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INRODUCTION: Bispectral Index is an objective tool to assess electroencephalographic activity and measure the effect of certain sedatives and hypnotics on the brain. In addition, there are certain subjective tools such as the observer's assessment of alertness and sedation which are used. The correlation between BIS and the concentration of propofol in the brain, and the relationship between these subjective and objective tools in assessing sedation levels are the subject of this study. METHODS: Thirty healthy volunteers enrolled in this prospective observational study. They were sedated with a target controlled infusion of propofol with an initial target of 0.8 µg.mL(-1) and an increase in target to 0.2 µg.mL(-1) ten minutes after equilibration of the predicted and set target concentrations. In each sedation score, the Bispectral Index value and predicted effect site concentration of propofol were recorded and analyzed. Analysis of variance and significant differences between groups were analyzed by paired t-test. Correlations between Bispectral Index and effect site concentration of propofol at each sedation score and the relationship of BIS and effect site concentration of propofol to each sedation score were assessed and analyzed by nonparametric Spearman's rho. RESULTS: The means of Bispectral Index and effect site concentration of propofol at each sedation score showed a significant difference with the following score. Additionally, Bispectral Index and effect site concentration of propofol showed a significant negative correlation in sedation scores 3 and 2 when inducing sedation. In other sedation scores or when reversing the sedation, no strong correlation was noted. CONCLUSION: Both Bispectral Index and effect site concentration of propofol indicate a good estimate of sedation levels; however their correlations are significant and negative only at moderate and deep sedation levels, and during the induction of sedation. [ABSTRACT FROM AUTHOR]

Coumarin, a naturally occurring compound found in various plants, has a rich history of use in traditional medicine. Recent research has highlighted its anti-inflammatory properties, positioning it as a promising candidate for treating inflammatory disorders such as rheumatoid arthritis, asthma, and inflammatory bowel disease. This narrative review aims to comprehensively summarize the current knowledge regarding coumarin's pharmacological effects in alleviating inflammatory conditions by analyzing preclinical and clinical studies. The review focuses on elucidating the mechanisms through which coumarin exerts its anti-inflammatory effects, including its antioxidant activity, inhibiting pro-inflammatory cytokine production, and modulation of immune cell functions. Additionally, the paper addresses potential limitations of using coumarin, such as concerns about toxicity at high doses or with prolonged use. Before widespread clinical application, further investigation is needed to fully understand coumarin's potential benefits and risks., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier B.V.)

Long-lived PFKFB3-expressing β-cells are dysfunctional partly because of prevailing glycolysis that compromises metabolic coupling of insulin secretion. Their accumulation in type 2 diabetes (T2D) appears to be related to the loss of apoptotic competency of cell fitness competition that maintains islet function by favoring constant selection of healthy "winner" cells. To investigate how PFKFB3 can disguise the competitive traits of dysfunctional "loser" β-cells, we analyzed the overlap between human β-cells with bona fide "loser signature" across diabetes pathologies using the HPAP scRNA-seq and spatial transcriptomics of PFKFB3-positive β-cells from nPOD T2D pancreata. The overlapping transcriptional profile of "loser" β-cells was represented by down-regulated ribosomal biosynthesis and genes encoding for mitochondrial respiration. PFKFB3-positive "loser" β-cells had the reduced expression of HLA class I and II genes. Gene-gene interaction analysis revealed that PFKFB3 rs1983890 can interact with the anti-apoptotic gene MAIP1 implicating positive epistasis as a mechanism for prolonged survival of "loser" β-cells in T2D. Inhibition of PFKFB3 resulted in the clearance of dysfunctional "loser" β-cells leading to restored glucose tolerance in the mouse model of T2D., (© 2024 Raval et al.)

Background: During bone drilling, a common procedure in clinical surgeries, excessive heat generation and drilling force can cause damage to bone tissue, potentially leading to failure of implants and fixation screws or delayed healing. With this in mind, the aim of this study was to evaluate the efficiency of ultrasonic-assisted drilling compared to conventional drilling as a potential method for bone drilling., Methods: This study examined optimal drilling parameters based on previous findings and investigated both cortical and cancellous bone. In addition to evaluating drilling force and temperature elevation, the effects of these factors on osteonecrosis and micro-crack formation were explored in ultrasonic-assisted and conventional drilling through histopathological assessment and microscopic imaging. To this end, three drilling speeds and two drilling feed-rates were considered as variables in the in vitro experiments. Furthermore, numerical modeling provided insight into temperature distribution during the drilling process in both methods and compared three different vibration amplitudes., Results: Although temperature elevations were lower in the conventional drilling, ultrasonic-assisted drilling produced less drilling force. Additionally, the latter method resulted in smaller osteonecrosis regions and did not produce micro-cracks in cortical bone or structural damage in cancellous bone., Conclusions: Ultrasonic-assisted drilling, which caused less damage to bone tissue in both cortical and cancellous bone, was comparatively more advantageous. Notably, this study demonstrated that to determine the superiority of one method over the other, we cannot rely solely on temperature variation results. Instead, we must consider the cumulative effect of both temperature elevation and drilling force., Competing Interests: The authors declare that they have no competing interests., (© 2024 The Authors.)

Inflammatory bowel disease (IBD) manifests as chronic inflammation within the gastrointestinal tract. The study focuses on a long noncoding RNA (lncRNA) known as Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1). MALAT1's misregulation has been linked with various autoimmune diseases and regulates proinflammatory cytokines. The role of IL6 in immune-triggered conditions, including IBD, is another focal point. In this research, the expression of MALAT1 and IL6 in IBD patients was meticulously analyzed to uncover potential interactions. The study involved 33 IBD patients (13 with Crohn's disease and 20 with ulcerative colitis) and 20 healthy counterparts. Quantitative real-time polymerase chain reaction determined the MALAT1 and IL6 gene expression levels. The competitive endogenous RNA (ceRNA) regulatory network was constructed using several tools, including LncRRIsearch and Cytoscape. A deep dive into the Inflammatory Bowel Disease database was undertaken to understand IL6's role in IBD. Drugs potentially targeting these genes were also pinpointed using DGIdb. Results indicated a notable elevation in the expression levels of MALAT1 and IL6 in IBD patients versus healthy controls. MALAT1 and IL6 did not show a direct linear correlation, but IL6 could serve as MALAT1's target. Analyses unveiled interactions between MALAT1 and IL6, regulated by hsa-miR-202-3p, hsa-miR-1-3p, and has-miR-9-5p. IL6's pivotal role in IBD-associated inflammation, likely interacting with other cytokines, was accentuated. Moreover, potential drugs like CILOBRADINE for MALAT1 and SILTUXIMAB for IL6 were identified. This research underscored MALAT1 and IL6's potential value as targets in diagnosis and treatment for IBD patients.

N-acetyl cysteine (NAC) is a potent antioxidant that modulates glutamatergic signalling which is thought to play a role in alcohol use disorder (AUD). There have been no clinical trials investigating NAC for AUD. We aimed to conduct a 28 day double-blind, placebo-controlled (PL) randomized trial of NAC in the treatment of AUD (NCT03879759). A total of 42 participants with AUD (56% alcohol-related liver disease) were randomized to receive placebo or NAC 2400 mg/day. Feasibility outcomes included treatment retention and adverse events. Primary clinical outcomes included alcohol consumption (heavy drinking days, standard drinks per drinking day). Secondary clinical outcome measures included craving, liver tests, and psychological outcomes. There were no significant differences in overall retention between treatment groups (χ2(1) = 0.14, P = 0.71: 86% vs 76% for placebo and NAC, respectively). The most commonly reported adverse event in NAC-treated individuals included headache (14%). For standard drinks per drinking day, there was a significant overall effect of time (F = 9.18, P < 0.001), no significant effect of treatment (F = 0.75, P = 0.79), and a significant time x treatment (NAC vs PL) effect (F = 2.73, P < 0.05). For number of heavy drinks per day, there was a significant overall effect of time (F = 3.16, P < 0.05) but no significant effect of treatment or time x treatment (P = 0.17). There were no significant NAC vs PL effects on secondary clinical outcome measures. In the first trial of NAC for the management of AUD, NAC appears to be feasible and safe. Although there was a significant effect of NAC vs placebo on some alcohol measures such as drinks per drinking day, there does appear to be a variable pattern of effect across time suggesting that a larger trial incorporating a longer treatment duration is now required to determine efficacy., (© The Author(s) 2023. Medical Council on Alcohol and Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Non-alcoholic fatty liver disease is a multifaceted disease that progresses through multiple phases; it involves metabolic as well as structural changes. These alterations can be measured directly or indirectly through blood, non-invasive imaging, and/or tissue analyses. While some studies have evaluated the correlations between two sets of measurements (e.g., histopathology with cross-sectional imaging or blood biomarkers), the interrelationships, if any, among histopathology, clinical blood profiles, cross-sectional imaging, and metabolomics in a pediatric cohort remain unknown. We created a multiparametric clinical MRI-histopathologic NMR network map of pediatric NAFLD through multimodal correlation networks, in order to gain insight into how these different sets of measurements are related. We found that leptin and other blood markers were correlated with many other measurements; however, upon filtering out the blood biomarkers, the network was decomposed into three independent hubs centered around histopathological features, each with associated MRI and plasma metabolites. These multi-modality maps could serve as a framework for characterizing disease status and progression and could potentially guide medical interventions.

Aims: Buprenorphine is effective at reducing relapse to opioid misuse, morbidity and mortality in opioid-dependent patients. Urine drug screening (UDS) to assess adherence is used routinely in opioid agonist treatment (OAT). The primary aim of this study was to determine factors which may be associated with a negative qualitative urine drug screen for buprenorphine in OAT patients., Methods: This prospective pilot study was conducted at a tertiary addiction medicine centre. Twenty participants on stable treatment underwent supervised administration of sublingual buprenorphine. Matched urine and blood samples were collected prior to and 2, 4 and 6 hours after buprenorphine administration. Qualitative urine drug screen results were obtained using gas chromatography-mass spectrometry (GC-MS), while quantitative blood and urine results were obtained using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS)., Results: Qualitative urine assay yielded a negative result for buprenorphine in 57% of tested samples. The median concentration of urinary buprenorphine was 167 mcg/L (range: 2-1730 mcg/L). Thirty percent of all blood samples did not detect buprenorphine (range 0-18 mcg/L). Positive qualitative urine drug screen results were associated with higher urine (343 mcg/L compared with 75 mcg/L; P < .05) and blood (4 mcg/L compared with 2 mcg/L; P < .05) buprenorphine concentrations. Median urine concentrations of buprenorphine were highest at 2 hours and were higher in participants receiving CYP3A4 inhibitors., Conclusion: Interpretation of qualitative urine drug screens to assess adherence in OAT is complex. Poor adherence with treatment cannot be assumed in patients returning a negative qualitative GC-MS urine drug screen., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

High uric acid is associated with gout, hypertension, metabolic syndrome, cardiovascular disease, and kidney disease. URAT1 (SLC22A12), originally discovered in mice as Rst, is generally considered a very selective uric acid transporter compared to other closely-related kidney uric acid transporters such as OAT1 (SLC22A6, NKT) and OAT3 (SLC22A8). While the role of URAT1 in regulating human uric acid is well-established, in recent studies the gene has been linked to redox regulation in flies as well as progression of renal cell carcinoma. We have now identified over twenty metabolites in the Urat1 knockout that are generally distinct from metabolites accumulating in the Oat1 and Oat3 knockout mice, with distinct molecular properties as revealed by chemoinformatics and machine learning analysis. These metabolites are involved in seemingly disparate aspects of cellular metabolism, including pyrimidine, fatty acid, and amino acid metabolism. However, through integrative systems metabolic analysis of the transcriptomic and metabolomic data using a human metabolic reconstruction to build metabolic genome-scale models (GEMs), the cellular response to loss of Urat1/Rst revealed compensatory processes related to reactive oxygen species handling and maintaining redox state balances via Vitamin C metabolism and cofactor charging reactions. These observations are consistent with the increasingly appreciated role of the antioxidant properties of uric acid. Collectively, the results highlight the role of Urat1/Rst as a transporter strongly tied to maintaining redox homeostasis, with implications for metabolic side effects from drugs that block its function.

Background: Pancreatic adenocarcinoma (PDAC) persists as a malignancy with high morbidity and mortality that can benefit from new means to characterize and detect these tumors, such as radiogenomics. In order to address this gap in the literature, constructed a transcriptomic-CT radiogenomic (RG) map for PDAC., Methods: In this Institutional Review Board approved study, a cohort of subjects (n = 50) with gene expression profile data paired with histopathologically confirmed resectable or borderline resectable PDAC were identified. Studies with pre-operative contrast-enhanced CT images were independently assessed for a set of 88 predefined imaging features. Microarray gene expression profiling was then carried out on the histopathologically confirmed pancreatic adenocarcinomas and gene networks were constructed using Weighted Gene Correlation Network Analysis (WCGNA) (n = 37). Data were analyzed with bioinformatics analyses, multivariate regression-based methods, and Kaplan-Meier survival analyses., Results: Survival analyses identified multiple features of interest that were significantly associated with overall survival, including Tumor Height (P = 0.014), Tumor Contour (P = 0.033), Tumor-stroma Interface (P = 0.014), and the Tumor Enhancement Ratio (P = 0.047). Gene networks for these imaging features were then constructed using WCGNA and further annotated according to the Gene Ontology (GO) annotation framework for a biologically coherent interpretation of the imaging trait-associated gene networks, ultimately resulting in a PDAC RG CT-transcriptome map composed of 3 stage-independent imaging traits enriched in metabolic processes, telomerase activity, and podosome assembly (P < 0.05)., Conclusions: A CT-transcriptomic RG map for PDAC composed of semantic and quantitative traits with associated biology processes predictive of overall survival, was constructed, that serves as a reference for further mechanistic studies for non-invasive phenotyping of pancreatic tumors., (© 2023. The Author(s).)

Purpose: This study was conducted to evaluate a smartphone-based online electronic logbook used to assess the clinical skills of nurse anesthesia students in Iran., Methods: This randomized controlled study was conducted after tool development at Ahvaz Jundishapur University of Medical Sciences in Ahvaz, Iran from January 2022 to December 2022. The online electronic logbook involved in this study was an Android-compatible application used to evaluate the clinical skills of nurse anesthesia students. In the implementation phase, the online electronic logbook was piloted for 3 months in anesthesia training in comparison with a paper logbook. For this purpose, 49 second- and third-year anesthesia nursing students selected using the census method were assigned to intervention (online electronic logbook) and control (paper logbook) groups. The online electronic logbook and paper logbook were compared in terms of student satisfaction and learning outcomes., Results: A total of 39 students participated in the study. The mean satisfaction score of the intervention group was significantly higher than that of the control group (P=0.027). The mean score of learning outcomes was also significantly higher for the intervention than the control group (P=0.028)., Conclusion: Smartphone technology can provide a platform for improving the evaluation of the clinical skills of nursing anesthesia students, leading to increased satisfaction and improved learning outcomes.

In vitro and in vivo studies have established the organic anion transporters OAT1 (SLC22A6, NKT) and OAT3 (SLC22A8) among the main multi-specific "drug" transporters. They also transport numerous endogenous metabolites, raising the possibility of drug-metabolite interactions (DMI). To help understand the role of these drug transporters on metabolism across scales ranging from organ systems to organelles, a formal multi-scale analysis was performed. Metabolic network reconstructions of the omics-alterations resulting from Oat1 and Oat3 gene knockouts revealed links between the microbiome and human metabolism including reactions involving small organic molecules such as dihydroxyacetone, alanine, xanthine, and p-cresol-key metabolites in independent pathways. Interestingly, pairwise organ-organ interactions were also disrupted in the two Oat knockouts, with altered liver, intestine, microbiome, and skin-related metabolism. Compared to older models focused on the "one transporter-one organ" concept, these more sophisticated reconstructions, combined with integration of a multi-microbial model and more comprehensive metabolomics data for the two transporters, provide a considerably more complex picture of how renal "drug" transporters regulate metabolism across the organelle (e.g. endoplasmic reticulum, Golgi, peroxisome), cellular, organ, inter-organ, and inter-organismal scales. The results suggest that drugs interacting with OAT1 and OAT3 can have far reaching consequences on metabolism in organs (e.g. skin) beyond the kidney. Consistent with the Remote Sensing and Signaling Theory (RSST), the analysis demonstrates how transporter-dependent metabolic signals mediate organ crosstalk (e.g., gut-liver-kidney) and inter-organismal communication (e.g., gut microbiome-host)., (© 2022. The Author(s).)

The aryl hydrocarbon receptor (AHR) is a transcription factor with roles in detoxification, development, immune response, chronic kidney disease and other syndromes. It regulates the expression of drug transporters and drug metabolizing enzymes in a proposed Remote Sensing and Signaling Network involved in inter-organ communication via metabolites and signaling molecules. Here, we use integrated omics approaches to analyze its contributions to metabolism across multiple scales from the organ to the organelle. Global metabolomics analysis of Ahr -/- mice revealed the role of AHR in the regulation of 290 metabolites involved in many biochemical pathways affecting fatty acids, bile acids, gut microbiome products, antioxidants, choline derivatives, and uremic toxins. Chemoinformatics analysis suggest that AHR plays a role in determining the hydrophobicity of metabolites and perhaps their transporter-mediated movement into and out of tissues. Of known AHR ligands, indolepropionate was the only significantly altered molecule, and it activated AHR in both human and murine cells. To gain a deeper biological understanding of AHR, we employed genome scale metabolic reconstruction to integrate knockout transcriptomics and metabolomics data, which indicated a role for AHR in regulation of organic acids and redox state. Together, the results indicate a central role of AHR in metabolism and signaling between multiple organs and across multiple scales., (© 2022. The Author(s).)

Regarding the existence of similar helices on the structure of different proteins, recently, novel variants of Chondroitinase ABC I (cABC I) have been constructed, where a representative helix between two structural motifs in Chondroitinase ABC I from Proteus vulgaris has been replaced by similar versions of helices found in other proteins. The previous study has revealed that the structural features and the activity of double mutants M886A/G887E (inspired by the 30 S ribosomal protein S1 from Geminocystis herdmanii) and M889I/Q891K (inspired by the chondroitin lyase from Proteus mirabilis) is comparable with that of wild-type (WT) cABC I. Here, the kinetic parameters of the enzyme activity for the WT and double mutants were determined. Of the recombinant double mutants, M889I/Q891K gave the highest catalytic efficiency with the k cat /K m value of approximately 2.3-fold increase, as compared with the WT and M886A/G887E. Modeling of experimental data showed that the mechanism of the heat-induced structural alteration, and the enzyme-substrate complex formation, changed upon mutation. These natural versions of the connecting helix can be used as an efficient linker in protein engineering studies as well as those investigations involving the use of biological linkers., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Multiple studies have created state-of-the-art liver segmentation models using Deep Convolutional Neural Networks (DCNNs) such as the V-net and H-DenseUnet. Oversegmentation however continues to be a problem. We set forth to address these limitations by developing a an automated workflow that leverages the strengths of different DCNN architectures, resulting in a pipeline that enables fully automated liver segmentation. A Pipeline for Automated Deep Learning Liver Segmentation (PADLLS) was developed and implemented that cascades multiple DCNNs that were trained on more than 200 CT scans. First, a V-net is used to create a rough liver, spleen, and stomach mask. After stomach and spleen pixels are removed using their respective masks and ascites is removed using a morphological algorithm, the scan is passed to a H-DenseUnet to yield the final segmentation. The segmentation accuracy of the pipleline was compared to the H-DenseUnet and the V-net using the SLIVER07 and 3DIRCADb datasets as benchmarks. The PADLLS Dice score for the SLIVER07 dataset was calculated to be 0.957 ± 0.033 and was significantly better than the H-DenseUnet's score of 0.927 ± 0.044 (p = 0.0219) and the V-net's score of 0.872 ± 0.121 (p = 0.0067). The PADLLS Dice score for the 3DIRCADb dataset was 0.965 ± 0.016 and was significantly better than the H-DenseUnet's score of 0.930 ± 0.041 (p = 0.0014) the V-net's score of 0.874 ± 0.060 (p &lt; 0.001). In conclusion, our pipeline (PADLLS) outperforms existing liver segmentation models, serves as a valuable tool for image-based analysis, and is freely available for download and use., (© 2022. The Author(s).)

The "gunsight approach" was initially described as the use of overlapping snares and through- and-through puncture of the portal vein and inferior vena cava for the creation of a transcaval portosystemic shunt. This technique can be adapted for the creation of an extra-anatomic chan- nel between any 2 locations where snares can be deployed. We explain the technique, discuss finer technical points, and describe 2 cases where refractory vascular occlusions are crossed using this technique. The first case involves an extensively calcified femoral arterial chronic total occlusion where subintimal tracking past the occlusion is achieved, but luminal re-entry is ham- pered by dense calcific plaque refractory to multiple re-entry devices. The second case involves a chronic venous occlusion along the femoral vein with loss of in-line flow due to prior stenting. In both cases, the gunsight technique was successfully used as a bailout option after standard recanalization techniques were unsuccessful.

Lanthanide-based beta-tricalcium phosphate (β-TCP) upconversion nanoparticles are exploited as a non-viral vector for imaging guided-gene therapy by virtue of their unique optical properties and multi-modality imaging ability, high transfection efficiency, high biocompatibility, dispersibility, simplicity of synthesis and surface modification. Ytterbium and thulium-doped β-TCP nanoparticles (βTCPYbTm) are synthesized via co-precipitation method, coated with polyethylenimine (PEI) and functionalized with a nuclear-targeting peptide (TAT). Further, in vitro studies revealed that the nanotheranostic carriers are able to transfect cells with the plasmid eGFP at a high efficiency, with approximately 60% of total cells producing the fluorescent green protein. The optimized protocol developed comprises the most efficient βTCPYbTm/PEI configuration, the amount and the order of assembly of βTCPYbTm:PEI, TAT, plasmid DNA and the culturing conditions. With having excellent dispersibility and high chemical affinity toward nucleic acid, calcium ions released from βTCPYbTm:PEI nanoparticles can participate in delivering nucleic acids and other therapeutic molecules, overcoming the nuclear barriers and improving the transfection efficacy. Equally important, the feasibility of the upconversion multifunctional nanovector to serve as an effective contrast agent for imaging modality, capable of converting low-energy light to higher-energy photons via a multi-photons mechanism, endowing greater unique luminescent properties, was successfully demonstrated., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: COVID-19 and Fontan physiology have each been associated with an elevated risk of venous thromboembolism (VTE), however little is known about the risks and potential consequences of having both., Case Presentation: A 51 year old male with tricuspid atresia status post Fontan and extracardiac Glenn shunt, atrial flutter, and sinus sick syndrome presented with phlegmasia cerulea dolens (PCD) of the left lower extremity in spite of supratherapeutic INR in the context of symptomatic COVID-10 pneumonia. He was treated with single session, catheter directed mechanical thrombectomy that was well-tolerated., Conclusions: This report of acute PCD despite therapeutic anticoagulation with a Vitamin K antagonist, managed with emergent mechanical thrombectomy, calls to attention the importance of altered flow dynamics in COVID positive patients with Fontan circulation that may compound these independent risk factors for developing deep venous thrombosis with the potential for even higher morbidity., (© 2021. The Author(s).)

Hepatocellular carcinoma (HCC) occurs in nearly three-quarters of all primary liver cancers, with the majority not amenable to curative therapies. We therefore aimed to re-evaluate the safety, efficacy, and survival benefits of treating patients with drug-eluting beads transcatheter arterial chemoembolization (DEB-TACE) compared to the conventional transcatheter arterial chemoembolization (C-TACE). Several databases were searched with a strict eligibility criterion for studies reporting on adult patients with unresectable or recurrent HCC. The pooled analysis included 34 studies involving 4841 HCC patients with a median follow-up of 1.5 to 18 months. There were no significant differences between DEB-TACE and C-TACE with regard to complete response, partial response and disease stability. However, disease control (OR: 1.42 (95% CI (1.03,1.96) and objective response (OR: 1.33 (95% CI (0.99, 1.79) were significantly more effective for DEB-TACE treatment with fewer severe complications and all-cause mortality. The pooled-analysis did not find superiority of DEB-TACE in complete or partial response, disease stability, controlling disease progression, and 30 day or end-mortality. However, results showed that DEB-TACE is associated with a better objective response, disease control, and lower all-cause mortality with severe complications compared to C-TACE treatment. Given that the safety outcomes are based on limited studies with a potential for bias, there was no clear improvement of DEB-TACE over C-TACE treatment.

The pathogenesis of inflammatory bowel disease (IBD) is influenced by immune system malfunction, particularly innate immune receptors such as toll-like receptors. Furthermore, it is critical to investigate the extremely close association between viruses and IBD incidence. Toll-like receptors (TLRs) 3, 5, and 7 are involved in antiviral immune responses. Finding a relationship between TLR-related virus and IBD is important not only for understanding the disease pathogenesis, but also for developing effective therapies. It has been shown that influenza is expressed more severely in patients with IBD who use immune system inhibitors, and the influenza vaccine is less effective in these patients. In dendritic cells, TLR7 and TLR8 regulate the production of interferons (IFNs) and inflammatory mediators. COVID-19 causes the production of IL-6, possibly due to the induction of TLR pathways. TLR activation by SARS-CoV-2 causes inflammation and IL-1 production, which induces the production of IL-6. Understanding TLR-associated viruses' molecular mechanisms can greatly help improve the quality of life of people with IBD. Therefore, the present study reviewed the role of TLR7, 8, and 3 in inflammatory bowel disease as well as their association with viral infections and evaluated different antagonists for the treatment of IBD., Competing Interests: The authors declare that they have no conflict of interest., (©2021 RIGLD, Research Institute for Gastroenterology and Liver Diseases.)

Emerging evidence suggest association of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with the development of many liver abnormalities. The overarching aim of this study was therefore to assess the available evidence on the clinical effects of SARS-CoV-2 on the profiles of liver chemistries and coagulation in COVID-19 diagnosed patients. We considered all study designs including epidemiological and observational that reported liver function test abnormalities in patients confirmed with SARS-CoV-2 infection. Medline, Embase databases and Google Scholar as well as relevant reviews were searched to identify appropriate studies from inception to 31st of August 2020. We calculated the pooled mean with 95% confidence intervals (95% CI) through a random-effect model meta-analysis. A total of 35 studies with 10,692 participants were considered for the review from which 23 studies with sufficient quantitative data were included in the meta-analysis. The pooled mean for liver enzymes and coagulation parameters did not significantly change in patients diagnosed with COVID-19 and remained within normal range. Notwithstanding potential bias from confounding factors in interpretation of data in this review, findings from the observational studies and case reports suggest that COVID-19 does not appear to have a significant impact on the transaminases or total bilirubin levels of patients with confirmed SARS-CoV-2 infection. Further controlled studies and larger sample size observational studies are needed with adequate reporting of other liver function parameters are warranted.

Mitochondrial dysfunction and neurodegeneration underlie movement disorders such as Parkinson's disease, Huntington's disease and Manganism among others. As a corollary, inhibition of mitochondrial complex I (CI) and complex II (CII) by toxins 1-methyl-4-phenylpyridinium (MPP + ) and 3-nitropropionic acid (3-NPA) respectively, induced degenerative changes noted in such neurodegenerative diseases. We aimed to unravel the down-stream pathways associated with CII inhibition and compared with CI inhibition and the Manganese (Mn) neurotoxicity. Genome-wide transcriptomics of N27 neuronal cells exposed to 3-NPA, compared with MPP + and Mn revealed varied transcriptomic profile. Along with mitochondrial and synaptic pathways, Autophagy was the predominant pathway differentially regulated in the 3-NPA model with implications for neuronal survival. This pathway was unique to 3-NPA, as substantiated by in silico modelling of the three toxins. Morphological and biochemical validation of autophagy markers in the cell model of 3-NPA revealed incomplete autophagy mediated by mechanistic Target of Rapamycin Complex 2 (mTORC2) pathway. Interestingly, Brain Derived Neurotrophic Factor (BDNF), which was elevated in the 3-NPA model could confer neuroprotection against 3-NPA. We propose that, different downstream events are activated upon neurotoxin-dependent CII inhibition compared to other neurotoxins, with implications for movement disorders and regulation of autophagy could potentially offer neuroprotection.

Organic anion transporter 1 (OAT1/SLC22A6) is a drug transporter with numerous xenobiotic and endogenous substrates. The Remote Sensing and Signaling Theory suggests that drug transporters with compatible ligand preferences can play a role in "organ crosstalk," mediating overall organismal communication. Other drug transporters are well known to transport lipids, but surprisingly little is known about the role of OAT1 in lipid metabolism. To explore this subject, we constructed a genome-scale metabolic model using omics data from the Oat1 knockout mouse. The model implicated OAT1 in the regulation of many classes of lipids, including fatty acids, bile acids, and prostaglandins. Accordingly, serum metabolomics of Oat1 knockout mice revealed increased polyunsaturated fatty acids, diacylglycerols, and long-chain fatty acids and decreased ceramides and bile acids when compared with wildtype controls. Some aged knockout mice also displayed increased lipid droplets in the liver when compared with wildtype mice. Chemoinformatics and machine learning analyses of these altered lipids defined molecular properties that form the structural basis for lipid-transporter interactions, including the number of rings, positive charge/volume, and complexity of the lipids. Finally, we obtained targeted serum metabolomics data after short-term treatment of rodents with the OAT-inhibiting drug probenecid to identify potential drug-metabolite interactions. The treatment resulted in alterations in eicosanoids and fatty acids, further supporting our metabolic reconstruction predictions. Consistent with the Remote Sensing and Signaling Theory, the data support a role of OAT1 in systemic lipid metabolism., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Unretrievable foreign bodies are associated with high morbidity and mortality. While the majority of reported cases involve the venous circulation, intra-arterial foreign body displacement have the potential to migrate more distally with a higher risk for dissection and hemorrhagic complications during retrieval. As the number of intravascular procedures continues to increase, there is also likely to be a concomittant increase in the number of retrieval procedures, particular for fractured catheters and sheaths. Although snaring is frequently the traditional, 'go-to' method for retrieval, there are inherent risks of further dislodgement or fracture., Case Report: We describe a case that involves retrieval of a fractured sheath that originated in the common femoral artery but migrated into the popliteal artery. Different retrieval approaches were employed, however ultimately balloon assisted, over-the-wire retrieval was the successful approach., Conclusions: We anticipate that over-the-wire, inline-retrieval approaches will continue to grow in popularity and use, particularly with respect to manipulation within the arterial circulation.

Understanding the mechanisms for cellular aging is a fundamental question in biology. Normal red blood cells (RBCs) survive for approximately 100 days, and their survival is likely limited by functional decline secondary to cumulative damage to cell constituents, which may be reflected in altered metabolic capabilities. To investigate metabolic changes during in vivo RBC aging, labeled cell populations were purified at intervals and assessed for abundance of metabolic intermediates using mass spectrometry. A total of 167 metabolites were profiled and quantified from cell populations of defined ages. Older RBCs maintained ATP and redox charge states at the cost of altered activity of enzymatic pathways. Time-dependent changes were identified in metabolites related to maintenance of the redox state and membrane structure. These findings illuminate the differential metabolic pathway usage associated with normal cellular aging and identify potential biomarkers to determine average RBC age and rates of RBC turnover from a single blood sample., Competing Interests: The authors declare no competing interests., (© 2020 The Author(s).)

Prostate cancer is a major cause of death among men worldwide. Recent preclinical evidence implicates cannabinoids as powerful regulators of cell growth and differentiation, as well as potential anti-cancer agents. The aim of this review was to evaluate the effect of cannabinoids on in vivo prostate cancer models. The databases searched included PubMed, Embase, Scopus, and Web of Science from inception to August 2020. Articles reporting on the effect of cannabinoids on prostate cancer were deemed eligible. We identified six studies that were all found to be based on in vivo/xenograft animal models. Results: In PC3 and DU145 xenografts, WIN55,212-2 reduced cell proliferation in a dose-dependent manner. Furthermore, in LNCaP xenografts, WIN55,212-2 reduced cell proliferation by 66-69%. PM49, which is a synthetic cannabinoid quinone, was also found to result in a significant inhibition of tumor growth of up to 90% in xenograft models of LNCaP and 40% in xenograft models of PC3 cells, respectively. All studies have reported that the treatment of prostate cancers in in vivo/xenograft models with various cannabinoids decreased the size of the tumor, the outcomes of which depended on the dose and length of treatment. Within the limitation of these identified studies, cannabinoids were shown to reduce the size of prostate cancer tumors in animal models. However, further well-designed and controlled animal studies are warranted to confirm these findings.

Melanoma is the fourth most common type of cancer diagnosed in Australians after breast, prostate, and colorectal cancers. While there has been substantial progress in the treatment of cancer in general, malignant melanoma, in particular, is resistant to existing medical therapies requiring an urgent need to develop effective treatments with lesser side effects. Several studies have shown that "cannabinoids", the major compounds of the Cannabis sativa L. plant, can reduce cell proliferation and induce apoptosis in melanoma cells. Despite prohibited use of Cannabis in most parts of the world, in recent years there have been renewed interests in exploiting the beneficial health effects of the Cannabis plant-derived compounds. Therefore, the aim of this study was in the first instance to review the evidence from in vivo studies on the effects of cannabinoids on melanoma. Systematic searches were carried out in PubMed, Embase, Scopus, and ProQuest Central databases for relevant articles published from inception. From a total of 622 potential studies, six in vivo studies assessing the use of cannabinoids for treatment of melanoma were deemed eligible for the final analysis. The findings revealed cannabinoids, individually or combined, reduced tumor growth and promoted apoptosis and autophagy in melanoma cells. Further preclinical and animal studies are required to determine the underlying mechanisms of cannabinoids-mediated inhibition of cancer-signaling pathways. Well-structured, randomized clinical studies on cannabinoid use in melanoma patients would also be required prior to cannabinoids becoming a viable and recognized therapeutic option for melanoma treatment in patients.

Background: During drilling of bone, which is common in clinical surgeries, heat generation increases local temperature in the drilling site. Transmission of excessive heat to the surrounding bone tissue can cause thermal osteonecrosis. Consequently, it may lead to failure of implants and fixation screws or delay in healing process. Using cooling is a method for limiting temperature elevation., Materials and Methods: In this study, through comparing three conditions of drilling without cooling, external cooling with normal saline, and external cooling with OpSite spray, the efficiency of OpSite as coolant is studied. In this regard, 2 drill bit diameters, 3 drilling speeds, and 3 drilling feed-rates are considered as drilling variables in the experiments., Results: For the whole experiments, while cooling with normal saline resulted in lower maximum temperatures than without cooling condition, OpSite had even better results and limited the temperature elevation during drilling of bone efficiently., Conclusion: OpSite spray, which has lower infection risks than normal saline on one hand and lower maximum temperature rise with all combinations of drilling parameters on the other hand, can be considered in clinical surgeries for cooling applications.

Background: Accidental ingestion or consumption of supra-therapeutic doses of methadone can result in neurological sequelae in humans. We aimed to determine the neurological deficits of methadone-poisoned patients admitted to a referral poisoning hospital using brain magnetic resonance (MR) and diffusion weighted (DW) imaging., Methods: In this retrospective study, brain MRIs of the patients admitted to our referral center due to methadone intoxication were reviewed. Methadone intoxication was confirmed based on history, congruent clinical presentation, and confirmatory urine analysis. Each patient had an MRI with Echo planar T1, T2, FLAIR, and DWI and apparent deficient coefficient (ADC) sequences without contrast media. Abnormalities were recorded and categorized based on their anatomic location and sequence., Results: Ten patients with abnormal MRI findings were identified. Eight had acute- and two had delayed-onset encephalopathy. Imaging findings included bilateral confluent or patchy T2 and FLAIR high signal intensity in cerebral white matter, cerebellar involvement, and bilateral occipito-parietal cortex diffusion restriction in DWI. Internal capsule involvement was identified in two patients while abnormality in globus pallidus and head of caudate nuclei were reported in another. Bilateral cerebral symmetrical confluent white matter signal abnormality with sparing of subcortical U-fibers on T2 and FLAIR sequences were observed in both patients with delayed-onset encephalopathy., Conclusions: Acute- and delayed-onset encephalopathies are two rare adverse events detected in methadone-intoxicated patients. Brain MRI findings can be helpful in detection of methadone-induced encephalopathy.

Introduction: On entry into the clinical environment, nursing students are confronted with many challenges. It is a common problem throughout the world, including Iran. Although many studies have been conducted on the problems of nursing students in the clinical environment, limited information is available on nursing students' experiences of the clinical learning environment and the way they respond to these experiences. Identifying nursing students' experiences is essential to develop interventions to reduce challenges., Objective: This study aimed to explore nursing students' experiences in a clinical learning environment and the way they responded to these experiences., Design: The present study was conducted based on the qualitative research design of the grounded theory methodology., Setting: This study was conducted at schools of nursing in academic settings in Iran., Participants: The participants included 19 nursing students, 4 nursing instructors and 3 clinical nurses., Methods: The data were collected using semistructured interviews, field notes and observation, and were analysed using Strauss and Corbin's approach., Results: Students, as a result of the inadequacy of the educational environment, were faced with 'confusion of identity', stating this as their main concern. When confronted with this concern, they employed specific strategies, some of which prevented them from getting into unpleasant conditions. These strategies did not help students solve their problems and also prevented them from accepting their professional roles and responsibilities. Conversely, some other strategies led them to advanced professional development and enabled them to accept their role and the clinical environment., Conclusion: According to the results of this study, educational policymakers should focus on improving the clinical environment. Identifying professional models and increasing their influence on management, education and clinical education, as well as teaching positive and constructive strategies, will promote positive strategies in coping with inadequate educational contexts. This is necessary for the professional development of nursing students., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Concurrent advancements in imaging and genomic biomarkers have created opportunities to identify non-invasive imaging surrogates of molecular phenotypes. In order to develop such imaging surrogates radiomics and radiogenomics/imaging genomics will be necessary; there has been consistent progress in these fields for primary liver cancers. In this article we evaluate the current status of the field specifically with regards to hepatocellular carcinoma and intrahepatic cholangiocarcinoma, highlighting some of the up and coming results that were presented at the annual Radiological Society of North America Conference in 2017. There are an increasing number of studies in this area with a bias towards quantitative feature measurement, which is expected to benefit reproducibility of the findings and portends well for the future development of biomarkers for diagnosis, prognosis, and treatment response assessment. We review some of the advancements and look forward to some of the exciting future applications that are anticipated as the field develops.

Competing Interests: Nazila Jamshidi was the editorial registrar for Australian Prescriber in 2018.

Aim: to describe trends in baclofen reports to Australia's largest Poisons Information Centre (PIC) and present a case series detailing severity of overdoses., Short Summary: PBS data demonstrates baclofen use is increasing in Australia, while calls to NSWPIC illustrate an increase in number of exposures associated with toxicity. Baclofen toxicity may require prolonged intensive care admission. To minimize harms associated, especially with off-label baclofen prescribing for AUD, prescribers should pay careful attention to psychiatric comorbidities, and closely monitor treatment and dispensing., Methods: this is a retrospective observational study of baclofen overdoses reported to New South Wales PIC (NSWPIC) from January 1 2004 to 31 December 2016. In addition, referrals to a metropolitan toxicology service relating to baclofen toxicity from 2014 to 2017 were analysed. The number of Pharmaceutical Benefit Scheme (PBS) claims for baclofen were also reviewed., Results: during the 13-year study period, 403 cases of baclofen toxicity were reported to NSWPIC. There was a 230% increase in annual exposures over this period, 71% of patients were symptomatic, with 77% requiring hospitalization. Coingestants were reported in 53%, with 57% being psychoactive medications (including alcohol). An increase in number of baclofen dispensing episodes was also noted. From the five cases of deliberate self-harm reported to the metropolitan toxicology service, three obtained baclofen for management of alcohol use disorder (AUD) and required prolonged treatment in the intensive care unit (ICU)., Conclusions: NSWPIC data shows an increase in number of calls regarding intentional baclofen exposures in parallel with increase the number of baclofen PBS claims. These closely parallel the increase in dispensing of baclofen since 2008. Case studies presented reinforce the severity of baclofen toxicity. Together, they demonstrate the potential risk of harm of baclofen prescribing, and the greater need for caution. Baclofen should be considered carefully in patients high risk of overdose or be used only in specialist services with close monitoring.

Background and Aims: There is little information with regards to the efficacy of baclofen among alcohol patients concurrently receiving antidepressants (AD). The present study aimed to conduct a secondary analysis of the moderating role of antidepressants in the BacALD trial which evaluated the efficacy of baclofen to reduce alcohol consumption in alcohol dependent patients. Methods: Alcohol dependent patients ( N = 104) were treated for 12 weeks with 30 mg/day of baclofen (21 = AD and 15 = no AD), 75 mg baclofen (19 = AD and 16 = no AD) or placebo (17 = AD and 16 = no AD). Patients were included in the trial if they were concurrently receiving anti-depressants upon enrolment but were excluded if they commenced antidepressants 2 months prior to enrolment. Patients were also excluded in the case of concurrent psychotropic medications, active major mental disorder such as bipolar disorder, psychosis, or history of suicide attempt. Predefined primary outcomes included time to lapse (any drinking), relapse (>5 drinks per day in men and >4 in women). Other outcomes included drinks per drinking day, number of heavy drinking days, and percentage days abstinent and frequency of adverse events. Results: For the number of days to first lapse, there was a trend of significance for the interaction baclofen × AD (Log Rank: χ 2 = 2.98, P = 0.08, OR: 0.41, 95%CI: 0.15-1.12). For the number of days to relapse, there was a trend of significance for the interaction of baclofen × AD (Log Rank: χ 2 = 3.72, P = 0.05, OR: 3.40, 95%CI: 1.01-11.46). Placing significant baseline variables into the models as covariates (tobacco, ALD) weakened these interactions ( P 's > 0.15). There were no significant effects of ADs on the frequency of adverse events reported ( P 's > 0.19). Conclusion: Concurrent receipt of ADs commenced more than 2 months prior to baclofen treatment did not negatively impact on drinking outcomes. Future research examining the interaction between commencing ADs during baclofen treatment on alcohol dependent patients is required. Trial Registration: ClinicalTrials.gov, NCT01711125, https://clinicaltrials.gov/ct2/show/NCT01711125.

Several antimalarial drugs exist, but differences between life cycle stages among malaria species pose challenges for developing more effective therapies. To understand the diversity among stages and species, we reconstructed genome-scale metabolic models (GeMMs) of metabolism for five life cycle stages and five species of Plasmodium spanning the blood, transmission, and mosquito stages. The stage-specific models of Plasmodium falciparum uncovered stage-dependent changes in central carbon metabolism and predicted potential targets that could affect several life cycle stages. The species-specific models further highlight differences between experimental animal models and the human-infecting species. Comparisons between human- and rodent-infecting species revealed differences in thiamine (vitamin B1), choline, and pantothenate (vitamin B5) metabolism. Thus, we show that genome-scale analysis of multiple stages and species of Plasmodium can prioritize potential drug targets that could be both anti-malarials and transmission blocking agents, in addition to guiding translation from non-human experimental disease models.

Background: The traction bed is a noninvasive device for treating lower back pain caused by herniated intervertebral discs. In this study, we investigated the impact of the traction bed on the lower back as a means of increasing the disc height and creating a gap between facet joints., Methods: Computed tomography (CT) images were obtained from a female volunteer and a three-dimensional (3D) model was created using software package MIMICs 17.0. Afterwards, the 3D model was analyzed in an analytical software (Abaqus 6.14). The study was conducted under the following traction loads: 25%, 45%, 55%, and 85% of the whole body weight in different angles., Results: Results indicated that the loading angle in the L3-4 area had 36.8%, 57.4%, 55.32%, 49.8%, and 52.15% effect on the anterior longitudinal ligament, posterior longitudinal ligament, intertransverse ligament, interspinous ligament, and supraspinous ligament, respectively. The respective values for the L4-5 area were 32.3%, 10.6%, 53.4%, 56.58%, and 57.35%. Also, the body weight had 63.2%, 42.6%, 44.68%, 50.2%, and 47.85% effect on the anterior longitudinal ligament, posterior longitudinal ligament, intertransverse ligament, interspinous ligament, and supraspinous ligament, respectively. The respective values for the L4-5 area were 67.7%, 89.4%, 46.6%, 43.42% and 42.65%. The authenticity of results was checked by comparing with the experimental data., Conclusions: The results show that traction beds are highly effective for disc movement and lower back pain relief. Also, an optimal angle for traction can be obtained in a 3D model analysis using CT or magnetic resonance imaging images. The optimal angle would be different for different patients and thus should be determined based on the decreased height of the intervertebral disc, weight and height of patients., Competing Interests: CONFLICT OF INTEREST: No potential conflict of interest relevant to this article was reported.

Aim: To reduce post treatments of kyphoplasty, as a common treatment for osteoporotic vertebrae., Methods: This study suggests a new method for treating vertebrae by setting the hexagonal porous structure instead of the rigid bone cement mass in the kyphoplasty (KP). The KP procedure was performed on the fresh ovine vertebra of the level L1. Micro finite element modeling was performed based on micro computed tomography of ovine trabecular cube. The hexagonal porous structure was set on one cube instead of the bone cement mass. For the implant designing, two geometrical parameters were considered: Spacing diameter and thickness., Results: The results of micro finite element analyses indicated the improvement in the mechanical behavior of the vertebra treated by the hexagonal porous structures, as compared to those treated by vertebroplasty (VP) and KP under static loading. The improvement in the mechanical behavior of the vertebra, was observed as 54% decrease in the amount of maximum Von Misses stress (improvement of stress distribution), in trabecular cube with embedded hexagonal structure, as compared to VP and KP. This is comparable to the results of the experimental study already performed; it was shown that the improvement of mechanical behavior of the vertebra was observed as: 83% increase in the range of displacements before getting to the ultimate strength (increasing the toughness) after setting hexagonal pearls inside vertebrae. Both the material and geometry of implant influenced the amount of Von Mises stress in the structure., Conclusion: The new proposed method can be offered as a substitute for the KP. The implant geometry had a more obvious effect on the amount of Von Mises stress, as compared to the implant material., Competing Interests: Conflict-of-interest statement: To the best of our knowledge no conflict of interest exists.

The Warburg effect (WE), or aerobic glycolysis, is commonly recognized as a hallmark of cancer and has been extensively studied for potential anti-cancer therapeutics development. Beyond cancer, the WE plays an important role in many other cell types involved in immunity, angiogenesis, pluripotency, and infection by pathogens (e.g., malaria). Here, we review the WE in non-cancerous context as a "hallmark of rapid proliferation." We observe that the WE operates in rapidly dividing cells in normal and pathological states that are triggered by internal and external cues. Aerobic glycolysis is also the preferred metabolic program in the cases when robust transient responses are needed. We aim to draw attention to the potential of computational modeling approaches in systematic characterization of common metabolic features beyond the WE across physiological and pathological conditions. Identification of metabolic commonalities across various diseases may lead to successful repurposing of drugs and biomarkers.