Quantification and characterization of granulocyte macrophage colony-stimulating factor activated human peripheral blood mononuclear cells by fluorine-19 cellular MRI in an immunocompromised mouse model.

PURPOSE: The purpose of this study was to test fluorine-19 (19F) cellular magnetic resonance (MRI) as a non-invasive imaging modality to track therapeutic cell migration as a surrogate marker of immunotherapeutic effectiveness. MATERIALS AND METHODS: Human peripheral blood mononuclear cell- (PBMC)-derived antigen presenting cell (APC) were labeled with a 19F-perfluorocarbon (PFC) and/or activated with granulocyte macrophage colony-stimulating factor (GM-CSF). Viability, phenotype and cell lineage characterization preceded 19F cellular MRI of PFC+ PBMC under both pre-clinical 9.4 Tesla (T) and clinical 3T conditions in a mouse model. RESULTS: A high proportion of PBMC incorporated PFC without affecting viability, phenotype or cell lineage composition. PFC+ PBMC were in vivo migration-competent to draining and downstream lymph nodes. GM-CSF addition to culture increased PBMC migration to, and persistence within, secondary lymphoid organs. CONCLUSION: 19F cellular MRI is a non-invasive imaging technique capable of detecting and quantifying in vivo cell migration in conjunction with an established APC-based immunotherapy model. 19F cellular MRI can function as a surrogate marker for assessing and improving upon the therapeutic benefit that this immunotherapy provides.

Automated arteriole and venule classification using deep learning for retinal images from the UK Biobank cohort.

The morphometric characteristics of the retinal vasculature are associated with future risk of many systemic and vascular diseases. However, analysis of data from large population based studies is needed to help resolve uncertainties in some of these associations. This requires automated systems that extract quantitative measures of vessel morphology from large numbers of retinal images. Associations between retinal vessel morphology and disease precursors/outcomes may be similar or opposing for arterioles and venules. Therefore, the accurate detection of the vessel type is an important element in such automated systems. This paper presents a deep learning approach for the automatic classification of arterioles and venules across the entire retinal image, including vessels located at the optic disc. This comprises of a convolutional neural network whose architecture contains six learned layers: three convolutional and three fully-connected. Complex patterns are automatically learnt from the data, which avoids the use of hand crafted features. The method is developed and evaluated using 835,914 centreline pixels derived from 100 retinal images selected from the 135,867 retinal images obtained at the UK Biobank (large population-based cohort study of middle aged and older adults) baseline examination. This is a challenging dataset in respect to image quality and hence arteriole/venule classification is required to be highly robust. The method achieves a significant increase in accuracy of 8.1% when compared to the baseline method, resulting in an arteriole/venule classification accuracy of 86.97% (per pixel basis) over the entire retinal image.

Assessing the feasibility of the Effectiveness of Discontinuing Bisphosphonates trial: a pilot study.

The Effectiveness of Discontinuing Bisphosphonates (EDGE) study is a planned pragmatic clinical trial to guide "drug holiday" clinical decision making. This pilot study assessed work flow and feasibility of such a study. While participant recruitment and treatment adherence were suboptimal, administrative procedures were generally feasible and minimally disrupted clinic flow. INTRODUCTION: The comparative effectiveness of continuing or discontinuing long-term alendronate (ALN) on fractures is unknown. A large pragmatic ALN discontinuation study has potential to answer this question. METHODS: We conducted a 6-month pilot study of the planned the EDGE study among current long-term ALN users (women aged ≥65 with ≥3 years of ALN use) to determine study work flow and feasibility including evaluating the administrative aspects of trial conduct (e.g., time to contract, institutional review board (IRB) approval), assessing rates of site and participant recruitment, and evaluating post-randomization outcomes, including adherence, bisphosphonate-associated adverse events, and participant and site satisfaction. We assessed outcomes 1 and 6 months after randomization. RESULTS: Nine sites participated, including seven community-based medical practices and two academic medical centers. On average (SD), contract execution took 3.4 (2.3) months and IRB approval took 13.9 (4.1) days. Sites recruited 27 participants (13 to continue ALN and 14 to discontinue ALN). Over follow-up, 22% of participants did not adhere to their randomization assignment: 30.8% in the continuation arm and 14.3% in the discontinuation arm. No fractures or adverse events were reported. Sites reported no issues regarding work flow, and participants were highly satisfied with the study. CONCLUSIONS: Administrative procedures of the EDGE study were generally feasible, with minimal disruption to clinic flow. In this convenience sample, participant recruitment was suboptimal across most practice sites. Accounting for low treatment arm adherence, a comprehensive recruitment approach will be needed to effectively achieve the scientific goals of the EDGE study.

A technician-delivered 'virtual clinic' for triaging low-risk glaucoma referrals.

PurposeThe purpose of this study is to describe the outcomes of a technician-delivered glaucoma referral triaging service with 'virtual review' of resultant data by a consultant ophthalmologist.Patients and methodsThe Glaucoma Screening Clinic reviewed new optometrist or GP-initiated glaucoma suspect referrals into a specialist ophthalmic hospital. Patients underwent testing by three ophthalmic technicians in a dedicated clinical facility. Data were reviewed at a different time and date by a consultant glaucoma ophthalmologist. Approximately 10% of discharged patients were reviewed in a face-to-face consultant-led clinic to examine the false-negative rate of the service.ResultsBetween 1 March 2014 and 31 March 2016, 1380 patients were seen in the clinic. The number of patients discharged following consultant virtual review was 855 (62%). The positive predictive value of onward referrals was 84%. Three of the 82 patients brought back for face-to-face review were deemed to require treatment, equating to negative predictive value of 96%.ConclusionsOur technician-delivered glaucoma referral triaging clinic incorporates consultant 'virtual review' to provide a service model that significantly reduces the number of onward referrals into the glaucoma outpatient department. This model may be an alternative to departments where there are difficulties in implementing optometrist-led community-based referral refinement schemes.

Automated retinal image quality assessment on the UK Biobank dataset for epidemiological studies.

Morphological changes in the retinal vascular network are associated with future risk of many systemic and vascular diseases. However, uncertainty over the presence and nature of some of these associations exists. Analysis of data from large population based studies will help to resolve these uncertainties. The QUARTZ (QUantitative Analysis of Retinal vessel Topology and siZe) retinal image analysis system allows automated processing of large numbers of retinal images. However, an image quality assessment module is needed to achieve full automation. In this paper, we propose such an algorithm, which uses the segmented vessel map to determine the suitability of retinal images for use in the creation of vessel morphometric data suitable for epidemiological studies. This includes an effective 3-dimensional feature set and support vector machine classification. A random subset of 800 retinal images from UK Biobank (a large prospective study of 500,000 middle aged adults; where 68,151 underwent retinal imaging) was used to examine the performance of the image quality algorithm. The algorithm achieved a sensitivity of 95.33% and a specificity of 91.13% for the detection of inadequate images. The strong performance of this image quality algorithm will make rapid automated analysis of vascular morphometry feasible on the entire UK Biobank dataset (and other large retinal datasets), with minimal operator involvement, and at low cost.

A pragmatic randomized trial comparing tablet computer informed consent to traditional paper-based methods for an osteoporosis study.

OBJECTIVE: Methods to improve informed consent efficiency and effectiveness are needed for pragmatic clinical trials. We compared informed consent using a tablet computer to a paper approach to assess comprehension and satisfaction of patients and clinic staff for a future osteoporosis clinical trial. METHODS: Nine community-based practices identified and recruited patients to compare the informed consent processes (tablet vs. paper) in a mock osteoporosis clinical trial. The tablet informed consent included an animation summarizing the trial, complete informed consent document, and questions to assess and reinforce comprehension of the study. Participants were women age ≥55 years with ≥1 year of alendronate use. We surveyed participants to assess comprehension and satisfaction and office staff for satisfaction and perceived time demands. RESULTS: The nine practices enrolled 33 participants. There was not a significant difference in comprehension between the tablet vs. paper informed consent [mean (SD) tablet: 12.2 (1.0) vs. paper: 11.4 (1.7)]. Office staff preferred the tablet to the paper informed consent for identifying potential study participants (two-sided t-test p = 0.02) despite an increased perceived time spent to complete the tablet process [tablet: 28.3 min (SD 16.3) vs. paper: 19.0 min (SD 6.9); p = 0.08]. CONCLUSIONS: Although, there were no significant differences in participant satisfaction and comprehension with the tablet informed consent compared to a paper informed consent, patients and office staff trended towards greater satisfaction with the tablet informed consent. Larger studies are needed to further evaluate the utility of electronic informed consent in pragmatic clinical trials.

Measures of socioeconomic status and self-reported glaucoma in the U.K. Biobank cohort.

PURPOSE: To determine ocular, demographic, and socioeconomic associations with self-reported glaucoma in the U.K. Biobank. METHODS: Biobank is a study of U.K. residents aged 40-69 years registered with the National Health Service. Data were collected on visual acuity, intraocular pressure (IOP), corneal biomechanics, and questionnaire from 112,690 participants. Relationships between ocular, demographic, and socioeconomic variables with reported diagnosis of glaucoma were examined. RESULTS: In all, 1916 (1.7%) people in U.K. Biobank reported glaucoma diagnosis. Participants reporting glaucoma were more likely to be older (mean 61.4 vs. 56.7 years, P<0.001) and male (2.1% vs. 1.4%, P=0.001). The rate of reported glaucoma was significantly higher in Black (3.28%, P<0.001) and Asian (2.14%, P=0.009) participants compared with White participants (1.62%, reference). Cases of reported glaucoma had a higher mean IOP (18 mm Hg both eyes, P<0.001), lower corneal hysteresis (9.96 right eye, 9.89 left eye, P<0.001), and lower visual acuity (0.09 logMAR right eye, 0.08 logMAR left eye, P<0.001) compared with those without (16 mm Hg both eyes, hysteresis 10.67 right eye, 10.63 left eye, 0.03 logMAR right eye, 0.02 logMAR left eye). The mean Townsend deprivation index was -0.72 for those reporting glaucoma and -0.95 for those without (P<0.001), indicating greater relative deprivation in those reporting glaucoma. Multivariable logistic regression showed that people in the lowest income group (<£18,000/year) were significantly more likely to report a diagnosis of glaucoma compared with any other income level (P<0.01). We observed increasing glaucoma risk across the full range of income categories, with highest risk among those of lowest income, and no evidence of a threshold effect. CONCLUSIONS: In a large U.K. cohort, individuals reporting glaucoma had more adverse socioeconomic characteristics. Study of the mechanisms explaining these effects may aid our understanding of health inequality and will help inform public health interventions.

Automated retinal vessel recognition and measurements on large datasets.

The characteristics of the retinal vascular network have been prospectively associated with many systemic and vascular diseases. QUARTZ is a fully automated software that has been developed to localize and quantify the morphological characteristics of blood vessels in retinal images for use in epidemiological studies. This software was used to analyse a dataset containing 16,000 retinal images from the EPIC-Norfolk cohort study. The objective of this paper is to both assess the suitability of this dataset for computational analysis and to further evaluate the QUARTZ software.

Epidemiology of myopia.

Myopia is one of the most prevalent disorders of the eye. Higher myopia is associated with comorbidities that increase risks of severe and irreversible loss of vision, such as retinal detachment, subretinal neovascularization, dense cataract, and glaucoma. In recent years, reports from population-based prevalence studies carried out in various geographical areas now give a clear picture of the current distribution of refractive error. The scarcity of data from well-designed longitudinal cohort studies is still yet to be addressed. These studies have confirmed the previous data indicating that prevalence of refractive error varies according to ethnicity and geographic regions, and also point to an increase in myopia prevalence over the past half-century. The problem is particularly pronounced in affluent, industrialised areas of East Asia. Environmental risk factors for myopia related to socioeconomic status and lifestyle have been identified. The past decade has seen a greater understanding of the molecular biological mechanisms that determine refractive error, giving further support to the belief that myopia is the result of a complex interaction between genetic predisposition and environmental exposures. This review summarizes data on the prevalence, incidence, progression, associations, risk factors, and impact from recent epidemiological studies on myopia.

In vivo MRI discrimination between live and lysed iron-labelled cells using balanced steady state free precession.

OBJECTIVES: The goal of this study was to evaluate the ability of balanced steady state free precession (b-SSFP) magnetic resonance imaging sequence to distinguish between live and lysed iron-labelled cells. METHODS: Human breast cancer cells were labelled with iron oxide nanoparticles. Cells were lysed using sonication. Imaging was performed at 3 T. The timing parameters for b-SSFP and the number of iron-labelled cells in samples were varied to optimise the b-SSFP signal difference between live and lysed iron-labelled cell samples. For in vivo experiments, cells were mixed with Matrigel and implanted into nude mice. Three mice implanted with live labelled cancer cells were irradiated to validate this method. RESULTS: Lysed iron-labelled cells have a significantly higher signal compared with live, intact iron-labelled cells in bSSFP images. The contrast between live and dead cells can be maximised by careful optimisation of timing parameters. A change in the b-SSFP signal was measured 6 days after irradiation, reflecting cell death in vivo. Histology confirmed the presence of dead cells in the implant. CONCLUSIONS: Our results show that the b-SSFP sequence can be optimised to allow for the discrimination of live iron-labelled cells and lysed iron-labelled cells in vitro and in vivo.

Comparing approaches to screening for angle closure in older Chinese adults.

AIMS: Primary angle-closure glaucoma is expected to account for nearly 50% of bilateral glaucoma blindness by 2020. This study was conducted to assess the performance of the scanning peripheral anterior chamber depth analyzer (SPAC) and limbal anterior chamber depth (LACD) as screening methods for angle closure. METHODS: This study assessed two clinical populations to compare SPAC, LACD, and gonioscopy: the Zhongshan Angle-closure Prevention Trial, from which 370 patients were eligible as closed-angle participants and the Liwan Eye Study, from which 72 patients were selected as open-angle controls. Eligible participants were assessed by SPAC, LACD, and gonioscopy. RESULTS: Angle status was defined by gonioscopy. Area under the receiver operating characteristic curve (AUROC) for SPAC was 0.92 (0.89-0.95) whereas AUROC for LACD was 0.94 (0.92-0.97). Using conventional cutoff points, sensitivity/specificity was 93.0%/70.8% for SPAC and 94.1%/87.5% for LACD. Sequential testing using both SPAC and LACD increased the specificity to 94.4% and decreased the sensitivity to 87.0%. CONCLUSION: SPAC has significantly lower specificity than LACD measurement using conventional cutoffs but interpretation of the findings can be performed by modestly trained personnel.

Labeling of multiple cell lines using a new iron oxide agent for cell tracking by MRI.

Stem cells, cancer cells and immune cells were labeled by co-incubation with a new ultra-small iron oxide nanoparticle called Molday ION Rhodamine-B (MIRB). Iron staining, fluorescence imaging, transmission electron microscopy and flow cytometry were used to assess cell viability, function and labeling efficiency. This study has shown that MIRB can be used to label both adherent and nonadherent cell lines, with high viability and loading levels sufficient for their detection in vivo by MRI at 3 T.

Refractive error, axial length and anterior chamber depth of the eye in British adults: the EPIC-Norfolk Eye Study.

PURPOSE: To describe the distribution, and demographic and socioeconomic correlates of refractive error and related ocular biometry in an older British population. METHODS: Refractive error was measured using an auto-refractor without cycloplegia. Pseudophakic individuals and those who had undergone refractive surgery were excluded from analysis. Axial length and anterior chamber depth were measured using partial coherence laser interferometry. Occupation category and highest educational achievement were recorded. RESULTS: Biometric data were available for 2519 people (1090 men, 1429 women; 93.2% of all participants) aged 48 to 88 years. Refractive data were available for both eyes in 2210 bilaterally phakic participants. Among phakic individuals, axial length of the eye was strongly inversely correlated with refractive error in both men and women (p<0.001). Axial length of the eye was strongly, independently related to height, weight and social class, but most strongly related to educational achievement. In contrast, anterior chamber depth varied with age and sex, but not with socioeconomic status. There was a significant inverse association between anterior chamber depth and refraction in women (p<0.001) but not in men (p=0.495). CONCLUSION: Refractive error in this predominantly white older UK population was associated with axial biometry and sociodemographic characteristics. Educational status was the strongest determinant of axial length.

Prophylactic laser peripheral iridotomy and cataract progression.

PURPOSE: To determine whether prophylactic laser peripheral iridotomy (LPI) for primary angle closure (PAC) is associated with cataract progression. METHODS: In 1999, Mongolian volunteers aged>or=50 years were invited to participate in a longitudinal study. Glaucoma was excluded in all participants and 712 of them were selected to undergo a full ophthalmic examination as part of the study protocol. Lenses were graded and PAC diagnosed using international classification systems. In 2005, all traced participants underwent a similar dilated examination. Diagnosis of cataract progression was based on the inter-observer variation +2 standard deviations. The association between LPI at baseline and cataract progression was assessed using chi2-test and logistic regression. RESULTS: Of 712 participants, 158 were diagnosed with occludable angles and treated with LPI. In 2005, 137 participants (19.2%) had died, 315 (315/575=54.8%) were traced, and dilated examination was performed on 276 (48%) of them. Progression of nuclear opacity (NO), cortical, and posterior subcapsular (PSC) opacities were evident in 40 (14.5%, 95% confidence interval (CI)=10.6-19.2%), 89 (32.2%, 95% CI=26.8-38.1%), and 11 participants (4.0%, 95% CI=2.0-7.0%), respectively. Although NO was more likely to progress in those with LPI in a crude analysis (odds ratio (OR)=2.02, 95% CI=1.00-4.11, P=0.05), no evidence of an independent association was detected in multivariate analysis adjusting for age, sex, and baseline Schaffer grading (adjusted OR=1.24, 0.41-3.75, P=0.7). There was no evidence of an association between LPI and progression of PSC or cortical opacities. CONCLUSIONS: There is no evidence that prophylactic LPI is independently associated with cataract progression in this study.

Is measurement of adult height useful in screening for primary angle closure?

BACKGROUND: Adult height is independently related to ocular dimensions and shorter people have shorter globes and shallower anterior chambers. We investigated the relationship between adult height and angle dimensions to explore measuring height as a possible screening test for angle closure. METHODS: A population-based, cross-sectional survey of adult Chinese living in the Tanjong Pagar district, Singapore was conducted. Anterior chamber depth, gonioscopic angle width and height were assessed using standardized protocols. RESULTS: Data were available for 996 persons. Shorter people had shallower anterior chamber depth (2.35 mm for persons <144 cm vs 2.72 mm for persons >170 cm, P=0.008) and smaller gonioscopic angles (22 degrees for <144 cm vs 30 degrees for >170 cm, P=0.079). After controlling for age and gender, adult height was significantly related to anterior chamber depth (P=0.008) but not significantly related to gonioscopic angle width (P=0.079). Female sex and age > or = 50 years used together correctly identified 45/66 (68.2%) individuals with an occludable angle (sensitivity 68.2%, specificity 61.3%). Fewer people, 41/66 (62.1%), were correctly identified when height <160 cm was added to female sex and age 50 > or = years (sensitivity was 62.1% and specificity was 64.7%). CONCLUSIONS: Shorter adult height is significantly associated with a shallower anterior chamber depth, but the addition of height contributed little to demographics (age and gender) as the preliminary screening criteria to identify individuals at risk of an occludable angle.

The morphology of the optic nerve head in the Singaporean Chinese population (the Tanjong Pagar study): part 1--Optic nerve head morphology.

BACKGROUND/AIMS: To investigate the correlation between optic disc parameters and their association with demographic variables in a Chinese population. METHODS: Disc data were obtained from 929 subjects aged > or = 40 years from the Tanjong Pagar glaucoma survey of Singapore, using a novel planimetric method of sequential stereo-photographs. Biometric data (refractive error, keratometry, axial length, anterior chamber depth, lens thickness) were used to calculate ocular magnification. Camera magnification was quantified with a model eye. A "normal" dataset of 622 subjects was generated by exclusion of subjects with abnormal results on psychophysical testing, an occludable angle or an intraocular pressure > 97.5th percentile in either eye. RESULTS: Median disc area (DA), cup area (CA), and rim area (RA) were 2.09 (range 1.28-4.01) mm2, 0.69 (0.01-1.90) mm2 and 1.38 (0.82-2.50) mm2, respectively. There was strong evidence of an association between DA and RA (Spearman's rho 0.624, p<0.001). DA and RA were significantly greater in men (median DA = 2.20; range 1.30-3.56; median RA, 1.45; range 0.85-2.30) than women (median DA, 2.00; range 1.28-4.01; median RA, 1.36; range 0.82-2.49, p<0.001). DA increased with age (Spearman's rho 0.115, p = 0.004), while RA was unrelated (rho -0.041; p = 0.308). CONCLUSIONS: The morphometric characteristics of optic discs in Chinese Singaporeans are very similar to those described in other groups, with the temporal sector rim having the smallest area. Disc and rim areas vary with sex (men > women). Disc area (but not that of the rim) increases with age.