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Background: Ambulance-based telestroke may be a promising solution to improving stroke care. We assessed the technical feasibility and reliability of prehospital evaluations using commercial mobile phones with fifth-generation wireless communication technology., Methods: Six standardized patients portrayed scripted stroke scenarios during ambulance transport in an urban city and were remotely evaluated by independent raters using tablets (three neurologists and three emergency physicians) in a hospital, assisted by paramedics (trained in National Institute of Health Stroke Scale [NIHSS] assessment) in the ambulance; commercial cellular networks were utilized for videoconferencing transmission. The primary outcomes were mean difference (MD) and correlation of NIHSS scores between the face-to-face and remote assessments. We also examined the Bland-Altman plot for itemized NIHSS components, and Kaplan-Meier curves were used to compare the differences in the duration of the two evaluations between neurologists and emergency physicians., Results: We conducted 32 ambulance runs and successfully completed all NIHSS examinations. No significant difference was found between the face-to-face and remote evaluations (MD, 0.782; 95% confidence interval [CI], -0.520-0.395). The correlation of NIHSS scores between the two methods was 0.994 (95% CI, 0.945-1.026), and three items exhibited the highest frequency of runs, with score differences between the two methods. There were no significant differences between neurologists and emergency physicians in the mean evaluation duration and NIHSS scores for the two methods., Conclusion: Prehospital evaluation using commercial mobile phones with fifth-generation wireless communication technology is feasible and reliable during ambulance transport in urban areas. Emergency physicians and neurologists performed similarly in stroke evaluations., Competing Interests: Declaration of competing interest None declared., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Objective: Recurrent stroke after revascularization surgeries predicts poor outcome in patients with moyamoya disease (MMD). Early identification of patients with stroke risk paves the way for rescue intervention. This study aimed to investigate the role of ultrasound in identifying patients at risk of post-operative ischemic events (PIEs)., Methods: This prospective study enrolled patients with symptomatic MMD who underwent indirect revascularization surgeries. Ultrasound examinations were performed preoperatively and at 3 mo post-operatively to evaluate the hemodynamic changes in extracranial and intracranial arteries on the operated side. PIE was defined as ischemic stroke or transient ischemic attack in the operated hemisphere within 1 y. The areas under receiver operating characteristic curves were compared between models for prediction of PIE., Results: A total of 56 operated hemispheres from 36 patients (mean age, 23.0 ± 18.5 y) were enrolled in this study, and 27% developed PIE. In multivariate logistic regression models, PIE was associated with lower end-diastolic velocity and flow volume (FV) of the ipsilateral external carotid artery (ECA), and lower FV of ipsilateral superficial temporal artery and occipital artery at 3 mo post-operatively (all p < 0.05). Moreover, the post-operative FV of the ipsilateral ECA was the only one factor that significantly increased the areas under receiver operating characteristic curves from 0.727 to 0.932 when adding to a clinical-angiographic model for prediction of PIE (p = 0.017). This parameter was significantly lower in hemispheres with PIE, both in adult and pediatric patients., Conclusion: After indirect revascularization, surgeries in patients with symptomatic MMD, FV of ipsilateral ECA at 3 mo helps clinicians to identify patients at risk of PIE., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2024 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

This study used epigenomic methylation differential expression analysis to identify primary biomarkers in patients with amyotrophic lateral sclerosis (ALS). We combined electronic medical record datasets from MIMIC-IV (United States) and NHIRD (Taiwan) to explore ALS comorbidities in depth and discover any comorbidity-related biomarkers. We also applied word2vec to these two clinical diagnostic medical databases to measure similarities between ALS and other similar diseases and evaluated the statistical assessment of the odds ratio to discover significant comorbidities for ALS subjects. Important and representative DNA methylation biomarker candidates could be effectively selected by cross-comparing similar diseases to ALS, comorbidity-related genes, and differentially expressed methylation loci for ALS subjects. The screened epigenomic and comorbidity-related biomarkers were clustered based on their genetic functions. The candidate DNA methylation biomarkers associated with ALS were comprehensively discovered. Gene ontology annotations were then applied to analyze and cluster the candidate biomarkers into three different groups based on gene function annotations. The results showed that a potential testing kit for ALS detection can be composed of SOD3 , CACNA1H , and ERBB4 for effective early screening of ALS using blood samples. By developing an effective DNA methylation biomarker screening mechanism, early detection and prophylactic treatment of high-risk ALS patients can be achieved.

Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease characterized by progressive weakness and atrophy of skeletal muscles. With homozygous survival motor neuron 1 (SMN1) gene mutation, all SMA patients have at least one copy of the SMN2 gene, which provides an opportunity for drug targeting to enhance SMN expression. Current three disease modifying drugs, including nusinersen, onasemnogene abeparvovec, and risdiplam, have demonstrated impressive effectiveness in SMA treatment. Nusinersen is an antisense oligonucleotide targeting SMN2 pre-messenger RNA (mRNA) to modify alternative splicing and is effective in SMA children and adults, administrating via intermittent intrathecal injection. Onasemnogene abeparvovec is an adeno-associated viral vector carrying human SMN1 gene, featuring intravenous injection once in a lifetime for SMA patients less than 2 years of the age. Risdiplam is a small molecule also targeting SMN2 pre-mRNA and is effective in SMA children and adults with administration via oral intake once per day. Patients with SMA should receive these disease modifying therapies as soon as possible to not only stabilize disease progression, but potentially obtain neurological improvement. The development in these therapies has benefited patients with SMA and will potentially provide insight in future drug discovery for other neurodegenerative diseases. Keywords: Adeno-associated viral vector, antisense oligonucleotide, disease modifying therapy, gene therapy, motor neuron disease, spinal muscular atrophy.

Purpose of Review: Intracerebral hemorrhage (ICH) is a devastating stroke with limited medical treatments; thus, timely exploration of emerging therapeutic targets is essential. This review focuses on the latest strategies to mitigate secondary brain injury post-ICH other than targeting surgery or hemostasis, addressing a significant gap in clinical practice and highlighting potential improvements in patient outcomes., Recent Findings: Promising therapeutic targets to reduce secondary brain injury following ICH have recently been identified, including attenuation of iron toxicity and inhibition of ferroptosis, enhancement of endogenous resorption of hematoma, and modulation of perihematomal inflammatory responses and edema. Additionally, novel insights suggest the lymphatic system of the brain may potentially play a role in hematoma clearance and edema management. Various experimental and early-phase clinical trials have demonstrated these approaches may potentially offer clinical benefits, though most research remains in the preliminary stages., Summary: Continued research is essential to identify multifaceted treatment strategies for ICH. Clinical translation of these emerging targets could significantly enhance the efficacy of therapeutic interventions and potentially reduce secondary brain damage and improve neurological recovery. Future efforts should focus on large-scale clinical trials to validate these approaches, to pave the way for more effective treatment protocols for spontaneous ICH., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Nuclear receptor interaction protein (NRIP) is versatile and engages with various proteins to execute its diverse biological function. NRIP deficiency was reported to cause small myofibre size in adult muscle regeneration, indicating a crucial role of NRIP in myoblast fusion., Methods: The colocalization and interaction of NRIP with actin were investigated by immunofluorescence and immunoprecipitation assay, respectively. The participation of NRIP in myoblast fusion was demonstrated by cell fusion assay and time-lapse microscopy. The NRIP mutants were generated for mechanism study in NRIP-null C2C12 (termed KO19) cells and muscle-specific NRIP knockout (NRIP cKO) mice. A GEO profile database was used to analyse NRIP expression in Duchenne muscular dystrophy (DMD) patients., Results: In this study, we found that NRIP directly and reciprocally interacted with actin both in vitro and in cells. Immunofluorescence microscopy showed that the endogenous NRIP colocalized with components of invadosome, such as actin, Tks5, and cortactin, at the tips of cells during C2C12 differentiation. The KO19 cells were generated and exhibited a significant deficit in myoblast fusion compared with wild-type C2C12 cells (3.16% vs. 33.67%, p < 0.005). Overexpressed NRIP in KO19 cells could rescue myotube formation compared with control (3.37% vs. 1.00%, p < 0.01). We further confirmed that NRIP directly participated in cell fusion by using a cell-cell fusion assay. We investigated the mechanism of invadosome formation for myoblast fusion, which depends on NRIP-actin interaction, by analysing NRIP mutants in NRIP-null cells. Loss of actin-binding of NRIP reduced invadosome (enrichment ratio, 1.00 vs. 2.54, p < 0.01) and myotube formation (21.82% vs. 35.71%, p < 0.05) in KO19 cells and forced NRIP expression in KO19 cells and muscle-specific NRIP knockout (NRIP cKO) mice increased myofibre size compared with controls (over 1500 μm 2 , 61.01% vs. 20.57%, p < 0.001). We also found that the NRIP mRNA level was decreased in DMD patients compared with healthy controls (18 072 vs. 28 289, p < 0.001, N = 10 for both groups)., Conclusions: NRIP is a novel actin-binding protein for invadosome formation to induce myoblast fusion., (© 2024 The Author(s). Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

Background: Fibrin and platelet (FP)-rich clots have been shown to be associated with cancer-related stroke. This study aims to investigate the prognostic role of thrombus composition in clinical outcomes among cancer patients who experienced stroke and received endovascular thrombectomy (EVT)., Methods: We included acute ischemic stroke patients who underwent EVT between March 2015 and November 2021. These patients were categorized into three groups: those with active cancer, those with non-active cancer, and those without cancer. The percentages of FP in clots were quantified under hematoxylin and eosin staining. The primary outcome was defined as any stroke recurrence or mortality within 90 days following the index stroke event., Results: A total of 420 patients with retrieved clots were included in the study. This cohort comprised 50 patients with active cancer, 23 patients with non-active cancer, and 347 patients without cancer. The percentage of FP was significantly higher in thrombi retrieved from patients with active cancer compared with the other two groups. Patients in the active cancer group exhibited a higher rate of the primary outcome compared with the other groups. After adjusting for clinical variables, a higher percentage of FP in thrombi remained significantly associated with the primary outcome in the active cancer group (adjusted odds ratio (aOR) =1.03 (1.00-1.06), P=0.028), but not in the other two groups., Conclusion: Among stroke patients receiving EVT, thrombi with a higher percentage of FP not only identify individuals with active cancer but also predict stroke recurrence or mortality within 90 days., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Neurological deterioration within 24 h after intravenous thrombolysis with tissue plasminogen activator (tPA) is associated with poor outcomes in patients with acute ischemic stroke (AIS). This study aimed to elucidate the features of neurological deterioration specifically during tPA infusion in these patients., Methods: We analyzed patients with AIS receiving thrombolysis between January 2018 and December 2021. Very early neurological deterioration (VEND) was defined as an increase of 4 or more points in the National Institutes of Health Stroke Scale (NIHSS) score during tPA infusion. Poor functional outcome was defined as a modified Rankin Scale score of 3-6 at three months., Results: Among the 345 patients with AIS who received tPA, 8.4% had VEND; all of which were caused by ischemic progression. Patients with VEND had a higher prevalence of intracranial atherosclerotic disease (41% vs. 17%, P = 0.005). VEND independently predicted poor functional outcome in both groups with minor (NIHSS score <6) and non-minor (NIHSS score >6) stroke. Among patients with minor stroke, those with VEND were more likely to undergo endovascular thrombectomy (EVT) than those without (38% vs. 5%, P = 0.019). In patients receiving EVT after VEND, the NIHSS scores at 24 h, which were correlated with 3-month functional outcome, were lower in those with successful recanalization than in those without (12 ± 9 vs. 26 ± 7, P = 0.047)., Conclusion: VEND predicted poor functional outcomes in patients with AIS. Timely and successful recanalization using EVT potentially alleviates the negative impact of VEND on long-term outcomes., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

The clinical manifestations of sporadic amyotrophic lateral sclerosis (ALS) vary widely. However, the current classification of ALS is mainly based on clinical presentations, while the roles of electrophysiological and biomedical biomarkers remain limited. Herein, we investigated a group of patients with sporadic ALS and an ALS mouse model with superoxide dismutase 1 (SOD1)/G93A transgenes using nerve excitability tests (NET) to investigate axonal membrane properties and chemical precipitation, followed by enzyme-linked immunosorbent assay analysis to measure plasma misfolded protein levels. Six of 19 patients (31.6%) with sporadic ALS had elevated plasma misfolded SOD1 protein levels. In sporadic ALS patients, only those with elevated misfolded SOD1 protein levels showed an increased inward rectification in the current-threshold (I/V) curve and an increased threshold reduction in the hyperpolarizing threshold electrotonus (TE) in the NET study. Two familial ALS patients with SOD1 mutations also exhibited similar electrophysiological patterns of NET. For patients with sporadic ALS showing significantly increased inward rectification in the I/V curve, we noted an elevation in plasma misfolded SOD1 level, but not in total SOD1, misfolded C9orf72, or misfolded phosphorylated TDP43 levels. Computer simulations demonstrated that the aforementioned axonal excitability changes are likely associated with an increase in hyperpolarization-activated cyclic nucleotide-gated (HCN) current. In SOD1/G93A mice, NET also showed an increased inward rectification in the I/V curve, which could be reversed by a single injection of the HCN channel blocker, ZD7288. Daily treatment of SOD1/G93A mice with ZD7288 partially prevented the early motor function decline and spinal motor neuron death. In summary, sporadic ALS patients with elevated plasma misfolded SOD1 exhibited similar patterns of motor axonal excitability changes as familial ALS patients and ALS mice with mutant SOD1 genes, suggesting the existence of SOD1-associated sporadic ALS. The observed NET pattern of increased inward rectification in the I/V curve was attributable to an elevation in the HCN current in SOD1-associated ALS., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron (MN) degeneration, leading to neuromuscular junction (NMJ) dismantling and severe muscle atrophy. The nuclear receptor interaction protein (NRIP) functions as a multifunctional protein. It directly interacts with calmodulin or α-actinin 2, serving as a calcium sensor for muscle contraction and maintaining sarcomere integrity. Additionally, NRIP binds with the acetylcholine receptor (AChR) for NMJ stabilization. Loss of NRIP in muscles results in progressive motor neuron degeneration with abnormal NMJ architecture, resembling ALS phenotypes. Therefore, we hypothesize that NRIP could be a therapeutic factor for ALS., Methods: We used SOD1 G93A mice, expressing human SOD1 with the ALS-linked G93A mutation, as an ALS model. An adeno-associated virus vector encoding the human NRIP gene (AAV-NRIP) was generated and injected into the muscles of SOD1 G93A mice at 60 days of age, before disease onset. Pathological and behavioral changes were measured to evaluate the therapeutic effects of AAV-NRIP on the disease progression of SOD1 G93A mice., Results: SOD1 G93A mice exhibited lower NRIP expression than wild-type mice in both the spinal cord and skeletal muscle tissues. Forced NRIP expression through AAV-NRIP intramuscular injection was observed in skeletal muscles and retrogradely transduced into the spinal cord. AAV-NRIP gene therapy enhanced movement distance and rearing frequencies in SOD1 G93A mice. Moreover, AAV-NRIP increased myofiber size and slow myosin expression, ameliorated NMJ degeneration and axon terminal denervation at NMJ, and increased the number of α-motor neurons (α-MNs) and compound muscle action potential (CMAP) in SOD1 G93A mice., Conclusions: AAV-NRIP gene therapy ameliorates muscle atrophy, motor neuron degeneration, and axon terminal denervation at NMJ, leading to increased NMJ transmission and improved motor functions in SOD1 G93A mice. Collectively, AAV-NRIP could be a potential therapeutic drug for ALS., (© 2024. The Author(s).)

Research Question: Can spermatozoa penetrate maturing metaphase I (MI) oocytes, and render subsequent development following conventional IVF in a mouse model?, Design: ICR mice were used in this study. Metaphase II (MII) cumulus-oocyte complexes (COC) harvested 15 h after injection of human chorionic gonadotrophin (HCG) were used for IVF as the control group (Group 1). In the treatment group (Group 2), maturing MI COC harvested 7 h after HCG injection were used for IVF. Fertilization, pronuclear formation, cleavage, blastocyst formation, DNA methylation status, chromosome number and live birth rates were used to evaluate the developmental dynamics and competency of maturing MI oocytes following conventional IVF., Results: Maturing MI COC were fertilized using conventional IVF, and sperm penetration at MI-telophase I triggered oocyte activation. Most embryos resulting from fertilized MI oocytes developed to blastocyst stage during preimplantation development, albeit a substantial proportion of them were triploids due to the absence of the second meiotic division. Some of the embryos derived from fertilization of maturing oocytes were able to implant and gave rise to full-term development., Conclusion: Maturing MI COC from follicles before ovulation could be used for mouse IVF, and fertilized MI oocytes had high potential for development. Healthy offspring can be generated from maturing MI COC following conventional IVF. MI COC may represent a valuable source of 'usable' biomaterial in assisted reproduction. However, many embryos derived from MI COC via IVF have abnormal chromosome numbers in the mouse model. The implications of these findings for human IVF remain to be investigated., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: To investigate the peripheral nervous system involvement in S  sialidosis with typical features of myoclonus, seizure, and giant waves in somatosensory evoked potentials suggesting hyperexcitability in the central nervous system., Methods: The clinical presentation of patients with genetically confirmed sialidosis was recorded. Neurophysiological studies, including nerve conduction studies (NCSs), F-wave studies, and needle electromyography (EMG), were performed on these patients., Results: Six patients (M/F: 2:4) were recruited. In addition to the classical presentation, intermittent painful paresthesia was noted in four patients, and three of whom reported it as the earliest symptom. In the NCSs, one patient had reduced compound muscle action potential amplitudes in the right ulnar nerve, while another patient had prolonged distal motor latency in the bilateral tibial and peroneal nerves. Prolonged F-wave latency (83.3%), repeater F-waves (50%), and neurogenic polyphasic waves in EMG (in 2 out of 3 examined patients) were also noted. Interestingly, a very late response was noted in the F-wave study of all patients, probably indicating lesions involving the proximal peripheral nerve or spinal cord., Conclusion: In addition to the central nervous system, the peripheral nervous system is also involved in sialidosis, with corresponding clinical symptoms. Further study on these phenomena is indicated., (© 2024. The Author(s).)

The cytoophidium is an evolutionarily conserved subcellular structure formed by filamentous polymers of metabolic enzymes. In vertebrates, inosine monophosphate dehydrogenase (IMPDH), which catalyses the rate-limiting step in guanosine triphosphate (GTP) biosynthesis, is one of the best-known cytoophidium-forming enzymes. Formation of the cytoophidium has been proposed to alleviate the inhibition of IMPDH, thereby facilitating GTP production to support the rapid proliferation of certain cell types such as lymphocytes, cancer cells and pluripotent stem cells (PSCs). However, past studies lacked appropriate models to elucidate the significance of IMPDH cytoophidium under normal physiological conditions. In this study, we demonstrate that the presence of IMPDH cytoophidium in mouse PSCs correlates with their metabolic status rather than pluripotency. By introducing IMPDH2 Y12C point mutation through genome editing, we established mouse embryonic stem cell (ESC) lines incapable of forming IMPDH polymers and the cytoophidium. Our data indicate an important role of IMPDH cytoophidium in sustaining a positive feedback loop that couples nucleotide biosynthesis with upstream metabolic pathways. Additionally, we find that IMPDH2 Y12C mutation leads to decreased cell proliferation and increased DNA damage in teratomas, as well as impaired embryo development following blastocoel injection. Further analysis shows that IMPDH cytoophidium assembly in mouse embryonic development begins after implantation and gradually increases throughout fetal development. These findings provide insights into the regulation of IMPDH polymerisation in embryogenesis and its significance in coordinating cell metabolism and development., (© 2024. The Author(s).)

Tau, a hallmark of Alzheimer's disease, is poorly characterized in cerebral amyloid angiopathy. We aimed to assess the clinico-radiological correlations between tau positron emission tomography scans and cerebral amyloid angiopathy. We assessed cerebral amyloid and hyperphosphorylated tau in patients with probable cerebral amyloid angiopathy ( n = 31) and hypertensive small vessel disease ( n = 27) using 11 C-Pittsburgh compound B and 18 F-T807 positron emission tomography. Multivariable regression models were employed to assess radio-clinical features related to cerebral tau pathology in cerebral amyloid angiopathy. Cerebral amyloid angiopathy exhibited a higher cerebral tau burden in the inferior temporal lobe [1.25 (1.17-1.42) versus 1.08 (1.05-1.22), P < 0.001] and all Braak stage regions of interest ( P < 0.05) than hypertensive small vessel disease, although the differences were attenuated after age adjustment. Cerebral tau pathology was significantly associated with cerebral amyloid angiopathy-related vascular markers, including cortical superficial siderosis ( β = 0.12, 95% confidence interval 0.04-0.21) and cerebral amyloid angiopathy score ( β = 0.12, 95% confidence interval 0.03-0.21) after adjustment for age, ApoE4 status and whole cortex amyloid load. Tau pathology correlated significantly with cognitive score (Spearman's ρ =-0.56, P = 0.001) and hippocampal volume (-0.49, P = 0.007), even after adjustment. In conclusion, tau pathology is more frequent in sporadic cerebral amyloid angiopathy than in hypertensive small vessel disease. Cerebral amyloid angiopathy-related vascular pathologies, especially cortical superficial siderosis, are potential markers of cerebral tau pathology suggestive of concomitant Alzheimer's disease., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Primary aldosteronism is associated with various types of cardiovascular and cerebrovascular damage independently of hypertension. Although chronic hypertension and related cerebral arteriosclerosis are the main risk factors for intracerebral hemorrhage, the effects of aldosteronism remain poorly understood. We enrolled 90 survivors of hypertensive intracerebral hemorrhage, 21 of them with aldosteronism and 69 with essential hypertension as controls in this study. Clinical parameters and neuroimaging markers of cerebral small vessel disease were recorded, and its correlations with aldosteronism were investigated. Our results showed that the aldosteronism group (55.2 ± 9.7 years, male 47.6%) had similar hypertension severity but exhibited a higher cerebral microbleed count (interquartile range) (8.5 [2.0‒25.8] vs 3 [1.0‒6.0], P = 0.005) and higher severity of dilated perivascular space in the basal ganglia (severe perivascular space [number >20], 52.4% vs. 24.6%, P = 0.029; large perivascular space [>3 mm], 52.4% vs. 20.3%, P = 0.010), compared to those with essential hypertension (53.8 ± 11.7 years, male 73.9%). In multivariate models, aldosteronism remained an independent predictor of a higher (>10) microbleed count (odds ratio = 8.60, P = 0.004), severe perivascular space (odds ratio = 4.00, P = 0.038); the aldosterone-to-renin ratio was associated with dilated perivascular space (P = 0.043) and large perivascular space (P = 0.008). In conclusions, survivors of intracerebral hemorrhage with aldosteronism showed a tendency towards more severe hypertensive arteriopathy than the essential hypertension counterparts independently of blood pressure; aldosteronism may contribute to dilated perivascular space around the deep perforating arteries. Aldosteronism is associated with more severe cerebral small vessel disease in hypertensive intracerebral hemorrhage., (© 2023. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Lobar cerebral microbleeds are a characteristic neuroimaging finding in cerebral amyloid angiopathy (CAA) but can also be found in hypertensive arteriolosclerosis. We aimed to investigate whether CAA is more associated with intracortical lobar microbleeds than hypertensive arteriosclerosis. Ninety-one survivors of spontaneous intracerebral hemorrhage with at least one lobar microbleed were included and underwent brain MRI and amyloid PET. We categorized lobar microbleeds as intracortical, juxtacortical, or subcortical. We assessed the associations between the lobar microbleed categories and microangiopathy subtypes or cerebral amyloid load based on the Pittsburgh Compound-B PET standardized uptake value ratio (SUVR). Patients with CAA had a higher prevalence of intracortical lobar microbleeds (80.0% vs. 50.8%, P = 0.011) and lower prevalence of subcortical lobar microbleeds (13.3% vs. 60.1%, P < 0.001) than patients with hypertensive arteriolosclerosis. Strictly intracortical/juxtacortical lobar microbleeds were associated with CAA (OR 18.9 [1.9-191.4], P = 0.013), while the presence of subcortical lobar microbleeds was associated with hypertensive arteriolosclerosis (OR 10.9 [1.8-68.1], P = 0.010). Amyloid retention was higher in patients with strictly intracortical/juxtacortical CMBs than those without (SUVR = 1.15 [1.05-1.52] vs. 1.08 [1.02-1.19], P = 0.039). Amyloid retention positively correlated with the number of intracortical lobar microbleeds (P < 0.001) and negatively correlated with the number of subcortical lobar microbleeds (P = 0.018). CAA and cortical amyloid deposition are more strongly associated with strictly intracortical/juxtacortical microbleeds than subcortical lobar microbleeds. Categorization of lobar microbleeds based on anatomical location may help differentiate the underlying microangiopathy and potentially improve the accuracy of current neuroimaging criteria for cerebral small vessel disease., (© 2024. The Author(s).)

Objective: F-18-fluorothymidine (FLT) is a positron emission tomography (PET) tracer for imaging cell proliferation in vivo. We aimed to assess FLT uptake as a marker for cerebral cell proliferation in a rat model of ischemic stroke and patients with cerebral infarct, correlating with disease severity and outcomes., Methods: Cerebral FLT PET was performed in rats subjected to transient middle cerebral artery occlusion (MCAO) and patients with cerebral infarct. PET data were analyzed and expressed as average standardized uptake value ratios (SUVRs) using cerebellar cortex as reference. Infarct volume was analyzed by 2,3,5-triphenyltetrazolium chloride staining in rats and by magnetic resonance imaging in patients. Neurological function was assessed using modified Neurological Severity Score (mNSS) for rats and National Institutes of Health Stroke Scale (NIHSS) for patients., Results: Seven days post-MCAO, rats' FLT PET displayed higher SUVRs in the infarcted brain, declining gradually until Day 28. FLT-binding ratio (SUVR in the infarcted brain divided by that in contralateral side) correlated positively with stroke severity (p < 0.001), and to early mNSS decline in rats with mild to moderate stroke severity (p = 0.031). In 13 patients with cerebral infarct, FLT PET showed high SUVR in the infarcted regions. FLT-binding ratio correlated positively with infarct volume (p = 0.006). Age-adjusted initial NIHSS (p = 0.035) and early NIHSS decline (p = 0.076) showed significance or a trend toward positive correlation with the FLT-binding ratio., Interpretation: In vivo FLT PET detects poststroke cerebral cell proliferation, which is associated with stroke severity and/or outcomes in MCAO rats and patients with cerebral infarct., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Introduction: Orangutans, classified under the Pongo genus, are an endangered non-human primate (NHP) species. Derivation of induced pluripotent stem cells (iPSCs) represents a promising avenue for conserving the genetic resources of these animals. Earlier studies focused on deriving orangutan iPSCs (o-iPSCs) from Sumatran orangutans (Pongo abelii). To date, no reports specifically target the other Critically Endangered species in the Pongo genus, the Bornean orangutans ( Pongo pygmaeus ). Methods: Using Sendai virus-mediated Yamanaka factor-based reprogramming of peripheral blood mononuclear cells to generate iPSCs (bo-iPSCs) from a female captive Bornean orangutan. In this study, we evaluate the colony morphology, pluripotent markers, X chromosome activation status, and transcriptomic profile of the bo-iPSCs to demonstrate the pluripotency of iPSCs from Bornean orangutans. Results: The bo-iPSCs were successfully derived from Bornean orangutans, using Sendai virus-mediated Yamanaka factor-based reprogramming of peripheral blood mononuclear cells. When a modified 4i/L/A (m4i/L/A) culture system was applied to activate the WNT signaling pathway in these bo-iPSCs, the derived cells (m-bo-iPSCs) manifested characteristics akin to human naive pluripotent stem cells, including high expression levels of KLF17, DNMT3L, and DPPA3/5, as well as the X chromosome reactivation. Comparative RNA-seq analysis positioned the m-bo-iPSCs between human naive and formative pluripotent states. Furthermore, the m-bo-iPSCs express differentiation capacity into all three germlines, evidenced by controlled in vitro embryoid body formation assay. Discussion: Our work establishes a novel approach to preserve the genetic diversity of endangered Bornean orangutans while offering insights into primate stem cell pluripotency. In the future, derivation of the primordial germ cell-like cells (PGCLCs) from m-bo-iPSCs is needed to demonstrate the further specific application in species preservation and broaden the knowledge of primordial germ cell specification across species., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Chang, Tsai, Peng, Lyu, Yu, Tsai and Sung.)

Background: Patients with end-stage renal disease (ESRD) are often excluded from clinical trials of endovascular thrombectomy (EVT). This study investigated the outcome in these patients., Methods: From September 2014 to July 2021, all patients undergoing EVT for anterior circulation stroke in two stroke centers in Taiwan were included. They were divided into no renal dysfunction (non-RD, estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m 2 ), RD (eGFR <60 mL/min/1.73 m 2 but no dialysis), and ESRD undergoing dialysis (ESRD-dialysis). The clinical features and outcomes were compared., Results: Of 482 patients included, there were 20 ESRD-dialysis, 110 RD, and 352 non-RD patients. The Alberta Stroke Program Early CT Score (ASPECTS), National Institutes of Health Stroke Scale (NIHSS), use of intravenous thrombolysis, EVT-related time metrics, and successful recanalization rates were comparable among the three groups. However, the ESRD-dialysis patients had more symptomatic intracerebral hemorrhage (ICH, 15% vs 3.6% vs 3.7%), more contrast-induced encephalopathy (15% vs 1.8% vs 0.9%), and a higher mortality at 90 days (35% vs 18% vs 11%) than the other groups. Multivariable analysis revealed that ESRD-dialysis was associated with a less favorable outcome (OR 0.21, 95% CI 0.04 to 0.77) and more severe disability or mortality (modified Rankin Scale 5 or 6; OR 13.1, 95% CI 3.93 to 48.1) at 90 days. In the ESRD-dialysis group, the patients with premorbid functional dependence had a significantly higher mortality than those without (75% vs 8.3%; P=0.004)., Conclusion: ESRD-dialysis patients were associated with symptomatic ICH and less favorable outcome at 90 days. Patients with premorbid functional dependency had an excessively high mortality., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: In eukaryotic cells, DNA double strand breaks (DSB) are primarily repaired by canonical non-homologous end joining (c-NHEJ), homologous recombination (HR) and alternative NHEJ (alt-NHEJ). Zinc finger and SCAN domain containing 4 (ZSCAN4), sporadically expressed in 1-5% mouse embryonic stem cells (mESCs), is known to regulate genome stability by promoting HR., Results: Here we show that ZSCAN4 promotes DNA repair by acting with Poly (ADP-ribose) polymerase 1 (PARP1), which is a key member of the alt-NHEJ pathway. In the presence of PARP1, ZSCAN4-expressing mESCs are associated with lower extent of endogenous or chemical induced DSB comparing to ZSCAN4-negative ones. Reduced DSBs associated with ZSCAN4 are abolished by PARP1 inhibition, achieved either through small molecule inhibitor or gene knockout in mESCs. Furthermore, PARP1 binds directly to ZSCAN4, and the second ⍺-helix and the fourth zinc finger motif of ZSCAN4 are critical for this binding., Conclusions: These data reveal that PARP1 and ZSCAN4 have a protein-protein interaction, and shed light on the molecular mechanisms by which ZSCAN4 reduces DSB in mESCs., (© 2023. Society of Chinese Bioscientists in America (SCBA).)

Ferroptosis, an iron-dependent form of cell death, is characterized by intracellular accumulation of iron and reactive oxygen species-induced lipid peroxidation. Animal experiments have shown the important roles of ferroptosis in ischemic stroke, but the evidence in human stroke is insufficient. This prospective study evaluated the associations between plasma ferroptosis biomarkers at hyperacute stage and long-term outcomes in patients with acute ischemic stroke undergoing endovascular thrombectomy (EVT). The plasma samples were collected immediately before and after EVT (T1 and T2) and at 24 h (T3) for the 126 stroke patients and once for the 50 stroke-free control subjects. Compared with controls, stroke patients had higher 4-hydroxynonenal (4-HNE) levels at T1 and T2 while lower homocysteine and soluble transferrin receptor (sTfR) levels at T3. In stroke patients, higher National Institutes of Health Stroke Scale scores at admission were correlated with higher 4-HNE and lower sTfR levels. Lower Alberta Stroke Program Early CT (ASPECT) scores and larger infarct core volumes on CT perfusion before EVT were correlated with higher 4-HNE and homocysteine levels. After adjusting for significant parameters, homocysteine levels at T2 were significantly associated with poor functional outcome and mortality at 3 months. In the receiver operating characteristic (ROC) models, adding homocysteine levels at T2 and hemoglobin levels to the reference model for predicting poor functional outcome significantly increased the area under the ROC curve. In summary, this study provides evidence that ferroptosis is associated with stroke severity and outcomes in patients with acute ischemic stroke undergoing EVT., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background/purpose: A prehospital bypass strategy was suggested for large vessel occlusion. This study aimed to evaluate the effect of a bypass strategy using the gaze-face-arm-speech-time test (G-FAST) implemented in a metropolitan community., Methods: Pre-notified patients with positive Cincinnati Prehospital Stroke Scale and symptom onset <3 h from July 2016 to December 2017 (pre-intervention period) and those with positive G-FAST and symptom onset <6 h from July 2019 to December 2020 (intervention period) were included. Patients aged <20 years and those with missing in-hospital data were excluded. The primary outcomes were the rates of receiving endovascular thrombectomy (EVT) and intravenous thrombolysis (IVT). The secondary outcomes were total prehospital time, door-to-computed tomography (CT) time, door-to-needle (DTN) time, and door-to-puncture (DTP) time., Results: We included 802 and 695 pre-notified patients from the pre-intervention and intervention periods, respectively. The characteristics of the patients in the two periods were similar. In the primary outcomes, pre-notified patients during the intervention period showed higher rates of receiving EVT (4.49% vs. 15.25%, p < 0.001) and IVT (15.34% vs. 21.58%, p = 0.002). In the secondary outcomes, pre-notified patients during intervention period had longer total prehospital time (mean 23.38 vs 25.23 min, p < 0.001), longer door-to-CT time (median 10 vs 11 min, p < 0.001), longer DTN time (median 53 vs 54.5 min, p < 0.001) but shorter DTP time (median 141 vs 139.5 min, p < 0.001)., Conclusion: The prehospital bypass strategy with G-FAST showed benefits for stroke patients., (Copyright © 2023. Published by Elsevier B.V.)

Background: To investigate the association between cerebral amyloid deposition and long-term cognitive outcomes in patients with hemorrhagic small vessel disease (SVD) and survivors of intracerebral hemorrhage (ICH)., Methods: Patients experiencing an ICH without overt dementia were prospectively recruited (n = 68) for brain MRI and Pittsburgh compound B (PiB) positron emission tomography scans at baseline. Cognitive function was assessed using the mini-mental status examination (MMSE) and clinical dementia rating after an overall median follow-up of 3.8 years. A positive amyloid scan was defined as a global PiB standardized uptake value ratio >1.2. Associations between follow-up cognitive outcomes and neuroimaging markers were explored using multivariable Cox regression models., Results: PiB(+) patients were older (72.1 ± 7.8 vs. 59.9 ± 11.7, p = .002) and more frequently had cerebral amyloid angiopathy (CAA) (63.6% vs. 15.8%, p = .002) than PiB(-) patients. PiB(+) was associated with a higher risk of dementia conversion (32.9 vs. 4.0 per 100-person-years, hazard ratio [HR] = 15.7 [3.0-80.7], p = .001) and MMSE score decline (58.8 vs. 9.9 per 100-person-years, HR = 6.2 [1.9-20.0], p = .002). In the non-CAA subgroup (n = 52), PiB(+) remained an independent predictor of dementia conversion, p = .04). In the Cox models, PiB(+) was an independent predictor of dementia conversion (HR = 15.8 [2.6-95.4], p = .003) and MMSE score decline (HR = 5.7 [1.6-20.3], p = .008) after adjusting for confounders., Conclusions: Cerebral amyloid deposition potentially contributes to long-term cognitive decline in SVD-related ICH., (© 2023 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

The multifaceted nature and swift progression of Amyotrophic Lateral Sclerosis (ALS) pose considerable challenges to our understanding of its evolution and interplay with comorbid conditions. This study seeks to elucidate the temporal dynamics of ALS progression and its interaction with associated diseases. We employed a principal tree-based model to decipher patterns within clinical data derived from a population-based database in Taiwan. The disease progression was portrayed as branched trajectories, each path representing a series of distinct stages. Each stage embodied the cumulative occurrence of co-existing diseases, depicted as nodes on the tree, with edges symbolizing potential transitions between these linked nodes. Our model identified eight distinct ALS patient trajectories, unveiling unique patterns of disease associations at various stages of progression. These patterns may suggest underlying disease mechanisms or risk factors. This research re-conceptualizes ALS progression as a migration through diverse stages, instead of the perspective of a sequence of isolated events. This new approach illuminates patterns of disease association across different progression phases. The insights obtained from this study hold the potential to inform doctors regarding the development of personalized treatment strategies, ultimately enhancing patient prognosis and quality of life.

Background: Acute blood pressure (BP) reduction is the first-line treatment for acute spontaneous intracerebral hemorrhage (ICH); however, recent research suggests that intensive BP reduction along with cerebral small vessel disease (cSVD) is a risk factor for remote DWI lesions (RDWILs). We aimed to delineate the interplay between cSVD and BP reduction therapy on the risk of RDWILs., Methods: We enrolled 303 patients who underwent brain magnetic resonance imaging within 7 days after acute spontaneous ICH. RDWILs were categorized as occurring in borderzone (BZ) or non-BZ areas. We examined the effect of cSVD, acute BP reduction, and their interaction on RDWILs., Results: RDWILs were observed in 34 (11%) patients (59.8 ± 10.3-years-old, 24% male). RDWILs were associated with a larger acute weighted average mean arterial pressure (MAP) reduction in the initial 24 h after ICH onset and a higher total cerebral microbleed (CMB) count. Intensive MAP changes (odds ratio (OR) per 10 mmHg 1.76, 95% confidence interval (CI) 1.03-3.20), total CMBs burden (OR per 10 CMBs 1.21, 95% CI 1.08-1.39), and presence of lobar CMBs (OR 7.33, 95% CI 1.59-55.6) were risk factors for RDWILs at BZ, but not at non-BZ. Furthermore, a significant interaction was observed between lobar CMBs and MAP reduction on increased risk of RDWILs at BZ ( p  = 0.030)., Conclusion: cSVD modulates the effect of acute BP reduction on the risk of RDWILs. Patients with extensive microangiopathy have a higher risk of developing cerebral ischemic changes in BZ during unstable hemodynamic status.

Objective: This study aimed to explore the clinical significance of brain imaging signatures in the context of clinical neurological deficits in association with upper and lower motor neuron degeneration in amyotrophic lateral sclerosis (ALS)., Methods: We performed brain MRI examinations to quantitatively evaluate (1) gray matter volume and (2) white matter tract fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD). Image-derived indices were correlated with (1) global neurological deficits of MRC muscle strength sum score, revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R), and forced vital capacity (FVC), and (2) focal scores of University of Pennsylvania Upper motor neuron score (Penn score) and the summation of compound muscle action potential Z scores (CMAP Z sum score)., Results: There were 39 ALS patients and 32 control subjects matched for age and gender. Compared to controls, ALS patients had a lower gray matter volume in the precentral gyrus of the primary motor cortex, which was correlated with FA of corticofugal tracts. The gray matter volume of the precentral gyrus was correlated with FVC, MRC sum score, and CMAP Z sum score, while the FA of the corticospinal tract was linearly associated with CMAP Z sum score and Penn score on multivariate linear regression model., Interpretation: This study indicated that clinical assessment of muscle strength and routine measurements on nerve conduction studies provided surrogate markers of brain structural changes for ALS. Furthermore, these findings suggested parallel involvement of both upper and lower motor neurons in ALS., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Postradiotherapy carotid vasculopathy is a clinically relevant complication in patients with head and neck cancer receiving radiotherapy. In this study, we investigated the factors associated with the development and progression of carotid artery stenosis (CAS) in such patients., Methods: Patients who received radiotherapy for head and neck cancers between October 2011 and May 2019 at a medical center in Taiwan were eligible for inclusion in this study. This study included patients who underwent two consecutive carotid duplex examinations within an interval of 1 to 3 years. The factors associated with ≥50% CAS at baseline and follow-up were analyzed., Results: In total, 694 patients (mean age, 57.8 ± 9.9 years; men, 75.2%; nasopharyngeal cancer, 73.3%) were included. The mean interval between radiotherapy and carotid duplex examination was 9.9 ± 5.9 years. At baseline, 103 patients had ≥50% CAS, which was significantly associated with tobacco smoking, hypercholesterolemia, and a prolonged interval between radiotherapy and carotid duplex examination. A total of 586 patients did not have CAS at baseline; of them, 68 developed ≥50% CAS during follow-up. Hypertension and hypercholesterolemia were identified as independent risk factors for CAS progression., Conclusion: Modifiable vascular risk factors, such as hypertension and hypercholesterolemia, appear to be significantly associated with the rapid progression of postradiotherapy CAS in patients with head and neck cancer., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2023, the Chinese Medical Association.)

A real-world association between direct oral anticoagulant (DOAC) concentration and clinical outcomes among Asian patients with atrial fibrillation (AF) is reported herein. Patients with AF aged ≥ 20 years who used DOAC for ≥ 3 days were enrolled. Trough and peak DOAC concentrations were measured and compared with the expected range reported in clinical trials. The Cox proportional hazard model was used to investigate the association between concentration and outcomes. From January 2016 to July 2022, a total of 859 patients were enrolled. Among them, 22.5%, 24.7%, 36.4%, and 16.4% were on dabigatran, rivaroxaban, apixaban, and edoxaban, respectively. Compared with clinical trials, the proportion of DOAC concentrations higher or lower than the expected range were 9.0% and 14.6% for trough, respectively, and 20.9% and 12.1% for peak, respectively. The average follow-up duration was 2.4 ± 1.6 years. The incidence of stroke and systemic thromboembolism (SSE) was 1.31 per 100-person years, and low trough concentration predicted SSE (hazard ratio (HR) = 2.78 (1.20, 6.46)). The incidence of major bleeding was 1.64 per 100-person years, and high trough was associated with major bleeding (HR = 2.63 (1.09, 6.39)). The association between peak concentration and SSE or major bleeding was nonsignificant. Off-label underdosing (odds ratio (OR) = 2.69 (1.70, 4.26)), once daily DOAC dosing (OR = 3.22 (2.07, 5.01)), and high creatinine clearance (OR = 1.02 (1.01, 1.03)) caused low trough concentration. Contrarily, congestive heart failure was significantly associated with high trough concentration (OR = 1.71 (1.01, 2.92)). In conclusion, trough DOAC concentration measurements should be considered among patients at risk of out-of-expected range DOAC concentrations., (© 2023 The Authors. Clinical Pharmacology & Therapeutics © 2023 American Society for Clinical Pharmacology and Therapeutics.)

Introduction: Temporalis muscle thickness (TMT) is a surrogate marker for sarcopenia. This study investigated the association of TMT with clinical outcomes in patients receiving endovascular thrombectomy (EVT) for stroke involving acute large vessel occlusion (LVO)., Material and Methods: We enrolled consecutive patients who had undergone EVT between September 2014 and December 2021 at three thrombectomy-capable institutes. TMT was measured through preprocedural computerized tomography angiography. The clinical variables affecting TMT were investigated. The associations between TMT and clinical functional outcomes, defined using the modified Rankin scale, were also studied., Results: A total of 657 patients were included (mean age: 72.0 ± 12.7 years; male: 52.1%). The mean TMT was 6.35 ± 1.84 mm. Younger age, male sex, higher body mass index, and premorbid functional independence were associated with larger TMT in both univariate and multivariate linear regression (P <.05). Ordinal logistic regression revealed that TMT was associated with better clinical outcomes at 90 days (P trend  = 0.047); multivariate logistic regression indicated that larger TMT was an independent predictor (adjusted odds ratio: 1.14, 95% confidence interval: 1.03-1.27, P = 0.02) of favorable functional independence (modified Rankin scale score: 0-2). The effect was stronger in older patients (≥80 years) than younger patients, as revealed by interaction modeling analysis (P interaction  = 0.06)., Conclusion: TMT is associated with age, sex, body mass index, and premorbid functional status. Larger TMT is associated with better outcomes after EVT. The effects of TMT are more pronounced in older adults, indicating that sarcopenia may have influence on stroke outcomes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Intracerebral hemorrhage (ICH) enhances neurogenesis in the subventricular zone (SVZ); however, the mechanism is not fully understood. We investigated the role of brain-derived neurotrophic factor (BDNF) in post-ICH neurogenesis in a rodent model and in patients with ICH using cerebrospinal fluid (CSF)., Methods: A rat model of ICH was constructed via stereotaxic injection of collagenase into the left striatum. Patients with ICH receiving an external ventricular drain were prospectively enrolled. CSF was collected from rats and patients at different post-ICH times. Primary cultured rat neural stem cells (NSCs) were treated with CSF with or without BDNF-neutralized antibody. Immunohistochemistry and immunocytochemistry were used to detect NSC proliferation and differentiation. The BDNF concentration in CSF was quantified using enzyme-linked immunosorbent assays (ELISA)., Results: In the rat model of ICH, the percentage of proliferating NSCs and neuroblasts in SVZ was elevated in bilateral hemispheres. The cultured rat NSCs treated with CSF from both rats and patients showed an increased capacity for proliferation and differentiation toward neuroblasts. BDNF concentration was higher in CSF collected from rats and patients with ICH than in controls. Blocking BDNF decreased the above-noted promotion of proliferation and differentiation of cultured NSCs by CSF treatment. In patients with ICH, the BDNF concentration in CSF and the neurogenesis-promoting capacity of post-ICH CSF correlated positively with ICH volume., Conclusion: BDNF in CSF contributes to post-ICH neurogenesis, including NSC proliferation and differentiation toward neuroblasts in a rat model and patients with ICH., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lin, Tsai, Chen, Young, Wu, Chiang, Kao, Huang, Hsu, Chen and Tsai.)

Background: Cerebral venous outflow alterations contribute to central nervous system pathology in aging and neurodegenerative disorders and are potentially linked to underlying cerebral microangiopathy. We investigated whether cerebral venous reflux (CVR) is more closely associated with cerebral amyloid angiopathy (CAA) than hypertensive microangiopathy in intracerebral hemorrhage (ICH) survivors., Methods: This cross-sectional study included 122 patients of spontaneous ICH with magnetic resonance and positron emission tomography imaging studies (2014-2022) in Taiwan. The presence of CVR was defined as abnormal signal intensity in the dural venous sinus or internal jugular vein on magnetic resonance angiography. Cerebral amyloid load was measured using the Pittsburgh compound B standardized uptake value ratio. Clinical and imaging characteristics associated with CVR were evaluated in univariable and multivariable analyses. In the subset of patients with CAA, we applied univariable and multivariable linear regression analyses to evaluate the association between CVR and cerebral amyloid retention., Results: Compared with patients without CVR (n=84, 64.5±12.1 years), patients with CVR (n=38, 69.4±11.5 years) were significantly more likely to have CAA-ICH (53.7% versus 19.8%; P< 0.001) and had a higher cerebral amyloid load (standardized uptake value ratio [interquartile range], 1.28 [1.12-1.60] versus 1.06 [1.00-1.14]; P< 0.001). In a multivariable model, CVR was independently associated with CAA-ICH (odds ratio, 4.81 [95% CI, 1.74-13.27]; P =0.002) after adjustment for age, sex and conventional small vessel disease markers. In CAA-ICH, higher PiB retention was observed in patients with CVR than patients without CVR (standardized uptake value ratio [interquartile range], 1.34 [1.08-1.56] versus 1.09 [1.01-1.26]; P <0.001). In multivariable analysis after adjustment for potential confounders, the presence of CVR was independently associated with a higher amyloid load (standardized β=0.40; P =0.001)., Conclusions: In spontaneous ICH, CVR is associated with CAA and a higher amyloid burden. Our results suggest venous drainage dysfunction potentially plays a role in CAA and cerebral amyloid deposition.

Background: A risk stratification scale is essential to identify high-risk patients who had transient ischemic attack (TIA) to prevent subsequent permanent disability caused by ischemic stroke., Objective: This study aimed to develop and validate a scoring system to predict acute ischemic stroke within 90 days after TIA in an emergency department (ED)., Methods: We retrospectively analyzed the data of patients with TIA in a stroke registry between January 2011 and September 2018. Characteristics, medication history, electrocardiogram (ECG), and imaging findings were collected. Univariable and multivariable stepwise logistic regression analyses were performed to create an integer point system. The area under the receiver operating characteristic curve (AUC) and the Hosmer-Lemeshow (HL) test were used to examine discrimination and calibration. Youden's Index was also used to determine the best cutoff value., Results: A total of 557 patients were included, and the occurrence rate of acute ischemic stroke within 90 days after TIA was 5.03%. After multivariable analysis, a new integer point system was created-MESH (Medication Electrocardiogram Stenosis Hypodense) score-which contained medication history (antiplatelet medication taken before admission, 1 point), right bundle branch block on electrocardiogram (1 point), intracranial stenosis ≥ 50% (1 point), and size of the hypodense area on computed tomography (diameter ≥ 4 cm, 2 points). The MESH score showed adequate discrimination (AUC = 0.78) and calibration (HL test = 0.78). The best cutoff value was 2 points, with a sensitivity of 60.71% and specificity of 81.66%., Conclusions: The MESH score indicated improved accuracy for TIA risk stratification in the ED setting., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Whole-exome sequencing (WES) facilitates the diagnosis of hereditary neuromuscular disorders. To achieve an accurate diagnosis, physicians should interpret the genetic report carefully along with clinical information and examinations. We described our experience with (1) clinical validation in patients with variants found using WES and (2) a diagnostic approach for those with negative findings from WES., Methods: WES was performed on patients with the clinical impression of hereditary neuromuscular disorders. Information on clinical manifestations, neurological examination, electrodiagnostic studies, histopathology of muscle and nerve, and laboratory tests were collected., Results: Forty-one patients (Male/Female: 18/23, age of onset: 34.5±15.9) accepted WES and were categorized into four scenarios: (1) patients with a positive WES result, (2) patients with an inconclusive WES result but supporting clinical data, (3) negative findings from WES, but a final diagnosis after further work-up, and (4) undetermined etiology from WES and in further work-ups. The yield rate of the initial WES was 63.4% (26/41). Among these, seventeen patients had positive WES result, while the other nine patients had inconclusive WES result but supporting clinical data. Notably, in the fifteen patients with negative findings from WES, four patients (26.7%) achieved a diagnosis after further workup: tumor-induced osteomalacia, metabolic myopathy with pathogenic variants in mitochondrial DNA, microsatellite expansion disease, and vasculitis-related neuropathy. The etiologies remained undetermined in eleven patients (myopathy: 7, neuropathy: 4) after WES and further workup., Conclusions: It is essential to design genotype-guided molecular studies to correlate the identified variants with their clinical features. For patients who had negative findings from WES, acquired diseases, mitochondrial DNA disorders and microsatellite expansion diseases should be considered.

Background: Post-stroke inflammation contributes to poor outcomes, but its impact on patients with stroke receiving endovascular thrombectomy (EVT) remains unknown., Methods: We enrolled adult patients with stroke who received EVT, with blood sampling immediately before (T1) and after EVT (T2), and at 24 hours after EVT (T3). Non-stroke controls and patients with non-EVT stroke were also enrolled. The medical information, image findings and levels of serum amyloid A (SAA) and C-reactive protein (CRP) were analyzed to clarify the association with poor functional outcome (modified Rankin Scale 4-6) at 3 months after stroke., Results: A total of 93 patients with stroke receiving EVT, 51 non-stroke controls, and 64 with non-EVT stroke were enrolled in this study. The SAA and CRP levels at T1 to T3 in patients with stroke receiving EVT were higher compared with those in controls (all p<0.001), and their levels at T3 were significantly higher than those at T1 (both p<0.0001) while similar to those in patients with non-EVT stroke. The SAA levels at the three time points were significantly associated with poor functional outcome (p=0.003 to 0.009). Furthermore, adding SAA level at T3 significantly improved the basic prediction model for 3-month poor functional outcome by receiver operating characteristic (ROC) analysis (areas under ROC curves from 0.803 to 0.878, p=0.03)., Conclusions: Our findings demonstrate that plasma levels of SAA at an early stage are significant predictors for poor functional outcomes at 3 months in patients with stroke receiving EVT, indicating the substantial role of systemic inflammation in shaping stroke outcomes following EVT., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Perihematomal edema of intracerebral hemorrhage (ICH) is caused by a hematoma-induced inflammatory reaction, which usually contributes to delayed deterioration of neurological function and poor outcomes. Celecoxib is a commonly used nonsteroidal anti-inflammatory drug that selectively inhibits cyclooxygenase-2. High-dose celecoxib (400 mg twice daily) for 14 days has been shown to reduce perihematomal edema and hematoma enlargement in patients with ICH, but without improvement in long-term functional outcome, which may be confounded by the heterogeneity of hematoma location. Low-dose celecoxib may be an effective management for symptoms caused by perihematomal edema in patients with ICH, particularly those involving the thalamus., Case Report: We reported two patients with acute thalamic ICH; a common symptom between the two was delayed onset of drowsiness caused by perihematomal edema involving the thalamus. Their consciousness improved after low-dose celecoxib (200 mg once daily) administration for 3 and 2 days in case A and B, respectively. Furthermore, other symptoms that concomitantly improved included poor appetite caused by perihematomal edema involving the left hypothalamus in case A, and limb weakness caused by perihematomal edema of the internal capsule in case B., Conclusion: These cases revealed that low-dose celecoxib may be an effective management for symptoms caused by perihematomal edema in patients with ICH, particularly those involving the thalamus.

Purpose: Autonomic dysfunction is an underrecognized complication of acute ischemic stroke. The cortical regulation of sympathetic activation is predominantly lateralized to the right hemisphere and parasympathetic activation to the left hemisphere. However, prior evidence is lacking regarding ischemic lesions in unilateral hemisphere that concomitantly cause sympathetic and parasympathetic dysfunction., Case Report: We present the case of a 73-year-old woman with acute ischemic stroke in the left middle cerebral artery territory, whose neurological symptoms improved significantly after thrombolysis and endovascular thrombectomy. She presented residual scattered small infarctions involving the left insula and lateral parietal cortex. However, she experienced obvious autonomic symptoms that included orthostatic hypotension, which is indicative of sympathetic dysfunction, and micturition difficulty with exaggerated reflex tachycardia, indicative of parasympathetic dysfunction. The sympathetic and parasympathetic functions sequentially resolved on days 10 and 20 after stroke onset, respectively., Conclusion: The case revealed insight into the phenomenon and recovery course of concurrent sympathetic and parasympathetic dysfunction associated with ischemic lesions in the left hemisphere.

Purposes: This study investigated the impact of posterior limb of internal capsule (PLIC) infarct on outcomes of acute internal carotid artery (ICA) occlusion after endovascular thrombectomy (EVT) and the diagnostic accuracy of pretreatment noncontrast computerized tomography (NCCT) and computerized tomography angiography (CTA) findings., Methods: Patients who underwent EVT for acute ICA occlusion between September 2014 and August 2020 were included in the study. The patients were dichotomized as PLIC infarct or spared. The risk factors for PLIC infarct were investigated, and the association between infarct patterns and clinical outcomes were assessed using logistic regression analysis. Pretreatment NCCT and CTA findings, including PLIC hypodensity, choroid plexus enhancement (CPE), and posterior cerebral artery (PCA) flow status, were calculated for diagnosis of PLIC infarct., Results: Among 72 patients, the mean age was 70.9 years, and the mean stroke scale was 19.4. PLIC infarct was identified in 15 patients (20.8%). PLIC infarct was associated with worse 90-day functional outcome (P = 0.01, shift test). Lack of CPE is the only independent predictor of PLIC infarct (odds ratio: 127.48, P = 0.001). Lack of CPE and impaired PCA flow produce greater diagnostic accuracy for PLIC infarct than does NCCT hypodensity (area under the receiver operating characteristics curve: 0.85 and 0.76, P = 0.0005 and 0.02, respectively)., Conclusions: In acute ICA occlusion, PLIC infarct is an independent risk factor for worse clinical outcome at 90 days. The lack of CPE was associated with PLIC infarct, and pretreatment CTA can be useful for early diagnosis., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Objective: Indirect revascularization surgery reduce the risk of recurrent vascular events in patients with moyamoya disease (MMD), but the roles of postoperative angiography and ultrasonography in predicting these events remain unclear., Methods: This prospective study enrolled patients with MMD who would undergo their first unilateral indirect revascularization surgery. They received preoperative and postoperative ultrasound examination at 1, 3, and 6 months and conventional cerebral angiography. On ultrasonography, postoperative emerging flow (PEF) in an intracranial artery was defined as emerging flow postoperatively with absence of flow preoperatively. Predictors of vascular event frequency reduction were identified from angiographic and ultrasonographic parameters., Results: In total, 52 patients (including 24 pediatric and 24 male patients), who underwent 52 preoperative and 82 postoperative ultrasound examinations, were enrolled. Significant postoperative changes were noted in all the ultrasonographic parameters of ipsilateral superficial temporal artery (STA) and the end-diastolic velocity and flow volume in contralateral STA. During a median follow-up of 5.3 years, indirect revascularization surgery significantly reduced the occurrence of ipsilateral vascular events. Predictors of vascular event frequency reduction included Matsushima grade A or B on the ipsilateral side on angiography (odds ratio [OR] = 22.00, P = 0.002) and lower resistance index (RI) in ipsilateral STA (OR = 0.0001, P = 0.012) but no PEF pattern in ipsilateral middle cerebral artery (OR = 0.14, P = 0.029) on ultrasonography performed within 6 months., Conclusions: Reduction of long-term vascular event frequency probably can be predicted through postoperative angiography and ultrasonography within 6 months after indirect revascularization surgery., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Haploinsufficiency of genes that participate in telomere elongation and maintenance processes, such as telomerase RNA component ( Terc ) and telomere reverse transcriptase ( Tert ), often leads to premature aging-related diseases such as dyskeratosis congenita and aplastic anemia. Previously, we reported that when mouse Terc +/- tail tip fibroblasts (TTFs) were used as donor cells for somatic cell nuclear transfer (SCNT, also known as cloning), the derivative embryonic stem cells (ntESCs) had elongated telomeres. In the present work, we are interested to know if an additional round of SCNT, or recloning, could lead to further elongation of telomeres. Terc +/- TTFs were used to derive the first-generation (G1) ntESCs, followed by a second round of SCNT using G1- Terc +/- ntESCs as donor cells to derive G2- Terc +/- ntESCs. Multiple lines of G1- and G2- Terc +/- ntESCs were efficiently established, and all expressed major pluripotent markers and supported efficient chondrocyte differentiation in vitro. Compared with donor TTFs, telomere lengths of G1 ntESCs were elongated to the level comparable with that in wild-type ntESCs. Interestingly, recloning did not further elongate the telomere lengths of Terc +/- ntESCs. Together, our work demonstrates that while a single round of SCNT is a viable means to reprogram Terc haploinsufficient cells to the ESC state, and to elongate these cells' telomere lengths, a second round of SCNT does not necessarily further elongate the telomeres.

Background: Few studies documented incidence rates of different types of stroke among patients with polycystic kidney disease (PKD)., Methods: We conducted a retrospective cohort study based on the National Health Insurance (NHI) Database of Taiwan. The PKD cohort comprised patients aged≥20 years diagnosed with PKD using inpatient claims from 1998 to 2011, excluding prior stroke. The reference cohort was established by inpatients without PKD using 1:4 frequency-matched with age, gender, and baseline comorbidities. The two cohorts were followed-up until stroke hospitalization, death, withdrawal from the NHI program, or the end of 2012. To account for competing risks of death, we used multivariable competing risks regression models to estimate sub-distribution hazard ratio (SHR) adjusted for age, gender, baseline comorbidities and end stage renal disease., Results: 7837 PKD patients and 31,211 reference subjects were followed up through 2012. A total of 955 cases of stroke were identified in the PKD cohort, including 441 ischemic stroke (IS), 289 intracranial hemorrhage (ICH), 73 subarachnoid hemorrhage (SAH) and 232 other stroke. The incidence rates of overall stroke, IS, ICH, and SAH were 21.3, 10.2, 6.8, and 1.7 per 1000 person-years, respectively. The SHR for overall stroke was 1.39 [95% confidence interval (CI) 1.28-1.50]. SAH had the highest SHR, 4.55 [95% CI 3.26-6.37], followed by ICH (1.84), other stroke (1.24), and IS (1.22)., Conclusion: This study illustrated the incidence rates of stroke among inpatient of PKD. The PKD patients had a significantly increased risk of all kinds of stroke after adjusting baseline comorbidities., Competing Interests: Conflicts of interest None declared., (Copyright © 2021 Chang Gung University. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Cerebral venous flow alterations potentially contribute to age-related white matter changes, but their role in small vessel disease has not been investigated., Methods: This study included 297 patients with hypertensive intracerebral hemorrhages (ICH) who underwent magnetic resonance imaging. Cerebral venous reflux (CVR) was defined as the presence of abnormal signal intensity in the dural venous sinuses or internal jugular vein on time-of-flight angiography. We investigated the association between CVR, dilated perivascular spaces (PVS), and recurrent stroke risk., Results: CVR was observed in 38 (12.8%) patients. Compared to patients without CVR those with CVR were more likely to have high grade (>20 in the number) dilated PVS in the basal ganglia (60.5% vs. 35.1%; adjusted odds ratio [aOR], 2.64; 95% confidence interval [CI], 1.25 to 5.60; P=0.011) and large PVS (>3 mm in diameter) (50.0% vs. 18.5%; aOR, 3.87; 95% CI, 1.85 to 8.09; P<0.001). During a median follow-up of 18 months, patients with CVR had a higher recurrent stroke rate (13.6%/year vs. 6.2%/year; aOR, 2.53; 95% CI, 1.09 to 5.84; P=0.03) than those without CVR., Conclusions: CVR may contribute to the formation of enlarged PVS and increase the risk of recurrent stroke in patients with hypertensive ICH.

Background/purpose: Recently optimized models for selecting the locations of hospitals capable of providing endovascular thrombectomy (EVT) did not consider the accuracy of the prehospital stroke scale assessment and possibility of secondary transport. Our study aimed to propose a new model for selecting existing hospitals with intravenous thrombolysis capability to become EVT-capable hospitals., Methods: A sequential order was provided to upgrade hospitals providing intravenous thrombolysis, using a mixed integer programming model based on current medical resource allocation. In addition, we drafted a centralized plan to redistribute existing EVT resources by redetermining locations of EVT-capable hospitals. Using historical data of 7679 on-scene patients with suspected stroke, the model was implemented to determine the hospital that maximizes the number of patients receiving EVT treatment within call-to-definitive-treatment time., Results: All suspected stroke patients were sent to EVT-capable hospitals directly under the current medical resource allocation model. After upgrading one additional hospital to become an EVT-capable hospital, the percentage of patients receiving definitive treatment within the standard call-to-definitive-treatment time was elevated from 68.82% to 72.97%. In the model, assuming that there is no hospital providing EVT, all patients suspected of stroke will be sent to EVT-capable hospitals directly after upgrading three or more hospitals to be able to provide treatment., Conclusion: All patients eligible for acute stroke treatment are sent to EVT-capable hospitals in the simulation under the current medical resource allocation model. This model can be utilized to provide insights for capacity redistribution in other regions., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2021 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Background To mitigate uncertainty that may arise in the judgment of emergency medical technicians when relying on a prehospital stroke scale at the scene, we propose a hospital selection protocol that considers the uncertainty of a prehospital stroke scale and the actual door-to-treatment durations, and we have developed a web-based system to be used with mobile devices. Methods and Results This hospital selection protocol incorporates real-time, estimated transport time obtained from Google Maps, historical median door-to-treatment duration at hospitals that only provide the standard intravenous thrombolysis treatment, and at hospitals with endovascular thrombectomy for probable large-vessel occlusion cases. We have validated the efficiency of the proposed protocol and compared it with other strategies used by emergency medical technicians when deciding on a receiving hospital. Using the proposed protocol for the triage reduces the time from onset to receiving definitive treatment by nearly 11 minutes. We found that the nearest endovascular thrombectomy-capable hospital from the scene may not be the most ideal if the door-to-treatment durations are discriminative. The results show that, when the tolerable bypass transport threshold and administration time are reduced to 9 minutes and 30.5 minutes, respectively, 228 patients out of 7678 cases, whose receiving hospitals were changed to endovascular thrombectomy-capable hospitals, received definitive treatment in a shorter time. The results of our analysis give recommendations for appropriate allowable bypass transport time for regional planning. Conclusions By applying almost-real value parameters, we have validated a web-based model, which can be universally adapted for optimal, time-saving hospital selection for patients with stroke.

Background: The efficacy and safety of intravenous alteplase administered 3-4.5 h after acute ischemic stroke have been demonstrated. However, whether responses differ between low-dose and standard-dose alteplase during this time window and whether certain subgroups benefit more remain unknown., Patients and Methods: The current analysis was based on a multicenter matched-cohort study conducted in Taiwan. The treatment group comprised 378 patients receiving intravenous alteplase 3-4.5 h after stroke onset, and the control group comprised 378 age- and sex-matched patients who did not receive alteplase treatment during the same period. Standard- and low-dose alteplase was administered to patients at the physician's discretion., Results: Overall, patients receiving alteplase exhibited more favorable outcomes than did controls [34.0 vs. 22.7%; odds ratio (OR): 1.75, 95% confidence interval (CI): 1.27-1.42], and the effectiveness was consistent in all subgroups. Although patients in the standard-dose group ( n = 182) were younger than those in the low-dose ( n = 192) group, the proportions of patients with favorable outcomes (36.3 vs. 31.8%; OR: 1.22, 95% CI: 0.80-1.88) and symptomatic hemorrhage (2.8 vs 4.2%; OR: 0.65, 95% CI: 0.21-2.02) were consistently comparable in a covariate-adjusted model and an age-matched cohort. In the subgroup analysis, patients with cardioembolism, atrial fibrillation, and hypercholesterolemia were more likely to achieve favorable outcomes after receiving standard-dose than low-dose alteplase., Conclusion: In the 3-4.5 h time window, the effectiveness and safety of standard-dose and low-dose alteplase may be comparable. A standard dose may be selected for patients with cardioembolism, atrial fibrillation, or hypercholesterolemia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Tang, Chen, Chen, Tsai, Sung, Lin, Huang, Po, Sun, Chen, Chan, Wei, Lee, Hsieh, Lin, Lien and Jeng.)

Ischemic stroke with a mismatch between diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) or T2-weighted images indicates onset within 4.5 h, but the pathological substrates in the DWI-T2 mismatch and T2(+) areas remain elusive. In this study, proteomics was used to explore (1) the protein expression profiles in the T2(+), mismatch, and contralateral areas, and (2) the protein with the highest expression in the T2(+) area in the brains of male Sprague-Dawley rats within 4.5 h after middle cerebral artery occlusion (MCAO). The expression of the candidate protein was further validated in (1) rat brain subjected to MCAO, (2) rat primary cortical neuronal culture with oxygen-glucose deprivation (OGD), and (3) infarcted human brain tissues. This study showed that apoptosis was observed in the T2(+) and mismatch regions and necroptosis in the T2(+) region of rat brains after MCAO. We identified capping protein regulator and myosin 1 linker 3 (CARMIL3) as the candidate molecule in the T2(+) and mismatch areas, exclusively in neurons, predominantly in the cytoplasm, and most abundant in the mismatch area. The CARMIL3(+) neurons and neurites in the mismatch and T2(+) areas were larger than those in the control area, and associated with (1) increased expression of sulfonylurea receptor 1 (SUR1), indicating edema, (2) accumulation of p62, indicating impaired autophagy, and (3) increase in 8-hydroxy-2'-deoxyguanosine (8-OHdG), indicating oxidative stress. The increased expression of CARMIL3 was validated in a cell model of cortical neurons after OGD and in infarcted human brain tissues. In conclusion, this study shows that the mismatch and T2(+) areas within 4.5 h after ischemia are characterized by upregulated expression of CARMIL3 in neurons, particularly the mismatch area, which is associated with neuronal edema, impaired autophagy, and oxidative stress, indicating that CARMIL3 serves as a molecular signature of brain ischemia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Yeh, Hsu, Yeh, Yang, Chang, Chiang, Tang, Tsai, Jeng and Hsieh.)

Cerebral small vessel disease is one of the most common causes of cognitive decline and stroke. While several lines of evidence have established a relationship between inflammation and cerebrovascular pathology, the mechanistic link has not yet been elucidated. Recent studies suggest activation of immune mediators, including the soluble form of triggering receptor expressed on myeloid cells 2 (TREM2), may be critical regulators. In this study, we compared the plasma levels of soluble TREM2 and its correlations with neuroimaging markers and cerebral amyloid load in 10 patients with Alzheimer's disease and 66 survivors of spontaneous intracerebral haemorrhage with cerebral amyloid angiopathy or hypertensive small vessel disease, two of the most common types of sporadic small vessel disease. We performed brain MRI and 11C-Pittsburgh compound B PET for all participants to evaluate radiological small vessel disease markers and cerebral amyloid burden, and 18F-T807 PET in a subgroup of patients to evaluate cortical tau pathology. Plasma soluble TREM2 levels were comparable between patients with Alzheimer's disease and small vessel disease (P = 0.690). In patients with small vessel disease, plasma soluble TREM2 was significantly associated with white matter hyperintensity volume (P < 0.001), but not with cerebral amyloid load. Among patients with Alzheimer's disease and cerebral amyloid angiopathy, plasma soluble TREM2 was independently associated with a tau-positive scan (P = 0.001) and white matter hyperintensity volume (P = 0.013), but not amyloid load (P = 0.221). Our results indicate plasma soluble TREM2 is associated with white matter hyperintensity independent of amyloid and tau pathology. These findings highlight the potential utility of plasma soluble TREM2 as a strong predictive marker for small vessel disease-related white matter injury and hold clinical implications for targeting the innate immune response when treating this disease., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Our living environment has been full of electromagnetic radiation (EMR) due to the prevailing electronic devices and equipment. Intermediate frequency electromagnetic field (IF-EMF) or waves constitute a significant part of EMR; therefore, an increasing number of household electrical appliances have become a source of IF-EMF, and concerns about IF-EMF on health are gaining more attention. However, little information is available about its impact on female reproductive traits, such as germ cell viability and early embryonic development, particularly at the cellular and molecular levels. In this study, we used porcine oocytes as a model system to explore the effect of IF-EMF at various intensities on the in vitro maturation (IVM) of oocytes and their subsequent embryonic development. Our results showed that no difference in oocyte maturation rates was detected among groups, but the cleavage and blastocyst rates of parthenotes derived from EMF-treated oocytes decreased with the weaker IF-EMF intensity (25 and 50 Gauss) groups compared to the control group (P < 0.05). For cytoplasmic maturation, the weaker IF-EMF intensity groups also showed a peripheral pattern of mitochondrial distribution resembling that of immature oocytes and increased autophagy activity. No obvious differences in cytoskeletal distribution and total cell numbers of blastocysts were investigated in the four IF-EMF treatments compared to those in the control group. Although the underlying mechanism associated with EMF effects on oocytes and embryos is still elusive, we have demonstrated that low intensity IF-EMF exerts harmful effects on porcine oocytes during the maturation stage, carrying over such effects to their subsequent embryonic development.

Transposable elements (TEs) initially attracted attention because they comprise a major portion of the genomic sequences in plants and animals. TEs may jump around the genome and disrupt both coding genes as well as regulatory sequences to cause disease. Host cells have therefore evolved various epigenetic and functional RNA-mediated mechanisms to mitigate the disruption of genomic integrity by TEs. TE associated sequences therefore acquire the tendencies of attracting various epigenetic modifiers to induce epigenetic alterations that may spread to the neighboring genes. In addition to posting threats for (epi)genome integrity, emerging evidence suggested the physiological importance of endogenous TEs either as cis-acting control elements for controlling gene regulation or as TE-containing functional transcripts that modulate the transcriptome of the host cells. Recent advances in long-reads sequence analysis technologies, bioinformatics and genetic editing tools have enabled the profiling, precise annotation and functional characterization of TEs despite their challenging repetitive nature. The importance of specific TEs in preimplantation embryonic development, germ cell differentiation and meiosis, cell fate determination and in driving species specific differences in mammals will be discussed., (© 2021. The Author(s).)