Visual conditions affecting eye growth alter diurnal levels of vitreous DOPAC.

In chicks, the diurnal patterns of retinal dopamine synthesis and release are associated with refractive development. To assess the within-day patterns of dopamine release, we assayed vitreal levels of DOPAC (3,4-dihydroxyphenylacetic acid) using high performance liquid chromatography with electrochemical detection, at 4-h intervals over 24 h in eyes with experimental manipulations that change ocular growth rates. Chicks were reared under a 12 h light/12 h dark cycle; experiments began at 12 days of age. Output was assessed by modelling using the robust variance structure of Generalized Estimating Equations. Continuous spectacle lensdefocus or form deprivation: One group experienced non-restricted visual input to both eyes and served as untreated "normal" controls. Three experimental cohorts underwent monocular visual alterations known to alter eye growth and refraction: wearing a diffuser, a negative lens or a positive lens. After one full day of device-wear, chicks were euthanized at 4-h intervals over 24 h (8 birds per time/condition). Brief hyperopic defocus: Chicks wore negative lenses for only 2 daily hours either in the morning (starting at ZT 0; n = 16) or mid-day (starting at ZT 4; n = 8) for 3 days. Vitreal DOPAC was assayed. In chicks with bilateral non-restricted vision, or with continuous defocus or form-deprivation, there was a diurnal variation in vitreal DOPAC levels for all eyes (p < 0.001 for each). In normal controls, DOPAC was highest during the daytime, lowest at night, and equivalent for both eyes. In experimental groups, regardless of whether experiencing a growth stimulatory input (diffuser; negative lens) or growth inhibitory input (positive lens), DOPAC levels were reduced compared both to fellow eyes and to those of normal controls (p < 0.001 for each). These diurnal variations in vitreous DOPAC levels under different visual conditions indicate a complexity for dopaminergic mechanisms in refractive development that requires further study.

3D optic disc reconstruction via a global fundus stereo algorithm.

This paper presents a novel method to recover 3D structure of the optic disc in the retina from two uncalibrated fundus images. Retinal images are commonly uncalibrated when acquired clinically, creating rectification challenges as well as significant radiometric and blur differences within the stereo pair. By exploiting structural peculiarities of the retina, we modified the Graph Cuts computational stereo method (one of current state-of-the-art methods) to yield a high quality algorithm for fundus stereo reconstruction. Extensive qualitative and quantitative experimental evaluation (where OCT scans are used as 3D ground truth) on our and publicly available datasets shows the superiority of the proposed method in comparison to other alternatives.

Associations between hepatocyte growth factor, c-Met, and basic fibroblast growth factor and survival in endometrial cancer patients.

BACKGROUND: Hepatocyte growth factor (HGF), c-Met, and basic fibroblast growth factor (bFGF) are molecular markers that contribute to angiogenesis and proliferation in numerous cancers. We assessed the prognostic significance of these factors in tumour and stroma of endometrial cancer (EC) patients (n=211). METHODS: Immunohistochemistry (IHC) was used to detect tumour and stromal protein expression of the biomarkers. Associations between expression and clinicopathological factors were assessed using Chi-square tests. Kaplan-Meier curves, log-rank tests, and Cox regression were used to summarise associations between biomarker expression and overall survival (OS) and recurrence-free survival (RFS). RESULTS: Tumour bFGF was significantly associated with high-grade endometrioid and clear cell histology (P<0.001), advanced stage (P=0.008), positive lymph-node involvement (P=0.002), poor OS (log-rank test, P=0.009), and poor RFS (P<0.001). In multivariable analyses, cases with HGF-positive, stromal bFGF-positive tumours had a lower risk of death compared with cases with HGF-positive, stromal bFGF-negative tumours (hazard ratio (HR): 0.14, 95% CI: 0.03, 0.60). Cases with HGF-positive, bFGF-positive tumours had a higher risk of recurrence compared with cases with negative expression of both markers (HR: 9.88, 95% CI: 2.63, 37.16). CONCLUSION: These IHC data show that tumour and stromal bFGF expression have opposite associations with survival outcomes in EC patients. If confirmed in larger studies, tumour-derived bFGF could be an attractive target in EC therapy.

Changes in NHS organization of care and management of hospital admissions with COPD exacerbations between the national COPD audits of 2003 and 2008.

BACKGROUND: The 2003 UK Chronic Obstructive Pulmonary Disease (COPD) audit revealed wide variability between hospital units in care delivered. AIMS: To assess whether processes of care, patient outcomes and organization of care have improved since 2003. DESIGN: A UK national audit was performed in 2008 to survey the organization and delivery of clinical care provided to patients admitted to hospital with COPD. METHODS: All UK acute hospital Trusts (units) were invited to participate. Each unit completed cross-sectional resource and organization questionnaires and a prospective clinical audit comprising up to 60 consecutively admitted cases of COPD exacerbation. Comparison between 2003 and 2008 includes aggregated statistics for units participating in both audit rounds. RESULTS: A total of 192 units participated in both audit rounds (6197 admissions in 2003 and 8170 in 2008). In 2008, patients were older and of a poorer functional class. Overall mortality was unchanged but adjusting for age and performance status, inpatient mortality (P = 0.05) and 90-day mortality (P = 0.001) were both reduced in 2008. More patients were discharged under a respiratory specialist (P < 0.01), treated with non-invasive ventilation if acidotic (P < 0.001) and accepted onto early discharge schemes (P < 0.01) while median length of stay fell from 6 to 5 days (P < 0.001). Within these mean data, however, there remains considerable inter-unit variation in organization, resources and outcomes. CONCLUSION: Overall improvements in resources and organization are accompanied by reduced mortality, shorter admissions and greater access to specialist services. There remains, however, considerable variation in the quality of secondary care provided between units.

Acidosis, non-invasive ventilation and mortality in hospitalised COPD exacerbations.

BACKGROUND: Reports of non-invasive ventilation (NIV) use in clinical practice reveal higher mortality rates than in corresponding randomised clinical trials. AIM: To explore factors related to chronic obstructive pulmonary disease (COPD) admissions and NIV use that may explain some of the previously reported high mortality rates. METHODS: National UK audit of clinical care of consecutive COPD admissions from March to May 2008. Retrospective case note audit with prospective case ascertainment. Participating units completed a web-based audit proforma of process and outcomes of clinical care. RESULTS: 232 hospital units collected data on 9716 patients, mean age 73, 50% male. 1678 (20%) of those with gases recorded on admission were acidotic and another 6% became acidotic later. 1077 patients received NIV, 55% had a pH<7.26 and 49% (305/618) had or were still receiving high flow oxygen. 30% (136/453) patients with persisting respiratory acidosis did not receive NIV while 11% (15/131) of acidotic admissions had a pure metabolic acidosis and did. Hospital mortality was 25% (270/1077) for patients receiving NIV but 39% (86/219) for those with late onset acidosis and was higher in all acidotic groups receiving NIV than those treated without. Only 4% of patients receiving NIV who died had invasive mechanical ventilation. CONCLUSIONS: COPD admissions treated with NIV in usual clinical practice were severely ill, many with mixed metabolic acidosis. Some eligible patients failed to receive NIV, others received it inappropriately. NIV appears to be often used as a ceiling of treatment including patient groups in whom efficacy of NIV is uncertain. The audit raises concerns that challenge the respiratory community to lead appropriate clinical improvements across the acute sector.

A randomised trial of peer review: the UK National Chronic Obstructive Pulmonary Disease Resources and Outcomes Project.

Peer review has been widely employed within the NHS to facilitate health quality improvement but has not been rigorously evaluated. This article reports the largest randomised trial of peer review ever conducted in the UK. The peer review intervention was a reciprocal supportive exercise that included clinicians, hospital management, commissioners and patients which focused on the quality of the provision of four specific evidence-based aspects of chronic obstructive pulmonary disease care. Follow up at 12 months demonstrated few quantitative differences in the number or quality of services offered in the two groups. Qualitative data in contrast suggested many benefits of peer review in most but not all intervention units and some control teams. Findings suggest peer review in this format is a positive experience for most participants but is ineffective in some situations. Its longer term benefits and cost effectiveness require further study. The generic findings of this study have potential implications for the application of peer review throughout the NHS.

Clinician perceived good practice in end-of-life care for patients with COPD.

Patients with chronic obstructive pulmonary disease (COPD) have significant end-of-life needs, but are much less likely than patients with cancer to access or receive appropriate palliative care. Little is known about the existing availability or quality of available services within the United Kingdom. We surveyed 100 NHS acute hospitals enquiring into the provision of care for patients with COPD and requesting examples of current good practice that might be used to set standards. Forty-two percent of hospitals had formal palliative care arrangements for patients with COPD, whereas 59% had plans to develop or further develop services. Analysis of qualitative data suggested four strands that highlighted good practice; teams, care pathways, service components and linkages. These data may help to inform the debate leading to the development of standards in end-of-life care for patients with COPD.

Validation of a clinical prognostic model to identify low-risk patients with pulmonary embolism.

OBJECTIVE: To validate the Pulmonary Embolism Severity Index (PESI), a clinical prognostic model which identifies low-risk patients with pulmonary embolism (PE). DESIGN: Validation study using prospectively collected data. SETTING: A total of 119 European hospitals. SUBJECTS: A total of 899 patients diagnosed with PE. INTERVENTION: The PESI uses 11 clinical factors to stratify patients with PE into five classes (I-V) of increasing risk of mortality. We calculated the PESI risk class for each patient and the proportion of patients classified as low-risk (classes I and II). The outcomes were overall and PE-specific mortality for low-risk patients at 3 months after presentation. We calculated the sensitivity, specificity and predictive values to predict overall and PE-specific mortality and the discriminatory power using the area under the receiver operating characteristic curve. RESULTS: Overall and PE-specific mortality was 6.5% (58/899) and 2.3% (21/899) respectively. Forty-seven per cent of patients (426/899) were classified as low-risk. Low-risk patients had an overall mortality of only 1.2% (5/426) and a PE-specific mortality of 0.7% (3/426). The sensitivity was 91 [95% confidence interval (CI): 81-97%] and the negative predictive value was 99% (95% CI: 97-100%) for overall mortality. The sensitivity was 86% (95% CI: 64-97%) and the negative predictive value was 99% (95% CI: 98-100%) for PE-specific mortality. The areas under the receiver operating characteristic curve for overall and PE-specific mortality were 0.80 (95% CI: 0.75-0.86) and 0.77 (95% CI: 0.68-0.86) respectively. CONCLUSIONS: This validation study confirms that the PESI reliably identifies low-risk patients with PE who are potential candidates for less costly outpatient treatment.

Eye growth changes in myopic children in Singapore.

AIMS: To assess the longitudinal changes in biometric parameters and associated factors in young myopic children aged 7--9 years followed prospectively in Singapore. METHODS: Children aged 7--9 years from three Singapore schools were invited to participate in the SCORM (Singapore Cohort study Of the Risk factors for Myopia) study. Yearly eye examinations involving biometry measures were performed in the schools. Only myopic children (n=543) with 3 year follow up data were included in this analysis. RESULTS: The 3 year increases in axial length, anterior chamber depth, lens thickness, vitreous chamber depth, and corneal curvature were 0.89 mm, -0.02 mm, -0.01 mm, 0.92 mm, and 0.01 mm, respectively. Children who were younger, female, and who had a parental history of myopia were more likely to have greater increases in axial length. After adjustment for school, age, sex, race, parental myopia and reading in books per week, the age (p<0.001), sex (p=0.012), and parental myopia (p=0.027) remained significantly associated with the 3 year change in axial length. Reading in books per week, however, was not associated with axial length change. Children with faster rates of progression of myopia had greater increases in axial length (Pearson correlation coefficient (r)=-0.69) and vitreous chamber depth (r=-0.83). CONCLUSIONS: The 3 year change in axial length of Singapore children aged 7--9 years at baseline was high and greater in younger children, females, and children with a parental history of myopia. Myopia progression was driven largely by vitreous chamber depth increase.

Differential P1-purinergic modulation of human Schlemm's canal inner-wall cells.

Intraocular pressure is directly dependent on aqueous humor flow into, and resistance to flow out of, the eye. Adenosine has complex effects on intraocular pressure. Stimulation of A1 and A2A adenosine receptors changes intraocular pressure oppositely, likely through opposing actions on the outflow of aqueous humor. While the cellular sites regulating outflow resistance are unknown, the cells lining the inner wall of Schlemm's canal (SC) are a likely regulatory site. We applied selective adenosine receptor agonists to SC cells in vitro to compare the responses to A1 and A2A stimulation. Parallel studies were conducted with human inner-wall SC cells isolated by a novel enzyme-assisted technique and with cannula-derived mixed inner- and outer-wall SC cells. A1 agonists increased whole cell currents of both inner-wall and cannula-derived SC cells. An A2A agonist reduced currents most consistently in specifically inner-wall SC cells. Those currents were also increased by A2B, but not consistently affected by A3, stimulation. A1, A2A, and A3 agonists all increased SC-cell intracellular Ca2+. The electrophysiological results are consistent with the possibility that inner-wall SC cells may mediate the previously reported modulatory effects of adenosine on outflow resistance. The results are also consistent with the presence of functional A2B, as well as A1, A2A, and A3 adenosine receptors in SC cells.

Childhood myopia and parental smoking.

AIM: To examine the relation between exposure to passive parental smoke and myopia in Chinese children in Singapore. METHODS: 1334 Chinese children from three schools in Singapore were recruited, all of whom were participants in the Singapore Cohort study Of the Risk factors for Myopia (SCORM). Information on whether the father or mother smoked, number of years smoked, and the number of cigarettes smoked per day during the child's lifetime were derived. These data were correlated with contemporaneously obtained data available in SCORM. The children's cycloplegic autorefraction, corneal curvature radius, and biometry measures were compared with reported parental smoking history. RESULTS: There were 434 fathers (33.3%) and 23 mothers (1.7%) who smoked during their child's lifetime. There were no significant trends observed between paternal smoking and refractive error or axial length. After controlling for age, sex, school, mother's education, and mother's myopia, children with mothers who had ever smoked during their lifetime had more "positive" refractions (adjusted mean -0.28 D v -1.38 D) compared with children whose mother did not smoke (p = 0.012). CONCLUSIONS: The study found no consistent evidence of association between parental smoking and refractive error. There was a suggestion that children whose mothers smoked cigarettes had more hyperopic refractions, but the absence of a relation with paternal smoking and the small number of mothers who smoked in this sample preclude definite conclusions about a link between passive smoking exposure and myopia.

Ocular shape and myopia.

INTRODUCTION: To learn if eye shape might be a useful parameter in refractive research. MATERIALS AND METHODS: Laboratory research on eye growth mechanisms is summarised. The available clinical literature relating refraction to eye shape and peripheral refraction is critically assessed in the context of the laboratory research on refractive development. RESULTS: Almost all refraction research assesses optical and length parameters exclusively along the visual axis. Contemporary laboratory research demonstrates a remarkable phylogenic conservation of the neural mechanisms regulating refractive development. On-axis image quality regulates central refractive development in animals and probably, to some extent, in humans. Off-axis image quality at the retina depends on anterior segment geometry and optics, and on the 3-dimensional conformation of the retina. In chicks, eye shape is a predictable parameter linked to the underlying neural mechanisms modulating eye development. Based on the sparse clinical literature in human adults and children, the eye shapes induced in chicks are also seen in human subjects in patterns suggesting that eye shape may be a useful parameter in clinical studies. CONCLUSION: The diverse findings suggest that incorporating the 3-dimensional conformation of the eye into future clinical studies may help resolve many of the ambiguities in contemporary refractive research.

Cutaneous wound analysis using hyperspectral imaging.

A correlative bright-field and hyperspectral analysis of full-thickness, cutaneous wounds in a porcine model was undertaken to investigate the efficacy of hyperspectral imaging as an alternate method for wound identification. Analysis of a randomly selected specimen yielded distinct spectral signatures for cutaneous regions of interest including the epidermis, injured dermis, and normal dermis. The scanning of the entire specimen group using these hyperspectral signatures revealed an exclusionary, pseudo-color pattern whereby a central wound region was consistently defined by a unique spectral signature. An algorithm was derived as an objective tool for the comparison of the wound regions defined by the hyperspectral classification versus the pathologists' manual tracings. The dimensions of the wound identified in the hyperspectral assay did not differ significantly from the wound region identified by the pathologists using standard bright-field microscopy. These data indicate that hyperspectral analysis may provide a high-throughput alternative for wound estimation that approximates standard bright-field imaging and pathologist evaluation.

A(1)-, A(2A)- and A(3)-subtype adenosine receptors modulate intraocular pressure in the mouse.

Despite the potential importance of the mouse in studying the pharmacology of aqueous dynamics, measurement of intraocular pressure (IOP) in its very small eye has been problematic. Utilizing a novel servo-null electrophysiologic approach recently applied to the mouse, we have identified a diversity of adenosine-receptor mechanisms in modulating IOP in this species. We report the first evidence that A(3) receptors increase IOP in any species, and verify in the mouse reports with larger mammals that A(1) receptors lower and A(2A) receptors increase IOP.

Historical cohort study of US man-made vitreous fiber production workers: I. 1992 fiberglass cohort follow-up: initial findings.

This 1986 to 1992 update and expansion of an earlier historical cohort study examined the 1946 to 1992 mortality experience of 32,110 workers employed for 1 year or more during 1945 to 1978 at any of 10 US fiberglass (FG) manufacturing plants. Included are (1) a new historical exposure reconstruction for respirable glass fibers and several co-exposures (arsenic, asbestos, asphalt, epoxy, formaldehyde, polycyclic aromatic hydrocarbons, phenolics, silica, styrene, and urea); and (2) a nested, matched case-control study of 631 respiratory system cancer (RSC) deaths in male workers during 1970 to 1992 with interview data on tobacco smoking history. Our findings to date from external comparisons based on standardized mortality ratios (SMRs) in the cohort study provide no evidence of excess mortality risk from all causes combined, all cancers combined, and non-malignant respiratory disease. Also, excluding RSC, we observed no evidence of excess mortality risk from any of the other cause-of-death categories considered. For RSC among the total cohort, we observed a 6% excess (P = 0.05) based on 874 deaths. Among long-term workers (5 or more years of employment) we observed a not statistically significant 3% excess based on 496 deaths. Among the total cohort, we observed increases in RSC SMRs with calendar time and time since first employment, but these were less pronounced among long-term workers. RSC SMRs were not related to duration of employment among the total cohort or long-term workers. In an externally controlled analysis of male workers at risk between 1970 and 1992, we observed no association between RSC SMRs and increasing exposure to respirable FG. Our findings to date from internal comparisons based on rate ratios in the case-control study of RSC were limited to analyses of categorized study variables with and without adjustment for smoking. On the basis of these analyses, the duration of exposure and cumulative exposure to respirable FG at the levels encountered at the study plants did not appear to be associated with an increased risk of RSC. RSC risk also did not seem to increase with time since first employment. There is some evidence of elevated RSC risk associated with non-baseline levels of average intensity of exposure to respirable glass, but when adjusted for smoking this was not statistically significant, and there was no apparent trend with increasing exposure. This same pattern of findings was observed for duration of exposure, cumulative exposure, and average intensity of exposure to formaldehyde. None of the other individual co-exposures encountered in the study plants appeared to be associated with an increased risk of RSC. The primary focus of ongoing analyses is to determine the extent to which our present findings are robust to alternative characterizations of exposure.

Historical cohort study of US man-made vitreous fiber production workers: III. Analysis of exposure-weighted measures of respirable fibers and formaldehyde in the nested case-control study of respiratory system cancer.

The most recent findings of our nested case-control study of respiratory system cancer (RSC) among male fiberglass workers showed some evidence of elevated RSC risk associated with non-baseline levels of average intensity of exposure (AIE) to respirable fibers (RFib). When adjusted for smoking, this was not statistically significant, and no trend was apparent with increasing levels of exposure. Similar findings for RSC were noted for both cumulative exposure (Cum) and AIE to formaldehyde (FOR). In this reanalysis of our nested case-control study, we explored a possible exposure-response relationship between RSC and exposure to RFib or FOR using exposure weighting as an alternative characterization of exposure. Because of the uncertainties in selecting an appropriate exposure-weighting scheme, a range of plausible time lags and unlagged/lagged time windows was considered. As in the initial analysis of the nested case-control study, RFib and FOR exposures were categorized at the deciles of the RSC case distribution. For none of the exposure weighting schemes considered did we observe an increasing RSC risk with increasing levels of RFib_Cum or RFib_AIE. The exposure-weighted estimated risk ratios (RR) for both RFib_Cum and RFib_AIE were generally lower than those obtained from an unweighted model. For FOR_Cum, RRs were generally lower for the time-lagged and unlagged time window models than for the unweighted models, although some decile-specific RRs were higher for the lagged time window models. The exposure-weighted RRs for FOR_AIE were generally lower than the unweighted RRs for all of the weighting schemes considered. This reanalysis in terms of categorized exposures reveals no exposure-response relationships that were undetected in the original analysis where unweighted exposure measures were used. In the schemes considered, exposure weighting generally reduced the estimated risk of RSC.

Historical cohort study of US man-made vitreous fiber production workers: IV. Quantitative exposure-response analysis of the nested case-control study of respiratory system cancer.

As part of the 1992 update of an historical cohort study of 32,110 workers employed for at least 1 year in any of 10 US fiberglass manufacturing plants, a nested case-control study was done in which data on tobacco smoking were obtained for 631 male case subjects with respiratory system cancer (RSC) and 570 control subjects matched on age and year of birth. In this more extensive analysis of the nested case-control data, we provide a detailed assessment of the most prominent findings from the initial report. We expand the scope of the analysis to consider quantitative measures of exposure to respirable fibers (RFib), formaldehyde (FOR), and silica (Sil) and consider these and other exposures together in the same model. We investigate the functional form of possible exposure-response relationships between RSC risk, RFib, and FOR. In addition, we address the statistical issues of collinearity, effect modification, and potential confounding by coexposures. All analyses are adjusted for smoking. Neither measure of exposure to RFib (average intensity of exposure or cumulative exposure) was statistically significantly associated with RSC risk in any of the hundreds of fractional polynomial models considered. This more extensive analysis has substantiated our initial finding of no apparent exposure-response relationship between RSC risk and either cumulative or average intensity of exposure to RFib at the levels experienced by these workers. This study provides some evidence of increased RSC risk among workers at the higher observed levels of average intensity of exposure to FOR and/or Sil. No positive associations were identified between RSC risk and any of the other exposures considered in this case-control study.

Historical cohort study of US man-made vitreous fiber production workers: VII. Overview of the exposure assessment.

Data and procedures used to reconstruct the history of exposures at each of the 15 plants (19 distinct sites) are presented. The assessment consisted of five steps: (1) develop a Technical History of operations, stable periods, and time points of changes relevant for exposures, and identify the presence of potentially confounding co-exposures; (2) develop a set of unique department-job names with descriptions and a Job Dictionary for all verbatim names in work histories; (3) collect all company and other exposure data (> 1600 observed), and develop quantitative fiber, formaldehyde, and silica exposure estimates; (4) integrate estimates with the Technical History to make Exposure Extrapolation Tables; and (5) use the the Tables with job data to develop an Exposure Matrix for each plant. Nineteen Exposure Matrices were made, with 82 to 621 lines, covering up to 54 years of operations.

Historical cohort study of US man-made vitreous fiber production workers: VIII. Exposure-specific job analysis.

UNLABELLED: All jobs held by a cohort of US man-made vitreous fiber production workers were analyzed for airborne fiber exposure. This exposure-specific job analysis was part of an exposure assessment for an epidemiologic study of mortality patterns, with particular focus on respiratory cancer, among 35,145 workers employed in 10 fiberglass and five rock or slag wool plants. The exposure assessment was conducted from the start-up date of each plant (1917 to 1946) to 1990. For the job analysis, 15,465 crude department names and 47,693 crude job titles were grouped into 1668 unique department and job pairs (UDJobs), which represented a job title linked to a specific department within each plant. Every UDJob was evaluated according to a set of job elements related to airborne fiber exposure. The distribution of the cohort person-years by UDJob and the job-exposure elements was then evaluated. The results show the main departments and jobs that employed the workers for each plant. The distribution of person-years varies across the job-exposure elements. The same job title was used in different departments within and across plants. When job titles not linked to departments were evaluated, the values of the job-exposure elements varied considerably across all plants and within plant. IN CONCLUSION: (1) exposure misclassification could occur if job title alone were used for the exposure assessment; (2) the job-exposure elements analysis provides an efficient way to identify major job determinants of exposure without relying on the more detailed, resource-intensive task-based approach; and (3) the evaluation of the cohort person-years by UDJobs and job-exposure elements is an effective way to identify which plants, departments, and jobs have sufficient information for making precise risk estimates in the broader epidemiologic study.

Accounting for covariate measurement error in a Cox model analysis of recurrence of depression.

When a covariate measured with error is used as a predictor in a survival analysis using the Cox model, the parameter estimate is usually biased. In clinical research, covariates measured without error such as treatment procedure or sex are often used in conjunction with a covariate measured with error. In a randomized clinical trial of two types of treatments, we account for the measurement error in the covariate, log-transformed total rapid eye movement (REM) activity counts, in a Cox model analysis of the time to recurrence of major depression in an elderly population. Regression calibration and two variants of a likelihood-based approach are used to account for measurement error. The likelihood-based approach is extended to account for the correlation between replicate measures of the covariate. Using the replicate data decreases the standard error of the parameter estimate for log(total REM) counts while maintaining the bias reduction of the estimate. We conclude that covariate measurement error and the correlation between replicates can affect results in a Cox model analysis and should be accounted for. In the depression data, these methods render comparable results that have less bias than the results when measurement error is ignored.