Telaprevir user's guide

Telaprevir is a potent HCV NS3/4A protease inhibitor. A completed development program has demonstrated the superior efficacy of a regimen of telaprevir combined with pegylated interferon alfa and ribavirin (PR) over PR alone in patients with HCV genotype 1. In the ADVANCE trial in treatment-na?ve patients, 12 weeks of telaprevir, peginterferon alfa-2a and ribavirin followed by either 12 or 36 weeks of PR alone (depending upon extended rapid virologic response, or eRVR, i.e. HCV RNA undetectability at weeks 4 and 12), was associated with sustained virological response (SVR) in 75% of patients compared with 46% receiving PR for 48 weeks. The ILLUMINATE trial established the foundation for response-guided therapy in patients with eRVR. The REALIZE trial in treatment-experienced patients showed a gradient of SVR from prior relapsers (86%) to partial responders (57%) to null responders (31%), with rates of virologic failure and emergent resistance highest in the latter group. Incremental adverse effects of telaprevir include rash, anemia, pruritus, diarrhea, and nausea. Treatment na?ve patients and relapsers are eligible for response-guided therapy. Stopping rules of telaprevir-based treatment include HCV RNA > 1000 IU/ml at weeks 4 and 12.     

Telaprevir user's guide

For a decade, standard therapy for patients with genotype 1 chronic HCV (HCV G1) consisted of pegylated interferon (Peg-IFN) alfa-2a or Peg-IFN alfa-2b, combined with ribavirin. Despite the improved efficacy of this therapy over others, the overall sustained virologic response rate in patients with HCV G1 was still low. This article discusses phase I, II, and III trials examining telaprevir's role in treating patients with HCV. We have now entered an era of combination therapy utilizing direct acting anti-virals, the start of which was marked by the FDA approval of HCV protease inhibitors.     

Boceprevir: a user's guide

Given its essential role in the process of hepatitis C virus (HCV) replication, the viral NS3/4A serine protease is arguably the most thoroughly characterized HCV enzyme and the most intensively pursued anti-HCV target for drug development thus far. Recent data have demonstrated promise for the NS3 protease inhibitor boceprevir, which, when added to the standard of care peginterferon and ribavirin, improves sustained virological response while shortening duration of therapy in genotype-1-infected individuals. This review discusses the mechanism of action of boceprevir, its effects on HCV, and its viral resistance.     

Holding and manipulating the endoscope: A user's guide

The way endoscopists hold and manipulate the endoscope during examination varies. The lack of a standard manual on how to hold and manipulate the endoscope has perhaps contributed to the variation seen in practice. Unfortunately, the knowledge of how to properly hold the endoscope is not innate. What seems to be the simplest form may actually be incorrect. Developing the ability to hold and to manipulate the endoscope correctly requires practice and time. We are very pleased to contribute to this chapter given the paucity of literature and the importance of this foundational technique when performing endoscopy.     

A user's guide to the interactive Web database of factor H-associated hemolytic uremic syndrome

Atypical hemolytic uremic syndrome (aHUS) mutations have been reported in the complement regulatory proteins factor H, factor I, and membrane cofactor protein (MCP). Mutations within factor H are also associated with membranoproliferative glomerulonephritis and age-related macular degeneration. The increasing amount of information on aHUS requires organization if it is to be usable. Accordingly, an interactive factor H aHUS Web database has been developed (http://www.fh-hus.org) that integrates genotypic, phenotypic, and structural information for mutations within human factor H. This provides a valuable tool for the interpretation of previously reported aHUS mutations, and provides prediction and analysis tools for new mutations. It will be extended to include mutations in factor I and MCP. Here, we describe how to use this Web database as a research tool, and indicate possible future directions depending on feedback from the clinical community.     

Infliximab in the treatment of Crohn's disease: a user's guide for clinicians

Induction therapy with infliximab is indicated for treatment of signs and symptoms, and induction and maintenance of remission in patients with moderate to severely active inflammatory Crohn's disease with an inadequate response to conventional therapy, and for reduction in the number of draining fistulas in patients with fistulizing Crohn's disease. Emerging indications for infliximab therapy in patients with Crohn's disease include maintenance of fistula improvement (reduction in the number of draining perianal or enterocutaneous fistulas) and complete fistula response (no draining fistulas) in patients with fistulizing Crohn's disease, steroid sparing in steroid-treated patients, early use in hospitalized patients who have not failed conventional medical therapy where there is either a severe clinical presentation or a rapid onset of action is desired, and in a variety of unusual and extra-intestinal manifestations of Crohn's disease. An infliximab dose of 5 mg/kg is recommended initally, but some patients who require maintenance dosing may benefit from increasing the infliximab dose over a range of 5-10 mg/kg. An induction regimen of 3 doses at 0, 2, and 6 weeks is the preferred dosing strategy for inducing remission. The optimal dosing interval for patients who require retreatment appears to be every 8 weeks for most patients. Concomitant immunosuppressive therapy with azathioprine, 6-mercaptopurine, or methotrexate may result in improved outcomes due to a reduction in the frequency of human anti-chimeric antibody formation, acute infusion reactions, and a reduced risk of delayed hypersensitivity-like reactions and formation of antinuclear antibodies. Pretreatment with diphenhydramine (and in selected cases of acetaminophen and, rarely, corticosteroids) is recommended in patients with a history of infusion reactions and patients at risk for delayed hypersensitivity-like reactions. Patients with evidence of active infection should not receive infliximab until the infection is adequately treated, and all patients should be screened for tuberculosis prior to initiating infliximab therapy.     

A user's guide to enhancing geriatrics in an undergraduate medical school curriculum: the ten-step model to winning the "geriatric game"

In 1999, the University of Rochester School of Medicine and Dentistry committed to major restructuring of its undergraduate medical school curriculum. A distinguishing feature of this reform was the planned emphasis on and integration of several core topics or themes throughout the 4 years of the curriculum. One of these curricular themes was aging. The faculty in geriatrics was presented with an unparalleled opportunity to develop a geriatrics curriculum of major proportions through the development of an aging theme. Through a user's guide approach based on the authors' experience to date, this article identifies the 10 steps necessary to "win the geriatric game" successfully integrating an aging theme into an undergraduate medical school curriculum. Since the initiation of the aging theme, several new courses, cases, and conferences have been added or enhanced, affecting all 4 years of the curriculum. Key operational challenges included successful engagement of course directors, tracking the actual experience of the aging theme, and evaluation of students' attainment of learning objectives and eventual career choices. The authors' experience suggests that an aging theme can successfully enhance the geriatrics curricular content of undergraduate education and strongly affect students across all 4 years. This 10-step approach may serve as a model for other universities committed to integrating geriatrics across the full undergraduate medical curriculum.     

A consumer's guide to subgroup analyses.

The extent to which a clinician should believe and act on the results of subgroup analyses of data from randomized trials or meta-analyses is controversial. Guidelines are provided in this paper for making these decisions. The strength of inference regarding a proposed difference in treatment effect among subgroups is dependent on the magnitude of the difference, the statistical significance of the difference, whether the hypothesis preceded or followed the analysis, whether the subgroup analysis was one of a small number of hypotheses tested, whether the difference was suggested by comparisons within or between studies, the consistency of the difference, and the existence of indirect evidence that supports the difference. Application of these guidelines will assist clinicians in making decisions regarding whether to base a treatment decision on overall results or on the results of a subgroup analysis.     

Ventricular arrhythmias. A guide to their localisation.

An electrocardiographic atlas of ventricular tachycardias was produced by pacing 27 epicardial sections of the heart and the mitral papillary muscles to simulate focal ventricular arrhythmias and simultaneously recording their 12 lead electrocardiographic appearances. One hundred and twenty nine patients undergoing cardiac surgery were studied. In five patients all 27 epicardial sites were paced at operation and in 124 individual sections were paced postoperatively with temporary epicardial wires and the electrocardiograms analysed in terms of frontal and horizontal plan QRS axis, maximum limb lead QRS amplitude, and QRS duration. Each ventricular region paced produced a distinctive 12 lead electrocardiographic pattern. Simulated right ventricular arrhythmias had either inferior frontal plane QRS axes (from the anterobasal region) or superior frontal plane QRS axes (from the apical and posterior right ventricular sections). Horizontal plane QRS axes were directed leftwards, with some posterior shift in the anteroapical regions. Simulated arrhythmias from the base of the left ventricle (anteriorly and laterally) had inferior frontal plane QRS and anterorightward horizontal plane QRS axes. Left ventricular arrhythmias with a superior frontal plane QRS axis were readily distinguished by their horizontal plane QRS axes: posterorightwards from the anterior and anterorightwards from the posterior left ventricular sections. Standard errors of the paced QRS axes for the various epicardial sections paced postoperatively ranged from 3.0 degrees to 6.0 degrees using the frontal plane axis. The electrocardiogram was most accurate in localising ventricular arrhythmias from the anterior left ventricle and least accurate for those arising from the inferior right ventricle. The appearance of the paced electrocardiograms was slightly modified by underlying disease such as myocardial infarction and left ventricular hypertrophy. This atlas may be useful in comparing the localisation of ventricular tachycardia with the site of underlying cardiac disease and may facilitate mapping in patients with refractory ventricular tachycardia requiring ablation (either surgical or by high energy impulses).     

Ventricular arrhythmias. A guide to their localisation

An electrocardiographic atlas of ventricular tachycardias was produced by pacing 27 epicardial sections of the heart and the mitral papillary muscles to simulate focal ventricular arrhythmias and simultaneously recording their 12 lead electrocardiographic appearances. One hundred and twenty nine patients undergoing cardiac surgery were studied. In five patients all 27 epicardial sites were paced at operation and in 124 individual sections were paced postoperatively with temporary epicardial wires and the electrocardiograms analysed in terms of frontal and horizontal plan QRS axis, maximum limb lead QRS amplitude, and QRS duration. Each ventricular region paced produced a distinctive 12 lead electrocardiographic pattern. Simulated right ventricular arrhythmias had either inferior frontal plane QRS axes (from the anterobasal region) or superior frontal plane QRS axes (from the apical and posterior right ventricular sections). Horizontal plane QRS axes were directed leftwards, with some posterior shift in the anteroapical regions. Simulated arrhythmias from the base of the left ventricle (anteriorly and laterally) had inferior frontal plane QRS and anterorightward horizontal plane QRS axes. Left ventricular arrhythmias with a superior frontal plane QRS axis were readily distinguished by their horizontal plane QRS axes: posterorightwards from the anterior and anterorightwards from the posterior left ventricular sections. Standard errors of the paced QRS axes for the various epicardial sections paced postoperatively ranged from 3.0 degrees to 6.0 degrees using the frontal plane axis. The electrocardiogram was most accurate in localising ventricular arrhythmias from the anterior left ventricle and least accurate for those arising from the inferior right ventricle. The appearance of the paced electrocardiograms was slightly modified by underlying disease such as myocardial infarction and left ventricular hypertrophy. This atlas may be useful in comparing the localisation of ventricular tachycardia with the site of underlying cardiac disease and may facilitate mapping in patients with refractory ventricular tachycardia requiring ablation (either surgical or by high energy impulses).     

Effective communication skills. A guide for physician assistants.

Communication is a two-way process in which meaning is shared. To be effective, clinicians must assess appearance, environment, field of experience, language skills, tone of voice, listening abilities, cultural differences, and body language. Conscious awareness and continual evaluation of all elements of the communication process can significantly improve diagnostic skills and patient compliance, as well as strengthen the bond between patient and provider.     

Colchicine in clinical medicine. A guide for internists

Colchicine (COL) has been used in medicine for a long time. It is well recognized as a valid therapy in acute flares of gouty arthritis, familial Mediterranean fever (FMF), Behçet's disease, and recurring pericarditis with effusion. It has also been used to treat many inflammatory disorders prone to fibrosis, mostly with disappointing therapeutic results.The pharmacotherapeutic mechanism of action of COL in diverse diseases is not fully understood, thought it is known that the drug accumulates preferentially in neutrophils, and this effect is useful in FMF.COL shows a large interindividual bioavailability. Furthermore, interactions with drugs interfering with CYP3A4 dependent enzymes and P-glycoprotein occur and are clinically important. The dosage of COL must be reduced in patients with relevant hepatic and/or renal dysfunction. However, when appropriately used and contraindications have been excluded, oral COL is a safe treatment.