Gludgallagher2013

There is a need for more formalised but flexible mentorship initiative in the CARTA fellowship to facilitate enduring relationships for career development.Background and purpose Because of several methodological limitations, previous studies focusing on the prevalence of large vessel occlusion in ischemic stroke (IS) patients provided conflicting results. We evaluated the incidence of IS with a visible arterial occlusion using a comprehensive population-based registry. Methods Patients with acute IS were prospectively identified among residents of Dijon, France, using a population-based registry (2013-2017). Selleckchem AZ191 All arterial imaging exams were reviewed to assess arterial occlusion. Annual incidence rates of IS (first-ever and recurrent events) and IS with a visible occlusion were calculated. Results One thousand sixty cases of IS were recorded (mean age 76.0±15.8 years, 53.9% women). Information about arterial imaging was available in 971 (91.6%) of them, and only preexisting dementia was independently associated with having missing information (odds ratio=0.34 [95% CI, 0.18-0.65], P=0.001). Among these patients, 284 (29.2%) had a visible arterial occlusion. Occlusion site was the anterior circulation in 226 patients (23.3% of overall patients with available data) and the posterior circulation in 58 patients (6.0%). A proximal occlusion of the anterior circulation was observed in 167 patients (17.2%). The crude annual incidence rate of total IS per 100 000 was 138 (95% CI, 129-146). Corresponding standardized rates were 66 (95% CI, 50-82) to the World Health Organization and 141 (95% CI, 118-164) to the 2013 European populations. The crude annual incidence rate of IS with a visible arterial occlusion per 100 000 was 37 (95% CI, 33-41) and that of IS with a proximal occlusion of the anterior circulation was 22 (95% CI, 18-25). Corresponding standardized rates were 18 (95% CI, 10-26) and 10 (95% CI, 8-13) to the World Health Organization population, and 38 (95% CI, 26-50) and 23 (95% CI, 19-26) to the 2013 European population, respectively. Conclusions These results will be helpful to plan the need for thrombectomy-capable stroke center resources.Background and purpose The optimal recanalization strategy for acute ischemic stroke with large vessel occlusion continues to be an area of active interest. Network meta-analysis can provide insight when direct comparative evidence is lacking. Methods A systematic review of the literature using PubMed, Embase, the Cochrane Central Register of Controlled Trials, and SinoMed was performed, and a search was conducted for clinical trials on ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform, and StrokeCenter.org. Four independent reviewers conducted the study selection, data abstraction, and quality assessments. Results The literature review identified 17 trials including 3236 patients and 8 ongoing clinical trials. Sample sizes ranged from 7 to 656 participants. Intravenous thrombolysis (IVT) was the most common intervention, followed by IVT plus mechanical thrombectomy (MT), IVT plus intraarterial thrombolysis, intraarterial thrombolysis alone, and MT alone. In the pooled network meta-analysis, IVT+MT was associated with a higher rate of independent functioning. In contrast, IVT was ranked as the most ineffective treatment strategy with respect to neurological functions, while direct MT was ranked as the least safe intervention with respect to all-cause mortality. Also, irrespective of assessment tools, endovascular treatment plus IVT led to higher successful recanalization rate than thrombolysis alone. Conclusions Compared with other recanalization treatments, IVT+MT seems to be the most effective strategy, without increasing detrimental effects, for thrombolysis-eligible patients with large vessel occlusion-acute ischemic stroke. To improve the current evidentiary basis for recanalization treatment, future trials and real-world studies are warranted and should use unified definitions of symptomatic intracranial hemorrhage and recanalization.Background and purpose In unruptured brain arteriovenous malformations (bAVMs), microhemorrhage portends a higher risk of future rupture and may represent a transitional state along the continuum of destabilization. Exploration of the molecular and cellular mechanisms of microhemorrhage will provide a possible target for medical treatment to prevent bAVM bleeding. Methods We performed RNA sequencing analysis on 34 unruptured bAVM surgical samples. Functional pathway analysis was performed to identify potential signals associated with the microhemorrhagic phenotype. Candidate gene was then investigated in bAVM specimens by immunohistochemical staining. Several functional assays were used to investigate the effects of candidate genes on the phenotypic properties of cultured human umbilical vein endothelial cells. Then, Masson trichrome staining and immunofluorescence staining were used to evaluate the phenotypic and molecular changes in bAVM tissue. Results Via RNA sequencing, we identified differential gene expression between 18 microhemorrhagic bAVMs and 16 nonmicrohemorrhagic bAVMs. TGFβ (transforming growth factor-beta)/BMP (bone morphogenetic protein) signaling was associated with the bAVM microhemorrhage group when SMAD6 (SMAD family member 6) was downregulated. Immunohistochemical staining showed that the vascular endothelium of microhemorrhagic bAVMs exhibited decreased SMAD6 expression. Functional assays revealed that SMAD6 downregulation promoted the formation of endothelial cell tubes with deficient cell-cell junctions and facilitated the acquisition of mesenchymal behavior by endothelial cells. Masson trichrome and immunofluorescence staining demonstrated that mesenchymal phenotype of endothelial cells is promoted in microhemorrhagic bAVMs. Conclusions TGFβ/BMP signaling mediated by SMAD6 in vascular endothelial cells is associated with microhemorrhagic bAVMs, and mesenchymal behavior of endothelial cells induced by SMAD6 downregulation is related with bAVM microhemorrhage.Neurodegeneration is one of the greatest threats to global public health. Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease are among the major causes of chronic neurological conditions in the elderly populations. Hence, neuroprotection is at the epicenter of the current 21st-century research agenda in biomedicine. Yet, novel molecular targets are limited and solely needed for neuroprotection. Marked person-to-person variations in outcomes require a deeper understanding of drug targets in neurology and clinical neurosciences. In this context, traditional medicines offer untapped potentials for discovery and translation of novel molecular targets to human neurodegenerative disease research and clinical neurology. This expert review offers a synthesis of the prospects and challenges of harnessing new molecular targets from traditional medicines, with a view to applications for neuroprotection in human neurodegenerative diseases.Dielectric elastomer actuators (DEAs) have been shown to produce electrically induced strains beyond 500%. The ability to undergo large deformation allows the DEA to store large amounts of elastic energy by electrical actuation; it also allows the DEA to perform flexibly in a diverse range of motions. Existing studies used different methods to maximize actuation strain for soft robotic applications. In this article, we examine the actuation of our antagonistically coupled DEAs, reminiscent to that of human muscles. We perform an analysis to reveal optimal conditions that maximize its actuation stroke, actuation force, and output energy. We quantify actuation stroke by the displacement sweep due to electrical actuation, between two fixed points, expressed as a percentage, and refer to this as "actuation sweep." From the analysis, we predicted an optimal prestretch for the DEA that corresponds to a 59% actuation sweep. In our experiment, we realized a 55% actuation sweep. We further characterized the output force and the mechanical work done for complete performance appraisal of the antagonistic system both theoretically and experimentally. We realized an antagonistic soft actuator system with simple geometry that provides significant electrically induced displacement, force, and work done, similar to that of biological muscle systems, and demonstrated its efficacy.Activated protein C (APC) is a serine protease with anticoagulant and cytoprotective activities. Nonanticoagulant APC mutants show beneficial effects as cytoprotective agents. To study, if such biased APC signaling can be achieved by APC-binding ligands, the aptamer technology has been used. A G-quadruplex-containing aptamer, G-NB3, has been selected that binds to the basic exosite of APC with a KD of 0.2 nM and shows no binding to APC-related serine proteases or the zymogen protein C. G-NB3 inhibits the inactivation of activated cofactors V and VIII with IC50 values of 11.6 and 13.1 nM, respectively, without inhibiting the cytoprotective and anti-inflammatory functions of APC as tested using a staurosporine-induced apoptosis assay and a vascular barrier protection assay. In addition, G-NB3 prolongs the plasma half-life of APC through inhibition of APC-serine protease inhibitor complex formation. These physicochemical and functional characteristics qualify G-NB3 as a promising therapeutic agent usable to enhance the cytoprotective functions of APC without increasing the risk of APC-related hemorrhage.Benign prostatic hyperplasia (BPH) is one of the most common diseases of the genitourinary system. The prevalence of BPH increases in men with advancing age. While transurethral resection of the prostate gland entails complications such as retrograde ejaculation, urinary incontinence, hematuria, urethral strictures, bladder neck sclerosis, and other adverse events, it is necessary to apply minimally invasive surgical methods such as superselective embolization of the prostatic arteries (PAE), particularly Proximal Embolization First Then Distal Embolization (PErFecTED). The data from 1,015 BPH patients who underwent endovascular surgery demonstrate the benefits of PErFecTED treatment during 24 months after surgery. Both Quality of Life score and International Prostate Symptom Score were around three times better in the PErFecTED group and remained stable during the entire observation period. However, the technique needs to be improved due to the high risk of postembolization syndrome.Background. The English National Health Service publishes hospital performance indicators based on average postoperative EQ-5D index scores after hip replacement surgery to inform prospective patients' choices of hospital. Unidimensional index scores are derived from multidimensional health-related quality-of-life data using preference weights estimated from a sample of the UK general population. This raises normative concerns if general population preferences differ from those of the patients who are to be informed. This study explores how the source of valuation affects hospital performance estimates. Methods. Four different value sets reflecting source of valuation (general population v. patients), valuation technique (visual analog scale [VAS] v. time tradeoff [TTO]), and experience with health states (currently experienced vs. experimentally estimated) were used to derive and compare performance estimates for 243 hospitals. Two value sets were newly estimated from EQ-5D-3L data on 122,921 hip replacement patients and 3381 members of the UK general public.