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.     

Intracranial circulation: pulse-sequence considerations in three- dimensional (volume) MR angiography

The technique and feasibility of magnetic resonance (MR) angiography of intracranial vessels were studied in 35 healthy volunteers. Variations in image orientation, repetition time (TR), and flip angle were evaluated to determine their effects on flow-related enhancement. Gradient modifications--including echo time (TE), motion compensation, bandwidth, and field of view--were also studied in an effort to reduce motion-induced phase shifts. Results indicated that a FISP (fast imaging with steady precession) sequence with a TR of 50 msec, TE of 15 msec, velocity compensation in the read and section-select directions, acceleration compensation in the read direction, anisotropic volume, and a 1.25-mm partition thickness produced three-dimensional angiographic MR images that were accurate and reproducible in the depiction of the major intracranial vessels. Difficulties with field of view, persistent signal void secondary to higher-order motion, and spatial resolution remain major problems requiring additional study.     

Statistical clues to postoperative blood loss: Moving averages applied to medical data

With the advent of computerized databases, medical data has become easy to accumulate; however, effective use of this data continues to pose significant problems. In other circumstances, smoothing algorithms have been used to uncover non-obvious correlations, trends and relationships in noisy data. We have applied four such algorithms to a large dataset of postoperative blood replacement in cardiopulmonary bypass patients. When applied to this dataset, one of the algorithms proved surprisingly effective. It confirmed several previously observed correlations, and also provided an additional series of counterintuitive and apparently unrelated associations. These associations have been explored in an accompanying paper.     

Femoral attachment of the anterior cruciate ligament

Endoscopic anterior cruciate ligament (ACL) reconstruction is one of the most popular orthopaedic procedures. Correct tunnel positioning is a prerequisite to success. Current surgical techniques are unable to duplicate the complex anatomy and function of the native ACL. Surgery mainly aims at restoring anteroposterior laxity. The ACL is not isometric and only a few fibers are nearly isometric over the full range of motion. However, a nearly isometric behaviour of the ACL graft is desirable. Isometry is mainly influenced by femoral attachment; thus the femoral tunnel position has a greater effect than the tibial on graft length changes. The purpose of this article is to describe the anatomy of the femoral ACL insertion and to discuss the surgical techniques used to replicate it.     

How Can and Do Australian Doctors Promote Physical Activity?

Background.Physical inactivity is recognized as an important public health issue. Yet little is known about doctors' knowledge, attitude, skills, and resources specifically relating to the promotion of physical activity. Our survey assessed the current practice, perceived desirable practice, confidence, and barriers related to the promotion of physical activity in family practice.Methods.A questionnaire was developed and distributed to all 1,228 family practitioners in Perth, Western Australia.Results.We received a 71% response (n= 789). Family practitioners are most likely to recommend walking to sedentary adults to improve fitness and they are aware of the major barriers to patients participating in physical activity. Doctors are less confident at providing specific advice on exercise and may require further skills, knowledge, and experience. Although they promote exercise to patients through verbal advice in the consultation, few use written materials or referral systems.Conclusions.There are significant differences between self-reports of current practice and perceived desirable practice in the promotion of physical activity by doctors. Future strategies need to address the self-efficacy of family physicians and involve resources of proven effectiveness. The potential of referral systems for supporting efforts to increase physical activity by Australians should be explored.