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.     

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.     

Suppurative corneal ulceration in Bangladesh

Suppurative keratitis is an important preventable cause of blindness, particularly in the developing world. This study analyses 142 cases of suppurative keratitis referred to Chittagong Eye Infirmary, Bangladesh. Some 53.5% of cases were bacterial and 35.9% were fungal. The five most common pathogens were: Pseudomonas sp. 24%, Streptococcus pneumoniae 17%, Aspergillus sp. 13%, Fusarium sp. 7% and Curvularia sp. 6%. Gram stain and culture results were consistent in 62.6% of cases. Previous antibiotic treatment was a significant factor for failure of culture isolation and less so for Gram stain failure. On Gram stain, 55.9% of pseudomonal cases were missed, but only 2% of fungal cases were missed. Over all, Gram stain had a sensitivity of 62% and positive predictive value of 84% for bacterial cases, and 98% and 94% for fungal cases, respectively. Fungal ulcers were typically filamentous, but an antecedent history of trauma was not common. The most frequent injury was due to rice grains, but the inoculum appeared to be introduced during eye washing with contaminated water. Pseudomonal ulcers occurred most frequently in the monsoon season, and Fusarium cases were seen only in the hot, dry season.     

Copper-containing IUDs are not associated with an increase of malondialdehyde levels in cervical mucus

The malondialdehyde (MDA) content of cervical mucus from 23 healthy adult females was measured using an ion-pairing HPLC method capable of detecting 10 pmol MDA. Ten of the women were wearing copper IUDs, four were wearing plastic IUDs, and nine controls were not wearing an IUD. Cervical mucus was sampled during the follicular, periovulatory, luteal, and menstrual phases. The study was designed to determine if there is a relationship between MDA formation and the use of a copper IUD. A total of 79 samples were analyzed. Only 16 of the samples had sufficient MDA for reliable quantitation with the level ranging from 0.1 nmol/g to 2.32 nmol/g. In 19 of the samples, trace levels (less than 0.06 nmol/g) were detected but could not be reliably quantitated. In the remaining 44 samples, no MDA was detectable. There was no correlation between the presence of copper- or non-copper-containing IUDs and the level of MDA. These results are contrary to a previously published report that used a less specific method for MDA analysis.