Assessing TCR identity, knock-in efficiency, and potency for individualized TCR-T cell therapy.

Advances in mass spectrometry, genome sequencing techniques, and bioinformatic strategies have accelerated the discovery of cancer-specific neoantigens. Tumors express multiple immunogenic neoantigens, and neoantigen-specific T cell receptors (TCRs) can be identified in peripheral blood's mononuclear cells in cancer patients. Therefore, individualized TCR-based therapies are a promising approach whereby multiple neoantigen-specific TCRs can be selected in each patient, potentially leading to a highly effective treatment for cancer patients. We developed three multiplex analytical assays to determine the quality attributes of the TCR-T cell drug product with a mixture of five engineered TCRs. The identity of each TCR was determined by two NGS-based methods, Illumina MiSeq and PacBio platforms. This approach not only confirms the expected TCR sequences but also differentiates them by their variable regions. The five individual TCR and total TCR knock-in efficiencies were measured by droplet digital PCR using specific reverse primers. A potency assay based on transfection of antigen-encoding-RNA was developed to assess the dose-dependent activation of T cells for each TCR by measuring the surface activation marker CD137 expression and cytokine secretion. This work provides new assays to characterize individualized TCR-T cell products and insights into quality attributes for the control strategy.

Surveillance, Diversity and Vegetative Compatibility Groups of Fusarium oxysporum f. sp. vasinfectum Collected in Cotton Fields in Australia (2017 to 2022)

Cotton (Gossypium hirsutum) is a billion-dollar crop in regional New South Wales (NSW) and Queensland, Australia. Fusarium wilt (FW) caused by Fusarium oxysporum f. sp. vasinfectum (Fov) is an economically important disease. Initial disease losses of up to 90% when the disease was first detected resulted in fields being taken out of cotton production. The disease is now well-managed due to the adoption of highly resistant varieties. However, annual disease surveys recently revealed that the disease dynamic has changed in the past few seasons. With relatively mild and wet weather conditions during the 2021/22 growing season, FW was detected in eight surveyed valleys in NSW and Queensland, with the disease incidence as high as 44.5% and 98.5% in individual fields in early and late seasons, respectively. Fov is genetically distinct and evolved from local Fusarium oxysporum strains. Additionally, the pathogen was reported to evolve rapidly under continuous cotton cropping pressure. However, our knowledge of the genetic composition of the prevailing population is limited. Sequences of the translation elongation factor alpha 1 (TEF1) revealed that 94% of Fusarium isolates recovered from FW-infected cotton were clustered together with known Australian Fov and relatively distant related to overseas Fov races. All these isolates, except for nine, were further confirmed positive with a specific marker based on the Secreted in Xylem 6 (SIX6) effector gene. Vegetative compatibility group (VCG) analyses of 166 arbitrarily selected isolates revealed a predominance of VCG01111. There was only one detection of VCG01112 in the Border Rivers valley where it was first described. In this study, the exotic Californian Fov race 4 strain was not detected using a specific marker based on the unique Tfo1 insertion in the phosphate (PHO) gene. This study indicated that the prevalence and abundance of Fov across NSW and Queensland in the past five seasons was probably independent of its genetic diversity.

An automated feeding system for the African killifish reveals the impact of diet on lifespan and allows scalable assessment of associative learning.

The African turquoise killifish is an exciting new vertebrate model for aging studies. A significant challenge for any model organism is the control over its diet in space and time. To address this challenge, we created an automated and networked fish feeding system. Our automated feeder is designed to be open-source, easily transferable, and built from widely available components. Compared to manual feeding, our automated system is highly precise and flexible. As a proof of concept for the feeding flexibility of these automated feeders, we define a favorable regimen for growth and fertility for the African killifish and a dietary restriction regimen where both feeding time and quantity are reduced. We show that this dietary restriction regimen extends lifespan in males (but not in females) and impacts the transcriptomes of killifish livers in a sex-specific manner. Moreover, combining our automated feeding system with a video camera, we establish a quantitative associative learning assay to provide an integrative measure of cognitive performance for the killifish. The ability to precisely control food delivery in the killifish opens new areas to assess lifespan and cognitive behavior dynamics and to screen for dietary interventions and drugs in a scalable manner previously impossible with traditional vertebrate model organisms.

Long-Term Outcomes of Elderly Patients Managed Without Early Cholecystectomy After Endoscopic Retrograde Cholangiopancreatography and Sphincterotomy for Choledocholithiasis.

Background Prophylactic cholecystectomy following endoscopic retrograde cholangiopancreatography with sphincterotomy (ERCP-S) remains the gold standard management of choledocholithiasis. Some clinicians propose ERCP-S alone as the definitive management in the elderly, given perioperative complication risks. This retrospective cohort study aimed to assess the long-term efficacy and safety of non-operative management of choledocholithiasis in adults aged ≥70. Methodology A total of 252 patients aged ≥70 underwent ERCP from 2004 to 2014 at a single institution. The rates of cholecystectomy, ERCP, complications, and mortality were gathered. Data were linked to a provincial health database to capture follow-up visits to alternate hospitals. Predictors of operation, recurrence, and mortality were analyzed using multivariable regression. Results Following ERCP, of the 252 patients, 33 (13.1%) underwent prophylactic cholecystectomy within three months, while 219 (86.9%) were initially managed conservatively. Of the 219 patients, 147 (67.1%) experienced no further choledocholithiasis after conservative management, while 23 (10.5%) patients underwent cholecystectomy. The mean follow-up was 2.9 years. Delayed operative patients were younger (mean age: 77.56 vs. 82.90; p < 0.001) and had lower Charlson Comorbidity Index (CCI) (1.04 vs. 1.84; p = 0.030). When adjusted for age, CCI score, and sex, cholecystectomy was associated with increased survival, with an odds ratio of 0.48 (95% confidence interval = 0.26-0.90; p = 0.021). Perioperative complications occurred in 7/56 (12.5%) patients. Conclusions Recurrent choledocholithiasis is common in elderly patients. Despite recurrent symptoms, these patients are unlikely to undergo cholecystectomy. Surgeons operate on patients with greater life expectancy and fewer comorbidities with high success despite advanced patient age. Future prospective studies should examine objective criteria for prophylactic cholecystectomy in this population, given purported safety and benefits.

SeMSA: a compact super absorber optimised for broadband, low-frequency noise attenuation.

The attenuation of low-frequency broadband noise in a light, small form-factor is an intractable challenge. In this paper, a new technology is presented which employs the highly efficient visco-thermal loss mechanism of a micro-perforated plate (MPP) and successfully lowers its frequency response by combining it with decorated membrane resonators (DMR). Absorption comes from the membranes but primarily from the MPP, as the motion of the two membranes causes a pressure differential across the MPP creating airflow through the perforations. This combination of DMR and MPP has led to the Segmented Membrane Sound Absorber (SeMSA) design, which is extremely effective at low-frequency broadband sound absorption and which can achieve this at deep sub-wavelength thicknesses. The technology is compared to other absorbers to be found in the literature and the SeMSA outperforms them all in either the 20-1000 Hz or 20-1200 Hz range for depths of up to 120 mm. This was verified through analytical, finite element and experimental analyses.

Cell-Type-Specific Metabolic Profiling Achieved by Combining Desorption Electrospray Ionization Mass Spectrometry Imaging and Immunofluorescence Staining.

Cell-type-specific metabolic profiling in tissue with heterogeneous composition has been of great interest across all mass spectrometry imaging (MSI) technologies. We report here a powerful new chemical imaging capability in desorption electrospray ionization (DESI) MSI, which enables cell-type-specific and in situ metabolic profiling in complex tissue samples. We accomplish this by combining DESI-MSI with immunofluorescence staining using specific cell-type markers. We take advantage of the variable frequency of each distinct cell type in the lateral septal nucleus (LSN) region of mouse forebrain. This allows computational deconvolution of the cell-type-specific metabolic profile in neurons and astrocytes by convex optimization-a machine learning method. Based on our approach, we observed 107 metabolites that show different distributions and intensities between astrocytes and neurons. We subsequently identified 23 metabolites using high-resolution mass spectrometry (MS) and tandem MS, which include small metabolites such as adenosine and N-acetylaspartate previously associated with astrocytes and neurons, respectively, as well as accumulation of several phospholipid species in neurons which have not been studied before. Overall, this method overcomes the relatively low spatial resolution of DESI-MSI and provides a new platform for in situ metabolic investigation at the cell-type level in complex tissue samples with heterogeneous cell-type composition.

The self-perceived role of sedation-trained dental nurses within a Community Dental Service: a qualitative study.

Background Dental nurses trained in assisting with relative analgesia with nitrous oxide (RA) play an important role in patient care. Provision of RA is a service provided in the Community Dental Service based in Doncaster, Barnsley and Rotherham.Aim To explore how sedation-trained dental nurses perceive their role within a Community Dental Service, and to explore what motivates them and how they feel changes could enhance the provision of care.Methods Twelve nurses who had experience of assisting with RA for at least one year in three community clinics in a South Yorkshire-based Community Dental Service were recruited and undertook a semi-structured interview. All interviews were transcribed verbatim and subsequent thematic analysis of the manuscripts was undertaken.Results Five major themes were identified: 1) motivation; 2) role; 3) training and continuing professional development; 4) pressures on the service; and 5) service enhancements.Conclusion Within this qualitative study, the dental nurses perceived that they had a crucial role in patient and parent behavioural management and keeping the patient safe during treatment. Helping patients to accept planned dental treatment gave them significant job satisfaction. Overall, this study has shown that they feel that they have a crucial role in assisting with RA treatment.

Tocilizumab in patients with anti-TNF refractory juvenile idiopathic arthritis-associated uveitis (APTITUDE): a multicentre, single-arm, phase 2 trial.

BACKGROUND: Uveitis associated with juvenile idiopathic arthritis is a cause of major ocular morbidity. A substantial proportion of children are refractory to systemic methotrexate and TNF inhibitors. Our aim was to study the safety and efficacy of tocilizumab in children with juvenile idiopathic arthritis-associated uveitis refractory to both methotrexate and TNF inhibitors. METHODS: This multicentre, single-arm, phase 2 trial was done following a Simon's two-stage design at seven tertiary hospital sites in the UK. Patients aged 2-18 years with active juvenile idiopathic arthritis-associated uveitis were eligible. All patients had been on a stable dose of methotrexate for at least 12 weeks and had not responded to treatment with a TNF inhibitor. Patients weighing 30 kg or more were treated with 162 mg subcutaneous tocilizumab every 2 weeks for 24 weeks, and participants weighing less than 30 kg were treated with 162 mg every 3 weeks for 24 weeks. The primary outcome was treatment response defined as a two-step decrease, or decrease to zero, from baseline in the level of inflammation (anterior chamber cells) at week 12, per the standardisation of uveitis nomenclature criteria. A phase 3 trial would be justified if more than seven patients responded to treatment. An interim analysis was planned to assess whether the trial would be stopped for futility, with futility defined as two or fewer treatment responses among ten participants. Adverse events were collected up to 30 calendar days after treatment cessation. The primary analysis was done in the intention-to-treat population and the safety analysis was done in all patients who started the treatment. This trial is registered with the International Standard Randomised Controlled Trial Number registry (ISRCTN95363507) and EU Clinical Trials Register (EudraCT 2015-001323-23). FINDINGS: 22 participants were enrolled to the trial between Dec 3, 2015, and March 9, 2018, and 21 participants received treatment. One participant was found to be ineligible immediately after enrolment and was therefore withdrawn. Seven of 21 (median unbiased estimate of proportion 34% [95% CI 25-57]) responded to treatment (p=0·11). Safety results were consistent with the known safety profile of tocilizumab. INTERPRETATION: The primary endpoint was not met, and thus the results do not support a phase 3 trial of tocilizumab in patients with juvenile idiopathic arthritis-associated uveitis. Importantly, data on the use of tocilizumab in clinical practice is now captured in national registries. Despite this trial not meeting the threshold required to justify a larger phase 3 trial, several patients responded to treatment; as such, tocilzumab might still be a therapeutic option in some children with uveitis refractory to anti-TNF drugs, given the absence of other treatment options. FUNDING: Versus Arthritis and the National Institute for Health Research Clinical Research Network: Children.

Use of routinely collected data in a UK cohort of publicly funded randomised clinical trials.

Routinely collected data about health in medical records, registries and hospital activity statistics is now routinely collected in an electronic form. The extent to which such sources of data are now being routinely accessed to deliver efficient clinical trials, is unclear. The aim of this study was to ascertain current practice amongst a United Kingdom (UK) cohort of recently funded and ongoing randomised controlled trials (RCTs) in relation to sources and use of routinely collected outcome data. Recently funded and ongoing RCTs were identified for inclusion by searching the National Institute for Health Research journals library. Trials that have a protocol available were assessed for inclusion and those that use or plan to use routinely collected health data (RCHD) for at least one outcome were included. RCHD sources and outcome information were extracted. Of 216 RCTs, 102 (47%) planned to use RCHD. A RCHD source was the sole source of outcome data for at least one outcome in 46 (45%) of those 102 trials. The most frequent sources are Hospital Episode Statistics (HES) and Office for National Statistics (ONS), with the most common outcome data to be extracted being on mortality, hospital admission, and health service resource use. Our study has found that around half of publicly funded trials in a UK cohort (NIHR HTA funded trials that had a protocol available) plan to collect outcome data from routinely collected data sources.

Epidemiology, clinical treatment patterns, and survival of hepatocellular carcinoma in Manitoba.

Background: Hepatocellular carcinoma (HCC) has a very poor survival rate, especially for those who do not receive a potentially curative therapy. Methods: Treatment details were collected for 320 HCC patients diagnosed in Manitoba between January 2011 and December 2015. Patients had a mean age of 67.3 years, and 71.6% were men. Of these patients, 67 (20.9%) received curative treatment, 36 (11.3%) received non-curative treatment, and 217 (67.8%) received supportive care only; 71.3% of patients had liver cirrhosis. Alcoholic cirrhosis was the most common etiology of chronic liver disease (22.2%). Results: Those who received curative treatment had a significantly lower incidence of portal vein thrombosis and multinodular disease than those in other groups. Patients who received supportive care only had a higher incidence of ascites. We found no difference in the distribution of cirrhosis or portal hypertension among the treatment groups. The 2- and 5-year overall survival rates for the whole cohort were 27% and 14%, respectively. No significant change was found in 2-year survival for patients diagnosed in each year from 2011 to 2015 (p = 0.250). Also, we found no significant change in proportion of treatment given to patients over the same period (p = 0.432). Conclusion: The poor survival rate of HCC patients in Manitoba could potentially be improved by maximizing the use of local therapy and by implementing multidisciplinary-based case discussion. Efforts should also be directed toward early management of infective, alcoholic, and non-alcoholic steatohepatitis, which will, we hope, lead to a reduction in the incidence of HCC.

The Association Between Wait Times for Colorectal Cancer Treatment and Health Care Costs: A Population-Based Analysis.

BACKGROUND: Health care costs and wait times for colorectal cancer treatment are increasing in Canada, but the association between the 2 remains unclear. OBJECTIVE: This study aimed to determine the association between wait times and health care costs and utilization. DESIGN: This is a population-based retrospective cohort study. SETTING: This study was conducted in Manitoba, Canada. PATIENTS: Patients diagnosed with colorectal cancer between 2004 and 2014 were sorted and ranked into quintiles based on the time from index contact for a colorectal cancer-related symptom to first treatment. MAIN OUTCOME MEASURES: The primary outcome is risk-adjusted health care costs, and the secondary outcomes include health care utilization and overall mortality. RESULTS: We included a total of 6936 patients. Total wait times ranged between 0 and 762 days. In comparison with very short wait times, longer wait times were associated with significantly increased costs (short: mean cost ratio 1.21; 95% CI, 1.10-1.32; moderate: mean cost ratio 1.30; 95% CI, 1.19-1.43; long: mean cost ratio 1.48; 95% CI, 1.33-1.64; and very long: mean cost ratio 1.39; 95% CI, 1.26-1.54). Compared with very short wait times, longer wait times were associated with significantly lower risk of mortality (short: HR, 0.78; 95% CI, 0.71-0.86; moderate: HR, 0.72; 95% CI, 0.65-0.80; long: HR, 0.73; 95% CI, 0.66-0.82; very long: HR, 0.76; 95% CI, 0.68-0.85). The median number of pretreatment radiological and endoscopic investigations and surgeon clinic visits increased over the study period across all wait time categories. LIMITATIONS: This is a nonrandomized, retrospective cohort study with potentially limited generalizability. CONCLUSION: Patients with very short and short wait times are likely those diagnosed with life-threatening complications of colorectal cancer. Outside this window, patients with longer wait times experience increased health care costs and utilization with similar overall mortality. Improved care coordination and patient navigation may help contain the increasing wait times and associated increasing health care costs and utilization. See Video Abstract at http://links.lww.com/DCR/B81. ASOCIACIÓN ENTRE LOS TIEMPOS DE ESPERA PARA EL TRATAMIENTO DE UN CÁNCER COLORRECTAL Y LOS COSTOS DE ATENCIÓN MÉDICA: UN ANÁLISIS DE POBLACIÓN: los costos de atención médica y los tiempos de espera para el tratamiento del cáncer colorrectal están aumentando en Canadá, pero la asociación entre los dos sigue sin estar clara.determinar la asociación entre los tiempos de espera y los costos y la utilización de la atención médicaun estudio de cohorte retrospectivo basado en la población.Manitoba, Canadálos pacientes diagnosticados con cáncer colorrectal entre 2004-2014 se clasificaron y sub-clasificaron en quintiles según el tiempo desde el primer contacto índice de síntomas relacionados con cáncer colorrectal hasta el primer tratamiento.El resultado primario son los costos de atención médica ajustados al riesgo, y los resultados secundarios incluyen la utilización de la atención médica y la mortalidad general.Incluimos un total de 6,936 pacientes. Los tiempos de espera totales oscilaron entre 0-762 días. En comparación con los tiempos de espera muy cortos, los tiempos de espera más largos se asociaron con costos significativamente mayores (Corto: relación de costo promedio 1.21, intervalo de confianza del 95% 1.10-1.32; Moderado: relación de costo promedio 1.30, intervalo de confianza del 95% 1.19-1.43; Largo: media relación de costo 1.48, intervalo de confianza del 95% 1.33-1.64; Muy largo: relación de costo promedio 1.39, intervalo de confianza del 95% 1.26-1.54). En comparación con tiempos de espera muy cortos, los tiempos de espera más largos se asociaron con un riesgo de mortalidad significativamente menor (Corto: razón de riesgo 0.78, intervalo de confianza del 95% 0.71-0.86; Moderado: razón de riesgo 0.72, intervalo de confianza del 95% 0.65-0.80; Largo: peligro cociente 0.73, intervalo de confianza del 95% 0.66-0.82; Muy largo: cociente de riesgos 0.76, intervalo de confianza del 95% 0.68-0.85). La mediana del número de investigaciones radiológicas y endoscópicas previas al tratamiento y las visitas al cirujano aumentaron durante el período de estudio en todas las categorías de tiempo de espera.estudio de cohortes retrospectivo, no aleatorio con generalización potencialmente limitadalos pacientes con tiempos de espera « muy cortos ¼ y « cortos ¼ son probablemente aquellos diagnosticados con complicaciones potencialmente mortales del cáncer colorrectal. Fuera de esta ventana, los pacientes con tiempos de espera más largos experimentan mayores costos de atención médica y utilización con una mortalidad general similar. La coordinación mejorada de la atención y la navegación del paciente pueden ayudar a contener el aumento de los tiempos de espera y el aumento de los costos y la utilización de la atención médica. Consulte Video Resumen en http://links.lww.com/DCR/B81. (Traducción-Dr. Edgar Xavier Delgadillo).

Timing of Palliative Care in Colorectal Cancer Patients: Does It Matter?

BACKGROUND: Palliative care can improve end-of-life care and reduce health care expenditures, but the optimal timing for initiation remains unclear. We sought to characterize the association between timing of palliative care, in-hospital deaths, and health care costs. METHODS: This is a retrospective cohort study including all patients who were diagnosed and died of colorectal cancer between 2004 and 2012 in Manitoba, Canada. The primary exposure was timing of palliative care, defined as no involvement, late involvement (less than 14 d before death), early involvement (14 to 60 d before death), and very early involvement (>60 d before death). The primary outcome was in-hospital deaths and end-of-life health care costs. RESULTS: A total of 1607 patients were included; 315 (20%) received palliative care and 162 (10%) died in hospital. Compared to those who did not receive palliative care, patients with early and very early involvement experienced significantly decreased odds of dying in hospital (OR 0.21 95% CI 0.06-0.69 P = 0.01 and OR 0.11 95% CI 0.01-0.78 P = 0.03, respectively) and significantly lower health care costs. There were no significant differences in in-hospital deaths and health care costs between patients without palliative care and those who received late palliative care. CONCLUSIONS: Early palliative care involvement is associated with decreased odds of dying in hospital and lower health care utilization and costs in patients with colorectal cancer. These findings provide real-world evidence supporting early integration of palliative care, although the optimal timing (early versus very early) remains a matter of debate.

Continuous subcutaneous insulin infusion versus multiple daily injection regimens in children and young people at diagnosis of type 1 diabetes: pragmatic randomised controlled trial and economic evaluation.

OBJECTIVE: To compare the efficacy, safety, and cost utility of continuous subcutaneous insulin infusion (CSII) with multiple daily injection (MDI) regimens during the first year following diagnosis of type 1 diabetes in children and young people. DESIGN: Pragmatic, multicentre, open label, parallel group, randomised controlled trial and economic evaluation. SETTING: 15 paediatric National Health Service (NHS) diabetes services in England and Wales. The study opened to recruitment in May 2011 and closed in January 2017. PARTICIPANTS: Patients aged between 7 months and 15 years, with a new diagnosis of type 1 diabetes were eligible to participate. Patients who had a sibling with the disease, and those who took drug treatments or had additional diagnoses that could have affected glycaemic control were ineligible. INTERVENTIONS: Participants were randomised, stratified by age and treating centre, to start treatment with CSII or MDI within 14 days of diagnosis. Starting doses of aspart (CSII and MDI) and glargine or detemir (MDI) were calculated according to weight and age, and titrated according to blood glucose measurements and according to local clinical practice. MAIN OUTCOME MEASURES: Primary outcome was glycaemic control (as measured by glycated haemoglobin; HbA1c) at 12 months. Secondary outcomes were percentage of patients in each treatment arm with HbA1c within the national target range, incidence of severe hypoglycaemia and diabetic ketoacidosis, change in height and body mass index (as measured by standard deviation scores), insulin requirements (units/kg/day), partial remission rate (insulin dose adjusted HbA1c <9), paediatric quality of life inventory score, and cost utility based on the incremental cost per quality adjusted life year (QALY) gained from an NHS costing perspective. RESULTS: 294 participants were randomised and 293 included in intention to treat analyses (CSI, n=144; MDI, n=149). At 12 months, mean HbA1c was comparable with clinically unimportant differences between CSII and MDI participants (60.9 mmol/mol v 58.5 mmol/mol, mean difference 2.4 mmol/mol (95% confidence interval -0.4 to 5.3), P=0.09). Achievement of HbA1c lower than 58 mmol/mol was low among the two groups (66/143 (46%) CSII participants v 78/142 (55%) MDI participants; relative risk 0.84 (95% confidence interval 0.67 to 1.06)). Incidence of severe hypoglycaemia and diabetic ketoacidosis were low in both groups. Fifty four non-serious and 14 serious adverse events were reported during CSII treatment, and 17 non-serious and eight serious adverse events during MDI treatment. Parents (but not children) reported superior PedsQL scores for those patients treated with CSII compared to those treated with MDI. CSII was more expensive than MDI by £1863 (€2179; $2474; 95% confidence interval £1620 to £2137) per patient, with no additional QALY gains (difference -0.006 (95% confidence interval -0.031 to 0.018)). CONCLUSION: During the first year following type 1 diabetes diagnosis, no clinical benefit of CSII over MDI was identified in children and young people in the UK setting, and treatment with either regimen was suboptimal in achieving HbA1c thresholds. CSII was not cost effective. TRIAL REGISTRATION: Current Controlled Trials ISRCTN29255275; European Clinical Trials Database 2010-023792-25.

Adalimumab in combination with methotrexate for refractory uveitis associated with juvenile idiopathic arthritis: a RCT.

BACKGROUND: Children with juvenile idiopathic arthritis (JIA) are at risk of uveitis. The role of adalimumab (Humira®; AbbVie Inc., Ludwigshafen, Germany) in the management of uveitis in children needs to be determined. OBJECTIVE: To compare the efficacy, safety and cost-effectiveness of adalimumab in combination with methotrexate (MTX) versus placebo with MTX alone, with regard to controlling disease activity in refractory uveitis associated with JIA. DESIGN: This was a randomised (applying a ratio of 2 : 1 in favour of adalimumab), double-blind, placebo-controlled, multicentre parallel-group trial with an integrated economic evaluation. A central web-based system used computer-generated tables to allocate treatments. A cost-utility analysis based on visual acuity was conducted and a 10-year extrapolation by Markov modelling was also carried out. SETTING: The setting was tertiary care centres throughout the UK. PARTICIPANTS: Patients aged 2-18 years inclusive, with persistently active JIA-associated uveitis (despite optimised MTX treatment for at least 12 weeks). INTERVENTIONS: All participants received a stable dose of MTX and either adalimumab (20 mg/0.8 ml for patients weighing < 30 kg or 40 mg/0.8 ml for patients weighing ≥ 30 kg by subcutaneous injection every 2 weeks based on body weight) or a placebo (0.8 ml as appropriate according to body weight by subcutaneous injection every 2 weeks) for up to 18 months. A follow-up appointment was arranged at 6 months. MAIN OUTCOME MEASURES: Primary outcome - time to treatment failure [multicomponent score as defined by set criteria based on the Standardisation of Uveitis Nomenclature (SUN) criteria]. Economic outcome - incremental cost per quality-adjusted life-year (QALY) gained from the perspective of the NHS in England and Personal Social Services providers. Full details of secondary outcomes are provided in the study protocol. RESULTS: A total of 90 participants were randomised (adalimumab, n = 60; placebo, n = 30). There were 14 (23%) treatment failures in the adalimumab group and 17 (57%) in the placebo group. The analysis of the data from the double-blind phase of the trial showed that the hazard risk (HR) of treatment failure was significantly reduced, by 75%, for participants in the adalimumab group (HR 0.25, 95% confidence interval 0.12 to 0.51; p < 0.0001 from log-rank test). The cost-effectiveness of adalimumab plus MTX was £129,025 per QALY gained. Adalimumab-treated participants had a much higher incidence of adverse and serious adverse events. CONCLUSIONS: Adalimumab in combination with MTX is safe and effective in the management of JIA-associated uveitis. However, the likelihood of cost-effectiveness is < 1% at the £30,000-per-QALY threshold. FUTURE WORK: A clinical trial is required to define the most effective time to stop therapy. Prognostic biomarkers of early and complete response should also be identified. TRIAL REGISTRATION: Current Controlled Trials ISRCTN10065623 and European Clinical Trials Database number 2010-021141-41. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 15. See the NIHR Journals Library website for further project information. This trial was also funded by Arthritis Research UK (grant reference number 19612). Two strengths of adalimumab (20 mg/0.8 ml and 40 mg/0.8 ml) and a matching placebo were manufactured by AbbVie Inc. (the Marketing Authorisation holder) and supplied in bulk to the contracted distributor (Sharp Clinical Services, Crickhowell, UK) for distribution to trial centres.

Juvenile idiopathic arthritis (JIA) is one of the most common rheumatic diseases in children and young people, who are at risk of developing inflammation in an area of the eye called the uvea (called uveitis). The purpose of the study was to look at how effective the use of adalimumab in combination with methotrexate (MTX) is compared with using MTX alone to treat JIA-associated uveitis. A total of 90 children (aged 2­18 years) taking MTX with JIA-associated uveitis took part in the study. If the inflammation in a patient's eye or eyes was not getting better during the 18 months, the patient was told to stop taking the study drug. It was found that those patients who were taking placebo and MTX in the trial stopped taking the study drug sooner than those who were taking adalimumab and MTX. This means that adalimumab and MTX was better at treating uveitis than MTX alone. It was found that more patients taking adalimumab and MTX together either reduced or stopped taking topical steroids than the patients taking placebo and MTX. It was found that patients taking adalimumab and MTX together experienced more side effects than those taking placebo with MTX. However, these were expected based on what was already known about adalimumab's side effects. An economic evaluation was conducted to estimate whether or not adalimumab would represent value for money for the NHS for this condition. This included long-term effects based on information about patients' clarity of vision. The analysis showed that adalimumab may not be cost-effective, as the additional costs of treatment may not be justified by the benefits. The final results show that although adalimumab used in combination with MTX does help to treat patients with JIA and uveitis, it may not represent good value for the NHS.

Cost-Effectiveness Analysis of Adalimumab for the Treatment of Uveitis Associated with Juvenile Idiopathic Arthritis.

PURPOSE: To investigate the cost effectiveness of adalimumab in combination with methotrexate, compared with methotrexate alone, for the management of uveitis associated with juvenile idiopathic arthritis (JIA). DESIGN: A cost-utility analysis based on a clinical trial and decision analytic model. PARTICIPANTS: Children and adolescents 2 to 18 years of age with persistently active uveitis associated with JIA, despite optimized methotrexate treatment for at least 12 weeks. METHODS: The SYCAMORE (Randomised controlled trial of the clinical effectiveness, SafetY and Cost effectiveness of Adalimumab in combination with MethOtRExate for the treatment of juvenile idiopathic arthritis associated uveitis) trial (identifier, ISRCTN10065623) of methotrexate (up to 25 mg weekly) with or without fortnightly administered adalimumab (20 or 40 mg, according to body weight) provided data on resource use (based on patient self-report and electronic records) and health utilities (from the Health Utilities Index questionnaire). Surgical event rates and long-term outcomes were based on data from a 10-year longitudinal cohort. A Markov model was used to extrapolate the effects of treatment based on visual impairment. MAIN OUTCOME MEASURES: Medical costs to the National Health Service in the United Kingdom, utility of defined health states, quality-adjusted life-years (QALYs), and incremental cost per QALY. RESULTS: Adalimumab in combination with methotrexate resulted in additional costs of £39 316, with a 0.30 QALY gain compared with methotrexate alone, resulting in an incremental cost-effectiveness ratio of £129 025 per QALY gained. The probability of cost effectiveness at a threshold of £30 000 per QALY was less than 1%. Based on a threshold analysis, a price reduction of 84% would be necessary for adalimumab to be cost effective. CONCLUSIONS: Adalimumab is clinically effective in uveitis associated with JIA; however, its cost effectiveness is not demonstrated compared with methotrexate alone in the United Kingdom setting.

Continuous subcutaneous insulin infusion versus multiple daily injections in children and young people at diagnosis of type 1 diabetes: the SCIPI RCT.

BACKGROUND: The risk of developing long-term complications of type 1 diabetes (T1D) is related to glycaemic control and is reduced by the use of intensive insulin treatment regimens: multiple daily injections (MDI) (≥ 4) and continuous subcutaneous insulin infusion (CSII). Despite a lack of evidence that the more expensive treatment with CSII is superior to MDI, both treatments are used widely within the NHS. OBJECTIVES: (1) To compare glycaemic control during treatment with CSII and MDI and (2) to determine safety and cost-effectiveness of the treatment, and quality of life (QoL) of the patients. DESIGN: A pragmatic, open-label randomised controlled trial with an internal pilot and 12-month follow-up with 1 : 1 web-based block randomisation stratified by age and centre. SETTING: Fifteen diabetes clinics in hospitals in England and Wales. PARTICIPANTS: Patients aged 7 months to 15 years. INTERVENTIONS: Continuous subsutaneous insulin infusion or MDI initiated within 14 days of diagnosis of T1D. DATA SOURCES: Data were collected at baseline and at 3, 6, 9 and 12 months using paper forms and were entered centrally. Data from glucometers and CSII were downloaded. The Health Utilities Index Mark 2 was completed at each visit and the Pediatric Quality of Life Inventory (PedsQL, diabetes module) was completed at 6 and 12 months. Costs were estimated from hospital patient administration system data. OUTCOMES: The primary outcome was glycosylated haemoglobin (HbA1c) concentration at 12 months. The secondary outcomes were (1) HbA1c concentrations of < 48 mmol/mol, (2) severe hypoglycaemia, (3) diabetic ketoacidosis (DKA), (4) T1D- or treatment-related adverse events (AEs), (5) change in body mass index and height standard deviation score, (6) insulin requirements, (7) QoL and (8) partial remission rate. The economic outcome was the incremental cost per quality-adjusted life-year (QALY) gained. RESULTS: A total of 293 participants, with a median age of 9.8 years (minimum 0.7 years, maximum 16 years), were randomised (CSII, n = 149; MDI, n = 144) between May 2011 and January 2015. Primary outcome data were available for 97% of participants (CSII, n = 143; MDI, n = 142). At 12 months, age-adjusted least mean squares HbA1c concentrations were comparable between groups: CSII, 60.9 mmol/mol [95% confidence interval (CI) 58.5 to 63.3 mmol/mol]; MDI, 58.5 mmol/mol (95% CI 56.1 to 60.9 mmol/mol); and the difference of CSII - MDI, 2.4 mmol/mol (95% CI -0.4 to 5.3 mmol/mol). For HbA1c concentrations of < 48 mmol/mol (CSII, 22/143 participants; MDI, 29/142 participants), the relative risk was 0.75 (95% CI 0.46 to 1.25), and for partial remission rates (CSII, 21/86 participants; MDI, 21/64), the relative risk was 0.74 (95% CI 0.45 to 1.24). The incidences of severe hypoglycaemia (CSII, 6/144; MDI, 2/149 participants) and DKA (CSII, 2/144 participants; MDI, 0/149 participants) were low. In total, 68 AEs (14 serious) were reported during CSII treatment and 25 AEs (eight serious) were reported during MDI treatment. Growth outcomes did not differ. The reported insulin use was higher with CSII (mean difference 0.1 unit/kg/day, 95% CI 0.0 to 0.2 unit/kg/day; p = 0.01). QoL was slightly higher for those randomised to CSII. From a NHS perspective, CSII was more expensive than MDI mean total cost (£1863, 95% CI £1620 to £2137) with no additional QALY gains (-0.006 QALYs, 95% CI -0.031 to 0.018 QALYs). LIMITATIONS: Generalisability beyond 12 months is uncertain. CONCLUSIONS: No clinical benefit of CSII over MDI was identified. CSII is not a cost-effective treatment in patients representative of the study population. FUTURE WORK: Longer-term follow-up is required to determine if clinical outcomes diverge after 1 year. A qualitative exploration of patient and professional experiences of MDI and CSII should be considered. TRIAL REGISTRATION: Current Controlled Trials ISRCTN29255275 and EudraCT 2010-023792-25. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 42. See the NIHR Journals Library website for further project information. The cost of insulin pumps and consumables supplied by F. Hoffman-La Roche AG (Basel, Switzerland) for the purpose of the study were subject to a 25% discount on standard NHS costs.

Lysosome activation clears aggregates and enhances quiescent neural stem cell activation during aging.

In the adult brain, the neural stem cell (NSC) pool comprises quiescent and activated populations with distinct roles. Transcriptomic analysis revealed that quiescent and activated NSCs exhibited differences in their protein homeostasis network. Whereas activated NSCs had active proteasomes, quiescent NSCs contained large lysosomes. Quiescent NSCs from young mice accumulated protein aggregates, and many of these aggregates were stored in large lysosomes. Perturbation of lysosomal activity in quiescent NSCs affected protein-aggregate accumulation and the ability of quiescent NSCs to activate. During aging, quiescent NSCs displayed defects in their lysosomes, increased accumulation of protein aggregates, and reduced ability to activate. Enhancement of the lysosome pathway in old quiescent NSCs cleared protein aggregates and ameliorated the ability of quiescent NSCs to activate, allowing them to regain a more youthful state.