Publications by authors named "Edmund Arthur"

12 Publications

  • Page 1 of 1

The relationship between cerebral and retinal microbleeds in cerebral amyloid angiopathy (CAA): A pilot study.

J Neurol Sci 2021 04 1;423:117383. Epub 2021 Mar 1.

Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI, USA; George and Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI, USA; Department of Neurology, Alpert Medical School of Brown University, Providence, RI, USA; Department of Surgery (Ophthalmology), Alpert Medical School of Brown University, Providence, RI, USA.

Background: The standard in vivo diagnostic imaging technique for cerebral amyloid angiopathy (CAA) is costly and thereby of limited utility for point-of-care diagnosis and monitoring of treatment efficacy. Recent recognition that retinal changes may reflect cerebral changes in neurodegenerative disease provides an ideal opportunity for development of accessible and cost-effective biomarkers for point-of-care use in the detection and monitoring of CAA. In this pilot study, we examined structural and angiographic retinal changes in CAA patients relative to a control group, and compared retinal and cerebral pathology in a group of CAA patients.

Methods: We used spectral domain optical coherence tomography (SD-OCT) to image the retina and compared retinal microbleeds to both cerebral microbleeds and white matter hyperintensities (WMH) in CAA patients, as seen on MRI. We compared retinal angiographic changes, along with structural retinal neuronal layer changes in CAA patients and cognitively normal older adults, and examined the relationship between retinal and cerebral microbleeds and cognition in CAA patients.

Results: We found a trend level correlation between retinal and cerebral microbleeds in CAA patients. Moreover, we found a significant correlation between retinal microbleeds and episodic memory performance in CAA patients. There were no significant group differences between CAA patients and cognitively normal older adults on retinal angiographic or structural measurements.

Conclusion: Retinal microbleeds may reflect degree of cerebral microbleed burden in CAA. This picture was complicated by systolic hypertension in the CAA group, which is a confounding factor for the interpretation of these data. Our results stimulate motivation for pursuit of a more comprehensive prospective study to determine the feasibility of retinal biomarkers in CAA.
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http://dx.doi.org/10.1016/j.jns.2021.117383DOI Listing
April 2021

Safety and Tolerability of APOE Genotyping and Disclosure in Cognitively Normal Volunteers From the Butler Alzheimer's Prevention Registry.

J Geriatr Psychiatry Neurol 2021 Feb 8:891988721993575. Epub 2021 Feb 8.

Butler Hospital Memory & Aging Program, Providence, RI, USA.

Aims: Alzheimer's disease (AD) is a gradually progressive neurodegenerative disease that ultimately results in total loss of cognitive and functional independence in older adults. This study aimed to examine the safety and tolerability of disclosure in community-dwelling, cognitively normal (CN) older adults from the Butler Alzheimer's Prevention Registry (BAPR), and to determine whether disclosure impacted participant's decisions to participate in AD clinical research.

Methods: 186 (N = 106 ∊4 non-carriers, 80 ∊4 carriers) CN older adults aged 58-78 from the BAPR completed 2 visits: one for psychological readiness screening and genotyping and one for disclosure. Online follow-ups were completed 3 days, 6 weeks, and 6 months post-disclosure. Primary outcomes were scores on self-report measures of depression, anxiety, impact of events, and perceived risk of AD, along with enrollment in AD clinical trials.

Results: ∊4 carriers and non-carriers did not differ significantly on measures of depression, anxiety, or suicidal ideation over the 6-month follow-up period. ∊4 carriers reported higher impact of disclosure than non-carriers immediately after disclosure, but both groups' scores on impact of events measures remained sub-clinical. ∊4 carriers and non-carriers were equally likely to participate in AD research after disclosure, with genotype-dependent differences in type of clinical trial enrollment.

Conclusions: genotyping and disclosure was safe and well tolerated in a group of CN, community-dwelling older adults, who were pre-screened after volunteering for AD research through BAPR. Implications for the inclusion of genotyping and disclosure at AD clinical trial sites are discussed.
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http://dx.doi.org/10.1177/0891988721993575DOI Listing
February 2021

Portable, non-invasive video imaging of retinal blood flow dynamics.

Sci Rep 2020 11 19;10(1):20236. Epub 2020 Nov 19.

Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, 1638 N.W. 10th Avenue, Room 509, Miami, FL, 33136, USA.

Retinal blood flow (RBF) information has the potential to offer insight into ophthalmic health and disease that is complementary to traditional anatomical biomarkers as well as to retinal perfusion information provided by fluorescence or optical coherence tomography angiography (OCT-A). The present study was performed to test the functional attributes and performance of the XyCAM RI, a non-invasive imager that obtains and assesses RBF information. The XyCAM RI was installed and used in two different settings to obtain video recordings of the blood flow in the optic nerve head region in eyes of healthy subjects. The mean blood flow velocity index (BFVi) in the optic disc and in each of multiple arterial and venous segments was obtained and shown to reveal a temporal waveform with a peak and trough that correlates with a cardiac cycle as revealed by a reference pulse oximeter (correlation between respective peak-to-peak distances was 0.977). The intra-session repeatability of the XyCAM RI was high with a coefficient of variation (CV) of 1.84 ± 1.13% across both sites. Artery-vein comparisons were made by estimating, in a pair of adjacent arterial and venous segments, various temporal waveform metrics such as pulsatility index, percent time in systole and diastole, and change in vascular blood volume over a cardiac cycle. All arterial metrics were shown to have significant differences with venous metrics (p < 0.001). The XyCAM RI, therefore, by obtaining repeatable blood flow measurements with high temporal resolution, permits the differential assessment of arterial and venous blood flow patterns in the retina that may facilitate research into disease pathophysiology and biomarker development for diagnostics.
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http://dx.doi.org/10.1038/s41598-020-76407-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677377PMC
November 2020

A recommended "minimum data set" framework for SD-OCT retinal image acquisition and analysis from the Atlas of Retinal Imaging in Alzheimer's Study (ARIAS).

Alzheimers Dement (Amst) 2020 1;12(1):e12119. Epub 2020 Nov 1.

Department of Biomedical and Pharmaceutical Sciences University of Rhode Island Kingston Rhode Island USA.

Introduction: We propose a minimum data set framework for the acquisition and analysis of retinal images for the development of retinal Alzheimer's disease (AD) biomarkers. Our goal is to describe methodology that will increase concordance across laboratories, so that the broader research community is able to cross-validate findings in parallel, accumulate large databases with normative data across the cognitive aging spectrum, and progress the application of this technology from the discovery stage to the validation stage in the search for sensitive and specific retinal biomarkers in AD.

Methods: The proposed minimum data set framework is based on the Atlas of Retinal Imaging Study (ARIAS), an ongoing, longitudinal, multi-site observational cohort study. However, the ARIAS protocol has been edited and refined with the expertise of all co-authors, representing 16 institutions, and research groups from three countries, as a first step to address a pressing need identified by experts in neuroscience, neurology, optometry, and ophthalmology at the Retinal Imaging in Alzheimer's Disease (RIAD) conference, convened by the Alzheimer's Association and held in Washington, DC, in May 2019.

Results: Our framework delineates specific imaging protocols and methods of analysis for imaging structural changes in retinal neuronal layers, with optional add-on procedures of fundus autofluorescence to examine beta-amyloid accumulation and optical coherence tomography angiography to examine AD-related changes in the retinal vasculature.

Discussion: This minimum data set represents a first step toward the standardization of retinal imaging data acquisition and analysis in cognitive aging and AD. A standardized approach is essential to move from discovery to validation, and to examine which retinal AD biomarkers may be more sensitive and specific for the different stages of the disease severity spectrum. This approach has worked for other biomarkers in the AD field, such as magnetic resonance imaging; amyloid positron emission tomography; and, more recently, blood proteomics. Potential context of use for retinal AD biomarkers is discussed.
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http://dx.doi.org/10.1002/dad2.12119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604454PMC
November 2020

Disruption of cholinergic neurotransmission, within a cognitive challenge paradigm, is indicative of Aβ-related cognitive impairment in preclinical Alzheimer's disease after a 27-month delay interval.

Alzheimers Res Ther 2020 03 24;12(1):31. Epub 2020 Mar 24.

Department of Biological & Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, 75 Lower College Road, 2nd Floor, Kingston, RI, USA.

Background: Abnormal beta-amyloid (Aβ) is associated with deleterious changes in central cholinergic tone in the very early stages of Alzheimer's disease (AD), which may be unmasked by a cholinergic antagonist (J Prev Alzheimers Dis 1:1-4, 2017). Previously, we established the scopolamine challenge test (SCT) as a "cognitive stress test" screening measure to identify individuals at risk for AD (Alzheimer's & Dementia 10(2):262-7, 2014) (Neurobiol. Aging 36(10):2709-15, 2015). Here we aim to demonstrate the potential of the SCT as an indicator of cognitive change and neocortical amyloid aggregation after a 27-month follow-up interval.

Methods: Older adults (N = 63, aged 55-75 years) with self-reported memory difficulties and first-degree family history of AD completed the SCT and PET amyloid imaging at baseline and were then seen for cognitive testing at 9, 18, and 27 months post-baseline. Repeat PET amyloid imaging was completed at the time of the 27-month exam.

Results: Significant differences in both cognitive performance and in Aβ neocortical burden were observed between participants who either failed vs. passed the SCT at baseline, after a 27-month follow-up period.

Conclusions: Cognitive response to the SCT (Alzheimer's & Dementia 10(2):262-7, 2014) at baseline is related to cognitive change and PET amyloid imaging results, over the course of 27 months, in preclinical AD. The SCT may be a clinically useful screening tool to identify individuals who are more likely to both have positive evidence of amyloidosis on PET imaging and to show measurable cognitive decline over several years.
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http://dx.doi.org/10.1186/s13195-020-00599-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093953PMC
March 2020

Developing retinal biomarkers for the earliest stages of Alzheimer's disease: What we know, what we don't, and how to move forward.

Alzheimers Dement 2020 01;16(1):229-243

Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island, USA.

The last decade has seen a substantial increase in research focused on the identification, development, and validation of diagnostic and prognostic retinal biomarkers for Alzheimer's disease (AD). Sensitive retinal biomarkers may be advantageous because they are cost and time efficient, non-invasive, and present a minimal degree of patient risk and a high degree of accessibility. Much of the work in this area thus far has focused on distinguishing between symptomatic AD and/or mild cognitive impairment (MCI) and cognitively normal older adults. Minimal work has been done on the detection of preclinical AD, the earliest stage of AD pathogenesis characterized by the accumulation of cerebral amyloid absent clinical symptoms of MCI or dementia. The following review examines retinal structural changes, proteinopathies, and vascular alterations that have been proposed as potential AD biomarkers, with a focus on studies examining the earliest stages of disease pathogenesis. In addition, we present recommendations for future research to move beyond the discovery phase and toward validation of AD risk biomarkers that could potentially be used as a first step in a multistep screening process for AD risk detection.
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http://dx.doi.org/10.1002/alz.12006DOI Listing
January 2020

Distinguishing cognitive impairment by using singularity spectrum and lacunarity analysis of the retinal vascular network.

Neurophotonics 2019 Oct 23;6(4):041109. Epub 2019 Sep 23.

University of Miami, Bascom Palmer Eye Institute, Department of Ophthalmology, Miami, Florida, United States.

The development of effective therapies for cognitive impairment (CI), especially due to Alzheimer's disease, demands diagnosing the condition during the prodromal phase. The diagnosis of CI involves expensive and invasive methods, such as positron emission tomography and cerebrospinal fluid assessment via spinal tap. Hence, a comparatively lower cost and noninvasive method of diagnosis is imperative. The human retina is an extension of the brain characterized by similarities in vascular and neural structures. The complications of CI are not only limited to the brain but also affect the retina for which the loss of retinal ganglion cells has been associated with neurodegeneration in the brain. The loss of retinal ganglion cells in individuals with CI may be related to reduced vascular demand and a potential remodeling of the retinal vascular branching complexity. Retinal imaging biomarkers may provide a low cost and noninvasive alternative for the diagnosis of CI. In this study, the retinal vascular branching complexity of patients with CI was characterized using the singularity spectrum multifractal dimension and lacunarity parameter. A reduced vascular branching complexity was observed in subjects with CI when compared to age- and sex-matched cognitively healthy controls. Significant associations were also found between retinal vascular and functional parameters.
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http://dx.doi.org/10.1117/1.NPh.6.4.041109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756485PMC
October 2019

Distances From Capillaries to Arterioles or Venules Measured Using OCTA and AOSLO.

Invest Ophthalmol Vis Sci 2019 05;60(6):1833-1844

Indiana University School of Optometry, Bloomington, Indiana, United States.

Purpose: To investigate distances from retinal capillaries to arterioles or venules noninvasively.

Methods: An adaptive optics scanning laser ophthalmoscope (AOSLO) and optical coherence tomography angiography (OCTA) imager acquired detailed maps of retinal vasculature. Using OCTA, we quantified the distance from the edge of an arteriole or venule to the middle of the nearest capillaries (periarteriole or perivenule capillary-free zones, respectively) within the superficial vascular plexus of 20 young healthy subjects with normal axial lengths. These distances were compared to AOSLO images for three subjects. We tested the relation between the peripheral capillary-free zones and FAZ horizontal, vertical, effective diameters, and asymmetry indices in the deep vascular plexus. We examined enlargement with OCTA of capillary-free zones in a type 2 diabetic patient.

Results: The periarteriole capillary-free zone (67.2 ± 25.3 μm) was readily visible and larger than the perivenule capillary-free zone (42.7 ± 14.4 μm), F(1, 998) = 771, P < 0.0001. The distance from foveal center (P = 0.003) and diameter (P = 0.048) were predictive of perivenule capillary-free zone values. OCTA and AOSLO corresponded for arterioles. FAZ effective diameter was positively associated with asymmetry indices, r = 0.49, P = 0.028, but not peripheral capillary-free zones, although focal enlargements were found in a diabetic patient.

Conclusions: For normal retinas, periarteriole and perivenule capillary-free zones are readily visible with OCTA and AOSLO. Periarteriole capillary-free zones were larger, consistent with arterioles carrying oxygen rich blood that diffuses to support the retina.
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http://dx.doi.org/10.1167/iovs.18-25294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892442PMC
May 2019

Central Macular Thickness in Diabetic Patients: A Sex-based Analysis.

Optom Vis Sci 2019 04;96(4):266-275

School of Optometry, University of California Berkeley, Berkeley, California.

Significance: The pathological changes in clinically significant diabetic macular edema lead to greater retinal thickening in men than in women. Therefore, male sex should be considered a potential risk factor for identifying individuals with the most severe pathological changes. Understanding this excessive retinal thickening in men may help preserve vision.

Purpose: The purpose of this study was to investigate the sex differences in retinal thickness in diabetic patients. We tested whether men with clinically significant macular edema had even greater central macular thickness than expected from sex differences without significant pathological changes. This study also aimed to determine which retinal layers contribute to abnormal retinal thickness.

Methods: From 2047 underserved adult diabetic patients from Alameda County, CA, 142 patients with clinically significant macular edema were identified by EyePACS-certified graders using color fundus images (Canon CR6-45NM). First, central macular thickness from spectral domain optical coherence tomography (iVue; Optovue Inc.) was compared in 21 men versus 21 women without clinically significant macular edema. Then, a planned comparison contrasted the greater values of central macular thickness in men versus women with clinically significant macular edema as compared with those without. Mean retinal thickness and variability of central macular layers were compared in men versus women.

Results: Men without clinically significant macular edema had a 12-μm greater central macular thickness than did women (245 ± 21.3 and 233 ± 13.4 μm, respectively; t40 = -2.18, P = .04). Men with clinically significant macular edema had a 67-μm greater central macular thickness than did women (383 ± 48.7 and 316 ± 60.4 μm, P < .001); that is, men had 55 μm or more than five times more (t20 = 2.35, P = .02). In men, the outer-nuclear-layer thickness was more variable, F10,10 = 9.34.

Conclusions: Underserved diabetic men had thicker retinas than did women, exacerbated by clinically significant macular edema.
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http://dx.doi.org/10.1097/OPX.0000000000001363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445750PMC
April 2019

Investigating Multimodal Diagnostic Eye Biomarkers of Cognitive Impairment by Measuring Vascular and Neurogenic Changes in the Retina.

Front Physiol 2018 6;9:1721. Epub 2018 Dec 6.

Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami, Miami, FL, United States.

Previous studies have demonstrated that cognitive impairment (CI) is not limited to the brain but also affects the retina. In this pilot study, we investigated the correlation between the retinal vascular complexity and neurodegenerative changes in patients with CI using a low-cost multimodal approach. Quantification of the retinal structure and function were conducted for every subject ( = 69) using advanced retinal imaging, full-field electroretinogram (ERG) and visual performance exams. The retinal vascular parameters were calculated using the Singapore Institute Vessel Assessment software. The Montreal Cognitive Assessment was used to measure CI. Pearson product moment correlation was performed between variables. Of the 69 participants, 32 had CI (46%). We found significantly altered microvascular network in individuals with CI (larger venular-asymmetry factor: 0.7 ± 0.2) compared with controls (0.6 ± 0.2). The vascular fractal dimension was lower in individuals with CI (capacity, information and correlation dimensions: D, D and D (mean ± SD): 1.57 ± 0.06; 1.56 ± 0.06; 1.55 ± 0.06; age 81 ± 6years) vs. controls (1.61 ± 0.03; 1.59 ± 0.03; 1.58 ± 0.03; age: 80 ± 7 years). Also, drusen-like regions in the peripheral retina along with pigment dispersion were noted in subjects with mild CI. Functional loss in color vision as well as smaller ERG amplitudes and larger peak times were observed in the subjects with CI. Pearson product moment correlation showed significant associations between the vascular parameters (artery-vein ratio, total length-diameter ratio, D, D, D and the implicit time (IT) of the flicker response but these associations were not significant in the partial correlations. This study illustrates that there are multimodal retinal markers that may be sensitive to CI decline, and adds to the evidence that there is a statistical trend pointing to the correlation between retinal neuronal dysfunction and microvasculature changes suggesting that retinal geometric vascular and functional parameters might be associated with physiological changes in the retina due to CI. We suspect our analysis of combined structural-functional parameters, instead of individual biomarkers, may provide a useful clinical marker of CI that could also provide increased sensitivity and specificity for the differential diagnosis of CI. However, because of our study sample was small, the full extent of clinical applicability of our approach is provocative and still to be determined.
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http://dx.doi.org/10.3389/fphys.2018.01721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291749PMC
December 2018

Subtle changes in diabetic retinas localised in 3D using OCT.

Ophthalmic Physiol Opt 2018 09 26;38(5):477-491. Epub 2018 Jul 26.

Indiana University School of Optometry, Bloomington, USA.

Purpose: To detect and localise subtle changes in retinas of diabetic patients who clinically have no diabetic retinopathy (DR) or non-proliferative DR (NPDR) as compared to age- and sex- matched controls. Spectral Domain Optical Coherence Tomography (SD-OCT) and software to examine all retinal layers, including deeper layers, were used to quantify foveal avascular zone size and inner and outer retinal layer thicknesses, as well as to detect axial location of prominent lesions.

Methods: Diabetic subjects, 19 total with 16 having no DR and three having non-proliferative retinopathy, were matched with 19 controls with respect to age and sex. Macular-centred SD-OCT grids of 20 × 15° were taken with the Spectralis. En face or transverse images were generated from the SD-OCT data by automatically segmenting all retinal layers. The transverse images were investigated for foveal avascular zone (FAZ) size, retinal vessel calibre, and structural changes. The size of the FAZ was compared for diabetics vs controls using vendor software and manual marking in Photoshop. Inner retinal layer (IRL ) and outer nuclear layer (ONL ) thicknesses at the margins of the FAZ were measured using vendor software.

Results: The FAZ area was larger for diabetics (mean ± S.D. = 0.388 ± 0.074 mm ) than controls (0.243 ± 0.113 mm ), t = 5.27, p < 0.0001, using vendor software. The mean IRL was thicker for the diabetics (86.8 ± 14.5 μm) than controls (65.2 ± 16.3 μm), t = 4.59, p = 0.00023, despite lack of exudation by clinical exam. There was no significant association between FAZ area and mean IRL for the diabetics, r = 0.099, p = 0.69. Vessels not clinically detected were visible in the NFL transverse image of most diabetics, especially for a mild NPDR patient. A prominent lesion found in the en face infra-red image of a mild NPDR subject was localised in the photoreceptor layer by SD-OCT, as well as additional outer retinal changes in other subjects.

Conclusions: Our results demonstrate changes in inner and outer diabetic retinas not readily detectable by clinical exam. IRL had not thinned at the margins of the large FAZs, indicating neural mass did not yet decrease despite potential ischemia.
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http://dx.doi.org/10.1111/opo.12578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202252PMC
September 2018

Postoperative Corneal and Surgically Induced Astigmatism following Superior Approach Manual Small Incision Cataract Surgery in Patients with Preoperative Against-the-Rule Astigmatism.

J Ophthalmol 2016 28;2016:9489036. Epub 2016 Dec 28.

Department of Optometry and Visual Science, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.

The aim of the study was to report postoperative corneal and surgically induced astigmatism (SIA) in patients with preoperative against-the-rule (ATR) astigmatism who underwent superior approach manual small incision cataract surgery (MSICS). 58 eyes of 58 cataract patients with preoperative ATR astigmatism were involved in this study. All patients had operable cataracts and underwent superior approach MSICS. Keratometric () readings were taken prior to surgery and at 12 weeks after surgery. Centroid values of SIA, preoperative astigmatism, and postoperative astigmatism were calculated using Cartesian coordinates based analysis. Wilcoxon signed rank test was used to compute statistical significance between mean preoperative and postoperative corneal astigmatism. Cohen's was used as effect size measure. Centroid values of 1.42 D × 179, 2.48 D × 0, and 1.07 D × 1 were recorded, respectively, for preoperative astigmatism, postoperative astigmatism, and SIA. Wilcoxon signed rank test indicated that mean ± SD postoperative corneal astigmatism (2.80 ± 1.40 D) was statistically significantly greater than preoperative corneal astigmatism (1.49 ± 1.34 D), = -6.263, < 0.0001. A high Cohen's of 1.32 was found. Our results suggest statistical and clinically significant greater postoperative corneal astigmatism than preoperative corneal astigmatism for ATR astigmatism cataract patients who underwent superior approach MSICS.
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http://dx.doi.org/10.1155/2016/9489036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5225371PMC
December 2016