A library of infectious hepatitis C viruses with engineered mutations in the E2 gene reveals growth-adaptive mutations that modulate interactions with scavenger receptor class B type I

While natural hepatitis C virus (HCV) infection results in highly diverse quasispecies of related viruses over time, mutations accumulate more slowly in tissue culture, in part because of the inefficiency of replication in cells. To create a highly diverse population of HCV particles in cell culture and identify novel growth-enhancing mutations, we engineered a library of infectious HCV with all codons represented at most positions in the ectodomain of the E2 gene. We identified many putative growth-adaptive mutations and selected nine highly represented E2 mutants for further study: Q412R, T416R, S449P, T563V, A579R, L619T, V626S, K632T, and L644I. We evaluated these mutants for changes in particle-to-infectious-unit ratio, sensitivity to neutralizing antibody or CD81 large extracellular loop (CD81-LEL) inhibition, entry factor usage, and buoyant density profiles. Q412R, T416R, S449P, T563V, and L619T were neutralized more efficiently by anti-E2 antibodies and T416R, T563V, and L619T by CD81-LEL. Remarkably, all nine variants showed reduced dependence on scavenger receptor class B type I (SR-BI) for infection. This shift from SR-BI usage did not correlate with a change in the buoyant density profiles of the variants, suggesting an altered E2-SR-BI interaction rather than changes in the virus-associated lipoprotein-E2 interaction. Our results demonstrate that residues influencing SR-BI usage are distributed across E2 and support the development of large-scale mutagenesis studies to identify viral variants with unique functional properties. IMPORTANCE Characterizing variant viruses can reveal new information about the life cycle of HCV and the roles played by different viral genes. However, it is difficult to recapitulate high levels of diversity in the laboratory because of limitations in the HCV culture system. To overcome this limitation, we engineered a library of mutations into the E2 gene in the context of an infectious clone of the virus. We used this library of viruses to identify nine mutations that enhance the growth rate of HCV. These growth-enhancing mutations reduced the dependence on a key entry receptor, SR-BI. By generating a highly diverse library of infectious HCV, we mapped regions of the E2 protein that influence a key virus-host interaction and provide proof of principle for the generation of large-scale mutant libraries for the study of pathogens with great sequence variability

Inter-reader agreement of high-resolution computed tomography findings in patients with COVID-19 pneumonia: A multi-reader study

Purpose: To investigate the inter-reader agreement in assessing high-resolution computed tomography (HRCT) features of coronavirus disease 2019 (COVID-19) pneumonia. Method: Seventy-seven consecutive patients (mean age, 64 \ub1 15\ua0years) with mild COVID-19 pneumonia that underwent HRCT were retrospectively included. Three radiologists [two devoted to thoracic imaging (R1, R2), and one generalist (R3)] on a per-examination basis independently assessed ground-glass opacity (GGO), consolidation, and crazy-paving pattern. The extent of each feature (total feature score, TFS) was semi-quantitatively assessed, and each TFS summed up to obtain total lung score (TLS). Presence of organizing pneumonia (OP) pattern was also recorded. The inter-reader agreement was calculated with Cohen\u2019s Kappa (k) and Free-Marginal Multirater k. Multivariable analysis was run to determine whether imaging features were predictive of short-term evolution to severe disease (need for ventilation). Results: Most features showed substantial inter-reader agreement, including TLS > 6 (k = 0.69), which was an independent predictor of short-term occurrence of severe disease, regardless of the reader (OR 9\u201353.19). Consolidation TFS > 2 and OP pattern showed substantial and moderate agreement, respectively, only when comparing R1 and R2. Consolidation TFS > 2 and OP pattern were independent predictors of severe disease for R2 (OR 4.87) and R1 (OR 6), respectively. Conclusions: The inter-reader agreement for most HRCT features of COVID-19 pneumonia ranges moderate-to-substantial, though it depends on readers\u2019 experience in the case of consolidation and OP pattern

Abbreviated Versus Multiparametric Prostate MRI in Active Surveillance for Prostate-Cancer Patients: Comparison of Accuracy and Clinical Utility as a Decisional Tool

(1) Purpose: To compare the diagnostic accuracy between full multiparametric contrast-enhanced prostate MRI (mpMRI) and abbreviated dual-sequence prostate MRI (dsMRI) in men with clinically significant prostate cancer (csPCa) who were candidates for active surveillance. (2) Materials and Methods: Fifty-four patients with a diagnosis of low-risk PCa in the previous 6 months had a mpMRI scan prior to a saturation biopsy and a subsequent MRI cognitive transperineal targeted biopsy (for PI-RADS ≥ 3 lesions). The dsMRI images were obtained from the mpMRI protocol. The images were selected by a study coordinator and assigned to two readers blinded to the biopsy results (R1 and R2). Inter-reader agreement for clinically significant cancer was evaluated with Cohen’s kappa. The dsMRI and mpMRI accuracy was calculated for each reader (R1 and R2). The clinical utility of the dsMRI and mpMRI was investigated with a decision-analysis model. (3) Results: The dsMRI sensitivity and specificity were 83.3%, 31.0%, 75.0%, and 23.8%, respectively, for R1 and R2. The mpMRI sensitivity and specificity were 91.7%, 31.0%, 83.3%, and 23.8%, respectively, for R1 and R2. The inter-reader agreement for the detection of csPCa was moderate (k = 0.53) and good (k = 0.63) for dsMRI and mpMRI, respectively. The AUC values for the dsMRI were 0.77 and 0.62 for the R1 and R2, respectively. The AUC values for the mpMRI were 0.79 and 0.66 for R1 and R2, respectively. No AUC differences were found between the two MRI protocols. At any risk threshold, the mpMRI showed a higher net benefit than the dsMRI for both R1 and R2. (4) Conclusions: The dsMRI and mpMRI showed similar diagnostic accuracy for csPCa in male candidates for active surveillance

Comparison between two packages for pectoral muscle removal on mammographic images

Background: Pectoral muscle removal is a fundamental preliminary step in computer-aided diagnosis systems for full-field digital mammography (FFDM). Currently, two open-source publicly available packages (LIBRA and OpenBreast) provide algorithms for pectoral muscle removal within Matlab environment. Purpose: To compare performance of the two packages on a single database of FFDM images. Methods: Only mediolateral oblique (MLO) FFDM was considered because of large presence of pectoral muscle on this type of projection. For obtaining ground truth, pectoral muscle has been manually segmented by two radiologists in consensus. Both LIBRA’s and OpenBreast’s removal performance with respect to ground truth were compared using Dice similarity coefficient and Cohen-kappa reliability coefficient; Wilcoxon signed-rank test has been used for assessing differences in performances; Kruskal–Wallis test has been used to verify possible dependence of the performance from the breast density or image laterality. Results: FFDMs from 168 consecutive women at our institution have been included in the study. Both LIBRA’s Dice-index and Cohen-kappa were significantly higher than OpenBreast (Wilcoxon signed-rank test P < 0.05). No dependence on breast density or laterality has been found (Kruskal–Wallis test P > 0.05). Conclusion: Libra has a better performance than OpenBreast in pectoral muscle delineation so that, although our study has not a direct clinical application, these results are useful in the choice of packages for the development of complex systems for computer-aided breast evaluation

Breast imaging and cancer diagnosis during the COVID-19 pandemic: recommendations from the Italian College of Breast Radiologists by SIRM

The Italian College of Breast Radiologists by the Italian Society of Medical Radiology (SIRM) provides recommendations for breast care provision and procedural prioritization during COVID-19 pandemic, being aware that medical decisions must be currently taken balancing patient\u2019s individual and community safety: (1) patients having a scheduled or to-be-scheduled appointment for in-depth diagnostic breast imaging or needle biopsy should confirm the appointment or obtain a new one; (2) patients who have suspicious symptoms of breast cancer (in particular: new onset palpable nodule; skin or nipple retraction; orange peel skin; unilateral secretion from the nipple) should request non-deferrable tests at radiology services; (3) asymptomatic women performing annual mammographic follow-up after breast cancer treatment should preferably schedule the appointment within 1\ua0year and 3\ua0months from the previous check, compatibly with the local organizational conditions; (4) asymptomatic women who have not responded to the invitation for screening mammography after the onset of the pandemic or have been informed of the suspension of the screening activity should schedule the check preferably within 3\ua0months from the date of the not performed check, compatibly with local organizational conditions. The Italian College of Breast Radiologists by SIRM recommends precautions to protect both patients and healthcare workers (radiologists, radiographers, nurses, and reception staff) from infection or disease spread on the occasion of breast imaging procedures, particularly mammography, breast ultrasound, breast magnetic resonance imaging, and breast intervention procedures

Evidence-based robust optimization of pulsed laser orbital debris removal under epistemic uncertainty

An evidence-based robust optimization method for pulsed laser orbital debris removal (LODR) is presented. Epistemic type uncertainties due to limited knowledge are considered. The objective of the design optimization is set to minimize the debris lifetime while at the same time maximizing the corresponding belief value. The Dempster–Shafer theory of evidence (DST), which merges interval-based and probabilistic uncertainty modeling, is used to model and compute the uncertainty impacts. A Kriging based surrogate is used to reduce the cost due to the expensive numerical life prediction model. Effectiveness of the proposed method is illustrated by a set of benchmark problems. Based on the method, a numerical simulation of the removal of Iridium 33 with pulsed lasers is presented, and the most robust solutions with minimum lifetime under uncertainty are identified using the proposed method

Effectiveness of GNSS disposal strategies

The management of the Global Navigation Satellite Systems (GNSS) and of the Medium Earth Orbit (MEO) region as a whole is a subject that cannot be deferred, due to the growing exploitation and launch rate in that orbital regime. The advent of the European Galileo and the Chinese Beidou constellations significantly added complexity to the system and calls for an adequate global view on the four constellations present in operation. The operation procedures, including maintenance and disposal practices, of the constellations currently deployed were analyzed in order to asses a proper reference simulation scenario. The complex dynamics of the MEO region with all the geopotential and lunisolar resonances was studied to better identify the proper end-of-life orbit for every proposed strategy, taking into account and, whenever possible, exploiting the orbital dynamics in this peculiar region of space. The possibility to exploit low thrust propulsion or non gravitational perturbations with passive de-orbiting devices (and a combination of the two) was analyzed, in view of possible applications in the design of the future generations of the constellations satellites. Several upgrades in the long-term evolution software SDM and DAMAGE were undertaken to properly handle the constellation simulations in every aspect from constellation maintenance to orbital dynamics. A thorough approach considering the fulltime evolving covariance matrix associated with every object was implemented in SDM to compute the collision risk and associated maneuver rate for the constellation satellites. Once the software upgrades will be completed, the effectiveness of the different disposal strategies will be analyzed in terms of residual collision risk and avoidance maneuvers rate

Screening and diagnostic breast MRI: how do they impact surgical treatment? Insights from the MIPA study

Objectives: To report mastectomy and reoperation rates in women who had breast MRI for screening (S-MRI subgroup) or diagnostic (D-MRI subgroup) purposes, using multivariable analysis for investigating the role of MRI referral/nonreferral and other covariates in driving surgical outcomes. Methods: The MIPA observational study enrolled women aged 18–80 years with newly diagnosed breast cancer destined to have surgery as the primary treatment, in 27 centres worldwide. Mastectomy and reoperation rates were compared using non-parametric tests and multivariable analysis. Results: A total of 5828 patients entered analysis, 2763 (47.4%) did not undergo MRI (noMRI subgroup) and 3065 underwent MRI (52.6%); of the latter, 2441/3065 (79.7%) underwent MRI with preoperative intent (P-MRI subgroup), 510/3065 (16.6%) D-MRI, and 114/3065 S-MRI (3.7%). The reoperation rate was 10.5% for S-MRI, 8.2% for D-MRI, and 8.5% for P-MRI, while it was 11.7% for noMRI (p ≤ 0.023 for comparisons with D-MRI and P-MRI). The overall mastectomy rate (first-line mastectomy plus conversions from conserving surgery to mastectomy) was 39.5% for S-MRI, 36.2% for P-MRI, 24.1% for D-MRI, and 18.0% for noMRI. At multivariable analysis, using noMRI as reference, the odds ratios for overall mastectomy were 2.4 (p < 0.001) for S-MRI, 1.0 (p = 0.957) for D-MRI, and 1.9 (p < 0.001) for P-MRI. Conclusions: Patients from the D-MRI subgroup had the lowest overall mastectomy rate (24.1%) among MRI subgroups and the lowest reoperation rate (8.2%) together with P-MRI (8.5%). This analysis offers an insight into how the initial indication for MRI affects the subsequent surgical treatment of breast cancer. Key Points: • Of 3065 breast MRI examinations, 79.7% were performed with preoperative intent (P-MRI), 16.6% were diagnostic (D-MRI), and 3.7% were screening (S-MRI) examinations. • The D-MRI subgroup had the lowest mastectomy rate (24.1%) among MRI subgroups and the lowest reoperation rate (8.2%) together with P-MRI (8.5%). • The S-MRI subgroup had the highest mastectomy rate (39.5%) which aligns with higher-than-average risk in this subgroup, with a reoperation rate (10.5%) not significantly different to that of all other subgroups

Breast tumor characteristics of BRCA1 and BRCA2 gene mutation carriers on MRI

The appearance of malignant lesions in BRCA1 and BRCA2 mutation carriers (BRCA-MCs) on mammography and magnetic resonance imaging (MRI) was evaluated. Thus, 29 BRCA-MCs with breast cancer were retrospectively evaluated and the results compared with an age, tumor size and tumor type matched control group of 29 sporadic breast cancer cases. Detection rates on both modalities were evaluated. Tumors were analyzed on morphology, density (mammography), enhancement pattern and kinetics (MRI). Overall detection was significantly better with MRI than with mammography (55/58 vs 44/57, P = 0.021). On mammography, lesions in the BRCA-MC group were significantly more described as rounded (12//19 vs 3/13, P = 0.036) and with sharp margins (9/19 vs 1/13, P = 0.024). On MRI lesions in the BRCA-MC group were significantly more described as rounded (16/27 vs 7/28, P = 0.010), with sharp margins (20/27 vs 7/28, P < 0.001) and with rim enhancement (7/27 vs 1/28, P = 0.025). No significant difference was found for enhancement kinetics (P = 0.667). Malignant lesions in BRCA-MC frequently have morphological characteristics commonly seen in benign lesions, like a rounded shape or sharp margins. This applies for both mammography and MRI. However the possibility of MRI to evaluate the enhancement pattern and kinetics enables the detection of characteristics suggestive for a malignancy