4.4 Interim Financial Statements

2.1 Applicatio

TABLE OF CONTENTS PART I SURFACE WATER STANDARDS WITH GENERAL, STATEWIDE APPLICATION

9 VAC 25-260-10 Designation of Uses page 5 9 VAC 25-260-20 General Criteria/Mixing Zones page

The cooperative health statistics system : its mission and program: final report from the Task Force on Definitions to the Cooperative Health Statistics Advisory Committee, August 30, 1976

DHEW publication no. (HRA) 77-1456

A systematic review of biomarkers for disease progression in Parkinson's disease

Peer reviewedPublisher PD

Blood Cytokines as Biomarkers of In Vivo Toxicity in Preclinical Safety Assessment: Considerations for Their Use

In the drive to develop drugs with well-characterized and clinically monitorable safety profiles, there is incentive to expand the repertoire of safety biomarkers for toxicities without routine markers or premonitory detection. Biomarkers in blood are pursued because of specimen accessibility, opportunity for serial monitoring, quantitative measurement, and the availability of assay platforms. Cytokines, chemokines, and growth factors (here referred to collectively as cytokines) show robust modulation in proximal events of inflammation, immune response, and repair. These are key general processes in many toxicities; therefore, cytokines are commonly identified during biomarker discovery studies. In addition, multiplexed cytokine immunoassays are easily applied to biomarker discovery and routine toxicity studies to measure blood cytokines. However, cytokines pose several challenges as safety biomarkers because of a short serum half-life; low to undetectable baseline levels; lack of tissue-specific or toxicity-specific expression; complexities related to cytokine expression with multiorgan involvement; and species, strain, and interindividual differences. Additional challenges to their application are caused by analytical, methodological, and study design–related variables. A final consideration is the strength of the relationship between changes in cytokine levels and the development of phenotypic or functional manifestations of toxicity. These factors should inform the integrated judgment-based qualification of novel biomarkers in preclinical, and potentially clinical, risk assessment. The dearth of robust, predictive cytokine biomarkers for specific toxicities is an indication of the significant complexity of these challenges. This review will consider the current state of the science and recommendations for appropriate application of cytokines in preclinical safety assessment

The attachment system and physiology in adulthood: normative processes, individual differences, and implications for health.

Attachment theory provides a conceptual framework for understanding intersections between personality and close relationships in adulthood. Moreover, attachment has implications for stress-related physiology and physical health. We review work on normative processes and individual differences in the attachment behavioral system, as well as their associations with biological mechanisms related to health outcomes. We highlight the need for more basic research on normative processes and physiology and discuss our own research on individual differences in attachment and links with physiology. We then describe a novel perspective on attachment and physiology, wherein stress-related physiological changes may also be viewed as supporting the social-cognitive and emotion regulatory functions of the attachment system through providing additional energy to the brain, which has implications for eating behavior and health. We close by discussing our work on individual differences in attachment and restorative processes, including sleep and skin repair, and by stressing the importance of developing biologically plausible models for describing how attachment may impact chronic illness

Luminally expressed gastrointestinal biomarkers

Introduction: A biomarker is a measurable indicator of normal biologic processes, pathogenic processes or pharmacological responses. The identification of a useful biomarker is challenging, with several hurdles to overcome before clinical adoption. This review gives a general overview of a range of biomarkers associated with inflammatory bowel disease or colorectal cancer along the gastrointestinal tract. Areas covered: These markers include those that are already clinically accepted, such as inflammatory markers such as faecal calprotectin, S100A12 (Calgranulin C), Fatty Acid Binding Proteins (FABP), malignancy markers such as Faecal Occult Blood, Mucins, Stool DNA, Faecal microRNA (miRNA), other markers such as Faecal Elastase, Faecal alpha-1-antitrypsin, Alpha2-macroglobulin and possible future markers such as microbiota, volatile organic compounds and pH. Expert commentary: There are currently a few biomarkers that have been sufficiently validated for routine clinical use at present such as FC. However, many of these biomarkers continue to be limited in sensitivity and specificity for various GI diseases. Emerging biomarkers have the potential to improve diagnosis and monitoring but further study is required to determine efficacy and validate clinical utility

Peripheral blood biomarkers in multiple sclerosis.

Multiple sclerosis is the most common autoimmune disorder affecting the central nervous system. The heteroge-neity of pathophysiological processes in MS contributes to the highly variable course of the disease and unpre-dictable response to therapies. The major focus of the research on MS is the identification of biomarkers inbiologicalfluids, such as cerebrospinalfluid or blood, to guide patient management reliably. Because of the diffi-culties in obtaining spinalfluid samples and the necessity for lumbar puncture to make a diagnosis has reduced,the research of blood-based biomarkers may provide increasingly important tools for clinical practice. However,currently there are no clearly established MS blood-based biomarkers. The availability of reliable biomarkerscould radically alter the management of MS at critical phases of the disease spectrum, allowing for interventionstrategies that may prevent evolution to long-term neurological disability. This article provides an overview ofthis researchfield and focuses on recent advances in blood-based biomarker researc

Tear fluid biomarkers in ocular and systemic disease: potential use for predictive, preventive and personalised medicine

In the field of predictive, preventive and personalised medicine, researchers are keen to identify novel and reliable ways to predict and diagnose disease, as well as to monitor patient response to therapeutic agents. In the last decade alone, the sensitivity of profiling technologies has undergone huge improvements in detection sensitivity, thus allowing quantification of minute samples, for example body fluids that were previously difficult to assay. As a consequence, there has been a huge increase in tear fluid investigation, predominantly in the field of ocular surface disease. As tears are a more accessible and less complex body fluid (than serum or plasma) and sampling is much less invasive, research is starting to focus on how disease processes affect the proteomic, lipidomic and metabolomic composition of the tear film. By determining compositional changes to tear profiles, crucial pathways in disease progression may be identified, allowing for more predictive and personalised therapy of the individual. This article will provide an overview of the various putative tear fluid biomarkers that have been identified to date, ranging from ocular surface disease and retinopathies to cancer and multiple sclerosis. Putative tear fluid biomarkers of ocular disorders, as well as the more recent field of systemic disease biomarkers, will be shown