Inhibitors of the Hepatitis C Virus Polymerase; Mode of Action and Resistance

The hepatitis C virus (HCV) is a pandemic human pathogen posing a substantial health and economic burden in both developing and developed countries. Controlling the spread of HCV through behavioural prevention strategies has met with limited success and vaccine development remains slow. The development of antiviral therapeutic agents has also been challenging, primarily due to the lack of efficient cell culture and animal models for all HCV genotypes, as well as the large genetic diversity between HCV strains. On the other hand, the use of interferon-α-based treatments in combination with the guanosine analogue, ribavirin, achieved limited success, and widespread use of these therapies has been hampered by prevalent side effects. For more than a decade, the HCV RNA-dependent RNA polymerase (RdRp) has been targeted for antiviral development. Direct acting antivirals (DAA) have been identified which bind to one of at least six RdRp inhibitor-binding sites, and are now becoming a mainstay of highly effective and well tolerated antiviral treatment for HCV infection. Here we review the different classes of RdRp inhibitors and their mode of action against HCV. Furthermore, the mechanism of antiviral resistance to each class is described, including naturally occurring resistance-associated variants (RAVs) in different viral strains and genotypes. Finally, we review the impact of these RAVs on treatment outcomes with the newly developed regimens.     

Measurement of xenon diffusing capacity in the rat lung by hyperpolarized 129Xe MRI and dynamic spectroscopy in a single breath-hold.

We used the dual capability of hyperpolarized 129Xe for spectroscopy and imaging to develop new measures of xenon diffusing capacity in the rat lung that (analogously to the diffusing capacity of carbon monoxide or DLCO) are calculated as a product of total lung volume and gas transfer rate constants divided by the pressure gradient. Under conditions of known constant pressure breath-hold, the volume is measured by hyperpolarized 129Xe MRI, and the transfer rate is measured by dynamic spectroscopy. The new quantities (xenon diffusing capacity in lung parenchyma (DLXeLP)), xenon diffusing capacity in RBCs (DLXeRBC), and total lung xenon diffusing capacity (DLXe)) were measured in six normal rats and six rats with lung inflammation induced by instillation of fungal spores of Stachybotrys chartarum. DLXeLP, DLXeRBC, and DLXe were 56 +/- 10 ml/min/mmHg, 64 +/- 35 ml/min/mmHg, and 29 +/- 9 ml/min/mmHg, respectively, for normal rats, and 27 +/- 9 ml/min/mmHg, 42 +/- 27 ml/min/mmHg, and 16 +/- 7 ml/min/mmHg, respectively, for diseased rats. Lung volumes and gas transfer times for LP (TtrLP) were 16 +/- 2 ml and 22 +/- 3 ms, respectively, for normal rats and 12 +/- 2 ml and 35 +/- 8 ms, respectively, for diseased rats. Xenon diffusing capacities may be useful for measuring changes in gas exchange associated with inflammation and other lung diseases.     

Making clinical decisions for dental care: concepts to consider

Clinical decisions are often made with incomplete information, yet patient care decisions are made every day. Patients vary clinically, uncertainty exists in diagnostic and prognostic information, and many preventive and treatment alternatives have not been formally assessed for their effectiveness. Because scientific information will never answer all clinical questions, clinical decisions are partially based on probabilistic information.
This paper describes how to apply clinical decision making to diagnosing and managing dental caries and periodontal diseases. By using explicit information to quantify probabilities and outcomes, clinical decision making analyzes decisions made under uncertain conditions and the uncertain impact of clinical information.
Clinical decision making incorporates concepts for preventing, diagnosing and treating dental caries and periodontal diseases: risk assessment, evidence-based dentistry, and multiple oral health outcomes. This information can serve as a tool for clinicians to augment clinical judgment and expertise.     

A37 REACTIVITY OF PLATELET AUTOANTIBODIES WITH PAPAIN TREATED PLATELETS AND COMPARISON WITH GLYCOPROTEIN SPECIFICITY.

A1 INFLUENCE OF POSTURE ON REACTIONS IN NEW BLOOD DONORS. A2 A CONFIDENTIAL UNIT EXCLUSION SYSTEM IDENTIFIES DONORS WITH A POTENTIAL FOR HIV INFECTION. A3 A STABLE BLOOD SUPPLY FOR THE FUTURE: THE RECRUITMENT OF 16 TO 18 YEAR OLD DONORS TODAY AND THEI CONTRIBUTION AS COMMITTED REGULAR DONORS OF TOMORROW. A4 APPROACH TO A SUPPLY CRISIS OF HYPERIMMUNE RHESUS PLASMA FOR THE PRODUCTION OF RhD IMMUNOGLOBULIN A5 THE INFLUENCE OF AGE, SEX AND ABO BLOOD GROUP ON THE INCIDENCE OF CMV ANTIBODIES IN SYDNEY BLOOD DONORS. A6 THE INCIDENCE OF CATEGORY VI AMONGST WEAK Rh(D) POSITIVE SYDNEY BLOOD DONORS. A7 A MODIFIED METHOD FOR DETECTING HIGH TITRE ANTI-A AND ANTI-B IN GROUP O DONORS A8 IMPROVING THE CLINICAL SPECIFICITY OF ALANINE AMINO TRANSFERASE (ALT) TEST RESULTS WITHIN THE NORMAL BLOOD DONOR POPULATION OF QUEENSLAND. A9 EXTRACTION OF HCV RNA USING A GUANIDINE ISOTHIOCYNATE METHOD. A10 HEPATITIS C VIRUS (HCV) ANTIBODY DETECTION IN TASMANIAN BLOOD DONORS. A11 EFFECTIVE INTERNAL QUALITY CONTROL FOR ENZYME IMMUNOASSAYS A12 DETECTION OF ANTIBODY TO NON-PATHOGENIC RETROVIRUSES (SPUMAVIRUSES) IN HUMAN SERUM A13 DETECTION OF ANTIBODY TO NON-PATHOGENIC RETROVIRUSES (SPUMAVIRUSES) IN HUMAN SERUM A14 A NOVEL BLOOD BAG SYSTEM WITH POTENTIAL, FOR THE ASIA-PACIFIC MARKET. A15 DESIGN OF CONTAINERS SUITABLE FOR THE TRANSPORT OF RED CELL, PLATELET AND FROZEN PLASMA PRODUCTS. A16 EVALUATION OF INDICATOR LABELS FOR QUALITY ASSURANCE OF IRRADIATION PROCEDURE OF BLOOD PRODUCTS. A17 MOLECULAR TYPING FOR UNUSUAL ABO TYPES. A18 AN EXAMPLE OF THE RARE ABO SUBGROUP, A19 RFLP ANALYSIS OF A RH NULL BLOOD DONOR. A20 A RELATIONSHIP BETWEEN LEWIS ERYTHROCYTE PHENOTYPES AND COLORECTAL CANCER. A21 PATERNITY TESTING USING SINGLE LOCUS DNA PROBES: OBSERVATIONS ON THE REFERENCE DATA BASE SIZE A22 USE OF FAMILY AND POPULATION STUDIES TO DETERMINE THE SPECIFICITY AND INHERITANCE OF NEUTROPHIL ANTIGENS DEFINED BY PLANT LECTINS. A23 SAMPLING PLANS: IS THERE RELEVANCE FOR BLOOD COMPONENT QC? A24 QUALITY MANAGEMENT: HOW DO WE DO IT IN A STATE THE SIZE OF QUEENSLAND? A26 THE ENERGY METABOLISM OF CIRCULATING CELLS. A27 ACETATE UTILISATION RATES AND THE EFFECT OF GLUCOSE-FREE PLASMA IN PLATELET CONCENTRATE STORED IN A MIMIMAL MEDIUM (MPM). A28 IMPROVED LEVELS OF 2,3 DJPHOSPHOGLYCERATE IN RED CELL SUSPENSIONS PREPARED FROM BLOOD COLLECTED INTO DEXTROSE-FREE ANTICOAGULANT. A29 EVALUATION OF RED CELL FREEZING METHODS AS A PRELUDE TO ADOPTING -80° C FREEZING IN HIGH GLYCEROL IN ROUTINE PRACTICE. A30 CLUMPING IN PLATELET CONCENTRATES - AN UNSOLVED PROBLEM. A31 AUTOLOGOUS BLOOD: SAFE FOR OTHERS OR NOT? A32 ESTABLISHMENT OF AN AUSTRALIAN HAEMOPHILIA TREATMENT CENTRE DATA BANK. A33 EXPERIENCE IN THE USE OF ROBOTICS AND MICROPLATE TECHNOLOGY TO SEMI-AUTOMATE A ROUTINE HOSPITAL BLOOD BANK. A34 AN ANTI-IgAl/IgA2 ELISA ASSAY FOR THE INVESTIGATION OF HYPESENSITIVITY TRANSFUSION REACTIONS. A35 THE INFLUENCE OF IgG AGGREGATES AND FRESH NORMAL SERUM ON THE MONOCYTE MONOLAYER ASSAY A36 DETECTION OF Rh(D) POSITIVE FETAL CELLS IN PREGNANT Rh(D)-NEGATIVE WOMEN BY FLOW CYTOMETRY. A38 HAEMOSTAT-IX: A HIGH PURITY FACTOR CONCENTRATE FOR THE TREATMENT OF PATIENTS WITH HAEMOPHILIA B. A39 GRAVITY FILTRATION OF PLASMA FROM DONOR BLOOD UTILISING A HOLLOW FIBRE FILTER MEMBRANE DEVICE A40 The Therapeutic Device Problem Reporting Scheme, and the Victorian Red Cross Blood Bank A43 HIGH FREQUENCY ANTIBODIES AND THE ADVANTAGES OF MANUAL POLYBRENE. A44 FACTS AND FANTASY IN THE DEVELOPMENT OF PLATELET ADDITIVE SOLUTIONS. A45 LACK OF EFFECT OF STORAGE CONTAINER ON STORAGE OF PLATELETS PREPARED FROM DEXTROSE-FREE BLOOD, A46 PLATELETS PREPARED FROM DEXTROSE-FREE BLOOD MAY BE STORED WITHOUT AGITATION. A47 QUALITY OF BED CELL CONCENTRATE IN HOSPITALS COMPARED TO THE BLOOD BANK A48FLOW CYTOMETRIC CHARACTERISATION OF LEUCOCYTE - DEPLETED RED CELL CONCEHTRATES. A49 PRODUCTION AND CHARACTERISATION OF HUMAN MONOCLONAL ANTI-D ANTIBODIES. A50 CD55 AND CD59 SUSCEPTIBILITY TO PROTEASE TREATMENT AND THE RESULTANT EFFECT ON COMPLEMENT LYSIS OF RBCs. A51 DIRECT COMPARISON BETWEEN PLATELET STORAGE CONTAINERS - IMPROVEMENT IN STORAGE CHARACTERISTICS OF TUTA PLATELET BAGS OVER THE PAST FOUR YEARS. A52 IMPROVED SOLID-PHASE MIXED PASSIVE HAENAGGLUTININ ASSAY (MPHA) WITH FROZEN PANEL PLATELETS FOR THE DETECTION OF HUMAN PLATELET ANTIBODIES. A53 DEVELOPMENT OF A SOLVENT DETERGENT TREATED THROMBIN CONCENTRATE AS A COMPONENT OF A FIBRIN GLUE KIT. A54 Autologous blood transfusion: a promotional programme A55 AVAILABILITY OF BLOOD PRODUCTS FOR ACUTELY BLEEDING PATIENTS. A56 REMINISCENCES OF 50 YEARS A. A TRANSFUSION ST. A57 A NATIONAL SYSTEM FOR REPORTING TRANSFUSION REACTIONS TO FRACTIONATED BLOOD PRODUCTS. A58 EFFECT OF FLUORESCENT LIGHTING ON THE VISUAL APPEARANCE OF PLATELET CONCENTRATES A59 USING A MICROWAVE OVEN TO THAW FRESH FROZEN PLASMA. A60 COAGULATION CAPACITY OF POOLED PLATELET PLASMA. A61 A COMPARISON OF IMMUNOHAEMATOLOGY SURVEY PERFORMANCE BETWEEN NEK ZEALAND AND AUSTRALIA A62 COMPATIBILITY TESTING: ARE ENZYME TESTS REQUIRED? A63 AN EVALUATION OF THE DIAMED MEROTYPING SYSTEM FOR THE PERFORMANCE OF THE DIRKT ANTIGLOBUDIN TEST. A64 ASSESSMENT OF PERFORMANCE IN BLOOD GROUP ANTIBODY DETECTION. A65 CHARACTERISATION OF MABS TO THROMBIN-HIRUDIN COMPLEXES WITH IMMUNOASSAY POTENTIAL. A66 MONITORING ANTT-HPA-la (P1^A1) PLATELET ANTIBODY LEVELS DURING PREGNANCY USING THE MAIPA TEST. A67 COMPARISON OF PIFT AND MAIPA TEST“ IN THE DETECTION OF ANTI-HPA-la (PI^A1) PLATELET ANTIBODIES. A68 USE OF PLATELET-CROSSMATCHING IN SUPPORT OF A CASE OF MYELODYSPLASIA WTTH A PLATELET SPECIFIC AND B LYMPHOCYTE ANTIBODY A69 The Pattern of Leucocyte Antibody formation in Transfused Patients. A70 DETECTION OF HPA-Ia ANTIBODY IN BREAST MILK A71 ANALYSIS OF PRENATAL SCREENING. A72 DETECTION OF MINOR POPULATIONS OF ERYTHROCYTES A73 MODIFICATIONS TO THE MCNOCYTE-MEDIATED ADCC ASSAY. A74 AN AUTO ANTI-JMH; GAMMA-CLONE POLYSPECIFIC AHG AS A USEFUL TOOL. A75 CLINICALLY SIGNIFICANT ANTI-A1 DERIVED FROM B LYMPHOCYTES FOLLOWING SINGLE LUNG TRANSPLANTATION. A76 CONFIRMATION THAT ANTI-ELO CAUSES HAEMOLYTIC DISEASE OFTHE NEWBORN. A77 ANTI-Do^a STIMULATED BY PREGNANCY. A78 DONOR IgM ANTI-A ASSOCIATED WITH HAEMOLYTIC TRANSFUSION REACTION A79 COLLECTION OF GRANULOCYTES AND PLATELETS USING FENWALL CS 3000 AND HAEMONETICS 30 CELL SEPARATORS - A COMPARISON. A80 APPARENT LYMPHOPENIA IN PLASMAPHERESIS DONORS