A clinically interpretable convolutional neural network for the real time prediction of early squamous cell cancer of the esophagus; comparing diagnostic performance with a panel of expert European and Asian endoscopists

BACKGROUND AND AIMS: Intrapapillary capillary loops (IPCLs) are microvascular structures that correlate with invasion depth of early squamous cell neoplasia (ESCN) and allow accurate prediction of histology. Artificial intelligence may improve human recognition of IPCL patterns and prediction of histology to allow prompt access to endoscopic therapy of ESCN where appropriate METHODS: One hundred fifteen patients were recruited at 2 academic Taiwanese hospitals. ME-NBI videos of squamous mucosa were labeled as dysplastic or normal according to their histology and IPCL patterns classified by consensus of 3 experienced clinicians. A convolutional neural network (CNN) was trained to classify IPCLs, using 67742 high quality ME-NBI by 5-fold cross validation. Performance measures were calculated to give an average F1 score, accuracy, sensitivity, and specificity. A panel of 5 Asian and 4 European experts predicted the histology of a random selection of 158 images using the JES IPCL classification; accuracy, sensitivity, specificity, positive and negative predictive values were calculated. RESULTS: Expert European Union (EU) and Asian endoscopists attained F1 scores (a measure of binary classification accuracy) of 97.0% and 98%, respectively. Sensitivity and accuracy of the EU and Asian clinicians were 97%, 98% and 96.9%, 97.1% respectively. The CNN average F1 score was 94%, sensitivity 93.7% and accuracy 91.7%. Our CNN operates at video rate and generates class activation maps that can be used to visually validate CNN predictions. CONCLUSIONS: We report a clinically interpretable CNN developed to predict histology based on IPCL patterns, in real-time, using the largest reported dataset of images for this purpose. Our CNN achieved diagnostic performance comparable to an expert panel of endoscopists

Punica granatum (Pomegranate) juice provides an HIV-1 entry inhibitor and candidate topical microbicide

BACKGROUND: For ≈ 24 years the AIDS pandemic has claimed ≈ 30 million lives, causing ≈ 14,000 new HIV-1 infections daily worldwide in 2003. About 80% of infections occur by heterosexual transmission. In the absence of vaccines, topical microbicides, expected to block virus transmission, offer hope for controlling the pandemic. Antiretroviral chemotherapeutics have decreased AIDS mortality in industrialized countries, but only minimally in developing countries. To prevent an analogous dichotomy, microbicides should be: acceptable; accessible; affordable; and accelerative in transition from development to marketing. Already marketed pharmaceutical excipients or foods, with established safety records and adequate anti-HIV-1 activity, may provide this option. METHODS: Fruit juices were screened for inhibitory activity against HIV-1 IIIB using CD4 and CXCR4 as cell receptors. The best juice was tested for inhibition of: (1) infection by HIV-1 BaL, utilizing CCR5 as the cellular coreceptor; and (2) binding of gp120 IIIB and gp120 BaL, respectively, to CXCR4 and CCR5. To remove most colored juice components, the adsorption of the effective ingredient(s) to dispersible excipients and other foods was investigated. A selected complex was assayed for inhibition of infection by primary HIV-1 isolates. RESULTS: HIV-1 entry inhibitors from pomegranate juice adsorb onto corn starch. The resulting complex blocks virus binding to CD4 and CXCR4/CCR5 and inhibits infection by primary virus clades A to G and group O. CONCLUSION: These results suggest the possibility of producing an anti-HIV-1 microbicide from inexpensive, widely available sources, whose safety has been established throughout centuries, provided that its quality is adequately standardized and monitored

Shedding light on the elusive role of endothelial cells in cytomegalovirus dissemination.

Cytomegalovirus (CMV) is frequently transmitted by solid organ transplantation and is associated with graft failure. By forming the boundary between circulation and organ parenchyma, endothelial cells (EC) are suited for bidirectional virus spread from and to the transplant. We applied Cre/loxP-mediated green-fluorescence-tagging of EC-derived murine CMV (MCMV) to quantify the role of infected EC in transplantation-associated CMV dissemination in the mouse model. Both EC- and non-EC-derived virus originating from infected Tie2-cre(+) heart and kidney transplants were readily transmitted to MCMV-naïve recipients by primary viremia. In contrast, when a Tie2-cre(+) transplant was infected by primary viremia in an infected recipient, the recombined EC-derived virus poorly spread to recipient tissues. Similarly, in reverse direction, EC-derived virus from infected Tie2-cre(+) recipient tissues poorly spread to the transplant. These data contradict any privileged role of EC in CMV dissemination and challenge an indiscriminate applicability of the primary and secondary viremia concept of virus dissemination

HGF Mediates the Anti-inflammatory Effects of PRP on Injured Tendons

Platelet-rich plasma (PRP) containing hepatocyte growth factor (HGF) and other growth factors are widely used in orthopaedic/sports medicine to repair injured tendons. While PRP treatment is reported to decrease pain in patients with tendon injury, the mechanism of this effect is not clear. Tendon pain is often associated with tendon inflammation, and HGF is known to protect tissues from inflammatory damages. Therefore, we hypothesized that HGF in PRP causes the anti-inflammatory effects. To test this hypothesis, we performed in vitro experiments on rabbit tendon cells and in vivo experiments on a mouse Achilles tendon injury model. We found that addition of PRP or HGF decreased gene expression of COX-1, COX-2, and mPGES-1, induced by the treatment of tendon cells in vitro with IL-1β. Further, the treatment of tendon cell cultures with HGF antibodies reduced the suppressive effects of PRP or HGF on IL-1β-induced COX-1, COX-2, and mPGES-1 gene expressions. Treatment with PRP or HGF almost completely blocked the cellular production of PGE2 and the expression of COX proteins. Finally, injection of PRP or HGF into wounded mouse Achilles tendons in vivo decreased PGE2 production in the tendinous tissues. Injection of platelet-poor plasma (PPP) however, did not reduce PGE2 levels in the wounded tendons, but the injection of HGF antibody inhibited the effects of PRP and HGF. Further, injection of PRP or HGF also decreased COX-1 and COX-2 proteins. These results indicate that PRP exerts anti-inflammatory effects on injured tendons through HGF. This study provides basic scientific evidence to support the use of PRP to treat injured tendons because PRP can reduce inflammation and thereby reduce the associated pain caused by high levels of PGE2. © 2013 Zhang et al

Multiple imputation for estimation of an occurrence rate in cohorts with attrition and discrete follow-up time points: a simulation study

<p>Abstract</p> <p>Background</p> <p>In longitudinal cohort studies, subjects may be lost to follow-up at any time during the study. This leads to attrition and thus to a risk of inaccurate and biased estimations. The purpose of this paper is to show how multiple imputation can take advantage of all the information collected during follow-up in order to estimate the cumulative probability <it>P(E) </it>of an event <it>E</it>, when the first occurrence of this event is observed at <it>t </it>successive time points of a longitudinal study with attrition.</p> <p>Methods</p> <p>We compared the performance of multiple imputation with that of Kaplan-Meier estimation in several simulated attrition scenarios.</p> <p>Results</p> <p>In missing-completely-at-random scenarios, the multiple imputation and Kaplan-Meier methods performed well in terms of bias (less than 1%) and coverage rate (range = [94.4%; 95.8%]). In missing-at-random scenarios, the Kaplan-Meier method was associated with a bias ranging from -5.1% to 7.0% and with a very poor coverage rate (as low as 0.2%). Multiple imputation performed much better in this situation (bias <2%, coverage rate >83.4%).</p> <p>Conclusions</p> <p>Multiple imputation shows promise for estimation of an occurrence rate in cohorts with attrition. This study is a first step towards defining appropriate use of multiple imputation in longitudinal studies.</p

Retargeted adenoviruses for radiation-guided gene delivery

The combination of radiation with radiosensitizing gene delivery or oncolytic viruses promises to provide an advantage that could improve the therapeutic results for glioblastoma. X-rays can induce significant molecular changes in cancer cells. We isolated the GIRLRG peptide that binds to radiation-inducible 78 kDa glucose-regulated protein (GRP78), which is overexpressed on the plasma membranes of irradiated cancer cells and tumor-associated microvascular endothelial cells. The goal of our study was to improve tumor-specific adenovirus-mediated gene delivery by selectively targeting the adenovirus binding to this radiation-inducible protein. We employed an adenoviral fiber replacement approach to conduct a study of the targeting utility of GRP78-binding peptide. We have developed fiber-modified adenoviruses encoding the GRP78-binding peptide inserted into the fiber-fibritin. We have evaluated the reporter gene expression of fiber-modified adenoviruses in vitro using a panel of glioma cells and a human D54MG tumor xenograft model. The obtained results demonstrated that employment of the GRP78-binding peptide resulted in increased gene expression in irradiated tumors following infection with fiber-modified adenoviruses, compared with untreated tumor cells. These studies demonstrate the feasibility of adenoviral retargeting using the GRP78-binding peptide that selectively recognizes tumor cells responding to radiation treatment

The epidemiology and transmission of methicillin-resistant Staphylococcus aureus in the community in Singapore: study protocol for a longitudinal household study.

BACKGROUND/AIM: Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most common multidrug-resistant organisms in healthcare settings worldwide, but little is known about MRSA transmission outside of acute healthcare settings especially in Asia. We describe the methods for a prospective longitudinal study of MRSA prevalence and transmission. METHODS: MRSA-colonized individuals were identified from MRSA admission screening at two tertiary hospitals and recruited together with their household contacts. Participants submitted self-collected nasal, axilla and groin (NAG) swabs by mail for MRSA culture at baseline and monthly thereafter for 6 months. A comparison group of households of MRSA-negative patients provided swab samples at one time point. In a validation sub-study, separate swabs from each site were collected from randomly selected individuals, to compare MRSA detection rates between swab sites, and between samples collected by participants versus those collected by trained research staff. Information on each participant's demographic information, medical status and medical history, past healthcare facilities usage and contacts, and personal interactions with others were collected using a self-administered questionnaire. DISCUSSION/CONCLUSION: Understanding the dynamics of MRSA persistence and transmission in the community is crucial to devising and evaluating successful MRSA control strategies. Close contact with MRSA colonized patients may to be important for MRSA persistence in the community; evidence from this study on the extent of community MRSA could inform the development of household- or community-based interventions to reduce MRSA colonization of close contacts and subsequent re-introduction of MRSA into healthcare settings. Analysis of longitudinal data using whole-genome sequencing will yield further information regarding MRSA transmission within households, with significant implications for MRSA infection control outside acute hospital settings

Segmentation of Multi-Isotope Imaging Mass Spectrometry Data for Semi-Automatic Detection of Regions of Interest

Multi-isotope imaging mass spectrometry (MIMS) associates secondary ion mass spectrometry (SIMS) with detection of several atomic masses, the use of stable isotopes as labels, and affiliated quantitative image-analysis software. By associating image and measure, MIMS allows one to obtain quantitative information about biological processes in sub-cellular domains. MIMS can be applied to a wide range of biomedical problems, in particular metabolism and cell fate [1], [2], [3]. In order to obtain morphologically pertinent data from MIMS images, we have to define regions of interest (ROIs). ROIs are drawn by hand, a tedious and time-consuming process. We have developed and successfully applied a support vector machine (SVM) for segmentation of MIMS images that allows fast, semi-automatic boundary detection of regions of interests. Using the SVM, high-quality ROIs (as compared to an expert's manual delineation) were obtained for 2 types of images derived from unrelated data sets. This automation simplifies, accelerates and improves the post-processing analysis of MIMS images. This approach has been integrated into “Open MIMS,” an ImageJ-plugin for comprehensive analysis of MIMS images that is available online at http://www.nrims.hms.harvard.edu/NRIMS_ImageJ.php

Identification of the initial molecular changes in response to circulating angiogenic cells-mediated therapy in critical limb ischemia

BackgroundCritical limb ischemia (CLI) constitutes the most aggressive form of peripheral arterial occlusive disease, characterized by the blockade of arteries supplying blood to the lower extremities, significantly diminishing oxygen and nutrient supply. CLI patients usually undergo amputation of fingers, feet, or extremities, with a high risk of mortality due to associated comorbidities.Circulating angiogenic cells (CACs), also known as early endothelial progenitor cells, constitute promising candidates for cell therapy in CLI due to their assigned vascular regenerative properties. Preclinical and clinical assays with CACs have shown promising results. A better understanding of how these cells participate in vascular regeneration would significantly help to potentiate their role in revascularization.Herein, we analyzed the initial molecular mechanisms triggered by human CACs after being administered to a murine model of CLI, in order to understand how these cells promote angiogenesis within the ischemic tissues.MethodsBalb-c nude mice (n:24) were distributed in four different groups: healthy controls (C, n:4), shams (SH, n:4), and ischemic mice (after femoral ligation) that received either 50 mu l physiological serum (SC, n:8) or 5x10(5) human CACs (SE, n:8). Ischemic mice were sacrificed on days 2 and 4 (n:4/group/day), and immunohistochemistry assays and qPCR amplification of Alu-human-specific sequences were carried out for cell detection and vascular density measurements. Additionally, a label-free MS-based quantitative approach was performed to identify protein changes related.ResultsAdministration of CACs induced in the ischemic tissues an increase in the number of blood vessels as well as the diameter size compared to ischemic, non-treated mice, although the number of CACs decreased within time. The initial protein changes taking place in response to ischemia and more importantly, right after administration of CACs to CLI mice, are shown.ConclusionsOur results indicate that CACs migrate to the injured area; moreover, they trigger protein changes correlated with cell migration, cell death, angiogenesis, and arteriogenesis in the host. These changes indicate that CACs promote from the beginning an increase in the number of vessels as well as the development of an appropriate vascular network.Institute of Health Carlos III, ISCIII; Junta de Andaluci