White Matter Hyperintensities on Post-Stroke Balance and Gait Recovery: A Prospective Cohort Study Protocol.

INTRODUCTION: White matter hyperintensities (WMH) are commonly associated with balance and gait disturbances. Little is known whether WMH may affect post-stroke balance and gait recovery. We aim to investigate the association of post-stroke balance and gait recovery with imaging marker of WMH on magnetic resonance imaging (MRI). METHODS: This prospective cohort study will enroll consecutive patients with first-ever ischemic hemisphere stroke, between September 2023 and December 2024. Clinical data will be collected on day 30±3 and at 3-month after stroke onset. WMH on FLAIR are graded according to the modified Fazekas scale. Resting-state functional MRI (rs-fMRI) and diffusion tensor imaging (DTI) will be acquired to evaluate functional and structural connectivity. The primary endpoint is balance recovery, defined as a Postural Assessment Scale for Stroke score of 32 or higher at 3-month. The secondary endpoint is gait recovery, assessed using the modified Fugl-Meyer Gait Assessment at 3-month. We will investigate the association of post-stroke balance and gait recovery with WMH severity as well as WMH-related functional and structural connectivity. CONCLUSION: The study may contribute to clarify the effect of WMH on post-stroke balance and gait disorder recovery.

Orthogroup and phylotranscriptomic analyses identify transcription factors involved in the plant cold response: A case study of Arabidopsis BBX29.

C-repeat binding factors (CBFs) are well-known transcription factors (TFs) that regulate plant cold acclimation. RNA sequencing (RNA-seq) data from diverse plant species provide opportunities to identify other TFs involved in the cold response. However, this task is challenging because gene gain and loss has led to an intertwined community of co-orthologs and in-paralogs between and within species. Using orthogroup (closely related homologs) analysis, we identified 10,549 orthogroups in five representative eudicots. A phylotranscriptomic analysis of cold-treated seedlings from eudicots identified 35 high-confidence conserved cold-responsive transcription factor orthogroups (CoCoFos). These 35 CoCoFos included the well-known cold-responsive regulators CBFs, HSFC1, ZAT6/10, and CZF1 among others. We used Arabidopsis BBX29 for experimental validation. Expression and genetic analyses showed that cold-induction of BBX29 is CBF- and abscisic acid-independent, and BBX29 is a negative regulator of cold tolerance. Integrative RNA-seq and Cleavage Under Targets and Tagmentation followed by sequencing analyses revealed that BBX29 represses a set of cold-induced TFs (ZAT12, PRR9, RVE1, MYB96, etc.). Altogether, our analysis yielded a library of eudicot CoCoFos and demonstrated that BBX29 is a negative regulator of cold tolerance in Arabidopsis.

A phylotranscriptomic dataset of angiosperm species under cold stress.

Angiosperms are one of the most diverse and abundant plant groups that are widely distributed on Earth, from tropical to temperate and polar zones. The wide distribution of angiosperms may be attributed to the evolution of sophisticated mechanisms of environmental adaptability, including cold tolerance. Since the development of high-throughput sequencing, transcriptome has been widely utilized to gain insights into the molecular mechanisms of plants in response to cold stress. However, previous studies generally focused on single or two species, and comparative transcriptome analyses for multispecies responding to cold stress were limited. In this study, we selected 11 representative angiosperm species, performed phylotranscriptome experiments at four time points before and after cold stress, and presented a profile of cold-induced transcriptome changes in angiosperms. Our multispecies cold-responsive RNA-seq datasets provide valuable references for exploring conserved and evolutionary mechanisms of angiosperms in adaptation to cold stress.

Treadmill exercise exerts a synergistic effect with bone marrow mesenchymal stem cell-derived exosomes on neuronal apoptosis and synaptic-axonal remodeling.

Treadmill exercise and mesenchymal stem cell transplantation are both practical and effective methods for the treatment of cerebral ischemia. However, whether there is a synergistic effect between the two remains unclear. In this study, we established rat models of ischemia/reperfusion injury by occlusion of the middle cerebral artery for 2 hours and reperfusion for 24 hours. Rat models were perfused with bone marrow mesenchymal stem cell-derived exosomes (MSC-exos) via the tail vein and underwent 14 successive days of treadmill exercise. Neurological assessment, histopathology, and immunohistochemistry results revealed decreased neuronal apoptosis and cerebral infarct volume, evident synaptic formation and axonal regeneration, and remarkably recovered neurological function in rats subjected to treadmill exercise and MSC-exos treatment. These effects were superior to those in rats subjected to treadmill exercise or MSC-exos treatment alone. Mechanistically, further investigation revealed that the activation of JNK1/c-Jun signaling pathways regulated neuronal apoptosis and synaptic-axonal remodeling. These findings suggest that treadmill exercise may exhibit a synergistic effect with MSC-exos treatment, which may be related to activation of the JNK1/c-Jun signaling pathway. This study provides novel theoretical evidence for the clinical application of treadmill exercise combined with MSC-exos treatment for ischemic cerebrovascular disease.

Psychological stress and coping strategies among frontline healthcare workers supporting patients with coronavirus disease 2019: a retrospective study and literature review.

BACKGROUND: The coronavirus disease 2019 (COVID-19) outbreak might have a psychological impact on frontline healthcare workers. However, the effectiveness of coping strategies was less reported. OBJECTIVES: We aimed to investigate the sources of stress and coping strategies among frontline healthcare workers fighting against COVID-19. We also performed a literature review regarding the effects of coping methods on psychological health in this population. METHODS: We included frontline healthcare workers who completed an online survey using self-made psychological stress questionnaires in a cross-sectional study. We evaluated the association between potential factors and high-stressed status using a logistic regression model. We performed the principal component analysis with varimax rotation for factor analysis. We also performed a systematic review of published randomized controlled studies that reported the effects of coping methods on psychological health in COVID-19 healthcare workers. RESULTS: We included 107 [32 (29-36) years] respondents in the final analysis, with a response rate of 80.5%. A total of 41 (38.3%) respondents were high-stressed. Compared with the low-stressed respondents, those with high-stress were less likely to be male (46.3% versus 72.7%, p = 0.006), nurses (36.6% versus 80.3%, p < 0.001), and more likely to have higher professional titles (p = 0.008). The sources of high-stress in frontline healthcare workers were categorized into 'work factor', 'personal factor', and 'role factor'. A narrative synthesis of the randomized controlled studies revealed that most of the coping methods could improve the psychological stress in healthcare workers during the COVID-19 pandemic. CONCLUSION: Our findings suggest that some frontline healthcare workers experienced psychological stress during the early pandemic. Effective coping strategies are required to help relieve the stress in this population.

Determinants for a low dose of alteplase and its relationship to a lower intracerebral bleeding risk in acute ischemic stroke.

Background: Factors for the utilization of intravenous thrombolysis with a low-dose of alteplase (0.6mg/kg) and whether the low-dose of alteplase could reduce the risk of intracerebral bleeding in acute ischemic stroke (AIS) remains uncertain. Aims: We aimed to investigate determinants for the utilization of intravenous thrombolysis with a low-dose of alteplase. We further assessed the association between the low-dose of alteplase and the intracerebral bleeding risk in AIS patients. Method: We included AIS patients who received intravenous thrombolysis using alteplase in this multicenter retrospective observational study. We investigated the association between baseline characteristics and the utilization of a low-dose of alteplase to identify determinants. We assessed the association of the low-dose of alteplase with the risk of symptomatic intracranial hemorrhage (sICH) using a multivariable logistic regression model. We further compared the rate of sICH and any ICH in patients in the low-dose group to those in the standard-dose group, using propensity score-matching data. Results: A total of 506 AIS patients were included in this study. The mean age was 67 (interquartile range [IQR] 59-75), and 178 (35.2%) were women. A total of 96 patients were treated with the low-dose. Age (adjusted odds ratio [OR] 1.02, 95% confidence interval [CI] 1.00 -1.04, p = 0.042), having a previous ischemic stroke (adjusted OR 2.01, 95%CI 1.11 - 3.64 p = 0.021) and increasing baseline systolic blood pressure (adjusted OR 1.12, 95%CI 1.00 - 1.26, p = 0.049) were determinants for the utilization of the low-dose. Multivariable logistic regression analysis showed that the low-dose was significantly associated with a reduced risk of sICH (adjusted OR 0.13, 95%CI 0.03 - 0.62, p = 0.01). Propensity score analysis showed that the rate of sICH was significantly lower in the low-dose group compared to standard-dose group (2 [2.3%] vs 10 [11.4%], p = 0.032). There was no significant difference in the rate of any ICH between two groups (14 [15.9%] vs 18 [20.5%], p = 0.434). Conclusions: Patients with increasing age, a higher baseline systolic blood pressure, and previous ischemic stroke were at a higher odd of receiving a low-dose of alteplase. The low-dose was associated with a lower risk of developing symptomatic intracranial hemorrhage.

Association Between Previous Stroke and Severe COVID-19: A Retrospective Cohort Study and an Overall Review of Meta-Analysis.

Objective: The objective of this study was to investigate the association between previous stroke and the risk of severe coronavirus disease 2019 (COVID-19). Methods: We included 164 (61.8 ± 13.6 years) patients with COVID-19 in a retrospective study. We evaluated the unadjusted and adjusted associations between previous stroke and severe COVID-19, using a Cox regression model. We conducted an overall review of systematic review and meta-analysis to investigate the relationship of previous stroke with the unfavorable COVID-19 outcomes. Results: The rate of severe COVID-19 in patients with previous stroke was 28.37 per 1,000 patient days (95% confidence interval [CI]: 10.65-75.59), compared to 3.94 per 1,000 patient days (95% CI: 2.66-5.82) in those without previous stroke (p < 0.001). Previous stroke was significantly associated with severe COVID-19 using a Cox regression model (unadjusted [hazard ratio, HR]: 6.98, 95% CI: 2.42-20.16, p < 0.001; adjusted HR [per additional 10 years]: 4.62, 95% CI: 1.52-14.04, p = 0.007). An overall review of systematic review and meta-analysis showed that previous stroke was significantly associated with severe COVID-19, mortality, need for intensive care unit admission, use of mechanical ventilation, and an unfavorable composite outcome. Conclusion: Previous stroke seems to influence the course of COVID-19 infection; such patients are at high risk of severe COVID-19 and might benefit from early hospital treatment measures and preventive strategies.

Elabela Attenuates the TGF-ß1-Induced Epithelial-Mesenchymal Transition of Peritoneal Mesothelial Cells in Patients Receiving Peritoneal Dialysis.

Peritoneal fibrosis (PF), a common complication in patients receiving peritoneal dialysis (PD), is primarily caused by the epithelial-mesenchymal transition (EMT) of human peritoneal mesothelial cells (HPMCs). PF is the main reason for patients on PD to withdraw from PD. Effective treatment is unavailable for this complication at present. Elabela (ELA) is a polypeptide hormone secreted by the vascular endothelium and kidney. Peptide hormones ELA and apelin (APLN) have various protective effects on the cardiovascular and urinary systems and have potential therapeutic effects on organ fibrosis. ELA and APLN are less studied in PD population. Here, we aimed to investigate the clinical significance of ELA in patients on PD and to evaluate the therapeutic effect of ELA on EMT of HPMCs. Compared with those in patients with stage 5 chronic kidney disease who are not on dialysis, serum ELA levels in patients on PD increased with the improvement of residual renal function at PD duration <36 months and decreased to pre-dialysis levels at PD duration ≥36 months, suggesting that dialysis duration is the main risk factor affecting serum ELA levels in patients on PD. In addition, serum APLN levels decreased in the early stage of PD and recovered to the pre-dialysis level with the prolongation of dialysis time. Notably, serum APLN levels were positively correlated with dialysis duration in patients undergoing PD. To establish the EMT model, we stimulated HPMCs using transforming growth factor-beta 1 (TGF-ß1) in cell experiments performed in vitro. ELA-32 treatment reversed the TGF-ß1-induced reduction in the expression of the epithelial cell marker and suppressed the expression of mesenchymal cell markers by inhibiting the phosphorylation of SMAD2/3, ERK1/2, and AKT. Therefore, our findings imply that ELA-32 can interfere with the EMT of HPMCs by inhibiting the activation of the TGF-ß/SMAD2/3, ERK1/2, and AKT pathways, providing novel insights on the potential therapeutic use of ELA for treating PD-related PF.

The Effect of Cerebellar Repetitive Transcranial Magnetic Stimulation on Dysphagia due to Posterior Circulation Stroke, a Randomized Controlled Trial Protocol.

INTRODUCTION: Cerebellum might be active during the task of swallowing. Little is known whether cerebellar repetitive transcranial magnetic stimulation (rTMS) could improve post-stroke dysphagia (PSD) due to occlusion in the posterior circulation. This paper describes the rationale and design of a randomized controlled trial that aims to determine the effect of cerebellar rTMS on dysphagia due to posterior circulation stroke. METHODS AND ANALYSIS: Thirty patients with PSD due to occlusion in the posterior circulation will be randomly divided to receive real (n = 20) or sham (n = 10) cerebellar rTMS. Patients in the real rTMS group will receive 250 pulses rTMS at a low intensity with 10 Hz frequency for 10 days (five consecutive days per week). The severity of dysphagia will be assessed with videofluoroscopic swallowing study (VFSS) using the Rosenbek penetration aspiration scale (PAS), the pharyngeal constriction ratio (PCR), and the dysphagia outcome and severity scale (DOSS) before and immediately after the last session and then again after 1 and 3 months. The functional magnetic resonance imaging (fMRI) will be assessed before and after the last session and then again after 1 month and 3 months. The primary outcome is the improvement of swallowing function determined by PAS, PCR, and DOSS. The secondary outcomes include changes in brain connectivity network detected using fMRI. DISCUSSION: This study will determine whether cerebellar rTMS improves dysphagia due to posterior circulation stroke in Chinese patients. Our findings will contribute to a new approach for swallowing function recovery after posterior circulation stroke.

Total Cerebral Small Vessel Disease Score and Cerebral Bleeding Risk in Patients With Acute Stroke Treated With Intravenous Thrombolysis.

Objective: The aim of this study was to investigate the association of total cerebral small vessel disease (cSVD) score with the risk of intracerebral hemorrhage (ICH) in patients with acute ischemic stroke who received intravenous thrombolysis (IVT) using recombinant tissue-plasminogen activator (rt-PA). Methods: We retrospectively reviewed clinical data from two stroke registries of patients with acute ischemic stroke treated with IVT. We assessed the baseline magnetic resonance (MR) visible cSVD markers and total cSVD score (ranging from 0 to 4) between patients with and without ICH after IVT. Logistic regression analysis was used to determine the association of total cSVD score with the risk of ICH after IVT, adjusted for cofounders selected by least absolute shrinkage and selection operator (LASSO). We additionally performed an E-value analysis to fully explain away a specific exposure-outcome association. Receiver operating characteristic (ROC) curve analysis was used to quantify the predictive potential of the total cSVD score for any ICH after IVT. Results: Among 271 eligible patients, 55 (20.3%) patients experienced any ICH, 16 (5.9%) patients experienced a symptomatic ICH (sICH), and 5 (1.85%) patients had remote intracranial parenchymal hemorrhage (rPH). Logistic regression analysis showed that the risk of any ICH increased with increasing cSVD score [per unit increase, adjusted odds ratio (OR) 2.03, 95% CI 1.22-3.41, P = 0.007]. Sensitivity analyses using E-value revealed that it would need moderately robust unobserved confounding to render the exposure-outcome (cSVD-any ICH) association null. ROC analysis showed that compared with the National Institutes of Health Stroke Scale (NIHSS) score alone, a combination of cSVD and NIHSS score had a larger area under the curve for any ICH (0.811, 95% CI 0.756-0.866 vs. 0.784, 95% CI 0.723-0.846, P = 0.0004). Conclusion: The total cSVD score is associated with an increased risk of any ICH after IVT and improves prediction for any ICH compared with NIHSS alone.

Six-month follow-up of functional status in discharged patients with coronavirus disease 2019.

BACKGROUND: The long-term functional outcome of discharged patients with coronavirus disease 2019 (COVID-19) remains unresolved. We aimed to describe a 6-month follow-up of functional status of COVID-19 survivors. METHODS: We reviewed the data of COVID-19 patients who had been consecutively admitted to the Tumor Center of Union Hospital (Wuhan, China) between 15 February and 14 March 2020. We quantified a 6-month functional outcome reflecting symptoms and disability in COVID-19 survivors using a post-COVID-19 functional status scale ranging from 0 to 4 (PCFS). We examined the risk factors for the incomplete functional status defined as a PCFS > 0 at a 6-month follow-up after discharge. RESULTS: We included a total of 95 COVID-19 survivors with a median age of 62 (IQR 53-69) who had a complete functional status (PCFS grade 0) at baseline in this retrospective observational study. At 6-month follow-up, 67 (70.5%) patients had a complete functional outcome (grade 0), 9 (9.5%) had a negligible limited function (grade 1), 12 (12.6%) had a mild limited function (grade 2), 7 (7.4%) had moderate limited function (grade 3). Univariable logistic regression analysis showed a significant association between the onset symptoms of muscle or joint pain and an increased risk of incomplete function (unadjusted OR 4.06, 95% CI 1.33-12.37). This association remained after adjustment for age and admission delay (adjusted OR 3.39, 95% CI 1.06-10.81, p = 0.039). CONCLUSIONS: A small proportion of discharged COVID-19 patients may have an incomplete functional outcome at a 6-month follow-up; intervention strategies are required.

Selective targeting of MYC mRNA by stabilized antisense oligonucleotides.

MYC is a prolific proto-oncogene driving the malignant behaviors of numerous common cancers, yet potent and selective cell-permeable inhibitors of MYC remain elusive. In order to ultimately realize the goal of therapeutic MYC inhibition in cancer, we have initiated discovery chemistry efforts aimed at inhibiting MYC translation. Here we describe a series of conformationally stabilized synthetic antisense oligonucleotides designed to target MYC mRNA (MYCASOs). To support bioactivity, we designed and synthesized this focused library of MYCASOs incorporating locked nucleic acid (LNA) bases at the 5'- and 3'-ends, a phosphorothioate backbone, and internal DNA bases. Treatment of MYC-expressing cancer cells with MYCASOs leads to a potent decrease in MYC mRNA and protein levels. Cleaved MYC mRNA in MYCASO-treated cells is detected with a sensitive 5' Rapid Amplification of cDNA Ends (RACE) assay. MYCASO treatment of cancer cell lines leads to significant inhibition of cellular proliferation while specifically perturbing MYC-driven gene expression signatures. In a MYC-induced model of hepatocellular carcinoma, MYCASO treatment decreases MYC protein levels within tumors, decreases tumor burden, and improves overall survival. MYCASOs represent a new chemical tool for in vitro and in vivo modulation of MYC activity, and promising therapeutic agents for MYC-addicted tumors.

Does pre-existent physical inactivity have a role in the severity of COVID-19?

BACKGROUND AND AIMS: Physical inactivity is considered an important lifestyle factor for overweight and cardiovascular disease. We aimed to investigate the association between pre-existent physical inactivity and the risk of severe coronavirus disease 2019 (COVID-19). METHODS: We included 164 (61.8 ± 13.6 years) patients with COVID-19 who were admitted between 15 February and 14 March 2020 in this retrospective study. We evaluated the association between pre-existent physical inactivity and severe COVID-19 using a logistic regression model. RESULTS: Of 164 eligible patients with COVID-19, 103 (62.8%) were reported to be physically inactive. Univariable logistic regression analysis showed that physical inactivity was associated with an increased risk of severe COVID-19 [unadjusted odds ratio (OR) 6.53, 95% confidence interval (CI) 1.88-22.62]. In the multivariable regression analysis, physical inactivity remained significantly associated with an increased risk of severe COVID-19 (adjusted OR 4.12, 95% CI 1.12-15.14) after adjustment for age, sex, stroke, and overweight. CONCLUSION: Our data showed that pre-existent physical inactivity was associated with an increased risk of experiencing severe COVID-19. Our findings indicate that people should be encouraged to keep physically active to be at a lower risk of experiencing a severe illness when COVID-19 infection seems unpredicted.The reviews of this paper are available via the supplemental material section.