Neuropathic pain develops normally in mice lacking both Na(v)1.7 and Na(v)1.8

Two voltage gated sodium channel α-subunits, Na(v)1.7 and Na(v)1.8, are expressed at high levels in nociceptor terminals and have been implicated in the development of inflammatory pain. Mis-expression of voltage-gated sodium channels by damaged sensory neurons has also been implicated in the development of neuropathic pain, but the role of Na(v)1.7 and Na(v)1.8 is uncertain. Here we show that deleting Na(v)1.7 has no effect on the development of neuropathic pain. Double knockouts of both Na(v)1.7 and Na(v)1.8 also develop normal levels of neuropathic pain, despite a lack of inflammatory pain symptoms and altered mechanical and thermal acute pain thresholds. These studies demonstrate that, in contrast to the highly significant role for Na(v)1.7 in determining inflammatory pain thresholds, the development of neuropathic pain does not require the presence of either Na(v)1.7 or Na(v)1.8 alone or in combination

The clinical and cost effectivementss of cognitive behavioural therapy plus treatment as usual for the treatment of depression in advanced cancer (CanTalk):study protocol for a radomised controlled trial

BACKGROUND: The prevalence of depressive disorder in adults with advanced cancer is around 20 %. Although cognitive behavioural therapy (CBT) is recommended for depression and may be beneficial in depressed people with cancer, its use for depression in those with advanced disease for whom cure is not likely has not been explored. METHODS: People aged 18 years and above with advanced cancer attending General Practitioner (GP), oncology or hospice outpatients from centres across England will be screened to establish a DSM-IV diagnosis of depression. Self-referral is also accepted. Eligible consenters will be randomised to a single blind, multicentre, randomised controlled trial of the addition to treatment as usual (TAU) of up to 12 one-hour weekly sessions of manualised CBT versus TAU alone. Sessions are delivered in primary care through Increasing Access to Psychological Care (IAPT) service, and the manual includes a focus on issues for people approaching the end of life. The main outcome is the Beck Depression Inventory-II (BDI-II). Subsidiary measures include the Patient Health Questionnaire, quality of life measure EQ-5D, Satisfaction with care, Eastern Cooperative Oncology Group-Performance Status and a modified Client Service Receipt Inventory. At 90 % power, we require 240 participants to enter the trial. Data will be analysed using multi-level (hierarchical) models for data collected at baseline, 6, 12, 18 and 24 weeks. Cost effectiveness analysis will incorporate costs related to the intervention to compare overall healthcare costs and QALYs between the treatment arms. We will conduct qualitative interviews after final follow-up on patient and therapist perspectives of the therapy. DISCUSSION: This trial will provide data on the clinical and cost effectiveness of CBT for people with advanced cancer and depression. We shall gain an understanding of the feasibility of delivering care to this group through IAPT. Our findings will provide evidence for policy-makers, commissioners and clinicians in cancer and palliative care, and in the community. TRIAL REGISTRATION: Controlled Trials ISRCTN07622709 , registered 15 July 2011

Manualised cognitive behavioural therapy in treating depression in advanced cancer:The CanTalk RCT

BACKGROUND: With a prevalence of up to 16.5%, depression is one of the commonest mental disorders in people with advanced cancer. Depression reduces the quality of life (QoL) of patients and those close to them. The National Institute for Health and Care Excellence (NICE) guidelines recommend treating depression using antidepressants and/or psychological treatments, such as cognitive-behavioural therapy (CBT). Although CBT has been shown to be effective for people with cancer, it is unclear whether or not this is the case for people with advanced cancer and depression. OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of treatment as usual (TAU) plus manualised CBT, delivered by high-level Improving Access to Psychological Therapy (IAPT) practitioners, versus TAU for people with advanced cancer and depression, measured at baseline, 6, 12, 18 and 24 weeks. DESIGN: Parallel-group, single-blind, randomised trial, stratified by whether or not an antidepressant was prescribed, comparing TAU with CBT plus TAU. SETTING: Recruitment took place in oncology, hospice and primary care settings. CBT was delivered in IAPT centres or/and over the telephone. PARTICIPANTS: Patients (N = 230; n = 115 in each arm) with advanced cancer and depression. Inclusion criteria were a diagnosis of cancer not amenable to cure, a DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) diagnosis of depressive disorder using the Mini-International Neuropsychiatric Interview, a sufficient understanding of English and eligibility for treatment in an IAPT centre. Exclusion criteria were an estimated survival of < 4 months, being at high risk of suicide and receiving, or having received in the last 2 months, a psychological intervention recommended by NICE for treating depression. INTERVENTIONS: (1) Up to 12 sessions of manualised individual CBT plus TAU delivered within 16 weeks and (2) TAU. OUTCOME MEASURES: The primary outcome was the Beck Depression Inventory, version 2 (BDI-II) score at 6, 12, 18 and 24 weeks. Secondary outcomes included scores on the Patient Health Questionnaire-9, the Eastern Cooperative Oncology Group Performance Status, satisfaction with care, EuroQol-5 Dimensions and the Client Services Receipt Inventory, at 12 and 24 weeks. RESULTS: A total of 80% of treatments (185/230) were analysed: CBT (plus TAU) (n = 93) and TAU (n = 92) for the BDI-II score at all time points using multilevel modelling. CBT was not clinically effective [treatment effect -0.84, 95% confidence interval (CI) -2.76 to 1.08; p = 0.39], nor was there any benefit for other measures. A subgroup analysis of those widowed, divorced or separated showed a significant effect of CBT on the BDI-II (treatment effect -7.21, 95% CI -11.15 to -3.28; p < 0.001). Economic analysis revealed that CBT has higher costs but produces more quality-adjusted life-years (QALYs) than TAU. The mean service costs for participants (not including the costs of the interventions) were similar across the two groups. There were no differences in EQ-5D median scores at baseline, nor was there any advantage of CBT over TAU at 12 weeks or 24 weeks. There was no statistically significant improvement in QALYs at 24 weeks. LIMITATIONS: Although all participants satisfied a diagnosis of depression, for some, this was of less than moderate severity at baseline, which could have attenuated treatment effects. Only 64% (74/115) took up CBT, comparable to the general uptake through IAPT. CONCLUSIONS: Cognitive-behavioural therapy (delivered through IAPT) does not achieve any clinical benefit in advanced cancer patients with depression. The benefit of CBT for people widowed, divorced or separated is consistent with other studies. Alternative treatment options for people with advanced cancer warrant evaluation. Screening and referring those widowed, divorced or separated to IAPT for CBT may be beneficial. Whether or not improvements in this subgroup are due to non-specific therapeutic effects needs investigation. TRIAL REGISTRATION: Current Controlled Trials ISRCTN07622709. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 19. See the NIHR Journals Library website for further project information

Localism and energy: Negotiating approaches to embedding resilience in energy systems

Tensions are evident in energy policy objectives between centralised top-down interconnected energy systems and localised distributed approaches. Examination of these tensions indicates that a localised approach can address a systemic problem of interconnected systems; namely vulnerability. The challenge for energy policy is to realise the interrelated goals of energy security, climate and environmental targets and social and economic issues such as fuel poverty, whilst mitigating vulnerability. The effectiveness of conventional approaches is debateable. A transition to a low carbon pathway should focus on resilience, counter to vulnerability. This article draws from on-going work which evaluates the energy aspects of a Private Finance Initiative (PFI) project to refurbish and re-build a local authority’s entire stock of sheltered accommodation to high environmental standards. Initial findings suggest that whereas more conventional procurement processes tend to increase systemic vulnerability, a user focussed process driven through PFI competitive dialogue is beginning to motivate some developers to adopt innovative approaches to energy system development. Conceptually these findings strongly suggest that embedding ‘Open Source’ principles in energy system development acts to work against systemic vulnerabilities by embedding resilience

Design and control of a bio-inspired soft wearable robotic device for ankle-foot rehabilitation

Abstract We describe the design and control of a wearable robotic device powered by pneumatic artificial muscle actuators for use in ankle-foot rehabilitation. The design is inspired by the biological musculoskeletal system of the human foot and lower leg, mimicking the morphology and the functionality of the biological muscle-tendon-ligament structure. A key feature of the device is its soft structure that provides active assistance without restricting natural degrees of freedom at the ankle joint. Four pneumatic artificial muscles assist dorsiflexion and plantarflexion as well as inversion and eversion. The prototype is also equipped with various embedded sensors for gait pattern analysis. For the subject tested, the prototype is capable of generating an ankle range of motion of 27 • (14 • dorsiflexion and 13 • plantarflexion). The controllability of the system is experimentally demonstrated using a linear time-invariant (LTI) controller. The controller is found using an identified LTI model of the system, resulting from the interaction of the soft orthotic device with a human leg, and model-based classical control design techniques. The suitability of the proposed control strategy is demonstrated with several angle-reference following experiments

Global supply chains and social relations at work : brokering across boundaries

Global supply chains are not just instruments for the exchange of economic goods and flow of capital across borders. They also connect people in unprecedented ways across social and cultural boundaries and have created new, interrelated webs of social relationships that are socially embedded. However, most of the existing theories of work are mainly based at the level of the corporation, not on the network of relations that interlink them, and how this may impact on work and employment relations. We argue that this web of relations should not just be seen in economic, but also social terms, and that the former are embedded and enabled by the latter. This article argues for the value of focusing on the role of brokers and boundary workers in mediating social relations across global supply chains. It develops four approaches that lie on a spectrum from structural perspectives focused on brokers who link otherwise unconnected actors to more constructivist ones focused on boundary workers performing translation work between domains

Initial response of young people with thyrotoxicosis to block and replace or dose titration thionamide

\ua9 2022 The authors Published by Bioscientifica Ltd.Objective: Patients with thyrotoxicosis are treated with anti-thyroid drug (ATD) using block and replace (BR) or a smaller, titrated dose of ATD (dose titration, DT). Design: A multi-centre, phase III, open-label trial of newly diagnosed paediatric thyrotoxicosis patients randomised to BR/DT. We compared the biochemical response to BR/DT in the first 6 months of therapy. Methods: Patients commenced 0.75 mg/kg carbimazole (CBZ) daily with randomisation to BR/DT. We examined baseline patient characteristics, CBZ dose, time to serum thyroid-stimulating hormone (TSH)/free thyroxine (FT4) normalisation and BMI Z-score change. Results: There were 80 patients (baseline) and 78 patients (61 female) at 6 months. Mean CBZ dose was 0.9 mg/kg/day (BR) and 0.5 mg/kg/day (DT). There was no difference in time to non-suppressed TSH concentration; 16 of 39 patients (BR) and 11 of 39 (DT) had suppressed TSH at 6 months. Patients with suppressed TSH had higher mean baseline FT4 levels (72.7 vs 51.7 pmol/L; 95% CI for difference 1.73, 31.7; P = 0.029). Time to normalise FT4 levels was reduced in DT (log-rank test, P = 0.049) with 50% attaining normal FT4 at 28 days (95% CI 25, 32) vs 35 days in BR (95% CI 28, 58). Mean BMI Z-score increased from 0.10 to 0.81 at 6 months (95% CI for difference 0.57, 0.86; P &lt; 0.001) and was greatest in patients with higher baseline FT4 concentrations. Conclusions: DT-treated patients normalised FT4 concentrations more quickly than BR. Overall, 94% of patients have normal FT4 levels after 6 months, but 33% still have TSH suppression. Excessive weight gain occurs with both BR and DT therapy

Making champs and super-champs - Current views, contradictions, and future directions

In our 2016 paper (Collins et al., 2016a), we proposed that superchamps (athletes who have achieved the highest level in their sport) were differentiated from their less successful counterparts by their use of positive proactive coping and a "learn from it" approach to challenge. This skill-based focus to talent development (TD) is supported extensively in the literature (e.g., MacNamara et al., 2010a,b) and suggests that the differences between levels of adult achievement relate more to what performers bring to the challenges than what they experience (Collins et al., 2016a). In this focused review we present and discuss a number of key concepts related to this paper and other parallel research in TD. We begin by presenting our pragmatic objectives and the importance of considering how we evaluate the research with an emphasis on its application to the applied setting. We then consider commonalities and differences in recent psychological approaches to TD, namely the experiential, attitudinal, and skill-based. The paper then provides further exploration of the Psychological Characteristics of Developing Excellence and their role in TD processes. We conclude with a consideration of future research and the application of research in TD. Reflecting our pragmatic stance as researchers, we hope that this focused review provides suggestions for progress and stimulates critical debate amongst practitioners, researchers and policy makers