The role of the CCN family of proteins in blood cancers

Haematopoiesis is the term used to describe the production of blood cells. This is a tightly regulated hierarchical system in which mature circulating blood cells develop from a small population of haematopoietic stem (HSC) and progenitor cells within the microenvironment of the bone marrow. Molecular and genetic abnormalities arising in these stem cells lead to a block in the normal programme of proliferation and differentiation and result in the development of the blood cancers known as the leukaemias and lymphomas. Recently the regulatory role of the bone marrow microenvironment or niche has also become increasingly recognised. The interface between the bone and bone marrow (endosteum) and the region surrounding the blood vessels (perivascular) provide distinct niches harbouring quiescent HSC or proliferative HSC respectively. Current chemotherapeutic regimes can often successfully target the proliferative HSC but disease relapse occurs due to residual quiescent HSC. Understanding these developmental and regulatory processes and the associated cell communication mechanisms are thus crucial to the development of new treatment strategies. The CCN family of proteins have been recognised to play a key role in all aspects of haematopoiesis

Topological mechanics of gyroscopic metamaterials

Topological mechanical metamaterials are artificial structures whose unusual properties are protected very much like their electronic and optical counterparts. Here, we present an experimental and theoretical study of an active metamaterial -- comprised of coupled gyroscopes on a lattice -- that breaks time-reversal symmetry. The vibrational spectrum of these novel structures displays a sonic gap populated by topologically protected edge modes which propagate in only one direction and are unaffected by disorder. We present a mathematical model that explains how the edge mode chirality can be switched via controlled distortions of the underlying lattice. This effect allows the direction of the edge current to be determined on demand. We envision applications of these edges modes to the design of loss-free, one-way, acoustic waveguides and demonstrate this functionality in experiment

Systematic overview of economic evaluations of health-related rehabilitation

Background: Health related rehabilitation is instrumental in improving functioning and promoting participation by people with disabilities. To make clinical and policy decisions about health-related rehabilitation, resource allocation and cost issues need to be considered. Objectives: To conduct an overview of systematic reviews (SRs) on economic evaluations of health-related rehabilitation. Methods: We searched multiple databases to identify relevant SRs of economic evaluations of health-related rehabilitation. Review quality was assessed by AMSTAR checklist. Results: We included 64 SRs, most of which included economic evaluations alongside randomised controlled trials (RCTs). The review quality was low to moderate (AMSTAR score 5-8) in 35, and high (score 9-11) in 29 of the included SRs. The included SRs addressed various health conditions, including spinal or other pain conditions (n=14), age-related problems (11), stroke (7), musculoskeletal disorders (6), heart diseases (4), pulmonary (3), mental health problems (3), and injury (3). Physiotherapy was the most commonly evaluated rehabilitation intervention in the included SRs (n=24). Other commonly evaluated interventions included multidisciplinary programmes (14); behavioural, educational or psychological interventions (11); home-based interventions (11); complementary therapy (6); self-management (6); and occupational therapy (4). Conclusions: Although the available evidence is often described as limited, inconsistent or inconclusive, some rehabilitation interventions were cost-effective or showed cost-saving in a variety of disability conditions. Available evidence comes predominantly from high income countries, therefore economic evaluations of health-related rehabilitation are urgently required in less resourced settings

The matricellular protein CCN3 regulates NOTCH1 signalling in chronic myeloid leukaemia

Deregulated NOTCH1 has been reported in lymphoid leukaemia, although its role in chronic myeloid leukaemia (CML) is not well established. We previously reported BCR-ABL down-regulation of a novel haematopoietic regulator, CCN3, in CML; CCN3 is a non-canonical NOTCH1 ligand. This study characterizes the NOTCH1–CCN3 signalling axis in CML. In K562 cells, BCR-ABL silencing reduced full-length NOTCH1 (NOTCH1-FL) and inhibited the cleavage of NOTCH1 intracellular domain (NOTCH1-ICD), resulting in decreased expression of the NOTCH1 targets c-MYC and HES1. K562 cells stably overexpressing CCN3 (K562/CCN3) or treated with recombinant CCN3 (rCCN3) showed a significant reduction in NOTCH1 signalling (> 50% reduction in NOTCH1-ICD, p < 0.05). Gamma secretase inhibitor (GSI), which blocks NOTCH1 signalling, reduced K562/CCN3 colony formation but increased that of K562/control cells. GSI combined with either rCCN3 or imatinib reduced K562 colony formation with enhanced reduction of NOTCH1 signalling observed with combination treatments. We demonstrate an oncogenic role for NOTCH1 in CML and suggest that BCR-ABL disruption of NOTCH1–CCN3 signalling contributes to the pathogenesis of CML

‘We’re passengers sailing in the same ship, but we have our own berths to sleep in’: Evaluating patient and public involvement within a regional research programme: An action research project informed by Normalisation Process Theory

© 2019 Keenan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background: Patient and public involvement (PPI) is a requirement for UK health and social care research funding. Evidence for how best to implement PPI in research programmes, such as National Institute for Health Research (NIHR) Collaborations for Applied Health Research and Care (CLAHRCs), remains limited. This paper reports findings from an action research (AR) project called IMPRESS, which aims to strengthen PPI within CLAHRC East of England (EoE). IMPRESS combines AR with Normalisation Process Theory (NPT) to explore PPI within diverse case study projects, identifying actions to implement, test and refine to further embed PPI.Methods:We purposively selected CLAHRC EoE case study projects for in-depth analysis of PPI using NPT. Data were generated from project PPI documentation, semi-structured qualitative interviews with researchers and PPI contributors and focus groups. Transcripts and documents were subjected to abductive thematic analysis and triangulation within case. Systematic across case comparison of themes was undertaken with findings and implications refined through stakeholder consultation.Results:We interviewed 24 researchers and 13 PPI contributors and analysed 28 documents from 10 case studies. Three focus groups were held: two with researchers (n = 4 and n = 6) and one with PPI contributors (n = 5). Findings detail to what extent projects made sense of PPI, bought in to PPI, operationalised PPI and appraised it, thus identifying barriers and enablers to fully embedded PPI.Conclusion:Combining NPT with AR allows us to assess the embeddedness of PPI within projects and programme, to inform specific local action and report broader conceptual lessons for PPI knowledge and practice informing the development of an action framework for embedding PPI in research programmes. To embed PPI within similar programmes teams, professionals, disciplines and institutions should be recognised as variably networked into existing PPI support. Further focus and research is needed on sharing PPI learning and supporting innovation in PPI.Peer reviewedFinal Published versio

Nurse-Facilitated Health Checks for Persons With Severe Mental Illness: A Cluster-Randomized Controlled Trial

Objective: This study tested the effectiveness of a nurse-delivered health check with the Health Improvement Profile (HIP), which takes approximately 1.5 hours to complete and code, for persons with severe mental illness. Methods: A single-blind, cluster-randomized controlled trial was conducted in England to test whether health checks improved the general medical well-being of persons with severe mental illness at 12-month follow-up. Results: Sixty nurses were randomly assigned to the HIP group or the treatment-as-usual group. From their case lists, 173 patients agreed to participate. HIP group nurses completed health checks for 38 of their 90 patients (42%) at baseline and 22 (24%) at follow-up. No significant between-group differences were noted in patients’ general medical well-being at follow-up. Conclusions: Nurses who had volunteered for a clinical trial administered health checks only to a minority of participating patients, suggesting that it may not be feasible to undertake such lengthy structured health checks in routine practice

Modelling strategies to break transmission of lymphatic filariasis : aggregation, adherence and vector competence greatly alter elimination

Background: With ambitious targets to eliminate lymphatic filariasis over the coming years, there is a need to identify optimal strategies to achieve them in areas with different baseline prevalence and stages of control. Modelling can assist in identifying what data should be collected and what strategies are best for which scenarios. Methods: We develop a new individual-based, stochastic mathematical model of the transmission of lymphatic filariasis. We validate the model by fitting to a first time point and predicting future timepoints from surveillance data in Kenya and Sri Lanka, which have different vectors and different stages of the control programme. We then simulate different treatment scenarios in low, medium and high transmission settings, comparing once yearly mass drug administration (MDA) with more frequent MDA and higher coverage. We investigate the potential impact that vector control, systematic non-compliance and different levels of aggregation have on the dynamics of transmission and control. Results: In all settings, increasing coverage from 65 to 80 % has a similar impact on control to treating twice a year at 65 % coverage, for fewer drug treatments being distributed. Vector control has a large impact, even at moderate levels. The extent of aggregation of parasite loads amongst a small portion of the population, which has been estimated to be highly variable in different settings, can undermine the success of a programme, particularly if high risk sub-communities are not accessing interventions. Conclusion: Even moderate levels of vector control have a large impact both on the reduction in prevalence and the maintenance of gains made during MDA, even when parasite loads are highly aggregated, and use of vector control is at moderate levels. For the same prevalence, differences in aggregation and adherence can result in very different dynamics. The novel analysis of a small amount of surveillance data and resulting simulations highlight the need for more individual level data to be analysed to effectively tailor programmes in the drive for elimination

Randomised controlled trial of a theory-based behavioural intervention to reduce formula milk intake

Objective: To assess the efficacy of a theory-based behavioural intervention to prevent rapidweight gain in formula-milk fed infants.  Design: In this single (assessor) blind, randomised controlled trial, 669 healthy full-terminfants receiving formula-milk within 14 weeks of birth were individually-randomised tointervention (n=340) or attention-matched control (n=329) groups. The intervention aimed toreduce formula-milk intakes, and promote responsive feeding and growth monitoring toprevent rapid weight gain (>+ 0.67 standard deviation scores [SDS]). It was delivered tomothers by trained facilitators up to infant age 6 months through 3 face-to-face contacts, 2telephone contacts, and written materials.  Results: Retention was 93% (622) at 6 months, 88% (586) at 12 months, and 94% attended >4/5 sessions. The intervention strengthened maternal attitudes to following infant feedingrecommendations, reduced reported milk intakes at ages 3 (-14%; intervention vs controlinfants), 4 (-12%), 5 (-9%), and 6 (-7%) months, slowed initial infant weight gain frombaseline to 6 months (mean change 0.32 vs 0.42 SDS, baseline-adjusted difference(intervention vs control) -0.08 [95% CI; -0.17, -0.004] SDS), but had no effect on the primaryoutcome of weight gain to 12 months (baseline-adjusted difference -0.04 [-0.17, 0.10] SDS).By 12 months, 40.3% of infants in the intervention group and 45.9% in the control groupshowed rapid weight gain (OR: 0.84 [95% CI; 0.59, 1.17]).  Conclusions: Despite reducing milk intakes and initial weight gain, the intervention did notalter the high prevalence of rapid weight gain to age 12 months suggesting the need forsustained intervention