Disease progression in pre-dialysis patients: renal function, symptoms, and health-related quality of life

This thesis investigated the effect of several risk factors on objectively assessed disease progression (renal function decline and time until the start of renal replacement therapy) and subjectively assessed disease progression (disease-related symptoms and health-related quality of life) in patients with chronic kidney disease on specialized pre-dialysis care. Furthermore, we explored (un)known mechanisms that may determine renal function decline in pre-dialysis patients. The conclusions are: low blood pressure, low proteinuria levels, and low cholesterol levels are associated with a slower objectively assessed disease progression. However, in elderly patients low blood pressure is a marker for an earlier start of renal replacement therapy. Concerning subjectively assessed disease progression, only in young patients treated with anemia-medication, high hemoglobin levels are associated with a better health-relate d quality of life. Furthermore, symptoms increase and health-related quality of life decreases during pre-dialysis care. Therefore, these markers are good candidates for defining the optimal moment to start with dialysis. This thesis also showed that black patients experience a faster renal function decline than white patients. A possible explanation could be the stronger negative consequences of diabetes mellitus in black patients. Finally, at middle-age, renal function is higher in longevity families, revealing possible new genetic mechanisms.UBL - phd migration 201

RACIAL DIFFERENCES IN HEPATOCYTE GROWTH FACTOR GENE SIGNATURE EXPRESSION BY BREAST CANCER SUBTYPE AND ITS ASSOCIATION WITH SURVIVAL OUTCOMES

In the United States, African American women have a 41% higher mortality rate from breast cancer compared to Caucasian women. This disparity is believed to be partially caused by higher prevalence rates of triple negative and basal-like breast cancers among African American women. The triple negative/basal like subtype account for 22% of the breast cancers diagnosed in African American women, but only 10% of the breast cancers in white women. However, even within a given subtype, there may be other biological factors or tumor microenvironment features that affect outcomes. One possible biologic mechanism that may help to explain heterogeneity of survival within an intrinsic subtype is Hepatocyte growth factor (HGF), a protein in a signaling pathway that has been implicated in tumor progression and metastasis of breast cancer. HGF is a stroma derived factor that can indicate an activated stromal microenvironment that may be conducive for tumor promotion. The aims of this dissertation are: (1) to describe the patient and clinical characteristics associated with the HGF positive tumor phenotype, including distribution by intrinsic subtypes and race. (2) to assess if differential expression of the HGF genetic signature affects breast-cancer specific survival or disease-free survival among breast cancer patients, overall or stratified on subtype. HGF will be assessed using gene expression data based on Nanostring technology from invasive breast cancer cases in the Carolina Breast Cancer Study (CBCS, Phases 1-3, recruited from 1993-2013). Patients were followed up prospectively for survival via medical records or National Death Index through 2009. HGF genetic signature and intrinsic subtypes have been measured in 1,957 tumors. The study results will provide insights into the role of stromal microenvironment in breast cancer heterogeneity and survival. HGF signaling is also targetable, and therefore, results may suggest novel treatment strategies for breast cancer.Doctor of Philosoph

Aspects of quality of life in the patient journey in glaucoma

Open angle glaucoma is a chronic disease of the optic nerve, where damage to the visual field can result in loss of vision. There is currently no cure for the disease. The four studies presented within this thesis aimed to explore aspects of the impact of glaucoma on patients’ everyday living and quality of life. The studies were designed to capture aspects of the ‘journey’ in glaucoma which may be particularly challenging for the patient; the initial stage, where quality of life may be reduced and the accompanying burden of ongoing disease monitoring; and the end stage, where significant loss of vision will likely cause visual disability and the daunting prospect of undergoing high-stakes ocular surgery. In the first study, the relationship between visual field loss (measured using mean deviation [MD]) and vison-related quality of life was assessed. Evidence indicated that glaucoma has a negative impact on vision-related quality of life, even in the earliest stage of the disease. However, the relationship is likely to be non-linear, as certain phases of the disease are more likely to have a greater impact than others. Specifically, each 1 decibel reduction in MD was associated with a decline of 2.3 (out of 100) units on a quality of life metric in the early stage of glaucoma (p<0.001), and 4.6 units in advanced disease (p=0.009). In the second study, vision-related quality of life was assessed amongst a cohort of newly-diagnosed glaucoma patients taking part in a randomised glaucoma therapy clinical trial. Responses on patient-reported outcome measures (PROMs) were assessed for group differences between treatment arms of the trial. In addition, group differences in quality of life between the stable patients and those with glaucomatous progression was compared. There were no statistically significant differences on PROMs between the two trial arms. Differences between stable and progressing glaucoma patients were observed only on PROMs specific to glaucoma (Glaucoma Quality of Life-15, p = 0.02; Glaucoma Activity Limitation-9, p = 0.02). In the third study, the equivalence of visual field measurement outcomes were assessed between patients attending standard glaucoma care services and those attending a novel glaucoma service, a virtual clinic. Average MD measurements for 250 patients in the virtual clinic were compared with a ‘big data’ repository of patients in the standard glaucoma service, which was used to calculate expected MD values. The speed of visual field progression between the two groups was also assessed. In the first analysis, 12 (4.8%; 95% confidence interval 2.5% to 8.2%) virtual clinic patients scored outside the 90% expected values based on the big data repository. In the second analysis, 1.9% (95% confidence interval 0.4% to 5.4%) virtual clinic patients had visual field changes outside of the expected 90% limits. In the fourth study, patient and surgeon experiences of advanced glaucoma surgery were assessed in a qualitative analysis. Interview transcripts underwent thematic analysis where, for the patients, key emerging themes included the emotional impact surgery, developing coping mechanisms, and how to improve the patient’s surgical journey. For the surgeons, themes included strategies for risk reduction, views on training, and the emotional impact of performing surgery on advanced glaucoma patients. To conclude, these studies highlight aspects of the patient journey in glaucoma where the disease may be most burdensome and troubling for the patient. Some practical changes, such as performing monitoring measurements in a virtual clinic, or augmented surgical care services for patients with advanced disease may help to ease the burden of glaucoma. In addition, the findings from these studies can help to improve understanding of the glaucoma journey and serve as an effective resource for learning, support, and professional development for patients, relatives, and carers, as well as professionals specialising in eye care

Toxicological profile for parathion

A Toxicological Profile for Parathion, Draft for Public Comment was released in October 2014. This edition supersedes any previously released draft or final profile.tp205.pd

Proceedings of the International Workshop on 'Combined Environmental Exposure: Noise, Air Pollutants and Chemicals'

The issue of combined exposure to noise, air pollution and chemicals has raised recently the interest of several bodies of the European Commission such as DG Environment, DG SANCO and DG Research in the context of the EC 7th Framework Programme. There are open questions whether prevailing environmental concentrations of air pollutants and chemicals can lead to ototoxic health impacts. Therefore this issue needs to be thoroughly explored and investigated to help the EC to revise the existing standards and guidelines concerning combined exposure to noise, air pollutants and chemicals. The aim of the workshop was to review and discuss the existing scientific evidence whether prevailing environmental exposures to single and concomitant agents together with noise could lead to ototoxic or other health impacts. The final aim was to identify the research needs and to give recommendations for research and policy making in the EU level. It was agreed that research in the future should be focused on really established combinations (high correlations) and interactions (known effect) with main perspective on the traffic bundle of exposure. It was also discussed and agreed upon that the best knowledge exists on the health effects due to combined exposure to noise and solvents or heavy metals in occupational environments, especially on most of the auditory and non-auditory effects. Possible factors that may have confounding or aggravating effects on the results of noise studies were identified. Such factors are: age, gender, smoking, obesity, alcohol, socio-economic status, occupation, education, family status, active military, experience, hereditary disease, medication, medical status, race and ethnicity, physical activity, noisy leisure activities, stress reducing activities, diet & nutrition, housing condition (crowding), and residential status. Research priorities and recommendations for the future. The highest priority was given to issues related to research on noise and outdoor air pollutants. This is due to the fact that it may concern the largest population compared to the other stressors in this analysis and there is some evidence of serious health outcomes such as cardiovascular effects. The next priority was given to the research on the effects of noise and solvents in occupational settings and to research on noise and organophosphates. In the future research, priority should be given to: 1. evaluation of existing data collections whether re-analyses are possible with respect to combined exposure from traffic sources (road, rail and air), 2. analyses of existing data concerning noise and other stressors interactions in both occupational and environmental settings, 3. detailed assessment of combined exposures to noise, vibrations and PM, CO, NOx, and VOCs with specific studies in urban areas and, especially, cardiovascular health endpoints should be studied as priority health endpoints, 4. identification of causal mechanisms through careful review of toxicological experimental studies.JRC.I.5-Physical and chemical exposure

Ammonia

prepared by Syracuse Research Corporation.Chemical manager(s)/author(s): Nickolette Roney, ATSDR, Division of Toxicology, Atlanta, GA; Fernando Llados, Susan S. Little, David B. Knaebel,.Syracuse Research Corporation, North Syracuse, NY."Prepared by Syracuse Research Corporation under contract no. 205-1999-00024; prepared for U.S. Dept. of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry."205-1999-00024Includes bibliographical references and glossary (p. 171-223)