Introducing “Evidence for clinical practice” [Editorial]

Combining alternative medicine and conventional medicine approaches into an integral whole is called integrative medicine [1]. Combining the best research evidence with clinical expertise and patient values into an integral whole is called evidence-based medicine [2]. Evidence-based medicine (EBM) is neither alternative medicine nor conventional medicine (though the expectation for evidence-based medicine is increasingly conventional). Both integrative medicine and evidence-based medicine are closely aligned if not just different views to providing holistic care. Finding the best research evidence at the moment you need it is a challenge for clinicians, regardless of domain of practice. To address this challenge, DynaMed was created with a mission to provide the most useful information to health care professionals at the point of care. It is a point-of-care database systematically derived from and presenting the best available evidence across medicine, is used globally, and contains more than 200,000 citations after twenty years of systematic literature surveillance. In the last few years, the systematic effort to identify, critically appraise, synthesize and report evidence has been expanded to include guidance, and DynaMed Plus now provides systematically-derived recommendations for more than 1000 broad topics across medicine. Independent evaluations consistently find this to be the most current clinical reference with the highest-quality evidence summarized using explicit, transparent methods

Cultured Vestibular Ganglion Neurons Demonstrate Latent HSV1 Reactivation

Objectives/Hypothesis: Vestibular neuritis is a common cause of both acute and chronic vestibular dysfunction. Multiple pathologies have been hypothesized to be the causative agent of vestibular neuritis; however, whether herpes simplex type I (HSV1) reactivation occurs within the vestibular ganglion has not been demonstrated previously by experimental evidence. We developed an in vitro system to study HSV1 infection of vestibular ganglion neurons (VGNs) using a cell culture model system. Study Design: basic science study. Results: Lytic infection of cultured rat VGNs was observed following low viral multiplicity of infection (MOI). Inclusion of acyclovir suppressed lytic replication and allowed latency to be established. Upon removal of acyclovir, latent infection was confirmed with reverse-transcription polymerase chain reaction and by RNA fluorescent in situ hybridization for the latencyassociated transcript (LAT). A total of 29% cells in latently infected cultures were LAT positive. The lytic ICP27 transcript was not detected by reverse-transcription polymerase chain reaction (RT-PCR). Reactivation of HSV1 occurred at a high frequency in latently infected cultures following treatment with trichostatin A (TSA), a histone deactylase inhibitor. Conclusions: VGNs can be both lytically and latently infected with HSV1. Furthermore, latently infected VGNs can be induced to reactivate using TSA. This demonstrates that reactivation of latent HSV1 infection in the vestibular ganglion can occur in a cell culture model, and suggests that reactivation of HSV1 infection a plausible etiologic mechanism of vestibular neuritis

Small Polarons in Transition Metal Oxides

The formation of polarons is a pervasive phenomenon in transition metal oxide compounds, with a strong impact on the physical properties and functionalities of the hosting materials. In its original formulation the polaron problem considers a single charge carrier in a polar crystal interacting with its surrounding lattice. Depending on the spatial extension of the polaron quasiparticle, originating from the coupling between the excess charge and the phonon field, one speaks of small or large polarons. This chapter discusses the modeling of small polarons in real materials, with a particular focus on the archetypal polaron material TiO2. After an introductory part, surveying the fundamental theoretical and experimental aspects of the physics of polarons, the chapter examines how to model small polarons using first principles schemes in order to predict, understand and interpret a variety of polaron properties in bulk phases and surfaces. Following the spirit of this handbook, different types of computational procedures and prescriptions are presented with specific instructions on the setup required to model polaron effects.Comment: 36 pages, 12 figure

CDK-Mediated Regulation of Cell Functions via c-Jun Phosphorylation and AP-1 Activation

Cyclin-dependent kinases (CDKs) and their targets have been primarily associated with regulation of cell-cycle progression. Here we identify c-Jun, a transcription factor involved in the regulation of a broad spectrum of cellular functions, as a newly recognized CDK substrate. Using immune cells from mouse and human, and several complementary in vitro and in vivo approaches including dominant negative protein expression, pharmacologic inhibitors, kinase assays and CDK4 deficient cells, we demonstrate the ability of CDK4 to phosphorylate c-Jun. Additionally, the activity of AP-1, a ubiquitous transcription factor containing phosphorylated c-Jun as a subunit, was inhibited by abrogating CDK4. Surprisingly, the regulation of c-Jun phosphorylation by CDK4 occurred in non-dividing cells, indicating that this pathway is utilized for cell functions that are independent of proliferation. Our studies identify a new substrate for CDK4 and suggest a mechanism by which CDKs can regulate multiple cellular activation functions, not all of which are directly associated with cell cycle progression. These findings point to additional roles of CDKs in cell signaling and reveal potential implications for therapeutic manipulations of this kinase pathway

How does study quality affect the results of a diagnostic meta-analysis?

Background: The use of systematic literature review to inform evidence based practice in diagnostics is rapidly expanding. Although the primary diagnostic literature is extensive, studies are often of low methodological quality or poorly reported. There has been no rigorously evaluated, evidence based tool to assess the methodological quality of diagnostic studies. The primary objective of this study was to determine the extent to which variations in the quality of primary studies impact the results of a diagnostic meta-analysis and whether this differs with diagnostic test type. A secondary objective was to contribute to the evaluation of QUADAS, an evidence-based tool for the assessment of quality in diagnostic accuracy studies. Methods: This study was conducted as part of large systematic review of tests used in the diagnosis and further investigation of urinary tract infection (UTI) in children. All studies included in this review were assessed using QUADAS, an evidence-based tool for the assessment of quality in systematic reviews of diagnostic accuracy studies. The impact of individual components of QUADAS on a summary measure of diagnostic accuracy was investigated using regression analysis. The review divided the diagnosis and further investigation of UTI into the following three clinical stages: diagnosis of UTI, localisation of infection, and further investigation of the UTI. Each stage used different types of diagnostic test, which were considered to involve different quality concerns. Results: Many of the studies included in our review were poorly reported. The proportion of QUADAS items fulfilled was similar for studies in different sections of the review. However, as might be expected, the individual items fulfilled differed between the three clinical stages. Regression analysis found that different items showed a strong association with test performance for the different tests evaluated. These differences were observed both within and between the three clinical stages assessed by the review. The results of regression analyses were also affected by whether or not a weighting (by sample size) was applied. Our analysis was severely limited by the completeness of reporting and the differences between the index tests evaluated and the reference standards used to confirm diagnoses in the primary studies. Few tests were evaluated by sufficient studies to allow meaningful use of meta-analytic pooling and investigation of heterogeneity. This meant that further analysis to investigate heterogeneity could only be undertaken using a subset of studies, and that the findings are open to various interpretations. Conclusion: Further work is needed to investigate the influence of methodological quality on the results of diagnostic meta-analyses. Large data sets of well-reported primary studies are needed to address this question. Without significant improvements in the completeness of reporting of primary studies, progress in this area will be limited

Male circumcision and penile cancer: a systematic review and meta-analysis

OBJECTIVE: We systematically reviewed the evidence of an association between male circumcision and penile cancer. METHODS: Databases were searched using keywords and text terms for the epidemiology of penile cancer. Random effects meta-analyses were used to calculate summary odds ratios (ORs) and 95% confidence intervals (CI). RESULTS: We identified eight papers which evaluated the association of circumcision with penile cancer, of which seven were case-control studies. There was a strong protective effect of childhood/adolescent circumcision on invasive penile cancer (OR = 0.33; 95% CI 0.13-0.83; 3 studies). In two studies, the protective effect of childhood/adolescent circumcision on invasive cancer no longer persisted when analyses were restricted to boys with no history of phimosis. In contrast, there was some evidence that circumcision in adulthood was associated with an increased risk of invasive penile cancer (summary OR = 2.71; 95% CI 0.93-7.94; 3 studies). There was little evidence for an association of penile intra-epithelial neoplasia and in situ penile cancer with circumcision performed at any age. CONCLUSIONS: Men circumcised in childhood/adolescence are at substantially reduced risk of invasive penile cancer, and this effect could be mediated partly through an effect on phimosis. Expansion of circumcision services in sub-Saharan Africa as an HIV prevention strategy may additionally reduce penile cancer risk

A population-based study of human immunodeficiency virus in south India reveals major differences from sentinel surveillance-based estimates

BACKGROUND: The human immunodeficiency virus (HIV) burden among adults in India is estimated officially by direct extrapolation of annual sentinel surveillance data from public-sector antenatal and sexually transmitted infection (STI) clinics and some high-risk groups. The validity of these extrapolations has not been systematically examined with a large sample population-based study. METHODS: We sampled 13838 people, 15–49 years old, from 66 rural and urban clusters using a stratified random method to represent adults in Guntur district in the south Indian state of Andhra Pradesh. We interviewed the sampled participants and obtained dried blood spots from them, and tested blood for HIV antibody, antigen and nucleic acid. We calculated the number of people with HIV in Guntur district based on these data, compared it with the estimate using the sentinel surveillance data and method, and analysed health services use data to understand the differences. RESULTS: In total, 12617 people (91.2% of the sampled group) gave a blood sample. Adjusted HIV prevalence was 1.72% (95% confidence interval 1.35–2.09%); men 1.74% (1.27–2.21%), women 1.70% (1.36–2.04%); rural 1.64% (1.10–2.18%), urban 1.89% (1.39–2.39%). HIV prevalence was 2.58% and 1.20% in people in the lower and upper halves of a standard of living index (SLI). Of women who had become pregnant during the past 2 years, 21.1% had used antenatal care in large public-sector hospitals participating in sentinel surveillance. There was an over-representation of the lowest SLI quartile (44.7%) in this group, and 3.61% HIV prevalence versus 1.08% in the remaining pregnant women. HIV prevalence was higher in that group even when women were matched for the same SLI half (lower half 4.39%, upper 2.63%) than in the latter (lower 1.06%, upper 1.05%), due to referral of HIV-positive/suspected women by private practitioners to public hospitals. The sentinel surveillance method (HIV prevalence: antenatal clinic 3%, STI clinic 22.8%, female sex workers 12.8%) led to an estimate of 112635 (4.38%) people with HIV, 15–49 years old, in Guntur district, which was 2.5 times the 45942 (1.79%) estimate based on our population-based study. CONCLUSION: The official method in India leads to a gross overestimation of the HIV burden in this district due to addition of substantial extra HIV estimates from STI clinics, the common practice of referral of HIV-positive/suspected people to public hospitals, and a preferential use of public hospitals by people in lower socioeconomic strata. India may be overestimating its HIV burden with the currently used official estimation method

Children struggle beyond preschool-age in a continuous version of the ambiguous figures task

Children until the age of five are only able to reverse an ambiguous figure when they are informed about the second interpretation. In two experiments, we examined whether children’s difficulties would extend to a continuous version of the ambiguous figures task. Children (Experiment 1: 66 3- to 5-year olds; Experiment 2: 54 4- to 9-year olds) and adult controls saw line drawings of animals gradually morph—through well-known ambiguous figures—into other animals. Results show a relatively late developing ability to recognize the target animal, with difficulties extending beyond preschool-age. This delay can neither be explained with improvements in theory of mind, inhibitory control, nor individual differences in eye movements. Even the best achieving children only started to approach adult level performance at the age of 9, suggesting a fundamentally different processing style in children and adults

Broad-Spectrum Matrix Metalloproteinase Inhibition Curbs Inflammation and Liver Injury but Aggravates Experimental Liver Fibrosis in Mice

Background Liver fibrosis is characterized by excessive synthesis of extracellular matrix proteins, which prevails over their enzymatic degradation, primarily by matrix metalloproteinases (MMPs). The effect of pharmacological MMP inhibition on fibrogenesis, however, is largely unexplored. Inflammation is considered a prerequisite and important co-contributor to fibrosis and is, in part, mediated by tumor necrosis factor (TNF)-α-converting enzyme (TACE). We hypothesized that treatment with a broad-spectrum MMP and TACE-inhibitor (Marimastat) would ameliorate injury and inflammation, leading to decreased fibrogenesis during repeated hepatotoxin-induced liver injury.Methodology/Principal Findings Liver fibrosis was induced in mice by repeated carbon tetrachloride (CCl4) administration, during which the mice received either Marimastat or vehicle twice daily. A single dose of CCl4was administered to investigate acute liver injury in mice pretreated with Marimastat, mice deficient in Mmp9, or mice deficient in both TNF-α receptors. Liver injury was quantified by alanine aminotransferase (ALT) levels and confirmed by histology. Hepatic collagen was determined as hydroxyproline, and expression of fibrogenesis and fibrolysis-related transcripts was determined by quantitative reverse-transcription polymerase chain reaction. Marimastat-treated animals demonstrated significantly attenuated liver injury and inflammation but a 25% increase in collagen deposition. Transcripts related to fibrogenesis were significantly less upregulated compared to vehicle-treated animals, while MMP expression and activity analysis revealed efficient pharmacologic MMP-inhibition and decreased fibrolysis following Marimastat treatment. Marimastat pre-treatment significantly attenuated liver injury following acute CCl4-administration, whereas Mmp9 deficient animals demonstrated no protection. Mice deficient in both TNF-α receptors exhibited an 80% reduction of serum ALT, confirming the hepatoprotective effects of Marimastat via the TNF-signaling pathway.Conclusions/Significance Inhibition of MMP and TACE activity with Marimastat during chronic CCl4administration counterbalanced any beneficial anti-inflammatory effect, resulting in a positive balance of collagen deposition. Since effective inhibition of MMPs accelerates fibrosis progression, MMP inhibitors should be used with caution in patients with chronic liver diseases