SGLT2 inhibition, venous thrombolism, and death due to cardiac causes: a mediation Mendelian randomization study.

Objective: To investigate the causal role of venous thrombolism mediating sodium-glucose cotransporter 2 (SGLT2) inhibition in death due to cardiac causes using Mendelian randomization (MR). Methods: A two-sample two-step MR was used to determine (1) the causal effects of SGLT2 inhibition on death due to cardiac causes; (2) the causal effects of venous thrombolism on death due to cardiac causes; and (3) the mediation effects of venous thrombolism. Genetic proxies for SGLT2 inhibition were identified as variants in the SLC5A2 gene that were associated with both levels of gene expression and hemoglobin A1c. Additionally, employing MR to investigate the causal association between SGLT2 inhibition and cardiac arrest as well as coronary heart disease (CHD). Results: SGLT2 inhibition was associated with a lower risk of death due to cardiac causes (odds ratio [OR] = 0.983, [95% CI = 0.972, 0.993], P = 0.0016). Venous thrombolism was associated with death due to cardiac causes ([OR] = 1.031, [95% CI = 1.005, 1.057], P = 0.0199). Mediation analysis showed evidence of indirect effect of SGLT2 inhibition on death due to cardiac causes through venous thrombolism [ß = -0.0015, (95% CI = -0.0032 -0.0002), P = 0.042], with a mediated proportion of 8.9% (95% CI = 1.2%, 18.7%) of the total. Furthermore, SGLT2 inhibition was linked to a lower risk of cardiac arrest ([OR] = 0.097, [95% CI = 0.013, 0.742], P = 0.025). SGLT2 inhibition was linked to a lower risk of CHD ([OR] = 0.957, [95% CI = 0.932, 0.982], P = 0.0009). Conclusions: Our study identified the causal roles of SGLT2 inhibition in venous thrombolism. SGLT2 inhibition may influence death due to cardiac causes through venous thrombolism. Additionally, SGLT2 inhibition was associated with reduced risk of cardiac arrest and CHD.

The protective role of ginsenoside Rg3 in heart diseases and mental disorders.

Ginsenoside Rg3, a compound derived from Panax ginseng C. A. Mey., is increasingly recognized for its wide range of pharmacological effects. Under the worldwide healthcare challenges posed by heart diseases, Rg3 stands out as a key subject in modern research on Chinese herbal medicine, offering a novel approach to therapy. Mental illnesses are significant contributors to global disease mortality, and there is a well-established correlation between cardiac and psychiatric conditions. This connection is primarily due to dysfunctions in the sympathetic-adrenomedullary system (SAM), the hypothalamic-pituitary-adrenal axis, inflammation, oxidative stress, and brain-derived neurotrophic factor impairment. This review provides an in-depth analysis of Rg3's therapeutic benefits and its pharmacological actions in treating cardiac and mental health disorders respectively. Highlighting its potential for the management of these conditions, Rg3 emerges as a promising, multifunctional therapeutic agent.

Theta burst stimulation: what role does it play in stroke rehabilitation? A systematic review of the existing evidence.

Various post-stroke dysfunctions often result in poor long-term outcomes for stroke survivors, but the effect of conventional treatments is limited. In recent years, lots of studies have confirmed the effect of repetitive transcranial magnetic stimulation (rTMS) in stroke rehabilitation. As a new pattern of rTMS, theta burst stimulation (TBS) was proved recently to yield more pronounced and long-lasting after-effects than the conventional pattern at a shorter stimulation duration. To explore the role of TBS in stroke rehabilitation, this review summarizes the existing evidence from all the randomized controlled trials (RCTs) so far on the efficacy of TBS applied to different post-stroke dysfunctions, including cognitive impairment, visuospatial neglect, aphasia, dysphagia, spasticity, and motor dysfunction. Overall, TBS promotes the progress of stroke rehabilitation and may serve as a preferable alternative to traditional rTMS. However, it's hard to recommend a specific paradigm of TBS due to the limited number of current studies and their heterogeneity. Further high-quality clinical RCTs are needed to determine the optimal technical settings and intervention time in stroke survivors.

Intermittent theta burst stimulation for poststroke non-spatial attention deficit: a protocol of prospective, double-blinded, single-centre, randomised controlled trial in China.

INTRODUCTION: Attention deficit is the most common cognitive impairment after stroke, which can significantly hinder the recovery of both other cognitive domains and motor functions. Increasing evidence suggests that the left dorsolateral prefrontal cortex (DLPFC) is related to non-spatial attention functions, which indicates that it may be a promising target of repetitive transcranial magnetic stimulation (rTMS) for treating poststroke non-spatial attention deficit. Theta burst stimulation (TBS) is a modified pattern of rTMS that delivers shorter stimulation times and exhibits superior therapeutic efficacy. This study aims to provide evidence regarding the efficacy of intermittent TBS (iTBS) over the left DLPFC to improve poststroke non-spatial attention deficits and elucidate the potential neurophysiological mechanisms. METHODS AND ANALYSIS: In this single-centre, prospective, randomised, sham-controlled clinical trial, patients with non-spatial attention deficits (n=38) received 10 sessions of real iTBS (n=19) or sham iTBS (n=19) over the left DLPFC and a 30-min conventional attention training. Neuropsychological evaluations, electrophysiological examination and neuroimaging scan will be conducted at baseline, postintervention (second week) and 2-week follow-up (fourth week). The primary outcomes are the change in the Montreal Cognitive Assessment scores and the Digital Span Test scores from baseline to the end of the intervention (second week). The secondary outcomes comprise changes in magnetic resonance spectroscopy neuroimaging from baseline to the end of the intervention (second week) as well as attention test batteries (including tests of selective attention, sustained attention, divided attention and shifting attention) and ERP P300 from baseline to endpoint (fourth week). ETHICS AND DISSEMINATION: This study has been approved by the Institutional Ethical Committee of Tongji Hospital (ID: TJ-IRB20230879). All participants will sign the informed consent. Findings will be published in peer-reviewed journals and conference presentations. TRIAL REGISTRATION NUMBER: ChiCTR2300068669.

Exoskeleton-Assisted Sit-to-Stand Training Improves Lower-Limb Function Through Modifications of Muscle Synergies in Subacute Stroke Survivors.

Abnormal muscle synergies during sit-to-stand (STS) transitions have been observed post-stroke, which are associated with deteriorated lower-limb function and mobility. Although exoskeletons have been used in restoring lower-limb function, their effects on muscle synergies and lower-limb motor recovery remain unclear. Here, we characterized normal muscle synergy patterns during STS activity in ten healthy adults as a reference, comparing with pathological muscle synergy patterns in ten participants with subacute stroke. Moreover, we assessed the effects of a 3-week exoskeleton-assisted STS training intervention on muscle synergies and clinical scores in seven stroke survivors. We also investigated correlations between neuromuscular complexity of muscle synergies and clinical scores. Our results showed that the STS task involved three motor modules representing distinct biomechanical functions among healthy subjects. In contrast, stroke participants showed 3 abnormal modules for the paretic leg and 2 modules for the non-paretic leg. After the intervention, muscle synergies partially shifted towards the normal pattern observed in healthy subjects on the paretic side. On the non-paretic side, the synergy modules increased to three and neuromuscular coordination improved. Furthermore, the significant intervention-induced increases in Fugl-Meyer Assessment of Lower Extremity and Berg Balance Scale scores were associated with improved muscle synergies on the non-paretic side. These results indicate that the paretic side demonstrates abnormal changes in muscle synergies post-stroke, while the non-paretic side can synergistically adapt to post-stroke biomechanical deviations. Our data show that exoskeleton-based training improved lower-limb function post-stroke by inducing modifications in muscle synergies.

Altered frontoparietal activity in acoustic startle priming tasks during reticulospinal tract facilitation: An fNIRS study.

Background: Because it is one of the important pathways for promoting motor recovery after cortical injury, the function of the reticulospinal tract (RST) has received increasing attention in recent years. However, the central regulatory mechanism of RST facilitation and reduction of apparent response time is not well understood. Objectives: To explore the potential role of RST facilitation in the acoustic startle priming (ASP) paradigm and observe the cortical changes induced by ASP reaching tasks. Methods: Twenty healthy participants were included in this study. The reaching tasks were performed with their left and right hands. Participants were instructed to get ready after the warning cue and complete the reach as soon as they heard the Go cue. Half of the testing trials were set as control trials with an 80-dB Go cue. The other half of the trials had the Go cue replaced with 114-dB white noise to evoke the StartleReact effect, inducing reticulospinal tract facilitation. The response of the bilateral sternocleidomastoid muscle (SCM) and the anterior deltoid was recorded via surface electromyography. Startle trials were labeled as exhibiting a positive or negative StartleReact effect, according to whether the SCM was activated early (30-130 ms after the Go cue) or late, respectively. Functional near-infrared spectroscopy was used to synchronously record the oxyhemoglobin and deoxyhemoglobin fluctuations in bilateral motor-related cortical regions. The ß values representing cortical responses were estimated via the statistical parametric mapping technique and included in the final analyses. Results: Separate analyses of data from movements of the left or right side revealed significant activation of the right dorsolateral prefrontal cortex during RST facilitation. Moreover, left frontopolar cortex activation was greater in positive startle trials than in control or negative startle trials during left-side movements. Furthermore, decreased activity of the ipsilateral primary motor cortex in positive startle trials during ASP reaching tasks was observed. Conclusion: The right dorsolateral prefrontal cortex and the frontoparietal network to which it belongs may be the regulatory center for the StartleReact effect and RST facilitation. In addition, the ascending reticular activating system may be involved. The decreased activity of the ipsilateral primary motor cortex suggests enhanced inhibition of the non-moving side during the ASP reaching task. These findings provide further insight into the SE and into RST facilitation.

Epidemiology of autism spectrum disorders: Global burden of disease 2019 and bibliometric analysis of risk factors.

Background: To explore the geographical pattern and temporal trend of autism spectrum disorders (ASD) epidemiology from 1990 to 2019, and perform a bibliometric analysis of risk factors for ASD. Methods: In this study, ASD epidemiology was estimated with prevalence, incidence, and disability-adjusted life-years (DALYs) of 204 countries and territories by sex, location, and sociodemographic index (SDI). Age-standardized rate (ASR) and estimated annual percentage change (EAPC) were used to quantify ASD temporal trends. Besides, the study performed a bibliometric analysis of ASD risk factors since 1990. Publications published were downloaded from the Web of Science Core Collection database, and were analyzed using CiteSpace. Results: Globally, there were estimated 28.3 million ASD prevalent cases (ASR, 369.4 per 100,000 populations), 603,790 incident cases (ASR, 9.3 per 100,000 populations) and 4.3 million DALYs (ASR, 56.3 per 100,000 populations) in 2019. Increases of autism spectrum disorders were noted in prevalent cases (39.3%), incidence (0.1%), and DALYs (38.7%) from 1990 to 2019. Age-standardized rates and EAPC showed stable trend worldwide over time. A total of 3,991 articles were retrieved from Web of Science, of which 3,590 were obtained for analysis after removing duplicate literatures. "Rehabilitation", "Genetics & Heredity", "Nanoscience & Nanotechnology", "Biochemistry & Molecular biology", "Psychology", "Neurosciences", and "Environmental Sciences" were the hotspots and frontier disciplines of ASD risk factors. Conclusions: Disease burden and risk factors of autism spectrum disorders remain global public health challenge since 1990 according to the GBD epidemiological estimates and bibliometric analysis. The findings help policy makers formulate public health policies concerning prevention targeted for risk factors, early diagnosis and life-long healthcare service of ASD. Increasing knowledge concerning the public awareness of risk factors is also warranted to address global ASD problem.

Immediate and short-term effects of continuous theta burst transcranial magnetic stimulation over contralesional premotor area on post-stroke spasticity in patients with severe hemiplegia: Study protocol for a randomized controlled trial.

Background: Post-stroke spasticity is an important complication that greatly affects survivors' functional prognosis and daily activities. Increasing evidence points to aberrant contralesional neuromodulation compensation after brain injury as a possible culprit for increased spasticity in patients with severe stroke. Hyperactivity of the contralesional premotor area (cPMA) was supposed to be highly correlated with this progression. This study aims to demonstrate the immediate and short-term efficacy of continuous theta-burst stimulation (cTBS) targeting cPMA on upper limb spasticity in severe subacute stroke patients. Methods: This trial is a single-center, prospective, three-group randomized controlled trial. Forty-five eligible patients will be recruited and randomized into three groups: the sham-cTBS group (sham cTBS targeting contralesional PMA), the cTBS-cM1 group (cTBS targeting contralesional M1), and the cTBS-cPMA group (cTBS targeting contralesional PMA). All subjects will undergo comprehensive rehabilitation and the corresponding cTBS interventions once a day, five times a week for 4 weeks. Clinical scales, neurophysiological examinations, and neuroimaging will be used as evaluation tools in this study. As the primary outcome, clinical performance on muscle spasticity of elbow/wrist flexor/extensors and upper-limb motor function will be evaluated with the modified Ashworth scale and the Fugl-Meyer Assessment of Upper Extremity Scale, respectively. These scale scores will be collected at baseline, after 4 weeks of treatment, and at follow-up. The secondary outcomes were neurophysiological examinations and Neuroimaging. In neurophysiological examinations, motor evoked potentials, startle reflex, and H reflexes will be used to assess the excitability of the subject's motor cortex, reticulospinal pathway, and spinal motor neurons, respectively. Results of them will be recorded before and after the first cTBS treatment, at post-intervention (at 4 weeks), and at follow-up (at 8 weeks). Neuroimaging tests with diffusion tensor imaging for all participants will be evaluated at baseline and after the 4-week treatment. Discussion: Based on the latest research progress on post-stroke spasticity, we innovatively propose a new neuromodulation target for improving post-stroke spasticity via cTBS. We expected that cTBS targeting cPMA would have significant immediate and short-term effects on spasticity and related neural pathways. The effect of cTBS-cPMA may be better than that of cTBS via conventional cM1. The results of our study will provide robust support for the application of cTBS neuromodulation in post-stroke spasticity after a severe stroke. Clinical trial registration: This trial was registered with chictr.org.cn on June 13, 2022 (protocol version). http://www.chictr.org.cn/showproj.aspx?proj=171759.

Startle Increases the Incidence of Anticipatory Muscle Activations but Does Not Change the Task-Specific Muscle Onset for Patients After Subacute Stroke.

Objectives: To demonstrate the task-specificities of anticipatory muscle activations (AMAs) among different forward-reaching tasks and to explore the StartleReact Effect (SE) on AMAs in occurrence proportions, AMA onset latency or amplitude within these tasks in both healthy and stroke population. Methods: Ten healthy and ten stroke subjects were recruited. Participants were asked to complete the three forward-reaching tasks (reaching, reaching to grasp a ball or cup) on the left and right hand, respectively, with two different starting signals (warning-Go, 80 dB and warning-startle, 114 dB). The surface electromyography of anterior deltoid (AD), flexor carpi radialis (FCR), and extensor carpi radialis (ECR) on the moving side was recorded together with signals from bilateral sternocleidomastoid muscles (SCM), lower trapezius (LT), latissimus dorsi (LD), and tibialis anterior (TA). Proportions of valid trials, the incidence of SE, AMA incidence of each muscle, and their onset latency and amplitude were involved in analyses. The differences of these variables across different move sides (healthy, non-paretic, and paretic), normal or startle conditions, and the three tasks were explored. The ECR AMA onset was selected to further explore the SE on the incidence of AMAs. Results: Comparisons between move sides revealed a widespread AMA dysfunction in subacute stroke survivors, which was manifested as lower AMA onset incidence, changed onset latency, and smaller amplitude of AMAs in bilateral muscles. However, a significant effect of different tasks was only observed in AMA onset latency of muscle ECR (F = 3.56, p = 0.03, η 2 p = 0.011), but the significance disappeared in the subsequent analysis of the stroke subjects only (p > 0.05). Moreover, the following post-hoc comparison indicated significant early AMA onsets of ECR in task cup when comparing with reach (p < 0.01). For different stimuli conditions, a significance was only revealed on shortened premotor reaction time under startle for all participants (F = 60.68, p < 0.001, η p 2 = 0.056). Furthermore, stroke survivors had a significantly lower incidence of SE than healthy subjects under startle (p < 0.01). But all performed a higher incidence of ECR AMA onset (p < 0.05) than with normal signal. In addition, the incidence of ECR AMAs of both non-paretic and paretic sides could be increased significantly via startle (p ≤ 0.02). Conclusions: Healthy people have task-specific AMAs of muscle ECR when they perform forward-reaching tasks with different hand manipulations. However, this task-specific adjustment is lost in subacute stroke survivors. SE can improve the incidence of AMAs for all subjects in the forward-reaching tasks involving precision manipulations, but not change AMA onset latency and amplitude.