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Background: This study aimed to determine the relationship between neurological deterioration (ND) and blood viscosity (BV) in patients with lacunar stroke (LS).Methods: This was a single-hospital retrospective observational study of patients with LS. Patients were categorized into two groups: those with progressive symptoms and those without clinical worsening. Progression was defined as worsening by ≥2 points on the National Institutes of Health Stroke Scale (NIHSS) for motor function or ≥3 points on the total NIHSS score.Results: In total, 215 patients (26% of the total stroke population during the study period) who had experienced LS were screened for enrolment, and 182 were included in the final analysis. Of these, 40 patients (22%) showed clinical progressive symptoms. Among men, the progressive stroke group visited the hospital earlier with more severe symptoms than the non-progressive stroke group. Logistic linear regression analysis revealed that onset to admission ≤24 hours (odds ratio [OR], 4.03; 95% confidence interval [CI], 1.1-14.71; p=0.035), NIHSS ≥4 at admission (OR, 2.63; 95% CI, 1.03-6.71; p=0.043), systolic BV (OR, 3.57; 95% CI, 1.39-9.16; p=0.008), and diastolic BV (OR, 1.09; 95% CI, 1.02-1.16; p=0.012) were associated with progressive stroke. Whereas in women, only onset to admission ≤24 hour (OR, 17.92; 95% CI, 2.16-148.62; p=0.008) showed association.Conclusion: We found that admission within 24 hours, higher NIHSS score, and higher BV at admission were associated with an increased risk of ND in male patients with LS. Increased BV may play a role in reducing cerebral collateral circulation, thrombus propagation, or arterial reocclusion in progressive LS.

Background d ‐Dimer level is a marker of hypercoagulability, which is associated with thrombus formation and resolution. We investigated the value of d ‐dimer levels in predicting outcomes of acute ischemic stroke in patients who underwent endovascular treatment (EVT). Methods We analyzed data of patients who underwent only EVT from the SECRET (Selection Criteria in Endovascular Thrombectomy and Thrombolytic Therapy) registry. d ‐Dimer levels were routinely measured in 10 of 15 participating hospitals. Patients were grouped into tertiles (tertile 1, tertile 2, and tertile 3) according to d ‐dimer levels (lowest, moderate, and highest, respectively). We compared serial scores on the National Institutes of Health Stroke Scale at baseline, on day 1 of hospitalization, and at discharge; functional outcome 3 months after EVT; and rate of mortality within 6 months after EVT. Results In the 170 patients, the median d ‐dimer level was 477 ng/mL (interquartile range, 249–988 ng/mL). In tertile 3, the National Institutes of Health Stroke Scale score was higher at discharge than on day 1 of hospitalization. Poor outcome 3 months after EVT (modified Rankin Scale score, ≥3) was more common with high d ‐dimer levels (26.3% of tertile 1, 57.1% of tertile 2, and 76.4% of tertile 3; P d ‐dimer level was independently associated with poor outcome 3 months after EVT (odds ratio [OR], 4.399 [95% CI, 1.594–12.135]). Kaplan–Meier survival analysis showed that a high d ‐dimer level was independently associated with death within 6 months after EVT (OR, 5.441 [95% CI, 1.560–18.978]; log‐rank test, P d ‐dimer effect showed no heterogeneity across the subgroups for poor outcome 3 months after EVT or death within 6 months after EVT. The direction of effect was unfavorable for tertile 3 across all demographic strata. Conclusions High plasma d ‐dimer levels were predictive of early neurologic worsening, poor functional outcome 3 months after EVT, and death within 6 months after EVT. Registration URL: http://www.clinicaltrials.gov ; Unique identifier: NCT02964052.

Background: Recently, lateral differences in body surface temperature (BST) have been reported as a symptom of Wallenberg syndrome (WS), resulting from disturbances in the sympathetic nerve pathway. This study aimed to investigate the relationship between the laterality of BST and brain magnetic resonance imaging (MRI) findings in 12 patients with WS.Methods: BST was measured using an infrared thermal camera at 7±3 days and 90±30 days after symptom onset. The MRI findings were categorized as rostral, middle, and caudal medulla rostrocaudally and typical, ventral, large, dorsal, and lateral types in the horizontal direction.Results: MRI revealed medullary lesions on the right in five patients and on the left in seven patients. Two patients without lateralized BST had lateral caudal medullary infarction, and one patient had a dorsal middle medullary infarction. One patient with lateralized BST had a rostral medullary infarction and the other had a typical or large middle medulla infarction. Lateralized BST in patients with WS may disturb the sympathetic nervous system pathway that descends from the rostral ventrolateral medulla oblongata. Deficits in sweating and skin blood flow may cause BST laterality.Conclusion: This study showed that lateralized BST in patients with WS may be associated with disturbances in the sympathetic nervous pathway descending from the rostral ventrolateral medulla. These results support the assumption that autonomic dysfunction may be related to abnormal sensory symptoms in patients with WS.

Background: A high and low estimated glomerular filtration rate (eGFR) could affect outcomes after reperfusion therapy for ischemic stroke. This study aimed to determine whether renal function based on eGFR affects mortality risk in patients with ischemic stroke within 6 months following reperfusion therapy. Methods: This prospective registry–based cohort study included 2266 patients who received reperfusion therapy between January 2000 and September 2019 and were registered in the SECRET (Selection Criteria in Endovascular Thrombectomy and Thrombolytic Therapy) study or the Yonsei Stroke Cohort. A high and low eGFR were based on the Chronic Kidney Disease Epidemiology Collaboration equation and defined, respectively, as the 5th and 95th percentiles of age- and sex-specific eGFR. Occurrence of death within 6 months was compared among the groups according to their eGFR such as low, normal, or high eGFR. Results: Of the 2266 patients, 2051 (90.5%) had a normal eGFR, 110 (4.9%) a low eGFR, and 105 (4.6%) a high eGFR. Patients with high eGFR were younger or less likely to have hypertension, diabetes, or atrial fibrillation than the other groups. Active cancer was more prevalent in the high-eGFR group. During the 6-month follow-up, there were 24 deaths (22.9%) in the high-eGFR group, 37 (33.6%) in the low-eGFR group, and 237 (11.6%) in the normal-eGFR group. After adjusting for variables with P P =0.001) and low eGFR (HR, 2.29 [95% CI, 1.41–3.72]; P =0.001). These associations persisted regardless of treatment modality or various baseline characteristics. Conclusions: High eGFR as well as low eGFR were independently associated with 6-month mortality after reperfusion therapy. Kidney function could be considered a prognostic factor in patients with ischemic stroke after reperfusion therapy.

This study was conducted to identify potential risk factors for permanent clean intermittent catheterization (CIC) and incontinence in patients with lipomyelomeningocele (LMMC) and evaluate how LMMC affects bladder function prognosis, measured by urodynamic (UD) score.This retrospective study analyzed the electronic health records of patients who underwent primary neurosurgical repair for LMMC at a single tertiary referral center between January 2012 and December 2016 and were followed at least 3 years after surgery. Data regarding bladder function were obtained from medical records for multiple time points, including before surgery, after surgery but before hospital discharge, 3 months after surgery, and at outpatient visits during follow-up.This study enrolled 120 patients. At a mean follow-up of 62.6 ± 13.9 months after primary neurosurgical LMMC repair, 22 (18.3%) patients continued to require CIC for bladder emptying, only 7 (31.8%) of whom maintained bladder continence. A multivariate logistic regression model identified age at the time of surgery and the type of LMMC as significant presurgical prognostic risk factors for permanent CIC. In addition, postoperative urinary retention and a UD score greater than or equal to 5 measured 3 months after surgery were identified as significant postsurgical risk factors for permanent CIC and urinary incontinence. A linear mixed model adjusted for age at the time of surgery showed that patients with a transitional or chaotic LMMC type were more likely to experience gradual bladder function decline than patients with other LMMC types.This study identified both presurgical (age at the time of surgery, LMMC type) and postsurgical (postoperative urinary retention, UD score greater than or equal to 5 at 3 months postsurgery) risk factors for permanent CIC and urinary incontinence. In addition, LMMC type was identified as a prognostic risk factor for bladder function decline. These results will enhance the current understanding of bladder function outcomes in patients who undergo surgical treatment for LMMC.

Background: Wallenberg’s syndrome (WS) is caused by dorsal lateral medulla infarction. Clinical symptoms include hoarseness, dysphagia, sensory disturbance, vertigo, ataxia, and Horner’s syndrome. Recently, lateral difference of body surface temperature (BST) has been reported as a symptom of WS, resulting from the disturbances of the sympathetic nerve tract. Although sensory dysfunction is the major symptoms of WS, there is no evidence that BST influences these symptoms. We sought to evaluate the relationship between BST and sensory symptoms in WS using infrared thermography.Methods: Patients with WS within 7 days of symptom onset from June 2018 to December 2020 were enrolled. Infrared thermography was conducted at 7±30 days and 90±30 days after the onset of stroke. Laterality of BST was defined as being positive when macroscopically different and discrepancy >0.5°C in thermography.Results: The final analyses included 12 patients with a mean age of 59.9±11.85 years. Sensory symptoms in nine patients were most often described as numbness (56%), cold (44%), burning (33%), and heaviness (11%). Of these, burning symptoms lasted at 100%, cold 75%, and numbness 50% during 3 months follow-up. All patients with sensory dysfunction showed lateral BST differences. The BST laterality persisted in patients with remaining sensory dysfunction at 3 months follow-up.Conclusions: All patients with sensory dysfunction in WS showed lateral BST differences which was detected with thermography. Laterality of BST and sensory dysfunction in WS might be associated with the disturbance of the connecting pathway of skin blood flow descending from the rostral ventrolateral medulla.

Tumor-associated carcinoembryonic antigen (CEA) is a natural target for vaccines against colorectal cancers. Our previous experience with a DNA vaccine with scFv6.C4, a CEA surrogate, showed a CEA-specific immune response with 40% of tumor-free mice after challenge with B16F10-CEA and 47% with MC38-CEA cells. These percentages increased to 63% after using FrC as an adjuvant. To further enhance the vaccine efficacy, we tested GM-CSF and IFNγ as adjuvants. C57BL/6J-CEA2682 mice were immunized 4 times with uP-PS/scFv6.C4, uP-PS/scFv6.C4 + uP-IFNγ, or uP-PS/scFv6.C4 + uP-GMCSF. After one week, the mice were challenged with MC38-CEA, and tumor growth was monitored over 100 days. Immunization with scFv6.C4 and scFv6.C4 + GM-CSF resulted in a gradual increase in the anti-CEA antibody titer, while scFv6.C4 + IFNγ immunization led to a rapid and sustained increase in the titer. The addition of IFNγ also induced higher CD4 + and CD8 + responses. When challenged, almost 80% of the scFv6.C4 + IFNγ-vaccinated mice did not develop tumors, while the others had a significant tumor growth delay. The probability of being tumor-free was 2700% higher using scFv6.C4 + IFNγ than scFv6.C4. The addition of GM-CSF had no additional effect on tumor protection. DNA immunization with scFv6.C4 + IFNγ, but not GM-CSF, increased the antitumor effect via readily sustained specific humoral and cytotoxic responses to CEA.

Background and Purpose: Patients with acute stroke are often accompanied by comorbidities, such as active cancer. However, adequate treatment guidelines are not available for these patients. The purpose of this study was to evaluate the association between cancer and the outcomes of reperfusion therapy in patients with stroke. Methods: We compared treatment outcomes in patients who underwent reperfusion therapy, using a nationwide reperfusion therapy registry. We divided the patients into 3 groups according to cancer activity: active cancer, nonactive cancer, and without a history of cancer. We investigated reperfusion processes, 24-hour neurological improvement, adverse events, 3-month functional outcome, and 6-month survival and related factors after reperfusion therapy. Results: Among 1338 patients who underwent reperfusion therapy, 62 patients (4.6%) had active cancer, 78 patients (5.8%) had nonactive cancer, and 1198 patients (89.5%) had no history of cancer. Of the enrolled patients, 969 patients received intravenous thrombolysis and 685 patients underwent endovascular treatment (316 patients received combined therapy). Patients with active cancer had more comorbidities and experienced more severe strokes; however, they showed similar 24-hour neurological improvement and adverse events, including cerebral hemorrhage, compared with the other groups. Although the functional outcome at 3 months was poorer than the other groups, 36.4% of patients with active cancer showed functional independence. Additionally, 52.9% of the patients with determined stroke etiology showed functional independence despite active cancer. During the 6-month follow-up, 46.6% of patients with active cancer died, and active cancer was independently associated with poor survival (hazard ratio, 3.973 [95% CI, 2.528–6.245]). Conclusions: In patients with active cancer, reperfusion therapy showed similar adverse events and short-term outcomes to that of other groups. While long-term prognosis was worse in the active cancer group than the nonactive cancer groups, not negligible number of patients had good functional outcomes, especially those with determined stroke mechanisms.

Background The tendency of amyloid-β to form oligomers in the blood as measured with Multimer Detection System-Oligomeric Amyloid-β (MDS-OAβ) is a valuable biomarker for Alzheimer’s disease and has been verified with heparin-based plasma. The objective of this study was to evaluate the performance of ethylenediaminetetraacetic acid (EDTA)-based MDS-OAβ and to develop machine learning algorithms to predict amyloid positron emission tomography (PET) positivity. Methods The performance of EDTA-based MDS-OAβ in predicting PET positivity was evaluated in 312 individuals with various machine learning models. The models with various combinations of features (i.e., MDS-OAβ level, age, apolipoprotein E4 alleles, and Mini-Mental Status Examination [MMSE] score) were tested 50 times on each dataset. Results The random forest model best-predicted amyloid PET positivity based on MDS-OAβ combined with other features with an accuracy of 77.14 ± 4.21% and an F1 of 85.44 ± 3.10%. The order of significance of predictive features was MDS-OAβ, MMSE, Age, and APOE. The Support Vector Machine using the MDS-OAβ value only showed an accuracy of 71.09 ± 3.27% and F−1 value of 80.18 ± 2.70%. Conclusions The Random Forest model using EDTA-based MDS-OAβ combined with the MMSE and apolipoprotein E status can be used to prescreen for amyloid PET positivity.

Background and Purpose We aimed to develop a model predicting early recanalization after intravenous tissue plasminogen activator (t-PA) treatment in large-vessel occlusion.Methods Using data from two different multicenter prospective cohorts, we determined the factors associated with early recanalization immediately after t-PA in stroke patients with large-vessel occlusion, and developed and validated a prediction model for early recanalization. Clot volume was semiautomatically measured on thin-section computed tomography using software, and the degree of collaterals was determined using the Tan score. Follow-up angiographic studies were performed immediately after t-PA treatment to assess early recanalization.Results Early recanalization, assessed 61.0±44.7 minutes after t-PA bolus, was achieved in 15.5% (15/97) in the derivation cohort and in 10.5% (8/76) in the validation cohort. Clot volume (odds ratio [OR], 0.979; 95% confidence interval [CI], 0.961 to 0.997; P=0.020) and good collaterals (OR, 6.129; 95% CI, 1.592 to 23.594; P=0.008) were significant factors associated with early recanalization. The area under the curve (AUC) of the model including clot volume was 0.819 (95% CI, 0.720 to 0.917) and 0.842 (95% CI, 0.746 to 0.938) in the derivation and validation cohorts, respectively. The AUC improved when good collaterals were added (derivation cohort: AUC, 0.876; 95% CI, 0.802 to 0.950; P=0.164; validation cohort: AUC, 0.949; 95% CI, 0.886 to 1.000; P=0.036). The integrated discrimination improvement also showed significantly improved prediction (0.097; 95% CI, 0.009 to 0.185; P=0.032).Conclusions The model using clot volume and collaterals predicted early recanalization after intravenous t-PA and had a high performance. This model may aid in determining the recanalization treatment strategy in stroke patients with large-vessel occlusion.

Jung-Min Pyun,1 Ji Sun Ryu,2 Ryan Lee,2 Kyu Hawn Shim,3 Young Chul Youn,4 Nayoung Ryoo,5 Sang-Won Han,5 Young Ho Park,5 Sungmin Kang,2 Seong Soo A An,6 SangYun Kim5 1Department of Neurology, Uijeongbu Eulji Medical Center, Eulji University, Uijeongbu-si, Gyeonggi-do, Republic of Korea; 2Research and Development, PeopleBio Inc., Seongnam-si, Gyeonggi-do, Republic of Korea; 3Department of Neurology, Veterans Medical Research Institute, Veterans Health Service Medical Center, Seoul, Republic of Korea; 4Department of Neurology, Chung-Ang University College of Medicine, Seoul, Republic of Korea; 5Department of Neurology, Seoul National University College of Medicine and Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do, Republic of Korea; 6Department of Bionanotechnology, Gachon University, Seongnam-si, Gyeonggi-do, Republic of KoreaCorrespondence: SangYun KimDepartment of Neurology, Seoul National University Bundang Hospital, 82, Gumi-ro 173 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, Republic of KoreaTel +82 31 787 7462 Fax +82 31 787 4059Email neuroksy@snu.ac.krPurpose: Among other emerging amyloid-targeting blood-based biomarkers, Multimer Detection System-Oligomeric Amyloid-β (MDS-OAβ) measures dynamic changes in concentration of oligomeric amyloid-β (OAβ), which is considered the main pathogenic culprit of Alzheimer’s disease (AD), in plasma after spiking with synthetic amyloid-β (Aβ). We aimed to investigate the predictability of MDS-OAβ on amyloid positron emission tomography (PET) positivity.Patients and Methods: A total of 96 subjects who visited Seoul National University Bundang Hospital for medical check-up complaining of cognitive decline and had undergone extensive medical assessment were recruited. Amyloid statuses were dichotomized into positive or negative based on visual assessment of amyloid PET. Plasma OAβ concentration was measured by MDS-OAβ. In the previous validation study, 0.78ng/mL was established as the cut-off value and the plasma OAβ concentration higher than or equal to the cut-off value was defined as MDS-OAβ positive.Results: MDS-OAβ positivity could discriminate amyloid PET positivity with the AUC value of 0.855 (95% CI 0.776– 0.933). Adding MDS-OAβ positivity to prediction models including age, MMSE score, and APOE ϵ4 status improved performance up to the AUC value of 0.926 (95% CI 0.871– 0.980).Conclusion: The Aβ oligomerization tendency in plasma could predict amyloid PET positivity with high performance, and, when it is combined with age, MMSE score, and APOE ϵ4 status, predictability was improved substantially. This suggests the potential of MDS-OAβ as a useful initial stage test in the clinical and research fields of AD.Keywords: multimer detection system-oligomeric amyloid-β, Aβ oligomer, predictability, amyloidopathy, blood-based biomarker

Objective To report the outcome of buccal mucosa tube graft (BMTG) over time in correcting failed hypospadias. Methods We conducted a retrospective analysis, reviewing charts of all 69 patients who underwent BMTG to repair hypospadias between January 2005 and October 2016. Twenty-one patients were excluded, leaving 48 eligible study subjects. In patients with penile curvatures, corrective procedures (including urethral division, corporoplasty, and local skin flap) took place prior to grafting. Results Mean age at surgery was 8.96 years, and mean duration of follow-up was 73.10 ± 30.31 months. A mean of 1.88 previous surgeries was recorded. During follow-up, only 7 patients (14.5%) were complication free. The other 41 patients required at least 1 additional procedure. Stricture-free rates were 50%, 35.4%, and 27% at 1, 3, and 12 months after BMTG, respectively. Among 37 patients with postoperative stricture, 25 were treated only by endoscopic procedures. Single operation prior to BMTG (P= .004) and usage of larger catheter size (>8Fr) (P = .029) were confirmed significant factors associated with better stricture-free survival after BMTG by log-rank test. After several additional procedures, 46 patients (95.8%) reported normal urination with mean maximal urinary flow of 9.55 mL/s and post-void residual of 16.08 mL for at least 12 months on last visit. Conclusion BMTG after failed hypospadias repair seems prone to complications, primarily urethral stricture. However, a large number of patients with postoperative stricture could be treated simply by endoscopic procedures. Given the better results of staged approach, BMTG should be only applied to highly selected patients with failed hypospadias.

Purpose To present our experience in urethral duplication focusing on detailed surgical management. Methods We retrospectively reviewed the records of 12 male patients treated for urethral duplication between 2005 and 2017. Evaluations included ultrasound, retrograde urethrography, cystoscopy, and voiding cystourethrography. Results The age at presentation ranged from birth to 11 years. All 12 cases were classified using the Effmann classification. Case 1–4 patients with type I underwent excision of the dorsal accessory urethra by stripping technique. In case 5 patient(type IA) with two adjacent apical urethras, the septum was opened to form a single channel. Case 6 patient with type IB underwent visual internal urethrotomy near bulbous urethra to combine urethra into one channel. Five patients classified as type II (one with a type IIA1, and four with type IIA2 urethras). Urethral duplication was incidentally found during epispadias repair in case 7 patient with type IIA1, which was corrected by ventral plication, and excision of the dorsal epispadial urethra with stripping technique just below pubic bone. Case 8 patient with type IIA2 also required dorsal urethral excision with stripping technique. The two Y-type patients (case 10, 11) underwent urethrourethrostomy with a single-stage buccal mucosa tube graft, followed by repetitive surgeries owing to urethral stricture. One type III patient presented with penile inflammation and suprapubic pain, and underwent excision of both the dorsal urethra and nonfunctional anterior bladder. Conclusions Urethral duplication requires individualized surgical approaches based on the anatomical and functional characteristics. Because prognosis is variable depending on type and accompanied anomalies, these should be taken into account when planning a comprehensive workup and surgical management. Level of evidence Level IV.

Background and Purpose: Atrial fibrillation (AF) is the leading cause of ischemic stroke. Preventive antithrombotic use, especially for anticoagulation, reduces the incidence of ischemic stroke in patients with AF. Using data from the nationwide multicenter stroke registry, we investigated the trends of preceding antithrombotic medication use in patients with acute ischemic stroke (AIS) with AF and its association with initial stroke severity and in-hospital outcomes. Methods: This study included 6786 patients with AIS with known AF before stroke admission across 39 hospitals between June 2008 and December 2018. We collected the data on antithrombotic medication use (no antithrombotic/antiplatelet/anticoagulant) preceding AIS. Initial stroke severity was measured using the National Institutes of Health Stroke Scale, and in-hospital outcome was determined by modified Rankin Scale score at discharge. Results: During the study period, anticoagulant use continued to increase. However, nearly one-third of patients with AIS with known AF did not receive antithrombotics before stroke. Initial National Institutes of Health Stroke Scale scores varied according to preceding antithrombotic therapy ( P P Conclusions: Throughout the study period, the proportion of patients taking anticoagulants increased among patients with AIS with known AF. However, a large portion of AF patients still did not receive antithrombotics before AIS. Furthermore, prehospitalization use of anticoagulants was associated with a significantly higher likelihood of a mild initial neurological deficit and favorable outcome at discharge.

BACKGROUND AND PURPOSE The objective of this study was to investigate the association between body mass index (BMI) and both initial stroke severity at presentation and functional outcomes after acute ischaemic stroke (AIS) in patients with non-valvular atrial fibrillation (NVAF). METHODS Patients were categorized on the basis of their BMI into underweight (BMI

PURPOSE To determine the relationship among flow index (FI), uroflowmetry curve shape, and electromyography (EMG) lag time in children. MATERIALS AND METHODS A total of 294 children with lower urinary tract symptoms were included. The overall relationship between lag time and FI was investigated with curve estimation regression. Normal and primary bladder neck dysfunction was defined according to the previous classification, while patients with a lag time less than 2 seconds were grouped based on 2-second intervals. We also categorized cases into four groups (tower shaped, bell shaped, plateau shaped, and fractionated void) by FI and compared lag time. RESULTS The overall distribution chart demonstrated that FI was the highest at lag time 0 second and decreased with the change in lag time both ways. The best fitting model for maximum FI and lag time was a cubic model (R2 = .282; P 6 seconds) or delayed lag time (

Cell-penetrating peptides (CPPs) are a topical subject potentially exploitable for creating nanotherapeutics for the delivery of bioactive loads. These compounds are often classified into three major categories according to their physicochemical characteristics: cationic, amphiphilic, and hydrophobic. Among them, the group of hydrophobic CPPs has received increasing attention in recent years due to toxicity concerns posed by highly cationic CPPs. The hexapeptide PFVYLI (P, proline; F, phenylalanine; V, valine; Y, tyrosine; L, leucine; and I, isoleucine), a fragment derived from the C-terminal portion of α1-antitrypsin, is a prototypal example of hydrophobic CPP. This sequence shows reduced cytotoxicity and a capacity of nuclear localization, and its small size readily hints at its suitability as a building block to construct nanostructured materials. In this study, we examine the self-assembling properties of PFVYLI and investigate its ability to form noncovalent complexes with nucleic acids. By using a combination of biophysical tools including synchrotron small-angle X-ray scattering and atomic force microscopy-based infrared spectroscopy, we discovered that this CPP self-assembles into discrete nanofibrils with remarkable amyloidogenic features. Over the course of days, these fibrils coalesce into rodlike crystals that easily reach the micrometer range. Despite lacking cationic residues in the composition, PFVYLI forms noncovalent complexes with nucleic acids that retain β-sheet pairing found in amyloid aggregates.

Background: Optimal antithrombotic regimens to prevent recurrent stroke in patients with ischemic stroke due to atrial fibrillation (AF) and atherosclerotic large-vessel stenosis remain unknown. Aims: This study aimed to evaluate the effect of multiple antithrombotic therapies on outcomes at 1 year after ischemic stroke due to two or more causes. Methods: We identified 862 patients with ischemic stroke due to AF and large artery atherosclerosis from the linked data. These patients were categorized into three groups according to antithrombotic therapies at discharge: (1) antiplatelets, (2) oral anticoagulants (OAC), and (3) antiplatelets plus OAC. The study outcomes were recurrent ischemic stroke, composite outcomes for cardiovascular events, and major bleeding after 1 year. Inverse probability of treatment weighting (IPTW) was used to balance the three groups using propensity scores. Results: Among 862 patients, 169 (19.6%) were treated with antiplatelets, 405 (47.0%) were treated with OAC, and 288 (33.4%) were treated with antiplatelets and OAC. After applying IPTW, only OAC had a significant beneficial effect on the 1-year composite outcome (hazard ratio (HR): 0.37, 95% confidence interval (CI): 0.23–0.60, p Conclusion: This study demonstrated that OAC monotherapy was associated with lower risks of composite outcome and death in patients at 1 year after ischemic stroke due to AF and atherosclerotic stenosis. In addition, the combination of an antiplatelet and OAC had a high risk of major bleeding.

Although clinical studies have demonstrated that prior use of antiplatelets was associated with decreased blood viscosity (BV) in patients with acute ischemic stroke, the impact of previous anticoagulant use on blood viscosity in cardioembolic stroke with non-valvular AF (NVAF) has not yet been clearly studied. This single-center retrospective observational study aimed to determine the impact of prior antithrombotic (antiplatelet and anticoagulant) use on BV in patients with cardioembolic stroke (CES) due to NVAF. Patients with CES and NVAF were analyzed with the following inclusion criteria: (1) patients over 20 years of age admitted within five days of stroke onset; (2) ischemic stroke presumably due to an NVAF-derived embolus; (3) compatible cortical/subcortical lesion on brain computed tomography or magnetic resonance imaging; (4) hemoglobin level of 10–18 mg/dL; and (5) receiving antiplatelets within five days or anticoagulants within two days if previously medicated. From the screening of 195 patients (22% of the total stroke population during the study period) who had experienced ischemic stroke with AF, 160 were included for the final analysis. Eighty-nine patients (56%) were taking antithrombotics (antiplatelet, 57%; warfarin, 13%; NOACs, 30%) regularly. Compared to patients without previous antithrombotic use, those with previous antithrombotic use (antiplatelets, warfarin, and NOACs) were significantly associated with decreased systolic BV (SBV) and diastolic BV (DBV) (p < 0.036). In multiple linear regression analysis, hematocrit (Hct) level and prior antithrombotic use were significantly associated with decreased SBV and DBV. Hct was positively correlated with increased SBV and DBV. In Hct-adjusted partial correlation analysis, prior uses of any antithrombotic agents were associated with decreased SBV (r < −0.270, p < 0.015) and DBV (r < −0.183, p < 0.044). In conclusion, this study showed that prior antithrombotic use (antiplatelets, VKAs, and NOACs) was associated with decreased SBV and DBV in patients presenting with acute CES secondary to NVAF. Our results indicated that previous use of NOACs may be a useful hemorheological parameter in patients with acute CES due to NVAF. Accumulation of clinical data from a large number of patients with the risk of stroke occurrence, initial stroke severity, and functional outcome is necessary to assess the usefulness of BV.

Background: The CHADS2, CHA2DS2-VASc, ATRIA, and Essen scores have been developed for predicting vascular outcomes in stroke patients. We investigated the association between these stroke risk scores and unsuccessful recanalization after endovascular thrombectomy (EVT). Methods: From the nationwide multicenter registry (Selection Criteria in Endovascular Thrombectomy and Thrombolytic therapy (SECRET)) (Clinicaltrials.gov NCT02964052), we consecutively included 501 patients who underwent EVT. We identified pre-admission stroke risk scores in each included patient. Results: Among 501 patients who underwent EVT, 410 (81.8%) patients achieved successful recanalization (mTICI ≥ 2b). Adjusting for body mass index and p < 0.1 in univariable analysis revealed the association between all stroke risk scores and unsuccessful recanalization (CHADS2 score: odds ratio (OR) 1.551, 95% confidence interval (CI) 1.198–2.009, p = 0.001; CHA2DS2VASc score: OR 1.269, 95% CI 1.080–1.492, p = 0.004; ATRIA score: OR 1.089, 95% CI 1.011–1.174, p = 0.024; and Essen score: OR 1.469, 95% CI 1.167–1.849, p = 0.001). The CHADS2 score had the highest AUC value and differed significantly only from the Essen score (AUC of CHADS2 score; 0.618, 95% CI 0.554–0.681). Conclusion: All stroke risk scores were associated with unsuccessful recanalization after EVT. Our study suggests that these stroke risk scores could be used to predict recanalization in stroke patients undergoing EVT.

Ischemia occurs when blood flow is reduced or restricted, leading to a lack of oxygen and nutrient supply and removal of metabolites in a body part. Critical limb ischemia (CLI) is a severe clinical manifestation of peripheral arterial disease. Atherosclerosis serves as the main cause of CLI, which arises from the deposition of lipids in the artery wall, forming atheroma and causing inflammation. Although several therapies exist for the treatment of CLI, pharmacotherapy still has low efficacy, and vascular surgery often cannot be performed due to the pathophysiological heterogeneity of each patient. Gene and cell therapies have emerged as alternative treatments for the treatment of CLI by promoting angiogenesis. However, the delivery of autologous, heterologous or genetically modified cells into the ischemic tissue remains challenging, as these cells can die at the injection site and/or leak into other tissues. The encapsulation of these cells within hydrogels for local delivery is probably one of the promising options today. Hydrogels, three-dimensional (3D) cross-linked polymer networks, enable manipulation of physical and chemical properties to mimic the extracellular matrix. Thus, specific biostructures can be developed by adjusting prepolymer properties and encapsulation process variables, such as viscosity and flow rate of fluids, depending on the final biomedical application. Electrostatic droplet extrusion, micromolding, microfluidics, and 3D printing have been the most commonly used technologies for cell encapsulation due to their versatility in producing different hydrogel-based systems (e.g., microgels, fibers, vascularized architectures and perfusable single vessels) with great potential to treat ischemic diseases. This review discusses the cell encapsulation technologies associated with hydrogels which are currently used for advanced therapies applied to limb ischemia, describing their principles, advantages, disadvantages, potentials, and innovative therapeutic ideas.

Background: CHADS2, CHA2DS2-VASc, ATRIA, and Essen stroke risk scores are used to estimate thromboembolism risk. We aimed to investigate the association between unfavorable outcomes and stroke risk scores in patients who received endovascular thrombectomy (EVT). Methods: This study was performed using data from a nationwide, multicenter registry to explore the selection criteria for patients who would benefit from reperfusion therapies. We calculated pre-admission CHADS2, CHA2DS2-VASc, ATRIA, and Essen scores for each patient who received EVT and compared the relationship between these scores and 3-month modified Rankin Scale (mRS) records. Results: Among the 404 patients who received EVT, 213 (52.7%) patients had unfavorable outcomes (mRS 3–6). All scores were significantly higher in patients with unfavorable outcomes than in those with favorable outcomes. Multivariable logistic regression analysis indicated that CHADS2 and the ATRIA score were positively correlated with unfavorable outcomes after adjusting for body mass index and variables with p < 0.1 in the univariable analysis (CHADS2 score: odds ratio [OR], 1.484; 95% confidence interval [CI], 1.290–1.950; p = 0.005, ATRIA score, OR, 1.128; 95% CI, 1.041–1.223; p = 0.004). Conclusions: The CHADS2 and ATRIA scores were positively correlated with unfavorable outcomes and could be used to predict unfavorable outcomes in patients who receive EVT.

Background Peyronie's Disease (PD) is a connective tissue disorder that affects the tunica albuginea (TA) of the penis causing curvature and erectile dysfunction. The pathophysiology is not well understood and, for this reason, treatment options are limited. Objective The aim of the present study is to analyze and compare whether single or multiple instillations of plasma in the TA of rats is capable of triggering macroscopic, histopathological, and molecular changes consistent with PD. Material/methods Fifty male Wistar rats were divided into four groups: Group 1: a single instillation of plasma in the TA; Group 2: a single instillation of distilled water in the TA; Group 3: four instillations of plasma in the TA (1x per week); and Group 4: four instillations of distilled water in the TA (1× per week). Forty-five days after the last instillation a manual inspection of the corpus cavernosum, a penile erection test and a penectomy were performed to obtain material for histopathological and molecular analysis. Results It was observed that 31.25% of the rats that received repeated instillations of plasma presented penile curvature according to the erection test, while none of the rats from the control group or group with one instillation of plasma presented curvature. In the animals that received four instillations of plasma, the following differences were observed in relation to the control group: increase in fibrosis and the deposition of collagen I. The protein expression of heparanase (HPSE) and TGF-β increased in the groups that received a single or four instillations of plasma, and the protein expression of heparanase-2 (HPSE-2), metalloproteinases (MMP-2, MMP-9) and metalloproteinase inhibitor (TIMP-2) showed an increase in the group that received four instillations of plasma. There was a significant increase in the gene expression of HPSE, MMP-9, and TGF-β in the group that received four instillations of plasma. In the analysis of the glycosaminoglycans, an increase was observed in the secretion of galactosaminoglycans chondroitin sulfate and dermatan sulfate (CS/DS) in the group that received four instillations of plasma. Discussion Previous studies have demonstrated increased protein expression. of HPSE, MMP-9 and TGF-β with instillation of blood in the TA; however, there was no increase in gene expression. In the present study, the increase in the expression of TGF-β with plasma instillations, proved to be more reliable. The two models with plasma (one or four instillations) demonstrated significant histopathological and molecular changes when compared to the control group. However, only in the group with four plasma instillations there was a macroscopic change. The idea is that repeatedly extravasation of TGF-β present in plasma of predisposed individuals acts as a trigger for the development and maintenance of changes in the extracellular matrix that perpetuate an anomalous inflammatory process present in PD. Conclusion The present study shows that the repeated instillation of plasma is a low cost in vivo model for the study of PD.

The association of cationic carriers with different anionic mucoadhesive biopolymers has been widely explored as an alternative to improve their delivery routes and specific targeting. This work presents a complete analysis of the association between chondroitin sulfate (CS) and cationic liposomes (CLs)/lipoplex (CL-pDNA). In this study, plasmid DNA (pDNA) was used as a genetic cargo for association with carriers. Firstly, we measured the stoichiometry of pseudo complexes and evaluated their colloidal properties, structural and morphological characteristics. Optimized CL-pDNA lipoplexes (positive z-potential) and CL-CS / CL-pDNA-CS (negative z-potential with CS mass ratio of 9% (w/w)) were further studied in detail. Small-angle X-ray scattering analysis and cryo-transmission electron microscopy micrographs revealed that the electrostatic interaction between CS and CL / CL-pDNA easily reorganized the lipid bilayers resulting in nanoscale uni/multilamellar vesicles. A high CS mass ratio (9% (w/w)) led to the reassembly of liposomal structure, wherein the pDNA was easily exchanged for CS chains, forming more than 50% of dense multilamellar vesicles. This data evidenced that the association between CS and CLs is not a conventional coating process since it generates complex and hybrid structures. We believe that these obtained colloidal data may be used in the future to investigate polymer-tailored nanocarriers and their production process. In brief, the colloidal study of hybrid structures may open interesting perspectives for developing novel carriers for drug and gene delivery applications.

One of the most remarkable examples of cell-penetrating peptides (CPPs) is Penetratin, a 16-mer fragment derived from the Drosophila Antennapedia homeobox. Understanding the structure of Penetratin/DNA complexes is a key factor for the successful design of new vectors for gene delivery and may assist in optimizing molecular carriers based on CPPs. Herein, we present a comprehensive study on the nanoscale structure of noncovalent complexes formed between Penetratin and DNA. The strong cationic nature of the peptide makes it a very efficient agent for condensing DNA strands via electrostatic attraction, and we show for the first time that DNA condensation is accompanied by random-to-β-sheet transitions of Penetratin secondary structure, demonstrating that nucleic acids behave as a structuring agent upon complexation. For the first time, nanoscale-resolved spectroscopy is used to provide single-particle infrared data from DNA carriers based on CPPs, and they show that the structures are stabilized by Penetratin β-sheet cores, whereas larger DNA fractions are preferentially located in the periphery of aggregates. In-solution infrared assays indicate that phosphate diester groups are strongly affected upon DNA condensation, presumably as a consequence of charge delocalization induced by the proximity of cationic amide groups in Penetratin. The morphology is characterized by nanoassemblies with surface fractal features, and short-range order is found in the inner structure of the scaffolds. Interestingly, the formation of beads-on-a-string arrays is found, producing nanoscale architectures that resemble structures observed in early steps of chromatin condensation. A complexation pathway where DNA condensation and peptide pairing into β-sheets are key steps for organization is proposed.

To determine normal ranges for pediatric testicular volume and stiffness values (SV) on ultrasonography (US) and shear wave elastography (SWE) with respect to age and weight, testicular US scans (including SWE) of children (10 y old) performed from February 2015 to January 2017 were retrospectively reviewed; grossly normal testes or testes with small hydroceles were included. Correlations between age weight, and testicular volume or SV were evaluated. Among a total of 52 boys (1-92 mo, median = 23.5 mo), there were positive correlations between testicular volume and age (R

Treatment strategies for children with ectopic ureteroceles (EUs) and duplex collecting systems or vesicoureteral reflux are controversial. Transurethral incision (TUI) of EUs associated with duplex systems has been considered only as a temporizing technique. This study aimed to evaluate whether primary TUIs could be considered as an initial treatment option in EUs with duplex systems. Forty-seven children with EUs associated with duplex systems underwent primary TUIs at our institution between November 2007 and October 2017. We retrospectively analyzed patient characteristics such as age, sex, upper tract status, ureterocele location, differential renal function, and preoperative vesicoureteral reflux with regard to postoperative complications requiring additional surgery, postoperative incontinence, and renal function. The mean age at operation was 4.8 ± 4.7 months. Of the 47 patients, 26 (55.3%) underwent primary TUIs only, 3 (6.4%) underwent secondary TUIs, and 18 (38.3%) underwent other secondary procedures such as common-sheath reimplantation (CSR) and ureterocelectomy. Secondary surgeries in 21/47 (44.7%) patients occurred during a mean follow-up of 47.7 ± 23.3 months, and the most common type of secondary surgery was CSR. The most common reason for secondary surgery was febrile urinary tract infection (14/21 patients [66.7%]). There were three cases (3/26 [11.5%]) of voiding problems after primary TUI and two cases (2/15 [13.4%]) after secondary CSR. Primary TUIs should be considered as initial treatment options for EUs in duplex systems and not just a temporizing technique.

Antimuscarinics are the first pharmacological treatment option for neurogenic bladder in children with spina bifida but side effects limit their use. Mirabegron, a new β-3 adrenoceptor agonist with a distinct mechanism of action, is a potential agent for the treatment of neurogenic bladder; however, it has yet to be studied in the pediatric population. This study evaluated the efficacy and safety of mirabegron for treating neurogenic bladder in children with spina bifida. Clinical and urodynamic parameters were retrospectively studied in 66 children (under 18 years of age) with spina bifida who were treated for neurogenic bladder with mirabegron at Severance Children’s Hospital between July 2015 and December 2017. Pediatric patients received 50 mg mirabegron daily for at least 6 weeks either in addition to or instead of antimuscarinic therapy. Urodynamic parameters, including compliance, involuntary detrusor contraction, and maximum cystometric capacity, as well as patient-reported efficacy and adverse events, were measured. In both groups post-treatment, incontinence significantly improved. In addition, maximum cystometric capacity and compliance significantly increased post-treatment. Six patients reported side effects (constipation, 4.5%; headache, 3.0%; and hypertension, 1.5%) and three patients discontinued treatment. We evaluated the efficacy and safety of mirabegron for treating neurogenic bladder in pediatric patients with spina bifida. All clinical and urodynamic parameters improved with treatment. Prospective, placebo-controlled studies are necessary to confirm these findings.

Idiopathic normal pressure hydrocephalus (iNPH) is characterized by the classic triad of gait disturbance, urinary incontinence, and cognitive impairment in the presence of ventriculomegaly without known risk factors for communicating hydrocephalus.

Efficient delivery of nanometric vectors complexed with nanoparticles at a target tissue without spreading to other tissues is one of the main challenges in gene therapy. One means to overcome this problem is to confine such vectors within microgels that can be placed in a target tissue to be released slowly and locally. Herein, a conventional optical microscope coupled to a common smartphone was employed to monitor the microfluidic production of monodisperse alginate microgels containing nanoparticles as a model for the encapsulation of vectors. Alginate microgels (1.2%) exhibited an average diameter of 125 ± 3 μm, which decreased to 106 ± 5 μm after encapsulating 30 nm fluorescent nanoparticles. The encapsulation efficiency was 70.9 ± 18.9%. In a 0.1 M NaCl solution, 55 ± 5% and 92 ± 4.7% of nanoparticles were released in 30 minutes and 48 hours, respectively. Microgel topography assessment by atomic force microscopy revealed that incorporation of nanoparticles into the alginate matrix changes the scaffold's interfacial morphology and induces crystallization with the appearance of oriented domains. The high encapsulation rate of nanoparticles, alongside their continuous release of nanoparticles over time, makes these microgels and the production unit a valuable system for vector encapsulation for gene therapy research.

We compared heart rate variability parameters of patients with spina bifida with those of a control group during urodynamic study to evaluate the autonomic nervous system dysfunction of spina bifida. Continuous heart rate variability parameters were recorded during 3 successive periods (P0: 2 minutes before the start of filling; P1: start of filling to the first desire to void; P2: P1 to the end of filling or the start of voiding). Children with vesicoureteral reflux who underwent video-urodynamic study were established as a control group. We included 11 patients with spina bifida and 9 controls. At baseline, patients with spina bifida had lower values of RMSSD, pNN50, and HF, while LF/HF ratio was increased (5.04 ± 4.75 vs 0.67 ± 0.42, p = 0.014). During bladder filling, LF/HF values increased in the control group (P0 0.67 ± 0.42 vs P1 0.89 ± 0.34 vs P2 1.21 ± 0.64, p = 0.018) while it was decreased in spina bifida patients (P0 5.04 ± 4.75 vs P1 3.96 ± 4.35 vs P2 3.26 ± 4.03, p

Background Peripheral arterial disease (PAD) affects millions of people and compromises quality of life. Critical limb ischemia (CLI), which is the most advanced stage of PAD, can cause nonhealing ulcers and strong chronic pain, and it shortens the patients’ life expectancy. Cell-based angiogenic therapies are becoming a real therapeutic approach to treat CLI. Pericytes are cells that surround vascular endothelial cells to reinforce vessel integrity and regulate local blood pressure and metabolism. In the past decade, researchers also found that pericytes may function as stem or progenitor cells in the body, showing the potential to differentiate into several cell types. We investigated the gene expression profiles of pericytes during the early stages of limb ischemia, as well as the alterations in pericyte subpopulations to better understand the behavior of pericytes under ischemic conditions. Methods In this study, we used a hindlimb ischemia model to mimic CLI in C57/BL6 mice and explore the role of pericytes in regeneration. To this end, muscle pericytes were isolated at different time points after the induction of ischemia. The phenotypes and transcriptomic profiles of the pericytes isolated at these discrete time points were assessed using flow cytometry and RNA sequencing. Results Ischemia triggered proliferation and migration and upregulated the expression of myogenesis-related transcripts in pericytes. Furthermore, the transcriptomic analysis also revealed that pericytes induce or upregulate the expression of a number of cytokines with effects on endothelial cells, leukocyte chemoattraction, or the activation of inflammatory cells. Conclusions Our findings provide a database that will improve our understanding of skeletal muscle pericyte biology under ischemic conditions, which may be useful for the development of novel pericyte-based cell and gene therapies.

BACKGROUND AND PURPOSE Blood pressure (BP) control is strongly recommended, but BP control rate has not been well studied in patients with stroke. We evaluated the BP control rate with fimasartan-based antihypertensive therapy initiated in patients with recent cerebral ischemia. METHODS This multicenter, prospective, single-arm trial involved 27 centers in South Korea. Key inclusion criteria were recent cerebral ischemia within 90 days and high BP [systolic blood pressure (SBP) >140 mm Hg or diastolic blood pressure (DBP) >90 mm Hg]. BP lowering was initiated with fimasartan. BP management during the follow-up was at the discretion of the responsible investigators. The primary endpoint was the target BP goal achievement rate (

Study objective To present clinical features that characterize ovotesticular disorder of sex development (OT-DSD) in the Korean population. Among the patient cohort who were initially suspected to have OT-DSD, the actual OT-DSD patients and those of other disorder of sex development were compared. Design Retrospective medical chart review of patients who were initially suspected to have OT-DSD from 1984 to 2018 on the basis of clinical examination. Setting Tertiary care university hospital. Participants Of 26 patients with initial diagnosis of OT-DSD, 3 were excluded because of incomplete records, and finally, 23 patients were subjected to analysis. Various examinations were performed before the surgical confirmation of gonad histopathology. Interventions Medical records were reviewed for clinical, anatomical, biochemical, and cytogenic characteristics, gender assignment, medical treatment, and histopathologic diagnosis. Main Outcome Measures Characteristics of OT-DSD in a Korean population. Results Among 23 patients suspected to have OT-DSD, 13/23 (56.5%) were diagnosed as OT-DSD after histopathologic confirmation. Of the remaining 10 patients, 5/23 (21.7%) were diagnosed with mixed gonadal dysgenesis, 3 with Turner variant, 1 with 46,XX disorder of sex development, and 1 with Mayer-Rokitansky-Kuster-Hauser syndrome. Among the 13 OT-DSD cases, 9 patients presented with the 46,XX karyotype, 1 with the 46,XY, and 3 with the 46,XX/XY karyotype. Nine patients were assigned as male and 4 as female at birth. The most common gonad histology was ovotestis 10/26 (38%), followed by ovary and testis. Conclusion OT-DSD is one of the rarest disorders with various clinical presentations. A patient with ambiguous genitalia must be examined with a multidisciplinary approach with clinical suspicion for OT-DSD. Standardized procedure of evaluation and treatment is crucial.

Background After traumatic skeletal muscle injury, muscle healing is often incomplete and produces extensive fibrosis. The sequence of M1 and M2 macrophage accumulation and the duration of each subtype in the injured area may help to direct the relative extent of fibrogenesis and myogenesis during healing. We hypothesized that increasing the number of M1 macrophages early after traumatic muscle injury would produce more cellular and molecular substrates for myogenesis and fewer substrates for fibrosis, leading to better muscle healing. Methods To test this hypothesis, we transfected skeletal muscle with a plasmid vector to transiently express GM-CSF shortly after injury to drive the polarization of macrophages towards the M1 subset. C57BL/6 mouse tibialis anterior (TA) muscles were injured by contusion and electroporated with uP-mGM, which is a plasmid vector that transiently expresses GM-CSF. Myogenesis, angiogenesis, and fibrosis were evaluated by histology, immunohistochemistry, and RT-qPCR; subpopulations of macrophages by flow cytometry; and muscle functioning by the maximum running speed on the treadmill and the recovery of muscle mass. Results Muscle injury increased the number of local M1-like macrophages and decreased the number of M2-like macrophages on day 4, and uP-mGM treatment enhanced this variation. uP-mGM treatment decreased TGF-β1 protein expression on day 4, and the Sirius Red-positive area decreased from 35.93 ± 15.45% (no treatment) to 2.9% ± 6.5% (p Hgf, Hif1α, and Mtor gene expression; arteriole density; and muscle fiber number during regeneration. The improvement in the quality of the muscle tissue after treatment with uP-mGM affected the increase in the TA muscle mass and the maximum running speed on a treadmill. Conclusion Collectively, our data show that increasing the number of M1-like macrophages immediately after traumatic muscle injury promotes muscle recovery with less fibrosis, and this can be achieved by the transient expression of GM-CSF.