Reasons and experience for patients with amyotrophic lateral sclerosis using traditional Chinese medicine: a CARE-TCM based mixed method study.

BACKGROUND AND AIM: Traditional Chinese medicine (TCM) is widely used by patients with amyotrophic lateral sclerosis (ALS). However, their reasons and experience in using TCM have received insufficient attention. Therefore, we conducted a mixed method study to gain insights into this issue. MATERIALS AND METHODS: This study was conducted on the basis of the China Amyotrophic Lateral Sclerosis Registry of Patients with Traditional Chinese Medicine (CARE-TCM). Data were collected from Dongzhimen Hospital through a mixed method approach, including a questionnaire and a semi-structured interview. Patients with ALS who were using TCM when they were initially registered with CARE-TCM and who had been followed-up for over six months were recruited. The questionnaires' outcomes were statistically outlined, and the interview transcripts were thematically analysed to identify themes and sub-themes. RESULTS: Fifty-two and sixteen patients were included in the questionnaire and semi-structured interview groups, respectively. Patients used TCM with the hope of regulating their body holistically to improve nonmotor symptoms and quality of life (QOL). Those who recognised TCM as ineffective tended to discontinue it after a three-month trial period. Although quality was a major concern, herbal medicine (HM) was the most frequently used modality among all participants (n = 52), with the majority (n = 44, 84.6%) continuing to use it. Patients emphasised in-person consultations as a crucial part of TCM treatment. However, the disability caused by disease often made this interaction unattainable. CONCLUSION: Nonmotor symptoms and QOL hold substantial importance for patients with ALS using TCM. HM is a more suitable modality than other TCM treatment modalities, but patients are facing challenges in seeking HM treatment. It is necessary to promote the implementation of hierarchical diagnosis and treatment, thus making TCM more accessible. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04885374 (registered on May 13, 2021).

Vital real-world experience regarding Naoshuantong capsules for unselected ischemic stroke (VENUS): Rationale, design, and baseline of a prospective, multicenter, observational study.

Background: Naoshuantong capsules (NC) are commonly used for the treatment of ischemic stroke. Experimental research and small-sample clinical trials have demonstrated that NC is effective in improving neurological recovery. Yet, there is a substantial lack of high-quality evidence on the precision treatment population of NC and long-term safety when making real-world clinical decisions. The acquisition of prospective longitudinal data in the real-world setting is essential to fully characterize the effectiveness and safety profile of NC for patients with ischemic stroke. Methods: The Vital real-world Experience regarding Naoshuantong capsules for Unselected ischemic Stroke (VENUS) registry is a prospective, multicenter, observational study aiming to register 5,000 patients. Eligible adult patients diagnosed with ischemic stroke and newly treated with NC within 30 days of symptom onset will be consecutively registered from 84 participating sites across the Chinese mainland. Baseline data will be recorded at the patient registry, and all patients will be regularly followed up at 2, 4, 8, and 12 weeks after the initial patient registry, and 180 days after ischemic stroke onset. The primary outcome is the distribution of scores on the modified Rankin Scale at 12 weeks after initial patient registry. Adverse events will be recorded during the study for NC safety assessment. Results: A total of 4,185 patients with ischemic stroke were enrolled, among which 37.06% patients were female. The average age of all patients was 65.22 years. The proportion of patients whose course of ischemic stroke was less than 14 days accounted for 93.45%. Conclusion: The VENUS registry is designed to comprehensively document medical data regarding NC treatment for ischemic stroke in real-world settings. The findings of this study will provide valuable insights into the clinical management of patients with ischemic stroke and the subsequent outcomes of the use of NC when included in the best clinical practice. Study registration: This study was registered with the Chinese Clinical Trial Registry (URL: http://www.chictr.org.cn/index.aspx, Unique identifier: ChiCTR1900025053).

Effectiveness of herbal medicine on patients with amyotrophic lateral sclerosis: Analysis of the PRO-ACT data using propensity score matching.

BACKGROUND: Patients with amyotrophic lateral sclerosis (ALS) have restricted pharmacotherapy options and thus resort to herbal medicines (HMs), despite limited and conflicting evidence. Therefore, use of HMs needs to be assessed in patients with ALS. PURPOSE: This study aimed to evaluate the benefits of HMs in ALS and to describe the characteristics of HM users. STUDY DESIGN: The correlation between HMs and prognosis was determined based on data obtained from the largest ALS database with high-quality clinical trials. Propensity score (PS) matching was used to address confounding and selection bias. METHODS: In total, 321 and 231 HM users with at least a 4-week HM prescription were identified and PS-matched with non-HM users at a 1:1 ratio based on predefined confounders. Time-to-event models with censoring at 12 or 18 months were established for survival analyses. For evaluating activity limitation and respiratory function, 320 and 376 HM users were included, respectively, and analyzed using multivariate analysis of variance (MANOVA). RESULTS: The profiles of 321 HM users indicated a better condition compared with that of non-HM users before PS-matching, including higher weight (median [IQR], 77.90 [21.8] kg vs. 74.00 [21.2] kg, p < 0.01), higher body mass index (26.00 [5.4] vs. 25.20 [5.8], p < 0.01), more percentage of limb onset (261 [81.3%] vs. 2366 [67.2%], p < 0.01), and slower progression (0.47 [0.5] vs. 0.51 [0.5], p = 0.03). HM did not significantly affect survival at 12 months (adjusted hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.49-1.03; log-rank p = 0.069), but it significantly prolonged survival at 18 months (adjusted HR 0.74, 95% CI 0.56-0.98; log-rank p = 0.038). After imputation of missing data, MANOVA revealed significant effectiveness of HMs in improving activity limitation (Pillai trace, 0.0195; p = 0.03). CONCLUSION: PS-based methods eliminated baseline differences between HM and non-HM users. Overall, the use of HM to treat patients with ALS is favored based on their association with prolonged overall survival within 18 months and improved activity limitation.

Herbal medicine for amyotrophic lateral sclerosis: A systematic review and meta-analysis.

Background: The effect of herbal medicine (HM) on amyotrophic lateral sclerosis (ALS) is controversial. Clinical trials investigating HMs continue; however, the use of HM is still questioned. We aimed to systematically review the literature pertaining to the effects and safety of HM in ALS. Methods: Randomised controlled trials (RCTs) that investigated the efficacy of HMs in ALS patients compared to any types of controls were identified. Nine databases and six registers were searched from their inception dates to 25 March 2022. Per the PRISMA guidelines, trials were identified and extracted. The risk of bias was evaluated using the Cochrane's tool. Certainty of evidence was assessed as per the GRADE criteria. Forest plots were constructed to assess the effect size and corresponding 95% CIs using fixed-effect models, and random-effect models were employed when required. The primary outcome was the activity limitation measured by validated tools, such as the revised ALS Functional Rating Scale. Results: Twenty studies (N = 1,218) were eligible. Of these, only five studies were double-blinded, and two were placebo-controlled. Fourteen HMs (fifty-one single botanicals) were involved; Astragalus mongholicus Bunge, Atractylodes macrocephala Koidz., and Glycyrrhiza glabra L. were commonly used in nine, eight, and six trials, respectively. For delaying activity limitation, Jiweiling injection (MD, 2.84; 95% CI, 1.21 to 4.46; p = 0.0006) and Shenmai injection (SMD, 1.07; 0.69 to 1.45; p < 0.00001) were significantly more efficacious than Riluzole, but the evidence was low quality. For ameliorating motor neuron loss, Jiweiling injection [right abductor pollicis brevis (APB): MD, 32.42; 7.91 to 56.93; p = 0.01 and left APB: MD, 34.44; 12.85 to 56.03; p = 0.002] was favoured, but the evidence was very low quality. Nine studies reported one hundred and twenty-three adverse events, twenty-six of which occurred in the treatment groups and ninety-seven in the control groups. Conclusion: Very low to low quality of evidence suggests that HMs seem to produce superior treatment responses for ALS without increased risk of adverse events. Additional studies with homogeneous participants, reduced methodological issues, and more efficient outcome measures are required to provide confirmatory evidence. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42021277443.

Cerebral Small Vessel Disease: Neuroimaging Features, Biochemical Markers, Influencing Factors, Pathological Mechanism and Treatment.

Cerebral small vessel disease (CSVD) is the most common chronic vascular disease involving the whole brain. Great progress has been made in clinical imaging, pathological mechanism, and treatment of CSVD, but many problems remain. Clarifying the current research dilemmas and future development direction of CSVD can provide new ideas for both basic and clinical research. In this review, the risk factors, biological markers, pathological mechanisms, and the treatment of CSVD will be systematically illustrated to provide the current research status of CSVD. The future development direction of CSVD will be elucidated by summarizing the research difficulties.

China amyotrophic lateral sclerosis registry of patients with Traditional Chinese Medicine (CARE-TCM): Rationale and design.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicine (TCM) has become popular interventional treatment for amyotrophic lateral sclerosis (ALS). However, lack of knowledge about the general characteristics and long-term clinical outcomes hampers the development of herbal drugs for ALS. AIM OF THE STUDY: The China Amyotrophic Lateral Sclerosis Registry of Patients with Traditional Chinese Medicine (CARE-TCM) provides an opportunity to better understand which TCM interventions patients with ALS are receiving, what the characteristics of patients with ALS are, and how these interventions impact clinical measures. MATERIALS AND METHODS: This study includes a voluntary nationwide registry, and data will be collected prospectively using an electronic data system. Detailed data collection will be performed every 3 months for 5 years. Baseline characteristics and 5-year survival will be collected. This registry was initiated in March 2021. The number of participating medical centers will be about 30 hospitals, and the target procedure number will be 2000. We will also compare the results with those of other registries in China and other countries. DISCUSSION: The CARE-TCM registry will first provide real-world data regarding TCM and ALS in China, focusing on the clinical characteristics of ALS patients with TCM, disease phenotypes that respond best to TCM, and correlating clinical response with other parameters. The CARE-TCM can be very helpful to improve the efficiency and quality of TCM clinical trial design. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04885374 (registered on May 8, 2021).

Neuroprotective Effects of Shenqi Fuzheng Injection in a Transgenic SOD1-G93A Mouse Model of Amyotrophic Lateral Sclerosis.

Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease, in the pathogenesis of which oxidative stress (OS) was believed to play a key role. Shenqi Fuzheng Injection (SFI) concocted from two kinds of Chinese medicinal herbs, Radix Codonopsis and Radix Astragali, was proven to be eligible to reduce the OS injury and increase the activity of the nuclear factor-erythroid-2-related factor 2 (Nrf2) pathway, an antioxidant enzymes inducer. Objective: We aim to investigate the effects and potential mechanisms underlying the action of SFI on a well-established transgenic mouse model of ALS. Methods: Transgenic SOD1-G93A mice were intraperitoneally injected with SFI (40 ml/kg) three times a week from 87 days of age. Motor function, survival, pathological manifestations in the brain, and Nrf2 pathway-related assessments of the mice were performed. Results: SFI treatment efficiently postponed the disease onset (p = 0.022) and extended the overall survival (p = 0.038) of the SOD1-G93A mice. Moreover, SFI significantly reduced motor neuron loss (p < 0.001) and astrocytic activation (p < 0.05) in the motor cortex of the brain of SOD1-G93A mice at 130 days of age. The protective effects of SFI in the SOD1-G93A mice were associated with decreasing the level of malondialdehyde (p < 0.05) and increasing the levels of superoxide dismutase (p < 0.05), Nrf2 (p < 0.05), heme oxygenase-1 (p < 0.05), and glutathione S-transferase (p < 0.05) in the SOD1-G93A mice. Conclusion: The SFI treatment efficiently extended the overall survival and improved the pathological manifestations of the brain via alleviating the OS injury and activating the Nrf2 pathway in the animal model of ALS, which made SFI a potentially promising candidate for ALS treatment.

China Stroke Registry for Patients With Traditional Chinese Medicine (CASES-TCM): Rationale and Design of a Prospective, Multicenter, Observational Study.

Background: Given the complexity of stroke treatment and the current widespread use of traditional Chinese medicine (TCM) in the absence of robust, large, long-term effectiveness and safety studies, and the lack of nationwide epidemiology and clinical characteristics of patients with stroke receiving TCM treatment, the acquisition of data from longitudinal cohorts is essential. We intend to generate the major clinical characteristics of patients with stroke who receive TCM treatment and to investigate the effectiveness and safety of TCM in the Chinese population. Methods: The China Stroke Registry for Patients with Traditional Chinese Medicine (CASES-TCM) study is a prospective, multicenter, observational disease registry aiming to register 20,000 hospitalized patients. Eligible adult patients with clearly diagnosed acute ischemic stroke or intracerebral hemorrhage within 7 days of symptom onset will be consecutively registered from 126 participating sites across China. Baseline data will be recorded, and all patients will be regularly followed up at 3, 6, 12, and 24 months after stroke onset. Collected data will be entered into a web-based system with high-level data security. The primary outcomes include the distribution of scores on the modified Rankin Scale at the 3-months follow-up, and recurrent stroke events within the 12-months follow-up. Conclusion: To our knowledge, the CASES-TCM study is the first and largest nationwide registry to document comprehensive data on TCM treatment in patients with acute stroke. The findings of this study will be valuable to improve our knowledge about TCM treatment for patients with stroke and its subsequent outcomes in the actual clinical setting, consequently facilitating and standardizing the optimization of individualized interventions with TCM for stroke prevention and treatment in China. Study registration: This study was registered with Clinicaltrials.gov (URL: https://clinicaltrials.gov/, Unique identifier: NCT04921397).

HDAC1-mediated deacetylation of HIF1α prevents atherosclerosis progression by promoting miR-224-3p-mediated inhibition of FOSL2.

We intended to characterize functional relevance of microRNA (miR)-224-3p in endothelial cell (EC) apoptosis and reactive oxygen species (ROS) accumulation in atherosclerosis, considering also the integral involvement of histone deacetylase 1 (HDAC1)-mediated hypoxia-inducible factor-1α (HIF1α) deacetylation. The binding affinity between miR-224-3p and Fos-like antigen 2 (FOSL2) was predicted and validated. Furthermore, we manipulated miR-224-3p, FOSL2, HDAC1, and HIF1α expression in oxidized low-density lipoprotein (ox-LDL)-induced ECs, aiming to clarify their effects on cell activities, inflammation, and ROS level. Additionally, we examined the impact of miR-224-3p on aortic atherosclerotic plaque and lesions in a high-fat-diet-induced atherosclerosis model in ApoE-/- mice. Clinical atherosclerotic samples and ox-LDL-induced human aortic ECs (HAECs) exhibited low HDAC1/miR-224-3p expression and high HIF1α/FOSL2 expression. miR-224-3p repressed EC cell apoptosis, inflammatory responses, and intracellular ROS levels through targeting FOSL2. HIF1α reduced miR-224-3p expression to accelerate EC apoptosis and ROS accumulation. Moreover, HDAC1 inhibited HIF1α expression by deacetylation, which in turn enhanced miR-224-3p expression to attenuate EC apoptosis and ROS accumulation. miR-224-3p overexpression reduced atherosclerotic lesions in vivo. In summary, HDAC1 overexpression may enhance the anti-atherosclerotic and endothelial-protective effects of miR-224-3p-mediated inhibition of FOSL2 by deacetylating HIF1α, underscoring a novel therapeutic insight against experimental atherosclerosis.

Correlational Analysis of ALS Progression and Serum NfL Measured by Simoa Assay in Chinese Patients.

Background: Neurofilament light chain (NFL) was believed to be a promising biomarker for the diagnosis of Amyotrophic lateral sclerosis (ALS) and disease burden evaluation. Objective: To determine the serum NFL level and its clinical relevance, including its association with disease severity [evaluated by the ALS Functional Rating Scale-revised (ALSFRS-r) score and King's College staging system] and progression (evaluated by the disease progression rate (DPR) and diagnostic delay), in ALS patients in China. Method: Serum NFL levels were detected using the Single Molecule Array (Simoa) technology in 30 ALS patients and 20 healthy controls (HCs). Results: There were significantly elevated levels of serum NFL in patients with ALS than in the HCs (P < 0.001). The serum NFL levels were significantly higher in rapidly progressive ALS and patients in Stage 3 than in slowly progressive ALS and patients in Stage 2 (P DPR < 0.001, P Diagnosticdelay = 0.019; P stage = 0.033). Furthermore, the serum NFL levels negatively correlated with the diagnostic delay (R 2 = 0.23, P = 0.016), the ALSFRS-r score (R 2 = 0.15, P = 0.047) and disease duration (R 2 = 0.15, P = 0.034), and positively correlated with the DPR (R 2 = 0.42, P < 0.001). Conclusions: The present study preliminarily investigated the diagnostic value of serum NFL and its clinical relevance in the Chinese ALS population using the ultrasensitive Simoa technology. The results demonstrated that the level of serum NFL may become a potential biomarker for ALS diagnosis and indicate disease severity and progression.