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Previous observational studies revealed a potential but partially controversial relation between lipid metabolism and the risk of amyotrophic lateral sclerosis (ALS), potentially prone to bias. Therefore, we aimed to study whether lipid metabolism involves genetically determined risk factors for ALS through Mendelian randomization (MR) analysis.Using genome-wide association study summary-level data for total cholesterol (TC) (n = 188,578), high-density lipoprotein cholesterol (HDL-C) (n = 403,943), low-density lipoprotein cholesterol (LDL-C) (n = 440,546), apolipoprotein A1 (ApoA1) (n = 391,193), apolipoprotein B (ApoB) (n = 439,214), and ALS (12,577 cases and 23,475 controls), we implemented a bidirectional MR study to evaluate a genetic relation between lipids and ALS risk. We performed a mediation analysis to assess whether LDL-C is a potential mediator on the pathway from traits of LDL-C-related polyunsaturated fatty acids (PUFAs) to ALS risk.We identified genetically predicted increased lipid levels to be associated with the risk of ALS, whereby elevated LDL-C had the most potent effect (OR 1.028, 95% CI 1.008-1.049, p = 0.006). The effect of increased levels of apolipoproteins on ALS was similar to their corresponding lipoproteins. ALS did not cause any changes in lipid levels. We found no relation between LDL-C-modifying lifestyles and ALS. The mediation analysis revealed that LDL-C could act as an active mediator for linoleic acid, with the mediation effect estimated to be 0.009.We provided high-level genetic evidence verifying the positive link between preclinically elevated lipid and ALS risk that had been described in previous genetic and observational studies. We also demonstrated the mediating role of LDL-C in the pathway from PUFAs to ALS.

To investigate the causal role of lipid or apolipoprotein traits in intracerebral hemorrhage (ICH) and determine the effect of lipid-lowering interventions on the disease.Two-sample Mendelian randomization (MR) analyses were conducted to evaluate the associations of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), apolipoprotein (Apo)B and ApoA1 levels with risks for ICH, and those of LDL-C- (HMGCR, PCSK9, and NPC1L1) and TG-lowering targets (LPL and APOC3) with ICH.Increased levels of ApoB was associated with a decreased risk of overall ICH (OR 0.623, 95% CI 0.413-0.940; p = 0.024) and lobar ICH (OR 0.579, 95% CI 0.342-0.979; p = 0.042). The inverse relationship remained stable in multivariable MR. In addition, elevated TGs showed a causal effect on lobar ICH in multivariable MR (OR 1.600, 95% CI 1.009-2.537; p = 0.046). The LDL-C-reducing genetic variation alleles at or near the HMGCR gene (mimicking the effect of statins) were predicted to increase the overall and deep ICH risk. Additionally, genetic variation at or near the APOC3 gene suggested that genetically reducing the activity of APOC3 (mimicking antisense anti-apoC3 agents) was predicted to decrease lobar ICH.Genetically predicted elevated ApoB may have a protective effect on overall ICH and lobar ICH, whereas elevated TG was associated with a higher risk of lobar ICH conditional on LDL-C and ApoB. MR analysis supports the conclusion that statins may increase the risk of overall and deep ICH independent of their lipid-lowering effect. More specific lipid-lowering targets may end up being the future. ANN NEUROL 2022;92:390-399.

Background Intravenous thrombolysis (IVT) therapy with recombinant tissue plasminogen activator (rtPA) in acute ischemic stroke (AIS) has a known risk of intracerebral hemorrhage (ICH). We aimed to identify the predictive value of coagulation factor XIII (FXIII) on post-thrombolytic ICH risk in AIS patients. Methods The study cohort included 69 diagnosed AIS patients undergoing IVT treatment within 24 hours of symptom onset. Blood samples taken on admission were analyzed for FXIII antigen levels with an automated latex enhanced immunoassay. Conventional coagulation parameters including prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), and D-dimer (DD) were also tested. Results Of the 69 AIS patients, 23 (33.3%) developed post-thrombolytic ICH. Plasma FXIII levels showed a significant decrease, accompanied with elevated FIB and DD levels in AIS patients with post-thrombolytic ICH. Multivariable logistic regression (LR) revealed that FXIII and FIB were independently associated with post-thrombolytic ICH progression. Area under receiver operating characteristic curve of FXIII selected by the further forward logistic regression was 0.823 [95% confidence interval (CI): 0.712-0.904], and the cutoff value of 76.6% yielded good sensitivity at 91.3% and good negative predictive value (NPV) at 93.9%. Conclusions Our findings indicated that plasma FXIII level may be an independent determinant for predicting post-thrombolytic bleeding risk in AIS patients.

Observational studies have indicated that there is a high prevalence of habitual sleep disturbances in amyotrophic lateral sclerosis (ALS). However, the actual relationship between these symptoms and ALS remains unclear. We used 2-sample Mendelian randomization to determine whether the sleep disturbances associated with ALS are also related to the risk of ALS. The summary statistics we used were from recent, large genome-wide association studies on daytime sleepiness and other night sleep traits (n = 85,670–452,071) and ALS (n = 20,806 cases, n = 59,804 controls). The inverse variance-weighted (IVW) method was used as the main method for assessing causality. Daytime sleepiness might increase the risk of ALS (IVW odds ratio = 2.45, 95% confidence interval: 1.15—5.21; P = 0.020). ALS was not associated with sleep efficiency, number of sleep episodes or sleep duration. Our results provide novel evidence that daytime sleepiness increases the risk of ALS and points out the importance of daytime sleepiness that often goes unnoticed in ALS.

Objective To systematically investigate causal relationships between educational attainment, cognitive‐related phenotypes, and amyotrophic lateral sclerosis (ALS). Methods Summary statistics from genome‐wide association studies for educational attainment, math ability, highest math class taken, cognitive performance, intelligence, and ALS were used. A two‐sample Mendelian randomization (MR) design was applied to explore the potential causal associations between them. Results Genetically predisposition to longer educational attainment and harder math class taken were associated with significantly lower statistical odds ratio of ALS. For per year increase in education completed there was a 21% lower (95% confidence interval [CI] = 27–14%) in risk for ALS. For per 1‐SD increase in the highest math class taken obtained there was a 19% lower (95% CI = 9–28%) in risk for ALS. Genetically predisposition to math ability, cognitive performance, and intelligence did not decrease the risk of ALS. Interpretation This study provides genetic support for a causal association between higher educational attainment and a lower risk of ALS. The genes related to these phenotypes are involved in almost all aspects of neuron‐to‐neuron communication. ALS patients are occasionally accompanied by varying degrees of cognitive impairment. People with greater cognitive reserve may be better able to offset damages of degenerative brain changes associated with dementia or other brain diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, or ALS.

Type 2 diabetes mellitus (T2DM), characterized by insulin resistance and unclear pathogenesis, is a serious menace to human health. Bile acids are the end products of cholesterol catabolism and play an important role in maintaining cholesterol homeostasis. Furthermore, increasing studies suggest that bile acids may regulate glucose tolerance, insulin sensitivity, and energy metabolism, suggesting that bile acids may represent a potential therapeutic target for T2DM. This study summarizes the metabolism of bile acids and, more importantly, changes in their concentrations, constitution, and receptors in diabetes. Furthermore, we provide an overview of the mechanisms underlying the role of bile acids in glucose and lipid metabolism, as well as the occurrence and development of T2DM. Bile acid-targeted therapy may represent a valid approach for T2DM treatment.

A retrospective study on complete blood count (CBC) with differential results of patients who presented to the fever clinic of Tongji Hospital with symptoms of COVID-19-like illness between February 1, 2020 and February 20, 2020 was performed through case reviewing Inclusion criteria were fever with a body temperature above 37 3 degreesC, accompanied or not accompanied by cough, chest tightness, muscle ache, shortness of breath and diarrhea Patients with hematopathy, cancer and sepsis were excluded The SARS-CoV-2 reverse transcriptase polymerase chain reaction (RT-PCR) testing of throat swab was performed in the laboratory of Tongji Hospital These patients with COVID-19-like symptoms were divided into two groups Patients diagnosed with COVID-19 according to the WHO interim guidance and confirmed by RT-PCR testing were included in the SARS-CoV-2-positive patient group (SPPG) Patients with two or more consecutive negative RT-PCR test results were included in the SARS-CoV-2-negative patient group (SNPG) Patients with co-infection of SARS-CoV-2 and other respiratory viruses including influenza A/B, respiratory syncytial virus and adenovirus were also excluded in SPPG Sysmex XN-9000 hematology analyzer was used to obtain the CBC with differential results for patients in each group CBC with differential results at the request of clinicians at the initial evaluations was recorded along with age and gender for each patient Decreased WBC*LYM was observed in SARS-CoV-2-infected patients compared with SARS-CoV-2-negative patients with suspected symptoms in this study WBC*LYM can be used as a supplementary parameter to help clinicians in their first contact with suspected patients awaiting SARS-CoV-2 RT-PCR results

Background Observational studies have suggested a close but controversial relationship between blood pressure (BP) and amyotrophic lateral sclerosis (ALS). It remains unclear whether this association is causal. The authors employed a bidirectional two-sample Mendelian randomization (MR) approach to evaluate the causal relationship between BP and ALS. Genetic proxies for systolic blood pressure (SBP), diastolic blood pressure (DBP), antihypertensive drugs (AHDs), ALS, and their corresponding genome-wide association study (GWAS) summary datasets were obtained from the most recent studies with the largest sample sizes. The inverse variance weighted (IVW) method was adopted as the main approach to examine the effect of BP on ALS and four other MR methods were used for sensitivity analyses. To exclude the interference between SBP and DBP, a multivariable MR approach was used. Results We found that genetically determined increased DBP was a protective factor for ALS (OR = 0.978, 95% CI 0.960–0.996, P = 0.017) and that increased SBP was an independent risk factor for ALS (OR = 1.014, 95% CI 1.003–1.025, P = 0.015), which is supported by sensitivity analyses. The use of calcium channel blocker (CCB) showed a causal relationship with ALS (OR = 0.985, 95% CI 0.971–1.000, P = 0.049). No evidence was revealed that ALS caused changes in BP. Conclusions This study provides genetic support for a causal effect of BP and ALS that increased DBP has a protective effect on ALS, and increased SBP is a risk factor for ALS, which may be related to sympathetic excitability. Blood pressure management is essential in ALS, and CCB may be a promising candidate.

Previous studies have suggested a close but inconsistent relationship between essential nutrients and the risk of amyotrophic lateral sclerosis (ALS), and whether this association is causal remains unknown. We aimed to investigate the potential causal relation between essential nutrients (essential amino acids, essential fatty acids, essential minerals, and essential vitamins) and the risk of ALS using Mendelian randomization (MR) analysis. Large-scale European-based genome-wide association studies’ (GWASs) summary data related to ALS (assembling 27,205 ALS patients and 110,881 controls) and essential nutrient concentrations were separately obtained. MR analysis was performed using the inverse variance–weighted (IVW) method, and sensitivity analysis was conducted by the weighted median method, simple median method, MR–Egger method and MR–PRESSO method. We found a causal association between genetically predicted linoleic acid (LA) and the risk of ALS (OR: 1.066; 95% CI: 1.011–1.125; p = 0.019). An inverse association with ALS risk was noted for vitamin D (OR: 0.899; 95% CI: 0.819–0.987; p = 0.025) and for vitamin E (OR: 0.461; 95% CI: 0.340–0.626; p = 6.25 × 10−7). The sensitivity analyses illustrated similar trends. No causal effect was observed between essential amino acids and minerals on ALS. Our study profiled the effects of diet-derived circulating nutrients on the risk of ALS and demonstrated that vitamin D and vitamin E are protective against the risk of ALS, and LA is a suggested risk factor for ALS.

Background Growing evidence suggests a mutual interaction between gut microbiome alterations and ALS pathogenesis. However, previous studies were susceptible to potential confounding factors and reverse causation bias, likely leading to inconsistent and biased results. Objectives To decipher the potentially mutual relationship between gut microbiota and ALS, we used a bidirectional two-sample MR approach to examine the associations between the gut microbiome and ALS. Results Using the inverse variance-weighted method, OTU10032 unclassified Enterobacteriaceae species-level OTU and unclassified Acidaminococcaceae were associated with a higher risk of ALS (per relative abundance: OR, 1.04; 95% CI, 1.01–1.07; P = 0.011 and OR, 1.02; 95% CI, 1.01–1.04; P = 0.009, respectively). Importantly, Gamma-Glu-Phe was showed potential deleterious effects on the risk of ALS (genetically predicted per a 1-standard deviation increase in the level of Gamma-Glu-Phe: OR, 1.96; 95% CI, 1.50–2.55; P = 0.012). Sensitivity analysis of the two candidate genera and metabolites using the MR-Egger and weighted-median methods produced similar estimates, and no horizontal pleiotropy or outliers were observed. Intriguingly, genetically predicted ALS was associated with an increase in the relative abundance of OTU4607_Sutterella (per 1-unit higher log odds: β, 2.23; 95% CI, 1.27–3.18; P = 0.020) and Lactobacillales_ORDER (per 1-unit higher log odds: β, 0.51; 95% CI, 0.09–0.94; P = 0.019). Conclusions Our findings provide novel evidence supporting the bidirectional relationship between the gut microbiota and ALS. These results may contribute to designing microbiome- and microbiome-dependent metabolite interventions in future ALS clinical trials.

We aimed to investigate the causality between potentially modifiable risk factors and the risk of intracranial aneurysm. Genetic instruments for 51 modifiable factors and intracranial aneurysm data were obtained from recently published genome-wide association studies. We applied two-sample Mendelian randomization methods to investigate their causal relationships. Genetically predicted cigarettes per day, smoking initiation, systolic blood pressure, hypertension and body fat percentage were significantly associated with an increased risk of intracranial aneurysm [odds ratios (OR) 2.67, 95% confidence interval (CI) 1.75–4.07, p = 5.36 × 10–6, OR 1.53, 95% CI 1.32–1.77, p = 9.58 × 10–9, OR 1.05, 95% CI 1.02–1.08, p = 1.18 × 10–3, OR 1.65, 95% CI 1.19–2.28, p = 2.56 × 10–3 and OR 1.29, 95% CI 1.11–1.52, p = 1.33 × 10–3, respectively]. Type 2 diabetes mellitus was significantly associated with a decreased risk of intracranial aneurysm (OR 0.89, 95% CI 0.83–0.95, p = 8.54 × 10–4). Body fat percentage was significantly associated with subarachnoid haemorrhage (p = 5.70 × 10–5). This study provided genetic evidence of causal effects of smoking, blood pressure, type 2 diabetes mellitus and obesity on the risk of intracranial aneurysm.

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.

Objective: To assess the role of premorbid type 2 diabetes in patients with amyotrophic lateral sclerosis (ALS) in China.Methods: We compared data from ALS patients with premorbid type 2 diabetes (...

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.

Physical activity (PA) participation has been noted as a potential risk factor for amyotrophic lateral sclerosis (ALS) for decades. However, current studies have been unable to pinpoint the exact relationship between them. Here, we used 2-sample Mendelian randomization (MR), a novel method to systematically investigate causal relationships between PA and ALS. Summary-level data for accelerometer-based and self-reported PA phenotypes were obtained from 2 large genome-wide association studies (GWASs; n = 91,105–377,234), and the ALS summary statistics were from a GWAS of 20,806 cases and 59,804 healthy participants. The present MR study affords no support for causality between 5 included activity habits and ALS. We conclude that PA in the general population is unlikely to affect ALS incidence.

Background Voltage-gated calcium channels (VGCCs) dysfunction is involved in the development of acute ischemic stroke (AIS). As a subunit of VGCC complexes, we detected the levels of α2δ-1 subunit in serum and cerebrospinal fluid (CSF) specimens from AIS patients. Methods The study included 105 patients with first-ever AIS, who were admitted within 48 hours after stroke onset. The serum and CSF levels of α2δ-1 were measured with ELISA and the severity of AIS patients was evaluated according to the National Institutes of Health Stroke Scale (NIHSS) score. The cerebral infarct volume was calculated through the Pullicino formula based on the cranial CT or MRI scan. C-reactive protein (CRP) and serum amyloid A (SAA) were measured using the latex-enhanced immunoturbidimetric assay. Results Compared to the control subjects, the serum α2δ-1 level was significantly increased in AIS patients with large infarct volume and in severe AIS cases with high NIHSS score, which correlated positively with the inflammatory markers CRP and SAA. Furthermore, the concentration of α2δ-1 in CSF was elevated with the infarct volume, which was higher in severe AIS patients. Conclusion Our study suggests that the increased α2δ-1 levels in serum and CSF specimens may be used as a potential marker for reflecting VGCCs dysfunction, illness severity and neuroinflammation in AIS patients.

BACKGROUND Two editions of the International Classification of Headache Disorders (ICHD) diagnostic criteria for "Headache attributed to an intracranial endovascular procedure" have been published, in 2004 and 2013.1,2 Despite studies that have suggested that the former is not very practical, the ICHD-3 beta did not contain major changes. Moreover, so far no consensus exists regarding characteristics of headache after intracranial endovascular procedure. Thus, there is a need for sound suggestions to improve the ICHD-3 beta diagnostic criteria. METHODS Using a prospective design, we identified consecutive patients with unruptured intracranial aneurysms (UIAs) with neuroendovascular treatment from January 2014 to December 2014. RESULTS In total, 73 patients were enrolled, and 58 patients ultimately completed the 6-month follow-up. After the procedure, five of the 29 patients (17.2%) with pre-existing headache experienced marked worsening after the procedure, while seven of the 29 patients without prior headache developed new-onset headache post-procedurally. The headaches started within 24 hours, with a mean duration of 24-72 hours. The headaches were moderate to severe. The eligibility of these events to be considered headaches caused by neuroendovascular procedures according to the ICHD-3 beta diagnostic criteria for designation was far from ideal. CONCLUSIONS Most cases of markedly worsening headaches and new-onset headaches started within 24 hours and persisted longer than that specified in the ICHD-3 beta diagnostic criteria. Moreover, considering that some items are not very practical, the ICHD-3 beta diagnostic criteria should be revised in the light of recent literature reports.

By phagocytosing cancer cells and their cellular debris, macrophages play a critical role in nonspecific defense (innate immunity) and, as antigen presenters, they help initiate specific defense mechanisms (adaptive immunity). Malignant melanoma is a lethal disease due to its aggressive capacity for metastasis and resistance to therapy. For decades, considerable effort has gone into development of an effective immunotherapy for treatment of metastatic melanoma. In this review, we focus on the anti-tumor activities of macrophages in melanoma and their potential as therapeutic targets in melanoma. Although macrophages can be re-educated through intercellular signaling to promote tumor survival owing to their plasticity, we expect that targeting the anti-tumor activity of macrophages remains a promising strategy for melanoma inhibition. The combination of tumoricidal macrophage activation and other treatments such as surgery, chemotherapy, and radiotherapy, may provide an effective and comprehensive anti-melanoma strategy.

Epithelial ovarian cancer is one of the most common and aggressive diseases among the female reproductive organ malignancies, and the molecular mechanism underlying this disease remains largely unknown. EMSY, a binding partner of BRCA2, has been reported to be amplified in ovarian cancer. However, the expression pattern and biological functions of EMSY in the progression of ovarian cancer are not fully understood. In this study, it was found that the expression of EMSY was significantly elevated in ovarian cancer samples compared to their adjacent normal tissues. Moreover, overexpression of EMSY promoted the growth and migration of ovarian cancer cells, while knocking down the expression of EMSY inhibited the growth, migration, and tumorigenesis of ovarian cancer cells in vitro and in vivo. Mechanistically, EMSY was found to interact with beta-catenin and activate beta-catenin/TCF signaling. Our study demonstrated that EMSY played an oncogenic role in the progression of ovarian cancer cells and EMSY might be a promising target for the treatment.

MicroRNA-203 (miR-203), possessing tumor suppressive or promotive activities, has been found to be downregulated or upregulated in different cancer types. The purpose of this study was to investigate whether the increased expression of miR-203 can be used as a noninvasive diagnostic and prognostic biomarker in epithelial ovarian cancer (EOC). Real-time quantitative PCR was performed to detect the expression levels of miR-203 in EOC tissues. The expression levels of miR-203 were significantly higher in EOC tissues compared to adjacent non-cancerous tissues (p