Comparing the imaging characteristics of middle-aged patients with multiple sclerosis and CADASIL: A retrospective cross-sectional study.

BACKGROUND: Few studies have quantitatively analyzed the imaging disparities between multiple sclerosis (MS) and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We aimed to compare the imaging characteristics of MS and CADASIL in middle-aged patients. MATERIALS AND METHODS: This retrospective study used a single-center database and included patients aged 40-60 years with MS and CADASIL who underwent the designated imaging protocol including 3D T1-weighted imaging and fluid attenuated inversion recovery (FLAIR), diffusion tensor imaging and susceptibility-weighted imaging between January 2018 and March 2023. Patients with MRI-detected macrobleeds were excluded. RESULTS: A total of 27 patients with MS (mean age, 46.7 years ± 4.4, 8 men) and 30 patients with CADASIL (mean age, 51.6 years ± 5.8, 14 men) were included. No significant differences were observed in the Fazekas grades of white matter lesions (WMLs). Patients with CADASIL exhibited greater external capsule involvement (56.7% vs.18.5 %; p = 0.006), whereas the MS group had more lesions in the corpus callosum (81.5% vs. 53.3 %, p = 0.02) and brainstem (74.1% vs. 46.7 %, p = 0.04). The CADASIL group exhibited a higher incidence of microbleeds (12.07 vs. 0.11, p = 0.001). The WMLs in the MS group exhibited a lower T1 lesion/cerebrospinal fluid signal index (2.206 vs. 2.882, p < 0.001). A value of ≤2.57 demonstrated a sensitivity of 92.6 % and a specificity of 90.0 % in differentiating MS. Patients with MS had a thinner corpus callosum (7.18 mm vs 7.86 mm, p = 0.04), while patients with CADASIL showed significantly higher mean diffusivity (0.8776 × 10-3 vs. 0.7637 × 10-3 mm2/s, p = 0.03) and lower fractional anisotropy (0.7581 vs. 0.8389, p = 0.04) in the splenium of the corpus callosum. CONCLUSION: Middle-aged patients with MS and CADASIL showed comparable Fazekas grades for WMLs. However, lesion distribution, T1 signal characteristics, and splenic diffusivity changes can help differentiate between MS and CADASIL.

Bone Tissue Engineering with Adipose-Derived Stem Cells in Polycaprolactone/Graphene Oxide/Dexamethasone 3D-Printed Scaffolds.

We fabricated three-dimensional (3D)-printed polycaprolactone (PCL) and PCL/graphene oxide (GO) (PGO) scaffolds for bone tissue engineering. An anti-inflammatory and pro-osteogenesis drug dexamethasone (DEX) was adsorbed onto GO and a 3D-printed PGO/DEX (PGOD) scaffold successfully improved drug delivery with a sustained release of DEX from the scaffold up to 1 month. The physicochemical properties of the PCL, PGO, and PGOD scaffolds were characterized by various analytical techniques. The biological response of these scaffolds was studied for adherence, proliferation, and osteogenic differentiation of seeded rabbit adipose-derived stem cells (ASCs) from DNA assays, alkaline phosphatase (ALP) production, calcium quantification, osteogenic gene expression, and immunofluorescence staining of osteogenic marker proteins. The PGOD scaffold was demonstrated to be the best scaffold for maintaining cell viability, cell proliferation, and osteogenic differentiation of ASCs in vitro. In vivo biocompatibility of PGOD was confirmed from subcutaneous implantation in nude mice where ASC-seeded PGOD can form ectopic bones, demonstrated by microcomputed tomography (micro-CT) analysis and immunofluorescence staining. Furthermore, implantation of PGOD/ASCs constructs into critical-sized cranial bone defects in rabbits form tissue-engineered bones at the defect site, observed using micro-CT and histological analysis.

Unveiling the dynamics of respiratory infections revealed by multiplex PCR testing during the COVID-19 pandemic in Taiwan, 2020-2023.

BACKGROUND: The emergence of SARS-CoV-2 in late 2019 sparked the global COVID-19 pandemic, leading to varied vaccine policies worldwide. The evolving patterns of respiratory pathogens, aside from SARS-CoV-2, during the pandemic have had a significant impact on the development of vaccine strategies. METHODS: This study explores the landscape of respiratory pathogens, encompassing SARS-CoV-2, respiratory syncytial virus (RSV), and influenza viruses, through a retrospective analysis of data obtained from the BioFire Respiratory Panel 2.1 (RP 2.1) at China Medical University Hospital (Taichung, Taiwan) spanning from January 2020 to November 2023. RESULTS: Among the 7950 respiratory samples studied, pediatric cases exhibited higher positivity (64.9%, 2488/3835) and mixed detection rates (43.8%, 1090/2488) than adults. Annual mixed detection rates increased (27.9-48%). Prevalence analysis revealed diverse patterns across age groups, with higher rates in pediatrics. Notably, human rhinovirus/enterovirus predominated (48.1%). Mixed detection illustrated viral co-detections, notably with parainfluenza viruses and adenovirus. Government policies and pandemic dynamics influenced infection patterns, with RSV resurgence after May 2022. Age-specific RSV detection demonstrated a shift, influencing vaccine considerations. Amid global vaccine initiatives, RSV's increasing trend in adults warrants attention. CONCLUSIONS: This comprehensive analysis emphasizes the importance of multiplex PCR testing in shaping targeted vaccination strategies during evolving respiratory pathogen landscapes.

Very early neurological deterioration during intravenous thrombolysis in patients with acute ischemic stroke.

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.

High fibrin and platelet clot predicts stroke recurrence or mortality after thrombectomy in patients with active cancer.

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.

Hemorrhagic Transformation in Noncardioembolic Acute Ischemic Stroke: MRI Analysis From PACIFIC-STROKE.

BACKGROUND: In the phase 2 PACIFIC-STROKE trial (Proper Dosing and Safety of the Oral FXIa Inhibitor BAY 2433334 in Patients Following Acute Noncardioembolic Stroke), asundexian, an oral factor XIa inhibitor, did not increase the risk of hemorrhagic transformation (HT). In this secondary analysis, we aimed to investigate the frequency, types, and risk factors of HT on brain magnetic resonance imaging (MRI). METHODS: This was a secondary analysis of the PACIFIC-STROKE trial. Patients with mild-to-moderate acute noncardioembolic ischemic stroke were randomly assigned to asundexian or placebo plus guideline-based antiplatelet therapy. Brain MRIs were required at baseline (≤120 hours after stroke onset) and at 26 weeks or end-of-study. HT was defined using the Heidelberg classification and classified as early HT (identified on baseline MRI) or late HT (new HT by 26 weeks) based on iron-sensitive sequences. Multivariable logistic regression models were used to test factors that are associated with early HT and late HT, respectively. RESULTS: Of 1745 patients with adequate baseline brain MRI (mean age, 67 years; mean National Institutes of Health Stroke Scale score, 2.8), early HT at baseline was detected in 497 (28.4%). Most were hemorrhagic infarctions (hemorrhagic infarction type 1: 15.2%; HI2: 12.7%) while a few were parenchymal hematomas (parenchymal hematoma type 1: 0.4%; parenchymal hematoma type 2: 0.2%). Early HT was more frequent with longer symptom onset-to-MRI interval. Male sex, diabetes, higher National Institutes of Health Stroke Scale large (>15 mm) infarct size, cortical involvement by infarct, higher number of acute infarcts, presence of chronic brain infarct, cerebral microbleed, and chronic cortical superficial siderosis were independently associated with early HT in the multivariable logistic regression model. Of 1507 with follow-up MRI, HT was seen in 642 (42.6%) overall, including 361 patients (23.9%) with late HT (new HT: 306; increased grade of baseline HT: 55). Higher National Institutes of Health Stroke Scale, large infarct size, cortical involvement of infarct, and higher number of acute infarcts predicted late HT. CONCLUSIONS: About 28% of patients with noncardioembolic stroke had early HT, and 24% had late HT detectable by MRI. Given the high frequency of HT on MRI, more research is needed on how it influences treatment decisions and outcomes.

Prevalence and clinical features of carotid artery web in patients undergoing endovascular thrombectomy for acute ischemic stroke.

PURPOSE: Carotid artery web (CaW) is a rare focal fibromuscular dysplasia that can lead to embolic strokes with large vessel occlusion. This condition can be effectively treated with endovascular thrombectomy (EVT). Our study aims to assess the prevalence of CaW among patients with acute ischemic stroke (AIS) who underwent EVT and to compare the clinical characteristics of CaW with other carotid artery pathologies. METHODS: We enrolled consecutive patients with AIS who underwent EVT at a single medical center and two regional teaching hospitals in Taiwan from September 2014 to December 2021. We compared CaW with carotid dissection (CaD) and carotid large artery atherosclerosis (CaLAA) in terms of patient demographics and thrombus histological findings. RESULTS: Of the 576 AIS patients who underwent EVT, four (mean age: 50 years) were diagnosed with CaW, resulting in a prevalence of 0.69%. Among these four patients, three experienced successful reperfusion after EVT and achieved functional independence (defined as a modified Rankin Scale score ≤2) three months post-stroke. Importantly, none of the CaW patients suffered a recurrent stroke within one year. Patients with CaW were younger than those with CaD or CaLAA, and exhibited fewer vascular risk factors. Additionally, CaW was associated with distal occlusion sites. The thrombus composition in CaW patients was similar to that in CaD patients. CONCLUSIONS: In conclusion, CaW is a rare finding among Asian patients with carotid artery disease who undergo for AIS. It is more prevalent in younger patients with a limited number of vascular risk factors.

Remote Ischemic Conditioning in Stroke Recovery.

Remote ischemic conditioning (RIC) is a therapeutic strategy to protect a vital organ like the brain from ischemic injury through brief and repeat cycles of ischemia and reperfusion in remote body parts such as arm or leg. RIC has been applied in different aspects of the stroke field and has shown promise. This narrative review will provide an overview of how to implement RIC in stroke patients, summarize the clinical evidence of RIC on stroke recovery, and discuss unresolved questions and future study directions.

A Study on Decision-Making for Improving Service Efficiency in Hospitals.

The provision of efficient healthcare services is essential, driven by the increasing demand for healthcare resources and the need to optimize hospital operations. In this context, the motivation to innovate and improve services while addressing urgent concerns is critical. Hospitals face challenges in managing internal dispatch services efficiently. Outsourcing such services can alleviate the burden on hospital staff, reduce costs, and introduce professional expertise. However, the pressing motivation lies in enhancing service quality, minimizing costs, and exploring innovative approaches. With the rising demand for healthcare services, there is an immediate need to streamline hospital operations. Delays in internal transportation services can have far-reaching implications for patient care, necessitating a prompt and effective solution. Drawing upon dispatch data from a healthcare center in Taiwan, this study constructed a decision-making model to optimize the allocation of hospital service resources. Employing simulation techniques, we closely examine how hospital services are currently organized and how they work. In our research, we utilized dispatch data gathered from a healthcare center in Taichung, Taiwan, spanning from January 2020 to December 2020. Our findings underscore the potential of an intelligent dispatch strategy combined with deployment restricted to the nearest available workers. Our study demonstrates that for cases requiring urgent attention, delay rates that previously ranged from 5% to 34% can be notably reduced to a much-improved 3% to 18%. However, it is important to recognize that the realm of worker dispatch remains subject to a multifaceted array of influencing factors. It becomes evident that a comprehensive dispatching mechanism must be established as part of a broader drive to enhance the efficiency of hospital service operations.

Giant Interpectoral Lipoma Causing Venous Thoracic Outlet Syndrome: A Rare Case Presentation.

Lipomas are the most prevalent type of benign soft tissue tumors, primarily composed of adipocytes, and typically remain asymptomatic unless they reach a significant size. Although giant lipomas are infrequent, their occurrence on the chest wall, particularly in the interpectoral region, is exceedingly rare. We present a unique case of a 48-year-old man with a massive interpectoral lipoma measuring 19.4 × 12.9 × 9.4 cm, which resulted in venous thoracic outlet syndrome by compressing the subclavian vein. This case highlights the clinical challenges in diagnosing deep-seated chest wall lipomas and underscores the necessity of considering thoracic outlet syndrome as a potential complication, even in the absence of direct neural or arterial compression. The presentation of thoracic outlet syndrome can vary, and a comprehensive evaluation is imperative for accurate diagnosis and management.

Comparing Low- or Standard-Dose Alteplase in Endovascular Thrombectomy: Insights From a Nationwide Registry.

BACKGROUND: Timely intravenous thrombolysis and endovascular thrombectomy are the standard reperfusion treatments for large vessel occlusion stroke. Currently, it is unknown whether a low-dose thrombolytic agent (0.6 mg/kg alteplase) can offer similar efficacy to the standard dose (0.9 mg/kg alteplase). METHODS: We enrolled consecutive patients in the multicenter Taiwan Registry of Endovascular Thrombectomy for Acute Ischemic Stroke who had received combined thrombolysis (within 4.5 hours of onset) and thrombectomy treatment from January 2019 to April 2023. The choice of low- or standard-dose alteplase was based on the physician's discretion. The outcomes included successful reperfusion (modified Thrombolysis in Cerebral Infarction score, 2b-3), symptomatic intracerebral hemorrhage, 90-day modified Rankin Scale score, and 90-day mortality. The outcomes between the 2 groups were compared using multivariable logistic regression and inverse probability of treatment weighting-adjusted analysis. RESULTS: Among the 2242 patients in the Taiwan Registry of Endovascular Thrombectomy for Acute Ischemic Stroke, 734 (33%) received intravenous alteplase. Patients in the low-dose group (n=360) were older, had more women, more atrial fibrillation, and longer onset-to-needle time compared with the standard-dose group (n=374). In comparison to low-dose alteplase, standard-dose alteplase was associated with a lower rate of successful reperfusion (81% versus 87%; adjusted odds ratio, 0.63 [95% CI, 0.40-0.98]), a numerically higher incidence of symptomatic intracerebral hemorrhage (6.7% versus 3.9%; adjusted odds ratio, 1.81 [95% CI, 0.88-3.69]), but better 90-day modified Rankin Scale score (functional independence [modified Rankin Scale score, 0-2], 47% versus 31%; adjusted odds ratio, 1.91 [95% CI, 1.28-2.86]), and a numerically lower mortality rate (9% versus 15%; adjusted odds ratio, 0.73 [95% CI, 0.43-1.25]) after adjusting for covariates. Similar results were observed in the inverse probability of treatment weighting-adjusted models. The results were consistent across predefined subgroups and age strata. CONCLUSIONS: Despite the lower rate of successful reperfusion and higher risk of symptomatic intracerebral hemorrhage with standard-dose alteplase, standard-dose alteplase was associated with a better functional outcome in patients receiving combined thrombolysis and thrombectomy.

Facial Anthropometric Analysis of Gender-Related Characteristics in Computed Tomography.

BACKGROUND: In recent years, facial feminization surgery (FFS) has gained increasing popularity because of increases in transgender individuals and the acceptance of diversity in gender identity. However, there is still a scarcity of anthropometric research to guide evidence-based practices for FFS in Taiwan. AIM AND OBJECTIVES: The purpose of this study was to provide a reference for surgeons to achieve optimal outcomes for patients undergoing FFS. The anthropometric analysis could help surgeons meet patients' specific requirements and improve patients' alignment with their gender identity. MATERIALS AND METHODS: The study group consisted of 100 patients (50 males and 50 females) who had undergone cranial computed tomography at Chang Gung Memorial Hospital in Taiwan because of the indication of blunt injuries to the head and face with suspected skull and facial fractures. The computed tomography images were imported into the OsiriX image software to conduct an anthropometric evaluation. The parameters used in the measurements included 2 aspects: bone and soft tissue anthropometric analysis. RESULTS: Anthropometric data were obtained from 50 males (age 32.6 ± 11.4 years) and 50 females (age 33.7 ± 10.3 years). The results for bone measurements showed that both the forehead bossing length and nasal bone width in the male group were significantly greater. The frontal angle in both bone and soft tissue in the male group was significantly smaller. The chin height and bigonial width in both bone and soft tissue in the male group were significantly greater. Although the average gonial angle was greater in the female group, the difference was not significant. For the measurements of lip projection, the results showed that there was no significant difference. Although this group of Asian males had more acute nasolabial angles, the difference was not statistically significant. However, the average nasofrontal angle among females was significantly more obtuse than among males. CONCLUSION: The results revealed that Asian males tend to have more prominent superior orbital rims, wider nasal bones, and wider and taller mandibles compared with Asian females. Despite showing some trends, the gonial angle and lip projections did not reveal any significant differences, which is likely because of a large amount of variation.

Effect of the Factor XIa Inhibitor Asundexian According to Baseline Infarct Pattern and on MRI Covert Infarct Outcomes.

BACKGROUND: Exploratory analysis of the phase 2 PACIFIC-Stroke (Program of Anticoagulation via Inhibition of FXIa by the Oral Compound BAY 2433334-Non-Cardioembolic Stroke) randomized trial suggested that asundexian, an oral factor XIa inhibitor, prevents recurrent stroke and transient ischemic attacks in patients with atherosclerotic stroke. In this post hoc exploratory analysis, we hypothesized that asundexian would be more effective in patients enrolled with large, multiple, or cortical acute infarcts on magnetic resonance imaging than in patients enrolled with a single small subcortical acute infarct, and asundexian would prevent incident cortical covert infarcts. METHODS: In this placebo-controlled double-blinded randomized controlled trial, patients with mild-to-moderate noncardioembolic ischemic stroke were assigned to asundexian (10, 20, or 50 mg once daily) or placebo, in addition to antiplatelet therapy. Brain magnetic resonance imagings were required within 72 hours of randomization and repeated at 26 weeks or at discontinuation of the study drug. RESULTS: Of 1808 randomized patients, 1780 (98.5%) had interpretable baseline magnetic resonance imagings, of which 1628 (91.5%) had ≥1 diffusion-weighted imaging positive acute infarcts. Magnetic resonance imaging follow-up was obtained in 1439 patients, of whom 1358 had no symptomatic stroke during the trial period. Compared with placebo, asundexian 50 mg daily conferred a trend toward reduced risk of recurrent ischemic stroke or incident covert infarcts (hazard ratio, 0.71 [95% CI, 0.45-1.11]) and recurrent ischemic stroke or transient ischemic attack (secondary outcome; hazard ratio, 0.59 [95% CI, 0.33-1.06]) that was not evident in patients with single small subcortical infarcts (hazard ratios, 1.14 [95% CI, 0.62-2.10] and 0.93 [95% CI, 0.28-3.06]). Incident cortical covert infarcts were reduced in patients taking asundexian 50 mg, but the difference was not statistically significant (crude incidence ratio, 0.56 [95% CI, 0.28-1.12]). CONCLUSIONS: These exploratory, unconfirmed results suggest that asundexian may prevent new embolic infarcts but not small artery occlusion. The hypothesis that subtypes of covert brain infarcts respond differently to anticoagulant prevention should be tested in future trials. REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT04304508.

Effect of Needle-To-Puncture Time on Reperfusion Outcome in Acute Ischemic Stroke.

INTRODUCTION: The aim of the study was to investigate the impact of time interval between start of intravenous thrombolysis (IVT) to start of endovascular thrombectomy (EVT) on stroke outcomes. METHODS: Data from the Quality Improvement and Clinical Research (QuICR) provincial stroke registry from Alberta, Canada, were used to identify stroke patients who received IVT and EVT from January 2015 to December 2019. We assessed the impact of the time interval between IVT bolus to EVT puncture (needle-to-puncture times [NPT]) on outcomes. Radiological outcomes included successful initial recanalization (revised Arterial Occlusive Lesion 2b-3), successful initial and final reperfusion (modified thrombolysis in cerebral infarction 2b-3). Clinical outcomes were 90-day modified Rankin Scale (mRS) and mortality. RESULTS: Of the 680 patients, 233 patients (median age: 73, 41% females) received IVT + EVT. Median NPT was 38 min (IQR, 24-60). Arrival during working hours was independently associated with shorter NPT (p < 0.001). Successful initial recanalization and initial and final reperfusion were observed in 12%, 10%, and 83% of patients, respectively. NPT was not associated with initial successful recanalization (OR 0.97 for every 10-min increase of NPT, 95% CI: 0.91-1.04), initial successful reperfusion (OR 1.01, 95% CI: 0.96-1.07), or final successful reperfusion (OR: 1.03, 95% CI: 0.97-1.08). Every 10-min delay in NPT was associated with lower odds of functional independence at 90 days (mRS ≤2; OR: 0.93; 95% CI, 0.88-0.97). Patients with shorter NPT (≤38 min) had lower 90-day mRS scores (median 1 vs. 3; OR: 0.54 [0.31-0.91]) and had lower mortality (6.1% vs. 21.2%; OR, 0.23 [0.10-0.57]) than the longer NPT group. CONCLUSION: Shorter NPT did not impact reperfusion outcomes but was associated with better clinical outcome.

Modifiable vascular risk factors contribute to stroke in 1080 NOTCH3 R544C carriers in Taiwan Biobank.

BACKGROUND AND AIM: Previous studies have suggested cardiovascular risk factors increase the risk of not only common sporadic stroke but also of stroke in patients with monogenic stroke disorders including CADASIL. We investigated the effects of the NOTCH3 Arg544Cys (R544C) variant and associated vascular risk factors on stroke in the Taiwanese population. METHODS: This study was conducted using data from the Taiwan Biobank, consisting of at least 130,000 Han Chinese participants. The genotype was derived from customized genome-wide arrays for 650,000 to 750,000 single-nucleotide polymorphisms (SNPs). Individuals with NOTCH3 R544C were subsequently matched with noncarriers based on the propensity score at a 1:10 ratio by demographic and cardiovascular risk factors. The odds ratio (OR) for stroke or other phenotypes in NOTCH3 R544C carriers and matched noncarriers was then calculated. Univariate and multivariate regression analyses were performed on cardiovascular risk factors in NOTCH3 R544C carriers with and without stroke. The polygenic risk score (PRS) model, adopted from the UK Biobank, was then applied to evaluate the role of NOTCH3 R544C in stroke. RESULTS: From the 114,282 participants with both genotype and questionnaire results, 1080 (0.95%) harbored the pathogenic NOTCH3 R544C variant. When compared to the matched controls (n = 10,800), the carriers presented with a history of stroke (OR: 2.52, 95% confidence interval (CI) (1.45, 4.37)), dementia (OR: 30.1, 95% CI (3.13, 289.43)), and sibling history of stroke (OR: 2.48, 95% CI (1.85, 3.34)) phenotypes. The risk of stroke increased with every 10-year increase in age (p = 0.006, Cochran-Mantel-Haenszel test). Among NOTCH3 R544C carriers, 16 (1.3%) of the 1080 carriers with a stroke history were older, male, and more likely to have hypertension, diabetes, dyslipidemia, and a family history of stroke. In the stepwise multivariate analysis, hypertension (OR: 11.28, 95% CI (3.54, 43.3)) and diabetes mellitus (OR: 4.10, 95% CI (1.31, 12.4)) were independently associated with stroke. Harboring the NOTCH3 R544C variant in the Taiwan Biobank is comparable with a 6.74 standard deviations increase in individual's polygenic risk score for stroke. CONCLUSION: While the NOTCH3 R544C variant alone increased the risk of stroke, modifiable vascular risk factors also played a role in the occurrence of stroke in Taiwanese community-dwelling individuals carrying the NOTCH3 variant.

Impact of cerebral small vessel disease burden and drug level at admission on direct oral anticoagulant associated intracerebral hemorrhage.

INTRODUCTION: Direct oral anticoagulant (DOAC)-associated intracerebral hemorrhage (ICH) is a catastrophic complication. The aim of this study was to investigate the association between computed tomography (CT)-based cerebrovascular small vessel disease (SVD) burden and DOAC-ICH as well as the DOAC concentration upon hospital admission and ICH outcome. PATIENTS AND METHODS: The study included two cohorts: (1) DOAC-ICH: patients who suffered from DOAC-ICH and underwent drug level measurements upon admission; (2) DOAC-non-ICH: stable DOAC users who underwent head CT without ICH during treatment. We categorized the DOAC levels of the DOAC-ICH patients as low (<50 ng/mL), medium (50-300 ng/mL), and high (>300 ng/mL). The CT-based SVD burden (including white matter lesions [WML], lacunes, and cerebral atrophy) was evaluated, and SVD scores (range, 0-3) were used to evaluate SVD severity. RESULTS: A total of 43 DOAC-ICH patients and 177 DOAC-non-ICH patients were enrolled. DOAC-ICH patients were more likely to have WML, lacunes, or cerebral atrophy compared to DOAC-non-ICH patients. After adjustment, the SVD burden was associated with DOAC-ICH, with a higher risk of more severe SVD (SVD score of 2; odds ratio [OR], 10.3 [3.17, 33.3]; score of 3; OR, 16.8 [4.50, 62.6]). The proportions of patients with high, medium, and low drug levels in the DOAC-ICH group were 16.3%, 55.8%, and 27.9%, respectively. Additionally, the high-level group displayed a larger hematoma size and had worse functional outcomes at 3 months than the other two groups. DISCUSSION AND CONCLUSION: The severity of SVD burden was associated with DOAC-ICH. Furthermore, high DOAC levels in ICH were associated with unfavorable clinical outcomes. To address the potential selection bias from these two cohorts, a prospective study to investigate the co-contribution of drug levels and SVD to DOAC-ICH is essential.

Associations of Cerebral Small Vessel Disease on the Features of Hematoma and Hematoma Expansion in Intracerebral Hemorrhage.

INTRODUCTION: Several early noncontrast CT (NCCT) signs of spontaneous intracerebral hemorrhage (ICH) can predict hematoma expansion (HE). However, the associations of underlying cerebral small vessel disease (SVD) on early NCCT signs and HE have been less explored. METHODS: We conducted an analysis of all patients with spontaneous supratentorial ICH and received follow-up imaging between 2016 and 2020 at a stroke center. The early NCCT signs were categorized as shape or density signs. HE was defined as an increase in hematoma volume ≥6 mL or 33% from baseline. The severity of SVD was assessed by both a 3-point CT-based and a 4-point magnetic resonance imaging (MRI)-based SVD score. Regression models were used to examine the associations between SVD score and hematoma volume, NCCT signs, and HE. RESULTS: A total of 328 patients (median age: 64 years; 38% female) were included. The median baseline ICH volume was 8.6 mL, with 38% of the patients had shape signs and 52% had density signs on the initial NCCT. Higher MRI-SVD scores were associated with smaller ICH volumes (p = 0.0006), fewer shape (p = 0.001), or density signs (p = 0.0003). Overall, 16% of patients experienced HE. A higher MRI-SVD score was inversely associated with HE (adjusted odds ratio 0.71, 95% CI: 0.53-0.96). Subgroup analysis revealed that this association was primarily observed in patients who were younger (<65 years), male, had deep hemorrhage, or did not meet the criteria for cerebral amyloid angiopathy diagnosis. CONCLUSIONS: In patients with spontaneous ICH, a more severe SVD was associated with smaller hematoma volume, fewer NCCT signs, and a lower risk of HE. Further research is required to investigate why a higher burden of severely diseased cerebral small blood vessels is associated with less bleeding.

Surface Modification of Polylactic Acid Bioscaffold Fabricated via 3D Printing for Craniofacial Bone Tissue Engineering.

Bone tissue engineering is a promising solution for advanced bone defect reconstruction after severe trauma. In bone tissue engineering, scaffolds in three-dimensional (3D) structures are crucial components for cell growth, migration, and infiltration. The three-dimensional printing technique is well suited to manufacturing scaffolds since it can fabricate scaffolds with highly complex designs under good internal structural control. In the current study, the 3D printing technique was utilized to produce polylactic acid (PLA) scaffolds. BMSCs were seeded onto selected scaffolds, either hydrogel-mixed or not, and cultivated in vitro to investigate the osteogenic potential in each group. After osteogenic incubation in vitro, BMSC-seeded scaffolds were implanted onto rat cranium defects, and bone regeneration was observed after 12 weeks. Our results demonstrated that BMSCs were able to seed onto 3D-printed PLA scaffolds under high-resolution observation. Real-time PCR analysis showed their osteogenic ability, which could be further improved after BMSCs were mixed with hydrogel. The in vivo study showed significantly increased bone regeneration when rats' cranium defects were implanted with a hydrogel-mixed BMSC-seeded scaffold compared to the control and those without cell or hydrogel groups. This study showed that 3D-printed PLA scaffolds are a feasible option for BMSC cultivation and osteogenic differentiation. After mixing with hydrogel, BMSC-seeded 3D-printed scaffolds can facilitate bone regeneration.

Contribution of the APOE Genotype to Cognitive Impairment in Individuals With NOTCH3 Cysteine-Altering Variants.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most prevalent monogenic cerebral small-vessel disease. Phenotype variability in CADASIL suggests the possible role of genetic modifiers. We aimed to investigate the contributions of the APOE genotype and Neurogenic locus notch homolog protein 3 (NOTCH3) variant position to cognitive impairment associated with CADASIL. METHODS AND RESULTS: Patients with the cysteine-altering NOTCH3 variant were enrolled in a cross-sectional study, including the Mini-Mental State Examination (MMSE), brain magnetic resonance imaging, and APOE genotyping. Cognitive impairment was defined as an MMSE score <24. The associations between the MMSE score and genetic factors were assessed using linear regression models. Bayesian adjustment for confounding was used to identify clinical confounders. A total of 246 individuals were enrolled, among whom 210 (85%) harbored the p.R544C variant, 96 (39%) had cognitive impairment, and 150 (61%) had a history of stroke. The APOE ɛ2 allele was associated with a lower MMSE score (adjusted B, -4.090 [95% CI, -6.708 to -1.473]; P=0.023), whereas the NOTCH3 p.R544C variant was associated with a higher MMSE score (adjusted B, 2.854 [95% CI, 0.603-5.105]; P=0.0132) after adjustment for age, education, and history of ischemic stroke. Mediation analysis suggests that the associations between the APOE ɛ2 allele and MMSE score and between the NOTCH3 p.R544C variant and MMSE score are mediated by mesial temporal atrophy and white matter hyperintensity, respectively. CONCLUSIONS: APOE genotype may modify cognitive impairment in CADASIL, whereby individuals carrying the APOE ɛ2 allele may present a more severe cognitive impairment.