Image processing techniques for identifying Mycobacterium tuberculosis in Ziehl-Neelsen stains.

Worldwide, laboratory technicians tediously read sputum smears for tuberculosis (TB) diagnosis. We demonstrate proof of principle of an innovative computational algorithm that successfully recognizes Ziehl-Neelsen (ZN) stained acid-fast bacilli (AFB) in digital images. Automated, multi-stage, color-based Bayesian segmentation identified possible 'TB objects', removed artifacts by shape comparison and color-labeled objects as 'definite', 'possible' or 'non-TB', bypassing photomicrographic calibration. Superimposed AFB clusters, extreme stain variation and low depth of field were challenges. Our novel method facilitates electronic diagnosis of TB, permitting wider application in developing countries where fluorescent microscopy is currently inaccessible and unaffordable. We plan refinement and validation in the future.

Recurrent tuberculosis and its risk factors: adequately treated patients are still at high risk.

Recurrent tuberculosis (TB) poses significant threats, including drug resistance, to TB control programs. However, recurrence and its causes, particularly in the era of epidemic human immunodeficiency virus (HIV), have not been well described. We systematically searched published material for studies reporting on recurrent TB following completion of standard treatment regimens to provide data on the issue. A total of 32 studies were reviewed. Among controlled trials, the overall recurrence rates (per 100,000 person-years) were respectively 3,010 (95%CI 2,230-3,970) and 2,290 (95%CI 1,730-2,940) at 6 and 12 months after treatment completion. Recurrence rates were higher among observational studies compared to controlled trials and in countries with high versus low background TB incidence. TB recurrence (%) was higher among HIV-infected (6.7, 95%CI 5.9-7.6) than non-HIV-infected individuals (3.3, 95%CI 2.8-3.9). Factors independently associated with recurrence in the literature included residual cavitation, greater area of involved lung tissue, positive sputum culture at 2 months of treatment and HIV infection. Among those with HIV infection, recurrent TB was associated with a low initial CD(4) count and receiving less than 37 weeks of anti-tuberculosis treatment. We argue that adequately treated patients are still at high risk for recurrent disease and should be considered in case-finding strategies. Moreover, those with multiple risk factors may benefit from modification of standard treatment.

Delayed tuberculosis diagnosis and tuberculosis transmission.

SETTING: Tuberculosis (TB) patients and their close contacts reported to the Maryland Department of Health and Mental Hygiene from 1 June 2000 to 30 November 2001. OBJECTIVES: A recent prospective study found that 49% of pulmonary TB patients had total treatment delays > or = 90 days. This cohort was analyzed to determine the association between total treatment delay and TB transmission. DESIGN: TB patient data were collected as part of a prospective cohort study; contact data were collected from local health departments. RESULTS: Close contacts of 54 US-born patients (n = 310) and those of 70 foreign-born cases (n = 393) received tuberculin skin tests (TSTs). Among contacts of US-born patients with a total treatment delay of > or = 90 days, 40% had positive TSTs vs. 24% contacts of patients with shorter delays (aOR 2.34; P = 0.03). Other patient factors associated with TST positivity among contacts of US-born cases were black race (aOR 3.03; P = 0.05), sputum smear positive for AFB (aOR 3.29; P = 0.01) and chest radiograph with cavitation (aOR 3.11; P = 0.01). No associations were observed between foreign-born patients and risk of TST positivity among their contacts. CONCLUSION: Among US-born patients, delay in TB diagnosis is associated with greater transmission of infection to contacts and could be used independently of other index patient factors to identify contacts at greatest risk of TB infection.

A cross-sectional study of vitamin C and cognitive function in older adults: the differential effects of gender.

Previous studies have suggested that vitamin C status may be associated with cognitive function in community-dwelling populations. However, this has not been consistent across all studies due to methodological differences. This cross-sectional study assessed the association between vitamin C and cognitive function in 544 community-dwelling older adults aged 65 or older who participated in both the Cardiovascular Health Study (CHS) and the CLUE II study in 1989. Three percent of the subjects had low plasma vitamin C concentrations (< 40 mg/dL) and 15% had low total vitamin C intake (< 60 mg/day). Most participants (96.7 percent) had normal cognitive function. In the unadjusted analyses, the highest fifth of plasma vitamin C concentration was associated with better Digit Symbol Substitution Test (DSST) scores and marginally associated with Mini-Mental State Examination (MMSE) compared to the lowest fifth. Total vitamin C intake, measured by Block's food frequency questionnaire, was generally associated with higher MMSE scores, though it was not significant. Adjusting for numerous factors did not substantially change results. In a stratified analysis by gender, higher plasma concentrations or intake were associated with higher MMSE scores for men but not for women. These mixed results do not provide strong evidence of an association between vitamin C concentrations or intake and cognitive function.

Active case finding of tuberculosis: historical perspective and future prospects.

Despite a history of remarkable scientific achievements in microbiology and therapeutics, tuberculosis (TB) continues to pose an extraordinary threat to human health. Case finding and treatment of TB disease are the principal means of controlling transmission and reducing incidence. This review presents a historical perspective of active case finding (ACF) of TB, detailing case detection strategies that have been used over the last century. This review is divided into the following sections: mass radiography, house-to-house surveys, out-patient case detection, enhanced case finding, high-risk populations and cost-effectiveness. The report concludes with a discussion and recommendations for future case finding strategies. Understanding the strengths and weaknesses of these methods will help inform and shape ACF as a TB control policy in the twenty-first century.

Patient and health care system delays in pulmonary tuberculosis diagnosis in a low-incidence state.

SETTING: Tuberculosis (TB) patients reported to the Maryland Department of Health and Mental Hygiene from 1 June 2000 to 30 November 2001. OBJECTIVE: To determine the extent of delayed diagnosis of TB and to assess patient and provider factors associated with delays. DESIGN: A prospective cohort study. RESULTS: Median patient, health care and total delays were 32, 26 and 89 days, respectively, for 158 patients. Non-white (relative hazard [RH] 0.62; 95% CI 0.39-0.98) and less educated (RH 0.43; 95% CI 0.26-0.72) patients had longer patient delays. English-speaking patients (RH 0.40; 95% CI 0.24-0.68) had increased health care delays, as did patients who received a diagnosis of a respiratory illness and non-TB antibiotics (RH 0.69; 95% CI 0.49-0.96) prior to a TB diagnosis. Patients first presenting to a private physician (51 days) rather than a hospital emergency room (18 days; RH 1.87; 95% CI 1.05-3.33) or public health clinic (10 days; RH 1.79; 95% CI 1.21-2.63) had longer health care delays. When a TB diagnostic tool (chest radiograph or AFB culture) was utilized, a more rapid diagnosis of TB was made. CONCLUSION: Education of the patient population about TB symptoms might reduce delays. Increased physician awareness of the current epidemiology of TB and better use of available diagnostic tools will reduce delays and may reduce TB transmission.

Latent tuberculosis infection among undergraduate medical students in Rio de Janeiro State, Brazil.

SETTING: Five medical schools in three cities with different tuberculosis (TB) incidence rates in Rio de Janeiro State, Brazil. OBJECTIVE: To estimate prevalence of and associated factors for latent tuberculosis infection (LTBI) among medical students. DESIGN: A cross-sectional survey was conducted among undergraduate students in pre-clinical, early and late clinical years from schools in cities with low (28/100,000), intermediate (63/100,000) and high (114/100,000) TB incidence rates. Information on socio-demographic profile, previous BCG vaccination, potential TB exposure, co-morbidity and use of respiratory protective masks was obtained. A tuberculin skin test (TST) was performed using the Mantoux technique by an experienced professional. A positive TST, defined as induration > or = 10 mm, was considered LTBI. RESULTS: LTBI prevalence was 6.9% (95%CI 5.4-8.6). In multivariate analysis, male sex (adjusted odds ratio [aOR] 1.8; 95% CI 1.1-3.0), late clinical years (aOR 1.9; 95% CI 1.01-3.5), intermediate TB incidence (aOR 4.3; 95% CI 1.3-14.6) and high TB incidence in the city of medical school (aOR 5.1; 95% CI 1.6-16.8) were significantly associated with LTBI. CONCLUSIONS: The higher prevalence of LTBI in late clinical years suggests that medical students are at increased risk for nosocomial Mycobacterium tuberculosis infection. The implementation of a TB control program may be necessary in medical schools, particularly in cities with higher TB incidence.

Comparison of erythema and induration as results of tuberculin tests.

SETTING: Schoolchildren, tuberculosis (TB) patients, and hospital employees in Tokyo, Japan. OBJECTIVE: To compare erythema and induration resulting from tuberculin tests among TB patients, normal children, and hospital employees with and without evidence of atopy. DESIGN: The distributions of diameters of erythema and induration were compared among three groups: 951 TB patients, 6139 first-grade and 6185 seventh-grade children, and 97 volunteer employees classified as atopic or non-atopic on the basis of skin tests and serum immunoglobulin E (IgE) concentrations. RESULTS: Erythema and induration were highly correlated. The distribution of erythema diameters was unimodal, and the distribution of induration diameters was bimodal. Erythema was considerably greater than induration among persons classified as being atopic. CONCLUSION: Both erythema and induration appear to be adequate indices of tuberculin sensitivity. However, because most of the world uses induration as the index and virtually all studies of tuberculin sensitivity rely on induration, there are advantages in the use of induration. It would be desirable to initiate a large prospective study to see whether erythema or induration is the better predictor of subsequent tuberculous disease, and to confirm our finding that erythema is more likely to be confounded by atopy than induration.

Impact of empiric antibiotics and chest radiograph on delays in the diagnosis of tuberculosis.

SETTING: Maryland Department of Health and Mental Hygiene, Division of Tuberculosis (TB) Control. OBJECTIVES: To assess the implications of antibiotic treatment of presumed community-acquired pneumonia (CAP) on delays in the diagnosis of TB, and to assess the frequency with which chest radiographs (CXRs) were utilized before a diagnosis of pneumonia or pulmonary TB was made. DESIGN: A nested case-control study within a prospective study conducted to assess factors associated with delays in the diagnosis of TB. RESULTS: Cases (n = 85; 54%) were patients who received antibiotics for non-TB diagnoses/indications prior to TB diagnosis, and controls (n = 73; 46%) were patients who had initially received TB therapy. Median health care delay for cases was 39 days vs. 15 days (P < 0.01) for controls. Median antibiotic delay was similar among all antibiotic classes. Of 54 patients who did not have a CXR at their first health care visit, 41 (79%) received empiric antibiotics, compared to 44/105 (42%) who had a CXR (P < 0.01). Only 31/54 (57%) patients initially diagnosed with CAP had a CXR at the time of diagnosis. CONCLUSION: More widespread use of CXR when diagnosing CAP should reduce delays in diagnosing TB, and the unnecessary use of antibiotics.

Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women.

BACKGROUND: Obesity is associated with increased breast cancer risk among postmenopausal women. We examined whether this association could be explained by the relationship of body mass index (BMI) with serum sex hormone concentrations. METHODS: We analyzed individual data from eight prospective studies of postmenopausal women. Data on BMI and prediagnostic estradiol levels were available for 624 case subjects and 1669 control subjects; data on the other sex hormones were available for fewer subjects. The relative risks (RRs) with 95% confidence intervals (CIs) of breast cancer associated with increasing BMI were estimated by conditional logistic regression on case-control sets, matched within each study for age and recruitment date, and adjusted for parity. All statistical tests were two-sided. RESULTS: Breast cancer risk increased with increasing BMI (P(trend) =.002), and this increase in RR was substantially reduced by adjustment for serum estrogen concentrations. Adjusting for free estradiol reduced the RR for breast cancer associated with a 5 kg/m2 increase in BMI from 1.19 (95% CI = 1.05 to 1.34) to 1.02 (95% CI = 0.89 to 1.17). The increased risk was also substantially reduced after adjusting for other estrogens (total estradiol, non-sex hormone-binding globulin-bound estradiol, estrone, and estrone sulfate), and moderately reduced after adjusting for sex hormone-binding globulin, whereas adjustment for the androgens (androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone) had little effect on the excess risk. CONCLUSION: The results are compatible with the hypothesis that the increase in breast cancer risk with increasing BMI among postmenopausal women is largely the result of the associated increase in estrogens, particularly bioavailable estradiol.

A high tuberculosis case-fatality rate in a setting of effective tuberculosis control: implications for acceptable treatment success rates.

Worldwide, the case-fatality rate of smear-positive pulmonary tuberculosis among persons on treatment is 3.8%. We assessed the case-fatality rate among such patients in Baltimore between January 1993 and June 1998. Tuberculosis incidence was < 17/100 000 population, and 99% of patients received directly observed therapy. Of 174 patients, 42 (24%) died on treatment. Patients who died were older (mean age 62 vs. 47 years; P < 0.001) and were more likely to have underlying medical conditions. In multivariate analyses, older age, diabetes mellitus, and renal failure were independently associated with an increased risk of death. With effective control, tuberculosis may become concentrated in older persons with chronic diseases and be associated with high case-fatality rates. In such settings, acceptable treatment success rates may need to be revised.

Cohort analysis: W.H. Frost's contributions to the epidemiology of tuberculosis and chronic disease.

Although Wade Hampton Frost was not the first to develop cohort analysis, it was the post-humous publication of his study of age and time trends of tuberculosis mortality that directed attention to this method of analysis. Frost's developing interest in and contributions to the epidemiology of chronic disease are reviewed in connection with a summary of his professional career.

Cancer incidence after childhood nasopharyngeal radium irradiation: a follow-up study in Washington County, Maryland.

A population from a hearing clinic in Washington County, Maryland, in 1943-1960 was followed to assess the risk of developing neoplasms from radium treatment of the nasopharynx for adenoid hypertrophy. Of the 2,925 subjects who attended the clinic, 904 received radium treatment. A nonconcurrent prospective study compared the cancer incidence among the irradiated persons with that among persons with other treatments. Seven brain tumor cases (three malignant and four benign) were identified in the irradiated group versus none in the nonirradiated group (relative risk = 14.8, 95% confidence interval: 0.76, 286.3). A nonsignificant excess risk of thyroid cancer was detected in the irradiated group based on two cases in the exposed group and one case in the nonexposed group (relative risk = 4.2, 95% confidence interval: 0.38, 46.6). Decreased risks of breast cancer, female genital cancers, and prostate cancer were observed among the irradiated individuals, although these deficits were not statistically significant individually. The decreased risk of sex hormone-related cancers in the irradiated group suggests possible radiation damage to the pituitary, with consequent reduction in pituitary hormone output and alterations in sexual and other hormonal development in early life. This hypothesis needs further evaluation.

The repeatability of serum carotenoid, retinoid, and tocopherol concentrations in specimens of blood collected 15 years apart.

Community-wide programs to collect blood for a research serum bank were carried out in Washington County, Maryland in 1974 and 1989. Of the 8395 persons who participated in both programs, 64 were controls in a nested case-control study of the association of antioxidant micronutrients with subsequent breast cancer, and 30 and 166 were controls in similar studies of lung and prostate cancer. Assay results for five carotenoids, two retinoids, and two tocopherols in samples of blood collected 15 years apart were thus available for comparisons of micronutrient concentrations. The mean Spearman rank order correlation coefficient for all comparisons was 0.44, with two coefficients greater than 0.60 and two less than 0.30. Blood pressure readings at the two blood collections had a mean rank order correlation coefficient of 0.46. Because blood pressure readings in 1974 were shown to be significantly predictive of atherosclerosis 15-18 years later, the present results suggest that ranked concentrations of antioxidant micronutrients from a single sample are sufficiently representative to be used as predictors of subsequent concentrations and are thus suitable for assessment as risk factors for subsequent illnesses.

Serum dehydroepiandrosterone and dehydroepiandrosterone sulfate and risk of melanoma or squamous cell carcinoma of the skin.

BACKGROUND: Dehydroepiandrosterone (DHEA) and its analogs have potent chemoprotective actions in mouse skin tumorigenesis models. To assess this association in humans, we investigated the relationship of prediagnostic serum concentrations of DHEA and dehydroepiandrosterone sulfate (DHEAS) to the subsequent risk of developing malignant melanoma and squamous cell carcinoma of the skin in residents of Washington County, Maryland, USA. PATIENTS AND METHODS: In a nested case-control study, serum that had been stored in 1974 was thawed and assayed for DHEA and DHEAS for 23 cases of malignant melanoma and 28 cases of squamous cell carcinoma and 1-2 matched controls per case. RESULTS: The mean serum concentrations of DHEA or DHEAS were similar in cases and controls. There were no statistically significant trends in the risk of developing malignant melanoma or squamous cell skin cancer by concentration of either steroid (all p-for-trends >0.30). CONCLUSION: The results of this study do not support the hypothesis that physiological concentrations of DHEA or DHEAS protect against skin cancer in humans.