A novel, robust peptidyl-lys metalloendopeptidase from Trametes coccinea recombinantly expressed in Komagataella phaffii.

A novel peptidyl-lys metalloendopeptidase (Tc-LysN) from Tramates coccinea was recombinantly expressed in Komagataella phaffii using the native pro-protein sequence. The peptidase was secreted into the culture broth as zymogen (~38 kDa) and mature enzyme (~19.8 kDa) simultaneously. The mature Tc-LysN was purified to homogeneity with a single step anion-exchange chromatography at pH 7.2. N-terminal sequencing using TMTpro Zero and mass spectrometry of the mature Tc-LysN indicated that the pro-peptide was cleaved between the amino acid positions 184 and 185 at the Kex2 cleavage site present in the native pro-protein sequence. The pH optimum of Tc-LysN was determined to be 5.0 while it maintained ≥60% activity between pH values 4.5-7.5 and ≥30% activity between pH values 8.5-10.0, indicating its broad applicability. The temperature maximum of Tc-LysN was determined to be 60 °C. After 18 h of incubation at 80 °C, Tc-LysN still retained ~20% activity. Organic solvents such as methanol and acetonitrile, at concentrations as high as 40% (v/v), were found to enhance Tc-LysN's activity up to ~100% and ~50%, respectively. Tc-LysN's thermostability, ability to withstand up to 8 M urea, tolerance to high concentrations of organic solvents, and an acidic pH optimum make it a viable candidate to be employed in proteomics workflows in which alkaline conditions might pose a challenge. The nano-LC-MS/MS analysis revealed bovine serum albumin (BSA)'s sequence coverage of 84% using Tc-LysN which was comparable to the sequence coverage of 90% by trypsin peptides. KEY POINTS: •A novel LysN from Trametes coccinea (Tc-LysN) was expressed in Komagataella phaffii and purified to homogeneity •Tc-LysN is thermostable, applicable over a broad pH range, and tolerates high concentrations of denaturants •Tc-LysN was successfully applied for protein digestion and mass spectrometry fingerprinting.

Transcriptional Factors Mediated Reprogramming to Pluripotency.

A unique kind of pluripotent cell, i.e., Induced pluripotent stem cells (iPSCs), now being targeted for iPSC synthesis, are produced by reprogramming animal and human differentiated cells (with no change in genetic makeup for the sake of high efficacy iPSCs formation). The conversion of specific cells to iPSCs has revolutionized stem cell research by making pluripotent cells more controllable for regenerative therapy. For the past 15 years, somatic cell reprogramming to pluripotency with force expression of specified factors has been a fascinating field of biomedical study. For that technological primary viewpoint reprogramming method, a cocktail of four transcription factors (TF) has required: Kruppel-like factor 4 (KLF4), four-octamer binding protein 34 (OCT3/4), MYC and SOX2 (together referred to as OSKM) and host cells. IPS cells have great potential for future tissue replacement treatments because of their ability to self-renew and specialize in all adult cell types, although factor-mediated reprogramming mechanisms are still poorly understood medically. This technique has dramatically improved performance and efficiency, making it more useful in drug discovery, disease remodeling, and regenerative medicine. Moreover, in these four TF cocktails, more than 30 reprogramming combinations were proposed, but for reprogramming effectiveness, only a few numbers have been demonstrated for the somatic cells of humans and mice. Stoichiometry, a combination of reprogramming agents and chromatin remodeling compounds, impacts kinetics, quality, and efficiency in stem cell research.

Development of the PSYCHS: Positive SYmptoms and Diagnostic Criteria for the CAARMS Harmonized with the SIPS.

AIM: To harmonize two ascertainment and severity rating instruments commonly used for the clinical high risk syndrome for psychosis (CHR-P): the Structured Interview for Psychosis-risk Syndromes (SIPS) and the Comprehensive Assessment of At-Risk Mental States (CAARMS). METHODS: The initial workshop is described in the companion report from Addington et al. After the workshop, lead experts for each instrument continued harmonizing attenuated positive symptoms and criteria for psychosis and CHR-P through an intensive series of joint videoconferences. RESULTS: Full harmonization was achieved for attenuated positive symptom ratings and psychosis criteria, and modest harmonization for CHR-P criteria. The semi-structured interview, named Positive SYmptoms and Diagnostic Criteria for the CAARMS Harmonized with the SIPS (PSYCHS), generates CHR-P criteria and severity scores for both CAARMS and SIPS. CONCLUSIONS: Using the PSYCHS for CHR-P ascertainment, conversion determination, and attenuated positive symptom severity rating will help in comparing findings across studies and in meta-analyses.

No Sex Differences in Mechanical Thrombectomy Time Metrics and Outcomes in Saskatchewan.

BACKGROUND AND PURPOSE: Numerous studies have shown longer pre-hospital and in-hospital workflow times and poorer outcomes in women after acute ischemic stroke (AIS) in general and after endovascular treatment (EVT) in particular. We investigated sex differences in acute stroke care of EVT patients over 5 years in a comprehensive Canadian provincial registry. METHODS: Clinical data of all AIS patients who underwent EVT between January 2017 and December 2022 in the province of Saskatchewan were captured in the Canadian OPTIMISE registry and supplemented with patient data from administrative data sources. Patient baseline characteristics, transport time metrics, and technical EVT outcomes between female and male EVT patients were compared. RESULTS: Three-hundred-three patients underwent EVT between 2017 and 2022: 144 (47.5%) women and 159 (52.5%) men. Women were significantly older (median age 77.5 [interquartile range: 66-85] vs.71 [59-78], p < 0.001), while men had more intracranial internal carotid artery occlusions (48/159 [30.2%] vs. 26/142 [18.3%], p = 0.03). Last-known-well to comprehensive stroke center (CSC)-arrival time (median 232 min [interquartile range 90-432] in women vs. 230 min [90-352] in men), CSC-arrival-to-reperfusion time (median 108 min [88-149] in women vs. 102 min [77-141] in men), reperfusion status (successful reperfusion 106/142 [74.7%] in women vs. 117/158 [74.1%] in men) as well as modified Rankin score at 90 days did not differ significantly. This held true after adjusting for baseline variables in multivariable analyses. CONCLUSION: While women undergoing EVT in the province of Saskatchewan were on average older than men, they were treated just as fast and achieved similar technical and clinical outcomes compared to men.

Development of the PSYCHS: Positive SYmptoms and Diagnostic Criteria for the CAARMS Harmonized with the SIPS.

Aim: To harmonize two ascertainment and severity rating instruments commonly used for the clinical high risk syndrome for psychosis (CHR-P): the Structured Interview for Psychosis-risk Syndromes (SIPS) and the Comprehensive Assessment of At-Risk Mental States (CAARMS). Methods: The initial workshop is described in the companion report from Addington et al. After the workshop, lead experts for each instrument continued harmonizing attenuated positive symptoms and criteria for psychosis and CHR-P through an intensive series of joint videoconferences. Results: Full harmonization was achieved for attenuated positive symptom ratings and psychosis criteria, and partial harmonization for CHR-P criteria. The semi-structured interview, named P ositive SY mptoms and Diagnostic Criteria for the C AARMS H armonized with the S IPS (PSYCHS), generates CHR-P criteria and severity scores for both CAARMS and SIPS. Conclusion: Using the PSYCHS for CHR-P ascertainment, conversion determination, and attenuated positive symptom severity rating will help in comparing findings across studies and in meta-analyses.

Preclinical Large Animal Porcine Models for Cardiac Regeneration and Its Clinical Translation: Role of hiPSC-Derived Cardiomyocytes.

Myocardial Infarction (MI) occurs due to a blockage in the coronary artery resulting in ischemia and necrosis of cardiomyocytes in the left ventricular heart muscle. The dying cardiac tissue is replaced with fibrous scar tissue, causing a decrease in myocardial contractility and thus affecting the functional capacity of the myocardium. Treatments, such as stent placements, cardiac bypasses, or transplants are beneficial but with many limitations, and may decrease the overall life expectancy due to related complications. In recent years, with the advent of human induced pluripotent stem cells (hiPSCs), newer avenues using cell-based approaches for the treatment of MI have emerged as a potential for cardiac regeneration. While hiPSCs and their derived differentiated cells are promising candidates, their translatability for clinical applications has been hindered due to poor preclinical reproducibility. Various preclinical animal models for MI, ranging from mice to non-human primates, have been adopted in cardiovascular research to mimic MI in humans. Therefore, a comprehensive literature review was essential to elucidate the factors affecting the reproducibility and translatability of large animal models. In this review article, we have discussed different animal models available for studying stem-cell transplantation in cardiovascular applications, mainly focusing on the highly translatable porcine MI model.

Desired Qualities of Endovascular Tools and Barriers to Treating Medium Vessel Occlusion MeVO : Insights from the MeVO-FRONTIERS International Survey.

BACKGROUND: Endovascular treatment (EVT) for stroke due to medium vessel occlusion (MeVO) can be technically challenging and specific endovascular tools are needed to safely and effectively recanalize these relatively small and fragile vessels. We aimed to gain insight into availability and desired qualities of endovascular devices used in MeVO stroke and examined barriers to adoption of MeVO EVT in clinical practice on a global scale. METHODS: We conducted a case-based international survey among neurointerventionalists. As a part of the survey, participants were asked whether they felt appropriate endovascular tools for MeVO stroke exist and are available to them in their clinical practice. We then examined barriers to adopting MeVO EVT and analyzed them by geographic regions. RESULTS: A total of 263 neurointerventionists participated, of which 178 (67.7%) and 83 (31.6%) provided responses on desired qualities of MeVO EVT tools and on barriers to their adoption in local practice, respectively. The majority 121/178 (68%) felt there was substantial room for improvement regarding existing tools. A large proportion 131/178 (73.6%) felt they had appropriate access to existing tools. The most commonly mentioned barrier for adopting MeVO EVT in North America was "awaiting better tools" (9/28 responses, 32.1%), while "awaiting better evidence" (8/26 responses, 30.8%), and the need for improved "funding" (7/26 responses, 26.9%) were important barriers in Europe. CONCLUSION: The majority of surveyed neurointerventionalists felt that dedicated MeVO EVT tools can be substantially improved upon. Different regions face various challenges in adoption of MeVO EVT, but overall, physicians are mostly awaiting better MeVO EVT tools.

Modulation of Mitochondrial Bioenergetics by Polydopamine Nanoparticles in Human iPSC-Derived Cardiomyocytes.

Myocardial infarction (MI) leads to the formation of an akinetic scar on the heart muscle causing impairment in cardiac contractility and conductance, leading to cardiac remodeling and heart failure (HF). The current pharmacological approaches for attenuating MI are limited and often come with long-term adverse effects. Therefore, there is an urgent need to develop novel multimodal therapeutics capable of modulating cardiac activity without causing any major adverse effects. In the current study, we have demonstrated the applicability of polydopamine nanoparticles (PDA-NPs) as a bioactive agent that can enhance the contractility and beat propagation of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Treatment of hiPSC-CMs with PDA-NPs demonstrated accumulation of the latter into mitochondria and significantly enhanced time-dependent adenosine triphosphate (ATP) production in these cells, indicating improved mitochondrial bioenergetics. Furthermore, the effect of PDA-NPs on hiPSC-CM activity was evaluated by measuring calcium transients. Treatment with PDA-NPs increased the calcium cycling in hiPSC-CMs in a temporal manner. Our results demonstrated a significant reduction in peak amplitude, transient duration, time to peak, and transient decay time in the PDA-NPs-treated hiPSC-CMs as compared to untreated hiPSC-CMs. Additionally, treatment of isolated perfused rat heart ex vivo with PDA-NPs demonstrated cardiotonic effects on the heart and significantly improved the hemodynamic function, suggesting its potential for enhancing whole heart contractility. Lastly, the gene expression analysis data revealed that PDA-NPs significantly upregulated cardiac-specific genes (ACADM, MYL2, MYC, HCN1, MYL7, GJA5, and PDHA1) demonstrating the ability to modulate genetic expression of cardiomyocytes. Taken together, these findings suggest PDA-NPs capability as a versatile nanomaterial with potential uses in next-generation cardiovascular applications.

Purification and characterization of a fungal aspartic peptidase from Trichoderma reesei and its application for food and animal feed protein hydrolyses.

BACKGROUND: Various neutral and alkaline peptidases are commercially available for use in protein hydrolysis under neutral to alkaline conditions. However, the hydrolysis of proteins under acidic conditions by applying fungal aspartic peptidases (FAPs) has not been investigated in depth so far. The aim of this study, thus, was to purify a FAP from the commercial enzyme preparation, ROHALASE® BXL, determine its biochemical characteristics, and investigate its application for the hydrolysis of food and animal feed proteins under acidic conditions. RESULTS: A Trichoderma reesei derived FAP, with an apparent molecular mass of 45.8 kDa (sodium dodecyl sulfate-polyacrylamide gel electrophoresis; SDS-PAGE) was purified 13.8-fold with a yield of 37% from ROHALASE® BXL. The FAP was identified as an aspartate protease (UniProt ID: G0R8T0) by inhibition and nano-LC-ESI-MS/MS studies. The FAP showed the highest activity at 50°C and pH 4.0. Monovalent cations, organic solvents, and reducing agents were tolerated well by the FAP. The FAP underwent an apparent competitive product inhibition by soy protein hydrolysate and whey protein hydrolysate with apparent Ki -values of 1.75 and 30.2 mg*mL-1 , respectively. The FAP showed promising results in food (soy protein isolate and whey protein isolate) and animal feed protein hydrolyses. For the latter, an increase in the soluble protein content of 109% was noted after 30 min. CONCLUSION: Our results demonstrate the applicability of fungal aspartic endopeptidases in the food and animal feed industry. Efficient protein hydrolysis of industrially relevant substrates such as acidic whey or animal feed proteins could be conducted by applying fungal aspartic peptidases. © 2022 Society of Chemical Industry.

Mesenchymal Stem Cells: From Regeneration to Drug Delivery Systems.

Targeting drug delivery has been a focus of researchers in recent years for cancer and other diseases. Many approaches such as liposomes, exosomes, nanoparticles (magnetic), encapsulation etc. have been developed and investigated for their clinical applications. But disadvantages linked to these therapies limit them to be used in clinical settings. Cell based drug delivery systems has emerged as an alternative for these therapies. Among cell types, mesenchymal stem cells (MSCs) proved to a potential cell type for research due to its many characteristics including low immunogenicity, chemotaxis and homing to tumor sites which are considered mandatory for drug delivery. This chapter focuses on the challenges and opportunities in using MSCs as therapeutic carrier of drugs in different ailments.

Dysregulation of circulating miRNAs promotes the pathogenesis of diabetes-induced cardiomyopathy.

Diabetic Cardiomyopathy (DCM) is characterized by myocardial dysfunction caused by diabetes mellitus. After-effects of diabetic cardiomyopathy are far more lethal than non-diabetic cardiomyopathy. More than 300 million people suffer from diabetes and cardiovascular disorder which is expected to be elevated to an alarming figure of 450 million by 2030. Recent studies suggested that miRNA plays important role in the onset of diabetic cardiomyopathy. This study was designed to identify the miRNA that is responsible for the onset of diabetic cardiomyopathy using in silico and in vitro approaches. In this study, to identify the miRNA responsible for the onset of diabetic cardiomyopathy, in silico analysis was done to predict the role of these circulating miRNAs in type 2 diabetic cardiomyopathy. Shared miRNAs that are present in both diseases were selected for further analysis. Total RNA and miRNA were extracted from blood samples taken from type 2 diabetic patients as well as healthy controls to analyze the expression of important genes like AKT, VEGF, IGF, FGF1, ANGPT2 using Real-time PCR. The expression of ANGPT2 was up-regulated and AKT, VEGF, IGF, FGF1 were down-regulated in DCM patients as compared to healthy controls. The miRNA expression of miR-17 was up-regulated and miR-24, miR-150, miR-199a, miR-214, and miR-320a were down-regulated in the DCM patients as compared to healthy controls. This shows that dysregulation of target genes and miRNA may contribute towards the pathogenesis of DCM and more studies should be conducted to elucidate the role of circulating miRNAs to use them as therapeutic and diagnostic options.

Stem cells based in vitro models: trends and prospects in biomaterials cytotoxicity studies.

Advanced biomaterials are increasingly used for numerous medical applications from the delivery of cancer-targeted therapeutics to the treatment of cardiovascular diseases. The issues of foreign body reactions induced by biomaterials must be controlled for preventing treatment failure. Therefore, it is important to assess the biocompatibility and cytotoxicity of biomaterials on cell culture systems before proceeding to in vivo studies in animal models and subsequent clinical trials. Direct use of biomaterials on animals create technical challenges and ethical issues and therefore, the use of non-animal models such as stem cell cultures could be useful for determination of their safety. However, failure to recapitulate the complex in vivo microenvironment have largely restricted stem cell cultures for testing the cytotoxicity of biomaterials. Nevertheless, properties of stem cells such as their self-renewal and ability to differentiate into various cell lineages make them an ideal candidate for in vitro screening studies. Furthermore, the application of stem cells in biomaterials screening studies may overcome the challenges associated with the inability to develop a complex heterogeneous tissue using primary cells. Currently, embryonic stem cells, adult stem cells, and induced pluripotent stem cells are being used as in vitro preliminary biomaterials testing models with demonstrated advantages over mature primary cell or cell line based in vitro models. This review discusses the status and future directions of in vitro stem cell-based cultures and their derivatives such as spheroids and organoids for the screening of their safety before their application to animal models and human in translational research.

Pathogenesis of Diabetic Cardiomyopathy and Role of miRNA.

Diabetic cardiomyopathy is characterized as abnormal function and structure of myocardium associated with diabetes irrespective of other cardiac risk factors like hypertension or coronary artery disease (CAD). The pathogenesis of DCM was not well understood in the past due to its complexity but it has been discovered recently. Various factors are found to be associated with the onset of DCM including impaired calcium handling, remodeling of extracellular matrix (ECM), increased oxidative stress, altered metabolism, mitochondrial dysfunction, and endothelial dysfunction. Micro-RNAs (miRNAs) are also found to be of great importance in the pathogenesis of DCM. Different miRNAs like miR-126, miR-24, miR-1, miR-155, miR-499, and miR-199a are found to be associated with different types of heart diseases like CAD and myocardial infarction. Studies have shown that the miRNA plays a crucial role in the development of DCM and it was found that the expression levels of different miRNAs differ in patients as compared to healthy individuals. This review focuses on the pathogenesis of DCM and various factors involved in the onset of diabetic car-diomyopathy. Moreover, the probable role of miRNA in the pathogenesis of DCM is also discussed.

Understanding the Trends and Variability in Procedures Performed During Orthopedic Spine Surgery Fellowship Training: An Analysis of ACGME Case Log Data.

OBJECTIVE: To understand trends and variability of procedures performed by orthopedic spine surgery fellows during training. DESIGN: Cross-sectional survey. SETTING: Accreditation Council on Graduate Medical Education (ACGME) case logs. PARTICIPANTS: Fellows enrolled in ACGME-accredited "Orthopaedic Surgery of the Spine" fellowships from 2010 to 2015. RESULTS: The 2010 to 2015 ACGME fellowship case logs for "Orthopaedic Surgery of the Spine" were retrieved. Spine cases in case logs are grouped into the following categories: (1) Excision, (2) Osteotomy, (3) Fracture and/or Dislocation, (4) Decompression, (5) Anterior fusion/arthrodesis, (6) Posterior fusion, (7) Deformity surgery, (8) Exploration, (9) Instrumentation, and (10) other/uncategorized. The total number of spine cases logged by each fellow increased from 821 in 2010 to 1134 in 2015 (38.2% increase). The greatest increases were noted from fracture/dislocation cases (77.9%), followed by posterior fusions (62.2%), anterior fusions (43.6%), decompressions (36.3%), and instrumentation (29.5%). The average number of deformity cases decreased from 23 in 2010 to 19 in 2016 (18.6% decrease). The average number of adult-only cases increased from 770 in 2010 to 1100 in 2015 (42.8% increase), whereas the average number of pediatric-only cases declined from 51 in 2010 to 35 in 2015 (32.1% decrease). Based on case logs from 2015, the greatest variation in case volume between the 10th centile and 90th centile of fellows was noted for deformity cases, followed by decompressions and posterior fusions. CONCLUSIONS: Even though there has been a 38% increase in the overall number of spine cases performed by fellows during training, a large amount of variation in type of case exposure exists between fellowships. The findings of our study call for the establishment of minimal case volumes and/or uniformity of training spectrums across the nation to ensure appropriate surgical care is made accessible to all patients.

Computational screening of phytochemicals against survivin protein: A potent target for cancer.

Survivin (IAP proteins) is considered as a significant target for anticancer drug research owing to its upregulation in tumor cells to mediate resistance to apoptotic stimulus. The current study aimed to investigate phytochemicals as inhibitors of survivin with caspases to reactivate the functioning of caspases through molecular docking. The compounds namely 2(R), 4(R)-dihydroxypyrrolidine, 4-hydroxy-2-(4-methoxyphenyl)-1,1-dioxo-3,4-dihydrothieno[3,2-e]thiazine-6-sulfonamide, 2,3-Diketo-L-gulonic acid, (3-hydroxy-2-octadeca-9,12-dienoyloxypropyl) octadecanoate, 2-[[4-[[4-[(4-formamido-1-methylimidazole-2-carbonyl)amino]-1-methylimidazole-2-carbonyl]amino]-1-methylimidazole-2-carbonyl]amino]ethyl-dimethylazanium, Picolinic acid and (2-Hydroxy-5-nitrophenyl) dihydrogen phosphate successfully bind inside the pocket of survivin. ADMETsar was used to evaluate the anticancer potential of selected compounds. These compounds can be proposed as effective inhibitors, disrupting the survivin-caspases interaction and reactivating the caspases function of apoptosis. The study might facilitate the development of cost-effective and natural drugs against cancer. However, further validation is essential for confirmation of its drug efficacy and bio-compatibility.

Risperidone for psychosis-induced aggression or agitation (rapid tranquillisation).

BACKGROUND: Aggressive, agitated or violent behaviour due to psychosis constitutes an emergency psychiatric treatment where fast-acting interventions are required. Risperidone is a widely accessible antipsychotic that can be used to manage psychosis-induced aggression or agitation. OBJECTIVES: To examine whether oral risperidone alone is an effective treatment for psychosis-induced aggression or agitation. SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials (up to April 2017); this register is compiled by systematic searches of major resources (including AMED, BIOSIS CINAHL, Embase, MEDLINE, PsycINFO, PubMed, and registries of clinical trials) and their monthly updates, handsearches, grey literature, and conference proceedings. There are no language, date, document type, or publication status limitations for inclusion of records into the register. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing rapid use of risperidone and other drugs, combinations of drugs or placebo for people exhibiting aggression or agitation (or both) thought to be due to psychosis. DATA COLLECTION AND ANALYSIS: We independently inspected all citations from searches, identified relevant abstracts, and independently extracted data from all included studies. For binary data we calculated risk ratio (RR) and for continuous data we calculated mean difference (MD), all with 95% confidence intervals (CI) and used a fixed-effect model. We assessed risk of bias for the included studies and used the GRADE approach to produce a 'Summary of findings' tables. MAIN RESULTS: The review now contains data from nine trials (total n = 582) reporting on five comparisons. Due to risk of bias, small size of trials, indirectness of outcome measures and a paucity of investigated and reported 'pragmatic' outcomes, evidence was graded as very-low quality. None of the included studies provided useable data on our primary outcome 'tranquillisation or asleep' by 30 minutes, repeated need for tranquillisation or any economic outcomes. Data were available for our other main outcomes of agitation or aggression, needing restraint, and incidence of adverse effects.Risperidone versus haloperidol (up to 24 hours follow-up)For the outcome, specific behaviour - agitation, no clear difference was found between risperidone and haloperidol in terms of efficacy, measured as at least 50% reduction in the Positive and Negative Syndrome Scale - Psychotic Agitation Sub-score (PANSS-PAS) (RR 1.04, 95% CI 0.86 to 1.26; participants = 124; studies = 1; very low-quality evidence) and no effect was observed for need to use restraints (RR 2.00, 95% CI 0.43 to 9.21; participants = 28; studies = 1; very low-quality evidence). Incidence of adverse effects was similar between treatment groups (RR 0.94, 95% CI 0.54 to 1.66; participants = 124; studies = 1; very low-quality evidence).Risperidone versus olanzapineOne small trial (n = 29) reported useable data for the comparison risperidone versus olanzapine. No effect was observed for agitation measured as PANSS-PAS endpoint score at two hours (MD 2.50, 95% CI -2.46 to 7.46; very low-quality evidence); need to use restraints at four days (RR 1.43, 95% CI 0.39 to 5.28; very-low quality evidence); specific movement disorders measured as Behavioural Activity Rating Scale (BARS) endpoint score at four days (MD 0.20, 95% CI -0.43 to 0.83; very low-quality evidence).Risperidone versus quetiapineOne trial reported (n = 40) useable data for the comparison risperidone versus quetiapine. Aggression was measured using the Modified Overt Aggression Scale (MOAS) endpoint score at two weeks. A clear difference, favouring quetiapine was observed (MD 1.80, 95% CI 0.20 to 3.40; very-low quality evidence). No evidence of a difference between treatment groups could be observed for incidence of akathisia after 24 hours (RR 1.67, 95% CI 0.46 to 6.06; very low-quality evidence). Two participants allocated to risperidone and one allocated to quetiapine experienced myocardial ischaemia during the trial.Risperidone versus risperidone + oxcarbazepineOne trial (n = 68) measured agitation using the Positive and Negative Syndrome Scale - Excited Component.(PANSS-EC) endpoint score and found a clear difference, favouring the combination treatment at one week (MD 2.70, 95% CI 0.42 to 4.98; very low-quality evidence), but no effect was observed for global state using Clinical Global Impression - Improvement (CGI-I) endpoint score at one week (MD -0.20, 95% CI -0.61 to 0.21; very-low quality evidence). Incidence of extrapyramidal symptoms after 24 hours was similar between treatment groups (RR 1.59, 95% CI 0.49 to 5.14; very-low quality evidence).Risperidone versus risperidone + valproic acidTwo trials compared risperidone with a combination of risperidone plus valproic acid. No clear differences between the treatment groups were observed for aggression (MOAS endpoint score at three days: MD 1.07, 95% CI -0.20 to 2.34; participants = 54; studies = 1; very low-quality evidence) or incidence of akathisia after 24 hours: RR 0.75, 95% CI 0.28 to 2.03; participants = 122; studies = 2; very low-quality evidence). AUTHORS' CONCLUSIONS: Overall, results for the main outcomes show no real effect for risperidone. The only data available for use in this review are from nine under-sampled trials and the evidence available is of very low quality. This casts uncertainty on the role of risperidone in rapid tranquillisation for people with psychosis-induced aggression. High-quality pragmatic RCTs are feasible and are needed before clear recommendations can be drawn on the use of risperidone for psychosis-induced aggression or agitation.

Cerebral Microbleeds are an Independent Predictor of Hemorrhagic Transformation Following Intravenous Alteplase Administration in Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Intravenous alteplase (rt-PA) increases the risk of hemorrhagic transformation of acute ischemic stroke. The objective of our study was to evaluate clinical, laboratory, and imaging predictors on forecasting the risk of hemorrhagic transformation following treatment with rt-PA. We also evaluated the factors associated with cerebral microbleeds that increase the risk of hemorrhagic transformation. METHODS: Consecutive patients with acute ischemic stroke admitted between January 1, 2009 and December 31, 2013 were included in the study if they received IV rt-PA, had magnetic resonance imaging (MRI) of the brain on admission, and computed tomography or MRI of the brain at 24 (18-36) hours later to evaluate for the presence of hemorrhagic transformation. The clinical data, lipid levels, platelet count, MRI, and computed tomography images were retrospectively reviewed. RESULTS: The study included 366 patients, with mean age 67 ± 15 years; 46% were women and 88% were white. The median National Institutes of Health Stroke Scale (NIHSS) score was 6 (interquartile range 3-15). Hemorrhagic transformation was observed in 87 (23.8%) patients and cerebral microbleeds were noted in 95 (25.9%). Patients with hemorrhagic transformation tended to be older, nonwhite, have atrial fibrillation, higher baseline NIHSS score, lower cholesterol and triglyceride levels, and cerebral microbleeds and nonlacunar infarcts. Patients with cerebral microbleeds were more likely to be older, have hypertension, hyperlipidemia, previous history of stroke, and prior use of antithrombotics. On multivariate analysis race, NIHSS score, nonlacunar infarct, and presence of cerebral microbleeds were independently associated with hemorrhagic transformation following treatment with rt-PA. CONCLUSIONS: Presence of cerebral microbleeds is an independent predictor of hemorrhagic transformation of acute ischemic stroke following treatment with rt-PA.

Smartphone Usage Patterns by Canadian Neurosurgery Residents: A National Cross-Sectional Survey.

BACKGROUND: Smartphones and their apps are used ubiquitously in medical practice. However, in some cases their use can be at odds with current patient data safety regulations such as Canada's Personal Health Information Protection Act of 2004. To assess current practices and inform mobile application development, we sought to better understand mobile device usage patterns among Canadian neurosurgery residents. METHODS: Through the Canadian Neurosurgery Research Collaborative, an online survey characterizing smartphone ownership and usage patterns was developed and sent to all Canadian neurosurgery resident in April of 2016. Questionnaires were collected and completed surveys analyzed. RESULTS: Of 146 eligible residents, 76 returned completed surveys (52% response rate). Of these 99% of respondents owned a smartphone, with 79% running on Apple's iOS. Four general mobile uses were identified: 1) communication between members of the medical team, 2) decision support, 3) medical reference, and 4) documentation through medical photography. Communication and photography were areas where the most obvious breaches in the Canadian Personal Health Information Protection Act were noted, with 89% of respondents taking pictures of patients' radiologic studies and 75% exchanging them with Short Message System. Hospital policies had no impact on user behaviors. CONCLUSIONS: Smartphones are used daily by most neurosurgery residents. Identified usage patterns are associated with perceived gains in efficacy and challenges in privacy and data reliability. We believe creating and improving workflows that address these usage patterns has a greater potential to improve privacy than changing policies and enforcing regulations.

Spinal dural arteriovenous fistula: a case series and review of imaging findings.

INTRODUCTION: Spinal dural arteriovenous fistulae (sdAVF) are rare lesions. Patients typically present with slowly progressive myelopathy that is often mistaken for degenerative cervical or lumbar stenosis. On spinal magnetic resonance imaging (MRI), multisegmental T2 hyperintensities along with associated flow voids are pathognomonic of sdAVF. However, diagnosis can be difficult. Definitive diagnosis and localization is achieved with complete spinal angiography. Treatment options include open surgical ligation, endovascular embolization or multimodality treatment. The purpose of this study is to present a series of cases to aid in the assessment, diagnosis and treatment of this unusual pathology. CASE PRESENTATION: We present 10 cases of sdAVF treated at our center over an 8-year period. Seventy percent of patients were male. The mean age of presentation was 62.6 years. The most common lesion was a dorsal dural AVF with single feeder. All patients underwent open surgical ligation, six having preoperative coil embolization of the radicular artery to allow for intraoperative localization of the fistula. Eight patients showed improvement following treatment as graded by the Nurick system. Two patients failed to improve. None of the patients worsened. One patient had a radiation burn from the spinal angiogram requiring secondary closure and one patient had a pseudomeningocele at the site of surgery that resolved. DISCUSSION: The successful treatment of sdAVF requires a detailed understanding of clinical presentation and imaging findings to allow for precise treatment. Owing to the rarity of the condition, clinicians must continue to share their experiences to advance our knowledge.

Canadian Registry of LVIS Jr for Treatment of Intracranial Aneurysms (CaRLA).

INTRODUCTION: Stents reduce the rate of angiographic recurrence of intracranial aneurysms. The newest stent for intracranial use is the Low-profile Visible Intraluminal Support device (LVIS Jr). OBJECTIVE: To assess the efficacy of the new stent in a multicenter retrospective registry. MATERIALS AND METHOD: Centers across Canada using LVIS Jr were contacted and asked to participate in a retrospective registry of consecutive patients treated with LVIS Jr for intracranial aneurysms between January 2013 and July 2015. RESULTS: A total of 102 patients, with saccular aneurysms in 100 patients (72 women; age range 21-78 years; mean 56.0 years; median 57.5 years) were treated with a LVIS Jr stent. The mean maximum diameter of the dome and neck of the aneurysm and dome to neck ratios were 8.3 mm±7.7 mm, 4.4 mm±1.9 mm, and 1.86±1.22, respectively. Angiographic complications arose in 23 patients, clinical complications in 9 patients, and only 3% of permanent neurological deficits occurred. Death occurred in 1 patient, unrelated to the stent. The ruptured status of the aneurysms (OR=3.29; p=0.046) and use of LVIS Jr for bailout (OR=2.54; p=0.053) showed a trend towards significant association with higher angiographic complications. At the last available follow-up, 68 class I, 20 class II, and 12 class III results were seen. CONCLUSIONS: The LVIS Jr stent is a safe and effective device for stent-assisted coiling, with 3% permanent neurological complications. Stent-assisted coiling continues to be technically challenging in cases of ruptured aneurysms and bailout situations.