Universal cannabis outcomes from the Climate and Preventure (CAP) study : a cluster randomised controlled trial

Background: The Climate and Preventure (CAP) study was the first trial to assess and demonstrate the effectiveness of a combined universal and selective approach for preventing alcohol use and related harms among adolescents. The current paper reports universal effects from the CAP study on cannabis-related outcomes over three years. Methods: A cluster randomized controlled trial was conducted with 2190 students from twenty-six Australian high schools (mean age: 13.3 yrs., SD 0.48). Participants were randomised to one of four conditions; universal prevention for all students (Climate); selective prevention for high-risk students (Preventure); combined universal and selective prevention (Climate and Preventure; CAP); or health education as usual (Control). Participants were assessed at baseline, post intervention (6–9 months post baseline), and at 12-, 24- and 36-months, on measures of cannabis use, knowledge and related harms. This paper compares cannabis-related knowledge, harms and cannabis use in the Control, Climate and CAP groups as specified in the protocol, using multilevel mixed linear models to assess outcomes. Results: Compared to Control, the Climate and CAP groups showed significantly greater increases in cannabis-related knowledge initially (p < 0.001), and had higher knowledge at the 6, 12 and 24-month follow-ups. There was no significant difference between the Climate and CAP groups. While no differences were detected between Control and the CAP and Climate groups on cannabis use or cannabis-related harms, the prevalence of these outcomes was lower than anticipated, possibly limiting power to detect intervention effects. Additional Bayesian analyses exploring confidence in accepting the null hypothesis showed there was insufficient evidence to conclude that the interventions had no effect, or to conclude that they had a meaningfully large effect. Conclusions: Both the universal Climate and the combined CAP programs were effective in increasing cannabisrelated knowledge for up to 2 years. The evidence was inconclusive regarding whether the interventions reduced cannabis use and cannabis-related harms. A longer-term follow-up will ascertain whether the interventions become effective in reducing these outcomes as adolescents transition into early adulthood

Statistical analysis plan for the COMPARE trial: a 3-arm randomised controlled trial comparing the effectiveness of Constraint-induced Aphasia Therapy Plus and Multi-modality Aphasia Therapy to usual care in chronic post-stroke aphasia (COMPARE)

BackgroundWhile high-quality meta-analyses have confirmed the effectiveness of aphasia therapy after stroke, there is limited evidence for the comparative effectiveness of different aphasia interventions. Two commonly used interventions, Constraint-induced Aphasia Therapy Plus (CIAT Plus) and Multi-modality Aphasia Therapy (M-MAT), are hypothesised to rely on diverse underlying neural mechanisms for recovery and may be differentially responsive to aphasia severity. COMPARE is a prospective randomised open-blinded end-point trial designed to determine whether, in people with chronic post-stroke aphasia living in the community, CIAT Plus and M-MAT provide greater therapeutic benefit compared to usual care, are differentially effective according to aphasia severity, and are cost-effective. This paper details the statistical analysis plan for the COMPARE trial developed prior to data analysis.MethodsParticipants (n = 216) are randomised to one of three arms, CIAT Plus, M-MAT or usual care, and undertake therapy with a study trained speech pathologist in groups of three participants stratified by aphasia severity. Therapy occurs for 3 h blocks per day for 10 days across 2 weeks. The primary clinical outcome is aphasia severity as measured by the Western Aphasia Battery-Revised Aphasia Quotient (WAB-R-AQ) immediately post intervention. Secondary outcomes include WAB-R-AQ at 12-week follow-up, and functional communication, discourse efficiency, multimodal communication, and health-related quality of life immediately post intervention and at 12-week follow-up.ResultsLinear mixed models (LMMs) will be used to analyse differences between M-MAT and UC, and CIAT-Plus and UC on each outcome measure immediately and at 12 weeks post-intervention. The LMM for WAB-R-AQ will assess the differences in efficacy between M-MAT and CIAT-Plus. All analyses will control for baseline aphasia severity (fixed effect) and for the clustering effect of treatment groups (random effect).DiscussionThis trial will provide relative effectiveness data for two common interventions for people with chronic post-stroke aphasia, and highlight possible differential effects based on aphasia severity. Together with the health economic analysis data, the results will enable more informed personalised prescription for aphasia therapy after stroke.Trial registrationAustralian New Zealand Clinical Trials Registry: ACTRN 12615000618550 . Registered on 15 June 2016

The cheerleader effect is robust to experimental manipulations of presentation time

The “cheerleader effect” occurs when the same face is perceived to be significantly more attractive when seen among a group of faces compared to alone. Since perceived attractiveness decreases with additional viewing time, we investigated whether the cheerleader effect occurs simply because the target face is seen for less time in a group than it is alone. Observers rated the attractiveness of each target face twice; once in a group, and once alone. We manipulated the amount of time that each group image was presented for prior to the cue toward the target face (300, 1000, 2000, 3000, or 7000 milliseconds). Faces were perceived to be significantly more attractive in each group condition, regardless of presentation time, replicating the cheerleader effect. Furthermore, uncued presentation time did not modulate the magnitude of this increase, demonstrating that a presentation time discrepancy does not contribute to the size of the typical cheerleader effect

Convergent Bayesian global fits of 4D composite Higgs models

Models in which the Higgs boson is a composite pseudo-Nambu-Goldstone boson offer attractive solutions to the Higgs mass naturalness problem. We consider three such models based on the minimal SO(5) → SO(4) symmetry breaking pattern, and perform convergent global fits on the models under a Bayesian framework in order to find the regions of their parameter spaces that best fit a wide range of constraints, including recent Higgs measurements. We use a novel technique to analyse the fine-tuning of the models, quantifying the tuning as the Kullback-Leibler divergence from the prior to the posterior probability on the parameter space. Each model is found to be able to satisfy all constraints at the 3σ level simultaneously. As a by-product of the fits, we analyse the collider phenomenology of our models in these viable regions. In two of the three models, we find that the gg → H → γγ cross section is less than ∼90% that predicted by the SM, which is already in slight tension with experiment and could potentially be ruled out in the future high-luminosity run of the LHC. In addition, the lightest fermions F arising from the new strong dynamics in these models are seen in general to lie above ∼1.1 TeV, with the F → tW+ and F → b¯¯W+ decays offering particularly promising channels for probing these models in future collider searches.Ethan Carragher, Will Handley, Daniel Murnane, Peter Stangl, Wei Su, Martin White, Anthony G. William

Acceptability, feasibility and preliminary efficacy of low-moderate intensity Constraint Induced Aphasia Therapy and Multi-Modality Aphasia Therapy in chronic aphasia after stroke

Background: High-intensity Constraint-Induced Aphasia Therapy Plus (CIAT-Plus) and Multi-Modality Aphasia Therapy (M-MAT) are effective interventions for chronic post-stroke aphasia but challenging to provide in clinical practice. Providing these interventions may be more feasible at lower intensities, but comparative evidence is lacking. We therefore explored feasibility, acceptability, and preliminary efficacy of the treatments at a lower intensity. Methods: A multisite, single-blinded, randomized Phase II trial was conducted within the Phase III COMPARE trial. Groups of participants with chronic aphasia from the usual care arm of the COMPARE trial were randomized to M-MAT or CIAT-Plus, delivered at the same dose as the COMPARE trial but at lower intensity (6 hours/week × 5 weeks rather than 15 hours/week × 2 weeks). Blinded assessors measured aphasia severity (Western Aphasia Battery-Revised Aphasia Quotient), word retrieval, connected speech, multimodal communication, functional communication, and quality of life immediately post interventions and after 12 weeks. Feasibility and acceptability were explored. Results: Of 70 eligible participants, 77% consented to the trial; 78% of randomized participants completed intervention and 98% of assessment visits were conducted. Fatigue and distress ratings were low with no related withdrawals. Adverse events related to the trial (n = 4) were mild in severity. Statistically significant treatment effects were demonstrated on word retrieval and functional communication and both interventions were equally effective. Conclusions: Low–moderateintensity CIAT-Plus and M-MAT were feasible and acceptable. Both interventions show preliminary efficacy at a low–moderate intensity. These results support a powered trial investigating these interventions at a low–moderate intensity

The Growth and Tumor Suppressors NORE1A and RASSF1A Are Targets for Calpain-Mediated Proteolysis

Background: NORE1A and RASSF1A are growth and tumour suppressors inactivated in a variety of cancers. Methylation of NORE1A and RASSF1A promoters is the predominant mechanism for downregulation of these proteins; however, other mechanisms are likely to exist. Methodology/Principal Findings: Here we describe a proteolysis of NORE1A and RASSF1A by calpains as alternative mechanism of their downregulation. Extracts of H358 cell line, a human bronchoalveolar carcinoma, and H460, a large cell carcinoma, were capable of proteolysis of NORE1A protein in the calpain-dependent manner. Likewise, RASSF1A tumor suppressor was proteolyzed by the H358 cell extract. Addition of calpain inhibitor to H358 and H460 cells growing in tissue culture resulted in re-expression of endogenous NORE1A. A survey of 10 human lung tumours revealed that three of them contain an activity capable of inducing NORE1A degradation. Conclusions/Significance: Thus, degradation by calpains is a novel mechanism for downregulation of NORE1A and RASSF1A proteins and might be the mechanism allowing cancer cells to escape growth suppression

Unnatural Amino Acid Incorporation into Virus-Like Particles

Virus-like particles composed of hepatitis B virus (HBV) or bacteriophage Qβ capsid proteins have been labeled with azide- or alkyne-containing unnatural amino acids by expression in a methionine auxotrophic strain of E. coli. The substitution does not affect the ability of the particles to self-assemble into icosahedral structures indistinguishable from native forms. The azide and alkyne groups were addressed by Cu(I)-catalyzed [3 + 2] cycloaddition: HBV particles were decomposed by the formation of more than 120 triazole linkages per capsid in a location-dependent manner, whereas Qβ suffered no such instability. The marriage of these well-known techniques of sense-codon reassignment and bioorthogonal chemical coupling provides the capability to construct polyvalent particles displaying a wide variety of functional groups with near-perfect control of spacing

Brain microenvironment-driven resistance to immune and targeted therapies in acral melanoma.

BACKGROUND: Combination treatments targeting the MEK-ERK pathway and checkpoint inhibitors have improved overall survival in melanoma. Resistance to treatment especially in the brain remains challenging, and rare disease subtypes such as acral melanoma are not typically included in trials. Here we present analyses from longitudinal sampling of a patient with metastatic acral melanoma that became resistant to successive immune and targeted therapies. METHODS: We performed whole-exome sequencing and RNA sequencing on an acral melanoma that progressed on successive immune (nivolumab) and targeted (dabrafenib) therapy in the brain to identify resistance mechanisms. In addition, we performed growth inhibition assays, reverse phase protein arrays and immunoblotting on patient-derived cell lines using dabrafenib in the presence or absence of cerebrospinal fluid (CSF) in vitro. Patient-derived xenografts were also developed to analyse response to dabrafenib. RESULTS: Immune escape following checkpoint blockade was not due to loss of tumour cell recognition by the immune system or low neoantigen burden, but was associated with distinct changes in the microenvironment. Similarly, resistance to targeted therapy was not associated with acquired mutations but upregulation of the AKT/phospho-inositide 3-kinase pathway in the presence of CSF. CONCLUSION: Heterogeneous tumour interactions within the brain microenvironment enable progression on immune and targeted therapies and should be targeted in salvage treatments

Morphological profiling in human neural progenitor cells classifies hits in a pilot drug screen for Alzheimer's disease

Alzheimer's disease accounts for 60-70% of dementia cases. Current treatments are inadequate and there is a need to develop new approaches to drug discovery. Recently, in cancer, morphological profiling has been used in combination with high-throughput screening of small-molecule libraries in human cells in vitro. To test feasibility of this approach for Alzheimer's disease, we developed a cell morphology-based drug screen centred on the risk gene, SORL1 (which encodes the protein SORLA). Increased Alzheimer's disease risk has been repeatedly linked to variants in SORL1, particularly those conferring loss or decreased expression of SORLA, and lower SORL1 levels are observed in post-mortem brain samples from individuals with Alzheimer's disease. Consistent with its role in the endolysosomal pathway, SORL1 deletion is associated with enlarged endosomes in neural progenitor cells and neurons. We, therefore, hypothesized that multi-parametric, image-based cell phenotyping would identify features characteristic of SORL1 deletion. An automated morphological profiling method (Cell Painting) was adapted to neural progenitor cells and used to determine the phenotypic response of SORL1-/- neural progenitor cells to treatment with compounds from a small internationally approved drug library (TargetMol, 330 compounds). We detected distinct phenotypic signatures for SORL1-/- neural progenitor cells compared to isogenic wild-type controls. Furthermore, we identified 16 compounds (representing 14 drugs) that reversed the mutant morphological signatures in neural progenitor cells derived from three SORL1-/- induced pluripotent stem cell sub-clones. Network pharmacology analysis revealed the 16 compounds belonged to five mechanistic groups: 20S proteasome, aldehyde dehydrogenase, topoisomerase I and II, and DNA synthesis inhibitors. Enrichment analysis identified DNA synthesis/damage/repair, proteases/proteasome and metabolism as key pathways/biological processes. Prediction of novel targets revealed enrichment in pathways associated with neural cell function and Alzheimer's disease. Overall, this work suggests that (i) a quantitative phenotypic metric can distinguish induced pluripotent stem cell-derived SORL1-/- neural progenitor cells from isogenic wild-type controls and (ii) phenotypic screening combined with multi-parametric high-content image analysis is a viable option for drug repurposing and discovery in this human neural cell model of Alzheimer's disease.</p

Influenza nucleoprotein delivered with aluminium salts protects mice from an influenza virus that expresses an altered nucleoprotein sequence

Influenza virus poses a difficult challenge for protective immunity. This virus is adept at altering its surface proteins, the proteins that are the targets of neutralizing antibody. Consequently, each year a new vaccine must be developed to combat the current recirculating strains. A universal influenza vaccine that primes specific memory cells that recognise conserved parts of the virus could prove to be effective against both annual influenza variants and newly emergent potentially pandemic strains. Such a vaccine will have to contain a safe and effective adjuvant that can be used in individuals of all ages. We examine protection from viral challenge in mice vaccinated with the nucleoprotein from the PR8 strain of influenza A, a protein that is highly conserved across viral subtypes. Vaccination with nucleoprotein delivered with a universally used and safe adjuvant, composed of insoluble aluminium salts, provides protection against viruses that either express the same or an altered version of nucleoprotein. This protection correlated with the presence of nucleoprotein specific CD8 T cells in the lungs of infected animals at early time points after infection. In contrast, immunization with NP delivered with alum and the detoxified LPS adjuvant, monophosphoryl lipid A, provided some protection to the homologous viral strain but no protection against infection by influenza expressing a variant nucleoprotein. Together, these data point towards a vaccine solution for all influenza A subtypes