Implant delivering hydroxychloroquine attenuates vaginal T lymphocyte activation and inflammation

The final publication is available at Elsevier via https://doi.org/10.1016/j.jconrel.2018.03.010 © 2018. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/Evidence suggests that women who are naturally resistant to HIV infection exhibit low baseline immune activation at the female genital tract (FGT). This “immune quiescent” state is associated with lower expression of T-cell activation markers, reduced levels of gene transcription and pro-inflammatory cytokine or chemokine production involved in HIV infection while maintaining an intact immune response against pathogens. Therefore, if this unique immune quiescent state can be pharmacologically induced locally, it will provide an excellent women-oriented strategy against HIV infection To our knowledge, this is the first research article evaluating in vivo, an innovative trackable implant that can provide controlled delivery of hydroxychloroquine (HCQ) to successfully attenuate vaginal T lymphocyte activation and inflammation in a rabbit model as a potential strategy to induce an “immune quiescent” state within the FGT for the prevention of HIV infection. This biocompatible implant can deliver HCQ above therapeutic concentrations in a controlled manner, reduce submucosal immune cell recruitment, improve mucosal epithelium integrity, decrease protein and gene expression of T-cell activation markers, and attenuate the induction of key pro-inflammatory mediators. Our results suggest that microbicides designed to maintain a low level of immune activation at the FGT may offer a promising new strategy for reducing HIV infection.Canadian Institutes of Health Research (CIHR) Operating Grant (MOP110981) CIHR Canadian HIV Vaccine Initiative Grant (OCH-126275) Research Manitoba Graduate Studentship Leslie F. Buggy Graduate Scholarship in Pharmacy from the University of Manitob

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Genome sequencing reveals Zika virus diversity and spread in the Americas

Although the recent Zika virus (ZIKV) epidemic in the Americas and its link to birth defects have attracted a great deal of attention, much remains unknown about ZIKV disease epidemiology and ZIKV evolution, in part owing to a lack of genomic data. Here we address this gap in knowledge by using multiple sequencing approaches to generate 110 ZIKV genomes from clinical and mosquito samples from 10 countries and territories, greatly expanding the observed viral genetic diversity from this outbreak. We analysed the timing and patterns of introductions into distinct geographic regions; our phylogenetic evidence suggests rapid expansion of the outbreak in Brazil and multiple introductions of outbreak strains into Puerto Rico, Honduras, Colombia, other Caribbean islands, and the continental United States. We find that ZIKV circulated undetected in multiple regions for many months before the first locally transmitted cases were confirmed, highlighting the importance of surveillance of viral infections. We identify mutations with possible functional implications for ZIKV biology and pathogenesis, as well as those that might be relevant to the effectiveness of diagnostic tests

An investigation of gantry angle data accuracy for cine-mode EPID images acquired during arc IMRT

EPID images acquired in cine mode during arc therapy have inaccurate gantry angles recorded in their image headers. In this work, methods were developed to assess the accuracy of the gantry potentiometer for linear accelerators. As well, assessments of the accuracy of other, more accessible, sources of gantry angle information (i.e., treatment log files, analysis of EPID image headers) were investigated. The methods used in this study are generally applicable to any linear accelerator unit, and have been demonstrated here with Clinac/Trilogy systems. Gantry angle data were simultaneously acquired using three methods: i) a direct gantry potentiometer measurement, ii) an incremental rotary encoder, and iii) a custom-made radiographic gantry-angle phantom which produced unique wire intersections as a function of gantry angle. All methods were compared to gantry angle data from the EPID image header and the linac MLC DynaLog file. The encoder and gantry-angle phantom were used to validate the accuracy of the linac's potentiometer. The EPID image header gantry angles and the DynaLog file gantry angles were compared to the potentiometer. The encoder and gantry-angle phantom mean angle differences with the potentiometer were 0.13° ± 0.14° and 0.10°± 0.30°, respectively. The EPID image header angles analyzed in this study were within ± 1° of the potentiometer angles only 35% of the time. In some cases, EPID image header gantry angles disagreed by as much as 3° with the potentiometer. A time delay in frame acquisition was determined using the continuous acquisition mode of the EPID. After correcting for this time delay, 75% of the header angles, on average, were within ± 1° of the true gantry angle, compared to an average of only 35% without the correction. Applying a boxcar smoothing filter to the corrected gantry angles further improved the accuracy of the header-derived gantry angles to within ± 1° for almost all images (99.4%). An angle accuracy of 0.11° ± 0.04° was determined using a point-by-point comparison of the gantry angle data in the MLC DynaLog file and the potentiometer data. These simple correction methods can be easily applied to individual treatment EPID images in order to more accurately define the gantry angle

Low-cost optical scanner and 3-dimensional printing technology to create lead shielding for radiation therapy of facial skin cancer: First clinical case series

Purpose: Three-dimensional printing has been implemented at our institution to create customized treatment accessories, including lead shields used during radiation therapy for facial skin cancer. To effectively use 3-dimensional printing, the topography of the patient must first be acquired. We evaluated a low-cost, structured-light, 3-dimensional, optical scanner to assess the clinical viability of this technology. Methods and materials: For ease of use, the scanner was mounted to a simple gantry that guided its motion and maintained an optimum distance between the scanner and the object. To characterize the spatial accuracy of the scanner, we used a geometric phantom and an anthropomorphic head phantom. The geometric phantom was machined from plastic and included hemispherical and tetrahedral protrusions that were roughly the dimensions of an average forehead and nose, respectively. Polygon meshes acquired by the optical scanner were compared with meshes generated from high-resolution computed tomography images. Most optical scans contained minor artifacts. Using an algorithm that calculated the distances between the 2 meshes, we found that most of the optical scanner measurements agreed with those from the computed tomography scanner within approximately 1 mm for the geometric phantom and approximately 2 mm for the head phantom. We used this optical scanner along with 3-dimensional printer technology to create custom lead shields for 10 patients receiving orthovoltage treatments of nonmelanoma skin cancers of the face. Patient, tumor, and treatment data were documented. Results: Lead shields created using this approach were accurate, fitting the contours of each patient's face. This process added to patient convenience and addressed potential claustrophobia and medical inability to lie supine. Conclusions: The scanner was found to be clinically acceptable, and we suggest that the use of an optical scanner and 3-dimensional printer technology become the new standard of care to generate lead shielding for orthovoltage radiation therapy of nonmelanoma facial skin cancer

Impact of measurement method on interobserver variability of apparent diffusion coefficient of lesions in prostate MRI.

PurposeTo compare the inter-observer variability of apparent diffusion coefficient (ADC) values of prostate lesions measured by 2D-region of interest (ROI) with and without specific measurement instruction.MethodsForty lesions in 40 patients who underwent prostate MR followed by targeted prostate biopsy were evaluated. A multi-reader study (10 readers) was performed to assess the agreement of ADC values between 2D-ROI without specific instruction and 2D-ROI with specific instruction to place a 9-pixel size 2D-ROI covering the lowest ADC area. The computer script generated multiple overlapping 9-pixel 2D-ROIs within a 3D-ROI encompassing the entire lesion placed by a single reader. The lowest mean ADC values from each 2D-small-ROI were used as reference values. Inter-observer agreement was assessed using the Bland-Altman plot. Intraclass correlation coefficient (ICC) was assessed between ADC values measured by 10 readers and the computer-calculated reference values.ResultsTen lesions were benign, 6 were Gleason score 6 prostate carcinoma (PCa), and 24 were clinically significant PCa. The mean±SD ADC reference value by 9-pixel-ROI was 733 ± 186 (10-6 mm2/s). The 95% limits of agreement of ADC values among readers were better with specific instruction (±112) than those without (±205). ICC between reader-measured ADC values and computer-calculated reference values ranged from 0.736-0.949 with specific instruction and 0.349-0.919 without specific instruction.ConclusionInterobserver agreement of ADC values can be improved by indicating a measurement method (use of a specific ROI size covering the lowest ADC area)