Extended nonlinear analytical models of compliant parallelogram mechanisms: third-order models

This paper proposes extended nonlinear analytical models, third-order models, of compliant parallelogram mechanisms. These models are capable of capturing the accurate effects from the very large axial force within the transverse motion range of 10% of the beam length through incorporating the terms associated with the high-order (up to third-order) axial force. Firstly, the free-body diagram method is employed to derive the nonlinear analytical model for a basic compliant parallelogram mechanism based on load-displacement relations of a single beam, geometry compatibility conditions, and load-equilibrium conditions. The procedures for the forward solutions and inverse solutions are described. Nonlinear analytical models for guided compliant multi-beam parallelogram mechanisms are then obtained. A case study of the compound compliant parallelogram mechanism, composed of two basic compliant parallelogram mechanisms in symmetry, is further implemented. This work intends to estimate the internal axial force change, the transverse force change, and the transverse stiffness change with the transverse motion using the proposed third-order model in comparison with the first-order model proposed in the prior art. In addition, FEA (finite element analysis) results validate the accuracy of the third-order model for a typical example. It is shown that in the case study the slenderness ratio affects the result discrepancy between the third-order model and the first-order model significantly, and the third-order model can illustrate a non-monotonic transverse stiffness curve if the beam is thin enough.

Immune and stress factors in the pathophysiology of the mdx mouse model of Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy (DMD) is a fatal multi-system neuromuscular disease caused by loss of dystrophin. The loss of dystrophin from membranes of contractile muscle cells and the dysregulation of the DAPC, induces chronic inflammation due to tissue necrosis and eventual replacement with collagen which weakens muscular force and strength. Dystrophin deficiency may cause under-diagnosed features of DMD include mood disorders such as depression and anxiety and dysfunction of the gastrointestinal tract. The first study in the thesis examined mood in the dystrophin-deficient mdx mouse model of DMD and examined the effects of the tri-cyclic antidepressant, amitriptyline on behaviours. Amitriptyline had anti-depressant and anxiolytic effects in the mdx mice possibly through effects on stress factors such as corticotrophin-releasing factor (CRF). This antidepressant also reduced skeletal muscle inflammation and caused a reduction in circulating interleukin (IL)-6 levels. In the second and third studies, we specifically blocked IL-6 signalling and used Urocortin 2, CRFR2 agonist to investigate their potential as therapeutic targets in mdx mice pathophysiology. Isometric and isotonic contractile properties of the diaphragm, were compared in mdx mice treated with anti IL-6 receptor antibodies (anti IL-6R) and/or Urocortin 2. Deficits in force production, work and power detected in mdx mice were improved with treatment. In study three I investigated contractile properties in gastrointestinal smooth muscle. As compared to wild type mice, mdx mice had slower faecal transit times, shorter colons with thickened muscle layers and increased contractile activity in response to recombinant IL-6. Blocking IL-6 signalling resulted in an increase in colon length, normalised faecal output times and a reduction in IL-6-evoked contractile activity. The findings from these studies indicate that for both diaphragm and gastrointestinal function in a dystrophin-deficient model, targeting of IL-6 and CRFR2 signalling has beneficial therapeutic effects.

Synthesis and reactivity of pyridine substituted α-diazocarbonyl compounds and exploration of rhodium carboxylates as asymmetric catalysts

The primary objective of this thesis was the preparation of a series of pyridine-containing α-diazocarbonyl compounds and subsequent investigation of the reactivity of these compounds on exposure to transition metal catalysts. In particular, the reactivity of the pyridyl α-diazocarbonyls was compared to that of the analogous phenyl α-diazocarbonyl compounds to ascertain the impact of replacement of the phenyl ring with pyridine. The first chapter initially provides a brief introduction into α-diazocarbonyl chemistry, comprising a compendium of well-established and recently developed methods in the preparation of these compounds, as well as an outline of the reactivity of these versatile substrates. The substantive element of this introductory chapter comprises a detailed review focused on transition metal-catalysed transformations of heterocyclic α-diazocarbonyl compounds, highlighting the extraordinary diversity of reaction products which can be accessed. This review is undertaken to set the work of this thesis in context. The results of this research are discussed in the second and third chapters together with the associated experimental details, including spectroscopic and analytical data obtained in the synthesis of all compounds during this research. The second chapter describes the preparation of a range of novel pyridine-containing α-diazocarbonyl compounds via a number of synthetic strategies including both acylation and diazo transfer methodologies. In contrast to the phenyl analogues, the generation of the pyridine α-diazocarbonyl substrates was complicated by a number of factors including the inherent basicity of the pyridine ring, tautomerism and existence of rotamers. Rhodium- and copper-mediated transformations of the pyridine-containing α-diazocarbonyl compounds is discussed in detail displaying very different reactivity patterns to those seen with the phenyl analogues; oxidation to 2,3- diketones, 1,2-hydride shift to form enones and oxonium and sulfonium ylide formation/rearrangement are prominent in the pyridyl series, with no evidence of aromatic addition to the pyridine ring. The third chapter focuses on exploration of novel chiral rhodium(II) catalysts, developed in the Maguire team, in both intermolecular cyclopropanations and intramolecular C–H insertion reactions. In this chapter, the studies are focused on standard α-diazocarbonyl compounds without heteroaryl substituents. The most notable outcome was the achievement of high enantiopurities for intramolecular C–H insertions, which were competitive with, and even surpassed, established catalyst systems in some cases. This work has provided insight into solvent and temperature effects on yields as well as enantio- and diastereoselectivity, thereby providing guidance for future development and design of chiral rhodium carboxylate catalysts. While this is a preliminary study, the significance of the results lie in the fact that these are the first reactions to give substantial asymmetric induction with these novel rhodium carboxylates. While the majority of the α-diazocarbonyl compounds explored in this work were α-diazoketones, a number of α-diazoesters are also described. Details of chiral stationary phase HPLC analysis, single crystal analysis and 2D NMR experiments are included in the Appendix (Appendix III-V).

Risk of repeated self-harm and associated factors in children, adolescents and young adults

Background: Repeated self-harm represents the single strongest risk factor for suicide. To date no study with full national coverage has examined the pattern of hospital repeated presentations due to self-harm among young people. Methods: Data on consecutive self-harm presentations were obtained from the National Self-Harm Registry Ireland. Socio-demographic and behavioural characteristics of individuals aged 10–29 years who presented with self-harm to emergency departments in Ireland (2007–2014) were analysed. Risk of long-term repetition was assessed using survival analysis and time differences between the order of presentations using generalised estimating equation analysis. Results: The total sample comprised 28,700 individuals involving 42,642 presentations. Intentional drug overdose was the most prevalent method (57.9%). Repetition of self-harm occurred in 19.2% of individuals during the first year following a first presentation, of whom the majority (62.7%) engaged in one repeated act. Overall, the risk of repeated self-harm was similar between males and females. However, in the 20–24-year-old age group males were at higher risk than females. Those who used self-cutting were at higher risk for repetition than those who used intentional drug overdose, particularly among females. Age was associated with repetition only among females, in particular adolescents (15–19 years old) were at higher risk than young emerging adults (20–24 years old). Repeated self-harm risk increased significantly with the number of previous self-harm episodes. Time differences between first self-harm presentations were detected. Time between second and third presentation increased compared to time between first and second presentation among low frequency repeaters (patients with 3 presentations only within 1 year following a first presentation). The same time period decreased among high frequency repeaters (patients with at least 4 to more than 30 presentations). Conclusion: Young people with the highest risk for repeated self-harm were 15–19-year-old females and 20–24-year-old males. Self-cutting was the method associated with the highest risk of self-harm repetition. Time between first self-harm presentations represents an indicator of subsequent repetition. To prevent risk of repeated self-harm in young people, all individuals presenting at emergency departments due to self-harm should be provided with a risk assessment including psychosocial characteristics, history of self-harm and time between first presentations.

Synthesis and reactivity of α-diazosulfoxide and α-diazosulfone derivatives

The research described in this thesis involves the synthesis of α-diazo-β-oxo sulfoxides, and exploration of their reactivity. The first chapter includes an introduction to diazocarbonyl chemistry, specifically focusing on the synthesis of diazo compounds, and diazosulfoxide derivatives. The chemistry of sulfines, in particular the generation of α-oxo sulfines and their subsequent trapping as cycloadducts and dimerisation is discussed. The results of this research are discussed in the second and third chapters. The design, synthesis and reactivity of α-diazo-β-oxo sulfoxides is described in chapter 2 where diazo transfer adjacent to sulfoxides to form stable α-diazo-β-oxo sulfoxides has been achieved in cyclic systems. Decomposition of theses α-diazosulfoxides using rhodium carboxylate or carboxamide catalysts is also described. These processes proceed via a Wolff type rearrangement to form α-oxo sulfine intermediates, which were trapped as cycloadducts with dienes. In the absence of a diene trap, dimerisation of the sulfine intermediate was observed. Intramolecular C-H insertion reasctios of α-diazo-α-sulfonyl esters to form substituted sulfolane esters is described in chapter 3. The reactivity of these sulfolane esters is briefly explored. The fourth chapter contains the experimental details and the spectral and analytical data for all new compounds reported.

The spiritual and professional impact of stillbirth

Stillbirth is without question one of the most devastating experiences of grief for parents and families. The death of a baby is also a distressing experience for healthcare professionals who share hopes of a live healthy baby at the end of pregnancy. It is a sad reality however, that in Ireland one in 238 babies will die before birth. The creation and nurture of new life in pregnancy is a spiritual experience as a new baby is at the same time experienced and anticipated. There is little in the published literature concerning the spiritual impact of stillbirth on healthcare chaplains who are the main providers of spiritual care for parents and staff colleagues in Irish maternity units. In addition there are few qualitative studies that explore the impact of stillbirth on consultant obstetricians and no published studies on the spiritual impact of stillbirth on bereaved parents. This study explored the spiritual and professional impact of stillbirth on Irish maternity healthcare chaplains, consultant obstetricians and bereaved parents. Following an overall review of spiritual care provision following stillbirth in the Irish maternity services, thematic analysis was used in the first phase of the study following in-depth interviews with maternity healthcare chaplains. Interpretative Phenomenological Analysis was used in the second and third phases with consultant obstetricians and bereaved parents respectively. The data from both maternity healthcare chaplains and consultant obstetricians revealed that stillbirth posed immense personal, spiritual and professional challenges. Chaplains expressed the spiritual and professional impact of stillbirth in terms of perception of their role, suffering, doubt and presence as they provided care for bereaved parents. A review of spiritual care provision in the Irish maternity services revealed a diversity of practice. The data from consultant obstetricians identified considerable personal, professional and spiritual impact following stillbirth that was identified in superordinate themes of human response to stillbirth, weight of professional responsibility, conflict of personal faith and incongruence between personal faith and professional practice. Data from bereaved parents revealed that stillbirth was spiritually challenging and all parents expressed that stillbirth posed considerable challenge to their faith/ belief structure. The parents of only three babies felt that their spiritual needs were adequately addressed while in hospital. The data had six superordinate themes of searching for meaning, maintaining hope, importance of personhood, protective care, questioning core beliefs and relationships. Other findings from the data from bereaved parents outlined the importance of environment of care and communication. This study has revealed the immense impact of stillbirth on healthcare chaplains, consultant obstetricians and most especially the spiritual impact for bereaved parents. Recommendations are made for improvements in clinical and spiritual care for bereaved parents following stillbirth and for staff wellbeing and support initiatives. Further research areas are recommended in the areas of spiritual care, theological reflection, bereavement care, post-mortem consent procedures and staff wellbeing.