Summary Background Despite preventive vaccines for oncogenic human papillomaviruses (HPVs), cervical intraepithelial neoplasia (CIN) is common, and current treatments are ablative and can lead to ...long-term reproductive morbidity. We assessed whether VGX-3100, synthetic plasmids targeting HPV-16 and HPV-18 E6 and E7 proteins, delivered by electroporation, would cause histopathological regression in women with CIN2/3. Methods Efficacy, safety, and immunogenicity of VGX-3100 were assessed in CIN2/3 associated with HPV-16 and HPV-18, in a randomised, double-blind, placebo-controlled phase 2b study. Patients from 36 academic and private gynaecology practices in seven countries were randomised (3:1) to receive 6 mg VGX-3100 or placebo (1 mL), given intramuscularly at 0, 4, and 12 weeks. Randomisation was stratified by age (<25 vs ≥25 years) and CIN2 versus CIN3 by computer-generated allocation sequence (block size 4). Funder and site personnel, participants, and pathologists were masked to treatment. The primary efficacy endpoint was regression to CIN1 or normal pathology 36 weeks after the first dose. Per-protocol and modified intention-to-treat analyses were based on patients receiving three doses without protocol violations, and on patients receiving at least one dose, respectively. The safety population included all patients who received at least one dose. The trial is registered at ClinicalTrials.gov (number NCT01304524 ) and EudraCT (number 2012-001334-33). Findings Between Oct 19, 2011, and July 30, 2013, 167 patients received either VGX-3100 (n=125) or placebo (n=42). In the per-protocol analysis 53 (49·5%) of 107 VGX-3100 recipients and 11 (30·6%) of 36 placebo recipients had histopathological regression (percentage point difference 19·0 95% CI 1·4–36·6; p=0·034). In the modified intention-to-treat analysis 55 (48·2%) of 114 VGX-3100 recipients and 12 (30·0%) of 40 placebo recipients had histopathological regression (percentage point difference 18·2 95% CI 1·3–34·4; p=0·034). Injection-site reactions occurred in most patients, but only erythema was significantly more common in the VGX-3100 group (98/125, 78·4%) than in the placebo group (24/42, 57·1%; percentage point difference 21·3 95% CI 5·3–37·8; p=0·007). Interpretation VGX-3100 is the first therapeutic vaccine to show efficacy against CIN2/3 associated with HPV-16 and HPV-18. VGX-3100 could present a non-surgical therapeutic option for CIN2/3, changing the treatment outlook for this common disease. Funding Inovio Pharmaceuticals.
AbstractObjectiveQuantification of carotid plaque morphology (geometry and tissue composition) may help stratify risk for future stroke and assess plaque progression or regression in response to ...medical risk factor modification. We assessed the feasibility and reliability of morphologic measurements of carotid plaques using computed tomography angiography (CTA) and determined the minimum detectable change in plaque features by this approach. MethodsCTA images of both carotid arteries in 50 patients were analyzed by two observers using a semiautomatic image analysis program, yielding 93 observations per user (seven arteries were excluded because of prior stenting). One observer repeated the analyses 4 weeks later. Measurements included total plaque volume; percentage stenosis (by diameter and area); and tissue composition for calcium, lipid-rich necrotic core (LRNC), and intraplaque hemorrhage (IPH). Reliability of measurements was assessed by intraclass and interclass correlation and Bland-Altman plots. Dice similarity coefficient (DSC) and modified Hausdorff distance (MHD) assessed reliability of geometric shape measurements. We additionally computed the minimum amount of change in these features detectable by our approach. ResultsThe cohort was 51% male (mean age, 70.1 years), and 56% had a prior stroke. The mean (± standard deviation) plaque volume was 837.3 ± 431.3 mm 3, stenosis diameter was 44.5% ± 25.6%, and stenosis area was 58.1% ± 29.0%. These measurements showed high reliability. Intraclass correlation coefficients for plaque volume, percentage stenosis by diameter, and percentage stenosis by area were 0.96, 0.87, and 0.83, respectively; interclass correlation coefficients were 0.88, 0.84, and 0.78. Intraclass correlations for tissue composition were 0.99, 0.96, and 0.86 (calcium, LRNC, and IPH, respectively), and interclass correlations were 0.99, 0.92, and 0.92. Shape measurements showed high intraobserver (DSC, 0.95 ± 0.04; MHD, 0.16 ± 0.10 mm) and interobserver (DSC, 0.94 ± 0.05; MHD, 0.19 ± 0.12 mm) luminal agreement. This approach can detect a change of at least 3.9% in total plaque volume, 1.2 mm 3 in calcium, 4.3 mm 3 in LRNC, and 8.6 mm 3 in IPH with the same observer repeating measurements and 9.9% in plaque volume, 1.9 mm 3 in calcium, 7.9 mm 3 in LRNC, and 6.8 mm 3 in IPH for two different observers. ConclusionsCarotid plaque geometry (total volume, diameter stenosis, and area stenosis) and tissue composition (calcium, LRNC, and IPH) are measured reliably from clinical CTA images using a semiautomatic image analysis program. The minimum change in plaque volume detectable is ∼4% if the same observer makes both measurements and ∼10% for different observers. Small changes in plaque composition can also be detected reliably. This approach can facilitate longitudinal studies for identifying high-risk plaque features and for quantifying plaque progression or regression after treatment.
Abstract Objective Current risk stratification of internal carotid artery plaques based on diameter-reducing percentage stenosis may be unreliable because ischemic stroke results from plaque ...disruption with atheroembolization. Biomechanical forces acting on the plaque may render it vulnerable to rupture. The feasibility of ultrasound-based quantification of plaque displacement and strain induced by hemodynamic forces and their relationship to high-risk plaques have not been determined. We studied the feasibility and reliability of carotid plaque strain measurement from clinical B-mode ultrasound images and the relationship of strain to high-risk plaque morphology. Methods We analyzed carotid ultrasound B-mode cine loops obtained in patients with asymptomatic ≥50% stenosis during routine clinical scanning. Optical flow methods were used to quantify plaque motion and shear strain during the cardiac cycle. The magnitude (maximum absolute shear strain rate MASSR) and variability (entropy of shear strain rate ESSR and variance of shear strain rate VSSR) of strain were combined into a composite shear strain index (SSI), which was assessed for interscan repeatability and correlated with plaque echolucency. Results Nineteen patients (mean age, 70 years) constituting 36 plaques underwent imaging; 37% of patients (n = 7) showed high strain (SSI ≥0.5; MASSR, 2.2; ESSR, 39.7; VSSR, 0.03) in their plaques; the remaining clustered into a low-strain group (SSI <0.5; MASSR, 0.58; ESSR, 21.2; VSSR, 0.002). The area of echolucent morphology was greater in high-strain plaques vs low-strain plaques (28% vs 17%; P = .018). Strain measurements showed low variability on Bland-Altman plots with cluster assignment agreement of 76% on repeated scanning. Two patients developed a stroke during 2 years of follow-up; both demonstrated high SSI (≥0.5) at baseline. Conclusions Carotid plaque strain is reliably computed from routine B-mode imaging using clinical ultrasound machines. High plaque strain correlates with known high-risk echolucent morphology. Strain measurement can complement identification of patients at high risk for plaque disruption and stroke.
Abstract Objective Vessel wall volume (VWV) assessed by three-dimensional duplex ultrasound (3DUS) imaging provides a more comprehensive measure of plaque burden than conventional two-dimensional ...measures of diameter stenosis. We previously demonstrated that manual outlining of the arterial lumen-intima boundary and outer wall boundary can be performed reliably on images obtained with a commercially available 3D-DUS transducer. Manual segmentation, however, is time consuming (∼45 minutes), limiting its clinical translation. We have developed a semiautomatic algorithm (manual selection of the carotid bifurcation image with subsequent automatic plaque outlining) to outline carotid plaques on 3DUS data sets. In this study, we investigated the accuracy, reproducibility, reliability, and time taken by this algorithm. Methods 3DUS data sets from 30 patients with asymptomatic ≥50% carotid stenosis underwent manual outlining of lumen-intima boundary and outer wall boundary to measure VWV. Two observers implemented a semiautomatic segmentation algorithm. The algorithm's accuracy was compared with manual outlining using the Pearson correlation coefficient. The Dice similarity coefficient (DSC) and modified-Hausdorff distance (MHD) were used to quantify the geometric similarity of the outlines. We also compared results after an intermediate stage of the algorithm vs the complete algorithm. Reproducibility and the least amount of detectable change in plaque volume were computed for each method. Intraobserver and interobserver metrics for each method were computed using the intraclass correlation coefficient (ICC), coefficient of variability (CV), minimum detectable change (MDC), and standard error of measurement (SEM) of the VWV. Results Plaque volume estimates obtained from the semiautomatic algorithm were accurate compared with manual outlining. The Pearson correlation coefficient was 0.76 ( P < .001), and measurements were geometrically similar (DSC, 0.85; MHD, 0.48 mm). The algorithm was more reproducible and reliable and could detect smaller changes in plaque volume on repeat imaging (low interobserver variability: ICC, 0.9; CV, 8.22%; MDC, 5.57%; SEM, 1.45%; DSC, 0.88; MHD, 0.43 mm). Intraobserver variability was even lower (ICC, 0.9; CV, 8%; MDC, 3.62%; SEM, 1.31%; DSC, 0.89; MHD, 0.37 mm). Plaque volume estimates at the intermediate stage of the algorithm matched results from the full algorithm (Pearson correlation coefficient, 0.76; DSC, 0.84; MHD, 0.52 mm). The intermediate approach, however, was less reliable than the full algorithm (interobserver: ICC, 0.81; CV, 11.7%; MDC, 9.58%; SEM, 3.46%; DSC, 0.88; MHD, 0.42 mm; intraobserver: ICC, 0.87; CV, 8.6%; MDC, 4.55%; SEM, 1.64%; DSC, 0.89; MHD, 0.38 mm). The full algorithm required ∼14 minutes to implement. However, a quick (7 minutes) and accurate assessment of VWV can be obtained by running only the intermediate stage of the algorithm, although with a loss in repeatability and reliability. Conclusions We present a unique algorithm to perform semiautomatic quantification of carotid plaque volume using 3DUS imaging. It is quick (mean time, 14 minutes), accurate, repeatable, and implementable in a clinical environment and in longitudinal studies tracking plaque progression. It reliably detects plaque volume changes as low as 4% to 6% with 95% confidence.
This study evaluated the efficacy of education versus audit and feedback in decreasing vancomycin utilization. Data were collected prospectively from October 1, 2012-April 30, 2014 over the following ...3 periods: baseline, after education and introduction of a late-onset sepsis treatment guideline, and after prospective audit-feedback to physicians. Vancomycin utilization and administration duration >3 days significantly decreased with education and guideline use, but it was not affected by addition of audit and feedback.
Worldwide, haemoglobin E β-thalassaemia is the most common genotype of severe β-thalassaemia. The paucity of long-term data for this form of thalassaemia makes evidence-based management challenging. ...We did a long-term observational study to define factors associated with survival and complications in patients with haemoglobin E thalassaemia.
In this prospective, longitudinal cohort study, we included all patients with haemoglobin E thalassaemia who attended the National Thalassaemia Centre in Kurunegala, Sri Lanka, between Jan 1, 1997, and Dec 31, 2001. Patients were assessed up to three times a year. Approaches to blood transfusions, splenectomy, and chelation therapy shifted during this period. Survival rates between groups were evaluated using Kaplan-Meier survival function estimate curves and Cox proportional hazards models were used to identify risk factors for mortality.
109 patients (54 50% male; 55 50% female) were recruited and followed up for a median of 18 years (IQR 14–20). Median age at recruitment was 13 years (range 8–21). 32 (29%) patients died during follow-up. Median survival in all patients was 49 years (95% CI 45–not reached). Median survival was worse among male patients (hazard ratio HR 2·51, 95% CI 1·16–5·43), patients with a history of serious infections (adjusted HR 8·49, 2·90–24·84), and those with higher estimated body iron burdens as estimated by serum ferritin concentration (adjusted HR 1·03, 1·01–1·06 per 100 units). Splenectomy, while not associated with statistically significant increases in the risks of death or serious infections, ultimately did not eliminate a requirement for scheduled transfusions in 42 (58%) of 73 patients. Haemoglobin concentration less than or equal to 4·5 g/dL (vs concentration >4·5 g/dL), serum ferritin concentration more than 1300 μg/L (vs concentration ≤1300 μg/L), and liver iron concentration more than 5 mg/g dry weight of liver (vs concentration ≤5 mg/g) were associated with poorer survival.
Patients with haemoglobin E thalassaemia often had complications and shortened survival compared with that reported in high-resource countries for thalassaemia major and for thalassaemia intermedia not involving an allele for haemoglobin E. Approaches to management in this disorder remain uncertain and prospective studies should evaluate if altered transfusion regimens, with improved control of body iron, can improve survival.
Wellcome Trust, Medical Research Council, US March of Dimes, Anthony Cerami and Ann Dunne Foundation for World Health, and Hemoglobal.
Afghanistan that remained the epicenter of terrorism and insurgency in the post 9/11 incident, suffered irreparable loss in both human and infrastructure, is now heading towards an era of peace and ...political stability. The signing of the peace agreement on February 29, 2020 by both the US government and the Taliban is a great development for strengthening democratization and power-sharing among the stakeholders in Afghanistan. However, certain hurdles stand in the way of peace and stability. This paper discusses some of the key areas such as the dilemma of Afghan presidential elections, Pakistan’s controversial role, role of neighboring countries and the Indo-Afghan Nexus. Lacunae in the US-Taliban agreement to the exclusion of the Afghan government in the agreement and the threat of the ISIS are some of the other hurdles in bringing peace and stability in the country. Bargaining among the US and Taliban and the various stakeholders of Afghanistan is the only viable solution to the problem which provides the basis for theoretical framework. Keywords: Peace, Hurdles, Afghanistan, Taliban, US
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