Dual antiplatelet therapy in acute ischaemic stroke with or without cerebral microbleeds.

Antiplatelet therapy (APT) plays an important role in the prevention of ischaemic stroke (IS). Our aim was to assess the influence of short-term single APT (SAPT) and dual APT (DAPT) on the prognosis of patients with acute IS with and without cerebral microbleeds (CMBs). We conducted a single-centre, retrospective, observational cohort study of patients with acute IS who underwent susceptibility-weighted imaging (SWI) to determine the presence of CMBs between January 2015 and December 2020. The patients were treated with either DAPT or SAPT and followed up for at least 2 years. The primary endpoint was a composite of recurrent IS and intracerebral haemorrhage (ICH), while either recurrent IS or ICH was considered as other endpoints. We computed weighted Kaplan-Meier curves and identified risk factors using the Cox proportional hazards model. Among the 581 enrolled patients, those with CMBs (n = 225; P = 0.004) had a higher risk of the primary endpoint than those without CMBs (n = 356), especially higher risk of recurrent IS (P = 0.029). In the SAPT group, the presence of CMBs increased the risk of the primary endpoint (P = 0.013), especially that of recurrent IS (P = 0.019). In the DAPT group, the occurrence of ICH was higher in patients with CMBs (P = 0.031). The CMB distribution did not influence the risk of recurrent IS or ICH. In patients with acute IS and CMBs, DAPT may offset the risk of recurrent IS due to CMBs but increase the risk of ICH.

Role of cerebral microbleeds in acute ischemic stroke and atrial fibrillation.

Cerebral microbleeds (CMBs) are commonly detected in the brains of patients with acute ischemic stroke (AIS). With the development of neuroimaging, clinicians are paying more attention to the presence of CMBs. CMBs were found to significantly increase the risk of intracranial hemorrhagic transformation and hemorrhage in patients with AIS, especially in patients with concurrent atrial fibrillation (AF). Additionally, the presence of CMBs is thought to be a symbol of a high risk of recurrent ischemic stroke (IS). A few researchers have found that the presence of CMBs has no significant effect on the prognosis of patients with AIS. Therefore, the current views on the role of CMBs in the prognoses of patients with IS are controversial. The use of anticoagulants and other drugs has also become a dilemma due to the special influence of CMBs on the prognosis of these patients. Due to the large number of patients with AF and CMBs, many studies have been conducted on the effects of CMBs on these patients and subsequent pharmacological treatments. However, at present, there are no relevant guidelines to guide the secondary preventive treatment of patients with stroke, CMBs, and AF. In this paper, we summarized the role of CMBs in AIS combined with AF and relevant preventive measures against the recurrence of stroke and the occurrence of intracerebral hemorrhage to help clarify the specifics of drug therapies for this group of patients.

Adult-onset vanishing white matter in a patient with EIF2B3 variants misdiagnosed as multiple sclerosis.

BACKGROUND: Vanishing white matter (VWM) is an autosomal recessive disorder characterized by childhood ataxia with central hypomyelination. Adult-onset VWM should be considered as a differential diagnosis for suspected cases of multiple sclerosis (MS). METHODS: Targeted region sequencing (TRS) and Sanger sequencing validation were performed to identify and validate the likely pathogenic mutations in a family with VWM. RESULTS: The main clinical manifestations of the proband included decreased vision and sleepiness accompanied by atrophy of the corpus callosum, affected inner rim of the corpus callosum, decreased apparent diffusion coefficient value or persistent hyperintensity-diffusion-weighted imaging, atrophied optic nerve, and no recordable visual evoked potentials. Due to the slow development and atypical VWM image features, MS was initially suspected. After prednisone was administered, the patient's condition did not improve significantly, and other diseases were considered. The TRS and Sanger sequencing identified compound heterozygous mutations of EIF2B3 in the proband; c.965C > G /p.Ala322Gly in exon 8 and c.130G > A/p.Glu44Lys in exon 2 were missense mutations inherited from the mother and father, respectively. The proband's oldest brother had the same compound heterozygous mutations but showed no symptoms. CONCLUSION: This is the first report of adult-onset VWM in a Chinese family. Initially, MS was suspected, and genetic testing confirmed the diagnosis of VWM. This study may further broaden the clinical spectrum of EIF2B3, thus providing a foundation for further research on the pathogenesis and genetic therapy for VWM.

Enhancing Edge Attack Strategy via an OWA Operator-Based Ensemble Design in Real-World Networks.

Network disintegration has been an important research hotspot in complex networks for a long time. From the perspective of node attack, researchers have devoted to this field and carried out numerous works. In contrast, the research on edge attack strategy is insufficient. This paper comprehensively evaluates the disintegration effect of each structural similarity index when they are applied to the weighted-edge attacks model. Experimental results show that the edge attack strategy based on a single similarity index will appear limited stability and adaptability. Thus, motivated by obtaining a stable disintegration effect, this paper designs an edge attack strategy based on the ordered weighted averaging (OWA) operator. Through final experimental results, we found that the edge attack strategy proposed in this paper not only achieves a more stable disintegration effect on eight real-world networks, but also significantly improves the disintegration effect when applied on a single network in comparison with the original similarity index.

Novel 1,3,4-Oxadiazole Derivatives Containing a Cinnamic Acid Moiety as Potential Bactericide for Rice Bacterial Diseases.

Rice bacterial leaf blight and leaf streak are two important bacterial diseases of rice, which can result in yield loss. Currently, effective antimicrobials for rice bacterial diseases are still lacking. Thus, to develop highly effective and low-risk bactericides, 31 novel 1,3,4-oxadiazole derivatives containing a cinnamic acid moiety were designed and synthesized. Bioassay results demonstrated that all compounds exhibited good antibacterial activities in vitro. Significantly, compounds 5r and 5t showed excellent antibacterial activities against Xanthomonas oryzae pv. oryzae (Xoo) and X. oryzae pv. oryzicola (Xoc), with the 50% effective concentration (EC50) values of 0.58 and 0.34, and 0.44 and 0.20 µg/mL, respectively. These compounds were much better than thiodiazole copper (123.10 and 161.52 µg/mL) and bismerthiazol (85.66 and 110.96 µg/mL). Moreover, compound 5t had better protective and curative activities against rice bacterial leaf blight and leaf streak than thiodiazole copper and bismerthiazol in vivo. Simultaneously, the in vivo efficacy of the compounds was demonstrated by real-time quantitative PCR to quantify bacterial titers. In addition, a three-dimensional quantitative structure⁻activity relationship model was created and presented good predictive ability. This work provides support for 1,3,4-oxadiazole derivatives containing a cinnamic acid moiety as a potential new bactericide for rice bacterial diseases.

Effects of particle size and adaptation duration on the digestible and metabolizable energy contents and digestibility of various chemical constituents in wheat for finishing pigs determined by the direct or indirect method.

OBJECTIVE: This experiment was conducted as a 3×2×2 factorial design to examine the effects of particle size (mean particle size of 331, 640, or 862 µm), evaluation method (direct vs indirect method) and adaptation duration (7 or 26 days) on the energy content and the apparent total tract digestibility (ATTD) of various chemical components in wheat when fed to finishing pigs. METHODS: Forty-two barrows (Duroc×Landrace×Yorkshire) with an initial body weight of 63.0±0.8 kg were individually placed in metabolic cages and randomly allotted to 1 of 7 diets with 6 pigs fed each diet. For the indirect method, the pigs were fed either a corn-soybean meal based basal diet or diets in which 38.94% of the basal diet was substituted by wheat of the different particle sizes. In the direct method, the diets contained 97.34% wheat with the different particle sizes. For both the direct and indirect methods, the pigs were adapted to their diets for either 7 or 26 days. RESULTS: A reduction in particle size linearly increased the digestible energy (DE) and metabolizable energy (ME) contents as well as the ATTD of gross energy, crude protein, organic matter, ether extract (EE) and acid detergent fiber (ADF) (p<0.05), and had a trend to increase the ATTD of dry matter of wheat (p = 0.084). The DE, ME contents, and ATTD of gross energy, crude protein, dry matter and organic matter were higher (p<0.05) when determined by the direct method, but the ATTD of ADF, EE, and neutral detergent fiber were higher when determined by the indirect method (p<0.05). Prolongation of the adaption duration decreased the ATTD of neutral detergent fiber (p<0.05) and had a trend to increase the ATTD of EE (p = 0.061). There were no interactions between particle size and the duration of the adaptation duration. The ATTD of EE in wheat was influenced by a trend of interaction between method and adaptation duration (p = 0.074). The ATTD of ADF and EE in wheat was influenced by an interaction between evaluation method and wheat particle size such that there were linear equations (p<0.01) about ATTD of ADF and EE when determined by the direct method but quadratic equations (p = 0.073 and p = 0.088, respectively) about ATTD of ADF and EE when determined by the indirect method. CONCLUSION: Decreasing particle size can improve the DE and ME contents of wheat; both of the direct and indirect methods of evaluation are suitable for evaluating the DE and ME contents of wheat with different particle sizes; and an adaptation duration of 7 d is sufficient to evaluate DE and ME contents of wheat in finishing pigs.

Effects of solvent on inclusion complexation of a chiral dipeptide toward racemic BINOL.

The effects of reaction solvent on inclusion complexation of a chiral dipeptide (3S,6S)-1 derived from (S)-proline toward racemic BINOL was investigated, discovering that the reaction solvent played a crucial role in determining the inclusion complexation behavior of dipeptide (3S,6S)-1 toward rac-BINOL. (3S,6S)-1 did not show any chiroselective or achiroselective complexation toward rac-BINOL in polar protic solvents such as methanol and ethanol, polar aprotic solvents including trichloromethane and THF, while in polar aprotic solvent ethyl acetate and apolar aprotic solvents benzene, (3S,6S)-1 displayed achiroselective complexation toward rac-BINOL. However, the resulting heterocomplex HC-2 from benzene and HC-3 from ethyl acetate have a different composition. Single crystal X-ray diffraction analysis demonstrates that the two heterocomplexes are formed via different H-bond interaction patterns, in which the reaction solvent has a dramatic effect. Furthermore, this work provides a relatively green method for quantitative enantiomeric enrichment of nonracemic BINOL, in which unacceptable and toxic benzene was replaced by ethyl acetate.

FastEval Parkinsonism: an instant deep learning-assisted video-based online system for Parkinsonian motor symptom evaluation.

The Motor Disorder Society's Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is designed to assess bradykinesia, the cardinal symptoms of Parkinson's disease (PD). However, it cannot capture the all-day variability of bradykinesia outside the clinical environment. Here, we introduce FastEval Parkinsonism ( https://fastevalp.cmdm.tw/ ), a deep learning-driven video-based system, providing users to capture keypoints, estimate the severity, and summarize in a report. Leveraging 840 finger-tapping videos from 186 individuals (103 patients with Parkinson's disease (PD), 24 participants with atypical parkinsonism (APD), 12 elderly with mild parkinsonism signs (MPS), and 47 healthy controls (HCs)), we employ a dilated convolution neural network with two data augmentation techniques. Our model achieves acceptable accuracies (AAC) of 88.0% and 81.5%. The frequency-intensity (FI) value of thumb-index finger distance was indicated as a pivotal hand parameter to quantify the performance. Our model also shows the usability for multi-angle videos, tested in an external database enrolling over 300 PD patients.

The evolution of the spike protein and hACE2 interface of SARS-CoV-2 omicron variants determined by hydrogen bond formation.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first detected in December 2019. As of mid-2021, the delta variant was the primary type; however, in January 2022, the omicron (BA.1) variant rapidly spread and became the dominant type in the United States. In June 2022, its subvariants surpassed previous variants in different temporal and spatial situations. To investigate the high transmissibility of omicron variants, we assessed the complex of spike protein 1 receptor-binding domain (S1RBD) and human angiotensin-converting enzyme 2 (hACE2) from the Protein Data Bank (6m0j, 7a91, 7mjn, 7v80, 7v84, 7v8b, 7wbl and 7xo9) and directly mutated specific amino acids to simulate several variants, including variants of concern (alpha, beta, gamma, delta), variants of interest (delta plus, epsilon, lambda, mu, mu without R346K) and omicron variants (BA.1, BA.2, BA.2.12.1, BA.4, BA.5). Molecular dynamics (MD) simulations for 100 ns under physiological conditions were then performed. We found that the omicron S1RBD-hACE2 complexes become more compact with increases in hydrogen-bond interactions at the interface, which is related to the transmissibility of SARS-CoV-2. Moreover, the relaxation time of hydrogen bonds is relatively short among the omicron variants, which implies that the interface conformation alterations are fast. From the molecular perspective, PHE486 and TYR501 in omicron S1RBDs need to involve hydrogen bonds and hydrophobic interactions on the interface. Our study provides structural features of the dominant variants that explain the evolution trend and their increased contagiousness and could thus also shed light on future variant changes.

Inactivating Activities and Mechanism of Imidazo[1,2-c]pyrimidin-5(6H)-one Nucleoside Derivatives Incorporating a Sulfonamide Scaffold.

Twenty-eight imidazo[1,2-c]pyrimidin-5(6H)-one nucleoside derivatives incorporating a sulfonamide scaffold with preferable inactivating activities on pepper mild mottle virus (PMMoV) were designed and synthesized. Then, compound B29 with illustrious inactivating activity against PMMoV was received on the basis of the three-dimensional quantitative structure-activity relationship (3D-QSAR) model, with the EC50 of 11.4 µg/mL, which was superior to ningnanmycin (65.8 µg/mL) and template molecule B16 (15.3 µg/mL). Furthermore, (1) transmission electron microscopy (TEM) indicated that B29 could cause severe fracture of virions; (2) microscale thermophoresis (MST) and molecular docking further demonstrated that B29 had faintish binding affinities with PMMoV CPR62A (Kd = 202.84 µM), PMMoV CPL144A (Kd = 141.57 µM), and PMMoV CPR62A,L144A (Kd = 332.06 µM) compared to PMMoV CP (Kd = 4.76 µM); and (3) western blot and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) results of pCB-GFP-PMMoV CPR62A, pCB-GFP-PMMoV CPL144A, and pCB-GFP-PMMoV CPR62A,L144A were consistent with MST and confocal. In brief, the above results indicated that the amino acids at positions 62 and 144 of PMMoV CP might be the key amino acid sites of B29 acted on.

Comparative effectiveness of dual to single antiplatelet therapy after one year versus seven years in patients with acute ischemic stroke combined with cerebral microbleeds.

BACKGROUND: Cerebral microbleeds (CMBs) were thought to be associated with stroke. The relationship CMBs, antiplatelet therapy and prognosis is still unclear. Our aim here was to compare the long-term risk of stoke between dual and single antiplatelet therapies in patients of acute ischemic stroke (IS) combined with CMBs. METHOD: We conducted a retrospective cohort study of 1017 acute IS patients received susceptibility weighted imaging (SWI) magnetic resonance imaging (MRI) sequences. We constructed a sample of patients received short-term dual antiplatelet therapy (DAPT) (n = 154) and received single antiplatelet therapy (SAPT) (n = 125), followed them for up to 7 years (median 33 months). DAPT was prescribed for at least 3 weeks, followed by using SAPT. The primary endpoint was a composite of all-cause death, recurrence IS or intracerebral hemorrhage (ICH). Secondary endpoints were a composite of recurrent IS or ICH, and the recurrent IS. RESULT: At last follow-up, rated of the endpoints were similar in patients treated with SAPT and DAPT (P > 0.05). The IS risk was higher in patients treated with SAPT in the first year after the occurrence of acute IS (P = 0.035). And in 0-1 year or in 1-7 year, the risk of primary endpoint and main secondary endpoint were similar among patients treated with SAPT and DAPT (P > 0.05). CONCLUSION: The study is limited due to different baseline characteristics. We initially consider that the short-term DAPT may be considered to potentially reduce the rate of recurrent IS in the first year. In patients of IS combined with CMBs, the short-term DAPT may be recommended to reduce the recurrent IS.

Enlarged Perivascular Spaces and Age-Related Clinical Diseases.

Perivascular spaces are the fluid-filled areas surrounding small blood vessels in the brain, and they may play a role similar to lymphatic vessels in clearing metabolic waste. When their diameters exceed 1 mm, as measured by structural magnetic resonance imaging, they are classified as enlarged perivascular spaces (EPVS). Previously, EPVS were considered to be benign, but increasing evidence suggests that their existence may be associated with various clinical diseases. Here, we review recent clinical studies to understand the potential clinical implications of EPVS. We also review the anatomy and imaging characteristics of EPVS and discuss four causal hypotheses for their formation and associated risk factors. Due to differences in research methods and concerns across studies, unified conclusions are difficult to achieve. Overall, more basic high-quality research is needed to clarify the subject and provide more concrete theoretical support.

Cerebellar and/or Brainstem Lesions Indicate Poor Prognosis in Multiple Sclerosis: A Systematic Review.

Multiple sclerosis is a serious neurological disease that affects millions of people worldwide. Cerebellar and brainstem symptoms are common in the course of multiple sclerosis, but their prognostic value is unclear. This systematic review aimed to determine the relationship between the location of lesions in the cerebellum and/or brainstem and the prognosis in multiple sclerosis. In this systematic review, we searched and comprehensively read articles related to this research topic in Chinese and English electronic databases (PubMed, Embase, Cochrane Library, CNKI, and CBM) using search terms "multiple sclerosis," "cerebellum," "brainstem," "prognosis," and others. Cerebellar and brainstem clinically isolated syndromes and clinically definite multiple sclerosis were important predictors of transformation (hazard ratio, 2.58; 95% confidence interval, 1.58-4.22). Cerebellar and/or brainstem lesions indicate a poor overall prognosis in multiple sclerosis, but because of inconsistency, more clinical data are needed.

First Discovery of Novel Cytosine Derivatives Containing a Sulfonamide Moiety as Potential Antiviral Agents.

A series of cytosine derivatives containing a sulfonamide moiety were designed and synthesized, and their antiviral activities against pepper mild mottle virus (PMMoV) were systematically evaluated. Then, a three-dimensional quantitative structure-activity relationship (3D-QSAR) model was constructed to study the structure-activity relationship according to the pEC50 of the compounds' protective activities. Next, compound A32 with preferable antiviral activity on PMMoV was obtained based on the CoMSIA and CoMFA models, with an EC50 of 19.5 µg/mL, which was superior to the template molecule A25 (21.3 µg/mL) and ningnanmycin (214.0 µg/mL). In addition, further studies showed that the antiviral activity of compound A32 against PMMoV was in accord with the up-regulation of proteins expressed in the defense response and carbon fixation in photosynthetic organisms. These results indicated that cytosine derivatives containing a sulfonamide moiety could be used as novel potential antiviral agents for further research and development.

Purine Nucleoside Derivatives Containing a Sulfa Ethylamine Moiety: Design, Synthesis, Antiviral Activity, and Mechanism.

To find efficient and broad-spectrum viral agents, a series of purine nucleoside derivatives containing sulfa ethylamine moieties was designed and synthesized, and their antiviral activities against tobacco mosaic virus (TMV), cucumber mosaic virus (CMV), and potato virus Y (PVY) were evaluated. Some target compounds displayed good antiviral activities. Among them, compound 3 showed excellent protective activity against CMV and PVY with 50% effective concentration values (EC50) of 137 and 209 µg/mL, respectively, which were better than that of the control agent ningnanmycin (508 and 431 µg/mL). Moreover, the EC50 value of compound 3 for the inactivating activity against TMV was 48 µg/mL, which was better than that of ningnanmycin (88 µg/mL). In addition, compound 3 not only destroyed the structure of the TMV virus but also had a good interaction with the coat protein of the TMV virus. Therefore, compound 3 may further destroy the structure of the virus by binding to the coat protein of the TMV virus, thereby weakening the infectivity of the virus.

Discovery of Dithioacetal Derivatives Containing Sulfonamide Moiety of Novel Antiviral Agents by TMV Coat Protein as a Potential Target.

Tobacco mosaic virus coat protein (TMV CP) plays an important role in viral replication, translation, and intracellular and intercellular movements. Thus, TMV CP could be regarded as a potential target for antiviral agents. In this study, in order to find out whether dithioacetal derivatives act on the CP target, a series of dithioacetal derivatives containing sulfonamide moiety was first designed and synthesized. Bioassay results demonstrated that Y14, Y18, and Y21 exhibited excellent activities against TMV, with half-maximal effective concentrations (EC50) of the curative, protective, and inactivate activities being 183.0 ± 3.2, 252.3 ± 2.6, and 63.8 ± 1.2 µg/mL, 270.6 ± 3.7, 249.7 ± 3.5, and 57.7 ± 1.4 µg/mL, and 329.5 ± 1.5, 269.2 ± 3.7, and 48.1 ± 2.0 µg/mL for Y14, Y18, and Y21, respectively, which were higher than those for the control agents ningnanmycin (331.0 ± 2.8, 271.0 ± 2.8, and 77.4 ± 1.3 µg/mL, respectively) and d2 (471.5 ± 1.4, 447.2 ± 2.1, and 91.7 ± 1.8 µg/mL, respectively). Transmission electron microscopy showed that the particle morphology of TMV was destroyed by Y21, and microscale thermophoresis (MST) showed that Y21 bonded to CP with a dissociation constant (K d) of 9.7 ± 1.7 µM. Then, molecular docking and MST further illustrated that Y21 had a weak binding affinity with the TMV mutant protein (K d = 561.3 ± 83.2 µM). Thus, we deduced that the dithioacetal derivative Y21 may inhibit TMV activity by binding TMV CP. This work provides some new insights for the design and optimization of novel anti-TMV agents.

Manifold Learning of Dynamic Functional Connectivity Reliably Identifies Functionally Consistent Coupling Patterns in Human Brains.

Most previous work on dynamic functional connectivity (dFC) has focused on analyzing temporal traits of functional connectivity (similar coupling patterns at different timepoints), dividing them into functional connectivity states and detecting their between-group differences. However, the coherent functional connectivity of brain activity among the temporal dynamics of functional connectivity remains unknown. In the study, we applied manifold learning of local linear embedding to explore the consistent coupling patterns (CCPs) that reflect functionally homogeneous regions underlying dFC throughout the entire scanning period. By embedding the whole-brain functional connectivity in a low-dimensional manifold space based on the Human Connectome Project (HCP) resting-state data, we identified ten stable patterns of functional coupling across regions that underpin the temporal evolution of dFC. Moreover, some of these CCPs exhibited significant neurophysiological meaning. Furthermore, we apply this method to HCP rsfMR and tfMRI data as well as sleep-deprivation data and found that the topological organization of these low-dimensional structures has high potential for predicting sleep-deprivation states (classification accuracy of 92.3%) and task types (100% identification for all seven tasks).In summary, this work provides a methodology for distilling coherent low-dimensional functional connectivity structures in complex brain dynamics that play an important role in performing tasks or characterizing specific states of the brain.

[Clinincal application of self-made eccentric traction belt in the treatment of distal radial fractures].

OBJECTIVE: To observe the curative effect of self-made eccentric traction belt as a manipulative reduction tool in the treatment of the distal radial fracture. METHODS: From February 2011 to June 2012,62 patients with distal radial closed fractures were treated by manipulative reduction with self-made wristlet-eccentric traction belt and combined with the small splint and plaster external fixation. Among them, 59 cases were Colles fractures, 2 were Smith fractures, 1 was Barton fracture. After the reduction, lateral X-ray imaging was used to evaluate curative effect immediately. RESULTS: All the patients obtained excellent and good reduction in standard of fractures, only 1 case didn't. According to functonal assessment of Dienst, the results were excellent in 49 cases, good in 11, fair in 1, and poor in 1. CONCLUSION: Self-made wristlet-eccentric traction belt as a manipulative reduction tool to treat distal radius fractures, can make fractures close to the anatomic reduction, and can significantly improve the manual reduction success rate.