Safety, tolerability, and efficacy of fixed combination therapy with dorzolamide hydrochloride 2% and timolol maleate 0.5% in glaucoma and ocular hypertension.

Glaucoma is a collection of diseases characterized by multifactorial progressive changes leading to visual field loss and optic neuropathy most frequently due to elevated intraocular pressure (IOP). The goal of treatment is the lowering of the IOP to prevent additional optic nerve damage. Treatment usually begins with topical pharmacological agents as monotherapy, progresses to combination therapy with agents from up to 4 different classes of IOP-lowering medications, and then proceeds to laser or incisional surgical modalities for refractory cases. The fixed combination therapy with the carbonic anhydrase inhibitor dorzolamide hydrochloride 2% and the beta blocker timolol maleate 0.5% is now available in a generic formulation for the treatment of patients who have not responded sufficiently to monotherapy with beta adrenergic blockers. In pre- and postmarketing clinical studies, the fixed combination dorzolamide-timolol has been shown to be safe and efficacious, and well tolerated by patients. The fixed combination dorzolamide-timolol is convenient for patients, reduces their dosing regimen with the goal of increasing their compliance, reduces the effects of "washout" when instilling multiple drops, and reduces the preservative burden by reducing the number of drops administered per day.

Elevated albumin in retinas of monkeys with experimental glaucoma.

PURPOSE: To establish the identity of a prominent protein, approximately 70 kDa, that is markedly increased in the retina of monkeys with experimental glaucoma compared with the fellow control retina, the relationship to glaucoma severity, and its localization in the retina. METHODS: Retinal extracts were subjected to 2-D gel electrophoresis to identify differentially expressed proteins. Purified peptides from the abundant 70 kDa protein were analyzed and identified by liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS) separation, and collision-induced dissociation sequencing. Protein identity was performed on MASCOT (Matrix Science, Boston, MA) and confirmed by Western blot. The relationship between the increase in this protein and glaucoma severity was investigated by regression analyses. Protein localization in retina was evaluated by immunohistochemistry with confocal imaging. RESULTS: The abundant protein was identified as Macaca mulatta serum albumin precursor (67 kDa) from eight non-overlapping proteolytic fragments, and the identity was confirmed by Western blot. The average increase in retinal albumin content was 2.3 fold (P = 0.015). In glaucoma eyes, albumin was localized to some neurons of the inner nuclear layer, in the inner plexiform layer, and along the vitreal surface, but it was only found in blood vessels in control retinas. CONCLUSIONS: Albumin is the abundant protein found in the glaucomatous monkey retinas. The increased albumin is primarily localized to the inner retina where oxidative damage associated with experimental glaucoma is known to be prominent. Since albumin is a major antioxidant, the increase of albumin in the retinas of eyes with experimental glaucoma may serve to protect the retina against oxidative damage.

BAYESIAN PHASE I DOSE FINDING IN CANCER TRIALS

This dissertation explores phase I dose-finding designs in cancer trials from three perspectives: the alternative Bayesian dose-escalation rules, a design based on a time-to-dose-limiting toxicity (DLT) model, and a design based on a discrete-time multi-state (DTMS) model. We list alternative Bayesian dose-escalation rules and perform a simulation study for the intra-rule and inter-rule comparisons based on two statistical models to identify the most appropriate rule under certain scenarios. We provide evidence that all the Bayesian rules outperform the traditional ``3+3'' design in the allocation of patients and selection of the maximum tolerated dose. The design based on a time-to-DLT model uses patients' DLT information over multiple treatment cycles in estimating the probability of DLT at the end of treatment cycle 1. Dose-escalation decisions are made whenever a cycle-1 DLT occurs, or two months after the previous check point. Compared to the design based on a logistic regression model, the new design shows more safety benefits for trials in which more late-onset toxicities are expected. As a trade-off, the new design requires more patients on average. The design based on a discrete-time multi-state (DTMS) model has three important attributes: (1) Toxicities are categorized over a distribution of severity levels, (2) Early toxicity may inform dose escalation, and (3) No suspension is required between accrual cohorts. The proposed model accounts for the difference in the importance of the toxicity severity levels and for transitions between toxicity levels. We compare the operating characteristics of the proposed design with those from a similar design based on a fully-evaluated model that directly models the maximum observed toxicity level within the patients' entire assessment window. We describe settings in which, under comparable power, the proposed design shortens the trial. The proposed design offers more benefit compared to the alternative design as patient accrual becomes slower.

Risk Index Score (RISc)

The main objective of this study was to develop and validate a computer-based statistical algorithm based on a multivariable logistic model that can be translated into a simple scoring system in order to ascertain stroke cases using hospital admission medical records data. This algorithm, the Risk Index Score (RISc), was developed using data collected prospectively by the Brain Attack Surveillance in Corpus Christ (BASIC) project. The validity of the RISc was evaluated by estimating the concordance of scoring system stroke ascertainment to stroke ascertainment accomplished by physician review of hospital admission records. The goal of this study was to develop a rapid, simple, efficient, and accurate method to ascertain the incidence of stroke from routine hospital admission hospital admission records for epidemiologic investigations. ^ The main objectives of this study were to develop and validate a computer-based statistical algorithm based on a multivariable logistic model that could be translated into a simple scoring system to ascertain stroke cases using hospital admission medical records data. (Abstract shortened by UMI.)^

Systematic review of genetic risk score in coronary heart disease and other diseases

In order to better take advantage of the abundant results from large-scale genomic association studies, investigators are turning to a genetic risk score (GRS) method in order to combine the information from common modest-effect risk alleles into an efficient risk assessment statistic. The statistical properties of these GRSs are poorly understood. As a first step toward a better understanding of GRSs, a systematic analysis of recent investigations using a GRS was undertaken. GRS studies were searched in the areas of coronary heart disease (CHD), cancer, and other common diseases using bibliographic databases and by hand-searching reference lists and journals. Twenty-one independent case-control studies, cohort studies, and simulation studies (12 in CHD, 9 in other diseases) were identified. The underlying statistical assumptions of the GRS using the experience of the Framingham risk score were investigated. Improvements in the construction of a GRS guided by the concept of composite indicators are discussed. The GRS will be a promising risk assessment tool to improve prediction and diagnosis of common diseases.^

External validation study of a clinical prediction rule for ambulation outcomes after traumatic spinal cord injury

The main objective of this study was to determine the external validity of a clinical prediction rule developed by the European Multicenter Study on Human Spinal Cord Injury (EM-SCI) to predict the ambulation outcomes 12 months after traumatic spinal cord injury. Data from the North American Clinical Trials Network (NACTN) data registry with approximately 500 SCI cases were used for this validity study. The predictive accuracy of the EM-SCI prognostic model was evaluated using calibration and discrimination based on 231 NACTN cases. The area under the receiver-operating-characteristics curve (ROC) curve was 0.927 (95% CI 0.894 – 0.959) for the EM-SCI model when applied to NACTN population. This is lower than the AUC of 0.956 (95% CI 0.936 – 0.976) reported for the EM-SCI population, but suggests that the EM-SCI clinical prediction rule distinguished well between those patients in the NACTN population who were able to achieve independent ambulation and those who did not achieve independent ambulation. The calibration curve suggests that higher the prediction score is, the better the probability of walking with the best prediction for AIS D patients. In conclusion, the EM-SCI clinical prediction rule was determined to be generalizable to the adult NACTN SCI population.^