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For reliable and practical application of structural health monitoring approaches in conjunction with dense sensor arrays deployed on ''smart'' systems, there is a need to develop and evaluate alternate strategies for efficient problem decomposition to rapidly and accurately determine the occurrence, location and level of small changes in the underlying structural characteristics of a monitored system based on its vibrational signature. Furthermore, there is also a need to quantify the level of uncertainties in the identified system characteristics so as to have a measurable level of confidence in the parameters to be relied on for the detection of genuine changes (damage) in the monitored system. This study presents the results of two time-domain identification techniques applied to a full-scale 17-story building, based on ambient vibration measurements. The Factor building is a steel frame structure located on the UCLA campus. This building was instrumented permanently with a dense array of 72-channel accelerometers, and the acceleration data are being continuously recorded. The first identification method used in this study is the NExT/ERA, which is regarded as a global (or centralized) approach, since it deals with the global dynamic properties of the structure. The second method is a time-domain identification technique for chain-like MDOF systems. Since in this method the identification of each link of the chain is performed independently, it is regarded as a local (or decentralized) identification methodology. For the same reason, this method can be easily adopted for large-scale sensor network architectures in which the centralized approaches are not feasible due to massive storage, power, bandwidth and computational requirements. To have a statistically meaningful results, 50 days of recorded data are considered in this study. The modal parameter and chain identification procedures are performed over time windows of 2 h each and with 50% overlap. Using the NExT/ERA method, 12 dominant modes of the building were identified. It was observed that variations in the frequency estimation are relatively small; the coefficient of variation is about 1-2% for most of the estimated modal frequencies. Chain system identification was successfully implemented using the output-only data acquired from the Factor building. Probability distributions of the estimated coefficients of displacement and velocity terms in the interstory restoring functions (which are the mass-normalized local stiffness and damping values) that were found based on the chain system identification are presented. The variability of the estimated parameters due to temperature fluctuations is investigated. It is shown that there is a strong correlation between the modal frequency variations and the temperature variations in a 24 h period. [ABSTRACT FROM AUTHOR]

Background: Among patients treated with a novel oral anticoagulant (NOAC) undergoing percutaneous coronary intervention (PCI), combination therapy with clopidogrel (ie, known as dual antithrombotic therapy [DAT]) is the treatment of choice. However, there are concerns for individuals with impaired response to clopidogrel., Objectives: The authors sought to assess the pharmacodynamic (PD) effects of clopidogrel vs low-dose ticagrelor in patients with impaired clopidogrel response assessed by the ABCD-GENE score., Methods: This was a prospective, randomized PD study of NOAC-treated patients undergoing PCI. Patients with an ABCD-GENE score ≥10 (n = 39), defined as having impaired clopidogrel response, were randomized to low-dose ticagrelor (n = 20; 60 mg twice a day) or clopidogrel (n = 19; 75 mg once a day). Patients with an ABCD-GENE score <10 (n = 42) were treated with clopidogrel (75 mg once a day; control cohort). PD assessments at baseline and 30 days post-randomization (trough and peak) were performed to assess P2Y 12 signaling (VerifyNow P2Y 12 reaction units [PRU], light transmittance aggregometry, and vasodilator-stimulated phosphoprotein); makers of thrombosis not specific to P2Y 12 signaling were also assessed. The primary endpoint was PRU (trough levels) at 30 days., Results: At 30 days, PRU levels were reduced with ticagrelor-based DAT compared with clopidogrel-based DAT at trough (23.0 [Q1-Q3: 3.0-46.0] vs 154.5 [Q1-Q3: 77.5-183.0]; P < 0.001) and peak (6.0 [Q1-Q3: 4.0-14.0] vs 129.0 [Q1-Q3: 66.0-171.0]; P < 0.001). Trough PRU levels in the control arm (104.0 [Q1-Q3: 35.0-167.0]) were higher than ticagrelor-based DAT (P = 0.005) and numerically lower than clopidogrel-based DAT (P = 0.234). Results were consistent by light transmittance aggregometry and vasodilator-stimulated phosphoprotein. Markers measuring other pathways leading to thrombus formation were largely unaffected., Conclusions: In NOAC-treated patients undergoing PCI with an ABCD-GENE score ≥10, ticagrelor-based DAT using a 60-mg, twice-a-day regimen reduced platelet P2Y 12 reactivity compared with clopidogrel-based DAT. (Tailoring P2Y12 Inhibiting Therapy in Patients Requiring Oral Anticoagulation After PCI [SWAP-AC-2]; NCT04483583)., Competing Interests: Funding Support and Author Disclosures The study was funded by institutional grants from the University of Florida. Dr Franchi has received consulting fees or honoraria from AstraZeneca; and institutional grants from PLx Pharma and the Scott R. MacKenzie Foundation. Dr Galli has received consulting fees or honoraria from Terumo, outside the present work. Dr Ajjan has received institutional research grants and honoraria/educational support/consultancy from Abbott Diabetes Care, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Menarini Pharmaceuticals, Novo Nordisk, and Roche. Dr Angiolillo has received consulting fees or honoraria from Abbott, Amgen, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, CSL Behring, Daiichi-Sankyo, Eli Lilly, Faraday, Haemonetics, Janssen, Merck, Novartis, PhaseBio, PLx Pharma, Pfizer, and Sanofi; and has received institutional research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Faraday, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, and the Scott R. MacKenzie Foundation. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Hospitalist-run procedure teams enable expedited care in the inpatient setting. However, wait times for outpatient interventional radiology (IR) are long at our institution. Our study thus aims to compare the safety and wait times between procedural teams and IR placement of outpatient temporary hemodialysis catheters (THDC) for patients undergoing Chimeric antigen receptor T-cell (CAR-T) therapy apheresis. A retrospective chart review was conducted on all patients receiving outpatient THDC for CAR-T therapy from August 2019 until November 2022. During our study period, only 7 of the central lines were placed by IR, while 75 were placed by the procedure service. The average wait time from CAR-T consenting to procedure was 8.9 days for the procedure service and 14.7 days for IR. The 30 day minor complication rate was low - 2.7% in the procedure group, and 0% in the IR group. No major complications were noted in either group., Competing Interests: Declaration of Competing Interest The authors declare no associated conflict of interest for this publication., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This prospective ex vivo and in vitro pharmacodynamic (PD)/pharmacokinetic investigation was conducted in patients with diabetes mellitus with (n = 31) and without chronic kidney disease (n = 30). PD assessments included platelet reactivity index, maximum platelet aggregation, and P2Y 12 reaction units. Ex vivo pharmacokinetic assessments included plasma levels of clopidogrel and its active metabolite. In vitro PD assessments were conducted on baseline samples incubated with escalating concentrations of clopidogrel and its active metabolite. Among patients with diabetes mellitus treated with clopidogrel, impaired renal function was associated with increased maximum platelet aggregation. This finding could be attributed partially to upregulation of the P2Y 12 activity without differences in drug absorption or metabolism. (Impact of Chronic Kidney Disease on Clopidogrel Effects in Diabetes Mellitus; NCT03774394)., Competing Interests: This study was funded by an investigator-initiated grant from the University of Florida and the Scott R. MacKenzie Foundation. The Scott R. MacKenzie Foundation had no role in the study design conception, conduct of the study, or decision to publish these results. Work by Drs Cavallari, Angiolillo, and Franchi is supported by the National Institutes of Health National Heart, Lung, and Blood Institute (1R01HL149752). Dr Franchi has received payment as an individual for consulting fee or honoraria from AstraZeneca, Bayer and Sanofi; and institutional payments for grants from PLx Pharma and The Scott R. MacKenzie Foundation. Dr Galli has received consulting fees or honoraria from Terumo, outside the present work. Dr Cavallari has received research support from Accriva Diagnostics. Dr Angiolillo has received consulting fees or honoraria from Abbott, Amgen, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, CSL Behring, Daiichi-Sankyo, Eli Lilly, Faraday, Haemonetics, Janssen, Merck, Novartis, PhaseBio, PLx Pharma, Pfizer, Sanofi, and Vectura; h and his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Faraday, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co. Merck, Novartis, and the Scott R. MacKenzie Foundation. Dr Jakubowski was an employee of Eli Lilly and Company at the time of the studies. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background:  To date, there are no data on switching to dual pathway inhibition (DPI) patients who have completed a guideline-recommended dual antiplatelet therapy (DAPT) regimen., Objectives:  To assess the feasibility of switching from DAPT to DPI and to compare the pharmacodynamic (PD) profiles of these treatments., Methods:  This was a prospective, randomized, PD study conducted in 90 patients with chronic coronary syndrome (CCS) on DAPT with aspirin (81 mg/qd) plus a P2Y 12 inhibitor (clopidogrel [75 mg/qd; n  = 30], ticagrelor [90 mg/bid; n  = 30], or prasugrel [10 mg/qd; n  = 30]). Patients in each cohort were randomized to maintain DAPT or switch to DPI (aspirin 81 mg/qd plus rivaroxaban 2.5 mg/bid). PD assessments included: VerifyNow P2Y 12 reaction units; light transmittance aggregometry following stimuli with adenosine diphosphate (ADP), tissue factor (TF), and a combination of collagen, ADP, and TF (maximum platelet aggregation %); thrombin generation (TG). Assays were performed at baseline and 30 days postrandomization., Results:  Switching from DAPT to DPI occurred without major side effects. DAPT was associated with enhanced P2Y 12 inhibition, while DPI with reduced TG. Platelet-mediated global thrombogenicity (primary endpoint) showed no differences between DAPT and DPI in the ticagrelor (14.5% [0.0-63.0] vs. 20.0% [0.0-70.0]; p  = 0.477) and prasugrel (20.0% [0.0-66.0] vs. 4.0% [0.0-70.0]; p  = 0.482), but not clopidogrel (27.0% [0.0-68.0] vs. 53.0% [0.0-81.0]; p  = 0.011), cohorts., Conclusion:  In patients with CCS, switching from different DAPT regimens to DPI was feasible, showing enhanced P2Y 12 inhibition with DAPT and reduced TG with DPI, with no differences in platelet-mediated global thrombogenicity between DPI and ticagrelor- and prasugrel-, but not clopidogrel-, based DAPT., Clinical Trial Registration:  http://www., Clinicaltrials: gov Unique Identifier: NCT04006288., Competing Interests: F.F. declares that he has received payment as an individual for consulting fee or honoraria from AstraZeneca, Bayer, and Sanofi; and institutional payments for grants from PLx Pharma and The Scott R. MacKenzie Foundation. D.J.A. declares that he has received consulting fees or honoraria from Abbott, Amgen, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, CSL Behring, Daiichi-Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, Novartis, PhaseBio, PLx Pharma, Pfizer, Sanofi and Vectura; D.J.A. also declares that his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, and the Scott R. MacKenzie Foundation. Other authors have nothing to declare., (Thieme. All rights reserved.)

Severe tricuspid regurgitation (TR) is a common pathology in the daily practice of a cardiologist. This disease entity is associated with significant morbidity and mortality if left untreated. Classically, surgical repair or replacement were the only therapeutic options present and were often not performed due to high postprocedural mortality. Transcatheter tricuspid valve intervention has emerged as a novel and effective therapeutic option for the treatment of significant TR. Several devices have been developed with different mechanisms of action. In this review, we will provide an overview of transcatheter edge-to-edge repair of TR using the TriClip device (Abbott, Santa Clara, CA, USA)., Competing Interests: Disclosures: Christophe Caussin is a proctor for Abbott and Edwards. Kamal Matli, Georges Namnoum, Soad Al-Osta, Alaa Masri, Aurelie Veugeois, Christelle Diakov and George Ghanem have no financial or non-financial relationships or activities to declare in relation to this article., (© Touch Medical Media 2024.)

Despite advancements in treating metastatic melanoma, many patients exhibit resistance to targeted therapies. Our study focuses on ATP1A1, a sodium pump subunit associated with cancer development. We aimed to assess ATP1A1 prognostic value in melanoma patients and examine the impact of its ligand, bufalin, on melanoma cell lines in vitro and in vivo. High ATP1A1 expression (IHC) correlated with reduced overall survival in melanoma patients. Resistance to BRAF inhibitor was linked to elevated ATP1A1 levels in patient biopsies (IHC, qPCR) and cell lines (Western blot, qPCR). Additionally, high ATP1A1 mRNA expression positively correlated with differentiation/pigmentation markers based on data from The Cancer Genome Atlas (TCGA) databases and Verfaillie proliferative gene signature analysis. Bufalin specifically targeted ATP1A1 in caveolae, (proximity ligation assay) and influenced Src phosphorylation (Western blot), thereby disrupting multiple signaling pathways (phosphokinase array). In vitro, bufalin induced apoptosis in melanoma cell lines by acting on ATP1A1 (siRNA experiments) and, in vivo, significantly impeded melanoma growth using a nude mouse xenograft model with continuous bufalin delivery via an osmotic pump. In conclusion, our study demonstrates that ATP1A1 could serve as a prognostic marker for patient survival and a predictive marker for response to BRAF inhibitor therapy. By targeting ATP1A1, bufalin inhibited cell proliferation, induced apoptosis in vitro, and effectively suppressed tumor development in mice. Thus, our findings strongly support ATP1A1 as a promising therapeutic target, with bufalin as a potential agent to disrupt its tumor-promoting activity., (© 2024. The Author(s).)

Background: In long-distance spaceflight, the challenges of communication delays and the impracticality of rapid evacuation necessitate the management of medical emergencies by onboard physicians. Consequently, these physicians must be proficient in tools, such as ultrasound, which has proven itself a strong diagnostic imaging tool in space. Yet, there remains a notable gap in the discourse surrounding its efficacy in handling acute medical scenarios. This scoping review aims to present an updated analysis of the evidence supporting the role of ultrasound in diagnosing acute conditions within microgravity environments., Methods: A systematic search was executed across three bibliographic databases: PubMed, EMBASE (Embase.com), and the Web of Science Core Collection. We considered articles published up to February 25, 2023, that highlighted the application of ultrasound in diagnosing acute medical conditions in either microgravity or microgravity-simulated settings. Exclusions were made for review papers, abstracts, and in-vitro studies., Results: After removing duplicates, and filtering papers by pre-determined criteria, a total of 15 articles were identified that discuss the potential use of ultrasound in managing acute medical conditions in space. The publication date of these studies ranged from 1999 to 2020. A relatively similar proportion of these studies were conducted either on the International Space Station or in parabolic flight, with one performed in supine positioning to simulate weightlessness. The included studies discuss acute pathologies, such as abdominal emergencies, decompression sickness, deep venous thrombosis, acute lung pathologies, sinusitis, musculoskeletal trauma, genitourinary emergencies, and ocular emergencies., Conclusions: While ultrasound has shown promise in addressing various acute conditions, significant knowledge gaps remain, especially in gastrointestinal, cardiac, vascular, and reproductive emergencies. As we venture further into space, expanding our medical expertise becomes vital to ensure astronaut safety and mission success., (© 2023. The Author(s).)

Background: A drug-drug interaction (DDI) may occur when transitioning from intravenous P2Y 12 inhibition with cangrelor to oral P2Y 12 inhibition with prasugrel. However, this has never been tested in patients undergoing percutaneous coronary intervention (PCI)., Objectives: This study sought to rule out a DDI when cangrelor and prasugrel are concomitantly administered in PCI patients., Methods: SWAP-6 (Switching Antiplatelet-6) was a prospective, randomized, 3-arm, open-label pharmacokinetic (PK) and pharmacodynamic (PD) study. Patients (N = 77) were randomized to 1) prasugrel only at the start of PCI, 2) cangrelor plus prasugrel concomitantly at the start of PCI, or 3) cangrelor at the start of PCI plus prasugrel at the end of infusion. Cangrelor infusion was maintained for 2 hours. PK/PD assessments were performed at baseline and 6 time points postrandomization. The primary endpoint was noninferiority in VerifyNow (Werfen) P2Y 12 reaction units measured at 4 hours after randomization between cangrelor plus prasugrel concomitantly administered vs prasugrel only. PK assessments included plasma levels of the active metabolite of prasugrel., Results: Compared with prasugrel, cangrelor further enhances P2Y 12 inhibitory effects. At 4 hours postrandomization, P2Y 12 reaction unit levels were significantly lower with prasugrel only compared to cangrelor and prasugrel concomitantly administered (least squares means difference = 130; 95% CI: 85-176), failing to meet the prespecified noninferiority margin. Findings were corroborated by multiple PD assays. The active metabolite of prasugrel levels were not affected by concomitant administration of cangrelor and were low at the end of cangrelor infusion., Conclusions: In patients undergoing PCI, concomitant administration of prasugrel with cangrelor leads to a marked increase in platelet reactivity after stopping cangrelor infusion, supporting the presence of a DDI. (Switching Antiplatelet Therapy-6 [SWAP-6]; NCT04668144)., Competing Interests: Funding Support and Author Disclosures This study was funded by an investigator-initiated grant from the Scott R. MacKenzie Foundation. The Scott R. MacKenzie Foundation had no role in the study design conception, conduct of the study, or decision to publish these results. Dr Franchi has received payment as an individual for consulting fees or honoraria from AstraZeneca, Bayer, and Sanofi; and has received institutional payments for grants from PLx Pharma and the Scott R. MacKenzie Foundation. Dr Angiolillo has received consulting fees or honoraria from Abbott, Amgen, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, CSL Behring, Daiichi Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, Novartis, PhaseBio, PLx Pharma, Pfizer, Sanofi, and Vectura; and his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, Celo-Nova, CSL Behring, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co, Merck, Novartis, and the Scott R. MacKenzie Foundation. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Elevated intracranial pressure (eICP) is a serious medical emergency that requires prompt identification and monitoring. The current gold standards of eICP detection require patient transportation, radiation, and can be invasive. Ocular ultrasound has emerged as a rapid, non-invasive, bedside tool to measure correlates of eICP. This systematic review seeks to explore the utility of ultrasound detected optic disc elevation (ODE) as an ultrasonographic finding of eICP and to study its sensitivity and specificity as a marker of eICP., Methods: This systematic review followed the preferred reporting items for systematic reviews and meta-analyses guidelines. We systematically searched PubMed, EMBASE, and Cochrane Central for English articles published before April 2023; yielding 1,919 total citations. After eliminating duplicates, and screening the records, we identified 29 articles that addressed ultrasonographically detected ODE., Results: The 29 articles included a total of 1249 adult and pediatric participants. In patients with papilledema, the mean ODE ranged between 0.6 mm and 1.2 mm. Proposed cutoff values for ODE ranged between 0.3 mm and 1 mm. The majority of studies reported a sensitivity between 70 and 90%, and specificity ranged from 69 to 100%, with a majority of studies reporting a specificity of 100%., Conclusions: ODE and ultrasonographic characteristics of the optic disc may aid in differentiating papilledema from other conditions. Further research on ODE elevation and its correlation with other ultrasonographic signs is warranted as a means to increase the diagnostic accuracy of ultrasound in the setting of eICP., (© 2023. The Author(s).)

Objectives: Undergraduate ultrasound education is becoming increasingly important, but its expansion is limited by time, space and the availability of trained faculty. In order to validate an alternative and more accessible teaching model, our aim was to assess whether combining teleguidance and peer-assisted learning to teach ultrasound is as effective as traditional in-person methods., Methods: Peer instructors taught 47 second-year medical students ocular ultrasound via either teleguidance or traditional in-person methods. Proficiency was assessed using a multiple-choice knowledge test and objective structured clinical examination (OSCE). Confidence, overall experience, and experience with a peer instructor were measured using a 5-point Likert scale. Two one-sided t-tests were used to measure equivalency between the two groups. The null hypothesis that the two groups were not different was rejected when P < 0.05., Results: The teleguidance group performed as well as the traditional in-person group in terms of knowledge change, confidence change, OSCE time and OSCE score (p = 0.011, p = 0.006, p = 0.005 and  = 0.004, respectively, indicating the two groups are statistically equivalent). The teleguidance group rated the experience highly overall (4.06/5), but less than the traditional group (4.47/5; P = 0.448, indicating statistical difference). Peer instruction was rated 4.35/5 overall., Conclusion: Peer-instructed teleguidance was equivalent to in-person instruction with respect to knowledge change, confidence gain and OSCE performance in basic ocular ultrasound., Competing Interests: None of the study authors had any financial conflict of interest, and no members of Butterfly Network Inc. had any involvement in the conception, design, implementation, analysis or drafting of this study., (© 2023 Australasian Society for Ultrasound in Medicine.)

Background: There are no studies specifically designed to rule out a drug-drug interaction (DDI) when cangrelor is used among patients who have been pretreated with ticagrelor., Objectives: This study sought to rule out a DDI among cangrelor-treated patients who have been pretreated with ticagrelor., Methods: In this prospective, randomized, double-blind, placebo-controlled, crossover, pharmacokinetic (PK) and pharmacodynamic (PD) study, patients with coronary artery disease (N = 20) were pretreated with a 180-mg ticagrelor loading dose and after 1 hour randomized to placebo or cangrelor (bolus and infusion for 2 hours). Patients crossed over after 1 to 4 weeks of washout. PK analysis included ticagrelor plasma levels and its active metabolite. PD assessments included VerifyNow P2Y 12 reaction units (PRU), light transmittance aggregometry, vasodilator-stimulated phosphoprotein, and Total Thrombus-Formation Analysis System. PK/PD assessments were performed at 7 time points., Results: Compared with placebo, adding cangrelor to patients pretreated with ticagrelor resulted in a significant reduction in PRU at 30 minutes and 1 hour after starting infusion. At 2 hours after stopping cangrelor/placebo infusion, PRU were low and similar in both groups (16.9 vs 12.6; mean difference: 4.3; 95% CI: -28.6 to 37.3), meeting the noninferiority primary endpoint (predefined noninferiority margin 45 PRU). Consistent findings were shown with all PD assays. PK tracked PD findings with no differences between groups in plasma levels of ticagrelor and its metabolite., Conclusions: Compared with placebo, the use of cangrelor in patients pretreated with ticagrelor results in enhanced platelet inhibition with no differences in PK/PD profiles after discontinuation of drug infusion indicating the absence of a DDI. (PD and PK Profiles of Switching Between Cangrelor and Ticagrelor Following Ticagrelor Pre-treatment [SWAP-5]; NCT04634162)., Competing Interests: Funding Support and Author Disclosures The present study was funded by an investigator-initiated grant from The Scott R. MacKenzie Foundation. The Scott R. MacKenzie Foundation had no role in the study design conception, conduct of the study, or decision to publish these results. Dr Franchi has received consulting fees or honoraria from AstraZeneca, Bayer, and Sanofi; and has received institutional payments for grants from PLx Pharma and The Scott R. MacKenzie Foundation. Dr Angiolillo has received consulting fees or honoraria from Abbott, Amgen, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, Daiichi Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, Novartis, PhaseBio, PLx Pharma, Pfizer, and Sanofi; and has received research grants to the institution from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co, Merck, Novartis, and The Scott R. MacKenzie Foundation. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Coronavirus disease 2019 (COVID-19) is associated with endothelial dysfunction. Pharmacologically targeting the different mechanisms of endothelial dysfunction may improve clinical outcomes and lead to reduced morbidity and mortality. In this pilot, double-blind, placebo-controlled, randomized clinical trial, we assigned patients who were admitted to the hospital with mild, moderate, or severe COVID-19 infection to receive, on top of optimal medical therapy, either an endothelial protocol consisting of (Nicorandil, L-arginine, folate, Nebivolol, and atorvastatin) or placebo for up to 14 days. The primary outcome was time to recovery, measured by an eight category ordinal scale and defined by the time to being discharged from the hospital or hospitalized for infection-control or other nonmedical reasons. Secondary outcomes included the composite outcome of intensive care unit (ICU) admission or the need for mechanical ventilation, all-cause mortality, and the occurrence of side effects. Of 42 randomized patients, 37 were included in the primary analysis. The mean age of the patients was 57 years; the mean body mass index of study participants was 29.14. History of hypertension was present in 27% of the patients, obesity in 45%, and diabetes mellitus in 21.6%. The median (interquartile range) time to recovery was not significantly different between the endothelial protocol group (6 [4-12] days) and the placebo group (6 [5-8] days; p value = 0.854). Furthermore, there were no statistically significant differences in the need for mechanical ventilation or ICU admission, all-cause mortality, or the occurrence of side effects between the endothelial protocol group and the placebo group. Among patients hospitalized with mild, moderate, or severe COVID-19 infection, targeting endothelial dysfunction by administering Nicorandil, L-arginine, Folate, Nebivolol, and Atorvastatin on top of optimal medical therapy did not decrease time to recovery. Based on this study's findings, targeting endothelial dysfunction did not result in a clinically significant improvement in outcome and, as such, larger trials targeting this pathway are not recommended., (© 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Severe tricuspid regurgitation (TR) is an undertreated common pathology associated with significant morbidity and mortality. Classically, surgical repair or valve replacement were the only therapeutic options and are associated with up to 10% postprocedural mortality. Transcatheter tricuspid valve interventions are a novel and effective therapeutic option for the treatment of significant TR. Several devices have been developed with different mechanisms of action. They are classified as annuloplasty devices, replacement devices, caval valve implantation and coaptation devices. In this review, we provide a step-by-step description of the procedural steps and techniques of every device along with video support., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Trauma patients who present to the emergency department (ED) intoxicated or with an alcohol use disorder (AUD) undergo more procedures and have an increased risk of developing complications. However, how AUD and blood alcohol concentration (BAC) impact a trauma patient's disposition from the ED remains inconclusive. In this study we aimed to identify the associations between positive BAC or an AUD with admission to the hospital, including the intensive care unit (ICU)., Methods: This was a retrospective study analyzing data from 2010-2018 at a university-based, Level I trauma ED. Included in the study were 4,699 adult trauma patients who completed the Alcohol Use Disorders Identification Test (AUDIT) and had blood alcohol content test results., Results: Positive BAC was associated with hospital admission and ICU admission after adjusting for injury severity score (ISS) (odds ratio 1.5 and 1.3, respectively). The AUDIT was only correlated with hospital and ICU admission in patients with ISS of 1 to 15. By increasing risk of AUD (low, moderate, high, and likely alcohol dependent) the proportion of ICU admissions rose from 29.3% to 37.3%, 40.0% and 42.0% (P <0.01). The results did not change significantly by adjustment for the age of patients., Conclusion: BAC is associated with increasing ED disposition to the hospital or ICU. Furthermore, self-reported alcohol use was associated with an increased risk of hospital or ICU admission in patients with minor or moderate injuries. Further studies to determine viable options to decrease admission rates in these patients are warranted.

TP53 mutation is one of the most frequent genetic alterations in head and neck squamous cell carcinoma (HNSCC) and results in an accumulation of p53 protein in tumor cells. This makes p53 an attractive target to improve HNSCC therapy by restoring the tumor suppressor activity of this protein. Therapeutic strategies targeting p53 in HNSCC can be divided into three categories related to three subtypes encompassing WT p53, mutated p53 and HPV-positive HNSCC. First, compounds targeting degradation or direct inhibition of WT p53, such as PM2, RITA, nutlin-3 and CH1iB, achieve p53 reactivation by affecting p53 inhibitors such as MDM2 and MDMX/4 or by preventing the breakdown of p53 by inhibiting the proteasomal complex. Second, compounds that directly affect mutated p53 by binding it and restoring the WT conformation and transcriptional activity (PRIMA-1, APR-246, COTI-2, CP-31398). Third, treatments that specifically affect HPV + cancer cells by targeting the viral enzymes E6/E7 which are responsible for the breakdown of p53 such as Ad-E6/E7-As and bortezomib. In this review, we describe and discuss p53 regulation and its targeting in combination with existing therapies for HNSCC through a new classification of such cancers based on p53 mutation status and HPV infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 de Bakker, Journe, Descamps, Saussez, Dragan, Ghanem, Krayem and Van Gestel.)

Background: COVID-19 is a respiratory disease that results in a prothrombotic state manifesting as thrombotic, microthrombotic and thromboembolic events. As a result, several antithrombotic modalities have been implicated in the treatment of this disease. This study aimed to identify if therapeutic anticoagulation (TAC) or concurrent use of antiplatelet and anticoagulants was associated with an improved outcome in this patient population., Methods: A retrospective observational cohort study of adult patients admitted to a single university hospital for COVID-19 infection was performed. The primary outcome was a composite of in-hospital mortality, intensive care unit (ICU) admission or the need for mechanical ventilation. The secondary outcomes were each of the components of the primary outcome, in-hospital mortality, ICU admission, or the need for mechanical ventilation., Results: 242 patients were included in the study and divided into four subgroups: Therapeutic anticoagulation (TAC), prophylactic anticoagulation+antiplatelet (PACAP), TAC+antiplatelet (TACAP) and prophylactic anticoagulation (PAC) which was the reference for comparison. Multivariable Cox regression analysis and propensity matching were done and showed when compared with PAC, TACAP and TAC were associated with less in-hospital all-cause mortality with an adjusted HR (aHR) of 0.113 (95% CI 0.028 to 0.449) and 0.126 (95% CI 0.028 to 0.528), respectively. The number needed to treat in both subgroups was 11. Furthermore, PACAP was associated with a reduced risk of invasive mechanical ventilation with an aHR of 0.07 (95% CI 0.014 to 0.351). However, the was no statistically significant difference in the occurrence of major or minor bleeds, ICU admission or the composite outcome of in-hospital mortality, ICU admission or the need for mechanical ventilation., Conclusion: The use of combined anticoagulant and antiplatelet agents or TAC alone in hospitalised patients with COVID-19 was associated with a better outcome in comparison to PAC alone without an increase in the risk of major and minor bleeds. Sufficiently powered randomised controlled trials are needed to further evaluate the safety and efficacy of combining antiplatelet and anticoagulants agents or using TAC in the management of patients with COVID-19 infection., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Given the general lack of literature on opioid and naloxone prescribing guidelines for patients with substance use disorder, we aimed to explore how a physician's behavior and prescribing habits are altered by knowledge of the patient's concomitant use of psychotropic compounds as evident on urine and serum toxicology screens., Methods: We conducted a retrospective chart review study at a tertiary, academic, Level I trauma center between November 2017-October 2018 that included 358 patients who were discharged from the emergency department (ED) with a diagnosis of fracture, dislocation, or amputation and received an opioid prescription upon discharge. We extracted urine and serum toxicology results, number and amount of prescription opioids upon discharge, and the presence of a naloxone script., Results: The study population was divided into five subgroups that included the following: negative urine and serum toxicology screen; depressants; stimulants; mixed; and no toxicology screens. When comparing the 103 patients in which toxicology screens were obtained to the 255 patients without toxicology screens, we found no statistically significant differences in the total prescribed morphine milligram equivalent (75.0 and 75.0, respectively) or in the number of pills prescribed (15.0 and 13.5, respectively). Notably, none of the 103 patients who had toxicology screens were prescribed naloxone upon discharge., Conclusion: Our study found no association between positive urine toxicology results for psychotropically active substances and the rates of opioid prescribing within a single-center, academic ED. Notably, none of the 103 patients who had toxicology screens were prescribed naloxone upon discharge. More research on the associations between illicit drug use, opioids, and naloxone prescriptions is necessary to help establish guidelines for high-risk patients.

Targeting non-apoptotic modalities might be therapeutically promising in diffuse large B cell lymphoma (DLBCL) patients with compromised apoptotic pathways. Thymoquinone (TQ) has been reported to promote apoptosis in cancer cells, but little is known about its effect on non-apoptotic pathways. This work investigates TQ selectivity against DLBCL cell lines and the cell death mechanisms. TQ reduces cell viability and kills cell lines with minimal toxicity on normal hematological cells. Mechanistically, TQ promotes the mitochondrial caspase pathway and increases genotoxicity. However, insensitivity of most cell lines to caspase inhibition by z-VAD-fmk (benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone) pointed to a critical role of non-apoptotic signaling. In cells dying through non-apoptotic death, TQ increases endoplasmic reticulum (ER) stress markers and substantially increases cytosolic calcium ([Ca 2+ ] c ) through ER calcium depletion and activation of store-operated calcium entry (SOCE). Chelation of [Ca 2+ ] c , but not SOCE inhibitors, reduces TQ-induced non-apoptotic cell death, highlighting the critical role of calcium in a non-apoptotic effect of TQ. Investigations showed that TQ-induced [Ca 2+ ] c signaling is primarily initiated by necroptosis upstream to SOCE, and inhibition necroptosis by necrostatin-1 alone or with z-VAD-fmk blocks the cell death. Finally, TQ exhibits an improved selectivity profile over standard chemotherapy agents, suggesting a therapeutic relevance of the pro-necroptotic effect of TQ as a fail-safe mechanism for DLBCL therapies targeting apoptosis.

Although primarily affecting the respiratory system, COVID-19 causes multiple organ damage. One of its grave consequences is a prothrombotic state that manifests as thrombotic, microthrombotic and thromboembolic events. Therefore, understanding the effect of antiplatelet and anticoagulation therapy in the context of COVID-19 treatment is important. The aim of this rapid review was to highlight the role of thrombosis in COVID-19 and to provide new insights on the use of antithrombotic therapy in its management. A rapid systematic review was performed using preferred reporting items for systematic reviews. Papers published in English on antithrombotic agent use and COVID-19 complications were eligible. Results showed that the use of anticoagulants increased survival and reduced thromboembolic events in patients. However, despite the use of anticoagulants, patients still suffered thrombotic events likely due to heparin resistance. Data on antiplatelet use in combination with anticoagulants in the setting of COVID-19 are quite scarce. Current side effects of anticoagulation therapy emphasise the need to update treatment guidelines. In this rapid review, we address a possible modulatory role of antiplatelet and anticoagulant combination against COVID-19 pathogenesis. This combination may be an effective form of adjuvant therapy against COVID-19 infection. However, further studies are needed to elucidate potential risks and benefits associated with this combination., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Post-transcriptional modifications of RNA constitute an emerging regulatory layer of gene expression. The demethylase fat mass- and obesity-associated protein (FTO), an eraser of N 6 -methyladenosine (m 6 A), has been shown to play a role in cancer, but its contribution to tumor progression and the underlying mechanisms remain unclear. Here, we report widespread FTO downregulation in epithelial cancers associated with increased invasion, metastasis and worse clinical outcome. Both in vitro and in vivo, FTO silencing promotes cancer growth, cell motility and invasion. In human-derived tumor xenografts (PDXs), FTO pharmacological inhibition favors tumorigenesis. Mechanistically, we demonstrate that FTO depletion elicits an epithelial-to-mesenchymal transition (EMT) program through increased m 6 A and altered 3'-end processing of key mRNAs along the Wnt signaling cascade. Accordingly, FTO knockdown acts via EMT to sensitize mouse xenografts to Wnt inhibition. We thus identify FTO as a key regulator, across epithelial cancers, of Wnt-triggered EMT and tumor progression and reveal a therapeutically exploitable vulnerability of FTO-low tumors., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objectives: It is important to analyze the types of etiologies and provider demographics that drive opioid prescription in our emergency departments. Our study aimed to determine which patients in the ED are receiving opioid prescriptions, as well as their strength and quantity. Secondary outcomes included identifying difference in prescribing between provider classes., Methods: We conducted a retrospective study at a tertiary care university-based, level-one trauma ED from November 2017 to October 2018. We identified and analyzed data from 2,259 patients who were sent home with an opioid prescription. We retrieved patient and provider demographics, diagnosis, etiologies, and prescription information., Results: The mean age of a patient receiving an opioid prescription was 45, and 72.7% of patients were white. The most common diagnosis groups associated with an opioid prescription were abdominal pain (18.5%), nonfracture extremity pain (18.4%), and back/neck pain (12.5%). Hydrocodone-acetaminophen 5-325 mg was the most commonly prescribed (67.4%). The median total prescribed milligram morphine equivalent (MME) was highest for extremity fracture (75.0; IQR 54.0-100.0). The median total prescribed amount of pills was highest for patients with extremity fractures (15.0; IQR 12.0-20.0)., Conclusions: Our study elucidates the prescribing patterns of an academic level 1 trauma center and should pave the way for future studies looking to maximize effectiveness at ways to curb ED opioid prescription., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Justin Yanuck et al.)

Background: This study assessed the inconsistencies between self-reported alcohol consumption and blood alcohol content (BAC) in trauma patients. We aimed to identify the incidence of positive BAC in trauma patients who reported a zero score on the Alcohol Use Disorders Identification Test (AUDIT). We also sought to identify characteristics of individuals who were likely to negate alcohol use, yet yielded a positive BAC, to improve our ability to provide alcohol screening and healthcare to these at-risk alcohol consumers. Methods: We conducted a retrospective study from 2010 to 2018 at a university-based, level-one trauma emergency department. We identified 2581 adult trauma patients who reported a zero score on the AUDIT from the trauma registry. We collected BAC, age, gender, race, education level, mechanism of injury, language and injury severity score (ISS) from patient charts, and used descriptive analyses and multivariate logistic regression to analyze the data. Results: One hundred and thirty-one (5.08%) trauma patients who reported AUDIT of zero had a positive BAC. We found that being male (OR 1.53), assaulted or injured from a penetrating mechanism (OR 2.29) and having an ISS greater than 25 (OR 3.76) were independent positive predictors of trauma patients who reported an AUDIT of zero and had a positive BAC. Age (OR 0.99) was an independent negative predictor of trauma patients who reported an AUDIT of zero and had a positive BAC in this cohort. Conclusions: Inaccurate self-reporting of alcohol drinking behavior does exist in trauma patients. A composite of objective alcohol screening modalities, in addition to AUDIT, is needed to screen for alcohol use in this population. Healthcare providers should remain highly suspicious of alcohol-related injuries in individuals with the identified characteristics.

Background: Patients with an alcohol use disorder (AUD) have an increased risk of developing complications during their hospital stays; however, how AUD impacts the length of stay (LOS) and the utilization of hospital resources remains inconclusive., Aim: This study aimed to identify the associations between AUD, defined by self-reported alcohol consumption, blood alcohol content (BAC), and hospital LOS (HLOS) including intensive care unit (ICU) LOS in the trauma patient population., Study Design: We conducted a retrospective study analyzing data obtained from 2010 to 2018 at a university-based, level-one trauma emergency department. We identified 1689 adult trauma patients who completed the AUDs identification test (AUDIT) and were admitted to the hospital. We retrieved BAC, age, gender, LOS, and injury severity score (ISS) from the patient charts. The independent samples' median test was used to assess the association of HLOS and ICULOS with ISS, BAC levels, or AUDIT scores., Results: ISS was directly associated with higher HLOS ( P < 0.001) and ICULOS ( P < 0.001); however there was no statistically significant association between AUDIT scores and ICULOS ( P = 0.21) or HLOS ( P = 0.86). There was also no statistically significant association between BAC and HLOS ( P = 0.09) or ICULOS ( P = 0.07)., Conclusions: Our study found no associations between AUDIT, BAC, and both hospital and ICU LOS in trauma patients even though the literature supported an increased risk of medical complications in the AUD patients., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Journal of Emergencies, Trauma, and Shock.)

Melanoma is the most common cancer in young adults, with a constantly increasing incidence. Metastatic melanoma is a very aggressive cancer with a 5-year survival rate of about 22-25%. This is, in most cases, due to a lack of therapies which are effective on the long term. Hence, it is crucial to find new therapeutic agents to increase patient survival. Toad venoms are a rich source of potentially pharmaceutically active compounds and studies have highlighted their possible effect on cancer cells. We focused on the venoms of two different toad species: Bufo bufo and Rhinella marina . We screened the venom crude extracts, the fractions from crude extracts and isolated biomolecules by studying their antiproliferative properties on melanoma cells aiming to determine the compound or the combination of compounds with the highest antiproliferative effect. Our results indicated strong antiproliferative capacities of toad venoms on melanoma cells. We found that these effects were mainly due to bufadienolides that are cardiotonic steroids potentially acting on the Na + /K + ATPase pump which is overexpressed in melanoma. Finally, our results indicated that bufalin alone was the most interesting compound among the isolated bufadienolides because it had the highest antiproliferative activity on melanoma cells.

Melanoma cells can switch between a melanocytic and a mesenchymal-like state. Scattered evidence indicates that additional intermediate state(s) may exist. Here, to search for such states and decipher their underlying gene regulatory network (GRN), we studied 10 melanoma cultures using single-cell RNA sequencing (RNA-seq) as well as 26 additional cultures using bulk RNA-seq. Although each culture exhibited a unique transcriptome, we identified shared GRNs that underlie the extreme melanocytic and mesenchymal states and the intermediate state. This intermediate state is corroborated by a distinct chromatin landscape and is governed by the transcription factors SOX6, NFATC2, EGR3, ELF1 and ETV4. Single-cell migration assays confirmed the intermediate migratory phenotype of this state. Using time-series sampling of single cells after knockdown of SOX10, we unravelled the sequential and recurrent arrangement of GRNs during phenotype switching. Taken together, these analyses indicate that an intermediate state exists and is driven by a distinct and stable 'mixed' GRN rather than being a symbiotic heterogeneous mix of cells.

Purpose: To evaluate immediate and long-term clinical results of percutaneous mitral commissurotomy (PMC) in patients with severe mitral stenosis., Methods: In a retrospective study, data were included from 317 patients over 18 years of age (mean age 45) who had been treated for mitral stenosis between January 1993 and March 2015 with PMC using the Inoue balloon technique. Immediate results: Valvular function improved as evidenced by an increase in mitral valve area from 1.01 ± 0.24 cm 2 to 2 ± 0.31 cm 2 (P < 0.001) and a decrease in mean mitral gradient from 13.64 ± 6.03 mm Hg to 5.40 ± 2.49 mm Hg. Long-term follow-up: At 5-15 years (mean 10.2 years, Inter-quartile range 8.25), 105 (33.1%) of the 317 patients were available for follow-up, 95 living patients and 10 deceased. Of the deceased, average time from PMC to death was 8 years. Results were strongly significant showing that age at the time of PMC and surface area before the procedure were the best predictors of survival at 15 years follow-up, showing significance values of P = 0.022 and P = 0.001, respectively., Conclusions: PMC using the Inoue balloon technique improves morbidity and long-term mortality rates in patients with severe mitral stenosis. Lower Wilkins score and NYHA class at baseline were not found to be significant predictors of mortality in older patients (age > 45). Overall, 65 (61.9%) had survived at 5-15 years follow-up without further cardiac intervention., Competing Interests: None.

Background: Thromboprophylaxis dosing strategies using enoxaparin in elderly patients with renal disease are limited, while dose adjustments or monitoring of anti-Xa levels are recommended. We sought to evaluate the efficacy and safety of enoxaparin 20 mg versus 30 mg subcutaneously daily by comparing anti-Xa levels, thrombosis and bleeding., Methods: We conducted a prospective, single-blinded, single-center randomized clinical trial including non-surgical patients, 70 years of age or older, with renal disease requiring thromboprophylaxis. Patients were randomized to receive either 20 mg or 30 mg of enoxaparin. The primary endpoint was peak anti-Xa levels on day 3. Secondary endpoints included trough anti-Xa levels on day 3, achievement of within range prophylactic target peak anti-Xa levels and the occurrence of hemorrhage, thrombosis, thrombocytopenia or hyperkalemia during hospitalization., Results: Thirty-two patients were recruited and sixteen patients were randomized to each arm. Mean peak anti-Xa level was significantly higher in 30 mg arm (n = 13) compared to the 20 mg arm (n = 11) 0.26 ± 0.11, 95%CI (0.18-0.34), versus 0.14 ± 0.09, 95CI (0.08-0.19) UI/ml, respectively; p = 0.004. Mean trough anti-Xa level was higher in 30 mg arm (n = 10) compared to the 20 mg arm (n = 16), 0.06 ± 0.03, 95CI (0.04-0.08) versus 0.03 ± 0.03, 95CI (0.01-0.05) UI/ml, respectively; p = 0.044. Bleeding events reported in the 30 mg arm were one retroperitoneal bleed requiring multiple transfusions, and in the 20 mg arm one hematuria. No thrombotic events were reported., Conclusion: Peak anti-Xa levels provided by enoxaparin 20 mg were lower than the desired range for thromboprophylaxis in comparison to enoxaparin 30 mg., Trial Registration: The trial was retrospectively registered on ClinicalTrials.gov identifier: NCT03158792 . Registered: May 18, 2017.

Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine involved in the carcinogenesis of many cancer types. Here, we review the published experimental and clinical data for MIF and its involvement in melanoma. All reported data show that MIF is overexpressed in melanoma cells, especially in case of metastatic disease. Clinical studies also indicate that high MIF expression is positively associated with aggressiveness of the disease. Some data also highlight the implication of MIF in angiogenesis, immunity and metastasis in melanoma cell lines, as well as the availability of different therapeutic options targeting MIF for the treatment of metastatic melanoma. Indeed, the main problem in metastatic melanoma is the lack of long-term effective treatment. This is linked to the capacity of melanoma cells to mutate very quickly and/or activate alternative signaling pathways. Thus, MIF targeting therapies could provide a new effective way of treating melanoma. Moreover, cell sensitivity to MIF depletion does not correlate with the BRAF mutational status. Regarding the fact that many melanoma patients carry a BRAF mutation, and that they develop resistance to BRAF inhibitors, this observation is very interesting as MIF inhibitors could be used to treat many patients in relapse after treatment with an inhibitor of the mutant BRAF protein.

Background: In this study, the authors utilized the IMPROVE (International Medical Prevention Registry on Venous Thromboembolism) bleeding definition to explore the safety profile of pharmacologic venous thromboembolism (VTE) prophylaxis in patients with chronic liver disease (CLD) and concurrent coagulopathy (INR ≥1.5)., Methods: A retrospective study was conducted on 193 adult patient admissions with a diagnosis of CLD and INR ≥1.5 not due to therapeutic anticoagulation. Patients were stratified based on their receipt of pharmacological thromboprophylaxis or not during hospitalization. The rates of overall bleeding, defined as the composite of major bleeding and clinically relevant non-major bleeding; major bleeding; and clinically relevant non-major bleeding, within 14 days of admission were evaluated. Secondary endpoints included the rates of thrombosis and mortality., Results: The composite of overall bleeding occurred in 17.6% of the admissions. More patients in the group not receiving pharmacological thromboprophylaxis had overall bleeding (18.5% vs 10%), major bleeding (13.3% vs 10%), and clinically relevant non-major bleeding (14.5% vs 5%), with overlapping 95% CI. When stratified per pharmacological thromboprophylaxis status, IMPROVE bleeding risk score (BRS) ≥ 7 was associated with higher rates of overall bleeding, major bleeding, and clinically relevant non-major bleeding as compared to IMPROVE BRS <7, whether patients received or did not receive pharmacological thromboprophylaxis. The overall incidence of in-hospital mortality among our study population was 15.5%. Receiving pharmacological thromboprophylaxis was markedly associated with higher in-hospital mortality (OR = 16.58, 95% CI = 4.47-61.45)., Conclusion: This study shows that the IMPROVE BRS calculated on admission may serve as a guide for omission of thromboprophylaxis in advanced CLD.

Competing Interests: Conflicts of Interest: By the CPC-EM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. The authors disclosed none.

p53 protects cells from genetic assaults by triggering cell-cycle arrest and apoptosis. Inactivation of p53 pathway is found in the vast majority of human cancers often due to somatic missense mutations in TP53 or to an excessive degradation of the protein. Accordingly, reactivation of p53 appears as a quite promising pharmacological approach and, effectively, several attempts have been made in that sense. The most widely investigated compounds for this purpose are PRIMA-1 (p53 reactivation and induction of massive apoptosis )and PRIMA-1 Met (APR-246), that are at an advanced stage of development, with several clinical trials in progress. Based on publications referenced in PubMed since 2002, here we review the reported effects of these compounds on cancer cells, with a specific focus on their ability of p53 reactivation, an overview of their unexpected anti-cancer effects, and a presentation of the investigated drug combinations., Competing Interests: The authors declare no conflict of interest.

Competition among RNAs to bind miRNA is proposed to influence biological systems. However, the role of this competition in disease onset is unclear. Here, we report that TYRP1 mRNA, in addition to encoding tyrosinase-related protein 1 (TYRP1), indirectly promotes cell proliferation by sequestering miR-16 on non-canonical miRNA response elements. Consequently, the sequestered miR-16 is no longer able to repress its mRNA targets, such as RAB17, which is involved in melanoma cell proliferation and tumour growth. Restoration of miR-16 tumour-suppressor function can be achieved in vitro by silencing TYRP1 or increasing miR-16 expression. Importantly, TYRP1-dependent miR-16 sequestration can also be overcome in vivo by using small oligonucleotides that mask miR-16-binding sites on TYRP1 mRNA. Together, our findings assign a pathogenic non-coding function to TYRP1 mRNA and highlight miRNA displacement as a promising targeted therapeutic approach for melanoma.

Melanoma is the deadliest form of skin cancer and one of the most difficult cancers to treat. Overall, melanomas have more mutations than any other cancer type. Oncogenic mutations in c-KIT, NRAS and BRAF components of the MAPK pathway have been identified in nearly 90% of cutaneous melanoma and this information has been used to develop small molecules that inhibit their activity. Highly selective BRAF and MEK inhibitors have demonstrated impressive clinical results. However, the short duration of response, the acquired resistance in most cases and the toxicity issues support the rationale for drug combination approaches to improve the outcome of MAPK inhibitors, increase their efficacy, prevent and/or overcome resistance. This review discusses several promising rational combinatorial strategies investigated or could be investigated in clinical studies., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Trastuzumab remains an important drug in the management of human epidermal growth factor receptor 2 (HER2) overexpressing breast cancer (BC). Several studies reported resistance mechanisms to trastuzumab, including impaired HER2-accessibility caused by mucin 4 (MUC4). Previously, we demonstrated an increase of Zirconium-89-radiolabeled-trastuzumab ( 89 Zr-Trastuzumab) accumulation when MUC4-overexpressing BC-cells were challenged with the mucolytic drug N-Acetylcysteine (NAC). Hereby, using the same approach we investigated whether tumor exposure to NAC would also enhance trastuzumab-efficacy. Dual SKBr3 (HER2+/MUC4-, sensitive to trastuzumab) and JIMT1 (HER2+/MUC4+, resistant to trastuzumab) HER2-BC-bearing-xenografts were treated with trastuzumab and NAC. Treatment was monitored by molecular imaging evaluating HER2-accessibility/activity ( 89 Zr-Trastuzumab HER2-immunoPET) and glucose metabolism ( 18 F-FDG-PET/CT), as well as tumor volume and the expression of key proteins. In the MUC4-positive JIMT1-tumors, the NAC-trastuzumab combination resulted in improved tumor-growth control compared to trastuzumab alone; with smaller tumor volume/weight, lower 18F-FDG uptake, lower %Ki67 and pAkt-expression. NAC reduced MUC4-expression, but did not affect HER2-expression or the trastuzumab-sensitivity of the MUC4-negative SKBr3-tumors. These findings suggest that improving HER2-accessibility by reducing MUC4-masking with the mucolytic drug NAC, results in a higher anti-tumor effect of trastuzumab. This provides a rationale for the potential benefit of this approach to possibly treat a subset of HER2-positive BC overexpressing MUC4., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Purpose: To assess the applicability of active surveillance in patients with intermediate risk prostate cancer, we compared the survival outcomes of patients with low risk and intermediate risk disease., Materials and Methods: Active surveillance was offered to all patients with low risk (cT1-T2b and Gleason score 6 and prostate specific antigen 10 ng/ml or less) and select intermediate risk disease (age greater than 70 years with cT2c or prostate specific antigen 15 ng/ml or less, or Gleason score 3+4 or less). Data from November 1995 to May 2013 were extracted from a prospectively collected database. The primary outcome was metastasis-free survival, and secondary outcomes were overall survival, cause specific survival and treatment-free survival., Results: A total of 213 intermediate risk and 732 low risk cases were identified. Median age was 72 years (IQR 67.3, 76.8) in the intermediate risk cohort and 67 years (IQR 60.6, 71.9) in the low risk group. Median followup was comparable (6.7 years for intermediate risk vs 6.5 years for low risk). Gleason 7 disease comprised 60% of the intermediate risk cohort. The 15-year metastasis-free, overall, cause specific and treatment-free survival rates were inferior in the intermediate risk group (metastasis-free survival HR 3.14, 95% CI 1.51-6.53, p=0.001, 82% for intermediate risk vs 95% for low risk). On further evaluation the estimated 15-year metastasis-free survival for cases of Gleason 6 or less with prostate specific antigen less than 10 ng/ml was 94%, Gleason 6 or less with prostate specific antigen 10 to 20 ng/ml was 94%, Gleason 3+4 with prostate specific antigen 20 ng/ml or less was 84% and Gleason 4+3 with prostate specific antigen 20 ng/ml or less was 63%., Conclusions: These data support the use of active surveillance in low risk and intermediate risk cases of Gleason 6 but not Gleason 7 prostate cancer. Multiparametric magnetic resonance imaging and novel biomarkers might be vital in detecting favorable Gleason 7 disease., (Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

MEK kinase inhibitors (trametinib and selumetinib) or kinase inhibitors directed against mutated BRAF(V600E) (vemurafenib and dabrafenib) have initial encouraging effects in the treatment of melanoma but acquired resistance appears almost invariably after some months. Studies revealed mutually exclusive NRAS and BRAF activating mutations driving the MAPK/ERK pathway among human melanomas. Although combination therapy exerts significantly better antitumor cell efficacy, complete remission is rarely achieved. To employ an alternative approach, we have targeted the Hedgehog/GLI pathway, which is deregulated in melanomas, through the GLI1/2 inhibitor GANT61, alone or accompanied with the treatment by the BCL2 family inhibitor obatoclax in 9 melanoma cell lines. Thus, we targeted melanoma cells irrespective of their NRAS or BRAF mutational status. After GANT61 treatment, the cell viability was drastically diminished via apoptosis, as substantial nuclear DNA fragmentation was detected. In all tested melanoma cell lines, the combined treatment was more efficient than the application of each drug alone at the end of the cell growth with inhibitors. GANT61 was efficient also alone in most cell lines without the addition of obatoclax, which had only a limited effect when used as a single drug. In most cell lines, tumor cells were eradicated after 5-9 days of combined treatment in colony outgrowth assay. To conclude, GANT61 treatment might become a hopeful and effective anti-melanoma targeted therapy, especially when combined with the BCL2 family inhibitor obatoclax.

Purpose: Active surveillance is an approach to low and low intermediate risk prostate cancer that is designed to decrease overtreatment. Despite close monitoring a small subset of patients progress to metastatic disease. We analyzed the clinical and pathological correlates of surveillance in patients who eventually experienced metastasis., Materials and Methods: This was a single center, prospective cohort study. Eligible patients were treated with an expectant approach. The main outcome measure was metastasis-free survival. Predictive factors for metastasis were identified., Results: Metastasis developed in 30 of 980 patients, of whom 211 were classified at intermediate risk, including 14 who progressed to metastatic disease. Median followup was 6.3 years, median age was 70 years, median prostate specific antigen was 6.2 ng/ml and median time to metastasis was 8.9 years. Metastases developed in bone in 18 patients (60%) and in lymph nodes in 13 (43%). Prostate specific antigen doubling time less than 3 years (HR 3.7, 95% CI 1.4-9.4, p = 0.0006), Gleason score 7 (HR 3.0, 95% CI 1.2-7.3, p = 0.0018) and a total of 3 or more positive cores (HR 2.7, 95% CI 1.1-6.8, p = 0.0028) were independent predictors of metastasis. Although the intermediate risk group was at higher risk for metastasis, those with Gleason score 6 and prostate specific antigen greater than 10 ng/ml were not at increased risk for metastasis. Metastasis developed in only 2 patients with Gleason score 6 and neither had surgical pathology grading., Conclusion: Active surveillance appears safe in patients at low risk and in select patients at intermediate risk, particularly those with Gleason score 6 and prostate specific antigen greater than 10 ng/ml. Patients with elements of Gleason pattern 4 on diagnostic biopsy are at increased risk for eventual metastasis when treated with an initial conservative approach., (Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Intrinsic and acquired resistance of metastatic melanoma to (V600E/K)BRAF and/or MEK inhibitors, which is often caused by activation of the PI3K/AKT survival pathway, represents a major clinical challenge. Given that p53 is capable of antagonising PI3K/AKT activation we hypothesised that pharmacological restoration of p53 activity may increase the sensitivity of BRAF-mutant melanoma to MAPK-targeted therapy and eventually delay and/or prevent acquisition of drug resistance. To test this possibility we exposed a panel of vemurafenib-sensitive and resistant (innate and acquired) (V600E/K)BRAF melanomas to a (V600E/K)BRAF inhibitor (vemurafenib) alone or in combination with a direct p53 activator (PRIMA-1(Met)/APR-246). Strikingly, PRIMA-1(Met) synergised with vemurafenib to induce apoptosis and suppress proliferation of (V600E/K)BRAF melanoma cells in vitro and to inhibit tumour growth in vivo. Importantly, this drug combination decreased the viability of both vemurafenib-sensitive and resistant melanoma cells irrespectively of the TP53 status. Notably, p53 reactivation was invariably accompanied by PI3K/AKT pathway inhibition, the activity of which was found as a dominant resistance mechanism to BRAF inhibition in our lines. From all various combinatorial modalities tested, targeting the MAPK and PI3K signalling pathways through p53 reactivation or not, the PRIMA-1(Met)/vemurafenib combination was the most cytotoxic. We conclude that PRIMA-1(Met) through its ability to directly reactivate p53 regardless of the mechanism causing its deactivation, and thereby dampen PI3K signalling, sensitises (V600E/K)BRAF-positive melanoma to BRAF inhibitors., (Copyright © 2015 Elsevier Ltd. All rights reserved.)