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1.  Spatial analyses of wildlife contact networks 
Journal of the Royal Society Interface  2015;12(102):20141004.
Datasets from which wildlife contact networks of epidemiological importance can be inferred are becoming increasingly common. A largely unexplored facet of these data is finding evidence of spatial constraints on who has contact with whom, despite theoretical epidemiologists having long realized spatial constraints can play a critical role in infectious disease dynamics. A graph dissimilarity measure is proposed to quantify how close an observed contact network is to being purely spatial whereby its edges are completely determined by the spatial arrangement of its nodes. Statistical techniques are also used to fit a series of mechanistic models for contact rates between individuals to the binary edge data representing presence or absence of observed contact. These are the basis for a second measure that quantifies the extent to which contacts are being mediated by distance. We apply these methods to a set of 128 contact networks of field voles (Microtus agrestis) inferred from mark–recapture data collected over 7 years and from four sites. Large fluctuations in vole abundance allow us to demonstrate that the networks become increasingly similar to spatial proximity graphs as vole density increases. The average number of contacts, , was (i) positively correlated with vole density across the range of observed densities and (ii) for two of the four sites a saturating function of density. The implications for pathogen persistence in wildlife may be that persistence is relatively unaffected by fluctuations in host density because at low density is low but hosts move more freely, and at high density is high but transmission is hampered by local build-up of infected or recovered animals.
doi:10.1098/rsif.2014.1004
PMCID: PMC4277090  PMID: 25411407
epidemiology; mathematical model; field vole; Microtus agrestis; graph; dissimilarity measure
2.  Borrelia burgdorferi Promotes the Establishment of Babesia microti in the Northeastern United States 
PLoS ONE  2014;9(12):e115494.
Babesia microti and Borrelia burgdorferi, the respective causative agents of human babesiosis and Lyme disease, are maintained in their enzootic cycles by the blacklegged tick (Ixodes scapularis) and use the white-footed mouse (Peromyscus leucopus) as primary reservoir host. The geographic range of both pathogens has expanded in the United States, but the spread of babesiosis has lagged behind that of Lyme disease. Several studies have estimated the basic reproduction number (R0) for B. microti to be below the threshold for persistence (<1), a finding that is inconsistent with the persistence and geographic expansion of this pathogen. We tested the hypothesis that host coinfection with B. burgdorferi increases the likelihood of B. microti transmission and establishment in new areas. We fed I. scapularis larva on P. leucopus mice that had been infected in the laboratory with B. microti and/or B. burgdorferi. We observed that coinfection in mice increases the frequency of B. microti infected ticks. To identify the ecological variables that would increase the probability of B. microti establishment in the field, we integrated our laboratory data with field data on tick burden and feeding activity in an R0 model. Our model predicts that high prevalence of B. burgdorferi infected mice lowers the ecological threshold for B. microti establishment, especially at sites where larval burden on P. leucopus is lower and where larvae feed simultaneously or soon after nymphs infect mice, when most of the transmission enhancement due to coinfection occurs. Our studies suggest that B. burgdorferi contributes to the emergence and expansion of B. microti and provides a model to predict the ecological factors that are sufficient for emergence of B. microti in the wild.
doi:10.1371/journal.pone.0115494
PMCID: PMC4278703  PMID: 25545393
3.  Pilot Study of Intravenous Glyburide in Patients With a Large Ischemic Stroke 
Background and Purpose
Preclinical and retrospective clinical data indicate that glyburide, a selective inhibitor of sulfonylurea receptor 1-transient receptor potential melastatin 4, is effective in preventing edema and improving outcome after focal ischemia. We assessed the feasibility of recruiting and treating patients with severe stroke while obtaining preliminary information on the safety and tolerability of RP-1127 (glyburide for injection).
Methods
We studied 10 patients with acute ischemic stroke, with baseline diffusion-weighted imaging lesion volumes of 82 to 210 cm3, whether treated with intravenous recombinant tissue-type plasminogen activator, age 18 to 80 years, and time to RP-1127 ≤10 hours.
Results
Recruitment was completed within 10 months. The mean age was 50.5 years, and baseline diffusion-weighted image lesion volume was 102±23 cm3. There were no serious adverse events related to drug and no symptomatic hypoglycemia. The increase in ipsilateral hemisphere volume was 50±33 cm3. The proportion of 90-day modified Rankin Scale ≤4 was 90% (40% modified Rankin Scale, ≤3).
Conclusions
RP-1127 at a dose of 3 mg/d was well tolerated and did not require any dose reductions. A clinical trial of RP-1127 is feasible.
doi:10.1161/STROKEAHA.113.003352
PMCID: PMC4235339  PMID: 24193798
acute treatment; brain swelling; cerebral edema; glyburide; hemorrhagic transformation; ischemic stroke
4.  Vessel Occlusion, Penumbra, and Reperfusion – Translating Theory to Practice 
doi:10.3389/fneur.2014.00194
PMCID: PMC4179714  PMID: 25324826
stroke; reperfusion; recanalization; thrombolysis; collateral flow; perfusion imaging
5.  Worse Stroke Outcome in Atrial Fibrillation Is Explained By More Severe Hypoperfusion, Infarct Growth And Hemorrhagic Transformation 
Background
Atrial Fibrillation (AF) is associated with greater baseline neurological impairment and worse outcomes following ischemic stroke. Previous studies suggest that greater volumes of more severe baseline hypoperfusion in patients with history of AF may explain this association. We further investigated this association by comparing patients with and without AF on initial examination following stroke using pooled multimodal magnetic resonance imaging (MRI) and clinical data from the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) and the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution (DEFUSE) studies.
Methods
EPITHET was a trial of 101 ischemic stroke patients randomized to IV tissue plasminogen activator (tPA) or placebo and DEFUSE was a prospective cohort of 74 ischemic stroke patients treated with IV tPA at 3–6 hours following symptom onset. Patients underwent multimodal MRI before treatment, at 3–5 days and 3 months after stroke in EPITHET; before treatment, 3–6 hours after treatment and 1 month after stroke in DEFUSE. Patients were assessed with the National institutes of Health Stroke Scale (NIHSS) and the modified Rankin Scale (mRS) before treatment and at 3 months after stroke. Patients were categorized into definite AF (present on initial examination), probable AF (history but no AF on initial examination) and no AF. Perfusion data were reprocessed with automated MRI analysis software (RAPID, Stanford University, Stanford, CA., USA). Hypoperfusion volumes were defined using Time to maximum (Tmax) delays in 2-second increments from >4 to >8 seconds. Hemorrhagic transformation was classified according to the European Cooperative Acute Stroke Studies criteria.
Results
Of the 175 patients, 28 had definite AF, 30 probable AF, 111 no AF and 6 were excluded due to insufficient imaging data. At baseline, patients with definite AF had more severe hypoperfusion (median Tmax>8 seconds volume 48 vs. 29mL, p=0.02) compared to patients with no AF. At outcome, patients with definite AF had greater infarct growth (median volume 47 vs. 8mL, p=0.001), larger infarcts (median volume 75 vs. 23mL, p=0.001), more frequent parenchymal hematoma grade hemorrhagic transformation (30 vs. 10%, p=0.03), worse functional outcomes (median mRS score 4 vs. 3, p=0.03) and higher mortality (36 vs. 16%, p=0.03) compared to patients with no AF. Definite AF was independently associated with increased parenchymal hematoma [odds ratio (OR) = 6.05, 95% confidence interval (CI) 1.60–22.83) but not poor functional outcome (mRS 3–6, OR=0.99, 95%CI 0.35–2.80) or mortality (OR=2.54, 95%CI 0.86–7.49) 3 months following stroke, after adjusting for other baseline imbalances.
Conclusion
AF is associated with greater volumes of more severe baseline hypoperfusion, leading to higher infarct growth, more frequent severe hemorrhagic transformation and worse stroke outcomes.
doi:10.1111/ijs.12007
PMCID: PMC3688700  PMID: 23489996
Atrial fibrillation; brain ischemia; cerebrovascular disease; magnetic resonance imaging; stroke outcome
6.  Acute Stroke Imaging Research Roadmap II 
doi:10.1161/STROKEAHA.113.002015
PMCID: PMC4040226  PMID: 23860298
7.  Disseminated mucormycosis in a paediatric patient: Lichthemia corymbifera successfully treated with combination antifungal therapy 
Mucormycosis is a severe fungal infection that largely affects immunocompromised individuals. It carries a high morbidity and mortality rate and is characterised by extensive angioinvasion and necrosis of host tissue. This case report details success in treating disseminated mucormycosis in a paediatric patient with an underlying haematological malignancy. Treatment included institution of combination antifungal therapy with liposomal amphotericin B and caspofungin, aggressive surgical debridement of infected tissue and reversal of underlying immunosuppression.
doi:10.1016/j.mmcr.2014.08.002
PMCID: PMC4216331  PMID: 25379392
Mucormycosis; Lichthemia Corymbifera; Combination antifungal therapy; Neutropenia
8.  Failure of collateral blood flow is associated with infarct growth in ischemic stroke 
Changes in collateral blood flow, which sustains brain viability distal to arterial occlusion, may impact infarct evolution but have not previously been demonstrated in humans. We correlated leptomeningeal collateral flow, assessed using novel perfusion magnetic resonance imaging (MRI) processing at baseline and 3 to 5 days, with simultaneous assessment of perfusion parameters. Perfusion raw data were averaged across three consecutive slices to increase leptomeningeal collateral vessel continuity after subtraction of baseline signal analogous to digital subtraction angiography. Changes in collateral quality, Tmax hypoperfusion severity, and infarct growth were assessed between baseline and days 3 to 5 perfusion–diffusion MRI. Acute MRI was analysed for 88 patients imaged 3 to 6 hours after ischemic stroke onset. Better collateral flow at baseline was associated with larger perfusion–diffusion mismatch (Spearman's Rho 0.51, P<0.001) and smaller baseline diffusion lesion volume (Rho −0.70, P<0.001). In 30 patients without reperfusion at day 3 to 5, deterioration in collateral quality between baseline and subacute imaging was strongly associated with absolute (P=0.02) and relative (P<0.001) infarct growth. The deterioration in collateral grade correlated with increased mean Tmax hypoperfusion severity (Rho −0.68, P<0.001). Deterioration in Tmax hypoperfusion severity was also significantly associated with absolute (P=0.003) and relative (P=0.002) infarct growth. Collateral flow is dynamic and failure is associated with infarct growth.
doi:10.1038/jcbfm.2013.77
PMCID: PMC3734777  PMID: 23652626
collateral blood flow; ischemic stroke; magnetic resonance imaging; perfusion imaging; thrombolysis
9.  Validating Imaging Biomarkers of Cerebral Edema in Patients with Severe Ischemic Stroke 
Background and Purpose
There is no validated neuroimaging marker for quantifying brain edema. We sought to test whether MRI-based metrics would reliably change during the early subacute period in a manner consistent with edema and whether they would correlate with relevant clinical endpoints.
Methods
Serial MRI studies from patients in the EPITHET trial with initial diffusion weighted imaging (DWI) lesion volume >82 cm3 were analyzed. Two independent readers outlined the hemisphere and lateral ventricle on the involved side and calculated respective volumes at baseline and day 3 to 5. We assessed inter-rater agreement, volume change between scans and the association of volume change with early neurological deterioration (END: NIHSS score worsening ≥4 points), 90-day modified Rankin Scale (mRS) score 0–4 and mortality.
Results
Of 12 patients who met study criteria, average baseline and follow-up DWI lesion size was 138 cm3 and 234 cm3, respectively. Mean time to follow-up MRI was 62 hours. Concordance correlation coefficients between readers were >0.90 for both hemisphere and ventricle volume assessment. Mean percent hemisphere volume increase was 16.2±8.3% (p<.0001), and mean percent ventricle volume decrease was 45.6±16.9% (p<0.001). Percent hemisphere growth predicted END (area under the curve [AUC]=0.92, p=0.0005) and 90-day mRS 0–4 (AUC 0.80, p=0.02).
Conclusions
In this exploratory analysis of severe ischemic stroke patients, statistically significant changes in hemisphere and ventricular volumes within the first week are consistent with expected changes of cerebral edema. MRI-based analysis of hemisphere growth appears to be a suitable biomarker for edema formation.
doi:10.1016/j.jstrokecerebrovasdis.2012.01.002
PMCID: PMC3529850  PMID: 22325573
Acute Ischemic Stroke; Cerebral Edema; Malignant Stroke; MRI; Biomarker
10.  Are Medical Students Aware of Their Anti-Obesity Bias? 
Purpose
Anti-obesity prejudices affect the quality of care obese individuals receive. The authors sought to determine the prevalence of weight-related biases among medical students and whether they were aware of their biases.
Method
Between 2008 and 2011, the authors asked all third-year medical students at Wake Forest School of Medicine to complete the Weight Implicit Association Test (IAT), a validated measure of implicit preferences for “fat” or “thin” individuals. Students also answered a semantic differential item assessing their explicit weight-related preferences. The authors determined students’ awareness of their biases by examining the correlation between students’ explicit preferences and their IAT scores.
Results
Of 354 medical students, 310 (88%) completed valid surveys and consented to participate. Overall, 33% (101/310) self-reported a significant (“moderate” or “strong”) explicit anti-fat bias. No students self-reported a significant explicit anti-thin bias. According to the IAT scores, over half of students had a significant implicit weight bias: 39% (121/310) had an anti-fat bias and 17% (52/310) an anti-thin bias. Two-thirds of students (67%, 81/121) were unaware of their implicit anti-fat bias. Only male gender predicted an explicit anti-fat bias (odds ratio 3.0, 95% confidence interval 1.8 – 5.3). No demographic factors were associated with an implicit anti-fat bias. Students’ explicit and implicit biases were not correlated (Pearson r = 0.03, P = .58).
Conclusions
Over one-third of medical students had a significant implicit anti-fat bias; few were aware of that bias. Accordingly, medical schools’ obesity curricula should address weight-related biases and their potential impact on care.
doi:10.1097/ACM.0b013e318294f817
PMCID: PMC3930920  PMID: 23702519
11.  Proximal Hyperdense Middle Cerebral Artery Sign Predicts Poor Response to Thrombolysis 
PLoS ONE  2014;9(5):e96123.
The aim of our study was to compare the rapid neurological improvement after intravenous recombinant tissue-type plasminogen activator (rtPA) in patients with proximal hyperdense middle cerebral artery sign (p-HMCAS) to those without the sign and those with the distal hyperdense middle cerebral artery sign (d-HMCAS). Admission and 24 hour non-contrast CT scans of 120 patients with middle cerebral artery (MCA) territory stroke who were treated with intravenous rtPA were assessed for the presence of p-HMCAS and d-HMCAS. The sign was classified according to the site of occlusion. Rapid neurological improvement was defined as ≥50% improvement in the NIHSS score at 24 hours after thrombolysis. Rapid neurological recovery after thrombolysis was assessed and compared between the subgroups. Rapid neurological recovery was less common in the pooled group of patients with either p-HMCAS or d-HMCAS than those without the sign (p<0.01). Patients with p-HMCAS were less likely to have rapid neurological recovery than those with d-HMCAS (p<0.01). However, there was no difference in early neurological recovery between patients with d-HMCAS and those without any hyperdense sign. Our study showed that poor neurological recovery post rtPA was confined to p-HMCAS and not to d-HMCAS, indicating that these signs have quite different prognostic significance.
doi:10.1371/journal.pone.0096123
PMCID: PMC4013049  PMID: 24804962
12.  A review of the efficacy and safety of oral antidiabetic drugs 
Expert opinion on drug safety  2012;12(2):153-175.
Introduction
Additional oral antidiabetic agents to metformin, sulfonylureas (SU) and thiazolidinediones (TZD) are approved for the treatment of type 2 diabetes.
Areas covered
The efficacy and safety of metformin, SUs, TZDs, dipeptidyl peptidase-IV (DPP-4) inhibitors, meglitinide analogs, α-glucosidase inhibitors (AGIs), bile-acid sequestrants (BAS) and bromocriptine will be reviewed.
Expert opinion
Several new oral agents have been approved for type 2 diabetes management in recent years. It is important to understand the efficacy and safety of these medications in addition to the older agents to best maximize oral drug therapy for diabetes. Of the recently introduced oral hypoglycemic/antihyperglycemic agents, the DPP-4 inhibitors are moderately efficacious compared with mainstay treatment with metformin with a low side-effect profile and have good efficacy in combination with other oral agents and insulin. They are a recommended alternative when metformin use is limited by gastrointestinal (GI) side effects or when SU treatment results in significant hypoglycemia or weight gain. Meglitinide analogs are limited by their frequent dosing, expense and hypoglycemia (repaglinide > nateglinide), while AGIs are also limited by their dosing schedule and GI side-effect profile. BAS and bromocriptine have the lowest efficacy with regard to HbA1c reduction, also are plagued by GI adverse reactions, but have a low risk of hypoglycemia.
doi:10.1517/14740338.2013.752813
PMCID: PMC3977601  PMID: 23241069
α-glucosidase inhibitor; bile-acid sequestrant; bromocriptine; DPP-4 inhibitor; meglitinide; metformin; sulfonylurea; thiazolidinedione; type 2 diabetes
13.  Advanced Imaging Improves Prediction of Hemorrhage after Stroke Thrombolysis 
Annals of neurology  2013;73(4):510-519.
Objective
Very low cerebral blood volume (VLCBV), diffusion and hypoperfusion lesion volumes have been proposed as predictors of hemorrhagic transformation following stroke thrombolysis. We aimed to compare these parameters, validate VLCBV in an independent cohort using DEFUSE study data and investigate the interaction of VLCBV with regional reperfusion.
Methods
The EPITHET and DEFUSE studies obtained diffusion and perfusion MRI in patients 3–6 hours from onset of ischemic stroke. EPITHET randomized patients to tPA or placebo, and all DEFUSE patients received tPA. VLCBV was defined as CBV<2.5th percentile of brain contralateral to the infarct. Parenchymal hematoma (PH) was defined using ECASS criteria. Reperfusion was assessed using subacute perfusion MRI co-registered to baseline imaging.
Results
In DEFUSE, 69 patients were analyzed including 9 who developed PH. The >2mL VLCBV threshold defined in EPITHET predicted parenchymal hematoma (PH) with 100% sensitivity, 72% specificity, 35% positive predictive value and 100% negative predictive value. Pooling EPITHET and DEFUSE (163 patients including 23 with PH), regression models using VLCBV (p<0.001) and tPA (p=0.02) predicted PH independent of clinical factors better than models using diffusion or Tmax>8sec lesion volumes. Excluding VLCBV in regions without reperfusion improved specificity from 61% to 78% in the pooled analysis.
Interpretation
VLCBV predicts PH after stroke thrombolysis and appears to be a more powerful predictor than baseline diffusion or hypoperfusion lesion volumes. Reperfusion of regions of VLCBV is strongly associated with post-thrombolysis PH. VLCBV may be clinically useful to identify patients at significant risk of hemorrhage following reperfusion.
doi:10.1002/ana.23837
PMCID: PMC3665631  PMID: 23444008
Stroke; Hemorrhagic transformation; Thrombolytic therapy; MRI; very low cerebral blood volume
14.  Percutaneous Bone Marrow Transplantation Using Fractional Ablative Erbium:YAG Laser 
PLoS ONE  2014;9(3):e93004.
Topical application of therapeutic agents has been a mainstay in Dermatology for the treatment of skin disorders but is not commonly used for systemic delivery. For a topically applied agent to reach distant body sites it must first overcome the barrier function of the skin and then penetrate into deeper structures before reaching the systemic circulation. This has limited the use of topically applied agents to those having specific charge, solubility and size restrictions. Pretreatment of the skin with ablative fractional laser appears to enhance the uptake of some topically applied drugs but the ability to effectively deliver agents to distant sites is largely unproven. In this report we used a fractional ablative Erb:YAG (Erbium/Yttrium Aluminum Garnet) laser to facilitate the transfer of bone marrow stem cells through the skin in a murine bone marrow transplant model. Chimerism could be detected in the peripheral blood of recipient C57BL/6 mice that were pretreated with ablative fractional laser and had topically applied enhanced green fluorescent protein (GFP) labeled bone marrow cells from syngeneic donor transgenic mice. This study indicates that fractional laser can be used to deliver stem cells through the skin and remain functionally intact.
doi:10.1371/journal.pone.0093004
PMCID: PMC3965514  PMID: 24667438
15.  Expression Variants of the Lipogenic AGPAT6 Gene Affect Diverse Milk Composition Phenotypes in Bos taurus 
PLoS ONE  2014;9(1):e85757.
Milk is composed of a complex mixture of lipids, proteins, carbohydrates and various vitamins and minerals as a source of nutrition for young mammals. The composition of milk varies between individuals, with lipid composition in particular being highly heritable. Recent reports have highlighted a region of bovine chromosome 27 harbouring variants affecting milk fat percentage and fatty acid content. We aimed to further investigate this locus in two independent cattle populations, consisting of a Holstein-Friesian x Jersey crossbreed pedigree of 711 F2 cows, and a collection of 32,530 mixed ancestry Bos taurus cows. Bayesian genome-wide association mapping using markers imputed from the Illumina BovineHD chip revealed a large quantitative trait locus (QTL) for milk fat percentage on chromosome 27, present in both populations. We also investigated a range of other milk composition phenotypes, and report additional associations at this locus for fat yield, protein percentage and yield, lactose percentage and yield, milk volume, and the proportions of numerous milk fatty acids. We then used mammary RNA sequence data from 212 lactating cows to assess the transcript abundance of genes located in the milk fat percentage QTL interval. This analysis revealed a strong eQTL for AGPAT6, demonstrating that high milk fat percentage genotype is also additively associated with increased expression of the AGPAT6 gene. Finally, we used whole genome sequence data from six F1 sires to target a panel of novel AGPAT6 locus variants for genotyping in the F2 crossbreed population. Association analysis of 58 of these variants revealed highly significant association for polymorphisms mapping to the 5′UTR exons and intron 1 of AGPAT6. Taken together, these data suggest that variants affecting the expression of AGPAT6 are causally involved in differential milk fat synthesis, with pleiotropic consequences for a diverse range of other milk components.
doi:10.1371/journal.pone.0085757
PMCID: PMC3897493  PMID: 24465687
16.  Measuring Medical Student Attitudes and Beliefs Regarding Obese Patients 
Purpose
Obesity bias has been shown to undermine the patient-doctor relationship and lead to substandard care. A valid and reliable instrument was developed to measure medical students’ attitudes and beliefs about obese patients.
Method
The authors conducted a literature search to identify validated measures of obesity bias. Since no appropriate scale was located, the decision to design a novel survey instrument, titled the NEW (Nutrition, Exercise and Weight Management) Attitudes Scale, was made. An expert panel generated items which were then discussed in focus groups of third year medical students. Experienced medical educators served as judges, weighting the items using a Thurstone scale. Second and fourth year medical students completed these items alongside two previously validated measures of obesity bias, the Anti-Fat Attitudes Questionnaire (AFA) and Beliefs About Obese Persons Scale (BAOP). Third year students completed the NEW scales before and after a simulated encounter with an obese standardized patient instructor.
Results
Thirty one items comprised the final instrument. A sample of 201 judges rated the positivity of items. A sample of 111 second and fourth year medical students completed the survey (mean score 24.4, range −37 to 76 out of a possible −118 to 118); Pearson correlations between AFA and BAOP were −0.47 and 0.23, respectively. Test-retest reliability was 0.89. Students scored 27% higher after completing the standardized patient-instructor encounter (P<.001).
Conclusion
The NEW Attitudes Scale had good validity and reliability and may be used in future studies to measure medical students’ attitudes towards obese patients.
doi:10.1097/ACM.0b013e31827c028d
PMCID: PMC3826984  PMID: 23269296
17.  Potential corridors and barriers for plague spread in central Asia 
Background
Plague (Yersinia pestis infection) is a vector-borne disease which caused millions of human deaths in the Middle Ages. The hosts of plague are mostly rodents, and the disease is spread by the fleas that feed on them. Currently, the disease still circulates amongst sylvatic rodent populations all over the world, including great gerbil (Rhombomys opimus) populations in Central Asia. Great gerbils are social desert rodents that live in family groups in burrows, which are visible on satellite images. In great gerbil populations an abundance threshold exists, above which plague can spread causing epizootics. The spatial distribution of the host species is thought to influence the plague dynamics, such as the direction of plague spread, however no detailed analysis exists on the possible functional or structural corridors and barriers that are present in this population and landscape. This study aims to fill that gap.
Methods
Three 20 by 20 km areas with known great gerbil burrow distributions were used to analyse the spatial distribution of the burrows. Object-based image analysis was used to map the landscape at several scales, and was linked to the burrow maps. A novel object-based method was developed – the mean neighbour absolute burrow density difference (MNABDD) – to identify the optimal scale and evaluate the efficacy of using landscape objects as opposed to square cells. Multiple regression using raster maps was used to identify the landscape-ecological variables that explain burrow density best. Functional corridors and barriers were mapped using burrow density thresholds. Cumulative resistance of the burrow distribution to potential disease spread was evaluated using cost distance analysis. A 46-year plague surveillance dataset was used to evaluate whether plague spread was radially symmetric.
Results
The burrow distribution was found to be non-random and negatively correlated with Greenness, especially in the floodplain areas. Corridors and barriers showed a mostly NWSE alignment, suggesting easier spreading along this axis. This was confirmed by the analysis of the plague data.
Conclusions
Plague spread had a predominantly NWSE direction, which is likely due to the NWSE alignment of corridors and barriers in the burrow distribution and the landscape. This finding may improve predictions of plague in the future and emphasizes the importance of including landscape analysis in wildlife disease studies.
doi:10.1186/1476-072X-12-49
PMCID: PMC4228490  PMID: 24171709
Landscape epidemiology; Disease ecology; Infectious disease; Remote sensing; Persistence; GIS; Multiple regression; Landscape configuration; Steppe; Bubonic plague
18.  Hypoglycemia and Vascular Disease 
Clinical chemistry  2010;57(2):258-260.
doi:10.1373/clinchem.2010.148247
PMCID: PMC3748719  PMID: 20974800
19.  Stroke: Working toward a Prioritized World Agenda 
Background and Purpose
The aim of the Synergium was to devise and prioritize new ways of accelerating progress in reducing the risks, effects, and consequences of stroke.
Methods
Preliminary work was performed by 7 working groups of stroke leaders followed by a synergium (a forum for working synergistically together) with approximately 100 additional participants. The resulting draft document had further input from contributors outside the synergium.
Results
Recommendations of the Synergium are: Basic Science, Drug Development and Technology: There is a need to develop: (1) New systems of working together to break down the prevalent ‘silo’ mentality; (2) New models of vertically integrated basic, clinical, and epidemiological disciplines; and (3) Efficient methods of identifying other relevant areas of science. Stroke Prevention: (1) Establish a global chronic disease prevention initiative with stroke as a major focus. (2) Recognize not only abrupt clinical stroke, but subtle subclinical stroke, the commonest type of cerebrovascular disease, leading to impairments of executive function. (3) Develop, implement and evaluate a population approach for stroke prevention. (4) Develop public health communication strategies using traditional and novel (e.g., social media/marketing) techniques. Acute Stroke Management: Continue the establishment of stroke centers, stroke units, regional systems of emergency stroke care and telestroke networks. Brain Recovery and Rehabilitation: (1) Translate best neuroscience, including animal and human studies, into poststroke recovery research and clinical care. (2) Standardize poststroke rehabilitation based on best evidence. (3) Develop consensus on, then implementation of, standardized clinical and surrogate assessments. (4) Carry out rigorous clinical research to advance stroke recovery. Into the 21st Century: Web, Technology and Communications: (1) Work toward global unrestricted access to stroke-related information. (2) Build centralized electronic archives and registries. Foster Cooperation Among Stakeholders (large stroke organizations, nongovernmental organizations, governments, patient organizations and industry) to enhance stroke care. Educate and energize professionals, patients, the public and policy makers by using a ‘Brain Health’ concept that enables promotion of preventive measures.
Conclusions
To accelerate progress in stroke, we must reach beyond the current status scientifically, conceptually, and pragmatically. Advances can be made not only by doing, but ceasing to do. Significant savings in time, money, and effort could result from discontinuing practices driven by unsubstantiated opinion, unproven approaches, and financial gain. Systematic integration of knowledge into programs coupled with careful evaluation can speed the pace of progress
doi:10.1111/j.1747-4949.2010.00442.x
PMCID: PMC3712839  PMID: 20636706
Prevention; Rehabilitation; Stroke; Translational; Treatment
20.  Stroke: Working Toward a Prioritized World Agenda 
Background and Purpose
The aim of the Synergium was to devise and prioritize new ways of accelerating progress in reducing the risks, effects, and consequences of stroke.
Methods
Preliminary work was performed by 7 working groups of stroke leaders followed by a synergium (a forum for working synergistically together) with approximately 100 additional participants. The resulting draft document had further input from contributors outside the synergium.
Results
Recommendations of the Synergium are:
Basic Science, Drug Development and Technology: There is a need to develop: (1) New systems of working together to break down the prevalent “silo” mentality; (2) New models of vertically integrated basic, clinical, and epidemiological disciplines; and (3) Efficient methods of identifying other relevant areas of science.
Stroke Prevention: (1) Establish a global chronic disease prevention initiative with stroke as a major focus. (2) Recognize not only abrupt clinical stroke, but subtle subclinical stroke, the commonest type of cerebrovascular disease, leading to impairments of executive function. (3) Develop, implement and evaluate a population approach for stroke prevention. (4) Develop public health communication strategies using traditional and novel (eg, social media/marketing) techniques.
Acute Stroke Management: Continue the establishment of stroke centers, stroke units, regional systems of emergency stroke care and telestroke networks.
Brain Recovery and Rehabilitation: (1) Translate best neuroscience, including animal and human studies, into poststroke recovery research and clinical care. (2) Standardize poststroke rehabilitation based on best evidence. (3) Develop consensus on, then implementation of, standardized clinical and surrogate assessments. (4) Carry out rigorous clinical research to advance stroke recovery.
Into the 21st Century: Web, Technology and Communications: (1) Work toward global unrestricted access to stroke-related information. (2) Build centralized electronic archives and registries.
Foster Cooperation Among Stakeholders (large stroke organizations, nongovernmental organizations, governments, patient organizations and industry) to enhance stroke care.
Educate and energize professionals, patients, the public and policy makers by using a “Brain Health” concept that enables promotion of preventive measures.
Conclusions
To accelerate progress in stroke, we must reach beyond the current status scientifically, conceptually, and pragmatically. Advances can be made not only by doing, but ceasing to do. Significant savings in time, money, and effort could result from discontinuing practices driven by unsubstantiated opinion, unproven approaches, and financial gain. Systematic integration of knowledge into programs coupled with careful evaluation can speed the pace of progress.
doi:10.1161/STROKEAHA.110.586156
PMCID: PMC3712843  PMID: 20498453
prevention; rehabilitation; stroke; translational; treatment
21.  The effect of nicotine on anti-VEGF therapy in a mouse model of neovascular age-related macular degeneration 
Retina (Philadelphia, Pa.)  2012;32(6):1171-1180.
Purpose
Evaluate the effect of nicotine on anti-VEGF therapy in the treatment of neovascular age-related macular degeneration (AMD).
Methods
One group of mice received nicotine in drinking water and the other group received water only. Choroidal neovascularization (CNV) was induced with a laser. Nicotinic acetylcholine receptor (nAChR) α7 expression was evaluated by immunohistochemistry (IHC). Bevacizumab or adiponectin peptide II (APNpII) was injected intravitreally on day 7 post-laser and the effects were evaluated on days 14 and 21. α-bungerotoxin was injected intraperitoneally on days 2–5 and its effect evaluated on day 14.
Results
Expression of nAChR α7 was 2–7 times higher between days 3 and 7 post-laser compared to naïve mice. In water fed mice, APNpII, bevacizumab, and α-bungarotoxin significantly reduced CNV size. In nicotine fed mice, treatment with APNpII or bevacizumab did not significantly reduce CNV size, whereas α-bungerotoxin did have an effect. Comparing water and nicotine mice, CNV size was 61–86% smaller in water mice except for the α-bungarotoxin group where there was no difference. PDGF and VEGF expression was 1.5–2.5 fold higher at day 14 in nicotine treated mice.
Conclusions
Nicotine significantly blocks the effect of anti-VEGF therapy in the treatment of laser induced neovascular AMD. nAChR α7 is significantly up-regulated during the formation of CNV and treatment with a nAChR α7 antagonist decreases CNV size irrespective of nicotine administration-
doi:10.1097/IAE.0b013e31823496b8
PMCID: PMC3563266  PMID: 22088983
Adiponectin; age-related macular degeneration; Bevacizumab; choroidal neovascularization; mouse model; nicotine acetylcholine receptor; platelet derived growth factor; smoking; vascular endothelial growth factor; α-bungerotoxin
22.  Isolation of microsatellite markers in a chaparral species endemic to southern California, Ceanothus megacarpus (Rhamnaceae)1 
Applications in Plant Sciences  2013;1(5):apps.1200393.
• Premise of the study: Microsatellite (simple sequence repeat [SSR]) markers were developed for Ceanothus megacarpus, a chaparral species endemic to coastal southern California, to investigate potential processes (e.g., fragmentation, genetic drift, and interspecific hybridization) responsible for the genetic structure within and among populations distributed throughout mainland and island populations.
• Methods and Results: Four SSR-enriched libraries were used to develop and optimize 10 primer sets of microsatellite loci containing either di-, tri-, or tetranucleotide repeats. Levels of variation at these loci were assessed for two populations of C. megacarpus. Observed heterozygosity ranged from 0.250 to 0.885, and number of alleles ranged between four and 21 per locus. Eight to nine loci also successfully amplified in three other species of Ceanothus.
• Conclusions: These markers should prove useful for evaluating the influence of recent and historical processes on genetic variation in C. megacarpus and related species.
doi:10.3732/apps.1200393
PMCID: PMC4105035  PMID: 25202542
Ceanothus; chaparral; microsatellites; Rhamnaceae
23.  A Triad of Highly Divergent Polymeric Immunoglobulin Receptor (PIGR) Haplotypes with Major Effect on IgA Concentration in Bovine Milk 
PLoS ONE  2013;8(3):e57219.
The aim of this study was to determine a genetic basis for IgA concentration in milk of Bos taurus. We used a Holstein-Friesian x Jersey F2 crossbred pedigree to undertake a genome-wide search for QTL influencing IgA concentration and yield in colostrum and milk. We identified a single genome-wide significant QTL on chromosome 16, maximising at 4.8 Mbp. The polymeric immunoglobulin receptor gene (PIGR) was within the confidence interval of the QTL. In addition, mRNA expression analysis revealed a liver PIGR expression QTL mapping to the same locus as the IgA quantitative trait locus. Sequencing and subsequent genotyping of the PIGR gene revealed three divergent haplotypes that explained the variance of both the IgA QTL and the PIGR expression QTL. Genetic selection based on these markers will facilitate the production of bovine herds producing milk with higher concentrations of IgA.
doi:10.1371/journal.pone.0057219
PMCID: PMC3594236  PMID: 23536764
24.  Interactions of Methicillin Resistant Staphylococcus aureus USA300 and Pseudomonas aeruginosa in Polymicrobial Wound Infection 
PLoS ONE  2013;8(2):e56846.
Understanding the pathology resulting from Staphylococcus aureus and Pseudomonas aeruginosa polymicrobial wound infections is of great importance due to their ubiquitous nature, increasing prevalence, growing resistance to antimicrobial agents, and ability to delay healing. Methicillin-resistant S. aureus USA300 is the leading cause of community-associated bacterial infections resulting in increased morbidity and mortality. We utilized a well-established porcine partial thickness wound healing model to study the synergistic effects of USA300 and P. aeruginosa on wound healing. Wound re-epithelialization was significantly delayed by mixed-species biofilms through suppression of keratinocyte growth factor 1. Pseudomonas showed an inhibitory effect on USA300 growth in vitro while both species co-existed in cutaneous wounds in vivo. Polymicrobial wound infection in the presence of P. aeruginosa resulted in induced expression of USA300 virulence factors Panton-Valentine leukocidin and α-hemolysin. These results provide evidence for the interaction of bacterial species within mixed-species biofilms in vivo and for the first time, the contribution of virulence factors to the severity of polymicrobial wound infections.
doi:10.1371/journal.pone.0056846
PMCID: PMC3579943  PMID: 23451098
25.  The infarct core is well represented by the acute diffusion lesion: sustained reversal is infrequent 
Diffusion-weighted imaging (DWI) is commonly used to assess irreversibly infarcted tissue but its accuracy is challenged by reports of diffusion lesion reversal (DLR). We investigated the frequency and implications for mismatch classification of DLR using imaging from the EPITHET (Echoplanar Imaging Thrombolytic Evaluation Trial) and DEFUSE (Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution) studies. In 119 patients (83 treated with IV tissue plasminogen activator), follow-up images were coregistered to acute diffusion images and the lesions manually outlined to their maximal visual extent in diffusion space. Diffusion lesion reversal was defined as voxels of acute diffusion lesion that corresponded to normal brain at follow-up (i.e., final infarct, leukoaraiosis, and cerebrospinal fluid (CSF) voxels were excluded from consideration). The appearance of DLR was visually checked for artifacts, the volume calculated, and the impact of adjusting baseline diffusion lesion volume for DLR volume on perfusion–diffusion mismatch analyzed. Median DLR volume reduced from 4.4 to 1.5 mL after excluding CSF/leukoaraiosis. Visual inspection verified 8/119 (6.7%) with true DLR, median volume 2.33 mL. Subtracting DLR from acute diffusion volume altered perfusion–diffusion mismatch (Tmax>6 seconds, ratio>1.2) in 3/119 (2.5%) patients. Diffusion lesion reversal between baseline and 3 to 6 hours DWI was also uncommon (7/65, 11%) and often transient. Clinically relevant DLR is uncommon and rarely alters perfusion–diffusion mismatch. The acute diffusion lesion is generally a reliable signature of the infarct core.
doi:10.1038/jcbfm.2011.102
PMCID: PMC3323290  PMID: 21772309
brain ischemia; cerebrovascular disease; diffusion-weighted MRI; MRI; thrombolysis

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