Publications by authors named "Alan Murray"

151 Publications

Adhesion and Growth of Neuralized Mouse Embryonic Stem Cells on Parylene-C/SiO Substrates.

Materials (Basel) 2021 Jun 9;14(12). Epub 2021 Jun 9.

School of Biological Sciences, University of Reading, Reading RG6 6DH, UK.

Neuronal patterning on microfabricated architectures has developed rapidly over the past few years, together with the emergence of soft biocompatible materials and tissue engineering scaffolds. Previously, we introduced a patterning technique based on serum and the biopolymer parylene-C, achieving highly compliant growth of primary neurons and astrocytes on different geometries. Here, we expanded this technique and illustrated that neuralized cells derived from mouse embryonic stem cells (mESCs) followed stripes of variable widths with conformity equal to or higher than that of primary neurons and astrocytes. Our results indicate the presence of undifferentiated mESCs, which also conformed to the underlying patterns to a high degree. This is an exciting and unexpected outcome, as molecular mechanisms governing cell and ECM protein interactions are different in stem cells and primary cells. Our study enables further investigations into the development and electrophysiology of differentiating patterned neural stem cells.
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http://dx.doi.org/10.3390/ma14123174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8226677PMC
June 2021

Predictive and Diagnostic Biomarkers of Anastomotic Leakage: A Precision Medicine Approach for Colorectal Cancer Patients.

J Pers Med 2021 May 25;11(6). Epub 2021 May 25.

Department of Surgery, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.

Development of an anastomotic leak (AL) following intestinal surgery for the treatment of colorectal cancers is a life-threatening complication. Failure of the anastomosis to heal correctly can lead to contamination of the abdomen with intestinal contents and the development of peritonitis. The additional care that these patients require is associated with longer hospitalisation stays and increased economic costs. Patients also have higher morbidity and mortality rates and poorer oncological prognosis. Unfortunately, current practices for AL diagnosis are non-specific, which may delay diagnosis and have a negative impact on patient outcome. To overcome these issues, research is continuing to identify AL diagnostic or predictive biomarkers. In this review, we highlight promising candidate biomarkers including ischaemic metabolites, inflammatory markers and bacteria. Although research has focused on the use of blood or peritoneal fluid samples, we describe the use of implantable medical devices that have been designed to measure biomarkers in peri-anastomotic tissue. Biomarkers that can be used in conjunction with clinical status, routine haematological and biochemical analysis and imaging have the potential to help to deliver a precision medicine package that could significantly enhance a patient's post-operative care and improve outcomes. Although no AL biomarker has yet been validated in large-scale clinical trials, there is confidence that personalised medicine, through biomarker analysis, could be realised for colorectal cancer intestinal resection and anastomosis patients in the years to come.
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http://dx.doi.org/10.3390/jpm11060471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8229046PMC
May 2021

Planning for classroom physical distancing to minimize the threat of COVID-19 disease spread.

Authors:
Alan T Murray

PLoS One 2020 4;15(12):e0243345. Epub 2020 Dec 4.

Department of Geography, University of California, Santa Barbara, CA, United States of America.

The coronavirus disease 2019 is a respiratory illness spread between people. A primary weapon for reducing or eliminating this disease involves physical distancing to thwart transmission. Efforts to keep the economy moving include enacting physical distancing strategies that will increase the safety of workplaces, schools, businesses, etc. Given that education is a critical economic sector that impacts essentially all other sectors in some way, this paper details a planning approach for classroom physical distancing supported by spatial optimization. Devising a configuration of desks and/or workspaces that are physically distant is a type of dispersion problem that can be formalized mathematically and solved. Planning efforts for a university campus serve to illustrate how spatial optimization can support safety enhancements.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243345PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717562PMC
January 2021

Age-related changes in pulse risetime measured by multi-site photoplethysmography.

Physiol Meas 2020 08 11;41(7):074001. Epub 2020 Aug 11.

Centre for Intelligent Healthcare, Coventry University, Coventry, CV1 5FB, United Kingdom. Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, United Kingdom.

Objective: It is accepted that changes in the peripheral pulse waveform characteristics occur with ageing. Pulse risetime is one important feature which has clinical value. However, it is unclear how it varies across the full age spectrum from child to senior and for different peripheral measurement sites. The objectives of this study were to determine the association between age and pulse risetime characteristics over an 8-decade age range at the ears, fingers, and toes, and to consider effects arising from differences in systolic blood pressure (SBP), height and heart rate.

Approach: Multi-site photoplethysmography (MPPG) pulse waveforms were recorded non-invasively from the right and left ears, fingers, and toes of 304 normal healthy human subjects (range 6-87 years; 156 male and 148 female). SBP, height, and heart rate were also measured. Multi-site PPG pulse risetimes, and their site differences, were determined.

Main Results: Univariate regression analysis showed positive correlations with risetime for age (ears, fingers and toes: + 0.8, + 1.9, and + 1.1 ms/year, respectively), SBP (+0.5, + 1.3, and + 0.9 ms/mmHg) and height (+0.5, + 1.2, and + 1.0 ms/cm), but with a clear inverse association with heart rate (-1.8, - 2.5, and - 1.6 ms min) (P < 0.0001). No significant differences between male and female subjects were found for pulse risetime.

Significance: Normative multi-site PPG risetime characteristics have been defined in over 300 subjects and are shown to increase with age linearly up to the 8th decade. In contrast, we have shown that heart rate has a clear inverse relationship with risetime for all measurement sites.
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http://dx.doi.org/10.1088/1361-6579/ab9b67DOI Listing
August 2020

Differential Transcription of Selected Cytokine and Neuroactive Ligand-receptor Genes in Peripheral Leukocytes from Calves in Response to Cautery Disbudding.

Animals (Basel) 2020 Jul 14;10(7). Epub 2020 Jul 14.

School of Veterinary Science, Massey University, Palmerston North 4410, New Zealand.

Calf disbudding is a painful husbandry practice on dairy and beef cattle farms. An objective measurement of pain is useful to reliably evaluate the pain intensity and anti-nociceptive (analgesic) efficacy of therapeutic agents. The aim of this study was to investigate the changes in peripheral leucocyte inflammatory cytokine gene expression in calves after disbudding, and to assess whether the changes in cytokine gene expression could be an indicator of the efficacy of analgesic drugs. In a randomised controlled study, 16 calves (aged 31 to 41 days and weighing 58 to 73 kg), undergoing routine disbudding, were randomly allocated into two groups ( = 8 in each group). Calves in the control group received no analgesic, while those in the treatment group received 0.5 mg kg meloxicam subcutaneously prior to disbudding. Disbudding was performed using an electric debudder. Blood (10 mL) was sampled from the jugular vein just before and 4 and 24 h post-disbudding, RNA was extracted from leukocytes, and the transcription of 12 genes of interest was assessed using nCounter gene expression assay. The results showed significantly higher transcription (compared to baseline values) of the studied genes (except , , and ) in the control group calves at either 4 or 24 h post-disbudding. The administration of meloxicam one hour before disbudding significantly attenuated the upregulation of , , , , and gene transcription post-disbudding, while it did not suppress the elevated transcription of acute and pro-inflammatory cytokines such as , , , and genes. In conclusion, nCounter gene expression assay seems to be a promising tool to study the expression of cytokine genes and thus could be used for the pre-clinical evaluation of novel analgesics.
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http://dx.doi.org/10.3390/ani10071187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7401531PMC
July 2020

Miniaturisation of a peptide-based electrochemical protease activity sensor using platinum microelectrodes.

Analyst 2020 Feb;145(3):975-982

School of Engineering, Institute for Bioengineering, The University of Edinburgh, The King's Buildings, Mayfield Road, Edinburgh EH9 3JL, UK.

Proteases are ideal target biomarkers as they have been implicated in many disease states, including steps associated with cancer progression. Electrochemical peptide-based biosensors have attracted much interest in recent years. However, the significantly large size of the electrodes typically used in most of these platforms has led to performance limitations. These could be addressed by the enhancements offered by microelectrodes, such as rapid response times, improved mass transport, higher signal-to-noise and sensitivity, as well as more localised and less invasive measurements. We present the production and characterisation of a miniaturised electrochemical biosensor for the detection of trypsin, based on 25 μm diameter Pt microelectrodes (rather than the ubiquitous Au electrodes), benchmarked by establishing the equivalent Pt macroelectrode response in terms of quantitative response to the protease, the kinetics of cleavage and the effects of non-specific protein binding and temperature. Interestingly, although there was little difference between Au and Pt macroelectrode response, significant differences were observed between the responses of the Pt macroelectrode and microelectrode systems indicative of increased reproducibility in the microelectrode SAM structure and sensor performance between the electrodes, increased storage stability and a decrease in the cleavage rate at functionalised microelectrodes, which is mitigated by measurement at normal body temperature. Together, these results demonstrate the robustness and sensitivity of the miniaturised sensing platform and its ability to operate within the clinically-relevant concentration ranges of proteases in normal and disease states. These are critical features for its translation into implantable devices.
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http://dx.doi.org/10.1039/c9an02321fDOI Listing
February 2020

Massive Automatic Identification System Sensor Trajectory Data-Based Multi-Layer Linkage Network Dynamics of Maritime Transport along 21st-Century Maritime Silk Road.

Sensors (Basel) 2019 Sep 27;19(19). Epub 2019 Sep 27.

School of Geography and Tourism, Shaanxi Normal University, Xi'an 710119, China.

Automatic Identification System (AIS) data could support ship movement analysis, and maritime network construction and dynamic analysis. This study examines the global maritime network dynamics from multi-layers (bulk, container, and tanker) and multidimensional (e.g., point, link, and network) structure perspectives. A spatial-temporal framework is introduced to construct and analyze the global maritime transportation network dynamics by means of big trajectory data. Transport capacity and stability are exploited to infer spatial-temporal dynamics of system nodes and links. Maritime network structure changes and traffic flow dynamics grouping are then possible to extract. This enables the global maritime network between 2013 and 2016 to be investigated, and the differences between the countries along the 21st-century Maritime Silk Road and other countries, as well as the differences between before and after included by 21st-century Maritime Silk Road to be revealed. Study results indicate that certain countries, such as China, Singapore, Republic of Korea, Australia, and United Arab Emirates, build new corresponding shipping relationships with some ports of countries along the Silk Road and these new linkages carry significant traffic flow. The shipping dynamics exhibit interesting geographical and spatial variations. This study is meaningful to policy formulation, such as cooperation and reorientation among international ports, evaluating the adaptability of a changing traffic flow and navigation environment, and integration of the maritime economy and transportation systems.
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http://dx.doi.org/10.3390/s19194197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6806348PMC
September 2019

A Dual Killing Strategy: Photocatalytic Generation of Singlet Oxygen with Concomitant Pt Prodrug Activation.

Angew Chem Int Ed Engl 2019 10 30;58(40):14189-14192. Epub 2019 Aug 30.

EaStChem School of Chemistry, University of Edinburgh, David Brewster Road, Edinburgh, UK.

A ruthenium-based mitochondrial-targeting photosensitiser that undergoes efficient cell uptake, enables the rapid catalytic conversion of Pt prodrugs into their active Pt counterparts, and drives the generation of singlet oxygen was designed. This dual mode of action drives two orthogonal cancer-cell killing mechanisms with temporal and spatial control. The designed photosensitiser was shown to elicit cell death of a panel of cancer cell lines including those showing oxaliplatin-resistance.
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http://dx.doi.org/10.1002/anie.201908511DOI Listing
October 2019

A Novel Translational Ovine Pulmonary Adenocarcinoma Model for Human Lung Cancer.

Front Oncol 2019 19;9:534. Epub 2019 Jun 19.

The Royal (Dick) School of Veterinary Studies and Roslin Institute, University of Edinburgh, Easter Bush, Edinburgh, United Kingdom.

cell line and murine models have historically dominated pre-clinical cancer research. These models can be expensive and time consuming and lead to only a small percentage of anti-cancer drugs gaining a license for human use. Large animal models that reflect human disease have high translational value; these can be used to overcome current pre-clinical research limitations through the integration of drug development techniques with surgical procedures and anesthetic protocols, along with emerging fields such as implantable medical devices. Ovine pulmonary adenocarcinoma (OPA) is a naturally-occurring lung cancer that is caused by the jaagsiekte sheep retrovirus. The disease has similar histological classification and oncogenic pathway activation to that of human lung adenocarcinomas making it a valuable model for studying human lung cancer. Developing OPA models to include techniques used in the treatment of human lung cancer would enhance its translational potential, making it an excellent research tool in assessing cancer therapeutics. In this study we developed a novel OPA model to validate the ability of miniaturized implantable O and pH sensors to monitor the tumor microenvironment. Naturally-occurring pre-clinical OPA cases were obtained through an on-farm ultrasound screening programme. Sensors were implanted into OPA tumors of anesthetized sheep using a CT-guided trans-thoracic percutaneous implantation procedure. This study reports the findings from 9 sheep that received sensor implantations. Time taken from initial CT scans to the placement of a single sensor into an OPA tumor was 45 ± 5 min, with all implantations resulting in the successful delivery of sensors into tumors. Immediate post-implantation mild pneumothoraces occurred in 4 sheep, which was successfully managed in all cases. This is, to the best of our knowledge, the first description of the use of naturally-occurring OPA cases as a pre-clinical surgical model. Through the integration of techniques used in the treatment of human lung cancer patients, including ultrasound, general anesthesia, CT and surgery into the OPA model, we have demonstrated its translational potential. Although our research was tailored specifically for the implantation of sensors into lung tumors, we believe the model could also be developed for other pre-clinical applications.
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http://dx.doi.org/10.3389/fonc.2019.00534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611418PMC
June 2019

In vivo validation of a miniaturized electrochemical oxygen sensor for measuring intestinal oxygen tension.

Am J Physiol Gastrointest Liver Physiol 2019 08 12;317(2):G242-G252. Epub 2019 Jun 12.

Department of Surgery, Western General Hospital, Edinburgh, United Kingdom.

Recent advances in the fields of electronics and microfabrication techniques have led to the development of implantable medical devices for use within the field of precision medicine. Monitoring visceral surface tissue O tension () by means of an implantable sensor is potentially useful in many clinical situations, including the perioperative management of patients undergoing intestinal resection and anastomosis. This concept could provide a means by which treatment could be tailored to individual patients. This study describes the in vivo validation of a novel, miniaturized electrochemical O sensor to provide real-time data on intestinal . A single O sensor was placed onto the serosal surface of the small intestine of anesthetized rats that were exposed to ischemic (superior mesenteric artery occlusion) and hypoxemic (alterations in inspired fractional O concentrations) insults. Control experiments demonstrated that the sensors can function and remain stable in an in vivo environment. Intestinal decreased following superior mesenteric artery occlusion and with reductions in inspired O concentrations. These results were reversible after reinstating blood flow or by increasing inspired O concentrations. We have successfully developed an anesthetized rat intestinal ischemic and hypoxic model for validation of a miniaturized O sensor to provide real-time measurement of intestinal . Our results support further validation of the sensors in physiological conditions using a large animal model to provide evidence of their use in clinical applications where monitoring visceral surface tissue O tension is important. This is the first report of real-time continuous measurements of intestinal oxygen tension made using a microfabricated O sensor. Using a developed rodent model, we have validated this sensor's ability to accurately measure dynamic and reversible changes in intestinal oxygenation that occur through ischemic and hypoxemic insults. Continuous monitoring of local intestinal oxygenation could have value in the postoperative monitoring of patients having undergone intestinal surgery.
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http://dx.doi.org/10.1152/ajpgi.00050.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734375PMC
August 2019

Ovine Pulmonary Adenocarcinoma: A Unique Model to Improve Lung Cancer Research.

Front Oncol 2019 26;9:335. Epub 2019 Apr 26.

The Royal (Dick) School of Veterinary Studies and Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom.

Lung cancer represents a major worldwide health concern; although advances in patient management have improved outcomes for some patients, overall 5-year survival rates are only around 15%. studies and mouse models are commonly used to study lung cancer and their use has increased the molecular understanding of the disease. Unfortunately, mouse models are poor predictors of clinical outcome and seldom mimic advanced stages of the human disease. Animal models that more accurately reflect human disease are required for progress to be made in improving treatment outcomes and prognosis. Similarities in pulmonary anatomy and physiology potentially make sheep better models for studying human lung function and disease. Ovine pulmonary adenocarcinoma (OPA) is a naturally occurring lung cancer that is caused by the jaagsiekte sheep retrovirus. The disease is endemic in many countries throughout the world and has several features in common with human lung adenocarcinomas, including histological classification and activation of common cellular signaling pathways. Here we discuss the and OPA models that are currently available and describe the advantages of using pre-clinical naturally occurring OPA cases as a translational animal model for human lung adenocarcinoma. The challenges and options for obtaining these OPA cases for research purposes, along with their use in developing novel techniques for the evaluation of chemotherapeutic agents or for monitoring the tumor microenvironment in response to treatment, are also discussed.
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http://dx.doi.org/10.3389/fonc.2019.00335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6498990PMC
April 2019

Development and characterisation of acquired radioresistant breast cancer cell lines.

Radiat Oncol 2019 Apr 15;14(1):64. Epub 2019 Apr 15.

The Royal (Dick) School of Veterinary Studies and Roslin Institute, University of Edinburgh, Edinburgh, Scotland.

Background: Radiotherapy plays an important role in the multimodal treatment of breast cancer. The response of a breast tumour to radiation depends not only on its innate radiosensitivity but also on tumour repopulation by cells that have developed radioresistance. Development of effective cancer treatments will require further molecular dissection of the processes that contribute to resistance.

Methods: Radioresistant cell lines were established by exposing MDA-MB-231, MCF-7 and ZR-751 parental cells to increasing weekly doses of radiation. The development of radioresistance was evaluated through proliferation and colony formation assays. Phenotypic characterisation included migration and invasion assays and immunohistochemistry. Transcriptomic data were also generated for preliminary hypothesis generation involving pathway-focused analyses.

Results: Proliferation and colony formation assays confirmed radioresistance. Radioresistant cells exhibited enhanced migration and invasion, with evidence of epithelial-to-mesenchymal-transition. Significantly, acquisition of radioresistance in MCF-7 and ZR-751 cell lines resulted in a loss of expression of both ERα and PgR and an increase in EGFR expression; based on transcriptomic data they changed subtype classification from their parental luminal A to HER2-overexpressing (MCF-7 RR) and normal-like (ZR-751 RR) subtypes, indicating the extent of phenotypic changes and cellular plasticity involved in this process. Radioresistant cell lines derived from ER+ cells also showed a shift from ER to EGFR signalling pathways with increased MAPK and PI3K activity.

Conclusions: This is the first study to date that extensively describes the development and characterisation of three novel radioresistant breast cancer cell lines through both genetic and phenotypic analysis. More changes were identified between parental cells and their radioresistant derivatives in the ER+ (MCF-7 and ZR-751) compared with the ER- cell line (MDA-MB-231) model; however, multiple and likely interrelated mechanisms were identified that may contribute to the development of acquired resistance to radiotherapy.
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http://dx.doi.org/10.1186/s13014-019-1268-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466735PMC
April 2019

Complete Genome Sequence of the Telford Type S Strain of Mycobacterium avium subsp. paratuberculosis.

Microbiol Resour Announc 2019 Mar 14;8(11). Epub 2019 Mar 14.

AgResearch Ltd., Hopkirk Research Institute, Palmerston North, New Zealand

subsp. is the causative agent of Johne's disease (JD). Here, we report the complete genome sequence of Telford 9.2, a well-characterized representative strain of the subsp. S subtype that is endemic in New Zealand and Australian sheep.
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http://dx.doi.org/10.1128/MRA.00004-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424202PMC
March 2019

Preclinical Organotypic Models for the Assessment of Novel Cancer Therapeutics and Treatment.

Curr Top Microbiol Immunol 2019 Mar 12. Epub 2019 Mar 12.

The Royal (Dick) School of Veterinary Studies and Roslin Institute, University of Edinburgh, Easter Bush, Roslin, Midlothian, EH25 9RG, Edinburgh, UK.

The immense costs in both financial terms and preclinical research effort that occur in the development of anticancer drugs are unfortunately not matched by a substantial increase in improved clinical therapies due to the high rate of failure during clinical trials. This may be due to issues with toxicity or lack of clinical effectiveness when the drug is evaluated in patients. Currently, much cancer research is driven by the need to develop therapies that can exploit cancer cell adaptations to conditions in the tumor microenvironment such as acidosis and hypoxia, the requirement for more-specific, targeted treatments, or the exploitation of 'precision medicine' that can target known genomic changes in patient DNA. The high attrition rate for novel anticancer therapies suggests that the preclinical methods used in screening anticancer drugs need improvement. This chapter considers the advantages and disadvantages of 3D organotypic models in both cancer research and cancer drug screening, particularly in the areas of targeted drugs and the exploitation of genomic changes that can be used for therapeutic advantage in precision medicine.
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http://dx.doi.org/10.1007/82_2019_159DOI Listing
March 2019

Horizon scanning implanted biosensors in personalising breast cancer management: First pilot study of breast cancer patients views.

Health Sci Rep 2018 Apr;1(4):30

Edinburgh Cancer Research Centre, Institute of Genetic and Molecular Medicine, Western General Hospital, Edinburgh, Scotland.

Aims: This study aimed to explore breast cancer patients' understanding and acceptability of implanted biosensors (BS) within the primary tumour to personalise adjuvant radiotherapy, and to determine optimal design and number of BS, and evaluate potential clinical benefits as well as concerns about tolerance, toxicity, dwell time, and confidentiality of data.

Patients And Methods: A total of 32 patients treated by surgery (29 breast conserving, 3 mastectomy), postoperative radiotherapy and systemic therapy for early breast cancer, were recruited from a posttreatment radiotherapy clinic at a cancer centre. Patients participated in semistructured interviews. Interview transcripts were analysed using qualitative methods.

Results: Participants were aged 39 to 87 years, with a median age of 62 years. Most (N = 23[72%]) were unfamiliar with biosensors. The majority (N = 29[90.6%]) were supportive of the technology's potential use in future breast cancer treatment and were willing to accept biosensors (N = 28[88%]) if they were endorsed by their breast cancer consultant. Only 3 patients expressed concerns, predominantly about uncertainties on their role in the diagnostic and treatment pathway. Patients were flexible about the size and shape of BS, but had a preference for small size (N = 28 [87.5%]). Most (N = 22[69%]) would accept implantation of more than 5 BS and were flexible (N = 22[69%]) about indefinite dwell time. Patients had a strong preference for wireless powering of the BS (N = 28[87.5%]). Few had concerns about loss of confidentiality of data collected. All patients considered biosensors to be potentially of important clinical benefit.

Conclusions: While knowledge of biosensors was limited, patients were generally supportive of biosensors implanted within the primary tumour to collect data that might personalise and improve breast cancer radiotherapy in future.
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http://dx.doi.org/10.1002/hsr2.30DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6266376PMC
April 2018

Effect of Respiration on the Characteristic Ratios of Oscillometric Pulse Amplitude Envelope in Blood Pressure Measurement.

Annu Int Conf IEEE Eng Med Biol Soc 2018 Jul;2018:3646-3649

Systolic and diastolic blood pressures (BPs) are important physiological parameters for disease diagnosis. Systolic and diastolic characteristic ratios derived from oscillometric pulse waveform have been widely used to estimate automated non-invasive BPs in oscillometric BP measurement devices. The oscillometric pulse waveform is easily influenced by respiration, which may cause variability to the characteristic ratios and subsequently BP measurement. This study quantitatively investigated how respiration patterns (i.e., normal breathing and deep breathing) affect the systolic and diastolic characteristic ratios. The study was performed with clinical data collected from 39 healthy subjects, and each subject conducted BP measurements during normal and deep breathings. Analytical results showed that the systolic characteristic ratio increased significantly from 0.52 ± 0.13 under normal breathing to 0.58 ± 0.14under deep breathing (p < 0.05), and the diastolic characteristic ratio was not significantly affected from 0.75 ± 0.12 under normal breathing to 0.76 ± 0.13 under deep breathing (p = 0.48). In conclusion, deep breathing significantly affected the systolic characteristic ratio, suggesting that automated oscillometric BP device which is validated under resting condition should be strictly used for measurements under resting condition.
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http://dx.doi.org/10.1109/EMBC.2018.8512996DOI Listing
July 2018

Biocompatibility of common implantable sensor materials in a tumor xenograft model.

J Biomed Mater Res B Appl Biomater 2019 07 27;107(5):1620-1633. Epub 2018 Oct 27.

The Royal (Dick) School of Veterinary Studies and Roslin Institute, University of Edinburgh, Edinburgh, EH25 9RG, UK.

Real-time monitoring of tumor microenvironment parameters using an implanted biosensor could provide valuable information on the dynamic nature of a tumor's biology and its response to treatment. However, following implantation biosensors may lose functionality due to biofouling caused by the foreign body response (FBR). This study developed a novel tumor xenograft model to evaluate the potential of six biomaterials (silicon dioxide, silicon nitride, Parylene-C, Nafion, biocompatible EPOTEK epoxy resin, and platinum) to trigger a FBR when implanted into a solid tumor. Biomaterials were chosen based on their use in the construction of a novel biosensor, designed to measure spatial and temporal changes in intra-tumoral O , and pH. None of the biomaterials had any detrimental effect on tumor growth or body weight of the murine host. Immunohistochemistry showed no significant changes in tumor necrosis, hypoxic cell number, proliferation, apoptosis, immune cell infiltration, or collagen deposition. The absence of biofouling supports the use of these materials in biosensors; future investigations in preclinical cancer models are required, with a view to eventual applications in humans. To our knowledge this is the first documented investigation of the effects of modern biomaterials, used in the production of implantable sensors, on tumor tissue after implantation. © 2018 The Authors. Journal of Biomedical Materials Research Part B: Applied Biomaterials published by Wiley Periodicals, Inc. J Biomed Mater Res Part B, 2018. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 1620-1633, 2019.
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http://dx.doi.org/10.1002/jbm.b.34254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767110PMC
July 2019

Electrochemical sensing of human neutrophil elastase and polymorphonuclear neutrophil activity.

Biosens Bioelectron 2018 Nov 9;119:209-214. Epub 2018 Aug 9.

EaStCHEM, School of Chemistry, University of Edinburgh, Joseph Black Building, West Mains Road, Edinburgh EH9 3FJ, UK. Electronic address:

Human neutrophil elastase (HNE) is a serine protease, produced by polymorphonuclear neutrophils (PMNs), whose uncontrolled production has been associated with various inflammatory disease states as well as tumour proliferation and metastasis. Here we report the development and characterisation of an electrochemical peptide-based biosensor, which enables the detection of clinically relevant levels of HNE. The sensing platform was characterised in terms of its analytical performance, enzymatic cleavage kinetics and cross-reactivity and applied to the quantitative detection of protease activity from PMNs from human blood.
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http://dx.doi.org/10.1016/j.bios.2018.08.013DOI Listing
November 2018

Electrodrugs: an electrochemical prodrug activation strategy.

Chem Commun (Camb) 2018 Aug;54(66):9242-9245

EaStChem School of Chemistry, University of Edinburgh, David Brewster Rd, Edinburgh, EH9 3FJ, Scotland, UK.

The term electroceutical has been used to describe implanted devices that deliver electrical stimuli to modify biological function. Herein, we describe a new concept in electroceuticals, demonstrating for the first time the electrochemical activation of metal-based prodrugs. This is illustrated by the controlled activation of Pt(iv) prodrugs into their active Pt(ii) forms within a cellular context allowing selectivity and control of where, when and how much active drug is generated.
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http://dx.doi.org/10.1039/c8cc04151bDOI Listing
August 2018

Innovative multi-site photoplethysmography measurement and analysis demonstrating increased arterial stiffness in paediatric heart transplant recipients.

Physiol Meas 2018 08 1;39(7):074007. Epub 2018 Aug 1.

Microvascular Diagnostics, Northern Medical Physics and Clinical Engineering, Newcastle upon Tyne, NE7 7DN, United Kingdom. Department of Paediatric Cardiology, Freeman Hospital, Newcastle upon Tyne, NE7 7DN, United Kingdom. Sharkey and Di Maria to be assigned as joint first authors.

Objective: It has been documented that heart transplantation in children is often complicated by arterial hypertension and increased arterial stiffness. We use innovative multi-site photoplethysmography (MPPG) pulse measurement and analysis technology to assess changes in arterial stiffness in paediatric heart transplant recipients (HTRs) in comparison with healthy control (HC) children.

Approach: A group of 20 HTRs (median age 13.5 years, eight male) were compared to an overall age- and gender-matched group of 161 HCs (median age 11.6 years, 74 male). Peripheral pulse was recorded bilaterally using MPPG at the ear lobe, index finger and great toe sites, along with an electrocardiogram cardiac timing reference. Segmental pulse arrival times between peripheral sites (finger-ear, PATf-e; toe-finger, PATt-f; and toe-ear PATt-e) were calculated as arterial stiffness measures, and differences between subject groups were tested using multivariate analysis. Normalised ear, finger and toe pulse shapes were also studied and compared between groups.

Main Results: After correction for heart rate and diastolic and mean arterial blood pressures, the HTR group was found to have significantly lower segmental PATt-e and PATt-f measurements, with median values of 150 ms versus 172 ms in the HC group (p  =  0.02), and 104 ms versus 118 ms in the HC group (p  =  0.01), respectively, consistent with increased arterial stiffness in the patient group. The normalised ear, finger and toe sites showed only a mild elongation in each pulse rise time for the transplant group.

Significance: This study shows that innovative and easy-to-do MPPG gives further evidence for increased arterial stiffness in children who have undergone successful cardiac transplantation.
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http://dx.doi.org/10.1088/1361-6579/aac76aDOI Listing
August 2018

Novel optical assessments of tissue composition and viability using fluorescence spectroscopy and tissue oxygenation spectrophotometry in patients with systemic sclerosis: a pilot study.

Physiol Meas 2018 04 3;39(3):03NT02. Epub 2018 Apr 3.

Microvascular Diagnostics Service, Northern Medical Physics and Clinical Engineering Directorate, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom. Faculty of Medical Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.

Objective: Patients with systemic sclerosis (SSc) experience significant morbidity and mortality, therefore, the development of tests to aid its early diagnosis are very important. The aim of this pilot study was to assess the diagnostic value of novel optical non-invasive skin fluorescence spectroscopy (FS) and tissue oxygen saturation (TOS) viability measurements in patients with established SSc.

Approach: Two groups were studied, comprising 14 SSc patients and nine healthy controls (93% and 73% females, respectively). FS and TOS measurements were collected from three body sites: the forearm, chest, and calf. Fluorescence intensities at wavelengths attributed to collagen, elastin, and L-tryptophan were computed, with adjustment for melanin, and a normalised combined fluorescence score (NCFS) was determined.

Main Results: The NCFS was significantly higher (p  <  0.001) and the combined TOS significantly lower (p  <  0.001) in the SSc group. TOS measurements alone showed good classification accuracy (95.7%) at separating SSc from healthy control participants, with some clustering of values close to the 50% oxygenation level in both groups. When the composition and viability measures were combined and modelled using binary logistic regression, excellent results for the sample were obtained following leave one out cross validation (100%).

Significance: The results of this pilot study demonstrate the potential diagnostic utility of FS and TOS assessments in SSc patients and further work is now needed to validate these techniques prospectively in a larger group of SSc patients across the spectrum of the disease, and also patients with other types of vasculopathy and conditions that can cause skin fibrosis.
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http://dx.doi.org/10.1088/1361-6579/aab1a4DOI Listing
April 2018

A Universal Standard for the Validation of Blood Pressure Measuring Devices: Association for the Advancement of Medical Instrumentation/European Society of Hypertension/International Organization for Standardization (AAMI/ESH/ISO) Collaboration Statement.

Hypertension 2018 03 31;71(3):368-374. Epub 2018 Jan 31.

From the Hypertension Center STRIDE-7, National and Kapodistrian University of Athens, School of Medicine, Third Department of Medicine, Sotiria Hospital, Athens, Greece (G.S.S.); University of Tennessee Health Science Center (B.A.); Physikalisch-Technische Bundesanstalt, Berlin, Germany (S.M.); Foundation, Medical Research Institutes, Paris, France (R.A.); Medaval, Dublin, Ireland (N.A.); Clinic for Cardiology, Herz- und Diabeteszentrum NRW, Ruhr-Universität Bochum, Bad Oeynhausen, Germany (S.E.); Microlife, Switzerland (G.F.); General Electric Healthcare Technologies, USA (B.F.); Dräger, Lübeck, Germany (T.G.); Omron Healthcare, Kyoto, Japan (T.I.); Departments of Medicine and of Health Research and Policy, Stanford University School of Medicine, and Department of Statistics, Stanford University School of Humanities and Sciences, Stanford, USA (J.P.I); Institute of Cardiovascular Science, University College London and the National Institute for Health Research University College London Hospitals Biomedical Research Centre, United Kingdom (P.L.); Nuffield Department of Primary Care Health Sciences, Green Templeton College, University of Oxford, United Kingdom (R.M.); Newcastle University, United Kingdom (A.M.); Schulich Heart Program, Division of Cardiology, Sunnybrook Health Sciences Centre, University of Toronto, Canada (M.M.); Department of Medicine, University of Padova, Italy (P.P.); Department of Medicine and Surgery, University of Milano-Bicocca; Cardiology Unit and Department of Cardiovascular, Neural and Metabolic Sciences, S.Luca Hospital, Istituto Auxologco Italiano, Milano, Italy (G.P.); Welch Allyn, USA (D.Q.); PharmaSmart International, USA (J.S.); St. Thomas' Hospital, King's College London, United Kingdom (A.S.); Nihon Kohden, Tokyo, Japan (T.U.); Shanghai Institute of Hypertension, Department of Hypertension, Centre for Epidemiological Studies and Clinical Trials, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, China (J.W.); Office of Biostatistics Research, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD (C.O.W.); and The Conway Institute, University College Dublin, Ireland (E.O.B.).

In the past 30 years, several organizations, such as the US Association for the Advancement of Medical Instrumentation (AAMI), the British Hypertension Society, the European Society of Hypertension (ESH) Working Group on Blood Pressure (BP) Monitoring, and the International Organization for Standardization (ISO), have developed protocols for clinical validation of BP measuring devices. However, it is recognized that science, as well as patients, consumers, and manufacturers, would be best served if all BP measuring devices were assessed for accuracy according to an agreed single validation protocol that had global acceptance. Therefore, an international initiative was taken by the AAMI, ESH, and ISO experts who agreed to develop a universal standard for device validation. This statement presents the key aspects of a validation procedure, which were agreed by the AAMI, ESH, and ISO representatives as the basis for a single universal validation protocol. As soon as the AAMI/ESH/ISO standard is fully developed, this will be regarded as the single universal standard and will replace all other previous standards/protocols.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.117.10237DOI Listing
March 2018

A universal standard for the validation of blood pressure measuring devices: Association for the Advancement of Medical Instrumentation/European Society of Hypertension/International Organization for Standardization (AAMI/ESH/ISO) Collaboration Statement.

J Hypertens 2018 03;36(3):472-478

The Conway Institute, University College Dublin, Ireland.

: In the last 30 years, several organizations, such as the US Association for the Advancement of Medical Instrumentation (AAMI), the British Hypertension Society, the European Society of Hypertension (ESH) Working Group on Blood Pressure (BP) Monitoring and the International Organization for Standardization (ISO) have developed protocols for clinical validation of BP measuring devices. However, it is recognized that science, as well as patients, consumers and manufacturers would be best served if all BP measuring devices were assessed for accuracy according to an agreed single validation protocol that had global acceptance. Therefore, an international initiative was taken by AAMI, ESH and ISO experts who agreed to develop a universal standard for device validation. This statement presents the key aspects of a validation procedure, which were agreed by the AAMI, ESH and ISO representatives as the basis for a single universal validation protocol. As soon as the AAMI/ESH/ISO standard is fully developed, this will be regarded as the single universal standard and will replace all other previous standards/protocols.
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http://dx.doi.org/10.1097/HJH.0000000000001634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5796427PMC
March 2018

Variation of the Korotkoff Stethoscope Sounds During Blood Pressure Measurement: Analysis Using a Convolutional Neural Network.

IEEE J Biomed Health Inform 2017 11;21(6):1593-1598

Korotkoff sounds are known to change their characteristics during blood pressure (BP) measurement, resulting in some uncertainties for systolic and diastolic pressure (SBP and DBP) determinations. The aim of this study was to assess the variation of Korotkoff sounds during BP measurement by examining all stethoscope sounds associated with each heartbeat from above systole to below diastole during linear cuff deflation. Three repeat BP measurements were taken from 140 healthy subjects (age 21 to 73 years; 62 female and 78 male) by a trained observer, giving 420 measurements. During the BP measurements, the cuff pressure and stethoscope signals were simultaneously recorded digitally to a computer for subsequent analysis. Heartbeats were identified from the oscillometric cuff pressure pulses. The presence of each beat was used to create a time window (1 s, 2000 samples) centered on the oscillometric pulse peak for extracting beat-by-beat stethoscope sounds. A time-frequency two-dimensional matrix was obtained for the stethoscope sounds associated with each beat, and all beats between the manually determined SBPs and DBPs were labeled as "Korotkoff." A convolutional neural network was then used to analyze consistency in sound patterns that were associated with Korotkoff sounds. A 10-fold cross-validation strategy was applied to the stethoscope sounds from all 140 subjects, with the data from ten groups of 14 subjects being analyzed separately, allowing consistency to be evaluated between groups. Next, within-subject variation of the Korotkoff sounds analyzed from the three repeats was quantified, separately for each stethoscope sound beat. There was consistency between folds with no significant differences between groups of 14 subjects (P = 0.09 to P = 0.62). Our results showed that 80.7% beats at SBP and 69.5% at DBP were analyzed as Korotkoff sounds, with significant differences between adjacent beats at systole (13.1%, P = 0.001) and diastole (17.4%, P < 0.001). Results reached stability for SBP (97.8%, at sixth beat below SBP) and DBP (98.1%, at sixth beat above DBP) with no significant differences between adjacent beats (SBP P = 0.74; DBP P = 0.88). There were no significant differences at high-cuff pressures, but at low pressures close to diastole there was a small difference (3.3%, P = 0.02). In addition, greater within subject variability was observed at SBP (21.4%) and DBP (28.9%), with a significant difference between both (P < 0.02). In conclusion, this study has demonstrated that Korotkoff sounds can be consistently identified during the period below SBP and above DBP, but that at systole and diastole there can be substantial variations that are associated with high variation in the three repeat measurements in each subject.
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http://dx.doi.org/10.1109/JBHI.2017.2703115DOI Listing
November 2017

Heart sound classification from unsegmented phonocardiograms.

Physiol Meas 2017 Jul 31;38(8):1658-1670. Epub 2017 Jul 31.

School of Engineering and Computer Science, University of Hull, Hull, United Kingdom.

Objective: Most algorithms for automated analysis of phonocardiograms (PCG) require segmentation of the signal into the characteristic heart sounds. The aim was to assess the feasibility for accurate classification of heart sounds on short, unsegmented recordings.

Approach: PCG segments of 5 s duration from the PhysioNet/Computing in Cardiology Challenge database were analysed. Initially the 5 s segment at the start of each recording (seg 1) was analysed. Segments were zero-mean but otherwise had no pre-processing or segmentation. Normalised spectral amplitude was determined by fast Fourier transform and wavelet entropy by wavelet analysis. For each of these a simple single feature threshold-based classifier was implemented and the frequency/scale and thresholds for optimum classification accuracy determined. The analysis was then repeated using relatively noise free 5 s segments (seg 2) of each recording. Spectral amplitude and wavelet entropy features were then combined in a classification tree.

Main Results: There were significant differences between normal and abnormal recordings for both wavelet entropy and spectral amplitude across scales and frequency. In the wavelet domain the differences between groups were greatest at highest frequencies (wavelet scale 1, pseudo frequency 1 kHz) whereas in the frequency domain the differences were greatest at low frequencies (12 Hz). Abnormal recordings had significantly reduced high frequency wavelet entropy: (Median (interquartile range)) 6.63 (2.42) versus 8.36 (1.91), p  <  0.0001, suggesting the presence of discrete high frequency components in these recordings. Abnormal recordings exhibited significantly greater low frequency (12 Hz) spectral amplitude: 0.24 (0.22) versus 0.09 (0.15), p  <  0.0001. Classification accuracy (mean of specificity and sensitivity) was greatest for wavelet entropy: 76% (specificity 54%, sensitivity 98%) versus 70% (specificity 65%, sensitivity 75%) and was further improved by selecting the lowest noise segment (seg 2): 80% (specificity 65%, sensitivity 94%) versus 71% (specificity 63%, sensitivity 79%). Classification tree with combined features gave accuracy 79% (specificity 80%, sensitivity 77%).

Significance: The feasibility of accurate classification without segmentation of the characteristic heart sounds has been demonstrated. Classification accuracy is comparable to other algorithms but achieved without the complexity of segmentation.
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http://dx.doi.org/10.1088/1361-6579/aa724cDOI Listing
July 2017

A method for extracting respiratory frequency during blood pressure measurement, from oscillometric cuff pressure pulses and Korotkoff sounds recorded during the measurement.

Annu Int Conf IEEE Eng Med Biol Soc 2016 Aug;2016:4268-4271

Respiratory frequency is an important physiological feature commonly used to assess health. However, the current measurements involve dedicated devices which not only increase the medical cost but also make health monitoring inconvenient. Earlier studies have shown that respiratory frequency could be extracted from electrocardiography (ECG) signal, but little was done to assess the possibility of extracting respiratory frequency from oscillometric cuff pressure pulses (OscP) or Korotkoff sounds (KorS), which are normally used for measuring blood pressure and more easily accessible than the ECG signal. This study presented a method to extract respiratory frequency from OscP and KorS during clinical blood pressure measurement. The method was evaluated with clinical data collected from 15 healthy participants, and its measurement accuracy was compared with a reference respiratory rate obtained with a magnetometer. Experimental results showed small non-significant mean absolute bias (0.019 Hz for OscP and 0.024 Hz for KorS) and high correlation (0.7 for both OscP and KorS) between the reference respiratory frequency and respiratory frequency extracted from OscP or KorS, indicating the high reliability of extracting respiratory frequency from OscP and KorS during normal blood pressure measurement.
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http://dx.doi.org/10.1109/EMBC.2016.7591670DOI Listing
August 2016

Investigating parylene-HT as a substrate for human cell patterning.

Annu Int Conf IEEE Eng Med Biol Soc 2016 Aug;2016:141-144

We demonstrate, for the first time, how parylene-HT on SiO2 substrates can be used as a human cell patterning platform. We demonstrate this platform with hNT astrocytes, derived from the human NTera2.D1 cell line. We show how hNT astrocytes are attracted to Parylene-HT and repelled by the SiO2 and are shown to adopt a similar morphology as that attained on standard tissue culture polystyrene. Furthermore, parylene-HT was capable of patterning the astrocytes achieving a ratio of 8:1 for cells on parylene compared to SiO2. Thus, as parylene-HT has similar physical properties to parylene-C with the addition of UV and thermal resistance, parylene-HT represents a desirable alternative substrate for human cell patterning.
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http://dx.doi.org/10.1109/EMBC.2016.7590660DOI Listing
August 2016

Experimental infection of New Zealand Merino sheep with a suspension of Mycobacterium avium subspecies paratuberculosis (Map) strain Telford: Kinetics of the immune response, histopathology and Map culture.

Vet Microbiol 2016 Nov 23;195:136-143. Epub 2016 Sep 23.

Institute of Veterinary, Animal and Biomedical Sciences, Massey University, Private Bag 11222, Palmerston North, New Zealand; Unité de Génétique Mycobactérienne, Institut Pasteur, Paris Cedex 15, France.

A long-term study was undertaken to monitor immune responses, faecal cultures and clinical disease in sheep experimentally infected with Mycobacterium avium subspecies paratuberculosis (Map) strain Telford. New Zealand Merino lambs (N=56) were challenged with three oral doses of Map suspension. The lambs were weighed and faecal and blood samples obtained at different time-points. At 63 weeks post-challenge, surviving sheep were euthanised and samples of liver, ileo-caecal valve and mesenteric lymph node were collected for histopathology and Map culture. High IFN-γ and antibody responses were evident as early as 8 weeks post-C1 which persisted until the end of the trial. Approximately 92% of the sheep shed Map in faeces at 36 weeks post-challenge, with the prevalence decreasing to around 40% at the end of the trial. Thirteen sheep progressively lost weight and were euthanised between weeks 32 and 58 post-challenge. Nearly 58% of surviving sheep exhibited histo-pathological lesions in at least one of the three tissues sampled, while 42% showed acid-fast bacilli in at least one tissue. A positive Map culture in at least one tissue was obtained from approximately 85% of sheep. These results indicate that the three doses of Map challenge were highly effective in establishing Johne's disease in NZ Merino lambs.
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http://dx.doi.org/10.1016/j.vetmic.2016.09.018DOI Listing
November 2016

Comparative approaches for assessing access to alcohol outlets: exploring the utility of a gravity potential approach.

Popul Health Metr 2016 2;14:25. Epub 2016 Aug 2.

School of Criminal Justice, University at Albany, State University of New York, 1400 Washington Ave., Albany, NY 12222 USA.

Background: A growing body of research recommends controlling alcohol availability to reduce harm. Various common approaches, however, provide dramatically different pictures of the physical availability of alcohol. This limits our understanding of the distribution of alcohol access, the causes and consequences of this distribution, and how best to reduce harm. The aim of this study is to introduce both a gravity potential measure of access to alcohol outlets, comparing its strengths and weaknesses to other popular approaches, and an empirically-derived taxonomy of neighborhoods based on the type of alcohol access they exhibit.

Methods: We obtained geospatial data on Seattle, including the location of 2402 alcohol outlets, United States Census Bureau estimates on 567 block groups, and a comprehensive street network. We used exploratory spatial data analysis and employed a measure of inter-rater agreement to capture differences in our taxonomy of alcohol availability measures.

Results: Significant statistical and spatial variability exists between measures of alcohol access, and these differences have meaningful practical implications. In particular, standard measures of outlet density (e.g., spatial, per capita, roadway miles) can lead to biased estimates of physical availability that over-emphasize the influence of the control variables. Employing a gravity potential approach provides a more balanced, geographically-sensitive measure of access to alcohol outlets.

Conclusions: Accurately measuring the physical availability of alcohol is critical for understanding the causes and consequences of its distribution and for developing effective evidence-based policy to manage the alcohol outlet licensing process. A gravity potential model provides a superior measure of alcohol access, and the alcohol access-based taxonomy a helpful evidence-based heuristic for scholars and local policymakers.
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http://dx.doi.org/10.1186/s12963-016-0097-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4969650PMC
September 2017
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