Recognizing speculative language in biomedical research articles: a linguistically motivated perspective

We explore a linguistically motivated approach to the problem of recognizing speculative language (“hedging”) in biomedical research articles. We describe a method, which draws on prior linguistic work as well as existing lexical resources and extends them by introducing syntactic patterns and a simple weighting scheme to estimate the speculation level of the sentences. We show that speculative language can be recognized successfully with such an approach, discuss some shortcomings of the method and point out future research possibilities.

Mechanism of completion of peptidyltransferase centre assembly in eukaryotes.

During their final maturation in the cytoplasm, pre-60S ribosomal particles are converted to translation-competent large ribosomal subunits. Here, we present the mechanism of peptidyltransferase centre (PTC) completion that explains how integration of the last ribosomal proteins is coupled to release of the nuclear export adaptor Nmd3. Single-particle cryo-EM reveals that eL40 recruitment stabilises helix 89 to form the uL16 binding site. The loading of uL16 unhooks helix 38 from Nmd3 to adopt its mature conformation. In turn, partial retraction of the L1 stalk is coupled to a conformational switch in Nmd3 that allows the uL16 P-site loop to fully accommodate into the PTC where it competes with Nmd3 for an overlapping binding site (base A2971). Our data reveal how the central functional site of the ribosome is sculpted and suggest how the formation of translation-competent 60S subunits is disrupted in leukaemia-associated ribosomopathies.Bloodwise, MRC, Wellcome Trus

Cyclosporine A Impairs Norepinephrine-Induced Vascular Contractility

Usage of cyclosporine A (CsA) after kidney transplantation may be associated with development of nephrotoxicity and vasculopathy, but the mechanisms by which CsA causes vascular dysfunction are still under scrutiny. We established a transplantation model and investigated the effect of CsA on vascular contractility with the aid of a pressurized myograph in comparison with control and unilaterally nephrectomized rats. Results were correlated with mRNA expression studies of α- and β-adrenoreceptors, in mesenteric resistance arteries versus the thoracic aorta. Consequences of everolimus on functional properties as well as adrenoreceptor expression were also studied. CsA significantly downregulated expression of mesenteric adrenoreceptors, whereas no effect on aortic adrenoreceptors was seen. Administration of everolimus had no influence on mRNA adrenoreceptor expression in mesenteric resistance arteries. Furthermore, contractile responses of mesenteric resistance arteries to norepinephrine were markedly reduced after treatment with CsA, while there was no difference in contraction by endothelin. Everolimus did not alter the contractility response at all. In summary, norepinephrine-induced, but not endothelin-induced, contractile responses of mesenteric resistance arteries are blunted in CsA-treated rats. This finding was accompanied by a marked downregulation of adrenoreceptors in mesenteric resistance arteries and was limited to the usage of CsA

Tricuspid regurgitation is associated with increased risk of mortality in patients with low-flow low-gradient aortic stenosis and reduced ejection fraction : results of the multicenter TOPAS study (true or pseudo-severe aortic stenosis)

Objectives : This study sought to examine the impact of tricuspid regurgitation (TR) on mortality in patients with low-flow, low-gradient (LF-LG) aortic stenosis (AS) and reduced left ventricular ejection fraction (LVEF). Background : TR is often observed in patients with LF-LG AS and low LVEF, but its impact on prognosis remains unknown. Methods : A total of 211 patients (73 ± 10 years of age; 77% men) with LF-LG AS (mean gradient <40 mm Hg and indexed aortic valve area [AVA] =0.6 cm2/m2) and reduced LVEF (=40%) were prospectively enrolled in the TOPAS (True or Pseudo-Severe Aortic Stenosis) study and 125 (59%) of them underwent aortic valve replacement (AVR) within 3 months following inclusion. The severity of AS was assessed by the projected AVA (AVAproj) at normal flow rate (250 ml/s), as previously described and validated. The severity of TR was graded according to current guidelines. Results : Among the 211 patients included in the study, 22 (10%) had no TR, 113 (54%) had mild (grade 1), 50 (24%) mild-to-moderate (grade 2), and 26 (12%) moderate-to-severe (grade 3) or severe (grade 4) TR. During a mean follow-up of 2.4 ± 2.2 years, 104 patients (49%) died. Univariable analysis showed that TR =2 was associated with increased risk of all-cause mortality (hazard ratio [HR]: 1.82, 95% confidence interval [CI]: 1.22 to 2.71; p = 0.004) and cardiovascular mortality (HR: 1.85, 95% CI: 1.20 to 2.83; p = 0.005). After adjustment for age, sex, coronary artery disease, AVAproj, LVEF, stroke volume index, right ventricular dysfunction, mitral regurgitation, and type of treatment (AVR vs. conservative), the presence of TR =2 was an independent predictor of all-cause mortality (HR: 1.88, 95% CI: 1.08 to 3.23; p = 0.02) and cardiovascular mortality (HR: 1.92, 95% CI: 1.05 to 3.51; p = 0.03). Furthermore, in patients undergoing AVR, TR =3 was an independent predictor of 30-day mortality compared with TR = 0/1 (odds ratio [OR]: 7.24, 95% CI: 1.56 to 38.2; p = 0.01) and TR = 2 (OR: 4.70, 95% CI: 1.00 to 25.90; p = 0.05). Conclusions : In patients with LF-LG AS and reduced LVEF, TR is independently associated with increased risk of cumulative all-cause mortality and cardiovascular mortality regardless of the type of treatment. In patients undergoing AVR, moderate/severe TR is associated with increased 30-day mortality. Further studies are needed to determine whether TR is a risk marker or a risk factor of mortality and whether concomitant surgical correction of TR at the time of AVR might improve outcomes for this high-risk population

Recent advances in cardio-oncology:a report from the 'Heart Failure Association 2019 and World Congress on Acute Heart Failure 2019'

While anti-cancer therapies, including chemotherapy, immunotherapy, radiotherapy, and targeted therapy, are constantly advancing, cardiovascular toxicity has become a major challenge for cardiologists and oncologists. This has led to an increasing demand of cardio-oncology units in Europe and a growing interest of clinicians and researchers. The Heart Failure 2019 meeting of the Heart Failure Association of the European Society of Cardiology in Athens has therefore created a scientific programme that included four dedicated sessions on the topic along with several additional lectures. The major points that were discussed at the congress included the implementation and delivery of a cardio-oncology service, the collaboration among cardio-oncology experts, and the risk stratification, prevention, and early recognition of cardiotoxicity. Furthermore, sessions addressed the numerous different anti-cancer therapies associated with cardiotoxic effects and provided guidance on how to treat cancer patients who develop cardiovascular disease before, during, and after treatment

Renal function during rofecoxib therapy in patients with metastatic cancer: retrospective analysis of a prospective phase II trial

German Clinical Trials Register DRKS: DRKS0000011

Extensive myocardial infiltration by hemopoietic precursors in a patient with myelodysplastic syndrome

BACKGROUND: Although myocardial infiltration with leukemic blasts is a known finding in patients with acute leukemia, this phenomenon in myelodysplasia is not reported in the literature. Cardiac symptoms in patients with myelodysplasia are often due to anemia and may be due to iron overload and side effects of therapy. CASE PRESENTATION: Herein we report the first case of neoplastic infiltration of the heart with associated myocardial necrosis in a patient with myelodysplasia. It was associated with unicellular and multifocal geographic areas of necrosis in the left ventricle and the interventricular septum. It is likely that cardiac compromise in our patient was due to a combination of restrictive cardiomyopathy due to leukemic infiltration, concomitant anemia, cardiac dilatation, conduction blocks and myocardial necrosis. Myocardial necrosis was most likely due to a combination of ischemic damage secondary to anemia and prolonged hypotension and extensive leukemic infiltration. Markedly rapid decrease in ejection fraction from 66% to 33% also suggests the role of ischemia, since leukemic infiltration is not expected to cause this degree of systolic dysfunction over a 24-hour period. The diagnosis was not suspected during life due to concomitant signs and symptoms of anemia, pulmonary infections, and pericardial and pleural effusions. The patient succumbed to cardiac failure. CONCLUSION: Hemopoietic cell infiltration was not considered in the differential diagnosis and contributed to this patient's morbidity and mortality. This case highlights the clinical importance of considering myocardial infiltration in patients with myelodysplasia and cardiac symptoms

2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS)

info:eu-repo/semantics/publishe

Validating the predictive ability of the 2MACE score for major adverse cardiovascular events in patients with atrial fibrillation: results from phase II/III of the GLORIA-AF registry

The 2MACE score was specifically developed as a risk-stratification tool in atrial fibrillation (AF) to predict cardiovascular outcomes. We evaluated the predictive ability of the 2MACE score in the GLORIA-AF registry. All eligible patients from phase II/III of the prospective global GLORIA-AF registry were included. Major adverse cardiac events (MACEs) were defined as the composite outcome of stroke, myocardial infarction and cardiovascular death. Cox proportional hazards were used to examine the relationship between the 2MACE score and study outcomes. Predictive capability of the 2MACE score was investigated using receiver-operating characteristic curves. A total of 25,696 patients were included (mean age 71 years, female 44.9%). Over 3 years, 1583 MACEs were recorded. Patients who had MACE were older, with more cardiovascular risk factors and were less likely to be managed using a rhythm-control strategy. The median 2MACE score in the MACE and non-MACE groups were 2 (IQR 1-3) and 1 (IQR 0-2), respectively (p &lt; 0.001). The 2MACE score was positively associated with an increase in the risk of MACE, with a score of &amp; GE; 2 providing the best combination of sensitivity (69.6%) and specificity (51.6%), HR 2.47 (95% CI, 2.21-2.77). The 2MACE score had modest predictive performance for MACE in patients with AF (AUC 0.655 (95% CI, 0.641-0.669)). Our analysis in this prospective global registry demonstrates that the 2MACE score can adequately predict the risk of MACE (defined as myocardial infarction, CV death and stroke) in patients with AF. Clinical trial registration:. Unique identifiers: NCT01468701, NCT01671007 and NCT0193737

Contrasting Roles for TLR Ligands in HIV-1 Pathogenesis

The first line of a host's response to various pathogens is triggered by their engagement of cellular pattern recognition receptors (PRRs). Binding of microbial ligands to these receptors leads to the induction of a variety of cellular factors that alter intracellular and extracellular environment and interfere directly or indirectly with the life cycle of the triggering pathogen. Such changes may also affect any coinfecting microbe. Using ligands to Toll-like receptors (TLRs) 5 and 9, we examined their effect on human immunodeficiency virus (HIV)-1 replication in lymphoid tissue ex vivo. We found marked differences in the outcomes of such treatment. While flagellin (TLR5 agonist) treatment enhanced replication of CC chemokine receptor 5 (CCR 5)-tropic and CXC chemokine receptor 4 (CXCR4)-tropic HIV-1, treatment with oligodeoxynucleotide (ODN) M362 (TLR9 agonist) suppressed both viral variants. The differential effects of these TLR ligands on HIV-1 replication correlated with changes in production of CC chemokines CCL3, CCL4, CCL5, and of CXC chemokines CXCL10, and CXCL12 in the ligand-treated HIV-1-infected tissues. The nature and/or magnitude of these changes were dependent on the ligand as well as on the HIV-1 viral strain. Moreover, the tested ligands differed in their ability to induce cellular activation as evaluated by the expression of the cluster of differentiation markers (CD) 25, CD38, CD39, CD69, CD154, and human leukocyte antigen D related (HLA)-DR as well as of a cell proliferation marker, Ki67, and of CCR5. No significant effect of the ligand treatment was observed on apoptosis and cell death/loss in the treated lymphoid tissue ex vivo. Our results suggest that binding of microbial ligands to TLRs is one of the mechanisms that mediate interactions between coinfected microbes and HIV-1 in human tissues. Thus, the engagement of appropriate TLRs by microbial molecules or their mimetic might become a new strategy for HIV therapy or prevention