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Background: Data on the early course of stroke-related aphasia after thrombolysis are scant. Aims: The aim of this study was to describe recovery patterns of aphasia after thrombolysis in a large sample of stroke patients. Methods & Procedures: Clinical and radiological data of consecutive stroke patients treated with thrombolysis over a 5-year period were routinely entered into prospective registries at two stroke units. Recovery was evaluated using the National Institutes of Health Stroke Scale (NIHSS) at baseline, after 24 hr, and on day 7. Aphasia was defined as a score >0 on item 9 of the NIHSS (measurement of language skills), aphasia improvement as any decrease in the item-9 score, and aphasia resolution as an item-9 score of 0. To assess global motor and language impairments, we created a composite language score obtained by summing the scores for items 1b, 1c, and 9; and a composite motor score obtained by summing the scores for items 4, 5, and 6. Outcomes & Results: Out of the 338 patients treated with thrombolysis, 137 (40.5%) had aphasia. In patients with both aphasia and motor deficits (n = 109), these two impairments showed similar recovery patterns. Aphasia recovered significantly better in patients without limb motor deficits (n = 28) than those with limb motor deficits (n = 109), both after 24 hr (p < 0.05) and after 7 days (p < 0.0001). These results were supported by findings from a group-based trajectory modelling methods (p < 0.005). Conclusions: Language impairments and limb motor deficits show similar recovery after thrombolysis in a given patient. Aphasia recovery is significantly better in the absence of limb motor deficits. [ABSTRACT FROM AUTHOR]

Abstract: Expression of the thrombomodulin (TM) variant c.1611C>A (p.Cys537Stop) leads to the synthesis of a protein with no cytoplasmic tail and a transmembrane domain shortened by 3 amino acids (TM536). However, little is known regarding the release mechanism and properties of TM536. Using umbilical vein endothelial cells and peripheral blood-derived endothelial colony-forming cells from a heterozygous carrier of the TM536 variant as well as overexpression cell models, we demonstrated that TM536 is released from cells by an unusual mechanism. First, TM536 is inserted into the endoplasmic reticulum (ER) membrane, then, because of the low hydrophobicity of its intramembrane domain, it escapes from it and follows the conventional secretory pathway to be released into the extracellular compartment without the involvement of proteolysis. This particular secretion mechanism yields a soluble TM536, which is poorly modified by chondroitin sulfate glycosaminoglycan compared with conventionally secreted soluble forms of TM, and therefore has a suboptimal capacity to mediate thrombin-dependent activation of protein C (PC). We also showed that TM536 cellular trafficking was altered, with retention in the early secretory pathway and increased sensitivity to ER-associated degradation. As expected, activation of ER-associated degradation increased TM536 degradation and reduced its release. The expression of TM536 at the cell surface was low, and its distribution in lipid raft-like membrane microdomains was altered, resulting in low thrombin-dependent PC activation on the cell surface., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: There is a lack of standardized assessment tools for poststroke aphasia in Brazil, particularly bedside screenings for early identification of patients with suspected language disorders. The Language Screening Test (LAST) is a valid and reliable method for screening hospitalized patients following a stroke. This tool was first developed in French and then translated and validated in other languages., Purpose: This study aimed to translate, culturally adapt, and validate the LAST into Brazilian Portuguese., Method: Following a systematic, multistep approach to translation and cultural adaptation of language instruments, this study developed the two parallel versions of the Brazilian Portuguese LAST (pLAST) Versions A and B. The final versions were applied to 70 healthy and 30 poststroke adults across age and educational levels. Subtests of the Boston Diagnostic Aphasia Examination (BDAE) were used to assess the external validity of the pLAST., Results: Findings showed that the two versions (A and B) of the pLAST were equivalent (intraclass correlation coefficient = .91; p < .001). No floor or ceiling effects were observed, and internal validity was excellent (Cronbach's α = .85). Moreover, its external validity against the BDAE was moderate to strong. Test sensitivity and specificity were 0.88 and 1, respectively, and accuracy was 0.96., Conclusion: The Brazilian Portuguese version of the LAST is a valid, simple, easy, and rapid test to screen poststroke aphasia in hospital settings., Supplemental Material: https://doi.org/10.23641/asha.23548911.

Re-education of the tumor microenvironment with immune checkpoint inhibitors (ICI) has provided the most significant advancement in cancer management, with impressive efficacy and durable response reported. However, low response rates and a high frequency of immune-related adverse events (irAEs) remain associated with ICI therapies. The latter can be linked to their high affinity and avidity for their target that fosters on-target/off-tumor binding and subsequent breaking of immune self-tolerance in normal tissues. Many multispecific protein formats have been proposed to increase the tumor cell's selectivity of ICI therapies. In this study, we explored the engineering of a bispecific Nanofitin by the fusion of an anti-epidermal growth factor receptor (EGFR) and anti-programmed cell death ligand 1 (PDL1) Nanofitin modules. While lowering the affinity of the Nanofitin modules for their respective target, the fusion enables the simultaneous engagement of EGFR and PDL1, which translates into a selective binding to tumor cells co-expressing EGFR and PDL1 only. We demonstrated that affinity-attenuated bispecific Nanofitin could elicit PDL1 blockade exclusively in an EGFR-directed manner. Overall, the data collected highlight the potential of this approach to enhance the selectivity and safety of PDL1 checkpoint inhibition.

Background: Stroke is a high burden illness and the second leading cause of worldwide disability with generally poor recovery rates. Robust benefits of hippotherapy, a novel neurorehabilitation approach, in functional recovery following various severe neurological disabling conditions has been shown. In the present study, we will analyze the effect of a hippotherapy program on the outcome of post-stroke patients in the first year post-stroke., Method: A randomized controlled clinical trial on the effectiveness of hippotherapy (4 weeks/18 weeks hippotherapy/conventional neurorehabilitation) versus conventional neurorehabilitation alone (22 weeks) will be conducted over 48 weeks. In the treated group, one-hour daily hippotherapy sessions will be exclusively conducted during the hippotherapy's cycles, alternated with periods of conventional neurorehabilitation. A test battery will measure both the functional and psychological outcomes. The primary endpoint will be the patient's functional independence. The secondary endpoints will measure the sensorimotor function, autonomy, and quality of life, as well as the caregivers' quality of life., Results and Conclusion: Individual brain connectome, life history and personality construct influence the brain's functional connectivity and are central to developing optimal tailored neurorehabilitation strategies. According to our current practice, hippotherapy allows the enhancement of substantial neuroplastic changes in the injured brain with significant neurological recovery. The protocol aims to confirm those issues. Trial registration in ClinicalTrials.gov NCT04759326 accessed on 19 February 2021.

Background: Neurophobia is a chronic disease of medical students and junior doctors. Early detection is needed to facilitate prevention and management as this fear can negatively impact patient care., Methods: We conducted a two-part mono-centric study at the faculty of Medicine, Sorbonne University, in Paris. Part one: a cross-sectional study to validate a newly constructed neurophobia scale, NeuroQ. Part two: a prospective longitudinal study to assess the impact of The Move on student neurophobia using NeuroQ. A population-based sample of second-year medical students of the 2019 and 2020 class of the Faculty of Medicine of Sorbonne University were invited to participate., Results: NeuroQ incorporates the main themes of the neurophobia definition and demonstrates uni-dimensionality. Three hundred and ninety-five medical students participated in the study (mean age was 20.0 years, SD: 2.1 years) assessing the effect of The Move teaching on neurophobia. Two hundred and eighty-eight (72.9%) students were female. After the Move teaching the mean NeuroQ score was significantly lower compared to the baseline NeuroQ score (mean [SD] variation, -1.1 [2.6], p < 0.001). There was a 22.3% relative reduction in the number of neurophobic students after The Move teaching., Conclusion: Our results highlight the utility of NeuroQ in assessing (i) baseline neurophobia and (ii) the impact of pre-clinical educational interventions on neurophobia. Furthermore, we have shown the importance of pre-clinical educational interventions, such as The Move, in tackling neurophobia., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Primary progressive aphasias (PPA) have been investigated by clinical, therapeutic, and fundamental research but examiner-consistent language tests for reliable reproducible diagnosis and follow-up are lacking. Methods: We developed and evaluated a rapid language test for PPA ("PARIS") assessing its inter-examiner consistency, its power to detect and classify PPA, and its capacity to identify language decline after a follow-up of 9 months. To explore the reliability and specificity/sensitivity of the test it was applied to PPA patients ( N = 36), typical amnesic Alzheimer's disease (AD) patients ( N = 24) and healthy controls ( N = 35), while comparing it to two rapid examiner-consistent language tests used in stroke-induced aphasia ("LAST", "ART"). Results: The application duration of the "PARIS" was ~10 min and its inter-rater consistency was of 88%. The three tests distinguished healthy controls from AD and PPA patients but only the "PARIS" reliably separated PPA from AD and allowed for classifying the two most frequent PPA variants: semantic and logopenic PPA. Compared to the "LAST" and "ART," the "PARIS" also had the highest sensitivity for detecting language decline. Conclusions: The "PARIS" is an efficient, rapid, and highly examiner-consistent language test for the diagnosis, classification, and follow-up of frequent PPA variants. It might also be a valuable tool for providing end-points in future therapeutic trials on PPA and other neurodegenerative diseases affecting language processing., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Epelbaum, Saade, Flamand Roze, Roze, Ferrieux, Arbizu, Nogues, Azuar, Dubois, Tezenas du Montcel and Teichmann.)

Scientists have to perform multiple experiments producing qualitative and quantitative data to determine if a compound is able to bind to a given target. Due to the large diversity of the potential ligand chemical space, the possibility of experimentally exploring a lot of compounds on a target rapidly becomes out of reach. Scientists therefore need to use virtual screening methods to determine the putative binding mode of ligands on a protein and then post-process the raw docking experiments with a dedicated scoring function in relation with experimental data. Two of the major difficulties for comparing docking predictions with experiments mostly come from the lack of transferability of experimental data and the lack of standardisation in molecule names. Although large portals like PubChem or ChEMBL are available for general purpose, there is no service allowing a formal expert annotation of both experimental data and docking studies. To address these issues, researchers build their own collection of data in flat files, often in spreadsheets, with limited possibilities of extensive annotations or standardisation of ligand descriptions allowing cross-database retrieval. We have conceived the dockNmine platform to provide a service allowing an expert and authenticated annotation of ligands and targets. First, this portal allows a scientist to incorporate controlled information in the database using reference identifiers for the protein (Uniprot ID) and the ligand (SMILES description), the data and the publication associated to it. Second, it allows the incorporation of docking experiments using forms that automatically parse useful parameters and results. Last, the web interface provides a lot of pre-computed outputs to assess the degree of correlations between docking experiments and experimental data.

The execution of coordinated hand movements requires complex interactions between premotor and primary motor areas in the two hemispheres. The supplementary motor area (SMA) is involved in movement preparation and bimanual coordination. How the SMA controls bimanual coordination remains unclear, although there is evidence suggesting that the SMA could modulate interhemispheric interactions. With a delayed-response task, we investigated interhemispheric interactions underlying normal movement preparation and the role of the SMA in these interactions during the delay period of unimanual or bimanual hand movements. We used functional MRI and transcranial magnetic stimulation in 22 healthy volunteers (HVs), and then in two models of SMA dysfunction: (a) in the same group of HVs after transient disruption of the right SMA proper by continuous transcranial magnetic theta-burst stimulation; (b) in a group of 22 patients with congenital mirror movements (CMM), whose inability to produce asymmetric hand movements is associated with SMA dysfunction. In HVs, interhemispheric connectivity during the delay period was modulated according to whether or not hand coordination was required for the forthcoming movement. In HVs following SMA disruption and in CMM patients, interhemispheric connectivity was modified during the delay period and the interhemispheric inhibition was decreased. Using two models of SMA dysfunction, we showed that the SMA modulates interhemispheric interactions during movement preparation. This unveils a new role for the SMA and highlights its importance in coordinated movement preparation., (© 2019 Wiley Periodicals, Inc.)

Basic examination and diagnostic skills in neurology are important for every graduating medical student. However, a majority of medical students consider neurology as complex and difficult to master. We evaluate the impact a learner-friendly, innovative simulation-based training programme has on long-term retention and delayed recall of neurological semiology amongst third-year medical students from the University Pierre et Marie Curie in Paris, France. The 2013 class received standard teaching in neurological semiology. The 2015 class who received the same standard teaching in neurological semiology were also invited to voluntarily participate in The Move, a mime-based role-play training programme of neurological semiology. During the Move, students were trained to simulate a patient with a neurological syndrome or the physician examining the patient. Students were evaluated with an assessment thirty months after their neurological rotation, including 15 questions to evaluate long-term retention of neurological semiology, and 10 to test background knowledge in general semiology. The semiology test was performed by 366/377 students from the 2013 class (standard education group) and by 272/391 students from the 2015 class, among which 186 participated in The Move (The Move group) and 86 did not (standard education group). The mean neurological semiology score was higher in the 2015 class compared to the 2013 class (p = 0.007) and remained so after adjustment for the general semiology performance (p = 0.003). The adjusted mean neurological semiology score was 1.21/15 points higher [95% CI 0.66, 1.75] in The Move group compared to the standard education group, corresponding to a 14% better ranking. The Move programme improves medical student's long-term retention and delayed recall of neurological semiology. This learner-friendly interactive teaching may in turn enhance clinical proficiency of future physicians in neurological semiology., (Copyright © 2018. Published by Elsevier B.V.)

[This corrects the article DOI: 10.1371/journal.pone.0196646.].

There is a severe lack of aphasia screening tools for bedside use in Chinese. A number of aphasia assessment tools have recently been developed abroad, but some of these scales were not suitable for patients with acute stroke. The Language Screening Test (which includes two parallel versions [a/b]) in French has been proven to be an effective and time-saving aphasia screening scale for early-stage stroke patients. Therefore, we worked out a Chinese version of the LAST taking into consideration Chinese language and culture. Two preliminary parallel versions (a/b) were tested on 154 patients with stroke at acute phase and 107 patients with stroke at non-acute phase, with the Western Aphasia Battery serving as a gold standard. The equivalence between the two parallel versions and the reliability/validity of each version were assessed. The median time to complete one preliminary Chinese version (each had some item redundancy) was 98 seconds. Two final parallel versions were established after adjustment/elimination of the redundant items and were found to be equivalent (intra-class correlation coefficient: 0.991). Internal consistency is(Cronbach α for each version [a/b] was 0.956 and 0.965, respectively) good. Internal validity was fine: (a) no floor or ceiling effect/item redundancy; (b) construct validity revealed a 1-dimension structure, just like the French version. The higher educated subjects scored higher than their lower educated counterparts (p<0.01). The external validity: at the optimum cut-off point where the score of version a/b <14 in higher educated group(<13 in lower): the specificity of each version was 0.878/0.902(1/1 in lower) and sensitivity was 0.972/0.944(0.944/0.944 in lower). Inter-rater equivalence (intra-class correlation coefficient) was 1. The Chinese version of the Language Screening Test was proved to be an efficient and time-saving bedside aphasia screening tool for stroke patients at acute phase and can be used by an average medical physician.

Background: Based on the hypothesis of a brain energy deficit, we investigated the safety and efficacy of triheptanoin on paroxysmal episodes in patients with alternating hemiplegia of childhood due to ATP1A3 mutations., Methods: We conducted a randomized, double-blind, placebo-controlled crossover study of triheptanoin, at a target dose corresponding to 30% of daily calorie intake, in ten patients with alternating hemiplegia of childhood due to ATP1A3 mutations. Each treatment period consisted of a 12-week fixed-dose phase, separated by a 4-week washout period. The primary outcome was the total number of paroxysmal events. Secondary outcomes included the number of paroxysmal motor-epileptic events; a composite score taking into account the number, severity and duration of paroxysmal events; interictal neurological manifestations; the clinical global impression-improvement scale (CGI-I); and safety parameters. The paired non-parametric Wilcoxon test was used to analyze treatment effects., Results: In an intention-to-treat analysis, triheptanoin failed to reduce the total number of paroxysmal events (p = 0.646), including motor-epileptic events (p = 0.585), or the composite score (p = 0.059). CGI-I score did not differ between triheptanoin and placebo periods. Triheptanoin was well tolerated., Conclusions: Triheptanoin does not prevent paroxysmal events in Alternating hemiplegia of childhood. We show the feasibility of a randomized placebo-controlled trial in this setting., Trial Registration: The study has been registered with clinicaltrials.gov ( NCT002408354 ) the 03/24/2015.

Objectives: To conduct a systematic review to elucidate the frequency, recovery, and associated outcomes for poststroke aphasia over the long-term., Data Sources: Using the Cochrane Stroke Strategy, we searched 10 databases, 13 journals, 3 conferences, and the gray literature., Study Selection: Our a priori protocol criteria included unselected samples of adult stroke patients from randomized controlled trials or consecutive cohorts. Two independent reviewers rated abstracts and articles for exclusion or inclusion, resolving discrepancies by consensus., Data Extraction: We documented aphasia frequencies by stroke type and setting, and computed odds ratios (ORs) with their 95% confidence intervals (CIs) for outcomes., Data Synthesis: We retrieved 2168 citations, reviewed 248 articles, and accepted 50. Median frequencies for mixed stroke (ischemic and hemorrhagic) were 30% and 34% for acute and rehabilitation settings, respectively. Frequencies by stroke type were lowest for acute subarachnoid hemorrhage (9%) and highest for acute ischemic stroke (62%) when arrival to the hospital was ≤3 hours from stroke onset. Articles monitoring aphasia for 1 year demonstrated aphasia frequencies 2% to 12% lower than baseline. Negative outcomes associated with aphasia included greater odds of in-hospital death (OR=2.7; 95% CI, 2.4-3.1) and longer mean length of stay in days (mean=1.6; 95% CI, 1.0-2.3) in acute settings. Patients with aphasia had greater disability from 28 days (OR=1.5; 95% CI, 1.3-1.7) to 2 years (OR=1.7; 95% CI, 1.6-2.0) than those without aphasia. By 2 years, they used more rehabilitation services (OR=1.5; 95% CI, 1.3-1.6) and returned home less frequently (OR=1.4; 95% CI, 1.2-1.7)., Conclusions: Reported frequencies of poststroke aphasia range widely, depending on stroke type and setting. Because aphasia is associated with mortality, disability, and use of health services, we recommend long-term interdisciplinary vigilance in the management of aphasia., (Copyright © 2016 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)