Three-Year Changes in Visual Function in the Placebo Group of a Randomized Double-Blind International Multicenter Safety Study: Analysis of Electroretinography, Perimetry, Color Vision, and Visual Acuity in Individuals With Chronic Stable Angina Pectoris.

Purpose: To determine whether significant deteriorations in objective (electroretinography [ERG]) and subjective (standard automated and semi-automated kinetic perimetry; color discrimination; and best-corrected visual acuity) tests of visual function, potentially attributable to aging, occurred in the group randomized to placebo of a 3-year prospective multicenter ocular safety study of ivabradine for chronic stable angina pectoris. Methods: The multicenter trial was conducted at 11 international ophthalmic centers. Changes in visual function between baseline and month 36 were analyzed by means of a two-tailed Wilcoxon signed-rank test, based on the Hodges and Lehman estimator of the median difference, with the 95% confidence intervals derived by Walsh averages. Results: Thirty-eight participants from the placebo group completed the study (mean [SD], age, 62.7 [8.1] years). The group exhibited in each eye small, but statistically significant, reductions in the amplitudes of the dark-adapted (DA) ERG 3.0 a-wave, and light-adapted (LA) 3.0 b-wave, as well as increases in peak time for the DA 0.01 b-wave, DA 3.0 a-wave, LA 3.0 b-wave, and LA 3.0 30-Hz flicker response and in the isopter area I3e of the visual field. Conclusions: Statistically significant deteriorations occurred in visual function over a period of 3 years, potentially attributable to age, within a group of individuals with chronic stable angina pectoris and unremarkable ophthalmological findings other than those attributable to age. Translational Relevance: A longitudinal correction factor for age-related change in visual function may be useful in future trials to determine whether an observed deterioration in visual function is related to intervention or to aging.

Direct to Implant Breast Reconstruction With Prepectoral Micropolyurethane Foam-Coated Implant: Analysis of Patient Satisfaction.

BACKGROUND: Immediate implant reconstruction after mastectomy with submuscular implant placement is widely used in order to avoid implant exposure, capsular contracture and poor aesthetic result. Postoperative complications can be reduced by maintain mastectomy flap thickness and asses flap vascularity with near infrared imaging. The prepectoral reconstruction with polyurethane implants has been utilized with encouraging results. Postoperative patient satisfaction was assessed with the BREAST-Q scores in patients who underwent prepectoral reconstruction with polyurethane implants. Additionally the impact of mastectomy flap thickness on breast reconstruction was investigated. MATERIALS AND METHODS: The Breast Q-scores of satisfaction with the breast, the postoperative outcome and physical well-being of the chest in 70 patients underwent immediate implant breast reconstructions with prepectoral polyurethane implant were retrospectively reviewed. The correlation between mastectomy flap thickness and satisfaction with breast was analyzed. RESULTS: At 12-month follow-up the mean Q-score for satisfaction with breast was 71.73 (standard deviation: 13.31), and for physical well-being chest was 70.73 (standard deviation: 7.94). A positive linear correlation between mastectomy flap thickness and satisfaction with the breast was identified. CONCLUSIONS: The postoperative Q-scores are encouraging in the use of polyurethane prepectoral implants in immediate breast reconstruction, especially in patients with "thick" mastectomy flaps.

Quality Control Procedures and Baseline Values for Electroretinography, Perimetry, Color Vision, and Visual Acuity in an International Multicenter Study: Observations from a Safety Trial in Chronic Stable Angina Pectoris.

Purpose: To describe quality control procedures and baseline values of electroretinography (ERG), kinetic and static perimetry, color discrimination, and best-corrected visual acuity from a multicenter ocular safety study. Methods: A multicenter prospective longitudinal randomized placebo-controlled study was conducted at 11 ophthalmic centers that had received certification following training, instruction, and monitoring. ERGs were obtained with the Espion E2 Ganzfeld console, perimetry with the Octopus 101 perimeter, color discrimination with the Lanthony desaturated D15 test, and best-corrected visual acuity with the Early Treatment Diabetic Retinopathy Study chart. Ophthalmic eligibility required satisfactory outcomes for ERG and perimetry by the second or third pre-inclusion attempts, respectively. Quality control for the ERG was undertaken by two central readers. Results: The mean (SD) age of the 97 individuals was 63.5 (7.9) range, 44-83 years. The overall coefficients of variation (CVs) for the ERG peak times were less than those of the only comparable single-center study. The CV for the mean defect of standard automated perimetry was approximately one-third that of the Ocular Hypertension Treatment Study. With increasing age, ERG peak times and color discrimination Total Error Score increased while ERG amplitudes and isopter area all decreased. Conclusions: The data illustrate the benefit of identical equipment, stringent on-site instruction and training, quality control, certification, and validation methods. The latter are recommended for planning and conducting multicenter trials using ERG and perimetry to monitor safety and/or efficacy of treatment intervention. Translational Relevance: Stringent quality control procedures and reliable reference values are indispensable prerequisites for informative clinical trials.

Objective Derivation of the Morphology and Staging of Visual Field Loss Associated with Long-Term Vigabatrin Therapy.

BACKGROUND: The morphology and between-eye symmetry of the visual field loss associated with the antiepileptic drug vigabatrin (VAVFL) has received little attention. OBJECTIVE: Our objective was to model the appearance and ensuing staging of VAVFL derived with the European Medicines Agency-approved perimetric protocol. METHODS: This was a retrospective, cross-sectional, observational study that identified 123 adults who had received vigabatrin for refractory seizures and who had no evidence of co-existing retino-geniculo-cortical visual pathway abnormality. A further 38 adults with refractory seizures and identical inclusion criteria but no exposure to vigabatrin acted as controls. For each group, the median outcome at each stimulus location in each eye (of absolute loss, relative loss or Pattern Deviation probability level, as appropriate) was derived for each successive ten pairs of fields, ranked for severity. Between-eye symmetry was quantified by an index that accounted for severity of loss and that was referenced to the likelihood of the occurrence of symmetry due to chance. RESULTS: The modelled VAVFL was bilateral and highly symmetrical and was described by six stages that were all independent of the extent of vigabatrin exposure. The loss originated in the extreme temporal periphery and encroached centripetally along all meridians towards fixation. The initial appearance within the central field (Stage 2) occurred inferior-nasally. Subsequent stages exhibited increasing loss, which was greater nasally than temporally. Stage 6 described concentric loss extending to approximately 15° eccentricity from fixation. CONCLUSION: The model exhibited a consistent pattern of VAVFL. The staging of the loss could assist the risk:benefit analysis of vigabatrin for the treatment of epilepsy.

The Topographical Relationship between Visual Field Loss and Peripapillary Retinal Nerve Fibre Layer Thinning Arising from Long-Term Exposure to Vigabatrin.

BACKGROUND: The antiepileptic drug vigabatrin is associated with characteristic visual field loss (VAVFL) and thinning of the peripapillary retinal nerve fibre layer (PPRNFL); however, the relationship is equivocal. OBJECTIVE: The aim of this study was to determine the function-structure relationship associated with long-term exposure to vigabatrin, thereby improving the risk/benefit analysis of the drug. METHODS: A cross-sectional observational design identified 40 adults who had received long-term vigabatrin for refractory seizures, who had no evidence of co-existing retino-geniculo-cortical visual pathway abnormality, and who had undergone a standardized protocol of perimetry and of optical coherence tomography (OCT) of the PPRNFL. Vigabatrin toxicity was defined as the presence of VAVFL. The function-structure relationship for the superior and inferior retinal quadrants was evaluated by two established models applicable to other optic neuropathies. RESULTS: The function-structure relationship for each model was consistent with an optic neuropathy. PPRNFL thinning, expressed in micrometres, asymptoted at an equivalent visual field loss of worse than approximately - 10.0 dB, thereby preventing assessment of more substantial thinning. Transformation of the outcomes to retinal ganglion cell soma and axon estimates, respectively, resulted in a linear relationship. CONCLUSIONS: Functional and structural abnormality is strongly related in individuals with vigabatrin toxicity and no evidence of visual pathway comorbidity, thereby implicating retinal ganglion cell dysfunction. OCT affords a limited measurement range compared with perimetry: severity cannot be directly assessed when the PPRNFL quadrant thickness is less than approximately 65 µm, depending on the tomographer. This limitation can be overcome by transformation of thickness to remaining axons, an outcome requiring input from perimetry.

Correction to: A meta-analysis of consanguinity and breast cancer.

The original version of this article contained an author name error. Gabiella Jones has been corrected to Gabriela Jones. The original article has been corrected.

Microperimetry in Age-Related Macular Degeneration: An Evidence-Base for Pattern Deviation Probability Analysis in Microperimetry.

PURPOSE: The "traffic light" color designation of differential light sensitivity used in a number of microperimeters does not encompass the conventional Total and Pattern Deviation probability analyses adopted by standard automated perimetry. We determined whether the color designation is indicative of abnormality as represented by the "gold standard" Pattern Deviation probability analysis. METHODS: Total and Pattern Deviation probability levels, using two different methods, were derived at each of 40 stimulus locations, within 7° eccentricity, from 66 ocular healthy individuals (66 eyes) who had undergone microperimetry with the Macular Integrity Assessment microperimeter. The probability levels were applied to the corresponding fields from each of 45 individuals (45 eyes) with age-related macular degeneration (AMD) and evaluated in relation to the color designation. RESULTS: Sensitivities designated in orange encompassed the entire range of Pattern Deviation probability levels (from normal to P ≤ 1%). Those designated in green were mostly normal; those in red/black generally corresponded to the ≤1% probability level. CONCLUSIONS: The green and the red/black designations are generally indicative of normal and abnormal probability values, respectively. The orange designation encompassed all probability outcomes and should not be relied upon for visual field interpretation. The evidence base indicates replacement of the color designation of sensitivity in AMD by Total Deviation and Pattern Deviation analyses. TRANSLATIONAL RELEVANCE: The use of Total and Pattern Deviation probability analyses is not universal in all microperimeters, and the derivation of these values indicates that color coding will lead to errors in evaluating visual field loss.

Microperimetry and multimodal imaging in polypoidal choroidal vasculopathy.

Polypoidal choroidal vasculopathy (PCV) is a degenerative macular disease. The study determined the topographical concordance in the areal extent of PCV, defined by indocyanine green angiography (ICGA), and the corresponding outcomes from spectral-domain optical coherence tomography (SD-OCT) and microperimetry, in 25 individuals (25 eyes) who had undergone 3 months of anti-vascular endothelial growth factor treatment. The differential light sensitivity within 10° eccentricity was evaluated by Pattern Deviation probability analysis. The concordances and proportional areal extents of the abnormality for ICGA, SD-OCT and microperimetry were compared. The concordance in the areal extent between all three modalities was 59%. The median concordance between ICGA and microperimetry was 60%; between ICGA and SD-OCT, 70%; and between SD-OCT and microperimetry, 72%. SD-OCT and microperimetry each identified a greater areal extent (>20%) compared to ICGA in 13 and 19 eyes, respectively. A greater areal extent (>20%) was present in 9 eyes for microperimetry compared to SD-OCT and in 5 eyes for SD-OCT compared to microperimetry. SD-OCT and microperimetry each identified a greater area of abnormality than ICGA which supports the clinical utility of SD-OCT. Strong concordance was present between SD-OCT and microperimetry; however, microperimetry identified additional areas of functional abnormality.

A meta-analysis of consanguinity and breast cancer.

BACKGROUND: There have been various publications stating that consanguinity both increases and decreases the risk of breast cancer. AIMS: The objective of this study was to determine the impact of consanguinity upon breast cancer. We conducted a systematic review of the literature and meta-analysis. METHODS: Eligible studies were identified on Medline and EMBASE updated to the 19 of September 2017. Studies with sufficient comparative data were included in a meta-analysis. Analyses were carried out using RevMan software. RESULTS: Three comparative studies with a total of 317 individuals with breast cancer and 1459 controls. Reviewing the literature demonstrated conflicting conclusions of the influence of consanguinity upon breast cancer. The meta-analysis showed that there were no statistically significant associations between consanguinity and breast cancer though there was a trend protection from a history of consanguinity. CONCLUSION: Though there is limited literature published on the effects of parental consanguinity, the available data does not demonstrate that it is a risk factor for breast cancer.

The use of microperimetry in assessing visual function in age-related macular degeneration.

Microperimetry is a novel technique for assessing visual function that appears particularly suitable for age-related macular degeneration (AMD). Compared with standard automated perimetry, microperimetry offers several unique features. It simultaneously images the fundus, incorporates an eye-tracking system to correct the stimulus location for fixation loss, and identifies any preferred retinal loci. We identified 52 articles that met the inclusion criteria for a systematic review of microperimetry in the assessment of visual function in AMD. We discuss microperimetry and AMD in relation to disease severity, structural imaging outcomes, other measures of visual function, and evaluation of the efficacy of surgical and/or medical therapies in clinical trials. The evidence for the use of microperimetry in the functional assessment of AMD is encouraging. Disruptions of the ellipsoid zone band and retinal pigment epithelium are clearly associated with reduced differential light sensitivity despite the maintenance of good visual acuity. Reduced differential light sensitivity is also associated with outer segment thinning and retinal pigment epithelium thickening in early AMD and with both a thickening and a thinning of the whole retina in choroidal neovascularization. Microperimetry, however, lacks the robust diffuse and focal loss age-corrected probability analyses associated with standard automated perimetry, and the technique is currently limited by this omission.

Outcomes Following Limb Crossing in Endovascular Aneurysm Repairs.

BACKGROUND: Crossing the limbs of the stent during endovascular aneurysm repair (EVAR) is often used to aid cannulation of the contralateral limb. This study assessed outcomes following the use of this technique. METHODS: Retrospective review of crossed (n = 43) and uncrossed (n = 269) EVARs was performed at a tertiary vascular center over 5 years. Primary end points were graft limb occlusion (GLO), endoleak, and sac expansion rates. Indications for limb crossing were also assessed. RESULTS: Two-year GLO (P = .34) and type 1 endoleak (P = .413) rates were similar between groups. Patients undergoing crossed EVAR experienced more type 2 endoleaks (P = .002) at 24 months but no increase in sac expansion rates was observed (P = .275). Thirty-day (P = .57) and late (P = .268) mortalities were similar between groups. The main indication for limb crossing was distal aortic angulation (48.8%). CONCLUSIONS: Crossed EVAR does not increase the risk of GLOs or clinically significant endoleaks. Further studies are needed to determine the effect on type 2 endoleak rates.

Effect of anticoagulation and antiplatelet therapy on incidence of endoleaks and sac size expansions after endovascular aneurysm repair.

BACKGROUND: The effects of anticoagulation or antiplatelet therapy on the incidence of endoleak and aneurysm sac size after endovascular aneurysm repair (EVAR) are unclear. This study aims to determine whether these therapies affect the incidence of endoleaks or sac size expansions after EVAR. METHODS: The case notes of 407 patients (367 men and 40 women, mean age 74.7 years) who underwent elective EVAR between January 2006 and November 2011 were reviewed for medication history and EVAR-related outcomes. RESULTS: The median follow-up period was 18 months. There were 45 (11.1%) patients on warfarin (WA), 292 (71.7%) on antiplatelet therapy (AT) (aspirin, clopidogrel, or dipyridamole modified release), and 70 (17.2%) on no anticoagulation or antiplatelet therapy (NA). During the study period, 51 (12.5%) endoleaks were documented, 8 type I (AT = 6, NA = 0, and WA = 2) and 42 type II (AT = 31, NA = 9, and WA = 2). Medication did not significantly affect the incidence of type I (P = 0.24) (based on chi-squared analysis), type II (P = 0.33), or type III (P = 0.82) endoleaks, or sac expansions (P = 0.95). CONCLUSIONS: Warfarin and antiplatelet therapies are not associated with increased incidence of postoperative endoleaks or aneurysm sac expansion after EVAR. The data in this study support safe use of anticoagulant and antiplatelet medications in patients undergoing EVAR.

Endovascular aortic aneurysm repair in patients with hostile neck anatomy.

PURPOSE: To report a systematic review and meta-analysis of outcomes following endovascular aneurysm repair (EVAR) in patients with hostile neck anatomy (HNA) vs. those with favorable neck anatomy (FNA). METHODS: Systematic review and meta-analysis of data on EVAR in patients with HNA and FNA was performed by 2 reviewers in February 2013. An eligible study was required to have at least 50 participants and to incorporate one or more of the HNA criteria of neck length <15 mm, neck diameter >28 mm, and/or angulation >60°. Of the 24 full-length articles ultimately reviewed, 8 were excluded, resulting in 16 articles that were suitable for inclusion in the meta-analysis. The study size ranged from 55 to 5183 participants, with a total of 8920 patients in the FNA group and 3039 patients in the HNA group. Mean follow-up ranged from 9 to 49 months. RESULTS: Analysis of the pooled data revealed a significant increase in 30-day mortality (2.4% FNA vs. 3.5% HNA; OR 1.60, 95% CI 1.13 to 2.27; p<0.01), intraoperative adjuncts (8.8% FNA vs. 15.4% HNA; OR 1.88, 95% CI 1.15 to 3.07; p=0.01), and 30-day migration (0.9% FNA vs. 1.6% HNA; OR 2.08, 95% CI 1.20 to 3.62; p=0.009) in patients with HNA. A decrease in primary technical success (97.5% FNA vs. 93.8% HNA; OR 0.41, 95% CI 0.18 to 0.93; p=0.03) was significant when all 3 criteria were used to define HNA. For outcomes at >30 days, the increase in secondary interventions (OR 1.29, 95% CI 1.00 to 1.66; p=0.05) approached significance, but aneurysm-related mortality, all-cause mortality, migration, and aortic rupture did not achieve statistical significance. There was no difference in rates of sac expansion. Analysis of endoleak rates revealed a significant increase in 30-day type I endoleaks (OR 2.92, 95% CI 1.61 to 5.30; p<0.001) and late type I endoleaks (OR 1.71, 95% CI 1.31 to 2.23; p<0.0001) in patients with HNA. CONCLUSION: These results suggest that performing EVAR in patients with HNA increases the technical difficulty and results in poorer short-term outcomes. The higher rates of early and late type I endoleaks, along with secondary interventions, suggest that increased monitoring should be performed in this category of patient to ensure rapid treatment.

Differential microRNA expression profiles in peripheral arterial disease.

BACKGROUND: Peripheral arterial disease (PAD) is a clinical condition caused by an atherosclerotic process affecting the arteries of the limbs. Despite major improvements in surgical endovascular techniques, PAD is still associated with high mortality and morbidity. Recently, microRNAs (miRNAs), a class of short noncoding RNA controlling gene expression, have emerged as major regulators of multiple biological processes. METHODS AND RESULTS: A whole-miRNA transcriptome profiling was performed in peripheral blood from an initial sample set of patients and controls. A 12-miRNA PAD-specific signature, which includes let 7e, miR-15b, -16, -20b, -25, -26b, -27b, -28-5p, -126, -195, -335, and -363, was further investigated and validated in 2 additional sample sets. Each of these 12 miRNAs exhibited good diagnostic value as evidenced by receiver operating characteristic curve analyses. Pathway enrichment analysis using predicted and validated targets identified several signaling pathways relevant to vascular disorders. Several of these pathways, including cell adhesion molecules, were confirmed by quantifying the expression level of several candidate genes regulating the initial stages of the inflammatory atherosclerotic process. The expression level of 7 of these candidate genes exhibits striking inverse correlation with that of several, if not all, of the miRNAs of the PAD-specific miRNA signature. CONCLUSIONS: These results demonstrate the potential of miRNAs for the diagnosis of PAD and provide further insight into the molecular mechanisms leading to the development of PAD, with the potential for future therapeutic targets.

A variant in LDLR is associated with abdominal aortic aneurysm.

BACKGROUND: Abdominal aortic aneurysm (AAA) is a common cardiovascular disease among older people and demonstrates significant heritability. In contrast to similar complex diseases, relatively few genetic associations with AAA have been confirmed. We reanalyzed our genome-wide study and carried through to replication suggestive discovery associations at a lower level of significance. METHODS AND RESULTS: A genome-wide association study was conducted using 1830 cases from the United Kingdom, New Zealand, and Australia with infrarenal aorta diameter≥30 mm or ruptured AAA and 5435 unscreened controls from the 1958 Birth Cohort and National Blood Service cohort from the Wellcome Trust Case Control Consortium. Eight suggestive associations with P<1×10(-4) were carried through to in silico replication in 1292 AAA cases and 30,503 controls. One single-nucleotide polymorphism associated with P<0.05 after Bonferroni correction in the in silico study underwent further replication (706 AAA cases and 1063 controls from the United Kingdom, 507 AAA cases and 199 controls from Denmark, and 885 AAA cases and 1000 controls from New Zealand). Low-density lipoprotein receptor (LDLR) rs6511720 A was significantly associated overall and in 3 of 5 individual replication studies. The full study showed an association that reached genome-wide significance (odds ratio, 0.76; 95% confidence interval, 0.70-0.83; P=2.08×10(-10)). CONCLUSIONS: LDLR rs6511720 is associated with AAA. This finding is consistent with established effects of this variant on coronary artery disease. Shared causal pathways with other cardiovascular diseases may present novel opportunities for preventative and therapeutic strategies for AAA.

Modelling the risk of visual field loss arising from long-term exposure to the antiepileptic drug vigabatrin: a cross-sectional approach.

BACKGROUND: The antiepileptic drug vigabatrin has been used widely since 1989, but has only been approved for use in the US since 2009. The risk:benefit of vigabatrin is generally predicated upon an assumed frequency of associated visual field loss (VAVFL) of approximately 31 %. This estimate is based upon relatively short-term usage (up to 4-5 years) and it is essential to determine whether the frequency of VAVFL increases with longer-term usage. OBJECTIVE: The aim of this study was to model, from cross-sectional evidence, over greater ranges of treatment duration and cumulative dose than previously evaluated, the risk (frequency) of VAVFL with increasing exposure to vigabatrin. STUDY DESIGN AND SETTING: This was a retrospective cohort study undertaken in a regional hospital epilepsy clinic. PATIENTS: The cohort comprised 147 consecutive patients treated with vigabatrin for refractory complex partial (focal) seizures, who had all undergone ophthalmological examination and who had undertaken perimetry, reliably, according to a standard and robust protocol. The visual field plots were evaluated masked to treatment duration and dose. MAIN OUTCOME MEASURE: The risk (frequency) of VAVFL with increasing exposure to vigabatrin was modelled, from the cross-sectional evidence, by standard and plateau logistic regression. RESULTS: The cohort comprised 80 females and 67 males (mean age 40.3 years, standard deviation 13.7). The median duration of vigabatrin exposure was 7.9 years (interquartile range 3.6-11.0, range 0.2-16.1 years); 46 patients (31 %) had received vigabatrin for over 10 years. Eighty-seven patients (59 %) exhibited VAVFL; the proportion with VAVFL was higher in males (66 %) than females (54 %). The plateau model for duration and for cumulative dose exhibited a better fit than the standard model (both p < 0.001). The modelled frequency of VAVFL increased with increasing exposure up to approximately 6 years duration and 5 kg cumulative dose, and plateaued at approximately 76 % (95 % CI 67-85) and 79 % (95 % CI 70-87), respectively. Severity of VAVFL, classified in terms of the visual field index Mean Deviation, was not significantly associated with either duration or cumulative dose of therapy. CONCLUSION: Clinicians and patients, in enabling informed choice, should be alert to the possible substantial increased risk:benefit for VAVFL with increasing long-term exposure to vigabatrin and the ensuing increased cost:benefit resulting from the necessary additional visual assessments.

The accuracy of the inferior>superior>nasal>temporal neuroretinal rim area rule for diagnosing glaucomatous optic disc damage.

PURPOSE: To determine the accuracy with which the optic disc can be diagnosed as normal or glaucomatous according to the ISNT rule, whereby, in the normal eye, the neuroretinal rim area follows the order inferior (I) > superior (S) > nasal (N) > temporal (T). DESIGN: Prospective, cross-sectional, observational, case series. PARTICIPANTS: Fifty-one normal individuals and 78 individuals with open-angle glaucoma exhibiting field loss (median mean deviation, -4.37 dB; interquartile range [IQR], -2.10 to -7.96 dB; median pattern standard deviation, 5.65 dB; IQR, 2.94 to 8.56 dB). The reference diagnosis was made by 2 experts on the basis of the appearance of the optic disc and of the corresponding visual field. METHODS: Stereoscopic optic disc photographs, acquired for each individual, were digitized at high resolution and analyzed using a digital, quad-buffered, stereoscopic viewing system in which a Z screen was used to dissociate the images to the 2 eyes of the observer. Three expert observers, trained to fellowship standard in glaucoma, independently undertook planimetry of the neuroretinal rim and of the disc margin from 1 eye of each individual, using a cursor moving in stereoscopic space to minimize parallax errors. Software automatically calculated the neuroretinal rim area in 10°, 30°, 40°, and 90° segments. For the ISNT rule to be obeyed, the 3 Boolean comparisons of the neuroretinal rim area, I>S, S>N, and N>T, had to be true. If any of the comparisons returned false, the rule was considered not to have been obeyed. Values were compared at a precision of 0.0001 mm(2). MAIN OUTCOME MEASURES: The outcome of the ISNT rule in terms of the 3 Boolean comparisons of the neuroretinal rim area was specified in terms of the sensitivity, specificity, and hence, the positive and negative likelihood ratios. RESULTS: Based on the ISNT rule being obeyed for 10° segments, the positive likelihood ratio among the 3 observers was 1.11 (95% confidence interval [CI], 0.99-1.25), 1.07 (95% CI, 0.94-1.21), and 1.06 (95% CI, 0.96-1.18), respectively. It was similar for the other segment sizes. Variants of the rule were not appreciably better. CONCLUSIONS: The ISNT rule has limited utility in the diagnosis of open-angle glaucoma.

Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1.

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10(-5)) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10(-5)). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10(-10), odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression.