Young people with diabetes and their peers

Type 1 Diabetes (T1D) is amongst the most common form of chronic illness affecting young people in the UK. Self- management is crucial, but managing their T1D is often difficult for young people

The experiences of being diagnosed with Parkinson’s Disease

Being diagnosed with a chronic illness such as Parkinson’s disease (PD) can have a considerable psychological impact on a person’s life. However, this has been little explored and therefore it is unclear what support may be most beneficial at this time. This study therefore explored personal experiences of being diagnosed with PD. Six participants were interviewed and data analysed using thematic analysis. Three over-arching themes emerged: 1) “Understanding it is an important thing” – The value of knowledge; 2) "You’ve got to get used to accepting the fact that you need help" - The social implications of being diagnosed with PD; and 3) "I think you need to talk to somebody" - The importance of supportive others. The process of diagnosis was complex and often challenging for participants, with respect to their own understanding and that of others. Recommendations for future practice within specialist PD services are made, to improve the support that is offered at this time

Genomic priming of the antisecretory response to estrogen in rat distal colon throughout the estrous cycle.

The secretion of Cl(-) across distal colonic crypt cells provides the driving force for the movement of fluid into the luminal space. 17beta-Estradiol (E2) produces a rapid and sustained reduction in secretion in females, which is dependent on the novel protein kinase C delta (PKC delta) isozyme and PKA isoform I targeting of KCNQ1 channels. This sexual dimorphism in the E2 response is associated with a higher expression level of PKC delta in female compared with the male tissue. The present study revealed the antisecretory response is regulated throughout the female reproductive (estrous) cycle and is primed by genomic regulation of the kinases. E2 (1-10 nm) decreased cAMP-dependent secretion in colonic epithelia during the estrus, metestrus, and diestrus stages. A weak inhibition of secretion was demonstrated in the proestrus stage. The expression levels of PKC delta and PKA fluctuated throughout the estrous cycle and correlated with the potency of the antisecretory effect of E2. The expression of PKC delta and PKA were up-regulated by estrogen at a transcriptional level via a PKC delta-MAPK-cAMP response element-binding protein-regulated pathway indicating a genomic priming of the antisecretory response. PK Cdelta was activated by the membrane-impermeant E2-BSA, and this response was inhibited by the estrogen receptor antagonist ICI 182,780. The 66-kDa estrogen receptor-alpha isoform was present at the plasma membrane of female colonic crypt cells with a lower abundance found in male colonic crypts. The study demonstrates estrogen regulation of intestinal secretion both at a rapid and transcriptional level, demonstrating an interdependent relationship between both nongenomic and genomic hormone responses

Exploring how young people think about and respond to diabetes in their peers

Adolescence is a difficult time for people with diabetes and it is often accompanied by a deterioration in blood glucose control. This article looks at the effect the attitudes of peers can have on adolescents with diabetes. Three focus groups of 12–14-year-olds were asked about their knowledge of diabetes and were then presented with realistic vignettes about the condition, which they discussed. They then took part in a mythbusting session to help address misconceptions. The research team identified themes that emerged from the focus groups. Their findings suggest that a supportive peer network may be a valuable resource in good management of diabetes in young people. The research team suggest that more education about the condition is needed in schools and should be designed in collaboration with young people with diabetes

Empirical Challenges in Organizational Aesthetics Research: Towards a Sensual Methodology

Despite growing scholarly interest in aesthetic dimensions of organizational life, there is a lack of literature expressly engaging with the methodological mechanics of 'doing aesthetics research'. This article addresses that gap. It begins with an overview of the conceptual idiosyncrasies of 'aesthetics' as a facet of human existence and maps out the challenges these pose for empirical research methodology. A review of methodological approaches adopted to date in empirical studies of organizational aesthetics is then presented. The remainder of the article draws on the author's experiences and suggests methods and techniques to address both conceptual and practical challenges encountered during the execution of an organizational aesthetics research project. The article calls for a firmer focus on the aesthetic experiences of organizational members in addition to those of researchers and concludes with some suggestions as to the future of such 'sensual methodologies' </jats:p

Structural consequences of nucleophosmin mutations in acute myeloid leukemia.

Mutations affecting NPM1 (nucleophosmin) are the most common genetic lesions found in acute myeloid leukemia (AML). NPM1 is one of the most abundant proteins found in the nucleolus and has links to the MDM2/p53 tumor suppressor pathway. A distinctive feature of NPM1 mutants in AML is their aberrant localization to the cytoplasm of leukemic cells. This mutant phenotype is the result of the substitution of several C-terminal residues, including one or two conserved tryptophan residues, with a leucine-rich nuclear export signal. The exact molecular mechanism underlying the loss of nucleolar retention, and the role of the tryptophans, remains unknown. In this study we have determined the structure of an independently folded globular domain in the C terminus of NPM1 using NMR spectroscopy, and we report that the conserved tryptophans are critical for structure. This domain is necessary for the nucleolar targeting of NPM1 and is disrupted by mutations in AML with cytoplasmic NPM1. Furthermore, we identify conserved surface-exposed lysine residues that are functionally rather than structurally important for nucleolar localization. This study provides new focus for efforts to understand the pathogenesis of AML with cytoplasmic NPM1 and may be used to aid the design of small molecules that target the C-terminal domain of NPM1 to act as novel anti-proliferative and anti-leukemia therapeutics

Use of external comparators for health technology assessment submissions based on single-arm trials

Background: Single-arm trial (SAT) data is increasingly reviewed for drug approvals by regulators and Health Technology Assessment (HTA) bodies. Supplementary data in the form of external comparators (ECs) can be used to provide clinical context to support these drug evaluations. In this study we characterized HTAs for SAT-based submissions, the use of supplementary EC data and outcomes from HTA review. Methods: HTA Accelerator database was used to describe SAT-based HTA submissions with decisions (2011-2019). Results: A total of 433 SAT-based HTA submissions were identified between 2011 and 2019 with a 13-fold increase during this period. Around 65%(283/433) were in oncology or hem-oncology. Around 52%(226/433) of submissions contained some type of EC data, including prior clinical trials (24%, 104) and real-world data (RWD) (20%, 87), but 40%(175) contained no EC data. The overall acceptance rate for SAT-based submissions was 48% and with RWD EC data acceptance was 59%. In the latest 5-year period (2015-2019), use of RWD ECs increased 22% as a proportion of submissions per year, whereas, prior trial ECs decreased (–14%) and use of no EC remained stable (–2%). Between 2015 to 2017 and 2018 to 2019, acceptance rate for RWD ECs increased by 20% (41% in 2015-2017 to 61% in 2018-2019) whereas prior trial EC use decreased by 10% and no EC submissions decreased 16%. Of 226 submissions using ECs, only 29%(66) used an adjusted indirect treatment comparison method. Conclusions: SAT-based submissions to HTA bodies are rapidly evolving in terms of composition and acceptance. Types of EC and methodological approach used are important determinants of positive outcomes

Screening of siRNA Nanoparticles for Delivery to Airway Epithelial Cells Using High Content Analysis

Background: Delivery of siRNA to the lungs via inhalation offers a unique opportunity to develop novel methods of treating a range of poorly treated respiratory conditions. However progress has been greatly hindered by safety and delivery issues. This study developed a high-throughput method for screening novel nanotechnologies for pulmonary siRNA delivery Methodology: Following physico-chemical analysis, the ability of PEI-PEG/siRNA nanoparticles to facilitate siRNA delivery was determined using high content analysis (HCA) in Calu-3 cells. Results obtained from HCA were validated using confocal microscopy. Finally, cytotoxicity of the PEI-PEG/siRNA particles was analysed by HCA using the Cellomics® multiparamter cytotoxicity assay. Conclusions: PEI-PEG/siRNA nanoparticles facilitated increased siRNA uptake and luciferase knockdown in Calu-3 cells compared to PEI/siRNA

Seasonal Biotic Processes Vary the Carbon Turnover by Up To One Order of Magnitude in Wetlands

Soil Organic Carbon (SOC) turnover t in wetlands and the corresponding governing processes are still poorly represented in numerical models. t is a proxy to the carbon storage potential in each SOC pool and C fluxes within the whole ecosystem; however, it has not been comprehensively quantified in wetlands globally. Here, we quantify the turnover time t of various SOC pools and the governing biotic and abiotic processes in global wetlands using a comprehensively tested process-based biogeochemical model. Globally, we found that t ranges between 1 and 1,000 years and is controlled by anaerobic (in 78% of global wetlands area) and aerobic (15%) respiration, and by abiotic destabilization from soil minerals (5%). t in the remaining 2% of wetlands is controlled by denitrification, sulfur reduction, and leaching below the subsoil. t can vary by up to one order of magnitude in temperate, continental, and polar regions due to seasonal temperature and can shift from being aerobically controlled to anaerobically controlled. Our findings of seasonal variability in SOC turnover suggest that wetlands are susceptible to climate-induced shifts in seasonality, thus requiring better accounting of seasonal fluctuations at geographic scales to estimate C exchanges between land and atmosphere

A guide to behavioural experiments in bipolar disorder

Behavioural experiments are an important component of cognitive-behavioural therapy. However, there exists little up-to-date guidance on how to conduct these in people with a diagnosis of bipolar disorder. This paper provides recommendations on how to conduct behavioural experiments in this population. The aim is to upskill and empower clinicians to conduct behavioural experiments. The paper combines the expertise of senior clinicians working in the United Kingdom. The article starts by providing general advice on conducting behavioural experiments in people with bipolar disorder. It then offers specific examples of behavioural experiments targeting cognitions around the uncontrollability and danger of affective states, and related behavioural strategies, which have been implicated in the maintenance of bipolar mood swings. The article finishes by providing examples of behavioural experiments for non-mood related difficulties that commonly occur with bipolar experiences including perfectionistic thinking, need for approval, and intrusive memories. Behavioural experiments offer a useful therapeutic technique for instigating cognitive and behavioural change in bipolar disorder. Conducted sensitively and collaboratively, in line with people's recovery-focused goals, behavioural experiments can be used to overcome mood- and non-mood related difficulties