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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.)

Aims: To compare a low-dosing protocol to standard practice for methadone-buprenorphine transfers., Methods: We undertook a nonrandomized open-label clinical trial across 8 sites from NSW, Australia. Participants prescribed methadone wishing to transfer to buprenorphine could either choose or be randomized to a low-dose transfer or standard care transfer as per NSW health guidelines. The low-dose protocol started at 0.2 mg BD and increased to 16 mg on day 6, with flexible dosing thereafter. The primary outcome was continuation of buprenorphine 1 week post-transfer. Binary logistic regression was used to access the primary outcome with demographic differences between the groups included as covariates., Results: There were 117 participants who commenced the study, 101 in the low-dose arm and 16 in standard care. Mean methadone dose was 82 mg in the low-dose arm and 46 mg in standard care. The primary outcome was met by 81 participants in the low-dose arm (80%) and 13 participants in standard care (81%). There was no significant between-arm difference in the odds of the primary outcome (OR = 2.22; 95% CI: 0.45-10.91; P = 0.327). Four participants (4%) in the low-dose arm experienced precipitated withdrawal against 1 (6%) in standard care. Higher methadone dose decreased the odds of successful transfer by 20% (OR = 0.8 per 10 mg methadone; 95% CI: 0.7-0.99; P = 0.04). Withdrawal scores between the 2 arms were similar., Conclusions: We were unable to detect a difference between low dosing and standard care for methadone to buprenorphine transfers. Increasing methadone dose was a predictor of success; setting (ambulatory or inpatient) was not., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 American Society of Addiction Medicine.)

Despite technological advances and readily available point of care test (POCT) devices with rapid turn-around results for respiratory tract infection (RTI) management, their adoption in primary care remains low. This paper summarises the challenges and facilitators of POCT implementation for RTIs in primary care settings in high-income countries. The review of 28 studies identified by systematic searches of electronic databases improves our understanding of the current state and will help guide the design and implementation of strategies to improve widespread POCT adoption. To effectively implement respiratory POCT in primary care, it is crucial to address several key challenges. These include ensuring the availability of resources to alleviate time pressures and costs, enhancing training, increasing quality control, improving device feasibility, and managing patient expectations. In doing so, diagnostic POCTs can contribute to an accurate, rapid, and evidence-based diagnosis of RTIs to reduce antimicrobial use and improve antimicrobial stewardship and patient outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

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.)

Objective: To evaluate the feasibility of developing a computer vision algorithm that uses preoperative computed tomography (CT) scans to predict superior mesenteric artery (SMA) margin status in patients undergoing Whipple for pancreatic ductal adenocarcinoma (PDAC), and to compare algorithm performance to that of expert abdominal radiologists and surgical oncologists., Summary Background Data: Complete surgical resection is the only chance to achieve a cure for PDAC; however, current modalities to predict vascular invasion have limited accuracy., Methods: Adult patients with PDAC who underwent Whipple and had preoperative contrast-enhanced CT scans were included (2010-2022). The SMA was manually annotated on the CT scans, and we trained a U-Net algorithm for SMA segmentation and a ResNet50 algorithm for predicting SMA margin status. Radiologists and surgeons reviewed the scans in a blinded fashion. SMA margin status per pathology reports was the reference., Results: Two hundred patients were included. Forty patients (20%) had a positive SMA margin. For the segmentation task, the U-Net model achieved a Dice Similarity Coefficient of 0.90. For the classification task, all readers demonstrated limited sensitivity, although the algorithm had the highest sensitivity at 0.43 (versus 0.23 and 0.36 for the radiologists and surgeons, respectively). Specificity was universally excellent, with the radiologist and algorithm demonstrating the highest specificity at 0.94. Finally, the accuracy of the algorithm was 0.85 versus 0.80 and 0.76 for the radiologists and surgeons, respectively., Conclusions: We demonstrated the feasibility of developing a computer vision algorithm to predict SMA margin status using preoperative CT scans, highlighting its potential to augment the prediction of vascular involvement., Competing Interests: Conflicts of Interest: None, (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: In overdose, gamma-hydroxybutyrate (GHB) and its precursors can cause decreased levels of consciousness, coma and death. Here, we aim to describe reported exposure to GHB at four EDs in Sydney, New South Wales (NSW), Australia., Methods: We searched the ED databases of four Sydney metropolitan hospitals for presentations relating to GHB exposure between 2012 and 2021. We calculated annual number of presentations stratified by hospital, age, sex, mode of arrival and triage category., Results: A total of 3510 GHB-related presentations to ED were recorded across the four hospitals. Data for all hospitals were only available from 2015 onwards and between 2015 and 2021; there was a 114% increase in annual presentations (from 228 to 487). Males represented 68.7% of all presentations and the median age was 31 years (range 16-74 years). There was an increase in the proportion of female presentations between 2012 and 2021 (from 27.9% to 37.9%) along with the severity of presentation over the same period, with the proportion of presentations with a triage category 1 increasing from 19.7% to 34.5%., Conclusions: Increases in recorded absolute number and severity of GHB-related presentations to Sydney EDs are a major public health concern. There may also be shifts in the demographics of those with GHB-related presentations. Renewed efforts are required to understand the drivers of these increases to optimally target harm reduction approaches., (© 2024 The Authors. Emergency Medicine Australasia published by John Wiley & Sons Australia, Ltd on behalf of Australasian College for Emergency Medicine.)

Renewable energy has gained significant attention due to the growing concern for environmental sustainability and the high reliance on energy imports in European countries. In this study, we use a two- stage approach to assess renewable energy efficiency (REEF) of European countries. Initially, we employ the data envelopment analysis (DEA) method to quantify the efficiency of renewable energy. Subsequently, we investigate the factors influencing REEF between 2005 and 2020. Our findings reveal a generally high level of REEF across European countries, but some countries have become worse in this regard (e.g., France, Ukraine, Russia, Belgium, Germany, Norway, and Serbia). In order to find the causes of these changes, we considered the explanatory variables of gross domestic product (GDP), energy price, renewable energy consumption, information and communications technology (ICT), and industrial value added in a spatial system generalized method of moments (spatial SYS-GMM) model. The findings provide confirmation of the spatial spillover effects of REEF within European countries. The strongest positive effect is related to energy prices. In simpler terms, as energy prices rise, the efficiency of renewable energy has increased in European countries. Additionally, ICT and renewable energy consumption have positive impacts, too. But GDP and industrial value added, have decreasing effects. Based on these findings, we put forth several policy suggestions aimed at enhancing the efficiency of renewable energy in European countries., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: There have been no well-controlled and well-powered comparative trials of topiramate with other pharmacotherapies for alcohol use disorder (AUD), such as naltrexone. Moreover, the literature is mixed on the effects of two polymorphisms-rs2832407 (in GRIK1 ) and rs1799971 (in OPRM1 )-on response to topiramate and naltrexone, respectively. The authors sought to examine the comparative effectiveness of topiramate and naltrexone in improving outcomes in AUD and to examine the role of the rs2832407 and rs1799971 polymorphisms, respectively, on response to these medications., Methods: In a 12-week, double-blind, placebo-controlled, randomized, multisite, genotype-stratified (rs2832407 and rs1799971) clinical trial comparing topiramate and naltrexone in treating AUD, 147 patients with AUD were randomly assigned to treatment with topiramate or naltrexone, stratified by genotype (rs2832407*CC and *AC/AA genotypes and rs1799971*AA and *AG/GG genotypes). The predefined primary outcome was number of heavy drinking days per week. Predefined secondary outcomes included standard drinks per drinking day per week, body mass index (BMI), craving, markers of liver injury, mood, and adverse events., Results: For the number of heavy drinking days per week, there was a near-significant time-by-treatment interaction. For the number of standard drinks per drinking day per week, there was a significant time-by-treatment interaction, which favored topiramate. There were significant time-by-treatment effects, with greater reductions observed with topiramate than naltrexone for BMI, craving, and gamma-glutamyltransferase level. Withdrawal due to side effects occurred in 8% and 5% of the topiramate and naltrexone groups, respectively. Neither polymorphism showed an effect on treatment response., Conclusions: Topiramate is at least as effective and safe as the first-line medication, naltrexone, in reducing heavy alcohol consumption, and superior in reducing some clinical outcomes. Neither rs2832407 nor rs1799971 had effects on topiramate and naltrexone treatments, respectively., Competing Interests: Dr. Kranzler has served on advisory boards for Dicerna Pharmaceuticals, Sophrosyne Pharmaceuticals, Entheon Pharmaceuticals, and Clearmind Medicine and as a consultant for Sobrera Pharmaceuticals; he has received research funding and medication supplies for an investigator-initiated study from Alkermes; he is a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which was supported in the past 3 years by Alkermes, Dicerna, Ethypharm, Lundbeck, Mitsubishi, Otsuka, and Pear Therapeutics; and he is a holder of a patent for genotype-guided dosing of opioid agonists (U.S. 10,900,082). Dr. Tremonti has served as a speaker for Invidior. Dr. Haber has received research funding from Invidior. The other authors report no financial relationships with commercial interests.

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.)

In vitro cell models have undergone a shift from 2D models on glass slides to 3D models that better reflect the native 3D microenvironment. 3D bioprinting promises to progress the field by allowing the high-throughput production of reproducible cell-laden structures with high fidelity. The current stiffness range of printable matrices surrounding the cells that mimic the extracellular matrix environment remains limited. The work presented herein aims to expand the range of stiffnesses by utilizing a four-armed polyethylene glycol with maleimide-functionalized arms. The complementary cross-linkers comprised a matrix metalloprotease-degradable peptide and a four-armed thiolated polymer which were adjusted in ratio to tune the stiffness. The modularity of this system allows for a simple method of controlling stiffness and the addition of biological motifs. The application of this system in drop-on-demand printing is validated using MCF-7 cells, which were monitored for viability and proliferation. This study shows the potential of this system for the high-throughput investigation of the effects of stiffness and biological motif compositions in relation to cell behaviors.

Background: There is growing concern, globally, regarding use of nitrous oxide (N 2 O) for intoxication purposes. This paper aims to examine trends in: (i) past six month N 2 O use among a sample of people who use regularly use ecstasy and/or other illicit stimulants (2003-2020); (ii) volume of N 2 O-related Google searches and social media posts (2009-2020); and (iii) N 2 O-related calls to Poisons Information Centres (PIC) (2004-2020)., Methods: Data were obtained from annual interviews with sentinel samples of Australians aged ≥16 years who used ecstasy and/or other illicit stimulants ≥monthly and resided in a capital city (∼800 each year); Google search activity; social media posts; and exposure calls to four PIC., Results: Among samples of people who regularly use ecstasy and/or other illicit stimulants, past six-month N 2 O use increased 10% each year from 2009 to 2020, with the sharpest increase observed between 2015 and 2018 (25.4% p/year; 95% CI: 14.6-37.1). Frequency and quantity of N 2 O use remained stable and low. Google search probabilities increased by 1.8% each month from January 2009 and December 2019 (95% CI: 1.5-2.2), with the sharpest increase observed between July 2016 to December 2017 (6.0% p/month; 95% CI: 4.4-7.5). Social media posts increased 2.0% per month from January 2009 and December 2019 (95% CI: 1.1-3.0), with the sharpest increase observed between March and October 2017 (19.2% p/month; 95% CI: 1.7-39.7). The number of N 2 O-related calls to Australian PIC increased sixfold between 2016 (16) and 2020 (111)., Conclusions: Triangulation of various data sources indicate significant shifts in N 2 O use and harms in Australia. This includes increases in use, Google searches and social media posts, although these have plateaued in recent years, coupled with increased rates of harm. These findings correspond with evidence of a global increase in N 2 O use and harm, highlighting the need for education of both people who use N 2 O and health professionals., Competing Interests: Declaration of Competing Interest 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., (Copyright © 2023. Published by Elsevier B.V.)

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.)

Evidence shows that the European Union (EU) is a leader in using financial innovation to overcome environmental challenges and ensure sustainable development. This study explores the heterogeneous effects of financial innovations on carbon dioxide emissions (CO2) due to their destructive effects in the context of the EU, by employing the novel Method of Moments Quantile Regression (MM-QR). The study also evaluates the environmental Kuznets hypothesis during the period of 2000-2020. We used four proxies for financial innovation; the ratio of the aggregate money supply to narrow money (M3/M1), the ratio of broad to narrow money (M2/M1), the percentage change in domestic credit to the private sector (% of GDP) and a composite index of these indices using the Principal Component Analysis technique. The findings indicate that raising three financial innovation proxies can effectively raise environmental quality. It should be noted that while M3/M1 has a stronger and negative effect on CO2 emissions in low quantiles, M2/M1 has a stronger and negative effect on CO2 emissions in high quantiles. Therefore, it is recommended that a larger amount of M2 and M3 resources be directed towards green projects for financing in countries with both high and low levels of CO2 emissions, respectively., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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).)

Introduction and Hypothesis: This study aims to develop a fluid-structural interaction (FSI) method to pinpoint the effects of pressure changes inside the bladder and their impact on the supporting structure and the urethra mobility., Methods: A physiological model of the nulliparous female pelvis, including the organs, supportive structures, and urine, was developed based on magnetic resonance images. Soft tissues with nonlinear hyperelastic material characteristics were modeled. The Navier-Stokes equations governing the fluid flow within the computational domain (urine) were solved. The urine and soft tissue interactions were simulated by the FSI method. The vesical pressure and its impact on the urethral mobility and supportive structures were investigated during the Valsalva maneuver. Moreover, the simulation results were validated by comparing with a urodynamic test and other research., Results: The results demonstrated that the vesical pressure simulated by the FSI method could predict the nonlinear behavior of the urodynamic test pressure. The urethra retropubic bladder neck and the bladder neck-pubic bone angle changed 58.92% and -55.76%, respectively. The retropubic urethral length distance changed by -48.74%. The error compared to the statistical results of other research is < 5%., Conclusions: The total deformation and mobility of the urethra predicted by the FSI model were consistent with clinical observations in a subject. The urethra supports dependence on the tissues' mechanical properties, interaction between the tissues, and effect of urine fluid inside the bladder. This simulation effectively depicts the patterns of urethra mobility, which provides a better understanding of the behavior of the pelvic floor., (© 2022. The International Urogynecological Association.)

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.)

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.)

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).)

Menisci are fibrocartilaginous structures in the knee joint with an inadequate regenerative capacity, which causes low healing potential and further leads to osteoarthritis. Recently, three-dimensional (3D) printing techniques and ultrasound treatment have gained plenty of attention for meniscus tissue engineering. The present study investigates the effectiveness of low-intensity pulsed ultrasound stimulations (LIPUS) on the proliferation, viability, morphology, and gene expression of the chondrocytes seeded on 3D printed polyurethane scaffolds dip-coated with gellan gum, hyaluronic acid, and glucosamine. LIPUS stimulation was performed at 100, 200, and 300 mW/cm 2 intensities for 20 min/day. A faster gap closure (78.08 ± 2.56%) in the migration scratch assay was observed in the 200 mW/cm 2 group after 24 h. Also, inverted microscopic and scanning electron microscopic images showed no cell morphology changes during LIPUS exposure at different intensities. The 3D cultured chondrocytes under LIPUS treatment revealed a promotion in cell proliferation rate and viability as the intensity doses increased. Additionally, LIPUS could stimulate chondrocytes to overexpress the aggrecan and collagen II genes and improve their chondrogenic phenotype. This study recommends that the combination of LIPUS treatment and 3D hybrid scaffolds can be considered as a valuable treatment for meniscus regeneration based on our in vitro data., (© 2022 John Wiley & Sons Ltd.)

Introduction: Barium poisoning is rare but potentially severe. We describe a case of acute barium carbonate poisoning with cardiac arrest, managed with intravenous potassium, dialysis and endoscopic removal of retained ceramic glazes., Case Report: A 38-year-old woman presented with vomiting 90 min after ingesting 3 cups of barium and strontium carbonate. Initial bloods noted potassium 2.8 mmol/L and creatinine 53 μmol/L. Electrocardiogram demonstrated prolonged corrected QT interval 585msec. Initial management included intravenous potassium. Four hours post-ingestion she developed proximal muscle weakness in upper limbs with a potassium of 2.2 mmol/L. At 15 h post-ingestion she developed profound muscle weakness, polymorphic ventricular tachycardia and cardiac arrest. Treatment included defibrillation, endotracheal intubation and continuous veno-venous haemodialysis (CVVHD) for metabolic derangement and enhanced elimination of barium. Chest X-ray 17 h post-ingestion demonstrated a large radio-opaque mass in the stomach, thought to be the ceramic glaze. Endoscopy removed the retained material 41 h post-ingestion. She was extubated 58 h post-ingestion and CVVHD was ceased on day 3. Serum creatinine peaked at 348 μmol/L on day 7, but normalised by discharge. Biphasic barium concentrations were noted, notably 94 μmol/L on admission, 195 μmol/L at 16 h, 95 μmol/L at 20 h, and 193 μmol/L at 30 h post-ingestion., Conclusion: In barium poisoning with hypokalaemia, prompt potassium supplementation is required but rebound hyperkalaemia can occur. Endoscopic removal of ceramic glazes may be useful more than 12 h post-ingestion. Consider extracorporeal methods to enhance barium elimination in severe cases.

The article focuses on the cytotoxic activity and phytochemical composition of Artemisia biennis essential oils at different growth stages. Topics include the analysis of chemical constituents through gas chromatography-mass spectrometry, the evaluation of cytotoxic effects on various cell lines, and the influence of growth stages on essential oil yield and bioactivity.

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.

The meniscus has inadequate intrinsic regenerative capacity and its damage can lead to degeneration of articular cartilage. Meniscus tissue engineering aims to restore an injured meniscus followed by returning its normal function through bioengineered scaffolds. In the present study, the structural and biological properties of 3D-printed polyurethane (PU) scaffolds dip-coated with gellan gum (GG), hyaluronic acid (HA), and glucosamine (GA) were investigated. The optimum concentration of GG was 3% (w/v) with maintaining porosity at 88.1%. The surface coating of GG-HA-GA onto the PU scaffolds increased the compression modulus from 30.30 kPa to 59.10 kPa, the water uptake ratio from 27.33% to 60.80%, degradation rate from 5.18% to 8.84%, whereas the contact angle was reduced from 104.8° to 59.3°. MTT assay, acridine orange/ethidium bromide (AO/EB) fluorescent staining, and SEM were adopted to assess the behavior of the seeded chondrocytes on scaffolds, and it was found that the ternary surface coating stimulated the cell proliferation, viability, and adhesion. Moreover, the coated scaffolds showed higher expression levels of collagen II and aggrecan genes at day 7 compared to the control groups. Therefore, the fabricated PU-3% (w/v) GG-HA-GA scaffold can be considered as a promising scaffold for meniscus tissue engineering., (Copyright © 2022. Published by Elsevier B.V.)

Oral squamous cell carcinoma (OSCC) are one of the major causes of cancer morbidity and mortality worldwide. Dental microbiome has been considered as inducing agents in oral carcinogenesis. Therefore, the objective of this study was to investigate the interaction of the gene expression of the dental microbiome and OSCC patients. A cross-sectional study was designed by recruiting confirmed OSCC patients attending the University hospital during October 2018 and July 2019. The dental bacteria were isolated and confirmed by PCR technique. The expression of host and bacterial virulence genes was determined using qPCR. This study shows that 54% of T. forsythia found to be the most predominant organisms in 30 positive cases, followed by 34% of Campylobacter rectus and 29% of Prevotella intermedia. The expression of mRNA levels of bspA, csxA, fadA and interpain A in the OSCC- bacteria positive cases was significantly higher than the control group (P < 0.001). It was further found that interpainA, csxA, fadA, and bspA genes have the potential effects on the cellular gene expression in OSCC patients. A significant correlation was seen between expression patterns of CXCL10, DIAPH1, NCLN and MMP9 genes with interpain A, fadA, and bspA involved in OSCC cases The results indicate that the species specific bacteria may play a role in triggering chronic inflammation in OSCC patients. Therefore, alteration in the gene expression through the dental microbiome could be used as an alternative target in the clinical practice to detect OSCC., (Copyright © 2020. Published by Elsevier Ltd.)

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).)