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Abstract Dexamethasone is the standard of care for critically ill patients with COVID-19, but the mechanisms by which it decreases mortality and its immunological effects in this setting are not understood. Here we perform bulk and single-cell RNA sequencing of samples from the lower respiratory tract and blood, and assess plasma cytokine profiling to study the effects of dexamethasone on both systemic and pulmonary immune cell compartments. In blood samples, dexamethasone is associated with decreased expression of genes associated with T cell activation, including TNFSFR4 and IL21R. We also identify decreased expression of several immune pathways, including major histocompatibility complex-II signaling, selectin P ligand signaling, and T cell recruitment by intercellular adhesion molecule and integrin activation, suggesting these are potential mechanisms of the therapeutic benefit of steroids in COVID-19. We identify additional compartment- and cell- specific differences in the effect of dexamethasone that are reproducible in publicly available datasets, including steroid-resistant interferon pathway expression in the respiratory tract, which may be additional therapeutic targets. In summary, we demonstrate compartment-specific effects of dexamethasone in critically ill COVID-19 patients, providing mechanistic insights with potential therapeutic relevance. Our results highlight the importance of studying compartmentalized inflammation in critically ill patients.

Abstract Background In chronic pulmonary diseases characterized by inflammation and airway obstruction, such as asthma and COPD, there are unmet needs for improved treatment. Quinolines is a group of small heterocyclic compounds that have a broad range of pharmacological properties. Here, we investigated the airway relaxant and anti-inflammatory properties of a novel quinoline (RCD405). Methods The airway relaxant effect of RCD405 was examined in isolated airways from humans, dogs, rats and mice. Murine models of ovalbumin (OVA)-induced allergic asthma and LPS-induced airway inflammation were used to study the effects in vivo. RCD405 (10 mg/kg) or, for comparisons in selected studies, budesonide (3 mg/kg), were administered intratracheally 1 h prior to each challenge. Airway responsiveness was determined using methacholine provocation. Immune cell recruitment to bronchi was measured using flow cytometry and histological analyses were applied to investigate cell influx and goblet cell hyperplasia of the airways. Furthermore, production of cytokines and chemokines was measured using a multiplex immunoassay. The expression levels of asthma-related genes in murine lung tissue were determined by PCR. The involvement of NF-κB and metabolic activity was measured in the human monocytic cell line THP-1. Results RCD405 demonstrated a relaxant effect on carbachol precontracted airways in all four species investigated (potency ranking: human = rat > dog = mouse). The OVA-specific IgE and airway hyperresponsiveness (AHR) were significantly reduced by intratracheal treatment with RCD405, while no significant changes were observed for budesonide. In addition, administration of RCD405 to mice significantly decreased the expression of proinflammatory cytokines and chemokines as well as recruitment of immune cells to the lungs in both OVA- and LPS-induced airway inflammation, with a similar effect as for budesonide (in the OVA-model). However, the effect on gene expression of Il-4, IL-5 and Il-13 was more pronounced for RCD405 as compared to budesonide. Finally, in vitro, RCD405 reduced the LPS-induced NF-κB activation and by itself reduced cellular metabolism. Conclusions RCD405 has airway relaxant effects, and it reduces AHR as well as airway inflammation in the models used, suggesting that it could be a clinically relevant compound to treat inflammatory airway diseases. Possible targets of this compound are complexes of mitochondrial oxidative phosphorylation, resulting in decreased metabolic activity of targeted cells as well as through pathways associated to NF-κB. However, further studies are needed to elucidate the mode of action.

Abstract Ulcerative colitis (UC) is driven by immune and stromal subsets, culminating in epithelial injury. Vedolizumab (VDZ) is an anti-integrin antibody that is effective for treating UC. VDZ is known to inhibit lymphocyte trafficking to the intestine, but its broader effects on other cell subsets are less defined. To identify the inflammatory cells that contribute to colitis and are affected by VDZ, we perform single-cell transcriptomic and proteomic analyses of peripheral blood and colonic biopsies in healthy controls and patients with UC on VDZ or other therapies. Here we show that VDZ treatment is associated with alterations in circulating and tissue mononuclear phagocyte (MNP) subsets, along with modest shifts in lymphocytes. Spatial multi-omics of formalin-fixed biopsies demonstrates trends towards increased abundance and proximity of MNP and fibroblast subsets in active colitis. Spatial transcriptomics of archived specimens pre-treatment identifies epithelial-, MNP-, and fibroblast-enriched genes related to VDZ responsiveness, highlighting important roles for these subsets in UC.

Objective: In patients who underwent mitral valve replacement for infectious endocarditis, we evaluated the association of prosthesis choice with readmission rates and causes (the primary outcomes), as well as with in-hospital mortality, cost, and length of stay (the secondary outcomes). Methods: Patients with infectious endocarditis who underwent isolated mitral valve replacement from January 2016 to December 2018 were identified in the United States Nationwide Readmissions Database and stratified by valve type. Propensity score matching was used to compare adjusted outcomes. Results: A weighted total of 4206 patients with infectious endocarditis underwent bioprosthetic mitral valve replacement (n = 3132) and mechanical mitral valve replacement (n = 1074) during the study period. Patients in the bioprosthetic mitral valve replacement group were older than those in the mechanical mitral valve replacement group (median 57 vs 46 y, P

Neuroinflammation is a recognized complication of immunotherapeutic approaches such as immune checkpoint inhibitor treatment, chimeric antigen receptor therapy, and graft versus host disease (GVHD) occurring after allogeneic hematopoietic stem cell transplantation. While T cells and inflammatory cytokines play a role in this process, the precise interplay between the adaptive and innate arms of the immune system that propagates inflammation in the central nervous system remains incompletely understood. Using a murine model of GVHD, we demonstrate that type 2 cannabinoid receptor (CB2R) signaling plays a critical role in the pathophysiology of neuroinflammation. In these studies, we identify that CB2R expression on microglial cells induces an activated inflammatory phenotype that potentiates the accumulation of donor-derived proinflammatory T cells, regulates chemokine gene regulatory networks, and promotes neuronal cell death. Pharmacological targeting of this receptor with a brain penetrant CB2R inverse agonist/antagonist selectively reduces neuroinflammation without deleteriously affecting systemic GVHD severity. Thus, these findings delineate a therapeutically targetable neuroinflammatory pathway and have implications for the attenuation of neurotoxicity after GVHD and potentially other T cell-based immunotherapeutic approaches., Introduction Neurological inflammation and cognitive dysfunction are increasingly recognized complications of cancer immunotherapeutic approaches such as immune checkpoint inhibitor treatment (1, 2), chimeric antigen receptor therapy (3, 4), and graft [...]

Veterinary medications are constantly being used for the diagnosis, treatment, and prevention of diseases in livestock. However, untreated veterinary drug active compounds are interminably discharged into numerous water bodies and terrestrial ecosystems, during production procedures, improper disposal of empty containers, unused medication or animal feed, and treatment procedures. This exhaustive review describes the different pathways through which veterinary medications enter the environment, discussing the role of agricultural practices and improper disposal methods. The detrimental effects of veterinary drug compounds on aquatic and terrestrial ecosystems are elaborated with examples of specific veterinary drugs and their known impacts. This review also aims to detail the mechanisms by which microbes degrade veterinary drug compounds as well as highlighting successful case studies and recent advancements in microbe-based bioremediation. It also elaborates on microbial electrochemical technologies as an eco-friendly solution for removing pharmaceutical pollutants from wastewater. Lastly, we have summarized potential innovations and challenges in implementing bioremediation on a large scale under the section prospects and advancements in this field.

Engineering transition metal dichalcogenides-based semiconducting two-dimensional (2D) layered materials for photo(electro)chemical (PEC) hydrogen evolution reaction (HER) by water splitting is an enduring challenge. Here, alloy-assisted photoconductivity and photoresponse from CVD-grown MoS2(1-x)Se2x (MSSE) 2D ternary atomic layered alloy-based photodetector device is presented for the realization of PEC HER. The explicit role of ‘S–Se’ and ‘Se2’ atomic alloy sites including chalcogen-induced vacancy defects on the photoconductivity/photoresponse and PEC HER performance of MSSE 2D alloy is investigated. Alloy formation, atomic site-by-site ‘Se’ composition and atomic structure are characterized using Raman/Photoluminescence (PL) spectroscopy, high-angle annular dark field (HAADF)- scanning transmission electron microscopy (STEM) extensively and supported with Auger Electron Spectroscopy (AES) mapping. Further, the local density and concentration of S–Se, Se2 atomic sites and defects were quantitatively estimated using HAADF-STEM image analysis in correlation with AES and it is found between the range of ∼15–20 % in MSSE alloy. A 10-fold high photoresponsivity in the case of MSSE concerning as-grown MS having fast photocurrent growth time and the prolonged decay time originates from the ‘Se’ and this alloy assisted states to enhance the PEC performance of MSSE alloy. The enhanced PEC HER activity of MSSE alloy was identified in terms of overpotential and current density. In addition, increased density of states as a function of ‘Se’ alloying, shifts in a p-band centre and lowers ΔGH* according to density functional theory calculations, which makes MSSE alloy an efficient HER activity. Further, the PEC stability and presence of the ‘S–Se’ and ‘Se2’ alloying and their role towards HER have been correlated by the spectral line shape analysis of PL and Raman spectra from post-PEC HER catalysts. These experimental and theoretical findings establish the role of chalcogen, and transition metal-based 2D alloy, leading to the design of new PECs of engineered 2D atomic layer interfaces.

Cancer is a broad classification of diseases that can affect any organ or body tissue due to aberrant cellular proliferation for unknown reasons. Many present chemotherapeutic drugs are highly toxic and have little selectivity. Additionally, they lead to the development of medication resistance. Therefore, developing tailored chemotherapeutic drugs with minimal side effects and good selectivity is crucial for cancer treatment. 2-(1H)-Quinazolinone is one of the vital scaffold and anticancer activity is one of the prominent biological activities of this class. Here we report the novel set of amide-enriched 2-(1H)-quinazolinone derivatives (7a-j) and their apoptotic activity with the help of MTT assay method against four human cancer cell lines: PC3 (prostate cancer), DU-145 (prostate cancer), A549 (lung cancer), and MCF7 (breast cancer). When compared to etoposide, every synthetic test compound (7a-j) exhibited moderate to excellent activity. The IC50 values of the new amide derivatives (7a-j) varied from 0.07 ± 0.0061 μM to 10.8 ± 0.69 μM. While the positive control, etoposide, exhibited 1.97 ± 0.45 μM to 3.08 ± 0.135 μM range. Among the novel amide derivatives (7a-j), in particular, 7i and 7j showed strong apoptotic activity against MCF7; 7h showed against PC3, and 7g showed against DU-145. Molecular docking studies of test compounds (7a-j) with the EGFR tyrosine kinase domain (PDB ID: 1M17) protein provided the significant docking scores for each test compound (7a-j) (−9.00 to −9.67 kcal/mol). Additionally, DFT investigations and MD simulations validated the predictions of molecular docking. According to the findings of the ADME analysis, oral absorption by humans is anticipated to be higher than 85 % for all test compounds.

Purpose: To evaluate common morphological types of cataracts in patients with hypertension (HTN) alone (hypertensive patients) planned for cataract surgery. Methods: It is a prospective cross-sectional study. It was conducted in the Department of Ophthalmology at a tertiary eye care centre from January 2022 to June 2022. Hypertensive patients, without any other systemic diseases, who presented with cataract in either of their eyes were included in the study. The classification of cataract was performed according to the Lens Opacities Classification System III. Results: Two hundred and eighty eyes of 140 patients were included in the study. The mean age of presentation was 64.9 ± 7.38 years (median 67 years; range 39–81 years). There were 63 (45%) males, and the rest were females. Of 140, 14 patients were below the age of 55 years, 2 patients were above 75 years, and the majority (42 patients) belonged to the age group between 67 and 70 years. Nuclear sclerosis (NS) cataract was the most common morphological type found in the eyes of hypertensive patients followed by posterior subcapsular cataract (PSC). PSC significantly correlated with HTN when compared to other types of cataracts excluding NS (P < 0.0001). No significant relation was found between the grade of HTN and the grade of NS. Conclusion: Apart from the risk of formation of any type of cataract, NS and PSC were more commonly found in patients with HTN. Moreover, PSC was closely related to HTN when compared to other types of cataracts excluding NS.

Objective: To identify potential socioeconomic disparities in the procedural choice of patients undergoing surgical aortic valve replacement (SAVR) versus transcatheter aortic valve replacement (TAVR) and in readmission outcomes after SAVR or TAVR. Methods: The Nationwide Readmissions Database was queried to identify a total of 243,691 patients who underwent isolated SAVR and TAVR between January 2016 and December 2018. Patients were stratified according to a tiered socioeconomic status (SES) metric comprising patient factors including education, literacy, housing, employment, insurance status, and neighborhood median income. Multivariable analyses were used to assess the effect of SES on procedural choice and risk-adjusted readmission outcomes. Results: SAVR (41.4%; 100,833 of 243,619) was performed less frequently than TAVR (58.6%; 142,786 of 243,619). Lower SES was more frequent among patients undergoing SAVR (20.2% [20,379 of 100,833] vs 19.4% [27,791 of 142,786]; P

Objective: We determined the utilization rate of surgical ablation (SA) during coronary artery bypass grafting (CABG) and compared outcomes between CABG with or without SA in a national cohort. Methods: The January 2016 to December 2018 Nationwide Readmissions Database was searched for all patients undergoing isolated CABG with preoperative persistent or chronic atrial fibrillation by using the International Classification of Diseases, 10th Revision classification. Propensity score matching and multivariate logistic regressions were performed to compare outcomes, and Cox proportional hazards model was used to assess risk factors for 1-year readmission. Results: Of 18,899 patients undergoing CABG with nonparoxysmal atrial fibrillation, 78% (n = 14,776) underwent CABG alone and 22% (n = 4123) underwent CABG with SA. In the propensity score-matched cohort (n = 8116), CABG with SA (n = 4054) (vs CABG alone [n = 4112]) was not associated with increased in-hospital mortality (3.4% [139 out of 4112] vs 3.9% [159 ut of 4054]; P = .4), index-hospitalization length of stay (10 days vs 10 days; P = .3), 30-day readmission (19.1% [693 out of 3362] vs 17.2% [609 out of 3537]; P = .2), or 90-day readmission (28.9% [840 out of 2911] vs 26.2% [752 out of 2875]; P = .1). Index hospitalization costs were significantly higher for those undergoing SA ($52,556 vs $47,433; P

Abstract Green walls are gaining attention for greywater management in the imminent terrestrial space and land constraint scenario. They have been tested primarily with greywater from a single source such as showers, hand or wash basins, laundry, and kitchen or a mix of a couple of these sources but barely with mixed greywater from all these household activities. Here, a green wall system coupled with a slow sand filter (SSF) was tested for managing household greywater. It consisted of a set of five serial hydraulic flow-connected reactors and an SSF unit. Each reactor housed an Epipremnum aureum sapling embedded in the support bed matrix, consisting of cocopeat and granular activated charcoal. The system operated at 150 cm d−1 hydraulic loading rate (HLR) achieved 90 ± 0.7%, 85 ± 4.5%, 72.9 ± 4.4%, and 60.6 ± 5.1% removal efficiencies for turbidity, chemical oxygen demand (COD), total nitrogen (TN), and total phosphorous (TP), respectively. The system maintained similar treatment performance with varying greywater strength when COD and TN were below ~400 and ~15 mg L−1, respectively. The polished effluent produced by SSF operated at 187 cm d−1 HLR, with characteristics

Aims and objective: The main aim of this study was to employ non-invasive methodologies, such as evaluating the portal vein diameter (PVD) and the size of the spleen, as well as the ratio of platelet count to splenic length, in order to identify individuals with cirrhosis who are at a heightened risk of developing esophageal varices. Materials and Methods: The present study utilized a descriptive analysis methodology to investigate a cohort of 50 individuals who received a diagnosis of liver cirrhosis. The individuals, ranging in age from 35 to 70 years, were subjected to both ultrasonography and upper gastrointestinal endoscopy. The statistical analysis was performed utilizing the one-way analysis of variance (ANOVA) and chi-square tests within the Stata 14 software. Results: In the sample of 50 patients, it was shown that 23 individuals (46%) demonstrated a PVD greater than 12mm. Additionally, a statistically significant correlation was observed between an increase in PVD and a rise in variceal grading. Additionally, it was noted that a total of 31 individuals, including 62% of the sample, displayed a splenic size above 13 cm. Nevertheless, no statistically significant positive connection was observed between the increase in splenic size and the grading of varices. The positive predictive value of a platelet count/spleen length ratio less than 909 is 100%. Conclusion: The application of ultrasound-guided measurement of PVD exceeding 12.0 mm and splenic size exceeding 13.0 cm can be considered a dependable and independent approach for predicting the presence of varices in persons with a diagnosis of cirrhosis. The reliability of predicting esophageal varices is higher when using the platelet count/spleen length ratio of less than 909, as opposed to relying solely on spleen size. However, in cases where there has been no previous instance of gastrointestinal bleeding, it is recommended to consider the use of surveillance endoscopy if any of these predictors are identified in individuals with cirrhosis.

Aims and Objectives: The study aimed to assess the efficacy of incisional negative pressure wound therapy (iNPWT) in reducing the risk of suture site infections (SSI) in patients undergoing post-operative emergency non-traumatic laparotomy. Materials and Methods: A cross-sectional observational prospective study was conducted in a tertiary care setup in a rural area between March 2018 and July 2018. Fifty emergency exploratory laparoto-mies performed for non-traumatic reasons were included. Patients were randomized into two groups: one receiving conventional povidone-iodine dressing and the other receiving iNPWT over the main wound. After 7 days, SSI was assessed using the center for disease control and prevention's criteria. Results: iNPWT demonstrated a significant reduction in the risk of SSI development when compared to conventional povidone-iodine dressing (p

An innovative approach to this research is to evaluate the effects of different concentrations of biodiesel with premixed ammonia energy in a dual-fuel combustion engine and determine the best operating conditions for optimal engine responses. Experimental results of a 40% ammonia energy premixing fraction with direct injection of a biodiesel blend of 30% (40%AEPF + B30) at 80% load improved brake thermal efficiency (BTE) by 8.42% while reducing brake specific energy consumption (BSEC) by 13.28%. It also reduces the hydrocarbon (HC) emission by 16.8%, the carbon monoxide (CO) emission by 15.06%, and the smoke opacity by 26.8%. As opposed to this, carbon dioxide (CO2) and nitrogen oxide (NOx) emissions are elevated by 21.5% and 16.54%, respectively, relative to the 40% ammonia energy premixing fraction with direct injection of diesel (40%AEPF + Diesel). Thereafter, the ANOVA technique is also utilized to analyze the impact of operational parameters, and the findings show that the responses are statistically significant. Additionally, the results are utilized in a grey relational analysis (GRA) based optimization process to determine the appropriate operational variables. According to optimization results, 40%AEPF + B30 at 80% load provides the most efficiency and fuel economy. It is capable of being used as an alternate fuel instead of conventional diesel.

Since the FDA’s approval of chimeric antigen receptor (CAR) T cells in 2017, significant improvements have been made in the design of chimeric antigen receptor constructs and in the manufacturing of CAR T cell therapies resulting in increased in vivo CAR T cell persistence and improved clinical outcome in certain hematological malignancies. Despite the remarkable clinical response seen in some patients, challenges remain in achieving durable long-term tumor-free survival, reducing therapy associated malignancies and toxicities, and expanding on the types of cancers that can be treated with this therapeutic modality. Careful analysis of the biological factors demarcating efficacious from suboptimal CAR T cell responses will be of paramount importance to address these shortcomings. With the ever-expanding toolbox of experimental approaches, single-cell technologies, and computational resources, there is renowned interest in discovering new ways to streamline the development and validation of new CAR T cell products. Better and more accurate prognostic and predictive models can be developed to help guide and inform clinical decision making by incorporating these approaches into translational and clinical workflows. In this review, we provide a brief overview of recent advancements in CAR T cell manufacturing and describe the strategies used to selectively expand specific phenotypic subsets. Additionally, we review experimental approaches to assess CAR T cell functionality and summarize current in silico methods which have the potential to improve CAR T cell manufacturing and predict clinical outcomes.

Inflammation of the gums and other tissues supporting the teeth, as well as gradual loss of attachment and bone, are the results of chronic periodontitis, an infectious illness. During inflammation, a group of low molecular weight proteins called cytokines facilitate a complex interaction between inflammatory cells (such neutrophils) and other cellular components in connective tissue. The cytokine interleukin-8 (IL-8) is a potent neutrophil chemoattractant. Therefore, it is possible that IL-8 is crucial to the development of periodontitis's pathology. Objectives: 1) To estimate concentration of IL-8 levels in healthy individuals and chronic periodontitis individuals. 2) To compare IL-8 levels in healthy and chronic periodontitis individuals. Materials and Methods: Participants in this research will be recruited from among those who visit the outpatient department (OPD) at the NGH Institute of Dental Sciences and Research Centre, Belagavi, run by the Maratha Mandal. Control Group: Subjects with no clinical attachment loss (CAL) and a probing depth of 3.0 mm are considered to be periodontally healthy. Those in Group 2 (chronic periodontitis) have a chronic form of the disease, as shown by a probing pocket depth (PPD) of less than 5 mm and CAL of less than 2 mm. Unstimulated saliva sample will be collected in a 5 mL wide-mouthed sterile container by spitting method. Samples collected will be centrifuged. The supernatant is collected and stored at –80oC and then assayed for IL-8 concentration by using the standardized IL-8 ELISA kit.