Assessing the Correlation of Rate of Pathological Complete Response and Outcome in Post Neoadjuvant Chemotherapy Setting and Molecular Subtypes of Breast Cancer.

Background Neoadjuvant chemotherapy (NAC) is being widely used in treating breast cancer (BC). This study aimed to analyze the correlation between clinicopathological features, immunohistochemistry (IHC)-based molecular subtypes, and the pathological response to NAC and its relationship with disease-free survival (DFS) and overall survival (OS). Materials and methods A retrospective analysis of 211 breast cancer patients who received NAC between 2008 and 2018 was performed. Tumors were classified by IHC into luminal A, luminal B, human epidermal growth factor receptor 2 (HER2)-enriched, and triple-negative subtypes. The chi-square test was used to assess the association between pathological response and clinicopathological parameters. Cox regression analysis was used to assess factors related to DFS and OS. Results Post NAC, 19.4% of patients achieved a pathologic complete response (pCR). Estrogen receptor (ER), progesterone receptor (PR), HER2 (p<0.001, 0.005, and 0.02), Ki67 (p=0.03), molecular subtypes (p<0.001), T stage (p=0.04), and N stage (p=0.01) were significantly associated with pathological response. The rate of pCR was highest among HER2-enriched and triple-negative tumors (45.2% and 28%, respectively) with OR=0.13 and p<0.001 for the HER2-enriched subtype. Patients with pCR were 61% less likely to develop metastasis (adjusted hazard ratio [aHR]=0.39, p=0.06, 95% CI=0.14-1.06) and were significantly associated with better OS (aHR=0.07, p=0.02, 95% CI=0.01-0.61). Patients who were ≤40 years old (aHR=2.1, p=0.01), with T4 (aHR=3.4, p=0.02), grade 3 (aHR=2.5, p=0.01), and node-positive disease (HR=2.24, p=0.02) were at an increased risk of developing metastasis. High Ki67 was found to be significantly associated with better DFS (p=0.006). Conclusion HER2-enriched and triple-negative BC were associated with a higher rate of pCR. Patients with pCR had significantly better DFS and OS. Younger age, advanced stage, higher grade, and lymph node involvement were risk factors for metastasis.

Assessing and optimizing the hydrological performance of Grey-Green infrastructure systems in response to climate change and non-stationary time series.

Climate change has led to the increased intensity and frequency of extreme meteorological events, threatening the drainage capacity in urban catchments and densely built-up cities. To alleviate urban flooding disasters, strategies coupled with green and grey infrastructure have been proposed to support urban stormwater management. However, most strategies rely largely on diachronic rainfall data and ignore long-term climate change impacts. This study described a novel framework to assess and to identify the optimal solution in response to uncertainties following climate change. The assessment framework consists of three components: (1) assess and process climate data to generate long-term time series of meteorological parameters under different climate conditions; (2) optimise the design of Grey-Green infrastructure systems to establish the optimal design solutions; and (3) perform a multi-criteria assessment of economic and hydrological performance to support decision-making. A case study in Guangzhou, China was carried out to demonstrate the usability and application processes of the framework. The results of the case study illustrated that the optimised Grey-Green infrastructure could save life cycle costs and reduce total outflow (56-66%), peak flow (22-85%), and TSS (more than 60%) compared to the fully centralised grey infrastructure system, indicating its high superior in economic competitiveness and hydrological performance under climate uncertainties. In terms of spatial configuration, the contribution of green infrastructure appeared not as critical as the adoption of decentralisation of the drainage networks. Furthermore, under extreme drought scenarios, the decentralised infrastructure system exhibited an exceptionally high degree of removal performance for non-point source pollutants.

Multi-stage planning of LID-GREI urban drainage systems in response to land-use changes.

Long-term planning of urban drainage systems aimed at maintaining the sustainability of urban hydrology remains challenging. In this study, an innovative multi-stage planning framework involving two adaptation pathways for optimizing hybrid low impact development and grey infrastructure (LID-GREI) layouts in opposing chronological orders was explored. The Forward Planning and Backward Planning are adaptation pathways to increase LID in chronological order based on the initial development stage of an urban built-up area and reduce LID in reverse chronological order based on the final development stage, respectively. Two resilience indicators, which considered potential risk scenarios of extreme storms and pipeline failures, were used to evaluate the performance of optimized layouts when land-use changed and evolved over time. Compared these two pathways, Forward Planning made the optimized layouts more economical and resilient in most risk scenarios when land-use changed, while the layouts optimized by Backward Planning showed higher resilience only in the initial stage. Furthermore, a decentralized scheme in Forward Planning was chosen as the optimal solution when taking costs, reliability, resilience, and land-use changes into an overall consideration. Nevertheless, this kind of reverse optimization order offers a novel exploration in planning pathways for discovering the alternative optimization schemes. More comprehensive solutions can be provided to decision-makers. The findings will shed a light on the exploration of optimized layouts in terms of spatial configuration and resilience performance in response to land-use changes. This framework can be used to support long-term investment and planning in urban drainage systems for sustainable stormwater management.

Effectiveness of Suprachoroidal Injection of Triamcinolone Acetonide in Resistant Diabetic Macular Edema Using a Modified Microneedle.

Purpose: The present study evaluated the effectiveness of suprachoroidal injection of triamcinolone acetonide (TA) in resistant diabetic macular edema (DME) using a modified microneedle. Patients and Methods: This is a prospective nonrandomized interventional study that was conducted on 55 eyes of 39 patients with centrally involving DME resistant to previous antivascular endotheli qal growth factor (VEGF) agents. All patients received suprachoroidal injection of triamcinolone acetonide 4 mg/0.1 mL by a modified specialized microneedle. Results: The mean central macular thickness (CMT) decreased sign ificantly from 478.7±170.2 µm before injection to 230.2±47.4 µm after 12 months with p-value <0.001. Significant improvement of the mean best corrected visual acuity (BCVA) from 1.193±0.2 by logMAR at the baseline to 0.76±0.3 by logMAR was achieved after 12 months with p-value <0.001. The IOP increased significantly at one month after injection and returned to the baseline value at the third month. Eyes with more baseline CMT and worse baseline BCVA achieved worse final BCVA 12 months after injection. Eyes with inner segment/outer segment (IS/OS) disruption and neurosensory detachment (NSD) showed worse final visual outcomes. IS/OS segment disruption, NSD and baseline BCVA were the main independent predictors of the final BCVA. Conclusion: Suprachoroidal injection of TA using this new modified microneedle resulted in marked anatomical and functional results in cases of DME resistant to previous anti-VEGF drugs with no serious ocular or systemic side effects. The study was prospectively registered with clinical trial.gov ID (NCT04690608) in 27-12-2020.

Battle of centralized and decentralized urban stormwater networks: From redundancy perspective.

Recent research underpinned the effectiveness of topological decentralization for urban stormwater networks (USNs) during the planning stage in terms of both capital savings and resilience enhancement. However, how centralized and decentralized USNs' structures with various degrees of redundancy (i.e., redundant water flow pathways) project resilience under functional and structural failure remains an unresolved issue. In this work, we present a systemic and generic framework to investigate the impact of adding redundant flow paths on resilience based on three strategies for optimal centralized versus decentralized USNs. Furthermore, a tailored graph-theory based measure (i.e., eigenvector centrality) is proposed to introduce redundant paths to the critical locations of USNs. The proposed framework is then applied to a real large-scale case study. The results confirm the critical role of layout decentralization under both functional (e.g., extreme precipitation events), and structural failure (e.g., pipe collapse). Moreover, the findings indicate that the implementation of redundant paths could increase resilience performance by up to 8% under functional failure without changing the network's major structural characteristics (i.e., sewer diameters, lengths, and storage capacity), only by leveraging the effective flow redistribution. The scheme proposed in this study can be a fruitful initiative for further improving the USNs' resilience during both planning and rehabilitation stages.

Switching to ziv-aflibercept in resistant diabetic macular edema non responsive to ranibizumab injection.

BACKGROUND: Diabetic macular edema (DME) is a leading cause of visual loss in diabetic patients and is managed using multiple anti-vascular endothelial growth factor (VEGF) agents such as bevacizumab, ranibizumab and aflibercept. The present study evaluates effectiveness of intravitreal injection of ziv-aflibercept in resistant diabetic macular edema. METHODS: This is a prospective interventional study that was carried out on 59 eyes of 40 diabetic patients with diabetic macular edema resistant to three prior consecutive ranibizumab injections. On all patients, thorough ophthalmic evaluation including optical coherence tomography was performed. In patients with persistent intraretinal or subretinal fluid, ziv- aflibercept 1.25 mg (0.05 ml) was administered by intravitreal injection monthly during the 6 month study period from June to December 2019. RESULTS: The central macular thickness (CMT) decreased significantly from 395.08 ± 129.9 um at baseline to 282.39 ± 95.278, 245.36 ± 79.861 and 201.17 ± 54.042 after 1, 3 and 6 months of treatment respectively (p < 0.001). Best corrected visual acuity (BCVA) in log MAR units was significantly improved from 0.95 ± 0.21 to 0.51 ± 0.23 after 6 months (p = 0.001). After treatment, negative correlations were detected between age, number of injections, duration of DM and level of glycated hemoglobin (HbA1c) and variation of both CMT and BCVA. The only significant predictor for low final CMT after 6 months of injection was the CMT after 3 months of injection (p = 0.001). CONCLUSION: Ziv-aflibercept is a highly effective and safe drug in cases of DME resistant to previous ranibizumab injections especially in low-income countries. TRIAL REGISTRATION: This study was retrospectively registered at clinicaltrials.gov (ID: NCT04290195) on 28-2-2020.

Modified Microneedle for Suprachoroidal Injection of Triamcinolone Acetonide Combined with Intravitreal Injection of Ranibizumab in Branch Retinal Vein Occlusion Patients.

Purpose: The present study evaluated the efficacy of combined suprachoroidal injection of triamcinolone acetonide (TA) using a modified microneedle with intravitreal injection of ranibizumab in branch retinal vein occlusion (BRVO) patients. Patients and methods: This is a prospective randomised interventional study that was conducted on 60 eyes of 60 patients with non ischemic BRVO. Patients were divided in two groups, group (1) 30 patients who received intravitreal injection of 0.05 mL (0.5 mg) of ranibizumab, group (2) included 30 patients who received baseline combined intravitreal injection of 0.05 mL (0.5 mg) of ranibizumab and suprachoroidal injection of triamcinolone acetonide (4mg/0.1mL), both groups received monthly injection of ranibizumab on pro-re-nata (PRN) regimen for 1 year duration of the study. Results: Group 2 received less number of injections (2.47 ± 1.2) as compared to group 1 (4.4 ± 1.5). Both groups achieved significant reduction of central macular thickness (CMT) after 12 months of injection with p value <0.001. Both groups showed significant improvement of best corrected visual acuity (BCVA) after 12 months with p value <0.001. Group 2 showed more significant improvement of BCVA after 6 and 12 months. The baseline CMT and the number of injections were the main predictors of the final BCVA in group 1, while the baseline BCVA was the only predictor of final BCVA in group 2. Conclusion: Combined suprachoroidal injection of TA using this modified microneedle with intravitreal injection of ranibizumab resulted in more significant improvement of BCVA and reduction of CMT compared with ranibizumab monotherapy with no reported ocular or systemic side effects. The study was prospectively registered with clinical trial.gov ID (NCT04690608) in 27-12-2020.

Designing coupled LID-GREI urban drainage systems: Resilience assessment and decision-making framework.

As flooding risks rise in urban areas, research suggests combining low impact development (LID) and grey infrastructure (GREI) in urban drainage systems. Several frameworks have been proposed to plan such coupled systems, but there is not a comprehensive framework to assess their resilience under diverse failure scenarios and sources of uncertainty. This study proposes a framework which considers both technological and operational resilience. Technological resilience has to do with the performance of the system under extreme loads. Operational resilience has to do with the performance and long-term efficiency of the system after structural damage or degradation, using appropriate probability distributions to quantify the likelihood of failures. The proposed framework is based on an optimization and multi-criteria decision-making platform. It improves on previous research, which lacked consideration of uncertainty in resilience over the life span. We also apply the proposed framework to a real-world test case, and find that in a high-density urban area, a coupled system is more cost-effective than GREI alone. Furthermore, decentralized systems with greater flexibility show significantly better technological and operational resilience. The proposed framework can better support decision-making for planning robust and cost-effective urban drainage systems, particularly in highly urbanized areas.

Radiologist-Level Performance by Using Deep Learning for Segmentation of Breast Cancers on MRI Scans.

PURPOSE: To develop a deep network architecture that would achieve fully automated radiologist-level segmentation of cancers at breast MRI. MATERIALS AND METHODS: In this retrospective study, 38 229 examinations (composed of 64 063 individual breast scans from 14 475 patients) were performed in female patients (age range, 12-94 years; mean age, 52 years ± 10 [standard deviation]) who presented between 2002 and 2014 at a single clinical site. A total of 2555 breast cancers were selected that had been segmented on two-dimensional (2D) images by radiologists, as well as 60 108 benign breasts that served as examples of noncancerous tissue; all these were used for model training. For testing, an additional 250 breast cancers were segmented independently on 2D images by four radiologists. Authors selected among several three-dimensional (3D) deep convolutional neural network architectures, input modalities, and harmonization methods. The outcome measure was the Dice score for 2D segmentation, which was compared between the network and radiologists by using the Wilcoxon signed rank test and the two one-sided test procedure. RESULTS: The highest-performing network on the training set was a 3D U-Net with dynamic contrast-enhanced MRI as input and with intensity normalized for each examination. In the test set, the median Dice score of this network was 0.77 (interquartile range, 0.26). The performance of the network was equivalent to that of the radiologists (two one-sided test procedures with radiologist performance of 0.69-0.84 as equivalence bounds, P < .001 for both; n = 250). CONCLUSION: When trained on a sufficiently large dataset, the developed 3D U-Net performed as well as fellowship-trained radiologists in detailed 2D segmentation of breast cancers at routine clinical MRI.Keywords: MRI, Breast, Segmentation, Supervised Learning, Convolutional Neural Network (CNN), Deep Learning Algorithms, Machine Learning AlgorithmsPublished under a CC BY 4.0 license. Supplemental material is available for this article.

Evaluation of optical coherence tomography angiography findings in patients with multiple sclerosis.

Purpose: To evaluate optical coherence tomography angiography findings in patients with multiple sclerosis (MS). Methods: This prospective noninterventional study was conducted on 30 eyes of relapsing-remitting MS patients. Group (1) included 10 eyes with a history of optic neuritis (ON), group (2) included 10 eyes without any history of optic neuritis (MS-ON), and group (3) included 10 eyes of normal age/sex/refraction matched participants. Optical coherence tomography (OCT) and OCT-A (ZEISS Cirrus™ HD-OCT Model 4000 (Carl Zeiss-Meditec, Dublin, CA) of the optic disc were done for all patients. Results: The best-corrected visual acuity was diminished in MS cases, especially in patients with ON with P value <0.001. The retinal nerve fiber layer (RNFL) thickness showed a significant decrease in the average thickness and in all quadrants, notably the temporal quadrant in group 1 (P < 0.001). Ganglion cell layer thickness was diminished in average thickness and in all quadrants in both groups of MS, but only the first group showed statistical significance with P value <0.001). In respect to optic disc perfusion, Average, superficial, and deep vascular density index (AVDI, VDI 1, VDI 2) were statistically significantly lower in groups 1, 2 with (P-value < 0.001). Conclusion: Decreased vascular perfusion of the optic nerve in MS patients, especially in those with ON is strongly correlated with the damage of RNFL and ganglion cell layer detected by OCT.

The Level of Agreement Among Medical Oncologists on Adjuvant Chemotherapy Decision for Breast Cancer in Pre and Post-Oncotype DX Settings.

INTRODUCTION: The Oncotype DX assay plays an important role in the identification of the specific subset of hormone receptor (HR)-positive and node-negative breast cancer (BC) patients, who would benefit the most from adjuvant chemotherapy. The current study aimed at assessing the level of agreement among medical oncologists on adjuvant chemotherapy decisions before and after Oncotype DX, as well as the intra-observer agreement of each medical oncologist's decision of prescribing adjuvant chemotherapy based on clinicopathological and immunohistochemical parameters only and followed by Oncotype DX recurrence score (RS) results. METHODS: A retrospective analysis of data related to clinicopathological and immunohistochemical parameters, and Oncotype DX RS result for 145 female, estrogen receptor (ER)-positive, HER2 negative, and both node-negative and positive BC patients was performed. Initially, the data without Oncotype DX RS was sent to 16 oncologists in multiple centers in the Middle East. After one week, the same data with the shuffling of cases were sent to the oncologists with the addition of the Oncotype DX RS result for each patient. The inter and intra-observer agreement (kappa and Fleiss multi-rater kappa) among oncologists' decision of prescribing adjuvant chemotherapy pre and post-Oncotype DX RS results were assessed. Oncotype DX risk scores were used as continuous variables as well as based on old RS grouping, categorized into low (0-17), intermediate (18-30), and high risk (≥ 31) groups. A test with a p-value of < 0 .05 will be considered statistically significant. RESULTS: The mean age ± SD of the cohort was 51.9 ± 9.4 years. Sixty-nine patients (47.6%) were premenopausal whereas 76 patients (52.4%) were postmenopausal. The mean Oncotype DX RS was 17.8 ± 8.6 and 54.5% had low recurrence risk (RR), 37.9% had intermediate RR and only 7.6% had high RR. The majority of our cases were grade two (53.1%) and T stage one (49%), whereas 29.7% had positive one to three lymph nodes. The addition of Oncotype DX results improved the agreement among oncologists' decision from fair to moderate (kappa = 0.52; p <0.001). On average, an oncologist's decision of prescribing adjuvant chemotherapy pre and post-Oncotype DX had an agreement in 70.6% of the cases, with agreement observed mostly for cases where the initial decision of adjuvant chemotherapy was (no) and it was retained with post-Oncotype DX assay (46.1%), compared to 24.5% cases where the initial decision was (yes) and it was retained with post-Oncotype DX assay (kappa = 0.39; p <0.001). The addition of the Oncotype DX RS result avoided chemotherapy in 20.4% of cases and identified 9% of cases as candidates for adjuvant chemotherapy (kappa = 0.38; p <0.001). The disagreement was highest among cases with intermediate RR (33.6%) followed by high and low RR (31.3% and 21.6%) with a statistical significance of <0.001. CONCLUSION: We conclude that the Oncotype DX RS significantly influenced the decision to prescribe adjuvant chemotherapy among HR-positive, HER2 negative, and both node-negative and positive patients, as it increased the level of agreement among oncologists and led to a decrease in the use of adjuvant chemotherapy compared to the pre-Oncotype recommendations.

Mesenteric cystic lymphangioma: A case report.

INTRODUCTION AND IMPORTANCE: Mesenteric cystic lymphangiomas are rare benign lesions of the abdominal cavity characterized by lymphatic vessels malformation with an unknown etiology. Despite the silent clinical course of mesenteric cystic lymphangiomas, they are considered as clinically tricky lesions with an immense spectrum of presentations. CASE PRESENTATION: We present a case of abdominal mesenteric cystic lymphangioma in a 1-year 9-month-old female patient, who complained of fever and abdominal pain for 10 days duration. Laboratory investigations, abdominal X-ray, ultrasonography, computed tomography and histopathological examination were all used to establish the diagnosis. CLINICAL DISCUSSION: A trial of true-cut biopsies performed by an interventional radiologist was not informative, so a multidisciplinary team decision was made to excise the mass. Intraoperative findings include multiloculated fused cystic lesion (8.0 × 5.0 × 4.0 cm) on the descending mesocolon. Histopathological examination revealed the diagnosis of a mesenteric cystic lymphangioma. The postoperative period was not complicated. CONCLUSION: Mesenteric cystic lymphangiomas are mostly asymptomatic in nature, yet predisposed to life threating events. Surgical excision is the modality of treatment characterized by low recurrence rate and a non-complicated postoperative period.

Pilot study of ziv-aflibercept in myopic choroidal neovascularisation patients.

BACKGROUND: Myopic choroidal neovascularization (CNV) is the most common sight-threatening complication associated with high myopia. The present study evaluated the efficacy and safety of the intravitreal injection of ziv-aflibercept in patients with myopic CNV. METHODS: This prospective interventional study was conducted on 20 eyes of 20 patients with active myopic CNV. Twelve patients were 40 years or older. This study was performed in the Ophthalmology Department of Tanta University Eye Hospital, Tanta University, Egypt. Optical coherence tomography (OCT) was performed for all patients at baseline and monthly after injection during the 6-month follow up period. The main outcome measures were changes in BCVA and CMT. The exploratory outcome measures were CNV size, IOP and the number of injections needed in each age group during the study period. RESULTS: Patients with myopic CNV younger than 40 years needed fewer injections (2.00 ± 0.76) than patients older than 40 years (2.50 ± 1.00), with no statistical significance detected between the two groups (p-value 0.246). CNV was smaller in the younger age group (p-value 0.209), best corrected visual acuity (BCVA) improved significantly in the younger and older age groups (p-values 0.001 and 0.028, respectively), and central macular thickness (CMT) decreased significantly after 6 months, from 242.88 ± 23.83 µm to 191.13 ± 13.83 µm in the younger age group and from 251.33 ± 26.60 µm to 197.08 ± 17.64 µm in the older age group (p = 0.001). No significant correlation was found between the final BCVA and either the spherical equivalent or central macular thickness after 6 months, with p-values of 0.135 and 0.145, respectively. No significant changes in IOP were detected in either group after the intravitreal injection. CONCLUSION: Ziv-aflibercept is a highly effective and safe drug in cases of active myopic CNV; however, a larger number of patients and a longer follow-up period are needed to confirm our results. This study was retrospectively registered at clinicaltrials.gov (ID: NCT04290195) on 26-2-2020.

Feasibility Study of Thorium-Plutonium Mixed Oxide Assembly In Light Water Reactors.

Thorium-plutonium mixed oxide, (Th,Pu)OX, is currently used as an alternative fuel in the light water reactors in the world. The main objective of this paper is not only to show the benefits of using the thorium, but mainly to study how the way thorium is introduced in the fuel affects the neutron parameters. Among these benefits is the possibility of extending the operating cycle length and the reduction of the increasing stockpiles of plutonium. The first investigated method is introducing thorium as (Th,Pu)OX. The second one is a homogeneous model of thorium plutonium oxide. It is carried out by adding an amount of plutonium separated from the uranium oxide cycle at 50 GWd/ton of heavy metal to the same amount of thorium. Thus, we studied three assemblies; the reference assembly is uranium oxide of 4.2% enrichment containing borated water as a moderator of concentration 500 ppm (part per million) of B-10. The second is a (Th,Pu)OX and the third one is an assembly with homogenized thorium plutonium. All three assemblies are modeled using MCNPX. A comparison is held between the results of the three lattices. The factors compared are the effective multiplication factor, the inventory of plutonium and uranium isotopes, and the depletion of B-10, the pin by pin power distribution at 0 and 60 GWd/ton and the relative pin radial power for the three lattices. The comparison is aimed to show the effect on the cycle length, the reduction in the Pu content and the power flattening across the assembly. It is found that the evolution of the multiplication factors shows a similar behaviour using (Th-Pu)OX fuel in the assembly as UOX cycle inspite of lowering the K-eff of fresh (Th-Pu)OX fuel (1.19847). The power flattening which is favorable in reactor operation is clearer in (Th,Pu)OX fuel. It is noticed that the mass of Pu-239 decreases by 1.07% from its initial value at the end of life. For homogeneous (Th,Pu)OX, the mass decreases by 0.0832%. The high power peaking factor for (Th,Pu)OX is not expected to cause significant effects during reactor operation but it can be reduced by adding burnable poisons.

Hybrid green-blue-gray decentralized urban drainage systems design, a simulation-optimization framework.

Recent studies suggested hybrid green-blue-gray infrastructures (HGBGI) as the most promising urban drainage systems that can simultaneously combine reliability, resilience, and acceptability of gray infrastructures (networks of pipes) with multi-functionality, sustainability, and adaptability of green-blue infrastructures (GBI). Combining GBI and gray measures for designing new urban drainage systems forms a nonlinear multimodal mixed integer-real optimization problem that is highly constrained and intractable. For this purpose, this study presents a simulation-optimization framework to optimize urban drainage systems considering HGBGI alternatives and different degrees of centralization. The proposed framework begins with the characterization of the site under design and drawing the base graph. Then, different layouts with different degrees of centralization are generated and hydraulically designed using a recent algorithm called hanging gardens algorithm. After introducing the feasible GBI to the model, we now perform second optimization to find the optimum distribution of GBIs in a way that minimizes total life cycle costs of GBIs and pipe networks. Finally, resiliency and sustainability of different scenarios are evaluated using several design storms that provide material for final assessment and decision-making. The performance of the proposed framework is evaluated using a real large-scale case study, a part of the city of Ahvaz in Iran. Finally, results are presented and discussed with recommendations for future studies.

Clinical and economic impact of compression in the acute phase of deep vein thrombosis.

Essentials The value of compression therapy in acute phase of deep vein thrombosis is still unclear. Patients with deep vein thrombosis received acute compression hosiery, bandaging, or none. Acute compression reduces irreversible skin signs related to post thrombotic syndrome. Compression hosiery may be the preferred choice for the acute phase SUMMARY: Background The effectiveness of compression therapy in the acute phase of deep vein thrombosis (DVT) is not yet determined. Objectives To investigate the impact of compression therapy in the acute phase of DVT on determinants of the Villalta score, health-related quality of life (HRQOL), and costs. Patients/Methods Eight hundred and sixty-five patients with proximal DVT (substudy of the IDEAL DVT study) received, immediately after DVT diagnosis, either no compression, multilayer bandaging, or hosiery. In the acute phase and 3 months after diagnosis, HRQOL was determined by use of the EQ-5D, SF6D, and VEINES-QoL intrinsic method (VEINES-QoLint ). At 3 months, signs and symptoms were assessed for the total and separate items of the Villalta score, and healthcare costs were calculated. Results The compression groups had lower overall objective Villalta scores than the no-compression group (1.47 [standard deviation (SD) 1.570] and 1.59 [SD 1.64] versus 2.21 [SD 2.15]). The differences were mainly attributable to irreversible skin signs (induration, hyperpigmentation, and venectasia) and pain on calf compression. Subjective and total Villalta scores were similar across groups. Differences in HRQOL were only observed at 1 month; HRQOL was better for hosiery (EQ-5D 0.86 [SD 0.18]; VEINES-QoLint  0.66 [SD 0.18]) than for multilayer compression bandaging (EQ-5D 0.81 [SD 0.23; VEINES-QoLint  0.62 [SD 0.19]). Mean healthcare costs per patient were €417.08 (€354.10 to €489.30) for bandaging, €114.25 (€92.50 to €198.43) for hosiery, and €105.86 (€34.63 to €199.30) for no compression. Conclusions Initial compression reduces irreversible skin signs, edema, and pain on calf compression. Multilayer bandaging is slightly more effective than hosiery, but has substantially higher costs, without a gain in HRQOL. From a patient and economic perspective, compression hosiery would be preferred when initial compression is applied. TRIAL REGISTRATION: IDEAL DVT study ClinicalTrials.gov number, NCT01429714.

RNA Helicase DDX1 Converts RNA G-Quadruplex Structures into R-Loops to Promote IgH Class Switch Recombination.

Class switch recombination (CSR) at the immunoglobulin heavy-chain (IgH) locus is associated with the formation of R-loop structures over switch (S) regions. While these often occur co-transcriptionally between nascent RNA and template DNA, we now show that they also form as part of a post-transcriptional mechanism targeting AID to IgH S-regions. This depends on the RNA helicase DDX1 that is also required for CSR in vivo. DDX1 binds to G-quadruplex (G4) structures present in intronic switch transcripts and converts them into S-region R-loops. This in turn targets the cytidine deaminase enzyme AID to S-regions so promoting CSR. Notably R-loop levels over S-regions are diminished by chemical stabilization of G4 RNA or by the expression of a DDX1 ATPase-deficient mutant that acts as a dominant-negative protein to reduce CSR efficiency. In effect, we provide evidence for how S-region transcripts interconvert between G4 and R-loop structures to promote CSR in the IgH locus.

Structural and immunologic correlates of chemically stabilized HIV-1 envelope glycoproteins.

Inducing broad spectrum neutralizing antibodies against challenging pathogens such as HIV-1 is a major vaccine design goal, but may be hindered by conformational instability within viral envelope glycoproteins (Env). Chemical cross-linking is widely used for vaccine antigen stabilization, but how this process affects structure, antigenicity and immunogenicity is poorly understood and its use remains entirely empirical. We have solved the first cryo-EM structure of a cross-linked vaccine antigen. The 4.2 Å structure of HIV-1 BG505 SOSIP soluble recombinant Env in complex with a CD4 binding site-specific broadly neutralizing antibody (bNAb) Fab fragment reveals how cross-linking affects key properties of the trimer. We observed density corresponding to highly specific glutaraldehyde (GLA) cross-links between gp120 monomers at the trimer apex and between gp120 and gp41 at the trimer interface that had strikingly little impact on overall trimer conformation, but critically enhanced trimer stability and improved Env antigenicity. Cross-links were also observed within gp120 at sites associated with the N241/N289 glycan hole that locally modified trimer antigenicity. In immunogenicity studies, the neutralizing antibody response to cross-linked trimers showed modest but significantly greater breadth against a global panel of difficult-to-neutralize Tier-2 heterologous viruses. Moreover, the specificity of autologous Tier-2 neutralization was modified away from the N241/N289 glycan hole, implying a novel specificity. Finally, we have investigated for the first time T helper cell responses to next-generation soluble trimers, and report on vaccine-relevant immunodominant responses to epitopes within BG505 that are modified by cross-linking. Elucidation of the structural correlates of a cross-linked viral glycoprotein will allow more rational use of this methodology for vaccine design, and reveals a strategy with promise for eliciting neutralizing antibodies needed for an effective HIV-1 vaccine.

Fricke gel dosimeter as a tool in quality assurance of the radiotherapy treatment plans.

Ferrous xylenol gel was evaluated as a dosimeter in verifications of treatment plans for treatments of female breast tumors in external-beam radiation therapy. The dosimeter was calibrated in a cubic wax phantom irradiated with 6 and 15MV beams of an Elekta clinical linear accelerator and then used for measurements of doses in an anthropomorphic phantom of a female torso, which mimicked female breasts after modified radical mastectomy and breast-conserving surgery. Doses measured with the gel in specific locations in the phantom were compared with values predicted by treatment plans created with the XiO treatment planning system (Elekta / IMPAQ) and with results of measurements with an IBA CC13 ionization chamber in the same locations. Differences between the values measured with the gel and predicted by the treatment planning system or measured with the ionization chamber were within 1.5% in most cases. In an area of as steep dose gradient, the difference reached 2.7%, which was explicable in terms of the finite size of the gel dosimeter. The dose response of the gel is dose rate and energy independent in the ranges used in most clinical linacs. The results have shown that ferrous xylenol gels can be used as dosimeters in quality assurance in radiation therapy.

Effect of perchloric acid on the performance of the Fricke xylenol gel dosimeter.

The conventional ferrous xylenol orange (XO) gel (FXG) dosimeter is being wildly investigated for radiotherapy dose measurements. Upon irradiation, its color turns red due to oxidation of Fe(2+) into Fe(3+), which forms a complex with xylenol orange. The effect of perchloric acid (PCA) on the dosimetric properties of the gel in the dose range of 1-15Gy was investigated using visual spectrophotometry. FXG-PCA responds to radiation dose linearly and exhibits higher radiation sensitivity than the conventional gel dosimeter. PCA in a concentration of 20mM enhances the radiation sensitivity ~44%. Stability of the absorbances of both the gels during storage under various conditions was investigated, and the uncertainty of dose measurements was estimated.