A statistical framework to evaluate virtual screening

Background  

Receiver operating characteristic (ROC) curve is widely used to evaluate virtual screening (VS) studies. However, the method fails to address the "early recognition" problem specific to VS. Although many other metrics, such as RIE, BEDROC, and pROC that emphasize "early recognition" have been proposed, there are no rigorous statistical guidelines for determining the thresholds and performing significance tests. Also no comparisons have been made between these metrics under a statistical framework to better understand their performances.     

Does HAART Efficacy Translate to Effectiveness? Evidence for a Trial Effect

Background

Patients who participate in clinical trials may experience better clinical outcomes than patients who initiate similar therapy within clinical care (trial effect), but no published studies have evaluated a trial effect in HIV clinical trials.

Methods

To examine a trial effect we compared virologic suppression (VS) among patients who initiated HAART in a clinical trial versus in routine clinical care. VS was defined as a plasma HIV RNA ≤400 copies/ml at six months after HAART initiation and was assessed within strata of early (1996–99) or current (2000–06) HAART periods. Risk ratios (RR) were estimated using binomial models.

Results

Of 738 persons initiating HAART, 30.6% were women, 61.7% were black, 30% initiated therapy in a clinical trial and 67% (n = 496) had an evaluable six month HIV RNA result. HAART regimens differed between the early and current periods (p<0.001); unboosted PI regimens (55.6%) were more common in the early and NNRTI regimens (46.4%) were more common in the current period. Overall, 78% (95%CI 74, 82%) of patients achieved VS and trial participants were 16% more likely to achieve VS (unadjusted RR 1.16, 95%CI 1.06, 1.27). Comparing trial to non-trial participants, VS differed by study period. In the early period, trial participants initiating HAART were significantly more likely to achieve VS than non-trial participants (adjusted RR 1.33; 95%CI 1.15, 1.54), but not in the current period (adjusted RR 0.98; 95%CI 0.87, 1.11).

Conclusions

A clear clinical trial effect on suppression of HIV replication was observed in the early HAART period but not in the current period.     

Combination of diffusion tensor and functional magnetic resonance imaging during recovery from the vegetative state

Background  

The rate of recovery from the vegetative state (VS) is low. Currently, little is known of the mechanisms and cerebral changes that accompany those relatively rare cases of good recovery. Here, we combined functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) to study the evolution of one VS patient at one month post-ictus and again twelve months later when he had recovered consciousness.     

Multivariate meta-analysis of proteomics data from human prostate and colon tumours

Background  

There is a vast need to find clinically applicable protein biomarkers as support in cancer diagnosis and tumour classification. In proteomics research, a number of methods can be used to obtain systemic information on protein and pathway level on cells and tissues. One fundamental tool in analysing protein expression has been two-dimensional gel electrophoresis (2DE). Several cancer 2DE studies have reported partially redundant lists of differently expressed proteins. To be able to further extract valuable information from existing 2DE data, the power of a multivariate meta-analysis will be evaluated in this work.     

R-wave synchronised atrial pacing in pediatric patients with postoperative junctional ectopic tachycardia: the atrioventricular interval investigated by computational analysis and clinical evaluation

Background

R-wave synchronised atrial pacing is an effective temporary pacing therapy in infants with postoperative junctional ectopic tachycardia. In the technique currently used, adverse short or long intervals between atrial pacing and ventricular sensing (AP–VS) may be observed during routine clinical practice.

Objectives

The aim of the study was to analyse outcomes of R-wave synchronised atrial pacing and the relationship between maximum tracking rates and AP–VS intervals.

Methods

Calculated AP–VS intervals were compared with those predicted by experienced pediatric cardiologist.

Results

A maximum tracking rate (MTR) set 10 bpm higher than the heart rate (HR) may result in undesirable short AP–VS intervals (minimum 83 ms). A MTR set 20 bpm above the HR is the hemodynamically better choice (minimum 96 ms). Effects of either setting on the AP–VS interval could not be predicted by experienced observers. In our newly proposed technique the AP–VS interval approaches 95 ms for HR > 210 bpm and 130 ms for HR < 130 bpm. The progression is linear and decreases strictly (? 0.4 ms/bpm) between the two extreme levels.

Conclusions

Adjusting the AP–VS interval in the currently used technique is complex and may imply unfavorable pacemaker settings. A new pacemaker design is advisable to allow direct control of the AP–VS interval.

     

The scaffolding protein Dlg1 is a negative regulator of cell-free virus infectivity but not of cell-to-cell HIV-1 transmission in T cells

Background

Cell-to-cell virus transmission of Human immunodeficiency virus type-1 (HIV-1) is predominantly mediated by cellular structures such as the virological synapse (VS). The VS formed between an HIV-1-infected T cell and a target T cell shares features with the immunological synapse (IS). We have previously identified the human homologue of the Drosophila Discs Large (Dlg1) protein as a new cellular partner for the HIV-1 Gag protein and a negative regulator of HIV-1 infectivity. Dlg1, a scaffolding protein plays a key role in clustering protein complexes in the plasma membrane at cellular contacts. It is implicated in IS formation and T cell signaling, but its role in HIV-1 cell-to-cell transmission was not studied before.

Methodology/Principal Findings

Kinetics of HIV-1 infection in Dlg1-depleted Jurkat T cells show that Dlg1 modulates the replication of HIV-1. Single-cycle infectivity tests show that this modulation does not take place during early steps of the HIV-1 life cycle. Immunofluorescence studies of Dlg1-depleted Jurkat T cells show that while Dlg1 depletion affects IS formation, it does not affect HIV-1-induced VS formation. Co-culture assays and quantitative cell-to-cell HIV-1 transfer analyses show that Dlg1 depletion does not modify transfer of HIV-1 material from infected to target T cells, or HIV-1 transmission leading to productive infection via cell contact. Dlg1 depletion results in increased virus yield and infectivity of the viral particles produced. Particles with increased infectivity present an increase in their cholesterol content and during the first hours of T cell infection these particles induce higher accumulation of total HIV-1 DNA.

Conclusion

Despite its role in the IS formation, Dlg1 does not affect the VS and cell-to-cell spread of HIV-1, but plays a role in HIV-1 cell-free virus transmission. We propose that the effect of Dlg1 on HIV-1 infectivity is at the stage of virus entry.     

Virtual slides in peer reviewed,open access medical publication

Background

Application of virtual slides (VS), the digitalization of complete glass slides, is in its infancy to be implemented in routine diagnostic surgical pathology and to issues that are related to tissue-based diagnosis, such as education and scientific publication.

Approach

Electronic publication in Pathology offers new features of scientific communication in pathology that cannot be obtained by conventional paper based journals. Most of these features are based upon completely open or partly directed interaction between the reader and the system that distributes the article. One of these interactions can be applied to microscopic images allowing the reader to navigate and magnify the presented images. VS and interactive Virtual Microscopy (VM) are a tool to increase the scientific value of microscopic images.

Technology and Performance

The open access journal Diagnostic Pathology http://www.diagnosticpathology.org has existed for about five years. It is a peer reviewed journal that publishes all types of scientific contributions, including original scientific work, case reports and review articles. In addition to digitized still images the authors of appropriate articles are requested to submit the underlying glass slides to an institution (DiagnomX.eu, and Leica.com) for digitalization and documentation. The images are stored in a separate image data bank which is adequately linked to the article. The normal review process is not involved. Both processes (peer review and VS acquisition) are performed contemporaneously in order to minimize a potential publication delay. VS are not provided with a DOI index (digital object identifier). The first articles that include VS were published in March 2011.

Results and Perspectives

Several logistic constraints had to be overcome until the first articles including VS could be published. Step by step an automated acquisition and distribution system had to be implemented to the corresponding article. The acceptance of VS by the reader is high as well as by the authors. Of specific value are the increased confidence to and reputation of authors as well as the presented information to the reader. Additional associated functions such as access to author-owned related image collections, reader-controlled automated image measurements and image transformations are in preparation.

Virtual Slides

The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1232133347629819.

     

The frequency and validity of self-reported diagnosis of Parkinson's Disease in the UK elderly: MRC CFAS cohort

Background  

Estimates of the incidence and prevalence of chronic diseases can be made using established cohort studies but these estimates may have lower reliability if based purely on self-reported diagnosis.     

Cardiovascular events in early RA are a result of inflammatory burden and traditional risk factors: a five year prospective study

Introduction  

Co-morbidity and mortality due to cardiovascular disease (CVD) are increased in patients with rheumatoid arthritis (RA). Most published studies in this field are retrospective or cross sectional. We investigated the presence of traditional and disease related risk factors for CVD at the onset of RA and during the first five years following diagnosis. We also evaluated their potential for predicting a new cardiovascular event (CVE) during the five-year follow-up period and the modulatory effect of pharmacological treatment.     

Novel multiplex technology for diagnostic characterization of rheumatoid arthritis

Introduction  

The aim of this study was to develop a clinical-grade, automated, multiplex system for the differential diagnosis and molecular stratification of rheumatoid arthritis (RA).     

Imagerie hybride dans l’embolie pulmonaire aiguë : apport de la TDM couplée à la tomoscintigraphie de ventilation et de perfusion

Purpose

V/P-SPECT lung scan can be combined with computerized tomography (CT) from hybrid camera. We investigated if CT data could be use only with perfusion scans for the diagnosis of acute pulmonary embolism (PE).

Patients and methods

In a retrospective study, 75 consecutives patients, referred for suspicion of PE, underwent SPECT ventilation and perfusion scans coupled with a CT on Symbia T2. The perfusion images (P-SPECT) were classified as normal or abnormal with systematized (segmental and sub-segmental) or not systematized perfusion abnormalities. The ventilation images (V-SPECT) were considered as normal or abnormal in light of perfusion defects. The same was done for CT images. Correlations between V-SPECT and CT were studied.

Results

Hence, 28 patients had a normal P-SPECT and did not have PE. Patients (47) had an abnormal P-SPECT (among them, 16 turned out to have PE and 31 did not). There were 192 perfusion abnormalities of which 81 were segmental and 81 sub-segmental. Corresponding to these abnormalities, V-SPECT and CT were concordant in 83 % of the cases. When not-concordant, V-SPECT abnormalities with normal CT were found in 14 % of the cases and CT abnormalities with normal V-SPECT were found in 3 % of the cases. According to the EANM guidelines for PE diagnosis, sensitivity was 88 % and specificity 93 % with V/P-SPECT and 100 % and 83 % respectively with CT/P-SPECT (p = NS).

Conclusion

V/P-SPECT remains slightly more specific for the diagnosis of PE. However, this study demonstrates that CT/P-SPECT obtained with hybrid camera could be used for PE diagnosis with performances similar to V/P-SPECT. If these results would be confirmed on larger populations, this could lead to a significant reduction of scanning time which would improve patient comfort and reduce the camera load.     

A Survey of the Knowledge of Venous Thromboembolism Prophylaxis among the Medical Staff of Intensive Care Units in North China

Background

Guideline concordance for venous thromboembolism (VTE) prophylaxis in critically ill patients in intensive care units (ICUs) varies across different countries.

Objective

To explore how the medical staff of ICUs in China comprehend and practice VTE prophylaxis.

Method

Questionnaires comprising 39 questions and including 4 dimensions of thromboprophylaxis were administered in ICUs in North China.

Results

In all, 52 ICUs at 23 tertiary hospitals in 7 Chinese provinces and municipalities were surveyed. A total of 2500 questionnaires were sent, and 1861 were returned, corresponding to a response rate of approximately 74.4%. Of all surveyed medical staff, 36.5% of physicians and 22.2% of nurses were aware of the guidelines in China, and 19.0% of physicians and 9.5% of nurses comprehended the 9^th edition of the guidelines of the American College of Chest Physicians (ACCP). Additionally, 37.6% of the medical staff chose a prophylaxis method based on the related guidelines, and 10.3% could demonstrate the exact indication for mechanical pattern application. Worries about skin injury, difficulty with removal and discomfort during mechanical thromboprophylaxis were cited by more than 30% of nurses, which was significantly more frequent than for physicians (graduated compression stockings: 54.3% VS 34.1%, 60.7% VS 49%, and 59.4% VS 54%, p = 0.000; intermittent pneumatic compression: 31% VS 22.2%, 19.2% VS 13.9%, and 37.8% VS 27.2%, p = 0.000).

Conclusions and Relevance

The knowledge of VTE prophylaxis among the medical staff of ICUs in North China remains limited, which may lead to a lack of standardization of VTE prophylaxis. Strengthened, standardized training may help medical staff to improve their comprehension of the relevant guidelines and may finally reduce the occurrence of VTE in ICUs and improve the prognosis of critically ill patients with VTE.     

Genetic and epigenetic alterations of the NF2 gene in sporadic vestibular schwannomas

Background

Mutations in the neurofibromatosis type 2 (NF2) tumor-suppressor gene have been identified in not only NF2-related tumors but also sporadic vestibular schwannomas (VS). This study investigated the genetic and epigenetic alterations in tumors and blood from 30 Korean patients with sporadic VS and correlated these alterations with tumor behavior.

Methodology/Principal Findings

NF2 gene mutations were detected using PCR and direct DNA sequencing and three highly polymorphic microsatellite DNA markers were used to assess the loss of heterozygosity (LOH) from chromosome 22. Aberrant hypermethylation of the CpG island of the NF2 gene was also analyzed. The tumor size, the clinical growth index, and the proliferative activity assessed using the Ki-67 labeling index were evaluated. We found 18 mutations in 16 cases of 30 schwannomas (53%). The mutations included eight frameshift mutations, seven nonsense mutations, one in-frame deletion, one splicing donor site, and one missense mutation. Nine patients (30%) showed allelic loss. No patient had aberrant hypermethylation of the NF2 gene and correlation between NF2 genetic alterations and tumor behavior was not observed in this study.

Conclusions/Significance

The molecular genetic changes in sporadic VS identified here included mutations and allelic loss, but no aberrant hypermethylation of the NF2 gene was detected. In addition, no clear genotype/phenotype correlation was identified. Therefore, it is likely that other factors contribute to tumor formation and growth.     

Leukocyte Mitochondrial DNA Copy Number Is Associated with Chronic Obstructive Pulmonary Disease

Background

Oxidative stress is known to be involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). Evidence suggests that leukocytes mitochondria DNA (mtDNA) is susceptible to undergo mutations, insertions, or depletion in response to reactive oxidative stress (ROS). We hypothesize that mtDNA copy number is associated with the development of COPD.

Methodology/Principal Findings

Relative mtDNA copy number was measured by a quantitative real-time PCR assay using DNA extracted from peripheral leukocytes. MtDNA copy number of peripheral leukocytes in the COPD group (n = 86) is significantly decreased compared with non-smoker group (n = 77) (250.3± 21.5 VS. 464.2± 49.9, P<0.001). MtDNA copy number in the COPD group was less than that in the healthy smoking group, but P value nearly achieved significance (250.3± 21.5 VS. 404.0± 76.7, P = 0.08) MtDNA copy number has no significance with age, gender, body mass index, current smoking, and pack-years in COPD group, healthy smoker group and no smoker group, respectively. Serum glutathione level in the COPD group is significantly decreased compared with healthy smoker and non-smoker groups (4.5± 1.3 VS. 6.2± 1.9 and 4.5± 1.3 VS. 7.1±1.1 mU/mL; P<0.001 respectively). Pearson correlation test shows a significant liner correlation between mtDNA copy number and serum glutathione level (R = 0.2, P = 0.009).

Conclusions/Significance

COPD is associated with decreased leukocyte mtDNA copy number and serum glutathione. COPD is a regulatory disorder of leukocytes mitochondria. However, further studies are needed to determine the real mechanisms about the gene and the function of mitochondria.     

Life cycle assessments of consumer electronics — are they consistent?

Background, aim, and scope  

During the last decades, the electronics industry has undergone tremendous changes due to intense research leading to advanced technology development. Multiple life cycle assessment (LCA) studies have been performed on the environmental implications of consumer electronics. The aim of this review is to assess the consistency between different LCA studies for desktop computers, laptop computers, mobile phones and televisions (TVs).     

The association of garlic with Helicobacter pylori infection and gastric cancer risk: A systematic review and meta‐analysis

Background

Garlic may be protective against Helicobacter pylori infection and gastric cancer development. We conducted this study to quantitatively update evidence on garlic intake and gastric cancer with the inclusion of most recent cohort studies and qualitatively summarize epidemiological studies of garlic consumption and Helicobacter pylori infection.

Materials and Methods

PubMed, Embase, MEDLINE, and Cochrane Library were searched on April 2018. We conducted a meta‐analysis to determine whether garlic intake reduced gastric cancer risk using random‐effect models and a systematic review to summarize evidence on the association between garlic consumption and Helicobacter pylori infection. Risk of bias was assessed using tools of Cochrane risk of bias and Robins‐I for randomized and nonrandomized studies, respectively.

Results

Meta‐analysis of 18 studies (142 921 subjects) demonstrated high garlic consumption (as comparing the highest category to the lowest) was associated with a reduced gastric cancer risk (OR = 0.51, 95% CI = 0.44‐0.57). This association became nonsignificant if only derived from the prospective studies (OR = 0.95, 95% CI = 0.66‐1.24). Thirteen studies (4889 participants) were included in the systematic review for garlic consumption and Helicobacter pylori infection; ten of which found no significant results. The majority of these studies were poor in quality given the small sample size and high risk of bias.

Conclusions

Pooled evidence, mainly from case‐control studies, suggested a significant inverse association of garlic intake with gastric cancer risk. Given the limitations of included studies, current epidemiological evidence is not sufficient to reach any definite conclusion regarding the association of garlic with Helicobacter pylori infection.     

Life or death: prognostic value of a resting EEG with regards to survival in patients in vegetative and minimally conscious States

Objective

To investigate the potentially prognostic value of a resting state electroencephalogram (EEG) with regards to the clinical outcome from vegetative and minimally conscious states (VS and MCS) in terms of survival six months after a brain injury.

Methods

We quantified a dynamic repertoire of EEG oscillations in resting condition with eyes closed in patients in VS and MCS. The exact composition of EEG oscillations was assessed by analysing the probability-classification of short-term EEG spectral patterns.

Results

Results demonstrated that (a) the diversity and the variability of EEG for Non-Survivors were significantly lower than for Survivors; and (b) a higher probability of mostly delta and slow-theta oscillations occurring either alone or in combination were found during the first assessment for patients with a bad outcome (i.e., those who died) within six months of an injury compared to patients who survived. At the same time, patients with a good outcome (i.e., those who survived) after six months post-injury had a higher probability of mostly fast-theta and alpha oscillations occurring either alone or in combination during the first assessment when compared to patients who died within six months of an injury.

Conclusions

Resting state EEGs properly analysed may have a potentially prognostic value with regards to the outcome from VS or MCS in terms of survival six months after a brain injury.

Significance

This work may have implications for clinical care, rehabilitative programmes and medical–legal decisions for patients with impaired consciousness states after being in a coma due to acute brain injuries.     

Differential diagnosis of tuberculous meningitis from partially-treated pyogenic meningitis by cell ELISA

Background  

Tuberculous meningitis (TBM) is a major global health problem, and it is sometimes difficult to perform a differential diagnosis of this disease from other diseases, particularly partially-treated pyogenic meningitis (PTPM). In an earlier study, we demonstrated the presence of a 30-kD protein antigen in cerebrospinal fluid (CSF) of TBM patients. We have also shown that lymphocytes from CSF of TBM patients respond differently to this antigen than do those from PTPM patients. The purpose of this study was to develop an assay that can discriminate between TBM and PTPM.