Highly efficient synthesis of heterocycles via 5-endo radical cyclisation

The principal aim of this project was to synthesise a range of functionalised heterocycles using novel transition metal promoted radical cyclisation reactions as an alternative to the well-established tin hydride method. On achieving this we hoped to successfully apply these methods towards the synthesis of natural product templates. In chapter two, a series of copper(l)-amine catalysts were employed to mediate the 5- endo-trig radical cyclisation of trichloroacetamides, which led to the formation of a variety of highly functionalised bicyclic y-Iactams in good to excellent yield. A variety of cyclisation precursors were examined. This work was also extended towards the synthesis of analogues of the heterocyclic ring fragment of non-peptide bradykinin inhibitor, L-755,807. In chapter 3, the reaction of a series of tertiary bromoacetamides with catalytic copper(I) bromide/N,N,N',N',N",N" -hexamethyltriethylenetetramine (Me6-tren) at room 'temperature is described. This reaction furnished regioisomeric mixtures of unsaturated pyrrolidinones via a highly efficient 5-endo-trig radical cyclisation reaction. We also illustrated that a variety of less activated secondary bromoacetamides undergo efficient 5-endo-trig radical cyclisation reactions to give a,l3-unsaturated monoene lactams under atom transfer conditions mediated by copper(l) bromide and tripyridylamine (TP A) in refluxing toluene. Changing the solvent for this reaction to 1,2-dichloroethane caused a,l3-unsaturated diene lactams to be produced instead. This approach was used towards the synthesis of analogues of the sesquiterpenic alkaloid, eremophilene y-Iactam. Chapter 4 describes an alternative route to constrained bicyclic ring systems mediated by ceric ammonium nitrate (CAN). In addition, the first reported 5-endo-trig radical cyclisation of l3-amido esters to afford functionalised y-Iactams was developed. This methodology was exploited in the production of analogues of the heterocyclic ring fragments of a' number of biologically active natural products

The dual endothelin converting enzyme/neutral endopeptidase inhibitor SLV-306 (daglutril), inhibits systemic conversion of big endothelin-1 in humans

Aims - Inhibition of neutral endopeptidases (NEP) results in a beneficial increase in plasma concentrations of natriuretic peptides such as ANP. However NEP inhibitors were ineffective anti-hypertensives, probably because NEP also degrades vasoconstrictor peptides, including endothelin-1 (ET-1). Dual NEP and endothelin converting enzyme (ECE) inhibition may be more useful. The aim of the study was to determine whether SLV-306 (daglutril), a combined ECE/NEP inhibitor, reduced the systemic conversion of big ET-1 to the mature peptide. Secondly, to determine whether plasma ANP levels were increased. Main methods - Following oral administration of three increasing doses of SLV-306 (to reach an average target concentration of 75, 300, 1200 ng ml− 1 of the active metabolite KC-12615), in a randomised, double blinded regime, big ET-1 was infused into thirteen healthy male volunteers. Big ET-1 was administered at a rate of 8 and 12 pmol kg− 1 min− 1 (20 min each). Plasma samples were collected pre, during and post big ET-1 infusion. ET-1, C-terminal fragment (CTF), big ET-1, and atrial natriuretic peptide (ANP) were measured. Key findings - At the two highest concentrations tested, SLV-306 dose dependently attenuated the rise in blood pressure after big ET-1 infusion. There was a significant increase in circulating big ET-1 levels, compared with placebo, indicating that SLV-306 was inhibiting an increasing proportion of endogenous ECE activity. Plasma ANP concentrations also significantly increased, consistent with systemic NEP inhibition. Significance - SLV-306 leads to inhibition of both NEP and ECE in humans. Simultaneous augmentation of ANP and inhibition of ET-1 production is of potential therapeutic benefit in cardiovascular disease

Substantial decline in hospital admissions for heart failure accompanied by increased community mortality during COVID-19 pandemic

Objective: We hypothesised that a decline in admissions with heart failure during COVID-19 pandemic would lead to a reciprocal rise in mortality for patients with heart failure in the community. Methods: We used national heart failure audit data to identify 36,974 adults who had a hospital admission with a primary diagnosis of heart failure between February and May in either 2018, 2019 or 2020. Results: Hospital admissions for heart failure in 2018/19 averaged 160/day but were much lower in 2020, reaching a nadir of 64/day on 27th March-2020 (incidence rate ratio:0.40, 95% CI:0.38-0.42). The proportion discharged on guideline-recommended pharmacotherapies was similar in 2018/19 compared to the same period in 2020. Between 1st February-2020 and 31st May-2020, there was a 29% decrease in hospital deaths related to heart failure (IRR:0.71,95% CI:0.67-0.75; estimated decline of 448 deaths), a 31% increase in heart failure deaths at home (IRR:1.31,95% CI:1.24-1.39; estimated excess 539) and a 28% increase in heart failure deaths in care homes and hospices (IRR:1.28,95% CI:1.18-1.40; estimated excess 189). All-cause, in-patient death was similar in the COVID-19 and pre-COVID-19 periods (OR:1.02,95% CI: 0.94–1.10). After hospital discharge, 30-day mortality was higher in 2020 compared to 2018/19 (OR:1.57, 95% CI:1.38–1.78). Conclusion: Compared with the rolling daily average in 2018/19, there was a substantial decline in admissions for heart failure but an increase in deaths from heart failure in the community. Despite similar rates of prescription of guideline-recommended therapy, mortality 30-days from discharge was higher during the COVID-19 pandemic period

‘The Rest is Silence’:Psychogeography, Soundscape and Nostalgia in Pat Collins’ Silence

Guy Debord defines the term psychogeography as 'the study of the precise laws and specific effects of the geographical environment, consciously organised or not, on the emotions and behaviour of individuals' (Debord 1955: 23). Similar to the belief of psychogeographers that the geography of an environment has a psychological effect on the human mind, proponents of acoustic ecology such as R. Murray Schafer hold that humans are affected by the sound of the environment in which they find themselves. Further to this, they examine the extent to which soundscapes can be shaped by human behaviour. Recently a body of Irish films has emerged that directly engages with the Irish soundscape and landscape on a psychogeographical level. Rather than using landscape as a physical space for the locus of action, these representations of the Irish landscape allow for an engagement with the aesthetic effects of the geographical landscape as a reflection of the psychological states of the protagonists. Bearing this in mind, this article examines how Silence (Collins 2012) arguably demonstrates the most overt and conscious incursion into this area to date. It specifically interrogates how the filmic representation of the psychogeography and soundscape of the Irish rural landscape can serve to express emotion, alienation and nostalgia, thus confronting both the Irish landscape and the weight of its associated history

Diquat Derivatives: Highly Active, Two-Dimensional Nonlinear Optical Chromophores with Potential Redox Switchability

In this article, we present a detailed study of structure−activity relationships in diquaternized 2,2′-bipyridyl (diquat) derivatives. Sixteen new chromophores have been synthesized, with variations in the amino electron donor substituents, π-conjugated bridge, and alkyl diquaternizing unit. Our aim is to combine very large, two-dimensional (2D) quadratic nonlinear optical (NLO) responses with reversible redox chemistry. The chromophores have been characterized as their PF_6^− salts by using various techniques including electronic absorption spectroscopy and cyclic voltammetry. Their visible absorption spectra are dominated by intense π → π^* intramolecular charge-transfer (ICT) bands, and all show two reversible diquat-based reductions. First hyperpolarizabilities β have been measured by using hyper-Rayleigh scattering with an 800 nm laser, and Stark spectroscopy of the ICT bands affords estimated static first hyperpolarizabilities β_0. The directly and indirectly derived β values are large and increase with the extent of π-conjugation and electron donor strength. Extending the quaternizing alkyl linkage always increases the ICT energy and decreases the E_(1/2) values for diquat reduction, but a compensating increase in the ICT intensity prevents significant decreases in Stark-based β_0 responses. Nine single-crystal X-ray structures have also been obtained. Time-dependent density functional theory clarifies the molecular electronic/optical properties, and finite field calculations agree with polarized HRS data in that the NLO responses of the disubstituted species are dominated by ‘off-diagonal’ β_(zyy) components. The most significant findings of these studies are: (i) β_0 values as much as 6 times that of the chromophore in the technologically important material (E)-4′-(dimethylamino)-N-methyl-4-stilbazolium tosylate; (ii) reversible electrochemistry that offers potential for redox-switching of optical properties over multiple states; (iii) strongly 2D NLO responses that may be exploited for novel practical applications; (iv) a new polar material, suitable for bulk NLO behavior

Percutaneous Revascularization for Ischemic Ventricular Dysfunction : Rationale and Design of the REVIVED-BCIS2 Trial: Percutaneous Coronary Intervention for Ischemic Cardiomyopathy

OBJECTIVES: Evaluate whether PCI in combination with optimal medical therapy (OMT) will reduce all-cause death and hospitalization for HF compared to a strategy of OMT alone. BACKGROUND: Ischemic cardiomyopathy (ICM) is the most common cause of heart failure (HF) and is associated with significant mortality and morbidity. Surgical revascularization has been shown to improve long-term outcomes in some patients, but surgery itself carries a major early hazard. Percutaneous coronary intervention (PCI) may allow a better balance between risk and benefit. METHODS: REVIVED-BCIS2 is a prospective, multi-center, open-label, randomized controlled trial, funded by the National Institute for Health Research in the United Kingdom. Follow-up will be for at least 2 years from randomization. Secondary outcomes include left ventricular ejection fraction (LVEF), quality of life scores, appropriate implantable cardioverter defibrillator therapy and acute myocardial infarction. Patients with LVEF ≤35%, extensive coronary disease and demonstrable myocardial viability are eligible for inclusion and those with a myocardial infarction within 4 weeks, decompensated HF or sustained ventricular arrhythmias within 72 h are excluded. A trial of 700 patients has more than 85% power to detect a 30% relative reduction in hazard. RESULTS: A total of 400 patients have been enrolled to date. CONCLUSIONS: International guidelines do not provide firm recommendations on the role of PCI in managing severe ICM, because of a lack of robust evidence. REVIVED-BCIS2 will provide the first randomized data on the efficacy and safety of PCI in ICM and has the potential to inform guidelines pertaining to both revascularization and HF. (Study of Efficacy and Safety of Percutaneous Coronary Intervention to Improve Survival in Heart Failure [REVIVED-BCIS2]; NCT01920048) (REVascularisation for Ischaemic VEntricular Dysfunction; ISRCTN45979711)

Reporting of Adverse Events in Published and Unpublished Studies of Health Care Interventions : A Systematic Review

BACKGROUND: We performed a systematic review to assess whether we can quantify the underreporting of adverse events (AEs) in the published medical literature documenting the results of clinical trials as compared with other nonpublished sources, and whether we can measure the impact this underreporting has on systematic reviews of adverse events. METHODS AND FINDINGS: Studies were identified from 15 databases (including MEDLINE and Embase) and by handsearching, reference checking, internet searches, and contacting experts. The last database searches were conducted in July 2016. There were 28 methodological evaluations that met the inclusion criteria. Of these, 9 studies compared the proportion of trials reporting adverse events by publication status. The median percentage of published documents with adverse events information was 46% compared to 95% in the corresponding unpublished documents. There was a similar pattern with unmatched studies, for which 43% of published studies contained adverse events information compared to 83% of unpublished studies. A total of 11 studies compared the numbers of adverse events in matched published and unpublished documents. The percentage of adverse events that would have been missed had each analysis relied only on the published versions varied between 43% and 100%, with a median of 64%. Within these 11 studies, 24 comparisons of named adverse events such as death, suicide, or respiratory adverse events were undertaken. In 18 of the 24 comparisons, the number of named adverse events was higher in unpublished than published documents. Additionally, 2 other studies demonstrated that there are substantially more types of adverse events reported in matched unpublished than published documents. There were 20 meta-analyses that reported the odds ratios (ORs) and/or risk ratios (RRs) for adverse events with and without unpublished data. Inclusion of unpublished data increased the precision of the pooled estimates (narrower 95% confidence intervals) in 15 of the 20 pooled analyses, but did not markedly change the direction or statistical significance of the risk in most cases. The main limitations of this review are that the included case examples represent only a small number amongst thousands of meta-analyses of harms and that the included studies may suffer from publication bias, whereby substantial differences between published and unpublished data are more likely to be published. CONCLUSIONS: There is strong evidence that much of the information on adverse events remains unpublished and that the number and range of adverse events is higher in unpublished than in published versions of the same study. The inclusion of unpublished data can also reduce the imprecision of pooled effect estimates during meta-analysis of adverse events

Causal Modeling Using Network Ensemble Simulations of Genetic and Gene Expression Data Predicts Genes Involved in Rheumatoid Arthritis

Tumor necrosis factor α (TNF-α) is a key regulator of inflammation and rheumatoid arthritis (RA). TNF-α blocker therapies can be very effective for a substantial number of patients, but fail to work in one third of patients who show no or minimal response. It is therefore necessary to discover new molecular intervention points involved in TNF-α blocker treatment of rheumatoid arthritis patients. We describe a data analysis strategy for predicting gene expression measures that are critical for rheumatoid arthritis using a combination of comprehensive genotyping, whole blood gene expression profiles and the component clinical measures of the arthritis Disease Activity Score 28 (DAS28) score. Two separate network ensembles, each comprised of 1024 networks, were built from molecular measures from subjects before and 14 weeks after treatment with TNF-α blocker. The network ensemble built from pre-treated data captures TNF-α dependent mechanistic information, while the ensemble built from data collected under TNF-α blocker treatment captures TNF-α independent mechanisms. In silico simulations of targeted, personalized perturbations of gene expression measures from both network ensembles identify transcripts in three broad categories. Firstly, 22 transcripts are identified to have new roles in modulating the DAS28 score; secondly, there are 6 transcripts that could be alternative targets to TNF-α blocker therapies, including CD86 - a component of the signaling axis targeted by Abatacept (CTLA4-Ig), and finally, 59 transcripts that are predicted to modulate the count of tender or swollen joints but not sufficiently enough to have a significant impact on DAS28