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A combined method of the Dirac-Hartree-Fock (DHF) method and the reference interaction-site model (RISM) theory is reported; this is the initial implementation of the coupling of the four-component relativistic electronic structure theory and an integral equation theory of molecular liquids. In the method, the DHF and RISM equations are solved self-consistently, and therefore the electronic structure of the solute, including relativistic effects, and the solvation structure are determined simultaneously. The formulation is constructed based on the variational principle with respect to the Helmholtz energy, and analytic free energy gradients are also derived using the variational property. The method is applied to the iodine ion (I

The binding process of angiotensin-converting enzyme 2 (ACE2) to the receptor-binding domain (RBD) of the severe acute respiratory syndrome-like coronavirus 2 spike protein was investigated using molecular dynamics simulation and the three-dimensional reference interaction-site model theory. The results suggested that the protein-binding process consists of a protein-protein approaching step, followed by a local structural rearrangement step. In the approaching step, the interprotein interaction energy decreased as the proteins approached each other, whereas the solvation free energy increased. As the proteins approached, the glycan of ACE2 first established a hydrogen bond with the RBD. Thereafter, the number of interprotein hydrogen bonds increased rapidly. The solvation free energy increased because of the desolvation of the protein as it approached its partner. The spatial distribution function of the solvent revealed the presence of hydrogen bonds bridged by water molecules on the RBD-ACE2 interface. Finally, principal component analysis revealed that ACE2 showed a pronounced conformational change, whereas there was no significant change in RBD.

Various embolic sources and pathogenetic mechanisms underlie cryptogenic stroke (CS). We investigated the association of etiological diversity with short-term outcomes in patients with CS using a modified atherosclerosis (A), small-vessel disease (S), cardiac pathology (C), other causes (O), and dissection (D) (ASCOD) system.Patients with CS who underwent transesophageal echocardiography were registered in this multicenter, observational study. In the modified classification system, O and D were inapplicable and thus excluded. Instead, atherosclerosis, small-vessel disease, cardiac pathology-CS classification was specifically constructed for the etiological diagnosis of CS. We utilized this system to explore the mechanism of CS by grading each pathology and evaluated its association with poorer modified Rankin Scale scores of 3-6 at hospital discharge.A total of 672 patients (68.7±12.8 years, 220 females) were analyzed. In the multiple logistic regression model, female sex (odds ratio [OR], 1.87 [1.15-3.04]; P=0.012), body mass index (OR, 0.93 [0.88-0.99]; P=0.025), National Institute of Health Stroke Scale score (OR, 1.16 [1.12-1.21]; P＜0.001), CHADS2 score (OR, 1.56 [1.30-1.86]; P＜0.001), D-dimer (OR, 1.04 [1.01-1.08]; P=0.015), diffusion-weighted image (DWI) lesion size (OR, 1.44 [1.10-1.89]; P=0.009), and S＋C score (OR, 1.26 [1.03-1.56]; P=0.029) were associated with poor functional outcome at discharge whereas the S＋C score was marginally associated with poor functional outcome after excluding 137 patients with a premorbid modified Rankin Scale score of ≥ 3.The coexistence of small-vessel disease and cardiac pathology might be associated with poor in-hospital functional outcome in CS.

The detection of underlying atrial fibrillation (AF) has become increasingly possible by insertable cardiac monitoring (ICM). During hospitalization for cryptogenic stroke, factors related to the early and late development of AF have not been studied. CHALLENGE ESUS/CS is a multicenter registry of cryptogenic stroke patients undergoing transesophageal echocardiography. Twelve-lead electrocardiogram, continuous cardiac monitoring, and 24-h Holter electrocardiogram were all used for the detection of AF. Early and late detection of AF was determined with an allocation ratio of 1:1 among patients with AF. A total of 677 patients (68.7 ± 12.8 years; 455 men) were enrolled, and 64 patients developed AF during hospitalization. Four days after admission was identified as the approximate median day to classify early and late phases to detect AF: ≤ 4 days, 37 patients; > 4 days, 27 patients. Multiple logistic regression analysis showed that spontaneous echo contrast (SEC) (OR 5.91; 95% CI 2.19–15.97; p 3 cm in diameter (OR 3.28; 95% CI 1.35–7.97; p = 0.009) was associated with AF > 4 days. SEC and large infarctions were important predictors of in-hospital AF detection, particularly in the early and late stages, respectively; thus, they could serve as indications for recommending ICM.

BackgroundWe aimed to identify the large ischemic core (LIC) volume ranges in acute ischemic stroke patients that can benefit from mechanical thrombectomy (MT).MethodsConsecutive patients within 24 hours of onset of anterior circulation ischemic stroke with large vessel occlusion and ischemic core volumes of 70–300 mL were included from our single-center prospective database from March 2014 to December 2019. Subjects were divided into three groups by baseline ischemic core volume (A: 70–100 mL; B: 101–130 mL; C: >130 mL). We compared modified Rankin Scale (mRS) score 0–2 at 3 months and parenchymal hematoma between patients receiving MT and standard medical treatment (SMT), and determined clinically treatable core volume ranges for MT.ResultsOf 157 patients (86 women; median age, 81 years; median ischemic core volume, 123 mL), 49 patients underwent MT. In Group A (n=52), MT patients (n=31) showed a higher proportion of mRS 0–2 at 3 months (52% vs 5%, PConclusionsIschemic core volumes between 70 and 100 mL may benefit from MT. The treatable upper core limit is approximately 120 mL in selected patients with LIC of 70–300 mL.

Background and purpose: The embolic stroke of undetermined source (ESUS) was introduced and expected the efficacy of anticoagulant. However, a large-scale clinical trial failed to reveal the superiority of rivaroxaban to aspirin. The heterogeneous pathology of ESUS may be a cause of this discrepancy. The prevalence of cerebral microbleeds (CMBs) is different among subtypes of ischemic stroke. In this study, we aimed to differentiate the underlying pathology of ESUS throughout analyzing CMBs. Methods: Acute ESUS patients who were admitted to our hospital between April 2014 and December 2016 were studied. In addition, findings of brain MRI including T2*-weighted imaging and transesophageal echocardiography (TEE) were collected to assess covert pathology of ESUS. Results: Of a total 1612 acute ischemic stroke patients, 221 (13.7%, 78 women, 71.9±12.7 years) met the criteria of ESUS and underwent brain MRI and TEE. Of these, 94 had CMBs (the CMB group) and 127 did not (the non-CMB group). The CMB group was more aged (75.3 ± 9.5 vs 69.5 ± 14.1 years, p=0.0006), more male (74.5% vs 57.5%, p=0.0104), and more hypertensive (94.7% vs 69.3%, p Conclusions: Because ESUS patients with CMBs more frequently had aortic complicated lesion and less frequently had atrial fibrillation than those without, CMBs may have a potential to discriminate underlying pathology of ESUS.