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ABSTRACTTranslation fidelity relies on accurate aminoacylation of transfer RNAs (tRNAs) by aminoacyl-tRNA synthetases (AARSs). AARSs specific for alanine (Ala), leucine (Leu), serine, and pyrrolysine do not recognize the anticodon bases. Single nucleotide anticodon variants in their cognate tRNAs can lead to mistranslation. Human genomes include both rare and more common mistranslating tRNA variants. We investigated three rare human tRNALeu variants that mis-incorporate Leu at phenylalanine or tryptophan codons. Expression of each tRNALeu anticodon variant in neuroblastoma cells caused defects in fluorescent protein production without significantly increased cytotoxicity under normal conditions or in the context of proteasome inhibition. Using tRNA sequencing and mass spectrometry we confirmed that each tRNALeu variant was expressed and generated mistranslation with Leu. To probe the flexibility of the entire genetic code towards Leu mis-incorporation, we created 64 yeast strains to express all possible tRNALeu anticodon variants in a doxycycline-inducible system. While some variants showed mild or no growth defects, many anticodon variants, enriched with G/C at positions 35 and 36, including those replacing Leu for proline, arginine, alanine, or glycine, caused dramatic reductions in growth. Differential phenotypic defects were observed for tRNALeu mutants with synonymous anticodons and for different tRNALeu isoacceptors with the same anticodon. A comparison to tRNAAla anticodon variants demonstrates that Ala mis-incorporation is more tolerable than Leu at nearly every codon. The data show that the nature of the amino acid substitution, the tRNA gene, and the anticodon are each important factors that influence the ability of cells to tolerate mistranslating tRNAs.

Modelling land-use/landcover (LULC) change is vital for addressing global environmental and sustainability issues and evaluating various land system scenarios. However, existing geosimulation methodologies for global LULC change fail to account for spatial distortions caused by the Earth’s curvature and do not consider multiple LULC change processes. Thus, this research study proposes an enhanced spherical geosimulation modelling approach that integrates deep learning (DL) to simulate change of multiple classes of LULC process under the shared socioeconomic pathways (SSP) at the global level. Based on the simulation results, the frontiers of urbanization, cropland expansion, and deforestation are indicated to be in developing countries particularly in Asia and Africa. The simulation outputs also reveal 42.5%–63.2% of new urban development would occur on croplands. The proposed modelling approach can serve as a valuable tool for spatial decision-making and environmental policy formulation at the global level.

Objectives There has been a recent proliferation in treatment options for patients with metastatic breast cancer. Such treatments often involve trade-offs between overall survival and side effects. Our study aims to estimate the trade-offs that could be used to inform decision-making at the individual and policy level.Design We designed a discrete choice experiment (DCE) to look at preferences for avoiding severity levels of side effects when choosing treatment for metastatic breast cancer. Treatment attributes were: fatigue, nausea, diarrhoea, other side effects (peripheral neuropathy, hand–foot syndrome and mucositis) and urgent hospital admission and overall survival. Responses were analysed using an error component logit model. We estimated the relative importance of attributes and minimum acceptable survival for improvements in side effects.Setting The DCE was completed online by UK residents with self-reported diagnoses of breast cancer.Participants 105 respondents participated, of which 72 patients had metastatic breast cancer and 33 patients had primary breast cancer.Results Overall survival had the largest relative importance, followed by other side effects, diarrhoea, nausea and fatigue. The risk of urgent hospital admission was not significant. While overall survival was the most important attribute, respondents were willing to forgo some absolute probability of overall survival for reductions in all Grade 2 side effects (12.02% for hand–foot syndrome, 11.01% for mucositis, 10.42% for peripheral neuropathy, 6.33% for diarrhoea and 3.62% for nausea). Grade 1 side effects were not significant, suggesting respondents have a general tolerance for them.Conclusions Patients are willing to forgo overall survival to avoid particular severity levels of side effects. Our results have implications for data collected in research studies and can help inform person-centred care and shared decision-making.

Background Colorectal cancer (CRC) is the fourth most common type of cancer in the United Kingdom and the second leading cause of cancer death. Despite improvements in CRC survival over time, Scotland lags behind its UK and European counterparts. In this study, we carry out an exploratory analysis which aims to provide contemporary, population level evidence on CRC treatment and survival in Scotland. Methods We conducted a retrospective population-based analysis of adults with incident CRC registered on the Scottish Cancer Registry (Scottish Morbidity Record 06 (SMR06)) between January 2006 and December 2018. The CRC cohort was linked to hospital inpatient (SMR01) and National Records of Scotland (NRS) deaths records allowing a description of their demographic, diagnostic and treatment characteristics. Cox proportional hazards regression models were used to explore the demographic and clinical factors associated with all-cause mortality and CRC specific mortality after adjusting for patient and tumour characteristics among people identified as early-stage and treated with surgery. Results Overall, 32,691 (73%) and 12,184 (27%) patients had a diagnosis of colon and rectal cancer respectively, of whom 55% and 53% were early-stage and treated with surgery. Five year overall survival (CRC specific survival) within this cohort was 72% (82%) and 76% (84%) for patients with colon and rectal cancer respectively. Cox proportional hazards models revealed significant variation in mortality by sex, area-based deprivation and geographic location. Conclusions In a Scottish population of patients with early-stage CRC treated with surgery, there was significant variation in risk of death, even after accounting for clinical factors and patient characteristics.

Chronic breathlessness, a persistent and disabling symptom despite optimal treatment of underlying causes, is a frightening symptom with serious and widespread impact on patients and their carers. Clinical guidelines support the use of morphine for the relief of chronic breathlessness in common long-term conditions, but questions remain around clinical effectiveness, safety and longer term (>7 days) administration. This trial will evaluate the effectiveness of low-dose oral modified-release morphine in chronic breathlessness. This is a multicentre, parallel group, double-blind, randomised, placebo-controlled trial. Participants (n=158) will be opioid-naïve with chronic breathlessness due to heart or lung disease, cancer or post-coronavirus disease 2019. Participants will be randomised 1:1 to 5 mg oral modified-release morphine/placebo twice daily and docusate/placebo 100 mg twice daily for 56 days. Non-responders at Day 7 will dose escalate to 10 mg morphine/placebo twice daily at Day 15. The primary end-point (Day 28) measure will be worst breathlessness severity (previous 24 h). Secondary outcome measures include worst cough, distress, pain, functional status, physical activity, quality of life, and early identification and management of morphine-related side-effects. At Day 56, participants may opt to take open-label, oral modified-release morphine as part of usual care and complete quarterly breathlessness and toxicity questionnaires. The study is powered to be able to reject the null hypothesis and an embedded normalisation process theory-informed qualitative substudy will explore the adoption of morphine as a first-line pharmacological treatment for chronic breathlessness in clinical practice if effective.

Abstract Background Despite rehabilitation being increasingly advocated for people living with incurable cancer, there is limited evidence supporting efficacy or component parts. The progressive decline in function and nutritional in this population would support an approach that targets these factors. This trial aimed to assess the feasibility of an exercise and nutrition based rehabilitation programme in people with incurable cancer. Methods We randomized community dwelling adults with incurable cancer to either a personalized exercise and nutrition based programme (experimental arm) or standard care (control arm) for 8 weeks. Endpoints included feasibility, quality of life, physical activity (step count), and body weight. Qualitative and health economic analyses were also included. Results Forty‐five patients were recruited (23 experimental arm, 22 control arm). There were 26 men (58%), and the median age was 78 years (IQR 69–84). At baseline, the median BMI was 26 kg/m2 (IQR: 22–29), and median weight loss in the previous 6 months was 5% (IQR: −12% to 0%). Adherence to the experimental arm was >80% in 16/21 (76%) patients. There was no statistically significant difference in the following between trial arms: step count − median % change from baseline to endpoint, per trial arm (experimental −18.5% [IQR: −61 to 65], control 5% [IQR: −32 to 50], P = 0.548); weight − median % change from baseline to endpoint, per trial arm (experimental 1%[IQR: −3 to 3], control −0.5% [IQR: −3 to 1], P = 0.184); overall quality of life − median % change from baseline to endpoint, per trial arm (experimental 0% [IQR: −20 to 19], control 0% [IQR: −23 to 33], P = 0.846). Qualitative findings observed themes of capability, opportunity, and motivation amongst patients in the experimental arm. The mean incremental cost of the experimental arm versus control was £‐319.51 [CI −7593.53 to 6581.91], suggesting the experimental arm was less costly. Conclusions An exercise and nutritional rehabilitation intervention is feasible and has potential benefits for people with incurable cancer. A larger trial is now warranted to test the efficacy of this approach.

Longitudinal studies conducted within the social economy have the potential to provide useful insights by tracing participant experiences and illuminating long-term outcomes of program interventions. However, longitudinal studies are challenging, not only due to retention of participants, but also when a longitudinal study covers a broad geographic area. The authors collaborated in a five-year pan-Canadian longitudinal study following youth participants in work-integration social enterprise (WISE) training programs. This article traces the experiences of study teams in Ontario and Greater Vancouver, providing accounts of the approaches and challenges encountered when working in geographically and socio-economically diverse locales over time with youth participants facing social marginalization. This article highlights three aspects of data collection—recruitment, retention, and research methods and logistics—offering insights into how each team devised its own strategies to fit with local circumstances while maintaining consistency across research sites.

Abstract Background As the demand for palliative care increases, more information is needed on how efficient different types of palliative care models are for providing care to dying patients and their caregivers. Evidence on the economic value of treatments and interventions is key to informing resource allocation and ultimately improving the quality and efficiency of healthcare delivery. We assessed the available evidence on the economic value of palliative and end-of-life care interventions across various settings. Methods Reviews published between 2000 and 2019 were included. We included reviews that focused on cost-effectiveness, intervention costs and/or healthcare resource use. Two reviewers extracted data independently and in duplicate from the included studies. Data on the key characteristics of the studies were extracted, including the aim of the study, design, population, type of intervention and comparator, (cost-) effectiveness resource use, main findings and conclusions. Results A total of 43 reviews were included in the analysis. Overall, most evidence on cost-effectiveness relates to home-based interventions and suggests that they offer substantial savings to the health system, including a decrease in total healthcare costs, resource use and improvement in patient and caregivers’ outcomes. The evidence of interventions delivered across other settings was generally inconsistent. Conclusions Some palliative care models may contribute to dual improvement in quality of care via lower rates of aggressive medicalization in the last phase of life accompanied by a reduction in costs. Hospital-based palliative care interventions may improve patient outcomes, healthcare utilization and costs. There is a need for greater consistency in reporting outcome measures, the informal costs of caring, and costs associated with hospice.

In this paper, we carry out a retrospective analysis of the Scottish and English cancer registries for the case of colorectal cancer. We aim to assess the comparability of variable coding between the datasets and create derived variables and open access code for use by researchers working with linked Scottish and English cancer registry data. We bring together the national data dictionaries for the Scottish and English cancer registries and define a list of targeted variables. We establish the consistency of variable coding across the two registries, identifying fully complete, near complete, partial, composite and impossible matched variables. In the case of near complete, partial and composite matches, we create derived variables between the two registries. We liaise with NHS staff working within the retrospective registry teams to validate the derivations. Finally, we produce corresponding documentation for the dissemination and preservation of final data items. We considered 63 variables for analysis. Preliminary results show that there is a high degree of similarity between the Scottish and English cancer registries. In particular, 82% of variables were fully, nearly or partially matched, with the remaining 12% and 6% composite matches and impossible matches respectively. The session with the respective cancer registry teams will take place in May 2022. At which point we will present our existing results and seek their input into the final derived data items. Following this, we will publish documentation detailing the derived variables and associated code, to be made available to other researchers working with the Scottish and English cancer registries. This study provides a useful starting point for any researchers seeking to use the linked Scottish and English cancer registry data for applied research. Whilst our analysis has focused on colorectal cancer, the majority of variables are applicable for any cancer. Future research should extend this work to include staging variables for other cancers.

The objective of this paper is to explore how a colorectal cancer (CRC) diagnosis influences an individual’s use of social care services in Scotland. In particular, we aim to compare this use to individual’s diagnosed with other cancers and to those without a cancer diagnosis. We use a linked health and social care dataset of the Scottish population aged 50 and over in the financial year 2015/16. Our approach involves several methods to estimate the effect of a CRC diagnosis on social care use. Firstly, we conduct difference in means tests. Secondly, we estimate two-part models of the utilisation of social care for the CRC, other cancer and non-cancer groups. Lastly, we use propensity score matching. Models are estimated for those diagnosed during 2015/16 and for those diagnosed during 2015/16 or with an historical diagnosis. Preliminary results reveal that the likelihood of receipt of social care services is higher for those diagnosed with CRC compared to those without a cancer diagnosis. Further, individuals with a non-CRC cancer diagnosis are more likely to receive social care services compared to those without a cancer diagnosis, but they are less likely to receive social care compared to those with a CRC diagnosis. Further, the likelihood of care receipt for the CRC and other cancer group increases as the number of years since a cancer diagnosis increases. In terms of the number of services received, CRC patients and those with other types of cancer receive fewer services when compared to those without a cancer diagnosis. Our paper has demonstrated that a CRC diagnosis has a significant impact on an individual’s use of social care services. However, conditional on receiving social care, the number of services received is lower for individuals with CRC. Further research is required to understand whether the needs of those individuals are being met.

This poster aims to highlight the impact of a public/patient group (PPG) involved in two large programmes that are researching bowel cancer using routine, linked administrative datasets in England and Scotland. The PPG consists of ten independent patients or carers who have lived, or shared, experiences of bowel cancer. Members are involved in the full life cycle of individual research projects from project development, to research in progress and onto dissemination of the work once published. They are actively involved in shaping the strategic direction of the programmes and are a key part of the data access process. The group meets once a month and acts as a ‘critical friend’ to the researchers. The PPG have produced over 18 plain language summaries to ensure accessibility of the programmes’ research to everyone and that it reaches those directly affected by bowel cancer. They have produced four publications including one Editorial, one Opinion piece and two co-authored manuscripts. The group have also co-developed patient information sheets and consent forms with clinicians that are now used in various cancer centres across Yorkshire. Furthermore, one of the PPG members co-presenting a webinar, which highlighted their involvement in developing a unique linked bowel cancer dataset to an international audience of over 100 people. The PPG has demonstrated that involving the public and patients in the development of data linkage research is hugely beneficial. Their experience and knowledge shapes research that ultimately improves care. The success of our PPG is an exemplar for embedding patients and public involvement in research.

Background: Deaths due to non-communicable diseases are rising worldwide, with low-income and middle- income countries (LMICs) particularly affected. Palliative care can reduce pain and suffering for patients with incurable disease. A gap in access to palliative care and research to support its implementation exists in LMICs, and cancer care is a particularly problematic area. We designed a pragmatic study to better understand the implementation of home-based palliative care, patient-reported outcomes, costs, and consequences in Addis Ababa, Ethiopia. Methods: A single-blind, single-site, randomised, controlled trial of standard cancer care versus standard cancer care plus early integrated palliative care in patients newly diagnosed with cancer was performed at the Black Lion Outpatient Oncology Clinic (Addis Ababa, Ethiopia). The palliative care intervention was home-based and delivered by Hospice Ethiopia nurses. Follow-up was done at 4–12 weeks and at 8–16 weeks at the discretion of the oncologist. Sample size was determined by ability to detect a change in mean African Palliative Care Association Palliative Outcome Score. A cost–consequence analysis was done for patients who completed all three study visits. Ethical approval was granted by Addis Ababa University and Yale University. All participants signed or thumb-printed written informed consent. The study is registered at ClinicalTrials.gov, NCT03712436. Findings: 98 adults were enrolled. The mean age was 49·5 years and 66% of participants were women. 27 participants completed all three study visits. Significant improvements in patient-reported outcomes were seen (p=0·0025). Mean total health-care costs to the patient were Ethiopian birr (ETD) 40 430 (US$979); mean palliative care costs to Hospice Ethiopia were ETD 765 ($19) per patient. Those receiving standard cancer care reported higher out-of-pocket payments for medical care and increased lost wages of an informal caregiver. Out-of-pocket payments for medical care and lost wages were multiple times higher than an average yearly salary (ETD 5810 [$141] and ETD 74900 birr [$1814·9] respectively). By the end of study, health-care costs, health-use, and mortality had all increased. Interpretation: Delivery and integration of early, home-based, and low-cost palliative care into cancer care is possible in a LMIC setting. Widespread implementation of palliative care is likely to be a resource-sparing and poverty-reducing strategy in LMICs. Funding: Department of Emergency Medicine, Yale University.

Abstract We propose a novel problem revolving around two tasks: (i) given a scene, recommend objects to insert, and (ii) given an object category, retrieve suitable background scenes. A bounding box for the inserted object is predicted in both tasks, which helps downstream applications such as semiautomated advertising and video composition. The major challenge lies in the fact that the target object is neither present nor localized in the input, and furthermore, available datasets only provide scenes with existing objects. To tackle this problem, we build an unsupervised algorithm based on object-level contexts, which explicitly models the joint probability distribution of object categories and bounding boxes using a Gaussian mixture model. Experiments on our own annotated test set demonstrate that our system outperforms existing baselines on all sub-tasks, and does so using a unified framework. Future extensions and applications are suggested.

We report findings from an experimental study of the impacts of employer-paid transit subsidies on workers at downtown hotels in Vancouver, British Columbia, Canada. Partnering with the union and management of seven hotels, the regional transit agency and city government, we collected representative surveys of commuting behavior in three waves, each six months apart, in 2018 and 2019. Four of the hotels had offered a 15% transit subsidy prior to the study. We grouped six of the hotels in three similarly located pairs with the same initial subsidy condition. After the first survey wave, we provided an experimental subsidy at four hotels: 25% at one hotel in each of three pairs, and 15% at the seventh hotel. After the second survey we further increased the subsidy to 50% at two hotels. The larger the transit subsidy offered, the more employees become transit riders and the more transit-only commuting increased. Overall, a modest increase in transit-only commuting was accompanied by a reduction in auto-only and auto-and-transit commuting. It appears that transit subsidy acceptance and effectiveness can be dampened by factors such as the availability of cheap parking, or greater distance between the workplace and rapid transit, leading to variability in outcomes.

Background: The addition of adjuvant trastuzumab to chemotherapy has significantly improved outcomes for people with human epidermal growth factor receptor 2 (HER2)-positive, early, potentially curable breast cancer. Twelve months’ trastuzumab, tested in registration trials, was adopted as standard adjuvant treatment in 2006. Subsequently, similar outcomes were demonstrated using 9 weeks of trastuzumab. Shorter durations were therefore tested for non-inferiority. Objectives: To establish whether or not 6 months’ adjuvant trastuzumab is non-inferior to 12 months’ in the treatment of HER2-positive early breast cancer using a primary end point of 4-year disease-free survival. Design: This was a Phase III randomised controlled non-inferiority trial. Setting: The setting was 152 NHS hospitals. Participants: A total of 4088 patients with HER2-positive early breast cancer who it was planned would receive both chemotherapy and trastuzumab took part. Intervention: Randomisation (1 : 1) to 6 months’ or 12 months’ trastuzumab treatment. Main outcomes: The primary end point was disease-free survival. The secondary end points were overall survival, cost-effectiveness and cardiac function during treatment with trastuzumab. Assuming a 4-year disease-free survival rate of 80% with 12 months’ trastuzumab, 4000 patients were required to demonstrate non-inferiority of 6 months’ trastuzumab (5% one-sided significance, 85% power), defining the non-inferiority limit as no worse than 3% below the standard arm. Costs and quality-adjusted life-years were estimated using a within-trial analysis and a lifetime decision-analytic model. Results: Between 4 October 2007 and 31 July 2015, 2045 patients were randomised to 12 months’ trastuzumab and 2043 were randomised to 6 months’ trastuzumab. Sixty-nine per cent of patients had ER-positive disease; 90% received anthracyclines (49% with taxanes; 41% without taxanes); 10% received taxanes without anthracyclines; 54% received trastuzumab sequentially after chemotherapy; and 85% received adjuvant chemotherapy (58% were node negative). At 6.1 years’ median follow-up, with 389 (10%) deaths and 566 (14%) disease-free survival events, the 4-year disease-free survival rates for the 4088 patients were 89.5% (95% confidence interval 88.1% to 90.8%) in the 6-month group and 90.3% (95% confidence interval 88.9% to 91.5%) in the 12-month group (hazard ratio 1.10, 90% confidence interval 0.96 to 1.26; non-inferiority p = 0.01), demonstrating non-inferiority of 6 months’ trastuzumab. Congruent results were found for overall survival (non-inferiority p = 0.0003) and landmark analyses 6 months from starting trastuzumab [non-inferiority p = 0.03 (disease-free-survival) and p = 0.006 (overall survival)]. Six months’ trastuzumab resulted in fewer patients reporting adverse events of severe grade [365/1929 (19%) vs. 460/1935 (24%) for 12-month patients; p = 0.0003] or stopping early because of cardiotoxicity [61/1977 (3%) vs. 146/1941 (8%) for 12-month patients; p

Patient-reported outcomes and economic aspects of Palliative Care (PC) provision in low-income countries (LIC) are under-studied. Demonstrating the economic value of PC is key to sustainability and guiding health care policy. Our preliminary data in Ethiopia demonstrated a widespread need for PC, poor access to it, and high out of pocket payments (OOP). We suspect that in this and other LIC, PC may function not only to reduce suffering but also as a poverty reduction strategy.We are conducting a randomized controlled trial of standard Oncology care versus standard Oncology care plus PC in newly diagnosed cancer patients in Addis Ababa. Ninety-seven adults presenting to Oncology Clinic will be randomized in a 1:1 ratio. Subjects receiving PC will meet with a PC provider at time of enrollment and at follow up visits in their homes. All subjects will be assessed via questionnaire at enrollment and follow-up Oncology visits at 8 ± 4 and 12 ± 4 weeks. A cost-consequence analysis will be performed, to include: patient-reported OOP and healthcare utilization, the latter to be assessed through chart adjudication. Outcomes will include change in African Palliative Care Association Palliative Outcome Score, changes in OOP and healthcare utilization.We hypothesize that the cost of home-based PC will be offset by improvements in patient-reported outcomes, decreased OOP and healthcare utilization, rendering PC cost-effective in this LIC. These findings may lead to widespread dissemination of an effective, sustainable and cost-saving public PC delivery strategy that would improve the quality of life and death for millions of people. Trial registration: Clinicaltrials.gov NCT03712436.

This mini-review considers the densification of biomass blended with plastic wastes as an approach for waste management and sustainable fuel production from two perspectives; (1) We overviewed the pollutants generated during plastics combustion and their hazards. The control of these pollutants can be achieved as both reported in literature and by currently in-service municipal waste plants. (2) Advantages from densifying biomass/plastic blends as a solid fuel are indicated. Biomass/plastic briquettes or pellets are a potentially promising solid fuel with low costs, high volumetric heating values, high resistance to mechanical damage, and good durability performance under humid conditions. Moreover, the combustion of biomass/plastic blends with

Abstract Detecting small objects is a challenging task. We focus on a special case: the detection and classification of traffic signals in street views. We present a novel framework that utilizes a visual attention model to make detection more efficient, without loss of accuracy, and which generalizes. The attention model is designed to generate a small set of candidate regions at a suitable scale so that small targets can be better located and classified. In order to evaluate our method in the context of traffic signal detection, we have built a traffic light benchmark with over 15,000 traffic light instances, based on Tencent street view panoramas. We have tested our method both on the dataset we have built and the Tsinghua–Tencent 100K (TT100K) traffic sign benchmark. Experiments show that our method has superior detection performance and is quicker than the general faster RCNN object detection framework on both datasets. It is competitive with state-of-the-art specialist traffic sign detectors on TT100K, but is an order of magnitude faster. To show generality, we tested it on the LISA dataset without tuning, and obtained an average precision in excess of 90%.

This keynote address explores the interplay between three forces that will shape the next few years of social economy practice and research. The first is variety, both with respect to existing and emergent social need, and with respect to the multiplicity of organizational forms adopted by social economy actors. The second concerns the forms of knowledge, ranging from instrumental knowledge to reflection and critique, which inform practices in the sector. Knowledge production is itself both enabled and constrained by the third force, professionalism, or the ways we structure the socialization and employment of those working in the sector. With variation an inherent characteristic of the social economy and with the ongoing search for appropriate models of professionalism, our collective knowledge production tasks remain unfinished. Ce discours principal explore les interactions entre trois forces qui vont façonner la pratique et la recherche en économie sociale au cours des prochaines années. La première est la variété, tant par rapport aux besoins sociaux actuels et naissants qu’à la multiplicité de formes organisationnelles adoptées par les acteurs de l’économie sociale. La seconde concerne les types de savoir informant les pratiques dans le secteur, du savoir instrumental jusqu’à la réflexion et la critique. La troisième force, le professionnalisme ou la manière dont on organise le recrutement et la socialisation de ceux et celles qui oeuvrent dans le secteur, permet la production du savoir tout en y imposant certaines contraintes. La variation étant une caractéristique intrinsèque de l’économie sociale, et la quête de modèles de professionnalisme appropriés se perpétuant, il est clair que nos tâches collectives de production du savoir demeurent inachevées.

Background: Delirium is a common and serious neuropsychiatric syndrome, usually triggered by illness or drugs. It remains underdetected. One reason for this is a lack of brief, pragmatic assessment tools. The 4 ‘A’s test (Arousal, Attention, Abbreviated Mental Test – 4, Acute change) (4AT) is a screening tool designed for routine use. This project evaluated its usability, diagnostic accuracy and cost. Methods: Phase 1 – the usability of the 4AT in routine practice was measured with two surveys and two qualitative studies of health-care professionals, and a review of current clinical use of the 4AT as well as its presence in guidelines and reports. Phase 2 – the 4AT’s diagnostic accuracy was assessed in newly admitted acute medical patients aged ≥ 70 years. Its performance was compared with that of the Confusion Assessment Method (CAM; a longer screening tool). The performance of individual 4AT test items was related to cognitive status, length of stay, new institutionalisation, mortality at 12 weeks and outcomes. The method used was a prospective, double-blind diagnostic test accuracy study in emergency departments or in acute general medical wards in three UK sites. Each patient underwent a reference standard delirium assessment and was also randomised to receive an assessment with either the 4AT (n = 421) or the CAM (n = 420). A health economics analysis was also conducted. Results: Phase 1 found evidence that delirium awareness is increasing, but also that there is a need for education on delirium in general and on the 4AT in particular. Most users reported that the 4AT was useful, and it was in widespread use both in the UK and beyond. No changes to the 4AT were considered necessary. Phase 2 involved 785 individuals who had data for analysis; their mean age was 81.4 (standard deviation 6.4) years, 45% were male, 99% were white and 9% had a known dementia diagnosis. The 4AT (n = 392) had an area under the receiver operating characteristic curve of 0.90. A positive 4AT score (> 3) had a specificity of 95% [95% confidence interval (CI) 92% to 97%] and a sensitivity of 76% (95% CI 61% to 87%) for reference standard delirium. The CAM (n = 382) had a specificity of 100% (95% CI 98% to 100%) and a sensitivity of 40% (95% CI 26% to 57%) in the subset of participants whom it was possible to assess using this. Patients with positive 4AT scores had longer lengths of stay (median 5 days, interquartile range 2.0–14.0 days) than did those with negative 4AT scores (median 2 days, interquartile range 1.0–6.0 days), and they had a higher 12-week mortality rate (16.1% and 9.2%, respectively). The estimated 12-week costs of an initial inpatient stay for patients with delirium were more than double the costs of an inpatient stay for patients without delirium (e.g. in Scotland, £7559, 95% CI £7362 to £7755, vs. £4215, 95% CI £4175 to £4254). The estimated cost of false-positive cases was £4653, of false-negative cases was £8956, and of a missed diagnosis was £2067. Limitations: Patients were aged ≥ 70 years and were assessed soon after they were admitted, limiting generalisability. The treatment of patients in accordance with reference standard diagnosis limited the ability to assess comparative cost-effectiveness. Conclusions: These findings support the use of the 4AT as a rapid delirium assessment instrument. The 4AT has acceptable diagnostic accuracy for acute older patients aged > 70 years. Future work: Further research should address the real-world implementation of delirium assessment. The 4AT should be tested in other populations. Trial registration: Current Controlled Trials ISRCTN53388093. 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. 40. See the NIHR Journals Library website for further project information. The funder specified that any new delirium assessment tool should be compared against the CAM, but had no other role in the study design or conduct of the study.

Electrochemical energy storage and conversion systems such as electrochemical capacitors, batteries and fuel cells are considered as the most important technologies proposing environmentally friendly and sustainable solutions to address rapidly growing global energy demands and environmental concerns. Their commercial applications individually or in combination of two or more devices are based on their distinguishing properties e.g., energy/power densities, cyclability and efficiencies. In this review article, we have discussed some of the major electrochemical energy storage and conversion systems and encapsulated their technological advancement in recent years. Fundamental working principles and material compositions of various components such as electrodes and electrolytes have also been discussed. Furthermore, future challenges and perspectives for the applications of these technologies are discussed.

In this study, RF-based un-doped and nitrogen-doped aerogels were produced by polymerisation reaction between resorcinol and formaldehyde with sodium carbonate as catalyst and melamine as the nitrogen source. Carbon/activated carbon aerogels were obtained by carbonisation of the gels under inert atmosphere (Ar) followed by activation of the carbons under CO2 at 800 °C. The BET analysis of the samples showed a more than two-fold increase in the specific Surf. area and pore volume of carbon from 537 to 1333 m2g−1 and 0.242 to 0.671 cm3g−1 respectively after nitrogen doping and activation. SEM and XRD analysis of the samples revealed highly porous amorphous nanostructures with denser inter-particle cross-linked pathways for the activated nitrogen-doped carbon. The X-Ray Photoelectron Spectroscopy (XPS) results confirmed the presence of nitrogen and oxygen heteroatoms on the Surf. and within the carbon matrix where improvement in wettability with the drop in the contact angle from 123° to 80° was witnessed after oxygen and nitrogen doping. A steady drop in the equivalent series (RS) and charge transfer (RCT) resistances was observed by electrochemical measurements after the introduction of nitrogen and oxygen heteroatoms. The highest specific capacitance of 289 Fg−1 with the lowest values of 0.11 Ω and 0.02 Ω for RS and RCT was achieved for nitrogen and oxygen dual-doped activated carbon in line with its improved Surf. chemistry and wettability, and its enhanced conductivity due to denser inter-particle cross-linked pathways.

Background: Planned neck dissection (ND) after radical chemoradiotherapy (CRT) for locally advanced nodal metastases in patients with head and neck squamous cell carcinoma (HNSCC) remains controversial. Thirty per cent of ND specimens show histological evidence of tumour. Consequently, a significant proportion of clinicians still practise planned ND. Fludeoxyglucose positron emission tomography (PET)–computerised tomography (CT) scanning demonstrated high negative predictive values for persistent nodal disease, providing a possible alternative paradigm to ND. Evidence is sparse and drawn mainly from retrospective single-institution studies, illustrating the need for a prospective randomised controlled trial. Objectives: To determine the efficacy and cost-effectiveness of PET–CT-guided surveillance, compared with planned ND, in a multicentre, prospective, randomised setting. Design: A pragmatic randomised non-inferiority trial comparing PET–CT-guided watch-and-wait policy with the current planned ND policy in HNSCC patients with locally advanced nodal metastases and treated with radical CRT. Patients were randomised in a 1 : 1 ratio. Primary outcomes were overall survival (OS) and cost-effectiveness [incremental cost per incremental quality-adjusted life-year (QALY)]. Cost-effectiveness was assessed over the trial period using individual patient data, and over a lifetime horizon using a decision-analytic model. Secondary outcomes were recurrence in the neck, complication rates and quality of life. The recruitment of 560 patients was planned to detect non-inferior OS in the intervention arm with a 90% power and a type I error of 5%, with non-inferiority defined as having a hazard ratio (HR) of no higher than 1.50. An intention-to-treat analysis was performed by Cox’s proportional hazards model. Settings: Thirty-seven head and neck cancer-treating centres (43 NHS hospitals) throughout the UK. Participants: Patients with locally advanced nodal metastases of oropharynx, hypopharynx, larynx, oral or occult HNSCC receiving CRT and fit for ND were recruited. Intervention: Patients randomised to planned ND before or after CRT (control), or CRT followed by fludeoxyglucose PET–CT 10–12 weeks post CRT with ND only if PET–CT showed incomplete or equivocal response of nodal disease (intervention). Balanced by centre, planned ND timing, CRT schedule, disease site and the tumour, node, metastasis stage. Results: In total, 564 patients were recruited (ND arm, n = 282; and surveillance arm, n = 282; 17% N2a, 61% N2b, 18% N2c and 3% N3). Eighty-four per cent had oropharyngeal cancer. Seventy-five per cent of tested cases were p16 positive. The median time to follow-up was 36 months. The HR for OS was 0.92 [95% confidence interval (CI) 0.65 to 1.32], indicating non-inferiority. The upper limit of the non-inferiority HR margin of 1.50, which was informed by patient advisors to the project, lies at the 99.6 percentile of this estimate (p = 0.004). There were no differences in this result by p16 status. There were 54 NDs performed in the surveillance arm, with 22 surgical complications, and 221 NDs in the ND arm, with 85 complications. Quality-of-life scores were slightly better in the surveillance arm. Compared with planned ND, PET–CT surveillance produced an incremental net health benefit of 0.16 QALYs (95% CI 0.03 to 0.28 QALYs) over the trial period and 0.21 QALYs (95% CI –0.41 to 0.85 QALYs) over the modelled lifetime horizon. Limitations: Pragmatic randomised controlled trial with a 36-month median follow-up. Conclusions: PET–CT-guided active surveillance showed similar survival outcomes to ND but resulted in considerably fewer NDs, fewer complications and lower costs, supporting its use in routine practice. Future work: PET–CT surveillance is cost-effective in the short term, and long-term cost-effectiveness could be addressed in future work. Trial registration: Current Controlled Trials ISRCTN13735240. 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. 21, No. 17. See the NIHR Journals Library website for further project information.

We’re all familiar with being told that on a global scale the rural world is going to town. In the developing world, in the Middle East and in much of the Far East and in Latin America, that is undoubtedly true. And throughout the world people are coming together on a vast scale. Travelling on the London Underground and listening to all the many tongues that people are using as they talk on their mobile phones, you could well believe that we have latter-day Towers of Babel in some of our great European cities.

Background: There is uncertainty about the chemotherapy sensitivity of some oestrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancers. Multiparameter assays that measure the expression of several tumour genes simultaneously have been developed to guide the use of adjuvant chemotherapy for this breast cancer subtype. The assays provide prognostic information and have been claimed to predict chemotherapy sensitivity. There is a dearth of prospective validation studies. The Optimal Personalised Treatment of early breast cancer usIng Multiparameter Analysis preliminary study (OPTIMA prelim) is the feasibility phase of a randomised controlled trial (RCT) designed to validate the use of multiparameter assay directed chemotherapy decisions in the NHS. Objectives: OPTIMA prelim was designed to establish the acceptability to patients and clinicians of randomisation to test-driven treatment assignment compared with usual care and to select an assay for study in the main RCT. Design: Partially blinded RCT with adaptive design. Setting: Thirty-five UK hospitals. Participants: Patients aged ≥ 40 years with surgically treated ER-positive HER2-negative primary breast cancer and with 1–9 involved axillary nodes, or, if node negative, a tumour at least 30 mm in diameter. Interventions: Randomisation between two treatment options. Option 1 was standard care consisting of chemotherapy followed by endocrine therapy. In option 2, an Oncotype DX® test (Genomic Health Inc., Redwood City, CA, USA) performed on the resected tumour was used to assign patients either to standard care [if ‘recurrence score’ (RS) was > 25] or to endocrine therapy alone (if RS was ≤ 25). Patients allocated chemotherapy were blind to their randomisation. Main outcome measures: The pre-specified success criteria were recruitment of 300 patients in no longer than 2 years and, for the final 150 patients, (1) an acceptance rate of at least 40%; (2) recruitment taking no longer than 6 months; and (3) chemotherapy starting within 6 weeks of consent in at least 85% of patients. Results: Between September 2012 and 3 June 2014, 350 patients consented to join OPTIMA prelim and 313 were randomised; the final 150 patients were recruited in 6 months, of whom 92% assigned chemotherapy started treatment within 6 weeks. The acceptance rate for the 750 patients invited to participate was 47%. Twelve out of the 325 patients with data (3.7%, 95% confidence interval 1.7% to 5.8%) were deemed ineligible on central review of receptor status. Interviews with researchers and recordings of potential participant consultations made as part of the integral qualitative recruitment study provided insights into recruitment barriers and led to interventions designed to improve recruitment. Patient information was changed as the result of feedback from three patient focus groups. Additional multiparameter analysis was performed on 302 tumour samples. Although Oncotype DX, MammaPrint®/BluePrint® (Agendia Inc., Irvine, CA, USA), Prosigna® (NanoString Technologies Inc., Seattle, WA, USA), IHC4, IHC4 automated quantitative immunofluorescence (AQUA®) [NexCourse BreastTM (Genoptix Inc. Carlsbad, CA, USA)] and MammaTyper® (BioNTech Diagnostics GmbH, Mainz, Germany) categorised comparable numbers of tumours into low- or high-risk groups and/or equivalent molecular subtypes, there was only moderate agreement between tests at an individual tumour level (kappa ranges 0.33–0.60 and 0.39–0.55 for tests providing risks and subtypes, respectively). Health economics modelling showed the value of information to the NHS from further research into multiparameter testing is high irrespective of the test evaluated. Prosigna is currently the highest priority for further study. Conclusions: OPTIMA prelim has achieved its aims of demonstrating that a large UK clinical trial of multiparameter assay-based selection of chemotherapy in hormone-sensitive early breast cancer is feasible. The economic analysis shows that a trial would be economically worthwhile for the NHS. Based on the outcome of the OPTIMA prelim, a large-scale RCT to evaluate the clinical effectiveness and cost-effectiveness of multiparameter assay-directed chemotherapy decisions in hormone-sensitive HER2-negative early breast would be appropriate to take place in the NHS. Trial registration: Current Controlled Trials ISRCTN42400492. 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. 20, No. 10. See the NIHR Journals Library website for further project information. The Government of Ontario funded research at the Ontario Institute for Cancer Research. Robert C Stein received additional support from the NIHR University College London Hospitals Biomedical Research Centre.

Western Canada has been the source of significant developments in the social enterprise sector over the past fifteen years. Among these developments one must include the formation of Enterprising Non-Profits in British Columbia, the Social Enterprise Fund in Alberta, and the Canadian CED Network in Manitoba. Underlying these more recent developments is a history of co-operative development and earned revenues by nonprofit organizations, reflecting a longstanding blend of entrepreneurship and community solidarity. This article highlights some of the more recent social enterprise developments in three Western provinces, profiling three independent cases that reflect the diversity of social enterprise activity in British Columbia, Alberta, and Manitoba, and providing the results of social enterprise sector surveys that took place in these same provinces in 2014. Depuis quinze ans, l’Ouest canadien a été la source de développements importants dans le secteur de l’entreprise sociale. Parmi ces développements, il faut inclure la formation : d’Enterprising Non-Profits en Colombie-Britannique; du Social Enterprise Fund en Alberta; et du Réseau canadien de DÉC au Manitoba. Sous-tendant ces progrès récents est une longue histoire de développements coopératifs et de revenus gagnés par des organismes sans but lucratif reflétant une combinaison d’entreprenariat et de solidarité communautaire. Cet article souligne certains des développements plus récents en entreprise sociale dans trois provinces de l’Ouest, recensant trois cas distincts qui reflètent la diversité des activités en entreprise sociale en Colombie-Britannique, en Alberta et au Manitoba, et présentant les résultats de sondages sur le secteur de l’entreprise sociale effectués dans ces trois provinces en 2014.

Background: Patients with the acute respiratory distress syndrome (ARDS) require artificial ventilation but this treatment may produce secondary lung damage. High-frequency oscillatory ventilation (HFOV) may reduce this damage. Objectives: To determine the clinical benefit and cost-effectiveness of HFOV in patients with ARDS compared with standard mechanical ventilation. Design: A parallel, randomised, unblinded clinical trial. Setting: UK intensive care units. Participants: Mechanically ventilated patients with a partial pressure of oxygen in arterial blood/fractional concentration of inspired oxygen (P : F) ratio of 26.7 kPa (200 mmHg) or less and an expected duration of ventilation of at least 2 days at recruitment. Interventions: Treatment arm HFOV using a Novalung R100® ventilator (Metran Co. Ltd, Saitama, Japan) ventilator until the start of weaning. Control arm Conventional mechanical ventilation using the devices available in the participating centres. Main outcome measures: The primary clinical outcome was all-cause mortality at 30 days after randomisation. The primary health economic outcome was the cost per quality-adjusted life-year (QALY) gained. Results: One hundred and sixty-six of 398 patients (41.7%) randomised to the HFOV group and 163 of 397 patients (41.1%) randomised to the conventional mechanical ventilation group died within 30 days of randomisation (p = 0.85), for an absolute difference of 0.6% [95% confidence interval (CI) −6.1% to 7.5%]. After adjustment for study centre, sex, Acute Physiology and Chronic Health Evaluation II score, and the initial P : F ratio, the odds ratio for survival in the conventional ventilation group was 1.03 (95% CI 0.75 to 1.40; p = 0.87 logistic regression). Survival analysis showed no difference in the probability of survival up to 12 months after randomisation. The average QALY at 1 year in the HFOV group was 0.302 compared to 0.246. This gives an incremental cost-effectiveness ratio (ICER) for the cost to society per QALY of £88,790 and an ICER for the cost to the NHS per QALY of £78,260. Conclusions: The use of HFOV had no effect on 30-day mortality in adult patients undergoing mechanical ventilation for ARDS and no economic advantage. We suggest that further research into avoiding ventilator-induced lung injury should concentrate on ventilatory strategies other than HFOV. Trial registration: Current Controlled Trials ISRCTN10416500. Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 23. See the NIHR Journals Library website for further project information.

We evaluated the utility of electronic loggers to measure the effects of a simple intervention designed to influence the rates of hand washing with soap within enclosed toilets and bathrooms in low-income urban households in Kerala, India. 58 households were given three items with embedded electronic loggers for a period of 2-5 days. Two logged soaps tracked hand and body washing in the bathroom. The third logged item was a water vessel used for flushing the toilet and for post-defecation anal cleansing; this served as a marker of toilet use. In addition, 28 households in a Soap by toilet arm were given an additional logged soap, to be kept by the toilet, and used for hand washing. Compared with the Soap in bathroom arm, the loggers in the Soap by toilet households recorded 73% greater daily use of soaps designated for hand washing (t(36)=2.92, p

Most firms in most countries find themselves taking up new technology in the wake of pioneers or first-movers. A central question is how (and whether) such firms can make a success of being followers--in the time-related sense of adopting subsequently. We take a novel approach to this question by drawing on the literature of leadership and followership within organisations. This literature employs characteristics in two dimensions to build a taxonomy of types of follower--in the hierarchical sense of working for and with an organisational superior. Using this approach, we generate hypotheses about the sorts of firms which are likely to prove more or less successful as early and later technology adopters. From the analysis, we are also able to identify ways in which the emerging followership literature requires strengthening.

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