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Trypanosomiasis is an important but neglected tropical diseases which continues to cause morbidity and mortality on a large scale in sub-Saharan Africa. In the present study, the aqueous leaf extract, flavonoid fraction, and subfractions of the flavonoid from A. senegalensis leaves were evaluated for their antitrypanosomal activities, effects on some hematological parameters, and some liver-based enzymes in mice infected with Trypanosoma brucei brucei. Mice treated with aqueous extract at a concentration range of 100–400 mg kg bw exhibited parasite inhibition range between 66.08 and 73.09% while mice treated with the flavonoid fraction (50-200 mg/kg bw) exhibited higher parasite inhibition (83.37-86.38%). Mice treated with subfractions of the flavonoids showed a significant decrease in parasite count ( p < 0.05 ), with subfraction 3 completely clearing parasites in the circulation after twenty-one days of treatment. Biochemical analysis revealed that the subfraction 3 restored the alterations in the serum aspartate transaminase (AST), alanine transaminase (ALT), and total protein concentrations that were observed in the infected nontreated mice. The subfraction 3 was subsequently characterized by HPLC analysis which revealed the presence of rutin (RT: 22.26, 65.34 ppm) as the most abundant bioactive compound that could be attributed to the bioactivity of the subfraction 3. Other polyphenolic compounds identified included gallic acid (RT: 4.39, 0.578 ppm), quercetin (RT: 37.27, 0.729 ppm), kaempferol (RT: 38.33, 1.52 ppm), and luteolin (RT; 39.173, 32.77 ppm). Taken together, subfraction 3 of the flavonoid fraction from of A. senegalensis demonstrated potent antitrypanosomal activities and therefore represents a reserve of bioactive metabolite worthy of further exploration for the treatment of trypanosomiasis.

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved. OBJECTIVES: The study compared the performance for detection and grading of coronary stenoses using artificial intelligence-enabled quantitative coronary computed tomography angiography (AI-QCT) analyses to core lab-interpreted coronary computed tomography angiography (CTA), core lab quantitative coronary angiography (QCA), and invasive fractional flow reserve (FFR). BACKGROUND: Clinical reads of coronary CTA, especially by less experienced readers, may result in overestimation of coronary artery disease stenosis severity compared with expert interpretation. AI-based solutions applied to coronary CTA may overcome these limitations. METHODS: Coronary CTA, FFR, and QCA data from 303 stable patients (64 ± 10 years of age, 71% male) from the CREDENCE (Computed TomogRaphic Evaluation of Atherosclerotic DEtermiNants of Myocardial IsChEmia) trial were retrospectively analyzed using an Food and Drug Administration-cleared cloud-based software that performs AI-enabled coronary segmentation, lumen and vessel wall determination, plaque quantification and characterization, and stenosis determination. RESULTS: Disease prevalence was high, with 32.0%, 35.0%, 21.0%, and 13.0% demonstrating ≥50% stenosis in 0, 1, 2, and 3 coronary vessel territories, respectively. Average AI-QCT analysis time was 10.3 ± 2.7 minutes. AI-QCT evaluation demonstrated per-patient sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 94%, 68%, 81%, 90%, and 84%, respectively, for ≥50% stenosis, and of 94%, 82%, 69%, 97%, and 86%, respectively, for detection of ≥70% stenosis. There was high correlation between stenosis detected on AI-QCT evaluation vs QCA on a per-vessel and per-patient basis (intraclass correlation coefficient = 0.73 and 0.73, respectively; P < 0.001 for both). False positive AI-QCT findings were noted in in 62 of 848 (7.3%) vessels (stenosis of ≥70% by AI-QCT and QCA of

The purpose of this study was to examine trends in the incidence of thoracic aortic aneurysm (TAA) repair and aortic dissection.A retrospective study was conducted of patients from the period 2005-2015 with thoracic aortic disease. Unadjusted mortality was compared in women vs men. Rates of scheduled TAA repair, dissection events, acute type A aortic dissection (TAAD) repair, and aorta-related mortality were obtained from our institution's clinical registry and administrative data sources and used to calculate the age-adjusted incidence for each sex, adjusted to the Canadian standard population. Weighted linear regression was performed to analyze trends over time.A total of 382 scheduled TAA repair operations, 345 dissection events, 85 TAAD repairs, and 182 aorta-related mortalities were identified. Women accounted for 23% of TAA repairs, 39% of dissection events, 22% of TAAD repairs, and 45% of aorta-related mortalities. The incidence of TAA repair was 3.5 per 100,000 person-years (95% confidence interval [CI]: 3.2-3.9), and increased in men (The incidence of TAA repair is increasing in men but not women. Although aorta-related mortality is decreasing overall, disparities exist between the male and female population.L’objectif de cette étude était d’examiner les tendances relatives à l’incidence des réparations d’anévrisme de l’aorte thoracique (AAT) et de dissection aortique.Nous avons mené une étude rétrospective de patients atteints d’une maladie de l’aorte thoracique de la période 2005-2015. Nous avons comparé la mortalité non ajustée entre les femmes et les hommes. Nous avons obtenu les taux de réparations planifiées d’AAT, de dissections, de dissections aortiques de type A (DATA) à la phase aiguë et de mortalité d’origine aortique du registre clinique de notre établissement et des sources de données administratives, et les avons utilisés pour calculer l’incidence ajustée selon l’âge pour chacun des sexes, ajustée à la population canadienne type. Nous avons effectué une régression linéaire pondérée pour analyser les tendances temporelles.Nous avons recensé un total de 382 réparations planifiées d’AAT, 345 dissections, 85 réparations de DATA et 182 cas de mortalité d’origine aortique. Les femmes représentaient 23 % des cas de réparation d’AAT, 39 % des cas de dissection, 22 % des cas de réparations de DATA et 45 % des cas de mortalité d’origine aortique. L’incidence des réparations d’AAT était de 3,5 par 100 000 années-personnes (intervalle de confiance [IC] à 95 % : 3,2-3,9) et augmentait chez les hommes (L’incidence des réparations d’AAT augmente chez les hommes, mais non chez les femmes. Bien que la mortalité d’origine aortique tende dans l’ensemble à diminuer, il existe des disparités entre la population masculine et la population féminine.

Different ethnomedical benefits have been documented on different parts of Ackee (Blighia sapida); however, their roles in ameliorating oxidative damages are not well established. CdCl2 inhibitory effects on some oxidative-stress biomarkers and ameliorative potentials of Ackee leaves (AL) and arils (AS) methanolic extracts were studied using Drosophila melanogaster as a model. One to 3-day-old D. melanogaster flies were orally exposed to different concentrations of CdCl2 in their diet for 7 days. The fly’s survival profile and negative geotaxis assays were subsequently analysed. Methanolic extracts of AL and AS treatments showed negative geotaxis behaviour, and extracts were able to ameliorate the effect of Cd2+ on catalase and GST activities and increase total thiol and GSH levels, while it reduced the H2O2 generation ( p ≤ 0.05 ) when compared to the control. Furthermore, Cd2+ exhibited noncompetitive and uncompetitive enzyme inhibition on catalase and GST activities, respectively, which may have resulted in the formation of Enzyme-substrate-Cd2+ transition complexes, thus inhibiting the conversion of substrate to product. This study, thus, suggests that the Cd2+ mechanism of toxicity was associated with oxidative damage, as evidenced by the alteration in the oxidative stress-antioxidant imbalance, and that the AL and AS extracts possess essential phytochemicals that could alleviate possibly deleterious oxidative damage effects of environmental pollutants such as CdCl2. Thus, Ackee plant parts possess essential phytonutrients which could serve as valuable resources in heavy metal toxicity management.

RATIONALECardiac rhythm, conduction and synchronization of electrical activity require the coordinated action of different types of ion channels that differ according to transmural and regional specificities. Classical pharmacology affects these ion channels in a non-regionalized way which explains why treating arrhythmias, that often occur in specific foci, has often limited efficacy in addition to negative side-effects on non-targeted organs. Photopharmacology is an emergent technology that has the potential to counteract all the negative aspects of classical pharmacology by restricting drug activity in a spatio-temporal manner.OBJECTIVEWe tested the potential of photopharmacology in specifically regulating heart activity by using a caged derivative of a natural peptide inhibitor of the ERG channel, BeKm1. The peptide was uncaged and activity monitoredin vitroon a cell line expressing the hERG channel, on human cardiomyocytes derived from iPS cells, andex vivoandin vivoon zebrafish larvae and rat hearts.METHODS AND RESULTSCaged BeKm-1 is inactive and fully active upon uncaging. Uncaging of the peptide on human iPS-derived cardiomyocytes enlarges the action potential duration and triggers arrhythmias. Uncaging also triggers bradycardia and disturbs cardiac conduction within the atria in perfused rat hearts upon illumination. The potency of photopharmacology for cardiac electrical modulation was further validated in zebrafish larvae where illumination of the caged compound induces bradycardia and atrio-ventricular desynchrony. Finally, in anesthetized rats, illumination of the caged peptide in the right atria, containing the sino-atrial node, leads to bradycardia without arrhythmia.CONCLUSIONSThis report demonstrates that photopharmacology, using the caged peptide strategy, can be used for dynamically regulating cardiac electrical activityin vivoand that spatial illumination restriction can dissociate the bradycardic effect from the arrhythmic one. The technology is applicable to all kinds of cardiac ion channels and regions of interest to create arrhythmogenic models or investigate new clinical applications.

Morbid obesity and prolonged pregnancy are independently associated with adverse delivery and perinatal outcomes. We conducted a retrospective observational study on otherwise uncomplicated women with a body mass index (BMI) ≥ 40 kg/m

Coronavirus disease 2019 (Covid-19) is a global diastrophic disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Covid-19 leads to inflammatory, immunological, and oxidative changes, by which SARS-CoV-2 leads to endothelial dysfunction (ED), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and multi-organ failure (MOF). Despite evidence illustrating that some drugs and vaccines effectively manage and prevent Covid-19, complementary herbal medicines are urgently needed to control this pandemic disease. One of the most used herbal medicines is berberine (BBR), which has anti-inflammatory, antioxidant, antiviral, and immune-regulatory effects; thus, BBR may be a prospective candidate against SARS-CoV-2 infection. This review found that BBR has anti-SARS-CoV-2 effects with mitigation of associated inflammatory changes. BBR also reduces the risk of ALI/ARDS in Covid-19 patients by inhibiting the release of pro-inflammatory cytokines and inflammatory signaling pathways. In conclusion, BBR has potent anti-inflammatory, antioxidant, and antiviral effects. Therefore, it can be utilized as a possible anti-SARS-CoV-2 agent. BBR inhibits the proliferation of SARS-CoV-2 and attenuates the associated inflammatory disorders linked by the activation of inflammatory signaling pathways. Indeed, BBR can alleviate ALI/ARDS in patients with severe Covid-19. In this sense, clinical trials and prospective studies are suggested to illustrate the potential role of BBR in treating Covid-19.

Where and what we attend is very much determined by what we have encountered in the past. Recent studies have shown that people learn to extract statistical regularities in the environment resulting in attentional suppression of locations that were likely to contain a distractor, effectively reducing the amount of attentional capture. Here, we asked whether this suppression effect due to statistical learning is dependent on the specific configuration within which it was learned. The current study employed the additional singleton paradigm using search arrays that had a configuration consisting of set sizes of either four or 10 items. Each configuration contained its own high probability distractor location. If learning would generalize across set size configurations, both high probability locations would be suppressed equally, regardless of set size. However, if learning to suppress is dependent on the configuration within which it was learned, one would expect only suppression of the high probability location that matched the configuration within which it was learned. The results show the latter, suggesting that implicitly learned suppression is configuration-dependent. Thus, we conclude that the high probability location is learned within the configuration context within which it is presented.

Aims Coronary flow reserve (CFR) assessment has proven clinical utility, but Doppler-based methods are sensitive to noise and operator bias, limiting their clinical applicability. The objective of the study is to expand the adoption of invasive Doppler CFR, through the development of artificial intelligence (AI) algorithms to automatically quantify coronary Doppler quality and track flow velocity. Methods and results A neural network was trained on images extracted from coronary Doppler flow recordings to score signal quality and derive values for coronary flow velocity and CFR. The outputs were independently validated against expert consensus. Artificial intelligence successfully quantified Doppler signal quality, with high agreement with expert consensus (Spearman’s rho: 0.94), and within individual experts. Artificial intelligence automatically tracked flow velocity with superior numerical agreement against experts, when compared with the current console algorithm [AI flow vs. expert flow bias −1.68 cm/s, 95% confidence interval (CI) −2.13 to −1.23 cm/s, P < 0.001 with limits of agreement (LOA) −4.03 to 0.68 cm/s; console flow vs. expert flow bias −2.63 cm/s, 95% CI −3.74 to −1.52, P < 0.001, 95% LOA −8.45 to −3.19 cm/s]. Artificial intelligence yielded more precise CFR values [median absolute difference (MAD) against expert CFR: 4.0% for AI and 7.4% for console]. Artificial intelligence tracked lower-quality Doppler signals with lower variability (MAD against expert CFR 8.3% for AI and 16.7% for console). Conclusion An AI-based system, trained by experts and independently validated, could assign a quality score to Doppler traces and derive coronary flow velocity and CFR. By making Doppler CFR more automated, precise, and operator-independent, AI could expand the clinical applicability of coronary microvascular assessment.

International audience; Dear Editor, Loss-of-function and gain-of-function mutations in the KCNH2 gene cause long and short-QT syndromes (LQTS or SQTS), respectively, predisposing to life-threatening F I G U R E 1 Repolarization power of wild-type (WT) hERG as a function of temperature. A simplified and optimized action potential was applied (AP-clamp) by an automated patch clamp system in 384-well plates on HEK293 cells stably expressing hERG. (A) Mean (± SEM) current recordings during AP-clamp at various temperatures (in pA, n = 194, 211, 114 and 172 cells at 22-37 • C, respectively). Dashed line: AP time course (voltage scale: right Y axis). (B) Mean (± SEM) current recordings during AP-clamp at 27 • C for AP of various durations (see inset for APs; for currents: n = 168−254 for Time x 0.5 to x 5). The small inward current observed in (A) and (B), when the AP is returning to resting values, is attributed to contamination of the intracellular solution by the extracellular Tyrode solution, intrinsic to the cell catch process in the automated patch clamp (see supplementary information). (C) Mean (± SEM) time integral of the recorded currents: repolarization power, at various temperatures versus time factor (n = 155−232, 168−254, 79−133 and 144−173 at 22-37 • C, respectively). Horizontal dashed line: repolarization power at 37 • C: 22.3 pA.s. (D) As in (B), at 27 • C, after time and current corrections using various factors from 1.5 to 3 on the respective recordings. For example, for the recordings obtained during the AP of 2 x duration, the time was divided by 2 and the current multiplied by 2. Note the overlap of the current corrected by the factor of 2 at 27 • C (black) with the reference current obtained during the standard AP at 37 • C (red).

SMN protein deficiency causes motoneuron disease spinal muscular atrophy (SMA). SMN-based therapies improve patient motor symptoms to variable degrees. An early hallmark of SMA is the perturbation of the neuromuscular junction (NMJ), a synapse between a motoneuron and muscle cell. NMJ formation depends on acetylcholine receptor (AChR) clustering triggered by agrin and its co-receptors lipoprotein receptor-related protein 4 (LRP4) and transmembrane muscle-specific kinase (MuSK) signalling pathway. We have previously shown that flunarizine improves NMJs in SMA model mice, but the mechanisms remain elusive. We show here that flunarizine promotes AChR clustering in cell-autonomous, dose- and agrin-dependent manners in C2C12 myotubes. This is associated with an increase in protein levels of LRP4, integrin-beta-1 and alpha-dystroglycan, three agrin co-receptors. Furthermore, flunarizine enhances MuSK interaction with integrin-beta-1 and phosphotyrosines. Moreover, the drug acts on the expression and splicing of Agrn and Cacna1h genes in a muscle-specific manner. We reveal that the Cacna1h encoded protein Cav3.2 closely associates in vitro with the agrin co-receptor LRP4. In vivo, it is enriched nearby NMJs during neonatal development and the drug increases this immunolabelling in SMA muscles. Thus, flunarizine modulates key players of the NMJ and identifies Cav3.2 as a new protein involved in the NMJ biology.

This article reports about a lesson series that focuses on engaging students in sustainability, plastics, and life cycle assessment (LCA). The purpose of the lesson series is to give students insights into sustainability in the context of plastics and to foster awareness of and insights into the benefits of the LCA method. The lesson series introduces students to sustainability by enabling them to watch a video, answer questions, read articles, conduct laboratory experiments, and experience the four stages of LCA. In general, the findings reveal that the lesson series evoked in students a more critical view of the life cycle of plastics. The students showed increasing awareness of the complexity of the sustainability issue at hand. In addition, students used their acquired knowledge about LCA and mentioned impact categories in their argumentation. The lesson series evoked predominantly life cycle thinking, and the qualitative part of an LCA, and might thus serve as a stepping stone toward the quantitative assessment. The preliminary results show that the lesson series is effective for evoking life cycle thinking among students and serves as a stepping stone towards life cycle assessment. Future research could focus on setting the goal and scope of the process to be assessed, with emphasis on the functional unit in the context of plastics, and providing students a complete and coherent understanding of the entire cycle of production, use and recycling of plastics.

BACKGROUND The association between travel time from the tertiary care centre and outcomes after aortic surgery is unknown. Our objective was to determine the effect of estimated travel time from tertiary care centre on outcomes in ascending aortic repair in Nova Scotia. METHODS AND RESULTS A retrospective analysis of all elective and emergent ascending thoracic aortic operations, performed either in isolation or in combination with other cardiac surgery procedures, from 2005 and 2015 was carried out. Clinical characteristics as well as in-hospital outcomes were recorded. Patient's residential geographical coordinates were used to calculate estimated driving time using geographic information system software (ArcMAP, ESRI). Socioeconomic deprivation quintiles were derived from the 2006 Census based on the patient's residential postal code. Long-term survival was identified through Vital Statistics database. Multivariable logistic regression was performed to determine the independent effect of estimated travel time ≥1 hour on in-hospital outcomes. Cox-proportional hazard modeling and Kaplan-Meier survival estimates were created to determine the independent effect of estimated travel time on long-term survival. A total of 476 patients underwent ascending thoracic aortic surgery from 2005 to 2015. Mean age was 59.1 (±13.3) years and 107 (22.5%) were female. Compared to patients at CONCLUSION Compared to patients who live in close proximity to the tertiary centre, patients at increased travel time experience equivalent in-hospital outcomes but decreased long-term survival following ascending aortic operations. Resource expansion to improve follow-up monitoring of patients who live remotely is needed.

PurposeThe present article analyses extreme context studies published in leading project management journals with the aim of developing a time-based typology that could be of value for the project community at large.Design/methodology/approachIn this study, the authors reviewed 62 articles on extreme contexts published in three main project management journals (IJMPB, PMJandIJPM) and two specialized outletsDisaster Prevention and Management (DPM)andInternational Journal of Disaster Resilience in the Built Environment (IJDRBE).FindingsThe authors present a typology, in which emergency, risky and disrupted (RED) contexts are related to the manageability of time. It shows that when pressure rises, due to high levels of urgency, uncertainty and ambiguity, control over time decreases, causing the organizational response to shift from formalized into improvised.Research limitations/implicationsBased on this review, the authors theorize the influence of extreme contexts on project management in general.Originality/valueThe study responds to the scholarly call to advance the academic debate on the relatedness of project and temporary organizations by perceiving temporality as a continuum.

Valérie de Crécy-Lagard: et al., Over the last 25 years, biology has entered the genomic era and is becoming a science of 'big data'. Most interpretations of genomic analyses rely on accurate functional annotations of the proteins encoded by more than 500 000 genomes sequenced to date. By different estimates, only half the predicted sequenced proteins carry an accurate functional annotation, and this percentage varies drastically between different organismal lineages. Such a large gap in knowledge hampers all aspects of biological enterprise and, thereby, is standing in the way of genomic biology reaching its full potential. A brainstorming meeting to address this issue funded by the National Science Foundation was held during 3-4 February 2022. Bringing together data scientists, biocurators, computational biologists and experimentalists within the same venue allowed for a comprehensive assessment of the current state of functional annotations of protein families. Further, major issues that were obstructing the field were identified and discussed, which ultimately allowed for the proposal of solutions on how to move forward., National Science Foundation (grant MCB-2129768) to V.d.C.-L; National Institutes of Health Intramural Research Program, National Library of Medicine (Z.L.).

Patients with coronavirus disease 2019 (COVID-19) were shown to have reduced serum testosterone levels compared to healthy individuals. Low testosterone levels are linked with the development of erectile dysfunction (ED). In this case-controlled study, 20 healthy controls and 39 patients with ED 3 months after recovering from mild-to-moderate COVID-19 pneumonia were studied. The patients ranged in age from 31 to 47 years. To identify early and late COVID-19 infections, real-time polymerase-chain reaction (RT-PCR) and COVID-19 antibody testing were done. The levels of luteinizing hormone (LH), follicular stimulating hormone (FSH), total testosterone (TT), free testosterone (FT), free androgenic index (FAI), and sex hormone-binding globulin (SHBG) were measured. The sexual health inventory for patients (SHIM) score was used to measure the erectile function of the patients and controls. When compared to the controls, the TT serum level in long COVID-19 (LC) patients with ED was low (p = 0.01). In contrast to controls, FT and FAI were both lower in LC patients with ED. (p = 0.001). FSH serum levels did not significantly differ (p = 0.07), but in ED patients, LH serum levels were elevated. SHIM scores were associated with low TT (p = 0.30), FT (p = 0.09), and high LH (p = 0.76) in LC patients with ED. Male patients with decreased serum levels of LH and testosterone may have hypothalamic-pituitary–gonadal axis dysfunction, which could lead to the development of LC-induced ED. Therefore, an in-depth research is necessary to confirm the causal link between COVID-19 and ED in LC patients.

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Leprosy is a neglected tropical disease that leads to physical disability and social discrimination. The active surveillance of new cases and vigilance for drug resistance can decrease the incidence, and improve the clinical outcomes of people affected by it. We analyzed, with molecular biology techniques, a set of skin biopsy samples from 25 Venezuelan patients. The patients had been diagnosed with leprosy in 2014 and early 2015, and 15 were relapse cases. The samples were tested for molecular drug resistance to dapsone, rifampicin, and fluoroquinolones. In addition, we performed molecular epidemiology analysis through multiple-locus variable-number tandem repeat analysis (MLVA) and single nucleotide polymorphism (SNP) typing. We did not find evidence of drug resistance and 76% of the samples (n = 16) had isolates belonging to SNP type 3. Genotype profiles allowed us to rule out the possibility of re-infection in a patient with persistent symptoms after treatment, as well as that of household transmission in two more patients. Although our sampling is relatively small, very similar or even identical Mycobacterium leprae genotypes were observed in Miranda State. The presence of this cluster is highly suggestive of high rates of local transmission and, in turn, the need to better control this disease. Finally, the copy number distribution of minisatellite 18–8 in a considerable number of SNP type 3 strains strongly suggests the presence of a sublineage of this disease that is particular to Venezuela.

hERG, the pore-forming subunit of the rapid component of the delayed rectifier K+ current, plays a key role in ventricular repolarization. Mutations in the KCNH2 gene encoding hERG are associated with several cardiac rhythmic disorders, mainly the Long QT syndrome (LQTS) characterized by prolonged ventricular repolarization, leading to ventricular tachyarrhythmias, sometimes progressing to ventricular fibrillation and sudden death. Over the past few years, the emergence of next-generation sequencing has revealed an increasing number of genetic variants including KCNH2 variants. However, the potential pathogenicity of the majority of the variants remains unknown, thus classifying them as variants of uncertain significance or VUS. With diseases such as LQTS being associated with sudden death, identifying patients at risk by determining the variant pathogenicity, is crucial. The purpose of this review is to describe, on the basis of an exhaustive examination of the 1322 missense variants, the nature of the functional assays undertaken so far and their limitations. A detailed analysis of 38 hERG missense variants identified in Long QT French patients and studied in electrophysiology also underlies the incomplete characterization of the biophysical properties for each variant. These analyses lead to two conclusions: first, the function of many hERG variants has never been looked at and, second, the functional studies done so far are excessively heterogeneous regarding the stimulation protocols, cellular models, experimental temperatures, homozygous and/or the heterozygous condition under study, a context that may lead to conflicting conclusions. The state of the literature emphasizes how necessary and important it is to perform an exhaustive functional characterization of hERG variants and to standardize this effort for meaningful comparison among variants. The review ends with suggestions to create a unique homogeneous protocol that could be shared and adopted among scientists and that would facilitate cardiologists and geneticists in patient counseling and management.

Background and purpose Protoxin II (ProTx II) is a high affinity gating modifier that is thought to selectively block the Nav 1.7 voltage-dependent Na+ channel, a major therapeutic target for the control of pain. We aimed at producing ProTx II analogues entitled with novel functionalities for cell distribution studies and biochemical characterization of its Nav channel targets. Experimental approach We took advantage of the high affinity properties of the peptide, combined to its slow off rate, to design a number of new tagged analogues useful for imaging and biochemistry purposes. We used high-throughput automated patch-clamp to identify the analogues best matching the native properties of ProTx II and validated them on various Nav -expressing cells in pull-down and cell distribution studies. Key results Two of the produced ProTx II analogues, Biot-ProTx II and ATTO488-ProTx II, best recapitulate the pharmacological properties of unlabelled ProTx II, while other analogues remain high affinity blockers of Nav 1.7. The biotinylated version of ProTx II efficiently works for the pull-down of several Nav isoforms tested in a concentration-dependent manner, while the fluorescent ATTO488-ProTx II specifically labels the Nav 1.7 channel over other Nav isoforms tested in various experimental conditions. Conclusions and implications The properties of these ProTx II analogues as tools for Nav channel purification and cell distribution studies pave the way for a better understanding of ProTx II channel receptors in pain and their pathophysiological implications in sensory neuronal processing. The new fluorescent ProTx II should also reveal itself useful for the design of new drug screening strategies.

Background: Despite advances in surgery and pharmacotherapy, there remains significant residual ischemic risk after coronary artery bypass grafting surgery. Methods: In REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial), a multicenter, placebo-controlled, double-blind trial, statin-treated patients with controlled low-density lipoprotein cholesterol and mild to moderate hypertriglyceridemia were randomized to 4 g daily of icosapent ethyl or placebo. They experienced a 25% reduction in risk of a primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina) and a 26% reduction in risk of a key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) when compared with placebo. The current analysis reports on the subgroup of patients from the trial with a history of coronary artery bypass grafting. Results: Of the 8179 patients randomized in REDUCE-IT, a total of 1837 (22.5%) had a history of coronary artery bypass grafting, with 897 patients randomized to icosapent ethyl and 940 to placebo. Baseline characteristics were similar between treatment groups. Randomization to icosapent ethyl was associated with a significant reduction in the primary end point (hazard ratio [HR], 0.76 [95% CI, 0.63–0.92]; P =0.004), in the key secondary end point (HR, 0.69 [95% CI, 0.56–0.87]; P =0.001), and in total (first plus subsequent or recurrent) ischemic events (rate ratio, 0.64 [95% CI, 0.50–0.81]; P =0.0002) compared with placebo. This yielded an absolute risk reduction of 6.2% (95% CI, 2.3%–10.2%) in first events, with a number needed to treat of 16 (95% CI, 10–44) during a median follow-up time of 4.8 years. Safety findings were similar to the overall study: beyond an increased rate of atrial fibrillation/flutter requiring hospitalization for at least 24 hours (5.0% vs 3.1%; P =0.03) and a nonsignificant increase in bleeding, occurrences of adverse events were comparable between groups. Conclusions: In REDUCE-IT patients with a history of coronary artery bypass grafting, treatment with icosapent ethyl was associated with significant reductions in first and recurrent ischemic events. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01492361.

The present study investigates the flexibility of statistically learned distractor suppression between different contexts. Participants performed the additional singleton task searching for a unique shape, while ignoring a uniquely colored distractor. Crucially, we created two contexts within the experiments, and each context was assigned its own high-probability distractor location, so that the location where the distractor was most likely to appear depended on the context. Experiment 1 signified context through the color of the background. In Experiment 2, we aimed to more strongly differentiate between the contexts using an auditory or visual cue to indicate the upcoming context. In Experiment 3, context determined the appropriate response ensuring that participants engaged the context in order to be able to perform the task. Across all experiments, participants learned to suppress both high-probability locations, even if they were not aware of these spatial regularities. However, these suppression effects occurred independent of context, as the pattern of suppression reflected a de-prioritization of both high-probability locations which did not change with the context. We employed Bayesian analyses to statistically quantify the absence of context-dependent suppression effects. We conclude that statistically learned distractor suppression is robust and generalizes across contexts.

The first workshop on Argumentation Knowledge Graphs (ArgKG) was held virtually at the Automated Knowledge Base Construction (AKBC 2021) conference on October 7, 2021. ArgKG @ AKBC 2021 brought together the Computational Argumentation and Knowledge Graphs communities, aiming to promote cross-pollination of ideas and encourage discussions and collaborations between the two communities. This paper describes the workshop and compiles several of its findings and insights. Date : 7 October, 2021. Website : https://argkg21.argmining.org.

Public systems are facing increasingly complex challenges such as poverty and terrorism. In this paper, we seek to demonstrate the theoretical as well as practical value of complexity science, by investigating how key characteristics of a Complex Adaptive System (CAS) work out in practice within the intelligence organization of the ongoing nation-building mission in Mali (MINUSMA). Our main finding is that the learning properties of the CAS suffer when its structural properties are not sufficiently developed. In MINUSMA, major improvements can especially be made in (re)developing the minimum specs—in which strategic and operational demands, ideally, converge.

Total hip arthroplasty is performed more frequently in younger patients nowadays, making long-term bone stock preservation an important topic. A mechanism for late implant failure is periprosthetic bone loss, caused by stress shielding around the hip stem due to different load distribution. Short stems are designed to keep the physical loading in the proximal part of the femur to reduce stress shielding. The aim of this review is to give more insight into how short and anatomic stems behave and whether they succeed in preservation of proximal bone stock. A systematic literature search was performed to find all published studies on bone mineral density in short and anatomic hip stems. Results on periprosthetic femoral bone mineral density, measured with dual-energy X-ray absorptiometry (DEXA), were compiled and analysed per Gruen zone in percentual change. A total of 29 studies were included. In short stems, Gruen 1 showed bone loss of 5% after one year (n = 855) and 5% after two years (n = 266). Gruen 7 showed bone loss of 10% after one year and –11% after two years. In anatomic stems, Gruen 1 showed bone loss of 8% after one year (n = 731) and 11% after two years (n = 227). Gruen 7 showed bone loss of 14% after one year and 15% after two years. Short stems are capable of preserving proximal bone stock and have slightly less proximal bone loss in the first years, compared to anatomic stems. Cite this article: EFORT Open Rev 2021;6:1040-1051. DOI: 10.1302/2058-5241.6.210030

OBJECTIVE: The role of combined FFR/CFR measurements in decision-making on coronary revascularization remains unclear. DEFINE-FLOW prospectively assessed the relationship of FFR/CFR agreement with 2-year major adverse cardiac event (MACE) and target vessel failure (TVF) rates, and uniquely included core-laboratory analysis of all pressure and flow tracings. We aimed to document the impact of core-laboratory analysis on lesion classification, and the relationship between core-laboratory fractional flow reserve (FFR) and coronary flow reserve (CFR) values with clinical outcomes and angina burden during follow-up.METHODS: In 398 vessels (348 patients) considered for intervention, ≥1 coronary pressure/flow tracing was approved by the core-laboratory. Revascularization was performed only when both FFR(≤0.80) and CFR(RESULTS: MACE was lowest for concordant normal FFR/CFR, but was not significantly different compared with either discordant group (low FFR/normal CFR: HR:1.63; 95%CI:0.61-4.40; P = 0.33; normal FFR/low CFR: HR:1.81; 95%CI:0.66-4.98; P = 0.25). Moreover, MACE did not differ between discordant groups treated medically and the concordant abnormal group undergoing revascularization (normal FFR/low CFR: HR:0.63; 95%CI:0.23-1.73;P = 0.37; normal FFR/low CFR: HR:0.70; 95%CI:0.22-2.21;P = 0.54). Similar findings applied to TVF.CONCLUSIONS: Patients with concordantly normal FFR/CFR have very low 2-year MACE and TVF rates. Throughout follow-up, there were no differences in event rates between patients in whom revascularization was deferred due to preserved CFR despite reduced FFR, and those in whom PCI was performed due to concordantly low FFR and CFR. These findings question the need for routine revascularization in vessels showing low FFR but preserved CFR.CLINICAL TRIAL REGISTRATION: http://ClinicalTrials.govNCT02328820.

Contains fulltext : 291333.pdf (Publisher’s version ) (Open Access) To optimize care for children with Marfan syndrome (MFS) in the Netherlands, Dutch MFS growth charts were constructed. Additionally, we aimed to investigate the effect of FBN1 variant type (haploinsufficiency [HI]/dominant negative [DN]) on growth, and compare MFS-related height increase across populations. Height and weight data of individuals with MFS aged 0-21 years were retrospectively collected. Generalized Additive Models for Location, Scale and Shape (GAMLSS) was used for growth chart modeling. To investigate genotype-phenotype relationships, FBN1 variant type was included as an independent variable in height-for-age and BMI-for-age models. MFS-related height increase was compared with that of previous MFS growth studies from the United States, Korea, and France. Height and weight data of 389 individuals with MFS were included (210 males). Height-for-age, BMI-for-age, and weight-for-height charts reflected the tall and slender MFS habitus throughout childhood. Mean increase in height of individuals with MFS compared with the general Dutch population was significantly lower than in the other three MFS populations compared to their reference populations. FBN1-HI variants were associated with taller height in both sexes, and decreased BMI in females (p-values

Objectives: This study evaluates the relationship between atherosclerotic plaque characteristics (APCs) and angiographic stenosis severity in patients with and without diabetes. Background: Whether APCs differ based on lesion severity and diabetic status is unknown. Methods: We retrospectively evaluated 303 subjects from the CREDENCE trial referred for invasive coronary angiography with coronary computed tomographic angiography (CCTA) and classified lesions as obstructive (>50% stenosed) or non-obstructive using blinded core laboratory analysis of quantitative coronary angiography. CCTA quantified APCs including plaque volume (PV), calcified plaque (CP), noncalcified plaque (NCP), low density noncalcified plaque (LD-NCP), lesion length, positive remodeling (PR), high-risk plaque (HRP) and percent atheroma volume (PAV; plaque volume normalized for vessel volume). The relationship between APCs, stenosis severity and diabetic status was assessed. Results: Among the 303 patients, 95 (31.4%) had diabetes. There were 117 lesions in the diabetic cohort, 58.1% of which were obstructive. Patients with diabetes had greater plaque burden (p=0.004). Patients with diabetes and nonobstructive disease had greater PV (p=0.02), PAV (p=0.02), NCP (p=0.03), PAV NCP (p=0.02), diseased vessels (p=0.03), and max stenosis (p=0.02) than nondiabetic patients with nonobstructive disease. APCs were similar between diabetics with non-obstructive disease and non-diabetic patients with obstructive disease. Diabetic status did not affect HRP or PR. Patients with diabetes had similar APCs in obstructive and non-obstructive lesions. Conclusions: Patients with diabetes and non-obstructive stenosis had an association to similar APCs as patients without diabetes who have obstructive stenosis. Among patients with non-obstructive disease, patients with diabetes had more total PV and NCP.

SARS-CoV-2 virus has rapidly spread worldwide since December 2019, causing COVID-19 disease. In-hospital mortality is a common indicator for evaluating treatment outcomes. Therefore, the developing and validating a simple score system from observational data could assist in modulating the management procedures. A retrospective cohort study included all data records of patients with positive PCR for SARS-CoV-2. The factors that associated with mortality were analyzed, then allocation of potential predictors of mortality was executed using different logistic regression modeling, subsequently scoring system was developed from the most weighted predictors. The mortality rate of patients with COVID-19 pneumonia was 28.5% and 28.74%, respectively. The most significant factors that affected in-hospital mortality were old age (> 60 years), delay in hospital admission (> 4 days), high neutrophil/lymphocyte ratio “NLR” (> 3); higher computed tomography severity score; and CT-SS (> 20), in addition to using remdesivir and tocilizumab in the treatment protocol (P

Marfan syndrome (MFS) is the most prevalent inherited connective tissue disorder, still remains uncurable, and is characterized by high mortality at early age driven by dissection and rupture of thoracic aortic aneurysms. MFS is caused by mutations in the fibrillin-1 gene and aberrant TGFß signaling.Here we addressed whether myeloperoxidase (MPO), a leukocyte derived enzyme with potent matrix modulating properties also influences the aortic phenotype in MFS.MFS patients displayed increased circulating MPO levels compared to controls as well as marked aortic MPO deposition. In an MFS mouse model, MPO induced inflammatory endothelial activation and endothelial to mesenchymal transition which triggered aortic leukocyte recruitment. Moreover, MPO directly contributed to adverse extracellular matrix remodeling by promoting oxidative stress and nitration of proteins within the vascular wall. Genetic MPO deficiency and pharmacological MPO inhibition attenuated MFS-related aneurysm formation. We herein identify MPO as a critical mediator of MFS-related thoracic aortic aneurysm formation and - in the absence of any pharmacological treatment so far in this disease - a first anti-inflammatory target to modulate disease progression.

Background To improve participation in the Dutch cervical cancer screening, a self-sampling device (SSD) was introduced in 2017 into the Dutch population-based screening programme (PBS) for the early detection of cervical cancer. The aim of this study was to gather potential preferences and experiences that might influence a woman's decision to use the SSD in the Dutch PBS. Methods A scoping review was performed in the PubMed database. Studies that assessed preferences and experiences of women regarding the SSD were included, and preferences and experiences were extracted. In addition, in a qualitative study, the list of potential preferences and experiences specific for the Dutch PBS was extended based on semi-structured interviews with SSD users as well as non-SSD users who recently participated in the PBS, analysed in a structured manner by translating full sentences to key words. Results Ninety-eight studies were included in the scoping review and 16 interviews were performed. Frequently mentioned reasons for using the SSD, in both the interviews and the literature, were practicality and comfort. Frequently mentioned reasons for not using the SSD were fear of not performing the SSD procedure correctly and doubts on whether the results of the high-risk human papillomavirus (hrHPV) test will be reliable. A new positive experience elicited in the interviews was accessibility. Negative preferences and experiences were not being aware the SSD was an option, and the inconvenience that after an hrHPV-positive test result of the SSD, an additional smear test at the GP is necessary. Conclusion Several preferences and experiences play a role in the choice whether or not to use the SSD. Based on the currently found preferences and experiences, an app will be developed in order to assess which of these are the most important for women participating in the Dutch population-based cervical screening programme.

OBJECTIVE: To describe risk factors and outcomes of pregnant women infected with SARS-CoV-2 admitted to South African healthcare facilities. METHODS: A population-based cohort study was conducted utilizing an amended International Obstetric Surveillance System protocol. Data on pregnant women with SARS-CoV-2 infection, hospitalized between April 14, 2020, and November 24, 2020, were analyzed. RESULTS: A total of 36 hospitals submitted data on 673 infected hospitalized pregnant women; 217 (32.2%) were admitted for COVID-19 illness and 456 for other indications. There were 39 deaths with a case fatality rate of 6.3%: 32 (14.7%) deaths occurred in women admitted for COVID-19 illness compared to 7 (1.8%) in women admitted for other indications. Of the women, 106 (15.9%) required critical care. Maternal tuberculosis, but not HIV co-infection or other co-morbidities, was associated with admission for COVID-19 illness. Rates of cesarean delivery did not differ significantly between women admitted for COVID-19 and those admitted for other indications. There were 179 (35.4%) preterm births, 25 (4.7%) stillbirths, 12 (2.3%) neonatal deaths, and 162 (30.8%) neonatal admissions. Neonatal outcomes did not differ significantly from those of infected women admitted for other indications. CONCLUSION: The maternal mortality rate was high among women admitted with SARS-CoV-2 infection and higher in women admitted primarily for COVID-19 illness with tuberculosis being the only co-morbidity associated with admission.

BACKGROUND We assessed nasopharyngeal pneumococcal carriage in Andean Kichwa children, the largest Amerindian indigenous population in the Ecuadorian Andes. All children in our study had been vaccinated with the 10-valent pneumococcal vaccine (PCV10). METHODS Nasopharyngeal swabs from 63 families, 100 children

Numerous microRNAs (miRNAs) have been found to have an aberrant expression in the peripheral blood or psoriasis patients' lesions. Psoriasis was shown to have the abnormal expression of microRNA-203 (miR-203). It is a skin-specific signal that governs cellular proliferation in a protein kinase C-dependent manner and is mostly generated by keratinocytes. This work evaluated the expression levels of the circulating miR-203 target genes SOCS3, SOCS6, TP63, TNF-, IL8, and IL24 in psoriasis patients. Using a relative quantitation PCR technique, we determined the expression levels of miR-203 and its target genes (SOCS3, SOCS6, TP63, TNF-, IL8, and IL24) in the plasma of 120 psoriatic patients and matched healthy controls. The disease characteristics of the patients were then correlated with the expression results. We also conducted numerous enrichment analyses for the diseases, functions, and pathways connected to the under-researched biomarkers. Compared to healthy controls, psoriatic patients had significantly increased levels of miR-203 expression; 7.1 (4.4–9.9). In contrast, psoriatic patients had significantly lower expression of all the examined genes compared to healthy controls. Regarding all the study biomarkers, the receiver operating characteristic (ROC) curve analysis demonstrated significant sensitivity and specificity for differentiating between psoriatic patients and healthy controls. According to the results of the disease matching score generated by miR-203 and its target genes, psoriasis was ranked first with a score of 4.45. The third-place finisher with a value of 3.98, it also demonstrated that miR-203 and its target genes are connected to various skin disorders. Our results show that miR-203 contributes to psoriasis pathogenesis not only locally in skin lesions but also in circulation, indicating that it may contribute to the systemic symptoms of the illness. MiR-203 overexpression in psoriasis suggests that miR-203 may be involved in an anti-inflammatory response because it targets both SOCS gene family members and pro-inflammatory cytokines.

International audience; SARS-CoV-2 triggered a worldwide medical crisis, affecting the world’s social, emotional, physical, and economic equilibrium. However, treatment choices and targets for finding a solution to COVID-19’s threat are becoming limited. A viable approach to combating the threat of COVID-19 is by unraveling newer pharmacological and therapeutic targets pertinent in the viral survival and adaptive mechanisms within the host biological milieu which in turn provides the opportunity to discover promising inhibitors against COVID-19. Therefore, using high-throughput virtual screening, manually curated compounds library from some medicinal plants were screened against four main drivers of SARS-CoV-2 (spike glycoprotein, PLpro, 3CLpro, and RdRp). In addition, molecular docking, Prime MM/GBSA (molecular mechanics/generalized Born surface area) analysis, molecular dynamics (MD) simulation, and drug-likeness screening were performed to identify potential phytodrugs candidates for COVID-19 treatment. In support of these approaches, we used a series of computational modeling approaches to develop therapeutic agents against COVID-19. Out of the screened compounds against the selected SARS-CoV-2 therapeutic targets, only compounds with no violations of Lipinski’s rule of five and high binding affinity were considered as potential anti-COVID-19 drugs. However, lonchocarpol A, diplacol, and broussonol E (lead compounds) were recorded as the best compounds that satisfied this requirement, and they demonstrated their highest binding affinity against 3CLpro. Therefore, the 3CLpro target and the three lead compounds were selected for further analysis. Through protein–ligand mapping and interaction profiling, the three lead compounds formed essential interactions such as hydrogen bonds and hydrophobic interactions with amino acid residues at the binding pocket of 3CLpro. The key amino acid residues at the 3CLpro active site participating in the hydrophobic and polar inter/intra molecular interaction were TYR54, PRO52, CYS44, MET49, MET165, CYS145, HIS41, THR26, THR25, GLN189, and THR190. The compounds demonstrated stable protein–ligand complexes in the active site of the target (3CLpro) over a 100 ns simulation period with stable protein–ligand trajectories. Drug-likeness screening shows that the compounds are druggable molecules, and the toxicity descriptors established that the compounds demonstrated a good biosafety profile. Furthermore, the compounds were chemically reactive with promising molecular electron potential properties. Collectively, we propose that the discovered lead compounds may open the way for establishing phytodrugs to manage COVID-19 pandemics and new chemical libraries to prevent COVID-19 entry into the host based on the findings of this computational investigation.

International audience; Lung cancer is the second most commonly diagnosed cancer in the world. In terms of the diagnosis of lung cancer, combination carcinoembryonic antigen (CEA) and cancer antigen 125 (CA125) detection had higher sensitivity, specificity, and diagnostic odds ratios than CEA detection alone. Most individuals with elevated serum CA125 levels had lung cancer that was either in stage 3 or stage 4. Serum CA125 levels were similarly elevated in lung cancer patients who also had pleural effusions or ascites. Furthermore, there is strong evidence that human lung cancer produces CA125 in vitro, which suggests that other clinical illnesses outside of ovarian cancer could also be responsible for the rise of CA125. MUC16 (CA125) is a natural killer cell inhibitor. As a screening test for lung and ovarian cancer diagnosis and prognosis in the early stages, CA125 has been widely used as a marker in three different clinical settings. MUC16 mRNA levels in lung cancer are increased regardless of gender. As well, increased expression of mutated MUC16 enhances lung cancer cells proliferation and growth. Additionally, the CA125 serum level is thought to be a key indicator for lung cancer metastasis to the liver. Further, CA125 could be a useful biomarker in other cancer types diagnoses like ovarian, breast, and pancreatic cancers. One of the important limitations of CA125 as a first step in such a screening technique is that up to 20% of ovarian tumors lack antigen expression. Each of the 10 possible serum markers was expressed in 29–100% of ovarian tumors with minimal or no CA125 expression. Therefore, there is a controversy regarding CA125 in the diagnosis and prognosis of lung cancer and other cancer types. In this state, preclinical and clinical studies are warranted to elucidate the clinical benefit of CA125 in the diagnosis and prognosis of lung cancer.