LinChemIn: Route Arithmetic─Operations on Digital Synthetic Routes.

Computational tools are revolutionizing our understanding and prediction of chemical reactivity by combining traditional data analysis techniques with new predictive models. These tools extract additional value from the reaction data corpus, but to effectively convert this value into actionable knowledge, domain specialists need to interact easily with the computer-generated output. In this application note, we demonstrate the capabilities of the open-source Python toolkit LinChemIn, which simplifies the manipulation of reaction networks and provides advanced functionality for working with synthetic routes. LinChemIn ensures chemical consistency when merging, editing, mining, and analyzing reaction networks. Its flexible input interface can process routes from various sources, including predictive models and expert input. The toolkit also efficiently extracts individual routes from the combined synthetic tree, identifying alternative paths and reaction combinations. By reducing the operational barrier to accessing and analyzing synthetic routes from multiple sources, LinChemIn facilitates a constructive interplay between artificial intelligence and human expertise.

LinChemIn: SynGraph-a data model and a toolkit to analyze and compare synthetic routes.

BACKGROUND: The increasing amount of chemical reaction data makes traditional ways to navigate its corpus less effective, while the demand for novel approaches and instruments is rising. Recent data science and machine learning techniques support the development of new ways to extract value from the available reaction data. On the one side, Computer-Aided Synthesis Planning tools can predict synthetic routes in a model-driven approach; on the other side, experimental routes can be extracted from the Network of Organic Chemistry, in which reaction data are linked in a network. In this context, the need to combine, compare and analyze synthetic routes generated by different sources arises naturally. RESULTS: Here we present LinChemIn, a python toolkit that allows chemoinformatics operations on synthetic routes and reaction networks. Wrapping some third-party packages for handling graph arithmetic and chemoinformatics and implementing new data models and functionalities, LinChemIn allows the interconversion between data formats and data models and enables route-level analysis and operations, including route comparison and descriptors calculation. Object-Oriented Design principles inspire the software architecture, and the modules are structured to maximize code reusability and support code testing and refactoring. The code structure should facilitate external contributions, thus encouraging open and collaborative software development. CONCLUSIONS: The current version of LinChemIn allows users to combine synthetic routes generated from various tools and analyze them, and constitutes an open and extensible framework capable of incorporating contributions from the community and fostering scientific discussion. Our roadmap envisages the development of sophisticated metrics for routes evaluation, a multi-parameter scoring system, and the implementation of an entire "ecosystem" of functionalities operating on synthetic routes. LinChemIn is freely available at https://github.com/syngenta/linchemin.

Ultrafast MRI using deep learning echoplanar imaging for a comprehensive assessment of acute ischemic stroke.

OBJECTIVES: Acute ischemic stroke (AIS) is an emergency requiring both fast and informative MR sequences. We aimed to assess the performance of an artificial intelligence-enhanced ultrafast (UF) protocol, compared to the reference protocol, in the AIS management. METHODS: We included patients admitted in the emergency department for suspected AIS. Each patient underwent a 3-T MR protocol, including reference acquisitions of T2-FLAIR, DWI, and SWI (duration: 7 min 54 s) and their accelerated multishot EPI counterparts for T2-FLAIR and T2*, complemented by a single-shot EPI DWI (duration: 1 min 54 s). Two blinded neuroradiologists reviewed each dataset, assessing DWI (detection, location, number of acute lesions), FLAIR (vascular hyperintensities, visibility of acute lesions), and SWI/T2* (hemorrhagic transformation, thrombus). We compared the agreement between the diagnoses obtained with both protocols using kappa coefficients. RESULTS: A total of 173 patients were included consecutively, of whom 80 with an AIS in DWI. We found an almost perfect agreement between the UF and reference protocols regarding the detection, distribution, number of AIS in DWI (κ = 0.98, 0.98, and 0.87 respectively), the presence of vascular hyperintensities, and the presence of a parenchymal hyperintensity in the AIS region in FLAIR (κ = 0.93 and 0.89 respectively). Agreement was substantial in T2*/SWI for thrombus detection, and fair for hemorrhagic transformation detection (κ = 0.64 and 0.38 respectively). Differential diagnoses were similarly detected by both protocols (κ = 1). CONCLUSIONS: Our AI-enhanced ultrafast MRI protocol allowed an effective detection and characterization of both AIS and differential diagnoses in less than 2 min. KEY POINTS: • The AI-enhanced ultrafast MRI protocol allowed an effective detection of acute stroke. • Characterization of stroke features with the UF protocol was equivalent to the reference sequences. • Differential diagnoses were detected similarly by the UF and reference protocols.

Albert Pitres: Charcot's Brilliant Student.

Albert Pitres (1848-1928) was an internist, neuropsychiatrist, professor of anatomy, pathology, and histology. He never really had a biography in English. However, the development of neurology and neurosciences in Bordeaux owes a lot to him, as to the psychiatrist Emmanuel Régis (1855-1918). The fact that his career was so closely linked with Charcot (1825-1893) should have secured him a more prominent place in neurology and the history of aphasiology. Pitres went on to co-author clinical and experimental research papers with Charcot that are considered some of the most notable ones among Charcot's publications. Both carried out studies about pathological correlations between cortical lesions and hemiplegia, published series of articles and two major books about neurophysiology of motor control. To convey the atmosphere and the importance of the neurological clinic of Pitres in the heyday, we illustrate this article with unpublished photos of him.

A Coarse-Grained Force Field for Silica-Polybutadiene Interfaces and Nanocomposites.

We present a coarse-grained force field for modelling silica-polybutadiene interfaces and nanocomposites. The polymer, poly(cis-1,4-butadiene), is treated with a previously published united-atom model. Silica is treated as a rigid body, using one Si-centered superatom for each SiO 2 unit. The parameters for the cross-interaction between silica and the polymer are derived by Boltzmann inversion of the density oscillations at model interfaces, obtained from atomistic simulations of silica surfaces containing both Q 4 (hydrophobic) and Q 3 (silanol-containing, hydrophilic) silicon atoms. The performance of the model is tested in both equilibrium and non-equilibrium molecular dynamics simulations. We expect the present model to be useful for future large-scale simulations of rubber-silica nanocomposites.

Tunable interaction potentials and morphology of polymer-nanoparticle blends.

We present the results of molecular dynamics simulations of a family of polymer nanocomposite systems. The polymer is described by a generic bead-and-spring model, while the polymer chains and the nanoparticles (NPs) interact by Hamaker-style potentials. The potential describing NP-NP interactions is modified by a tuning parameter f, which can be changed continuously between f = 0 (for fully developed van der Waals attractions between the NPs) and f = 1 (for completely repulsive interparticle interactions). We explore systematically the effect of the f parameter on the blend morphologies, for two representative NP sizes. When the polymer-NP attractions are decreased, the systems undergo a transition from dispersed to aggregated morphologies. The sharpness of the transition gradually increases with the interparticle attractions (i.e., decreasing f).

Synthetic T2 mapping is correlated with time from stroke onset: a future tool in wake-up stroke management?

OBJECTIVES: FLAIR-DWI mismatch is an effective method to select eligible wake-up stroke (WUS) patients for intravenous thrombolysis, but shows limitations in the case of subtle FLAIR hyperintensities. T2 mapping is a quantitative method, directly generated from synthetic MRI, which provides T2 relaxation times. We aimed to assess the correlation between T2 values and onset time in acute stroke patients. METHODS: We prospectively included stroke patients in the 4.5-h window undergoing brain MRI including MAGnetic resonance Image Compilation (MAGiC) from March to October 2017. T2 relaxation times and FLAIR signal intensities were measured in ischemic and contralateral nonischemic regions to calculate FLAIR signal intensity ratio (rSI), difference, and ratio of T2 values. Correlation analysis with time from the onset was achieved using Pearson or Spearman correlation coefficient (ρ) test. RESULTS: Forty-two patients were included. The strongest correlation with the time from onset was the difference in T2 relaxation times (ρ = 0.71; CI95% = [0.48; 0.85]), followed by the ratio (ρ = 0.65; CI95% = [0.37; 0.82]) and the absolute T2 relaxation time (ρ = 0.4; CI95% = [0.06; 0.66]), whereas the FLAIR rSI showed the weakest correlation (ρ = 0.18; CI95% = [- 0.16-0.51]). CONCLUSIONS: The difference and ratio in T2 relaxation times were correlated with the onset time in stroke patients in the 4.5-h window. T2 mapping generated from synthetic MRI may become a relevant tool to select WUS patients with subtle FLAIR hyperintensities. Given that no definitive statement can be made about its usefulness in the 4.5-h windows, further study including patients with an onset time > 4.5 h is required. KEY POINTS: • The difference and ratio in T2 relaxation times are each individually correlated with the time from stroke onset in the 4.5-h window. • FLAIR rSI showed a poor correlation with the time from stroke onset. • T2 mapping, directly generated from synthetic MRI, may be a suitable quantitative marker to select safely WUS patients with subtle FLAIR hyperintensities for intravenous thrombolysis.

Full quantum dynamical investigation of the Eley-Rideal reaction forming H2 on a movable graphitic substrate at T = 0 K.

The dynamics of the Eley-Rideal abstraction reaction of hydrogen atoms on a movable graphitic surface is investigated for the first time in a numerically exact fully quantum setting. A system-bath strategy was applied where the two recombining H atoms and a substrate C atom form a relevant subsystem, while the rest of the lattice takes the form of an independent oscillator bath. High-dimensional wavepacket simulations were performed in the collision energy range 0.2-1.0 eV with the help of the multi-layer multi-configuration time-dependent Hartree method, focusing on the collinear reaction on a zero-temperature surface. Results show that the dynamics is close to a sudden limit in which the reaction is much faster than the substrate motion. Unpuckering of the surface is fast (some tens of fs) but starts only after the formation of H2 is completed, thereby determining a considerable substrate heating (∼0.8 eV per reactive event). Energy partitioning in the product molecule favors translational over vibrational energy, and H2 molecules are vibrationally hot (∼1.5 eV) though to a lesser extent than previously predicted.

Quantum dynamical investigation of the isotope effect in H2 formation on graphite at cold collision energies.

The Eley-Rideal abstraction of hydrogen atoms on graphitic surfaces at cold collision energies was investigated using a time-dependent wave packet method within the rigid-flat surface approximation, with a focus on hydrogen-deuterium isotopic substitutions. It is found that the marked isotope effect of collinear collisions disappears when the full dimensionality of the problem is taken into account, thereby suggesting that abstraction is less direct than commonly believed and proceeds through glancing rather than head-on collisions. In contrast, a clear isotope effect is observed for "hot-atom" formation, which appears to be strongly favored for heavy projectiles because of their higher density of physisorbed states. Overall, the dynamics is essentially classical and reasonably well described by quasi-classical trajectory methods at all but the lowest energies (≲10 meV). A comparison of the results obtained in the (substrate) adiabatic and diabatic limits suggests that the reaction is only marginally affected by the lattice dynamics, but highlights the importance of including energy dissipation processes in order to accurately describe the internal excitation of the product molecules.

Incident Cerebral Microbleeds in a Cohort of Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: We aimed to identify prognostic and associated factors of incident cerebral microbleeds (CMBs) in intracerebral hemorrhage (ICH) survivors. METHODS: Observational prospective cohort of 168 ICH survivors who underwent 1.5T magnetic resonance imaging at ICH onset and during follow-up (median scan interval, 3.4; interquartile range, 1.4-4.7) years. We used logistic regression adjusted for age, sex, and scan interval. Analyses were stratified according to the index ICH location (58 lobar ICH, 103 nonlobar ICH, excluding patients with multiple or unclassifiable ICH). RESULTS: Eighty-nine (53%) patients had CMBs at ICH onset, and 80 (48%) exhibited incident CMBs during follow-up. Predictors of incident CMBs at ICH onset were ≥1 CMBs (adjusted odds ratio [aOR], 2.27; 95% confidence interval [CI], 1.18-4.35), old radiological macrohemorrhage (aOR, 6.78; 95% CI, 2.76-16.68), and CMBs in mixed location (aOR, 3.73; 95% CI, 1.67-8.31). When stratifying by ICH location, incident CMBs were associated in nonlobar ICH with incident lacunes (aOR, 2.86; 95% CI, 1.04-7.85) and with the use of antiplatelet agents (aOR, 2.89; 95% CI, 1.14-7.32). In lobar ICH, incident CMBs were associated with incident radiological macrohemorrhage (aOR, 9.76; 95% CI, 1.07-88.77). CONCLUSIONS: Prognostic and associated factors of incident CMBs differed according to the index ICH location. Whereas in lobar ICH, incident CMBs were associated with hemorrhagic biomarkers, in nonlobar ICH, ischemic burden also increased. CMBs may be interesting biomarkers to monitor in randomized trials on restarting antithrombotic drugs after ICH.

Variation in restarting antithrombotic drugs at hospital discharge after intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Whether intracerebral hemorrhage (ICH) survivors should restart antithrombotic drugs is unknown. We analyzed the frequency of restarting antithrombotic drugs in ICH survivors who had taken prophylactic antithrombotic drugs in atrial fibrillation or after thromboembolic disease in 5 cohorts and explored factors associated with doing so. METHODS: We compared the characteristics and proportions of patients taking antithrombotic drugs at ICH onset and discharge in 4 hospital-based cohorts (Lille, France, n=542; Utrecht, The Netherlands, n=389; multicenter Clinical Relevance of Microbleeds in Stroke-2 (CROMIS-2) ICH, United Kingdom, n=667; and Amsterdam, The Netherlands, n=403) and 1 community-based study (Lothian, Scotland, n=137), using bivariate analyses. We sought characteristics associated with restarting using bivariate and multivariable logistic regression analyses. RESULTS: A total of 942 (44%) patients with ICH took antithrombotic drugs at hospital admission (no difference between cohorts). Antithrombotic drugs were restarted in 96 (20%) of the 469 survivors who had taken antithrombotic drugs for secondary prevention or atrial fibrillation, but this proportion differed when stratified by the cohort of origin (Lille, 18%; Utrecht, 45%; Lothian, 15%; CROMIS-2 ICH, 11%; Amsterdam, 20%; P<0.001) and by type of antithrombotic drug pre-ICH (14% in patients with previous antiplatelet drugs versus 26% in patients with previous vitamin K antagonists and 41% in patients with both drugs; P<0.001). We did not find other consistent, independent associations with restarting antithrombotic drugs. CONCLUSIONS: The variation in clinical practice and lack of consistent associations with restarting antithrombotic drugs after ICH reflect current knowledge and support the need for randomized controlled trials to resolve this dilemma.

Vitamin K antagonists-associated cerebral hemorrhages: what are their characteristics?

BACKGROUND AND PURPOSE: The high prevalence of atrial fibrillation in aging populations leads to an increasing incidence of vitamin K antagonists-associated intracerebral hemorrhages (VKAs-ICH). It remains unclear whether VKAs are causes or risk factors for ICH. We aimed at identifying the specificities of VKAs-ICH. METHODS: We compared baseline characteristics of 545 consecutive patients receiving or not receiving VKAs before admission for spontaneous ICH. To determine whether the influence of VKAs depends on the underlying vasculopathy, that is, cerebral amyloid angiopathy in lobar, and deep perforating arteries vasculopathy in deep ICH, we compared characteristics of ICH (including volume) according to the anatomic distribution of ICH in multiple linear regression. RESULTS: VKAs-ICH accounted for 83 patients, that is, 15% (95% confidence intervals, 12-18) of ICH in our cohort. The use of VKAs did not influence anatomic distribution of ICH. The impact of VKAs on ICH volume differed according to ICH location: in nonlobar ICH, VKAs use was associated with significant larger ICH volumes (median volume 25 mL vs 12 mL; P=0.002). In lobar ICH, VKAs use did not influence the volume (median 26 mL vs 30 mL; P=0.507). CONCLUSIONS: A similar anatomic distribution of ICH in patients with or without VKAs suggests that VKAs should not be considered as a cause of ICH because both locations are usually due to different vasculopathies (deep perforating arteries vasculopathy in deep and cerebral amyloid angiopathy in lobar). The different impact of VKAs on ICH volumes according to location suggests a different susceptibility of these vasculopathies to VKAs. This finding may lead to specific therapeutic strategies.

[Cervical and intracranial fibromuscular dysplasia]. / Dysplasie fibromusculaire cervicale et intracrânienne.

Fibromuscular dysplasia (FMD) is an uncommon, segmental, nonatherosclerotic arterial disease of unknown etiology, involving intermediate-sized arteries in many areas of the body. It affects primarily women. FMD is often asymptomatic and discovered as an incidental finding. It can, however, be associated with ischemic stroke spontaneous dissection, intracranial aneurysm, and hemodynamic compromise of the distal circulation, and therefore can be a cause of cerebral ischemic symptoms or subarachnoid hemorrhage in some patients.

Fibromuscular dysplasia of cervical and intracranial arteries.

Fibromuscular dysplasia is an uncommon, segmental, nonatherosclerotic arterial disease of unknown aetiology. The disease primarily affects women and involves intermediate-sized arteries in many areas of the body, including cervical and intracranial arteries. Although often asymptomatic, fibromuscular dysplasia can also be associated with spontaneous dissection, severe stenosis that compromises the distal circulation, or intracranial aneurysm, and is therefore responsible for cerebral ischaemia or subarachnoid haemorrhage. Fibromuscular dysplasia affects middle and distal portions of the internal carotid and vertebral arteries, and occasionally, intracranial arteries. Several pathological and angiographic patterns exist. The most frequent pathological type is medial fibromuscular dysplasia, which is associated with the 'string of beads' angiographic pattern. Unifocal lesions are less common and can be associated with several pathological subtypes. The pathophysiology of the disease is widely unknown. Fibromuscular dysplasia may in fact result from various causes and reflect a non-specific response to different insults. The poor knowledge of the natural history and the lack of randomised trials that compared the different treatment options do not allow any satisfactory judgement to be made regarding the need for or the efficacy of any treatment.

Intra-cerebral haemorrhages: are there any differences in baseline characteristics and intra-hospital mortality between hospitaland population-based registries?

A better understanding of the natural history of intracerebral haemorrhages (ICH) with cohorts representing the whole spectrum of the disease is necessary to improve treatment. Our aim was to identify potential differences in baseline characteristics and short-term outcomes of patients with non-traumatic ICH, included in a hospital- and in a population-based stroke registry. We compared 373 patients recruited in a university hospital and the last 373 ICH patients included in a population-based registry. Both cohorts included consecutive patients with non-traumatic parenchymal haemorrhages. In the hospital cohort, we collected data from all patients admitted in the emergency room, irrespective of the clinical severity and of the specialist in charge of the patient.In the hospital cohort, patients were younger and more often alcoholic, but these differences may be explained by the younger age and a higher prevalence of alcoholism in this area. Patients also had more frequently hypercholesterolemia, and were more often under antiplatelet therapy. Both cohorts did not differ for intra-hospital casefatality rate.The characteristics of patients included in the hospital cohort were very close to those of patients from a population-based registry, and the differences observed are likely to be explained by differences in the characteristics of the populations in the two areas and different periods of recruitment. Recruiting patients in emergency rooms, and not in stroke units, neurological, or neurosurgical departments, has enabled us to build a cohort of ICH patients representative of the whole spectrum of the disease, with minimised recruitment bias and maximised precision of the variables collected. This cohort may, therefore, provide reliable information on the natural history of ICH.

Monitoring after the acute stage of stroke: a prospective study.

BACKGROUND AND PURPOSE: In the early stage of stroke, the occurrence of neurologic and medical complications is associated with clinical deterioration. Previous studies were focused on the first week after stroke onset. The aim of this study was to evaluate the impact of complications on clinical outcome in patients with stroke in the early subacute stage. METHODS: We prospectively evaluated the influence on the outcome of complications feasible (MC) and not feasible for monitoring (NMC) in all patients with stroke admitted consecutively in our subacute stroke unit. Patients were divided into three classes according to stroke severity evaluated by the National Institutes of Health Stroke Scale score. A change in the National Institutes of Health Stroke Scale score group from admission to discharge was considered clinically significant. RESULTS: We included 261 patients. Sixty percent of patients had complications (105 MC, 118 NMC). Hyperthermia (OR=14.12; 95% CI: 6.01 to 33.20), urinary infections (OR=4.92; 95% CI: 2.19 to 11.04), hypertension (OR=2.86; 95% CI: 1.21 to 6.76), hypoxia (OR=15.75; 95% CI: 6.73 to 36.84), and neuroradiologic damage progression (OR=58.31; 95% CI, 19.48 to 174.55) were associated with a change to a more severe class at discharge and with a higher risk of mortality. CONCLUSIONS: A high percentage of patients can develop both MC and NMC during this subacute stage of stroke. The occurrence of complications influences outcome and raises the question about the need for a prolonged stay in a dedicated ward for patients with stroke.

Insular infarcts and electrocardiographic changes at admission: results of the PRognostic of Insular CErebral infarctS Study (PRINCESS).

BACKGROUND AND PURPOSE: Previous studies showed that insular strokes are associated with electrocardiographic (ECG) changes. However, they did not take into account the 1(st) ECG recorded at admission, but continuous ECG recorded up to 72 hours after onset. Whether these changes are the consequence of the infarct, or are associated with a cardiac source of cerebral ischemia, remains unsettled. If ECG changes are the consequence of insular infarcts, they should not have developed by the time of admission. The aim of this study was to test the hypothesis that ECG changes in patients with insular infarcts are not present at admission. METHODS: We recruited consecutive patients admitted within 48 hours (median 3 hours) after the onset of symptoms of acute hemispheric cerebral ischemia. We compared ECG variables between patients with and without insular infarcts, and with left and right insular infarcts. RESULTS: The study population consisted of 208 patients (94 men; median age: 69 years). Seventy patients had a recent insular infarct (right in 33). ECG variables did not significantly differ between patients with and without insular infarcts, and with left and right insular infarcts. These results were not explained by a lack of statistical power (1-beta >/= 0.90). CONCLUSION: The lack of statistical link between insular infarcts and ECG changes at admission, suggests that ECG changes are not associated with the cause of insular infarcts, but are their consequence.