Phase 2 trial of tremelimumab in patients with metastatic urothelial cancer previously treated with programmed death 1/programmed death ligand 1 blockade.

INTRODUCTION: Programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) blockade has changed the landscape of treatment for metastatic urothelial cancer, but single-agent cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade in metastatic urothelial cancer has been underexplored. A prior phase 2 trial of tremelimumab in PD-1/PD-L1-blockade naive patients with metastatic urothelial cancer revealed activity comparable to that observed with PD-1/PD-L1 blockade raising the hypothesis that these classes of immune checkpoint inhibitors might be non-cross-resistant. METHODS: The current phase 2 trial treated patients with PD-1/PD-L1 blockade-resistant metastatic urothelial cancer with single-agent tremelimumab (750 mg intravenously every 28 days for up to 7 cycles). The primary end point was objective response rate. RESULTS: Twenty-six patients were enrolled and 24 patients were evaluable for response. The objective response rate was 8.3%, composed of a total of two partial responses that lasted 10.9 and 24.0 months. Stable disease was observed in another 20.8% of patients, with a median duration of stable disease of 5.4 months. Diarrhea occurred in 15 patients (58%), elevated hepatic transaminases occurred in seven patients (27%), and adrenal insufficiency occurred in two patients (8%); one patient died after experiencing immune-related hepatitis. CONCLUSIONS: High dose CTLA-4 blockade in patients with PD-1/PD-L1-resistant metastatic urothelial cancer has modest activity and is associated with treatment-related toxicity similar to prior reports.

A joint analysis of accessibility and household trip frequencies by travel mode.

This paper examines the endogenous relationship between residential level of accessibility and household trip frequencies to tease out the direct and indirect effects of observed behavioural differences. We estimate a multivariate ordered probit model system, which allows dependence in both observed and unobserved factors, using data from the 2016 Transportation Tomorrow Survey (TTS), a household travel survey in the Greater Golden Horseshoe Area (GGH) in Toronto. The modelling framework is used to analyse the influence of exogenous variables on eight outcome variables of accessibility levels and trip frequencies by four modes (auto, transit, bicycle and walk), and to explore the nature of the relationships between them. The results confirm our hypothesis that not only does a strong correlation exist between the residential level of accessibility and household trip frequency, but there are also direct effects to be observed. The complementarity effect between auto accessibility and transit trips, and the substitution effect observed between transit accessibility and auto trips highlight the residential neighbourhood dissonance of transit riders. It shows that locations with better transit service are not necessarily locations where people who make more transit trips reside. Essentially, both jointness (due to error correlations) as well as directional effects observed between accessibility and trip frequencies of multiple modes offer strong support for the notion that accessibility and trip frequency by mode constitute a bundled choice and need to be considered as such.

Precision Medicine in Urothelial Carcinoma: Current Markers to Guide Treatment and Promising Future Directions.

OPINION STATEMENT: The treatment landscape for urothelial cancer has changed dramatically in the last 10 years, with the approval of several new treatments. At the same time, profiling of individual tumors has become more commonplace with widespread availability of molecular testing and immunohistochemistry. For urothelial cancer, this has led to current guidelines recommending that molecular testing be obtained in the metastatic setting, and that it be considered in the setting of locally advanced disease. Between molecular testing and immunohistochemistry testing of tumors, the only current guideline-directed application of these tests is in the identification of FGFR3 or FGFR2 alterations for use of FGFR inhibitors. While additional recurrent molecular alterations linked to the pathogenesis of urothelial cancer have been identified, the ability to successfully "drug" the pathways association with such alterations remains limited. There has been extensive research into whether expression of particular proteins might inform specific treatment approaches such as the use of PD-L1 testing to guide immune checkpoint blockade. With the integration of antibody-drug conjugates into the treatment armamentarium for urothelial cancer, ongoing research is seeking to determine whether expression of the targets of these therapies, such as Nectin 4, Trop-2, or HER2, could help to guide treatment.

Evaluation of a commercial NGS service for detection of bacterial and fungal pathogens in infectious ulcerative keratitis.

OBJECTIVES: To compare results from a commercial next-generation sequencing (NGS) service to corneal cytology and culture for identification of causative organisms in veterinary patients presenting for infectious ulcerative keratitis (IUK). PROCEDURE: Swabs for corneal aerobic and fungal cultures and DNA swabs for NGS were submitted for canine and equine normal controls (n = 11 and n = 4, respectively) and IUK patients (n = 22 and n = 8, respectively) for which microbrush cytology specimens confirmed the presence of infectious organisms. The sensitivity of the NGS results was compared with bacterial and fungal culture results. Concordance between the NGS and culture results was determined. RESULTS: The NGS results were positive for bacterial and fungal organisms in 5 and 1 normal and 18 and 1 IUK cases, respectively. Bacterial and fungal cultures were positive for 7 and 2 normal and 20 and 5 IUK cases, respectively. Sensitivity of NGS was 82.14% (95% confidence interval (CI), 63.11% to 93.94%) and specificity was 76.47% (95% CI, 50.10% to 93.19%). Concordance (complete and partial) between identified bacterial and fungal organisms was found in 79% and 100% of cases, respectively. NGS identified organisms in 3 culture-negative IUK samples. CONCLUSION: A commercial NGS service may be useful in the identification of causative agents in IUK cases with a sensitivity greater than the sensitivity previously reported for aerobic culture. Further testing is needed to determine the clinical significance of additional organisms isolated by NGS from infected cases, as well as organisms isolated from normal corneas.

A Thematic Analysis of the Online Discussion Board, FrankTalk, Regarding Penile Implant.

INTRODUCTION: Medical websites and discussion boards are commonly used by patients to obtain information. The online forum FrankTalk.org provides a venue specifically for men to discuss sexual dysfunction and particularly inflatable penile prosthesis (IPP). By querying and better understanding the content of this forum related to implants, we can better understand patient concerns before and after IPP. AIM: The aim of this study is to understand the main topics being discussed about IPPs online and to use these topics to understand patient concerns and patient needs and to improve care. METHODS: Messages posted in a 6-month window from January 2018 to June 2018 under the topic "Implant" were identified on FrankTalk.org. Posts were broken down into preoperative and postoperative and then organized using a 3-stage analysis to determine central themes of each post: open coding, axial coding, and selective coding. MAIN OUTCOME MEASURE: The primary outcome measure is the prevalence of each selective code. RESULTS: Of all 587 posts, 304 were written preoperatively with the most common theme being "Size" (23.0%), followed by "seeking support" (18.4%). 283 posts were considered postoperative, of which the most common theme was "Concern about healing" (22.6 %) which questioned if they needed to see a physician, followed by size concerns (20.1%).When analyzed with the 3-stage coding system, there were a total of 41 axial codes which were organized into 6 selective codes: "Social Support" (27.8% of all posts), "Pre-Operative Worries" (23.58%),"Technical Issues" (11.1%), "Prosthesis Logistics" (14.37%), "Post-Operative Worries" (20.22%), "Forum and Misc" (2.93%) for topics outside the scope of penile prosthesis. CLINICAL IMPLICATIONS: The percentage of men seeking medical opinion is concerning, and providers should consider using resources to better educate patients on normal postoperative findings. Implanters should continue to preoperatively counsel patients on size-related changes with surgery. STRENGTH & LIMITATIONS: Strengths include the use of a common online website for men to discuss IPPs and a systematic coding system. Limitations include the applicability of these results to nonheterosexual men as these are likely oversampled in this population. The inherent bias of those willing to post on an online forum may have influenced results along with no oversight for factual accuracy. CONCLUSION: Patients use online discussion boards like FrankTalk.org for social support, medical advice, and validation of their concerns. Providers should be aware of these online topic focuses to help open a discussion with patients about concerns they may feel are difficult to approach with providers. Lu JY, Miller EJ, Welliver C. A Thematic Analysis of the Online Discussion Board, FrankTalk, Regarding Penile Implant. J Sex Med 2020;17:325-330.

Using minimum inhibitory concentration values of common topical antibiotics to investigate emerging antibiotic resistance: A retrospective study of 134 dogs and 20 horses with ulcerative keratitis.

OBJECTIVES: To identify the minimum inhibitory concentration (MIC) distribution for commonly used topical antibiotics from isolates of dogs and horses with ulcerative bacterial keratitis, and to investigate changes in MIC values over time and following treatment with topical fluoroquinolones. ANIMALS STUDIED: One hundred thirty-four client-owned dogs and 20 client-owned horses with bacterial ulcerative keratitis. PROCEDURE: Minimum inhibitory concentration values for 14 topical antibiotics were reported for canine and equine cases of bacterial ulcerative keratitis between 2013 and 2018. Changes in MIC values over time and after treatment with topical fluoroquinolones were reported. RESULTS: The three most common bacterial genera isolated were Staphylococcus, Streptococcus, and Pseudomonas. Together, these represented 79.4% of canine cases and 77.4% of equine cases. Overall, isolates from horses tended to have lower MIC values, as did Pseudomonas isolates from both dogs and horses, compared to other bacterial genera, especially Staphylococcus spp. The MIC values of erythromycin and trimethoprim sulfa for Staphylococcus spp., and the MIC value of moxifloxacin for Pseudomonas significantly increased over time. Previous topical fluoroquinolone use was associated with a significant increase in the MIC value of ofloxacin in canine and equine Staphylococcus isolates and current topical fluoroquinolone use was associated with significant increases in the MIC values of ciprofloxacin, moxifloxacin, and ofloxacin in canine Staphylococcus isolates. CONCLUSION: Patients previously or currently treated with topical fluoroquinolones, particularly in Staphylococcus infections, may require alternative antibiotics or additional antibiotic classes other than fluoroquinolones. Bacterial culture with MIC susceptibility testing should be highly recommended when a Staphylococcal infection is suspected.

Determination of trypan blue efficacy in the mitigation of ex vivo canine PCO formation.

PURPOSE: To determine whether trypan blue (TB) reduces canine lens epithelial cell (LEC) or corneal endothelial cell (CEC) viability in vitro; if cell death is noted, to subsequently evaluate the molecular mechanism. METHODS: Cellular viability was determined using a lactate dehydrogenase (LDH) assay. In TB-treated LECs, caspase 3/7 activity was assessed to evaluate apoptosis; autophagy was evaluated using immunoblotting against LC3 and p62. To evaluate the effects of TB on ex vivo posterior capsule opacification (PCO), following mock cataract surgery, lens capsules were treated with TB and subsequently maintained in culture to determine LEC migration and proliferation. RESULTS: Following acute exposure, TB did not significantly reduce LEC or CEC viability at any of the concentrations tested. Increased caspase 3/7 activity was found in LEC cultures treated with TB for an extended period of time; no change in LC3 or p62 expression was noted. Ex vivo PCO formation was not significantly altered by TB treatment. CONCLUSIONS: Acute exposure to TB did not reduce LEC or CEC viability, and only longer exposure to TB was able to initiate apoptosis. Treatment with intraocular TB at the time of cataract surgery is likely safe to the CECs but will not prevent PCO formation.

The Bioactive Protein-Ligand Conformation of GluN2C-Selective Positive Allosteric Modulators Bound to the NMDA Receptor.

N-methyl-d-aspartate (NMDA) receptors are ligand-gated, cation-selective channels that mediate a slow component of excitatory synaptic transmission. Subunit-selective positive allosteric modulators of NMDA receptor function have therapeutically relevant effects on multiple processes in the brain. A series of pyrrolidinones, such as PYD-106, that selectively potentiate NMDA receptors that contain the GluN2C subunit have structural determinants of activity that reside between the GluN2C amino terminal domain and the GluN2C agonist binding domain, suggesting a unique site of action. Here we use molecular biology and homology modeling to identify residues that line a candidate binding pocket for GluN2C-selective pyrrolidinones. We also show that occupancy of only one site in diheteromeric receptors is required for potentiation. Both GluN2A and GluN2B can dominate the sensitivity of triheteromeric receptors to eliminate the actions of pyrrolidinones, thus rendering this series uniquely sensitive to subunit stoichiometry. We experimentally identified NMR-derived conformers in solution, which combined with molecular modeling allows the prediction of the bioactive binding pose for this series of GluN2C-selective positive allosteric modulators of NMDA receptors. These data advance our understanding of the site and nature of the ligand-protein interaction for GluN2C-selective positive allosteric modulators for NMDA receptors.

Chloride is an Agonist of Group II and III Metabotropic Glutamate Receptors.

The elemental anion chloride is generally considered a passive participant in neuronal excitability, and has never been shown to function as an agonist in its own right. We show that the antagonist-mediated, glutamate-independent inverse agonism of group II and III metabotropic glutamate (mGlu) receptors results from inhibition of chloride-mediated activation. In silico molecular modeling, site-directed mutagenesis, and functional assays demonstrate (1) that chloride is an agonist of mGlu3, mGlu4, mGlu6, and mGlu8 receptors with its own orthosteric site, and (2) that chloride is not an agonist of mGlu2 receptors. Molecular modeling-predicted and site-directed mutagenesis supported that this unique property of mGlu2 receptors results from a single divergent amino acid, highlighting a molecular switch for chloride insensitivity that is transduced through an arginine flip. Ultimately, these results suggest that activation of group II and III mGlu receptors is mediated not only by glutamate, but also by physiologically relevant concentrations of chloride.

A real-time method for measuring cAMP production modulated by Gαi/o-coupled metabotropic glutamate receptors.

Group II and group III metabotropic glutamate (mGlu) receptors are G protein-coupled receptors (GPCRs) that inhibit adenylyl cyclase via activation of Gαi/o. The purpose of this study was to design a universal method that overcomes previous challenges in consistently measuring group II and group III mGlu-receptor (mGluR) activation in stably transfected systems. In Chinese hamster ovary (CHO) cells stably transfected with the GloSensor cAMP biosensor, we optimized conditions for simple and highly reproducible (<5% S.E.M.) measurements of cAMP in real time. The GloSensor cAMP biosensor is a recombinant firefly luciferase conjugated to a cAMP-binding domain, where cAMP binding promotes a conformational shift within the GloSensor protein, inducing luciferase activity; cAMP levels are positively correlated with light output resulting from the luciferase-mediated breakdown of d-luciferin. Each group II and group III mGluR was then stably transfected into the CHO-GloSensor cell line, and experimental conditions were optimized for each receptor. During assay optimization, we observed ion sensitivity of several receptors and inverse agonist activity of the antagonist, LY341495 [2-[(1S,2S)-2-carboxycyclopropyl]-3-(9H-xanthen-9-yl)-d-alanine]. Although these phenomena have been previously reported, they remain poorly understood, emphasizing the GloSensor assay as an important tool with which to study group II and group III mGlu receptors. Our results highlight many advantages of using the GloSensor method for measuring activation of group II and group III mGlu receptors, and they further suggest that corresponding methods designed to measure activation of any Gαi/o- or Gαs-coupled GPCR will be similarly advantageous.

Analyzing housing supply location choice: a comparative study of the modelling frameworks.

The purpose of this study is to predict the location of new housing supply and compare two different modelling frameworks. Housing supply significantly influences land use simulations in urban microsimulation systems, closely linked with demographic, transportation, and environmental modules. The supply of new dwellings in urban simulation models have evolved from static, exogenous inputs to dynamic, agent-based determinations. This study follows this trend to examine two approaches to modelling the spatial distribution of new housing supply: the first approach models the development choice of each location; the second approach models the location choice of each residential project. Multinomial logit and nested logit models are applied to a Toronto empirical dataset. The results show that although the first approach achieves higher goodness-of-fit and prediction accuracy, the second approach performs better in explaining the locational preference of individual projects. Project characteristics such as structure type and construction cost, as well as location characteristics such as housing price, number of sales, and population density affect the spatial distribution of new housing supply. Both approaches are evaluated regarding estimation, prediction, and microsimulation system integration. The findings enhance housing modelling literature and inform urban microsimulation's housing supply model configuration.

Discovery of 5'-Substituted 5-Fluoro-2'-deoxyuridine Monophosphate Analogs: A Novel Class of Thymidylate Synthase Inhibitors.

5-Fluorouracil and 5-fluorouracil-based prodrugs have been used clinically for decades to treat cancer. Their anticancer effects are most prominently ascribed to inhibition of thymidylate synthase (TS) by metabolite 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP). However, 5-fluorouracil and FdUMP are subject to numerous unfavorable metabolic events that can drive undesired systemic toxicity. Our previous research on antiviral nucleotides suggested that substitution at the nucleoside 5'-carbon imposes conformational restrictions on the corresponding nucleoside monophosphates, rendering them poor substrates for productive intracellular conversion to viral polymerase-inhibiting triphosphate metabolites. Accordingly, we hypothesized that 5'-substituted analogs of FdUMP, which is uniquely active at the monophosphate stage, would inhibit TS while preventing undesirable metabolism. Free energy perturbation-derived relative binding energy calculations suggested that 5'(R)-CH3 and 5'(S)-CF3 FdUMP analogs would maintain TS potency. Herein, we report our computational design strategy, synthesis of 5'-substituted FdUMP analogs, and pharmacological assessment of TS inhibitory activity.

A nonmetal approach to α-heterofunctionalized carbonyl derivatives by formal reductive X-H insertion.

Keeping it organic: A direct synthesis of α-alkoxy and α-amino ester derivatives by direct reductive coupling of widely available, stable α-keto esters and protic pronucleophiles is described (see scheme; X = OR, NR(2)). The method serves as a convenient nonmetal alternative to X-H insertion by diazo decomposition.

Effects of gabapentin and trazodone on electroretinographic responses in clinically normal dogs.

OBJECTIVE: To compare electroretinographic (ERG) responses obtained in dogs before and after oral administration of gabapentin, trazodone, and a combination of both medications. ANIMALS: 12 clinically normal dogs. PROCEDURES: A short-protocol ERG with 20 minutes of dark adaption was recorded for all dogs to establish baseline ERG responses. Dogs then received gabapentin (approx 30 mg/kg), trazadone (approx 20 mg/kg or approx 5 mg/kg), or a combination of gabapentin (approx 20 mg/kg) and trazodone (approx 5 mg/kg) orally, and the same ERG protocol was repeated 2 hours later. Dogs were given a washout period of at least 1 week between treatments. RESULTS: a-Wave amplitudes were significantly (P = 0.018) decreased after administration of the combination of gabapentin and trazodone. b-Wave amplitudes were significantly decreased after administration of the 20-mg/kg dose of trazodone (P = 0.006) and after administration of the combination of gabapentin and trazodone (P = 0.002). Heavier dogs that received higher total doses of trazodone had decreases in a-wave amplitude after administration of the 20-mg/kg dose of trazodone and in b-wave amplitude after administration of the 5-mg/kg dose of trazodone. CLINICAL RELEVANCE: High doses of trazodone and the combination of gabapentin and trazodone significantly decreased a-wave and b-wave amplitudes in clinically normal dogs. However, the effects on retinal responses had little clinical importance. Therefore, these medications can be used safely in a clinical setting; however, further studies are needed in dogs with retinal disease.

Easing or tightening control strategies: determination of COVID-19 parameters for an agent-based model.

Some agent-based models have been developed to estimate the spread progression of coronavirus disease 2019 (COVID-19) and to evaluate strategies aimed to control the outbreak of the infectious disease. Nonetheless, COVID-19 parameter estimation methods are limited to observational epidemiologic studies which are essentially aggregated models. We propose a mathematical structure to determine parameters of agent-based models accounting for the mutual effects of parameters. We then use the agent-based model to assess the extent to which different control strategies can intervene the transmission of COVID-19. Easing social distancing restrictions, opening businesses, speed of enforcing control strategies, quarantining family members of isolated cases on the disease progression and encouraging the use of facemask are the strategies assessed in this study. We estimate the social distancing compliance level in Sydney greater metropolitan area and then elaborate the consequences of moderating the compliance level in the disease suppression. We also show that social distancing and facemask usage are complementary and discuss their interactive effects in detail.

Antiplatelet medications and risk of intracranial hemorrhage in patients with metastatic brain tumors.

Although intracranial hemorrhage (ICH) is frequent in the setting of brain metastases, there are limited data on the influence of antiplatelet agents on the development of brain tumor-associated ICH. To evaluate whether the administration of antiplatelet agents increases the risk of ICH, we performed a matched cohort analysis of patients with metastatic brain tumors with blinded radiology review. The study population included 392 patients with metastatic brain tumors (134 received antiplatelet agents and 258 acted as controls). Non-small cell lung cancer was the most common malignancy in the cohort (74.0%), followed by small cell lung cancer (9.9%), melanoma (4.6%), and renal cell cancer (4.3%). Among those who received an antiplatelet agent, 86.6% received aspirin alone and 23.1% received therapeutic anticoagulation during the study period. The cumulative incidence of any ICH at 1 year was 19.3% (95% CI, 14.1-24.4) in patients not receiving antiplatelet agents compared with 22.5% (95% CI, 15.2-29.8; P = .22, Gray test) in those receiving antiplatelet agents. The cumulative incidence of major ICH was 5.4% (95% CI, 2.6-8.3) among controls compared with 5.5% (95% CI, 1.5-9.5; P = .80) in those exposed to antiplatelet agents. The combination of anticoagulation plus antiplatelet agents did not increase the risk of major ICH. The use of antiplatelet agents was not associated with an increase in the incidence, size, or severity of ICH in the setting of brain metastases.

Expanding the toolbox of metabolically stable lipid prodrug strategies.

Nucleoside- and nucleotide-based therapeutics are indispensable treatment options for patients suffering from malignant and viral diseases. These agents are most commonly administered to patients as prodrugs to maximize bioavailability and efficacy. While the literature provides a practical prodrug playbook to facilitate the delivery of nucleoside and nucleotide therapeutics, small context-dependent amendments to these popular prodrug strategies can drive dramatic improvements in pharmacokinetic (PK) profiles. Herein we offer a brief overview of current prodrug strategies, as well as a case study involving the fine-tuning of lipid prodrugs of acyclic nucleoside phosphonate tenofovir (TFV), an approved nucleotide HIV reverse transcriptase inhibitor (NtRTI) and the cornerstone of combination antiretroviral therapy (cART). Installation of novel lipid terminal motifs significantly reduced fatty acid hepatic ω-oxidation while maintaining potent antiviral activity. This work contributes important insights to the expanding repertoire of lipid prodrug strategies in general, but particularly for the delivery and distribution of acyclic nucleoside phosphonates.

Synthesis and Evaluation of Novel Tetrahydronaphthyridine CXCR4 Antagonists with Improved Drug-like Profiles.

Our first-generation CXCR4 antagonist TIQ15 was rationally modified to improve drug-like properties. Introducing a nitrogen atom into the aromatic portion of the tetrahydroisoquinoline ring led to several heterocyclic variants including the 5,6,7,8-tetrahydro-1,6-naphthyridine series, greatly reducing the inhibition of the CYP 2D6 enzyme. Compound 12a demonstrated the best overall properties after profiling a series of isomeric tetrahydronaphthyridine analogues in a battery of biochemical assays including CXCR4 antagonism, CYP 2D6 inhibition, metabolic stability, and permeability. The butyl amine side chain of 12a was substituted with various lipophilic groups to improve the permeability. These efforts culminated in the discovery of compound 30 as a potent CXCR4 antagonist (IC50 = 24 nM) with diminished CYP 2D6 activity, improved PAMPA permeability (309 nm/s), potent inhibition of human immunodeficiency virus entry (IC50 = 7 nM), a cleaner off-target in vitro safety profile, lower human ether a-go-go-related gene channel activity, and higher oral bioavailability in mice (% FPO = 27) compared to AMD11070 and TIQ15.

Sequestration and remobilization of radioiodine (129I) by soil organic matter and possible consequences of the remedial action at Savannah River Site.

In order to investigate the distributions and speciation of (129)I (and (127)I) in a contaminated F-Area groundwater plume of the Savannah River Site that cannot be explained by simple transport models, soil resuspension experiments simulating surface runoff or stormflow and erosion events were conducted. Results showed that 72-77% of the newly introduced I(-) or IO(3)(-) were irreversibly sequestered into the organic-rich riparian soil, while the rest was transformed by the soil into colloidal and truly dissolved organo-iodine, resulting in (129)I remobilization from the soil greatly exceeding the 1 pCi/L drinking water permit. This contradicts the conventional view that only considers I(-) or IO(3)(-) as the mobile forms. Laboratory iodination experiments indicate that iodine likely covalently binds to aromatic structures of the soil organic matter (SOM). Under very acidic conditions, abiotic iodination of SOM was predominant, whereas under less acidic conditions (pH ≥5), microbial enzymatically assisted iodination of SOM was predominant. The organic-rich soil in the vadose zone of F-Area thus acts primarily as a "sink," but may also behave as a potentially important vector for mobile radioiodine in an on-off carrying mechanism. Generally the riparian zone provides as a natural attenuation zone that greatly reduces radioiodine release.

Facemask and social distancing, pillars of opening up economies.

The COVID-19 pandemic has caused severe health and economic impacts globally. Strategies to safely reopen economies, travel and trade are a high priority. Until a reliable vaccine is available, non-pharmaceutical techniques are the only available means of disease control. In this paper, we aim to evaluate the extent to which social distancing (SD) and facemask (FM) use can mitigate the transmission of COVID-19 when restrictions are lifted. We used a microsimulation activity-based model for Sydney Greater Metropolitan Area, to evaluate the power of SD and FM in controlling the pandemic under numerous scenarios. The hypothetical scenarios are designed to picture feasible futures under different assumptions. Assuming that the isolation of infected cases and the quarantining of close contacts are in place, different numerical tests are conducted and a full factorial two-way MANOVA test is used to evaluate the effectiveness of the FM and SD control strategies. The main and interactive effects of the containment strategies are evaluated by the total number of infections, percentage of infections reduction, the time it takes to get the pandemic under control, and the intensity of active cases.