89 research outputs found
New flavonoid \u2013 N,N-dibenzyl(N-methyl)amine hybrids: Multi-target-directed agents for Alzheimer\ub4s disease endowed with neurogenic properties
The design of multi-target directed ligands (MTDLs) is a valid approach for obtaining effective drugs for complex pathologies. MTDLs that combine neuro-repair properties and block the first steps of neurotoxic cascades could be the so long wanted remedies to treat neurodegenerative diseases (NDs). By linking two privileged scaffolds with well-known activities in ND-targets, the flavonoid and the N,N-dibenzyl(N-methyl)amine (DBMA) fragments, new CNS-permeable flavonoid \u2013 DBMA hybrids (1\u201313) were obtained. They were subjected to biological evaluation in a battery of targets involved in Alzheimer\u2019s disease (AD) and other NDs, namely human cholinesterases (hAChE/hBuChE), \u3b2-secretase (hBACE-1), monoamine oxidases (hMAO-A/B), lipoxygenase-5 (hLOX-5) and sigma receptors (\u3c31R/\u3c32R). After a funnel-type screening, 6,7-dimethoxychromone \u2013 DBMA (6) was highlighted due to its neurogenic properties and an interesting MTD-profile in hAChE, hLOX-5, hBACE-1 and \u3c31R. Molecular dynamic simulations showed the most relevant drug-protein interactions of hybrid 6, which could synergistically contribute to neuronal regeneration and block neurodegeneration
Therapeutic angiogenesis following intramuscular gene transfer of vascular endothelial growth factor 121 in a dog model of hindlimb ischemia
Vascular endothelial growth factor (VEGF), an endothelial cell-specific
mitogen, has been shown to promote therapeutic angiogenesis in animal
models of critical limb ischemia. Ischemic skeletal muscle is
advantageous for taking up and expressing foreign genes transferred as
naked plasmid DNA. Accordingly, we investigated the hypothesis that
intramuscular administration of naked plasmid DNA encoding the
121-amino acid isoform of VEGF could augment collateral development and
tissue perfusion in a dog hindlimb ischemia model. Unilateral hindlimb
ischemia was surgically induced in Beagle dogs. Ten days later, animals
received intramuscular injections of pVEGF121 plasmid directly in the
ischemic muscles. Angiogenic effects were evaluated by angiography,
calf blood pressure ratio and vasomotor reserve analyses. Thirty days
after gene transfer, angiographically recognizable collateral vessels
were increased in pVEGF121-treated animals compared with controls.
Improvement in perfusion to the ischemic limb was documented by a
significantly higher calf blood pressure ratio for pVEGF121 (0.79
\ub1 0.05) versus controls (0.56 \ub1 0.14, P<0.01). Vasomotor
reserve assay suggested amelioration in blood availability at the
microcirculation level in pVEGF121-treated animals. Hematological
variables showed no significant modification due to the treatment. Our
results suggest that intramuscular gene transfer of VEGF121 may promote
therapeutic angiogenesis in critical limb vascular insufficiency
Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study
Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research
Large expert-curated database for benchmarking document similarity detection in biomedical literature search
Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe
The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2
Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age 6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score 652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701
Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial
Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials.
Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure.
Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen.
Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049
Evolution of the longitudinal and azimuthal structure of the near-side jet peak in Pb-Pb collisions at 1asNN = 2.76 TeV
In two-particle angular correlation measurements, jets give rise to a near-side peak, formed by particles associated to a higher-pT trigger particle. Measurements of these correlations as a function of pseudorapidity ( \u3b7) and azimuthal ( \u3c6) differences are used to extract the centrality and pT dependence of the shape of the near-side peak in the pT range 1 < pT < 8 GeV/c in Pb-Pb and pp collisions at 1asNN = 2.76 TeV. A combined fit of the near-side peak and long-range correlations is applied to the data and the peak shape is quantified by the variance of the distributions. While the width of the peak in the \u3c6 direction is almost independent of centrality, a significant broadening in the \u3b7 direction is found from peripheral to central collisions. This feature is prominent for the low-pT region and vanishes above 4 GeV/c. The widths measured in peripheral collisions are equal to those in pp collisions in the \u3c6 direction and above 3 GeV/c in the \u3b7 direction. Furthermore, for the 10% most central collisions and 1 < pT,assoc < 2 GeV/c, 1 < pT,trig < 3 GeV/c, a departure from a Gaussian shape is found: a depletion develops around the center of the peak. The results are compared to A Multi-Phase Transport (AMPT) model simulation as well as other theoretical calculations indicating that the broadening and the development of the depletion are connected to the strength of radial and longitudinal flow
Elliptic flow of identified hadrons in Pb-Pb collisions at 1asNN = 2.76 TeV
The elliptic flow coefficient (v2) of identified particles in Pb-Pb collisions at 1asNN = 2.76 TeV was measured with the ALICE detector at the Large Hadron Collider (LHC). The results were obtained with the Scalar Product method, a two-particle corre- lation technique, using a pseudo-rapidity gap of | 06\u3b7| > 0.9 between the identified hadron under study and the reference particles. The v2 is reported for \u3c0\ub1, K\ub1, K0S, p+p, \u3c6, \u39b+\u39b, \u39e 12+\u39e+ and \u3a9 12+\u3a9+ in several collision centralities. In the low transverse momentum (pT) region, pT 3 GeV/c
Centrality dependence of inclusive J/\u3c8 production in p-Pb collisions at 1asNN = 5.02 TeV
We present a measurement of inclusive J/\u3c8 production in p-Pb collisions at 1asNN = 5.02TeV as a function of the centrality of the collision, as estimated from the energy deposited in the Zero Degree Calorimeters. The measurement is performed with the ALICE detector down to zero transverse momentum, pT, in the backward ( 124.46 < ycms < 122.96) and forward (2.03 < ycms < 3.53) rapidity intervals in the dimuon decay channel and in the mid-rapidity region ( 121.37 < ycms < 0.43) in the dielectron decay channel. The backward and forward rapidity intervals correspond to the Pb-going and p-going direction, respectively. The pT-differential J/\u3c8 production cross section at backward and forward rapidity is measured for several centrality classes, together with the corresponding average pT and pT2 values. The nuclear modification factor is presented as a function of centrality for the three rapidity intervals, and as a function of pT for several centrality classes at backward and forward rapidity. At mid- and forward rapidity, the J/\u3c8 yield is suppressed up to 40% compared to that in pp interactions scaled by the number of binary collisions. The degree of suppression increases towards central p-Pb collisions at forward rapidity, and with decreasing pT of the J/\u3c8. At backward rapidity, the nuclear modification factor is compatible with unity within the total uncertainties, with an increasing trend from peripheral to central p-Pb collisions
Centrality dependence of high-pT D meson suppression in Pb-Pb collisions at 1asNN = 2.76 TeV
The nuclear modification factor, RAA, of the prompt charmed mesons D0, D+ and D 17+, and their antiparticles, was measured with the ALICE detector in Pb-Pb collisions at a centre-of-mass energy 1asNN = 2.76 TeV in two transverse momentum intervals, 5 < pT < 8GeV/c and 8 < pT < 16GeV/c, and in six collision centrality classes. The RAA shows a maximum suppression of a factor of 5\u20136 in the 10% most central collisions. The suppression and its centrality dependence are compatible within uncertainties with those of charged pions. A comparison with the RAA of non-prompt J/\u3c8 from B meson decays, measured by the CMS Collaboration, hints at a larger suppression of D mesons in the most central collisions
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