, serum marker evaluations and hematoxylin and eosin staining assessments. The synthetic SPN can be sensitively combined with different concentrations of ROS to produce different degrees of high-intensity CL in vitro and in vivo. Notably, the SPN shows an excellent correlation between CL intensity and AP severity. This nanoplatform represents a superior method to assess the severity of AP accurately and sensitively according to ROS related chemiluminescence signals. This research overcomes the shortcomings of AP diagnosis in clinical practice and provides a novel method for the clinical diagnosis of pancreatitis in the future.

Magnetic metal absorbing materials have exhibited excellent absorptance performance. However, their applications are still limited in terms of light weight, low thickness and wide absorption bandwidth. To address this challenge, we design a broadband and low-profile multilayer absorber using cobalt–iron (CoFe) alloys doped with rare earth elements (REEs) lanthanum (La) and Neodymium (Nd). An improved estimation of distribution algorithm (IEDA) is employed in conjunction with a mathematical model of multilayer absorbing materials (MAMs) to optimize both the relative bandwidth with reflection loss (RL) below −10 dB and the thickness. Firstly, the absorption performance of CoFe alloys doped with La/Nd with different contents is analysed. Subsequently, IEDA is introduced based on a mathematical model to achieve an optimal MAM design that obtains a balance between absorption bandwidth and thickness. To validate the feasibility of our proposed method, a triple-layer MAM is designed and optimized to exhibit wide absorption bandwidth covering C, X, and Ku bands (6.16–12.82 GHz) and a total thickness of 2.39 mm. Then, the electromagnetic (EM) absorption mechanisms of the triple-layer MAMs are systematically investigated. Finally, the triple-layer sample is further fabricated and measured. The experimental result is in good agreement with the simulated result. This paper presents a rapid and efficient optimization method for designing MAMs, offering promising prospects in microwave applications, such as radar-stealth technology, EM shielding, and reduced EM pollution for electronic devices.

BackgroundNumerous studies have demonstrated that fine particulate matter (PM2.5) is adversely associated with COVID-19 incidence. However, few studies have explored the spatiotemporal heterogeneity in this association, which is critical for developing cost-effective pollution-related policies for a specific location and epidemic stage, as well as, understanding the temporal change of association between PM2.5 and an emerging infectious disease like COVID-19.MethodsThe outcome was state-level daily COVID-19 cases in 49 native United States between April 1, 2020 and December 31, 2021. The exposure variable was the moving average of PM2.5 with a lag range of 0–14 days. A latest proposed strategy was used to investigate the spatial distribution of PM2.5-COVID-19 association in state level. First, generalized additive models were independently constructed for each state to obtain the rough association estimations, which then were smoothed using a Leroux-prior-based conditional autoregression. Finally, a modified time-varying approach was used to analyze the temporal change of association and explore the potential causes spatiotemporal heterogeneity.ResultsIn all states, a positive association between PM2.5 and COVID-19 incidence was observed. Nearly one-third of these states, mainly located in the northeastern and middle-northern United States, exhibited statistically significant. On average, a 1 μg/m3 increase in PM2.5 concentration led to an increase in COVID-19 incidence by 0.92% (95%CI: 0.63–1.23%). A U-shaped temporal change of association was examined, with the strongest association occurring in the end of 2021 and the weakest association occurring in September 1, 2020 and July 1, 2021. Vaccination rate was identified as a significant cause for the association heterogeneity, with a stronger association occurring at a higher vaccination rate.ConclusionShort-term exposure to PM2.5 and COVID-19 incidence presented positive association in the United States, which exhibited a significant spatiotemporal heterogeneity with strong association in the eastern and middle regions and with a U-shaped temporal change.

Study region: The Daitou Creek Watershed in Tong’an District, Xiamen City, southeast coastal China Study focus: Reclaiming and reusing wastewater is a viable strategy to mitigate water shortages and improve water quality in riverine ecosystems. There is an urgent need for modeling approaches to provide data support for the implementation of river management strategies. A coupled modeling framework, integrating Soil and Water Assessment Tool (SWAT), Qual2K, and scenario analysis, was developed in this study to assess the potential of reclaimed water supplement in Daitou Creek Watershed during different seasons. New hydrological insight for the region: The utilization of proposed framework has resulted in the successful reproduction of riverine streamflow and nutrient dynamics across different seasons. An optimal reclaimed water supplement scheme was identified for remediation of riverine water quality in Daitou Creek. Water quality standards can be attained with the following minimum total volume of reclaimed water supplement upstream and downstream: 3 × 104 m3/d and 7.5 × 104 m3/d in wet season, 2 × 104 m3/d and 10 × 104 m3/d in average season, and 3 × 104 m3/d and 10 × 104 m3/d in dry season, respectively. Total phosphorus represents the dominant limiting factor in achieving water quality restoration, requiring more reclaimed water to decrease concentration compared to ammonia nitrogen. The proposed framework facilitates the identification of optimal reclaimed water supplement schemes, presenting urban watersheds with viable solutions for local riverine water quality degradation.

Summary: Promoters are essential tools for basic and translational neuroscience research. An ideal promoter should possess the shortest possible DNA sequence with cell-type selectivity. However, whether ultra-compact promoters can offer neuron-specific expression is unclear. Here, we report the development of an extremely short promoter that enables selective gene expression in neurons, but not glial cells, in the brain. The promoter sequence originates from the human CALM1 gene and is only 120 bp in size. The CALM1 promoter (pCALM1) embedded in an adeno-associated virus (AAV) genome directed broad reporter expression in excitatory and inhibitory neurons in mouse and monkey brains. Moreover, pCALM1, when inserted into an all-in-one AAV vector expressing SpCas9 and sgRNA, drives constitutive and conditional in vivo gene editing in neurons and elicits functional alterations. These data demonstrate the ability of pCALM1 to conduct restricted neuronal gene expression, illustrating the feasibility of ultra-miniature promoters for targeting brain-cell subtypes.

Some novel 4-aryl-9H-carbazoles were designed as potential tubulin polymerization inhibitors through structural optimization and bioisosteric strategy. These compounds showed effective antiproliferative activities against a diverse set of cancer cell lines, including HeLa, HepG2, and SGC-7901 cells. Among them, compound 13k exerted the strongest inhibitory effect on HeLa cells with an IC50 of 1.2 ± 0.09 μM. Mechanism studies indicated that 13k significantly inhibited tubulin polymerization in vitro and disrupted the dynamic homeostasis of microtubules in HeLa cells. Furthermore, 13k concentration-dependently caused G2/M phase cell cycle arrest and apoptosis in HeLa cells. Molecular docking analysis demonstrated the interaction of 13k at the colchicine binding site of tubulin. In addition, the prediction of physicochemical properties studies shows that 13k has good pharmacokinetic properties. These preliminary results suggested that 13k is a new tubulin polymerization inhibitor and worthy of further investigation.

Abstract Background Depression increases the risk of adverse clinical outcomes in patients with chronic kidney disease. Physical activity has been shown to improve depressive symptoms in this population, but the relationship of sedentary behavior with depression has not been studied. In this study, we examined the relationship between sedentary behavior and depression in patients with chronic kidney disease. Methods This cross-sectional study included 5,205 participants aged ≥ 18 years with chronic kidney disease participating in the 2007–2018 National Health and Nutrition Examination Survey. Depression was assessed using the Patient Health Questionnaire-9 (PHQ-9). Recreation activity, work activity, walking or cycling for transportation, and sedentary behavior were measured using the Global Physical Activity Questionnaire. A series of weighted logistic regression models were used to investigate the aforementioned relationship. Results The prevalence of depression among US adults with chronic kidney disease was 10.97% in our study. In addition, sedentary behavior was strongly associated with higher levels of depressive symptoms, as measured by the PHQ-9 (P

Congenital heart disease (CHD) is one of the most common causes of major birth defects, with a prevalence of 1%. Although an increasing number of studies have reported the etiology of CHD, the findings scattered throughout the literature are difficult to retrieve and utilize in research and clinical practice. We therefore developed CHDbase, an evidence-based knowledgebase of CHD-related genes and clinical manifestations manually curated from 1114 publications, linking 1124 susceptibility genes and 3591 variations to more than 300 CHD types and related syndromes. Metadata such as the information of each publication and the selected population and samples, the strategy of studies, and the major findings of studies were integrated with each item of the research record. We also integrated functional annotations through parsing ∼ 50 databases/tools to facilitate the interpretation of these genes and variations in disease pathogenicity. We further prioritized the significance of these CHD-related genes with a gene interaction network approach and extracted a core CHD sub-network with 163 genes. The clear genetic landscape of CHD enables the phenotype classification based on the shared genetic origin. Overall, CHDbase provides a comprehensive and freely available resource to study CHD susceptibilities, supporting a wide range of users in the scientific and medical communities. CHDbase is accessible at http://chddb.fwgenetics.org.

Chemical drug design based on the biochemical characteristics of cancer cells has become an important strategy for discovering new anti-tumour drugs to improve tumour targeting effects and reduce off-target toxicities. Colchicine is one of the most prominent and historically microtubule-targeting drugs, but its clinical applications are hindered by notorious adverse effects. In this study, we presented a novel tumour-specific conjugate 9 that consists of deacetylcolchicine (Deac), biotin, and a cleavable disulphide linker. 9 was found to exhibit potent anti-tumour activity and exerted higher selectivity between tumour and nontarget cells than Deac. The targeting moiety biotin might enhance the transport capability and selectivity of 9 to tumour cells via biotin receptor-mediated endocytosis. The tubulin polymerisation activity of 9 (with DTT) was close to the parent drug Deac. These preliminary results suggested that 9 is a high potency and reduced toxicity antitumor agent and worthy of further investigation.

Objectives A long period of inappropriate proton pump inhibitors (PPI) treatment has been proved to be associated with adverse prognosis in general population and hemodialysis patients. This study was conducted to clarify the impact of PPI usage on mortality and adverse cardiovascular (CV) events in peritoneal dialysis (PD) patients.Methods and design This is a retrospective study. A total of 905 patients were enrolled from two PD centers, including 211 patients on PPI treatment and 618 patients not on PPIs. Kaplan–Meier curves were used to identify the incidence of adverse outcomes. Multivariate Cox regression models and inverse probability of treatment weighting (IPTW) were applied to analyze hazard ratios (HRs) for adverse outcomes.Results During follow-up, 162 deaths and 102 CV events were recorded. Kaplan–Meier curve demonstrated all-cause mortality (log-rank test p = .018) and CV events (log-rank test p = .024) were significantly higher in PPI usage group. Multivariate Cox regression models and IPTW showed that PPI usage was an indicator for all-cause mortality (HR = 1.35, 95%CI = 1.09–1.67, p = .006) and CV events (HR = 1.78, 95%CI = 1.35–2.32, p

Proteolysis-targeting chimaeras (PROTACs) have been developed to be an emerging technology for targeted protein degradation and attracted the favour of academic institutions, large pharmaceutical enterprises, and biotechnology companies. The mechanism is based on the inhibition of protein function by hijacking a ubiquitin E3 ligase for protein degradation. The heterobifunctional PROTACs contain a ligand for recruiting an E3 ligase, a linker, and another ligand to bind with the protein targeted for degradation. To date, PROTACs targeting ∼70 proteins, many of which are clinically validated drug targets, have been successfully developed with several in clinical trials for diseases therapy. In this review, the recent advances in PROTACs against clinically validated drug targets are summarised and the chemical structure, cellular and in vivo activity, pharmacokinetics, and pharmacodynamics of these PROTACs are highlighted. In addition, the potential advantages, challenges, and prospects of PROTACs technology in disease treatment are discussed.

BRDs proteins that recognise chromatin acetylation regulate gene expression, are epigenetic readers and master transcription coactivators. BRDs proteins are now emerging as targets for new therapeutic development. Blocking the function of any of BRDs proteins can be a control agent for diseases, such as cancer. Traditional drugs like enzyme inhibitors and protein–protein inhibitors have many limitations. The therapeutic efficacy of them remains to be proven. Recently, Proteolysis-Targeting Chimaeras (PROTACs) have become an advanced tool in therapeutic intervention as they remove disease-causing proteins. Extremely potent and efficacious small-molecule PROTACs of the BRDs proteins, based on available, potent, and selective BRDs inhibitors, have been reported. This review presents a comprehensive overview of the development of PROTACs for BRDs proteins regulation in cancer, and the chances and challenges associated with this area are also highlighted.

Background A large number of studies have shown that proton pump inhibitors (PPIs) are associated with infection events. Therefore, we retrospectively evaluated the association of PPI therapy with the occurrence of first pneumonia and peritoneal dialysis(PD)-related peritonitis events in the maintenance PD patients.Methods We collected PD patients in two large hospitals from January 1, 2012 to December 31, 2016, and divided them into the PPI group and the non-PPI group. Multivariate Cox proportional hazards models were applied to evaluate the cumulative incidence and hazard ratios (HRs). Inverse probability of treatment weight (IPTW) method was used to adjust for covariate imbalance between the two groups and further confirm our findings.Results Finally, 656 PD patients were included for data analysis, and the results showed that PPI usage was associated with an increased risk of pneumonia [HR 1.71; 95% CI 1.06-2.76; p = 0.027] and peritonitis [HR 1.73; 95% CI 1.24-2.40; p = 0.001]. IPTW-adjusted HRs for the association of PPIs with pneumonia and peritonitis were 1.58 (95% CI:1.18-2.12; p = 0.002) and 2.33 (95% CI:1.91-2.85; p