Improving catalyst activity in secondary amine catalysed transformations

The effect on catalyst performance of altering substituents at the 2-position of the Macmillan imidazolidinone has been examined. Condensation of L-phenylalanine N-methyl amide with acetophenone derivatives results in a series of imidazolidinones whose salts can be used to accelerate the Diels-Alder cycloaddition. Electron withdrawing groups significantly increases the overall rate of cycloaddition without compromise in selectivity. The most effective catalyst was shown to be efficient for a variety of substrates and the applicability of this catalyst to alternative secondary amine catalysed transformations is also discussed

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Photography-based taxonomy is inadequate, unnecessary, and potentially harmful for biological sciences

The question whether taxonomic descriptions naming new animal species without type specimen(s) deposited in collections should be accepted for publication by scientific journals and allowed by the Code has already been discussed in Zootaxa (Dubois & Nemésio 2007; Donegan 2008, 2009; Nemésio 2009a–b; Dubois 2009; Gentile & Snell 2009; Minelli 2009; Cianferoni & Bartolozzi 2016; Amorim et al. 2016). This question was again raised in a letter supported by 35 signatories published in the journal Nature (Pape et al. 2016) on 15 September 2016. On 25 September 2016, the following rebuttal (strictly limited to 300 words as per the editorial rules of Nature) was submitted to Nature, which on 18 October 2016 refused to publish it. As we think this problem is a very important one for zoological taxonomy, this text is published here exactly as submitted to Nature, followed by the list of the 493 taxonomists and collection-based researchers who signed it in the short time span from 20 September to 6 October 2016

Considerations and methods for placebo controls in surgical trials (ASPIRE guidelines)

Placebo comparisons are increasingly being considered for randomised trials assessing the efficacy of surgical interventions. The aim of this Review is to provide a summary of knowledge on placebo controls in surgical trials. A placebo control is a complex type of comparison group in the surgical setting and, although powerful, presents many challenges. This Review outlines what a placebo control entails and present understanding of this tool in the context of surgery. We consider when placebo controls in surgery are acceptable (and when they are desirable) in terms of ethical arguments and regulatory requirements, how a placebo control should be designed, how to identify and mitigate risk for participants in these trials, and how such trials should be done and interpreted. Use of placebo controls is justified in randomised controlled trials of surgical interventions provided there is a strong scientific and ethical rationale. Surgical placebos might be most appropriate when there is poor evidence for the efficacy of the procedure and a justified concern that results of a trial would be associated with high risk of bias, particularly because of the placebo effect. Feasibility work is recommended to optimise the design and implementation of randomised controlled trials. This Review forms an outline for best practice and provides guidance, in the form of the Applying Surgical Placebo in Randomised Evaluations (known as ASPIRE) checklist, for those considering the use of a placebo control in a surgical randomised controlled trial

Imidazolidinones in amine catalysis

This thesis was previously held under moratorium from 4th November 2014 until 2nd June 2020.Iminium ion activation is a rapidly expanding and contemporary area of synthetic chemistry in which a number of enantio- and diastereoselective transformations have been developed. Despite the substantial attributes of the area, high catalyst loadings, aldehyde substrate specificity and incomplete understanding of the catalytic process detracts from iminium ion activation being fully competitive with metal-based alternatives. Within this Thesis a series of investigations are presented to address some of these perceived shortcomings. In Chapter 2, a novel imidazolidinone containing an α-electron withdrawing group is evaluated as an asymmetric catalyst for Diels-Alder cycloaddition reactions. A substrate and reaction scope is presented and the conformational preference of the imidazolidinone is probed to rationalise the origins of enantioselectivity. In Chapter 3, further understanding of the conformational preference of the MacMillan first generation imidazolidinone is gained using chiral optical spectroscopic measurements. For the first time each proposed intermediate in the full catalytic cycle is observed using mass spectrometry. In Chapter 4, a hybrid secondary amine is designed based upon the diarylprolinol ether and imidazolidinone scaffold. In Chapter 5, the 3-position of the imidazolidinone ring is investigated as a potential site to install electron withdrawing groups to influence the catalytic cycle. In Chapter 6, efforts are made to tackle α,β-unsaturated aldehyde substrate specificity through the design of C2 symmetric amines suitable for use in iminium activation of α,β-unsaturated ketones. Chapter 7 and Chapter 8 are both outside the immediate subject area of this thesis. In Chapter 7 a novel amino acid amide dimer architecture is revealed. Investigations into substrate scope, stability and conformational rigidity are presented. In Chapter 8 a mechanistic investigation into the malonoyl peroxide mediated alkene dioxygenation reaction is made. DFT calculations and a mechanistic probe substrate are used to define the nature of the interaction between the peroxide and alkene. Chapter 9 summarises the work contained within Chapters 2-8 and suggests some avenues along which research could be continued.Iminium ion activation is a rapidly expanding and contemporary area of synthetic chemistry in which a number of enantio- and diastereoselective transformations have been developed. Despite the substantial attributes of the area, high catalyst loadings, aldehyde substrate specificity and incomplete understanding of the catalytic process detracts from iminium ion activation being fully competitive with metal-based alternatives. Within this Thesis a series of investigations are presented to address some of these perceived shortcomings. In Chapter 2, a novel imidazolidinone containing an α-electron withdrawing group is evaluated as an asymmetric catalyst for Diels-Alder cycloaddition reactions. A substrate and reaction scope is presented and the conformational preference of the imidazolidinone is probed to rationalise the origins of enantioselectivity. In Chapter 3, further understanding of the conformational preference of the MacMillan first generation imidazolidinone is gained using chiral optical spectroscopic measurements. For the first time each proposed intermediate in the full catalytic cycle is observed using mass spectrometry. In Chapter 4, a hybrid secondary amine is designed based upon the diarylprolinol ether and imidazolidinone scaffold. In Chapter 5, the 3-position of the imidazolidinone ring is investigated as a potential site to install electron withdrawing groups to influence the catalytic cycle. In Chapter 6, efforts are made to tackle α,β-unsaturated aldehyde substrate specificity through the design of C2 symmetric amines suitable for use in iminium activation of α,β-unsaturated ketones. Chapter 7 and Chapter 8 are both outside the immediate subject area of this thesis. In Chapter 7 a novel amino acid amide dimer architecture is revealed. Investigations into substrate scope, stability and conformational rigidity are presented. In Chapter 8 a mechanistic investigation into the malonoyl peroxide mediated alkene dioxygenation reaction is made. DFT calculations and a mechanistic probe substrate are used to define the nature of the interaction between the peroxide and alkene. Chapter 9 summarises the work contained within Chapters 2-8 and suggests some avenues along which research could be continued

Placebo comparator group selection and use in surgical trials: the ASPIRE project including expert workshop.

BACKGROUND The use of placebo comparisons for randomised trials assessing the efficacy of surgical interventions is increasingly being considered. However, a placebo control is a complex type of comparison group in the surgical setting and, although powerful, presents many challenges. OBJECTIVES To provide a summary of knowledge on placebo controls in surgical trials and to summarise any recommendations for designers, evaluators and funders of placebo-controlled surgical trials. DESIGN To carry out a state-of-the-art workshop and produce a corresponding report involving key stakeholders throughout. SETTING A workshop to discuss and summarise the existing knowledge and to develop the new guidelines. RESULTS To assess what a placebo control entails and to assess the understanding of this tool in the context of surgery is considered, along with when placebo controls in surgery are acceptable (and when they are desirable). We have considered ethics arguments and regulatory requirements, how a placebo control should be designed, how to identify and mitigate risk for participants in these trials, and how such trials should be carried out and interpreted. The use of placebo controls is justified in randomised controlled trials of surgical interventions provided that there is a strong scientific and ethics rationale. Surgical placebos might be most appropriate when there is poor evidence for the efficacy of the procedure and a justified concern that results of a trial would be associated with a high risk of bias, particularly because of the placebo effect. CONCLUSIONS The use of placebo controls is justified in randomised controlled trials of surgical interventions provided that there is a strong scientific and ethics rationale. Feasibility work is recommended to optimise the design and implementation of randomised controlled trials. An outline for best practice was produced in the form of the Applying Surgical Placebo in Randomised Evaluations (ASPIRE) guidelines for those considering the use of a placebo control in a surgical randomised controlled trial. LIMITATIONS Although the workshop participants involved international members, the majority of participants were from the UK. Therefore, although every attempt was made to make the recommendations applicable to all health systems, the guidelines may, unconsciously, be particularly applicable to clinical practice in the UK NHS. FUTURE WORK Future work should evaluate the use of the ASPIRE guidelines in making decisions about the use of a placebo-controlled surgical trial. In addition, further work is required on the appropriate nomenclature to adopt in this space. FUNDING Funded by the Medical Research Council UK and the National Institute for Health Research as part of the Medical Research Council-National Institute for Health Research Methodology Research programme