Assessing the mental health of 16 – 17 year olds in Manchester

AbstractCompulsory education in the United Kingdom ends at 16. This paper explores the challenges of attempting to find a representative sample of 16 – 17 year olds. The authors worked with Connexions, the careers advisory service and sent out a one stage postal questionnaire survey. Sixty young people returned questionnaires, information was also provided by parents and connexions workers. About 17% of young people identified that they needed professional help, as did a similar proportion of Connexions workers, while parents felt about 14% of adolescents needed professional help. Data from the Strengths and Difficulties Questionnaire identified that this sample had high levels of mental health needs

Viability of engineered biocatalysts in biotransformation

This project aims to exploit engineered biofilms as biocatalysts in the biotransformations of enantiomerically pure compounds for fine chemical and pharmaceutical industry. It aims for conditions to be designed which would improve reactions and formation of the engineered biofilms. Tsoligkas et al. (2012) has previously engineered a biofilm to act as a biocatalyst using tryptophan synthase, TrpBA produced from plasmid pSTB7 to catalyse the biotransformation of haloindoles to L-halotryptophans. To build on this work, biofilm formation and how the cells react to the biotransformation were investigated through flow cytometry and analysis of colony forming units (CFU). For biofilms to be formed from Escherichia coli (E. Coli) K-12, it was found that the plasmid pT7-csgD had to be present or the strain required an ompR234 point mutation to allow production of curli for extracellular polymeric substances to form a biofilm. This demonstrates the importance of CsgD as a regulator for formation, as without an increase in cellular concentration E. coli cells failed to attach to glass surfaces. From planktonic data it is apparent that carrying out the biotransformation with 5-chloroindole has a toxic effect on metabolically active E. coli PHL644 pSTB7. The source of this toxicity is not clear, it may be due to the products of the reaction, the chloroindole being metabolised or incorporated into the cellular proteins. Efflux data indicates that cells are incubated with fluoroindole have decreased efflux, an advantage for biotransformation

Developing a non-pharmacological intervention model to improve function and participation in people with primary Sjögren's syndrome

PhD ThesisBackground: Primary Sjögren’s syndrome (PSS) is an autoimmune disease which primarily targets secretory glands causing sicca/dryness symptoms. Patients with PSS also experience a range of other symptoms including fatigue, pain, sleep disturbances, low mood and anxiety. These symptoms impact on activities of daily living, participation and quality of life. PSS has been an under researched disease, and as a consequence many needs of patients remain unmet within clinical settings. Aim: To design a non-pharmacological intervention strategy for people with PSS focussing on patient-relevant targets in order to improve daily function and participation. Methods: In this project, I use a mixed methods approach. I conducted a systematic review of published interventions of non-pharmacological interventions for PSS. Then concept mapping, a participatory mixed methods approach, was used to identify factors which interfere with performance of daily activity for people with PSS. These results were discussed with a steering group and used as a basis to develop an intervention strategy. I then conducted focus groups with patients and their spouses to discuss the main factors deemed to interfere with activities, ascertain strategies patients use to manage these problems, and to determine the acceptability of potential future interventions to address these factors. Finally a model for the delivery of non-pharmacological interventions to address these factors was developed with patients. Results: The systematic review found there was insufficient published evidence to either support or refute non-pharmacological interventions for PSS. The concept mapping study revealed that in addition to dryness; fatigue, pain and sleep disturbances were priority targets for future interventions. The qualitative focus groups demonstrated that patients currently deploy a range of strategies to self-manage fatigue, sleep and v pain. However, these strategies are not always successful and patients require individualised therapies which target their own priorities and required level of support. Conclusion: The work within this thesis provides a comprehensive understanding of factors which influence daily function and participation in PSS patients. This work presents a stakeholder-informed model for delivering future non-pharmacological interventions to address stakeholder informed priorities. As such, a model has been developed which will ultimately support patients to manage symptoms of fatigue, sleep disturbances and pain, which are perceived by patients, their families and health professionals to impact on performance of daily activities and participation.Arthritis Research UK for awarding me a Nurse and Allied Health Professional Training Fellowship and to the United Kingdom Occupational Therapy Research Foundation for awarding me with a Research Career Development Award. This funding has meant that this research could take place

Effects of cigarette smoking on SARS-CoV-2 receptor ACE2 expression in the respiratory epithelium(dagger)

Due to the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic, the world is currently facing high morbidity and mortality rates as well as severe disruption to normal societal and social structures. SARS-CoV-2 uses the ACE2 receptor for cellular entry. In a recent publication of The Journal of Pathology, Liu and coworkers highlight the effects of cigarette smoking on ACE2 expression in the respiratory epithelium. The authors studied the effects of acute cigarette smoke exposure in a murine model and confirmed their findings in human lung tissues and gene expression datasets. Their findings demonstrate that cigarette smoking increases ACE2 expression specifically at the apical surface of the airway epithelium. Smoking cessation resulted in lower ACE2 expression, with implications for attenuating the risk of transmission of the virus. The role of ACE2 expression in the development of COVID-19 symptoms is still under investigation, with conflicting results from experimental models on the role of ACE2 expression in SARS-CoV-2-induced lung injury. In this commentary, we highlight the implications and limitations of the study of Liu et al as well as future therapeutic strategies directed towards ACE2. (c) 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland

Recent advances in chronic obstructive pulmonary disease pathogenesis : from disease mechanisms to precision medicine

Chronic obstructive pulmonary disease (COPD) is a devastating lung disease with a high personal and societal burden. Exposure to toxic particles and gases, including cigarette smoke, is the main risk factor for COPD. Together with smoking cessation, current treatment strategies of COPD aim to improve symptoms and prevent exacerbations, but there is no disease-modifying treatment. The biggest drawback of today's COPD treatment regimen is the 'one size fits all' pharmacological intervention, mainly based on disease severity and symptoms and not the individual's disease pathology. To halt the worrying increase in the burden of COPD, disease management needs to be advanced with a focus on personalized treatment. The main pathological feature of COPD includes a chronic and abnormal inflammatory response within the lungs, which results in airway and alveolar changes in the lung as reflected by (small) airways disease and emphysema. Here we discuss recent developments related to the abnormal inflammatory response, ECM and age-related changes, structural changes in the small airways and the role of sex-related differences, which are all relevant to explain the individual differences in the disease pathology of COPD and improve disease endotyping. Furthermore, we will discuss the most recent developments of new treatment strategies using biologicals to target specific pathological features or disease endotypes of COPD. (c) 2019 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland

Current perspectives on the role of interleukin-1 signalling in the pathogenesis of asthma and COPD

Asthma and chronic obstructive pulmonary disease (COPD) cause significant morbidity and mortality worldwide. In the context of disease pathogenesis, both asthma and COPD involve chronic inflammation of the lung and are characterised by the abnormal release of inflammatory cytokines, dysregulated immune cell activity and remodelling of the airways. To date, current treatments still only manage symptoms and do not reverse the primary disease processes. In recent work, interleukin (IL)-1α and IL-1β have been suggested to play important roles in both asthma and COPD. In this review, we summarise overwhelming pre-clinical evidence for dysregulated signalling of IL-1α and IL-1β contributing to disease pathogenesis and discuss the paradox of IL-1 therapeutic studies in asthma and COPD. This is particularly important given recent completed and ongoing clinical trials with IL-1 biologics that have had varying degrees of failure and success as therapeutics for disease modification in asthma and COPD

The air–liquid interface model

The airway epithelium lining the airways is in first contact with the inhaled environment, which contains allergens, gaseous pollutants, particulates, and pathogenic microorganisms. It forms an ion- and size-selective barrier between the inhaled environment and the underlying tissue by the formation of intercellular tight junctions and adhesion junctions. Additionally, the airway epithelium plays an important role in innate immune defense, expressing receptors that recognize molecular patterns from pathogenic microbes, parasites, fungi, and allergens and danger signals from damaged cells, directing proinflammatory processes. Chronic lung diseases, such as asthma and chronic obstructive pulmonary disease, involve changes in airway epithelial function. For valuable insights into these changes, in vitro models should closely recapitulate human airway epithelial composition, three-dimensional structure, and function as an immunological barrier. The goal of this chapter is to review the literature on the use of air–liquid interface cultures to model the lung epithelium in health and disease.</p

PANTHER: AZD8931, inhibitor of EGFR, ERBB2 and ERBB3 signalling, combined with FOLFIRI: a Phase I/II study to determine the importance of schedule and activity in colorectal cancer

BACKGROUND: Epidermal growth factor receptor (EGFR) is a therapeutic target to which HER2/HER3 activation may contribute resistance. This Phase I/II study examined the toxicity and efficacy of high-dose pulsed AZD8931, an EGFR/HER2/HER3 inhibitor, combined with chemotherapy, in metastatic colorectal cancer (CRC). METHODS: Treatment-naive patients received 4-day pulses of AZD8931 with irinotecan/5-FU (FOLFIRI) in a Phase I/II single-arm trial. Primary endpoint for Phase I was dose limiting toxicity (DLT); for Phase II best overall response. Samples were analysed for pharmacokinetics, EGFR dimers in circulating exosomes and Comet assay quantitating DNA damage. RESULTS: Eighteen patients received FOLFIRI and AZD8931. At 160 mg bd, 1 patient experienced G3 DLT; 160 mg bd was used for cohort expansion. No grade 5 adverse events (AE) reported. Seven (39%) and 1 (6%) patients experienced grade 3 and grade 4 AEs, respectively. Of 12 patients receiving 160 mg bd, best overall response rate was 25%, median PFS and OS were 8.7 and 21.2 months, respectively. A reduction in circulating HER2/3 dimer in the two responding patients after 12 weeks treatment was observed. CONCLUSIONS: The combination of pulsed high-dose AZD8931 with FOLFIRI has acceptable toxicity. Further studies of TKI sequencing may establish a role for pulsed use of such agents rather than continuous exposure. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number: NCT01862003

Recent advances in chronic obstructive pulmonary disease pathogenesis: from disease mechanisms to precision medicine

Chronic obstructive pulmonary disease (COPD) is a devastating lung disease with a high personal and societal burden. Exposure to toxic particles and gases, including cigarette smoke, is the main risk factor for COPD. Together with smoking cessation, current treatment strategies of COPD aim to improve symptoms and prevent exacerbations, but there is no disease-modifying treatment. The biggest drawback of today\'s COPD treatment regimen is the \xe2\x80\x98one size fits all\xe2\x80\x99 pharmacological intervention, mainly based on disease severity and symptoms and not the individual\'s disease pathology. To halt the worrying increase in the burden of COPD, disease management needs to be advanced with a focus on personalized treatment. The main pathological feature of COPD includes a chronic and abnormal inflammatory response within the lungs, which results in airway and alveolar changes in the lung as reflected by (small) airways disease and emphysema. Here we discuss recent developments related to the abnormal inflammatory response, ECM and age-related changes, structural changes in the small airways and the role of sex-related differences, which are all relevant to explain the individual differences in the disease pathology of COPD and improve disease endotyping. Furthermore, we will discuss the most recent developments of new treatment strategies using biologicals to target specific pathological features or disease endotypes of COPD