Efficacy and toxicity of primary re-irradiation for malignant spinal cord compression based on radiobiological modelling: a phase II clinical trial.

BACKGROUND: The efficacy and safety of primary re-irradiation for MSCC are not known. Our aim was to establish the efficacy and safety of biologically effective dose-based re-irradiation. METHODS: Patients presenting with MSCC at a previously irradiated spine segment, and not proceeding with surgical decompression, were eligible. A 3 Gray per fraction experimental schedule (minimum 18 Gy/6 fractions, maximum 30 Gy/10 fractions) was used, delivering a maximum cumulative spinal dose of 100 Gy2 if the interval since the last radiotherapy was within 6 months, or 130 Gy2 if longer. The primary outcome was a change in mobility from week 1 to week 5 post-treatment, as assessed by the Tomita score. The RTOG SOMA score was used to screen for spinal toxicity, and an MRI performed to assess for radiation-induced myelopathy (RIM). RESULTS: Twenty-two patients were enroled, of whom eleven were evaluable for the primary outcome. Nine of eleven (81.8%) had stable or improved Tomita scores at 5 weeks. One of eight (12.5%) evaluable for late toxicity developed RIM. CONCLUSIONS: Re-irradiation is an efficacious treatment for MSCC. There is a risk of RIM with a cumulative dose of 120 Gy2. CLINICAL TRIAL REGISTRATION: Cancer Trials Ireland (ICORG 07-11); NCT00974168.

Non-inferiority randomised phase 3 trial comparing two radiation schedules (single vs. five fractions) in malignant spinal cord compression.

BACKGROUND: The optimal EBRT schedule for MSCC is undetermined. Our aim was to determine whether a single fraction (SF) was non-inferior to five daily fractions (5Fx), for functional motor outcome. METHODS: Patients not proceeding with surgical decompression in this multicentre non-inferiority, Phase 3 trial were randomised to 10 Gy/SF or 20 Gy/5Fx. A change in mobility from baseline to 5 weeks for each patient, was evaluated by a Modified Tomita score: 1 = 'Walk unaided', 2 = 'With walking aid' and 3 = 'Bed-bound'. The margin used to establish non-inferiority was a detrimental change of -0.4 in the mean difference between arms. RESULTS: One-hundred and twelve eligible patients were enrolled. Seventy-three patients aged 30-87 were evaluated for the primary analysis. The 95% CI for the difference in the mean change in mobility scores between arms was -0.12 to 0.6. Since -0.4 is not included in the interval, there is evidence that 10 Gy/SF is non-inferior to 20 Gy/5Fx. One grade 3 AE was reported in the 5Fx arm. Twelve (26%) patients in the 5Fx arm had a Grade 2-3 AE compared with six (11%) patients in the SF arm (p = 0.093). CONCLUSION: For mobility preservation, one 10-Gy fraction is non-inferior to 20 Gy in five fractions, in patients with MSCC not proceeding with surgical decompression. CLINICAL TRIAL REGISTRATION: Cancer Trials Ireland ICORG 05-03; NCT00968643; EU-20952.

Secondary outcomes in a clinical trial of carotenoids with coantioxidants versus placebo in early age-related macular degeneration.

PURPOSE: To report the secondary outcomes in the Carotenoids with Coantioxidants in Age-Related Maculopathy trial. DESIGN: Randomized double-masked placebo-controlled clinical trial (registered as ISRCTN 94557601). PARTICIPANTS: Participants included 433 adults 55 years of age or older with early age-related macular degeneration (AMD) in 1 eye and late-stage disease in the fellow eye (group 1) or early AMD in both eyes (group 2). INTERVENTION: An oral preparation containing lutein (L), zeaxanthin (Z), vitamin C, vitamin E, copper, and zinc or placebo. Best-corrected visual acuity (BCVA), contrast sensitivity (CS), Raman spectroscopy, stereoscopic colour fundus photography, and serum sampling were performed every 6 months with a minimum follow-up time of 12 months. MAIN OUTCOME MEASURES: Secondary outcomes included differences in BCVA (at 24 and 36 months), CS, Raman counts, serum antioxidant levels, and progression along the AMD severity scale (at 12, 24, and 36 months). RESULTS: The differential between active and placebo groups increased steadily, with average BCVA in the former being approximately 4.8 letters better than the latter for those who had 36 months of follow-up, and this difference was statistically significant (P = 0.04). In the longitudinal analysis, for a 1-log-unit increase in serum L, visual acuity was better by 1.4 letters (95% confidence interval, 0.3-2.5; P = 0.01), and a slower progression along a morphologic severity scale (P = 0.014) was observed. CONCLUSIONS: Functional and morphologic benefits were observed in key secondary outcomes after supplementation with L, Z, and coantioxidants in persons with early AMD.

Tomographic Biomarkers Predicting Progression to Fibrosis in Treated Neovascular Age-Related Macular Degeneration: A Multimodal Imaging Study.

PURPOSE: To describe the photoreceptor-retinal pigment epithelium (RPE) interface changes and to analyze the relationships between these features and hyperreflective material (HRM) with scarring and atrophy at the macula of patients with neovascular age-related macular degeneration (nAMD). DESIGN: Retrospective single-center observational study. PARTICIPANTS: A total of 150 eyes from 144 patients with naive nAMD were included. METHODS: All patients had OCT (HRA-OCT Spectralis, Heidelberg Engineering, Heidelberg, Germany) at baseline and at 1, 3, 6, and 12 months. Macular scar and macular atrophy (MA) were determined on multimodal imaging, including color fundus (CF) and near-infrared imaging at baseline and month 12 (M12). MAIN OUTCOME MEASURES: Change in HRM type (undefined and well-defined) and location, development of fibrotic or nonfibrotic macular scar, MA, and best-corrected visual acuity (BCVA) at M12. RESULTS: At baseline, eyes with fibrin on CF had thicker and wider HRM on OCT that correlated strongly with presence of undefined HRM. The proportion of eyes with undefined HRM fell dramatically by month 1 but well-defined HRM increased. At M12 defined HRM was strongly associated with macular scar (chi-square, 82.1; P < 0.001). Ordinal regression showed that both the thickness and the width of HRM were significant risk factors for development of fibrotic scar (P < 0.001 and P = 0.02) but not nonfibrotic scars (P = 0.67 and P = 0.65). Fibrotic macular scar (P = 0.001) but not nonfibrotic scar (P = 0.129) negatively affected visual acuity at M12. Ordinal regression showed that the risk factors for progression to MA were reticular pseudodrusen and thinner HRM (P = 0.017 and P = 0.028, respectively). MA negatively affected BCVA at M12 (P < 0.001). CONCLUSION: Our study supports the role of HRM as an important biomarker for the evolution of macular scar and atrophy in patients with nAMD undergoing treatment with anti-VEGF therapies. Undefined HRM can resolve with treatment, whereas well-defined HRM likely contains vascular complexes and fibrotic elements.

Rasch analysis of the daily living tasks dependent on vision (DLTV).

PURPOSE: To examine internal consistency, refine the response scale, and obtain a linear scoring system for the visual function instrument, the Daily Living Tasks Dependent on Vision (DLTV). METHODS: Data were available from 186 participants with a clinical diagnosis of AMD who completed the 22-item DLTV (DLTV-22) according to four-point ordinal response scale. An independent group of 386 participants with AMD were administered a reduced version of the DLTV with 11 items (DLTV-11), according to a five-point response scale. Rasch analysis was performed on both datasets and used to generate item statistics for measure order, response odds ratios per item and per person, and infit and outfit mean square statistics. The Rasch output from the DLTV-22 was examined to identify redundant items and for factorial validity and person item measure separation reliabilities. RESULTS: The average rating for the DLTV-22 changed monotonically with the magnitude of the latent person trait. The expected versus observed average measures were extremely close, with step calibrations evenly separated for the four-point ordinal scale. In the case of the DLTV-11, step calibrations were not as evenly separated, suggesting that the five-point scale should be reduced to either a four- or three-point scale. Five items in the DLTV-22 were removed, and all 17 remaining items had good infit and outfit mean squares. PCA with residuals from Rasch analysis identified two domains containing 7 and 10 items each. The domains had high person separation reliabilities (0.86 and 0.77 for domains 1 and 2, respectively) and item measure reliabilities (0.99 and 0.98 for domains 1 and 2, respectively). CONCLUSIONS: With the improved internal consistency, establishment of the accuracy and precision of the rating scale for the DLTV and the establishment of a valid domain structure we believe that it constitutes a useful instrument for assessing visual function in older adults with age-related macular degeneration.

Severity staging by early features of age-related maculopathy exhibits weak relationships with functional deficits on SWS grating acuity.

PURPOSE: To examine the relationship between short-wavelength-sensitive (SWS) resolution acuity and epidemiologically defined stages of early age-related maculopathy (ARM). METHODS: Subjects consisted of 88 adults aged 51 to 87 years. Psychophysical testing was undertaken in only one eye of each subject (the study eye). All study eyes had a LogMAR acuity of 0.30 (20/40 Snellen) or better. SWS and achromatic grating resolution acuity were measured at 6 degrees eccentricity from the fovea. Stereoscopic color fundus photographs centered on the macula were taken on both eyes of each subject and were graded using the Wisconsin Age-Related Maculopathy Grading System (WARMGS). After grading, features of ARM were combined to assign a severity stage from 0 to 5 using the methods described by the Rotterdam Eye Study. Relationships between visual function, study eye ARM stage, and fellow eye status were examined with the use of standard statistical analysis. RESULTS: Although SWS resolution acuity was significantly reduced in eyes classified as having any ARM compared with eyes classified as having no ARM (P = 0.002), there was no relationship between the severity of functional deficits and the morphologic severity from stage 1 to stage 4. On reassigning subject eyes to a revised severity staging (stage 0, stages 1 to 4 combined, and stage 5), SWS acuity was significantly different among these three groups (P < 0.001). No significant relationship was found between achromatic resolution acuity and ARM staging. The status of the fellow eye (advanced macular degeneration present or absent) was not significantly related to visual function in the study eye. CONCLUSIONS: Significant functional deficits in SWS resolution acuity were found in eyes with ARM features, but the severity of functional loss did not correlate well with the currently accepted method of assigning a morphologic severity stage. Longitudinal studies may reveal further information on the relationships between functional deficits, ARM status, disease progression, and outcome.

Diagnostic performance on briefly presented digital pathology images.

BACKGROUND: Identifying new and more robust assessments of proficiency/expertise (finding new "biomarkers of expertise") in histopathology is desirable for many reasons. Advances in digital pathology permit new and innovative tests such as flash viewing tests and eye tracking and slide navigation analyses that would not be possible with a traditional microscope. The main purpose of this study was to examine the usefulness of time-restricted testing of expertise in histopathology using digital images. METHODS: 19 novices (undergraduate medical students), 18 intermediates (trainees), and 19 experts (consultants) were invited to give their opinion on 20 general histopathology cases after 1 s and 10 s viewing times. Differences in performance between groups were measured and the internal reliability of the test was calculated. RESULTS: There were highly significant differences in performance between the groups using the Fisher's least significant difference method for multiple comparisons. Differences between groups were consistently greater in the 10-s than the 1-s test. The Kuder-Richardson 20 internal reliability coefficients were very high for both tests: 0.905 for the 1-s test and 0.926 for the 10-s test. Consultants had levels of diagnostic accuracy of 72% at 1 s and 83% at 10 s. CONCLUSIONS: Time-restricted tests using digital images have the potential to be extremely reliable tests of diagnostic proficiency in histopathology. A 10-s viewing test may be more reliable than a 1-s test. Over-reliance on "at a glance" diagnoses in histopathology is a potential source of medical error due to over-confidence bias and premature closure.

Mobility and access to transport issues as experienced by people with vision impairment living in urban and rural Ireland.

PURPOSE: The loss of vision is associated with the impairment of functional ability, including a reduced ability to move around and to utilise all forms of transport. Walking in unfamiliar environments is challenging and driving becomes a legal prohibition. This article explores mobility and access to transport issues of urban and rural dwelling people with vision impairment in Ireland. METHODS: Fourteen focus groups took place consisting of 121 people with vision impairment resident in both urban and rural Ireland. Participant selection was representative of the vision impaired community. Data were recorded, transcribed and analysed using thematic analysis. RESULTS: Poor access to public transport and a perceived absence of public awareness about vision impairment are evident from this study. Customised disability awareness training is deemed essential for both the public and transport staff. Difficulties with access issues within the physical environment are highlighted. CONCLUSION: The lack of availability of accessible transport creates an increased dependency on friends and family, and restricts access to medical, social and rehabilitative services. This study highlights issues concerning inequality of access to appropriate transport for rural vision impaired persons. These issues need to be brought to the attention of social planners and local government.

Toward an affirmative lesbian, gay, bisexual, and transgender leadership paradigm.

This article presents an affirmative paradigm for understanding the leadership of sexual minorities-that is, lesbian, gay, bisexual, and transgender (LGBT) people. Although research on LGBT issues in leadership to date is almost nonexistent, there are several bodies of literature that can contribute to an understanding of the unique leadership challenges faced by sexual minority people. These include the literatures on stigma and marginalization, leadership in particular status groups (e.g., college students, women), and LGBT vocational issues (especially workplace climate and identity disclosure). We propose a new, multidimensional model of LGBT leadership enactment that incorporates sexual orientation (particularly regarding identity disclosure), gender orientation (including leader gender), and the situation (conceptualized here as group composition); the model also is embedded in context, the most relevant factors that affect the enactment of leadership being stigma and marginalization. We explicate this model with findings and concepts from relevant literatures, and we conclude the article with recommendations for building a scholarly literature in LGBT leadership.

Carotenoids and co-antioxidants in age-related maculopathy: design and methods.

Age-related macular degeneration (AMD), is the leading cause of blind registration in the Western World among individuals 65 years or older. Early AMD, a clinical state without overt functional loss, is said to be present clinically when yellowish deposits known as drusen and/or alterations of fundus pigmentation are seen in the macular retina. Although the etiopathogenesis of AMD remains uncertain, there is a growing body of evidence in support of the view that cumulative oxidative damage plays a causal role. Appropriate dietary antioxidant supplementation is likely to be beneficial in maintaining visual function in patients with AMD, and preventing or delaying the progression of early AMD to late AMD. The Carotenoids in Age-Related Maculopathy (CARMA) Study is a randomized and double-masked clinical trial of antioxidant supplementation versus placebo in 433 participants with either early AMD features of sufficient severity in at least one eye or any level of AMD in one eye with late AMD (neovascular AMD or central geographic atrophy) in the fellow eye. The aim of the CARMA Study is to investigate whether lutein and zeaxanthin, in combination with co-antioxidants (vitamin C, E, and zinc), has a beneficial effect on visual function and/or prevention of progression from early to late stages of disease. The primary outcome is improved or preserved distance visual acuity at 12 months. Secondary outcomes include improved or preserved interferometric acuity, contrast sensitivity, shape discrimination ability, and change in AMD severity as monitored by fundus photography. This article outlines the CARMA Study design and methodology, including its rationale.

Uptake of COX-2 selective inhibitors and influence on NSAID prescribing in Northern Ireland.

PURPOSE: Rofecoxib and celecoxib have been recently introduced and promoted as 'safer' non-steroidal anti-inflammatory drugs (NSAIDs) regarding gastric toxicity. The primary aim was to measure their uptake and any impact on conventional NSAID prescribing. A secondary aim was to assess any change in proton pump inhibitor (PPI) prescribing. METHODS: Prescribing data in terms of defined daily doses (DDDs) were pooled from 1997 onwards. Linear trends in the data were tested for using regression analyses. Direct comparisons were made between the April-June quarter of the year 1999 (i.e. before the introduction of rofecoxib and celecoxib) and the same quarter 3 years later. RESULTS: Overall NSAID prescribing in Northern Ireland was found to be increasing linearly at an estimated rate of 154,000 DDDs per quarter since the introduction of celecoxib and rofecoxib. The rate of increase in the volume of prescribing of the two new drugs was found to be four times the rate of decrease in prescribing of the 'older' NSAIDs. Overall prescribing of anti-inflammatory agents had increased from 37.8 to 47.7 DDDs/1000 patients/day over 3 years with no effect on the upward trend in PPI prescribing. CONCLUSIONS: The introduction of rofecoxib and celecoxib has increased prescribing volume of anti-inflammatory agents by 26% in Northern Ireland over the 3-year period. This could pose safety problems in the future as more people are being prescribed anti-inflammatory agents.

Risk adjustment for hospital use using social security data: cross sectional small area analysis.

OBJECTIVES: To identify demographic and socioeconomic determinants of need for acute hospital treatment at small area level. To establish whether there is a relation between poverty and use of inpatient services. To devise a risk adjustment formula for distributing public funds for hospital services using, as far as possible, variables that can be updated between censuses. DESIGN: Cross sectional analysis. Spatial interactive modelling was used to quantify the proximity of the population to health service facilities. Two stage weighted least squares regression was used to model use against supply of hospital and community services and a wide range of potential needs drivers including health, socioeconomic census variables, uptake of income support and family credit, and religious denomination. SETTING: Northern Ireland. MAIN OUTCOME MEASURE: Intensity of use of inpatient services. RESULTS: After endogeneity of supply and use was taken into account, a statistical model was produced that predicted use based on five variables: income support, family credit, elderly people living alone, all ages standardised mortality ratio, and low birth weight. The main effect of the formula produced is to move resources from urban to rural areas. CONCLUSIONS: This work has produced a population risk adjustment formula for acute hospital treatment in which four of the five variables can be updated annually rather than relying on census derived data. Inclusion of the social security data makes a substantial difference to the model and to the results produced by the formula.