Experimental and Theoretical Investigations of the Charge and Spin Densities of Small Molecules

The major part of this thesis is concerned with the determination of the charge densities of small organic molecules, using both experimental and theoretical methods. A smaller section details the theoretical determination of the spin densities of some sulfur-containing model systems. Chapter 1 traces the historical development of the theory of multipole modelling from the development of the first aspherical scattering factors. The practical implementation of the method. the experimental requirements and subsequent treatment of the data are also discussed. Chapter 2 gives a summary of ab burin molecular orbital methods. Particular attention is given to the way in which the atomic and molecular properties which are of interest to the chemist are obtained from the calculated wavefunction. Throughout the relevant results chapters the experimental and theoretical charge densities are analysed using Bader's theory of Atoms in Molecules. Chapter 3 gives an outline of this analytical approach. Chapter 4 reports the results of experimental and theoretical charge density studies of 3,3.6,6-tetramethyl-s-tetrathiane. Particular attention is given to the strength of the sulfur-sulfur bond. An ab wino study is made of the relative stabilities of the three possible conformers of the molecule. An experimental charge density study of hexakis(mercaptomethyl)benzene is reported in Chapter 5; evidence is found for the existence of intermolecular SH...S hydrogen bonding. Chapter 6 contains experimental and theoretical results for the charge density study of a salt of the antifungal compound E-tetraethyl-1.4-diammoniumbut-2-ene. A quite different area of physical chemistry is investigated in Chapter 7. The results of a series of calculations of the hyperfine coupling constants of muonium in sulfur environments are presented. This work was carried out in order to try to identify the muonic radical species which is observed by muSR when muons are introduced into elemental sulfur

The relative influence of intellectual disabilities and autism on mental and general health in Scotland: a cross-sectional study of a whole country of 5.3 million children and adults

Objectives: To determine the relative extent that autism and intellectual disabilities are independently associated with poor mental and general health, in children and adults. Design: Cross-sectional study. For Scotland’s population, logistic regressions investigated odds of intellectual disabilities and autism predicting mental health conditions, and poor general health, adjusted for age and gender. Participants: 1 548 819 children/youth aged 0-24 years, and 3 746 584 adults aged more than 25 years, of whom 9396/1 548 819 children/youth had intellectual disabilities (0.6%), 25 063/1 548 819 children/youth had autism (1.6%); and 16 953/3 746 584 adults had intellectual disabilities (0.5%), 6649/3 746 584 adults had autism (0.2%). These figures are based on self-report. Main outcome measures: Self-reported general health status and mental health. Results: In children/youth, intellectual disabilities (OR 7.04, 95% CI 6.30 to 7.87) and autism (OR 25.08, 95% CI 23.08 to 27.32) both independently predicted mental health conditions. In adults, intellectual disabilities (OR 3.50, 95% CI 3.20 to 3.84) and autism (OR 5.30, 95% CI 4.80 to 5.85) both independently predicted mental health conditions. In children/youth, intellectual disabilities (OR 18.34, 95% CI 17.17 to 19.58) and autism (OR 8.40, 95% CI 8.02 to 8.80) both independently predicted poor general health. In adults, intellectual disabilities (OR 7.54, 95% CI 7.02 to 8.10) and autism (OR 4.46, 95% CI 4.06 to 4.89) both independently predicted poor general health. Conclusions: Both intellectual disabilities and autism independently predict poor health, intellectual disabilities more so for general health and autism more so for mental health. Intellectual disabilities and autism are not uncommon, and due to their associated poor health, sufficient services/supports are needed. This is not just due to coexistence of these conditions or just to having intellectual disabilities, as the population with autism is independently associated with substantial health inequalities compared with the general population, across the entire life course

The Knee Arthroplasty Trial (KAT) : design features, baseline characteristics and two-year functional outcomes after alternative approaches to knee replacement

Background: The aim of continued development of total knee replacement systems has been the further improvement of the quality of life and increasing the duration of prosthetic survival. Our goal was to evaluate the effects of several design features, including metal backing of the tibial component, patellar resurfacing, and a mobile bearing between the tibial and femoral components, on the function and survival of the implant. Methods: A pragmatic, multicenter, randomized, controlled trial involving 116 surgeons in thirty-four centers in the United Kingdom was performed; 2352 participants were randomly allocated to be treated with or without a metal backing of the tibial component (409), with or without patellar resurfacing (1715), and/or with or without a mobile bearing (539). Randomization to more than one comparison was allowed. The primary outcome measures were the Oxford Knee Score (OKS), Short Form-12, EuroQol-5D, and the need for additional surgery. The results up to two years postoperatively are reported. Results: Functional status and quality-of-life scores were low at baseline but improved markedly across all trial groups following knee replacement (mean overall OKS, 17.98 points at baseline and 34.82 points at two years). Most of the change was observed at three months after the surgery. Six percent of the patients had additional knee surgery within two years. There was no evidence of differences in clinical, functional, or quality-of-life measures between the randomized groups at two years. Conclusions: Patients have substantial improvement following total knee replacement. This is the first adequately powered randomized controlled trial, of which we are aware, in which the effects of metal backing, patellar resurfacing, and a mobile bearing were investigated. We found no evidence of an effect of these variants on the rate of early complications or on functional recovery up to two years after total knee replacement. Level of Evidence: Therapeutic Level I. See Instructions to Authors for a complete description of levels of evidence.NIHR Health Technology Assessment Programme (Project Number 95/10/01); Howmedica Osteonics; Zimmer; DePuy, a Johnson and Johnson company; Corin Medical; Smith and Nephew Healthcare. Biomet Merck; and Wright CremascoliPeer reviewe

Single port/incision laparoscopic surgery compared with standard three-port laparoscopic surgery for appendicectomy : a randomized controlled trial

Acknowledgments The authors thank John Norrie for advice regarding the reporting of the study, and clinical staff in the Department of General Surgery, Aberdeen Royal Infirmary, for helping with the conduct of the study. This work was supported by a Grant from the Chief Scientist Office (CSO) of the Scottish Government Health Directorates (Grant Number reference CZG/2/498). Jonathan A. Cook held a Medical Research Council, UK, training fellowship (G0601938) while this research was undertaken. The Health Services Research Unit is funded by the CSO of the Scottish Government Health Directorates. The views expressed in this paper are those of the authors and may not necessarily be shared by the funding bodies. The study was overseen by an Advisory Group comprising Professor Marion Campbell (Director, Health Services Research Unit, Aberdeen), Professor John Norrie (CHaRT Director) and Professor Craig Ramsay (Health Care Assessment Programme Director, Health Services Research Unit, Aberdeen). Professor W. Alastair Chambers was the independent chair of the Trial Steering Committee. Contributing surgeons to the SCARLESS study (in alphabetical order): Bassam Alkari, Emad Aly, Norman Binnie, Duff Bruce, Jan Jansen, Peter King, Tim MacAdam, Aileen McKinley, Terry O’Kelly, Ken Park, Abdul Qadir. The National Health Service provided support through the contribution of the following research nurses: Anu Joyson, Hazel Forbes, and Julie Shotton.Peer reviewedPublisher PD

Systematic review of the agreement of tonometers with goldmann applanation tonometry

This review was part of the Surveillance for Ocular Hypertension study funded by the UK National Institute for Health Research Health Technology Assessment Programme (Project No. 07/46/02). J.C. held a Medical Research Council UK fellowship (G0601938). AA-B was a grantholder on an AstraZeneca (London, UK) funded study of a new medication for glaucoma. The Health Services Research Unit receives core funding from the Chief Scientist Office of the Scottish Government Health Directorates. Views and opinions expressed are those of the authors and do not necessarily reflect those of the Chief Scientist Office, National Institute for Health Research Health Technology Assessment Programme, or the Department of Health. None of the funders had a role in the design or conduct of this researchPeer reviewedPostprin

The ALLEGRO trial : a placebo controlled randomised trial of intravenous lidocaine in accelerating gastrointestinal recovery after colorectal surgery

Acknowledgements The authors wish to acknowledge the following persons who have helped deliver the ALLEGRO trial: the programming team based in the Centre for Healthcare Randomised Trials, for their work in developing the study web portal; Sharon Wren and Zoe Batham for their administrative support; ACCORD in Edinburgh; the Perioperative Medicine Clinical Trials Network (POMCTN) for adopting the trial for promotion; and the local recruiting teams and participants. We are also indebted to the late Professor Kenneth Fearon, University of Edinburgh, for protocol development and study design. The views and opinions expressed herein are those of the authors and do not necessarily reflect those of the Health Technology Assessment Programme, National Institute for Health Research (NIHR), NHS or the Department of Health. Funding The trial is funded by the NIHR Health and Technology Assessment programme, project number 15/130/95. The funding body had no role in the design of the study, collection of data or the writing of this paper, nor will the funding body have a role in analysis, interpretation of data or in writing future manuscripts. The co-sponsors are University of Edinburgh & Lothian Health Board (AC- CORD), The Queen’s Medical Research Institute, 47 Little France Crescent, Ed- inburgh EH16 4TJ.Peer reviewedPublisher PD

Effect of hands-on interprofessional simulation training for local emergencies in Scotland:the THISTLE stepped-wedge design randomised controlled trial

OBJECTIVE: To assess whether the implementation of an intrapartum training package (PROMPT (PRactical Obstetric Multi-Professional Training)) across a health service reduced the proportion of term babies born with Apgar score <7 at 5 min (<75mins). // DESIGN: Stepped-wedge cluster randomised controlled trial. SETTING: Twelve randomised maternity units with ≥900 births/year in Scotland. Three additional units were included in a supplementary analysis to assess the effect across Scotland. The intervention commenced in March 2014 with follow-up until September 2016. // INTERVENTION: The PROMPT training package (Second edition), with subsequent unit-level implementation of PROMPT courses for all maternity staff. // MAIN OUTCOME MEASURES: The primary outcome was the proportion of term babies with Apgar<75mins. // RESULTS: 87 204 eligible births (99.2% with an Apgar score), of which 1291 infants had an Apgar<75mins were delivered in the 12 randomised maternity units. Two units did not implement the intervention. The overall Apgar<75mins rate observed in the 12 randomised units was 1.49%, increasing from 1.32% preintervention to 1.59% postintervention. Once adjusted for a secular time trend, the 'intention-to-treat' analysis indicated a moderate but non-significant reduction in the rate of term babies with an Apgar scores <75mins following PROMPT training (OR=0.79 95%CI(0.63 to 1.01)). However, some units implemented the intervention earlier than their allocated step, whereas others delayed the intervention. The content and authenticity of the implemented intervention varied widely at unit level. When the actual date of implementation of the intervention in each unit was considered in the analysis, there was no evidence of improvement (OR=1.01 (0.84 to 1.22)). No intervention effect was detected by broadening the analysis to include all 15 large Scottish maternity units. Units with a history of higher rates of Apgar<75mins maintained higher Apgar rates during the study (OR=2.09 (1.28 to 3.41)) compared with units with pre-study rates aligned to the national rate. // CONCLUSIONS: PROMPT training, as implemented, had no effect on the rate of Apgar <75mins in Scotland during the study period. Local implementation at scale was found to be more difficult than anticipated. Further research is required to understand why the positive effects observed in other single-unit studies have not been replicated in Scottish maternity units, and how units can be best supported to locally implement the intervention authentically and effectively

Systematic review of the effectiveness of preventing and treating Staphylococcus aureus carriage in reducing peritoneal catheter-related infections

Objectives: To determine the clinical effectiveness and cost-effectiveness of (1) alternative strategies for the prevention of Staphylococcus aureus carriage in patients on peritoneal dialysis (PD) and (2) alternative strategies for the eradication of S. aureus carriage in patients on PD. Data sources: Major electronic databases were searched up to December 2005 (MEDLINE Extra up to 6 January 2006). Review methods: Electronic searches were undertaken to identify published and unpublished reports of randomised controlled trials and systematic reviews evaluating the effectiveness of preventing and treating S. aureus carriage on peritoneal catheterrelated infections. The quality of the included studies was assessed and data synthesised. Where data were not sufficient for formal meta-analysis, a qualitative narrative review looking for consistency between studies was performed. Results: Twenty-two relevant trials were found. These fell into several groups: the first split is between prophylactic trials, aiming to prevent carriage, and trials which aimed to eradicate carriage in those who already had it; the second split is between antiseptics and antibiotics; and the third split is between those that included patients having the catheter inserted before dialysis started and people already on dialysis. Many of the trials were small or short-term. The quality was often not good by today’s standards. The body of evidence suggested a reduction in exit-site infections, but this did not seem to lead to a significant reduction in peritonitis, although to some extent this reflected insufficient power in the studies and a low incidence of peritonitis in them. The costs of interventions to prevent or treat S. aureus carriage are relatively modest. For example, the annual cost of antibiotic treatment of S. aureus carriage per identified carrier of S. aureus was estimated at £179 (£73 screening and £106 cost of antibiotic). However, without better data on the effectiveness of the interventions, it is not clear whether such costs are offset by the cost of treating infections and averting changes from peritoneal dialysis to haemodialysis. Although treatment is not expensive, the lack of convincing evidence of clinical effectiveness made cost-effectiveness analysis unrewarding at present. However, consideration was given to the factors needed in a hypothetical model describing patient pathways from methods to prevent S. aureus carriage, its detection and treatment and the detection and treatment of the consequences of S. aureus (e.g. catheter infections and peritonitis). Had data been available, the model would have compared the costeffectiveness of alternative interventions from the perspective of the UK NHS, but as such it helped identify what future research would be needed to fill the gaps. Conclusions: The importance of peritonitis isnot in doubt. It is the main cause of people having to switch from peritoneal dialysis to haemodialysis, which then leads to reduced quality of life for patients and increased costs to the NHS. Unfortunately, the present evidence base for the prevention of peritonitis is disappointing; it suggests that the interventions reduce exit-site infections, but not peritonitis, although this may be due to trials being in too small numbers for too short periods. Trials are needed with larger numbers of patients for longer durations.No peer reviewPublisher PD

The relative influence of intellectual disabilities and autism on sensory impairments and physical disability:A whole‐country cohort of 5.3 million children and adults

Background: Intellectual disabilities and autism are lifelong and often co‐occur. Little is known on their extent of independent association with sensory impairments and physical disability. Methods: For Scotland's population, logistic regressions investigated age–gender‐adjusted odds ratios (OR) of associations, independently, of intellectual disabilities and autism with sensory impairments and physical disability. Results: 1,548,819 children/youth, and 3,746,584 adults. In children/youth, the effect size of intellectual disabilities and autism, respectively, was as follows: blindness (OR = 30.12; OR = 2.63), deafness (OR = 13.98; OR = 2.31), and physical disability (OR = 43.72; OR = 5.62). For adults, the effect size of intellectual disabilities and autism, respectively, was as follows: blindness (OR = 16.89; OR = 3.29), deafness (OR = 7.47; OR = 2.36), and physical disability (OR = 6.04; OR = 3.16). Conclusions: Intellectual disabilities have greater association with the population burden of sensory impairments/physical disability, but autism is also associated regardless of overlap with intellectual disabilities. These may impact further on communication limitations due to autism and intellectual disabilities, increasing complexity of assessments/management of other health conditions. Clinicians need to be aware of these important issues

Cohort profile:Scotland’s record-linkage e-cohorts of people with intellectual disabilities, and autistic people (SCIDA)

Purpose: To investigate health, mortality and healthcare inequalities experienced by people with intellectual disabilities, and autistic people, and their determinants; an important step towards identifying and implementing solutions to reduce inequalities. This paper describes the cohorts, record-linkages and variables that will be used. Participants: Scotland’s Census, 2011 was used to identify Scotland’s citizens with intellectual disabilities, and autistic citizens, and representative general population samples with neither. Using Scotland’s community health index, the Census data (demography, household, employment, long-term conditions) were linked with routinely collected health, death and healthcare data: Scotland’s register of deaths, Scottish morbidity data 06 (SMR06: cancer incidence, mortality, treatments), Prescribing Information System (identifying asthma/chronic obstructive pulmonary disease; angina/congestive heart failure/hypertension; peptic ulcer/reflux; constipation; diabetes; thyroid disorder; depression; bipolar disorders; anxiety/sleep; psychosis; attention deficit hyperactivity disorder; epilepsy; glaucoma), SMR01 (general/acute hospital admissions and causes, ambulatory care sensitive admissions), SMR04 (mental health admissions and causes), Scottish Care Information–Diabetes Collaboration (diabetic care quality, diabetic outcomes), national bowel screening programme and cervical screening. Findings to date: Of the whole population, 0.5% had intellectual disabilities, and 0.6% were autistic. Linkage was successful for &gt;92%. The resultant e-cohorts include: (1) 22 538 people with intellectual disabilities (12 837 men and 9701 women), 4509 of whom are children &lt;16 years, (2) 27 741 autistic people (21 390 men and 6351 women), 15 387 of whom are children &lt;16 years and (3) representative general population samples with neither condition. Very good general health was reported for only 3389 (15.0%) people with intellectual disabilities, 10 510 (38.0%) autistic people, compared with 52.4% general population. Mental health conditions were reported for 4755 (21.1%) people with intellectual disabilities, 3998 (14.4%) autistic people, compared with 4.2% general population. Future plans: Analyses will determine the extent of premature mortality, causes of death, and avoidable deaths, profile of health conditions and cancers, healthcare quality and screening and determinants of mortality and healthcare