Sarcopenia and metabolic dysfunction associated steatotic liver disease: Time to address both.

Sarcopenia and metabolic dysfunction associated steatotic liver disease (MASLD) are closely intertwined. Sarcopenia, traditionally a disease of the older adult and chronic disease population, has been closely studied as one of the pathophysiologic conditions at play in the development of MASLD. They share similar risk factors of insulin resistance and physical inactivity. Given similar pathophysiology along the liver-muscle axis, sarcopenia has been studied as a risk factor for MASLD, and vice versa. Current research suggests a bidirectional relationship. Given the chronicity of MASLD as a chronic inflammatory liver disease, it can break down muscle mass and lead to sarcopenia, while sarcopenia promotes intramuscular lipid accumulation that releases cytokines that can aggravate inflammation in the liver. However, for the longest time, a lack of consensus definition for MASLD and sarcopenia made it difficult to study their relationship and outcomes. A recent nomenclature update to diagnosing MASLD has made it easier for researchers to identify cohorts for study. However, no gold standard technique to measure muscle mass or consensus sarcopenia definition has been identified yet. Future studies are needed to reach a consensus and reduce diagnostic variation. With similar pathophysiology and shared risk factors between the two diseases, future research may also identify potential therapeutic targets along the liver-muscle axis that would benefit both sarcopenia and MASLD in order to maximize their outcomes.

Enhancement of Pulmonary Function and Reduction of Complications Through EIT-Guided Yoga Breathing Exercise After Esophagectomy.

BACKGROUND This study aimed to investigate the impact of EIT-guided yoga breathing training on postoperative pulmonary complications (PPCs) for esophageal cancer patients. MATERIAL AND METHODS Total of 62 patients underwent radical resections of esophageal cancer. Esophageal cancer patients were randomized to the standard care group, or the intervention group receiving an additional complete breathing exercise under the guidance of EIT in AICU. Following extubation after the esophagectomy, pulmonary functions were evaluated by EIT with center of ventilation (CoV), dependent silent spaces (DSS), and non-dependent silent spaces (NSS). RESULTS Sixty-one older esophageal cancer patients (31 in the Control group and 30 in the EIT group) were included in the final analysis. Forty-four patients experienced pulmonary complications after esophagectomy, 27 (87.1%) in the Control group and 17 (36.7%) in the EIT group (RR, 0.42 (95% CI: 0.26, 0.69). The most common pulmonary complication was pleural effusion, with an incidence of 30% in the EIT group and 74.2% in the Control group, with RR of 0.40 (95% CI: 0.23, 0.73). Time for the first pulmonary complication was significantly longer in the EIT group than in the Control group (hazard ratio, HR, 0.43; 95% CI 0.21 to 0.87; P=0.019). Patients in the EIT group had significantly higher scores in CoV, DSS, and NSS than in the Control group. CONCLUSIONS Guided by EIT, the addition of the postoperative breathing exercise to the standardized care during AICU could further improve pulmonary function, and reduce postoperative pulmonary complications after esophagectomy.

Polymer colloidal motors with photodynamic-regulated propulsion.

Artificial colloidal motors capable of converting various external energy into mechanical motion, have emerged as attractive photosensitizer (PS) nanocarriers with good deliverability for photodynamic therapy. However, photoactivated 3O2-to-1O2 transformation as the most crucial energy transfer of the photodynamic process itself is still challenging to convert into autonomous transport. Herein, we report on PS-loaded thiophane-containing semiconducting conjugated polymer (SCP)-based polymer colloidal motors with asymmetric geometry for photodynamic-regulated propulsion in the liquid. The asymmetrical presence of the SCP phases within the colloidal motors would lead to significant differences in the 3O2-to-1O2 transformation and 1O2 release manners between asymmetrical polymer phases, spontaneously creating asymmetrical osmotic pressure gradients across the nanoparticles for powering the self-propelled motion under photodynamic regulation. This photoactivated energy-converting behavior can be also combined with the photothermal conversion of the SCP phases to create two energy gradients exerting diffusiophoretic/thermophoretic force on the colloidal motors for achieving multimode synergistic propulsion. This unique motile feature endows the light-driven PS nanocarriers with good permeability against various physiological barriers in the tumor microenvironment for enhancing antitumor efficacy, showing great potential in phototherapy.

STimage-1K4M: A histopathology image-gene expression dataset for spatial transcriptomics.

Recent advances in multi-modal algorithms have driven and been driven by the increasing availability of large image-text datasets, leading to significant strides in various fields, including computational pathology. However, in most existing medical image-text datasets, the text typically provides high-level summaries that may not sufficiently describe sub-tile regions within a large pathology image. For example, an image might cover an extensive tissue area containing cancerous and healthy regions, but the accompanying text might only specify that this image is a cancer slide, lacking the nuanced details needed for in-depth analysis. In this study, we introduce STimage-1K4M, a novel dataset designed to bridge this gap by providing genomic features for sub-tile images. STimage-1K4M contains 1,149 images derived from spatial transcriptomics data, which captures gene expression information at the level of individual spatial spots within a pathology image. Specifically, each image in the dataset is broken down into smaller sub-image tiles, with each tile paired with 15,000 - 30,000 dimensional gene expressions. With 4,293,195 pairs of sub-tile images and gene expressions, STimage-1K4M offers unprecedented granularity, paving the way for a wide range of advanced research in multi-modal data analysis an innovative applications in computational pathology, and beyond.

A genome-wide association study of alloimmunization in the TOPMed OMG-SCD cohort identifies a locus on chromosome 12.

BACKGROUND: Red cell alloimmunization after exposure to donor red cells is a very common complication of transfusion for patients with sickle cell disease (SCD), resulting frequently in accelerated donor red blood cell destruction. Patients show substantial differences in their predisposition to alloimmunization, and genetic variability is one proposed component. Although several genetic association studies have been conducted for alloimmunization, the results have been inconsistent, and the genetic determinants of alloimmunization remain largely unknown. STUDY DESIGN AND METHODS: We performed a genome-wide association study (GWAS) in 236 African American (AA) SCD patients from the Outcome Modifying Genes in Sickle Cell Disease (OMG-SCD) cohort, which is part of Trans-Omics for Precision Medicine (TOPMed), with whole-genome sequencing data available. We also performed sensitivity analyses adjusting for different sets of covariates and applied different sample grouping strategies based on the number of alloantibodies patients developed. RESULTS: We identified one genome-wide significant locus on chr12 (p = 3.1e-9) with no evidence of genomic inflation (lambda = 1.003). Further leveraging QTL evidence from GTEx whole blood and/or Jackson Heart Study PBMC RNA-Seq data, we identified a number of potential genes, such as ARHGAP9, STAT6, and ATP23, that may be driving the association signal. We also discovered some suggestive loci using different analysis strategies. DISCUSSION: We call for the community to collect additional alloantibody information within SCD cohorts to further the understanding of the genetic basis of alloimmunization in order to improve transfusion outcomes.

Combination of microwave ablation and systemic treatments achieve a long survival time for a patient with metachronous advanced double primary lung and colon adenocarcinoma: A case report.

Despite significant improvements that have been made in terms of progression-free survival and overall survival rates brought about by targeted therapy in non-small cell lung cancer (NSCLC), the emergence of drug resistance remains a limiting factor. However, a previous study has shown promising results by combining local microwave ablation (MWA) with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy for patients with oligometastatic NSCLC. The current study presented the case of a Chinese female patient who was identified as having lung adenocarcinoma (LADC) with EGFR exon 19 deletions (Del) in January 2014, and who experienced multiple instances of oligoprogression but showed a positive response to a combination of chemotherapy, MWA and a TKI drug. First, the patient was treated with four cycles of chemotherapy (120 mg docetaxel on day 1 and 40 mg cisplatin on days 1, 2 and 3; every three weeks as one cycle) and gefitinib (Iressa; 250 mg/day), maintaining a partial response for 17 months. In August 2015, a new solitary lesion was identified in the right lung and erlotinib (Tarceva; 150 mg/day) was administered for 3 months thereafter. In response, the patient underwent ablation of both the new right lung lesion and the primary left lung lesion in January 2016. Subsequently, a treatment course consisting of six cycles of chemotherapy (0.8 g pemetrexed on day 1 and 70 mg nedaplatin on days 1 and 2; every three weeks as one cycle) resulted in stable disease. In May 2016, the patient began treatment with osimertinib (AZD9291; 80 mg/day), resulting in a rapid shrinkage of the mediastinal lymph node after one month, which has been providing a benefit for the patient for 82 months and counting. Of note, the patient also developed metachronous colon cancer in January 2020, followed by the identification of right posterior liver metastases in February 2020 and lung metastases in May 2021 and in February 2022. To address this, the patient underwent radical resection of colon cancer and liver metastasectomy and received a combination of chemotherapy with bevacizumab, along with MWA for lung metastases. Remarkably, the patient has achieved long-term survival of 110 months. In conclusion, this case highlights the promising potential of combining MWA with systemic therapy for a patient with advanced LADC harboring EGFR exon 19 Del and metachronous lung and liver-metastasized colon adenocarcinoma. MWA effectively controlled both in situ oligoprogression and new oligoprogression, thereby enhancing the efficacy of systematic chemotherapy/TKI therapy. Furthermore, this case report emphasizes the importance of repeated histologic biopsies and genetic testing as reliable indicators for adjusting treatment regimens. Physicians should also remain vigilant regarding the occurrence of secondary primary carcinomas, and timely and accurate adjustments to treatment plans will be of significant benefit to patients in terms of treatment efficacy and overall quality of life.

Development and validation of machine learning models to predict MDRO colonization or infection on ICU admission by using electronic health record data.

BACKGROUND: Multidrug-resistant organisms (MDRO) pose a significant threat to public health. Intensive Care Units (ICU), characterized by the extensive use of antimicrobial agents and a high prevalence of bacterial resistance, are hotspots for MDRO proliferation. Timely identification of patients at high risk for MDRO can aid in curbing transmission, enhancing patient outcomes, and maintaining the cleanliness of the ICU environment. This study focused on developing a machine learning (ML) model to identify patients at risk of MDRO during the initial phase of their ICU stay. METHODS: Utilizing patient data from the First Medical Center of the People's Liberation Army General Hospital (PLAGH-ICU) and the Medical Information Mart for Intensive Care (MIMIC-IV), the study analyzed variables within 24 h of ICU admission. Machine learning algorithms were applied to these datasets, emphasizing the early detection of MDRO colonization or infection. Model efficacy was evaluated by the area under the receiver operating characteristics curve (AUROC), alongside internal and external validation sets. RESULTS: The study evaluated 3,536 patients in PLAGH-ICU and 34,923 in MIMIC-IV, revealing MDRO prevalence of 11.96% and 8.81%, respectively. Significant differences in ICU and hospital stays, along with mortality rates, were observed between MDRO positive and negative patients. In the temporal validation, the PLAGH-ICU model achieved an AUROC of 0.786 [0.748, 0.825], while the MIMIC-IV model reached 0.744 [0.723, 0.766]. External validation demonstrated reduced model performance across different datasets. Key predictors included biochemical markers and the duration of pre-ICU hospital stay. CONCLUSIONS: The ML models developed in this study demonstrated their capability in early identification of MDRO risks in ICU patients. Continuous refinement and validation in varied clinical contexts remain essential for future applications.

Thrombocytopenia and hyperprogression after radiotherapy and camrelizumab treatment in an esophageal cancer patient with increased JAK2 gene copies: a case report.

Radiotherapy (RT) and immune checkpoint inhibitor (ICI) are important treatments for esophageal cancer. Some studies have confirmed the safety and effectiveness of using RT in combination with ICI, while serious side effects have been exhibited by some patients. We report a patient with metastatic esophageal cancer who received RT combined with ICI. The patient experienced severe thrombocytopenia, and treatment with thrombopoietin and corticosteroids were ineffective. Finally, the patient developed abscopal hyperprogression outside the radiation field. Interestingly, next-generation sequencing revealed increased JAK2 gene copies in the surgical slices. The JAK2/STAT3 pathway is involved in the regulation of megakaryocyte development. Recurrent thrombocytopenia may activate the JAK2/STAT3 pathway, leading to megakaryocyte differentiation and platelet biogenesis. However, persistent activation of the JAK2/STAT3 pathway has been associated with immune ICI resistance and tumor progression. This case indicates that thrombocytopenia and increased JAK2 gene copies may be risk factors for poor prognosis after ICI and RT treatment.

Pharmacological actions of the bioactive compounds of Epimedium on the male reproductive system: current status and future perspective.

ABSTRACT: Compounds isolated from Epimedium include the total flavonoids of Epimedium, icariin, and its metabolites (icaritin, icariside I, and icariside II), which have similar molecular structures. Modern pharmacological research and clinical practice have proved that Epimedium and its active components have a wide range of pharmacological effects, especially in improving sexual function, hormone regulation, anti-osteoporosis, immune function regulation, anti-oxidation, and anti-tumor activity. To date, we still need a comprehensive source of knowledge about the pharmacological effects of Epimedium and its bioactive compounds on the male reproductive system. However, their actions in other tissues have been reviewed in recent years. This review critically focuses on the Epimedium, its bioactive compounds, and the biochemical and molecular mechanisms that modulate vital pathways associated with the male reproductive system. Such intrinsic knowledge will significantly further studies on the Epimedium and its bioactive compounds that protect the male reproductive system and provide some guidances for clinical treatment of related male reproductive disorders.

Synthetic macrolides overcoming MLSBK-resistant pathogens.

Conventional macrolide-lincosamide-streptogramin B-ketolide (MLSBK) antibiotics are unable to counter the growing challenge of antibiotic resistance that is conferred by the constitutive methylation of rRNA base A2058 or its G2058 mutation, while the presence of unmodified A2058 is crucial for high selectivity of traditional MLSBK in targeting pathogens over human cells. The absence of effective modes of action reinforces the prevailing belief that constitutively antibiotic-resistant Staphylococcus aureus remains impervious to existing macrolides including telithromycin. Here, we report the design and synthesis of a novel series of macrolides, featuring the strategic fusion of ketolide and quinolone moieties. Our effort led to the discovery of two potent compounds, MCX-219 and MCX-190, demonstrating enhanced antibacterial efficacy against a broad spectrum of formidable pathogens, including A2058-methylated Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, and notably, the clinical Mycoplasma pneumoniae isolates harboring A2058G mutations which are implicated in the recent pneumonia outbreak in China. Mechanistic studies reveal that the modified quinolone moiety of MCX-190 establishes a distinctive secondary binding site within the nascent peptide exit tunnel. Structure-activity relationship analysis underscores the importance of this secondary binding, maintained by a sandwich-like π-π stacking interaction and a water-magnesium bridge, for effective engagement with A2058-methylated ribosomes rather than topoisomerases targeted by quinolone antibiotics. Our findings not only highlight MCX-219 and MCX-190 as promising candidates for next-generation MLSBK antibiotics to combat antibiotic resistance, but also pave the way for the future rational design of the class of MLSBK antibiotics, offering a strategic framework to overcome the challenges posed by escalating antibiotic resistance.

Association of muscle health impairment and atherosclerosis with major osteoporotic fracture risk in Taiwanese Vegetarians.

Objectives: Despite the beneficial effects of "vegetarian style" diet on atherosclerosis, it is also proven potentially detrimental to bone health. The influence of muscle health or atherosclerosis on major osteoporotic fracture (MOF) risk in vegetarians has rarely been explored. This prospective study aimed to investigate an association of MOF risk with muscle health and atherosclerosis in vegetarians. Materials and Methods: We conducted a questionnaire survey with the Mini-Nutritional Assessment (MNA) on 39 vegetarians. The 10-year probability of MOF was determined using the Taiwanese Fracture Risk Assessment (FRAX®) calculator. Appendicular skeletal muscle (ASM) mass and bone mineral density were measured with dual-energy X-ray absorptiometry. Physical performance was evaluated using the 6-min walk test (6MWT). Common carotid artery intima-media thickness (ccIMT) was determined using sonography. Serum levels of parathyroid hormone (PTH), Vitamin D, adiponectin, and leptin were measured. Results: Eleven (28.2%) of 39 vegetarians had a moderate-high risk of MOF, defined by FRAX-calculated risk ≥10%. These subjects had lower ASM (P < 0.005) and 6MWT distances (P < 0.01) but greater ccIMT than those with low risk. The MOF risk was negatively correlated with ASM (r = -0.51, P < 0.001) and 6MWT distances (r = -0.62, P < 0.001) but positively correlated with ccIMT (r = 0.56, P < 0.001). Linear regression analysis revealed that MOF risk scores were negatively associated with ASM and 6MWT distance while positively associated with ccIMT. There was no significant association of MOF risk with MNA scores, serum levels of PTH, Vitamin D, adiponectin, or leptin. Conclusion: Decreased ASM mass, reduced physical performance, and atherosclerosis are significantly associated with MOF risk in vegetarians.

Clarithromycin attenuates airway epithelial-mesenchymal transition in ovalbumin-induced asthmatic mice through modulation of Kv1.3 channels and PI3K/Akt signaling.

Airway epithelial-mesenchymal transition (EMT) is the important pathological feature of airway remodeling in asthma. While macrolides are not commonly used to treat asthma, they have been shown to have protective effects on the airways, in which mechanisms are not yet fully understood. This study aims to investigate the impact of clarithromycin on airway EMT in asthma and its potential mechanism. The results revealed an increase in Kv1.3 expression in the airways of ovalbumin (OVA)-induced asthmatic mice, with symptoms and pathological changes being alleviated after treatment with the Kv1.3 inhibitor 5-(4-phenoxybutoxy)psoralen (PAP-1). Clarithromycin was found to attenuate airway epithelial-mesenchymal transition through the inhibition of Kv1.3 and PI3K/Akt signaling. Further experiments in vitro confirmed that PAP-1 could mitigate EMT by modulating the PI3K/Akt signaling in airway epithelial cells undergoing transformation into mesenchymal cells. These findings confirmed that clarithromycin might have a certain protective effect on asthma-related airway remodeling and represent a promising treatment strategy.

DriveLLaVA: Human-Level Behavior Decisions via Vision Language Model.

Human-level driving is the ultimate goal of autonomous driving. As the top-level decision-making aspect of autonomous driving, behavior decision establishes short-term driving behavior strategies by evaluating road structures, adhering to traffic rules, and analyzing the intentions of other traffic participants. Existing behavior decisions are primarily implemented based on rule-based methods, exhibiting insufficient generalization capabilities when faced with new and unseen driving scenarios. In this paper, we propose a novel behavior decision method that leverages the inherent generalization and commonsense reasoning abilities of visual language models (VLMs) to learn and simulate the behavior decision process in human driving. We constructed a novel instruction-following dataset containing a large number of image-text instructions paired with corresponding driving behavior labels, to support the learning of the Drive Large Language and Vision Assistant (DriveLLaVA) and enhance the transparency and interpretability of the entire decision process. DriveLLaVA is fine-tuned on this dataset using the Low-Rank Adaptation (LoRA) approach, which efficiently optimizes the model parameter count and significantly reduces training costs. We conducted extensive experiments on a large-scale instruction-following dataset, and compared with state-of-the-art methods, DriveLLaVA demonstrated excellent behavior decision performance. DriveLLaVA is capable of handling various complex driving scenarios, showing strong robustness and generalization abilities.

Towards Robust Decision-Making for Autonomous Highway Driving Based on Safe Reinforcement Learning.

Reinforcement Learning (RL) methods are regarded as effective for designing autonomous driving policies. However, even when RL policies are trained to convergence, ensuring their robust safety remains a challenge, particularly in long-tail data. Therefore, decision-making based on RL must adequately consider potential variations in data distribution. This paper presents a framework for highway autonomous driving decisions that prioritizes both safety and robustness. Utilizing the proposed Replay Buffer Constrained Policy Optimization (RECPO) method, this framework updates RL strategies to maximize rewards while ensuring that the policies always remain within safety constraints. We incorporate importance sampling techniques to collect and store data in a Replay buffer during agent operation, allowing the reutilization of data from old policies for training new policy models, thus mitigating potential catastrophic forgetting. Additionally, we transform the highway autonomous driving decision problem into a Constrained Markov Decision Process (CMDP) and apply our proposed RECPO for training, optimizing highway driving policies. Finally, we deploy our method in the CARLA simulation environment and compare its performance in typical highway scenarios against traditional CPO, current advanced strategies based on Deep Deterministic Policy Gradient (DDPG), and IDM + MOBIL (Intelligent Driver Model and the model for minimizing overall braking induced by lane changes). The results show that our framework significantly enhances model convergence speed, safety, and decision-making stability, achieving a zero-collision rate in highway autonomous driving.

Sponge-derived alkaloid AP-7 as a sensitizer to cisplatin in the treatment of multidrug-resistant NSCLC via Chk1-dependent mechanisms.

Multidrug resistance is a substantial obstacle in treating non-small cell lung cancer (NSCLC) with therapies like cisplatin (DDP)-based adjuvant chemotherapy and EGFR-tyrosine kinase inhibitors (TKIs). Aaptamine-7 (AP-7), a benzonaphthyridine alkaloid extracted from Aaptos aaptos sponge, has been shown to exhibit a broad spectrum of anti-tumor activity. However, the anti-cancer activity of AP-7 in combination with DDP and its molecular mechanisms in multidrug-resistant NSCLC are not yet clear. Our research indicates that AP-7 bolsters the growth inhibition activity of DDP on multidrug-resistant NSCLC cells. AP-7 notably disrupts DDP-induced cell cycle arrest and amplifies DDP-induced DNA damage effects in these cells. Furthermore, the combination of AP-7 and DDP downregulates Chk1 activation, interrupts the DNA damage repair-dependent Chk1/CDK1 pathway, and helps to overcome drug resistance and boost apoptosis in multidrug-resistant NSCLC cells and a gefitinib-resistant xenograft mice model. In summary, AP-7 appears to enhance DDP-induced DNA damage by impeding the Chk1 signaling pathway in multidrug-resistant NSCLC, thereby augmenting growth inhibition, both in vitro and in vivo. These results indicate the potential use of AP-7 as a DDP sensitizer in the treatment of multidrug-resistant NSCLC.

Caucasian validation of downstaging from IIB to IIA in T1N1M0 patients within the 9th edition of the non-small cell lung cancer tumor-node-metastasis staging.

BACKGROUND: The 9th edition of the lung cancer tumor-node-metastasis (TNM) staging introduced adjustments, including the reclassification of T1N1M0 patients from stage IIB to IIA. This update used data mostly from Asian populations. However, the applicability of these adjustments to Caucasian patients remains uncertain. METHODS: Stage II non-small cell lung cancer (NSCLC) patients from the Surveillance, Epidemiology, and End Results (SEER) database were included. Kaplan-Meier analysis with log-rank testing compared overall survival (OS) and cancer-specific survival (CSS). Propensity score matching (PSM) balanced baseline characteristics. The least absolute shrinkage and selection operator (LASSO)-based Cox analyses identified prognostic factors. RESULTS: Among 10,470 eligible stage II NSCLC patients (median age: 69 years; male: 53.1%), there were 2736 in stage IIA, 2112 in IIA New, and 5622 in IIB groups. Before PSM, survival outcomes of stage IIA New patients were similar to those of stage IIA patients but better than those of stage IIB. After PSM, stage IIA New and IIB patients showed similar survival rates (OS, p = 0.276; CSS, p = 0.565). Conversely, stage IIA New patients had worse outcomes than stage IIA patients (OS, p < 0.001; CSS, p = 0.005). LASSO-based Cox analyses confirmed stage IIA New patients had inferior prognosis compared to stage IIA patients (OS HR: 1 vs. 1.325, p < 0.001; CSS HR: 1 vs. 1.327, p < 0.001). CONCLUSIONS: The downstaging of T1N1M0 patients from stage IIB to IIA in the 9th edition TNM staging remains unverified in Caucasians. Caution is warranted in assessing the staging and prognosis of these individuals. Further validation of our findings is necessary.

What are the benefits of therapeutic drug monitoring in the optimization of adalimumab therapy? a systematic review and meta-analysis up to 2022.

Aims: Persistent uncertainties exist surrounding the therapeutic drug monitoring (TDM) of adalimumab in clinical settings. To address these issues, we conducted a systematic review to assess the current evidence regarding the benefits of TDM for adalimumab. Methods: PubMed, EMBASE, and Cochrane Databases were searched from inception to October 2022. The trials regarding to the list three key questions were considered: 1) Could routine proactive TDM assist in improving outcomes in patients receiving adalimumab? 2) Could reactive TDM assist in guiding subsequent treatment strategies for patients with treatment failure to adalimumab? 3) Could TDM assist in informing dose reduction or discontinuation in patients with low disease activity or in remission treated with adalimumab? Two reviewers independently selected the studies and extracted the data. Meta-analysis was performed to calculate the relative risk (RR) and 95% confidence interval (CI). Results: A total of 9 studies was included in this review. For proactive TDM, meta-analysis indicated that proactive TDM (n = 163/257, 63.42%) showed no significant superiority over reactive TDM and/or conventional management (n = 336/606, 55.44%) in achieving and/or maintaining clinical remission by random effects model (RR: 1.24, 95% CI 0.98-1.58, I 2 = 73%). There were three studies that supporting the reactive TDM, low drug levels in the absence of anti-drug antibodies (ADA) strongly indicate the need for dose intensification, and infliximab is a feasible choice for patients with low drug levels and ADA positivity. While swapping to another class should be considered in patients with adequate drug levels. In addition, TDM can help clinicians optimize dosing schedules and prevent overtreatment in patients who have achieved low disease activity and sufficient drug concentrations, with no predictive value for successful adalimumab discontinuation. Conclusion: Current evidence suggests that proactive TDM is numerically but not statistically significant superiority over reactive TDM and/or conventional management. Reactive TDM can aid in understanding treatment failure and developing subsequent therapy. For patients reaching low disease activity and remission, TDM can help successful dose reduction, while it cannot inform the successful drug discontinuation. However, existing trials are limited, and more well-designed trials are necessary to clarify the role of TDM in adalimumab treatment.

Hinesol attenuates DSS-induced ulcerative colitis through the suppression of Src-mediated NF-κB and chemokine signaling pathway.

As a common inflammatory bowel disease, ulcerative colitis (UC) is featured with inflammation, oxidative damage, and the impairment of intestinal mucosal barrier, which bring threat to patients' quality of live. Hinesol, derived from Atractylodes lancea, is a unique sesquiterpenoid. Our study proposed to survey the effects and mechanism of hinesol in UC. UC mouse model was constructed using dextran sulfate sodium (DSS). Lipopolysaccharide (LPS) was applied for RAW264.7 cells stimulation to construct cell inflammatory model. The changes of disease activity index (DAI), body weight, colon length, and intestinal pathology in mice were analyzed to estimate the severity of colitis. Enzyme-linked immunosorbent assay was applied to check the changes of interleukin (IL)-1ß, IL-18, IL-6, and tumor necrosis factor (TNF)-α. The levels of myeloperoxidase (MPO), superoxide dismutase (SOD), glutathione peroxidase (GSH-px), catalase (CAT), and malondialdehyde (MDA) were estimated by corresponding reagent kit. The changes of phosphorylated (p)-NF-κB P65, and p-IκBα, ZO-1, Occludin, Claudin-1, Src, XCL1, CCL2, and CXCL16 protein were examined using western blot. Flow cytometry and cell counting kit-8 assay were utilized for assessment of cell apoptosis and viability. We found that DSS reduced mice body weight, increased DAI, shorten colon length, and led to severe enteric mucosal injury, while hinesol improved the above symptoms induced by DSS. In DSS mice, hinesol raised the levels of ZO-1, Occludin, Claudin-1, SOD, GSH-px, and CAT and decreased the levels of TNF-α, IL-18, IL-1ß, IL-6, MPO, and MDA. Additionally, in DSS mice and LPS-stimulated RAW264.7 cells, hinesol inhibited the high expression of Src, XCL1, CCL2, CXCL16, p-NF-κB P65, and p-IκBα. The molecular docking showed that there was a good interaction between hinesol and Src. Moreover, in LPS-stimulated RAW 264.7 cells, Src overexpression partially reversed the inhibition of hinesol on cell apoptosis, pro-inflammatory factors, and oxidative stress. In conclusion, hinesol alleviated DSS-induced colitis, which might have a bearing on the inhibition of Src-mediated NF-κB and chemokine signaling pathway.