Publications by authors named "Bernard Choi"

188 Publications

Simple methodology to visualize whole-brain microvasculature in three dimensions.

Neurophotonics 2021 Apr 19;8(2):025004. Epub 2021 Apr 19.

University of California, Irvine, Beckman Laser Institute and Medical Clinic, Irvine, California, United States.

To explore brain architecture and pathology, a consistent and reliable methodology to visualize the three-dimensional cerebral microvasculature is beneficial. Perfusion-based vascular labeling is quick and easily deliverable. However, the quality of vascular labeling can vary with perfusion-based labels due to aggregate formation, leakage, rapid photobleaching, and incomplete perfusion. We describe a simple, two-day protocol combining perfusion-based labeling with a two-day clearing step that facilitates whole-brain, three-dimensional microvascular imaging and characterization. The combination of retro-orbital injection of Lectin-Dylight-649 to label the vasculature, the clearing process of a modified iDISCO+ protocol, and light-sheet imaging collectively enables a comprehensive view of the cerebrovasculature. We observed increase in contrast-to-background ratio of Lectin-Dylight-649 vascular labeling over endogenous green fluorescent protein fluorescence from a transgenic mouse model. With light-sheet microscopy, we demonstrate sharp visualization of cerebral microvasculature throughout the intact mouse brain. Our tissue preparation protocol requires fairly routine processing steps and is compatible with multiple types of optical microscopy.
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http://dx.doi.org/10.1117/1.NPh.8.2.025004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056070PMC
April 2021

High-speed quantitative optical imaging of absolute metabolism in the rat cortex.

Neurophotonics 2021 Apr 8;8(2):025001. Epub 2021 Apr 8.

University of California, Beckman Laser Institute, Irvine, California, United States.

Quantitative measures of blood flow and metabolism are essential for improved assessment of brain health and response to ischemic injury. We demonstrate a multimodal technique for measuring the cerebral metabolic rate of oxygen ( ) in the rodent brain on an absolute scale ( ). We use laser speckle imaging at 809 nm and spatial frequency domain imaging at 655, 730, and 850 nm to obtain spatiotemporal maps of cerebral blood flow, tissue absorption ( ), and tissue scattering ( ). Knowledge of these three values enables calculation of a characteristic blood flow speed, which in turn is input to a mathematical model with a "zero-flow" boundary condition to calculate absolute . We apply this method to a rat model of cardiac arrest (CA) and cardiopulmonary resuscitation. With this model, the zero-flow condition occurs during entry into CA. The values calculated with our method are in good agreement with those measured with magnetic resonance and positron emission tomography by other groups. Our technique provides a quantitative metric of absolute cerebral metabolism that can potentially be used for comparison between animals and longitudinal monitoring of a single animal over multiple days. Though this report focuses on metabolism in a model of ischemia and reperfusion, this technique can potentially be applied to far broader types of acute brain injury and whole-body pathological occurrences.
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http://dx.doi.org/10.1117/1.NPh.8.2.025001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027868PMC
April 2021

Cerebral Blood Flow in Chronic Kidney Disease.

J Stroke Cerebrovasc Dis 2021 Mar 10:105702. Epub 2021 Mar 10.

Beckman Laser Institute and Medical Clinic, University of California, 1002 Health Sciences Road East, Irvine, CA 92612, United States; Department of Neurology, University of California Irvine, Orange, CA, United States. Electronic address:

The prevalence of mild cognitive impairment increases with age and is further exacerbated by chronic kidney disease (CKD). CKD is associated with (1) mild cognitive impairment, (2) impaired endothelial function, (3) impaired blood-brain barrier, (4) increased cerebral microhemorrhage burden, (5) increased cerebral blood flow (CBF), (6) impaired cerebral autoregulation, (7) impaired cerebrovascular reactivity, and (8) increased arterial stiffness. We report preliminary findings from our group that demonstrate altered cerebrovascular reactivity in a mouse model of CKD-associated vascular calcification. The CBF of CKD mice increased more quickly in response to hypercapnia (p < 0.05) but then decreased prematurely during hypercapnia challenge (p < 0.05). Together, these results indicate that altered kidney function can lead to alterations in the cerebral microvasculature, and hence brain health.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2021.105702DOI Listing
March 2021

Transcranial chronic optical access to longitudinally measure cerebral blood flow.

J Neurosci Methods 2021 Feb 16;350:109044. Epub 2020 Dec 16.

University of California Irvine, Department of Molecular Biology and Biochemistry, Irvine, 92697, USA; University of California Irvine, Institute for Immunology, Irvine, 92697, USA. Electronic address:

Background: The regulation of cerebral blood flow is critical for normal brain functioning, and many physiological and pathological conditions can have long-term impacts on cerebral blood flow. However, minimally invasive tools to study chronic changes in animal models are limited.

New Method: We developed a minimally invasive surgical technique (cyanoacrylate skull, CAS) allowing us to image cerebral blood flow longitudinally through the intact mouse skull using laser speckle imaging.

Results: With CAS we were able to detect acute changes in cerebral blood flow induced by hypercapnic challenge. We were also able to image cerebral blood flow dynamics with laser speckle imaging for over 100 days. Furthermore, the relative cerebral blood flow remained stable in mice from 30 days to greater than 100 days after the surgery.

Comparison With Existing Methods: Previously, achieving continuous long-term optical access to measure cerebral blood flow in individual vessels in a mouse model involved invasive surgery. In contrast, the CAS technique presented here is relatively non-invasive, as it allows stable optical access through an intact mouse skull.

Conclusions: The CAS technique allows researcher to chronically measure cerebral blood flow dynamics for a significant portion of a mouse's lifespan. This approach may be useful for studying changes in blood flow due to cerebral pathology or for examining the therapeutic effects of modifying cerebral blood flow in mouse models relevant to human disease.
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http://dx.doi.org/10.1016/j.jneumeth.2020.109044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095351PMC
February 2021

BIG DATA … small story.

Authors:
Bernard C K Choi

J Epidemiol Community Health 2021 Mar 28;75(3):309-310. Epub 2020 Oct 28.

Public Health Agency of Canada, Ottawa, Canada

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http://dx.doi.org/10.1136/jech-2020-215752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892384PMC
March 2021

The Canadian Health Clock and health calculators.

Can J Public Health 2020 10 14;111(5):726-736. Epub 2020 Jul 14.

Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

Setting: This paper documents a participatory process of Health Portfolio staff in the design of a clock, and announces the 2020 Canadian Health Clock, with links to numerous online health calculators. The clock is part of the Health Portfolio's celebration activities in 2019 of "100 Years of Health", as the Department of Health was established in Canada in 1919.

Intervention: The intervention was the development of a clock on the Government of Canada website with linkage to calculators as a health promotion tool. The clock was built on the concept of the 2004 Chronic Disease Clock, which shows the number of deaths so far today, and so far this year. The clock was developed using a consultative approach, following a review of the original clock.

Outcomes: The 2020 clock incorporates new data visualization concepts. New features, facilitated by improved technology, include: expansion to all causes of death; blinking red dots to enhance visual impact; and three clock versions (analogue, featuring a moving circle; digital, table format; and graphical, bar chart format). The clock also provides links to a number of health calculators, to allow people to seek personalized information to improve their health.

Implications: The online health clock and health calculators are good examples of innovation in health risk communication tools for effective knowledge translation and dissemination. They inform people about health statistics (clock) and their health (calculators). The clock engages people in the context of the Canadian population, whereas the calculators provide personalized information about improving an individual's future health.
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http://dx.doi.org/10.17269/s41997-020-00348-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359436PMC
October 2020

Core Competencies for Undergraduates in Bioengineering and Biomedical Engineering: Findings, Consequences, and Recommendations.

Ann Biomed Eng 2020 Mar 5;48(3):905-912. Epub 2020 Feb 5.

Department of Biomedical Engineering, University of California - Irvine, Irvine, CA, USA.

This paper provides a synopsis of discussions related to biomedical engineering core curricula that occurred at the Fourth BME Education Summit held at Case Western Reserve University in Cleveland, Ohio in May 2019. This summit was organized by the Council of Chairs of Bioengineering and Biomedical Engineering, and participants included over 300 faculty members from 100+ accredited undergraduate programs. This discussion focused on six key questions: QI: Is there a core curriculum, and if so, what are its components? QII: How does our purported core curriculum prepare students for careers, particularly in industry? QIII: How does design distinguish BME/BIOE graduates from other engineers? QIV: What is the state of engineering analysis and systems-level modeling in BME/BIOE curricula? QV: What is the role of data science in BME/BIOE undergraduate education? QVI: What core experimental skills are required for BME/BIOE undergrads? s. Indeed, BME/BIOI core curricula exists and has matured to emphasize interdisciplinary topics such as physiology, instrumentation, mechanics, computer programming, and mathematical modeling. Departments demonstrate their own identities by highlighting discipline-specific sub-specialties. In addition to technical competence, Industry partners most highly value our students' capacity for problem solving and communication. As such, BME/BIOE curricula includes open-ended projects that address unmet patient and clinician needs as primary methods to prepare graduates for careers in industry. Culminating senior design experiences distinguish BME/BIOE graduates through their development of client-centered engineering solutions to healthcare problems. Finally, the overall BME/BIOE curriculum is not stagnant-it is clear that data science will become an ever-important element of our students' training and that new methods to enhance student engagement will be of pedagogical importance as we embark on the next decade.
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http://dx.doi.org/10.1007/s10439-020-02468-2DOI Listing
March 2020

Dissociation of Cerebral Blood Flow and Femoral Artery Blood Pressure Pulsatility After Cardiac Arrest and Resuscitation in a Rodent Model: Implications for Neurological Recovery.

J Am Heart Assoc 2020 01 4;9(1):e012691. Epub 2020 Jan 4.

Beckman Laser Institute and Medical Clinic Irvine CA.

Background Impaired neurological function affects 85% to 90% of cardiac arrest (CA) survivors. Pulsatile blood flow may play an important role in neurological recovery after CA. Cerebral blood flow (CBF) pulsatility immediately, during, and after CA and resuscitation has not been investigated. We characterized the effects of asphyxial CA on short-term (<2 hours after CA) CBF and femoral arterial blood pressure (ABP) pulsatility and studied their relationship to cerebrovascular resistance (CVR) and short-term neuroelectrical recovery. Methods and Results Male rats underwent asphyxial CA followed by cardiopulmonary resuscitation. A multimodal platform combining laser speckle imaging, ABP, and electroencephalography to monitor CBF, peripheral blood pressure, and brain electrophysiology, respectively, was used. CBF and ABP pulsatility and CVR were assessed during baseline, CA, and multiple time points after resuscitation. Neuroelectrical recovery, a surrogate for neurological outcome, was assessed using quantitative electroencephalography 90 minutes after resuscitation. We found that CBF pulsatility differs significantly from baseline at all experimental time points with sustained deficits during the 2 hours of postresuscitation monitoring, whereas ABP pulsatility was relatively unaffected. Alterations in CBF pulsatility were inversely correlated with changes in CVR, but ABP pulsatility had no association to CVR. Interestingly, despite small changes in ABP pulsatility, higher ABP pulsatility was associated with worse neuroelectrical recovery, whereas CBF pulsatility had no association. Conclusions Our results reveal, for the first time, that CBF pulsatility and CVR are significantly altered in the short-term postresuscitation period after CA. Nevertheless, higher ABP pulsatility appears to be inversely associated with neuroelectrical recovery, possibly caused by impaired cerebral autoregulation and/or more severe global cerebral ischemia.
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http://dx.doi.org/10.1161/JAHA.119.012691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988151PMC
January 2020

Enhanced mitochondrial membrane potential and ATP synthesis by photobiomodulation increases viability of the auditory cell line after gentamicin-induced intrinsic apoptosis.

Sci Rep 2019 12 17;9(1):19248. Epub 2019 Dec 17.

Beckman Laser Institute Korea, Dankook University, 119, Dandae-ro, Dongnam-gu, Cheonan, Chungnam, 31116, Republic of Korea.

Photobiomodulation (PBM) has been suggested to have a therapeutic effect on irreversible hearing loss induced by aminoglycosides, including gentamicin (GM). However, its intracellular mechanism(s) in GM-induced ototoxicity remain poorly understood. In the present study, we investigated the effect of PBM in GM-induced ototoxicity in auditory cells. We tried to characterize the downstream process by PBM, and the process that triggered the increased cell viability of auditory cells. As a result, the effects of PBM against GM-induced ototoxicity by increasing ATP levels and mitochondrial membrane potential was confirmed. These results suggest a theory to explain the therapeutic effects and support the use of PBM for aminoglycoside-induced hearing loss.
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http://dx.doi.org/10.1038/s41598-019-55711-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917700PMC
December 2019

Intravital Vascular Phototheranostics and Real-Time Circulation Dynamics of Micro- and Nanosized Erythrocyte-Derived Carriers.

ACS Appl Mater Interfaces 2020 Jan 24;12(1):275-287. Epub 2019 Dec 24.

Department of Bioengineering , University of California, Riverside , Riverside , California 92521 , United States.

Erythrocyte-based carriers can serve as theranostic platforms for delivery of imaging and therapeutic payloads. Engineering these carriers at micro- or nanoscales makes them potentially useful for broad clinical applications ranging from vascular diseases to tumor theranostics. Longevity of these carriers in circulation is important in delivering a sufficient amount of their payloads to the target. We have investigated the circulation dynamics of micro (∼4.95 μm diameter) and nano (∼91 nm diameter) erythrocyte-derived carriers in real time using near-infrared fluorescence imaging, and evaluated the effectiveness of such carrier systems in mediating photothermolysis of cutaneous vasculature in mice. Fluorescence emission half-lives of micro- and nanosized carriers in response to a single intravenous injection were ∼49 and ∼15 min, respectively. A single injection of microsized carriers resulted in a 3-fold increase in signal-to-noise ratio that remained nearly persistent over 1 h of imaging time. Our results also suggest that a second injection of the carriers 7 days later can induce a transient inflammatory response, as manifested by the apparent leakage of the carriers into the perivascular tissue. The administration of the carriers into the mice vasculature reduced the threshold laser fluence to induce photothermolysis of blood vessels from >65 to 20 J/cm. We discuss the importance of membrane physicochemical and mechanical characteristics in engineering erythrocyte-derived carriers and considerations for their clinical translation.
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http://dx.doi.org/10.1021/acsami.9b18624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028219PMC
January 2020

Microvascular Effects of Pulsed Dye Laser in Combination With Oxymetazoline.

Lasers Surg Med 2020 01 22;52(1):17-22. Epub 2019 Nov 22.

Beckman Laser Institute and Medical Clinic, University of California, 1002 Health Sciences Rd, Irvine, California, 92617.

Background And Objective: Oxymetazoline, an α-1A agonist, is approved by the United States Food and Drug Administration (FDA) for treatment of persistent facial erythema associated with rosacea and induces vasoconstriction by interacting with α receptors. The objective of our study was to study the microvascular effects of oxymetazoline and pulsed dye laser (PDL).

Materials And Methods: A dorsal window chamber was surgically installed on 20 mice. Each animal was assigned to one of four experimental groups: saline alone, oxymetazoline alone (10 μl applied once daily × 7 days), saline + PDL (saline applied 5 minutes before PDL irradiation [10 mm spot, 1.5 ms pulse duration, 7 J/cm delivered to epidermis]), or oxymetazoline + PDL (10 μl oxymetazoline applied 5 minutes before PDL and then once daily × 7 days). Brightfield and laser speckle imaging were performed for 7 days to monitor vascular architectural and functional changes.

Results: We observed persistent blood flow in all of the saline-only and oxymetazoline-only experiments. A higher rate of vascular shutdown was observed with oxymetazoline + PDL (66.7%) compared with saline + PDL alone (16.7%). Oxymetazoline application increased venule diameter at 5 minutes post-application and decreased both arteriole and venule diameters at 60 minutes post-application.

Conclusion: The combination protocol of oxymetazoline + PDL induces persistent vascular shutdown observed 7 days after irradiation. This result may be associated with the acute vascular effects of oxymetazoline. Oxymetazoline + PDL should be evaluated as a treatment for cutaneous vascular disease, including rosacea and port wine birthmarks. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/lsm.23186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059989PMC
January 2020

Handheld motion stabilized laser speckle imaging.

Biomed Opt Express 2019 Oct 13;10(10):5149-5158. Epub 2019 Sep 13.

Beckman Laser Institute and Medical Clinic, University of California-Irvine, 1002 Health Sciences Road East, Irvine, CA 92612, USA.

Laser speckle imaging (LSI) is a wide-field, noninvasive optical technique that allows researchers and clinicians to quantify blood flow in a variety of applications. However, traditional LSI devices are cart or tripod based mounted systems that are bulky and potentially difficult to maneuver in a clinical setting. We previously showed that the use of a handheld LSI device with the use of a fiducial marker (FM) to account for motion artifact is a viable alternative to mounted systems. Here we incorporated a handheld gimbal stabilizer (HGS) to produce a motion stabilized LSI (msLSI) device to further improve the quality of data acquired in handheld configurations. We evaluated the msLSI device using flow phantom experiments and using a dorsal window chamber model. For experiments, we quantified the speckle contrast of the FM (K) using the mounted data set and tested 80% and 85% of K as thresholds for useable images (K and K). Handheld data sets using the msLSI device (stabilized handheld) and handheld data sets without the HGS (handheld) were collected. Using K and K as the threshold, the number of images above the threshold for stabilized handheld (38 ± 7 and 10 ± 2) was significantly greater (p = 0.031) than for handheld operation (16 ± 2 and 4 ± 1). We quantified a region of interest within the flow region (K), which led to a percent difference of 8.5% ± 2.9% and 7.8% ± 3.1% between stabilized handheld and handheld configurations at each threshold. For experiments, we quantified the speckle contrast of the window chamber (K) using the mounted data set and tested 80% of K (K). Stabilized handheld operation provided 53 ± 24 images above K, while handheld operation provided only 23 ± 13 images. We quantified the speckle flow index (SFI) of the vessels and the background to calculate a signal-to-background ratio (SBR) of the window chamber. Stabilized handheld operation provided a greater SBR (2.32 ± 0.29) compared to handheld operation (1.83 ± 0.21). Both the number of images above threshold and SBR were statistically significantly greater in the stabilized handheld data sets (p = 0.0312). These results display the improved usability of handheld data acquired with an msLSI device.
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http://dx.doi.org/10.1364/BOE.10.005149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6788584PMC
October 2019

Speckleplethysmographic (SPG) Estimation of Heart Rate Variability During an Orthostatic Challenge.

Sci Rep 2019 10 1;9(1):14079. Epub 2019 Oct 1.

Beckman Laser Institute and Medical Clinic, University of California, Irvine, California, 92612, USA.

Heart rate variability (HRV) provides insight into cardiovascular health and autonomic function. Electrocardiography (ECG) provides gold standard HRV measurements but is inconvenient for continuous acquisition when monitored from the extremities. Optical techniques such as photoplethysmography (PPG), often found in health and wellness trackers for heart rate measurements, have been used to estimate HRV peripherally but decline in accuracy during increased physical stress. Speckleplethysmography (SPG) is a recently introduced optical technique that provides benefits over PPG, such as increased signal amplitude and reduced susceptibility to temperature-induced vasoconstriction. In this research, we compare SPG and PPG to ECG for estimation of HRV during an orthostatic challenge performed by 17 subjects. We find that SPG estimations of HRV are highly correlated to ECG HRV for both time and frequency domain parameters and provide increased accuracy over PPG estimations of HRV. The results suggest SPG measurements are a viable alternative for HRV estimation when ECG measurements are impractical.
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http://dx.doi.org/10.1038/s41598-019-50526-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773734PMC
October 2019

Multi-exposure laser speckle contrast imaging using a video-rate multi-tap charge modulation image sensor.

Opt Express 2019 Sep;27(18):26175-26191

Multi-exposure laser speckle contrast imaging (MELSCI) systems based on high frame rate cameras are suitable for wide-field quantitative measurement of blood flow. However, high-speed camera-based MELSCI requires high power consumption, large memory, and high processing capability, which may lead to relatively large and expensive hardware. To realize a compact and cost-efficient MELSCI system, we discuss an application of the multi-tap CMOS image sensor originally designed for time-of-flight range imaging. This image sensor operated in the global shutter mode and every pixel was provided with multiple charge-storage diodes. Multiple images for different exposures were acquired simultaneously because exposure patterns were programmable to implement an arbitrary exposure duration for each tap. The frame rate was close to video frame rates (30 frames per second (fps)) regardless of the exposure pattern. The feasibility of the proposed method was verified by simulations that were performed with real speckle images captured by a high-speed camera at 40 kfps. Experiments with a four-tap CMOS image sensor demonstrated that a flow speed map was obtained at a moderate frame rate such as 35 fps for a moving ground glass plate and 45 fps for flowing Intralipose, which were linearly moved at speeds of 1-5 mm/s.
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http://dx.doi.org/10.1364/OE.27.026175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825609PMC
September 2019

The Pan American Health Organization-adapted Hanlon method for prioritization of health programs.

Rev Panam Salud Publica 2019 8;43:e61. Epub 2019 Jul 8.

Pan American Health Organization, Regional Office of the World Health Organization for the Americas Pan American Health Organization, Regional Office of the World Health Organization for the Americas Washington, DC United States of America Pan American Health Organization, Regional Office of the World Health Organization for the Americas, Washington, DC, United States of America.

Objectives: To document the underlying science of how the Pan American Health Organization (PAHO) adapted the Hanlon method, which prioritizes disease control programs, to its wider range of program areas and used it to implement the PAHO Strategic Plan 2014 - 2019.

Methods: In 2014, PAHO established a Strategic Plan Advisory Group (SPAG) with representatives from 12 Member States to work closely with the PAHO Technical Team to adapt the Hanlon method to disease and non-disease control programs. Three meetings were held in 2015 - 2016 during which SPAG reviewed existing priority-setting methods, assessed the original Hanlon method and subsequent revisions, and developed the adapted method. This project was initiated by Member States, facilitated by PAHO, and conducted jointly in transparent and horizontal technical cooperation.

Results: From the original Hanlon equation, the PAHO-adapted method maintains components A (size of problem), B (seriousness of problem), and C (effectiveness of intervention), drops component D (PEARL - Propriety, Economics, Acceptability, Resources, and Legality), and adds component E (inequity) and F (institutional positioning). The PEARL score was dropped because it serves a purpose for pre-screening process, but not in the priority-setting process for PAHO.

Conclusions: The PAHO-adapted Hanlon method provides a refined approach for prioritizing public health programs that include disease and non-disease control areas. The method may be useful for the World Health Organization and country governments with similar needs.
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http://dx.doi.org/10.26633/RPSP.2019.61DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611209PMC
July 2019

Quantitation of Super Basic Peptides in Biological Matrices by a Generic Perfluoropentanoic Acid-Based Liquid Chromatography-Mass Spectrometry Method.

J Am Soc Mass Spectrom 2019 Sep 27;30(9):1779-1789. Epub 2019 Jun 27.

Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., Rahway, NJ, 07065, USA.

Peptides represent a promising modality for the design of novel therapeutics that can potentially modulate traditionally non-druggable targets. Cell-penetrating peptides (CPPs) and antimicrobial peptides (AMPs) are two large families that are being explored extensively as drug delivery vehicles, imaging reagents, or therapeutic treatments for various diseases. Many CPPs and AMPs are cationic among which a significant portion is extremely basic and hydrophilic (e.g., nona-arginine). Despite their attractive therapeutic potential, it remains challenging to directly analyze and quantify these super cationic peptides from biological matrices due to their poor chromatographic behavior and MS response. Herein, we describe a generic method that combines solid phase extraction and LC-MS/MS for analysis of these peptides. As demonstrated, using a dozen strongly basic peptides, low μM concentration of perfluoropentanoic acid (PFPeA) in the mobile phase enabled excellent compound chromatographic retention, thus avoiding co-elution with solvent front ion suppressants. PFPeA also had a charge reduction effect that allowed the selection of parent/ion fragment pairs in the higher m/z region to further reduce potential low molecular weight interferences. When the method was coupled to the optimized sample extraction process, we routinely achieved low digit ng/ml sensitivity for peptides in plasma/tissue. The method allowed an efficient evaluation of plasma stability of CPPs/AMPs without fluorescence derivatization or other tagging methods. Importantly, using the widely studied HIV-TAT CPP as an example, the method enabled us to directly assess its pharmacokinetics and tissue distribution in preclinical animal models.
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http://dx.doi.org/10.1007/s13361-019-02257-9DOI Listing
September 2019

Optical clearing potential of immersion-based agents applied to thick mouse brain sections.

PLoS One 2019 10;14(5):e0216064. Epub 2019 May 10.

Department of Biomedical Engineering, University of California, Irvine, California, United States of America.

We have previously demonstrated that the use of a commercially-available immersion-based optical clearing agent (OCA) enables, within 3-6 hours, three-dimensional visualization of subsurface exogenous fluorescent and absorbing markers of vascular architecture and neurodegenerative disease in thick (0.5-1.0mm) mouse brain sections. Nonetheless, the relative performance of immersion-based OCAs has remained unknown. Here, we show that immersion of brain sections in specific OCAs (FocusClear, RIMS, sRIMS, or ScaleSQ) affects both their transparency and volume; the optical clearing effect occurs over the entire visible spectrum and is reversible; and that ScaleSQ had the highest optical clearing potential and increase in imaging depth of the four evaluated OCAs, albeit with the largest change in sample volume and a concomitant decrease in apparent microvascular density of the sample. These results suggest a rational, quantitative framework for screening and characterization of the impact of optical clearing, to streamline experimental design and enable a cost-benefit assessment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0216064PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6510422PMC
January 2020

Comparison of speckleplethysmographic (SPG) and photoplethysmographic (PPG) imaging by Monte Carlo simulations and measurements.

Biomed Opt Express 2018 Sep 15;9(9):4306-4316. Epub 2018 Aug 15.

Beckman Laser Institute and Medical Clinic, University of California-Irvine, 1002 Health Sciences Road East, Irvine, CA 92612, USA.

Noncontact photoplethysmography (PPG) is limited by a poor signal-to-noise ratio (SNR). A solution to this limitation is the use of alternate sources of optical contrast to generate a complementary pulsatile waveform. One such source is laser speckle contrast, which is modulated in biological tissues by the flow rate of red blood cells. Averaging a region of interest from a speckle contrast image over time allows for the calculation of a speckleplethysmogram (SPG). Similar to PPG, SPG enables monitoring of heart rate and respiratory rate. A gap in the knowledge base exists as to the precise spatiotemporal relationship between PPG and SPG signals. We have developed an eight-layer tissue model to simulate both PPG and SPG signals in a reflectance geometry via Monte Carlo methods. We modeled PPG by compression of the upper and lower blood nets due to expansion of the larger arterial layer below. The PPG peak-to-peak amplitude percent was greater at 532 nm than at 860 nm (5.6% vs. 3.0%, respectively), which matches trends from the literature. We modeled SPG by changing flow speeds of red blood cells in both the capillaries and arterioles over the cardiac cycle. The SPG peak-to-peak amplitude percent was 24% at 532 nm and 40% at 860 nm. results are similar to results measured with a two-camera set up for simultaneous imaging of PPG and SPG. Both and data suggest SPG has a much larger SNR than PPG, which may prove beneficial for noncontact, wide-field optical monitoring of cardiovascular health.
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http://dx.doi.org/10.1364/BOE.9.004306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6157764PMC
September 2018

Simultaneous Blood Flow Measurement and Dermoscopy of Skin Lesions Using Dual-Mode Dermascope.

Sci Rep 2018 11 16;8(1):16941. Epub 2018 Nov 16.

Beckman Laser Institute and Medical Clinic, University of California, Irvine, California, 92612, USA.

Dermascopes are commonly utilized for the qualitative visual inspection of skin lesions. While automated image processing techniques and varied illumination strategies have been used to aid in structural analysis of lesions, robust quantification of functional information is largely unknown. To address this knowledge gap, we have developed a compact, handheld dermascope that enables real-time blood flow measurements of skin during conventional visual inspection. In-vitro characterization demonstrated that the dermascope is capable of quantifying changes in flow across a physiologically relevant range even when used in a handheld manner with clinic lighting and dermascope LEDs on. In a small pilot clinical study, we demonstrated the dermascope's ability to detect flow differences between two distinct lesion types.
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http://dx.doi.org/10.1038/s41598-018-35107-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240112PMC
November 2018

Characterisation of impaired wound healing in a preclinical model of induced diabetes using wide-field imaging and conventional immunohistochemistry assays.

Int Wound J 2019 Feb 1;16(1):144-152. Epub 2018 Oct 1.

Beckman Laser Institute and Medical Clinic, University of California Irvine, Irvine, California.

Major complications of diabetes lead to inflammation and oxidative stress, delayed wound healing, and persistent ulcers. The high morbidity, mortality rate, and associated costs of management suggest a need for non-invasive methods that will enable the early detection of at-risk tissue. We have compared the wound-healing process that occurs in streptozotocin (STZ)-treated diabetic rats with non-diabetic controls using contrast changes in colour photography (ie, Weber Contrast) and the non-invasive optical method Spatial Frequency Domain Imaging (SFDI). This technology can be used to quantify the structural and metabolic properties of in-vivo tissue by measuring oxyhaemoglobin concentration (HbO ), deoxyhaemoglobin concentration (Hb), and oxygen saturation (StO ) within the visible boundaries of each wound. We also evaluated the changes in inducible nitric oxide synthase (iNOS) in the dermis using immunohistochemistry. Contrast changes in colour photographs showed that diabetic rats healed at a slower rate in comparison with non-diabetic control, with the most significant change occurring at 7 days after the punch biopsy. We observed lower HbO , StO , and elevated Hb concentrations in the diabetic wounds. The iNOS level was higher in the dermis of the diabetic rats compared with the non-diabetic rats. Our results showed that, in diabetes, there is higher level of iNOS that can lead to an observed reduction in HbO levels. iNOS is linked to increased inflammation, leading to prolonged wound healing. Our results suggest that SFDI has potential as a non-invasive assessment of markers of wound-healing impairment.
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http://dx.doi.org/10.1111/iwj.13005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6329645PMC
February 2019

Corrigendum to "The Past, Present, and Future of Public Health Surveillance".

Authors:
Bernard C K Choi

Scientifica (Cairo) 2018 2;2018:6943062. Epub 2018 Jul 2.

Injury Prevention Research Centre, Medical College of Shantou University, Shantou 515041, China.

[This corrects the article DOI: 10.6064/2012/875253.].
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http://dx.doi.org/10.1155/2018/6943062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6051005PMC
July 2018

Quantitative real-time optical imaging of the tissue metabolic rate of oxygen consumption.

J Biomed Opt 2018 03;23(3):1-12

Beckman Laser Institute and Medical Clinic, Laser Microbeam and Medical Program, Irvine, California, United States.

The tissue metabolic rate of oxygen consumption (tMRO2) is a clinically relevant marker for a number of pathologies including cancer and arterial occlusive disease. We present and validate a noncontact method for quantitatively mapping tMRO2 over a wide, scalable field of view at 16  frames  /  s. We achieve this by developing a dual-wavelength, near-infrared coherent spatial frequency-domain imaging (cSFDI) system to calculate tissue optical properties (i.e., absorption, μa, and reduced scattering, μs', parameters) as well as the speckle flow index (SFI) at every pixel. Images of tissue oxy- and deoxyhemoglobin concentration (  [  HbO2  ]   and [HHb]) are calculated from optical properties and combined with SFI to calculate tMRO2. We validate the system using a series of yeast-hemoglobin tissue-simulating phantoms and conduct in vivo tests in humans using arterial occlusions that demonstrate sensitivity to tissue metabolic oxygen debt and its repayment. Finally, we image the impact of cyanide exposure and toxicity reversal in an in vivo rabbit model showing clear instances of mitochondrial uncoupling and significantly diminished tMRO2. We conclude that dual-wavelength cSFDI provides rapid, quantitative, wide-field mapping of tMRO2 that can reveal unique spatial and temporal dynamics relevant to tissue pathology and viability.
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http://dx.doi.org/10.1117/1.JBO.23.3.036013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866507PMC
March 2018

Correcting for motion artifact in handheld laser speckle images.

J Biomed Opt 2018 03;23(3):1-7

Beckman Laser Institute and Medical Clinic, Irvine, California, United States.

Laser speckle imaging (LSI) is a wide-field optical technique that enables superficial blood flow quantification. LSI is normally performed in a mounted configuration to decrease the likelihood of motion artifact. However, mounted LSI systems are cumbersome and difficult to transport quickly in a clinical setting for which portability is essential in providing bedside patient care. To address this issue, we created a handheld LSI device using scientific grade components. To account for motion artifact of the LSI device used in a handheld setup, we incorporated a fiducial marker (FM) into our imaging protocol and determined the difference between highest and lowest speckle contrast values for the FM within each data set (Kbest and Kworst). The difference between Kbest and Kworst in mounted and handheld setups was 8% and 52%, respectively, thereby reinforcing the need for motion artifact quantification. When using a threshold FM speckle contrast value (KFM) to identify a subset of images with an acceptable level of motion artifact, mounted and handheld LSI measurements of speckle contrast of a flow region (KFLOW) in in vitro flow phantom experiments differed by 8%. Without the use of the FM, mounted and handheld KFLOW values differed by 20%. To further validate our handheld LSI device, we compared mounted and handheld data from an in vivo porcine burn model of superficial and full thickness burns. The speckle contrast within the burn region (KBURN) of the mounted and handheld LSI data differed by <4  %   when accounting for motion artifact using the FM, which is less than the speckle contrast difference between superficial and full thickness burns. Collectively, our results suggest the potential of handheld LSI with an FM as a suitable alternative to mounted LSI, especially in challenging clinical settings with space limitations such as the intensive care unit.
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http://dx.doi.org/10.1117/1.JBO.23.3.036006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5852319PMC
March 2018

Period Life Tables for Calculating Life Expectancy: Options to Assess and Minimize the Potential for Bias.

Am J Public Health 2018 03;108(3):e14

Colin Steensma and Lidia Loukine are with Health Canada, Ottawa, Ontario. Bernard C. K. Choi and Dena Schanzer are with the Public Health Agency of Canada, Ottawa.

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http://dx.doi.org/10.2105/AJPH.2017.304268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5803818PMC
March 2018

High-speed spatial frequency domain imaging of rat cortex detects dynamic optical and physiological properties following cardiac arrest and resuscitation.

Neurophotonics 2017 Oct 26;4(4):045008. Epub 2017 Dec 26.

University of California, Beckman Laser Institute, Irvine, California, United States.

Quantifying rapidly varying perturbations in cerebral tissue absorption and scattering can potentially help to characterize changes in brain function caused by ischemic trauma. We have developed a platform for rapid intrinsic signal brain optical imaging using macroscopically structured light. The device performs fast, multispectral, spatial frequency domain imaging (SFDI), detecting backscattered light from three-phase binary square-wave projected patterns, which have a much higher refresh rate than sinusoidal patterns used in conventional SFDI. Although not as fast as "single-snapshot" spatial frequency methods that do not require three-phase projection, square-wave patterns allow accurate image demodulation in applications such as small animal imaging where the limited field of view does not allow single-phase demodulation. By using 655, 730, and 850 nm light-emitting diodes, two spatial frequencies ([Formula: see text] and [Formula: see text]), three spatial phases (120 deg, 240 deg, and 360 deg), and an overall camera acquisition rate of 167 Hz, we map changes in tissue absorption and reduced scattering parameters ([Formula: see text] and [Formula: see text]) and oxy- and deoxyhemoglobin concentration at [Formula: see text]. We apply this method to a rat model of cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) to quantify hemodynamics and scattering on temporal scales ([Formula: see text]) ranging from tens of milliseconds to minutes. We observe rapid concurrent spatiotemporal changes in tissue oxygenation and scattering during CA and following CPR, even when the cerebral electrical signal is absent. We conclude that square-wave SFDI provides an effective technical strategy for assessing cortical optical and physiological properties by balancing competing performance demands for fast signal acquisition, small fields of view, and quantitative information content.
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http://dx.doi.org/10.1117/1.NPh.4.4.045008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5742642PMC
October 2017

Momentum transfer Monte Carlo for the simulation of laser speckle imaging and its application in the skin.

Biomed Opt Express 2017 Dec 17;8(12):5708-5723. Epub 2017 Nov 17.

Beckman Laser Institute, University of California-Irvine, 1002 Health Sciences Road East, Irvine, CA 92612, USA.

Due to its simplicity and low cost, laser speckle imaging (LSI) has achieved widespread use in biomedical applications. However, interpretation of the blood-flow maps remains ambiguous, as LSI enables only limited visualization of vasculature below scattering layers such as the epidermis and skull. Here, we describe a computational model that enables flexible study of the impact of these factors on LSI measurements. The model uses Monte Carlo methods to simulate light and momentum transport in a heterogeneous tissue geometry. The virtual detectors of the model track several important characteristics of light. This model enables study of LSI aspects that may be difficult or unwieldy to address in an experimental setting, and enables detailed study of the fundamental origins of speckle contrast modulation in tissue-specific geometries. We applied the model to an in-depth exploration of the spectral dependence of speckle contrast signal in the skin, the effects of epidermal melanin content on LSI, and the depth-dependent origins of our signal. We found that LSI of transmitted light allows for a more homogeneous integration of the signal from the entire bulk of the tissue, whereas epi-illumination measurements of contrast are limited to a fraction of the light penetration depth. We quantified the spectral depth dependence of our contrast signal in the skin, and did not observe a statistically significant effect of epidermal melanin on speckle contrast. Finally, we corroborated these simulated results with experimental LSI measurements of flow beneath a thin absorbing layer. The results of this study suggest the use of LSI in the clinic to monitor perfusion in patients with different skin types, or inhomogeneous epidermal melanin distributions.
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http://dx.doi.org/10.1364/BOE.8.005708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5745114PMC
December 2017

Histologic changes associated with talaporfin sodium-mediated photodynamic therapy in rat skin.

Lasers Surg Med 2017 10 10;49(8):767-772. Epub 2017 May 10.

Beckman Laser Institute and Medical Clinic, University of California, Irvine, California.

Background And Objective: Alternative treatments are needed to achieve consistent and more complete port wine stain (PWS) removal, especially in darker skin types; photodynamic therapy (PDT) is a promising alternative treatment. To this end, we previously reported on Talaporfin Sodium (TS)-mediated PDT. It is essential to understand treatment tissue effects to design a protocol that will achieve selective vascular injury without ulceration and scarring. The objective of this work is to assess skin changes associated with TS-mediated PDT with clinically relevant treatment parameters.

Study Design/materials And Methods: We performed TS (0.75 mg/kg)-mediated PDT (664 nm) on Sprague Dawley rats. Radiant exposures were varied between 15 and 100 J/cm . We took skin biopsies from subjects at 9 hours following PDT. We assessed the degree and depth of vascular and surrounding tissue injury using histology and immunohistochemical staining.

Results: TS-mediated PDT at 0.75 mg/kg combined with 15 and 25 J/cm light doses resulted in vascular injury with minimal epidermal damage. At light dose of 50 J/cm , epidermal damage was noted with vascular injury. At light doses >50 J/cm , both vascular and surrounding tissue injury were observed in the forms of vasculitis, extravasated red blood cells, and coagulative necrosis. Extensive coagulative necrosis involving deeper adnexal structures was observed for 75 and 100 J/cm light doses. Observed depth of injury increased with increasing radiant exposure, although this relationship was not linear.

Conclusion: TS-mediated PDT can cause selective vascular injury; however, at higher light doses, significant extra-vascular injury was observed. This information can be used to contribute to design of safe protocols to be used for treatment of cutaneous vascular lesions. Lasers Surg. Med. 49:767-772, 2017. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/lsm.22677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5603362PMC
October 2017

Evaluating compression or expansion of morbidity in Canada: trends in life expectancy and health-adjusted life expectancy from 1994 to 2010.

Health Promot Chronic Dis Prev Can 2017 Mar;37(3):68-76

Public Health Agency of Canada, Government of Canada, Ottawa, Ontario, Canada.

Introduction: The objective of this study was to investigate whether morbidity in Canada, at the national and provincial levels, is compressing or expanding by tracking trends in life expectancy (LE) and health-adjusted life expectancy (HALE) from 1994 to 2010. "Compression" refers to a decrease in the proportion of life spent in an unhealthy state over time. It happens when HALE increases faster than LE. "Expansion" refers to an increase in the proportion of life spent in an unhealthy state that happens when HALE is stable or increases more slowly than LE.

Methods: We estimated LE using mortality and population data from Statistics Canada. We took health-related quality of life (i.e. morbidity) data used to calculate HALE from the National Population Health Survey (1994-1999) and the Canadian Community Health Survey (2000-2010). We built abridged life tables for seven time intervals, covering the period 1994 to 2010 and corresponding to the year of each available survey cycle, for females and males, and for each of the 10 Canadian provinces. National and provincial trends were assessed at birth, and at ages 20 years and 65 years.

Results: We observed an overall average annual increase in HALE that was statistically significant in both Canadian females and males at each of the three ages assessed, with the exception of females at birth. At birth, HALE increased an average of 0.2% (p = .08) and 0.3% (p < .001) annually for females and males respectively over the 1994 to 2010 period. At the national level for all three age groups, we observed a statistically non-significant average annual increase in the proportion of life spent in an unhealthy state, with the exception of men at age 65, who experienced a non-significant decrease. At the provincial level at birth, we observed a significant increase in proportion of life spent in an unhealthy state for Newfoundland and Labrador (NL) and Prince Edward Island (PEI).

Conclusion: Our study did not detect a clear overall trend in compression or expansion of morbidity from 1994 to 2010 at the national level in Canada. However, our results suggested an expansion of morbidity in NL and PEI. Our study indicates the importance of continued tracking of the secular trends of life expectancy and HALE in Canada in order to verify the presence of compression or expansion of morbidity. Further study should be undertaken to understand what is driving the observed expansion of morbidity in NL and in PEI.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5602161PMC
http://dx.doi.org/10.24095/hpcdp.37.3.02DOI Listing
March 2017

Quantitative long-term measurements of burns in a rat model using Spatial Frequency Domain Imaging (SFDI) and Laser Speckle Imaging (LSI).

Lasers Surg Med 2017 03 21;49(3):293-304. Epub 2017 Feb 21.

Beckman Laser Institute Medical Clinic, University of California, Irvine, 1002 Health Sciences Road East, Irvine, California 92617.

Background And Ojectives: The current standard for diagnosis of burn severity and subsequent wound healing is through clinical examination, which is highly subjective. Several new technologies are shifting focus to burn care in an attempt to help quantify not only burn depth but also the progress of healing. While accurate early assessment of partial thickness burns is critical for dictating the course of treatment, the ability to quantitatively monitor wound status over time is critical for understanding treatment efficacy. SFDI and LSI are both non-invasive imaging modalities that have been shown to have great diagnostic value for burn severity, but have yet to be tested over the course of wound healing.

Methods: In this study, a hairless rat model (n = 6, 300-450 g) was used with a four pronged comb to create four identical partial thickness burns (superficial n = 3 and deep n = 3) that were used to monitor wound healing over a 28 days period. Weekly biopsies were taken for histological analysis to verify wound progression. Both SFDI and LSI were performed weekly to track the evolution of hemodynamic (blood flow and oxygen saturation) and structural (reduced scattering coefficient) properties for the burns.

Results: LSI showed significant changes in blood flow from baseline to 220% in superficial and 165% in deep burns by day 7. In superficial burns, blood flow returned to baseline levels by day 28, but not for deep burns where blood flow remained elevated. Smaller increases in blood flow were also observed in the surrounding tissue over the same time period. Oxygen saturation values measured with SFDI showed a progressive increase from baseline values of 66-74% in superficial burns and 72% in deep burns by day 28. Additionally, SFDI showed significant decreases in the reduced scattering coefficient shortly after the burns were created. The scattering coefficient progressively decreased in the wound area, but returned towards baseline conditions at the end of the 28 days period. Scattering changes in the surrounding tissue remained constant despite the presence of hemodynamic changes.

Conclusions: Here, we show that LSI and SFDI are capable of monitoring changes in hemodynamic and scattering properties in burn wounds over a 28 days period. These results highlight the potential insights that can be gained by using non-invasive imaging technologies to study wound healing. Further development of these technologies could be revolutionary for wound monitoring and studying the efficacy of different treatments. Lasers Surg. Med. 49:293-304, 2017. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/lsm.22647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5368004PMC
March 2017

Risk factors of bicycle traffic injury among middle school students in chaoshan rural areas of china.

Int J Equity Health 2017 01 26;16(1):28. Epub 2017 Jan 26.

Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.

Background: Bicycle injuries are a leading cause of accidental death among children in the world, and bicycle-related injuries are also very common in China, thus to find out bicycle injury risk factors is imperative. This study aims to identify the cyclist-, bicycle- and road-related risk factors of bicycle injury, to develop health education programs as an intervention and to provide a scientific basis for establishing policies against bicycle injury.

Methods: We selected two middle schools randomly among seven schools in Chaoshan rural areas,where the main means of transportation for students from home to school was bicycle. The subjects were middle school students from 7th to 9th grades from Gucuo Middle School and Hefeng Middle School. Cyclists were surveyed through questionnaires about bicycle injury in the past 12 months.

Results: Multivariable logistic analysis showed that compared with a combination-type road、 motor lane and a non-intact road were both risk factors of bicycle injuries. This was followed by riding with fatigue, non-motor lane and inattentive riding.

Conclusion: Bicycle injuries are frequent in China. Three risk factors on bicycle traffic injury among middle school students in Chaoshan rural areas of China were identified. This study provides important data to develop intervention strategies for China and other developing countries.
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http://dx.doi.org/10.1186/s12939-016-0512-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5267448PMC
January 2017