• IL-13 deficiency exacerbates lung damage and impairs epithelial-derived type 2 molecules during nematode infection.

      Chenery, Alistair L; orcid: 0000-0001-8755-461X; Rosini, Silvia; orcid: 0000-0002-7853-9300; Parkinson, James E; orcid: 0000-0003-4881-5121; Ajendra, Jesuthas; orcid: 0000-0002-9256-5396; Herrera, Jeremy A; orcid: 0000-0003-4845-8494; Lawless, Craig; orcid: 0000-0002-8240-3430; Chan, Brian Hk; orcid: 0000-0002-9451-4621; Loke, P'ng; orcid: 0000-0002-6211-3292; MacDonald, Andrew S; orcid: 0000-0002-5356-1149; Kadler, Karl E; orcid: 0000-0003-4977-4683; et al. (2021-06-14)
      IL-13 is implicated in effective repair after acute lung injury and the pathogenesis of chronic diseases such as allergic asthma. Both these processes involve matrix remodelling, but understanding the specific contribution of IL-13 has been challenging because IL-13 shares receptors and signalling pathways with IL-4. Here, we used infection as a model of acute lung damage comparing responses between WT and IL-13-deficient mice, in which IL-4 signalling is intact. We found that IL-13 played a critical role in limiting tissue injury and haemorrhaging in the lung, and through proteomic and transcriptomic profiling, identified IL-13-dependent changes in matrix and associated regulators. We further showed a requirement for IL-13 in the induction of epithelial-derived type 2 effector molecules such as RELM-α and surfactant protein D. Pathway analyses predicted that IL-13 induced cellular stress responses and regulated lung epithelial cell differentiation by suppression of Foxa2 pathways. Thus, in the context of acute lung damage, IL-13 has tissue-protective functions and regulates epithelial cell responses during type 2 immunity. [Abstract copyright: © 2021 Chenery et al.]
    • IL-17A both initiates, via IFNγ suppression, and limits the pulmonary type-2 immune response to nematode infection

      Ajendra, Jesuthas; Chenery, Alistair L.; Parkinson, James E.; Chan, Brian H. K.; Pearson, Stella; Colombo, Stefano A. P.; Boon, Louis; Grencis, Richard K.; Sutherland, Tara E.; email: tara.sutherland@manchester.ac.uk; Allen, Judith E.; orcid: 0000-0002-3829-066X; email: judi.allen@manchester.ac.uk (Nature Publishing Group US, 2020-07-07)
      Abstract: Nippostrongylus brasiliensis is a well-defined model of type-2 immunity but the early lung-migrating phase is dominated by innate IL-17A production. In this study, we confirm previous observations that Il17a-KO mice infected with N. brasiliensis exhibit an impaired type-2 immune response. Transcriptional profiling of the lung on day 2 of N. brasiliensis infection revealed an increased Ifng signature in Il17a-KO mice confirmed by enhanced IFNγ protein production in lung lymphocyte populations. Depletion of early IFNγ rescued type-2 immune responses in the Il17a-KO mice demonstrating that IL-17A-mediated suppression of IFNγ promotes type-2 immunity. Notably, later in infection, once the type-2 response was established, IL-17A limited the magnitude of the type-2 response. IL-17A regulation of type-2 immunity was lung-specific and infection with Trichuris muris revealed that IL-17A promotes a type-2 immune response in the lung even when infection is restricted to the intestine. Together our data reveal IL-17A as a major regulator of pulmonary type-2 immunity such that IL-17A supports early development of a protective type-2 response by suppression of IFNγ but subsequently limits excessive type-2 responses. A failure of this feedback loop may contribute to conditions such as severe asthma, characterised by combined elevation of IL-17 and type-2 cytokines.
    • 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.
    • Imaging translocator protein expression with positron emission tomography.

      Wimberley, Catriona; Buvat, Irene; Boutin, Hervé; email: herve.boutin@manchester.ac.uk (2021-11-03)
    • Immune infiltrate diversity confers a good prognosis in follicular lymphoma.

      Tsakiroglou, Anna-Maria; Astley, Susan; Dave, Manàs; Fergie, Martin; Harkness, Elaine; Rosenberg, Adeline; Sperrin, Matthew; West, Catharine; Byers, Richard; orcid: 0000-0003-0796-0365; email: richard.byers@mft.nhs.uk; Linton, Kim; email: kim.linton@manchester.ac.uk (2021-04-30)
      Follicular lymphoma (FL) prognosis is influenced by the composition of the tumour microenvironment. We tested an automated approach to quantitatively assess the phenotypic and spatial immune infiltrate diversity as a prognostic biomarker for FL patients. Diagnostic biopsies were collected from 127 FL patients initially treated with rituximab-based therapy (52%), radiotherapy (28%), or active surveillance (20%). Tissue microarrays were constructed and stained using multiplex immunofluorescence (CD4, CD8, FOXP3, CD21, PD-1, CD68, and DAPI). Subsequently, sections underwent automated cell scoring and analysis of spatial interactions, defined as cells co-occurring within 30 μm. Shannon's entropy, a metric describing species biodiversity in ecological habitats, was applied to quantify immune infiltrate diversity of cell types and spatial interactions. Immune infiltrate diversity indices were tested in multivariable Cox regression and Kaplan-Meier analysis for overall (OS) and progression-free survival (PFS). Increased diversity of cell types (HR = 0.19 95% CI 0.06-0.65, p = 0.008) and cell spatial interactions (HR = 0.39, 95% CI 0.20-0.75, p = 0.005) was associated with favourable OS, independent of the Follicular Lymphoma International Prognostic Index. In the rituximab-treated subset, the favourable trend between diversity and PFS did not reach statistical significance. Multiplex immunofluorescence and Shannon's entropy can objectively quantify immune infiltrate diversity and generate prognostic information in FL. This automated approach warrants validation in additional FL cohorts, and its applicability as a pre-treatment biomarker to identify high-risk patients should be further explored. The multiplex image dataset generated by this study is shared publicly to encourage further research on the FL microenvironment.
    • 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 failure in two silicates revealed by ultrafast, in situ, synchrotron X-ray microscopy

      Bourne, N. K.; email: neil.bourne@manchester.ac.uk; Mirihanage, W. U.; Olbinado, M. P.; Rack, A.; Rau, C. (Nature Publishing Group UK, 2020-06-25)
      Abstract: To travel safely behind screens that can protect us from stones and hail, we must understand the response of glass to impact. However, without a means to observe the mechanisms that fail different silicate architectures, engineering has relied on external sensors, post-impact examination and best-guess to glaze our vehicles. We have used single and multi-bunch, X-ray imaging to differentiate distinct phases of failure in two silicates. We identified distinct micromechanisms, operating in tandem and leading to failure in borosilicate glass and Z-cut quartz. A surface zone in the amorphous glass densifies before bulk fracture occurs and then fails the block, whilst in quartz, fast cracks, driven down cleavage planes, fails the bulk. Varying the rate at which ejecta escapes by using different indenter tip geometries controls the failed target’s bulk strength. This opens the way to more physically based constitutive descriptions for the glasses allowing design of safer, composite panels by controlling the impulses felt by protective screens.
    • Impact of Black Carbon on Surface Ozone in the Yangtze River Delta from 2015 to 2018

      Tan, Yue; orcid: 0000-0002-5198-9547; email: tanyue_focus@163.com; Zhao, Delong; email: zhaodelong@bj.cma.gov.cn; Wang, Honglei; email: hongleiwang@nuist.edu.cn; Zhu, Bin; email: binzhu@nuist.edu.cn; Bai, Dongping; email: dongpingbai@hotmail.com; Liu, Ankang; email: 20181203017@nuist.edu.cn; Shi, Shuangshuang; email: sss@nuist.edu.cn; Dai, Qihang; email: qihang.dai@student.manchester.ac.uk (MDPI, 2021-05-13)
      Despite the yearly decline in PM2.5 in China, surface ozone has been rapidly increasing recently, which makes it imperative to coordinate and control both PM2.5 and ozone in the atmosphere. This study utilized the data of pollutant concentrations and meteorological elements during 2015 to 2018 in Nanjing, China to analyze the daily correlation between black carbon and ozone (CBO), and the distribution of the pollutant concentrations under different levels of CBO. Besides, the diurnal variations of pollutant concentrations and meteorological elements under high positive and negative CBO were discussed and compared. The results show that the percentage of positive CBO had been increasing at the average rate of 7.1%/year, and it was 38.7% in summer on average, nearly twice of that in other seasons (19.2%). The average black carbon (BC), PM2.5 and NO2 under positive CBO was lower than those under negative CBO. It is noticeable that the surface ozone began to ascend when CBO was up to 0.2, with PM2.5 and NO2 decreasing and BC remaining steady. Under negative CBO, pollutant concentrations and meteorological elements showed obvious diurnal variations: BC showed a double-peak pattern and surface ozone, PM2.5, SO2 and CO showed single-peak patterns and NO2 showed a trough from 10:00 to 19:00. Wind speed and visibility showed a single-peak pattern with little seasonal difference. Relative humidity rose first, then it lowered and then it rose. Under positive CBO, the patterns of diurnal variations became less obvious, and some of them even showed no patterns, but just fluctuated at a certain level.
    • Impact of COVID-19 on diagnoses, monitoring, and mortality in people with type 2 diabetes in the UK.

      Carr, Matthew J; email: matthew.carr@manchester.ac.uk; Wright, Alison K; Leelarathna, Lalantha; Thabit, Hood; Milne, Nicola; Kanumilli, Naresh; Ashcroft, Darren M; Rutter, Martin K (2021-05-11)
    • Impact of COVID-19 restrictions on diabetes health checks and prescribing for people with type 2 diabetes: a UK-wide cohort study involving 618 161 people in primary care.

      Carr, Matthew J; orcid: 0000-0001-7336-1606; email: matthew.carr@manchester.ac.uk; Wright, Alison K; orcid: 0000-0002-8418-8332; Leelarathna, Lalantha; orcid: 0000-0001-9602-1962; Thabit, Hood; orcid: 0000-0001-6076-6997; Milne, Nicola; Kanumilli, Naresh; Ashcroft, Darren M; orcid: 0000-0002-2958-915X; Rutter, Martin K; orcid: 0000-0001-6380-539X (2021-10-12)
      To compare rates of performing National Institute for Health and Care Excellence-recommended health checks and prescribing in people with type 2 diabetes (T2D), before and after the first COVID-19 peak in March 2020, and to assess whether trends varied by age, sex, ethnicity and deprivation. We studied 618 161 people with T2D followed between March and December 2020 from 1744 UK general practices registered with the Clinical Practice Research Datalink. We focused on six health checks: haemoglobin A1c, serum creatinine, cholesterol, urinary albumin excretion, blood pressure and body mass index assessment. Regression models compared observed rates in April 2020 and between March and December 2020 with trend-adjusted expected rates derived from 10-year historical data. In April 2020, in English practices, rates of performing health checks were reduced by 76%-88% when compared with 10-year historical trends, with older people from deprived areas experiencing the greatest reductions. Between May and December 2020, the reduced rates recovered gradually but overall remained 28%-47% lower, with similar findings in other UK nations. Extrapolated to the UK population, there were ~7.4 million fewer care processes undertaken March-December 2020. In England, rates for new medication fell during April with reductions varying from 10% (95% CI: 4% to 16%) for antiplatelet agents to 60% (95% CI: 58% to 62%) for antidiabetic medications. Overall, between March and December 2020, the rate of prescribing new diabetes medications fell by 19% (95% CI: 15% to 22%) and new antihypertensive medication prescribing fell by 22% (95% CI: 18% to 26%), but prescribing of new lipid-lowering or antiplatelet therapy was unchanged. Similar trends were observed across the UK, except for a reduction in new lipid-lowering therapy prescribing in the other UK nations (reduction: 16% (95% CI: 10% to 21%)). Extrapolated to the UK population, between March and December 2020, there were ~31 800 fewer people with T2D prescribed a new type of diabetes medication and ~14 600 fewer prescribed a new type of antihypertensive medication. Over the coming months, healthcare services will need to manage this backlog of testing and prescribing. We recommend effective communications to ensure patient engagement with diabetes services, monitoring and opportunities for prescribing, and when appropriate use of home monitoring, remote consultations and other innovations in care. [Abstract copyright: © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.]
    • Impact of COVID-19 restrictions on diabetes health checks and prescribing for people with type 2 diabetes: a UK-wide cohort study involving 618 161 people in primary care.

      Carr, Matthew J; orcid: 0000-0001-7336-1606; email: matthew.carr@manchester.ac.uk; Wright, Alison K; orcid: 0000-0002-8418-8332; Leelarathna, Lalantha; orcid: 0000-0001-9602-1962; Thabit, Hood; orcid: 0000-0001-6076-6997; Milne, Nicola; Kanumilli, Naresh; Ashcroft, Darren M; orcid: 0000-0002-2958-915X; Rutter, Martin K; orcid: 0000-0001-6380-539X (2021-10-12)
      <h4>Objective</h4>To compare rates of performing National Institute for Health and Care Excellence-recommended health checks and prescribing in people with type 2 diabetes (T2D), before and after the first COVID-19 peak in March 2020, and to assess whether trends varied by age, sex, ethnicity and deprivation.<h4>Methods</h4>We studied 618 161 people with T2D followed between March and December 2020 from 1744 UK general practices registered with the Clinical Practice Research Datalink. We focused on six health checks: haemoglobin A1c, serum creatinine, cholesterol, urinary albumin excretion, blood pressure and body mass index assessment. Regression models compared observed rates in April 2020 and between March and December 2020 with trend-adjusted expected rates derived from 10-year historical data.<h4>Results</h4>In April 2020, in English practices, rates of performing health checks were reduced by 76%-88% when compared with 10-year historical trends, with older people from deprived areas experiencing the greatest reductions. Between May and December 2020, the reduced rates recovered gradually but overall remained 28%-47% lower, with similar findings in other UK nations. Extrapolated to the UK population, there were ~7.4 million fewer care processes undertaken March-December 2020. In England, rates for new medication fell during April with reductions varying from 10% (95% CI: 4% to 16%) for antiplatelet agents to 60% (95% CI: 58% to 62%) for antidiabetic medications. Overall, between March and December 2020, the rate of prescribing new diabetes medications fell by 19% (95% CI: 15% to 22%) and new antihypertensive medication prescribing fell by 22% (95% CI: 18% to 26%), but prescribing of new lipid-lowering or antiplatelet therapy was unchanged. Similar trends were observed across the UK, except for a reduction in new lipid-lowering therapy prescribing in the other UK nations (reduction: 16% (95% CI: 10% to 21%)). Extrapolated to the UK population, between March and December 2020, there were ~31 800 fewer people with T2D prescribed a new type of diabetes medication and ~14 600 fewer prescribed a new type of antihypertensive medication.<h4>Conclusions</h4>Over the coming months, healthcare services will need to manage this backlog of testing and prescribing. We recommend effective communications to ensure patient engagement with diabetes services, monitoring and opportunities for prescribing, and when appropriate use of home monitoring, remote consultations and other innovations in care.
    • Impact of E-Bikes on Cycling in Hilly Areas: Participants’ Experience of Electrically-Assisted Cycling in a UK Study

      Behrendt, Frauke; email: f.behrendt@tue.nl; Cairns, Sally; orcid: 0000-0002-1174-991X; email: S.Cairns2@leeds.ac.uk; Raffo, David; email: d.raffo@chester.ac.uk; Philips, Ian; email: I.Philips@leeds.ac.uk (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; 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 &lt; 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 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.
    • Impact Response of Curved Composite Laminates: Effect of Radius and Thickness

      Harris, William; orcid: 0000-0002-5775-2428; email: william.harris-4@postgrad.manchester.ac.uk; Soutis, Constantinos; email: constantinos.soutis@manchetser.ac.uk; Atkin, Christopher (Springer Netherlands, 2020-07-25)
      Abstract: This paper presents the results of drop-weight impact testing (5 J to 30 J) on curved ±55° E-glass-epoxy laminates of varying radii and wall thickness. Three radii (75 mm, 100 mm, and 125 mm) on laminates with an effective wall thickness of 2.5 mm, and three wall thicknesses (2.5 mm, 4.1 mm, and 6.6 mm) with a radius of 100 mm were investigated. The damage pattern remained consistent, with the exception of the damage area, across the tested energies and was dominated by internal matrix cracking and multiple delaminations. However, no damage was recorded following a 5 J impact on the 2.5 mm thick laminates with 100 mm and 125 mm radii, all energy was absorbed elastically, while the laminate with a 75 mm radius of curvature developed a damage area of over 80 mm2. The thicker laminates showed a reduced overall damage area but a greater number of delaminations. The relationship between laminate thickness and delamination threshold load was found to be in line with impact testing of flat plates, varying with the laminate thickness to the 3/2 power. However, the simplified beam theory and a fracture mechanics model developed for the prediction of delamination threshold of flat plates was found to underestimate the delamination threshold load (DTL) of the curved laminates studied by about 40%. An increase in the laminate’s flexural modulus of a factor of two is required to bring the model’s predictions in line with the DTL values measured experimentally, highlighting how curvature can enhance bending stiffness and alter damage evolution. Finally, a significant finding is that the DTL of the curved plates is around 15% lower than the value measured for the whole cylindrical pipe of same specifications. Testing curved sections rather than a whole pipe could reduce effort, but further work is required to confirm this statement.