Ellen Hertzmark

Reproducibility of Nerve Fiber Layer Thickness Measurements Using Optical Coherence Tomography

PURPOSE Optical coherence tomography (OCT) is a new technology that uses near-infrared light in an interferometer to produce approximately 10-microns resolution cross-sectional images of the tissue of interest. The authors performed repeated quantitative assessment of nerve fiber layer thickness in individuals with normal and glaucomatous eyes, and they evaluated the reproducibility of these measurements. METHODS The authors studied 21 eyes of 21 subjects by OCT. Each subject underwent five repetitions of a series of scans on five separate occasions within a 1-month period. Each series consisted of three circular scans around the optic nerve head (diameters, 2.9, 3.4, and 4.5 mm). Each series was performed separately using internal (fixation with same eye being studied) and external (fixation with contralateral eye) fixation techniques. The eye studied and the sequence of testing were assigned randomly. RESULTS Internal fixation (IF), in general, provides a slightly higher degree of reproducibility than external fixation (EF). Reproducibility was better in a given eye on a given visit than from visit to visit. Reproducibility as measured by intraclass correlation coefficients were as follows: circle diameter (CD), 2.9 mm, 0.51/0.57 (normal/glaucoma) (IF), 0.43/0.54 (EF); CD, 3.4 mm, 0.56/0.52 (IF), 0.43/0.61 (EF); CD, 4.5 mm, 0.53/0.43 (IF), 0.42/0.49 (EF). CONCLUSIONS Nerve fiber layer thickness can be reproducibly measured using OCT. Internal is superior to external fixation; each circle diameter tested provides adequate reproducibility.

Optical Coherence Tomography Measurement of Macular and Nerve Fiber Layer Thickness in Normal and Glaucomatous Human Eyes

PURPOSE To evaluate the hypothesis that macular thickness correlates with the diagnosis of glaucoma. DESIGN Cross-sectional study. PARTICIPANTS We studied 367 subjects (534 eyes), including 166 eyes of 109 normal subjects, 83 eyes of 58 glaucoma suspects, 196 eyes of 132 early glaucoma patients, and 89 eyes of 68 advanced glaucoma patients. METHODS We used optical coherence tomography (OCT) to measure macular and nerve fiber layer (NFL) thickness and to analyze their correlation with each other and with glaucoma status. We used both the commercial and prototype OCT units and evaluated correspondence between measurements performed on the same eyes on the same days. MAIN OUTCOME MEASURE Macular and NFL thickness as measured by OCT. RESULTS All NFL parameters both in prototype and commercial OCT units were statistically significantly different comparing normal subjects and either early or advanced glaucoma (P < 0.001). Inner ring, outer ring, and mean macular thickness both in prototype and commercial OCT devices were found to be significantly different between normal subjects and advanced glaucomatous eyes (P < 0.001). The outer ring was the only macular parameter that could significantly differentiate between normal and early glaucoma with either the prototype or commercial OCT unit (P = 0.003, P = 0.008, respectively). The area under the receiver operator characteristic (AROC) curves comparing mean NFL thickness between normal and advanced glaucomatous eyes was 1.00 for both the prototype and commercial OCT devices for eyes scanned on both machines on the same day. The AROC comparing mean macular thickness in normal and advanced glaucomatous eyes scanned on both machines on the same day was 0.88 for the prototype OCT device and 0.80 for the commercial OCT. CONCLUSIONS Both macular and NFL thickness as measured by OCT showed statistically significant correlations with glaucoma, although NFL thickness showed a stronger association than macular thickness. There was good correspondence between findings using both the prototype and commercial OCT units. Macular and NFL thickness measurements made with OCT may have usefulness in the clinical assessment of glaucoma.

Physical Activity, Body Mass Index, and Ovulatory Disorder Infertility

Few studies have examined whether activity and adiposity levels typical of American women affect their risk of ovulatory disorder infertility, and none has examined moderate and vigorous intensity exercise separately. We investigated these associations in the Nurses’ Health Study II, comparing prospectively collected data on adiposity and activity for 830 cases of incident ovulatory infertility and 26,125 pregnancies. We observed a U-shaped association between body mass index (BMI) and relative risk of ovulatory infertility, with increased risk for BMI below 20.0 or above 24.0 kg/m2. On the basis of the BMI distribution of U.S. women, these findings suggest that 12% (95% confidence interval = 7–20%) of ovulatory infertility in the U.S. may be attributable to underweight (BMI <20.0) and 25% (95% CI = 20–31%) to overweight (BMI ≥25.0). An increase in vigorous activity (but not moderate activity) was associated with reduced relative risk of ovulatory infertility. Each hour per week of vigorous activity was associated with a 7% (95% CI = 4–10%) lower relative risk of ovulatory infertility. After adjustment for BMI, a 5% (95% CI = 2–8%) reduction in relative risk per hour of weekly activity remained. These data suggest that, among American women, more ovulatory infertility is attributable to overweight and a sedentary lifestyle than to underweight and overexertion.

Point and interval estimates of partial population attributable risks in cohort studies: examples and software.

The concept of the population attributable risk (PAR) percent has found widespread application in public health research. This quantity describes the proportion of a disease which could be prevented if a specific exposure were to be eliminated from a target population. We present methods for obtaining point and interval estimates of partial PARs, where the impact on disease burden for some presumably modifiable determinants is estimated in, and applied to, a cohort study. When the disease is multifactorial, the partial PAR must, in general, be used to quantify the proportion of disease which can be prevented if a specific exposure or group of exposures is eliminated from a target population, while the distribution of other modifiable and non-modifiable risk factors is unchanged. The methods are illustrated in a study of risk factors for bladder cancer incidence (Michaud DS et al., New England J Med 340 (1999) 1390). A user-friendly SAS macro implementing the methods described in this paper is available via the worldwide web.

Different Rates of Disease Progression of HIV Type 1 Infection in Tanzania Based on Infecting Subtype

BACKGROUND Many different subtypes of human immunodeficiency virus (HIV) type 1 have been identified, particularly in sub-Saharan Africa. However, much remains unknown regarding the relative pathogenicity of these subtypes and their influence on the clinical progression of HIV infection. We examined prospectively the associations between HIV-1 subtypes A, C, and D and recombinant viruses, as well as the rates of disease progression in a cohort of seropositive women from Dar es Salaam, Tanzania. METHODS A total of 428 pregnant mothers participating in a larger controlled trial of the effect of vitamin supplements were selected for DNA sequencing of their HIV-1 subtype. Plasma viral load was measured at baseline, and CD4+ cell counts was assessed at baseline and at regular intervals throughout the follow-up period. Proportional hazards regression (hazards ratio [HR]) analysis was used to measure the association between viral subtype and the rate of disease progression. RESULTS Relative to patients with subtype A, patients with subtype D experienced the most rapid progression to death (HR, 2.27; 95% confidence interval [CI], 1.46-3.52) or to the World Health Organization stage 4 of illness (HR, 1.94; 95% CI, 1.20-3.14) and to a CD4+ cell count of <200 cells/mm3 (HR, 2.12; 95% CI, 1.42-3.17). After adjustment for viral load, CD4+ cell count, and other baseline covariates, the associations remained similar. CONCLUSIONS We observed heterogeneity in the rates of disease progression of HIV-1 disease in infected persons, on the basis of the infecting subtype. Subtype D was associated with the most rapid progression of the disease, relative to the other 3 categories of viruses in our cohort.

Vitamin D Status of HIV-Infected Women and Its Association with HIV Disease Progression, Anemia, and Mortality

Background Vitamin D has a potential role in slowing HIV disease progression and preventing mortality based on its extensive involvement in the immune system; however, this relationship has not been examined in large studies or in resource-limited settings. Methodology/Principal Findings Vitamin D levels were assessed in 884 HIV-infected pregnant women at enrollment in a trial of multivitamin supplementation (not including vitamin D) in Tanzania. Women were followed up for a median of 69.5 months, and information on hemoglobin levels, HIV disease progression, and mortality was recorded. Proportional hazard models and generalized estimating equations were used to assess the relationship of these outcomes with vitamin D status. Conclusions/Significance Low vitamin D status (serum 25-hydroxyvitamin D<32ng/mL) was significantly associated with progression to WHO HIV disease stage III or greater in multivariate models (incidence rate ratio [RR]: 1.25; 95% confidence intervals [CI]: 1.05, 1.50). No significant relationship was observed between vitamin D status and T-cell counts during follow-up. Women with low vitamin D status had 46% higher risk of developing severe anemia during follow-up, compared to women with adequate vitamin D levels (RR: 1.46; 95% CI: 1.09, 1.96). Women in the highest vitamin D quintile had a 42% lower risk of all-cause mortality, compared to the lowest quintile (RR: 0.58; 95% CI: 0.40, 0.84). Vitamin D status had a protective association with HIV disease progression, all-cause mortality, and development of anemia during follow-up in HIV-infected women. If confirmed in randomized trials, vitamin D supplementation could represent a simple and inexpensive method to prolonging the time to initiation of antiretroviral therapy in HIV-infected patients, particularly in resource-limited settings.

Perinatal Outcomes, Including Mother-to-Child Transmission of HIV, and Child Mortality and Their Association with Maternal Vitamin D Status in Tanzania

BACKGROUND Vitamin D is a strong immunomodulator and may protect against adverse pregnancy outcomes, mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV), and child mortality. METHODS A total of 884 HIV-infected pregnant women who were participating in a vitamin supplementation trial in Tanzania were monitored to assess pregnancy outcomes and child mortality. The association of these outcomes with maternal vitamin D status at enrollment was examined in an observational analysis. RESULTS No association was observed between maternal vitamin D status and adverse pregnancy outcomes, including low birth weight and preterm birth. In multivariate models, a low maternal vitamin D level (<32 ng/mL) was associated with a 50% higher risk (95% confidence interval [CI], 2%-120%) of MTCT of HIV at 6 weeks, a 2-fold higher risk of MTCT of HIV through breast-feeding among children who were HIV uninfected at 6 weeks (95% CI, 1.08-3.82), and a 46% higher overall risk of HIV infection (95% CI, 11%-91%). Children born to women with a low vitamin D level had a 61% higher risk of dying during follow-up (95% CI, 25%-107%). CONCLUSIONS If found to be efficacious in randomized trials, vitamin D supplementation could prove to be an inexpensive method of reducing the burden of HIV infection and death among children, particularly in resource-limited settings.

A Long-term Clinical Trial of Timolol Therapy Versus No Treatment in the Management of Glaucoma Suspects

One hundred seven patients with intraocular pressures (IOPs) between 22 and 28 mmHg with normal visual fields on Goldmann perimetry and without evidence of optic nerve damage were randomly assigned to either a timolol treatment (TT) or a no treatment (NT) arm in a prospective clinical trial. The patients were followed for an average of 56 and 51 months, respectively. Criteria for failure were a confirmed IOP of greater than 32 mmHg, stereophotographically documented optic nerve progression, or development of glaucomatous visual field loss by Goldmann or Octopus perimetry. Nine patients failed in the TT group and 17 in the NT group (P = 0.07). Of the nine TT group failures, six had discontinued timolol before failure (4 for greater than 6 months). In a Cox proportional hazards analysis controlling for confounding variables, timolol was found to be significantly protective with an adjusted risk ratio of 0.38 (95% confidence interval = 0.16-0.89, P = 0.03). When only field and disc failure criteria were considered, timolol treatment was found to be significantly protective in an analysis considering patients who stopped timolol as being lost to follow-up (P = 0.05). A higher tonographic facility of outflow was protective in all analyses. A trend toward a substantial loss of effectiveness of timolol on IOP was not observed. Seasonal fluctuations in IOP were observed (P = 0.0007), with higher IOP occurring in the winter. The results demonstrate a favorable influence of timolol therapy on the clinical course of patients with mildly elevated IOP.(ABSTRACT TRUNCATED AT 250 WORDS)

Randomized trial of vitamin supplements in relation to vertical transmission of HIV-1 in Tanzania.

Background: Observational studies suggest that poor nutritional status among HIVinfected pregnant women is associated with a higher risk of vertical transmission of HIV. Methods: We randomized 1083 pregnant women infected with HIV‐1 in a doubleblind, placebo‐controlled trial to examine the effects of supplements of vitamin A and/or multivitamins (excluding vitamin A) using a 2‐x‐2 factorial design. We report the effects of the supplements on HIV infection defined using polymerase chain reaction (PCR), or death up to 6 weeks postpartum. Results: Of babies in the multivitamin arm 38, (10.1%) were HIV‐positive at birth compared with 24 (6.6%) in the no‐multivitamin arm (relative risk [RR] = 1.54; 95% CI, 0.94‐2.51; p = .08). Of babies born to mothers in the vitamin A arm, 38 (10.0%) were HIV‐positive at birth compared with 24 (6.7%) in the no‐vitamin A arm (RR, 1.49; 95% CI, 0.91‐2.43; p = 0.11). Neither multivitamins nor vitamin A had an effect on HIV status at 6 weeks among those who were HIV‐negative at birth (RR = 1.04; 95% CI, 0.65‐1.66; p = 0.88) and (RR = 1.30; 95% CI, 0.80‐2.09; p = .29, respectively). Similarly, neither supplement was associated with being either HIVinfected or dead at birth (RR, 0.98; 95% CI, 0.76‐1.27; p = .89 and RR, 1.01; 95% CI, 0.78‐1.31; p = .95, respectively. A beneficial effect of multivitamins on birth weight was limited to babies who were HIV‐negative at birth; babies in the multivitamin arm weighed +94 g more compared with those in the no‐multivitamin arm (p = .02). Among babies who were HIV‐positive at birth, the corresponding difference was ‐31 g (p = .82). Conclusions: Vitamin A and multivitamins did not affect the risk of vertical transmission of HIV in utero nor during the intrapartum and early breastfeeding periods. Multivitamins resulted in a significant improvement in birth weight of babies who were HIV‐negative at birth but had no effect among those who were HIV‐positive. The effect of vitamin supplements on HIV transmission through breastfeeding and on clinical progression of HIV disease is yet to be ascertained.

Evaluation of focal defects of the nerve fiber layer using optical coherence tomography

OBJECTIVE To analyze glaucomatous eyes with known focal defects of the nerve fiber layer (NFL), relating optical coherence tomography (OCT) findings to clinical examination, NFL and stereoscopic optic nerve head (ONH) photography, and Humphrey 24-2 visual fields. DESIGN Cross-sectional prevalence study. PARTICIPANTS The authors followed 19 patients in the study group and 14 patients in the control group. INTERVENTION Imaging with OCT was performed circumferentially around the ONH with a circle diameter of 3.4 mm using an internal fixation technique. One hundred OCT scan points taken within 2.5 seconds were analyzed. MAIN OUTCOME MEASURES Measurements of NFL thickness using OCT were performed. RESULTS In most eyes with focal NFL defects, OCTs showed significant thinning of the NFL in areas closely corresponding to focal defects visible on clinical examination, to red-free photographs, and to defects on the Humphrey visual fields. Optical coherence tomography enabled the detection of focal defects in the NFL with a sensitivity of 65% and a specificity of 81%. CONCLUSION Analysis of NFL thickness in eyes with focal defects showed good structural and functional correlation with clinical parameters. Optical coherence tomography contributes to the identification of focal defects in the NFL that occur in early stages of glaucoma.