The case for intervention bias in the practice of medicine.

Bias is an inclination to present or hold a partial perspective at the expense of possibly equal or more valid alternatives. In this paper, we present a series of conditional arguments to prove that intervention bias exists in the practice of medicine. We then explore its potential causes, consequences, and criticisms. We use the term to describe the bias on the part of physicians and the medical community to intervene, whether it is with drugs, diagnostic tests, non-invasive procedures, or surgeries, when not intervening would be a reasonable alternative. The recognition of intervention bias in medicine is critically important given today\u27s emphasis on providing high-value care and reducing unnecessary and potentially harmful interventions

Silicon Sheets By Redox Assisted Chemical Exfoliation

In this paper, we report the direct chemical synthesis of silicon sheets in gram-scale quantities by chemical exfoliation of pre-processed calcium di-silicide (CaSi2). We have used a combination of X-ray photoelectron spectroscopy, transmission electron microscopy and Energy-dispersive X-ray spectroscopy to characterize the obtained silicon sheets. We found that the clean and crystalline silicon sheets show a 2-dimensional hexagonal graphitic structure.Comment: Accepted in J. Phys.: Condens. Matte

A Mouse Model of Huntington’s Disease Shows Altered Ultrastructure of Transverse Tubules in Skeletal Muscle Fibers

Huntington’s disease (HD) is a fatal and progressive condition with severe debilitating motor defects and muscle weakness. Although classically recognized as a neurodegenerative disorder, there is increasing evidence of cell autonomous toxicity in skeletal muscle. We recently demonstrated that skeletal muscle fibers from the R6/2 model mouse of HD have a decrease in specific membrane capacitance, suggesting a loss of transverse tubule (t-tubule) membrane in R6/2 muscle. A previous report also indicated that Cav1.1 current was reduced in R6/2 skeletal muscle, suggesting defects in excitation–contraction (EC) coupling. Thus, we hypothesized that a loss and/or disruption of the skeletal muscle t-tubule system contributes to changes in EC coupling in R6/2 skeletal muscle. We used live-cell imaging with multiphoton confocal microscopy and transmission electron microscopy to assess the t-tubule architecture in late-stage R6/2 muscle and found no significant differences in the t-tubule system density, regularity, or integrity. However, electron microscopy images revealed that the cross-sectional area of t-tubules at the triad were 25% smaller in R6/2 compared with age-matched control skeletal muscle. Computer simulation revealed that the resulting decrease in the R6/2 t-tubule luminal conductance contributed to, but did not fully explain, the reduced R6/2 membrane capacitance. Analyses of bridging integrator-1 (Bin1), which plays a primary role in t-tubule formation, revealed decreased Bin1 protein levels and aberrant splicing of Bin1 mRNA in R6/2 muscle. Additionally, the distance between the t-tubule and sarcoplasmic reticulum was wider in R6/2 compared with control muscle, which was associated with a decrease in junctophilin 1 and 2 mRNA levels. Altogether, these findings can help explain dysregulated EC coupling and motor impairment in Huntington’s disease

To what extent can behaviour change techniques be identified within an adaptable implementation package for primary care? A prospective directed content analysis

Interpreting evaluations of complex interventions can be difficult without sufficient description of key intervention content. We aimed to develop an implementation package for primary care which could be delivered using typically available resources and could be adapted to target determinants of behaviour for each of four quality indicators: diabetes control, blood pressure control, anticoagulation for atrial fibrillation and risky prescribing. We describe the development and prospective verification of behaviour change techniques (BCTs) embedded within the adaptable implementation packages

Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.

BACKGROUND: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function. METHODS: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis. RESULTS: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively. CONCLUSIONS: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function

Real-time imaging of hepatitis C virus infection using a fluorescent cell-based reporter system

Author Manuscript 2010 August 1Hepatitis C virus (HCV), which infects 2–3% of the world population, is a causative agent of chronic hepatitis and the leading indication for liver transplantation1. The ability to propagate HCV in cell culture (HCVcc) is a relatively recent breakthrough and a key tool in the quest for specific antiviral therapeutics. Monitoring HCV infection in culture generally involves bulk population assays, use of genetically modified viruses and/or terminal processing of potentially precious samples. Here we develop a cell-based fluorescent reporter system that allows sensitive distinction of individual HCV-infected cells in live or fixed samples. We demonstrate use of this technology for several previously intractable applications, including live-cell imaging of viral propagation and host response, as well as visualizing infection of primary hepatocyte cultures. Integration of this reporter with modern image-based analysis methods could open new doors for HCV research.New York (State). Dept. of Health (Empire State Stem Cell Fund Contract C023046)United States. Public Health Service (Grant R01 DK56966)National Institutes of Health (U.S.) (Roadmap for Medical Research Grant 1 R01 DK085713-01)Howard Hughes Medical Institute (Investigator

Identifying strategies to maximise recruitment and retention of practices and patients in a multicentre randomised controlled trial of an intervention to optimise secondary prevention for coronary heart disease in primary care

<p>Abstract</p> <p>Background</p> <p>Recruitment and retention of patients and healthcare providers in randomised controlled trials (RCTs) is important in order to determine the effectiveness of interventions. However, failure to achieve recruitment targets is common and reasons why a particular recruitment strategy works for one study and not another remain unclear. We sought to describe a strategy used in a multicentre RCT in primary care, to report researchers' and participants' experiences of its implementation and to inform future strategies to maximise recruitment and retention.</p> <p>Methods</p> <p>In total 48 general practices and 903 patients were recruited from three different areas of Ireland to a RCT of an intervention designed to optimise secondary prevention of coronary heart disease. The recruitment process involved telephoning practices, posting information, visiting practices, identifying potential participants, posting invitations and obtaining consent. Retention involved patients attending reviews and responding to questionnaires and practices facilitating data collection.</p> <p>Results</p> <p>We achieved high retention rates for practices (100%) and for patients (85%) over an 18-month intervention period. Pilot work, knowledge of the setting, awareness of change in staff and organisation amongst participant sites, rapid responses to queries and acknowledgement of practitioners' contributions were identified as being important. Minor variations in protocol and research support helped to meet varied, complex and changing individual needs of practitioners and patients and encouraged retention in the trial. A collaborative relationship between researcher and practice staff which required time to develop was perceived as vital for both recruitment and retention.</p> <p>Conclusion</p> <p>Recruiting and retaining the numbers of practices and patients estimated as required to provide findings with adequate power contributes to increased confidence in the validity and generalisability of RCT results. A continuous dynamic process of monitoring progress within trials and tailoring strategies to particular circumstances, whilst not compromising trial protocols, should allow maximal recruitment and retention.</p> <p>Trial registration</p> <p>ISRCTN24081411</p

Genetic Characterization of Zika Virus Strains: Geographic Expansion of the Asian Lineage

Zika virus (ZIKV) is a mosquito-transmitted flavivirus found in both Africa and Asia. Human infection with the virus may result in a febrile illness similar to dengue fever and many other tropical infections found in these regions. Previously, little was known about the genetic relationships between ZIKV strains collected in Africa and those collected in Asia. In addition, the geographic origins of the strains responsible for the recent outbreak of human disease on Yap Island, Federated States of Micronesia, and a human case of ZIKV infection in Cambodia were unknown. Our results indicate that there are two geographically distinct lineages of ZIKV (African and Asian). The virus has circulated in Southeast Asia for at least the past 50 years, whereupon it was introduced to Yap Island resulting in an epidemic of human disease in 2007, and in 2010 was the cause of a pediatric case of ZIKV infection in Cambodia. This study also highlights the danger of ZIKV introduction into new areas and the potential for future epidemics of human disease

Norovirus Regulation of the Innate Immune Response and Apoptosis Occurs via the Product of the Alternative Open Reading Frame 4

Small RNA viruses have evolved many mechanisms to increase the capacity of their short genomes. Here we describe the identification and characterization of a novel open reading frame (ORF4) encoded by the murine norovirus (MNV) subgenomic RNA, in an alternative reading frame overlapping the VP1 coding region. ORF4 is translated during virus infection and the resultant protein localizes predominantly to the mitochondria. Using reverse genetics we demonstrated that expression of ORF4 is not required for virus replication in tissue culture but its loss results in a fitness cost since viruses lacking the ability to express ORF4 restore expression upon repeated passage in tissue culture. Functional analysis indicated that the protein produced from ORF4 antagonizes the innate immune response to infection by delaying the upregulation of a number of cellular genes activated by the innate pathway, including IFN-Beta. Apoptosis in the RAW264.7 macrophage cell line was also increased during virus infection in the absence of ORF4 expression. In vivo analysis of the WT and mutant virus lacking the ability to express ORF4 demonstrated an important role for ORF4 expression in infection and virulence. STAT1-/- mice infected with a virus lacking the ability to express ORF4 showed a delay in the onset of clinical signs when compared to mice infected with WT virus. Quantitative PCR and histopathological analysis of samples from these infected mice demonstrated that infection with a virus not expressing ORF4 results in a delayed infection in this system. In light of these findings we propose the name virulence factor 1, VF1 for this protein. The identification of VF1 represents the first characterization of an alternative open reading frame protein for the calicivirus family. The immune regulatory function of the MNV VF1 protein provide important perspectives for future research into norovirus biology and pathogenesis