Publications by authors named "Mark Reed"

175 Publications

Results of a Randomized Trial of Screening, Brief Intervention, and Referral to Treatment (SBIRT) to Reduce Alcohol Misuse Among Active-Duty Military Personnel.

J Stud Alcohol Drugs 2021 Mar;82(2):269-278

Naval Health Research Center, San Diego, California.

Objective: Rates of heavy alcohol use among active-duty military personnel in the United States are high and negatively affect individuals within the service branches. This study tested the effectiveness of a military-focused screening, brief intervention, and referral to treatment (SBIRT) intervention for reducing risky alcohol use among active-duty patients.

Method: We used a randomized, parallel, two-group design to test the effectiveness of the SBIRT intervention in a convenience sample of service members recruited from the emergency department of a military hospital. A total of 791 participants were randomized to the SBIRT or usual care conditions, and 472 participants (59.7%) completed a 6-month follow-up. Fifteen percent of the sample was female. Self-reported Alcohol Use Disorders Identification Test (AUDIT), controlled drinking self-efficacy (CDSE), and readiness to change drinking behaviors were assessed at baseline and follow-up.

Results: Among higher risk participants (i.e., AUDIT ≥8), results of a complete case analysis showed a significant reduction in scores on the AUDIT-C (consumption questions from the AUDIT) and a significant increase in CDSE. Null findings were observed for intent-to-treat analyses testing the effectiveness of the SBIRT intervention; significant decreases in AUDIT and AUDIT-C scores and significant increases in CDSE were observed over time, irrespective of condition assignment for both complete case and intent-to-treat analyses.

Conclusions: Results of a complete case analysis provided some support for the effectiveness of the SBIRT intervention for higher risk participants. The results of the more conservative intent-to-treat analyses did not support any of the study hypotheses. Future SBIRT effectiveness trials should also test electronic SBIRT intervention approaches.
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March 2021

Discovery of a series of 2-((1-phenyl-1H-imidazol-5-yl)methyl)-1H-indoles as indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors.

ChemMedChem 2021 Mar 23. Epub 2021 Mar 23.

University Health Network, Krembil Research Institute, CANADA.

Indoleamine 2,3-dioxygenase 1 (IDO1) is a promising therapeutic target in cancer immunotherapy and neurological disease. Thus, searching for highly active inhibitors for use in human cancers is now a focus of widespread research and development efforts. In this study, we report the structure-based design of 2-(5-imidazolyl)indole derivatives, a series of novel IDO1 inhibitors which have been designed and synthesized based on our previous study using N1-substituted 5-indoleimidazoles. Among these, compound 12f exhibited a strong IDO1 inhibitory activity (IC50 = 0.16 µM, EC50= 0.3 µM). SAR and computational docking simulations suggest that a hydroxyl group favorably interacts with a proximal Ser167 residue in Pocket A, improving IDO1 inhibitory potency. The brain penetrance of potent compounds was estimated by calculation of the Blood Brain Barrier (BBB) Score and Brain Exposure Efficiency (BEE) Score. Many compounds had favorable scores and the most promising compounds, 9d and 12f, were advanced to a pharmacokinetic study which demonstrated that both compounds were brain penetrant. We have thus discovered a flexible scaffold for brain penetrant IDO1 inhibitors, exemplified by several potent, brain penetrant, agents. With this promising scaffold, we provide herein a basis for further development of brain penetrant IDO1 inhibitors.
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http://dx.doi.org/10.1002/cmdc.202100107DOI Listing
March 2021

Furazans in Medicinal Chemistry.

J Med Chem 2021 02 11;64(4):1786-1815. Epub 2021 Feb 11.

Treventis Corporation, Toronto, Ontario M5T 0S8, Canada.

Incorporation of heterocycles into drug molecules can enhance physical properties and biological activity. A variety of heterocyclic groups is available to medicinal chemists, many of which have been reviewed in detail elsewhere. Oxadiazoles are a class of heterocycle containing one oxygen and two nitrogen atoms, available in three isomeric forms. While the 1,2,4- and 1,3,4-oxadiazoles have seen widespread application in medicinal chemistry, 1,2,5-oxadiazoles (furazans) are less common. This Review provides a summary of the application of furazan-containing molecules in medicinal chemistry and drug development programs from analysis of both patent and academic literature. Emphasis is placed on programs that reached clinical or preclinical stages of development. The examples provided herein describe the pharmacology and biological activity of furazan derivatives with comparative data provided where possible for other heterocyclic groups and pharmacophores commonly used in medicinal chemistry.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01901DOI Listing
February 2021

Voice of the Victims: Accounts of Secondary Victimization With the Court System Among Homicide Co-victims.

J Interpers Violence 2021 Jan 29:886260521989732. Epub 2021 Jan 29.

Georgia State University, Atlanta, GA, USA.

The treatment homicide co-victims receive from the criminal justice system often leaves them aggrieved and feeling alienated. A neglected but important area of investigation is the courtroom workgroup's handling of murder cases. This exploratory study examines the nature and extent to which varying secondary victimization experiences are common among co-victims as the murder cases are processed through the court system. The sample consists of 27 co-victims connected to 24 separate cases where the murders occurred in a major metropolitan area in the southeastern United States. Drawing upon focus group data, Nvivo 10 was employed to identify themes that illustrate common secondary victimization experiences among co-victims along with positive and mixed reactions to court processes and personnel. The findings indicate that court requirements to provide notifications are infrequently met and attorney's practice to supply information about case progress and counseling to family members regarding plea-bargaining and sentencing decisions are greatly restrictive. When information is offered, it is often perceived as highly technical and when assistance is provided, it is frequently limited or intermittent. Despite the prevalence of negative experiences, there also were reports of positive interactions with the district attorney and victim advocates. The study concludes by identifying ways in which the courtroom workgroup can uphold the rights afforded to co-victims while at the same time meeting the duties and responsibilities of the workgroup.
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http://dx.doi.org/10.1177/0886260521989732DOI Listing
January 2021

A pilot study of a machine-learning tool to assist in the diagnosis of hand arthritis.

Intern Med J 2020 Dec 20. Epub 2020 Dec 20.

Hollywood Rheumatology, Australia.

Objective: Arthritis is a common condition, which frequently involves the hands. Patients with inflammatory arthritis have been shown to experience significant delays in diagnosis. We sought to develop and test a screening tool combining an image of a patient's hands, a short series of questions, and a single examination technique, to determine the most likely diagnosis in a patient presenting with hand arthritis. Machine learning techniques were used to develop separate algorithms for each component, which were combined to produce a diagnosis.

Methods: 280 consecutive new patients presenting to a Rheumatology practice with hand arthritis were enrolled. Each patient completed a 9-part questionnaire, had photographs taken of each hand, and had a single examination result recorded. The Rheumatologist diagnosis was recorded following a 45-minute consultation. The photograph algorithm was developed from 1000 previous hand images, and machine learning techniques were applied to the questionnaire results, training several models against the diagnosis from the Rheumatologist.

Results: The combined algorithms in this study were able to predict inflammatory arthritis with an accuracy, precision, recall and specificity of 96·8%, 97·2%, 98·6% and 90·5% respectively. Similar results were found when inflammatory arthritis was subclassified into rheumatoid arthritis and psoriatic arthritis. The corresponding figures for osteoarthritis were 79·6%, 85·9%, 61·9% and 92·6%.

Conclusion: This study demonstrates a novel application combining image-processing and a patient questionnaire with applied machine-learning methods, to facilitate the diagnosis of patients presenting with hand arthritis. Preliminary results are encouraging for the application of such techniques in clinical practice. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/imj.15173DOI Listing
December 2020

A Gd@C single-molecule electret.

Nat Nanotechnol 2020 Dec 12;15(12):1019-1024. Epub 2020 Oct 12.

National Laboratory of Solid State Microstructures, Collaborative Innovation Center of Advanced Microstructures, and School of Physics, Nanjing University, Nanjing, China.

Electrets are dielectric materials that have a quasi-permanent dipole polarization. A single-molecule electret is a long-sought-after nanoscale component because it can lead to miniaturized non-volatile memory storage devices. The signature of a single-molecule electret is the switching between two electric dipole states by an external electric field. The existence of these electrets has remained controversial because of the poor electric dipole stability in single molecules. Here we report the observation of a gate-controlled switching between two electronic states in Gd@C. The encapsulated Gd atom forms a charged centre that sets up two single-electron transport channels. A gate voltage of ±11 V (corresponding to a coercive field of ~50 mV Å) switches the system between the two transport channels with a ferroelectricity-like hysteresis loop. Using density functional theory, we assign the two states to two different permanent electrical dipole orientations generated from the Gd atom being trapped at two different sites inside the C cage. The two dipole states are separated by a transition energy barrier of 11 meV. The conductance switching is then attributed to the electric-field-driven reorientation of the individual dipole, as the coercive field provides the necessary energy to overcome the transition barrier.
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http://dx.doi.org/10.1038/s41565-020-00778-zDOI Listing
December 2020

Extending Voronoi-diagram based modeling of oil slick spreading to surface tension-viscous spreading regime.

Mar Pollut Bull 2020 Nov 11;160:111663. Epub 2020 Sep 11.

Department of Environmental Technology, SINTEF Materials and Chemistry, 7465 Trondheim, Norway.

An earlier paper demonstrated a methodology for modeling the spreading process with a Gaussian random walk procedure, but was limited to the gravity-viscous spreading regime. Here we extend the methodology of representing spread and transport of oil slicks on calm sea surface by updated Voronoi diagrams to account for the surface tension-viscous spreading regime as well. We have utilized the analogy between diffusion and spreading processes by defining a step length for the particle-based random walk scheme. In this study, calculation of the diffusive length is improved by including the surface tension term in the numerical solution method. The results from the numerical simulation of the spreading oil slick agree very well with the analytical solutions. The solution is robust in that good agreement is achieved for a large range of model and numerical solution parameters. This modeling procedure remains valid only for passive, quiescent spreading. The inclusion of spreading due to important horizontal and vertical turbulent shear processes in the Voronoi diagram paradigm remains a challenge for future work.
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http://dx.doi.org/10.1016/j.marpolbul.2020.111663DOI Listing
November 2020

Overcoming the sensitivity vs. throughput tradeoff in Coulter counters: A novel side counter design.

Biosens Bioelectron 2020 Nov 22;168:112507. Epub 2020 Aug 22.

Department of Electrical Engineering, Yale University, New Haven, CT, United States; Department of Applied Physics, Yale University, New Haven, CT, United States. Electronic address:

Microfabricated Coulter counters are attractive for point of care (POC) applications since they are label free and compact. However, these approaches inherently suffer from a trade off between sample throughput and sensitivity. The counter measures a change in impedance due to displaced fluid volume by passing cells, and thus the counter's signal increases with the fraction of the sensing volume displaced. Reducing the size of the sensing region requires reductions in volumetric throughput in the absence of increased hydraulic pressure and sensor bandwidth. The risk of mechanical clog formation, rendering the counter inoperable, increases markedly with reductions in the size of the constriction aperture. We present here a microfluidic coplanar Coulter counter device design that overcomes the problem of constriction clogging while capable of operating in microfluidic channels filled entirely with highly conductive sample. The device utilizes microfabricated planar electrodes projecting into one side of the microfluidic channel and is easily integrated with upstream electronic, hydrodynamic, or other focusing units to produce efficient counting which could allow for dramatically increased volumetric and sample throughput. The design lends itself to simple, cost effective POC applications.
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http://dx.doi.org/10.1016/j.bios.2020.112507DOI Listing
November 2020

Single ascospore detection for the forecasting of stem rot of canola.

Lab Chip 2020 09;20(19):3644-3652

Department of Electrical and Computer Engineering, University of Alberta, Edmonton, AB T6G 1H9, Canada.

Smart-agriculture technologies comprise a set of management systems designed to sustainably increase the efficiency and productivity of farming. In this paper, we present a lab-on-a-chip device that can be employed as a plant disease forecasting tool for canola crop. Our device can be employed as a platform to forecast potential outbreaks of one of the most devastating diseases of canola and other crops, Sclerotinia stem rot. The system consists of a microfluidic chip capable of detecting single airborne Sclerotinia sclerotiorum ascospores. Target ascospores are injected into the chip and selectively captured by dielectrophoresis, while other spores in the sample are flushed away. Afterward, captured ascospores are released into the flow stream of the channel and are detected employing electrochemical impedance spectroscopy and coplanar microelectrodes. Our device provides a design for a low-cost, miniaturized, and automated platform technology for airborne spore detection and disease prevention.
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http://dx.doi.org/10.1039/d0lc00426jDOI Listing
September 2020

Sleep Disturbance Forecasts β-Amyloid Accumulation across Subsequent Years.

Curr Biol 2020 Nov 3;30(21):4291-4298.e3. Epub 2020 Sep 3.

Center for Human Sleep Science, Department of Psychology, University of California, Berkeley, Berkeley Way West, Berkeley, CA 94720, USA; Helen Wills Neuroscience Institute, University of California, Berkeley, 132 Barker Hall, Berkeley, CA 94720, USA. Electronic address:

Experimental sleep-wake disruption in rodents and humans causally modulates β-amyloid (Aβ) dynamics (e.g., [1-3]). This leads to the hypothesis that, beyond cross-sectional associations, impaired sleep structure and physiology could represent prospective biomarkers of the speed with which Aβ accumulates over time. Here, we test the hypothesis that initial baseline measures of non-rapid eye movement (NREM) sleep slow-wave activity (SWA) and sleep quality (efficiency) provide future forecasting sensitivity to the rate of Aβ accumulation over subsequent years. A cohort of clinically normal older adults was assessed using objective sleep polysomnography in combination with longitudinal tracking of Aβ accumulation with [C]PiB positron emission tomography (PET) imaging. Both the proportion of NREM SWA below 1 Hz and the measure of sleep efficiency predicted the speed (slope) of subsequent Aβ deposition over time, and these associations remained robust when taking into account additional cofactors of interest (e.g., age, sex, sleep apnea). Moreover, these measures were specific, such that no other macro- and microphysiological architecture metrics of sleep demonstrated such sensitivity. Our data support the proposal that objective sleep markers could be part of a set of biomarkers that statistically forecast the longitudinal trajectory of cortical Aβ deposition in the human brain. Sleep may therefore represent a potentially affordable, scalable, repeatable, and non-invasive tool for quantifying of Aβ pathological progression, prior to cognitive symptoms of Alzheimer's disease (AD).
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http://dx.doi.org/10.1016/j.cub.2020.08.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642104PMC
November 2020

Small molecule therapeutics for COVID-19: repurposing of inhaled furosemide.

PeerJ 2020 7;8:e9533. Epub 2020 Jul 7.

Krembil Research Institute, University Health Network, Toronto, ON, Canada.

The novel coronavirus SARS-CoV-2 has become a global health concern. The morbidity and mortality of the potentially lethal infection caused by this virus arise from the initial viral infection and the subsequent host inflammatory response. The latter may lead to excessive release of pro-inflammatory cytokines, IL-6 and IL-8, as well as TNF-α ultimately culminating in hypercytokinemia ("cytokine storm"). To address this immuno-inflammatory pathogenesis, multiple clinical trials have been proposed to evaluate anti-inflammatory biologic therapies targeting specific cytokines. However, despite the obvious clinical utility of such biologics, their specific applicability to COVID-19 has multiple drawbacks, including they target only one of the multiple cytokines involved in COVID-19's immunopathy. Therefore, we set out to identify a small molecule with broad-spectrum anti-inflammatory mechanism of action targeting multiple cytokines of innate immunity. In this study, a library of small molecules endogenous to the human body was assembled, subjected to in silico molecular docking simulations and a focused in vitro screen to identify anti-pro-inflammatory activity via interleukin inhibition. This has enabled us to identify the loop diuretic furosemide as a candidate molecule. To pre-clinically evaluate furosemide as a putative COVID-19 therapeutic, we studied its anti-inflammatory activity on RAW264.7, THP-1 and SIM-A9 cell lines stimulated by lipopolysaccharide (LPS). Upon treatment with furosemide, LPS-induced production of pro-inflammatory cytokines was reduced, indicating that furosemide suppresses the M1 polarization, including IL-6 and TNF-α release. In addition, we found that furosemide promotes the production of anti-inflammatory cytokine products (IL-1RA, arginase), indicating M2 polarization. Accordingly, we conclude that furosemide is a reasonably potent inhibitor of IL-6 and TNF-α that is also safe, inexpensive and well-studied. Our pre-clinical data suggest that it may be a candidate for repurposing as an inhaled therapy against COVID-19.
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http://dx.doi.org/10.7717/peerj.9533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350920PMC
July 2020

Is Inhaled Furosemide a Potential Therapeutic for COVID-19?

Am J Med Sci 2020 09 1;360(3):216-221. Epub 2020 Jun 1.

Krembil Research Institute, University Health Network, Toronto, Ontario, Canada; Faculty of Medicine, University of Toronto, Medical Sciences Building, Toronto, Ontario, Canada. Electronic address:

The potentially lethal infection caused by the novel Severe Acute Respiratory Disease Coronavirus-2 (SARS-CoV-2) has evolved into a global crisis. Following the initial viral infection is the host inflammatory response that frequently results in excessive secretion of inflammatory cytokines (e.g., IL-6 and TNFα), developing into a self-targeting, toxic "cytokine storm" causing critical pulmonary tissue damage. The need for a therapeutic that is available immediately is growing daily but the de novo development of a vaccine may take years. Therefore, repurposing of approved drugs offers a promising approach to address this urgent need. Inhaled furosemide, a small molecule capable of inhibiting IL-6 and TNFα, may be an agent capable of treating the Coronavirus Disease 2019 cytokine storm in both resource-rich and developing countries. Furosemide is a "repurpose-able" small molecule therapeutics, that is safe, easily synthesized, handled, and stored, and is available in reasonable quantities worldwide.
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http://dx.doi.org/10.1016/j.amjms.2020.05.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833957PMC
September 2020

Imaging and Diagnostic Challenges in a Patient With Refractory Hypoglycemia Caused by Insulinomas Related to Multiple Endocrine Neoplasia Type 1.

Cureus 2020 May 20;12(5):e8208. Epub 2020 May 20.

Internal Medicine, University of Missouri Health Care, Columbia, USA.

Insulinoma is a rare neuroendocrine tumor. It may occur sporadically or as part of the genetic tumor syndrome multiple endocrine neoplasia type 1 (MEN1). Diagnosis is challenging because of the small size of insulin producing tumors that lead to hyperinsulinemia. Advances in imaging modalities may provide more accurate diagnosis of primary tumors, metastasis, and tumor functional status. Advances allow for improved medical and surgical management with new tools for research of neuroendocrine tumors. Surgical excision of the primary tumor is often curative; however, insulinomas in MEN1 syndrome are often multifocal with a high rate of recurrence presenting unique challenges in management. Here, we present the case of a 34-year-old male with recurrent hypoglycemic episodes and hyperparathyroidism diagnosed with multiple pancreatic insulinomas secondary to MEN1. Furthermore, we provide a brief review of the literature and discuss the approach to diagnosis and management in patients with MEN1 syndrome and future areas of investigation.
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http://dx.doi.org/10.7759/cureus.8208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305576PMC
May 2020

Continuous Label-Free Electronic Discrimination of T Cells by Activation State.

ACS Nano 2020 07 25;14(7):8646-8657. Epub 2020 Jun 25.

Department of Electrical Engineering, School of Engineering and Applied Sciences, Yale University, New Haven, Connecticut 06511, United States.

The sensitivity and speed with which the immune system reacts to host disruption is unrivaled by any detection method for pathogenic biomarkers or infectious signatures. Engagement of cellular immunity in response to infections or cancer is contingent upon activation and subsequent cytotoxic activity by T cells. Thus, monitoring T cell activation can reliably serve as a metric for disease diagnosis as well as therapeutic prognosis. Rapid and direct quantification of T cell activation states, however, has been hindered by challenges associated with antigen target identification, labeling requirements, and assay duration. Here we present an electronic, label-free method for simultaneous separation and evaluation of T cell activation states. Our device utilizes a microfluidic design integrated with nanolayered electrode structures for dielectrophoresis (DEP)-driven discrimination of activated naïve T cells at single-cell resolution and demonstrates rapid (<2 min) separation of T cells at high single-pass efficiency as quantified by an on-chip Coulter counter module. Our device represents a microfluidic tool for electronic assessment of immune activation states and, hence, a portable diagnostic for quantitative evaluation of immunity and disease state. Further, its ability to achieve label-free enrichment of activated immune cells promises clinical utility in cell-based immunotherapies.
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http://dx.doi.org/10.1021/acsnano.0c03018DOI Listing
July 2020

Fate and behavior of Sanchi oil spill transported by the Kuroshio during January-February 2018.

Mar Pollut Bull 2020 Mar 22;152:110917. Epub 2020 Jan 22.

National Satellite Ocean Application Service (NSOAS), MNR, Beijing 100081, China.

The fate and behavior of the Sanchi oil spill during January-February 2018 was simulated by coupling an oil spill model and satellite observations with meteo-oceanographic forcing. Extensive validation tests were performed for winds, currents, surface slick, stranded oil and oil fate. A series of hindcast experiments was designed to take into account the uncertainties in oil amount, environmental forcing and model parameters. The simulations confirmed that the stable large-scale Kuroshio acted as the primary driving force. Most oil followed the Kuroshio's large-meander path, rapidly passing through the East China Sea to the waters south of Japan. The wind, appearing as the secondary transport factor, did not change the path of this large-scale current, but did contribute to the drift of surface oil. The different fates for heavy fuel oil and condensate in the accident were also compared quantitatively and discussed in this study.
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http://dx.doi.org/10.1016/j.marpolbul.2020.110917DOI Listing
March 2020

Self-Reported Drug Use and Hearing Measures in Young Adults.

J Speech Lang Hear Res 2020 03 12;63(3):885-895. Epub 2020 Mar 12.

College of Health and Human Services, San Diego State University, CA.

Purpose The purpose of this study was to examine marijuana or other substance use on pure-tone thresholds and distortion product otoacoustic emissions (DPOAEs) in young adults. Method Young adults ( = 243; 182 women, 61 men; = 20.9 years, = 2.7 years) participated in this study. Survey data included personal music system use, marijuana use, and misuse of prescription medications. Otoscopy, tympanometry, pure-tone audiometry, and DPOAEs were obtained. Pure tones from octave frequencies of 0.25 through 8 kHz were obtained, and DPOAEs were recorded between f frequencies of 1 and 6 kHz using two continuously presented stimulus tones swept in frequency. Results Those who reported marijuana or stimulant use had similar pure-tone averages (0.5, 1, 2, and 4 kHz) compared to those who reported never using marijuana or stimulants. Women who reported marijuana use in the past 30 days > two times had statistically significant higher mean DPOAEs compared to women who reported ≤ two times or no marijuana use in the past 30 days. Men, however, who reported marijuana use in the past 30 days > two times had lower, but not statistically significant, mean DPOAEs compared to men who reported ≤ two times or no marijuana use in the past 30 days. Women who reported ever using stimulants had statistically significant higher mean DPOAEs compared to women who reported never using stimulants; for men, mean DPOAEs were similar between those who reported ever using stimulants and those who never used stimulants. Conclusions The results of this study demonstrate different and contradictory associations between marijuana use, stimulant use, and hearing outcomes as a function of sex. Future research is needed to explore these associations utilizing larger sample sizes while accounting for additional harmful exposures to other noise exposures.
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http://dx.doi.org/10.1044/2019_JSLHR-19-00180DOI Listing
March 2020

The Brain Exposure Efficiency (BEE) Score.

ACS Chem Neurosci 2020 01 27;11(2):205-224. Epub 2019 Dec 27.

Krembil Research Institute , University Health Network , 60 Leonard Avenue , Toronto , Ontario M5T 2S8 , Canada.

The blood-brain barrier (BBB), composed of microvascular tight junctions and glial cell sheathing, selectively controls drug permeation into the central nervous system (CNS) by either passive diffusion or active transport. Computational techniques capable of predicting molecular brain penetration are important to neurological drug design. A novel prediction algorithm, termed the Brain Exposure Efficiency Score (BEE), is presented. BEE addresses the need to incorporate the role of trans-BBB influx and efflux active transporters by considering key brain penetrance parameters, namely, steady state unbound brain to plasma ratio of drug () and dose normalized unbound concentration of drug in brain (). BEE was devised using quantitative structure-activity relationships (QSARs) and molecular modeling studies on known transporter proteins and their ligands. The developed algorithms are provided as a user-friendly open source calculator to assist in optimizing a brain penetrance strategy during the early phases of small molecule molecular therapeutic design.
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http://dx.doi.org/10.1021/acschemneuro.9b00650DOI Listing
January 2020

Random walk particle-tracking method for modeling changes of sediment characteristics in marine sediments after drilling discharges.

Mar Pollut Bull 2019 Aug 3;145:224-238. Epub 2019 Jun 3.

Department of Environmental Technology, SINTEF Materials and Chemistry, 7465 Trondheim, Norway.

Adverse impacts of drilling discharges on marine benthic environments have been observed since the advent of offshore drilling operations for exploration and production of oil and gas. This study utilizes a marine sediment model based on a system of equations that has been developed earlier to assess environmental impacts of drilling waste discharges. Bioturbation, bio-degradation and natural burial processes are included in the model. The model is based on the diagenetic equations, providing vertical concentration profiles of dissolved oxygen, naturally deposited substances and discharged substances in the marine sediment as a basis for marine risk assessment. The governing equations are solved by a random walk particle-tracking method for each constituent evaluated explicitly in time. The developed model is enhanced with a kernel smoothing method to obtain smooth concentration profiles. Simulation results reveal that the method demonstrates stable behavior for different model parameters, providing a promising alternative to finite difference approaches.
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http://dx.doi.org/10.1016/j.marpolbul.2019.05.039DOI Listing
August 2019

Enhancing Lithium Insertion with Electrostatic Nanoconfinement in a Lithography Patterned Precision Cell.

ACS Nano 2019 Jul 5;13(7):8481-8489. Epub 2019 Jul 5.

Department of Electrical Engineering , Yale University , New Haven , Connecticut 06511 , United States.

The rapidly growing demand for portable electronics, electric vehicles, and grid storage drives the pursuit of high-performance electrical energy storage (EES). A key strategy for improving EES performance is exploiting nanostructured electrodes that present nanoconfined environments of adjacent electrolytes, with the goal to decrease ion diffusion paths and increase active surface areas. However, fundamental gaps persist in understanding the interface-governed electrochemistry in such nanoconfined geometries, in part because of the imprecise and variable dimension control. Here, we report quantification of lithium insertion under nanoconfinement of the electrolyte in a precise lithography-patterned nanofluidic cell. We show a mechanism that enhances ion insertion under nanoconfinement, namely, selective ion accumulation when the confinement length is comparable to the electrical double layer thickness. The nanofabrication approach with uniform and accurate dimensional control provides a versatile model system to explore fundamental mechanisms of nanoscale electrochemistry, which could have an impact on practical energy storage systems.
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http://dx.doi.org/10.1021/acsnano.9b04390DOI Listing
July 2019

Trapping of sub-100 nm nanoparticles using gigahertz acoustofluidic tweezers for biosensing applications.

Nanoscale 2019 Aug;11(31):14625-14634

State Key Laboratory of Precision Measuring Technology & Instruments, College of Precision Instrument and Optoelectronics Engineering, Tianjin University, Tianjin 300072, China.

In this study, we present a nanoscale acoustofluidic trap (AFT) that manipulates nanoparticles in a microfluidic system actuated by a gigahertz acoustic resonator. The AFT generates independent standing closed vortices with high-speed rotation. Via careful design and optimization of geometric confinements, the AFT was able to effectively capture and enrich sub-100 nm nanoparticles with a low power consumption (0.25-5 μW μm-2) and rapid trapping (within 30 s), showing significantly enhanced particle-operating ability as compared to its acoustic and optical counterparts; using specifically functionalized nanoparticles (SFNPs) to selectively capture target molecules from the sample, the AFT led to the molecular concentration enhancement of ∼200 times. We investigated the feasibility of the SFNP-assisted AFT preconcentration method for biosensing applications and successfully demonstrated the capability of this method for the detection of serum prostate-specific antigen (PSA). The AFT was prepared via a fully CMOS-compatible process and thus could be conveniently integrated on a single chip, with potential for "lab-on-a-chip" or point-of-care (POC) nanoparticle-based biosensing applications.
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http://dx.doi.org/10.1039/c9nr03529jDOI Listing
August 2019

Headphones and other risk factors for hearing in young adults.

Noise Health 2019 May-Jun;21(100):116-124

School of Speech, Language, and Hearing Sciences, San Diego State University, San Diego, CA, USA.

Background: Personal listening device (PLD) use with headphones is increasing in young adults and in most listening environments occur in background noise. Headphone choice can be important because certain headphones are more effective in limiting background noise than stock earbuds. Binge drinking, marijuana, and hard drug use have also been associated with high-volume PLD use. The purpose of this study was to explore the relationship between preferred headphone type, listening level, and other health risk behaviors.

Methods: Two-hundred and twenty undergraduates were recruited and completed a PLD use and risk behavior survey. Survey data included self-reported alcohol and marijuana use. Bilateral otoscopy, tympanometry, and pure-tone threshold testing (0.25-8 kHz) were completed. Participants listened to one hour of music using preferred headphone type with a probe microphone in the ear canal to measure equivalent continuous sound level (LAeq).

Results: Mean LAeq was similar for the three types of headphones used. Participants who reported higher amounts of drinks per month and smoking marijuana within the last month had significantly higher LAeq levels than those who reported lower amounts of drinks per month and not smoking marijuana in the last month. There was no significant interaction between headphone type and reported drinks per month or marijuana use.

Conclusion: Young adults with normal hearing who have higher preferred listening levels also reported more alcohol and marijuana use, although headphone type was not associated with any of these variables.
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http://dx.doi.org/10.4103/nah.NAH_35_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532785PMC
July 2020

Sensing the electrical activity of single ion channels with top-down silicon nanoribbons.

Nano Futures 2018 Jun 12;2(2). Epub 2018 Jun 12.

Department of Electrical Engineering and Computer Science, University of California, Irvine, CA, United States of America.

Using top-down fabricated silicon nanoribbons, we measure the opening and closing of ion channels alamethicin and gramicidin A. A capacitive model of the system is proposed to demonstrate that the geometric capacitance of the nanoribbon is charged by ion channel currents. The integration of top-down nanoribbons with electrophysiology holds promise for integration of electrically active living systems with artificial electronics.
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http://dx.doi.org/10.1088/2399-1984/aac737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6390970PMC
June 2018

Improving oil spill trajectory modelling in the Arctic.

Mar Pollut Bull 2019 Mar 19;140:65-74. Epub 2019 Jan 19.

SINTEF Ocean, Trondheim, Norway.

As petroleum development and other activities move further north, the potential for oil spills in ice-covered waters is of great concern. As a tool for contingency planning and forecasting during response, oil spill models play a key role. With the development of new, high-resolution coupled ice-ocean models, better predictions of sea ice are becoming available. We have updated the OSCAR oil spill model to use sea-ice velocity and coverage fields from coupled ice-ocean models to improve simulation of oil fate and transport in ice-covered waters. We describe the implementation of oil transport in the presence of ice, and demonstrate the improvement by considering three case studies. We find clear improvement when taking ice velocity from a coupled ice-ocean model into account, compared to a heuristic model that uses surface current and wind velocity. The difference is found to be especially important in a response situation near the marginal ice zone.
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http://dx.doi.org/10.1016/j.marpolbul.2019.01.019DOI Listing
March 2019

A nanofluidic ion regulation membrane with aligned cellulose nanofibers.

Sci Adv 2019 Feb 22;5(2):eaau4238. Epub 2019 Feb 22.

Department of Materials Science and Engineering, University of Maryland College Park, College Park, MD 20742, USA.

The advancement of nanofluidic applications will require the identification of materials with high-conductivity nanoscale channels that can be readily obtained at massive scale. Inspired by the transpiration in mesostructured trees, we report a nanofluidic membrane consisting of densely packed cellulose nanofibers directly derived from wood. Numerous nanochannels are produced among an expansive array of one-dimensional cellulose nanofibers. The abundant functional groups of cellulose enable facile tuning of the surface charge density via chemical modification. The nanofiber-nanofiber spacing can also be tuned from ~2 to ~20 nm by structural engineering. The surface-charge-governed ionic transport region shows a high ionic conductivity plateau of ~2 mS cm (up to 10 mM). The nanofluidic membrane also exhibits excellent mechanical flexibility, demonstrating stable performance even when the membrane is folded 150°. Combining the inherent advantages of cellulose, this novel class of membrane offers an environmentally responsible strategy for flexible and printable nanofluidic applications.
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http://dx.doi.org/10.1126/sciadv.aau4238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386557PMC
February 2019

Prevalence and correlates of "popper" (amyl nitrite inhalant) use among HIV-positive Latinos living in the U.S.-Mexico border region.

J Ethn Subst Abuse 2020 Jul-Sep;19(3):435-452. Epub 2019 Jan 7.

School of Social Work, San Diego State University, San Diego, California.

Poppers (nitrite inhalants) are legal, commonly used by men who have sex with men, and associated with HIV acquisition, yet research is lacking on popper use and associated adverse outcomes. People living with HIV (PLWH) in the U.S.-Mexico border region lead binational lives, including accessing care and having sex and drug use partners on both sides of the border, with broad personal and public health implications. Understanding popper use provides crucial information to guide policy and develop targeted interventions for binational PLWH. We examine prevalence and correlates of popper use among HIV-positive Latinos in the border region, an underserved population at risk for poor health outcomes. This cross-sectional study recruited a convenience sample from agencies in San Diego and Tijuana to complete quantitative surveys. Participants ( = 121) were primarily male (82.6%) and gay/bisexual (62%). Lifetime substance use (excluding cannabis) was reported by 72% of participants, and 25.6% reported lifetime popper use. Individuals recruited in the U.S. were significantly more likely to report use of poppers than were participants recruited in Mexico. Our regression model found that identifying as gay/bisexual and having bought, sold, or traded sex for money, drugs, or other goods were independently associated with popper use. Findings shed light on the profile of individuals who use poppers and lay the foundation for further research to understand the context of popper use as it relates to high-risk behavior among PLWH in this region of high transborder mobility. Binational collaborative approaches are needed to improve regional HIV care outcomes and reduce transmission risk.
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http://dx.doi.org/10.1080/15332640.2018.1540955DOI Listing
January 2019

Can Self-Reported Personal Audio System Volume Predict Actual Listening Levels in Young Adults?

J Am Acad Audiol 2019 02 10;30(2):153-161. Epub 2018 Jan 10.

School of Social Work, San Diego State University, San Diego, CA.

Background: Most young adults report using personal audio systems (PAS) with earphones as part of their daily activities. PAS exposure is intermittent and research examining the levels these young adults are listening to is increasing. On average, preferred listening levels are below what would be considered at risk in an occupational setting.

Purpose: The purpose of this study was to evaluate how two questions predicted preferred listening level in young adults with normal hearing; specifically, whether these young adults could identify if they listen at a high level or not.

Study Sample: One hundred and sixty young adults (111 women, 49 men) with normal hearing completed a questionnaire that had questions about PAS listening habits and then had preferred listening level assessed using a probe microphone system while listening to 1 hour of music through earphones.

Data Collection And Analysis: Otoscopy, tympanometry, and pure-tone thresholds were completed in a randomly determined test ear. As part of the Risk Factors Survey, two closed-set questions were completed. First, "For a typical day, what is the most common volume used during this day?" with the following response options "Low," "Medium/Comfortable," "Loud," or "Very Loud." And second, "Do you listen to your personal music system at a volume where you…" with the following response options "Easily hear people," "Have a little trouble hearing people," "Have a lot of trouble hearing people," or "Cannot hear people." Using a probe microphone, chosen listening level (A-weighted, diffuse-field correction and a conversion to free-field equivalent [L]) was calculated over 1 hour while the participant listened to music with earphones. Sensitivity and specificity were determined to see how well young adults could identify themselves as listening at a high level (>85 dBA) or not. Linear regression analyses were performed to determine the amount of variance explained by the two survey questions as predictors of measured L.

Results: Almost half of the participants reported a longest single use of a PAS as <1 hour daily and more than half reported listening at a medium/comfortable volume and had a little trouble hearing people. Mean L was 72.5 dBA, with young adult men having a significantly higher mean L (76.5 dBA) compared with young adult women (70.8 dBA). Sensitivity was 88.9% and specificity was 70.6% for the question asking about volume on a typical day. For the question asking about being able to hear other people while listening to music sensitivity was 83.3% and specificity was 82.5%. Two variables, listening volume on a typical day and sex, accounted for 28.4% of the variability associated with L; the answer to the question asking about being able to hear others and sex accounted for 22.8% of the variability associated with L.

Conclusions: About 11% of young adults in the present study listen to a PAS with earphones at a high level (>85 dBA) while in a quiet background. The participants who do report listening at a high level, however, do well at self-reporting this risk behavior in survey questions.
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http://dx.doi.org/10.3766/jaaa.17104DOI Listing
February 2019

A complex consultation.

Authors:
Mark G Reed

Br J Gen Pract 2018 11;68(676):519

Woodley. Email:

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http://dx.doi.org/10.3399/bjgp18X699521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6193780PMC
November 2018

A Monolayer of Primary Colonic Epithelium Generated on a Scaffold with a Gradient of Stiffness for Drug Transport Studies.

Anal Chem 2018 11 30;90(22):13331-13340. Epub 2018 Oct 30.

Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States and North Carolina State University, Raleigh, North Carolina 27607, United States.

Animal models are frequently used for in vitro physiologic and drug transport studies of the colon, but there exists significant pressure to improve assay throughput as well as to achieve tighter control of experimental variables than can be achieved with animals. Thus, development of a primary in vitro colonic epithelium cultured as high resistance with transport protein expression and functional behavior similar to that of a native colonic would be of enormous value for pharmaceutical research. A collagen scaffold, in which the degree of collagen cross-linking was present as a gradient, was developed to support the proliferation of primary colonic cells. The gradient of cross-linking created a gradient in stiffness across the scaffold, enabling the scaffold to resist deformation by cells. mRNA expression and quantitative proteomic mass spectrometry of cells growing on these surfaces as a monolayer suggested that the transporters present were similar to those in vivo. Confluent monolayers acted as a barrier to small molecules so that drug transport studies were readily performed. Transport function was evaluated using atenolol (a substrate for passive paracellular transport), propranolol (a substrate for passive transcellular transport), rhodamine 123 (Rh123, a substrate for P-glycoprotein), and riboflavin (a substrate for solute carrier transporters). Atenolol was poorly transported with an apparent permeability ( P) of <5 × 10 cm s, while propranolol demonstrated a P of 9.69 × 10 cm s. Rh123 was transported in a luminal direction ( P/ P = 7) and was blocked by verapamil, a known inhibitor of P-glycoprotein. Riboflavin was transported in a basal direction, and saturation of the transporter was observed at high riboflavin concentrations as occurs in vivo. It is anticipated that this platform of primary colonic epithelium will find utility in drug development and physiological studies, since the tissue possesses high integrity and active transporters and metabolism similar to that in vivo.
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http://dx.doi.org/10.1021/acs.analchem.8b02845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339567PMC
November 2018

Building university-based boundary organisations that facilitate impacts on environmental policy and practice.

PLoS One 2018 13;13(9):e0203752. Epub 2018 Sep 13.

Centre for Rural Economy and Institute for Agri-Food Research and Innovation, School of Natural and Environmental Sciences, Newcastle University, Newcastle, United Kingdom.

Responding to modern day environmental challenges for societal well-being and prosperity necessitates the integration of science into policy and practice. This has spurred the development of novel institutional structures among research organisations aimed at enhancing the impact of environmental science on policy and practice. However, such initiatives are seldom evaluated and even in cases where evaluations are undertaken, the results are rarely made publicly available. As such there is very little empirically grounded guidance available to inform other organisations in this regard. To help address this, the aim of this study is to evaluate the Baltic Eye Project at Stockholm University-a unique team consisting of researchers from different fields, science communicators, journalists and policy analysts-working collectively to support evidence-informed decision-making relating to the sustainable management of the Baltic Sea environment. Specifically, through qualitative interviews, we (1) identify the impacts achieved by the Baltic Eye Project; (2) understand the challenges and barriers experienced throughout the Baltic Eye Project; and (3) highlight the key features that are needed within research organisations to enhance the impact of science on policy and practice. Results show that despite only operating for three years, the Baltic Eye Project has achieved demonstrable impacts on a range of levels: impacts on policy and practice, impacts to individuals working within the organisation and impacts to the broader University. We also identify a range of barriers that have limited impacts to date, such as a lack of clear goals at the establishment of the Baltic Eye Project and existing metrics of academic impact (e.g. number of publications). Finally, based on the experiences of employees at the Baltic Eye Project, we identify the key organisational, individual, financial, material, practical, political, and social features of university-based boundary organisations that have impact on policy and practice. In doing so this paper provides empirically-derived guidance to help other research organisations increase their capacity to achieve tangible impacts on environmental policy and practice.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0203752PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136716PMC
February 2019

Stakeholder engagement in the study and management of invasive alien species.

J Environ Manage 2019 Jan 1;229:88-101. Epub 2018 Aug 1.

Centre for Invasion Biology, Department of Botany and Zoology, Stellenbosch University, Matieland 7602, South Africa.

Invasive alien species are a major driver of global environmental change and a range of management interventions are needed to manage their effects on biodiversity, ecosystem services, human well-being and local livelihoods. Stakeholder engagement is widely advocated to integrate diverse knowledge and perspectives in the management of invasive species and to deal with potential conflicts of interest. We reviewed the literature in the ISI Web of Science on stakeholder engagement (the process of involving stakeholders (actors) in decision making, management actions and knowledge creation) in invasion science to assess and understand what has been done (looking at approaches and methodologies used, stakeholders involved, and outcomes from engagement) and to make recommendations for future work. Research on stakeholder engagement in invasion science has increased over the last decade, helping to improve scientific knowledge and contributing towards policy formulation and co-implementation of management. However, many challenges remain and engagement could be made more effective. For example, most studies engage only one stakeholder group passively using questionnaires, primarily for assessing local knowledge and perceptions. Although useful for management and policy planning, these stakeholders are not active participants and there is no two-way flow of knowledge. To make stakeholder involvement more useful, we encourage more integrative and collaborative engagement to (1) improve co-design, co-creation and co-implementation of research and management actions; (2) promote social learning and provide feedback to stakeholders; (3) enhance collaboration and partnerships beyond the natural sciences and academia (interdisciplinary and transdisciplinary collaboration); and (4) discuss some practical and policy suggestions for improving stakeholder engagement in invasion science research and management. This will help facilitate different stakeholders to work better together, allowing problems associated with biological invasions to be tackled more holistically and successfully.
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http://dx.doi.org/10.1016/j.jenvman.2018.04.044DOI Listing
January 2019