Gene silencing dynamics are modulated by transiently active regulatory elements.

Transcriptional enhancers have been extensively characterized, but cis-regulatory elements involved in acute gene repression have received less attention. Transcription factor GATA1 promotes erythroid differentiation by activating and repressing distinct gene sets. Here, we study the mechanism by which GATA1 silences the proliferative gene Kit during murine erythroid cell maturation and define stages from initial loss of activation to heterochromatinization. We find that GATA1 inactivates a potent upstream enhancer but concomitantly creates a discrete intronic regulatory region marked by H3K27ac, short noncoding RNAs, and de novo chromatin looping. This enhancer-like element forms transiently and serves to delay Kit silencing. The element is ultimately erased via the FOG1/NuRD deacetylase complex, as revealed by the study of a disease-associated GATA1 variant. Hence, regulatory sites can be self-limiting by dynamic co-factor usage. Genome-wide analyses across cell types and species uncover transiently active elements at numerous genes during repression, suggesting that modulation of silencing kinetics is widespread.

RUNX1-deficient human megakaryocytes demonstrate thrombopoietic and platelet half-life and functional defects.

Heterozygous defects in runt-related transcription factor 1 (RUNX1) are causative of a familial platelet disorder with associated myeloid malignancy (FPDMM). Because RUNX1-deficient animal models do not mimic bleeding disorder or leukemic risk associated with FPDMM, development of a proper model system is critical to understanding the underlying mechanisms of the observed phenotype and to identifying therapeutic interventions. We previously reported an in vitro megakaryopoiesis system comprising human CD34+ hematopoietic stem and progenitor cells that recapitulated the FPDMM quantitative megakaryocyte defect through a decrease in RUNX1 expression via a lentiviral short hairpin RNA strategy. We now show that shRX-megakaryocytes have a marked reduction in agonist responsiveness. We then infused shRX-megakaryocytes into immunocompromised NOD scid gamma (NSG) mice and demonstrated that these megakaryocytes released fewer platelets than megakaryocytes transfected with a nontargeting shRNA, and these platelets had a diminished half-life. The platelets were also poorly responsive to agonists, unable to correct thrombus formation in NSG mice homozygous for a R1326H mutation in von Willebrand Factor (VWFR1326H), which switches the species-binding specificity of the VWF from mouse to human glycoprotein Ibα. A small-molecule inhibitor RepSox, which blocks the transforming growth factor ß1 (TGFß1) pathway and rescued defective megakaryopoiesis in vitro, corrected the thrombopoietic defect, defects in thrombus formation and platelet half-life, and agonist response in NSG/VWFR1326H mice. Thus, this model recapitulates the defects in FPDMM megakaryocytes and platelets, identifies previously unrecognized defects in thrombopoiesis and platelet half-life, and demonstrates for the first time, reversal of RUNX1 deficiency-induced hemostatic defects by a drug.

Dynamic enhancer-gene body contacts during transcription elongation.

Enhancers govern transcription through multiple mechanisms, including the regulation of elongation by RNA polymerase II (RNAPII). We characterized the dynamics of looped enhancer contacts during synchronous transcription elongation. We found that many distal enhancers form stable contacts with their target promoters during the entire interval of elongation. Notably, we detected additional dynamic enhancer contacts throughout the gene bodies that track with elongating RNAPII and the leading edge of RNA synthesis. These results support a model in which the gene body changes its position relative to a stable enhancer-promoter complex, which has broad ramifications for enhancer function and architectural models of transcriptional elongation.

Mechanistic assessment of tolerance to iron deficiency mediated by Trichoderma harzianum in soybean roots.

AIMS: Iron (Fe) deficiency in soil is a continuing problem for soybean (Glycine max L.) production, partly as a result of continuing climate change. This study elucidates how Trichoderma harzianum strain T22 (TH) mitigates growth retardation associated with Fe-deficiency in a highly sensitive soybean cultivar. METHODS AND RESULTS: Soil TH supplementation led to mycelial colonization and the presence of UAOX1 gene in roots that caused substantial improvement in chlorophyll score, photosynthetic efficiency and morphological parameters, indicating a positive influence on soybean health. Although rhizosphere acidification was found to be a common feature of Fe-deficient soybean, the upregulation of Fe-reductase activity (GmFRO2) and total phenol secretion were two of the mechanisms that substantially increased the Fe availability by TH. Heat-killed TH applied to soil caused no improvement in photosynthetic attributes and Fe-reductase activity, confirming the active role of TH in mitigating Fe-deficiency. Consistent increases in tissue Fe content and increased Fe-transporter (GmIRT1, GmNRAMP2a, GmNRAMP2b and GmNRAMP7) mRNA levels in roots following TH supplementation were observed only under Fe-deprivation. Root cell death, electrolyte leakage, superoxide (O2 •- ) and hydrogen peroxide (H2 O2 ) substantially declined due to TH in Fe-deprived plants. Further, the elevation of citrate and malate concentration along with the expression of citrate synthase (GmCs) and malate synthase (GmMs) caused by TH suggest improved chelation of Fe in Fe-deficient plants. Results also suggest that TH has a role in triggering antioxidant defence by increasing the activity of glutathione reductase (GR) along with elevated S-metabolites (glutathione and methionine) to stabilize redox status under Fe-deficiency. CONCLUSIONS: TH increases the availability and mobilization of Fe by inducing Fe-uptake pathways, which appears to help provide resistance to oxidative stress associated with Fe-shortage in soybean. SIGNIFICANCE AND IMPACT OF THE STUDY: These findings indicate that while Fe deficiency does not affect the rate or degree of TH hyphal association in soybean roots, the beneficial effects of TH alone may be Fe deficiency-dependent.

Intravenous Brivaracetam in the Management of Acute Seizures in the Hospital Setting: A Scoping Review.

BACKGROUND: Clinical considerations for drug treatment of acute seizures involve variables such as safety, tolerability, drug-drug interactions, dosage, route of administration, and alterations in pharmacokinetics because of critical illness. Therapy options that are easily and quickly administered without dilution, well tolerated, and effective are needed for the treatment of acute seizures. The objective of this review is to focus on the clinical considerations relating to the use of intravenous brivaracetam (IV BRV) for the treatment of acute seizures in the hospital, focusing on critically ill patients. METHODS: This was a scoping literature review of PubMed from inception to April 13, 2021, and search of the American Academy of Neurology (AAN) 2021 Annual Meeting website for English language publications/conference abstracts reporting the results of IV BRV use in hospitalized patients, particularly in the critical care setting. Outcomes of interest relating to the clinical pharmacology, safety, tolerability, efficacy, and effectiveness of IV BRV were reviewed and are discussed. RESULTS: Twelve studies were included for analysis. One study showed that plasma concentrations of IV BRV 15 min after the first dose were similar between patients receiving IV BRV as bolus or infusion. IV BRV was generally well tolerated in patients with acute seizures in the hospital setting, with a low incidence of individual TEAEs classified as behavioral disorders. IV BRV demonstrated efficacy and effectiveness and had a rapid onset, with clinical and electrophysiological improvement in seizures observed within minutes. Although outside of the approved label, findings from several studies suggest that IV BRV reduces seizures and is generally well tolerated in patients with status epilepticus. CONCLUSIONS: IV BRV shows effectiveness, and is generally well tolerated in the management of acute seizures in hospitalized patients where rapid administration is needed, representing a clinically relevant antiseizure medication for potential use in the critical care setting.

Predicting Ventriculoperitoneal Shunt Dependence in High Grade Aneurysmal Subarachnoid Hemorrhage.

INTRODUCTION: Aneurysmal subarachnoid hemorrhage (aSAH) commonly presents with hydrocephalus due to obstruction of cerebrospinal fluid (CSF) passage across the ventricular system in the brain. Placement of an external ventricular device (EVD) and in some cases ventriculoperitoneal shunt (VPS) are often necessary for patients requiring prolonged CSF diversion. The study aimed at evaluating critical factors that play a role in determining the need for extended extraventricular drainage. METHODS: We performed a retrospective observational cohort study of two groups of patients with radiological imaging confirmed high grade aSAH (Hunt & Hess grades 3-5) who required VPS placement, shunt-dependent group, and who did not require long term CSF diversion, non-shunt-dependent group. We collected and analyzed data regarding the daily CSF output for 10 days following EVD placement, daily EVD height, intracranial pressure (ICP) and cerebral perfusion pressure (CPP), indicators of hydrocephalus, and CSF characteristics. RESULTS: The cohort, comprising of 8 patients in the shunt-dependent group and 32 patients in the non-shunt-dependent group, displayed median daily CSF output of 275.1 mL/day and 193.4 mL/day, respectively (P = .0005). ROC curve for CSF drainage for the two groups showed an area under the curve (AUC) of 0.71 with a 95% confidence interval (CI) 0.65 to 0.77. Qualitative analysis of CSF characteristics revealed that the shunt-dependent group had more proteinaceous, darker red color, and greater proportion of red blood cells (RBCs) although not statistically significant. CONCLUSIONS: Determinants of prolonged CSF drainage requirements in patients with high grade aSAH are not fully elucidated to this date and there is no standardized protocol for CSF diversion. Our study revealed potential markers that can be used in the assessment for the need for long term CSF diversion. Our limited sample size necessitates further research to establish clear correlations and cutoffs of these parameters in predicting long term CSF diversion requirements.

The Spot Sign and Intraventricular Hemorrhage are Associated with Baseline Coagulopathy and Outcome in Intracerebral Hemorrhage.

BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) is the second most prevalent subtype of stroke and has high mortality and morbidity. The utility of radiographic features to predict secondary brain injury related to hematoma expansion (HE) or increased intracranial pressure has been highlighted in patients with ICH, including the computed tomographic angiography (CTA) spot sign and intraventricular hemorrhage (IVH). Understanding the pathophysiology of spot sign and IVH may help identify optimal therapeutic strategies. We examined factors related to the spot sign and IVH, including coagulation status, hematoma size, and location, and evaluated their prognostic value in patients with ICH. METHODS: Prospectively collected data from a single center between 2012 and 2015 were analyzed. Patients who underwent thromboelastography within 24 h of symptom onset and completed follow-up brain imaging and CTA within 48 h after onset were included for analysis. Multivariate logistic regression analyses were performed to identify determinants of the spot sign and IVH and their predictive value for HE, early neurological deterioration (END), in-hospital mortality, and functional outcome at discharge. RESULTS: Of 161 patients, 50 (31.1%) had a spot sign and 93 (57.8%) had IVH. In multivariable analysis, the spot sign was associated with greater hematoma volume (odds ratio [OR] 1.02; 95% confidence interval [CI] 1.00-1.03), decreased white blood cell count (OR 0.88; 95% CI 0.79-0.98), and prolonged activated partial thromboplastin time (OR 1.14; 95% CI 1.06-1.23). IVH was associated with greater hematoma volume (OR 1.02; 95% CI 1.01-1.04) and nonlobar location of hematoma (OR 0.23; 95% CI 0.09-0.61). The spot sign was associated with greater risk of all adverse outcomes. IVH was associated with an increased risk of END and reduced HE, without significant impact on mortality or functional outcome. CONCLUSIONS: The spot sign and IVH are associated with specific hematoma characteristics, such as size and location, but are related differently to coagulation status and clinical course. A combined analysis of the spot sign and IVH can improve the understanding of pathophysiology and risk stratification after ICH.

Stroke Care during the COVID-19 Pandemic: International Expert Panel Review.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has placed a tremendous strain on healthcare services. This study, prepared by a large international panel of stroke experts, assesses the rapidly growing research and personal experience with COVID-19 stroke and offers recommendations for stroke management in this challenging new setting: modifications needed for prehospital emergency rescue and hyperacute care; inpatient intensive or stroke units; posthospitalization rehabilitation; follow-up including at-risk family and community; and multispecialty departmental developments in the allied professions. SUMMARY: The severe acute respiratory syndrome coronavirus 2 uses spike proteins binding to tissue angiotensin-converting enzyme (ACE)-2 receptors, most often through the respiratory system by virus inhalation and thence to other susceptible organ systems, leading to COVID-19. Clinicians facing the many etiologies for stroke have been sobered by the unusual incidence of combined etiologies and presentations, prominent among them are vasculitis, cardiomyopathy, hypercoagulable state, and endothelial dysfunction. International standards of acute stroke management remain in force, but COVID-19 adds the burdens of personal protections for the patient, rescue, and hospital staff and for some even into the postdischarge phase. For pending COVID-19 determination and also for those shown to be COVID-19 affected, strict infection control is needed at all times to reduce spread of infection and to protect healthcare staff, using the wealth of well-described methods. For COVID-19 patients with stroke, thrombolysis and thrombectomy should be continued, and the usual early management of hypertension applies, save that recent work suggests continuing ACE inhibitors and ARBs. Prothrombotic states, some acute and severe, encourage prophylactic LMWH unless bleeding risk is high. COVID-19-related cardiomyopathy adds risk of cardioembolic stroke, where heparin or warfarin may be preferable, with experience accumulating with DOACs. As ever, arteritis can prove a difficult diagnosis, especially if not obvious on the acute angiogram done for clot extraction. This field is under rapid development and may generate management recommendations which are as yet unsettled, even undiscovered. Beyond the acute management phase, COVID-19-related stroke also forces rehabilitation services to use protective precautions. As with all stroke patients, health workers should be aware of symptoms of depression, anxiety, insomnia, and/or distress developing in their patients and caregivers. Postdischarge outpatient care currently includes continued secondary prevention measures. Although hoping a COVID-19 stroke patient can be considered cured of the virus, those concerned for contact safety can take comfort in the increasing use of telemedicine, which is itself a growing source of patient-physician contacts. Many online resources are available to patients and physicians. Like prior challenges, stroke care teams will also overcome this one. Key Messages: Evidence-based stroke management should continue to be provided throughout the patient care journey, while strict infection control measures are enforced.

Silicon induces metallochaperone-driven cadmium binding to the cell wall and restores redox status through elevated glutathione in Cd-stressed sugar beet.

Cadmium (Cd) is toxic; however, whether silicon (Si) alleviates Cd toxicity was never studied in sugar beet. The study was conducted on 2-week-old sugar beet cultivated in the presence or absence of Cd (10 µM CdSO4 ) and Si (1 mM Na2 SiO3 ) in hydroponic conditions. The morphological impairment and cellular damages observed in sugar beet upon Cd toxicity were entirely reversed due to Si. Si substantially restored the energy-providing ability, absorbed energy flux, and electron transport toward PSII, which might be correlated with the upregulation of BvIRT1 and ferric chelate reductase activity leading to the restoration of Fe status in Cd-stressed sugar beet. Although Si caused a reduction of shoot Cd, the root Cd substantially increased under Cd stress, a significant part of which was retained in the cell wall rather than in the root vacuole. While the concentration of phytochelatin and the expression of BvPCS3 (PHYTOCHELATIN SYNTHASE 3) showed no changes upon Si exposure, Si induced the expression of BvHIPP32 (HEAVY METAL-ASSOCIATED ISOPRENYLATED PLANT PROTEIN 32) in the Cd-exposed root. The BvHIPP32 and AtHIPP32 metallochaperone proteins are localized in the cell wall and they share similar sequence alignment, physiochemical properties, secondary structure, cellular localization, motif locations, domain association, and metal-binding site (cd00371) linked to the metallochaperone-like protein. It suggests that Si reduces the Cd level in shoot by retaining the excess Cd in the cell wall of roots due to the induction of BvHIPP32 gene. Also, Si stimulates glutathione-related antioxidants along with the BvGST23 expression, inferring an ascorbate-glutathione ROS detoxification pathway in Cd-exposed plants.

Range Dividing MIMO Waveform for Improving Tracking Performance.

A multiple-input multiple-output (MIMO) method that shares the same frequency band can efficiently increase radar performance. An essential element of a MIMO radar is the orthogonality of the waveform. Typically, orthogonality is obtained by spreading different signals into divided domains such as in time-domain multiplexing, frequency-domain multiplexing, and code domain multiplexing. This paper proposes a method of spreading the interference signals outside the range bins of interest for pulse doppler radars. This is achieved by changing the pulse repetition frequency under certain constraints, and an additional gain can be obtained by doppler processing. This method is very effective for improving the angular accuracy of the MIMO radar for a small number of air targets, although it may have limitations in use for many targets or in high clutter environments.

Management Strategies for Intracranial Pressure Crises in Subarachnoid Hemorrhage.

Objectives: Standard management strategies for lowering intracranial pressure (ICP) in traumatic brain injury has been well-studied, but the use of lesser known interventions for ICP in subarachnoid hemorrhage (SAH) remains elusive. Searches were performed in PubMed and EBSCO Host to identify best available evidence for evaluation and management of medically refractory ICP in SAH. The role of standard management strategies such as head elevation, hyperventilation, mannitol and hypertonic saline as well as lesser known management such as sodium bicarbonate, indomethacin, tromethamine, decompressive craniectomy, decompressive laparotomy, hypothermia, and barbiturate coma are reviewed. We also included dose concentrations, dose frequency, infusion volume, and infusion rate for these lesser known strategies. Nonetheless, there is still a gap in the evidence to recommend optimal dosing, timing and its role in the improvement of outcomes but early diagnosis and appropriate management reduce adverse outcomes.

Dual Antiplatelet Therapy Is Associated With Coagulopathy Detectable by Thrombelastography in Acute Stroke.

BACKGROUND: Thrombelastography (TEG) provides a global, dynamic measure of coagulation. We examined the effect of antiplatelet (AP) medications on coagulation in patients with acute stroke as measured by TEG. METHODS: We reviewed prospectively collected data on patients presenting with acute ischemic stroke (AIS) and spontaneous intracerebral hemorrhage (ICH) between 2009 and 2014. Patient demographics and baseline TEG values were compared among 4 different drug use groups: aspirin only, clopidogrel only, both aspirin and clopidogrel, and no AP. Multivariable regression models were conducted to compare the differences in TEG components. RESULTS: A total of 202 patients were included, 139 with AIS and 63 with ICH. Forty-eight (24%) patients were taking aspirin alone, 12 (6%) were taking clopidogrel, 16 (8%) dual AP, and 126 (62%) no AP. Dual AP use was associated with prolonged mean R (time to initiate clotting) of 5.5 minutes as compared to no AP use (4.6 minutes, P = .04). Additionally, mean maximal amplitude (MA; final clot strength) and angle (rate of clot formation) were decreased in the dual AP group (MA = 59.3 mm, angle = 57.8°) as compared to the no AP group (MA = 64.5 mm, angle = 64.5°; P = .04 and P = .01, respectively). Patients on single AP therapy (either aspirin or clopidogrel) did not differ from those on no AP therapy in any TEG parameters measured. CONCLUSION: Dual AP therapy is associated with a detectable coagulopathy which may have implications in the management of patients with AIS and hemorrhagic stroke. The effects of single AP therapy may not be demonstrated by TEG.

Arbuscular Mycorrhizal Symbiosis Mitigates Iron (Fe)-Deficiency Retardation in Alfalfa (Medicago sativa L.) Through the Enhancement of Fe Accumulation and Sulfur-Assisted Antioxidant Defense.

Iron (Fe)-deficiency is one of the major constraints affecting growth, yield and nutritional quality in plants. This study was performed to elucidate how arbuscular mycorrhizal fungi (AMF) alleviate Fe-deficiency retardation in alfalfa (Medicago sativa L.). AMF supplementation improved plant biomass, chlorophyll score, Fv/Fm (quantum efficiency of photosystem II), and Pi_ABS (photosynthesis performance index), and reduced cell death, electrolyte leakage, and hydrogen peroxide accumulation in alfalfa. Moreover, AMF enhanced ferric chelate reductase activity as well as Fe, Zn, S and P in alfalfa under Fe-deficiency. Although Fe-transporters (MsIRT1 and MsNramp1) did not induce in root but MsFRO1 significantly induced by AMF under Fe deficiency in roots, suggesting that AMF-mediated Fe enhancement is related to the bioavailability of Fe at rhizosphere/root apoplast rather than the upregulation of Fe transporters under Fe deficiency in alfalfa. Several S-transporters (MsSULTR1;1, MsSULTR1;2, MsSULTR1;3, and MsSULTR3;1) markedly increased following AMF supplementation with or without Fe-deficiency alfalfa. Our study further suggests that Fe uptake system is independently influenced by AMF regardless of the S status in alfalfa. However, the increase of S in alfalfa is correlated with the elevation of GR and S-metabolites (glutathione and cysteine) associated with antioxidant defense under Fe deficiency.

Comparison of Clevidipine and Nicardipine for Acute Blood Pressure Reduction in Patients With Stroke.

OBJECTIVE: The aim of this study was to determine whether clevidipine (CLEV) achieved faster blood pressure control compared to nicardipine (NIC) in patients presenting with either an acute ischemic stroke (AIS) or a spontaneous intracerebral hemorrhage (ICH). METHODS: This was a retrospective, observational, cohort study conducted in patients with AIS or ICH admitted to the emergency department of a Comprehensive Stroke Center from November 2011 to June 2013 who received CLEV or NIC continuous infusion for acute blood pressure management. RESULTS: The study included 210 patients: 70 in the CLEV group and 140 in the NIC group. There was no difference in mean time (standard deviation [SD]) from initiation of the infusion to goal systolic blood pressure (SBP), CLEV: 50 (83) minutes versus NIC: 74 (103) minutes, P = .101. Comparison of the 2 agents within diagnosis showed no difference. Hypotension developed in 5 (7.1%) CLEV patients versus 14 (10%) NIC patients (P = .003). There was no difference in the percentage change at 2 hours; CLEV: -20% (16%) versus NIC: -16% (16%), P = .058. Mean (SD) time to alteplase administration from admission was 56 (22) minutes in the CLEV group versus 59 (25) minutes in the NIC group (P = .684). CONCLUSIONS: There was no difference in the mean time from initiation of the infusion to the SBP goal between agents or in the secondary outcomes. Due to the lack of differences observed, each agent should be considered based on the patient care needs of the institution.

A Dedicated Neurological Intensive Care Unit Offers Improved Outcomes for Patients With Brain and Spine Injuries.

BACKGROUND: Admission to an intensive care unit (ICU) specialized for brain and spine injury patients is associated with improved outcome. We investigated the effects of the first dedicated, combined neurological and neurosurgical ICU (NeuroICU) in Korea on patient outcomes. METHODS: The first dedicated NeuroICU in Korea was established in March 2013. We retrospectively analyzed the clinical data and compared the outcomes between patients admitted to the ICU before and after NeuroICU establishment. The predicted mortality of NeuroICU patients was calculated using their Acute Physiology and Chronic Health Evaluation II scores. Patients' functional outcomes were evaluated using their modified Rankin scale (mRS) scores at 6 months after ICU admission, which were obtained from medical records or telephone interviews. RESULTS: We included 2487 patients, 1572 and 915 of whom were admitted prior to and after NeuroICU establishment, respectively. The demographic characteristics, Glasgow Coma Scale scores, and disease proportions did not differ significantly between the groups. The length of ICU stay and the number of days on ventilation were significantly lower in NeuroICU patients than they were in general ICU patients ( P = .024, P = .001). Intensive care unit mortality was significantly lower in NeuroICU patients (7.3% vs 4.7%, P = .012). The predicted mortality was obtained from 473 NeuroICU patients. The mortality ratio (observed mortality/predicted mortality) was 0.34 (8.9%/26.1%), and 228 (48.1%) patients showed good functional recovery (mRS, 0-2). CONCLUSION: Our findings suggest that admission to a dedicated NeuroICU significantly improves the neurological outcomes of patients with brain and spine injuries, including their postoperative care, in Korea.

Multimodality Monitoring in Neurocritical Care: Decision-Making Utilizing Direct And Indirect Surrogate Markers.

Substantial progress has been made to create innovative technology that can monitor the different physiological characteristics that precede the onset of secondary brain injury, with the ultimate goal of intervening prior to the onset of irreversible neurological damage. One of the goals of neurocritical care is to recognize and preemptively manage secondary neurological injury by analyzing physiologic markers of ischemia and brain injury prior to the development of irreversible damage. This is helpful in a multitude of neurological conditions, whereby secondary neurological injury could present including but not limited to traumatic intracranial hemorrhage and, specifically, subarachnoid hemorrhage, which has the potential of progressing to delayed cerebral ischemia and monitoring postneurosurgical interventions. In this study, we examine the utilization of direct and indirect surrogate physiologic markers of ongoing neurologic injury, including intracranial pressure, cerebral blood flow, and brain metabolism.

Transcranial direct current stimulation for the treatment of motor impairment following traumatic brain injury.

After traumatic brain injury (TBI), motor impairment is less common than neurocognitive or behavioral problems. However, about 30% of TBI survivors have reported motor deficits limiting the activities of daily living or participation. After acute primary and secondary injuries, there are subsequent changes including increased GABA-mediated inhibition during the subacute stage and neuroplastic alterations that are adaptive or maladaptive during the chronic stage. Therefore, timely and appropriate neuromodulation by transcranial direct current stimulation (tDCS) may be beneficial to patients with TBI for neuroprotection or restoration of maladaptive changes.Technologically, combination of imaging-based modelling or simultaneous brain signal monitoring with tDCS could result in greater individualized optimal targeting allowing a more favorable neuroplasticity after TBI. Moreover, a combination of task-oriented training using virtual reality with tDCS can be considered as a potent tele-rehabilitation tool in the home setting, increasing the dose of rehabilitation and neuromodulation, resulting in better motor recovery.This review summarizes the pathophysiology and possible neuroplastic changes in TBI, as well as provides the general concepts and current evidence with respect to the applicability of tDCS in motor recovery. Through its endeavors, it aims to provide insights on further successful development and clinical application of tDCS in motor rehabilitation after TBI.

Stroke outcomes are worse with larger leukoaraiosis volumes.

Leukoaraiosis or white matter hyperintensities are frequently observed on magnetic resonance imaging of stroke patients. We investigated how white matter hyperintensity volumes affect stroke outcomes, generally and by subtype. In total, 5035 acute ischaemic stroke patients were enrolled. Strokes were classified as large artery atherosclerosis, small vessel occlusion, or cardioembolism. White matter hyperintensity volumes were stratified into quintiles. Mean age (± standard deviation) was 66.3 ± 12.8, 59.6% male. Median (interquartile range) modified Rankin Scale score was 2 (1-3) at discharge and 1 (0-3) at 3 months; 16.5% experienced early neurological deterioration, and 3.3% recurrent stroke. The Cochran-Mantel-Haenszel test with adjustment for age, stroke severity, sex, and thrombolysis status showed that the distributions of 3-month modified Rankin Scale scores differed across white matter hyperintensity quintiles (P < 0.001). Multiple ordinal logistic regression analysis showed that higher white matter hyperintensity quintiles were independently associated with worse 3-month modified Rankin Scale scores; adjusted odds ratios (95% confidence interval) for the second to fifth quintiles versus the first quintile were 1.29 (1.10-1.52), 1.40 (1.18-1.66), 1.69 (1.42-2.02) and 2.03 (1.69-2.43), respectively. For large artery atherosclerosis (39.0%), outcomes varied by white matter hyperintensity volume (P = 0.01, Cochran-Mantel-Haenszel test), and the upper three white matter hyperintensity quintiles (versus the first quintile) had worse 3-month modified Rankin Scale scores; adjusted odds ratios were 1.45 (1.10-1.90), 1.86 (1.41-2.47), and 1.89 (1.41-2.54), respectively. Patients with large artery atherosclerosis were vulnerable to early neurological deterioration (19.4%), and the top two white matter hyperintensity quintiles were more vulnerable still: 23.5% and 22.3%. Moreover, higher white matter hyperintensities were associated with poor modified Rankin Scale improvement: adjusted odds ratios for the upper two quintiles versus the first quintile were 0.66 (0.47-0.94) and 0.62 (0.43-0.89), respectively. For small vessel occlusion (17.8%), outcomes tended to vary by white matter hyperintensitiy volume (P = 0.10, Cochran-Mantel-Haenszel test), and the highest quintile was associated with worse 3-month modified Rankin Scale scores: adjusted odds ratio for the fifth quintile versus first quintile, 1.98 (1.23-3.18). In this subtype, worse white matter hyperintensities were associated with worse National Institute of Health Stroke Scale scores at presentation. For cardioembolism (20.6%), outcomes did not vary significantly by white matter hyperintensity volume (P = 0.19, Cochran-Mantel-Haenszel test); however, the adjusted odds ratio for the highest versus lowest quintiles was 1.62 (1.09-2.40). Regardless of stroke subtype, white matter hyperintensities were not associated with stroke recurrence within 3 months of follow-up. In conclusion, white matter hyperintensity volume independently correlates with stroke outcomes in acute ischaemic stroke. There are some suggestions that stroke outcomes may be affected by leukoaraiosis differentially depending on stroke subtypes, to be confirmed in future investigations.