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.

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.

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.

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.

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.

Exposure to food allergens through inflamed skin promotes intestinal food allergy through the thymic stromal lymphopoietin-basophil axis.

BACKGROUND: Exposure to food allergens through a disrupted skin barrier has been recognized as a potential factor in the increasing prevalence of food allergy. OBJECTIVE: We sought to test the immunologic mechanisms by which epicutaneous sensitization to food allergens predisposes to intestinal food allergy. METHODS: Mice were epicutaneously sensitized with ovalbumin or peanut on an atopic dermatitis-like skin lesion, followed by intragastric antigen challenge. Antigen-specific serum IgE levels and T(H)2 cytokine responses were measured by ELISA. Expression of type 2 cytokines and mast cell proteases in the intestine were measured by using real-time PCR. Accumulation of basophils in the skin and mast cells in the intestine was examined by using flow cytometry. In vivo basophil depletion was achieved by using diphtheria toxin treatment of Baso-DTR mice. For cell-transfer studies, the basophil population was expanded in vivo by means of hydrodynamic tail vein injection of thymic stromal lymphopoietin (TSLP) cDNA plasmid. RESULTS: Sensitization to food allergens through an atopic dermatitis-like skin lesion is associated with an expansion of TSLP-elicited basophils in the skin that promote antigen-specific T(H)2 cytokine responses, increased antigen-specific serum IgE levels, and accumulation of mast cells in the intestine, promoting the development of intestinal food allergy. Critically, disruption of TSLP responses or depletion of basophils reduced the susceptibility to intestinal food allergy, whereas transfer of TSLP-elicited basophils into intact skin promoted disease. CONCLUSION: Epicutaneous sensitization on a disrupted skin barrier is associated with accumulation of TSLP-elicited basophils, which are necessary and sufficient to promote antigen-induced intestinal food allergy.

Mapping parahippocampal systems for recognition and recency memory in the absence of the rat hippocampus.

The present study examined immediate-early gene expression in the perirhinal cortex of rats with hippocampal lesions. The goal was to test those models of recognition memory which assume that the perirhinal cortex can function independently of the hippocampus. The c-fos gene was targeted, as its expression in the perirhinal cortex is strongly associated with recognition memory. Four groups of rats were examined. Rats with hippocampal lesions and their surgical controls were given either a recognition memory task (novel vs. familiar objects) or a relative recency task (objects with differing degrees of familiarity). Perirhinal Fos expression in the hippocampal-lesioned groups correlated with both recognition and recency performance. The hippocampal lesions, however, had no apparent effect on overall levels of perirhinal or entorhinal cortex c-fos expression in response to novel objects, with only restricted effects being seen in the recency condition. Network analyses showed that whereas the patterns of parahippocampal interactions were differentially affected by novel or familiar objects, these correlated networks were not altered by hippocampal lesions. Additional analyses in control rats revealed two modes of correlated medial temporal activation. Novel stimuli recruited the pathway from the lateral entorhinal cortex (cortical layer II or III) to hippocampal field CA3, and thence to CA1. Familiar stimuli recruited the direct pathway from the lateral entorhinal cortex (principally layer III) to CA1. The present findings not only reveal the independence from the hippocampus of some perirhinal systems associated with recognition memory, but also show how novel stimuli engage hippocampal subfields in qualitatively different ways from familiar stimuli.

Effectiveness of Suprachoroidal Injection of Triamcinolone Acetonide in Diabetic Macular Edema Following Pars Plana Vitrectomy Using a Modified Custom Microneedle.

Purpose: The present study evaluated the efficacy of suprachoroidal injection of Triamcinolone Acetonide (SCTA) in diabetic macular edema (DME) following pars plana vitrectomy (PPV) using a modified microneedle. Patients and methods: A prospective interventional study was conducted on 60 eyes of 60 patients with centrally involved diabetic macular edema following pars plana vitrectomy (PPV). SCTA was performed at the baseline and repeated after 3 months in case of persistent subretinal or intraretinal fluid, central macular thickness (CMT) more than 300 µm or visual loss by more than one line of the Snellen chart. Results: The present study detected significant reduction of the CMT from 498.3 ± 94.8 µm at the baseline to 212.3 ± 11.9 µm after 12 months of injection with p < 0.001 and a significant improvement of best corrected visual acuity (BCVA) from 1 (0.9-1.2) at the baseline to 0.5 (0.3-0.7) after 12 months of injection with p < 0.001. The intraocular pressure (IOP) increased significantly after 3 months of injection with p < 0.001 and then gradually declined to its normal level after 6 months. Inner segment/outer segment (IS/OS) disruption was the only significant predictor of the final CMT; however, the number of injections, IS/OS disruption, baseline BCVA and the HbA1C level were the significant predictors of the final BCVA after injection. Conclusion: Suprachoroidal injection of TA using this microneedle resulted in significant anatomical and functional improvement in previously vitrectomized diabetic macular edema patients with no recorded ocular or systemic adverse events.

A randomized, double-blind phase 2b trial to evaluate efficacy of ChAd63-KH for treatment of post kala-azar dermal leishmaniasis.

In a recent phase 2a clinical trial, the candidate leishmaniasis vaccine ChAd63-KH was shown to be safe and immunogenic in Sudanese patients with post kala-azar dermal leishmaniasis (PKDL). However, its value as a stand-alone therapeutic was unknown. To assess the therapeutic efficacy of ChAd63-KH, we conducted a randomized, double-blind, placebo-controlled phase 2b trial (ClinicalTrials.gov: NCT03969134). Primary outcomes were safety and efficacy (≥90% improvement in clinical disease). Secondary outcomes were change in severity grade and vaccine-induced immune response. 86 participants with uncomplicated PKDL of ≥6 month duration were randomized to receive ChAd63-KH (7.5 × 1010 viral particles, once by the intramuscular route) or placebo. 75 participants (87%) completed the trial as per protocol. No severe or serious adverse events were observed. At day 90 post-vaccination, 6/40 (15%) and 4/35 (11%) participants in the vaccine and placebo groups, respectively, showed ≥90% clinical improvement (risk ratio [RR] 1.31 [95% confidence interval (CI), 0.40-4.28], p = 0.742). There were also no significant differences in PKDL severity grade between study arms. Whole-blood transcriptomic analysis identified transcriptional modules associated with interferon responses and monocyte and dendritic cell activation. Thus, a single vaccination with ChAd63-KH showed no therapeutic efficacy in this subset of Sudanese patients with PKDL.

Reactive carbonyls are a major Th2-inducing damage-associated molecular pattern generated by oxidative stress.

Oxidative stress is widespread and entwined with pathological processes, yet its linkage to adaptive immunity remains elusive. Reactive carbonyl (RC) adduction, a common feature of oxidative stress, has been shown to target proteins to the adaptive immune system. Because aldehydes are important mediators of carbonylation, we explored the immunomodulatory properties of model Ags modified by common bioactive aldehyde by-products of oxidative stress: 4-hydroxy-2-nonenal, malondialdehyde, and glycolaldehyde. Ag modification with all three aldehydes resulted in Ag-specific IgG1-dominated responses in adjuvant-free murine immunizations in an RC-dependent manner. The central role of RCs was confirmed, as their reduction into nonreactive groups abrogated all adaptive responses, despite the presence of other well-known aldehyde-driven adducts such as N(ε)-carboxymethyllysine and glycolaldehyde-pyridine. Moreover, Ag-specific Ab responses robustly correlated with the extent of RC adduction, regardless of the means of their generation. T cell responses mirrored the Th2-biased Ab isotypes by Ag-specific splenocyte production of IL-4, IL-5, and IL-13, but not IFN-γ. The RC-induced Th2 response was in sharp contrast to that induced by Th1/Th2 balanced or Th1-biasing adjuvants and was maintained in a range of mouse strains. In vitro studies revealed that RC adduction enhanced Ag presentation with Th2 polarization in the absence of conventional dendritic cell activation. Taken together, these data implicate commonly occurring RC as an important oxidation-derived Th2 immunomodulatory damage-associated molecular pattern with potentially important roles in health and disease.

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.

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.

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.

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.

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.

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.

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.

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.