New Compounds with Bioisosteric Replacement of Classic Choline Kinase Inhibitors Show Potent Antiplasmodial Activity

In the fight against Malaria, new strategies need to be developed to avoid resistance of the parasite to pharmaceutics and other prevention barriers. Recently, a Host Directed Therapy approach based on the suppression of the starting materials uptake from the host by the parasite has provided excellent results. In this article, we propose the synthesis of bioisosteric compounds that are capable of inhibiting Plasmodium falciparum Choline Kinase and therefore to reduce choline uptake, which is essential for the development of the parasite. Of the 41 bioisosteric compounds reported herein, none showed any influence of the linker on the antimalarial and enzyme inhibitory activity, whereas an effect of the type of cationic heads used could be observed. SARs determined that the thienopyrimidine substituted in 4 by a pyrrolidine is the best scaffold, independently of the chosen linker. The decrease in lipophilicity seems to improve the antimalarial activity but to cause an opposite effect on the inhibition of the enzyme. While potent compounds with similar good inhibitory values have been related to the proposed mechanism of action, some of them still show discrepancies and further studies are needed to determine their specific molecular target.

Round Robin Testing: Exploring Experimental Uncertainties through a Multifacility Comparison of a Hinged Raft Wave Energy Converter

The EU H2020 MaRINET2 project has a goal to improve the quality, robustness and accuracy of physical modelling and associated testing practices for the offshore renewable energy sector. To support this aim, a round robin scale physical modelling test programme was conducted to deploy a common wave energy converter at four wave basins operated by MaRINET2 partners. Test campaigns were conducted at each facility to a common specification and test matrix, providing the unique opportunity for intercomparison between facilities and working practices. A nonproprietary hinged raft, with a nominal scale of 1:25, was tested under a set of 12 irregular sea states. This allowed for an assessment of power output, hinge angles, mooring loads, and six-degree-of-freedom motions. The key outcome to be concluded from the results is that the facilities performed consistently, with the majority of variation linked to differences in sea state calibration. A variation of 5–10 % in mean power was typical and was consistent with the variability observed in the measured significant wave heights. The tank depth (which varied from 2–5 m) showed remarkably little influence on the results, although it is noted that these tests used an aerial mooring system with the geometry unaffected by the tank depth. Similar good agreement was seen in the heave, surge, pitch and hinge angle responses. In order to maintain and improve the consistency across laboratories, we make recommendations on characterising and calibrating the tank environment and stress the importance of the device–facility physical interface (the aerial mooring in this case).

A Comparative Study of English-Arabic-English Translation Constraints among EFL Students

Because most of the previous research on translation constraints in English-Arabic-English translation has separately investigated English-Arabic and Arabic-English translation problems, the current study is meant to compare the constraints that EFL students face across the two translation types. To attain this objective, English-Arabic and Arabic-English tests were administered to forty-seven (N= 47) EFL students in two Moroccan university educational settings to measure their abilities in the two translation domains. The results reveal that the participants' scores in both versions are not at the expected ability level due to the obstacles they encounter in the translation process. The study also shows that having a good ability in the English-Arabic version cannot strongly predict a similar good ability in Arabic-English translation because of the different natures of the two languages, which suggests taking more care of the student’s proficiency in English and Arabic languages and exposing students to their distinctive aspects for the sake of coming up with accurate and appropriate translations. The study ends with implications for pedagogy and recommendations for future researchers.

Mayo Endoscopic Score and Ulcerative Colitis Endoscopic Index Are Equally Effective for Endoscopic Activity Evaluation in Ulcerative Colitis Patients in a Real Life Setting

The role of endoscopic evaluation in ulcerative colitis (UC) is well recognized, but a universally accepted gold standard for endoscopic activity evaluation is still lacking, and many scores have been proposed to this purpose. Among these, the Mayo Endoscopic Score (MES) and the Ulcerative Colitis Endoscopic Index (UCEIS) are currently the most used in trials and clinical practice. The aim of the study is to evaluate feasibility and performance of MES and UCEIS among expert endoscopists with no specific expertise in inflammatory bowel diseases (IBD), in a single hospital center. Two minutes video recordings, from colonoscopy of 12 UC patients, were observed and scored, according to MES and UCEIS, by seven hospital gastroenterologists with experience in digestive endoscopy and no particular expertise in IBD. Knowledge and utilization of the two scores were investigated. Inter-observer agreement and agreement with an IBD-expert gastroenterologist of the same center (central reader), and correlation between the two scores, was calculated. Among the endoscopists, MES was much more known and currently used than UCEIS. Both the scores displayed a similar good performance. Agreement with central reader was moderate for MES and UCEIS, and interobserver agreement was good, for both MES and UCEIS. Correlation between the two scores was very good both for central reader and for the hospital endoscopists. This single center study confirmed potential feasibility and usefulness of MES and UCEIS for assessment of endoscopic activity in UC patients in a real-life setting.

Comparison of the Fitting Performance of Retention Models and Elution Strength Behaviour in Hydrophilic-Interaction and Reversed-Phase Liquid Chromatography

Hydrophilic interaction liquid chromatography (HILIC) is able to separate from polar to highly polar solutes, using similar eluents to those in the reversed-phase mode (RPLC) and a polar stationary phase, where water is adsorbed onto its surface. It is widely accepted that multiple modes of interaction take place in the HILIC environment, which can be far more complex than the interactions in an RPLC column. The behaviour in HILIC should be adequately modelled to predict the retention with optimisation purposes and improve the understanding on retention mechanisms, as is the case for RPLC. In this work, the prediction performance of several retention models is studied for seven HILIC columns (underivatised silica, and silica containing diol, amino and sulfobetaine functional groups, together with three columns recently manufactured with neutral, anionic, and cationic character), using uracil and six polar nucleosides (adenosine, cytidine, guanosine, thymidine, uridine, and xanthosine) as probe compounds. The results in HILIC are compared with those that were offered by the elution of several polar sulphonamides and diuretics analysed with two C18 columns (Chromolith Speed ROD and Zorbax Eclipse XDB). It is shown that eight retention models, which only consider partitioning or both partitioning and adsorption, give similar good accuracy in predictions for both HILIC and RPLC columns. However, the study on the elution strength behaviour, at varying mobile phase composition, reveals similarities (or differences) between RPLC and HILIC columns of diverse nature. The particular behaviour for the HILIC and RPLC columns was also revealed when the retention, in both modes, was fitted to a model that describes the change in the elution strength with the modifier concentration.

Abstract P548: Multiple Attempts Complete Reperfusion versus Single Pass Successful Reperfusion: A Sub-Analysis From the Select Study

Introduction: Successful and fast reperfusion with endovascular thrombectomy (EVT) improves outcomes in acute ischemic strokes due to large vessel occlusion (LVO). While complete reperfusion (mTICI 3) is the ideal target, multiple passes could prolong EVT and increase complications likelihood without improving clinical outcomes. We hypothesized that pts with a single pass mTICI2b would have similar good outcomes to those with multiple passes mTICI3 with a better safety profile. Methods: From the prospective multicenter cohort study of imaging selection (SELECT), EVT pts who achieved mTICI2b and mTICI3 were stratified into those with single pass vs multiple passes. Functional independence rates at 90 day mRS and safety (sICH, neuro-worsening and mortality) were compared between pts with single pass mTICI 2b and multiple passes mTICI 3. Results: Of 361 pts enrolled, 285 received EVT, of those 70 (25%) achieved mTICI 2b and 159 (56%) mTICI 3. 89 (31%) achieved mTICI 3 with single pass, 70 (25%) with multiple passes, 33 (12%) had mTICI 2b with a single pass and 37 (13%) with multiple passes. Baseline characteristics were similar between the two groups except for larger perfusion deficit (Tmax >6s) volume in pts with multiple passes mTICI3 55 (25, 99) cc vs first pass mTICI 2b 43 (4, 79), p=0.047). Functional independence rates were higher with single pass mTICI 2b as compared to multiple passes mTICI 3 (70% vs 56%, aOR=1.51, 95% CI=0.48-4.76, p=0.78), fig 1 but did not reach statistical significance. Multiple passes mTICI 3 was associated with numerically higher mortality (13% vs 3%, p=0.16) and Neuro-worsening (13% vs 3%, p=0.16) with similar sICH: 4% vs 3%, p=1.00 rates. Conclusion: Complete reperfusion with multiple passes did not confer better outcome rates than single pass mTICI 2b and was associated with worse safety profiles. These results suggest that in the absence of complete reperfusion on first attempt, a single pass mTICI 2b may be sufficient for a successful thrombectomy.

Microstructure and Mechanical Properties of Cu-Fe Alloys via Powder Metallurgy

Copper Ferro Alloys (CFAs) have an excellent shielding effect in the electromagnetic field, as well as the similar good conductivity and ductility with copper, and strong magnetism and toughness as analogous to iron. Consequently, it is considered to be novel structural and functional materials with huge development potential and wide application foreground. The influence of the content, size and distribution of Fe phase in the Cu matrix on the electromagnetic shielding property of CFAs is crucial. In the present study, CFAs with various Fe content were fabricated via powder metallurgy (P/M) combining with deformation processing. The microstructure, electrical conductivity, magnetic and mechanical properties of CFAs were investigated by optical microscopy (OM), scanning electron microscopy (SEM), X-Ray diffraction (XRD), and tensile test. The results indicated that P/M CFAs with the homogenous and fine in-situ Fe particles showed better comprehensive performance compared to those prepared by conventional casting. Based on the microstructure observation, mechanical properties were discussed.

Dosimetric and Radiobiological Comparison of Five Techniques for Postmastectomy Radiotherapy with Simultaneous Integrated Boost

Purpose. To compare five techniques for the postmastectomy radiotherapy (PMRT) with simultaneous integrated boost (SIB). Materials and Methods. Twenty patients with left-sided breast cancer were retrospectively selected. Five treatment plans were created for each patient: TomoDirect (TD), unblocked helical TomoTherapy (unb-HT), blocked HT (b-HT), hybrid intensity-modulated radiotherapy (hy-IMRT), and fixed-field IMRT (ff-IMRT). A dose of 50.4 Gy in 28 fractions to PTVtotal and 60.2 Gy in 28 fractions to PTVboost were prescribed. The dosimetric parameters for targets and organs at risk (OARs), the normal tissue complication probability (NTCP), the second cancer complication probability (SCCP) for OARs, and the treatment efficiency were assessed and compared. Results. TD plans and hy-IMRT plans had similar good dose coverage and homogeneity for both PTVboost and PTVtotal and superior dose sparing for the lungs and heart. The ff-IMRT plans had similar dosimetric results for the target volumes compared with the TD and hy-IMRT plans, but gave a relatively higher NTCP and SCCP for the lungs. The unb-HT plans exhibited the highest OAR mean dose, highest NTCP for the lungs (0.97±1.25‰) and heart (4.58±3.62%), and highest SCCP for the lungs (3.57±0.05%) and contralateral breast (2.75±0.29%) among all techniques. The b-HT plans significantly outperformed unb-HT plans with respect to the sparing of the lungs and heart. This technique also showed the best conformity index (0.73±0.08) for PTVboost and the optimal NTCP for the lungs (0.03±0.03‰) and heart (0.61±0.73%). Concerning the delivery efficiency, the hy-IMRT and ff-IMRT achieved much higher delivery efficiency compared with TomoTherapy plans. Conclusion. Of the five techniques studied, TD and hy-IMRT are considered the preferable options for PMRT with SIB for left-sided breast cancer treatment and can be routinely applied in clinical practice.

Repeated mechanical thrombectomy in short-term large vessel occlusion recurrence: multicenter study and systematic review of the literature

BackgroundData on the frequency and outcome of repeated mechanical thrombectomy (MT) in patients with short-term re-occlusion of intracranial vessels is limited. Addressing this subject, we report our multicenter experience with a systematic review of the literature.MethodsA retrospective analysis was conducted of consecutive acute stroke patients treated with MT repeatedly within 30 days at 10 tertiary care centers between January 2007 and January 2020. Baseline demographics, etiology of stroke, angiographic outcome and clinical outcome evaluated by the modified Rankin Scale (mRS) at 90 days were noted. Additionally, a systematic review of reports with repeated MT due to large vessel occlusion (LVO) recurrence was performed.ResultsWe identified 30 out of 7844 (0.4%) patients who received two thrombectomy procedures within 30 days due to recurrent LVO. Through systematic review, three publications of 28 participants met the criteria for inclusion. Combined, a total of 58 participants were analyzed: cardioembolic events were the most common etiology for the first (65.5%) and second LVO (60.3%), respectively. Median baseline NIHSS (National Institutes of Health Stroke Scale) was 13 (IQR 8–16) before the first MT and 15 (IQR 11–19) before the second MT (p=0.031). Successful reperfusion was achieved in 91.4% after the first MT and in 86.2% patients after the second MT (p=0.377). The rate of functional independence (mRS 0–2) was 46% at 90 days after the second procedure.ConclusionRepeated MT in short-term recurrent LVO is a rarity but appears to be safe and effective. The second thrombectomy should be pursued with the same extensive effort as the first procedure as these patients may achieve similar good outcomes.