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.     

On the Edge: a drama‐based mental health education programme on early psychosis for schools

Aims: On the Edge is a mental health education programme designed to support early intervention by increasing knowledge and understanding of early psychosis, reducing the stigma associated with mental health issues and improving awareness of avenues of help. The target audience was young people aged 14–22 years in schools and colleges. Methods: An interactive drama programme was developed through collaborative working across psychiatry, applied drama and those with direct experience of psychosis. A national tour engaged 2500 students in 71 performances that took place in 51 schools and colleges. The programme was evaluated against its aims with data collected both during and after the tour. Results: Quantitative and qualitative evaluation found significant gains with respect to all three aims. Thirty‐one schools developed supportive links with local mental health services. Conclusions: This programme shows the value and effectiveness of delivering health education on early psychosis through the medium of applied drama, and offers a model for a programme that can be incorporated into early intervention services. Lessons learned through delivering this programme are a valuable contribution towards future developments of mental health education programmes for schools.     

Neurological disorders and violence: a systematic review and meta-analysis with a focus on epilepsy and traumatic brain injury

The objectives of this study were to systematically review and meta-analyze the research literature on the association of common neurological disorders and violence. Keywords relating to neurological disorders and violence were searched between 1966 and August 2008. Case–control and cohort studies were selected. Odds ratios of violence risk in particular disorders compared with controls were combined using fixed-effects meta-analysis with the data presented in forest plots. Sensitivity analyses were conducted to identify possible differences in risk estimates across surveys. Information on risk factors for violence was extracted if replicated in more than one study. Nine studies were identified that compared the risk of violence in epilepsy or traumatic brain injury compared with unaffected controls. For the epilepsy studies, the overall pooled odds ratio for violent outcomes was 0.67 [95% confidence interval (CI) 0.46–0.96]. For traumatic brain injury, the odds ratio was 1.66 (95% CI 1.12–2.31). An additional 11 case–control studies investigated factors associated with violence in epilepsy and traumatic brain injury. It was not possible to meta-analyze these data. Comorbid psychopathology was associated with violence. Data on other neurological conditions was limited and unreplicated. In conclusion, although the evidence was limited and methodological quality varied, epilepsy and traumatic brain injury appeared to differ in their risk of violence compared with control populations. Longitudinal studies are required to replicate this review’s provisional findings that epilepsy is inversely associated with violence and that brain injury modestly increases the risk, and further research is needed to provide information on a broader range of risk factors.     

Consideration of barrier protection and latex protein allergy in the evaluation of medical gloves.

The issues surrounding medical gloves have become increasingly complicated over the past 15 years. The AIDS epidemic, allergies, needlesticks, new glove materials, and, most recently, an increased risk of biohazards all factor into the choice of medical gloves. This article examines the research available on two of the issues affecting medical glove choice: barrier protection and latex protein allergy.     

Multiple chop wounds in Hong Kong

Knife injuries can be classified into stabbing injuries and multiple laceration or multiple chops, the latter being much more common in Chinese communities. It is the mark of criminal gang attacks with their tendency to use long knives and choppers rather than guns. The intention is often to wound rather than kill. A survey of 89 cases revealed that 90% of the victims are men, with a mean age of 27 years; 75% was admitted to the hospital at night, and in 78% of the cases the assailants were persons unknown, or so we were told by the victims. The reasons for the attacks were also not given. Most of the women victims were assaulted by their spouse. Some 74% of the patients suffered three to six lacerations; 62% of the injuries were on the extensor surfaces of the upper limbs, while the hand and the back of the trunk were also common sites. The type of management differs from that for stabbing injuries. There were no fatalities, and less than half of the patients required blood transfusion. The average hospital stay was 6.2 days. The morbidity of these injuries involves damaged tendons and nerves.     

Changing prevalence and knowledge of urinary incontinence among Hong Kong Chinese women

A territory-wide telephone survey was conducted in Hong Kong to assess the prevalence, knowledge, and treatment-seeking behaviour of Chinese women with urinary incontinence, using validated Chinese version of Urogenital Distress Inventory (UDI-6) and Incontinence Impact Questionnaire (IIQ-7). Women, 540, aged between 17 to 77 years were interviewed. Of the respondents, 40.8% reported stress urinary incontinence, 20.4% had urge incontinence and 15.9% had mixed incontinence. Among these, 16.0% reported quality of life impairment; 9.3% felt frustrated with low morale, and 15.2% had nervous and anxiety problems. However, as many as 78.3% of the respondents did not know that stress urinary incontinence is a disease entity, and 60.6% thought that leakage of urine was a normal aging process. For those respondents having stress urinary incontinence, the first treatment of choice was physiotherapy. The second choice was medication, and surgical treatment was the last option. Respondents with stress urinary incontinence showed higher education level.     

Quantification of perfusion fMRI using a numerical model of arterial spin labeling that accounts for dynamic transit time effects.

A new approach to modeling the signal observed in arterial spin labeling (ASL) experiments during changing perfusion conditions is presented in this article. The new model uses numerical methods to extend first-order kinetic principles to include the changes in arrival time of the arterial tag that occur during neuronal activation. Estimation of the perfusion function from the ASL signal using this model is also demonstrated. The estimation algorithm uses a roughness penalty as well as prior information. The approach is demonstrated in numerical simulations and human experiments. The approach presented here is particularly suitable for fast ASL acquisition schemes, such as turbo continuous ASL (Turbo-CASL), which allows subtraction pairs to be acquired in less than 3 s but is sensitive to arrival time changes. This modeling approach can also be extended to other acquisition schemes.     

Pediatric nutrition surveillance system--United States, 1980-1991.

The CDC Pediatric Nutrition Surveillance System (PedNSS) monitors the general health and nutritional characteristics of low-income U.S. children who participate in multiple public health programs. This system is intended to characterize trends and patterns in key indicators of nutritional status so that the information can be used for program planning and targeting. The indicators monitored by PedNSS are birth weight, childhood growth status, anemia, and breast-feeding patterns. From 1980 through 1991, the trends for low birth weight, low height-for-age (shortness), low weight-for-height (thinness), and high weight-for-height (overweight) were stable for all children monitored by the PedNSS, with the exception of Asian children, who were predominantly of Southeast Asian refugee background. In the early 1980s, the prevalence of low birth weight and shortness was higher among Asian children than among children of other racial or ethnic groups who were monitored by the PedNSS. However, these prevalences declined steadily from 1980 through 1991. By 1991, the prevalences of low birth weight and shortness for Asian children were similar to those observed for children of other races/ethnic groups. Overall, low-income U.S. children had a slightly lower height-for-age than expected, indicating that some of these children were at a health and nutritional disadvantage. The prevalence of overweight varied among different racial/ethnic groups; Hispanic and Native American children had the highest prevalences of overweight. The 20%-30% prevalence of anemia among low-income children monitored by the PedNSS was higher than among the general population, reflecting in part the preferential enrollment and retention of anemic children by public health nutrition programs and also indicating that many children had inadequate iron nutrition. From 1980 through 1991, the prevalence of anemia declined > 5% for most of the age- and race/ethnicity-specific groups monitored by PedNSS. That decline represents an improvement in iron nutritional status. PedNSS is a useful system for the monitoring and characterization of the nutrition status of low-income children at both state and national levels.     

An evaluation of routine operative cholangiography

The value of routine use of operative cholangiography was evaluated in 225 patients. In 65 patients (29%), there was one or more clinical or operative indications for common duct exploration and only 21 cases showed positive cholangiographic findings and were explored. There were four negative explorations in this group. In the remaining 160 patients who had no indication for common duct exploration, 157 had a normal cholangiogram and three had false positive cholangiographic findings and were explored unnecessarily. If operative cholangiography had been performed only on those patients with clinical or operative indications for common duct exploration, no ductal stone would have been missed. A selective use of operative cholangiography is advocated and the investigation should be restricted to those patients with clinical or operative indications for exploration of the common bile-duct.