Causal Association of Iron Status With Functional Outcome After Ischemic Stroke.

BACKGROUND: Iron status has been associated with functional outcomes after ischemic stroke (IS). Nonetheless, this association may be affected by confounders. We perform Mendelian randomization to clarify the causal association between iron status and functional outcome after IS. METHODS: We obtained summary-level statistics related to iron status biomarkers from a meta-analysis of a gene-wide association study conducted by the Genetics of Iron Status Consortium, which included 11 discovery cohorts and 8 replication cohorts. We also took genetic variants related to 4 biomarkers of iron status from combining gene-wide association study results of Iceland, the United Kingdom, and Denmark to perform a replicate Mendelian randomization analysis. This data set included 4 iron status biomarkers, namely, ferritin, total iron binding capacity, iron, and transferrin saturation (TSAT). The confounders in these data sets have been adjusted to mitigate the collider bias. We acquired summary statistics data sets for functional outcomes following IS from the gene-wide association study meta-analysis conducted by the Genetics of Ischemic Stroke Functional Outcome Consortium. The genetic estimates for functional outcomes at 90 days after IS were evaluated by the modified Rankin Scale score, including 3741 cases with good functional outcomes (modified Rankin Scale score, 0-2) and 2280 subjects with poor functional outcomes poststroke (modified Rankin Scale score, 3-6). Inverse variance weighting was used as the primary method, complemented by sensitivity analyses for pleiotropy and increasing robustness. RESULTS: Reported with odds ratios (ORs) of stroke outcome with per SD unit increase in genetically determined iron status biomarker, TSAT and iron were associated with poor functional outcome after IS (TSAT: OR, 1.36 [95% CI, 1.23-1.50]; P=2.27×10-9; iron: OR, 1.44 [95% CI, 1.13-1.85]; P=0.0033). In replicate Mendelian randomization analysis, the detrimental effects of iron on poor functional outcome after IS remained stable (OR, 1.60 [95% CI, 1.24-2.08]; P=0.0003). In the meta-analysis, iron and TSAT were associated with poor functional outcomes after IS (TSAT: ORmeta, 1.35 [95% CI, 1.23-1.48]; iron: ORmeta, 1.51 [95% CI, 1.27-1.81]). Through sensitivity analyses and reverse Mendelian randomization analyses, we confirmed the robustness of the results. CONCLUSIONS: Our study provides evidence suggesting a potential causal relationship between iron status and poor functional outcomes after IS. Future studies are required to illuminate the underlying mechanism.

Causal association between circulating inflammatory cytokines and intracranial aneurysm and subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: The causal association between inflammatory cytokines and the development of intracranial aneurysm (IA), unruptured IA (uIA) and subarachnoid hemorrhage (SAH) lacks clarity. METHODS: The summary-level datasets for inflammatory cytokines were extracted from a genome-wide association study of the Finnish Cardiovascular Risk in Young Adults Study and the FINRISK survey. The summary statistics datasets related to IA, uIA and SAH were obtained from the genome-wide association study meta-analysis of the International Stroke Genetics Consortium and FinnGen Consortium. The primary method employed for analysis was inverse variance weighting (false discovery rate), supplemented by sensitivity analyses to address pleiotropy and enhance robustness. RESULTS: In the International Stroke Genetics Consortium, 10, six and eight inflammatory cytokines exhibited a causal association with IA, uIA and SAH, respectively (false discovery rate, p < 0.05). In FinnGen datasets, macrophage Inflammatory Protein-1 Alpha (MIP_1A), MIP_1A and interferon γ-induced protein 10 (IP_10) were verified for IA, uIA and SAH, respectively. In the reverse Mendelian randomization analysis, the common cytokines altered by uIA and SAH were vascular endothelial growth factor (VEGF), MIP_1A, IL_9, IL_10 and IL_17, respectively. The meta-analysis results show that MIP_1A and IP_10 could be associated with the decreased risk of IA, and MIP_1A and IP_10 were associated with the decreased risk of uIA and SAH, respectively. Notably, the levels of VEGF, MIP_1A, IL_9, IL_10 and TNF_A were increased with uIA. Comprehensive heterogeneity and pleiotropy analyses confirmed the robustness of these results. CONCLUSION: Our study unveils a bidirectional association between inflammatory cytokines and IA, uIA and SAH. Further investigations are essential to validate their relationship and elucidate the underlying mechanisms.

The association of glaucoma with ischemic stroke and functional outcome after ischemic stroke from the perspective of causality.

INTRODUCTION: Glaucoma may be related to ischemic stroke (IS) and poor outcomes after IS in observational studies, while the causal association remains unclear. METHODS: We obtained single nucleotide polymorphisms (SNPs) related to glaucoma from the gene-wide association study (GWAS) conducted by the FinnGen consortium. The GWAS included a total of 13,614 cases and 295,540 controls. The summary-level of datasets regarding IS were collected from the MEGASTROKE consortium, including 34,217 cases and 406,111 controls. Furthermore, we acquired summary statistics datasets for functional outcomes following IS from the GWAS meta-analysis conducted by the GISCOME consortium, which involved 6,021 individuals. The genetic association estimates for functional outcomes at 90 days after IS were evaluated by the modified Rankin Score (mRS), including 3,741 cases with good functional outcomes (mRS=0-2) and 2,280 subjects with poor functional outcomes post-stroke (mRS=3-6). Inverse variance weighting (IVW) was used as the primary method, complemented by sensitivity analyses for pleiotropy and increasing robustness. RESULTS: Genetically, glaucoma is associated with an increased risk of IS (odds ratio [OR]=1.08, 95% confidence interval [CI] = 1.02-1.14, P = 0.0039), as well as poor prognosis after IS with adjustment for severity (OR=1.64; 95% CI=1.27-2.13, P=0.0001) and functional outcome after IS (OR=1.45, 95% CI=1.12-1.87, P=0.0038). Through sensitivity analyses, we confirmed the robustness of the results. In addition, we did not identify any causal association between IS, functional outcome after IS, and glaucoma in reverse analysis. CONCLUSION: Our study provides evidence suggesting a potential genetic causal relationship between glaucoma and an increased risk of IS, as well as a poor functional outcome following IS. Future studies are necessary to confirm these findings.

A causal effects of gut microbiota in the development of migraine.

BACKGROUND: The causal association between the gut microbiome and the development of migraine and its subtypes remains unclear. METHODS: The single nucleotide polymorphisms concerning gut microbiome were retrieved from the gene-wide association study (GWAS) of the MiBioGen consortium. The summary statistics datasets of migraine, migraine with aura (MA), and migraine without aura (MO) were obtained from the GWAS meta-analysis of the International Headache Genetics Consortium (IHGC) and FinnGen consortium. Inverse variance weighting (IVW) was used as the primary method, complemented by sensitivity analyses for pleiotropy and increasing robustness. RESULTS: In IHGC datasets, ten, five, and nine bacterial taxa were found to have a causal association with migraine, MA, and MO, respectively, (IVW, all P < 0.05). Genus.Coprococcus3 and genus.Anaerotruncus were validated in FinnGen datasets. Nine, twelve, and seven bacterial entities were identified for migraine, MA, and MO, respectively. The causal association still exists in family.Bifidobacteriaceae and order.Bifidobacteriales for migraine and MO after FDR correction. The heterogeneity and pleiotropy analyses confirmed the robustness of IVW results. CONCLUSION: Our study demonstrates that gut microbiomes may exert causal effects on migraine, MA, and MO. We provide novel evidence for the dysfunction of the gut-brain axis on migraine. Future study is required to verify the relationship between gut microbiome and the risk of migraine and its subtypes and illustrate the underlying mechanism between them.

Deep Succinylproteomics of Brain Tissues from Intracerebral Hemorrhage with Inhibition of Toll-Like Receptor 4 Signaling.

It is unclear how Toll-like receptor (TLR) 4 signaling affects protein succinylation in the brain after intracerebral hemorrhage (ICH). Here, we constructed a mouse ICH model to investigate the changes in ICH-associated brain protein succinylation, following a treatment with a TLR4 antagonist, TAK242, using a high-resolution mass spectrometry-based, quantitative succinyllysine proteomics approach. We characterized the prevalence of approximately 6700 succinylation events and quantified approximately 3500 sites, highlighting 139 succinyllysine site changes in 40 pathways. Further analysis showed that TAK242 treatment induced an increase of 29 succinyllysine sites on 28 succinylated proteins and a reduction of 24 succinyllysine sites on 23 succinylated proteins in the ICH brains. TAK242 treatment induced both protein hypersuccinylations and hyposuccinylations, which were mainly located in the mitochondria and cytoplasm. GO analysis showed that TAK242 treatment-induced changes in the ICH-associated succinylated proteins were mostly located in synapses, membranes and vesicles, and enriched in many cellular functions/compartments, such as metabolism, synapse, and myelin. KEGG analysis showed that TAK242-induced hyposuccinylation was mainly linked to fatty acid metabolism, including elongation and degradation. Moreover, a combined analysis of the succinylproteomic data with previously published transcriptome data revealed that most of the differentially succinylated proteins induced by TAK242 treatment were mainly distributed throughout neurons, astrocytes, and endothelial cells, and the mRNAs of seven and three succinylated proteins were highly expressed in neurons and astrocytes, respectively. In conclusion, we revealed that several TLR4 signaling pathways affect the succinylation processes and pathways in mouse ICH brains, providing new insights on the ICH pathophysiological processes. Data are available via ProteomeXchange with identifier PXD025622.

Fast-developing fatal diffuse leptomeningeal dissemination of a pineal germinoma in a young child: a case report and literature review.

BACKGROUND: Intracranial germinomas are uncommon and constitute less than 1% of all intracranial tumors. They usually arise in the midline of the brain, most commonly in the pineal region. Pineal germinomas tend to spread through the cerebrospinal fluid (CSF). However, pineal germinomas with fast-developing diffuse subarachnoid/leptomeningeal dissemination are extremely rare, especially in young children. METHODS: The case of a 4-year-old boy with a pineal germinoma who died of diffuse subarachnoid/leptomeningeal dissemination 1 month after radiotherapy is reported. A PubMed search with specific key terms was used to review cases of pineal germinomas with metastasis. RESULTS: The patient presented with a two-week history of worsening headache, visual disturbances and nonprojectile vomiting. Parinaud's sign was positive on physical examination. Head computed tomography (CT)/magnetic resonance imaging (MRI) revealed a lesion in the pineal region with eccentric calcification and obvious supratentorial hydrocephalus. Pineal germinoma was suspected. A ventriculoperitoneal (VP) shunt followed by focal radiotherapy ameliorated the headaches and visual disturbances. The patient was discharged home without further treatment due to financial difficulties. One month after discharge, he was readmitted due to worsening headache, vomiting and lethargy. MRI showed a decrease in the size of the pineal lesion but revealed a diffuse leptomeningeal enhancement including the sulcus, basal cistern, prepontine cistern, and supravermian cistern. The patient's condition deteriorated rapidly, and he died 26 hours after readmission. The characteristics of pineal germinomas with metastasis are reported based on a review of the literature. CONCLUSIONS: Metastases in pineal germinomas predominately occur in adolescents or young adults, most commonly as spinal "drop metastases." Dissemination usually develops several years after the initial tumor diagnosis and has a relatively good clinical prognosis. However, fast widespread subarachnoid/leptomeningeal dissemination and sudden death may occur in a young child before salvage treatment, as in the presented case.

Identification of RPL5 and RPL10 as novel diagnostic biomarkers of Atypical teratoid/rhabdoid tumors.

BACKGROUND: Rhabdoid tumors (RTs) are aggressive tumors that occur most frequently in children under 2 years old, which often invade kidney (KRTs) and Center Nervous System, named Atypical teratoid/rhabdoid tumors (AT/RTs). RTs often progress fast and lead to a high lethality. RTs have a low incidence, we can hardly accumulate enough samples to elicit the diagnosis. More importantly, histologically, RTs present a host of neural, epithelial, mesenchymal, or ependymal patterns, which makes them rather variable and difficult to diagnose. Molecularly, RTs are diagnosed mainly on the lack of SMARCB1/INI1 protein expression, which, on the one hand, accounts for 75% of RTs, on the other hand, loss of expression of SMARCB1 is not exclusive to RTs. So, there is a need to find more accurate diagnose markers of RTs. METHODS: In this study, we analyzed 109 samples including AT/RT, KRT and corresponding normal samples downloaded form NCBI GEO database. First, we identified the differentially expressed lncRNAs and PCGs in AT/RT, KRT and corresponding normal samples. Second, we evaluated the co-expression relationship between lncRNA and PCG, and defined four types of the dysregulated PCG-lncRNA pairs. Third, we compared the differentially expressed genes, the dysregulated PCG-lncRNA pairs and commonly known cancer genes, we get potential diagnostic markers. Then, the potential diagnostic markers were subjected to Receiver operating characteristic (ROC) analysis to assess the diagnostic accuracy. Importantly, differential expression of the marker genes in different tumors was shown to distinguish AT/RT and KRT from other pediatric tumors specifically. RESULTS: We compared the expression profiles between 47 AT/RTs, 31 KRTs, 8 normal brain samples, and 23 normal kidney samples. After applying a stringent set of criteria on the gene expression profiles, we identified 3667 PCGs and 81 lncRNAs differentially expressed in AT/RT, 3809 PCGs and 34 lncRNAs differentially expressed in KRT tissues. Next, we compared the three sets(AT/RT versus control brain samples, KRT versus control kidney samples, and AT/RT versus KRT) of differentially expressed lncRNAs and PCGs, 491 PCGs and 2 lncRNAs appeared in all three sets. We examined the correlation of the expression levels of these genes in the 'three-set overlap' group and identified four types of dysregulated lncRNAs and PCGs. By compared these genes to the well-known cancer driver genes, 19 PCGs were selected as potential candidates of diagnostic markers. Filtered with the number of the corresponding co-expressed lncRNA (namely "degree"), eight PCGs with more than five lncRNAs in the 'three-set overlap' group were selected as candidate diagnostic markers. Among them, RPL5 and RPL10 exhibited high sensitivity and specificity in diagnosis of AT/RT and KRT. However, when these two genes were used to distinguish AT/RT and KRT from other pediatric tumors, only AT/RT can be distinguished from medulloblastoma. CONCLUSIONS: Our study mined existing GEO datasets for novel diagnostic markers associated with Rhabdoid tumors, and identified RPL5 and RPL10 as potential diagnostic markers for AT/RT. These two biomarkers may be used as supplementary biomarkers to canonical diagnostic tools such as biopsy and immunohistochemistry.

Hyperglycemia Predicts Blend Sign in Patients with Intracerebral Hemorrhage.

BACKGROUND Predictive values of admission blood glucose for early hematoma expansion in patients with intracranial hemorrhage (ICH) remain controversial. Blend sign is a novel image predictor for early hematoma growth that suggests presence of active bleeding. We investigated the association between hyperglycemia and blend sign in predicting early hematoma growth in ICH patients. MATERIAL AND METHODS All patients with intracranial hemorrhage were retrospectively reviewed. Clinical characteristics and radiological parameters were collected. Blood glucose was measured within 24 h after onset. CT scan results for hematoma expansion and blend sign were evaluated by 2 readers. Multivariate logistic regression analyses were applied to reveal the associations between hematoma growth and blend sign, as well as other variables. RESULTS Out of 164 patients with ICH, 52 exhibited early hematoma growth and 18 of these were diagnosed with blend sign. Average blood glucose was 7.53 mmol/L among all patients. By using multivariate analyses, the time of CT scan baseline, GCS score, hematoma size, blend sign, and blood glucose were associated with hematoma expansion, whereas only hyperglycemia was associated with blend sign. CONCLUSIONS Admission hyperglycemia is associated with hematoma expansion in the presence of blend sign. These findings suggest that elevated blood glucose is a possible factor predicting continuous bleeding. Strategies to control blood glucose and ameliorate hematoma growth are urgently needed and will be investigated in our future studies.

Effect of Admission Hyperglycemia on 6-Month Functional Outcome in Patients with Spontaneous Cerebellar Hemorrhage.

BACKGROUND Cerebellar hemorrhage (CH) has a quite different treatment strategy and prognostic factors compared with supratentorial intracerebral hemorrhage (ICH). The prognostic role of hyperglycemia has been discussed mainly in cases of supratentorial hemorrhage; it remains to be elucidated following CH. We aimed to determine the association of hyperglycemia on admission with 6-month functional outcome in CH patients. MATERIAL AND METHODS We retrospectively analyzed 77 patients with acute CH between September 2010 and April 2015 in West China Hospital. Blood glucose level was measured when the patients were admitted. Primary outcome was 6-month functional outcome, which could comprehensively reflect the patient's recovery of physical and social ability after stroke and was assessed by the modified Rankin scale (mRS). Association of hyperglycemia with functional outcome was identified in logistic regression models. RESULTS There were 50 (64.9%) patients with poor functional outcomes. Patients with poor outcome were much older (P<0.001) and had a significantly higher glucose level on admission (P<0.001), a lower Glasgow Coma Scale score (P<0.001), a larger hematoma (P=0.003), and a higher incidence of intraventricular extension (P=0.002), brainstem compression (P=0.013), and hydrocephalus (P=0.023). Multivariate analysis showed that hyperglycemia (OR 1.50, 95% CI 1.07-2.08, P=0.017 when glucose level was analyzed as a continuous variable; OR 7.46, 95% CI 1.41-39.51, P=0.018 when glucose level was dichotomized by the critical threshold of 6.78 mmol/L) emerged as an independent predictor for adverse functional outcome at 6 months. CONCLUSIONS To the best of our knowledge, this is the first study focusing on the relationship between hyperglycemia and long-term functional outcome after CH. The study combined with previous pertinent reports definitely indicates the poor effect of hyperglycemia on both supra- and infratentorial ICH independent of hemorrhage site. Therefore, further controlled trials are urgently needed to evaluate the benefits of glucose-lowing treatment.

Clinical Value of Neutrophil to Lymphocyte and Platelet to Lymphocyte Ratio After Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Inflammation and thrombosis are associated with the pathogenesis of aneurysmal subarachnoid hemorrhage (aSAH) and neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) are emerging as novel inflammatory markers in stroke. We aimed to identify the association of NLR and PLR with delayed cerebral ischemia (DCI) and 3-month outcome after aSAH. METHODS: Two hundred and forty-seven patients diagnosed with aSAH within 24 h of symptoms onset were enrolled. Clinical, neuroradiological, laboratory, and follow-up data were collected from electronic database. Functional outcome was assessed by modified Rankin Scale. Admission NLR, PLR, and combined NLR-PLR associated with outcomes were evaluated by logistic regression analysis, and we used receiver operating characteristic curves to detect the overall predictive accuracy of these markers. RESULTS: Fifty-five (22.3 %) patients had unfavorable outcome and 47 (19 %) developed DCI. Both NLR and PLR were correlated with WFNS grade (ρ = 0.35[p < 0.001], ρ = 0.28[p < 0.001]) and modified Fisher grade (ρ = 0.25[p = 0.001], ρ = 0.28[p = 0.003]) and independently related to DCI (OR 2.18, 95 %CI 1.51-3.15, p = 0.016; OR 2.21, 95 %CI 1.61-3.32, p = 0.008) and functional outcome (OR 1.89, 95 %CI 1.52-3.17, p = 0.015; OR 1.77, 95 %CI 1.48-3.21, p = 0.018) at 3 months after aneurysm repair. They had comparable predictive ability in DCI occurrence (area under the curve [AUC] 0.65, 95 %CI 0.55-0.74, p = 0.002; AUC 0.68, 95 %CI 0.60-0.76, p < 0.001) and poor outcome (AUC 0.70, 95 %CI 0.63-0.77, p < 0.001; AUC 0.65, 95 %CI 0.58-0.72, p = 0.001). However, combination of the two indexes showed a better predictive value than each alone (AUC 0.73, 95 %CI 0.66-0.81, p < 0.001 for DCI; AUC 0.76, 95 %CI 0.70-0.83, p < 0.001 for poor outcome). CONCLUSIONS: NLR and PLR as novel inflammatory biomarkers are independent predictors of DCI development and functional outcome after acute aSAH. When combined together, they may help to identify high-risk patients more powerfully.

The MTHFR C677T Polymorphism and Risk of Intracerebral Hemorrhage in a Chinese Han Population.

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism has been speculated to be and extensively investigated as a risk factor for various vascular diseases, including intracerebral hemorrhage (ICH). However, results from published studies regarding the role of C677T polymorphism in ICH risk in Chinese populations were contradictory rather than conclusive. MATERIAL/METHODS: In this study, a total of 180 ICH patients and 180 matched controls of Chinese Han ethnicity were enrolled. The MTHFR C677T polymorphism was genotyped by polymerase chain reaction-ligation detection reaction (PCR-LDR). A meta-analysis was conducted by combining our data with previous relevant studies in Chinese populations. RESULTS: In our case-control study, similar allele frequency (p=0.492) and genotype distribution (p=0.748) of MTHFR C677T polymorphism were detected between ICH patients and controls. Further analysis based on hematoma location did not show a significant association. When combined with previous studies, however, C677T polymorphism was found to be significantly associated with an increased risk for ICH in Chinese populations (recessive model: OR=1.57, 95%CI=1.29-1.91). When focusing on the Han ethnicity, carriers of the TT genotype had an increased risk of ICH (recessive model: OR=1.36, 95%CI=1.05-1.75). CONCLUSIONS: In this case-control study we did not observe that the MTHFR C677T polymorphism was associated with ICH risk in people of Chinese Han ethnicity. However, when combined with previous published studies, a significant association of C677T polymorphism with an increased risk of ICH was detected in Chinese populations, and also in the subgroup analysis focusing on Han ethnicity.

A Novel Brainstem Hemorrhage Model by Autologous Blood Infusion in Rat: White Matter Injury, Magnetic Resonance Imaging, and Neurobehavioral Features.

BACKGROUND: Primary brainstem hemorrhage (BSH) has the highest mortality and morbidity as a subtype of intracerebral hemorrhage. A major limitation of BSH research is the lack of a corresponding animal model. The purpose of this study was to establish a novel rat model of BSH and to characterize the resulting brain injury, especially focusing on white matter injury. METHODS: BSH was produced by stereotactically injecting autologous whole blood into the pons. Time course of hematoma resolution was observed by 7-T magnetic resonance imaging. White matter injury was evaluated in detail by multiple parameters including diffuse tensor imaging (DTI), demyelination, axonal injury, oligodendrocyte degeneration, and oligodendrocyte precursor cell proliferation. Brain water content and neurobehavior were also evaluated. RESULTS: Blood infusion (30 µL) led to a stable, reproducible hematoma in the right basotegmental pons. The hematoma absorption started, became obvious, and was nearly completed at 7, 14, and 30 days, respectively. Hematoma caused obvious brain edema at 3 days. White mater injury was observed pathologically, which was in line with decreased fractional anisotropy (FA) in DTI in the pons. FA reduction was also noticed in the cerebral peduncle and medulla. Behavioral abnormality persisted for at least 14 days and neurofunction was recovered within 1 month. CONCLUSIONS: This novel model can produce a stable hematoma resulting in brain edema, white matter injury, and neurofunctional deficits, which could be useful for future investigation of pathophysiological mechanisms and new treatment evaluation after BSH.

Malignant intraventricular meningioma with craniospinal dissemination and concurrent pulmonary metastasis.

BACKGROUND: Malignant intraventricular meningiomas are quite rare and may spread along the craniospinal axis or extraneurally. However, simultaneous cerebrospinal dissemination and distal extraneural metastasis has seldom been reported. CASE PRESENTATION: A 51-year-old woman presented with recurrent anaplastic meningioma in the trigone of right lateral ventricle over a 1.5-year period. Suggested radiotherapy was refused after each operation. The patient showed a local relapse and dissemination around the previous tumoral cavity and along the spinal canal during the last recurrence. Left pulmonary metastasis was also found. She died despite multiple lesion resections. CONCLUSIONS: Malignant intraventricular meningiomas are an uncommon subset of intracranial meningiomas, and have a great potential for intraneural and extraneural metastasis. Systemic investigation for metastasis is required after surgery, especially for those without adjuvant therapies.

Upper thoracic intradural-extramedullary cavernous malformation presenting as subarachnoid hemorrhage without spinal dysfunction: a case report and review of the literature.

A 45-year-old man had subarachnoid hemorrhage (SAH) which was confirmed by lumbar puncture, since it was negative on head computed tomography. The result of neurological examination was normal. Following pan-cerebral angiography and cranial magnetic resonance imaging (MRI) failed to find out the cause of bleeding. The whole spinal MRI revealed an intradural-extramedullary mass lesion at the upper thoracic level which was consistent with cavernous malformation after surgery. When patients presented with SAH of no spinal symptoms, the diagnosis of an intradural-extramedullary cavernous malformation is challenging. A whole spinal workup should be considered in a patient with spontaneous SAH when bleeding from intracranial origin is carefully excluded.

Potential Biomarkers in Cerebrospinal Fluid and Plasma for Dementia.

Background: The identification of biomarkers for different dementias in plasma and cerebrospinal fluid (CSF) has made substantial progress. However, they are observational studies, and there remains a lack of research on dementias with low incidence rates. Objective: We performed a comprehensive Mendelian randomization to identify potential biomarkers for different dementia type. Methods: The summary-level datasets encompassed 734 plasma and 154 cerebrospinal fluid proteins sourced from recently published genome-wide association studies (GWAS). Summary statistics for different dementias, including any dementia (refering to any type of dementia symptoms, 218,792 samples), Alzheimer's disease (AD, 63,926 samples), vascular dementia (212,389 samples), frontotemporal dementia (3,024 samples), dementia with Lewy bodies (DLB, 6,618 samples), and dementia in Parkinson's disease (216,895 samples), were collected from large GWAS. The primary method is inverse variance weighting, with additional sensitivity analyses conducted to ensure the robustness of the findings. Results: The molecules released into CSF, namely APOE2 for any dementia, APOE2 and Siglec-3 for AD, APOE2 for vascular dementia, and APOE2 for DLB, might be potential biomarkers. CD33 for AD and SNCA for DLB in plasma could be promising biomarkers. Conclusions: This is the first study to integrate plasma and CSF proteins to identify potential biomarkers for different dementias.

Potential causal association between gut microbiome and posttraumatic stress disorder.

BACKGROUND: The causal effects of gut microbiome and the development of posttraumatic stress disorder (PTSD) are still unknown. This study aimed to clarify their potential causal association using mendelian randomization (MR). METHODS: The summary-level statistics for gut microbiome were retrieved from a genome-wide association study (GWAS) of the MiBioGen consortium. As to PTSD, the Freeze 2 datasets were originated from the Psychiatric Genomics Consortium Posttraumatic Stress Disorder Working Group (PGC-PTSD), and the replicated datasets were obtained from FinnGen consortium. Single nucleotide polymorphisms meeting MR assumptions were selected as instrumental variables. The inverse variance weighting (IVW) method was employed as the main approach, supplemented by sensitivity analyses to evaluate potential pleiotropy and heterogeneity and ensure the robustness of the MR results. We also performed reverse MR analyses to explore PTSD's causal effects on the relative abundances of specific features of the gut microbiome. RESULTS: In Freeze 2 datasets from PGC-PTSD, eight bacterial traits revealed a potential causal association between gut microbiome and PTSD (IVW, all P < 0.05). In addition, Genus.Dorea and genus.Sellimonas were replicated in FinnGen datasets, in which eight bacterial traits revealed a potential causal association between gut microbiome and the occurrence of PTSD. The heterogeneity and pleiotropy analyses further supported the robustness of the IVW findings, providing additional evidence for their reliability. CONCLUSION: Our study provides the potential causal impact of gut microbiomes on the development of PTSD, shedding new light on the understanding of the dysfunctional gut-brain axis in this disorder. Our findings present novel evidence and call for investigations to confirm the association between their links, as well as to illuminate the underlying mechanisms.

A protective role of genetically predicted sex hormone-binding globulin on stroke.

Introduction: The role of sex hormone-binding globulin (SHBG) on stroke has been investigated in several observational studies. To provide the causal estimates of SHBG on stroke and its subtypes, bi-directional and multivariable Mendelian randomization (MR) analyses are performed. Methods: The genetic instruments of SHBG were obtained from the UK Biobank. Outcome datasets for stroke and its subtypes were taken from the MEGASTROKE Consortium. The main analysis used in this study is the inverse variance weighting, complemented by other sensitivity approaches to verify the conformity of findings. Results: We found that the risk of stroke grew by 13% (odd ratio [OR] = 0.87, 95% confidence interval [CI] = 0.79-0.95, P = 0.0041) and the risk of ischemic stroke grew by 15% (OR = 0.85, 95%CI = 0.77-0.95, P = 0.0038) caused by genetically predicted SHBG. The causal association remains robust in the reverse MR and multivariable MR analyses for stroke (reverse MR: all P > 0.01 for the IVW method; MVMR: OR = 0.72, 95%CI = 0.59-0.87, P = 0.0011) and ischemic stroke (reverse MR: all P > 0.01 for IVW; MVMR: OR = 0.70, 95%CI = 0.56-0.86, P = 0.0007). Conclusion: Our MR study provides novel evidence that SHBG has an inverse association with stroke and ischemic stroke, exerting protective effects on stroke.

Comprehensive analysis of immune cell infiltration and role of MSR1 expression in aneurysmal subarachnoid haemorrhage.

Aneurysmal subarachnoid haemorrhage (aSAH), resulting from the rupture of intracranial aneurysms, can yield high mortality and disability. This study aimed to explore the immune infiltration of aneurysmal tissues and investigate a novel mechanism underlying aSAH. We downloaded datasets containing expression profiles of aneurysmal and normal arterial tissues from the online database. Then a comprehensive bioinformatic strategy was conducted to select the biomarkers of aneurysmal tissues. Two calculation algorithms were performed to identify the unique immune characteristics between aneurysmal tissues and normal arteries. Double immunofluorescence staining was used to investigate the role of pathway-related proteins in the inflammatory process after aSAH. Six microarray datasets were integrated, and another RNA-sequencing dataset was used as the validation dataset. Functional enrichment analysis of the differentially expressed genes indicated that immune-related processes were closely related to the progression of aSAH. We then performed immune microenvironment infiltration analysis, and the results suggested macrophages were abnormally enriched in aneurysmal tissues. Core gene MSR1 was filtered through a comprehensive bioinformatic strategy. Our analysis suggested that MSR1 might be associated with macrophage activation and migration. Our study elucidated the impact of macrophage and MSR1 on aSAH progression. These findings were helpful in gaining insight into the immune heterogeneity of aneurysmal tissues and normal arteries, and in identifying patients who might benefit from immunotherapy.

Needle-tip electrocautery versus steel scalpel incision in neurosurgery: study protocol for a prospective single-centre randomised controlled double-blind trial.

INTRODUCTION: Electrocautery is used widely in surgical procedures, but making skin incision has routinely been performed with scalpel rather than electrocautery, for fear that electrocautery may cause poor incision healing, excessive scarring and increased wound complication rates. More and more studies on general surgery support the use of electrocautery for skin incision, but research comparing the two modalities for scalp incision in neurosurgery remains inadequate. This trial aims to evaluate the safety and efficacy of needle-tip monopolar for scalp incision in supratentorial neurosurgery compared with steel scalpel. METHODS AND ANALYSIS: In this prospective, randomised, double-blind trial, 120 eligible patients who are planned to undergo supratentorial neurosurgery will be enrolled. Patients will be randomly assigned to two groups. In controlled group scalp incision will be made with a scalpel from the epidermis to the galea aponeurotica, while in intervention group scalp will be first incised with a steel scalpel from the epidermis to the dermis, and then the subcutaneous tissue and galea aponeurotica will be incised with needle-tip monopolar on cutting mode. The primary outcomes are scar score (at 90 days). The secondary outcomes include incision pain (at 1 day, on discharge, at 90 days) and alopecia around the incision (at 90 days), incision blood loss and incision-related operation time (during operation), incision infection and incision healing (on discharge, at 2 weeks, 90 days). ETHICS AND DISSEMINATION: This trial will be performed according to the principles of Declaration of Helsinki and good clinical practice guidelines. This study has been validated by the ethics committee of West China Hospital. Informed consent will be obtained from each included patient and/or their designated representative. Final results from this trial will be promulgated through publications. TRIAL REGISTRATION NUMBER: ChiCTR2200063243.

Genetic Insights into the Risk of Metabolic Syndrome and Its Components on Dementia: A Mendelian Randomization.

BACKGROUND: The role of metabolic syndrome (MetS) on dementia is disputed. OBJECTIVE: We conducted a Mendelian randomization to clarify whether the genetically predicted MetS and its components are casually associated with the risk of different dementia types. METHODS: The genetic predictors of MetS and its five components (waist circumference, hypertension, fasting blood glucose, triglycerides, and high-density lipoprotein cholesterol [HDL-C]) come from comprehensive public genome-wide association studies (GWAS). Different dementia types are collected from the GWAS in the European population. Inverse variance weighting is utilized as the main method, complemented by several sensitivity approaches to verify the robustness of the results. RESULTS: Genetically predicted MetS and its five components are not causally associated with the increasing risk of dementia (all p > 0.05). In addition, no significant association between MetS and its components and Alzheimer's disease, vascular dementia, frontotemporal dementia, dementia with Lewy bodies, and dementia due to Parkinson's disease (all p > 0.05), except the association between HDL-C and dementia with Lewy bodies. HDL-C may play a protective role in dementia with Lewy bodies (OR: 0.81, 95% CI: 0.72-0.92, p = 0.0010). CONCLUSIONS: From the perspective of genetic variants, our study provides novel evidence that MetS and its components are not associated with different dementia types.