• <i>meta</i>-Selective olefination of fluoroarenes with alkynes using CO<sub>2</sub> as a traceless directing group.

      Spencer, Andrew R A; Korde, Rishi; Font, Marc; Larrosa, Igor; orcid: 0000-0002-5391-7424 (2020-03-31)
      Over the last few decades C-H olefination has received significant interest, due to the importance and usefulness of aryl olefins both as synthetic targets and intermediates. While a wide range of <i>ortho</i>-olefination protocols have been developed, only a small number of <i>meta</i>-olefinations are currently available. Importantly, the most common approach to <i>meta</i>-olefination, using a large <i>meta</i>-directing template, is not suitable for substrates such as fluorobenzenes, which cannot be derivatised. We report that the <i>meta</i>-selective olefination of fluoroarenes can be achieved <i>via</i> the use of CO<sub>2</sub> as a traceless directing group, which can be easily installed and removed in a one-pot process. Furthermore, this approach avoids the use of stoichiometric Ag(i)-salts, commonly used in C-H olefinations, and affords complete <i>meta</i>- over <i>ortho</i>/<i>para</i>-regioselectivity.
    • <i>Ortho</i> C-H arylation of arenes at room temperature using visible light ruthenium C-H activation.

      Sagadevan, Arunachalam; orcid: 0000-0001-9486-1706; Charitou, Anastasios; orcid: 0000-0002-9100-8950; Wang, Fen; Ivanova, Maria; Vuagnat, Martin; Greaney, Michael F; orcid: 0000-0001-9633-1135 (2020-04-07)
      A ruthenium-catalyzed <i>ortho</i> C-H arylation process is described using visible light. Using the readily available catalyst [RuCl<sub>2</sub>(<i>p</i>-cymene)]<sub>2</sub>, visible light irradiation was found to enable arylation of 2-aryl-pyridines at room temperature for a range of aryl bromides and iodides.
    • <i>‘I call it the hero complex’ –</i> Critical considerations of power and privilege and seeking to be an agent of change in qualitative researchers’ experiences

      Oakley, Lisa; orcid: 0000-0001-8909-7889; Fenge, Lee-Ann; orcid: 0000-0003-0896-7323; Taylor, Bethan (Informa UK Limited, 2020-01-30)
    • Identification of an Altered Matrix Signature in Kidney Aging and Disease.

      Randles, Michael; Lausecker, Franziska; Kong, Qing; Suleiman, Hani; Reid, Graeme; Kolatsi-Joannou, Maria; Tian, Pinyuan; Falcone, Sara; Davenport, Bernard; Potter, Paul; et al. (2021-05-28)
      Accumulation of extracellular matrix in organs and tissues is a feature of both aging and disease. In the kidney, glomerulosclerosis and tubulointerstitial fibrosis accompany the decline in function, which current therapies cannot address, leading to organ failure. Whilst histological and ultrastructural patterns of excess matrix form the basis of human disease classifications, comprehensive molecular resolution of abnormal matrix is lacking. Using mass spectrometry-based proteomics we resolved matrix composition over age in mouse models of kidney disease. We compared the changes in mice with a global characterization of human kidney matrix during aging and to existing kidney disease datasets to identify common molecular features. Ultrastructural changes in basement membranes are associated with altered cell adhesion and metabolic processes and with distinct matrix proteomes during aging and kidney disease progression in mice. Within the altered matrix, basement membrane components (laminins, type IV collagen, type XVIII collagen) were reduced and interstitial matrix proteins (collagens I, III, VI, XV, fibrinogens and nephronectin) were increased, a pattern also seen in human kidney aging. Indeed, this signature of matrix proteins was consistently modulated across all age and disease comparisons and the increase in interstitial matrix was also observed in human kidney disease datasets. This study provides deep molecular resolution of matrix accumulation in kidney aging and disease and identifies a common signature of proteins that provides insight into mechanisms of response to kidney injury and repair.
    • Identifying the content and context of pain within paediatric rheumatology healthcare professional curricula in the UK: a summative content analysis

      Lee, Rebecca Rachael; orcid: 0000-0002-4559-1647; email: rebecca.lee-4@manchester.ac.uk; McDonagh, Janet E.; Connelly, Mark; Peters, Sarah; Cordingley, Lis (BioMed Central, 2021-08-21)
      Abstract: Background: The curriculum for professionals working in paediatric rheumatology should include pain but it is unclear to what extent this currently occurs. The aim of this study was to identify pain-related curriculum content and the context in which pain is presented in educational and training documentation for healthcare professionals in this clinical speciality. Methods: Core curricula documents from UK based professional organisations were identified in partnership with healthcare professionals. Documents were analysed using a summative content analysis approach. Key pain terms were quantified and weighted frequencies were used to explore narrative pain themes. Latent content was interpreted qualitatively to explore the context within which pain terms were positioned. Results: Nine curriculum documents were identified and analysed from doctors, nurses, physiotherapists and occupational therapists specialising in paediatric rheumatology. Pain themes represented a mean percentage of 1.51% of text across all documents. Pain was rarely presented in the context of both inflammatory and non-inflammatory condition types despite being a common feature of each. Musculoskeletal pain was portrayed simply as a ‘somatic’ symptom, rather than as a complex phenomenon involving biological and psychosocial processes. Content around the assessment and management of pain was vague and inexplicit. Conclusion: Current educational and training documentation in paediatric rheumatology do not include core pain topics. Curricula for these healthcare professionals would benefit from updates in contemporary pain theories and examples of in-context, evidence-based pain practices. This should be a priority starting point for optimising patient pain care in paediatric musculoskeletal healthcare.
    • Identifying the content and context of pain within paediatric rheumatology healthcare professional curricula in the UK: a summative content analysis.

      Lee, Rebecca Rachael; orcid: 0000-0002-4559-1647; email: rebecca.lee-4@manchester.ac.uk; McDonagh, Janet E; Connelly, Mark; Peters, Sarah; Cordingley, Lis (2021-08-21)
      <h4>Background</h4>The curriculum for professionals working in paediatric rheumatology should include pain but it is unclear to what extent this currently occurs. The aim of this study was to identify pain-related curriculum content and the context in which pain is presented in educational and training documentation for healthcare professionals in this clinical speciality.<h4>Methods</h4>Core curricula documents from UK based professional organisations were identified in partnership with healthcare professionals. Documents were analysed using a summative content analysis approach. Key pain terms were quantified and weighted frequencies were used to explore narrative pain themes. Latent content was interpreted qualitatively to explore the context within which pain terms were positioned.<h4>Results</h4>Nine curriculum documents were identified and analysed from doctors, nurses, physiotherapists and occupational therapists specialising in paediatric rheumatology. Pain themes represented a mean percentage of 1.51% of text across all documents. Pain was rarely presented in the context of both inflammatory and non-inflammatory condition types despite being a common feature of each. Musculoskeletal pain was portrayed simply as a 'somatic' symptom, rather than as a complex phenomenon involving biological and psychosocial processes. Content around the assessment and management of pain was vague and inexplicit.<h4>Conclusion</h4>Current educational and training documentation in paediatric rheumatology do not include core pain topics. Curricula for these healthcare professionals would benefit from updates in contemporary pain theories and examples of in-context, evidence-based pain practices. This should be a priority starting point for optimising patient pain care in paediatric musculoskeletal healthcare.
    • Identity, Culture and Belonging: Educating Young Children for a Changing World

      Power, Michael; orcid: 0000-0002-9926-094X (Informa UK Limited, 2020-08-24)
    • Identity, Culture and Belonging: Educating Young Children for a Changing World

      Power, Michael; orcid: 0000-0002-9926-094X (Informa UK Limited, 2020-08-24)
    • Identity, Culture and Belonging: Educating Young Children for a Changing World

      Power, Michael; orcid: 0000-0002-9926-094X (Informa UK Limited, 2020-08-24)
    • IDPs in the Kurdistan Region of Iraq (KRI): Intractable Return and Absence of Social Integration Policy

      Khedir, Hewa Haji; orcid: 0000-0001-5257-2439; email: hewa.khedir@winchester.ac.uk (2020-05-27)
      Abstract: This paper examines the protracted nature of displacement in the Iraqi context and places emphasis on the need for a social integration policy to bridge the deep cleavages of Iraqi society. Methodologically, the paper utilizes qualitative data by conducting focus‐group discussions with IDPs and semi‐structured individual interviews in KRI. In terms of return possibilities, while return in many ways is perceived to be not practical and to involve future risks, research findings show that a community‐based distinction needs to be made between IDPs from minority backgrounds and IDPs who belong to demographic majorities in the homeland locations. A second distinction is a geographic and political one as findings indicate that IDPs who take refuge in KRI, though remain largely dissatisfied with displacement conditions, are willing to stay in KRI longer in the hope of further security and reconstruction process in the violence‐affected areas. With respect to social integration policy, the paper outlines institutional, political and cultural explanations for a virtually absolute absence of social integration policy on national and regional levels. The paper suggests that the proposed social integration policy can capitalize practical implications of Social Contact Theory (SCT) in enhancing the integration of IDPs in the host communities.
    • ILC3s control airway inflammation by limiting T cell responses to allergens and microbes.

      Teng, Fei; Tachó-Piñot, Roser; Sung, Biin; Farber, Donna L; Worgall, Stefan; Hammad, Hamida; Lambrecht, Bart N; Hepworth, Matthew R; email: matthew.hepworth@manchester.ac.uk; Sonnenberg, Gregory F; email: gfsonnenberg@med.cornell.edu (2021-11-23)
      Group 3 innate lymphoid cells (ILC3s) critically regulate host-microbe interactions in the gastrointestinal tract, but their role in the airway remains poorly understood. Here, we demonstrate that lymphoid-tissue-inducer (LTi)-like ILC3s are enriched in the lung-draining lymph nodes of healthy mice and humans. These ILC3s abundantly express major histocompatibility complex class II (MHC class II) and functionally restrict the expansion of allergen-specific CD4 T cells upon experimental airway challenge. In a mouse model of house-dust-mite-induced allergic airway inflammation, MHC class II ILC3s limit T helper type 2 (Th2) cell responses, eosinophilia, and airway hyperresponsiveness. Furthermore, MHC class II ILC3s limit a concomitant Th17 cell response and airway neutrophilia. This exacerbated Th17 cell response requires exposure of the lung to microbial stimuli, which can be found associated with house dust mites. These findings demonstrate a critical role for antigen-presenting ILC3s in orchestrating immune tolerance in the airway by restricting pro-inflammatory T cell responses to both allergens and microbes. [Abstract copyright: Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.]
    • The image makeover of Learning Resources at Chester College of Higher Education

      Walsh, Angela (SCONUL, 2002)
      In 2002, Learning Resources re-developed its user education materials. The library webpages were reorganised and updated, user education guides were updated to a common format and design, and a new logo was developed. The guides were promoted to students at the annual freshers fair. Difficulties with the project and future developments are discussed.
    • Immersive Virtual Reality for the Cognitive Rehabilitation of Stroke Survivors

      Chatterjee, Kausik; orcid: 0000-0002-3093-1469; Buchanan, Alastair; Cottrell, Katy; orcid: 0000-0002-1418-7676; Hughes, Sara; orcid: 0000-0001-6510-5960; Day, Thomas W.; orcid: 0000-0002-9153-4862; John, Nigel W.; orcid: 0000-0001-5153-182X (Institute of Electrical and Electronics Engineers (IEEE), 2022)
    • Immunomodulation by radiotherapy in tumour control and normal tissue toxicity.

      Cytlak, Urszula M; orcid: 0000-0002-2536-6012; email: urszula.cytlak-chaudhuri@manchester.ac.uk; Dyer, Douglas P; orcid: 0000-0001-5567-6241; Honeychurch, Jamie; orcid: 0000-0001-6938-0839; Williams, Kaye J; Travis, Mark A; orcid: 0000-0002-8485-2272; email: mark.travis-2@manchester.ac.uk; Illidge, Timothy M; orcid: 0000-0003-3191-7324; email: tim.illidge@manchester.ac.uk (2021-07-01)
      Radiotherapy (RT) is a highly effective anticancer treatment that is delivered to more than half of all patients with cancer. In addition to the well-documented direct cytotoxic effects, RT can have immunomodulatory effects on the tumour and surrounding tissues. These effects are thought to underlie the so-called abscopal responses, whereby RT generates systemic antitumour immunity outside the irradiated tumour. The full scope of these immune changes remains unclear but is likely to involve multiple components, such as immune cells, the extracellular matrix, endothelial and epithelial cells and a myriad of chemokines and cytokines, including transforming growth factor-β (TGFβ). In normal tissues exposed to RT during cancer therapy, acute immune changes may ultimately lead to chronic inflammation and RT-induced toxicity and organ dysfunction, which limits the quality of life of survivors of cancer. Here we discuss the emerging understanding of RT-induced immune effects with particular focus on the lungs and gut and the potential immune crosstalk that occurs between these tissues.
    • Impact of E-Bikes on Cycling in Hilly Areas: Participants’ Experience of Electrically-Assisted Cycling in a UK Study

      Behrendt, Frauke; Cairns, Sally; Raffo, David; Philips, Ian (MDPI, 2021-08-10)
      Electrically-assisted cycling can make a major contribution to sustainable mobility. For some people, hills are a barrier for cycling. This paper focuses on how and why electrically-assisted bikes make a difference to cycling in hilly contexts, and can thus be an important element of sustainable mobility in hilly geographies. It makes a novel contribution in being able to draw on recorded sensor data of the actual use of assistance in relation to the specific geography of the route cycled (GPS data), and interview/survey material. It shows that e-bikes extend the range, nature and scope of journeys manageable by bike, and therefore the general viability of e-bikes as alternative to other modes. It highlights that the benefits of using e-bikes are often also psychological, since they can change the overall enjoyability of the cycling experience in hilly areas. Resulting policy recommendations, that could lead to significant CO2 savings through the uptake of e-cycling in hilly contexts, include ‘try before you buy’ schemes, training for e-bike users and investing in relevant cycling infrastructure.
    • Impact of heart failure severity on ventricular assist device haemodynamics: a computational study

      McElroy, Michael; Xenakis, Antonios; Keshmiri, Amir; orcid: 0000-0003-4747-277X; email: a.keshmiri@manchester.ac.uk (Springer International Publishing, 2020-08-29)
      Abstract: Purpose: This computational fluid dynamics study investigates the necessity of incorporating heart failure severity in the preoperative planning of left ventricular assist device (LVAD) configurations, as it is often omitted from studies on LVAD performance. Methods: A parametric study was conducted examining a common range of LVAD to aortic root flow ratios (LVAD/AR-FR). A normal aortic root waveform was scaled by 5–30% in increments of 5% to represent the common range of flow pumped by the left ventricle for different levels of heart failure. A constant flow rate from the cannula compensated for the severity of heart failure in order to maintain normal total aortic flow rate. Results: The results show that LVAD/AR-FR can have a significant but irregular impact on the perfusion and shear stress-related haemodynamic parameters of the subclavian and carotid arteries. Furthermore, it is found that a larger portion of the flow is directed towards the thoracic aorta at the expense of the carotid and subclavian arteries, regardless of LVAD/AR-FR. Conclusion: The irregular behaviour found in the subclavian and carotid arteries highlights the necessity of including the LVAD/AR-FR in the preoperative planning of an LVAD configuration, in order to accurately improve the effects on the cardiovascular system post implantation.
    • Impact of hypoxia on cervical cancer outcomes.

      Datta, Anubhav; orcid: 0000-0002-5234-2315; email: anubhav.datta@manchester.ac.uk; West, Catharine; O'Connor, James P B; Choudhury, Ananya; Hoskin, Peter (2021-09-30)
      The annual global incidence of cervical cancer is approximately 604 000 cases/342 000 deaths, making it the fourth most common cancer in women. Cervical cancer is a major healthcare problem in low and middle income countries where 85% of new cases and deaths occur. Secondary prevention measures have reduced incidence and mortality in developed countries over the past 30 years, but cervical cancer remains a major cause of cancer deaths in women. For women who present with Fédération Internationale de Gynécologie et d'Obstétrique (FIGO 2018) stages IB3 or upwards, chemoradiation is the established treatment. Despite high rates of local control, overall survival is less than 50%, largely due to distant relapse. Reducing the health burden of cervical cancer requires greater individualization of treatment, identifying those at risk of relapse and progression for modified or intensified treatment. Hypoxia is a well known feature of solid tumors and an established therapeutic target. Low tumorous oxygenation increases the risk of local invasion, metastasis and treatment failure. While meta-analyses show benefit, many individual trials targeting hypoxia failed in part due to not selecting patients most likely to benefit. This review summarizes the available hypoxia-targeted strategies and identifies further research and new treatment paradigms needed to improve patient outcomes. The applications and limitations of hypoxia biomarkers for treatment selection and response monitoring are discussed. Finally, areas of greatest unmet clinical need are identified to measure and target hypoxia and therefore improve cervical cancer outcomes. [Abstract copyright: © IGCS and ESGO 2021. No commercial re-use. See rights and permissions. Published by BMJ.]
    • Impact of integrating mental health services within existing tuberculosis treatment facilities

      Pasha, Aneeta; orcid: 0000-0002-2699-4301; email: aneeta.pasha@ird.global; Siddiqui, Hasha; Ali, Shiza; Brooks, Meredith B; Maqbool, Naveen R; Khan, Aamir J (SAGE Publications, 2021-04-27)
      Introduction:: Depression and anxiety among tuberculosis (TB) patients can adversely affect TB treatment adherence and completion. Aim:: We studied whether integrating mental health services into existing TB treatment programs would reduce symptoms of depression and anxiety and improve treatment completion among patients with drug-susceptible TB. Methods:: Integrated practice units (IPUs) for TB and mental health were established within six existing TB treatment facilities in Karachi, Pakistan. Patients were screened for depression and anxiety and, if symptomatic, offered a mental health intervention consisting of at least four counseling sessions. We measured changes in reported levels of depression and anxiety symptoms from baseline following completion of counseling sessions, and rates of TB treatment completion. Results:: Between February 2017 and June 2018, 3500 TB patients were screened for depression and anxiety. 1057 (30.2%) symptomatic patients received a baseline adherence session. 1012 enrolled for a mental health intervention received at least 1 counseling session. 522 (51.5%) reported no symptoms after four to six sessions. Symptomatic patients who completed at least four counseling sessions had higher rates of TB treatment completion than those who did not (92.9% vs 75.1%; p < 0.0001). Conclusion:: Mental health interventions integrated within TB programs can help reduce symptoms of depression and anxiety and improve TB treatment completion.
    • Impact of sample size on the stability of risk scores from clinical prediction models: a case study in cardiovascular disease

      Pate, Alexander; orcid: 0000-0002-0849-3458; email: alexander.pate@manchester.ac.uk; Emsley, Richard; Sperrin, Matthew; Martin, Glen P.; van Staa, Tjeerd (BioMed Central, 2020-09-09)
      Abstract: Background: Stability of risk estimates from prediction models may be highly dependent on the sample size of the dataset available for model derivation. In this paper, we evaluate the stability of cardiovascular disease risk scores for individual patients when using different sample sizes for model derivation; such sample sizes include those similar to models recommended in the national guidelines, and those based on recently published sample size formula for prediction models. Methods: We mimicked the process of sampling N patients from a population to develop a risk prediction model by sampling patients from the Clinical Practice Research Datalink. A cardiovascular disease risk prediction model was developed on this sample and used to generate risk scores for an independent cohort of patients. This process was repeated 1000 times, giving a distribution of risks for each patient. N = 100,000, 50,000, 10,000, Nmin (derived from sample size formula) and Nepv10 (meets 10 events per predictor rule) were considered. The 5–95th percentile range of risks across these models was used to evaluate instability. Patients were grouped by a risk derived from a model developed on the entire population (population-derived risk) to summarise results. Results: For a sample size of 100,000, the median 5–95th percentile range of risks for patients across the 1000 models was 0.77%, 1.60%, 2.42% and 3.22% for patients with population-derived risks of 4–5%, 9–10%, 14–15% and 19–20% respectively; for N = 10,000, it was 2.49%, 5.23%, 7.92% and 10.59%, and for N using the formula-derived sample size, it was 6.79%, 14.41%, 21.89% and 29.21%. Restricting this analysis to models with high discrimination, good calibration or small mean absolute prediction error reduced the percentile range, but high levels of instability remained. Conclusions: Widely used cardiovascular disease risk prediction models suffer from high levels of instability induced by sampling variation. Many models will also suffer from overfitting (a closely linked concept), but at acceptable levels of overfitting, there may still be high levels of instability in individual risk. Stability of risk estimates should be a criterion when determining the minimum sample size to develop models.
    • The impact of severe haemophilia and the presence of target joints on health-related quality-of-life

      O’Hara, Jamie; Walsh, Shaun; Camp, Charlotte; Mazza, Giuseppe; Carroll, Liz; Hoxer, Christina; Wilkinson, Lars; University of Chester; HCD Economics; University College London; The Haemophilia Society; Novo Nordisk (BioMed Central, 2018-05-02)
      Background: Joint damage remains a major complication associated with haemophilia and is widely accepted as one of the most debilitating symptoms for persons with severe haemophilia. The aim of this study is to describe how complications of haemophilia such as target joints influence health-related quality of life (HRQOL). Methods: Data on hemophilia patients without inhibitors were drawn from the ‘Cost of Haemophilia across Europe – a Socioeconomic Survey’ (CHESS) study, a cost-of-illness assessment in severe haemophilia A and B across five European countries (France, Germany, Italy, Spain, and the UK). Physicians provided clinical and sociodemographic information for 1285 adult patients, 551 of whom completed corresponding questionnaires, including EQ-5D. A generalised linear model was developed to investigate the relationship between EQ-5D index score and target joint status (defined in the CHESS study as areas of chronic synovitis), adjusted for patient covariates including socio-demographic characteristics and comorbidities. Results: Five hundred and fifteen patients (42% of the sample) provided an EQ-5D response; a total of 692 target joints were recorded across the sample. Mean EQ-5D index score for patients with no target joints was 0.875 (standard deviation [SD] 0.179); for patients with one or more target joints, mean index score was 0.731 (SD 0.285). Compared to having no target joints, having one or more target joints was associated with lower index scores (average marginal effect (AME) -0.120; SD 0.0262; p < 0.000). Conclusions: This study found that the presence of chronic synovitis has a significant negative impact on HRQOL for adults with severe haemophilia. Prevention, early diagnosis and treatment of target joints should be an important consideration for clinicians and patients when managing haemophilia.