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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Amino-Heterocycle Tetrahydroisoquinoline CXCR4 Antagonists with Improved ADME Profiles via Late-Stage Buchwald Couplings.

This work surveys a variety of diamino-heterocycles as an isosteric replacement for the piperazine substructure of our previously disclosed piperarinyl-tetrahydroisoquinoline containing CXCR4 antagonists. A late-stage Buchwald coupling route was developed for rapid access to final compounds from commercial building blocks. Among 13 analogs in this study, compound 31 embodying an aza-piperazine linkage was found to have the best overall profile with potent CXCR4 inhibitory activity and favorable in vitro absorption, distribution, metabolism, and excretion (ADME) properties. An analysis of the calculated physiochemical parameters (ROF, cLogD) and the experimental ADME attributes of the analogs lead to the selection of 31 for pharmacokinetic studies in mice. Compared with the clinical compound AMD11070, compound 31 has no CYP450 3A4 or 2D6 inhibition, higher metabolic stability and PAMPA permeability, greatly improved physiochemical parameters, and superior oral bioavailability (%F = 24). A binding rationale for 31 within CXCR4 was elucidated from docking and molecular simulation studies.

ω-Functionalized Lipid Prodrugs of HIV NtRTI Tenofovir with Enhanced Pharmacokinetic Properties.

Tenofovir (TFV) is the cornerstone nucleotide reverse transcriptase inhibitor (NtRTI) in many combination antiretroviral therapies prescribed to patients living with HIV/AIDS. Due to poor cell permeability and oral bioavailability, TFV is administered as one of two FDA-approved prodrugs, both of which metabolize prematurely in the liver and/or plasma. This premature prodrug processing depletes significant fractions of each oral dose and causes toxicity in kidney, bone, and liver with chronic administration. Although TFV exalidex (TXL), a phospholipid-derived prodrug of TFV, was designed to address this issue, clinical pharmacokinetic studies indicated substantial hepatic extraction, redirecting clinical development of TXL toward HBV. To circumvent this metabolic liability, we synthesized and evaluated ω-functionalized TXL analogues with dramatically improved hepatic stability. This effort led to the identification of compounds 21 and 23, which exhibited substantially longer t1/2 values than TXL in human liver microsomes, potent anti-HIV activity in vitro, and enhanced pharmacokinetic properties in vivo.

Special Considerations for Supportive Care and Management of Complications in Elderly Patients With Multiple Myeloma.

Multiple myeloma is a progressive and incurable hematologic malignancy. It is predominantly a disease of older individuals, with a third of these patients considered to be elderly. In recent years, there has been a focus and emphasis on identifying and stratifying patients based on their functional status and frailty. There are several hallmark complications of the disease-hypercalcemia, renal insufficiency, anemia, bone pain-along with thromboembolism and compromised immunity that are common in patients with multiple myeloma. Due to the wide range of patient ages and functional status, there are, accordingly, different considerations for management of the above complications based on numerous factors, including frailty status. This review focuses on considerations and management of common complications of multiple myeloma in elderly patients. These include renal failure, skeletal complications, anemia, thromboembolism, and infectious complications.

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.

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.

Cause and Treatment of Exophthalmos in Aged Cotton Rats (Sigmodon hispidus).

Aged cotton rats (Sigmodon hispidus) from an established breeding colony displayed signs of spontaneous exophthalmos. Of a total of 118 colony animals that were older than 6 mo of age, 37 (31%) displayed signs of exophthalmos. These rats were clinically healthy and had no other signs of disease. Ophthalmic exams, molecular and microbiologic testing, and histopa- thology were performed to determine the cause of the exophthalmos and to provide appropriate treatment. Environmental monitoring records were also reviewed for vivarium rooms in which the cotton rats were housed. Histopathology findings supported that the exophthalmos in these cotton rats was secondary to retro-orbital thrombosis associated with cardiomyopathy. The exophthalmic eyes were treated by either removal of the affected eye (enucleation) or surgical closure of the eyelids (temporary tarsorraphy). Enucleation of the exophthalmic eye was the best intervention for these aged cotton rats. These findings demonstrate the potential for a high incidence of ocular problems occurring secondary to cardiomyopathy in aged cotton rats. Enucleation as a therapeutic intervention for exophthalmic eyes in aged cotton rats prolongs the morbidity-free time span during which these aged animals can be used experimentally.

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.

Small molecule and peptide-based CXCR4 modulators as therapeutic agents. A patent review for the period from 2010 to 2018.

Introduction: The chemokine receptor CXCR4 has been under intense study due to the central role it plays in immune system regulation and the pathology of many human diseases. The FDA approval of the first CXCR4 antagonist drug Plerixafor (i.e. AMD3100, Mozobil®) ushered in an increase in patent activity covering CXCR4 based therapeutic agents over the past decade.Areas covered: This article describes patent documents published during the period of 2010 through 2018 for both small molecules and peptide-based CXCR4 modulators as therapeutic agents. There is an expansion of intellectual property (IP) around existing and new small molecules of clinical interest, including new chemotypes featuring aromatic and aliphatic heterocycles. There is also significant IP covering peptide-based therapeutics, although about half as many in number as those covering small molecules.Expert opinion: In the last decade there has been significant interest in modulators of the CXCR4 receptor, as gauged by the number of patent filings and clinical investigations targeting this receptor for human disease intervention. Seven of the many CXCR4 modulators described herein, that are currently in human clinical trials, are likely to spur the creation of other FDA approved therapeutics in the near future, most likely as immune and oncology drugs.