The efficacy of infliximab combined with partial enteral nutrition in the treatment of Crohn’s disease: a cohort study

Background and aimsThe issue of loss of efficacy with infliximab (IFX) treatment in Crohn’s disease (CD) significantly limits its clinical use. This study aims to investigate the role of therapy combined with partial enteral nutrition (PEN) in maintaining the efficacy of infliximab.MethodsConsecutive CD patients undergoing IFX for induction and maintenance therapy were included, with a follow-up period of at least 54 weeks and endoscopy performed around 54 weeks. Subsequent longitudinal monitoring evaluated improvements in the Crohn’s Disease Activity Index (CDAI) score at 14 weeks and endoscopic remission at 54 weeks.ResultsAmong the 176 included patients, 99 (56%) were in the IFX monotherapy group, and 77 (44%) were in the IFX + PEN group. A significantly higher proportion of patients in the IFX + PEN group achieved clinical response (defined as a CDAI decrease ≥70 points) compared to those in the IFX group at 14 weeks (87.01% vs. 74.75%, p = 0.043), as well as a higher proportion achieving endoscopic remission at 54 weeks (84.42% vs. 65.66%, p = 0.005). Meanwhile, combination therapy with PEN emerged as an independent protective predictor of endoscopic remission at 54 weeks in two multivariate-adjusted models, with ORs of 3.34 and 3.33, respectively (both p < 0.05). Subgroup analysis and interaction test results further supported that all CD patients can benefit from combination therapy with PEN.ConclusionInfliximab treatment combined with partial enteral nutrition is beneficial for both short-term clinical response and long-term endoscopic remission in CD patients

Predicting In Vivo Anti-Hepatofibrotic Drug Efficacy Based on In Vitro High-Content Analysis

Background/Aims Many anti-fibrotic drugs with high in vitro efficacies fail to produce significant effects in vivo. The aim of this work is to use a statistical approach to design a numerical predictor that correlates better with in vivo outcomes. Methods High-content analysis (HCA) was performed with 49 drugs on hepatic stellate cells (HSCs) LX-2 stained with 10 fibrotic markers. ~0.3 billion feature values from all cells in >150,000 images were quantified to reflect the drug effects. A systematic literature search on the in vivo effects of all 49 drugs on hepatofibrotic rats yields 28 papers with histological scores. The in vivo and in vitro datasets were used to compute a single efficacy predictor (Epredict). Results We used in vivo data from one context (CCl4 rats with drug treatments) to optimize the computation of Epredict. This optimized relationship was independently validated using in vivo data from two different contexts (treatment of DMN rats and prevention of CCl4 induction). A linear in vitro-in vivo correlation was consistently observed in all the three contexts. We used Epredict values to cluster drugs according to efficacy; and found that high-efficacy drugs tended to target proliferation, apoptosis and contractility of HSCs. Conclusions The Epredict statistic, based on a prioritized combination of in vitro features, provides a better correlation between in vitro and in vivo drug response than any of the traditional in vitro markers considered.Institute of Bioengineering and Nanotechnology (Singapore)Singapore. Biomedical Research CouncilSingapore. Agency for Science, Technology and ResearchSingapore-MIT Alliance for Research and Technology Center (C-185-000-033-531)Janssen Cilag (R-185-000-182-592)Singapore-MIT Alliance Computational and Systems Biology Flagship Project (C-382-641-001-091)Mechanobiology Institute, Singapore (R-714-001-003-271

Free sulfurous acid (FSA) inhibition of biological thiosulfate reduction (BTR) in the sulfur cycle-driven wastewater treatment process

A sulfur cycle-based bioprocess for co-treatment of wet flue gas desulfurization (WFGD) wastes with freshwater sewage has been developed. In this process the removal of organic carbon is mainly associated with biological sulfate or sulfite reduction. Thiosulfate is a major intermediate during biological sulfate/sulfite reduction, and its reduction to sulfide is the rate-limiting step. In this study, the impacts of saline sulfite (the ionized form: HSO + SO ) and free sulfurous acid (FSA, the unionized form: HSO) sourced from WGFD wastes on the biological thiosulfate reduction (BTR) activities were thoroughly investigated. The BTR activity and sulfate/sulfite-reducing bacteria (SRB) populations in the thiosulfate-reducing up-flow anaerobic sludge bed (UASB) reactor decreased when the FSA was added to the UASB influent. Batch experiment results confirmed that FSA, instead of saline sulfite, was the true inhibitor of BTR. And BTR activities dropped by 50% as the FSA concentrations were increased from 8.0 × 10to 2.0 × 10mg HSO-S/L. From an engineering perspective, the findings of this study provide some hints on how to ensure effective thiosulfate accumulation in biological sulfate/sulfite reduction for the subsequent denitrification/denitritation. Such manipulation would result in higher nitrogen removal rates in this co-treatment process of WFGD wastes with municipal sewage

Comparison of proteomic landscape of extracellular vesicles in pleural effusions isolated by three strategies

Extracellular vesicles (EVs) derived from pleural effusion (PE) is emerging as disease biomarkers. However, the methods for isolation of EVs from PE (pEVs) were rarely studied. In our study, three methods for isolating pEVs of lung cancer patients were compared, including ultracentrifugation (UC), a combination of UC and size exclusion chromatography (UC-SEC) and a combination of UC and density gradient ultracentrifugation (UC-DGU). The subpopulation of pEVs was identified by nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), Western blotting (WB) and nano-flow cytometry (nFCM). Additionally, the proteomic landscape of pEVs was analyzed by Label-free proteomics. The results showed that, compared with UC and UC-DGU, the UC-SEC method separated pEVs with the highest purity. In the proteomic analysis, on average, 1595 proteins were identified in the pEVs isolated by UC-SEC, much more than pEVs isolated by UC (1222) or UC-DGU (807). Furthermore, approximately 90% of identified proteins in each method were found in the EVs public database ExoCarta. Consistent with this, GO annotation indicated that the core proteins identified in each method were mainly enriched in “extracellular exosome.” Many of the top 100 proteins with high expression in each method were suggested as protein markers to validate the presence of EVs in the MISEV2018 guidelines. In addition, combined with lung tissue-specific proteins and vesicular membrane proteins, we screened out and validated several novel protein markers (CD11C, HLA DPA1 and HLA DRB1), which were enriched in pEVs rather than in plasma EVs. In conclusion, our study shows that the method of UC-SEC could significantly improve the purity of EVs and the performance of mass spectrometry-based proteomic profiling in analyzing pEVs. The exosomal proteins CD11C, HLA DPA1 and HLA DRB1 may act as potential markers of pEVs. The proteomic analysis of pEVs provides important information and new ideas for studying diseases complicated with PE

Safety and Efficacy of Low-Dose Tirofiban Combined With Intravenous Thrombolysis and Mechanical Thrombectomy in Acute Ischemic Stroke: A Matched-Control Analysis From a Nationwide Registry

Purpose: Tirofiban administration to acute ischemic stroke patients undergoing mechanical thrombectomy with preceding intravenous thrombolysis remains controversial. The aim of the current study was to evaluate the safety and efficacy of low-dose tirofiban during mechanical thrombectomy in patients with preceding intravenous thrombolysis.Methods: Patients with acute ischemic stroke undergoing mechanical thrombectomy and preceding intravenous thrombolysis were derived from “ANGEL-ACT,” a multicenter, prospective registry study. The patients were dichotomized into tirofiban and non-tirofiban groups based on whether tirofiban was administered. Propensity score matching was used to minimize case bias. The primary safety endpoint was symptomatic intracerebral hemorrhage (sICH), defined as an intracerebral hemorrhage (ICH) associated with clinical deterioration as determined by the Heidelberg Bleeding Classification. All ICHs and hemorrhage types were recorded. Clinical outcomes included successful recanalization, dramatic clinical improvement, functional independence, and mortality at the 3-month follow-up timepoint. Successful recanalization was defined as a modified Thrombolysis in Cerebral Ischemia score of 2b or 3. Dramatic clinical improvement at 24 h was defined as a reduction in NIH stroke score of ≥10 points compared with admission, or a score ≤1. Functional independence was defined as a Modified Rankin Scale (mRS) score of 0–2 at 3-months.Results: The study included 201 patients, 81 in the tirofiban group and 120 in the non-tirofiban group, and each group included 68 patients after propensity score matching. Of the 201 patients, 52 (25.9%) suffered ICH, 15 (7.5%) suffered sICH, and 18 (9.0%) died within 3-months. The median mRS was 3 (0–4), 99 (49.3%) achieved functional independence. There were no statistically significant differences in safety outcomes, efficacy outcomes on successful recanalization, dramatic clinical improvement, or 3-month mRS between the tirofiban and non-tirofiban groups (all p > 0.05). Similar results were obtained after propensity score matching.Conclusion: In acute ischemic stroke patients who underwent mechanical thrombectomy and preceding intravenous thrombolysis, low-dose tirofiban was not associated with increased risk of sICH or ICH. Further randomized clinical trials are needed to confirm the effects of tirofiban in patients undergoing bridging therapy

8-Quinolinyl Oxazoline: Ligand Exploration in Enantioselective Ni-Catalyzed Reductive Carbamoyl-Alkylation of Alkene to Access the Chiral Oxindoles

AbstractChiral ligands play an essential role in transition-metal-catalyzed enantioselective transformations, in which chiral oxazoline-based scaffolds are the privileged chiral ligand. Nevertheless, 8-quinolinyl oxazoline (8-Quinox) ligands are underexplored in transition-metal-catalyzed asymmetric transformations since their development in 1998. Herein, we report an 8-Quinox ligand promoted Ni-catalyzed enantioselective reductive carbamoyl-alkylation of carbamoyl chloride tethered styrene with unactivated alkyl iodide, providing an expedient access to valuable enantioenriched oxindoles in good results.</jats:p

The Stiffness Change in Pre-Stressed Concrete T-Beams during Their Life-Cycle Based on a Full-Scale Destructive Test

In order to study the stiffness degradation of pre-stressed concrete T-beams throughout their entire service life, full-scale destructive tests were conducted on newly constructed T-beams. The test process characterized the relationship between load and deflection at different load levels. Meanwhile, the equivalent stiffness and short-term stiffness of the T-beams at different load levels were calculated based on formulas from the code, and a segmental stiffness back-calculation method for pre-stressed concrete T-beam bridges was proposed based on system identification theory. The results show that, during the destructive test process, the T-beams experienced complete, partial linear, and non-linear stages. By using the equivalent stiffness and short-term stiffness to predict the stiffness changes during the overall failure process of the T-beams, it was found that, when cracks appeared, the stiffness of the T-beams decreased by 31% compared to the initial value, and the stiffness continued to decrease as the cracks extended further. The segmental stiffness system identification back-calculation method more accurately described the destructive test process of each section of the T-beams. This method can help to evaluate the extent of damage in each section of the beams during the overall destructive test process and further assess the overall structural integrity of the beams

Arbutin Alleviates the Liver Injury of α-Naphthylisothiocyanate-induced Cholestasis Through Farnesoid X Receptor Activation

Cholestasis is a kind of stressful syndrome along with liver toxicity, which has been demonstrated to be related to fibrosis, cirrhosis, even cholangiocellular or hepatocellular carcinomas. Cholestasis usually caused by the dysregulated metabolism of bile acids that possess high cellular toxicity and synthesized by cholesterol in the liver to undergo enterohepatic circulation. In cholestasis, the accumulation of bile acids in the liver causes biliary and hepatocyte injury, oxidative stress, and inflammation. The farnesoid X receptor (FXR) is regarded as a bile acid–activated receptor that regulates a network of genes involved in bile acid metabolism, providing a new therapeutic target to treat cholestatic diseases. Arbutin is a glycosylated hydroquinone isolated from medicinal plants in the genus Arctostaphylos, which has a variety of potentially pharmacological properties, such as anti-inflammatory, antihyperlipidemic, antiviral, antihyperglycemic, and antioxidant activity. However, the mechanistic contributions of arbutin to alleviate liver injury of cholestasis, especially its role on bile acid homeostasis via nuclear receptors, have not been fully elucidated. In this study, we demonstrate that arbutin has a protective effect on α-naphthylisothiocyanate–induced cholestasis via upregulation of the levels of FXR and downstream enzymes associated with bile acid homeostasis such as Bsep, Ntcp, and Sult2a1, as well as Ugt1a1. Furthermore, the regulation of these functional proteins related to bile acid homeostasis by arbutin could be alleviated by FXR silencing in L-02 cells. In conclusion, a protective effect could be supported by arbutin to alleviate ANIT-induced cholestatic liver toxicity, which was partly through the FXR pathway, suggesting arbutin may be a potential chemical molecule for the cholestatic disease.</jats:p

Mask-Wearing and Handwashing Behaviors of Chinese Rural Residents during the Pandemic of COVID-19: A Cross-Sectional Survey

Objective: To understand mask-wearing and handwashing behaviors of Chinese rural residents during the COVID-19 pandemic and to analyze the associated factors. Methods: This study used a multi-stage random sampling method to conduct a cross-sectional questionnaire survey during the period of July to December of 2021, in six counties located in Shandong, Shanxi, and Yunnan provinces representing the eastern, central, and western regions of China, respectively. A total of 3864 villagers were surveyed with a questionnaire, and 3832 valid questionnaires were finally analyzed. Descriptive statistics and logistic regression analysis were used for statistical analysis. Results: Around ninety-four percent (93.6%) of rural residents reported mask-wearing during the COVID-19 pandemic, but only 44.5% of them could replace masks in time. Multivariate logistic regression analysis showed that those who were female, aged 15&ndash;59, had an education level of high school and above, were divorced/widowed, worked as farmers (workers), or were rural residents in Shandong Province were more likely to wear masks. Furthermore, those who were female, aged 15&ndash;59, had an education level of high school and above, were unmarried and married, were business and service workers, or were rural residents in Shandong and Shanxi Province replaced masks more timely. Around seventy percent (69.7%) of rural residents reported using soap when washing their hands, but only 38.0% of rural residents could wash their hands properly. Multivariate logistic regression analysis showed that rural residents who were aged 35&ndash;59, had an education of high school and above, or lived in Shandong Province and Shanxi Province were more likely to wash their hands with soap. Those who were aged 15&ndash;59, had an education of high school and above, worked as farmers (workers), were employees of governmental departments and retirees, were business and service workers, or were students had higher proper handwashing rates. Conclusion: During the COVID-19 pandemic, the proportion of Chinese rural residents wearing masks reached 93.6%, but only 44.5% were able to replace masks in time, gender, age, education level, marital status, occupation, and living place had an impact on mask-wearing. The proportion of Chinese rural residents who could wash hands with soap reached 69.7%, but only 38.0% could wash their hands properly. Age and education level were influencing factors for both washing-hand with soap and proper handwashing