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Biomedical subjects

W Rosenberg

Publications and source records attributed to W Rosenberg.

At least 19 recordsLinked to original sources
PubMed2006

Review article: management of patients with chronic hepatitis C virus infection and "normal" alanine aminotransferase activity.

BACKGROUND: Hepatitis C virus infection, a major cause of chronic liver disease, occurs with normal serum alanine aminotransferase activity in approximately 25% of patients. These patients have historically remained untreated but substantial evidence indicates liver damage, progression of disease and impaired quality of life in some individuals. AIM: To review the current management of patients with chronic hepatitis C and normal alanine aminotransferase activity. METHODS: This review represents the summary of discussions at a Clinical Workshop with a comprehensive literature searching of available databases (PubMed and Embase). RESULTS: Current limits defining normal serum alanine aminotransferase activity are not representative of a "healthy" status. Most patients with hepatitis C and normal alanine aminotransferase levels have histologically proven liver damage that, although generally mild, may be significant (> or =F2) in up to 20% of patients and progresses at approximately 50% of the rate in patients with elevated alanine aminotransferase levels. Some patients have persistently normal alanine aminotransferase activity and may have a more benign outcome, but a significant proportion (> or =20%) experience periods of increased serum alanine aminotransferase activity which may be associated with enhanced disease progression. CONCLUSIONS: A treatment approach that considers host and virus-related variables and optimizes patient and cost benefits may therefore provide more effective management of patients with chronic hepatitis C and normal alanine aminotransferase activity.

Alanine Transaminase↗
PubMed2005

Cost effectiveness of interferon alpha or peginterferon alpha with ribavirin for histologically mild chronic hepatitis C.

BACKGROUND: For patients with mild chronic hepatitis C the cost effectiveness of antiviral therapy is unknown. AIMS: To assess whether antiviral therapy (either interferon alpha or peginterferon alpha combined with ribavirin) is cost effective at a mild stage compared with waiting and only treating those cases who progress to moderate disease. PATIENTS: Cases with mild chronic hepatitis C. METHODS: A cost effectiveness model which estimates long term costs and outcomes for patients with mild chronic hepatitis C. The model uses effectiveness and cost data from the UK mild hepatitis C randomised controlled trial, combined with estimates of disease progression and cost from observational studies. RESULTS: Antiviral treatment at a mild rather than a moderate stage improved outcomes measured by quality adjusted life years (QALYS) gained. The mean cost per QALY gained from antiviral treatment with interferon alpha-2b and ribavirin, compared with no treatment at a mild stage, was 4535 pounds sterling (7108 dollars) for patients with genotype non-1 and 25,188 pounds sterling (39,480 dollars) for patients with genotype 1. Providing peginterferon alpha-2b and ribavirin at a mild rather than a moderate stage was also associated with a gain in QALYS; the costs per QALY gained were 7821 pounds sterling (12,259 dollars) for patients with genotype non-1 and 28,409 pounds sterling (44,528 dollars) for patients with genotype 1. CONCLUSIONS: For patients with chronic hepatitis C, it is generally more cost effective to provide antiviral treatment at a mild rather than a moderate disease stage. For older patients (aged 65 years or over) with genotype 1, antiviral treatment at a mild stage is not cost effective.

Adult↗
PubMed2005

Discontinuation of pegylated interferon plus ribavirin in patients who are not responding to therapy -- patients' views of early cessation of therapy.

BACKGROUND: Current therapy for chronic hepatitis C infection involves a course of pegylated interferon and ribavirin. Patients who do not show a virological response after 12 weeks of therapy have a low probability of sustained virological response and it is therefore recommended that such patients stop treatment. AIM: To assess patients' views of early treatment cessation. METHODS: We conducted a open-labelled study in three UK centres, in which patients with biopsy-proven chronic hepatitis C requiring therapy were offered the choice of a full course of therapy with 40 kDa pegylated interferon-alpha 2a plus ribavirin (24 or 48 weeks depending on viral genotype) or early cessation if therapy had failed after 12 weeks. RESULTS: Ninety-five participants were enrolled and the majority (69%) did not wish to discontinue therapy even if it had low probability of success. In this unselected UK population, very few patients (4%) did not achieve an early virological response with the 40-kDa pegylated interferon-alpha 2a plus ribavirin and two of the four early virological non-responders decided to continue therapy. CONCLUSION: Early discontinuation of 'ineffective' anti-viral therapy may prove less popular with patients than with health care providers, and further patient-directed education regarding the cost-effectiveness of therapy will be needed if early discontinuation of unsuccessful therapy is to be accepted by patients.

Adult↗
PubMed2002

Cost effectiveness of combination therapy for hepatitis C: a decision analytic model.

OBJECTIVE: To estimate the cost utility of treatment with combination therapy (ribavirin and interferon alpha) for hepatitis C compared with no treatment or monotherapy (interferon alpha) based on UK costs and clinical management. DESIGN: Decision analysis model using a Markov approach to simulate disease progression. SETTING: UK secondary care. PARTICIPANTS: Hypothetical cohort of patients with hepatitis C. MAIN OUTCOME MEASURES: Cost per quality adjusted life year (QALY) gained. RESULTS: Discounted cost per QALY for combination therapy over no treatment was 3791 pounds. Cost per QALY varied between 1646 pounds and 9170 pounds according to subgroup, with the lowest ratios being for genotype 2 or 3, women, those aged less than 40 years, and those with moderate hepatitis. The discounted cost per QALY of the combination over monotherapy was 3485 pounds. Similar findings were shown for subgroups as for the comparison with no treatment. One way sensitivity analysis showed that while drug costs were more important in the analysis than assumptions about disease progression or costs of treating hepatitis C disease, the results were robust to large changes in underlying assumptions. CONCLUSIONS: Combination therapy for hepatitis C is a cost effective treatment option and is superior to monotherapy. Considerable uncertainties remain over the appropriate management strategies in the populations excluded from randomised controlled trials and in whom treatment is currently being considered in the UK.

Adult↗
PubMed2001

DNA vaccination: a potential weapon against infection and cancer.

DNA vaccination is a novel approach for inducing immunity against target antigens. It provides a direct link between identification of genes encoding these antigens and incorporation of the gene sequences into a vaccine vehicle. Identification of candidate genes is proceeding very rapidly both for infectious organisms and for cancer cells. One advantage is that DNA appears to activate all pathways of immunity, especially cytotoxic T-cell responses, which have been difficult to induce with protein vaccines. For viruses, including those which have caused problems for blood transfusion, DNA vaccination could be used for prevention. However, for chronic infection, or for cancer, vaccination will be performed in a therapeutic setting. For this situation, it is probable that immune-activating sequences will have to be included in the vaccine. The ease of manipulation of gene sequences, together with the increasing knowledge of the operation of the immune system, means that we now have the tools to take vaccines into the next exciting stage of development.

Animals↗
PubMed2000

Diaries of evidence-based tutors: beyond 'numbers needed to teach'...

Interprofessional evidence-based health care courses have been held throughout the UK over the last few years, modelled on the approach used in McMaster University of using problem-based facilitated small-group formats to achieve the stated goals. Both delegates and tutors have been aware of the tensions which are inherent within these courses between: (a) the variation in learning cultures which is exhibited by the delegates and the effect this has on processes (i.e. the tension between the reductionist approach of bioscience and the more qualitative leanings of the applied and 'caring' disciplines); and (b) the conflict which arises between the goal of 'learning' applied healthcare biostatistics and the ability to leave the course with the skills to teach others. This qualitative study uses tutor-kept diaries to understand some of the tensions apparent to the teaching faculty during a week-long course in Wales, UK.

Evidence-Based Medicine↗
PubMed1999

What is the cost utility of screening for hepatitis C virus (HCV) in intravenous drug users?

OBJECTIVES: To model the likely cost utility of the prevalence round of a screening programme for hepatitis C (HCV) in intravenous drug users (IVDUs) in contact with services in the South and West health region of the UK. METHODS: Information on the prevalence of HCV, performance of diagnostic tests, and effectiveness of interferon alpha (IFN alpha) for treatment of chronic hepatitis were brought together with estimates of the costs of service provision. A simple spreadsheet model was used to estimate cost utility (cost/quality adjusted life year (QALY)). Assumptions (including use of ribavirin plus IFN alpha combination therapy) were tested by a one way sensitivity analysis. RESULTS: About 5600 IVDUs live in the region. A combination of enzyme linked immunosorbent assay (ELISA) and polymerase chain reaction (PCR) testing has high sensitivity and specificity for detecting HCV. There is excellent evidence that IFN alpha is effective in producing sustained normalisation of liver function and, by inference, eradicating HCV. Evidence for long term benefits comes from modelling studies based on progression of HBV or non-A, non-B hepatitis and is considerably less robust. The cost of the prevalence round of screening in IVDUs would be about 700,000 Pounds and is likely to identify about 1400 people, of whom about 270 would be eligible for treatment and 20 would respond to IFN alpha. This gives a cost/QALY of 9300 Pounds for the screening programme. However, much uncertainty around the estimates used to inform the cost utility calculation limits confidence in the value of screening IVDUs for HCV. Sensitivity analysis shows a range of possible cost utility from 3333 Pounds to 81,438 Pounds. Estimates are particularly sensitive to adherence to liver biopsy and treatment and to discounting of benefits. CONCLUSIONS: Although potentially cost effective, many important uncertainties surround the assumptions used to estimate the long term effectiveness of screening and treatment. There is insufficient evidence to inform policy development and further research is required in this rapidly changing field.

Comorbidity↗
PubMed1996

An HLA-B35-restricted epitope modified at an anchor residue results in an antagonist peptide.

Peptides associated with HLA-B35 commonly have a proline or occasionally a serine residue in the P2 anchor position of the peptide, with a tyrosine at the C terminus. Based on this motif, we identified an octamer epitope from influenza A matrix protein which is presented by HLA-B35. The requirements for MHC binding and T cell receptor contact have been analyzed using analogs of this peptide with substitutions at positions 1, 2, 4, 7 and 8. The natural epitope contains a serine residue at P2 of the peptide. Substitution of this residue with proline (the favored amino acid in this position in B35-associated peptides) considerably enhances binding to HLA-B35 in the T2-B35 cell line, but the peptide is not recognized by the majority of CTL clones and can antagonize recognition of the index peptide. This suggests that a conservative substitution at the P2 anchor position results in a conformational change in the peptide-MHC surface exposed to the T cell receptor.

Amino Acid Sequence↗
PubMed1995

Evidence based medicine: an approach to clinical problem-solving.

Doctors within the NHS are confronting major changes at work. While we endeavour to improve the quality of health care, junior doctors' hours have been reduced and the emphasis on continuing medical education has increased. We are confronted by a growing body of information, much of it invalid or irrelevant to clinical practice. This article discusses evidence based medicine, a process of turning clinical problems into questions and then systematically locating, appraising, and using contemporaneous research findings as the basis for clinical decisions. The computerisation of bibliographies and the development of software that permits the rapid location of relevant evidence have made it easier for busy clinicians to make best use of the published literature. Critical appraisal can be used to determine the validity and applicability of the evidence, which is then used to inform clinical decisions. Evidence based medicine can be taught to, and practised by, clinicians at all levels of seniority and can be used to close the gulf between good clinical research and clinical practice. In addition it can help to promote self directed learning and teamwork and produce faster and better doctors.

Clinical Medicine↗
PubMed1994

Cytotoxic T-cell activity antagonized by naturally occurring HIV-1 Gag variants.

Most asymptomatic individuals infected with HIV-1 have a cytotoxic T lymphocyte (CTL) response to the virus Gag proteins which can be demonstrated in vitro. Epitopes have been mapped in p17 Gag and p24 Gag restricted by HLA-B8 (p17-3 and p24-13) and -B27 (p24-14). Viruses isolated from patients who make CTL responses to these peptides vary within the genetic sequences encoding these epitopes and some mutations lead to reduction in killing activity in vitro. This was attributed to either failure of the variant epitope to bind major histocompatibility complex class I or failure of T-cell receptors to bind the presented peptide. But peptide variants of class I-restricted epitopes cause 'antagonism', that is, the presence of a variant epitope (in the form of peptide) inhibits normal lysis of targets presenting the original epitope. This mirrors similar findings in class II-restricted systems. Here we report that naturally occurring variant forms of p17-3, p24-13 and p24-14 may cause antagonism of CTL lines derived from the same individuals. The effect is present if the epitopes are derived from synthetic peptides and when they are processed from full-length proteins expressed by either recombinant vaccinia constructs or replicating HIV.

Amino Acid Sequence↗
PubMed1994

Information technology enters the doctor's office: Part II--Six lessons about intended ... and unintended ... results.

Part I of this article ("Six Design and Implementation Lessons," Physician Executive, Sept.-Oct. 1993, pp. 46-50) described an ambulatory utilization review (AUR) program designed and implemented by Metropolitan Life Insurance Company and reviewed some of the lessons learned over the past five years. Those lessons pertained to the tasks of inventing a new information technology to measure and evaluate ambulatory care and some of the practical implementation issues associated with review of 30,000 small dollar value claims per day in 19 claim offices nationwide. This article turns to the basic purpose of AUR--to review the medical necessity and appropriateness of ambulatory utilization. One lesson learned about AUR in this context is that AUR works: savings from the program outweigh costs by almost 5:1. The more important lessons, however, stem from understanding how the savings are achieved, and what some of the other unintended benefits of the program are.

Ambulatory Care↗
PubMed1993

A sequence pattern for peptides presented to cytotoxic T lymphocytes by HLA B8 revealed by analysis of epitopes and eluted peptides.

HLA B8-restricted cytotoxic T lymphocytes (CTL) specific for influenza A virus were generated and shown to recognize the nucleoprotein (NP). The dominant epitope was mapped using recombinant vaccinia viruses that expressed fragments of the NP and then synthetic peptides based on the NP amino acid sequence. The peptide 380-393 was first identified and further refined; it was shown that the glutamic acid at position 380 was essential for recognition by CTL and that the nonamer 380-388 was the optimum peptide. Six HLA B8-positive influenza immune donors that we have tested respond to this peptide as part of their influenza-specific CTL response. The amino acid sequence of the peptide epitope was compared to six other known virus peptides known to be restricted by HLA B8 and a sequence homology was identified, which predicted nonamer and octamer epitope sequences. Probable anchor residues were identified at peptide residues 3 (lysine/arginine), 5 (lysine/arginine) and 9 (leucine/isoleucine). Support for this pattern came from sequencing peptides eluted from purified HLA B8 molecules, where lysines were predominant at positions 3 and 5. One of the predicted epitope peptides was made and shown to be recognized by specific CTL. These and the two others were shown to compete with NP 380-388 for binding to HLA B8. A model was made of the HLA B8 molecule and negatively charged pockets predicted, which could accommodate the positively charged side chains of the peptide anchor residues.

Amino Acid Sequence↗