The pain trajectory of juvenile idiopathic arthritis (JIA): translating from adolescent patient report to behavioural sensitivity in a juvenile animal model

Background: While pain is a common symptom in JIA patients, it remains unclear why some JIA patients develop ongoing or persistent pain. Complex clinical and social settings confound analysis of individual factors that may contribute to this pain. To address this, we first undertook a retrospective analysis of pain reports in a JIA patient cohort with the aim of identifying potential factors contributing to persistent pain. We then carried out an experimental laboratory study, using joint inflammatory pain behaviour in rodents, to validate the role of these factors in the onset of persistent pain under controlled conditions. Methods: Patients: Retrospective analysis of anonymised pain visual analogue scale (VAS) scores and accompanying clinical scores from 97 JIA patients aged 13–19 (mean: 16.40 ± 1.21) collected over 50 weeks. Rats: Experimental study of pain behaviour following intra-articular microinjection of complete Freund’s adjuvant (CFA) in adolescents (n = 25) and young adults (n = 43). Some animals (n = 21) had been previously exposed to joint inflammation in infancy or adolescence. Results: Patients: Cluster analysis of patient pain VAS scores revealed three trajectories over 50 weeks: consistently low pain (n = 45), variable pain (n = 30) and persistently high pain (n = 22). Number of actively inflamed joints did not differ in the three groups. High pain at a single visit correlated with greater physician global assessment of disease activity, while a high pain trajectory over 50 weeks was associated with more limited joints but fewer actively inflamed joints. Rats: Rodents administered ankle joint CFA also exhibit low, medium and high joint pain sensitivities, independent of joint inflammation. Prolonged inflammatory pain behaviour was associated with high background pain sensitivity, following joint inflammation at an earlier stage in life. Conclusions: Both JIA patients and rodents differ in their individual pain sensitivity independent of the concurrent joint inflammation. Using experimental animal models allows us to isolate physiological factors underlying these differences, independently of social or clinical factors. The results suggest that a history of prior arthritic activity/joint inflammation may contribute to high pain sensitivity in adolescents with JIA

Glyceryl trinitrate for the treatment of ischaemic stroke: Determining efficacy in rodent and ovine species for enhanced clinical translation

Hypertension is a leading risk factor for death and dependency after ischaemic stroke. However, administering anti-hypertensive medications post-stroke remains contentious with concerns regarding deleterious effects on cerebral blood flow and infarct expansion. This study sought to determine the effect of glyceryl trinitrate (GTN) treatment in both lissencephalic and gyrencephalic pre-clinical stroke models. Merino sheep underwent middle cerebral artery occlusion (MCAO) followed by GTN or control patch administration (0.2 mg/h). Monitoring of numerous physiologically relevant measures over 24 h showed that GTN administration was associated with decreased intracranial pressure, infarct volume, cerebral oedema and midline shift compared to vehicle treatment (p ≤ 0.05). No significant changes in blood pressure or cerebral perfusion pressure were observed. Using optical imaging spectroscopy and laser speckle imaging, the effect of varying doses of GTN (0.69–50 µg/h) on cerebral blood flow and tissue oxygenation was examined in mice. No consistent effect was found. Additional mice undergoing MCAO followed by GTN administration (doses varying from 0–60 µg/h) also showed no improvement in infarct volume or neurological score within 24 h post-stroke. GTN administration significantly improved numerous stroke-related physiological outcomes in sheep but was ineffective in mice. This suggests that, whilst GTN administration could potentially benefit patients, further research into mechanisms of action are required

Antitumor activity in RAS-driven tumors by blocking AKT and MEK.

PURPOSE: KRAS is the most commonly mutated oncogene in human tumors. KRAS-mutant cells may exhibit resistance to the allosteric MEK1/2 inhibitor selumetinib (AZD6244; ARRY-142886) and allosteric AKT inhibitors (such as MK-2206), the combination of which may overcome resistance to both monotherapies. EXPERIMENTAL DESIGN: We conducted a dose/schedule-finding study evaluating MK-2206 and selumetinib in patients with advanced treatment-refractory solid tumors. Recommended dosing schedules were defined as MK-2206 at 135 mg weekly and selumetinib at 100 mg once daily. RESULTS: Grade 3 rash was the most common dose-limiting toxicity (DLT); other DLTs included grade 4 lipase increase, grade 3 stomatitis, diarrhea, and fatigue, and grade 3 and grade 2 retinal pigment epithelium detachment. There were no meaningful pharmacokinetic drug-drug interactions. Clinical antitumor activity included RECIST 1.0-confirmed partial responses in non-small cell lung cancer and low-grade ovarian carcinoma. CONCLUSION: Responses in KRAS-mutant cancers were generally durable. Clinical cotargeting of MEK and AKT signaling may be an important therapeutic strategy in KRAS-driven human malignancies (Trial NCT number NCT01021748).The Drug Development Unit of the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research is supported in part by a programme grant from Cancer Research UK (grant number: C347/A18077). Support was also provided by an Experimental Cancer Medicine Centre grant (no grant number) and the National Institute for Health Research Biomedical Research Centre (jointly to the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research) (grant numbers: A46/CCR - CCR4057 & CCR4058).This is the accepted manuscript of a paper published in Clinical Cancer Research, February 15, 2015 21; 739, doi: 10.1158/1078-0432.CCR-14-190

A pilot of the feasibility and usefulness of an aged obese model for use in stroke research

Background: Animal models of stroke have been criticised as having poor predictive validity, lacking risk factors prevalent in an aging population. This pilot study examined the development of comorbidities in a combined aged and high-fat diet model, and then examined the feasibility of modelling stroke in such rats. Methods: Twelve-month old male Wistar-Han rats (n=15) were fed a 60% fat diet for 8 months during which monthly serial blood samples were taken to assess the development of metabolic syndrome and pro-inflammatory markers. Following this, to pilot the suitability of these rats for undergoing surgical models of stroke, they underwent 30min of middle cerebral artery occlusion (MCAO) alongside younger controls fed a standard diet (n=10). Survival, weight and functional outcome were monitored, and blood vessels and tissues collected for analysis. Results: A high fat diet in aged rats led to substantial obesity. These rats did not develop type 2 diabetes or hypertension. There was thickening of the thoracic arterial wall and vacuole formation in the liver; but of the cytokines examined changes were not seen. MCAO surgery and behavioural assessment was possible in this model (with some caveats discussed in manuscript). Conclusions: This study shows MCAO is possible in aged, obese rats. However, this model is not ideal for recapitulating the complex comorbidities commonly seen in stroke patients

Teleophthalmology-enabled and artificial intelligence-ready referral pathway for community optometry referrals of retinal disease (HERMES): a Cluster Randomised Superiority Trial with a linked Diagnostic Accuracy Study-HERMES study report 1-study protocol

INTRODUCTION: Recent years have witnessed an upsurge of demand in eye care services in the UK. With a large proportion of patients referred to Hospital Eye Services (HES) for diagnostics and disease management, the referral process results in unnecessary referrals from erroneous diagnoses and delays in access to appropriate treatment. A potential solution is a teleophthalmology digital referral pathway linking community optometry and HES. METHODS AND ANALYSIS: The HERMES study (Teleophthalmology-enabled and artificial intelligence-ready referral pathway for community optometry referrals of retinal disease: a cluster randomised superiority trial with a linked diagnostic accuracy study) is a cluster randomised clinical trial for evaluating the effectiveness of a teleophthalmology referral pathway between community optometry and HES for retinal diseases. Nested within HERMES is a diagnostic accuracy study, which assesses the accuracy of an artificial intelligence (AI) decision support system (DSS) for automated diagnosis and referral recommendation. A postimplementation, observational substudy, a within-trial economic evaluation and discrete choice experiment will assess the feasibility of implementation of both digital technologies within a real-life setting. Patients with a suspicion of retinal disease, undergoing eye examination and optical coherence tomography (OCT) scans, will be recruited across 24 optometry practices in the UK. Optometry practices will be randomised to standard care or teleophthalmology. The primary outcome is the proportion of false-positive referrals (unnecessary HES visits) in the current referral pathway compared with the teleophthalmology referral pathway. OCT scans will be interpreted by the AI DSS, which provides a diagnosis and referral decision and the primary outcome for the AI diagnostic study is diagnostic accuracy of the referral decision made by the Moorfields-DeepMind AI system. Secondary outcomes relate to inappropriate referral rate, cost-effectiveness analyses and human-computer interaction (HCI) analyses. ETHICS AND DISSEMINATION: Ethical approval was obtained from the London-Bromley Research Ethics Committee (REC 20/LO/1299). Findings will be reported through academic journals in ophthalmology, health services research and HCI. TRIAL REGISTRATION NUMBER: ISRCTN18106677 (protocol V.1.1)

Bioreactors as engineering support to treat cardiac muscle and vascular disease

Cardiovascular disease is the leading cause of morbidity and mortality in the Western World. The inability of fully differentiated, load-bearing cardiovascular tissues to in vivo regenerate and the limitations of the current treatment therapies greatly motivate the efforts of cardiovascular tissue engineering to become an effective clinical strategy for injured heart and vessels. For the effective production of organized and functional cardiovascular engineered constructs in vitro, a suitable dynamic environment is essential, and can be achieved and maintained within bioreactors. Bioreactors are technological devices that, while monitoring and controlling the culture environment and stimulating the construct, attempt to mimic the physiological milieu. In this study, a review of the current state of the art of bioreactor solutions for cardiovascular tissue engineering is presented, with emphasis on bioreactors and biophysical stimuli adopted for investigating the mechanisms influencing cardiovascular tissue development, and for eventually generating suitable cardiovascular tissue replacements

Shattered pellet injection experiments at JET in support of the ITER disruption mitigation system design

A series of experiments have been executed at JET to assess the efficacy of the newly installed shattered pellet injection (SPI) system in mitigating the effects of disruptions. Issues, important for the ITER disruption mitigation system, such as thermal load mitigation, avoidance of runaway electron (RE) formation, radiation asymmetries during thermal quench mitigation, electromagnetic load control and RE energy dissipation have been addressed over a large parameter range. The efficiency of the mitigation has been examined for the various SPI injection strategies. The paper summarises the results from these JET SPI experiments and discusses their implications for the ITER disruption mitigation scheme

New H-mode regimes with small ELMs and high thermal confinement in the Joint European Torus

New H-mode regimes with high confinement, low core impurity accumulation, and small edge-localized mode perturbations have been obtained in magnetically confined plasmas at the Joint European Torus tokamak. Such regimes are achieved by means of optimized particle fueling conditions at high input power, current, and magnetic field, which lead to a self-organized state with a strong increase in rotation and ion temperature and a decrease in the edge density. An interplay between core and edge plasma regions leads to reduced turbulence levels and outward impurity convection. These results pave the way to an attractive alternative to the standard plasmas considered for fusion energy generation in a tokamak with a metallic wall environment such as the ones expected in ITER.& nbsp;Published under an exclusive license by AIP Publishing

Overview of JET results for optimising ITER operation

The JET 2019–2020 scientific and technological programme exploited the results of years of concerted scientific and engineering work, including the ITER-like wall (ILW: Be wall and W divertor) installed in 2010, improved diagnostic capabilities now fully available, a major neutral beam injection upgrade providing record power in 2019–2020, and tested the technical and procedural preparation for safe operation with tritium. Research along three complementary axes yielded a wealth of new results. Firstly, the JET plasma programme delivered scenarios suitable for high fusion power and alpha particle (α) physics in the coming D–T campaign (DTE2), with record sustained neutron rates, as well as plasmas for clarifying the impact of isotope mass on plasma core, edge and plasma-wall interactions, and for ITER pre-fusion power operation. The efficacy of the newly installed shattered pellet injector for mitigating disruption forces and runaway electrons was demonstrated. Secondly, research on the consequences of long-term exposure to JET-ILW plasma was completed, with emphasis on wall damage and fuel retention, and with analyses of wall materials and dust particles that will help validate assumptions and codes for design and operation of ITER and DEMO. Thirdly, the nuclear technology programme aiming to deliver maximum technological return from operations in D, T and D–T benefited from the highest D–D neutron yield in years, securing results for validating radiation transport and activation codes, and nuclear data for ITER