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Across the Mediterranean and the Black Sea, an improvement in technological adoption which optimizes the environmental benefits of fisheries is needed. The testing of quality standards in trawl fishing is one of the essential components. In an experiment, we tested four bottom trawl cod-ends in the western Black Sea to determine the characteristics of the catch composition. Fishing trials were conducted by 40 mm diamond (40D), 44 mm diamond (44D), 40 mm square (the 40S), and 40 mm 90-degree turned (40T) mesh cod-ends for 31 bottom trawling hauls. The multivariate analysis of catch composition indicated a significantly higher differentiation between 40D and 40T cod-ends, mainly characterized by five species: Merlangius merlangus, Mytilus galloprovincialis, Trachinus draco, Mullus barbatus, and Uranuscopus scaber. The difference in the shape of cod-end meshes reflected the variation in the catchability and catch composition. However, the 40S and 40T showed 80% similarity in catch composition. Among cod-ends, 40T yielded in lowest catch per unit effort for both commercial and other species. Adoption of gear specially made to catch more target species can help bottom trawl fisheries further improve their ecological and economic sustainability. [ABSTRACT FROM AUTHOR]

Background: Chronic myeloid leukaemia (CML) is a clonal disease of a hematopoietic stem cell. The incidence of this disease is about 15% of leukemias and may be present at any age. The presence of the Philadelphia (Ph) chromosome confirms the diagnosis of CML. The expression of the Patched homolog 1 gene (PTCH1) has been proposed as a prognostic marker of imatinib response in chronic phase chronic myeloid leukaemia (CP-CML) patients. Aim: This study aimed to measure the level of PTCH1 protein in newly diagnosed CP-CML and to find correlation between its level in those patients and response to first line of treatment, imatinib and other prognostic factors. Patients and Methods: Our study enrolled 50 patients of newly diagnosed CP-CML. We have measured the level of PTCH1 protein initially once the patient diagnosed and after 6 months of treatment with imatinib by ELISA test. Results: There was highly significant difference between initial PTCH1 level and its level after 6 months of imatinib treatment (P=0.000). The level of PTCH 1 was correlated significantly with the molecular response both at the beginning of treatment with imatinib and six months later. (P=0.002), (p=0.001) respectively. Conclusion: To the best of our knowledge that we are the first to report on PTCH1 protein as a new diagnostic and prognostic marker in CP-CML patients. [ABSTRACT FROM AUTHOR]

This paper proposes an optimization approach for day-ahead reactive power planning to improve voltage security in transmission networks. The problem is formulated as a voltage-secure multi-period optimal reactive power dispatch (MP-ORPD) problem. The optimization approach searches for optimal set-points of dynamic and static reactive power (var) resources. Specifically, the output includes set-points for switching shunts, transformer taps, and voltage magnitudes at the regulated buses. The primary goal is to maximize the dynamic reactive power reserve of the system, by minimizing the reactive power supplied by synchronous generators. As the size of the MP-ORPD problem increases significantly with increasing number of contingencies and time periods, efficiency is crucial for practical applications. In this paper, a decomposition technique based on consensus and alternating optimization, where integer variable targets are obtained via MILP, is used to partition the MP-ORPD problem into a set of subproblems, which can be solved in parallel to reduce the computation time. The proposed MP-ORPD problem and its solution algorithm are integrated into the EPRI-VCA software. The results of various power networks of large electric utilities in the Eastern interconnection demonstrate the effectiveness of the proposed algorithm in providing preventive control schedules. [ABSTRACT FROM AUTHOR]

Background & Objective: Awareness under anesthesia is defined as intraoperative consciousness and/or postoperative recall of surgical events. The isolated forearm technique (IFT) is a technique that has the ability to assess consciousness of the external world through a verbal command during general anesthesia. It provides live information about the presence of consciousness. We compared inhalational induction technique versus intravenous induction technique regarding awareness during laryngoscopy and intubation in elderly patients. Design: A prospective, randomized trial Methodology: A total of 50 patients scheduled for elective surgery under general anesthesia; aged 60 to 80 years were recruited. Patients were randomized into either Group A (inhalational induction group) or Group B (total intravenous induction group). Awareness reaction using IFT technique was observed during laryngoscopy and intubation phase to identify awareness incidence. A patient was considered a responder if IFT score > 2. Results : At laryngoscopy and intubation phase, 32% of cases had an awareness reaction in intravenous induction group (Group B): While in the inhalational induction group (Group A), only 8% of cases had an awareness reaction. Additionally, none of the patients, suffered from postoperative explicit recall as detected by modified Brice questionnaire (MBQ). Conclusions : On the basis of the results of our study, we conclude that intravenous induction of general anesthesia may subject old aged patients to a higher incidence of awareness when compared to inhalational induction technique. [ABSTRACT FROM AUTHOR]

The novel coronavirus disease COVID-19, caused by the virus SARS CoV-2, has exerted a significant unprecedented economic and medical crisis, in addition to its impact on the daily life and health care systems all over the world. Regrettably, no vaccines or drugs are currently available for this new critical emerging human disease. Joining the global fight against COVID-19, in this study we aim at identifying a potential novel inhibitor for SARS COV-2 2′-O-methyltransferase (nsp16) which is one of the most attractive targets in the virus life cycle, responsible for the viral RNA protection via a cap formation process. Firstly, nsp16 enzyme bound to Sinefungin was retrieved from the protein data bank (PDB ID: 6WKQ), then, a 3D pharmacophore model was constructed to be applied to screen 48 Million drug-like compounds of the Zinc database. This resulted in only 24 compounds which were subsequently docked into the enzyme. The best four score-ordered hits from the docking outcome exhibited better scores compared to Sinefungin. Finally, three molecular dynamics (MD) simulation experiments for 150 ns were carried out as a refinement step for our proposed approach. The MD and MM-PBSA outputs revealed compound 11 as the best potential nsp16 inhibitor herein identified, as it displayed a better stability and average binding free energy for the ligand-enzyme complex compared to Sinefungin. [ABSTRACT FROM AUTHOR]

Introduction: The most successful surgical management of periventricular and intraventricular cysts is still a matter of debate. Up to the early 1990s, open cyst fenestration and cystoperitoneal shunts were the only options available. Recently, different endoscopic approaches to these lesions have gained popularity. Methods: Eighteen endoscopic procedures were performed for the treatment of arachnoid cysts in 18 patients. Sylvian fissure arachnoid cysts were excluded from this study. Ten of them were females and eight were males with their ages ranging from 6 months to 50 years with a mean of 16 years. All patients were prospectively observed. Results: Seven of the arachnoid cysts were in the suprasellar region, 5 in the quadrigeminal region, 2 in the posterior fossa, 2 parietal, and 2 intraventricular. Seventeen cases (94%) had hydrocephalus. The main presenting manifestations were those of increased intracranial pressure. All fenestrations were done in the lateral ventricle except for the 2 cases with posterior fossa arachnoid cysts, the fenestrations were done to the fourth ventricle. Endoscopic ventriculocytostomies (VC) were performed in 14 cases without operative complications and no stents were placed. Endoscopic cystocisternostomies (C) were done in all suprasellar cases. Endoscopic cystoventriculostomies (CV) were done in 4 cases. The mean surgical time was 1 h. The mean follow-up period was 15 months. Symptoms improved in 17 cases. Seventeen cases demonstrated a significant decrease of the cysts' size in the postoperative computed tomography (CT) and magnetic resonance imaging (MRI). A single case developed a complication in the form of subdural hygroma which required no intervention and was managed conservatively. Conclusion: Endoscopic management of periventricular and intraventricular arachnoid cysts is a useful safe option in the management of arachnoid cysts related to the ventricular system. [ABSTRACT FROM AUTHOR]

Background: Colonoscopy is one of the commonly performed procedures for the diagnosis of colonic disorders. Several sedation regimens are administered during colonoscopy. To date, the propofol-based sedation regimen is commonly used, although it may have some risks. I studied the efficacy of dexmedetomidine–lidocaine combination as a substitution for propofol for sedation in colonoscopy procedures. It is a prospective randomized controlled study; 62 patients were recruited and divided into two equal groups: group P is the propofol group which included patients who received sedation with IV propofol using a loading dose of 50–100 mg of propofol and were continued on propofol IV infusion 25–75 μg/kg/min and group D-L is the dexmedetomidine–lidocaine group where patients received a loading dose of dexmedetomidine 1 μg/kg infused over 10 min followed by infusion of dexmedetomidine 0.2–0.7 μg/kg/h and lidocaine 1 mg/kg IV followed by an infusion of 1.5 mg/kg/h. The primary outcome was the median patients' satisfaction scores after recovery assessed by the Likert 5-item scoring system. Other outcomes included postprocedure pain score, mean arterial blood pressure, saturation, heart rate during the procedure, amount of fentanyl and midazolam used during the procedure, and the number of apneic attacks. Results: Patients in both groups were satisfied by the procedure, and the median and 1st–3rd IQ satisfaction scores were 5 (4.0–5.0) in group P and 4 (4.0–5.0) in group D-L; however, this difference was statistically significant (P value = 0.014), reflecting more satisfaction in patients who received propofol. Patients in group D-L required significantly more doses of midazolam and fentanyl to achieve an adequate sedation score, had a more significant drop in heart rate, and had significantly more postoperative pain scores than those in group P. Patients in group P had significantly more apneic attacks and lower intraprocedural oxygen saturation levels than those in group D-L. Conclusion: Dexmedetomidine–lidocaine combined IV infusion was found to be effective and safe for sedation in colonoscopy with less side effects in terms of apneic attacks and desaturation, although patient satisfaction was significantly higher in the propofol group, yet as per the sedation scores this was considered to be clinically non-significant. Trial registration: The study was registered by the Australian New Zealand Clinical Trials Registry (trial ID: 12620000249954). [ABSTRACT FROM AUTHOR]

In this study, we evaluated the changes in resting-state networks (RSNs) under anesthesia in neurosurgical patients. RSNs were analyzed in 12 patients with pituitary adenoma presented by chiasma compression operated via standard transsphenoidal approach under propofol anesthesia before and after tumor resection. All the patients had suprasellar tumor extension with compression of the optic chiasma. We investigated second-level effects by contrasting dummy-encoded covariates representing the effects of the sessions (first vs. second) on RSNs. We corrected for multiple comparisons using a false discovery rate of 0.05 (2-sided). Connectivity between the right and left precentral gyri (motor network) decreased significantly from the first to the second session (P = 0.0002), as did the connectivity between the postcentral gyri (P = 0.009). The same was valid for connectivity between the visual cortices (P = 0.0002). The salience network showed a significant decrease in the connectivity of the anterior part of the cingulate gyrus and insular cortex (P = 0.0001). The default mode network showed a decrease in the connectivity between the posterior part of the cingulate gyrus, parietal, and frontal cortices (P = 0.0002). There was no significant correlation between the reduction in connectivity and dose or duration of anesthesia. Different RSNs could be identified under anesthesia and used for intraoperative brain mapping and remapping during tumor resection. However, RSNs showed a significant decrease in connectivity with the continuation of anesthesia. [ABSTRACT FROM AUTHOR]

Background: Placenta accreta is an obstetric emergency and the main cause of maternal morbidity and mortality due to the associated bleeding and coagulopathy. Tranexamic acid has been widely used to decrease blood loss in trauma patients and patients with postpartum hemorrhage. We aimed at studying the effect of tranexamic acid in reducing blood loss and blood transfusion in patients with placenta accreta. Methods: In a double-blinded randomized controlled study, 46 patients were recruited and divided into two groups, Group A is the tranexamic group where patients received 10 mg/kg tranexamic acid after cord clamping and continued on tranexamic infusion 10 mg/kg/h till the end of the surgery. Group B is the placebo where patients received normal saline instead. Primary outcome was the amount of intraoperative blood loss, and other outcomes included the number of blood and blood products transfused intraoperative and in the first 24 h postoperative, the immediate postoperative Hb level, platelet count, and coagulation profile. Data were collected, coded, tabulated, and then analyzed using Minitab® 16.1.0 statistics software package. Variables were presented as mean and standard deviation and analyzed using unpaired t test. Any difference with p value < 0.05 was considered statistically significant. Results: Amount of intraoperative blood loss was significantly less in the tranexamic group 2232 ± 1204 ml compared to the placebo group 3405 ± 1193 ml (p value 0.002), and patients in the tranexamic group received less units of packed red blood cells, fresh frozen plasma, and platelets compared to those in the placebo group (4.2 ± 1.9 vs 6.1 ± 2.2 with p value 0.003, 3.4 ± 1.3 vs 4.2 ± 1.2 with P value 0.036 and 4.8 ± 2.1 vs 6.2 ± 2.4 with p value 0.041, respectively). There was no statistically significant difference in the first postoperative Hb level, platelet count, and coagulation profile between the two groups; however, the amount of blood and products transfused in the first 24 h postoperative were significantly less in the tranexamic group Conclusion: Tranexamic acid infusion was effective in reducing intraoperative blood loss and intraoperative and postoperative blood and blood products' transfusion. [ABSTRACT FROM AUTHOR]

Clipping of aneurysms located in the anterior communicating artery (AcomA) is considered a critical surgical procedure for neurosurgeons worldwide because of the complexity of the surgical area. The present study was conducted to discuss the importance of the geometric curvatures and the direction of the dominant A1 artery and their impact on aneurysmal growth direction and choice of side selection of the pterional surgical approach side. The present study enrolled 183 patients with ruptured AcomA-located aneurysms. The aneurysms were all treated surgically through a pterional approach. Because of multiple dominant A1 directions, we divided the artery into 2 segments, and based on the second segment direction, we categorized the patients into ascending A1, descending A1, and horizontal A1 groups. The ascending group includes the superiorly projecting aneurysms, whereas the horizontal and descending groups include the anteriorly and inferiorly projecting aneurysms, respectively. A contralateral pterional approach to the dominant A1 was chosen for aneurysms with an ascending artery. However, the ipsilateral pterional approach was conducted in the horizontal and descending A1 dominant groups. The aneurysmal growth projection axis always follows the direction of the second dominant A1 segment. Full neck control with satisfactory inspection of perforators was achieved through the contralateral approach in most cases of an ascending A1, especially if ipsilateral A2 was posterior to the neck. The A1 segment can be satisfactorily seen from the contralateral exposure before the aneurysmal neck is exposed in ascending A1 geometries. A1 direction is an important additional factor that is to be considered for side selection when deciding pterional exposure of A1 bifurcation aneurysms. Accessing the contralateral dominant ascending A1 has better visualization of the neck than entering from an ipsilateral approach, especially if the ipsilateral A2 was posterior to the neck. [ABSTRACT FROM AUTHOR]

Derivatives with tetrahydrobenzo[ h ]quinoline chemotype were synthesized via one-pot reactions and evaluated for their antileishmanial, antimalarial and antitubercular activities. Based on a structure-guided approach, they were designed to possess antileishmanial activity through antifolate mechanism, via targeting Leishmania major pteridine reductase 1 (Lm -PTR1). The in vitro antipromastigote and antiamastigote activity are promising for all candidates and superior to the reference miltefosine, in a low or sub micromolar range of activity. Their antifolate mechanism was confirmed via the ability of folic and folinic acids to reverse the antileishmanial activity of these compounds, comparably to Lm -PTR1 inhibitor trimethoprim. Molecular dynamics simulations confirmed a stable and high potential binding of the most active candidates against leishmanial PTR1. For the antimalarial activity, most of the compounds exhibited promising antiplasmodial effect against P. berghei with suppression percentage of up to 97.78%. The most active compounds were further screened in vitro against the chloroquine resistant strain P. falciparum, (RKL9) and showed IC 50 value range of 0.0198–0.096 μM, compared to IC 50 value of 0.19420 μM for chloroquine sulphate. Molecular docking of the most active compounds against the wild-type and quadruple mutant pf DHFR-TS structures rationalized the in vitro antimalarial activity. Some candidates showed good antitubercular activity against sensitive Mycobacterium tuberculosis in a low micromolar range of MIC, compared to 0.875 μM of isoniazid. The top active ones were further tested against a multidrug-resistant strain (MDR) and extensively drug-resistant strain (XDR) of Mycobacterium tuberculosis. Interestingly, the in vitro cytotoxicity test of the best candidates displayed high selectivity indices emphasizing their safety on mammalian cells. Generally, this work introduces a fruitful matrix for new dual acting antileishmanial-antimalarial chemotype graced with antitubercular activity. This would help in tackling drug-resistance issues in treating some Neglected Tropical Diseases. [Display omitted] • New tetrahydrobenzo[ h ]quinoline chemotype were synthesized via one-pot reactions. • They were designed to possess antileishmanial activity via antifolate mechanism. • Dual antileishmanial-antimalarial graced with antitubercular activity were observed. • Molecular docking and dynamics rationalized the observed antileishmanial activity. • Most actives candidates showed low toxicity and high safety. [ABSTRACT FROM AUTHOR]

Background and Aims: Paediatric cardiac surgery with cardiopulmonary bypass (CPB) is associated with a marked inflammatory response and triggers release of inflammatory cytokines. The aim of this study was to study the effect of ketamine on the inflammatory response during correction of congenital cyanotic heart diseases. Methods: Sixty-six patients with congenital cyanotic heart diseases scheduled for cardiac surgery were randomised into three groups. Group A patients did not receive ketamine (control group), Group B patients received 2 mg/kg ketamine intravenous (IV) and Group C patients received ketamine 2 mg/kg IV and an IV infusion of ketamine (50 μg/kg/min). Interleukin (IL) levels for IL-6, IL-8, IL-10, C-reactive protein (CRP) and tumour necrosis factor-α (TNF-α) levels were examined in the three groups at four timings: pre-operative (baseline), intraoperative (after weaning off the CPB) and post-operative (6 and 24 h after weaning off CPB). Paired sample t-test and ANOVA test were used for statistical analysis and P < 0.05 was considered statistically significant. Results: Within each group, the intra- and post-operative serum levels of IL-6, IL-8, IL-10 and CRP were significantly elevated from the baseline, however, TNF-α was not significantly elevated. There were no statistically significant differences in the IL, CRP or TNF-α levels between the three groups. Conclusion: Paediatric cardiac surgery for congenital cyanotic heart disease is a triggering factor for the inflammatory response, yet we could not detect any beneficial effect of ketamine on that response whether given either as an IV induction dose or continued as an IV infusion. [ABSTRACT FROM AUTHOR]

Context Postoperative pain management for renal transplant recipients is limited by considerations related mainly to the impaired renal functions. Patient-controlled analgesia (PCA) by fentanyl has been used and provides good pain control. The transversus abdominis plane (TAP) block provides good postoperative analgesia for abdominal surgeries Aims The aim of the present study was to examine the efficacy of the TAP block using 30 ml bupivacaine 0.25% in reducing the postoperative fentanyl requirements in renal transplant recipients Patients and materials This double-blinded, prospective, randomized, controlled study included 50 patients divided into two equal groups: group A, the control group, which included patients who received the TAP injection with only normal saline and kept on PCA fentanyl; and group B, the TAP block group, which included patients who received the TAP block using 30 ml of bupivacaine 0.25% in addition to PCA fentanyl. The primary outcome was the postoperative 24 h fentanyl consumption, whereas other outcomes included pain scores, heart rate, mean arterial blood pressure, and incidence of nausea, vomiting, excessive sedation, and respiratory depression. Results Postoperative 24 h PCA fentanyl consumption was significantly lower in the TAP block group (330.9±36.8) compared with the control group (636.9±40) (P<0.01). The pain scores recorded in the TAP group were significantly lower (P<0.01). Mean arterial blood pressure was also significantly lower in the TAP group; however, differences between the recorded heart rates were nonsignificant (P=<0.01 and 0.6, respectively). None of the patients developed excessive sedation or respiratory depression. Conclusion A TAP block with 30 ml bupivacaine 0.25% provides excellent postoperative analgesia for renal transplant recipients and significantly reduced the 24 h postoperative PCA fentanyl requirements and the pain scores. [ABSTRACT FROM AUTHOR]

Background: Structure-based virtual screening techniques can help to identify new lead structures and complement other screening approaches in drug discovery. Prior to docking, the data (protein crystal structures and ligands) should be prepared with great attention to molecular and chemical details. Results: Using a subset of 18 diverse targets from the recently introduced DEKOIS 2.0 benchmark set library, we found differences in the virtual screening performance of two popular docking tools (GOLD and Glide) when employing two different commercial packages (e.g. MOE and Maestro) for preparing input data. We systematically investigated the possible factors that can be responsible for the found differences in selected sets. For the Angiotensin-I-converting enzyme dataset, preparation of the bioactive molecules clearly exerted the highest influence on VS performance compared to preparation of the decoys or the target structure. The major contributing factors were different protonation states, molecular flexibility, and differences in the input conformation (particularly for cyclic moieties) of bioactives. In addition, score normalization strategies eliminated the biased docking scores shown by GOLD (ChemPLP) for the larger bioactives and produced a better performance. Generalizing these normalization strategies on the 18 DEKOIS 2.0 sets, improved the performances for the majority of GOLD (ChemPLP) docking, while it showed detrimental performances for the majority of Glide (SP) docking. Conclusions: In conclusion, we exemplify herein possible issues particularly during the preparation stage of molecular data and demonstrate to which extent these issues can cause perturbations in the virtual screening performance. We provide insights into what problems can occur and should be avoided, when generating benchmarks to characterize the virtual screening performance. Particularly, careful selection of an appropriate molecular preparation setup for the bioactive set and the use of score normalization for docking with GOLD (ChemPLP) appear to have a great importance for the screening performance. For virtual screening campaigns, we recommend to invest time and effort into including alternative preparation workflows into the generation of the master library, even at the cost of including multiple representations of each molecule. [ABSTRACT FROM AUTHOR]

Background: Caudal analgesia is the most commonly used technique providing intra- and postoperative analgesia for various pediatric infraumbilical surgical procedures but with the disadvantage of short duration of action after single injection. Caudal dexamethasone and magnesium could offer significant analgesic benefits. We compared the analgesic effects and side-effects of dexamethasone or magnesium added to caudal ropivacaine in pediatric patients undergoing inguinal hernia repair. Materials and Methods: A total of 105 (1-6 years) were randomly assigned into three groups in a double-blinded manner. After a standardized sevoflurane in oxygen anesthesia, each patient received a single caudal dose of ropivacaine 0.15% 1.5 mL/kg combined with either magnesium 50 mg in normal saline 1 mL (group RM), dexamethasone 0.1 mg/kg in normal saline 1 mL (group RD), or corresponding volume of normal saline (group R) according to group assignment. Postoperative analgesia, use of analgesics, and side-effects were assessed during the first 24 h. Results: Addition of magnesium or dexamethasone to caudal ropivacaine significantly prolonged analgesia duration 8 (5-11) h and 12 (8-16) h, respectively compared with 4 (3-5) h with the use of ropivacaine alone. The incidence of postoperative rescue analgesia was significantly higher in group R compared with groups RM and RD. The time to 1st analgesic dose was significantly longer in groups RM and RD (500 ± 190 and 730 ± 260 min) respectively compared with group R (260 ± 65 min). Group R patients achieved significantly higher Children's Hospital of Eastern Ontario Pain Scale and Faces Legs Activity Cry Consolability scores (4th hourly) compared with groups RM and RD patients (8th and 12th hourly, respectively). Conclusion: The addition of dexamethasone or magnesium to caudal ropivacaine significantly prolonged the duration of postoperative analgesia in children undergoing inguinal hernia repair. Also the time to 1st analgesic dose was longer and the need for rescue postoperative analgesic was reduced and without increase in incidence of side effects. [ABSTRACT FROM AUTHOR]

Background: Morbid obesity magnifies the importance of the fat-blood solubility coefficient of the anesthetic in its relation to emergence and recovery. Using bispectral index (BIS) monitoring for the titration of the administration of inhaled anesthetics such as desflurane may permit a less consumption and more rapid recovery from desflurane anesthesia in morbidly obese patients, which enables earlier maintenance of a patent airway, better protection against aspiration, and better oxygenation. Objective: The aim of this study was to investigate the effect of BIS monitoring on postoperative extubation and recovery times, and intraoperative desflurane consumption in morbidly obese patients undergoing laparoscopic sleeve gastrectomy under general anesthesia using desflurane for maintenance. Patients and Methods: Forty morbidly obese patients were randomly enrolled in this study and divided into two groups of 20 patients each: Non-BIS group and BIS group. End-tidal desflurane concentration, mean blood pressure, and heart rate were regularly recorded. Recovery times (eye opening to verbal commands, time to extubation, and orientation to time, place, and person) and the time to achieve a modified Aldrete score of ≥ 9 were recorded by blinded study anesthesia nurse. Desflurane consumption was calculated in milliliters through gas usage option of Datex-Ohmeda S/5 anesthesia machine. Results: The mean end-tidal concentrations of desflurane were significantly decreased in the BIS group compared to the non-BIS group (P < 0.05). The mean desflurane consumption and cost were significantly lower in the BIS group (124.8 ± 5.1 ml/patient) compared to the non-BIS group (150.6 ± 6.5 ml/patient) (P < 0.05). Recovery times were significantly shorter in the BIS group versus non-BIS group (P < 0.05). Conclusion: The use of BIS monitoring was effective in reducing intraoperative desflurane requirement (cost) and in shortening early recovery times after laparoscopic sleeve gastrectomy in morbidly obese patients without compromising the hemodynamic stability, adequacy of anesthesia, or patient outcome. [ABSTRACT FROM AUTHOR]

A new series of Schiff–benzimidazole hybrids 3a–o has been designed and synthesized. The structure of the target compounds was proved by different spectroscopic and elemental analysis tools. The target compounds were evaluated for their in vitro cytotoxic activity against 60 cancer cell lines according to NCI single- and five-dose protocols. Consequently, four compounds were further examined against the most sensitive lung cancer A549 and NCI-H460 cell lines. Compounds 3e and 3g were the most active, achieving 3.58 ± 0.53, 1.71 ± 0.17 and 1.88 ± 0.35, 0.85 ± 0.24 against A549 and NCI-H460 cell lines, respectively. Moreover, they showed remarkable inhibitory activity on the VEGFR-2 TK with 86.23 and 89.89%, respectively, as compared with Sorafenib (88.17%). Moreover, cell cycle analysis of NCI-H460 cells treated with 3e and 3g showed cellular cycle arrest at both G1 and S phases (supported by caspases-9 study) with significant pro-apoptotic activity, as indicated by annexin V-FITC staining. The binding interactions of these compounds were confirmed through molecular docking studies; the most active compounds displayed complete overlay with, and a similar binding mode and pose to, Sorafenib, a reference VEGFR-2 inhibitor. [ABSTRACT FROM AUTHOR]

Abstract: Two series of 4,6-diaryl-2-imino-1,2-dihydropyridine-3-carbonitriles and their isosteric 4,6-diaryl-2-oxo-1,2-dihydropyridine-3-carbonitriles were synthesized through a combinatorial approach. The prepared analogues were evaluated for their in vitro capacity to inhibit PDE3A and the growth of the human HT-29 colon adenocarcinoma tumor cell line. Compound 6-(4-bromophenyl)-4-(2-ethoxyphenyl)-2-imino-1,2-dihydropyridine-3-carbonitrile (Id) exhibited the strongest PDE3 inhibition when cGMP but not cAMP is the substrate with a IC50of 27μM, which indicates a highly selective mechanism of enzyme inhibition. On the other hand, compound 6-(1,3-benzodioxol-5-yl)-4-(2-ethoxyphenyl)-2-imino-1,2-dihydropyridine-3-carbonitrile (Ii) was the most active in inhibiting colon tumor cell growth with a IC50 of 3μM. The electronic effects, steric effects and conformational aspects of Id seem to be the most crucial for the PDE3 inhibition. Meanwhile, steric factors and the H-bonding capability seem to be the most important factors for tumor cell growth inhibitory activity. Conversely, there is no direct correlation between PDE3 inhibition and anticancer activity for the prepared compounds. An in silico docking experiment indicates the potential involvement of other potential molecular targets such as PIM-1 kinase to explain its tumor cell growth inhibitory activity. [Copyright &y& Elsevier]

In this paper, a multiport driving mechanism is numerically implemented at ultra high-field (UHF) magnetic resonance imaging (MRI) to provide 1) homogenous whole-slice (axial, sagittal, or coronal) and 2) highly localized radio frequency (RF) field excitation within the same slices, all with the same RF transmit array (here chosen to be a standard transverse electromagnetic (TEM) resonator/coil). The method is numerically tested using a full-wave model of a TEM coil loaded with a high-resolution/18-tissue/anatomically detailed human head mesh. The proposed approach is solely based on electromagnetic and phased array antenna theories. The results demonstrate that both homogenous whole-slice as well as localized RF excitation can be achieved within any slice of the head at 7 T (298 MHz for proton imaging). [ABSTRACT FROM AUTHOR]

The magnetic resonance imaging (MRI) coil's radio frequency (RF) field distribution has a strong effect on image quality as well as specific absorption rate. In this paper, a method of probing a coil's RF field distribution over any unoccupied region of the coil is presented. This technique is based on the use of infrared sensing. The proposed method was implemented and tested on a high field RF volume coil operating at 340 MHz. Very good agreement was achieved between the infrared measurements and numerical data obtained utilizing an in-house three-dimensional finite-difference time-domain package. The results demonstrate that the proposed technique is practical, robust, and efficient in making accurate measurements of the electric field distributions in loaded and unloaded MRI coils. [ABSTRACT FROM AUTHOR]

In this paper, two TEM resonators were evaluated experimentally and numerically at 8 tesla (T) (340 MHz for ¹H imaging). The coils were constructed to be 21.2cm long (standard) and 11-cm long (a proposed less claustrophobic design). The experimental evaluation was done on a single cadaver using an ultra high field, S T, whole-body magnet. The numerical modeling was performed using an in-house finite difference time domain packagethat treats the coil and the load (anatomically detailed human head model) as a single system. The coils were tested with quadrature excitation at different coil alignment positions with respect to human head. For head imaging at S T, the overall numerical and experimental results demonstrated that when compared to the longer coil, the shorter coil provides superior signal-to-noise ratio, coil sensitivity, and excite field in the biological regions that lie within both of the coils' structures. A study of the RF (excite/receive fields) homogeneity showed variations in the performance of both coils that are mostly dependant on the region of interest and the position of coil with respect to the head. As such, depending on the application, the shorter coil could be effectively utilized. [ABSTRACT FROM AUTHOR]

Abstract: Deterioration of radiofrequency (RF) inhomogeneity with increasing static magnetic field in magnetic resonance imaging (MRI) is one of the fundamental challenges preventing their clinical rendition and posing safety hazards. Variation in RF coil designs could help redistribute RF energy absorption over the imaged object. This work is intended to determine experimentally the difference in RF heating produced within a human head phantom by in situ measurement of RF inhomogeneity as a function of coil design utilized at 8 T. The heating patterns of 1/4 wavelength (long) and 1/8 wavelength 11-cm (short) transverse electromagnetic (TEM) coils loaded with a homogeneous human head phantom at 340 MHz were evaluated. In addition, different transmit/receive (T/R) configurations were used in search for the possibility of “hot-spot” formation. Fluoroptic thermometry was used to measure temperatures in multiple positions in a head phantom made of ground turkey breast for RF powers corresponding to a specific absorption rate (SAR) of 4.0 W/kg for 10 min. Numerical simulations were performed to study the general RF power deposition patterns in phantoms at 340 MHz including the effects of field polarization. The temperature increases varied from 0 to 0.8°C for the long RF coil, while the short RF coil produced a maximum temperature change of 0.5°C. Similar to ultra high-field electromagnetic simulations, these measurements revealed low peripheral and high deep-tissue heating at 8 T. The findings indicated that the largest temperature changes for both cases were less than 1°C. While these results showed an increase in localized heating due to RF pulses at 8 T, they highlight that RF inhomogeneity could be redistributed using different RF coil designs through which the hot spots could be made cooler. [Copyright &y& Elsevier]

In this paper, a numerical analysis of the radio-frequency (RF) power requirements in magnetic resonance imaging (MIII) is presented at frequencies that span 200-362 MHz. This was performed utilizing an anatomically detailed human head model and a high-frequency RF coil utilized in high-field Mill systems. For axial slices through the brain region, it is demonstrated that the power required in order to obtain an average flip angle across the slice increases with frequency plateauing at a certain value, and then dropping as the frequency increases. The results demonstrate the significance of the electromagnetic interactions between the load and coil and their effects on the so important issue of power-frequency dependence in MRI. [ABSTRACT FROM AUTHOR]

Background: Intravenous lidocaine has been shown to be an analgesic and anti-inflammatory medication with modulation of excessive inflammatory response. We investigated the efficacy of intraoperative lidocaine 2% infusion in reducing the postoperative Fentanyl requirements for analgesia in renal transplant recipients. Patients were assigned equally into two groups by computer-generated list compiled before the start of the study. Control group: fentanyl (F) group and study group: lidocaine 2% (L) group. Medication used is either lidocaine in the dose of 2 mg/kg/h and the other syringe contained saline both have been infused by rate of 10 ml/h. Fentanyl induction dose given for the two groups was 1.5 mcg/kg. Both groups have received extra fentanyl according to their intraoperative analgesic requirements, patients in the lidocaine group received the fentanyl induction dose accompanied by lidocaine 2% 1.5 mg/kg as loading dose, followed by maintenance dose of lidocaine 2% infusion 2 mg/kg/h. After transfer to the PACU nursing staff administered fentanyl 0.5 mcg/kg boluses for postoperative pain relief every 10 min up to 2 mcg/kg, the recovery nurse used the pain numerical score to assess pain. The recovery nurse referred the patient to the responsible anesthesiologist covering the recovery unit if he required more than 2 mcg/kg of fentanyl to control postoperative pain. Patient was then transferred to the RTU (renal transplant unit), postoperative pain and fentanyl PCA consumption were followed up during the first 24 h. Results: Our study detected increased fentanyl consumption in the recovery for the fentanyl group more than the lidocaine group. The request of the first dose of analgesic was significantly longer in lidocaine group than in fentanyl group. Conclusion: The usage of intraoperative lidocaine infusion decreased postoperative fentanyl requirements as analgesic in patients undergoing renal transplantation. Trial registration: Registration on ANZCTR number ACTRN12618001335280, REGISTERED 08 August 2018. [ABSTRACT FROM AUTHOR]

• New pyrazolo[3,4-d]pyrimidines and pyrazolo[4,3-e][1,2,4]triazolo[4,3-a]pyrimidines were designed and synthesized. • In vitro COX-1/COX-2 inhibitory assay. • In vivo formalin paw edema and cotton pellets induced granuloma assays. • Docking experiments rationalized in vitro COX-2 inhibitory activity. • In silico pharmacokinetics and drug-likeness predictions recommended acceptable profiles. New pyrazolo[3,4- d ]pyrimidinone and pyrazolo[4,3-e][1,2,4]triazolo[4,3- a ]pyrimidinone derivatives were synthesized. They have been evaluated for their anti-inflammatory activity using in vitro (COX-1/COX-2) inhibitory assay. Moreover, compounds with promising in vitro activity and COX-1/COX-2 selectivity indices were subjected for in vivo anti-inflammatory testing using formalin induced paw edema and cotton-pellet induced granuloma assays for acute and chronic models, respectively. Compounds (2c, 3i, 6a, 8 and 12) showed promising COX-2 inhibitory activity and high selectivity compared to celecoxib. Most of the compounds exhibited potential anti-inflammatory activity for both in vivo acute and chronic models. Almost all compounds displayed safe gastrointestinal profile and low ulcerogenic potential guided by histopathological examination. Furthermore, molecular docking experiments rationalized the observed i n vitro anti-inflammatory activity of selected candidates. In silico predictions of the pharmacokinetic and drug-likeness properties recommended accepted profiles of the majority of compounds. In conclusion, this work provides an extension of the chemical space of pyrazolopyrimidinone and pyrazolotriazolopyrimidinone chemotypes for the anti-inflammatory activity. [ABSTRACT FROM AUTHOR]

Background Purpose: Vein of Galen aneurysmal malformations (VGAM) may carry life-threatening and catastrophic sequelae in children. Their clinical presentations are differently variable between cardiac and cerebral syndromes. There may be a possible relationship between the Galenic angioarchitecture and the clinical presentation. We aimed to study the effect of the venous outflow impairment on the incidence of high-flow heart failure and the incidence of hydrocephalus. Materials and Methods: The angiographies of 21 patients with true VGAM have been studied. MR angiography, 3-dimensional CT angiogram (3D CTA), and conventional digital subtraction angiography were performed for all patients with true VGAM. Transarterial embolization was done in 1 or more sessions for all cases. Results: Among the 21 cases, 14 cases were mural type, 5 cases were choroidal type, and 2 cases were mixed. Hydrocephalus was observed more in infants (92.3%), mural types (92.9%), giant and supergiant (87.5%) aneurysms, and in cases with persistent limbic circle (90.91%). All cases of hydrocephalus were associated with significant stenosis (>70%) of the Falcine sinus draining system (100%). Conclusion: Significant stenosis (>70%) of the draining sinus is a significant factor for VGAM aneurysmal enlargement and occurrence of hydrocephalus. Probably, venous outflow impairment decreases the incidence of high-flow heart failure and increases the incidence of hydrocephalus. [ABSTRACT FROM AUTHOR]

The paraventricular nucleus of the hypothalamus (PVN) is uniquely capable of proximal control over autonomic and neuroendocrine stress responses, and the bed nucleus of the stria terminalis (BNST) directly modulates PVN function, as well as playing an important role in stress control itself. The dorsal BNST (dBNST) is predominantly preautonomic, while the ventral BNST (vBNST) is predominantly viscerosensory, receiving dense noradrenergic signaling. Distinguishing the dBNST and vBNST, along with the PVN, may facilitate our understanding of dynamic interactions among these regions. T1-weighted MPRAGE and high resolution gradient echo (GRE) modalities were acquired at 7T. GRE was coregistered to MPRAGE and segmentations were performed in MRIcroGL based on their Atlas of the Human Brain depictions. The dBNST, vBNST and PVN were manually segmented in 25 participants; 10 images were rated by 2 raters. These segmentations were normalized and probabilistic atlases for each region were generated in MNI space, now available as resources for future research. We found moderate–high inter-rater reliability [n = 10; Mean Dice (SD); PVN = 0.69 (0.04); dBNST = 0.77 (0.04); vBNST = 0.62 (0.04)]. Probabilistic atlases were reverse normalized into native space for six additional participants that were segmented but not included in the original 25. We also found moderate to moderate–high reliability between the probabilistic atlases and manual segmentations [n = 6; Mean Dice (SD); PVN = 0.55 (0.12); dBNST = 0.60 (0.10); vBNST = 0.47 (0.12 SD)]. By isolating these hypothalamic and BNST subregions using ultra-high field MRI modalities, more specific delineations of these regions can facilitate greater understanding of mechanisms underlying stress-related function and psychopathology. [ABSTRACT FROM AUTHOR]

Objectives A lack of "morningness" predicts greater depression symptom severity over time, including in a vulnerable group of older adults: family dementia caregivers (dCGs). Evidence regarding the neurobiological basis of these correlations is needed to guide future research towards biomarker-informed detection and prevention approaches. We therefore primarily aimed to identify simple resting-state biomarkers that correlated with a lack of "morningness" in dCGs. Method We examined 54 dCGs (mean age = 70, range: 61–84; 70% female) of whom 40% were definite "morning types" according to Composite Scale of Morningness (CSM). Using a 7 Tesla resting-state sequence, we compared the functional connectivity of nodes in networks previously implicated in depression (fronto-parietal, default mode, limbic, and salience) between caregivers who were and were not "morning types." Results Correcting for voxel-wise comparisons, "morning-type" dCGs had less amygdala–posterior cingulate connectivity (Cohen's d = −1.3), which statistically mediated ~32% of the association between the degree of "morningness" and lower depression severity. Post hoc analyses of CSM items found significant correlations, with both amygdala–posterior cingulate FC and depression severity, for 4/6 items pertaining to difficulty, 2/5 items pertaining to preference, and 0/2 items pertaining to typical patterns. Discussion Prior research shows that amygdala–posterior cingulate connectivity increases when allocating attention to peripheral aspects of negative emotional stimuli. As such, difficulty with morning activation may relate to the ongoing direction of focus around distressing content; in contrast, morning activity participation may serve to limit focus on distress. Replication and experimental studies are required to confirm these associations and their modifiability. [ABSTRACT FROM AUTHOR]

Background: Propofol use in MRI procedures is growing worldwide especially for infants and children. Propofol causes unintended deep sedation and respiratory depression. The safety and efficacy of dexmedetomidine–propofol versus ketamine–dexmedetomidine versus dexmedetomidine alone as a based sedation regimen in specific age range of children is the study concern. Objective: The aim of this study is to compare the efficacy of dexmedetomidine/propofol mixture, dexmedetomidine/ketamine, and dexmedetomidine alone for pediatric MRI sedation. Patients and methods: Ninty infants and children whose body weight is more than 10 kg were enrolled in a double-blind comparative study and assigned into three equal groups for sedation, group (DK) dexmedetomidine/ ketamine, group (DP) dexmedetomidine/propofol, and group (D) dexmedetomididne alone. All patients were given premedication in the form of oral midazolam 0.5 mg/kg 30 min before the procedure. Sedation was according to group: Group (DK) received ketamine 1.5 mg /kg intravenous bolus as a loading dose and maintenance dose done by dexmedetomidine infusion with a concentration of 0.004 mg/ml and infusion rate of 1 μg/kg/h for the first 10 min then reduced infusion dose to be in between 0.6 and 1 μg/kg/h to keep the patient sedated to a Ramsay sedation score more than 4. Group (DP) received propofol 1.5 mg/kg intravenous bolus as a loading dose, then maintenance dose infusion was a mixture of dexmedetomidine with a concentration of 0.004 mg/ml and propofol 4 mg/ml; this combination is compatible (Trissel et al., 2002; Cayo, 2013). This combination will be started by a loading dose of 1 μg/kg/h for the first 10 min then 0.6 to 1 μg/kg/h, sedated with a Ramsay sedation score of more than 4. Group (D) received dexmedetomidine with a dose of 2–3 μg/kg/h as loading for 10 min then 0.6 to 1 μg/kg/h to keep the patient sedated with a Ramsay sedation score of more than 4. Results: There was a significant difference between the DP group induction recovery time, hemodynamics, and Ramsey sedation score up to 5 min after the induction to the other two groups, and there was a significant difference between the DK group to the other two groups concerning emergence phenomena (agitation, altered perception, hallucination) and sedation failure. Conclusion: The combination of dexmedetomidine to propofol with a low dose for sedation during MRI gives better induction + recovery time, improves hemodynamics, and decreases incidence of emergence phenomena and sedation failure. [ABSTRACT FROM AUTHOR]

In our technical note, we have presented a technique of cranioplasty for large skull defects. A thin-slice computed tomography scan is performed. A model of the skull is constructed using a desktop 3-dimensional printer from the computed tomography scan. The skull model is filled with towels of soft cotton and inserted in a sterile thin plastic bag. The implant is molded intraoperatively on the skull model under sterile conditions. After surgical exposure of the skull defect, the implant is inserted and fixed using miniplates and miniscrews. The technique was used in 6 patients and described in 2 representative cases. The required time and cost are significantly lower than those for other techniques used for preoperative manufacture of implants. No technique-related complications occurred. The radiological and cosmetic results were satisfactory. In the present case series, no early or delayed complications occurred. The presented technique is simple, safe, and time- and cost-effective. The technique and results are reproducible. [ABSTRACT FROM AUTHOR]

Grade III brain arteriovenous malformation (AVM) is a distinct subgroup of AVMs that encompasses multiple subtypes according to the Spetzler-Martin classification. This retrospective study included 61 patients with grade III AVM who underwent embolization between 2010 and 2022. The study analyzed the angioarchitecture of the AVM nidus and evaluated the outcomes of the embolization procedures. There were 29 patients (47.5%) with subtype S1E1V1, 20 patients (32.8%) with subtype S2E1V0, and 12 patients (19.7%) with subtype S2E0V1. The rate of complete occlusion in all patients was 47.5% (29 patients). The rate of complete occlusion was higher in cases with a compact nidus (P < 0.001). Several parameters were associated with occlusion of the AVM nidus, including ≤3 arterial feeders (P = 0.017) and presentation with hemorrhage (P = 0.007), with the majority of patients with a compact nidus presenting with hemorrhage. Other factors associated with compact geometry were the presence of a single deep vein, ≤3 arterial feeders, ≤2 superficial draining veins, and an AVM nidus size ≤3 cm. The compact nature of grade III AVM is a crucial predictor for the success of embolization. Several characteristics associated with a compact nidus, such as presentation with hemorrhage and a lower number of arterial feeders, have a significantly higher closure rate. Other factors, such as a single deep draining vein, reduced superficial venous drainage, and small size, show a strong association with complete obliteration. [ABSTRACT FROM AUTHOR]

New quinoline-pyridine hybrids were designed and synthesised as PIM-1/2 kinase inhibitors. Compounds 5b, 5c, 6e, 13a, 13c, and 14a showed in-vitro low cytotoxicity against normal human lung fibroblast Wi-38 cell line and potent in-vitro anticancer activity against myeloid leukaemia (NFS-60), liver (HepG-2), prostate (PC-3), and colon (Caco-2) cancer cell lines. In addition, 6e, 13a, and 13c significantly induced apoptosis with percentage more than 66%. Moreover, 6e, 13a, and 13c significantly induced caspase 3/7 activation in HepG-2 cell line. Furthermore, 5c, 6e, and 14a showed potent in-vitro PIM-1 kinase inhibitory activity. While, 5b showed potent in-vitro PIM-2 kinase inhibitory activity. Kinetic studies using Lineweaver–Burk double-reciprocal plot indicated that 5b, 5c, 6e, and 14a behaved as competitive inhibitors while 13a behaved as both competitive and non-competitive inhibitor of PIM-1 kinase enzyme. Molecular docking studies indicated that, in-silico affinity came in coherence with the observed in-vitro inhibitory activities against PIM-1/2 kinases. [ABSTRACT FROM AUTHOR]

New spiro-piperidine derivatives were synthesised via the eco-friendly ionic liquids in a one-pot fashion. The in vitro antileishmanial activity against Leishmania major promastigote and amastigote forms highlighted promising antileishmanial activity for most of the derivatives, with superior activity compared to miltefosine. The most active compounds 8a and 9a exhibited sub-micromolar range of activity, with IC50 values of 0.89 µM and 0.50 µM, respectively, compared to 8.08 µM of miltefosine. Furthermore, the antileishmanial activity reversal of these compounds via folic and folinic acids displayed comparable results to the positive control trimethoprim. This emphasises that their antileishmanial activity is through the antifolate mechanism via targeting DHFR and PTR1. The most active compounds showed superior selectivity and safety profile compared to miltefosine against VERO cells. Moreover, the docking experiments of 8a and 9a against Lm-PTR1 rationalised the observed in vitro activities. Molecular dynamics simulations confirmed a stable and high potential binding to Lm-PTR1. [ABSTRACT FROM AUTHOR]

We investigated the added value of combining information from direction-encoded color (DEC) maps with high-resolution structural magnetic resonance imaging scans (T1-weighted images [T1WIs]) to improve the identification of regions of interest (ROIs) for fiber tracking during preoperative planning for patients with brain tumors. The dataset included 42 patients with gliomas and 10 healthy subjects from the Human Connectome Project. For identification of the ROIs, we combined the structural information from high-resolution T1WIs and the directional information from DEC maps. To test our hypothesis, we examined the interrater and intrarater agreement. We identified specific ROIs to extract the main white matter bundles. The directional information from the DEC maps combined with the T1WIs (T1WI–DEC maps) had significantly facilitated ROI identification in patients with brain tumors, especially patients in whom the tracts had been displaced by the mass effect of the tumor. Fiber tracking using the combined T1WI–DEC maps showed significantly greater inter- and intrarater agreement compared with using either T1WI or DEC maps alone. Combining the information from diffusion-derived color-encoded maps with high-resolution anatomical details from structural imaging (T1WI–DEC map), especially in patients with brain tumors, could be useful for accurate identification of the ROIs. [ABSTRACT FROM AUTHOR]

In this study we present the nature and characteristic of the fluctuation of blood oxygen level–dependent (BOLD) signals measured from brain tumors. Supratentorial astrocytomas, which were neither operated nor previously managed with chemotherapy or radiotherapy, were segmented, and the time series of the BOLD signal fluctuations were extracted. The mean (across patients) power spectra were plotted for the different World Health Organization tumor grades. One-way analysis of variance (ANOVA) was performed to identify significant differences between the power spectra of different tumor grades. Results were considered significant at P < 0.05. A total of 58 patients were included in the study. This group of patients included 1 patient with grade I glioma; 15 with grade II; 12 with grade III; and 30 with grade IV. The power spectra of the tumor time series were individually inspected, and all tumors exhibited high peaks at the lower frequency signals, but these were more pronounced in high-grade tumors. ANOVA showed a significant difference in power spectra between groups (P = 0.000). Post hoc analysis with Bonferroni correction showed a significant difference between grade II and grade III (P = 0.012) and grade IV (P = 0.000). There was no significant power spectra difference between grade III and IV tumors (P = 1). The power spectra of BOLD signals from tumor tissue showed fluctuations in the low-frequency signals and were significantly correlated with tumor grade. These signals could have a misleading effect when analyzing resting state functional magnetic resonance imaging and could be also viewed as a potential method of tumor characterization. [ABSTRACT FROM AUTHOR]

Measuring functional connectivity (FC) and resting state networks (RSNs) using resting state functional magnetic resonance imaging is a method of preoperative planning in patients with brain tumors. However, the baseline FC and RSNs are altered in patients with brain tumors. In this study, we examined changes in inter-network FC in patients with brain tumors. We performed region of interest (ROI) analysis of FC in 34 patients with supratentorial gliomas and 14 healthy subjects. We performed bivariate correlation analyses at the level of each subject. Resulting correlations were Fischer Z-transformed. The used nodes included 132 ROIs from the automated anatomical labeling atlas in addition to 32 ROIs representing the different functional brain networks. We investigated second-level effects by contrasting dummy encoded covariates representing the effects of group membership on functional connectivity. The significant 2-sided P value with corrected false discovery rate was set to 0.05. We set the t contrast between the group of patients with brain tumors and the group of healthy subjects to detect the effects of tumors on inter-network connectivity. Overall, the inter-network FC was significantly higher in patients with brain tumors compared with healthy subjects. The anterior and posterior cerebellar networks, as well as the supratentorial network, showed significantly higher connectivity in patients with brain tumors than in healthy subjects. Although brain tumors affect the FC and RSNs, the current study showed higher baseline inter-network connectivity in patients with brain tumors, which could indicate an intrinsic neural compensatory mechanism. [ABSTRACT FROM AUTHOR]

Herein we introduce new compounds as conjugates of arylnicotinic acids with aryl (thio)semicarbazide derivatives. Based on a structure-guided approach, they were designed to possess anti-leishmanial activity through anti-folate mechanism, via targeting Leishmania major pteridine reductase 1 (Lm -PTR1). The in vitro anti-promastigote and anti-amastigote activity were promising for many thiosemicarbazide derivatives and superior to the reference miltefosine. The most active compounds 8i and 8j exhibited their anti-amastigote activity with IC 50 values of 4.2 and 3.3 μM, respectively, compared to reference miltefosine (IC 50 value of 7.3). Their anti-folate mechanism was confirmed via the ability of folic and folinic acids to reverse the anti-leishmanial activity of these compounds, comparably to Lm -PTR1 inhibitor trimethoprim. Interestingly, the in vitro cytotoxicity test of the most active compounds displayed higher selectivity indices than that of miltefosine emphasizing their safety on mammalian cells. Furthermore, the docking experiments on Lm -PTR1 as a putative target rationalized the in vitro anti-leishmanial activity. The in silico predictions exhibited promising pharmacokinetics and drug-likeness profiles of the most active compounds. Generally, this work introduces a fruitful matrix for new anti-leishmanial chemotype which would extend the chemical space for the anti-leishmanial activity. Image 1 • Certain arylnicotinic acids conjugated with aryl (thio)semicarbazides were designed to target folate pathway of L. major , especially Lm -PTR1. • Reversal of anti-leishmanial activity of the most active compounds by folic acid and folinic acid validated the anti-folate mechanism. • The in vitro cytotoxicity test of the most active compounds displayed higher selectivity indices than that of miltefosine. • Docking experiments on Lm-PTR1 as a putative target rationalized the in vitro antileishmanial activity. • In silico predictions exhibited promising pharmacokinetics and drug-likeness profiles of the most active compounds. [ABSTRACT FROM AUTHOR]

Abstract In search for effective multi-targeting drug ligands (MTDLs) to address low-grade inflammatory changes of metabolic disorders, we rationally designed some novel glitazones-like compounds. This was achieved by incorporating prominent pharmacophoric motifs from previously reported COX-2, 15-LOX and PPARγ ligands. Challenging our design with pre-synthetic docking experiments on PPARγ showed encouraging results. In vitro tests have identified 4 compounds as simultaneous partial PPARγ agonist, potent COX-2 antagonist (nanomolar IC 50 values) and moderate 15-LOX inhibitor (micromolar IC 50 values). We envisioned such outcome as a prototypical balanced modulation of the 3 inflammatory targets. In vitro glucose uptake assay defined six compounds as insulin-sensitive and the other two as insulin-independent glucose uptake enhancers. Also, they were able to induce PPARγ nuclear translocation in immunohistochemical analysis. Their anti-inflammatory potential has been translated to effective inhibition of monocyte to macrophage differentiation, suppression of LPS-induced inflammatory cytokine production in macrophages, as well as significant in vivo anti-inflammatory activity. Ligand co-crystallized PPARγ X-ray of one of MTDLs has identified new clues that could serve as structural basis for its partial agonism. Docking of the most active compounds into COX-2 and 15-LOX active sites, pinpointed favorable binding patterns, similar to those of the co-crystallized ligands. Finally, in silico assessment of pharmacokinetics, physicochemical properties, drug-likeness and ligand efficiency indices was performed. Hence, we anticipate that the prominent biological profile of such series will rationalize relevant anti-inflammatory drug development endeavors. Graphical abstract Prototypical balanced modulation of 3 inflammatory targets offered by some novel glitazone-like compounds. Image 1 Highlights • 1,2,3-triazolyl-thiazolidinedione/rhodanine hybrids were rationally designed as PPARγ partial agonists/COX-2 and 15-LOX inhibitors. • COX-2 and 15-LOX in vitro assays identified 10 compounds as dual inhibitors. • Glucose uptake assay recognized 6 compounds as insulin-sensitive and 2 compounds as insulin-independent uptake enhancers, while PPARγ agonistic activity was confirmed via reporter assay and immunohistochemical analysis. • 4 Compounds showed potent inhibition of monocyte to macrophage differentiation as well as high in vivo anti-inflammatory activity. • Crystal structure of PPARγ ligand binding domain (LBD) in complex with the most active compound has been solved and demonstrated partial agonistic behavior. [ABSTRACT FROM AUTHOR]

New quinoline compounds comprising pyrazole scaffold through different amide linkages were synthesized. The synthesized compounds were evaluated for their anti-inflammatory activity. Eight compounds ( 5c , 11b,c , 12c , 14a,b , 20a and 21a ) were found to exhibit promising anti-inflammatory profiles in acute and sub-acute inflammatory models. They were screened for their ulcerogenic activity and none of them showed significant ulcerogenic activity comparable to the reference drug celecoxib and are well tolerated by experimental animals with high safety margin (ALD 50  > 0.3 g/kg). Compounds 5c , 11b,c , 12c , 14a,b , 20a and 21a showed significant in vitro LOX inhibitory activity higher than that of zileuton. In vitro COX-1/COX-2 inhibition study revealed that compounds 12c , 14a,b and 20a showed higher selectivity towards COX-2 than COX-1. Among the tested compounds, 12c , 14a and 14b showed the highest inhibitory activity against COX-2 with an IC 50 values of 0.1, 0.11 and 0.11 μM respectively. The docking experiments attempted to postulate the binding mode for the most active compounds in the binding site of COX-2 enzymes and confirmed the high selectivity binding towards COX-2 enzyme over COX-1. [ABSTRACT FROM AUTHOR]

Fascin is an actin-bundling protein overexpressed in various invasive metastatic carcinomas through promoting cell migration and invasion. Therefore, blocking Fascin binding sites is considered a vital target for antimetastatic drugs. This inspired us to find new Fascin binding site blockers. First, we built an active compound set by collecting reported small molecules binding to Fascin's binding site 2. Consequently, a high-quality decoys set was generated employing DEKOIS 2.0 protocol to be applied in conducting the benchmarking analysis against the selected Fascin structures. Four docking programs, MOE, AutoDock Vina, VinaXB, and PLANTS were evaluated in the benchmarking study. All tools indicated better-than-random performance reflected by their pROC-AUC values against the Fascin crystal structure (PDB: ID 6I18). Interestingly, PLANTS exhibited the best screening performance and recognized potent actives at early enrichment. Accordingly, PLANTS was utilized in the prospective virtual screening effort for repurposing FDA-approved drugs (DrugBank database) and natural products (NANPDB). Further assessment via molecular dynamics simulations for 100 ns endorsed Remdesivir (DrugBank) and NANPDB3 (NANPDB) as potential binders to Fascin binding site 2. In conclusion, this study delivers a model for implementing a customized DEKOIS 2.0 benchmark set to enhance the VS success rate against new potential targets for cancer therapies. [ABSTRACT FROM AUTHOR]

In a search for new drug candidates for one of the neglected tropical diseases, leishmaniasis, twenty quinoline-isatin hybrids were synthesized and tested for their in vitro antileishmanial activity against Leishmania major strain. All the synthesized compounds showed promising in vitro activity against the promastigote form in a low micromolar range (IC 50 = 0.5084–5.9486 μM) superior to the reference miltefosine (IC 50 = 7.8976 μM). All the target compounds were then tested against the intracellular amastigote form and showed promising inhibition effects (IC 50 = 0.60442–8.2948 μM versus 8.08 μM for miltefosine). Compounds 4e , 4b and 4f were shown to possess the highest antileishmanial activity against both promastigote and amastigote forms. The most active compounds were proven to exhibit their significant antileishmanial effects through antifolate mechanism, targeting DHFR-TS and PTR1. To evaluate the safety profile of the most active derivatives 4e , 4b and 4f, the in vitro cytotoxicity test was carried out and displayed higher selectivity indices than the reference miltefosine. Molecular docking within putative target protein PTR1 confirmed the high potentiality of the most active compounds 4e , 4b and 4f to block the catalytic activity of Lm-PTR1. [Display omitted] • New quinoline-isatin hybrids were synthesized as antileishmanial agents. • Compounds 4e , 4b and 4f showed the highest in vitro activity. • The most active derivatives acted as DHFR-TS/PTR1 inhibitors. • The promising compounds displayed low toxicity in VERO cells. • In silico studies of the promising compounds showed high docking scores. [ABSTRACT FROM AUTHOR]

Pharmacologic inhibition of the oncogenic protein kinases using small molecules is a promising strategy to combat several human malignancies. CDK1 is an example of such a valuable target for the management of pancreatic ductal adenocarcinomas (PDAC); its overexpression in PDAC positively correlates with the size, histological grade and tumor aggressiveness. Here we report the identification of novel series of 1-piperazinyl-4-benzylphthalazine derivatives (8a-g , 10a-i and 12a-d) as promising anticancer agents with CDK1 inhibitory activity. The anti-proliferative activity of these agents was first screened on a panel of 11 cell lines representing 5 cancers (pancreas, melanoma, leukemia, colon and breast), and then confirmed on two CDK1-overexpressing PDAC cell lines (MDA-PATC53 and PL45 cells). Phthalazines 8g , 10d and 10h displayed potent activity against MDA-PATC53 (IC 50 = 0.51, 0.88 and 0.73 μM, respectively) and PL45 (IC 50 = 0.74, 1.14 and 1.00 μM, respectively) cell lines. Furthermore, compounds 8g , 10d and 10h exhibited potent and selective inhibitory activity toward CDK1 with IC 50 spanning in the range 36.80–44.52 nM, whereas they exerted weak inhibitory effect on CDK2, CDK5, AXL, PTK2B, FGFR, JAK1, IGF1R and BRAF kinases. Western blotting of CDK1 in MDA-PATC53 cells confirmed the ability of target phthalazines to diminish the CDK1 levels, and cell cycle analyses revealed their ability to arrest the cell cycle at G2/M phase. In conclusion, a panel of potent and selective CDK1 inhibitors were identified which can serve as lead compounds for designing further CDK1 inhibitors. • Novel 1-piperazinyl-4-benzylphthalazine derivatives (8a-g , 10a-I, 12a-d) were developed. • They displayed potent anti-proliferative activity against two CDK1-overexpressing PDAC cell lines. • Compounds 8g , 10d and 10h exhibited potent and selective inhibitory activity toward CDK1. • They weakly inhibited CDK2, CDK5, AXL, PTK2B, FGFR, JAK1, IGF1R, BRAF kinases. • Molecular docking for the target phthalazines in CDK1 active site was carried out. [ABSTRACT FROM AUTHOR]

A structure-guided modelling approach using COX-2 as a template was used to investigate the effect of replacing the chloro atom located at the chlorophenyl ring of amide-linked bipyrazole moieties, aiming at attaining better anti-inflammatory effect with a good safety profile. Bromo, fluoro, nitro, and methyl groups were revealed to be ideal candidates. Consequently, new bipyrazole derivatives were synthesised. The in vitro inhibitory COX-1/COX-2 activity of the synthesised compounds exhibited promising selectivity. The fluoro and methyl derivatives were the most active candidates. The in vivo formalin-induced paw edoema model confirmed the anti-inflammatory activity of the synthesised compounds. All the tested derivatives had a good ulcerogenic safety profile except for the methyl substituted compound. In silico molecular dynamics simulations of the fluoro and methyl poses complexed with COX-2 for 50 ns indicated stable binding to COX-2. Generally, our approach delivers a fruitful matrix for the development of further amide-linked bipyrazole anti-inflammatory candidates. [ABSTRACT FROM AUTHOR]

Promising inhibitory activities of the parasite multiplication were obtained upon evaluation of in vivo anti-malarial activities of new pyrazolylpyrazoline derivatives against Plasmodium berghei infected mice. Further evaluation of 5b and 6a against chloroquine-resistant strain (RKL9) of P. falciparum showed higher potency than chloroquine. In vitro antileishmanial activity testing against Leishmania aethiopica promastigote and amastigote forms indicated that 5b, 6a and 7b possessed promising activity compared to miltefosine and amphotericin B deoxycholate. Moreover, antileishmanial activity reversal of the active compounds via folic and folinic acids showed comparable results to the positive control trimethoprim, indicating an antifolate mechanism via targeting leishmanial DHFR and PTR1. The compounds were nontoxic at 125, 250 and 500mg/kg. In addition, docking of the most active compound against putative malarial target Pf-DHFR-TS and leishmanial PTR1 rationalised the observed activities. Molecular dynamics simulations confirmed a stable and high potential binding of 7a against leishmanial PTR1. [ABSTRACT FROM AUTHOR]

Non-Structural Protein 6 (NSP6) has a protecting role for SARS-CoV-2 replication by inhibiting the expansion of autophagosomes inside the cell. NSP6 is involved in the endoplasmic reticulum stress response by binding to Sigma receptor 1 (SR1). Nevertheless, NSP6 crystal structure is not solved yet. Therefore, NSP6 is considered a challenging target in Structure-Based Drug Discovery. Herein, we utilized the high quality NSP6 model built by AlphaFold in our study. Targeting a putative NSP6 binding site is believed to inhibit the SR1-NSP6 protein-protein interactions. Three databases were virtually screened, namely FDA-approved drugs (DrugBank), Northern African Natural Products Database (NANPDB) and South African Natural Compounds Database (SANCDB) with a total of 8158 compounds. Further validation for 9 candidates via molecular dynamics simulations for 100 ns recommended potential binders to the NSP6 binding site. The proposed candidates are recommended for biological testing to cease the rapidly growing pandemic. [Display omitted] • Targeting a putative binding site of NSP6 is believed to inhibit SR1-NSP6 protein-protein interactions. • 8158 compounds of DrugBank, NANPDB and SANCDB were virtually screened. • Some candidates from DrugBank and Natural Products exhibited promising binding interactions. • 9 MD simulations for 100 ns revealed high stability of some candidates with NSP6. • The selected natural products showed promising in-silico pharmacokinetics properties. [ABSTRACT FROM AUTHOR]

High-precision neurosurgical targeting in nonhuman primates (NHPs) often requires presurgical anatomical mapping with noninvasive neuroimaging techniques (MRI, CT, PET), allowing for translation of individual anatomical coordinates to surgical stereotaxic apparatus. Given the varied tissue contrasts that these imaging techniques produce, precise alignment of imaging-based coordinates to surgical apparatus can be cumbersome. MRI-compatible stereotaxis with radiopaque fiducial markers offer a straight-forward and reliable solution, but existing commercial options do not fit in conformal head coils that maximize imaging quality. We developed a compact MRI-compatible stereotaxis suitable for a variety of NHP species (Macaca mulatta , Macaca fascicularis , and Cebus apella) that allows multimodal alignment through technique-specific fiducial markers. With the express purpose of compatibility with clinically available MRI, CT, and PET systems, the frame is no larger than a human head, while allowing for imaging NHPs in the supinated position. This design requires no marker implantation, special software, or additional knowledge other than the operation of a common large animal stereotaxis. We demonstrated the applicability of this 3D-printable apparatus across a diverse set of experiments requiring presurgical planning: 1) We demonstrate the accuracy of the fiducial system through a within-MRI cannula insertion and subcortical injection of a viral vector. 2) We also demonstrated accuracy of multimodal (MRI and CT) alignment and coordinate transfer to guide a surgical robot electrode implantation for deep-brain electrophysiology. The computer-aided design files and engineering drawings are publicly available, with the modular design allowing for low cost and manageable manufacturing. • We present a compact MRI-compatible stereotaxic frame for large nonhuman primates. • The design is 3D printable, inexpensive, and matches size of an adult human head. • Enabled real-time, accurate, MRI-guided deep-brain viral vector injection. • Facilitated multimodal alignment for deep-brain electrophysiology planning. • All computer-aided-design files are modularized and publicly available and editable. [ABSTRACT FROM AUTHOR]

• Three distinct FeHNANSA, NiHNANSA, and CuHNANSA have been prepared & characterized via a wide variety of analytical methods. • In vitro experiments were conducted to evaluate the antibacterial, antifungal, anti-inflammatory, and antioxidant properties of the prepared compounds. • The metal complexes have heightened biological efficacy as compared to the free HNANSA ligand. • The findings obtained from docking experiments indicate that these compounds may possess a physiological function. Three novel metal complexes of 2‑hydroxy-1-naphthaldehyde azine (HNANSA) with iron(III), nickel(II), and copper(II) have been synthesized and characterized. Various analytical methods, such as elemental analysis, infrared spectroscopy, mass spectrometry, ultraviolet–visible spectroscopy, conductivity, magnetic testing, and thermal analysis, have been used to determine the structural and physical properties of the HNANSA and its metal complexes. The results indicated that; the HNANSA acts as a monobasic bi-dentate NO donor ligand and that the metal complexes contain water molecules in different patterns. Also, density functional theory (DFT) calculations have been performed to confirm the molecular structures and to study the quantum chemical parameters of the HNANSA and its metal complexes. Furthermore, the antibacterial, antifungal, anti-inflammatory, and antioxidant activities of the HNANSA and its metal complexes have been in vitro evaluated. The findings revealed that; the metal complexes have higher bioactivty than the free HNANSA ligand. Furthermore, molecular docking analyses have been performed against 2VF5 (Escherichia coli), 3CKU (Aspergillus flavus), 5IKT (Human Cyclooxygenase-2), and 5IJT (human peroxiredoxin 2), to estimate the binding affinities and interactions of the HNANSA and its metal complexes with target proteins. The results suggest that the HNANSA and its metal complexes may have potential applications in the development of new therapeutic agents. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: While magnetic resonance images essentially contain a map of the both circularly polarized components of the RF transverse magnetic fields (B1 field), the thermal heat and electromagnetic power deposition is generated by the associated electric fields. Measurement of electric field distributions/intensities across a sample yields an indirect indication of possible cause of heating within the sample and potentially enables the detection of “hot spots,” which can be present within inhomogeneous radiofrequency (RF) fields, such as the case with magnetic resonance imaging at high field strength. As a result, establishing a valid technique for direct measurements of the electric field and its correlation, obtained using computational electromagnetics, is essential in assessing (1) the safety of the RF coil designs and (2) the validity of the calculations. In this work, a probe was built and used to measure the transverse electric field (E1 field) distributions within an empty 8 T (tuned to 340 MHz) RF head coil and within a saline water phantom loaded in the same coil. The measured E1 field distributions were favorably compared to the distributions obtained utilizing a finite difference time domain in-house package. [Copyright &y& Elsevier]

Recently cleared by the FDA, 7 Tesla (7 T) MRI is a rapidly growing technology that can provide higher resolution and enhanced contrast in human MRI images. However, the increased operational frequency (~ 297 MHz) hinders its full potential since it causes inhomogeneities in the images and increases the power deposition in the tissues. This work describes the optimization of an innovative radiofrequency (RF) head coil coupled design, named Tic Tac Toe, currently used in large scale human MRI scanning at 7 T; to date, this device was used in more than 1,300 neuro 7 T MRI scans. Electromagnetic simulations of the coil were performed using the finite-difference time-domain method. Numerical optimizations were used to combine the calculated electromagnetic fields produced by these antennas, based on the superposition principle, resulting in homogeneous magnetic field distributions at low levels of power deposition in the tissues. The simulations were validated in-vivo using the Tic Tac Toe RF head coil system on a 7 T MRI scanner. [ABSTRACT FROM AUTHOR]