Impact of optimised quasi-block structures on the properties of polymer electrolytes.

A set of ionic quasi-block copolymers were investigated to determine the effects of their composition and structure on their performance in their application as solid-state battery electrolytes. Diffusion and electrochemical tests have shown that these new quasi-block electrolytes have comparable performance to traditional block copolymers reaching ionic conductivities of 3.8 × 10-4 S cm-1 and lithium-ion diffusion of 4.6 × 10-12 m2 s-1 at 80 °C. It was illustrated that the mechanical properties of each quasi-block electrolyte are highly dependent on the order of monomer addition in polymer synthesis while the phase morphology hints at each of the quasi-blocks' unique compositional make up.

Understanding Polymerized Ionic Liquids as Solid Polymer Electrolytes for Sodium Batteries.

Solid polymer electrolytes (SPEs) have emerged as promising candidates for sodium-based batteries due to their cost-effectiveness and excellent flexibility. However, achieving high ionic conductivity and desirable mechanical properties in SPEs remains a challenge. In this study, we investigated an AB diblock copolymer, PS-PEA(BuImTFSI), as a potential SPE for sodium batteries. We explored binary and ternary electrolyte systems by combining the polymer with salt and [C3mpyr][FSI] ionic liquid (IL) and analyzed their thermal and electrochemical properties. Differential scanning calorimetry revealed phase separation in the polymer systems. The addition of salt exhibited a plasticizing effect localized to the polyionic liquid (PIL) phase, resulting in an increased ionic conductivity in the binary electrolytes. Introducing the IL further enhanced the plasticizing effect, elevating the ionic conductivity in the ternary system. Spectroscopic analysis, for the first time, revealed that the incorporation of NaFSI and IL influences the conformation of TFSI- and weakens the interaction between TFSI- and the polymer. This establishes correlations between anions and Na+, ultimately enhancing the diffusivity of Na ions. The electrochemical properties of an optimized SPE in Na/Na symmetrical cells were investigated, showcasing stable Na plating/stripping at high current densities up to 0.7 mA cm-2, maintaining its integrity at 70 °C. Furthermore, we evaluated the performance of a Na|NaFePO4 cell cycled at different rates (C/10 and C/5) and temperatures (50 and 70 °C), revealing remarkable high-capacity retention and Coulombic efficiency. This study highlights the potential of solvent-free diblock copolymer electrolytes for high-performance sodium-based energy storage systems, contributing to advanced electrolyte materials.

Effect of carrier molecular weight on physicochemical properties and the in vitro immune-stimulatory activity of the CpG-dextran conjugates.

The effect of dextran molecular weight on the in vitro physicochemical and immune properties of cytosine-phosphate-guanine (CpG) oligodeoxynucleotide-amino-dextran conjugates is investigated. CpG-1668 was conjugated at the 3'-end to amino-dextran of differing molecular weight (20, 40, 70 or 110-kDa) via a stable bis-aryl hydrazone linkage. Conjugate formation was confirmed by agarose gel electrophoresis and dynamic light scattering measured the size and surface charge of conjugates. Uptake and immune-stimulatory activity of CpG-dextran by antigen-presenting cells was evaluated by flow cytometry and confocal microscopy. Degradation by DNase I was monitored by loss of the fluorescent signal from labelled CpG and changes in size and zeta potential. Hydrazone bond formation (UV 354 nm) showed on average four CpG molecules conjugated per polymer. CpG-dextran prepared from 20 or 40-kDa dextran had a size of 17 nm while 70 or 110-kDa was 30 nm. CpG-dextran was preferentially taken up by dendritic cells, followed by macrophages and then B-cells. Only the 20-kDa dextran conjugate significantly enhanced uptake by bone-marrow derived dendritic cells (BMDCs) compared to free CpG. Confocal microscopy showed that CpG and CpG-dextran accumulates in the endo-lysosomal compartment of BMDCs at 24 h. All conjugates upregulated activation markers (CD40, CD80 or CD86) of BMDCs to a similar level as for free CpG. CpG-dextran 40-kDa produced highest levels of cytokines (TNF-α, IL-6, and IL-12p70) secreted by BMDCs. Enzymatic protection assays showed that the conjugate made from dextran 20-kDa provided no protection for CpG while the higher molecular weight conjugates reduced degradation by DNase I. The 40-kDa dextran conjugate produced the greatest in vitro immune activity, this was due to the conjugate being relatively small in size for cell uptake while sufficiently large enough to protect CpG from nuclease attack. These in vitro studies identify the need to consider the molecular weight of the carrier in bioconjugate design.

A landscape review of controlled release urea products: Patent objective, formulation and technology.

Fertiliser has been a vital part of agriculture due to it boosting crop productivity and preventing starvation throughout the world. Despite this huge contribution, the application of nitrogen (N) fertilisers results in N leaching and the formation of greenhouse gases, which threaten the environment and human health. To minimise the impacts, slow/controlled release fertilisers (S/CRFs) have been being developed since the beginning of the 20th century. Despite the efforts made over a century, the basic terminological and classification information of these fertilisers remains vague. The scientific knowledge published in S/CRF patents has also been overlooked since the beginning. This review focused on the information gaps, clarified the definitions, differentiation and classification methods that have been randomly used in previous literature. The objectives, formulations and technologies of 109 controlled release urea patents involving sulphur coated urea, polymer coated urea and urea matrix fertilisers published in the years since these products emerged were also reviewed to 1) highlight the overlooked scientific knowledge in the patents; 2) understand the evolutionary processes and current research states of the products; 3) clarify research preferences and challenges to date; 4) identify remaining gaps for the future direction. It is expected that the organised basic information and the patent knowledge highlighted in this paper can be new resources and foster the development of S/CRFs in the future.

Investigation on Formulation Strategies to Mitigate Compression-Induced Destabilization in Supersaturated Celecoxib Amorphous Solid Dispersions.

Compression-induced destabilization was investigated in various celecoxib amorphous solid dispersions containing hydroxypropyl methylcellulose (HPMC), poly(vinylpyrrolidone)/vinyl acetate copolymer (PVP/VA), or poly(vinylpyrrolidone) (PVP) at a concentration range of 1-10% w/w. Pharmaceutically relevant (125 MPa pressure with a minimal dwell time) and extreme (500 MPa pressure with a 60 s dwell time) compression conditions were applied to these systems, and the changes in their physical stability were monitored retrospectively (i.e., in the supercooled state) using dynamic differential scanning calorimetry (DSC) and low-frequency Raman (LFR) measurements over a broad temperature range (-90 to 200 and -150 to 140 °C, respectively). Both techniques revealed similar changes in the crystallization behavior between samples, where the application of a higher compression force of 500 MPa resulted in a more pronounced destabilization effect that was progressively mitigated with increasing polymer content. However, other aspects such as more favorable intermolecular interactions did not appear to have any effect on reducing this undesirable effect. Additionally, for the first time, LFR spectroscopy was used as a viable technique to determine the secondary or local glass-transition temperature, Tg,ß, a major indicator of the physical stability of neat amorphous pharmaceutical systems.

Electrospun Membranes as a Porous Barrier for Molecular Transport: Membrane Characterization and Release Assessment.

Electrospun nanofibers have been extensively studied for encapsulated drugs releasing from the inside of the fiber matrix, but have been barely looked at for their potential to control release as a semi-permeable membrane. This study investigated molecular transport behaviors across nanofiber membranes with different micro-structure sizes and compositions. Four types of membranes were made by 5% and 10% poly (ε-caprolactone) (PCL) solutions electro-spun with or without 50 nm calcium carbonate (CaCO3) nanoparticles. The membranes were tested for thickness, fiber diameter, pore size, porosity, tensile strength and elongation, contact angle of water and their impacts on molecular transport behaviors. The presence of the CaCO3 nanoparticles made the 5% membranes stronger and stiffer but the 10% membranes weaker and less stiff due to the different (covering or embedded) locations of the nanoparticles with the corresponding fibers. Solute transport studies using caffeine as the model drug found the 5% membranes further retarded release from the 10% membranes, regardless of only half the amount of material being used for synthesis. The addition of CaCO3 nanoparticles aided the water permeation process and accelerated initial transports. The difference in release profiles between 5% and 10% membranes suggests different release mechanisms, with membrane-permeability dominated release for 5% PCL membranes and solute-concentration-gradient dominated release for 10% PCL membranes.

Delivering Two Tumour Antigens Survivin and Mucin-1 on Virus-Like Particles Enhances Anti-Tumour Immune Responses.

Breast cancer (BC) is the most frequently diagnosed cancer in women, with many patients experiencing recurrence following treatment. Antigens delivered on virus-like particles (VLPs) induce a targeted immune response and here we investigated whether the co-delivery of multiple antigens could induce a superior anti-cancer response for BC immunotherapy. VLPs were designed to recombinantly express murine survivin and conjugated with an aberrantly glycosylated mucin-1 (MUC1) peptide using an intracellular cleavable bis-arylhydrazone linker. Western blotting, electron microscopy and UV absorption confirmed survivin-VLP expression and MUC1 conjugation. To assess the therapeutic efficacy of VLPs, orthotopic BC tumours were established by injecting C57mg.MUC1 cells into the mammary fat pad of mice, which were then vaccinated with surv.VLP-SS-MUC1 or VLP controls. While wild-type mice vaccinated with surv.VLP-SS-MUC1 showed enhanced survival compared to VLPs delivering either antigen alone, MUC1 transgenic mice vaccinated with surv.VLP-SS-MUC1 showed no enhanced survival compared to controls. Hence, while co-delivery of two tumour antigens on VLPs can induce a superior anti-tumour immune response compared to the delivery of single antigens, additional strategies must be employed to break tolerance when targeted tumour antigens are expressed as endogenous self-proteins. Using VLPs for the delivery of multiple antigens represents a promising approach to improving BC immunotherapy, and has the potential to be an integral part of combination therapy in the future.

Dry Formulation of Virus-Like Particles in Electrospun Nanofibers.

Biologics can be combined with liquid polymer materials and electrospun to produce a dry nanofibrous scaffold. Unlike spray-drying and freeze-drying, electrospinning minimizes the physiological stress on sensitive materials, and nanofiber mat properties such as hydrophobicity, solubility, and melting temperature can be tuned based on the polymer composition. In this study, we explored the dry formulation of a virus-like particle (VLP) vaccine by electrospinning VLP derived from rabbit hemorrhagic disease virus modified to carry the MHC-I gp100 tumor-associated antigen epitope. VLP were added to a polyvinylpyrrolidone (PVP) solution (15% w/v) followed by electrospinning at 24 kV. Formation of a nanofibrous mat was confirmed by scanning electron microscopy, and the presence of VLP was confirmed by transmission electron microscopy and Western blot. VLP from the nanofibers induced T-cell activation and interferon- (IFN-) γ production in vitro. To confirm in vivo cytotoxicity, Pmel mice treated by injection with gp100 VLP from nanofibers induced a gp100 specific immune response, lysing approximately 65% of gp100-pulsed target cells, comparable to mice vaccinated with gp100 VLP in PBS. VLP from nanofibers also induced an antibody response. This work shows that electrospinning can be used to dry-formulate VLP, preserving both humoral and cell-mediated immunity.

Data on the uptake of CpG-loaded amino-dextran nanoparticles by antigen-presenting cells.

Cytosine-phosphate-guanine (CpG) oligonucleotides are commonly-used vaccine adjuvants to promote the activation of antigen-presenting cells (APCs). To mount an effective immune response, CpG needs to be internalized and bind to its endosomal Toll-like receptor 9 (TLR-9) inside the APCs. Using flow cytometry and fluorescence microscopy, this article presents the cellular uptake data of the amino-dextran nanoparticle (aDNP) and aDNP loaded with CpG immobilized on its surface by either electrostatic adsorption or covalent conjugation. The uptake of fluorescently-labelled aDNPs by murine splenic dendritic cells and macrophages was determined by flow cytometry and uptake by murine bone-marrow-derived dendritic cells was evaluated by fluorescence microscopy. The data presented in this paper correlates with the in vitro immune-stimulatory activity observed for the two different CpG loading methods in the research article "Nanoparticle system based on amino-dextran as a drug delivery vehicle: immune-stimulatory CpG-oligonucleotide loading and delivery" (Nguyen et al., 2020) [1]. The data provide experimental evidence for a better understanding how the nanoparticle surface loading method of CpG influences the uptake of these nanoparticles by antigen-presenting cells as a step guide in the design of more effective vaccine formulations.

Decreased Stroke Presentation Rates at a Comprehensive Stroke Center during COVID-19.

We reviewed stroke care delivery during the COVID-19 pandemic at our stroke center and provincial telestroke system. We counted referrals to our prevention clinic, code strokes, thrombolysis, endovascular thrombectomies, and activations of a provincial telestroke system from February to April of 2017-2020. In April 2020, there was 28% reduction in prevention clinic referrals, 32% reduction in code strokes, and 26% reduction in telestroke activations compared to prior years. Thrombolysis and endovascular thrombectomy rates remained constant. Fewer patients received stroke services across the spectrum from prevention, acute care to telestroke care in Ontario, Canada, during the COVID-19 pandemic.

C-2 derivatized 8-sulfonamidoquinolines as antibacterial compounds.

A series of C-2 derivatized 8-sulfonamidoquinolines were evaluated for their antibacterial activity against the common mastitis causative pathogens Streptococcus uberis, Staphylococcus aureus and Escherichia coli, both in the presence and absence of supplementary zinc (50 µM ZnSO4). The vast majority of compounds tested were demonstrated to be significantly more active against S. uberis when in the presence of supplementary zinc (MICs as low as 0.125 µg/mL were observed in the presence of 50 µM ZnSO4). Compounds 5, 34-36, 39, 58, 79, 82, 94 and 95 were shown to display the greatest antibacterial activity against S. aureus (MIC ≤ 8 µg/mL; both in the presence and absence of supplementary zinc), while compounds 56, 58 and 66 were demonstrated to also exhibit activity against E. coli (MIC ≤ 16 µg/mL; under all conditions). Compounds 56, 58 and 66 were subsequently confirmed to be bactericidal against all three mastitis pathogens studied, with MBCs (≥3log10 CFU/mL reduction) of ≤ 32 µg/mL (in both the presence and absence of 50 µM ZnSO4). To validate the sanitizing activity of compounds 56, 58 and 66, a quantitative suspension disinfection (sanitizer) test was performed. Sanitizing activity (>5log10 CFU/mL reduction in 5 min) was observed against both S. uberis and E. coli at compound concentrations as low as 1 mg/mL (compounds 56, 58 and 66), and against S. aureus at 1 mg/mL (compound 58); thereby validating the potential of compounds 56, 58 and 66 to function as topical sanitizers designed explicitly for use in non-human applications.

Revised intracerebral hemorrhage expansion definitions: Relationship with care limitations.

BACKGROUND: Hematoma expansion is an important therapeutic target in intracerebral hemorrhage. Recently proposed hematoma expansion definitions have not been validated, and no previous definition has accounted for withdrawal of care. AIMS: To externally validate revised definitions of hematoma expansion that incorporate intraventricular hemorrhage, and to test their validity in the context of withdrawal of care. METHODS: We analyzed data from the Antihypertensive Treatment of Acute Cerebral Hemorrhage II trial, comparing revised definitions of hematoma expansion incorporating intraventricular hemorrhage expansion to the conventional definition of "≥6 mL or ≥33%." Primary outcome was modified Rankin Scale of 4-6 at 90 days. We calculated the incidence, sensitivity, specificity, positive and negative predictive values, and c-statistic for all definitions of hematoma expansion. Definitions were compared using nonparametric methods. Secondary analyses were performed after removing patients with withdrawal of care. RESULTS: Primary analysis included 948 patients. Using the conventional definition, the sensitivity was 37.1% and specificity was 83.2% for the primary outcome. Sensitivity improved with all three revised definitions (53.3%, 48.7%, and 45.3%, respectively), with minimal change to specificity (78.4%, 80.5%, and 81.0%, respectively). The greatest improvement was seen with the definition "≥6 mL or ≥33% or any intraventricular hemorrhage," with increased c-statistic from 60.2% to 65.9% (p < 0.001). Secondary analysis excluded 46 participants who experienced withdrawal of care. The revised definitions similarly outperformed the conventional definition in this population, with the greatest improvement in c-statistic using "≥6 mL or ≥33% or any intraventricular hemorrhage" (58.1% vs. 64.1%, p < 0.001). CONCLUSIONS: Revised hematoma expansion definitions incorporating intraventricular hemorrhage expansion outperformed conventional definitions for predicting poor outcome, even after accounting for care limitations.

Nanoparticle System Based on Amino-Dextran as a Drug Delivery Vehicle: Immune-Stimulatory CpG-Oligonucleotide Loading and Delivery.

The aim of this study is to prepare and characterize an amino-dextran nanoparticle (aDNP) platform and investigate two loading strategies for unmethylated cytosine-phosphate-guanine (CpG) oligonucleotide. aDNP was prepared by desolvation of amino-dextran followed by the chemical crosslinking of amino groups. Size, surface charge, and surface morphology of aDNP was determined by dynamic light scattering and transmission electron microscopy. CpG was either loaded onto aDNP by adsorption (CpG-adsorbed-aDNP) or conjugated to aDNP (CpG-conjugated-aDNP). In vitro cytokine production by bone marrow-derived dendritic cells (BMDCs) was measured by flow cytometry. aDNPs size and zeta potential could be controlled to produce uniform particles in the size range of 50 to 300 nm, surface charge of -16.5 to +14 mV, and were spherical in shape. Formulation control parameters investigated included the anti-solvent, water-to-anti-solvent ratio, level of amine functionality of dextran, and the molar ratio of glutaraldehyde to amine. aDNP could be lyophilized without additional cryoprotectant. Unloaded cationic aDNP (+13 mV) showed acceptable in vitro hemolysis. Unloaded and CpG-loaded aDNPs showed no cytotoxicity on BMDCs. CpG-loaded nanoparticles stimulated cytokine production by BMDCs, the level of cytokine production was higher for CpG-conjugated-aDNP compared to CpG-absorbed-aDNP. aDNP is a promising new drug delivery platform as its offers versatility in loading and tuning of particle properties.

Substituted sulfonamide bioisosteres of 8-hydroxyquinoline as zinc-dependent antibacterial compounds.

A series of substituted sulfonamide bioisosteres of 8-hydroxyquinoline were evaluated for their antibacterial activity against the common mastitis causative pathogens Streptococcus uberis, Staphylococcus aureus and Escherichia coli, both in the presence and absence of supplementary zinc. Compounds 9a-e, 10a-c, 11a-e, 12 and 13 were demonstrated to have MICs of 0.0625 µg/mL against S. uberis in the presence of 50 µM ZnSO4. Against S. aureus compounds 9g (MIC 4 µg/mL) and 11d (MIC 8 µg/mL) showed the greatest activity, whereas all compounds were found to be inactive against E. coli (MIC > 256 µg/mL); again in the presence of 50 µM ZnSO4. All compounds were demonstrated to be significantly less active in the absence of supplementary zinc. Compound 9g was subsequently confirmed to be bactericidal, with an MBC (≥3log10 cfu/mL reduction) of 0.125 µg/mL against S. uberis in the presence of 50 µM ZnSO4. To validate the sanitising activity of compound 9g in the presence of supplementary zinc, a quantitative suspension disinfection (sanitizer) test was performed. In this preliminary test, sanitizing activity (>5log10 reduction of CFU/mL in 5 min) was observed against S. uberis for compound 9g at concentrations as low as 1 mg/mL, validating the potential of this compound to function as a topical sanitizer against the major environmental mastitis-causing microorganism S. uberis.

Influence of Albumin in the Microfluidic Synthesis of PEG-PLGA Nanoparticles.

BACKGROUND: A key challenge in the manufacturing of polymeric colloids is producing nanoparticles with good batch-to-batch consistency. OBJECTIVE: Develop a robust microfluidics method for the preparation of PEG-PLGA nanoparticles using dimethyl sulfoxide (DMSO) as the organic phase solvent for the encapsulation of DMSO soluble agents. METHODS: Microfluidic process parameters, total flow rate (10 mL/min), flow rate ratio (1:1) of the aqueous phase and the organic polymer solution, and polymer concentration (5 mg/ml). Polyvinyl alcohol (PVA) or human serum albumin (HSA) was included in the aqueous phase. Dynamic light scattering and transmission electron microscopy were used to investigate the size and morphology of particles. RESULTS: PLGA nanoparticles made using DMSO with the aqueous solvent containing PVA (2%) had an average size of 60 nm while PLGA-PEG nanoparticles made with and without PVA (2%) had an average size of 70 and 100 nm, respectively. PLGA-PEG nanoparticles generated with or without PVA had a high batch-to-batch coefficient of variation for the particle size of 20% while for PLGA nanoparticles with PVA it was 4%. HSA added to the aqueous phase reduced the size and the zeta potential of PEG-PLGA nanoparticles as well the batch-to-batch coefficient of variation for particle size to < 5%. Nanoparticles were stable in solution and after lyophilized in the presence of sucrose. CONCLUSION: Albumin was involved in the self-assembly of PEG-PLGA nanoparticles altering the physicochemical properties of nanoparticles. Adding protein to the aqueous phase in the microfluidic fabrication process may be a valuable tool for tuning the properties of nanoparticles and improving batch-to-batch consistency.

Formulation of Broccoli Sprout Powder in Gastro-Resistant Capsules Protects against the Acidic pH of the Stomach In Vitro but Does Not Increase Isothiocyanate Bioavailability In Vivo.

Broccoli sprout powder is a rich source of glucosinolates, which are hydrolysed to isothiocyanates in the presence of the enzyme myrosinase. We showed that in vitro incubation of broccoli sprout powder extract with isolated lymphocytes resulted in the upregulation of transcription factor Nrf2, however, there was no increase in Nrf2 protein levels in lymphocytes isolated 3 h following the ingestion of broccoli sprout powder by healthy volunteers. This highlights the general issue that potential health benefits of food-derived compounds can be compromised by limitations in bioavailability. In vitro experiments showed that the generation of isothiocyanates was reduced when the powder was first exposed to the low pH (1.2) of the stomach and then transferred to the higher pH (6.8) of the intestine. The loss of activity due to pre-exposure to the low stomach pH indicates that formulating the broccoli sprout powder in gastro-resistant formulations should increase that amount of isothiocyanate generated in the intestine for absorption. Gelatin capsules were hand-coated with either Eudragit® L100 or Eudragit® L100-55 and were assessed for their gastro-resistant properties using paracetamol as a model active for dissolution studies. Disintegration and dissolution studies showed that Eudragit® L100-55 coated capsules and DRcapsTM (Capsugel®) failed the United States Pharmacopeia (USP) requirements for gastro-resistant capsules, whereas the Eudragit® L100 coated capsules passed. Five healthy participants were administered 1 g of broccoli sprout powder, ingested either with water or encapsulated in uncoated or gastro-resistant capsules. Urinary excretion of isothiocyanate metabolites over the 24 h period post ingestion was assessed by HPLC. Broccoli sprout powder and uncoated gelatin-encapsulated powder showed comparable excretion of isothiocyanate metabolites (18.4 ± 2.3 and 23.9 ± 2.7 µmol, respectively). The enteric coated capsules provided a significantly longer Tmax than the uncoated gelatin capsules (15.4 ± 2.3 versus 3.7 ± 0.7 h, respectively), indicating protection from disintegration in the stomach, however, the excretion of isothiocyanate metabolites was significantly decreased compared with uncoated capsules (i.e., 8.5 ± 1.1 µmol). The lower in vivo formation or absorption of isothiocyanates observed for the gastro-resistant capsules may be due to participant variation in intestinal pH or transit times, resulting in inappropriate pH conditions or insufficient time for the complete disintegration and dissolution of the capsules.

Data on the uptake of reducible antigen-adjuvant conjugates by dendritic cells.

This article contains the uptake data of two reducible antigen-adjuvant conjugates with different sensitivities to the extracellular and intracellular reductive environment. Using a linker with different redox sensitivity the adjuvant cytosine-phosphate-guanine (CpG) was conjugated to the fluorescently labeled model tumour antigen ovalbumin (OVA). The uptake of the conjugates by dendritic cells in a total splenocyte culture was determined using flow cytometry. The data presented in this paper supports the finding in the research article "Intracellular cleavable CpG oligodeoxynucleotide - antigen conjugate enhances anti-tumour immunity" (Kramer et al., 2016) [1].

Prehospital stroke scales as screening tools for early identification of stroke and transient ischemic attack.

BACKGROUND: Rapid and accurate detection of stroke by paramedics or other emergency clinicians at the time of first contact is crucial for timely initiation of appropriate treatment. Several stroke recognition scales have been developed to support the initial triage. However, their accuracy remains uncertain and there is no agreement which of the scales perform better. OBJECTIVES: To systematically identify and review the evidence pertaining to the test accuracy of validated stroke recognition scales, as used in a prehospital or emergency room (ER) setting to screen people suspected of having stroke. SEARCH METHODS: We searched CENTRAL, MEDLINE (Ovid), Embase (Ovid) and the Science Citation Index to 30 January 2018. We handsearched the reference lists of all included studies and other relevant publications and contacted experts in the field to identify additional studies or unpublished data. SELECTION CRITERIA: We included studies evaluating the accuracy of stroke recognition scales used in a prehospital or ER setting to identify stroke and transient Ischemic attack (TIA) in people suspected of stroke. The scales had to be applied to actual people and the results compared to a final diagnosis of stroke or TIA. We excluded studies that applied scales to patient records; enrolled only screen-positive participants and without complete 2 × 2 data. DATA COLLECTION AND ANALYSIS: Two review authors independently conducted a two-stage screening of all publications identified by the searches, extracted data and assessed the methodologic quality of the included studies using a tailored version of QUADAS-2. A third review author acted as an arbiter. We recalculated study-level sensitivity and specificity with 95% confidence intervals (CI), and presented them in forest plots and in the receiver operating characteristics (ROC) space. When a sufficient number of studies reported the accuracy of the test in the same setting (prehospital or ER) and the level of heterogeneity was relatively low, we pooled the results using the bivariate random-effects model. We plotted the results in the summary ROC (SROC) space presenting an estimate point (mean sensitivity and specificity) with 95% CI and prediction regions. Because of the small number of studies, we did not conduct meta-regression to investigate between-study heterogeneity and the relative accuracy of the scales. Instead, we summarized the results in tables and diagrams, and presented our findings narratively. MAIN RESULTS: We selected 23 studies for inclusion (22 journal articles and one conference abstract). We evaluated the following scales: Cincinnati Prehospital Stroke Scale (CPSS; 11 studies), Recognition of Stroke in the Emergency Room (ROSIER; eight studies), Face Arm Speech Time (FAST; five studies), Los Angeles Prehospital Stroke Scale (LAPSS; five studies), Melbourne Ambulance Stroke Scale (MASS; three studies), Ontario Prehospital Stroke Screening Tool (OPSST; one study), Medic Prehospital Assessment for Code Stroke (MedPACS; one study) and PreHospital Ambulance Stroke Test (PreHAST; one study). Nine studies compared the accuracy of two or more scales. We considered 12 studies at high risk of bias and one with applicability concerns in the patient selection domain; 14 at unclear risk of bias and one with applicability concerns in the reference standard domain; and the risk of bias in the flow and timing domain was high in one study and unclear in another 16.We pooled the results from five studies evaluating ROSIER in the ER and five studies evaluating LAPSS in a prehospital setting. The studies included in the meta-analysis of ROSIER were of relatively good methodologic quality and produced a summary sensitivity of 0.88 (95% CI 0.84 to 0.91), with the prediction interval ranging from approximately 0.75 to 0.95. This means that the test will miss on average 12% of people with stroke/TIA which, depending on the circumstances, could range from 5% to 25%. We could not obtain a reliable summary estimate of specificity due to extreme heterogeneity in study-level results. The summary sensitivity of LAPSS was 0.83 (95% CI 0.75 to 0.89) and summary specificity 0.93 (95% CI 0.88 to 0.96). However, we were uncertain in the validity of these results as four of the studies were at high and one at uncertain risk of bias. We did not report summary estimates for the rest of the scales, as the number of studies per test per setting was small, the risk of bias was high or uncertain, the results were highly heterogenous, or a combination of these.Studies comparing two or more scales in the same participants reported that ROSIER and FAST had similar accuracy when used in the ER. In the field, CPSS was more sensitive than MedPACS and LAPSS, but had similar sensitivity to that of MASS; and MASS was more sensitive than LAPSS. In contrast, MASS, ROSIER and MedPACS were more specific than CPSS; and the difference in the specificities of MASS and LAPSS was not statistically significant. AUTHORS' CONCLUSIONS: In the field, CPSS had consistently the highest sensitivity and, therefore, should be preferred to other scales. Further evidence is needed to determine its absolute accuracy and whether alternatives scales, such as MASS and ROSIER, which might have comparable sensitivity but higher specificity, should be used instead, to achieve better overall accuracy. In the ER, ROSIER should be the test of choice, as it was evaluated in more studies than FAST and showed consistently high sensitivity. In a cohort of 100 people of whom 62 have stroke/TIA, the test will miss on average seven people with stroke/TIA (ranging from three to 16). We were unable to obtain an estimate of its summary specificity. Because of the small number of studies per test per setting, high risk of bias, substantial differences in study characteristics and large between-study heterogeneity, these findings should be treated as provisional hypotheses that need further verification in better-designed studies.

Virus-like particle vaccines: immunology and formulation for clinical translation.

INTRODUCTION: Virus-like particle (VLP) vaccines face significant challenges in their translation from laboratory models, to routine clinical administration. While some VLP vaccines thrive and are readily adopted into the vaccination schedule, others are restrained by regulatory obstacles, proprietary limitations, or finding their niche amongst the crowded vaccine market. Often the necessity to supplant an existing vaccination regimen possesses an immediate obstacle for the development of a VLP vaccine, despite any preclinical advantages identified over the competition. Novelty, adaptability and formulation compatibility may prove invaluable in helping place VLP vaccines at the forefront of vaccination technology. AREAS COVERED: The purpose of this review is to outline the diversity of VLP vaccines, VLP-specific immune responses, and to explore how modern formulation and delivery techniques can enhance the clinical relevance and overall success of VLP vaccines. EXPERT COMMENTARY: The role of formation science, with an emphasis on the diversity of immune responses induced by VLP, is underrepresented amongst clinical trials for VLP vaccines. Harnessing such diversity, particularly through the use of combinations of select excipients and adjuvants, will be paramount in the development of VLP vaccines.