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Summary Background Patients with COVID-19 pneumonia can have increased inflammation and elevated cytokines, including interleukin (IL)-6, which might be deleterious. Thus, sarilumab, a high-affinity anti-IL-6 receptor antibody, might improve the outcome of patients with moderate-to-severe COVID-19 pneumonia. Methods We did a multicentric, open-label, Bayesian randomised, adaptive, phase 2/3 clinical trial, nested within the CORIMUNO-19 cohort, to test a superiority hypothesis. Patients 18 years or older hospitalised with COVID-19 in six French centres, requiring at least 3L/min of oxygen but without ventilation assistance and a WHO Clinical Progression Scale [CPS] score of 5 were enrolled. Patients were randomly assigned (1:1) via a web-based system, according to a randomisation list stratified on centre and with blocks randomly selected among 2 and 4, to receive usual care plus 400 mg of sarilumab intravenously on day 1 and on day 3 if clinically indicated (sarilumab group) or usual care alone (usual care group). Primary outcomes were the proportion of patients with WHO-CPS scores greater than 5 on the 10-point scale on day 4 and survival without invasive or non-invasive ventilation at day 14. This completed trial is closed to new participants and is registered with ClinicalTrials.gov , NCT04324073 . Findings 165 patients were recruited from March 27 to April 6, 2020, and 148 patients were randomised (68 patients to the sarilumab group and 80 to the usual care group) and followed up for 90 days. Median age was 61·7 years [IQR 53·0–71·1] in the sarilumab group and 62·8 years [56·0–71·7] in the usual care group. In the sarilumab group 49 (72%) of 68 were men and in the usual care group 59 (78%) of 76 were men. Four patients in the usual care group withdrew consent and were not analysed. 18 (26%) of 68 patients in the sarilumab group had a WHO-CPS score greater than 5 at day 4 versus 20 (26%) of 76 in the usual care group (median posterior absolute risk difference 0·2%; 90% credible interval [CrI] −11·7 to 12·2), with a posterior probability of absolute risk difference greater than 0 of 48·9%. At day 14, 25 (37%) patients in the sarilumab and 26 (34%) patients in the usual care group needed ventilation or died, (median posterior hazard ratio [HR] 1·10; 90% CrI 0·69–1·74) with a posterior probability HR greater than 1 of 37·4%. Serious adverse events occurred in 27 (40%) patients in the sarilumab group and 28 (37%) patients in the usual care group (p=0·73). Interpretation Sarilumab treatment did not improve early outcomes in patients with moderate-to-severe COVID-19 pneumonia. Further studies are warranted to evaluate the effect of sarilumab on long-term survival. Funding Assistance publique—Hopitaux de Paris

Mesenchymal stromal cells (MSC) are nonhematopoietic cells with fibroblast-like morphology and multipotent capacity that are widely used in pre-clinical and clinical investigations. Unfortunately, the efficiency of MSC treatment is hindered by the poor survival rate after transplantation at the damaged tissue. The goal of this study was to investigate the fate of MSC exposed to various stimuli mimicking the in vivo microenvironment post transplantation. To this aim, murine bone marrow–derived MSC were stimulated with IFNγ and TNFα under low oxygen (hypoxia) or atmospheric (normoxia) conditions for 24 to 72 hours, in order to better mimic an ischemic injury. The results showed that MSC pre-stimulation with TNFα and IFNγ enhanced immunosuppressive pathways by over-expression of NOS2, IDO, COX2 and production of NO. However, MSC viability was affected by these two cytokines in dose-dependent and time-dependent manners. Besides, priming with TNFα and/or IFNγ under low oxygen concentrations revealed that significantly increased cell mortality rate and decreased NO production. Our data suggest that both hypoxia and inflammation could impact the cell survival after transplantation and reinforces the necessity of further investigations to better understand MSC behavior after transplantation in order to identify the MSC-based strategies with the highest therapeutic potential.

Currently, an impressive number of patients have been diagnosed with atrial fibrillation (AF) receiving a reliable indication for oral anticoagulation therapy (OAT) either with vitamin K inhibitors...

Background Colonoscopy with biopsy is the "gold" standard for evaluating disease activity in inflammatory bowel diseases (IBD). Current research is geared toward finding non-invasive, cost-efficient methods that estimate disease activity. We aimed to develop a neural network (NN) model for the non-invasive prediction of histologic activity in IBD using routinely available clinical-biological parameters. Methods Standard clinical-biological parameters and histologic activity from 371 ulcerative colitis (UC) and 115 Crohn's disease (CD) patient records were collected. A training set, a test set, and a validation set were used for building/validating 2 models for each disease. All models had binary output predicting the active/inactive histologic disease status. For both diseases, the first model used both clinical and biological inputs, while the second used only biological data. Results First UC model obtained an accuracy of 95.59% on the test set and 96.67% on the validation set. The second UC model achieved accuracies of 88.24% and 86.67% on the test and validation sets, respectively. The First CD classifier resulted in 90.48% accuracy on the test set and 91.67% on the validation set. Finally, the second CD classifier obtained an accuracy of 85.71% on the test set and 91.67% on the validation set. Conclusions An accurate and non-invasive artificial intelligence system to predict histologic disease activity in IBD is designed. Our models achieved similar or better results compared to the documented performance of fecal calprotectin (the best non-invasive IBD biomarker to date). Given these favorable results, we anticipate the future utility in the clinical setting of a non-invasive disease activity prediction.

The melanoma, having its origin in the melanocyte cells, is one of the most aggressive forms of skin cancer in the world with one of the highest rates of brain metastasis. The incidence of cutaneous melanoma in the Mediterranean countries varies from three to five cases∕100 000 people∕year. Its prognosis is based on an early diagnosis. Sinonasal mucosal melanoma (SNMM) is an extremely rare tumor, accounting for 0.3-2% of all melanomas. The non-specific symptomatology is often delaying the presentation of the patient at the hospital and therefore the diagnosis. The SNMM is a highly aggressive tumor, and the presence of metastasis at the diagnosis usually implies a poor prognosis. The management of the melanomas requires a precise pre-therapeutic assessment and a multidisciplinary approach for the diagnosis, with surgical treatment or radiotherapy required in order to ensure a better a quality of life. In this paper, we retrospectively analyzed two cases of mucosal melanoma and one case of cutaneous melanoma of the nose.

Background A high prevalence of pulmonary embolism (PE) has been described during COVID‐19. Our aim was to identify predictive factors of PE in non‐ICU hospitalized COVID‐19 patients. Methods Data and outcomes were collected upon admission during a French multicenter retrospective study, including patients hospitalized for COVID‐19, with a CT pulmonary angiography (CTPA) performed in the emergency department for suspected PE. Predictive factors significantly associated with PE were identified through a multivariate regression model. Results A total of 88 patients (median [IQR] age of 68 years [60‐78]) were analyzed. Based on CTPA, 47 (53.4%) patients were diagnosed with PE, and 41 were not. D‐dimer ≥3000 ng/mL (OR 8.2 [95% CI] 1.3‐74.2, sensitivity (Se) 0.84, specificity (Sp) 0.78, P = .03), white blood count (WBC) ≥12.0 G/L (29.5 [2.3‐1221.2], Se 0.47, Sp 0.92, P = .02), and ferritin ≥480 µg/L (17.0 [1.7‐553.3], Se 0.96, Sp 0.44, P = .03) were independently associated with the PE diagnosis. The presence of the double criterion D‐dimer ≥3000 ng/mL and WBC ≥12.0 G/L was greatly associated with PE (OR 21.4 [4.0‐397.9], P = .004). Conclusion The white blood count, the D‐dimer and ferritin levels could be used as an indication for CTPA to confirm PE on admission in non‐ICU COVID‐19 patients.

Colonoscopy is the “gold” standard for evaluating disease activity in ulcerative colitis (UC). An important area of research is finding a cost-efficient, non-invasive solution for estimating disease activity. We aimed to develop and validate a neural network (NN) model that uses routinely available clinical–biological variables to predict UC activity. Standard clinical–biological parameters and endoscopic Mayo score from 386 UC patient records were collected. A training set (n = 285), a test set (n = 71) and a validation set (n=30) were used for constructing and validating three NN models. The first two models predicted the active/inactive endoscopic disease status through a binary output. The third model estimated the complete endoscopic Mayo score through a categorical output. First model (with seven categorical and 13 continuous input variables) obtained an accuracy of 94.37% on the test set and 93.33% on the validation set. The second model (with 12 biological input parameters) achieved an accuracy of 88.73% on the test set and 83.33% on the validation set. The third model used the same input variables as the first model obtaining an accuracy of 76.06% on the test set and 80% on the validation set. We designed an accurate and non-invasive artificial intelligence solution to estimate disease activity, other than colonoscopy. Our NN model achieved better results than pooled performance metrics of fecal calprotectin (the best non-invasive marker to date) investigated in UC. Given these promising results, we envision introducing of a non-invasive algorithm for routinely predicting disease activity shortly.

Introduction. Leptospirosis is a zoonosis caused by microorganisms of the genus Leptospira with a global spread. The main reservoir of leptospires are the small mammals, which survive after infection, spreading the causative agent in the environment with urine. Material and methods. The studied were conducted in 2017-2019 in different ecosystems, where 1617 small mammals were collected, investigated for the presence of specific antibodies to Leptospira spp. Ecological analysis of small mammal communities was performed and leptospire-carrier species were identified. Results. 17 species of the order Rodentia and Soricomorpha were identified. The most widespread are A. sylvaticus, A. flavicollis and A. agrarius with a frequency of 100%, abundant and dominant in most of the studied ecosystems. Antibodies specific to Leptospira spp. were detected in 9 species, the highest share of the species with leptospire belongs to A. agrarius (53.85%) and C. glareolus (11.54%). The serogroups Leptospira grippotyphosa, L. icterohaemorrhagiae and L. pomona were highlighted. Conclusions. The epizootiological process in leptospirosis is maintained active in nature by 9 species of small mammals, including one of the Europe species A. agrarius, the leptospire rate was determined at 53.85%. The intense circulation of leptospires in the small mammal population determines the need to monitor the multiannual dynamics of their in order to establish changes in natural foci of leptospirosis, forecast the epizootological situation and the risk of spreading of disease among the human population.

Background: Interpretation of thyroid function tests by means of biological variation (BV) data is essential to identify significant changes between serial measurements at an individual level. Data on thyroid parameters in adults are limited. Objectives: We aimed at determining the BV of four thyroid function test (thyroid-stimulating hormone (TSH), free thyroxin (FT4), free triiodothyronine (FT3) and thyroglobulin (Tg)) by applying recent recommendations to acquire BV data on a latest generation of immunoassay. Methods: Nineteen healthy volunteers (8 males and 11 females) were drawn every week during 5 consecutive weeks. Samples were analysed in duplicate on the Cobas 602 analyzer (Roche Diagnostics). After normality assessment, outlier exclusion and homogeneity of variance analysis, analytical variation (CVA), within-subject biological variation (CVI) and between-subject biological variation (CVG) were determined using nested ANOVA. Results: CVA, CVI and CVG were 0.9%, 19.7% and 37.6% for TSH; 3.6%, 4.6% and 10.8% for FT4; 2.2%, 6.0% and 8.6% for FT3; and 0.9%, 15.4% and 84.9% for Tg. Index of individuality (II) for all parameters was between 0.2 and 0.7. The percentage above which the change between two measures is truly significant (reference change value) was 54.7% for TSH, 16.2% for FT4, 17.7% for FT3 and 42.8% for Tg. Conclusion: Based on recent international recommendations, our study provides updated BV data for four thyroid function tests in European healthy volunteers. Reliable BV characteristics, and especially RCV, can facilitate the interpretation of consecutive thyroid function tests in an individual and therefore have the potential to efficiently support clinical decisions regarding thyroid diseases.

International audience

Dialysis patients manifest both an increased thrombotic risk and a haemorrhagic tendency. A great number of patients with chronic kidney disease requiring dialysis have cardiovascular comorbidities (coronary artery disease, atrial fibrillation or venous thromboembolism) and different indications for treatment with antithrombotics (primary or secondary prevention). Unfortunately, few randomized controlled trials deal with antiplatelet and/or anticoagulant therapy in dialysis. Therefore cardiology and nephrology guidelines offer ambiguous recommendations and often exclude or ignore these patients. In our opinion, there is a need for an expert consensus that provides physicians with useful information to make correct decisions in different situations requiring antithrombotics. Herein the European Dialysis Working Group presents up-to-date evidence about the topic and encourages practitioners to choose among alternatives in order to limit bleeding and minimize atherothrombotic and cardioembolic risks. In the absence of clear evidence, these clinical settings and consequent therapeutic strategies will be discussed by highlighting data from observational studies for and against the use of antiplatelet and anticoagulant drugs alone or in combination. Until new studies shed light on unclear clinical situations, one should keep in mind that the objective of treatment is to minimize thrombotic risk while reducing bleeding events.

The COVID-19 pandemic rapidly became a worldwide healthcare emergency affecting millions of people, with poor outcomes for patients with chronic conditions and enormous pressure on healthcare systems. Pulmonary fibrosis (PF) has been cited as a risk factor for a more severe evolution of COVID-19, primarily because its acute exacerbations are already associated with high mortality. We reviewed the available literature on biochemical, pathophysiological, and pharmacological mechanisms of PF and COVID-19 in an attempt to foresee the particular risk of infection and possible evolution of PF patients if infected with SARS-COV-2. We also analyzed the possible role of medication and risk factors (such as smoking) in the disease’s evolution and clinical course. We found out that there is a complexity of interactions between coexisting idiopathic pulmonary fibrosis/interstitial lung disease (ILD) and COVID-19 disease. Also, patients recovering from severe COVID-19 disease are at serious risk of developing PF. Smokers seem to have, in theory, a chance for a better outcome if they develop a severe form of COVID-19 but statistically are at much higher risk of dying if they become critically ill.

Nowadays, artificial intelligence (AI) is an important part of our life and it is a field which continues to grow, to develop and to be implemented in many aspects of our daily tasks. In addition, it continues to conquer many domains of health care with huge progress maid especially in medical image analysis, like radiography, computer tomography, magnetic resonance imaging, digital breast tomosynthesis, positron emission tomography scans or retinal images. The purpose of our work is to analyze the current state of AI systems and software in the practice of pathology. The digitalization process of pathology was possible due to development and improvement of several whole slide images systems in the last decade which provide a vast and rich image data to pathologists and researchers. The algorithmic base of AI is represented by machine learning (ML) and the basis of AI software reside in different statistical model and methods on large set of data. Initially, different mathematical models were used as toolset for ML like supervised and unsupervised learning, random forest, clustering algorithms or component analysis. In the present, deep learning subfield of ML with its neural networks (NN), artificial and convolutional NN, are frequently used in machine vision field. Other tools used in image analysis of digital slide are data augmentation, probability heat maps, patching and computer-aided diagnosis. All of them lead to a high valuable output from which an algorithm can be extracted and can assist the pathologist to render a final diagnosis. Even if there are a lot of challenges in integrated AI solutions in pathology department, they can streamline the diagnosis process in pathology with improvement of workflow, boosting the performance with a better and quicker diagnosis. Image analysis in pathology continues to expend and new branches emerge (digital pathology and pathology informatics) with huge potential for innovative discoveries.

Subcutaneous transplantation of mesenchymal stromal cells (MSC) emerged as an alternative to intravenous administration because it avoids the pulmonary embolism and prolongs post‐transplantation lifetime. The goal of this study was to investigate the mechanisms by which these cells could affect remote organs. To this aim, murine bone marrow–derived MSC were subcutaneously transplanted in different anatomical regions and the survival and behaviour have been followed. The results showed that upon subcutaneous transplantation in mice, MSC formed multicellular aggregates and did not migrate significantly from the site of injection. Our data suggest an important role of hypoxia‐inducible signalling pathways in stimulating local angiogenesis and the ensuing modulation of the kinetics of circulating cytokines with putative protective effects at distant sites. These data expand the current understanding of cell behaviour after subcutaneous transplantation and contribute to the development of a non‐invasive cell‐based therapy for distant organ protection.

Background. The purpose of this review is to depict current research and impact of artificial intelligence/machine learning (AI/ML) algorithms on dialysis and kidney transplantation. Published studies were presented from two points of view: What medical aspects were covered? What AI/ML algorithms have been used? Methods. We searched four electronic databases or studies that used AI/ML in hemodialysis (HD), peritoneal dialysis (PD), and kidney transplantation (KT). Sixty-nine studies were split into three categories: AI/ML and HD, PD, and KT, respectively. We identified 43 trials in the first group, 8 in the second, and 18 in the third. Then, studies were classified according to the type of algorithm. Results. AI and HD trials covered: (a) dialysis service management, (b) dialysis procedure, (c) anemia management, (d) hormonal/dietary issues, and (e) arteriovenous fistula assessment. PD studies were divided into (a) peritoneal technique issues, (b) infections, and (c) cardiovascular event prediction. AI in transplantation studies were allocated into (a) management systems (ML used as pretransplant organ-matching tools), (b) predicting graft rejection, (c) tacrolimus therapy modulation, and (d) dietary issues. Conclusions. Although guidelines are reluctant to recommend AI implementation in daily practice, there is plenty of evidence that AI/ML algorithms can predict better than nephrologists: volumes, Kt/V, and hypotension or cardiovascular events during dialysis. Altogether, these trials report a robust impact of AI/ML on quality of life and survival in G5D/T patients. In the coming years, one would probably witness the emergence of AI/ML devices that facilitate the management of dialysis patients, thus increasing the quality of life and survival.

In this issue of Clinical Kidney Journal, Park et al. presents the results of a nationwide population-based trial that included >5000 dialysis patients receiving a drug-eluting stent (DES). The main objective was to evaluate the effectiveness and the safety of prolonged dual antiplatelet therapy (DAPT). The primary outcome was a composite of mortality, non-fatal myocardial infarction, coronary revascularization and stroke, significantly lowered by a longer DAPT regimen at 12, 15 and 18 months, respectively. Longer DAPT tended to be correlated with higher bleeding events at all landmarks, with no statistical significance. An important element was that almost 75% of the index events were acute coronary syndromes. This study presents the first solid evidence for a significant benefit of prolonged DAPT in dialysis patients receiving a DES. We believe that end-stage renal disease is still in the middle of a rope game, being pulled to one side or another by other features, inclining towards a higher bleeding risk or towards higher ischaemic risk. The acute versus elective presentation seems to weigh in choosing the antiplatelet regimen. The ‘one-size-fits-all strategy’ is not suitable for this particular group. Probably in the future, practitioners will be provided with decision pathways generated by artificial intelligence algorithms yielding ‘truly individualized’ DAPT protocols for every single patient.

Introduction Marked isolated elevation of cardiac biomarkers (CK-MB, cardiac troponin I, heart-type fatty acid binding protein, hFABP) within 48 hours after coronary artery bypass surgery (CABG), even in the absence of electrocardiographic/angiographic evidence of myocardial infarction (MI), indicates prognostically significant cardiac procedural myocardial injury. There are no data exploring the relationship between the complexity of coronary atherosclerotic burden and early post-CABG myocardial injury. Aim To analyse correlations and predictive strength of the SYNTAX score (SS) for early myocardial injury after on-pump CABG. Material and methods One hundred and twenty consecutive patients undergoing CABG were included in the analysis. We obtained data on demographics, medical history, cardiovascular risk factors and echocardiography. Cardiac biomarkers were assessed at 6 hours after CABG. Multivariate linear regression analysis was performed to evaluate independent variables correlated with cardiac biomarkers. Results The most significant predictor for myocardial injury was SS, strongly correlated with the rise of all cardiac biomarkers (p < 0.001). Hypertension and creatinine clearance were associated with cTnI and hFABP. Diabetes was corelated with hFABP. In a multivariate analysis including all significant predictors, SS remained an independent predictor for myocardial injury, strongly associated with hFABP (p < 0.001, OR = 5.79, 95% CI: 3.59-7.98), cTnI (p < 0.001, OR = 6.49, 95% CI: 4.78-8.20), but not with CK-MB (95% CI: 0.61-1.07). Conclusions Defining myocardial injury as elevation of cardiac biomarkers between normal values and the cut-off for MI has a tremendous clinical significance as patients maintain high negative prognostic rates. SS could be used to predict post-operative rise of cardiac biomarkers, the correlation between SS and myocardial injury being very solid.

The novice anaesthesiology trainee must rapidly assimilate the cognitive, technical and non-technical skills necessary to competently respond to critical events in their new role. Providing trainees with the safe and controlled environment of high-fidelity patient simulation is one method to compensate for gaps in trainee experience, offering the potential for effective training. An anaesthesiology boot camp was set up to increase the knowledge, clinical, technical and non-technical competencies of the novice trainee, creating a framework for their future learning and practice. Anaesthetic nurses also attended to incorporated teamwork and collaboration into the boot camp. Seven novice anaesthesiology trainees and 3 anaesthetic nurses attended 3 4-h boot camp sessions. The boot camp consisted of the following: (1) interactive didactic lectures; (2) task-trainer technical skills teaching; and, (3) high-fidelity simulations. Pre- and post-course evaluation forms including a multiple-choice-questions (MCQ) assessing knowledge were completed. Nine participants fully completed the boot camp. There was a significant increase in post-MCQ score (p = 0.001). Feedback from participants included “well organised”, “helpful” and “structured approach” with all participants agreeing or strongly agreeing that it was relevant training for their practice. We have created the first Irish anaesthesiology boot camp, demonstrating the important role that simulation has in enhancing medical education. Our results showed both knowledge attainment and participant satisfaction in this method of learning. Anaesthesiology boot camps are the ideal method to provide novice trainees with a framework for their initial introduction into anaesthesia.

The health crisis generated by the COVID-19 pandemic has induced, among other things, an increase in the importance of remote work or teleworking (TL) in the current period. The objective of this research is to identify the economic and social impact of telework in changing the behavior of employees in Romania. The research was conducted approximately one year after the onset of the pandemic until the beginning of the vaccination period in Romania. The research proposed includes three main directions of analysis of the extracted data, which are related to telework efficiency, this being considered one of the most important indicators for a company. In order to obtain conclusive results, we used a mixed methodology, combining results obtained through a survey based on a self-administered electronic questionnaire, with a data mining analysis. Detailed analysis of the groups identified based on work efficiency allowed us to highlight the most common employee profiles. This analysis was doubled by a second classification experiment, which provided us a more detailed analysis of the groups identified based on job satisfaction and highlighted the most common employee profiles. The expansion of telework in various economic areas is a result of adaptation to the new economic and social conditions caused by the COVID-19 pandemic.

Sudden cardiac death (SCD) represents a major cause of death in end-stage kidney disease (ESKD). The precise estimate of its incidence is difficult to establish because studies on the incidence of SCD in ESKD are often combined with those related to sudden cardiac arrest (SCA) occurring during a haemodialysis (HD) session. The aim of the European Dialysis Working Group of ERA-EDTA was to critically review the current literature examining the causes of extradialysis SCD and intradialysis SCA in ESKD patients and potential management strategies to reduce the incidence of such events. Extradialysis SCD and intradialysis SCA represent different clinical situations and should be kept distinct. Regarding the problem, numerically less relevant, of patients affected by intradialysis SCA, some modifiable risk factors have been identified, such as a low concentration of potassium and calcium in the dialysate, and some advantages linked to the presence of automated external defibrillators in dialysis units have been documented. The problem of extra-dialysis SCD is more complex. A reduced left ventricular ejection fraction associated with SCD is present only in a minority of cases occurring in HD patients. This is the proof that SCD occurring in ESKD has different characteristics compared with SCD occurring in patients with ischaemic heart disease and/or heart failure and not affected by ESKD. Recent evidence suggests that the fatal arrhythmia in this population may be due more frequently to bradyarrhythmias than to tachyarrhythmias. This fact may partly explain why several studies could not demonstrate an advantage of implantable cardioverter defibrillators in preventing SCD in ESKD patients. Electrolyte imbalances, frequently present in HD patients, could explain part of the arrhythmic phenomena, as suggested by the relationship between SCD and timing of the HD session. However, the high incidence of SCD in patients on peritoneal dialysis suggests that other risk factors due to cardiac comorbidities and uraemia per se may contribute to sudden mortality in ESKD patients.

Cell biology, plant-based extracts, structural chemistry, and laboratory in vitro or in vivo experiments are the principal aspects or interfaces that can contribute to discovering new possibilities in cancer therapy and to developing improved chemotherapeutics. Forestry residues can be used for their wealthy resource in polyphenols and other phytoconstituents known for anticancer properties. This review is designed to bring together information on the in vitro or in vivo anticancer potential of woody vascular plants especially the bark extracts (BE) and biosynthesized metallic nanoparticles (BMN) using bark extracts. Type of extracts, main phytoconstituents found in extracts responsible for the anticancer activity, and targeted cancerous cell lines were followed. The literature data were collected via Clarivate Analytics, Science Direct, PubMed, and Google Academic (2011–2021). The search terms were: bark extracts, metallic nanoparticles, silver nanoparticles, gold nanoparticles, anticancer, cytotoxic activity, antiproliferative effect, and antimetastatic potential in vitro and in vivo. All of the search terms listed above were used in different combinations. The literature data highlight the efficaciousness of the BE and BMN as anticancer agents in in vitro experiments and showed the mechanism of action and their advantage of nontoxicity on normal cells. In vitro testing has shown promising results of the BE and BMN effect on different cancer cell lines. In vivo testing is lacking and more data is necessary for drug development on animal models.

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality among patients with end-stage renal disease (ESRD). Clustering of traditional atherosclerotic and non-traditional risk factors drive the excess rates of coronary and non-coronary CVD in this population. The incidence, severity and mortality of coronary artery disease (CAD) as well as the number of complications of its therapy is higher in dialysis patients than in non-chronic kidney disease patients. Given the lack of randomized clinical trial evidence in this population, current practice is informed by observational data with a significant potential for bias. Furthermore, guidelines lack any recommendation for these patients or extrapolate them from trials performed in non-dialysis patients. Patients with ESRD are more likely to be asymptomatic, posing a challenge to the correct identification of CAD, which is essential for appropriate risk stratification and management. This may lead to “therapeutic nihilism”, which has been associated with worse outcomes. Here, the ERA-EDTA EUDIAL Working Group reviews the diagnostic work-up and therapy of chronic coronary syndromes, unstable angina/non-ST elevation and ST-elevation myocardial infarction in dialysis patients, outlining unclear issues and controversies, discussing recent evidence, and proposing management strategies. Indications of antiplatelet and anticoagulant therapies, percutaneous coronary intervention and coronary artery bypass grafting are discussed. The issue of the interaction between dialysis session and myocardial damage is also addressed.

There is continuing interest in therapeutic applications of bone marrow-derived mesenchymal stromal cells (MSC). Unlike human counterparts, mouse MSC are difficult to propagate in vitro due to their contamination with adherent hematopoietic cells that overgrow the cultures. Here we investigated the properties of these contaminating cells, referred to as bone marrow-derived proliferating hematopoietic cells (BM-PHC). The results showed that both BM-PHC and MSC had strong immunomodulatory properties on T cells in vitro, with PGE2 and NO involved in this mechanism. However, BM-PHC were stronger immunomodulators than MSC, with CCL-6 identified as putative molecule responsible for superior effects. In vivo studies showed that, in contrast to BM-PHC, MSC endorsed a more rapid xenograft tumor rejection, thus indicating a particular context in which only MSC therapy would produce positive outcomes. In conclusion, bone marrow contains two cell populations with immunomodulatory properties, which are valuable sources for therapeutic studies in specific disease-relevant contexts.

(1) Background: Data suggest that patients with coronary chronic total occlusion (CTO) managed with percutaneous coronary intervention (PCI) could have better outcomes than those treated with optimal medical therapy alone. We aimed to systematically review dedicated scoring systems used to predict successful PCI in patients with CTO. (2) Methods: Electronic databases of MEDLINE (PubMed), Embase, and Cochrane were searched. (3) Results: 32 studies were included. We provided insights into all available predictive models of PCI success in CTO including predictive performance, validations, and comparisons between different scores and models’ limitations. Considering the differences in the population included, coronary lesions, and techniques applied across clinical studies, the most used scores displayed a modest to good predictive value, as follows: J-CTO (AUC, 0.55–0.868), PROGRESS-CTO (AUC, 0.557–0.788), CL (AUC, 0.624–0.800), CASTLE (AUC, 0.633–0.68), and KCCT (AUC, 0.703–0.776). As PCI for CTO is one of the most complex interventions, using dedicated scoring systems could ensure an adequate case selection as well as preparation for an appropriate recanalization technique in order to increase chances of successful procedure. (4) Conclusion: Clinical models appear to be valuable tools for the prediction of PCI success in CTO patients. Clinicians should be aware of the limitations of each model and should be able to correctly select the most appropriate score according to real-life case particularities such as lesion complexity and operator experience in order to maximize success and achieve the best patients’ outcomes.

Background and Objectives: Two-dimensional speckle tracking echocardiography (2D-STE) is viewed as an outstanding technique, competent of uncovering earlier subclinical myocardial anomalies compared to conventional echocardiography. A few endeavors adopted 2D-STE as a tool to estimate right ventricular (RV) function in subjects with end-stage kidney disease (ESKD). There is no published prospective study on an adult ESKD cohort exploring the consequences of commencing elective hemodialysis (HD) on RV behavior. Materials and Methods: We investigated the RV systolic function using traditional (tricuspid annular plane systolic excursion—TAPSE, RV fractional area change—FAC) and 2D-STE (RV free wall longitudinal strain—RVFWLS) parameters following the initiation of HD. We enrolled 79 consecutive patients with ESKD and assessed them in four steps—at baseline, before HD, and at 3, 6, and 12 months. Results: RVFWLS, FAC, and TAPSE values had a significant increase at 3, 6, and 12 months from baseline (p &lt, 0.001) and a significant increase at 6 months from 3 months (p &lt, 0.001). However, differences between 12 months and 6 months were not significant (p &gt, 0.05) according to Dunn–Bonferroni post hoc tests. Seventeen deaths were recorded before the completion of the study. RVFWLS, FAC, and TAPSE values significantly decreased at 3 and 6 months in all 17 deceased patients, in clear opposition with the values survivors had. All the studied parameters had a significant prediction power on mortality (p &lt, 0.001) having an outstanding performance: baseline-RVFWLS (AUC: 1.000 (95% C.I.: 1.000–1.000)), baseline-FAC (AUC: 0.974 (95% C.I.: 0.942–1.000)), and baseline-TAPSE (AUC: 0.962 (95% C.I.: 0.920–1.000). Conclusions: Our study is the first to investigate RV function by 2D-STE and correlate it with traditional methods in patients with ESKD before and after the initiation of HD. RV function was significantly ameliorated at 3, 6, and 12 months compared to the pre-HD values. FAC and RVFWLS gain an outstanding prognostic role on mortality in this population.

BackgroundWith the introduction of strict public health measures due to the coronavirus pandemic, we have had to change how we deliver simulation training. In order to reinstate the College of Anaesthesiologists Simulation Training (CAST) programme safely, we have had to make significant logistical changes. We discuss the process of reopening a national simulation anaesthesiology programme during a pandemic.MethodsWe approached how to reinstate the programme with three distinct but intertwined projects, as in the following: (1) a survey of effects of the pandemic on training opportunities for anaesthesiology trainees, (2) proposals for methods of reinstating simulation were developed under the headings avoidance, compromise, accommodation and collaboration. A small online video-assisted simulation pilot was carried out to test the compromise method, (3) having opted for combined accommodation (onsite with smaller participant numbers and safety measures) and collaboration (with other regional centres), a postreinstatement evaluation during a 4-month period was carried out.Results(1) Eighty-five per cent of 64 trainees surveyed felt that they had missed out not only just on simulation-based education (43%) but also on other training opportunities, (2) when five trainees were asked to state on a 1 to 5 Likert scale (strongly disagree, disagree, undecided, agree and strongly agree) whether online video-assisted simulation was similar to face-to-face simulation in four categories (realism, immersion, sense of crisis and stress), only 9 (45%) of the 20 answers agreed they were similar, (3) When onsite simulation was reinstated, the majority of trainees felt that training was similar to prepandemic and were happy to continue with this format.ConclusionIn order to reinstate simulation, we have identified that accommodation and collaboration best suited the CAST while compromise failed to rank high among trainees’ preferences. Onsite courses will continue to be delivered safely while meeting the high standards our trainees have come to expect.

Obesity and type 2 diabetes mellitus have become a significant public health problem in the past decades. Their prevalence is increasing worldwide each year, greatly impacting the economic and personal aspects, mainly because they frequently coexist, where the term “diabesity” may be used. The drug class of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) is one of the most modern therapy options in managing these metabolic disorders. This review focuses on the effects of liraglutide, a long-acting GLP-1 RA, in diabesity and non-diabetic excess weight. This drug class improves glycemic control by enhancing insulin secretion from the beta-pancreatic cells and inhibiting glucagon release. Furthermore, other effects include slowing gastric emptying, increasing postprandial satiety, and reducing the appetite and food consumption by influencing the central nervous system, with weight reduction effects. It also reduces cardiovascular events and has positive effects on blood pressure and lipid profile. A lower-dose liraglutide (1.2 or 1.8 mg/day) is used in patients with diabetes, while the higher dose (3.0 mg/day) is approved as an anti-obesity drug. In this review, we have summarized the role of liraglutide in clinical practice, highlighting its safety and efficacy as a glucose-lowering agent and a weight-reduction drug in patients with and without diabetes.

Objectives. We aimed to analyse data from our high-volume interventional centre (>1000 primary percutaneous coronary interventions (PCI) per year) searching for predictors of in-hospital mortality in acute myocardial infarction (MI) patients. Moreover, we looked for realistic strategies and interventions for lowering in-hospital mortality under the “5 percent threshold.” Background. Although interventional and medical treatment options are constantly expanding, recent studies reported a residual in-hospital mortality ranging between 5 and 10 percent after primary PCI. Current data sustain that mortality after ST-elevation MI will soon reach a point when cannot be reduced any further. Methods. In this retrospective observational single-centre cohort study, we investigated two-year data from a primary PCI registry including 2035 consecutive patients. Uni- and multivariate analysis were performed to identify independent predictors for in-hospital mortality. Results. All variables correlated with mortality in univariate analysis were introduced in a stepwise multivariate linear regression model. Female gender, hypertension, depressed left ventricular ejection fraction, history of MI, multivessel disease, culprit left main stenosis, and cardiogenic shock proved to be independent predictors of in-hospital mortality. The model was validated for sensitivity and specificity using receiver operating characteristic curve. For our model, variables can predict in-hospital mortality with a specificity of 96.60% and a sensitivity of 84.68% (p<0.0001, AUC = 0.93, 95% CI 0.922–0.944). Conclusions. Our analysis identified a predictive model for in-hospital mortality. The majority of deaths were due to cardiogenic shock. We suggested that in order to lower mortality under 5 percent, focus should be on creating a cardiogenic shock system based on the US experience. A shock hub-centre, together with specific transfer algorithms, mobile interventional teams, ventricular assist devices, and surgical hybrid procedures seem to be the next step toward a better management of ST-elevation MI patients and subsequently lower death rates.

HIV-associated neurocognitive disorder (HAND) is characterized by chronic immune activation. We aimed to identify biomarkers associated with HAND and to investigate their association with cognitive function and sex, in a homogenous cohort of HIV-infected (HIV+) young adults, parenterally infected during early childhood. One hundred forty-four HIV+ Romanian participants (51% women) without major confounders underwent standardized neurocognitive and medical evaluation in a cross-sectional study. IFN-γ, IL-1β, IL-6, CCL2, CXCL8, CXCL10, and TNF-α were measured in plasma in all participants and in cerebrospinal fluid (CSF) in a subgroup of 56 study participants. Biomarkers were compared with neurocognitive outcomes, and the influence of sex and HIV disease biomarkers was assessed. In this cohort of young adults (median age of 24years), the rate of neurocognitive impairment (NCI) was 36.1%. Median current CD4+ count was 479cells/mm3 and 36.8% had detectable plasma viral load. Women had better HIV-associated overall status. In plasma, controlling for sex, higher levels of IL-6 and TNF-α were associated with NCI (p

Low-density lipoprotein cholesterol (LDL-C) levels almost constantly increased in patients with nephrotic syndrome (NS). Protein convertase subtilisin/kexin type 9 (PCSK9) [accelerates LDL-receptor (LDL-R) degradation] is overexpressed by liver cells in NS. Their levels, correlated inversely to LDL-R expression and directly to LDL-C, seem to play a central role in hypercholesterolaemia in NS. Hypersynthesis resulting from sterol regulatory element-binding protein dysfunction, hyperactivity induced by c-inhibitor of apoptosis protein expressed in response to stimulation by tumour necrosis factor-α produced by damaged podocytes and hypo-clearance are the main possible mechanisms. Increased LDL-C may damage all kidney cell populations (podocytes, mesangial and tubular cells) in a similar manner. Intracellular cholesterol accumulation produces oxidative stress, foam cell formation and apoptosis, all favoured by local inflammation. The cumulative effect of cellular lesions is worsened proteinuria and kidney function loss. Accordingly, NS patients should be considered high risk and treated by lowering LDL-C. However, there is still not enough evidence determining whether lipid-lowering agents are helpful in managing dyslipidaemia in NS. Based on good efficacy and safety proved in the general population, therapeutic modulation of PCSK9 via antibody therapy might be a reasonable solution. This article explores the established and forthcoming evidence implicating PCSK9 in LDL-C dysregulation in NS.

Nontraditional cardiovascular risk factors such as lipoprotein(a) (Lp(a)), the genetic polymorphisms of apolipoprotein(a), apolipoprotein E (ApoE), and apolipoprotein B (ApoB) increase the prevalence of atherosclerosis in end-stage renal disease (ESRD) through quantitative and qualitative alterations. Given the high burden of cardiovascular fatal events in ESRD, this review aims to gather studies depicting apolipoproteins’ changes in ESRD, to describe current evidence and to explore potential lipid-lowering therapies. We searched the electronic database of PubMed, SCOPUS, EBSCO, and Cochrane CENTRAL for studies evaluating apolipoproteins in ESRD. Randomized controlled trials, observational studies (including case–control, prospective, or retrospective cohort), and reviews/meta-analysis were included if reference was made to apolipoproteins and cardiovascular consequences in ESRD. 21 studies met the inclusion criteria. We found a significant correlation between Lp(a) plasma concentrations and atherosclerosis. Lp(a) levels were independent risk factors for atherothrombosis and cardiovascular mortality. LMW apo(a) phenotype proved to be the best predictor for coronary events in ESRD. Single nucleotide polymorphisms in ApoE gene affected the expression and function of the protein, increasing the risk of cardiovascular events. ApoB had a significant correlation with the value of carotid intima–media thickness and vascular stiffness. The picture of “lipid milieu” in ESRD has not been clearly described. Novel studies show that specific apolipoproteins suffer modifications in uremic patients, being correlated with cardiovascular events. Probably in the next years, the treatment of dyslipidemia in ESRD will not merely target LDL or total cholesterol, but specific isoforms of apolipoproteins which seem to become the central part of the problem.

Heart failure with preserved ejection fraction (HFpEF) is a common disorder generating high mortality and important morbidity prevalence, with a very limited medical treatment available. Studies have shown that the pathophysiological hallmark of this condition is an elevated left intra-atrial pressure (LAP), exertional dyspnea being its clinical manifestation. The increasing pressure from LA is not based on volume overload (such as in heart failure with reduced ejection fraction) but on a diastolic left ventricular (LV) dysfunction combined with an inter-atrial dyssynchrony mimicking a pseudo-pacemaker syndrome. In this review, we aimed to summarize current knowledge and discuss future directions of the newest interventional percutaneous therapies of HFpEF. Novel interventional approaches developed to counter these mechanisms are as follows: LA decompression (inter-atrial shunt devices), enhancement of LV compliance (LV expanders), and inter-atrial resynchronization therapy (LA permanent pacing). To date, inter-atrial shunt devices (IASD) are the most studied, being the only devices currently tested in a phase 3 trial. Recent data showed that IASD are feasible, safe, and have a short-term clinical benefit in HFpEF patients. LV expanders and LA pacing therapy present with a smaller clinical benefit compared with IASD, but they are safe, without any major adverse outcomes currently noted. With further development and improvement of these mechanism-specific devices, it will be interesting to determine in the future whether a complex intervention of multiple HFpEF device implantation will be safe and have further benefits in HFpEF patients.

End-stage renal disease (ESRD) patients often report a combination of disturbing physical symptoms and psychological distress which result in significantly reduced quality of life (QoL). Coping with a chronic disease is a complex matter involving also the family and a multi-disciplinary team. Recently, observational studies suggested that spirituality (S) and religiosity (R) are two important determinants in coping with a chronic/terminal disease. Both concepts were studied in various settings, involving ESRD and QoL. This systematic review aims to synthesize all instruments used to assess R/S, to examine the strategies evaluating QoL of dialysis patients and to analyse their correlations. In accordance with the PRISMA, a systematic search was conducted in PubMed and SCOPUS (between Jan 1980—Dec 2018, PROSPERO number CRD42019116837). Eligible studies included patients on dialysis therapy, religiously/spiritually assessed and contained QoL evaluation. Of the initial 311 studies, 261 papers were excluded. Consequently, 50 papers with a total 9265 patients were available for inclusion. From a list of 177 R/S scales available worldwide, we identified 24 tools. We organized all QoL parameters into 10 classes. In all studies, R/S variables were positively correlated with at least one QoL variable. In this systematic review, we synthesized the studies involving R/S assessment in dialysis patients and their benefit on QoL. R/S has a positive impact on most QoL parameters in 5D-CKD. We suggest that nephrology guidelines on palliative care and/or elderly should include specific recommendations on R/S support and opportunities for integrated specific therapies.

Mesenchymal stromal cells (MSC) are promising candidates for regenerative therapy of the infarcted heart. However, poor cell retention within the transplantation site limits their potential. We hypothesized that MSC benefits could be enhanced through a dual-cell approach using jointly endothelial colony forming cells (ECFC) and MSC. To assess this, we comparatively evaluated the effects of the therapy with MSC and ECFC versus MSC-only in a mouse model of myocardial infarction. Heart function was assessed by echocardiography, and the molecular crosstalk between MSC and ECFC was evaluated in vitro through direct or indirect co-culture systems. We found that dual-cell therapy improved cardiac function in terms of ejection fraction and stroke volume. In vitro experiments showed that ECFC augmented MSC effector properties by increasing Connexin 43 and Integrin alpha-5 and the secretion of healing-associated molecules. Moreover, MSC prompted the organization of ECFC into vascular networks. This indicated a reciprocal modulation in the functionality of MSC and ECFC. In conclusion, the crosstalk between MSC and ECFC augments the therapeutic properties of MSC and enhances the angiogenic properties of ECFC. Our data consolidate the dual-cell therapy as a step forward for the development of effective treatments for patients affected by myocardial infarction.

Background and objectives: cardiovascular complications (CVC) are the leading cause of death in patients with chronic kidney disease (CKD). Standard cardiovascular disease risk prediction models used in the general population are not validated in patients with CKD. We aim to systematically review the up-to-date literature on reported outcomes of computational methods such as artificial intelligence (AI) or regression-based models to predict CVC in CKD patients. Materials and methods: the electronic databases of MEDLINE/PubMed, EMBASE, and ScienceDirect were systematically searched. The risk of bias and reporting quality for each study were assessed against transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD) and the prediction model risk of bias assessment tool (PROBAST). Results: sixteen papers were included in the present systematic review: 15 non-randomized studies and 1 ongoing clinical trial. Twelve studies were found to perform AI or regression-based predictions of CVC in CKD, either through single or composite endpoints. Four studies have come up with computational solutions for other CV-related predictions in the CKD population. Conclusions: the identified studies represent palpable trends in areas of clinical promise with an encouraging present-day performance. However, there is a clear need for more extensive application of rigorous methodologies. Following the future prospective, randomized clinical trials, and thorough external validations, computational solutions will fill the gap in cardiovascular predictive tools for chronic kidney disease.

Whether one wants to or not, interactions between the heart and the kidneys exist and manifest nevertheless. Both from theoretical and clinical perspectives, it seems the need for a subspecialty of cardionephrology seems justified. Our editorial is a cardiologist perspective on the article by Diez and Ortiz published in Clinical Kidney Journal related to the ‘need for a cardionephrology subspecialty’. We analysed the historical similarities of the emergence of already ingrained clinical fields with the current needs in the cardionephrology sector. We motivated our approach based on novel cardiovascular diagnostic and therapeutic developments and significant pathophysiological differences from a cardiological perspective, accounting for the foundation of a novel sustainable medical field. One of the sensitive issues we also addressed was the operationality and applicability of the principles. We answered with some examples from high-risk debatable contexts the question of where a cardionephrologist should be integrated. Clarifying the operationality aspects would be a positive shift towards improving guidelines adherence in managing complex patients. In conclusion, we underline that the necessity of a cardionephrologist must be addressed from an operational and scientific perspective, with the ultimate goal of reducing mortality and complications in cardiorenal patients.

Left atrial strain (LASr) represents a relatively new but promising technique for left atrial and left ventricle function evaluation. LASr was strongly linked to myocardial fibrosis and endocardial thickness, suggesting the utility of LASr in subclinical cardiac dysfunction detection. As CKD negatively impacts cardiovascular risk and mortality, underlying structural and functional abnormalities of cardiac remodeling are widely investigated. LASr could be used in LV diastolic dysfunction grading with an excellent discriminatory power. Our objectives were to assess the impact and existing correlations between LASr and cardiovascular outcomes, as reported in clinical trials, including patients with CKD. We searched PubMed, Web of Science, Embase, and the Cochrane Central Register of Controlled Trials for full-text papers. As reported in clinical studies, LASr was associated with adverse cardiovascular outcomes, including cardiovascular death and major adverse cardiovascular events (HR 0.89, 95% CI, 0.84–0.93, p < 0.01), paroxysmal atrial fibrillation (OR 0.847, 95% CI, 0.760–0.944, p = 0.003), reduced exercise capacity (AUC 0.83, 95% CI, 0.78–0.88, p < 0.01), diastolic dysfunction (p < 0.05), and estimated pulmonary capillary wedge pressure (p < 0.001). Despite limitations attributed to LA deformation imaging (image quality, inter-observer variability, software necessity, learning curve), LASr constitutes a promising marker for cardiovascular events prediction and risk evaluation in patients with CKD.

Early prognosis of severe disease and preventive actions hang around as the mainstay in managing the novel SARS-COV-2 outbreak due to the lack of robust therapeutic strategies. Krebs von den Lungen-6 (KL-6 or KL-6/MUC1) is a relatively new discovered transmembrane mucoprotein that was shown to be a good predictor of disease severity in interstitial lung diseases (ILD). We aimed to systematically research the literature in order to assess the relationship between the KL-6 biomarker and prognosis of SARS-CoV-2 infection. A literature search was performed in PubMed, Embase, and Cochrane library databases from inception to 8 March 2021. After eligibility assessment, eight studies were finally included in the present systematic review. All included studies are observational and single-center. The data gathered suggests the importance of prognostic implications of KL-6 in COVID-19 as patients with a more severe disease had significantly higher levels of KL-6 at admission. Moreover, the KL-6 biomarker was associated with COVID-19 severity, lung lesion areas on computed tomography, pulmonary fibrosis, and coagulation disorders. The association with mortality is unclear and needs further research. More extensive trials are required to prove that facile, inexpensive, and good predictors of severe outcomes, such as KL-6, could be safely integrated into the clinical decision-making in patients with COVID-19.

Diabetes mellitus (DM) is the most severe metabolic disease that reached the level of a global pandemic and is associated with high cardiovascular morbidity. Statins are the first–line lipid–lowering therapy in diabetic patients with or without a history of atherosclerotic disease. Although well tolerated, chronic treatment may result in side effects that lead to treatment interruption. Mitochondrial dysfunction has emerged as a central pathomechanism in DM– and statin–induced side effects. Assessment of mitochondrial respiration in peripheral platelets has been increasingly used as a mirror of organ mitochondrial dysfunction. The present study aimed to assess the: (i) changes in mitochondrial respiration elicited by statins in patients with type 2 DM and (ii) the effects of cell–permeable succinate (NV118) on respiratory parameters in platelets harvested from these patients. No significant changes were found in global mitochondrial respiration of intact platelets isolated from diabetic patients treated with either atorvastatin or rosuvastatin. Similarly, no significant changes in mitochondrial respiration of permeabilized platelets were found between diabetic patients treated with atorvastatin and healthy controls. Acute ex vivo administration of NV118 significantly improved respiration in isolated platelets. These results prompt further research on the role of permeable succinate as a therapeutic alternative for improving mitochondrial function in metabolic pathologies and point to the role of peripheral platelets as a potential biomarker of treatment response.