Validation of volatile organic compounds for the assessment of liver disease

Chronic liver disease is one of the few conditions with increasing morbidity and mortality rates. Up to 75% of individuals with cirrhosis are diagnosed during a decompensation episode, at which point the prognosis is poor. Cirrhotic patients also have an annual risk of 2 to 4% of developing hepatocellular carcinoma (HCC). HCC is currently the fourth leading cause of cancer-related mortality worldwide, which is at least in part due to late diagnosis and inadequate screening. Gas chromatography-mass spectrometry (GC-MS) analysis of volatile organic compounds (VOCs) in breath has the potential to form the basis of a non-invasive diagnostic test for chronic liver disease and HCC. However, exhaled VOCs can be influenced by multiple confounding factors and the equipment used to collect and analyse breath can be cost prohibitive. The aims of my PhD were four-fold. Firstly, to develop and validate a novel, cost-effective breath collection device and to formulate a standard operating procedure for its use in clinical studies. Secondly, to analyse the VOC profile of background room air within common clinical sampling locations and to assess their potential impact upon the collection of breath samples. Thirdly, to investigate a methodology for sample splitting using GC-MS as a way of facilitating sample analysis across multiple mass spectrometry platforms. With the information garnered from this methodology work, my final aim was to perform a clinical study to profile the VOCs in the exhaled breath of patients with cirrhosis, HCC, and normal liver parenchyma. Prior to this, I also performed a critical analysis of the pre-existing literature on VOCs for assessment of liver disease to help guide my study design. Analysis of the novel breath collection device revealed acceptable repeatability for a wide range of VOCs and optimum settings for flow rates and volumes of breath were determined and included within a standard operating procedure. Profiling the background air volatiles in sampling locations identified specific VOC signatures for each location. Breath samples did not separate by location but monitoring of background volatiles in parallel to breath sampling remains important for identification of contaminant VOCs. Splitting of desorbed breath samples via GC-MS and recollection of two samples back on to one thermal desorption tube provides the best discrimination between samples. For my main clinical study, breath samples of 149 patients were analysed using GC-MS. Elevated levels of limonene and 2-pentanone were identified in those with hepatopathology, validating the results of previous studies. Additional VOCs were also discovered as candidate biomarkers and further studies are required to validate these findings. The results of my clinical study have added to the existing literature that specific VOCs in exhaled breath have the potential to form a non-invasive diagnostic test for hepatopathology that could potentially help enhance earlier diagnosis of liver disease and reverse the trend in mortality rates.Open Acces

The Prevalence and Outcomes of Colorectal Cancer Surgery in the Very Elderly

Introduction: Sixty percent of all colorectal cancer patients in the UK undergo major surgery. Of these, 22% of patients are aged 80 years or older. Historically there has been a tendency to exclude very old patients from entering clinical trials (not just those within surgery), making evidence based clinical decision making more challenging [3]. It is difficult, therefore, to accurately guide this group of patients who have been assessed as fit for surgery. This is the first study to assess the outcomes for all older patients with colorectal cancer, regardless of whether they underwent surgical intervention or not. Results: Clinical case notes and electronic patients records were retrospectively reviewed for all patients admitted to North Bristol NHS Trust over a five-year period (January 2009 to February 2014). Patients presenting with a new diagnosis of colorectal cancer were identified. All patients aged 85 years and over were included in the study. Patients were stratified by clinical management strategy i.e. operative or non-operative management of their colorectal cancer. Primary outcome measure was overall survival. Methods: There were 199 patients included in the study, 50.8% (101) were male. Median age of all patients was 88 years (range 85-97 years) and 47% of all patients underwent surgery. More than half (57%) underwent right-sided resections (including hepatic flexure). Overall mean survival for non acute presentations of colorectal cancer were longer in both the operative group and non operative groups (p = 0.007 and p = 0.03 respectively). There was no difference between mean survival in patients presenting as acute surgical emergencies irrespective of operative or non-operative management (p = 0.31). Conclusion: A third of patients with colorectal cancer present as an acute surgical emergency. For this group of patients prognosis is poor and there does not appear to be a survival benefit in undergoing surgical resection

Malawi: Making Effective Use of Aid Resources

SUMMARY Malawi is perceived by many donors as a ‘virtuous case’ and a relatively effective user of aid. Although many of these perceptions date from the economic boom of the 1970s, performance in recovery from balance of payment difficulties has also been impressive as aid has shifted towards programme lending with linked policy reforms and away from new projects. This article considers these claims and reviews the effectiveness of donors' sectoral interventions, particularly in transport, agriculture and in technical assistance, scrutinises the ‘institutional destruction’ argument relating to donor proliferation; and analyses how conflicts over policy are resolved. It concludes by identifying the key factors from Malawi's experience with donors. SOMMAIRE Malawi: L'utilisation des resources de l'aide d'une manière efficace Le Malawi est considéré par plusieurs donneurs comme un ‘exemple vertueux’, qui utilise l'aide d'une manière efficace, relative aux autres pays recevants. Ces perceptions datent surtout de la période de haute conjoncture des années 70s. Les efforts de redressement de la balance des paiements, ont également été impressionants. Ceci a été accompagné d'une réorientation, des emprunts pour des nouveaux projets vers des emprunts pour des programmes, accompagnés d'une réformulation des politiques. Cet article examine ces arguments, ainsi que l'efficacité des interventions sectoriels des donneurs, surtout en ce qui a trait au transport à l'agriculture et à l'assistance technique. L'argument de la ‘destruction des institutions’, lié à la prolifération des donneurs est scruté, et une analyse de la manière de résoudre des conflits de politique est donnée. L'article conclut en identifiant les facteurs?clés de la pratique du Malawi et de ses rapports avec les pays donneurs. RESUMEN Malawi: hacienda uso efectivo de los recursos de la ayuda Malawi es considerado por muchos donantes como un ‘caso virtuoso’ y un usuario relativamente efectivo de la ayuda. Aunque muchas de estas percepciones se originaron en el boom económico de la década de 1970, el comportamiento en la recuperación de las dificultades de la balanza de pagos ha sido también impresionante, desde que la ayuda se modificó hacia programas de crédito relacionados con políticas reformistas y desvinculados de nuevos proyectos. Este artículo considera estas opiniones y revisa la efectividad de las intervenciones sectoriales de los donantes, particularmente en transporte, agricultura y asistencia técnica, examina minuciosamente el argumento de la ‘destrucción institucional’ adjudicada a la proliferación de donantes y analiza como son resueltos los conflictos sobre políticas. Concluye identificando los factores claves de la experiencia de Malawi con los donantes

Constraining High Redshift X-ray Sources with Next Generation 21 cm Power Spectrum Measurements

We use the Fisher matrix formalism and semi-numerical simulations to derive quantitative predictions of the constraints that power spectrum measurements on next-generation interferometers, such as the Hydrogen Epoch of Reionization Array (HERA) and the Square Kilometre Array (SKA), will place on the characteristics of the X-ray sources that heated the high redshift intergalactic medium. Incorporating observations between $z=5$ and $z=25$, we find that the proposed 331 element HERA and SKA phase 1 will be capable of placing $\lesssim 10\%$ constraints on the spectral properties of these first X-ray sources, even if one is unable to perform measurements within the foreground contaminated "wedge" or the FM band. When accounting for the enhancement in power spectrum amplitude from spin temperature fluctuations, we find that the observable signatures of reionization extend well beyond the peak in the power spectrum usually associated with it. We also find that lower redshift degeneracies between the signatures of heating and reionization physics lead to errors on reionization parameters that are significantly greater than previously predicted. Observations over the heating epoch are able to break these degeneracies and improve our constraints considerably. For these two reasons, 21\,cm observations during the heating epoch significantly enhance our understanding of reionization as well.Comment: 15 pages, 10 figures, Accepted to MNRA

Diabetes in the older person

Background. More people are being diagnosed and treated for diabetes who are aged over 75 years. Compared to younger diabetic populations there is less published evidence available in the older person. At the extremes of old age the evidence base is even smaller. Aim. To examine several aspects of diabetic epidemiology in the older person in order to expand the evidence base for practice and policy. Methods People with diabetes were identified from a representative community based sample of 15095 people aged at least 75 years old. Associations between diabetes and its end points were identified. Admission to hospital and death were assessed in an older diabetic population. Results. There were 1177 people identified with type 2 diabetes giving a prevalence of 7.80% (95% Cl, 7.11-8.47). The prevalence of diabetic complications of poor vision, proteinuria, raised creatinine, angina, myocardial infarction, cerebrovdscular accident and foot ulceration were all increased in the diabetic population. Older diabetic people demonstrated a good uptake of diabetic services including regular eye examination, annual chiropody and dietician attendance. However, the understanding of daily diabetic management was poor with a high prevalence of cognitive impairment (22.5%) in the diabetic population. The rate of admission to hospital and length of hospital stay were increased in the older diabetic person compared to the non diabetic person; rate ratio for admission, 1.31 (95% Cl, 1.23-1.39) and the length of stay 13.9 days versus 12.4 days, p<0.001. Finally, the risk of death among people with diabetes was higher than for people without diabetes, hazard ratio 1.50 (95% Cl, 1.38-1.65), p<0.001. The hazard ratio was similarly raised in both men and women with diabetes across the age ranges studied. Conclusion This thesis presents the largest community based study in the older diabetic person. Diabetes was shown to contribute to morbidity and mortality until the extremes of old age.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Cohort profile: the Welsh Geriatric Registrar-Led Research Network (WeGeN): rationale, design and description

Abstract Purpose Medical trainees are required to undertake audit and quality improvement projects. They must also have an understanding of the principles of research and are encouraged to participate in research projects. However, the constraints of time, a lack of formal training and rotation between different training posts create barriers to audit cycle completion and pursuing research. This leads to trainees being reluctant to undertake research, facilitates poor quality research and risks incomplete audit. Participants The Welsh Geriatricians Network (WeGeN) has been created with the aims of facilitating collaborative, trainee-led research within Geriatric Medicine in Wales, promoting research engagement and improving the research evidence base for older patients. By coordinating collaborative research projects across different sites within Wales, trainees continue existing projects at new sites, allowing completion of projects and establishing the long-term infrastructure and experienced personnel needed for high-quality research data to be gathered. Findings WeGeN has facilitated 4 national audits, all of which are intended for peer review publication. The first project considers the service provision for the older person in the emergency department, the second Parkinson's disease, the third reviews delirium management and the fourth project considers epidemiology of surgical disease in older people. Future plans The objective of this project is to further establish and develop WeGeN as a group which facilitates high-quality research and provides the opportunity for geriatric trainees to engage in research activity. It is anticipated that the establishment of this research platform will provide a blueprint for the development of other such networks in the UK and beyond

Feasibility of Transanal Minimally Invasive Surgery (TAMIS) for Rectal Tumours and Its Impact on Quality of Life ? The Bristol Series

Aim: We assessed feasibility of the transanal minimally invasive surgery (TAMIS) procedure and quality of life postoperatively. Patients and Methods: A total of 28 patients with rectal lesions were treated using TAMIS at Southmead Hospital, North Bristol NHS Trust. Outcome measures included feasibility of excision, negative margin (R0) resection rate, length of hospital stay, morbidity and mortality, and postoperative quality of life associated with anal incontinence. Results; TAMIS was feasible in 90% of cases. R0 resection was 82%. The mean length of hospital stay was 1.5 days. Six (21%) patients experienced acute urinary retention postoperatively. One (4%) patient was re-admitted with rectal bleeding. One patient experienced a perforation. Mortality was 0%. Postoperative quality of life indicated low severity of symptoms of anal incontinence. Conclusion: This study demonstrates that TAMIS is a feasible option in the treatment of rectal tumours and does not impair quality of life postoperatively

Do mobile phone applications improve glycemic control (HbA1c) in the self-management of diabetes? A systematic review, meta-analysis, and GRADE of 14 randomized trials

OBJECTIVE To investigate the effect of mobile phone applications (apps) on glycemic control (HbA1c) in the self-management of diabetes. RESEARCH DESIGN AND METHODS Relevant studies that were published between 1 January 1996 and 1 June 2015 were searched from five databases: Medline, CINAHL, Cochrane Library, Web of Science, and Embase. Randomized controlled trials that evaluated diabetes apps were included. We conducted a systematic review with meta-analysis and GRADE (Grading of Recommendations Assessment, Development and Evaluation) of the evidence. RESULTS Participants from 14 studies (n = 1,360) were included and quality assessed. Although there may have been clinical diversity, all type 2 diabetes studies reported a reduction in HbA1c. The mean reduction in participants using an app compared with control was 0.49% (95% Cl 0.30, 0.68; I2 = 10%), with a moderate GRADE of evidence. Subgroup analyses indicated that younger patients were more likely to benefit from the use of diabetes apps, and the effect size was enhanced with health care professional feedback. There was inadequate data to describe the effectiveness of apps for type 1 diabetes. CONCLUSIONS Apps may be an effective component to help control HbA1c and could be considered as an adjuvant intervention to the standard self-management for patients with type 2 diabetes. Given the reported clinical effect, access, and nominal cost of this technology, it is likely to be effective at the population level. The functionality and use of this technology need to be standardized, but policy and guidance are anticipated to improve diabetes self-management care

Influence of frailty in older patients undergoing emergency laparotomy: a UK-based observational study

Introduction The National Emergency Laparotomy Audit (NELA) has reported that older patients (≥65 years) form a large percentage of emergency high-risk cases with increased postoperative morbidity and mortality. With the population continuing to age rapidly, it is clear that a greater understanding of the factors affecting surgical outcomes in older patients is required. Frailty is a relatively new concept taking into account a variety of factors that increase an individual’s vulnerability to increased dependency and death. Research has suggested that high frailty scores increase postoperative complications, length of stay and mortality but the majority of these studies have been carried out on elective patients. Knowledge of how frailty affects patients in an emergency setting would aid clinicians’ and patients’ decision-making process. Methods and analysis This multicentre study will include consecutive adult patients aged 65 years and over undergoing emergency laparotomies over a 3-month period at 52 National Health Service hospitals across the UK. The primary outcome will be 90-day mortality. Secondary outcomes will include length of hospital stay, 30-day complications, change in level of independence and 30-day readmission. This study has been powered to detect a 10% change in mortality associated with frailty (n=500 patients). Ethics and dissemination This study has been approved by the National Health Service Research Ethics Committee. It has been registered centrally with HRA for English sites, NRSPCC for Scottish sites and Health and Care Research Permissions Service for sites in Wales.Dissemination will be via international and national surgical and geriatric conferences. In addition, manuscripts will be prepared following the close of the project. Trial registration number This study is also registered online at www.clinicaltrials.gov (registration number NCT02952430)

Resolving Shelf Break Exchange Around the European Northwest Shelf

Shelf seas act as a significant sink of carbon within the global ocean. This occurs as carbon is exported beneath the permanent oceanic thermocline through the downwelling circulation across the shelf break. This downwelling circulation is quantified here using two regional ocean model configurations of the European northwest shelf, with differing resolution (7‐ and 1.5‐km grid spacing). The dominant mechanisms and impact of model resolution are assessed along the length of the shelf break. The total downwelling circulation is stronger at higher resolution, due to an increased on‐shelf transport at internal depths (20–150 m) and increased off‐shelf transport at the base of the water column. At internal depths, these differences increase seasonally, influenced by stratification. Key processes in cross‐shelf exchange only begin to be resolved at O(1 km), implying that global models currently used to assess the carbon cycles will be missing these processes