Our staff editors continue to share exciting, interesting, and thought-provoking reading material in the recommended articles series.
This week, we would like to share several latest articles from Prof. Dongsheng Fan, our Editorial Board Member.
Title: A Mendelian randomization analysis of the relationship between cardioembolic risk factors and ischemic stroke
Authors: Danyang Tian, Linjing Zhang, Zhenhuang Zhuang, Tao Huang, Dongsheng Fan
Type: Article from Scientific Reports
Observational studies have shown that several risk factors are associated with cardioembolic stroke. However, whether such associations reflect causality remains unknown. We aimed to determine whether established and provisional cardioembolic risk factors are causally associated with cardioembolic stroke. Genetic instruments for atrial fibrillation (AF), myocardial infarction (MI), electrocardiogram (ECG) indices and N-terminal pro-brain natriuretic peptide (NT-pro BNP) were obtained from large genetic consortiums. Summarized data of ischemic stroke and its subtypes were extracted from the MEGASTROKE consortium. Causal estimates were calculated by applying inverse-variance weighted analysis, weighted median analysis, simple median analysis and Mendelian randomization (MR)-Egger regression. Genetically predicted AF was significantly associated with higher odds of ischemic stroke (odds ratio (OR): 1.20, 95% confidence intervals (CI): 1.16–1.24, P = 6.53 × 10–30) and cardioembolic stroke (OR: 1.95, 95% CI: 1.85–2.06, P = 8.81 × 10–125). Suggestive associations were found between genetically determined resting heart rate and higher odds of ischemic stroke (OR: 1.01, 95% CI: 1.00–1.02, P = 0.005), large-artery atherosclerotic stroke (OR: 1.02, 95% CI: 1.00–1.04, P = 0.026) and cardioembolic stroke (OR: 1.02, 95% CI: 1.00–1.04, P = 0.028). There was no causal association of P‐wave terminal force in the precordial lead V1 (PTFVI), P-wave duration (PWD), NT-pro BNP or PR interval with ischemic stroke or any subtype.
Access this article: https://doi.org/10.1038/s41598-021-93979-y
Title: A two-sample Mendelian randomization analysis of heart rate variability and cerebral small vessel disease
Authors: Danyang Tian, Linjing Zhang, Zhenhuang Zhuang, Tao Huang, Dongsheng Fan
Type: Original Article of Journal of Clinical Hypertension
Cerebral small vessel disease (cSVD) is correlated with a high risk of stroke and cognitive impairment. Previous studies between heart rate variability (HRV) and cSVD revealed paradoxical results. The authors aimed to investigate the relationship between HRV and cSVD using Mendelian randomization analysis. Genetic instruments for HRV were obtained from previous genome-wide association studies. They applied inverse variance-weighted analysis, weighted median analysis, simple median analysis, and Mendelian randomization–Egger regression to evaluate the associations of HRV with white matter hyperintensity (WMH) and small vessel stroke (SVS) in the UK Biobank neuroimaging dataset and the MEGASTROKE genome-wide association study dataset. Two genetically predicted traits of HRV (the root mean square of the successive differences of inter beat intervals [RMSSD] and the peak-valley respiratory sinus arrhythmia or high frequency power [pvRSA/HF]) were suggestively associated with WMH (β 0.26, 95% confidence interval [CI] 0.04–0.49, p = .02; β 0.14, 95% CI 0.02–0.27, p = .03, respectively). Genetically predicted traits of HRV were not significantly associated with SVS. This study provides genetic support for a suggestive causal effect of HRV (RMSSD, pvRSA/HF) on WMH but not SVS.
Access this article: https://doi.org/10.1111/jch.14316
Title: Using corneal confocal microscopy to compare Mecobalamin intramuscular injections vs oral tablets in treating diabetic peripheral neuropathy: a RCT
Authors: Yuanjin Zhang, Dongsheng Fan, Yixuan Zhang, Shuo Zhang, Haikun Wang, Ziyuan Liu, Hongli Wang
Type: Article of Scientific Reports
This randomized controlled study used corneal confocal microscopy (CCM) to compare the efficacy of Mecobalamin intramuscular injections vs oral tablets in treating mild to moderate diabetic peripheral neuropathy (DPN) by detecting early nerve fiber repair. Enrolled patients were randomized approximately 1:1 to receive Mecobalamin intramuscular injections (0.5 mg/day, 3 times/week) or Mecobalamin oral tablets (1.5 mg/day) for 8 weeks. Primary outcome was change of inferior whorl length (IWL) from baseline. Secondary outcomes included changes of corneal nerve fibre length (CNFL), corneal nerve fibre density (CNFD), corneal nerve branch density (CNBD) and the Survey of Autonomic Symptoms (SAS). 15 (93.75%) patients in the injection group and 17 (89.47%) patients in the tablet group completed the study. The injection treatment significantly improved patients’ IWL from baseline (21.64 ± 3.00 mm/mm2 vs 17.64 ± 4.83 mm/mm2, P < 0.01) while the tablet treatment didn’t. Additionally, the injection treatment led to significantly improved CNFL, CNBD and SAS from baseline (all P < 0.05) while the tablet treatment did not. No patient experienced any adverse events. In conclusion, CCM is sensitive enough to detect the superior efficacy of 8-week Mecobalamin intramuscular injection treatment for DPN compared to the oral tablet treatment.
Access this article: https://doi.org/10.1038/s41598-021-94284-4
Title: Painful Diabetic Peripheral Neuropathy Study of Chinese Outpatients (PDNSCOPE): A Multicentre Cross-Sectional Registry Study of Clinical Characteristics and Treatment in Mainland China
Authors: Yuanjin Zhang, Shaowei Zhang, Liya Pan, Baojun Wang, Yuanlin Sun, Lijun Gao, Ling Wang, Lijuan Cui, Qing Zhang, Heng Shang, Suqin Jin, Xing Qin, Deqin Geng, Xiaorong Yu, Lin Yang, Li Li, Zuoxiao Li, Chaoli Yan, Hongbin Sun, Tao Sun, Baoxin Du, Junying Cao, Fengyun Hu, Jianhua Ma, Shengnian Zhou, Fengli Zhao, Wei Li, Jianming Zheng, Yanhui Yi, Jianguo Xu, Bo Hu, Baoying Sheng, Zhaohui Li, Zhong Zhao, Ting Yang, Ni Wang, Hongdong Zhao, Dunzhu Mima, Huaiqian Qu, Yi Wang, Fuxia Song, Xinyi Li, Nan Li, Dongsheng Fan
Type: Original Research of Pain and Therapy
This aim of this study was to delineate current clinical scenarios of painful diabetic peripheral neuropathy (PDN) and associated anxiety and depression among patients in Mainland China, and to report current therapy and clinical practices.
A total of 1547 participants were enrolled in the study between 14 June 2018 and 11 November 2019. Recruitment was conducted using a multilevel sampling method. Participants’ demographics, medical histories, glucose parameters, Douleur Neuropathique 4 Questionnaire (DN4) scores, visual analogue scale (VAS) pain scores, Patient Health Questionnaire 9 (PHQ-9) scores, Generalised Anxiety Disorder 7 (GAD-7) scores and therapies were recorded.
The male-to-female ratio was 1.09:1 (807:740), and the mean age at onset was 61.28 ± 11.23 years. The mean DN4 score (± standard deviation) was 4.91 ± 1.88. The frequencies of DN4 sub-item phenotypes were: numbness, 81%; tingling, 68.71%; pins and needles, 62.90%; burning, 53.59%; hypoaesthesia to touch, 50.16%; electronic shocks, 43.31%; hypoaesthesia to pinprick, 37.94%; brushing, 37.82%; painful cold, 29.61%; and itching, 25.86%. Age, diabetic duration, depression history, PHQ-9 score and GAD-7 score were identified as risk factors for VAS pain score. Peripheral artery disease (PAD) was a protective factor for VAS pain score. For all participants currently diagnosed with PDN and for those previously diagnosed PDN, fasting blood glucose (FBG) was a risk factor for VAS; there was no association between FBG and VAS pain score for PDN diagnosed within 3 months prior to recruitment. Utilisation rate of opium therapies among enrolled participants was 0.71%, contradiction of first-line guideline recommendation for pain relief accounted for 9.43% (33/350) and contradiction of second-line guideline recommendation for opium dosage form was 0.57% (2/350).
Moderate to severe neuropathic pain in PDN was identified in 73.11% of participants. Age, diabetic duration, depression history, PHQ-9 score, GAD-7 score and FBG were risk factors for VAS pain scores. PAD was protective factor. The majority of pain relief therapies prescribed were in accordance with guidelines.
Access this article: https://doi.org/10.1007/s40122-021-00281-w
Title: Loss of appetite in patients with amyotrophic lateral sclerosis is associated with weight loss and anxiety/depression
Authors: Yajun Wang, Shan Ye, Lu Chen, Lu Tang, Dongsheng Fan
Type: Article of Scientific Reports
Weight loss is common in patients with Amyotrophic lateral sclerosis (ALS), and associated with disease progression. Loss of appetite has been shown to be a contributor to weight loss in patients with amyotrophic lateral sclerosis (ALS). However, the reason of loss of appetite is not clear. The Council on Nutrition appetite questionnaire (CNAQ) and the simplified nutritional appetite questionnaire (SNAQ) are short and simple appetite assessment tools, which were using in ALS patients. In our study, the CNAQ and SNAQ were translated into Chinese, and their reliability and validity were tested. The Chinese version of the CNAQ (CNAQ-C) presented more appropriate reliability and validity than the SNAQ. Among the 94 ALS patients, 50 patients (53.2%) had loss of appetite, and we found that anxiety and/or depression contributed to the loss of appetite in the ALS patients. We reconfirmed that loss of appetite was associated with greater weight loss but not with clinical features of ALS. The loss of appetite caused by emotional problems in ALS patients should be taken seriously, and early intervention should be implemented to reduce weight loss.
Access this article: https://doi.org/10.1038/s41598-021-88755-x
Title: Human endogenous retrovirus K (HERV-K) env in neuronal extracellular vesicles: a new biomarker of motor neuron disease
Authors: Yuan Li, Yong Chen, Nan Zhang, Dongsheng Fan
Type: Research Article of Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
Objective: Human endogenous retroviruses (HERVs) have been gradually confirmed to be involved in the onset and progression of motor neuron disease (MND). However, noninvasive detection of HERVs in the central nervous system is lacking. The aim of this study is to verify the relationship between the level of HERV-K env in neuronal extracellular vesicles in plasma and the onset and severity of MND. Methods: We extracted neuronal extracellular vesicles from plasma of 39 MND patients and 30 age- and sex-matched controls, and detected HERV-K env in extracellular vesicles by an enzyme-linked immunosorbent assay (ELISA). Results: Levels of HERV-K env in neuronal extracellular vesicles positively associated with range of lower motor neurons (LMNs) involved (1.66 ± 0.37 vs. 1.35 ± 0.34, p = 0.041), ALS phenotype (1.52 ± 0.31 vs. 1.24 ± 0.37, p = 0.013) and course of disease (1.83 ± 0.35 vs. 1.42 ± 0.22, p = 0.003), and increased in advanced-phase MND (definite and probable according to revised EI Escorial criteria) compared with early-phase MND (possible and lab-supported probable), albeit without very profound significance (1.52 ± 0.34 vs. 1.29 ± 0.36, p = 0.048). Conclusions: In conclusion, levels of HERV-K env in neuronal extracellular vesicles extracted from plasma can be used as a noninvasive biomarker of severity of MND.
Access this article: https://doi.org/10.1080/21678421.2021.1936061
Title: A 36-week multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial of sodium oligomannate for mild-to-moderate Alzheimer’s dementia
Authors: Shifu Xiao, Piu Chan, Tao Wang, Zhen Hong, Shuzhen Wang, Weihong Kuang, Jincai He, Xiaoping Pan, Yuying Zhou, Yong Ji, Luning Wang, Yan Cheng, Ying Peng, Qinyong Ye, Xiaoping Wang, Yuncheng Wu, Qiumin Qu, Shengdi Chen, Shuhua Li, Wei Chen, Jun Xu, Dantao Peng, Zhongxin Zhao, Yansheng Li, Junjian Zhang, Yifeng Du, Weixian Chen, Dongsheng Fan, Yong Yan, Xiaowei Liu, Wei Zhang, Benyan Luo, Wenyuan Wu, Lu Shen, Chunfeng Liu, Peixian Mao, Qiumei Wang, Qianhua Zhao, Qihao Guo, Yongtao Zhou, Yi Li, Lijun Jiang, Wenwei Ren, Yingjun Ouyang, Yan Wang, Shuai Liu, Jianjun Jia, Nan Zhang, Zhonglin Liu, Raoli He, Tingyi Feng, Wenhui Lu, Huidong Tang, Ping Gao, Yingchun Zhang, Lanlan Chen, Lei Wang, You Yin, Qun Xu, Jinsong Xiao, Lin Cong, Xi Cheng, Hui Zhang, Dan Gao, Minghua Xia, Tenghong Lian, Guoping Peng, Xu Zhang, Bin Jiao, Hua Hu, Xueyan Chen, Yihui Guan, Ruixue Cui, Qiu Huang, Xianliang Xin, Hongjian Chen, Yu Ding, Jing Zhang, Teng Feng, Marc Cantillon, Kewei Chen, Jeffrey L. Cummings, Jian Ding, Meiyu Geng, Zhenxin Zhang
Type: Research of Alzheimer's Research & Therapy
New therapies are urgently needed for Alzheimer’s disease (AD). Sodium oligomannate (GV-971) is a marine-derived oligosaccharide with a novel proposed mechanism of action. The first phase 3 clinical trial of GV-971 has been completed in China.
We conducted a phase 3, double-blind, placebo-controlled trial in participants with mild-to-moderate AD to assess GV-971 efficacy and safety. Participants were randomized to placebo or GV-971 (900 mg) for 36 weeks. The primary outcome was the drug-placebo difference in change from baseline on the 12-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog12). Secondary endpoints were drug-placebo differences on the Clinician’s Interview-Based Impression of Change with caregiver input (CIBIC+), Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, and Neuropsychiatric Inventory (NPI). Safety and tolerability were monitored.
A total of 818 participants were randomized: 408 to GV-971 and 410 to placebo. A significant drug-placebo difference on the ADAS-Cog12 favoring GV-971 was present at each measurement time point, measurable at the week 4 visit and continuing throughout the trial. The difference between the groups in change from baseline was − 2.15 points (95% confidence interval, − 3.07 to − 1.23; p < 0.0001; effect size 0.531) after 36 weeks of treatment. Treatment-emergent adverse event incidence was comparable between active treatment and placebo (73.9%, 75.4%). Two deaths determined to be unrelated to drug effects occurred in the GV-971 group.
GV-971 demonstrated significant efficacy in improving cognition with sustained improvement across all observation periods of a 36-week trial. GV-971 was safe and well-tolerated.
Access this article: https://doi.org/10.1186/s13195-021-00795-7