IP Pegasi: Investigation of the accretion disk structure. Searching evidences for spiral shocks in the quiescent accretion disk

We present the results of spectral investigations of the cataclysmic variable IP Peg in quiescence. Optical spectra obtained on the 6-m telescope at the Special Astrophysical Observatory (Russia), and on the 3.5-m telescope at the German-Spanish Astronomical Center (Calar Alto, Spain), have been analysed by means of Doppler tomography and Phase Modelling Technique. From this analysis we conclude that the quiescent accretion disk of IP Peg has a complex structure. There are also explicit indications of spiral shocks. The Doppler maps and the variations of the peak separation of the emission lines confirm this interpretation. We have detected that all the emission lines show a rather considerable asymmetry of their wings varying with time. The wing asymmetry shows quasi-periodic modulations with a period much shorter than the orbital one. This indicates the presence of an emission source in the binary rotating asynchronously with the binary system. We also have found that the brightness of the bright spot changes considerably during one orbital period. The spot becomes brightest at an inferior conjunction, whereas it is almost invisible when it is located on the distant half of the accretion disk. Probably, this phenomenon is due to an anisotropic radiation of the bright spot and an eclipse of the bright spot by the outer edge of the accretion disk.Comment: 13 pages, 11 figures (= 21 EPS files), accepted for publication in A&

Roche tomography of cataclysmic variables - II. Images of the secondary stars in AM Her, QQ Vul, IP Peg and HU Aqr

We present a set of Roche tomography reconstructions of the secondary stars in the cataclysmic variables AM Her, QQ Vul, IP Peg and HU Aqr. The image reconstructions show distinct asymmetries in the irradiation pattern for all four systems that can be attributed to shielding of the secondary star by the accretion stream/column in AM Her, QQ Vul and HU Aqr, and increased irradiation by the bright-spot in IP Peg. We use the entropy landscape technique to derive accurate system parameters (M1, M2, i and γ) for the four binaries. In principle, this technique should provide the most reliable mass determinations available, since the intensity distribution across the secondary star is known. We also find that the intensity distribution can systematically affect the value of γ derived from circular orbit fits to radial velocity variations

Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data

Background: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. Methods: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0–1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0–2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4–6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. Findings: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10–2·03]; p=0·011), with low heterogeneity across studies (I2=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05–1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06–2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4–6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52–1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03–4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [<1%], adjusted OR 5·58 [1·22–25·50]; p=0·024). Interpretation: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. Funding: None

Direct oral anticoagulants versus vitamin K antagonists after recent ischemic stroke in patients with atrial fibrillation

OBJECTIVE: We compared outcomes after treatment with direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) and a recent cerebral ischemia. METHODS: We conducted an individual patient data analysis of seven prospective cohort studies. We included patients with AF and a recent cerebral ischemia (<3 months before starting oral anticoagulation) and a minimum follow-up of 3 months. We analyzed the association between type of anticoagulation (DOAC versus VKA) with the composite primary endpoint (recurrent ischemic stroke [AIS], intracerebral hemorrhage [ICH], or mortality) using mixed-effects Cox proportional hazards regression models; we calculated adjusted hazard ratios (HRs) with 95% confidence intervals (95% CIs). RESULTS: We included 4,912 patients (median age, 78 years [interquartile range {IQR}, 71-84]; 2,331 [47.5%] women; median National Institute of Health Stroke Severity Scale at onset, 5 [IQR, 2-12]); 2,256 (45.9%) patients received VKAs and 2,656 (54.1%) DOACs. Median time from index event to starting oral anticoagulation was 5 days (IQR, 2-14) for VKAs and 5 days (IQR, 2-11) for DOACs (p = 0.53). There were 262 acute ischemic strokes (AISs; 4.4%/year), 71 intracranial hemorrrhages (ICHs; 1.2%/year), and 439 deaths (7.4%/year) during the total follow-up of 5,970 patient-years. Compared to VKAs, DOAC treatment was associated with reduced risks of the composite endpoint (HR, 0.82; 95% CI, 0.67-1.00; p = 0.05) and ICH (HR, 0.42; 95% CI, 0.24-0.71; p < 0.01); we found no differences for the risk of recurrent AIS (HR, 0.91; 95% CI, 0.70-1.19; p = 0.5) and mortality (HR, 0.83; 95% CI, 0.68-1.03; p = 0.09). INTERPRETATION: DOAC treatment commenced early after recent cerebral ischemia related to AF was associated with reduced risk of poor clinical outcomes compared to VKA, mainly attributed to lower risks of ICH. ANN NEUROL 2019

Neutrophil-to-Lymphocyte Ratio Is an Independent Predictor for In-Hospital Mortality in Spontaneous Intracerebral Hemorrhage

Background and Purpose: Stroke-associated immunosuppression and inflammation are increasingly recognized as factors that trigger infections and thus, potentially influence the outcome after stroke. Several studies demonstrated that elevated neutrophil-to-lymphocyte ratio (NLR) is a significant predictor of adverse outcomes in patients with ischemic stroke. However, little is known about the impact of NLR on short-term mortality in intracerebral hemorrhage (ICH). Methods: This observational study included 855 consecutive ICH-patients. Patient demographics, clinical, laboratory, and in-hospital measures as well as neuroradiological data were retrieved from institutional databases. Functional 3-months-outcome was assessed and categorized as favorable (modified Rankin Scale [mRS] 0-3) and unfavorable (mRS 4-6). We (i) studied the natural course of NLR in ICH, (ii) analyzed parameters associated with NLR on admission (NLROA), and (iii) evaluated the clinical impact of NLR on mortality and functional outcome. Results: The median NLROA of the entire cohort was 4.66 and it remained stable during the entire hospital stay. Patients with NLR ≥4.66 showed significant associations with poorer neurological status (National Institute of Health Stroke Scale [NIHSS] 18 [9-32] vs. 10 [4-21]; p 2.606 - presented with a better clinical status (NIHSS 12 [5-21] vs. 15 [6-28]; p = 0.005), lower hematoma volumes on admission (10.6 [3.6-30.1] vs. 15.1 [5.7-42.3] mL; p = 0.004) and showed a better functional outcome (3 months mRS 0-3: 82/214 [38.3%] vs. 185/641 [28.9%]; p = 0.009). Patients associated with high NLR (≥8.508 = above 75th-percentile) showed the worst neurological status on admission (NIHSS 21 [12-32] vs. 12 [5-23]; p < 0.001), larger hematoma volumes (21.0 [8.6-48.8] vs. 12.2 [4.1-34.9] mL; p < 0.001), and higher proportions of unfavorable functional outcome at 3 months (mRS 4-6: 173/214 vs. 418/641; p < 0.001). Further, NLR was linked to more frequently occurring infectious complications (pneumonia 107/214 vs. 240/641; p = 0.001, sepsis: 78/214 vs. 116/641; p < 0.001), and increased c-reactive-protein levels on admission (p < 0.001; R2 = 0.064). Adjusting for the above-mentioned baseline confounders, multivariable logistic analyses revealed independent associations of NLROA with in-hospital mortality (OR 0.967, 95% CI 0.939-0.997; p = 0.029). Conclusions: NLR represents an independent parameter associated with increased mortality in ICH patients. Stroke physicians should focus intensely on patients with increased NLR, as these patients appear to represent a population at risk for infectious complications and increased short-mortality. Whether these patients with elevated NLR may benefit from a close monitoring and specially designed therapies should be investigated in future studies

Learning from Nature: From a Marine Natural Product to Synthetic Cyclooxygenase-1 Inhibitors by Automated De Novo Design

The repertoire of natural products offers tremendous opportunities for chemical biology and drug discovery. Natural product-inspired synthetic molecules represent an ecologically and economically sustainable alternative to the direct utilization of natural products. De novo design with machine intelligence bridges the gap between the worlds of bioactive natural products and synthetic molecules. On employing the compound Marinopyrrole A from marine Streptomyces as a design template, the algorithm constructs innovative small molecules that can be synthesized in three steps, following the computationally suggested synthesis route. Computational activity prediction reveals cyclooxygenase (COX) as a putative target of both Marinopyrrole A and the de novo designs. The molecular designs are experimentally confirmed as selective COX-1 inhibitors with nanomolar potency. X-ray structure analysis reveals the binding of the most selective compound to COX-1. This molecular design approach provides a blueprint for natural product-inspired hit and lead identification for drug discovery with machine intelligence