CLEAR - clozapine in early psychosis: study protocol for a multi-centre, randomised controlled trial of clozapine vs other antipsychotics for young people with treatment resistant schizophrenia in real world settings.

BACKGROUND: Clozapine is an antipsychotic drug with unique efficacy, and it is the only recommended treatment for treatment-resistant schizophrenia (TRS: failure to respond to at least two different antipsychotics). However, clozapine is also associated with a range of adverse effects which restrict its use, including blood dyscrasias, for which haematological monitoring is required. As treatment resistance is recognised earlier in the illness, the question of whether clozapine should be prescribed in children and young people is increasingly important. However, most research to date has been in older, chronic patients, and evidence regarding the efficacy and safety of clozapine in people under age 25 is lacking. The CLEAR (CLozapine in EARly psychosis) trial will assess whether clozapine is more effective than treatment as usual (TAU), at the level of clinical symptoms, patient rated outcomes, quality of life and cost-effectiveness in people below 25 years of age. Additionally, a nested biomarker study will investigate the mechanisms of action of clozapine compared to TAU. METHODS AND DESIGN: This is the protocol of a multi-centre, open label, blind-rated, randomised controlled effectiveness trial of clozapine vs TAU (any other oral antipsychotic monotherapy licenced in the British National Formulary) for 12 weeks in 260 children and young people with TRS (12-24 years old). AIM AND OBJECTIVES: The primary outcome is the change in blind-rated Positive and Negative Syndrome Scale scores at 12 weeks from baseline. Secondary outcomes include blind-rated Clinical Global Impression, patient-rated outcomes, quality of life, adverse effects, and treatment adherence. Patients will be followed up for 12 months and will be invited to give consent for longer term follow-up using clinical records and potential re-contact for further research. For mechanism of action, change in brain magnetic resonance imaging (MRI) biomarkers and peripheral inflammatory markers will be measured over 12 weeks. DISCUSSION: The CLEAR trial will contribute knowledge on clozapine effectiveness, safety and cost-effectiveness compared to standard antipsychotics in young people with TRS, and the results may guide future clinical treatment recommendation for early psychosis. TRIAL REGISTRATION: ISRCTN Number: 37176025, IRAS Number: 1004947. TRIAL STATUS: In set-up. Protocol version 4.0 01/08/23. Current up to date protocol available here: https://fundingawards.nihr.ac.uk/award/NIHR131175# /.

Gender Differences in Anticipated but Not Behavioral Confrontation of Heterosexist Comments.

Heterosexist comments are prevalent, but they can be combatted by recognizing and confronting them. Using a 2 (participant gender: woman, man) by 2 (heterosexist comment: gender-policing, sexuality-based) design, we evaluated gender differences in ratings of offensiveness and confrontations of heterosexist comments. In Study 1 (N = 110), participants imagined interacting with a person who made a heterosexist comment. In Study 2 (N = 86), participants interacted in-person with a confederate who made a heterosexist comment. In both studies, non-target (heterosexual) women rated the comments as more offensive as compared to non-target men. Notably, women anticipated confronting with more strength than men (Study 1), but in actuality confronted with similar strength as men (Study 2). We explored perceived perpetrator sexism, beliefs about appearing gay, and prior contact with sexual minorities as potential variables impacting gender differences and predicting confronting. Differences between anticipated and actual confronting are discussed.

Laser-Fabricated 2D Molybdenum Disulfide Electronic Sensor Arrays for Rapid, Low-Cost, Ultrasensitive Detection of Influenza A and SARS-Cov-2.

Multiplex electronic antigen sensors for detection of SARS-Cov-2 spike glycoproteins and hemagglutinin from influenza A are fabricated using scalable processes for straightforward transition to economical mass-production. The sensors utilize the sensitivity and surface chemistry of a 2D MoS2 transducer for attachment of antibody fragments in a conformation favorable for antigen binding with no need for additional linker molecules. To make the devices, ultra-thin layers (3 nm) of amorphous MoS2 are sputtered over pre-patterned metal electrical contacts on a glass chip at room temperature. The amorphous MoS2 is then laser annealed to create an array of semiconducting 2H-MoS2 transducer regions between metal contacts. The semiconducting crystalline MoS2 region is functionalized with monoclonal antibody fragments complementary to either SARS-CoV-2 S1 spike protein or influenza A hemagglutinin. Quartz crystal microbalance experiments indicate strong binding and maintenance of antigen avidity for antibody fragments bound to MoS2. Electrical resistance measurements of sensors exposed to antigen concentrations ranging from 2-20 000 pg mL-1 reveal selective responses. Sensor architecture is adjusted to produce an array of sensors on a single chip suited for detection of analyte concentrations spanning six orders of magnitude from pg mL-1 to µg mL-1.

Templated α-Synuclein Inclusion Formation Is Independent of Endogenous Tau.

Synucleinopathies including Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are characterized by neuronal intracellular inclusions of α-synuclein. PD dementia (PDD) and DLB are collectively the second most common cause of neurodegenerative dementia. In addition to associated inclusions, Lewy body diseases (LBDs) have dopaminergic neurodegeneration, motor defects and cognitive changes. The microtubule-associated protein tau has been implicated in LBDs, but the exact role of the protein and how it influences formation of α-synuclein inclusions is unknown. Reducing endogenous tau levels is protective in multiple models of Alzheimer's disease (AD), tauopathies, and in some transgenic synucleinopathy mouse models. Recombinant α-synuclein and tau proteins interact in vitro Here, we show tau and α-synuclein colocalize at excitatory presynaptic terminals. However, tau heterozygous and tau knock-out mice do not show a reduction in fibril-induced α-synuclein inclusions formation in primary cortical neurons, or after intrastriatal injections of fibrils at 1.5 month or six months later. At six months following intrastriatal injections, wild-type, tau heterozygous and tau knock-out mice showed a 50% reduction in dopamine neurons in the substantia nigra pars compacta (SNc) compared with mice injected with α-synuclein monomer, but there were no statistically significant differences across genotypes. These data suggest the role of tau in the pathogenesis of LBDs is distinct from AD, and Lewy pathology formation may be independent of endogenous tau.

Biofunctionalized Two-dimensional MoS2 Receptors for Rapid Response Modular Electronic SARS-CoV-2 and Influenza A Antigen Sensors

Multiplex electronic antigen sensors for detection of SARS-Cov-2 spike glycoproteins or hemagglutinin from Influenza A in liquid samples with characteristics resembling extracted saliva were fabricated using scalable processes with potential for economical mass-production. The sensors utilize the sensitivity and surface chemistry of a two-dimensional MoS2 transducer for attachment of antibody fragments in a conformation favorable for antigen binding. Ultra-thin layers (3 nm) of amorphous MoS2 were directly sputtered over the entire sensor chip at room temperature and laser annealed to create an array of semiconducting 2H-MoS2 active sensor regions between metal contacts. The semiconducting region was functionalized with monoclonal antibody Fab (fragment antigen binding) fragments derived from whole antibodies complementary to either SARS-CoV-2 S1 spike protein or Influenza A hemagglutinin using a papain digestion to cleave the antibodies at the disulfide hinges. The high affinity for the MoS2 transducer surface with some density of sulfur vacancies for the antibody fragment base promoted chemisorption with antigen binding regions oriented for interaction with the sample. The angiostatin converting enzyme 2 (ACE2) receptor protein for the SARS-CoV-2 spike glycoprotein, was tethered to a hexa-histidine (his6) tag at its c-terminus both for purification purposes, as well as a motif for binding to MoS2. This modified protein was also investigated as a bio-recognition element. Electrical resistance measurements of sensors functionalized with antibody fragments and exposed to antigen concentrations ranging from 2-20,000 picograms per milliliter revealed selective responses in the presence of complementary antigens with sensitivity to SARS-CoV-2 or influenza A on the order of pg/mL and comparable to gold-standard diagnostics such as Polymerase Chain Reaction (PCR) analysis. Lack of antigen sensitivity for the larger ACE2 BRE further demonstrates the utility of the engineered antibody fragment/transducer interface in bringing the target antigen closer to the transducer surface for sensitivity required for early detection viral diagnostics.

Measuring Fidelity to Evidence-Based Practices: Psychometrics.

This special section presents the psychometric properties of fidelity scales used in a national mental health services project in Norway to improve the quality of care of people with psychoses. Across Norway, 39 clinical units in six health trusts participated. The project provided education, implementation support and fidelity assessments. The papers in the section address the psychometrics of fidelity measurement for the specific evidence-based practices: illness management and recovery, family psychoeducation, physical healthcare and antipsychotic medication management. Another paper analyzes the psychometrics of a scale measuring individualization and quality improvement that may be used in conjunction with fidelity scales for specific evidence-based practices. The first paper in the section presents the development and field of fidelity scales, and the two final papers with comments add some additional perspectives and discuss fidelity scales in a wider context. The psychometrics of the five scales were good to excellent. Fidelity assessment is a necessary and effective strategy for quality improvement.

The Family Psychoeducation Fidelity Scale: Psychometric Properties.

This study examined psychometric properties and feasibility of the Family Psychoeducation (FPE) Fidelity Scale. Fidelity assessors conducted reviews using the FPE fidelity scale four times over 18 months at five sites in Norway. After completing fidelity reviews, assessors rated feasibility of the fidelity review process. The FPE fidelity scale showed excellent interrater reliability (.99), interrater item agreement (88%), and internal consistency (mean = .84 across four time points). By the 18-month follow-up, all five sites increased fidelity and three reached adequate fidelity. Fidelity assessors rated feasibility as excellent. The FPE fidelity scale has good psychometric properties and is feasible for evaluating the implementation of FPE programs. Trial registration ClinicalTrials.gov Identifier: NCT03271242.

A core outcome set for future endometriosis research: an international consensus development study.

OBJECTIVE: To develop a core outcome set for endometriosis. DESIGN: Consensus development study. SETTING: International. POPULATION: One hundred and sixteen healthcare professionals, 31 researchers and 206 patient representatives. METHODS: Modified Delphi method and modified nominal group technique. RESULTS: The final core outcome set includes three core outcomes for trials evaluating potential treatments for pain and other symptoms associated with endometriosis: overall pain; improvement in the most troublesome symptom; and quality of life. In addition, eight core outcomes for trials evaluating potential treatments for infertility associated with endometriosis were identified: viable intrauterine pregnancy confirmed by ultrasound; pregnancy loss, including ectopic pregnancy, miscarriage, stillbirth and termination of pregnancy; live birth; time to pregnancy leading to live birth; gestational age at delivery; birthweight; neonatal mortality; and major congenital abnormalities. Two core outcomes applicable to all trials were also identified: adverse events and patient satisfaction with treatment. CONCLUSIONS: Using robust consensus science methods, healthcare professionals, researchers and women with endometriosis have developed a core outcome set to standardise outcome selection, collection and reporting across future randomised controlled trials and systematic reviews evaluating potential treatments for endometriosis. TWEETABLE ABSTRACT: @coreoutcomes for future #endometriosis research have been developed @jamesmnduffy.

Implementation of a Talbot-Lau x-ray deflectometer diagnostic platform for the OMEGA EP laser.

A Talbot-Lau X-ray Deflectometer (TXD) was implemented in the OMEGA EP laser facility to characterize the evolution of an irradiated foil ablation front by mapping electron densities >1022 cm-3 by means of Moiré deflectometry. The experiment used a short-pulse laser (30-100 J, 10 ps) and a foil copper target as an x-ray backlighter source. In the first experimental tests performed to benchmark the diagnostic platform, grating survival was demonstrated and x-ray backlighter laser parameters that deliver Moiré images were described. The necessary modifications to accurately probe the ablation front through TXD using the EP-TXD diagnostic platform are discussed.

Behavioral defects associated with amygdala and cortical dysfunction in mice with seeded α-synuclein inclusions.

Parkinson's disease (PD) is defined by motor symptoms such as tremor at rest, bradykinesia, postural instability, and stiffness. In addition to the classical motor defects that define PD, up to 80% of patients experience cognitive changes and psychiatric disturbances, referred to as PD dementia (PDD). Pathologically, PD is characterized by loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and intracellular inclusions, called Lewy bodies and Lewy neurites, composed mostly of α-synuclein. Much of PD research has focused on the role of α-synuclein aggregates in degeneration of SNpc dopamine neurons because of the impact of loss of striatal dopamine on the classical motor phenotypes. However, abundant Lewy pathology is also found in other brain regions including the cortex and limbic brain regions such as the amygdala, which may contribute to non-motor phenotypes. Little is known about the consequences of α-synuclein inclusions in these brain regions, or in neuronal subtypes other than dopamine neurons. This project expands knowledge on how α-synuclein inclusions disrupt behavior, specifically non-motor symptoms of synucleinopathies. We show that bilateral injections of fibrils into the striatum results in robust bilateral α-synuclein inclusion formation in the cortex and amygdala. Inclusions in the amygdala and prefrontal cortex primarily localize to excitatory neurons, but unbiased stereology shows no significant loss of neurons in the amygdala or cortex. Fibril injected mice show defects in a social dominance behavioral task and fear conditioning, tasks that are associated with prefrontal cortex and amygdala function. Together, these observations suggest that seeded α-synuclein inclusion formation impairs behaviors associated with cortical and amygdala function, without causing cell loss, in brain areas that may play important roles in the complex cognitive features of PDD.

Strategies for PET imaging of the receptor for advanced glycation endproducts (RAGE) / 药物分析学报

The implication of the receptor for advanced glycation end-products (RAGE) in numerous diseases and neurodegenerative disorders makes it interesting both as a therapeutic target and as an inflammatory biomarker. In the context of investigating RAGE as a biomarker, there is interest in developing radio-tracers that will enable quantification of RAGE using positron emission tomography (PET) imaging. We have synthesized potential small molecule radiotracers for both the intracellular ([18F]InRAGER) and extracellular ([18F]RAGER) domains of RAGE. Herein we report preclinical evaluation of both using in vitro (lead panel screens) and in vivo (rodent and nonhuman primate PET imaging) methods. Both radiotracers have high affinity for RAGE and show good brain uptake, but suffer from off-target binding. The source of the off-target PET signal is not attributable to binding to melatonin receptors, but remains unexplained. We have also investigated use of lipopolysaccharide (LPS)-treated mice as a possible animal model with upregulated RAGE for evaluation of new imaging agents. Immunoreactivity of the mouse brain sections revealed increases in RAGE in the male cohorts, but no difference in the female groups. However, it proves challenging to quantify the changes in RAGE due to off-target binding of the radio-tracers. Nevertheless, they are appropriate lead scaffolds for future development of 2nd generation RAGE PET radiotracers because of their high affinity for the receptor and good CNS penetration.

Magnetized Disruption of Inertially Confined Plasma Flows.

The creation and disruption of inertially collimated plasma flows are investigated through experiment, simulation, and analytical modeling. Supersonic plasma jets are generated by laser-irradiated plastic cones and characterized by optical interferometry measurements. Targets are magnetized with a tunable B field with strengths of up to 5 T directed along the axis of jet propagation. These experiments demonstrate a hitherto unobserved phenomenon in the laboratory, the magnetic disruption of inertially confined plasma jets. This occurs due to flux compression on axis during jet formation and can be described using a Lagrangian-cylinder model of plasma evolution implementing finite resistivity. The basic physical mechanisms driving the dynamics of these systems are described by this model and then compared with two-dimensional radiation-magnetohydrodynamic simulations. Experimental, computational, and analytical results discussed herein suggest that contemporary models underestimate the electrical conductivity necessary to drive the amount of flux compression needed to explain observations of jet disruption.

Defining α-synuclein species responsible for Parkinson's disease phenotypes in mice.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by fibrillar neuronal inclusions composed of aggregated α-synuclein (α-syn). These inclusions are associated with behavioral and pathological PD phenotypes. One strategy for therapeutic interventions is to prevent the formation of these inclusions to halt disease progression. α-Synuclein exists in multiple structural forms, including disordered, nonamyloid oligomers, ordered amyloid oligomers, and fibrils. It is critical to understand which conformers contribute to specific PD phenotypes. Here, we utilized a mouse model to explore the pathological effects of stable ß-amyloid-sheet oligomers compared with those of fibrillar α-synuclein. We biophysically characterized these species with transmission EM, atomic-force microscopy, CD spectroscopy, FTIR spectroscopy, analytical ultracentrifugation, and thioflavin T assays. We then injected these different α-synuclein forms into the mouse striatum to determine their ability to induce PD-related phenotypes. We found that ß-sheet oligomers produce a small but significant loss of dopamine neurons in the substantia nigra pars compacta (SNc). Injection of small ß-sheet fibril fragments, however, produced the most robust phenotypes, including reduction of striatal dopamine terminals, SNc loss of dopamine neurons, and motor-behavior defects. We conclude that although the ß-sheet oligomers cause some toxicity, the potent effects of the short fibrillar fragments can be attributed to their ability to recruit monomeric α-synuclein and spread in vivo and hence contribute to the development of PD-like phenotypes. These results suggest that strategies to reduce the formation and propagation of ß-sheet fibrillar species could be an important route for therapeutic intervention in PD and related disorders.

Development of a backlit-multi-pinhole radiography source.

Backlit-pinhole radiography uses a pinhole placed between an x-ray source and a sample. The backlit-multi-pinhole design uses two pinholes on the same substrate, which are separated by a wall, to create two radiographic images projected along similar axes. The wall, a 100-µm thick titanium foil, prevents x-rays generated near one pinhole from exiting the other pinhole. First results indicate that the multi-pinhole target can create two independent radiographs along similar axes. The images are recorded 2 ns apart. Details of our multi-pinhole design and our first results are discussed.

Experimental considerations to observe two ionizing fronts in systems with a sharp absorption edge.

This paper examines the experimental requirements to observe two shock fronts driven by a single x-ray source in systems with a sharp absorption edge. We consider systems where the peak of the x-ray radiation drive coincides with the K-edge of the carbon, which occurs at a photon energy of 284 eV, causing photons to be deposited in two regions. The low-energy photons (E < 284 eV) penetrate further and drive the main shock, while the higher-energy photons (E > 284 eV) are absorbed in the ablated plasma. These higher-energy photons create an ionization front, which then produces a second shock, termed an edge-shock. Using a different radiation-hydrodynamics code and different opacity and equation of state tables, we replicate the previous work and build upon them to explore the conditions required to form the edge shock. We find that having the material K-edge coincide with the spectral domain of the radiation source is necessary but not sufficient on its own to drive the edge-shock.

Diet Supplementation with Soy Protein Isolate, but Not the Isoflavone Genistein, Protects Against Alcohol-Induced Tumor Progression in DEN-Treated Male Mice.

Diethylnitrosamine-treated male mice were assigned to 4 groups: a casein-based 35% high fat ethanol liquid diet (EtOH), an EtOH diet made with soy protein isolate protein (EtOH/SOY), an EtOH liquid diet supplemented with genistein (EtOH/GEN) and a chow group. EtOH feeding, final concentration 5% (v/v), continued for 16 wks. EtOH increased incidence and multiplicity of basophilic lesions and adenomas compared to the chow group, (p < 0.05). The EtOH/SOY group had reduced adenoma progression when compared to the EtOH and EtOH/GEN group, (p < 0.05). Genistein supplementation had no protective effect. Soy feeding significantly reduced serum ALT concentrations (p < 0.05), decreased hepatic TNFα and CD-14 expression and decreased nuclear accumulation of NFκB protein in EtOH/SOY-treated mice compared to the EtOH group (p < 0.05). With respect to ceramides, high resolution MALDI-FTICR Imaging mass spectrometry revealed changes in the accumulation of long acyl chain ceramide species, in particular C18, in the EtOH group when compared to the EtOH/SOY group. Additionally, expression of acid ceramidase and sphingosine kinase 1 which degrade ceramide into sphingosine and convert sphingosine to sphingosine-1-phosphate (S1P) respectively and expression of S1P receptors S1PR2 and S1PR3 were all upregulated by EtOH and suppressed in the EtOH/SOY group, p < 0.05. EtOH feeding also increased hepatocyte proliferation and mRNA expression of ß-catenin targets, including cyclin D1, MMP7 and glutamine synthase, which were reduced in the EtOH/SOY group, p < 0.05. These findings suggest that soy prevents tumorigenesis by reducing inflammation and by reducing hepatocyte proliferation through inhibition of EtOH-mediated ß-catenin signaling. These mechanisms may involve blockade of sphingolipid signaling.

Femtosecond laser damage of germanium from near- to mid-infrared wavelengths.

Femtosecond laser-induced damage and ablation (fs-LIDA) is a rich field in extreme non-perturbative nonlinear optics with wide ranging applications, including laser micro- and nano-machining, waveguide writing, and eye surgery. Our understanding of fs-LIDA, however, is limited mostly to visible and near-infrared wavelengths. In this work, we systematically study single-shot, fs-laser ablation (fs-LIA) of single-crystal germanium from near- to mid-infrared wavelengths, and compare the fs-LIA wavelength scaling with two widely used models. We show that these models are inadequate, particularly at mid-infrared wavelengths. Instead, a hybrid model is proposed involving Keldysh ionization rates, a constant free-carrier density threshold, and multi-band effects, which yields good agreement with experimental observations. Aspects of this model may be applied to understanding other strong-field non-perturbative phenomena in solids.

How high energy fluxes may affect Rayleigh-Taylor instability growth in young supernova remnants.

Energy-transport effects can alter the structure that develops as a supernova evolves into a supernova remnant. The Rayleigh-Taylor instability is thought to produce structure at the interface between the stellar ejecta and the circumstellar matter, based on simple models and hydrodynamic simulations. Here we report experimental results from the National Ignition Facility to explore how large energy fluxes, which are present in supernovae, affect this structure. We observed a reduction in Rayleigh-Taylor growth. In analyzing the comparison with supernova SN1993J, a Type II supernova, we found that the energy fluxes produced by heat conduction appear to be larger than the radiative energy fluxes, and large enough to have dramatic consequences. No reported astrophysical simulations have included radiation and heat conduction self-consistently in modeling supernova remnants and these dynamics should be noted in the understanding of young supernova remnants.

An allogeneic 'off the shelf' therapeutic strategy for peripheral nerve tissue engineering using clinical grade human neural stem cells.

Artificial tissues constructed from therapeutic cells offer a promising approach for improving the treatment of severe peripheral nerve injuries. In this study the effectiveness of using CTX0E03, a conditionally immortalised human neural stem cell line, as a source of allogeneic cells for constructing living artificial nerve repair tissue was tested. CTX0E03 cells were differentiated then combined with collagen to form engineered neural tissue (EngNT-CTX), stable aligned sheets of cellular hydrogel. EngNT-CTX sheets were delivered within collagen tubes to repair a 12 mm sciatic nerve injury model in athymic nude rats. Autologous nerve grafts (autografts) and empty tubes were used for comparison. After 8 weeks functional repair was assessed using electrophysiology. Further, detailed histological and electron microscopic analysis of the repaired nerves was performed. Results indicated that EngNT-CTX supported growth of neurites and vasculature through the injury site and facilitated reinnervation of the target muscle. These findings indicate for the first time that a clinically validated allogeneic neural stem cell line can be used to construct EngNT. This provides a potential 'off the shelf' tissue engineering solution for the treatment of nerve injury, overcoming the limitations associated with nerve autografts or the reliance on autologous cells for populating repair constructs.