Theoretical investigation into asymmetric iminium ion organocatalysis

The scope of this thesis covered three main areas of this emerging area of chemistry. A reaction pathway is proposed for the formation of iminium ion intermediates from the reaction of secondary amines with carbonyl compounds. This suggests the deprotonation of the amine as the rate-determining step. The effect of modification of amine structure on this pathway was studied, and rationalised using Atoms-in-Molecules analysis. Molecular properties were used to describe a range of secondary amines with an aim to find a relationship between composition and reactivity. A number of catalytic candidates were suggested for synthesis. Two reaction types that directly and indirectly utilise iminium ions as catalysts or intermediates were covered. This included studies of model amines, as well as those in current use as asymmetric catalysts. The Diels-Alder reaction was studied in depth for a number of iminium ions. The alpha-acyloxylation of enamines was also studied, and reaction profiles in gas-phase and solvent identified, and possible mechanisms of asymmetric induction explored.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Theoretical investigation into asymmetric iminium ion organocatalysis

The scope of this thesis covered three main areas of this emerging area of chemistry. A reaction pathway is proposed for the formation of iminium ion intermediates from the reaction of secondary amines with carbonyl compounds. This suggests the deprotonation of the amine as the rate-determining step. The effect of modification of amine structure on this pathway was studied, and rationalised using Atoms-in-Molecules analysis. Molecular properties were used to describe a range of secondary amines with an aim to find a relationship between composition and reactivity. A number of catalytic candidates were suggested for synthesis. Two reaction types that directly and indirectly utilise iminium ions as catalysts or intermediates were covered. This included studies of model amines, as well as those in current use as asymmetric catalysts. The Diels-Alder reaction was studied in depth for a number of iminium ions. The alpha-acyloxylation of enamines was also studied, and reaction profiles in gas-phase and solvent identified, and possible mechanisms of asymmetric induction explored

Short total synthesis of ajoene

We describe a short total synthesis of ajoene, a major biologically active constituent of garlic. The instability of allicin as the only other known alternative starting material has led to the development of a reliable protocol for the synthesis of ajoene from simple building blocks also suitable for upscale operations

Short total synthesis of ajoene, (E ,Z )‐4,5,9‐Trithiadodeca‐1,6,11‐triene 9‐oxide, in batch and (E ,Z )‐4,5,9‐Trithiadodeca‐1,7,11‐triene in continuous flow

A short total synthesis of ajoene, (E,Z )‐4,5,9‐trithiadodeca‐1,6,11‐triene 9‐oxide, has been achieved over six steps. In addition, a continuous flow synthesis under mild reaction conditions to (E,Z )‐4,5,9‐trithiadodeca‐1,7,11‐triene is described starting from simple and easily accessible starting materials. Over four steps including propargylation, radical addition of thioacetate, deprotection, and disulfide formation/ allylation, the target product can be obtained at a rate of 0.26 g h−1 in an overall yield of 12 %

Engagement barriers and service inequities in the NHS Breast Screening Programme: Views from British-Pakistani women

Objectives: Previous research has largely attempted to explore breast screening experiences of South Asian women by combining opinions from Pakistani, Bangladeshi and Indian women. This research often fails to reach the most underserved sub-groups of this population, with socioeconomic status not routinely reported and English fluency being a participation requirement. With uptake low amongst British-Pakistani women, this study explores the experiences these women encounter when accessing the NHS Breast Screening Programme.Setting: Participants were from East Lancashire, UK. Methods: Nineteen one-to-one semi-structured interviews were carried out with British-Pakistani women. Fourteen interviews were conducted via an interpreter. Results: Data were analysed using thematic analysis. Three themes were identified: ‘Absence of autonomy in screening and healthcare access’ describes how currently the screening service does not facilitate confidentiality or independence. Access requires third-party intervention, with language barriers preventing self-expression. ‘Appraisal of information sources’ makes distinctions between community and NHS communication. Whereas community communication was invaluable, NHS materials were deemed inaccessible due to translation incongruences and incomprehensible terminology. ‘Personal suppositions of breast screening’ explores the subjective issues associated with disengagement, including, the cultural misalignment of the service and perceiving screening as a symptomatic service.Conclusions: British-Pakistani women face some unique challenges when accessing breast screening. To promote uptake, the service needs to address the translation of screening materials and optimise upon community networks to disseminate knowledge, including knowledge of the screening environment within the context of culture to promote informed choice about attendance

Cost-effectiveness of peer-supported self-management for people discharged from a mental health crisis team: methodological challenges and recommendations

Background Mental health acute crisis episodes are associated with high inpatient costs. Self-management interventions may reduce readmission by enabling individuals to manage their condition. Delivery of such interventions by Peer Support Workers (PSWs) may be cost-effective. CORE, a randomized control trial of a PSW self-management intervention compared to usual care, found a significant reduction in admissions to acute mental healthcare for participants receiving the intervention. This paper aims to evaluate the cost-effectiveness of the intervention over 12 months from a mental health service perspective. Analysis methods of increasing complexity were used to account for data missingness and distribution. Methods Participants were recruited from six crisis resolution teams in England from 12 March 2014 to 3 July 2015 (trial registration ISRCTN: 01027104). Resource use was collected from patient records at baseline and 12 months. The EQ-5D-3L was collected at baseline and 4 and 18 months, and linear interpolation was used to calculate 12-month values for quality-adjusted life-years (QALYs). The primary analysis of adjusted mean incremental costs and QALYs for complete cases are calculated separately using OLS regression. Secondly, a complete-case non-parametric two-stage bootstrap (TSB) was performed. The impacts of missing data and skewed cost data were explored using multiple imputation using chained equations and general linear models, respectively. Results Four hundred and forty-one participants were recruited to CORE; 221 randomized to the PSW intervention and 220 to usual care plus workbook. The probability that the PSW intervention was cost-effective compared with the workbook plus usual care control at 12 months varied with the method used, and ranged from 57% to 96% at a cost-effectiveness threshold of £20,000 per QALY gained. Discussion There was a minimum 57% chance that the intervention was cost-effective compared to the control using 12-month costs and QALYs. The probability varied by 40% when methods were employed to account for the relationship between costs and QALYs, but which restricted the sample to those who provided both complete cost and utility data. Caution should therefore be applied when selecting methods for the evaluation of healthcare interventions that aim to increase precision but may introduce bias if missing data are heavily unbalanced between costs and outcomes

Systematic Review of Respiratory Outbreaks Associated with Exposure to Water-Based Metalworking Fluids

Introduction: Potential demographic risk factors for outbreaks of respiratory disease due to water-based metalworking fluids (MWFs) were investigated through systematic review of published outbreak investigations. Methods: Search terms were selected by a multidisciplinary team, assisted by an experienced library information service. Several computerized literature databases were searched for articles published between January 1990 and October 2011, relating to ill health outbreaks due to MWFs. Papers meeting the search criteria were reviewed in detail, and their references checked for additional articles. Study design and demographic details of the outbreak were extracted from the selected articles and entered into standardized evidence tables. Results: Thirty-five articles relating to investigations of 27 outbreaks of respiratory ill health attributed to MWF exposure were identified. The majority of reports were case series of disease or observational cross-sectional studies of symptoms and hygiene measurements. Eight of the outbreak investigations included an element of case-control analysis. Most outbreaks were from the USA, had occurred in large car-or aeronautical-manufacturing plants, and were associated with the use of central shared sumps. Hygiene studies have not demonstrated consistent risk factors for respiratory outbreaks, in terms of the type of MWF utilized, degree of microbial contamination, or levels of personal exposure. Six studies were identified that found workers with MWF exposure during outbreaks were more likely to report respiratory or systemic symptoms than unexposed control workers. Six case-control analyses were also identified that found workers with extrinsic allergic alveolitis (EAA) were more likely to demonstrate certain immune responses to microbial contaminants and/or used MWFs than workers without EAA. Conclusion: Despite a number of detailed workplace and immunological studies of asthma and alveolitis outbreaks in MWF-exposed workforces, our understanding of their aetiology remains limited

Critical review of the current and future challenges associated with advanced in vitro systems towards the study of nanoparticle (secondary) genotoxicity.

With the need to understand the potential biological impact of the plethora of nanoparticles (NPs) being manufactured for a wide range of potential human applications, due to their inevitable human exposure, research activities in the field of NP toxicology has grown exponentially over the last decade. Whilst such increased research efforts have elucidated an increasingly significant knowledge base pertaining to the potential human health hazard posed by NPs, understanding regarding the possibility for NPs to elicit genotoxicity is limited. In vivo models are unable to adequately discriminate between the specific modes of action associated with the onset of genotoxicity. Additionally, in line with the recent European directives, there is an inherent need to move away from invasive animal testing strategies. Thus, in vitro systems are an important tool for expanding our mechanistic insight into NP genotoxicity. Yet uncertainty remains concerning their validity and specificity for this purpose due to the unique challenges presented when correlating NP behaviour in vitro and in vivo This review therefore highlights the current state of the art in advanced in vitro systems and their specific advantages and disadvantages from a NP genotoxicity testing perspective. Key indicators will be given related to how these systems might be used or improved to enhance understanding of NP genotoxicity

Extending screening intervals for women at low risk of breast cancer: do they find it acceptable?

From Springer Nature via Jisc Publications RouterHistory: received 2020-11-27, accepted 2021-04-13, registration 2021-05-12, pub-electronic 2021-05-29, online 2021-05-29, collection 2021-12Publication status: PublishedAbstract: Background: Trials of risk estimation in breast cancer screening programmes, in order to identify women at higher risk and offer extra screening/preventive measures, are ongoing. It may also be feasible to introduce less frequent screening for women at low-risk of breast cancer. This study aimed to establish views of women at low-risk of breast cancer regarding the acceptability of extending breast screening intervals for low-risk women beyond 3 y. Methods: Semi-structured interviews were used to explore views of low-risk women, where “low-risk” was defined as less than 2% estimated 10-year risk of breast cancer aged > 46 years. Low-risk women were identified via the BC-Predict study, where following routine screening, women were given their 10-year risk of breast cancer by letter, along with additional information explaining breast cancer risk factors. To gain diversity of views, purposive sampling by ethnicity and socioeconomic background was used to recruit women. Data were analysed using thematic analysis. Results: Twenty-three women participated in individual interviews. Three themes are reported: (1) A good opportunity to receive risk estimation, where women found it worthwhile to receive a low-risk result although some were surprised if expecting a higher risk result; (2) Multi-faceted acceptability of extended screening intervals, with reactions to less frequent screening dependent on whether women were confident in being low-risk status and current safety evidence, (3) Passive approval versus informed choice, highlighting that women found it difficult to consider choosing less frequent screening without professionals’ recommendations, as they generally viewed attending breast screening as positive. Conclusions: Risk assessment and receiving a low-risk of breast cancer is acceptable although, further research is required with more diverse samples of women. Any recommendation of less frequent screening in this risk group should be evidence-based in order to be acceptable. Communication needs to be carefully developed, with a focus on ensuring informed choice, prior to trialling any extended screening recommendations in future studies

Risk stratified breast cancer screening: UK healthcare policy decision-making stakeholders’ views on a low-risk breast screening pathway

From Springer Nature via Jisc Publications RouterHistory: received 2020-05-07, accepted 2020-07-09, registration 2020-07-10, pub-electronic 2020-07-22, online 2020-07-22, collection 2020-12Publication status: PublishedFunder: Manchester Biomedical Research Centre; doi: http://dx.doi.org/10.13039/100014653; Grant(s): IS-BRC-1215-200007Funder: Programme Grants for Applied Research; doi: http://dx.doi.org/10.13039/501100007602; Grant(s): RP-PG-1214-20016Funder: Breast Cancer Now; doi: http://dx.doi.org/10.13039/100009794; Grant(s): 2018RP005Abstract: Background: There is international interest in risk-stratification of breast screening programmes to allow women at higher risk to benefit from more frequent screening and chemoprevention. Risk-stratification also identifies women at low-risk who could be screened less frequently, as the harms of breast screening may outweigh benefits for this group. The present research aimed to elicit the views of national healthcare policy decision-makers regarding implementation of less frequent screening intervals for women at low-risk. Methods: Seventeen professionals were purposively recruited to ensure relevant professional group representation directly or indirectly associated with the UK National Screening Committee and National Institute for Health and Care Excellence (NICE) clinical guidelines. Interviews were analysed using thematic analysis. Results: Three themes are reported: (1) producing the evidence defining low-risk, describing requirements preceding implementation; (2) the impact of risk stratification on women is complicated, focusing on gaining acceptability from women; and (3) practically implementing a low-risk pathway, where feasibility questions are highlighted. Conclusions: Overall, national healthcare policy decision-makers appear to believe that risk-stratified breast screening is acceptable, in principle. It will however be essential to address key obstacles prior to implementation in national programmes