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1.  Visual Field Outcomes for the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) 
Purpose
The Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) showed that acetazolamide provided a modest, significant improvement in mean deviation (MD). Here, we further analyze visual field changes over the 6-month study period.
Methods
Of 165 subjects with mild visual loss in the IIHTT, 125 had perimetry at baseline and 6 months. We evaluated pointwise linear regression of visual sensitivity versus time to classify test locations in the worst MD (study) eye as improving or not; pointwise changes from baseline to month 6 in decibels; and clinical consensus of change from baseline to 6 months.
Results
The average study eye had 36 of 52 test locations with improving sensitivity over 6 months using pointwise linear regression, but differences between the acetazolamide and placebo groups were not significant. Pointwise results mostly improved in both treatment groups with the magnitude of the mean change within groups greatest and statistically significant around the blind spot and the nasal area, especially in the acetazolamide group. The consensus classification of visual field change from baseline to 6 months in the study eye yielded percentages (acetazolamide, placebo) of 7.2% and 17.5% worse, 35.1% and 31.7% with no change, and 56.1% and 50.8% improved; group differences were not statistically significant.
Conclusions
In the IIHTT, compared to the placebo group, the acetazolamide group had a significant pointwise improvement in visual field function, particularly in the nasal and pericecal areas; the latter is likely due to reduction in blind spot size related to improvement in papilledema. (ClinicalTrials.gov number, NCT01003639.)
doi:10.1167/iovs.15-18626
PMCID: PMC4777274  PMID: 26934136
idiopathic intracranial hypertension; pseudotumor cerebri; perimetry; visual field; clinical trial
2.  Livestock guardian dogs as surrogate top predators? How Maremma sheepdogs affect a wildlife community 
Ecology and Evolution  2016;6(18):6702-6711.
Abstract
Use of livestock guardian dogs (LGDs) to reduce predation on livestock is increasing. However, how these dogs influence the activity of wildlife, including predators, is not well understood. We used pellet counts and remote cameras to investigate the effects of free ranging LGDs on four large herbivores (eastern gray kangaroo, common wombat, swamp wallaby, and sambar deer) and one mesopredator (red fox) in Victoria, Australia. Generalized mixed models and one‐ and two‐species detection models were used to assess the influence of the presence of LGDs on detection of the other species. We found avoidance of LGDs in four species. Swamp wallabies and sambar deer were excluded from areas occupied by LGDs; gray kangaroos showed strong spatial and temporal avoidance of LGD areas; foxes showed moderately strong spatial and temporal avoidance of LGD areas. The effect of LGDs on wombats was unclear. Avoidance of areas with LGDs by large herbivores can benefit livestock production by reducing competition for pasture and disease transmission from wildlife to livestock, and providing managers with better control over grazing pressure. Suppression of mesopredators could benefit the small prey of those species. Synthesis and applications: In pastoral areas, LGDs can function as a surrogate top‐order predator, controlling the local distribution and affecting behavior of large herbivores and mesopredators. LGDs may provide similar ecological functions to those that in many areas have been lost with the extirpation of native large carnivores.
doi:10.1002/ece3.2412
PMCID: PMC5058539  PMID: 27777741
detection probability; large herbivore; LGD; LPD; mesopredator; top predator; trophic cascade
3.  Normative Databases for Imaging Instrumentation 
Journal of glaucoma  2015;24(6):480-483.
Purpose
To describe the process by which imaging devices undergo reference database development and regulatory clearance. The limitations and potential improvements of reference (normative) data sets for ophthalmic imaging devices will be discussed.
Methods
A symposium was held in July 2013 in which a series of speakers discussed issues related to the development of reference databases for imaging devices.
Results
Automated imaging has become widely accepted and used in glaucoma management. The ability of such instruments to discriminate healthy from glaucomatous optic nerves, and to detect glaucomatous progression over time is limited by the quality of reference databases associated with the available commercial devices. In the absence of standardized rules governing the development of reference databases, each manufacturer’s database differs in size, eligibility criteria, and ethnic make-up, among other key features.
Conclusions
The process for development of imaging reference databases may be improved by standardizing eligibility requirements and data collection protocols. Such standardization may also improve the degree to which results may be compared between commercial instruments.
doi:10.1097/IJG.0000000000000152
PMCID: PMC4699581  PMID: 25265003
Glaucoma; imaging; perimetry; reproducibility; database
4.  View-Dependent Streamline Deformation and Exploration 
Occlusion presents a major challenge in visualizing 3D flow and tensor fields using streamlines. Displaying too many streamlines creates a dense visualization filled with occluded structures, but displaying too few streams risks losing important features. We propose a new streamline exploration approach by visually manipulating the cluttered streamlines by pulling visible layers apart and revealing the hidden structures underneath. This paper presents a customized view-dependent deformation algorithm and an interactive visualization tool to minimize visual clutter in 3D vector and tensor fields. The algorithm is able to maintain the overall integrity of the fields and expose previously hidden structures. Our system supports both mouse and direct-touch interactions to manipulate the viewing perspectives and visualize the streamlines in depth. By using a lens metaphor of different shapes to select the transition zone of the targeted area interactively, the users can move their focus and examine the vector or tensor field freely.
doi:10.1109/TVCG.2015.2502583
PMCID: PMC4874923  PMID: 26600061
Flow visualization; streamline; white matter tracts; focus+context; deformation; occlusion
5.  Pyrodiversity is the coupling of biodiversity and fire regimes in food webs 
Fire positively and negatively affects food webs across all trophic levels and guilds and influences a range of ecological processes that reinforce fire regimes, such as nutrient cycling and soil development, plant regeneration and growth, plant community assembly and dynamics, herbivory and predation. Thus we argue that rather than merely describing spatio-temporal patterns of fire regimes, pyrodiversity must be understood in terms of feedbacks between fire regimes, biodiversity and ecological processes. Humans shape pyrodiversity both directly, by manipulating the intensity, severity, frequency and extent of fires, and indirectly, by influencing the abundance and distribution of various trophic guilds through hunting and husbandry of animals, and introduction and cultivation of plant species. Conceptualizing landscape fire as deeply embedded in food webs suggests that the restoration of degraded ecosystems requires the simultaneous careful management of fire regimes and native and invasive plants and animals, and may include introducing new vertebrates to compensate for extinctions that occurred in the recent and more distant past.
This article is part of the themed issue ‘The interaction of fire and mankind’.
doi:10.1098/rstb.2015.0169
PMCID: PMC4874407  PMID: 27216526
anthropogenic burning; ecosystem engineer; feedbacks; landscape fire; pyrogeography; trophic interactions
6.  Structure and flexibility of the endosomal Vps34 complex reveals the basis of its function on membranes 
Science (New York, N.Y.)  2015;350(6257):aac7365.
Phosphatidylinositol 3-kinase Vps34 complexes regulate intracellular membrane trafficking in endocytic sorting, cytokinesis and autophagy. We present the 4.4 Å crystal structure of the 385 kDa endosomal complex II (PIK3C3-CII), consisting of Vps34, Vps15 (p150), Vps30/Atg6 (Beclin 1) and Vps38 (UVRAG). The subunits form a Y-shaped complex, centered on the Vps34 C2 domain. Vps34 and Vps15 intertwine in one arm where the Vps15 kinase domain engages the Vps34 activation loop to regulate its activity. Vps30 and Vps38 form the other arm that brackets the Vps15/Vps34 heterodimer, suggesting a path for complex assembly. Hydrogen-Deuterium Exchange Mass Spectrometry (HDX-MS) revealed conformational changes accompanying membrane binding and identified a Vps30 loop that is critical for the ability of complex II to phosphorylate giant liposomes on which complex I is inactive.
doi:10.1126/science.aac7365
PMCID: PMC4601532  PMID: 26450213
7.  Measurement of estradiol, estrone, and testosterone in postmenopausal human serum by isotope dilution liquid chromatography tandem mass spectrometry without derivatization 
Steroids  2015;96:89-94.
Background
A high-throughput, sensitive, specific, mass spectrometry-based method for quantitating estrone (E1), estradiol (E2), and testosterone (T) in postmenopausal human serum has been developed for clinical research. The method consumes 100 ul human serum for each measurement (triplicates consume 300 ul) and does not require derivatization. We adapted a commercially available 96-well plate for sample preparation, extraction, and introduction into the mass spectrometer on a single platform.
Methods
Steroid extraction from serum samples and mass spectrometer operational parameters were optimized for analysis of estradiol and subsequently applied to other analytes. In addition to determining the limit of detection (LOD) and limit of quantitation (LOQ) from standard curves, a serum LOQ (sLOQ) was determined by addition of known steroid quantities to serum samples. Mass spectrometric method quantitative data were compared to results using a state-of-the-art ELISA (enzyme-linked immunosorbent assay) using stored serum samples from menopausal women.
Results
The LOD, LOQ, sLOQ was (0.1 pg, 0.3 pg, 1 pg/ml) for estrone, (0.3 pg, 1 pg, 3 pg/ml) for estradiol, and (0.3 pg, 1 pg, 30pg/ml) for testosterone, respectively. Mass spectrometry accurately determined concentrations of E2 that could not be quantified by immunochemical methods. E1 concentrations measured by mass spectrometry were in all cases significantly lower than the ELISA measurements, suggesting immunoreactive contaminants in serum may interfere with ELISA. The testosterone measurements broadly agreed with each other in that both techniques could differentiate between low, medium and high serum levels.
Conclusions
We have developed and validated a scalable, sensitive assay for trace quantitation of E1, E2 and T in human serum samples in a single assay using sample preparation method and stable isotope dilution mass spectrometry.
doi:10.1016/j.steroids.2015.01.007
PMCID: PMC4366052  PMID: 25617740
estradiol; estrone; estriol; testosterone; progesterone; tandem mass spectrometry
8.  Normal Values for the Full Visual Field, Corrected for Age- and Reaction Time, Using Semiautomated Kinetic Testing on the Octopus 900 Perimeter 
Purpose
To determine normal values of the visual field (VF), corrected for age and reaction time (RT) for semiautomated kinetic perimetry (SKP) on the Octopus 900 perimeter, create a model describing the age-dependency of these values, and assess test–retest reliability for each isopter.
Methods
Eighty-six eyes of 86 ophthalmologically healthy subjects (age 11–79 years, 34 males, 52 females) underwent full-field kinetic perimetry with the Octopus 900 instrument. Stimulus size, luminance, velocity, meridional angle, subject age, and their interactions, were used to create a smooth multiple regression mathematical model (V/4e, III/4e, I/4e, I/3e, I/2e, I/1e, and I/1a isopters). Fourteen subjects (2 from each of 7 age groups) were evaluated on three separate sessions to assess test–retest reliability of the isopters. Reaction time (RT) was tested by presenting 12 designated RT-vectors between 10° and 20° within the seeing areas for the III/4e isopter (stimulus velocity, 3°/second). Four RT- vectors were presented at the nasal (0° or 180°), superotemporal (45°), and inferior (270°) meridians.
Results
The model fit was excellent (r2 = 0.94). The test–retest variability was less than 5°, and the median decrease in this deviation attributed to aging, per decade, for all age groups and for all stimulus sizes was 0.8°. No significant learning effect was observed for any age group or isopter.
Conclusion
Age-corrected and RT-corrected normative threshold values for full-field kinetic perimetry can be adequately described by a smooth multiple linear regression mathematical model.
Translational Relevance
A description of the entire kinetic VF is useful for assessing a full characterization of VF sensitivity, determining function losses associated with ocular and neurologic diseases, and for providing a more comprehensive analysis of structure–function relationships.
doi:10.1167/tvst.5.2.5
PMCID: PMC4782826  PMID: 26966641
perimetry; visual fields; semiautomated kinetic testing; full visual field; normal values
9.  Research is ‘a step into the unknown’: an exploration of pharmacists’ perceptions of factors impacting on research participation in the NHS 
BMJ Open  2015;5(12):e009180.
Objective
This study explored National Health Service (NHS) pharmacists’ perceptions and experiences of pharmacist-led research in the workplace.
Design
Semistructured, face-to-face discussions continued until distinct clusters of opinion characteristics formed. Verbatim transcripts of audio-recordings were subjected to framework analysis.
Setting
Interviews were carried out with 54 pharmacists with diverse backgrounds and roles from general practices and secondary care in the UK's largest health authority.
Results
The purpose and potential of health services research (HSR) was understood and acknowledged to be worthwhile by participants, but a combination of individual and system-related themes tended to make participation difficult, except when this was part of formal postgraduate education leading to a qualification. Lack of prioritisation was routinely cited as the greatest barrier, with motivation, confidence and competence as additional impediments. System-related themes included lack of practical support and pharmacy professional issues. A minority of highly motivated individuals managed to embed research participation into routine activity.
Conclusions
Most pharmacists realised the desirability and necessity of research to underpin pharmacy service expansion, but a combination of individual and professional level changes is needed to increase activity. Our findings provide a starting point for better understanding the mindset of hospital-based and general practice-based pharmacists towards research, as well as their perceived barriers and supports.
doi:10.1136/bmjopen-2015-009180
PMCID: PMC4710811  PMID: 26719315
QUALITATIVE RESEARCH; EDUCATION & TRAINING (see Medical Education & Training); HEALTH SERVICES ADMINISTRATION & MANAGEMENT
10.  Babesiosis Occurrence among the Elderly in the United States, as Recorded in Large Medicare Databases during 2006–2013 
PLoS ONE  2015;10(10):e0140332.
Background
Human babesiosis, caused by intraerythrocytic protozoan parasites, can be an asymptomatic or mild-to-severe disease that may be fatal. The study objective was to assess babesiosis occurrence among the U.S. elderly Medicare beneficiaries, ages 65 and older, during 2006–2013.
Methods
Our retrospective claims-based study utilized large Medicare administrative databases. Babesiosis occurrence was ascertained by recorded ICD-9-CM diagnosis code. The study assessed babesiosis occurrence rates (per 100,000 elderly Medicare beneficiaries) overall and by year, age, gender, race, state of residence, and diagnosis months.
Results
A total of 10,305 elderly Medicare beneficiaries had a recorded babesiosis diagnosis during the eight-year study period, for an overall rate of about 5 per 100,000 persons. Study results showed a significant increase in babesiosis occurrence over time (p<0.05), with the largest number of cases recorded in 2013 (N = 1,848) and the highest rates (per 100,000) in five Northeastern states: Connecticut (46), Massachusetts (45), Rhode Island (42), New York (27), and New Jersey (14). About 75% of all cases were diagnosed from May through October. Babesiosis occurrence was significantly higher among males vs. females and whites vs. non-whites.
Conclusion
Our study reveals increasing babesiosis occurrence among the U.S. elderly during 2006–2013, with highest rates in the babesiosis-endemic states. The study also shows variation in babesiosis occurrence by age, gender, race, state of residence, and diagnosis months. Overall, our study highlights the importance of large administrative databases in assessing the occurrence of emerging infections in the United States.
doi:10.1371/journal.pone.0140332
PMCID: PMC4607449  PMID: 26469785
11.  Correlates of Recent Declines of Rodents in Northern and Southern Australia: Habitat Structure Is Critical 
PLoS ONE  2015;10(6):e0130626.
Australia has experienced dramatic declines and extinctions of its native rodent species over the last 200 years, particularly in southern Australia. In the tropical savanna of northern Australia significant declines have occurred only in recent decades. The later onset of these declines suggests that the causes may differ from earlier declines in the south. We examine potential regional effects (northern versus southern Australia) on biological and ecological correlates of range decline in Australian rodents. We demonstrate that rodent declines have been greater in the south than in the tropical north, are strongly influenced by phylogeny, and are consistently greater for species inhabiting relatively open or sparsely vegetated habitat. Unlike in marsupials, where some species have much larger body size than rodents, body mass was not an important predictor of decline in rodents. All Australian rodent species are within the prey-size range of cats (throughout the continent) and red foxes (in the south). Contrary to the hypothesis that mammal declines are related directly to ecosystem productivity (annual rainfall), our results are consistent with the hypothesis that disturbances such as fire and grazing, which occur in non-rainforest habitats and remove cover used by rodents for shelter, nesting and foraging, increase predation risk. We agree with calls to introduce conservation management that limits the size and intensity of fires, increases fire patchiness and reduces grazing impacts at ecological scales appropriate for rodents. Controlling feral predators, even creating predator-free reserves in relatively sparsely-vegetated habitats, is urgently required to ensure the survival of rodent species, particularly in northern Australia where declines are not yet as severe as those in the south.
doi:10.1371/journal.pone.0130626
PMCID: PMC4482364  PMID: 26111037
12.  Partial characterization of lipids that develop during the routine storage of blood and prime the neutrophil NADPH oxidase 
Factors developed during the routine storage of whole blood and packed red blood cells that primed the neutrophil (PMN) reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase significantly by 2 weeks of storage, with maximal priming activity by product outdate (2.5 to 3.7 fold). These agents appeared to be generated by cellular constituents because stored, acellular plasma did not demonstrate PMN priming. The priming activity was soluble in chloroform. Priming of the oxidase by plasma and plasma extracts was inhibited by WEB 2170, a platelet-activating factor (PAF) receptor antagonist. Separation of the chloroform-soluble compounds from plasma by normal phase high-performance liquid chromatography demonstrated two peaks of priming activity at the retention times of neutral lipids and lysophos-phatidylcholines (lyso-PCs) for both whole blood and packed red blood cells, Analysis of the latter peak of PMN priming by fast atom bombardment mass spectroscopy identified several specific lyso-PC species including C16 and C16 lyso-PAF. Further evaluation by gas chromatography/mass spectroscopy demonstrated that three of these species increased dramatically over product storage time, while the other two species increased modestly, and paralleled the Increase in priming activity. Commercially available, purified mixtures of these lyso-PCs primed the PMN oxidase by twofold. When PMNs were incubated with this mixture of lyso-PCs, acetylated analogs of these compounds rapidly accumulated. Thus lipids, including specific lyso-PC species, develop during routine storage of cellular blood components, prime PMNs, and possibly play a role in the severe complications of transfusion therapy.
PMCID: PMC4451958  PMID: 7964126
13.  VFMA: Topographic Analysis of Sensitivity Data From Full-Field Static Perimetry 
Purpose:
To analyze static visual field sensitivity with topographic models of the hill of vision (HOV), and to characterize several visual function indices derived from the HOV volume.
Methods:
A software application, Visual Field Modeling and Analysis (VFMA), was developed for static perimetry data visualization and analysis. Three-dimensional HOV models were generated for 16 healthy subjects and 82 retinitis pigmentosa patients. Volumetric visual function indices, which are measures of quantity and comparable regardless of perimeter test pattern, were investigated. Cross-validation, reliability, and cross-sectional analyses were performed to assess this methodology and compare the volumetric indices to conventional mean sensitivity and mean deviation. Floor effects were evaluated by computer simulation.
Results:
Cross-validation yielded an overall R2 of 0.68 and index of agreement of 0.89, which were consistent among subject groups, indicating good accuracy. Volumetric and conventional indices were comparable in terms of test–retest variability and discriminability among subject groups. Simulated floor effects did not negatively impact the repeatability of any index, but large floor changes altered the discriminability for regional volumetric indices.
Conclusions:
VFMA is an effective tool for clinical and research analyses of static perimetry data. Topographic models of the HOV aid the visualization of field defects, and topographically derived indices quantify the magnitude and extent of visual field sensitivity.
Translational Relevance:
VFMA assists with the interpretation of visual field data from any perimetric device and any test location pattern. Topographic models and volumetric indices are suitable for diagnosis, monitoring of field loss, patient counseling, and endpoints in therapeutic trials.
doi:10.1167/tvst.4.2.14
PMCID: PMC4413926  PMID: 25938002
visual fields; standard automated perimetry; retinitis pigmentosa; volumetric measures of the hill of vision; clinical trial endpoints
14.  Can severe aortic stenosis be identified by emergency physicians when interpreting a simplified two-view echocardiogram obtained by trained echocardiographers? 
Background
Aortic stenosis (AS) is a common valve problem that causes significant morbidity and mortality. The goal of this study was to determine whether an emergency physician (EP) could determine severe AS by reviewing only two B-mode echocardiographic views (parasternal long axis (PSLA) and parasternal short axis (PSSA)) obtained by trained echocardiographers.
Methods
A convenience sample of 60 patients with no AS, mild/moderate AS or severe AS was selected for health record and echocardiogram review. The echocardiograms were performed in an accredited echocardiography laboratory. An EP blinded to the cardiologist’s final report reviewed the PSLA and PSSA views after the cases were randomly sorted. Severe AS was defined as no cusp movement seen by the EP reviewers. A second EP independently reviewed 25% of randomly selected patients for inter-rater reliability. Collected data included patient demographics, EP interpretation and details of each echo view (quality, the number of cusps visualized, presence of calcification) and compared to final cardiology reports. Analyses included descriptive statistics, test characteristics for severe AS and kappa for agreement.
Results
The mean age was 75.3 years (range 18 to 90) with 36.7% females. The cardiologist’s diagnosis was as follows: 38.3% severe AS, 28.3% mild/moderate AS and 33.3% no AS. The PSSA view was poorer in quality compared with the PSLA (33.3% vs. 13.3%, p = 0.02), but the PSSA view was better than PSLA to visualize all three cusps (83.3% vs. 0%, p = 0.001). There was no difference in the presence of calcification between the mild/moderate and severe AS groups (94.1% vs. 100.0%, p = 0.46). The sensitivity and specificity for EP diagnosis of severe AS was 75.0% (95% CI 56.7% to 85.4%) and 92.5% (83.3% to 97.7%). The kappa for severe AS was 0.69 (0.41 to 0.85), and there was no significant difference between observers in the quality of the view, presence of aortic calcification and the number of cusps visible.
Conclusions
PSLA and PSSA views obtained by trained echocardiographers can be interpreted by an EP with appropriate training to identify severe AS with good specificity. Further larger prospective studies are required before widespread use by EPs.
Electronic supplementary material
The online version of this article (doi:10.1186/s13089-015-0022-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s13089-015-0022-8
PMCID: PMC4409610  PMID: 25932319
Aortic stenosis; Echocardiography; Point-of-care ultrasonography; FOCUS
15.  Optimising nutrition to improve growth and reduce neurodisabilities in neonates at risk of neurological impairment, and children with suspected or confirmed cerebral palsy 
BMC Pediatrics  2015;15:22.
Background
Neurological impairment is a common sequelae of perinatal brain injury. Plasticity of the developing brain is due to a rich substrate of developing neurones, synaptic elements and extracellular matrix. Interventions supporting this inherent capacity for plasticity may improve the developmental outcome of infants following brain injury. Nutritional supplementation with combination docosahexaenoic acid, uridine and choline has been shown to increase synaptic elements, dendritic density and neurotransmitter release in rodents, improving performance on cognitive tests. It remains elusive whether such specific ‘neurotrophic’ supplementation enhances brain plasticity and repair after perinatal brain injury.
Methods/Design
This is a two year double-blind, randomised placebo controlled study with two cohorts to investigate whether nutritional intervention with a neurotrophic dietary supplement improves growth and neurodevelopmental outcomes in neonates at significant risk of neurological impairment (the D1 cohort), and infants with suspected or confirmed cerebral palsy (the D2 cohort).
120 children will be randomised to receive dietetic and nutritional intervention, and either active supplement or placebo. Eligible D1 neonates are those born <30+6 weeks gestation with weight <9th centile, ≤30+6 weeks gestation and Grade II, III or IV Intra-Ventricular Haemorrhage or periventricular white matter injury, or those born at 31-40+28 weeks gestation, with Sarnat grade I or II or III Hypoxic Ischaemic Encephalopathy or neuroimaging changes compatible with perinatal brain injury. Eligible D2 infants are those aged 1-18 months with a suspected or confirmed clinical diagnosis of cerebral palsy. The primary outcome measure is composite cognitive score on the Bayley Scales of Infant and Toddler Development III at 24 months. Secondary outcomes include visuobehavioural and visual neurophysiological assessments, and growth parameters including weight, height, and head circumference.
Discussion
This is the first study to supplement neonates and infants with perinatal brain injury with the combination of factors required for healthy brain development, throughout the period of maximal brain growth. A further study strength is the comprehensive range of outcome measures employed. If beneficial, supplementation with brain phosphatide precursors could improve the quality of life of thousands of children with perinatal brain injury.
Trial registration
Current Controlled trials: ISRCTN39264076 (registration assigned 09/11/2012), ISRCTN15239951 (registration assigned 23/04/2010).
doi:10.1186/s12887-015-0339-2
PMCID: PMC4389808  PMID: 25885548
Docosahexaenoic acid; Choline; Uridine-5-monophosphate; Neonates; Infant; Neurodisability; Neurodevelopment; Cerebral palsy; Brain plasticity; Growth
16.  Identification of immune factors regulating anti-tumor immunity using polymeric vaccines with multiple adjuvants 
Cancer research  2014;74(6):1670-1681.
The innate cellular and molecular components required to mediate effective vaccination against weak tumor-associated antigens remain unclear. In this study we utilized polymeric cancer vaccines incorporating different classes of adjuvants to induce tumor protection, in order to identify dendritic cell subsets and cytokines critical to this efficacy. Three-dimensional, porous polymer matrices loaded with tumor lysates and presenting distinct combinations of GM-CSF and various TLR agonists effected 70–90% prophylactic tumor protection in B16-F10 melanoma models. In aggressive, therapeutic B16 models, the vaccine systems incorporating GM-CSF in combination with P(I:C) or CpG-ODN induced the complete regression of solid tumors (≤40mm2) resulting in 33% long-term survival. Regression analysis revealed that the numbers of vaccine-resident CD8(+) DCs and plasmacytoid DCs, along with local IL-12, and G-CSF concentrations correlated strongly to vaccine efficacy regardless of adjuvant type. Further, vaccine studies in Batf3−/− mice revealed that CD8(+) DCs are required to effect tumor protection, as vaccines in these mice were deficient in cytotoxic T cell priming, and IL-12 induction in comparison to wild-type. These studies broadly demonstrate that three-dimensional polymeric vaccines provide a potent platform for prophylactic and therapeutic protection, and can be used as a tool to identify critical components of a desired immune response. Specifically, these results suggest that CD8(+) DCs, plasmacytoid DCs, IL-12, and G-CSF play important roles in priming effective anti-tumor responses with these vaccines.
doi:10.1158/0008-5472.CAN-13-0777
PMCID: PMC3959905  PMID: 24480625
17.  From Quantification to Visualization: A Taxonomy of Uncertainty Visualization Approaches 
Quantifying uncertainty is an increasingly important topic across many domains. The uncertainties present in data come with many diverse representations having originated from a wide variety of disciplines. Communicating these uncertainties is a task often left to visualization without clear connection between the quantification and visualization. In this paper, we first identify frequently occurring types of uncertainty. Second, we connect those uncertainty representations to ones commonly used in visualization. We then look at various approaches to visualizing this uncertainty by partitioning the work based on the dimensionality of the data and the dimensionality of the uncertainty. We also discuss noteworthy exceptions to our taxonomy along with future research directions for the uncertainty visualization community.
doi:10.1007/978-3-642-32677-6_15
PMCID: PMC4319674  PMID: 25663949
uncertainty visualization
18.  Patient factors associated with SSRI dose for depression treatment in general practice: a primary care cross sectional study 
BMC Family Practice  2014;15:210.
Background
Antidepressant prescribing continues to rise. Increased long-term prescribing and higher doses are contributing to current growth; however, patient factors associated with the use of higher doses remain unknown. This study’s aim was to investigate patient factors associated with selective serotonin re-uptake inhibitor (SSRI) prescribed daily dose for depression treatment in general practice.
Methods
A stratified sample of low to high prescribing practices were selected. Routine individual patient-level data were extracted one practice at a time: September 2009 to January 2011. Patients included were ≥18 years, and prescribed an SSRI for depression. Logistic regression analysis was undertaken to assess individual predictor variables on SSRI daily dose by standard therapeutic dose versus higher dose, as SSRIs demonstrate flat dose response curves for depression treatment. Predictor variables included: age, gender, deprivation, co-morbidity, smoking status, being prescribed the same SSRI for ≥2 years, and patients’ general practice. For a subgroup of patients a second sub-group analysis included long-term benzodiazepine and/or z-hypnotic (B&Z) as a predictor variable.
Results
Inter-practice SSRI prescribing varied significantly; practice point prevalence ranged from 2.5% (94/3697) to 11.9% (359/3007) of the practice population ≥18 years old; median 7.3% (250/3421) (χ2 = 2277.2, df = 10, p < 0.001). Overall point prevalence was 6.3% (3518/52575), with 5.8% (3066/52575) prescribed SSRIs for depression of whom 84.7% (2596/3066) had data for regression analysis. Higher SSRI doses were significantly associated with, in descending order of magnitude, individual practice attended, being prescribed the same SSRI for ≥2 years (Odds Ratio (OR) 1.80, 95% CI 1.49 to 2.17, p < 0.001) and living in a more deprived area (OR 1.55, 95% CI 1.11 to 2.16, p = 0.009). Higher SSRI doses in the B&Z subgroup were significantly associated with individual practice attended, being prescribed a long-term B&Z (OR 2.05 95% CI 1.47 to 2.86, p < 0.001) and being prescribed the same SSRI for ≥2 years (OR 1.94, 95% CI 1.53 to 2.47, p < 0.001).
Conclusion
Higher SSRI doses for depression were associated with practice attended and being prescribed the same antidepressant for ≥2 years. As long-term antidepressant use increases, the use of higher doses may further contribute to prescribing growth.
Electronic supplementary material
The online version of this article (doi:10.1186/s12875-014-0210-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s12875-014-0210-9
PMCID: PMC4341873  PMID: 25540076
Family practice; Chronic disease; Depression; Antidepressive agents; Benzodiazepines
20.  Uncertainty Visualization in Forward and Inverse Cardiac Models 
Computing in cardiology  2013;40:57-60.
Quantification and visualization of uncertainty in cardiac forward and inverse problems with complex geometries is subject to various challenges. Specific to visualization is the observation that occlusion and clutter obscure important regions of interest, making visual assessment difficult. In order to overcome these limitations in uncertainty visualization, we have developed and implemented a collection of novel approaches. To highlight the utility of these techniques, we evaluated the uncertainty associated with two examples of modeling myocardial activity. In one case we studied cardiac potentials during the repolarization phase as a function of variability in tissue conductivities of the ischemic heart (forward case). In a second case, we evaluated uncertainty in reconstructed activation times on the epicardium resulting from variation in the control parameter of Tikhonov regularization (inverse case). To overcome difficulties associated with uncertainty visualization, we implemented linked-view windows and interactive animation to the two respective cases. Through dimensionality reduction and superimposed mean and standard deviation measures over time, we were able to display key features in large ensembles of data and highlight regions of interest where larger uncertainties exist.
PMCID: PMC4221850  PMID: 25383390
21.  Performance and Biocompatibility of Extremely Tough Alginate/Polyacrylamide Hydrogels 
Biomaterials  2013;34(33):8042-8048.
Although hydrogels now see widespread use in a host of applications, low fracture toughness and brittleness have limited their more broad use. As a recently described interpenetrating network (IPN) of alginate and polyacrylamide demonstrated a fracture toughness of ∼9000 J/m2, we sought to explore the biocompatibility and maintenance of mechanical properties of these hydrogels in cell culture and in vivo conditions. These hydrogels can sustain a compressive strain of over 90% with minimal loss of Young's Modulus as well as minimal swelling for up to 50 days of soaking in culture conditions. Mouse mesenchymal stem cells exposed to the IPN gel-conditioned media maintain high viability, and although cells exposed to conditioned media demonstrate slight reductions in proliferation and metabolic activity (WST assay), these effects are abrogated in a dose-dependent manner. Implantation of these IPN hydrogels into subcutaneous tissue of rats for 8 weeks led to mild fibrotic encapsulation and minimal inflammatory response. These results suggest the further exploration of extremely tough alginate/PAAM IPN hydrogels as biomaterials.
doi:10.1016/j.biomaterials.2013.06.061
PMCID: PMC3775708  PMID: 23896005
22.  Baseline Visual Field Findings in the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) 
Purpose.
To characterize visual field (VF) loss at the baseline visit and to evaluate VF quality control (QC) procedures in the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT).
Methods.
The Visual Field Reading Center (VFRC) evaluated 660 baseline VFs (1320 hemifields) from 165 enrolled patients. Three readers independently classified each superior and inferior hemifield and identified any abnormalities. A subset (20%) of the hemifields was reread to evaluate within- and between-reader agreements. The QC system addressed test parameters, patient data, and shipment errors.
Results.
The majority (60%) of the baseline hemifields consisted of localized nerve fiber bundle-type VF loss. Approximately one-third (31.5%) of all the classifications consisted of partial arcuate defects combined with an enlarged blind spot, making this the most common type of hemifield classification. Inferior hemifield loss was greater than superior loss for both study and nonstudy eyes. Reader agreements were >90% for both inferior and superior hemifields for two out of three readers. Test–retest reliability agreement for individual readers was 95% for both hemifields. There were few QC errors with only 5.48 error points per 100-point VF.
Conclusions.
The most common type of IIHTT baseline hemifield abnormality was a localized nerve fiber bundle-like defect. Localized inferior hemifield loss was more common than superior hemifield loss. Quality control and within- and between-reader agreement were excellent for the IIHTT (ClinicalTrials.gov number, NCT01003639).
The VFRC at the University of California-Davis was to provide consistent expert analysis and interpretation of visual field data and to ensure high-quality data for subjects participating in a clinical trial. The latter role was accomplished through the use of technician certification and QC.
doi:10.1167/iovs.14-14243
PMCID: PMC4031894  PMID: 24781936
visual fields; intracranial idiopathic hypertension; optic neuropathy; quality control
23.  Where Do Livestock Guardian Dogs Go? Movement Patterns of Free-Ranging Maremma Sheepdogs 
PLoS ONE  2014;9(10):e111444.
In many parts of the world, livestock guardian dogs (LGDs) are a relatively new and increasingly popular method for controlling the impact of wild predators on livestock. On large grazing properties in Australia, LGDs are often allowed to range freely over large areas, with minimal supervision by their owners. How they behave in this situation is mostly unknown. We fitted free-ranging Maremma sheepdogs with GPS tracking collars on three properties in Victoria, Australia; on two properties, four sheep were also fitted with GPS collars. We investigated how much time the Maremmas spent with their livestock, how far they moved outside the ranges of their stock, and tested whether they use their ranges sequentially, which is an effective way of maintaining a presence over a large area. The 95% kernel isopleth of the Maremmas ranged between 31 and 1161 ha, the 50% kernel isopleth ranged between 4 and 252 ha. Maremmas spent on average 90% of their time in sheep paddocks. Movements away from sheep occurred mostly at night, and were characterised by high-speed travel on relatively straight paths, similar to the change in activity at the edge of their range. Maremmas used different parts of their range sequentially, similar to sheep, and had a distinct early morning and late afternoon peak in activity. Our results show that while free-ranging LGDs spend the majority of their time with livestock, movements away from stock do occur. These movements could be important in allowing the dogs to maintain large territories, and could increase the effectiveness of livestock protection. Allowing LGDs to range freely can therefore be a useful management decision, but property size has to be large enough to accommodate the large areas that the dogs use.
doi:10.1371/journal.pone.0111444
PMCID: PMC4213034  PMID: 25353319
24.  Inverse Electrocardiographic Source Localization of Ischemia: An Optimization Framework and Finite Element Solution 
With the goal of non-invasively localizing cardiac ischemic disease using body-surface potential recordings, we attempted to reconstruct the transmembrane potential (TMP) throughout the myocardium with the bidomain heart model. The task is an inverse source problem governed by partial differential equations (PDE). Our main contribution is solving the inverse problem within a PDE-constrained optimization framework that enables various physically-based constraints in both equality and inequality forms. We formulated the optimality conditions rigorously in the continuum before deriving finite element discretization, thereby making the optimization independent of discretization choice. Such a formulation was derived for the L2-norm Tikhonov regularization and the total variation minimization. The subsequent numerical optimization was fulfilled by a primal-dual interior-point method tailored to our problem’s specific structure. Our simulations used realistic, fiber-included heart models consisting of up to 18,000 nodes, much finer than any inverse models previously reported. With synthetic ischemia data we localized ischemic regions with roughly a 10% false-negative rate or a 20% false-positive rate under conditions up to 5% input noise. With ischemia data measured from animal experiments, we reconstructed TMPs with roughly 0.9 correlation with the ground truth. While precisely estimating the TMP in general cases remains an open problem, our study shows the feasibility of reconstructing TMP during the ST interval as a means of ischemia localization.
doi:10.1016/j.jcp.2013.05.027
PMCID: PMC3727301  PMID: 23913980
Inverse Problem; Electrocardiography; Finite Element Method; PDE Optimization; Myocardial Ischemia; Bidomain Model; Total Variation
25.  Visual Field Profile of Optic Neuritis 
Archives of ophthalmology  2010;128(3):330-337.
Objective
To evaluate visual field abnormalities after an episode of optic neuritis among participants in the Optic Neuritis Treatment Trial.
Methods
Three readers independently evaluated 10 443 visual fields from 454 patients and classified visual field abnormalities into 21 different monocular categories representing 3 general types of visual loss: diffuse, localized, and artifactual. Classification frequency was determined and reader agreement was evaluated. The association of visual field abnormality classifications with mean deviation, pattern standard deviation, visual acuity, and foveal threshold was assessed.
Results
At baseline, diffuse loss accounted for 66.2% of the abnormalities in the affected eyes but only 6.2% of the abnormalities in the fellow eyes. During years 1 through 15, the affected and fellow eyes exhibited predominantly localized loss in the nerve fiber bundle region (partial arcuate, paracentral, and arcuate defects). At year 1, 35.7% of the abnormalities in the affected eyes and 34.4% in the fellow eyes consisted of localized defects. At year 15, 39.5% of abnormalities in the affected eyes and 26.3% in the fellow eyes consisted of localized defects. Foveal threshold was highly correlated with visual acuity and contrast sensitivity in the affected eye at baseline (−0.82 vs 0.79, respectively), 6 months (−0.84 vs 0.81), and 1 year (−0.84 vs 0.79).
Conclusions
Diffuse and central loss were more predominant in the affected eye at baseline, and nerve fiber bundle defects (partial arcuate, paracentral, and arcuate) were the most predominant localized abnormalities in both the affected and fellow eyes during the study.
doi:10.1001/archophthalmol.2010.16
PMCID: PMC4107874  PMID: 20212204

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