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Background: Anatomic severity grade (ASG) score is utilized to assess preoperative abdominal aortic aneurysms (AAA) and provide a quantitative data on its anatomic complexity. The aim of this study is to determine the anatomical differences and long-term survival between male and female patients undergoing elective AAA repair., Methods: All patients undergoing intact AAA repair from 2007 to 2014 were included. ASG scores were calculated based on preoperative anatomical characteristics including aortic neck, aneurysm, and iliac artery. Standard univariate analysis was used to evaluate patient and anatomical characteristics. Kaplan-Meier survival curves were used to evaluate long-term survival at 1 and 5 years., Results: A total of 379 patients were identified, of which, majority of them were males (80%). Females were on average 3 years older (mean [SD]: 74.32 [8.63] vs. 71.92 [8.64] years) and were more likely to undergo open repair (29.7% vs. 17.5%) (both P < 0.05). Both groups had similar comorbidities. The mean long-term follow-up (S.D.) was 6.21 (3.81) years. No significant difference was seen between males versus females in long-term survival at both 1 year (86.3% vs. 92.8, P = 0.06) and 5 year (68.5% vs. 72.7%, P = 0.38). In regard to the anatomical characteristics, females had shorter aortic neck length (mean in mm [S.D.]: 17.67 [1.41] vs. 27.20 [15.76]), increased tortuosity index [mean (S.D.): 1.11 (0.07) vs. 1.09 (0.07)]) and higher calcification [mean % (S.D.): 17.12 (21.17) vs. 10.59 (16.82)] (All P < 0.05). In contrast, males had larger aortic neck (mean in mm (S.D.): 23.81 (4.17) vs. 22.41 (4.16)] and iliac artery [mean in mm (S.D.): 7.70 (1.91) vs. 6.28 (1.67)] diameter (both P < 0.05). The mean total ASG score was significantly higher among females versus males [mean (S.D.): 17.23 (4.01) vs. 15.67 (3.96), P = 0.003]. After stratifying by ASG score ≥15, females had significantly lower survival at 1 year compared to males (82.6% vs. 92.1%, P = 0.04). However, this difference disappeared at 5 years., Conclusions: The data demonstrate that females present at an older age with more complex AAA anatomy than males. Based on anatomical complexities, females were more likely to undergo open repair, with a corresponding increase in 1-year mortality, but not at 5 year. The data suggest that care processes for optimization of aortic surgery in females are needed to improve 1-year survival., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: Investigate risk factors for SARS-CoV-2 infections in school students and staff., Methods: In the 2020/2021 school year, we administered polymerase chain reaction, antibody tests, and questionnaires to a sample of primary and secondary school students and staff, with data linkage to COVID-19 surveillance. We fitted logistic regression models to identify the factors associated with infection., Results: We included 6799 students and 5090 staff in the autumn and 11,952 students and 4569 staff in the spring/summer terms. Infections in students in autumn 2020 were related to the percentage of students eligible for free school meals. We found no statistical association between infection risk in primary and secondary schools and reported contact patterns between students and staff in either period in our study. Using public transports was associated with increased risk in autumn in students (adjusted odds ratio = 1.72; 95% confidence interval 1.31-2.25) and staff. One or more infections in the same household during either period was the strongest risk factor for infection in students and more so among staff., Conclusion: Deprivation, community, and household factors were more strongly associated with infection than contacts patterns at school; this suggests that the additional school-based mitigation measures in England in 2020/2021 likely helped reduce transmission risk in schools., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aims: Characterizing cannabinoid receptors (CBRs) expressed in Ewing sarcoma (EWS) cell lines as potential targets for anti-cancer drug development., Main Methods: CBR affinity and function were examined by competitive binding and G-protein activation, respectively. Cannabinoid-mediated cytotoxicity and cell viability were evaluated by LDH, and trypan blue assays, respectively., Key Findings: qRT-PCR detected CB1 (CB1R) and CB2 receptor (CB2R) mRNA in TC-71 cells. However, binding screens revealed that CBRs expressed exhibit atypical properties relative to canonical receptors, because specific binding in TC-71 could only be demonstrated by the established non-selective CB1/CB2R radioligand [ 3 H]WIN-55,212-2, but not CB1/CB2R radioligand [ 3 H]CP-55,940. Homologous receptor binding demonstrated that [ 3 H]WIN-55,212-2 binds to a single site with nanomolar affinity, expressed at high density. Further support for non-canonical CBRs expression is provided by subsequent binding screens, revealing that only 9 out of 28 well-characterized cannabinoids with high affinity for canonical CB1 and/or CB2Rs were able to displace [ 3 H]WIN-55,212-2, whereas two ligands enhanced [ 3 H]WIN-55,212-2 binding. Five cannabinoids producing the greatest [ 3 H]WIN-55,212-2 displacement exhibited high nanomolar affinity (K i ) for expressed receptors. G-protein modulation and adenylyl cyclase assays further indicate that these CBRs exhibit distinct signaling/functional profiles compared to canonical CBRs. Importantly, cannabinoids with the highest affinity for non-canonical CBRs reduced TC-71 viability and induced cytotoxicity in a time-dependent manner. Studies in a second EWS cell line (A-673) showed similar atypical binding properties of expressed CBRs, and cannabinoid treatment produced cytotoxicity., Significance: Cannabinoids induce cytotoxicity in EWS cell lines via non-canonical CBRs, which might be a potential therapeutic target to treat EWS., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The ascending aorta is the final segment of the aorta to be explored with endovascular stent grafts. With a patient population of increasingly advanced age and disease, there are situations where traditional open repair for ascending aneurysms or dissections may be prohibitive. However, the ascending aorta has multiple hostile characteristics that make endovascular treatment challenging. There is also a lack of approved specialized devices in the United States for this aortic territory. We demonstrate the feasibility of adapting an abdominal aortic graft to the ascending aorta for the treatment of a saphenous vein graft aneurysm with a discussion of the technical considerations for the operation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The human cannabinoid subtype 1 receptor (hCB 1 R) is highly expressed in the CNS and serves as a therapeutic target for endogenous ligands as well as plant-derived and synthetic cannabinoids. Unfortunately, acute use of hCB 1 R agonists produces unwanted psychotropic effects and chronic administration results in development of tolerance and dependence, limiting the potential clinical use of these ligands. Studies in β-arrestin knockout mice suggest that interaction of certain GPCRs, including μ-, δ-, κ-opioid and hCB 1 Rs, with β-arrestins might be responsible for several adverse effects produced by agonists acting at these receptors. Indeed, agonists that bias opioid receptor activation toward G-protein, relative to β-arrestin signaling, produce less severe adverse effects. These observations indicate that therapeutic utility of agonists acting at hCB 1 Rs might be improved by development of G-protein biased hCB 1 R agonists. Our laboratory recently reported a novel class of indole quinulidinone (IQD) compounds that bind cannabinoid receptors with relatively high affinity and act with varying efficacy. The purpose of this study was to determine whether agonists in this novel cannabinoid class exhibit ligand bias at hCB 1 receptors. Our studies found that a novel IQD-derived hCB 1 receptor agonist PNR-4-20 elicits robust G protein-dependent signaling, with transduction ratios similar to the non-biased hCB 1 R agonist CP-55,940. In marked contrast to CP-55,940, PNR-4-20 produces little to no β-arrestin 2 recruitment. Quantitative calculation of bias factors indicates that PNR-4-20 exhibits from 5.4-fold to 29.5-fold bias for G protein, relative to β-arrestin 2 signaling (when compared to G protein activation or inhibition of forskolin-stimulated cAMP accumulation, respectively). Importantly, as expected due to reduced β-arrestin 2 recruitment, chronic exposure of cells to PNR-4-20 results in significantly less desensitization and down-regulation of hCB 1 Rs compared to similar treatment with CP-55,940. PNR-4-20 (i.p.) is active in the cannabinoid tetrad in mice and chronic treatment results in development of less persistent tolerance and no significant withdrawal signs when compared to animals repeatedly exposed to the non-biased full agoinst JWH-018 or Δ 9 -THC. Finally, studies of a structurally similar analog PNR- 4-02 show that it is also a G protein biased hCB 1 R agonist. It is predicted that cannabinoid agonists that bias hCB 1 R activation toward G protein, relative to β-arrestin 2 signaling, will produce fewer and less severe adverse effects both acutely and chronically., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

This study determined the antinociceptive effects of morphine and morphine-6-O-sulfate (M6S) in both normal and diabetic rats, and evaluated the comparative role of mu-opioid receptors (mu-ORs) and delta-opioid receptors (delta-ORs) in the antinociceptive action of these opioids. In vitro characterization of mu-OR and delta-OR-mediated signaling by M6S and morphine in stably transfected Chinese hamster ovary (CHO-K1) cells showed that M6S exhibited a 6-fold higher affinity for delta-ORs and modulated G-protein and adenylyl cyclase activity via delta-ORs more potently than morphine. Interestingly, while morphine acted as a full agonist at delta-ORs in both functional assays examined, M6S exhibited either partial or full agonist activity for modulation of G-protein or adenylyl cyclase activity, respectively. Molecular docking studies indicated that M6S but not morphine binds equally well at the ligand binding site of both mu- and delta-ORs. In vivo analgesic effects of M6S and morphine in both normal and streptozotocin-induced diabetic Sprague-Dawley rats utilizing the hot water tail flick latency test showed that M6S produced more potent antinociception than morphine in both normal rats and diabetic rats. This difference in potency was abrogated following antagonism of delta- but not mu- or kappa (kappa-ORs) opioid receptors. During 9days of chronic treatment, tolerance developed to morphine-treated but not to M6S-treated rats. Rats that developed tolerance to morphine still remained responsive to M6S. Collectively, this study demonstrates that M6S is a potent and efficacious mu/delta opioid analgesic with a delayed tolerance profile when compared to morphine in both normal and diabetic rats., Perspective: This study demonstrates that M6S acts at both mu- and delta-ORs, and adds to the growing evidence that the use of mixed mu/delta opioid agonists in pain treatment may have clinical benefit., Competing Interests: The University of Kentucky holds a patent on the compound M6S described in the current work. A potential royalty stream to PAC may occur consistent with University of Kentucky policy., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Tamoxifen (Tam) is classified as a selective estrogen receptor modulator (SERM) and is used for treatment of patients with ER-positive breast cancer. However, it has been shown that Tam and its cytochrome P450-generated metabolite 4-hydroxy-Tam (4OH-Tam) also exhibit cytotoxic effects in ER-negative breast cancer cells. These observations suggest that Tam and 4OH-Tam can produce cytotoxicity via estrogen receptor (ER)-independent mechanism(s) of action. The molecular targets responsible for the ER-independent effects of Tam and its derivatives are poorly understood. Interestingly, similar to Tam and 4OH-Tam, cannabinoids have also been shown to exhibit anti-proliferative and apoptotic effects in ER-negative breast cancer cells, and estrogen can regulate expression levels of cannabinoid receptors (CBRs). Therefore, this study investigated whether CBRs might serve as novel molecular targets for Tam and 4OH-Tam. We report that both compounds bind to CB1 and CB2Rs with moderate affinity (0.9-3 μM). Furthermore, Tam and 4OH-Tam exhibit inverse activity at CB1 and CB2Rs in membrane preparations, reducing basal G-protein activity. Tam and 4OH-Tam also act as CB1/CB2R-inverse agonists to regulate the downstream intracellular effector adenylyl cyclase in intact cells, producing concentration-dependent increases in intracellular cAMP. These results suggest that CBRs are molecular targets for Tam and 4OH-Tam and may contribute to the ER-independent cytotoxic effects reported for these drugs. Importantly, these findings also indicate that Tam and 4OH-Tam might be used as structural scaffolds for development of novel, efficacious, non-toxic cancer drugs acting via CB1 and/or CB2Rs., (Copyright © 2013 Elsevier Inc. All rights reserved.)