Upper limb spasticity is a common and disabling complication of stroke. Botulinum toxin type A (BoNT-A) is widely used for focal spasticity treatment, but naturally derived products may present limitations related to immunogenicity and manufacturing variability. Recombinant botulinum toxin type A, produced by genetic engineering without complexing proteins, may provide improved product consistency. This Ib/II study evaluated the safety, tolerability, and preliminary efficacy of recombinant botulinum toxin type A in adults with post-stroke upper limb spasticity.This multicenter, seamless Ib/II clinical study included an open-label dose-escalation Ib phase and a randomized, double-blind, placebo-controlled II phase. Adult patients with post-stroke upper limb spasticity received a single intramuscular injection of recombinant botulinum toxin type A or placebo. The primary endpoint in Phase II was the change from baseline in the Modified Ashworth Scale (MAS) score of the primary target muscle group at Week 4. Secondary endpoints included MAS and Tardieu scale changes in individual muscle groups, Disability Assessment Scale (DAS), Physician's Global Assessment (PGA), and immunogenicity.The Ib phase showed improvements in MAS, DAS, and PGA, indicating an early efficacy signal. In Phase II, recombinant botulinum toxin type A produced a significant reduction in MAS score of the primary target muscle group at Week 4 compared with placebo, with effects sustained through Week 12. At Week 4, the PGA score in the Eveotox® group showed a statistically significant improvement compared with the placebo group. While MAS and PGA scores showed significant improvement, DAS functional scores did not differ statistically from the placebo group at week 4. The treatment was generally well tolerated, and low incidence of antibodies were observed.Recombinant botulinum toxin type A was safe and effective in reducing post-stroke upper limb spasticity after a single administration. These results support further Phase III clinical evaluation.

Background:Transcranial direct current stimulation (tDCS) may improve behavioral signs of consciousness in patients with disorders of consciousness (DoC), but evidence from randomized controlled trials (RCTs) and previous meta-analyses has remained inconsistent. We evaluated the efficacy and safety of tDCS in patients with DoC and explored potential effect modifiers. Methods:PubMed, Embase, Scopus, Web of Science, and the Cochrane Library were searched for RCTs comparing active tDCS with sham stimulation. For crossover trials, only first-period data were extracted. The primary outcome was the change in Coma Recovery Scale-Revised (CRS-R) score. Mean differences (MDs) with 95% confidence intervals (CIs) were pooled across studies. Subgroup analyses were performed according to baseline level of consciousness, etiology, disease duration, stimulation target, and total stimulation dose. Results:Fourteen trials including 330 patients were included. Active tDCS was associated with greater improvement in CRS-R change scores than sham stimulation (MD = 1.02, 95% CI 0.43-1.60; p < 0.001). A significant subgroup interaction was observed for etiology (p < 0.001), with significant improvements in patients with traumatic brain injury and cerebrovascular accident, but not in hypoxic-ischemic brain injury. Other analyses suggested trends toward improvement in minimally conscious state, left dorsolateral prefrontal cortex stimulation, and higher total stimulation dose, without significant between-subgroup differences. No definite tDCS-related serious adverse events were reported. Conclusion:tDCS may improve the level of consciousness in patients with DoC, with no definite tDCS-related serious adverse events identified. Treatment response may differ by etiology, but this finding requires confirmation because multiple subgroup comparisons were performed. Systematic review registration:Identifier CRD420261370518.

This prospective cohort study was designed to investigate and compare the effectiveness of rehabilitation training robots versus conventional rehabilitation training on stroke survivors by monitoring alterations in brain network of stroke patients before and after robot intervention. Between September 2020 and November 2021, stroke patients at four grade-A tertiary hospitals underwent limb rehabilitation training. Of the total of participants, 117 patients received conventional limb rehabilitation, 93 patients participated in upper-limb robot training, and 103 patients underwent lower-limb robot training. The measured outcomes included modified Barthel Index (MBI), Fugl-Meyer assessment subscale (FMA), and manual muscle testing (MMT). Functional magnetic resonance imaging (fMRI) was conducted on 30 patients to assess changes in the brain network. Data were mainly analyzed based on the Intention-to-Treat (ITT) principle. Post-interventional analysis utilizing linear mixed models in ITT analysis revealed that the robot training group had greater enhancements compared to the conventional limb rehabilitation training group. Notably, the shoulder flexor strength (P = 0.043) was significantly higher in the upper-limb group. On the other hand, hip flexor strength (P < 0.001), hip extensor strength (P < 0.001), knee extensor strength (P = 0.013), ankle dorsiflexion strength (P < 0.001) and ankle plantarflexor strength (P < 0.001) were significantly higher in the lower-limb group. In the upper-limb group, region-of-interest (ROI) -to-ROI analysis revealed enhanced functional connectivity between the left hemisphere’s motor control region and the auditory network. ROI-to-ROI analysis primarily showed enhanced interhemispheric functional connectivity in the lower-limb group, specifically between right the hemisphere’s motor control region (central opercular cortex) and left hemisphere’s primary motor area in the precentral gyrus. According to our research findings, upper- and lower-limb rehabilitation robots demonstrated great potential in promoting motor function recovery in stroke patients. Robot-assisted training offers an alternative treatment method with comparable efficacy to traditional rehabilitation. Large-scale randomized controlled trials are needed to confirm these results. Trial registration: The study was registered on the Chinese Clinical Trial Registry (ChiCTR1800019783).

Purpose:Accurate prediction of post-stroke upper limb motor recovery is crucial for developing stroke rehabilitation strategies. However, existing methods often focus on static predictions at a fixed post-stroke time point and fail to utilize unstructured textual data within electronic health records (EHRs). To overcome both limitations, we propose a new task which is to dynamically predict the recovery outcomes at variable time points based on the most recent EHR, and aim to address this task by leveraging the text in EHRs with uncertain knowledge graph (UKG) and large language model (LLM). Methods:The proposed method is developed using EHRs and their corresponding recovery outcomes at different follow-up time points (i.e., 3, 6 and 12 months post-stroke). We first transform EHRs comprising unstructured textual data, categorical data, and numerical data, into vector representations. Textual data enriched by UKG and LLM are embedded using a pretrained language model, and subsequently concatenated with the encoded one-hot representation of categorical data, and normalized numerical data. We then leverage a decision tree based model for feature selection, grouping features into distinct priority levels. We finally perform supervised learning to predict recovery outcomes, with a comparative evaluation of multiple models. Results:Extensive experiments demonstrate the superiority of the proposed method in different evaluation metrics, achieving 92.5% accuracy in dynamic predictions. After feature selection, the best model (i.e., Gradient Boosting Classifier) achieves a 7.9% increase in accuracy compared to the models using all features. Conclusion:Our study demonstrates that integrating UKG with LLM enables flexible and reliable post-stroke upper limb motor recovery prediction. By allowing dynamic predictions based on clinical needs and providing clear feature selection guidance, the proposed method has the potential for practical application to support the development of personalized rehabilitation strategies.

Despite advances in noninvasive neuromodulation for disorders of consciousness (DoC), the available evidence is inconclusive. We sought to elucidate the efficacy and safety of these interventions for DoC. We systematically searched Embase, EBSCO, CINAHL, Medline, PsycINFO, the Cochrane Library, and Web of Science from inception until 15 Mar, 2025, supplemented by manual searches from other sources. Randomised controlled trials (RCTs) comparing any noninvasive neuromodulation (e.g., transcranial direct current stimulation [tDCS], repetitive transcranial magnetic stimulation [rTMS], median nerve stimulation [MNS], trigeminal nerve stimulation [TNS], or transauricular vagus nerve stimulation [tVNS]) with sham control for DoC were selected. Relevant data were extracted. Primary efficacy outcome (change in levels of consciousness post intervention) and safety outcome (adverse events and dropout) were assessed. Effect sizes were pooled for standard pairwise meta-analyses using random-effects model and reported as Hedges’ g or risk ratio (RR) with 95

BACKGROUND:Disorders of consciousness (DoC) are characterized by a broad decline in background excitatory synaptic activity and varying levels of cerebral network disruption. Repetitive transcranial magnetic stimulation (rTMS), a neuromodulatory technique, is anticipated to assist the recovery of consciousness. Nonetheless, ongoing debates persist regarding its effectiveness, in light of the inconsistent results of recent research. OBJECTIVE:The purpose of this study is to investigate the efficacy of rTMS in promoting recovery of consciousness in patients with DoC and to probe its impact on activity of cerebral functional networks. METHODS:Forty-eight patients with DoC were included in this randomized controlled trial (Chinese Clinical Trial Registry: ChiCTR2100044930). Twenty-four patients in the control group accepted conventional therapy. Another 24 patients in the rTMS group received extra rTMS over the dorsolateral prefrontal cortex (DLPFC) once per workday during a 4-week intervention phase. Primary outcome was the proportion of patients emerging improvement on level of consciousness (LOC) based on coma recovery scale- revised (CRS-R) at the end of intervention. Furthermore, other behavioral scales such as the clinical global impression-improvement (CGI-I) and resting state-electroencephalography (rs-EEG) microstate were employed as secondary outcomes. Different microstates served as tools to detect the activity of respective corresponding resting state cerebral functional networks. RESULTS:In comparison to the control group, the rTMS group exhibited a higher proportion of patients emerging improvement on LOC at post-intervention, with a risk ratio of 3.06 (95 % CI 1.54 to 6.09, P = 0.001). The distribution of patients with each grade of CGI-I across the groups also implied a trend that favored the rTMS group (common odds ratio:0.20, 95 % CI 0.065 to 0.63, P = 0.006). With respect to microstate E, the rTMS group had a significantly reduced global explained variance (GEV) was observed in the rTMS group (Z = -2.61, Pbonf = 0.027). CONCLUSION:High-frequency rTMS over the DLPFC could promote recovery of consciousness in patients with DoC. It might get involved in modulating the balance among cerebral functional networks and facilitating consciousness recovery.

As an integral component of China's standardization system, rehabilitation medicine association standards play a pivotal role in regulating clinical practice, ensuring care quality, and nurturing rehabilitation professionals. Grounded in the Standardization Law of the People's Republic of China and drawing on the practical experience of standardization work by the Chinese Association of Rehabilitation Medicine, the formulation of the Guidelines for Standardization Work of Rehabilitation Medicine Association Standards aims to establish a systematic framework for the development of these standards and promote the standardized development of the rehabilitation medicine field. The guidelines detail the principles for the formulation of rehabilitation medicine association standards, scope of application, the qualifications of the entities involved, and the technical specifications. They highlight the importance of combining evidence-based practice with clinical experience in the development of these standards, clarify the fundamental principles of openness, transparency, and consensus, and outline the complete workflow from proposal, project approval, drafting, and solicitation of comments to final publication and periodic review, providing specific recommendations for the dissemination of the standards. By enhancing the quality of rehabilitation medicine association standards, the Guidelines will promote the standardization of rehabilitation medical services and advance the development of rehabilitation medicine in China.

Orofacial myofunctional therapy (OMT) has been recommended as a safe, effective, and low-cost option for treatment of obstructive sleep apnea–hypopnea syndrome (OSAHS). This study aims to evaluate the therapeutic effects of a WeChat mini-program-based OMT in adults with OSAHS compared to traditional home-based OMT. We hypothesize that patients trained with a WeChat mini-program-based OMT will show greater improvement in sleep quality, health-related quality of life, and exercise adherence than patients with traditional home-based rehabilitation therapy. This study is a single-center, prospective, assessor-blinded randomized controlled trial (RCT) conducted at the First Affiliated Hospital of Nanjing Medical University (Jiangsu Province Hospital). Patients in both groups received routine health education, with the intervention group additionally using a WeChat mini-program and the control group receiving traditional home-based OMT. The primary outcome measure is apnea–hypopnea index (AHI). Secondary outcome measures include lowest oxygen saturation (LSpO2), the Epworth Sleepiness Scale (ESS), the Pittsburgh Sleep Quality Index (PSQI), the Short-Form Health Survey-36 (SF-36), and exercise adherence. Outcomes will be assessed at baseline and 12 weeks post-intervention. This study attempts to evaluate the efficacy and safety of telerehabilitation among OSAHS patients in China, representing our efforts in the field of telemedicine. This RCT will provide valuable evidence for remoted home-based long-term management strategies for OSAHS patients. This study has received ethics approval from the Ethics Committee of the First Affiliated Hospital of Nanjing Medical University (Ref. No. 2022-SR-600). Findings will be disseminated in a peer-reviewed journal and presented at relevant conferences. ClinicalTrials.gov ChiCTR2300067637. Registered on January 16, 2023.

Spinal cord injury (SCI) is a severe condition that frequently leads to permanent disabilities and neurological dysfunction. Its progression is driven by a multifaceted pathophysiology, encompassing direct trauma, secondary injury cascades, and intricate cellular and molecular responses. While current therapies focus on alleviating symptoms and restoring functionality, achieving effective neural regeneration in the spinal cord continues to be a significant challenge. Hydrogels, recognized for their exceptional biocompatibility, conductivity, and injectability, have shown great potential as advanced scaffolds to support neuronal and axonal regeneration. Recently, these materials have attracted significant interest in the field of SCI rehabilitation research. This review concludes recent progress in hydrogel-based strategies for SCI rehabilitation, emphasizing their distinct properties, underlying mechanisms, and integration with bioactive molecules, stem cells, and complementary biomaterials. Hydrogels foster neuronal regeneration by providing a tailored microenvironment, while advanced features such as self-repair, electrical conductivity, and controlled drug release significantly enhance their therapeutic potential in experimental models. This review explores hydrogel technologies and their applications, underscoring their potential to address the challenges of SCI treatment and paving the way for future clinical implementation.

As an integral component of China's standardization system, rehabilitation medicine group standards play a pivotal role in regulating clinical practice, ensuring care quality, and nurturing rehabilitation professionals. Grounded in the Standardization Law of the People's Republic of China and drawing on the practical experience of the Chinese Association of Rehabilitation Medicine, the Guidelines for the Standardization of Rehabilitation Medicine Group Standards aim to establish a systematic framework for the development of these standards and foster the field's regulated development. The Guidelines detail the principles for the formulation of rehabilitation medicine group standards, their scope, the qualifications of the entities involved, and the technical specifications. They highlight the importance of combining evidence-based practices with clinical experience in the development of these standards, articulate the foundational principles of openness, transparency, and consensus, and outline the comprehensive workflow from proposal to final publication and periodic review, providing concrete recommendations for the dissemination of the standards. By enhancing the quality of rehabilitation medicine group standards, the Guidelines will promote the standardization of rehabilitation medical services and advance the development of rehabilitation medicine in China.

The present review was developed to critically evaluate the neuroprotective effects of edaravone for experimental rat models of spinal cord injury (SCI) and generalize the possible mechanisms. Systematic searches were carried out on databases including PubMed, Embase, Web of Science, Scopus, and Cochrane Library from their inception to March 2024. Controlled studies that assessed the neurological roles of edaravone on rats following SCI were selected. The Basso, Beattie, and Bresnahan (BBB) locomotor rating scale, residual white matter area, and malondialdehyde (MDA) level of the SCI rats were systematically searched by two reviewers. Ten eligible publications were included. Meta-analyses showed increased BBB scores in edaravone-treated rats compared with control ones. The effect size gradually increased from day 7 (seven studies, n = 246, weighted mean difference (WMD) = 1.96, 95% confidence interval (CI) = 1.23 to 2.68, P < 0.00001) to day 28 (seven studies, n = 222, WMD = 4.41, 95% CI = 3.19 to 5.63, P < 0.00001) after injury and then maintained stably in the following time. Meanwhile, edaravone treatment was associated with an amendment in the spared area of white matter and a lowering in the MDA expression in the lesion area. The subgroup analyses revealed that rats treated with edaravone exhibited superior locomotor recovery in compression injury models than contusion ones. In network analyses, the surface under the cumulative ranking curve gradually increased up to a dose of 5–6 mg/(kg·d) of edaravone, after which it plateaued. Mechanism analysis suggested edaravone can ameliorate oxidative stress, mitigate neuroinflammation, and counteract neuron apoptosis and ferroptosis via multiple signaling pathways to exert its neuroprotective effects. Collectively, with a protective effect and a systematic action mechanism, edaravone warrants further investigation in SCI research and treatment. Nonetheless, in light of the limitations in the included studies, the findings in this review should be interpreted with caution. https://www.crd.york.ac.uk/PROSPERO/view/CRD42022374914.

Background Current therapies for cognitive impairment, including Alzheimer's disease (AD) and mild cognitive impairment, are limited by a lack of universal treatment and adverse effects associated with polypharmacy. Investigating genetic and molecular mechanisms underlying cognitive decline is critical for the development of targeted therapeutics. Objective To identify causal genes and potential therapeutic targets for cognitive impairment through integrative genomic analyses. Methods Genome-wide association study data on cognitive impairment were combined with the expression quantitative trait loci (eQTL) data from the eQTLGen consortium. Mendelian randomization (MR) and colocalization analyses were employed to infer causal relationships. Gene Set Enrichment Analysis and Gene Set Variation Analysis evaluated the pathway and functional differences. Immune cell infiltration patterns and the immunometabolic pathways were assessed, followed by drug target prediction. Results MR analysis identified seven gene-eQTL pairs significantly associated with cognitive impairment. SMR colocalization prioritized three key genes: HNMT (histamine metabolism), TNFSF8 (inflammatory signaling), and S1PR5 (sphingolipid signaling). HNMT, TNFSF8, and S1PR5 had 39, 24, and 30 predicted targeted drugs, respectively, including arsenic trioxide, aspirin, and immunomodulators. Conclusions This study implicates HNMT, TNFSF8, and S1PR5 as potential therapeutic targets for cognitive impairment. Further validation is required to confirm their clinical relevance.

BackgroundPostoperative rehabilitation exercise training after percutaneous coronary intervention (PCI) is crucial for coronary heart disease (CHD) patients in restoring health and preventing recurrence, including high-intensity interval training (HIIT). However, the impact of HIIT on cardiopulmonary function, gut microbiome and metabolite remains underexplored.MethodsThis study included 60 patients with CHD who underwent percutaneous coronary intervention (PCI). Participants were divided into two groups: 33 in the moderate-intensity continuous training (MCT) group and 27 in the high-intensity interval training (HIIT) group. We assessed difference between two training in cardiopulmonary function, 6-minute walk test (6MWT) performance, biochemical indicators, plasma metabolites, and gut microbiome feature at baseline and after 3 months training. Furthermore, we analyzed 6MWT association to gut microbiome and metabolites with group differences.ResultsThe 6MWT showed significantly greater improvement in the HIIT group compared to the MCT group (P = 0.0024). Both groups showed reductions in low-density lipoprotein (LDL) levels and increases in peak oxygen uptake (VO2 peak) after training, but the HIIT group demonstrated a larger effect size in these measures. Moreover, subgroup analysis revealed that patients with a history of myocardial infarction (MI) in the HIIT group experienced a more substantial increase in VO2 peak compared to the MCT group (P = 0.04). In addition, we identified 29 gut microbial species and 30 plasma metabolites that were differentially enriched between the two groups, with some showing a significant impact on 6MWT performance.ConclusionsHigh-intensity interval training significantly improves 6MWT performance and exercise tolerance in cardiac rehabilitation patients, particularly enhancing VO2 peak in those with a history of MI. HIIT also appears to modulate the gut microbiome, increasing the abundance of Clostridiales and decreasing traumatic acid content, which may contribute to the observed improvements in exercise tolerance.

Introduction Prolonged disorders of consciousness (pDoC) are a catastrophic condition following brain injury with few therapeutic options. Transcutaneous auricular vagal nerve stimulation (taVNS), a safe, non-invasive intervention modulating thalamo-cortical connectivity and brain function, is a possible treatment option of pDoC. We developed a protocol for a randomised controlled study to evaluate the effectiveness of taVNS on consciousness recovery in patients with pDoC (TAVREC).Methods and analysis The TAVREC programme is a multicentre, triple-blind, randomised controlled trial with 4 weeks intervention followed by 4 weeks follow-up period. A minimum number of 116 eligible pDoC patients will be recruited and randomly receive either: (1) conventional therapy plus taVNS (30 s monophasic square current of pulse width 300 μs, frequency of 25 Hz and intensity of 1 mA followed by 30 s rest, 60 min, two times per day, for 4 weeks); or (2) conventional therapy plus taVNS placebo. Primary outcome of TAVREC is the rate of improved consciousness level based on the Coma Recovery Scale-Revised (CRS-R) at week 4. Secondary outcomes are CRS-R total and subscale scores, Glasgow Coma Scale score, Full Outline of UnResponsiveness score, ECG parameters, brainstem auditory evoked potential, upper somatosensory evoked potential, neuroimaging parameters from positron emission tomography/functional MRI, serum biomarkers associated with consciousness level and adverse events.Ethics and dissemination This study was reviewed and approved by the Research Ethics Committee of the First Affiliated Hospital of Nanjing Medical University (Reference number: 2023-SR-392). Findings will be disseminated in a peer-reviewed journal and presented at relevant conferences.Trial registration number ChiCTR2300073950.

Ischemic stroke is a major cause of disability and death worldwide, and its management requires urgent attention. Previous studies have shown that vagus nerve stimulation (VNS) exerts neuroprotection in ischemic stroke by inhibiting neuroinflammation and apoptosis. In this study, we evaluated the timing for VNS intervention in ischemic stroke, and the underlying mechanisms of VNS-induced neuroprotection. Mice were subjected to transient middle cerebral artery occlusion (tMCAO) for 60 min. The left vagus nerve at cervical level was exposed and attached to an electrode connected to a low-frequency electrical stimulator. Vagus nerve stimulation (VNS) was given for 60 min before, during and after tMCAO (Pre-VNS, Dur-VNS, Post-VNS). Neurological function was assessed 24 h after reperfusion. We found that all the three VNS significantly protected against the tMCAO-induced injury evidenced by improved neurological function and reduced infarct volume. Moreover, the Pre-VNS was the most effective against the ischemic injury. We found that tMCAO activated microglia in the ischemic core and penumbra regions of the brain, followed by the NLRP3 inflammasome activation-induced neuroinflammation, which finally triggered neuronal death. VNS treatment preserved α7nAChR expression in the penumbra regions, inhibited NLRP3 inflammasome activation and ensuing neuroinflammation, rescuing cerebral neurons. The role of α7nAChR in microglial NLRP3 inflammasome activation in ischemic stroke was further validated using genetic manipulations, including Chrna7 knockout mice and microglial Chrna7 overexpression mice, as well as pharmacological interventions using the α7nAChR inhibitor methyllycaconitine and agonist PNU-282987. Collectively, this study demonstrates the potential of VNS as a safe and effective strategy to treat ischemic stroke, and presents a new approach targeting microglial NLRP3 inflammasome, which might be therapeutic for other inflammation-related diseases.

Objective The purpose of the present study was to examine the association of oxidative stress markers with sarcopenia in the general United States population under the age of 60. Methods We used the National Health and Nutrition Examination Survey data from 2011‒2014 and performed Restricted Cubic Spline (RCS) plots, weighted multivariable logistic regression analysis to calculate ratio ratios and 95% Confidence Intervals, and subgroup analysis based on age, sex, hypertension, diabetes mellitus, and body mass index stratification to determine the association of markers of oxidative stress with the prevalence of sarcopenia. Results The present analysis included a total of 8,782 participants. Firstly, the RCS plots showed a roughly L-shaped curve association of total bilirubin and serum iron with a prevalence of sarcopenia. Secondly, albumin was negatively and linearly associated with the risk of sarcopenia. Finally, with the increase in gamma-glutamyl transferase, the prevalence of sarcopenia showed a trend of first rising and then declining as a result of the iron increase. Conclusions We demonstrated a nonlinear association between markers of oxidative stress and sarcopenia. The need to focus more on levels of oxidative stress in the body could provide better prevention strategies for sarcopenia.

Background:Disorders of consciousness (DoC) commonly occurs secondary to severe neurological injury. A considerable volume of research has explored the effectiveness of different non-invasive neuromodulation therapy (NINT) on awaking therapy, however, equivocal findings were reported. Objective:The aim of this study was to systematically investigate the effectiveness on level of consciousness of different NINT in patients with DoC and explore optimal stimulation parameters and characteristics of patients. Methods:PubMed, Embase, Web of Science, Scopus, and Cochrane central register of controlled trials were searched from their inception through November 2022. Randomized controlled trials, that investigated effectiveness on level of consciousness of NINT, were included. Mean difference (MD) with 95% confidence interval (CI) was evaluated as effect size. Risk of bias was assessed with revised Cochrane risk-of-bias tool. Results:A total of 15 randomized controlled trials with 345 patients were included. Meta-analysis was performed on 13 out of 15 reviewed trials indicating that transcranial Direct Current Stimulation (tDCS), Transcranial Magnetic Stimulation (TMS), and median nerve stimulation (MNS) all had a small but significant effect (MD 0.71 [95% CI 0.28, 1.13]; MD 1.51 [95% CI 0.87, 2.15]; MD 3.20 [95%CI: 1.45, 4.96]) on level of consciousness. Subgroup analyses revealed that patients with traumatic brain injury, higher initial level of consciousness (minimally conscious state), and shorter duration of prolonged DoC (subacute phase of DoC) reserved better awaking ability after tDCS. TMS also showed encouraging awaking effect when stimulation was applied on dorsolateral prefrontal cortex in patients with prolonged DoC. Conclusion:tDCS and TMS appear to be effective interventions for improving level of consciousness of patients with prolonged DoC. Subgroup analyses identified the key parameters required to enhance the effects of tDCS and TMS on level of consciousness. Etiology of DoC, initial level of consciousness, and phase of DoC could act as significant characteristics of patients related to the effectiveness of tDCS. Stimulation site could act as significant stimulation parameter related to the effectiveness of TMS. There is insufficient evidence to support the use of MNS in clinical practice to improve level of consciousness in patients with coma. Systematic review registration:https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=337780, identifier: CRD42022337780.

Spinal cord injury (SCI) is a catastrophic condition with few therapeutic options. Astaxanthin (AST), a natural nutritional supplement with powerful antioxidant activities, is finding its new application in the field of SCI. Here, we performed a systematic review to assess the neurological roles of AST in rats following SCI, and assessed the potential for clinical translation. Searches were conducted on PubMed, Embase, Cochrane Library, the Web of Science, China National Knowledge Infrastructure, WanFang data, Vip Journal Integration Platform, and SinoMed databases. Animal studies that evaluated the neurobiological roles of AST in a rat model of SCI were included. A total of 10 articles were included; most of them had moderate-to-high methodological quality, while the overall quality of evidence was not high. Generally, the meta-analyses revealed that rats treated with AST exhibited an increased Basso, Beattie, and Bresnahan (BBB) score compared with the controls, and the weighted mean differences (WMDs) between those two groups showed a gradual upward trend from days 7 (six studies, n = 88, WMD = 2.85, 95% CI = 1.83 to 3.87, p < 0.00001) to days 28 (five studies, n = 76, WMD = 6.42, 95% CI = 4.29 to 8.55, p < 0.00001) after treatment. AST treatment was associated with improved outcomes in spared white matter area, motor neuron survival, and SOD and MDA levels. Subgroup analyses indicated there were differences in the improvement of BBB scores between distinct injury types. The trial sequential analysis then firmly proved that AST could facilitate the locomotor recovery of rats following SCI. In addition, this review suggested that AST could modulate oxidative stress, neuroinflammation, neuron loss, and autophagy via multiple signaling pathways for treating SCI. Collectively, with a protective effect, good safety, and a systematic action mechanism, AST is a promising candidate for future clinical trials of SCI. Nonetheless, in light of the limitations of the included studies, larger and high-quality studies are needed for verification.

OBJECTIVE:Vagus nerve stimulation (VNS) plus rehabilitation (Rehab) has shown a potential effect on recovery with a stroke. We systematically synthesised studies examining VNS+Rehab for improving motor function, mental health and activities of daily living (ADL) postintervention and at the end of follow-up in patients with a stroke.METHODS:The search was performed in electronic databases EMBASE, Medline, EBSCO, Cochrane Library, PubMed, PsycINFO, CINAHL, CNKI, and WANFANG and three clinical trial registries from inception to February 2022. Randomised controlled trials (RCTs) applied VNS+Rehab in stroke were included.RESULTS:Seven RCTs involving 263 (analysed) participants was included. The effect size of VNS+Rehab over Rehab for motor function was medium postintervention (g=0.432; 95% CI 0.186 to 0.678) and large at the end of follow-up (g=0.840; 95% CI 0.288 to 1.392). No difference was found in the effect of VNS+Rehab over traditional rehabilitation for ADL, mental health or safety outcomes. Subgroup analyses revealed larger effects for patients received taVNS (transcutaneous auricular VNS) devices (at acute/subacute phase of stroke, with lower VNS stimulation frequency or pluses per session, greater VNS on-off time or sessions, higher VNS intervention weekly frequency).CONCLUSION:The results suggest VNS+Rehab showed better motor function outcomes in patients after stroke, while no better than Rehab on mental health or ADL. Combinations of phase of stroke, specific parameters of VNS and VNS intervention frequency are key modulators of VNS effects.TRIAL REGISTRATION NUMBER:CRD42022310194.

The successful use of exosomes in therapy after myocardial infarction depends on an improved understanding of their role in cardiac signaling and regulation. Here, we report that exosomes circulating after myocardial infarction (MI) carry LncRNA TUG1 which downregulates angiogenesis by disablement of the HIF-1α/VEGF-α axis and that this effect can be counterbalanced by remote ischemic conditioning (RIC). Rats with MI induced through left coronary artery ligation without (MI model) and with reperfusion (ischemia/reperfusion I/R model) were randomized to RIC, or MI (I/R) or sham-operated (SO) control. Data from one cohort study and one randomized-controlled trial of humans with MI were also utilized, the former involving patients who had not received percutaneous coronary intervention (PCI) and the latter patients with PCI. Exosome concentrations did not differ between intervention groups (RIC vs. control) in rats (MI and I/R model) as well as humans (with and without PCI). However, MI and I/R exosomes attenuated HIF-1α, VEGF-α, and endothelial function. LncRNA TUG1 was increased in MI and I/R exosomes, but decreased in SO and RIC exosomes. HIF-1α expression was downregulated with MI and I/R exosomes but increased with RIC exosomes. Exosome inhibition suppressed HIF-1α upregulation through RIC exosomes. VEGF-α was identified as HIF-1α-regulated target gene. Knockdown of HIF-1α decreased VEGF-α, endothelial cell capability, and tube formation. Overexpression of HIF-1α exerted opposite effects. Transfection and co-transfection of 293 T cells with exosome-inhibitor GW4869 and HIF-1α inhibitor si-HIF-1α confirmed the exosomal-LncRNA TUG1/HIF-1α/VEGF-α pathway. LncRNA TUG1 is a potential therapeutic target after MI with or without reperfusion through PCI.