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[The investigation of age-specific PSA reference range as the cut-off values in the mass screening for prostatic cancer].

BACKGROUND: The objective of this study is to determine age-specific PSA reference ranges in Japanese healthy men and investigate the effectiveness of these ranges as the cut-off values in the mas screening for prostatic cancer. METHODS: The study included a total of 5,206 male aged from 55 to 89 years old who wished to submit the mass screening for prostatic cancer in an urban area of Kyoto in 1995-1997, but had no evident prostatic cancer. We measured serum PSA levels by the filter paper method (Delfia PSA kit). RESULTS: We found the increase in serum PSA levels with the advancing age. With the 95th percentile for serum PSA as the upper limit, the age-specific PSA reference ranges were determined to be 2.1 ng/ml for patients aged 55 to 59 years old, 3.2 ng/ml for 60 to 69 years old, 4.4 ng/ml for 70 to 79 years old, 6.5 ng/ml for 80 to 89 years old. If we used these ranges as the cut-off values in the mass screening this time, five cases from 76 to 89 years old of prostatic cancer were overlooked. CONCLUSIONS: We found the increase in serum PSA levels with advancing age. But the positive proof of using this range to a mass screening for prostatic cancer was not certified, because time incidence of prostatic cancer in the examinees was uncertain and there is a possibility of overlooking some cases.

Age Factors↗

An optical practice based diabetic eye screening programme.

In many cases, blindness due to diabetic retinopathy can be prevented provided treatment with laser photocoagulation is used at the correct time. A screening programme is required to identify cases of sight threatening retinopathy. An optical practice based diabetic eye screening programme has been established in Dorset. The optometrist undertaking the examination is paid a fee. The findings are recorded on a coded form and sent to the hospital diabetologist who recalls positive cases. Seventy-six optical practices have joined the scheme and 3224 patients have been screened in the first 6 months (Dorset population 655,000). In the Poole area (population 230,000), 1922 patients were screened and 129 (6.7%) were recalled in 6 months. Outcome of 3 months screening, identified 59 recalls. Referral to the opthalmologist was made in 15 cases for potentially sight threatening retinopathy, 14 cases were followed in the diabetic clinic for significant background retinopathy, and 24 cases were returned to the annual screening in the optical practices. Six cases where the patients either failed or were unable to attend were reviewed by the GP. An optical practice based diabetic eye screening programme has been successful in screening a large number of patients.

Diabetic Retinopathy↗

How much of the recent rise in breast cancer incidence can be explained by increases in mammography utilization? A dynamic population model approach.

Largely unexplained increases in breast cancer incidence of about 1% per year have been documented back to the 1940s. Since 1982, breast cancer incidence in women aged 40 years and above has been increasing at a faster rate than this long-term secular trend, especially in women aged 60 years and above. Increases in the use of mammography since 1982 (which have been documented in population surveys of women) provide the most plausible explanation for the incidence increase over the long-term secular trend. A study by White et al. (J Natl Cancer Inst 1990;82:1546-52) found that, for women aged 45-64 years, the increase in mammography utilization could explain the incidence increase, while for women aged 65-74 years, it could account for only half the increase. The authors have developed an alternative model to that of White et al. that incorporates estimates of differential lead time (time from screen detection to clinical detection in the absence of screening) by age group. Using this model, the authors show that if older women have longer lead times, than similar increases in mammography utilization across age groups will lead to a larger incidence increase in older women. Thus, the observed increases in mammography utilization are generally concordant with increases in incidence, even in the older age groups.

Adult↗

Automated robotic liquid handling/laser-based nephelometry system for high throughput measurement of kinetic aqueous solubility.

The ability to rapidly and consistently measure aqueous solubility in a preclinical environment is critical to the successful identification of promising discovery compounds. The advantage of an early solubility screen is timely attrition of compounds likely to fail due to poor absorption or low bioavailability before more costly screens are performed. However, due to the large number of compounds and limited sample amounts, thermodynamic solubility measurements are not feasible at this stage. A kinetic solubility measurement is an alternative to thermodynamic measurements at the discovery stage that provides a rank listing of solubility values with minimal sample requirements. A kinetic solubility measurement is attractive from an automation vantage because it features rapid data acquisition and is amenable to multi-well formats. We describe the use of a robotic liquid/plate handler coupled to nephelometry detection for the measurement of kinetic solubility. We highlight the liquid handling validation, serial dilution parameters, and a comparison to the previous method. Experiments to further enhance throughput, or increase confidence in the automation steps, are described and the effects of these experiments are presented. In our integrated nephelometry method, we observe rapid liquid handling with an error of less than 10%, after a series of validation studies, and a sample throughput up to 1800 compounds per week. We compare the nephelometry method with our semi-thermodynamic flow-injection analysis (FIA) method, and find a 75% bin agreement between the methods.

Kinetics↗

Epidemiology of prostate cancer.

Prostate cancer incidence and mortality rates vary worldwide. In the United States, prostate cancer is the most common malignancy affecting men and is the second-leading cause of cancer death. Risk of developing prostate cancer is associated with advancing age, African American ethnicity, and a positive family history, and may be influenced by diet and other factors. The incidence of prostate cancer increased sharply after the introduction of widespread screening for prostate-specific antigen (PSA), although rates have now returned to levels seen before that time. PSA screening has been associated with a shift toward diagnosis of earlier-stage disease, but this has not been accompanied by a shift toward a lower histologic grade. Although overall prostate cancer mortality rates decreased during the 1990s, it was largely because of reductions in deaths among men diagnosed with distant disease. In contrast, mortality rates for men diagnosed with localized or regional disease increased gradually during most of the 1990s before decreasing slightly among white men and reaching plateaus among African Americans.

Black or African American↗

Calcium channel blocking agents and risk of cancer in patients with coronary heart disease. Benzafibrate Infarction Prevention (BIP) Study Research Group.

OBJECTIVES: This analysis sought to estimate the risk ratio for cancer incidence and cancer-related mortality associated with the use of calcium channel blocking agents (CCBs) in a large group of patients with chronic coronary heart disease (CHD). BACKGROUND: Recent publications contend that the use of short-acting CCBs may double the risk of cancer incidence and possibly increase mortality in hypertensive patients. METHODS: Cancer incidence data were obtained for 11,575 patients screened for the Bezafibrate Infarction Prevention (BIP) study, one-half of whom were treated at the time of screening with CCBs, over a mean follow-up period of 2.8 years. Cause-specific mortality was available through September 1996 (mean follow-up 5.2 years). The statistical power of detecting an odds ratio > or = 1.5 (given the cancer incidence rate of 2.1 in the nonusers of CCBs) was 0.91. The power declined to 0.77, 0.54 and 0.41, with declining odds ratios of 1.4, 1.3 and 1.25, respectively. RESULTS: Of 246 incident cancer cases, 129 occurred among the users (2.3%) and 117 among nonusers of CCBs (2.1%). After adjustment for age, gender and smoking, the odds ratio estimates for all cancers combined was 1.07 (95% confidence interval [CI] 0.83 to 1.37) for CCB users relative to nonusers. The adjusted risk ratio for all-cause mortality for age, gender and smoking and pertinent prognostic clinical characteristics was estimated at 0.94 (95% CI 0.85 to 1.04). The adjusted risk ratio for cancer-related mortality was 1.03 (95% CI 0.75 to 1.41). CONCLUSIONS: Patients with CHD treated with CCBs exhibited a similar risk of cancer incidence and total and cancer-related mortality compared with nonusers of CCBs. This analysis provides a certain assurance that CCB use in middle-aged and elderly patients with CHD is not associated with a meaningful difference in cancer incidence and related mortality.

Aged↗

Dietary risk factors for cancer and adenomas of the large intestine. A case-control study within a screening trial in Denmark.

The aims of the study were to estimate the importance of dietary habits for colorectal cancers and adenomas. By comparing risk factors among cancer and adenoma patients the adenoma cancer theory was indirectly evaluated. The study was performed as a case-control study within a large screening trial in Denmark. All cancer and adenoma patients diagnosed at the screening were recruited as cases; controls were selected among test negatives after matching for age, sex and time of screening. All those selected except 85, participated in a 7-day dietary recall. Altogether 49 colorectal cancer patients and 172 with adenomas were examined; 362 individuals who were test negatives in the Hemoccult-II screen served as controls. The intake of crude dietary fibres was shown to be associated with reduced risk of cancer as well as adenomas. Neither cancer nor adenoma occurrences were related to total energy intake or body mass. Vitamins E and A were negatively associated with adenoma occurrence.

Adenoma↗

Speckle coherence and implications for adaptive imaging.

Tissue speed of sound inhomogeneities cause significant degradation of medical ultrasound images. In certain cases these inhomogeneities can be modeled as a thin, spatially varying time delay screen located at the face of the transducer. Correction of such aberrators requires the addition of compensating time delays to the normal system focusing delays. These compensating delays are estimated from the arrival time differences between echoes received on different array elements. The accuracy with which these arrival time differences can be estimated is limited by the level of correlation between received speckle signals. This paper derives analytical expressions predicting the correlation between speckle signals acquired by a pulse echo system with either point or larger receive elements in the presence of near-field phase aberrations. Simulations are presented which are in good agreement with theoretical predictions. Similarities between the derived expressions and the Van Cittert-Zernike Theorem are discussed. These results indicate that near-field phase aberration correction may be far more difficult than previous analyses suggest because of the low correlation between echoes received by adjacent elements in elevation in 1.5-D arrays. Transmit aperture amplitude apodization and a new translating aperture technique are presented as methods for improving speckle correlation.

Algorithms↗

Spiral CT for lung cancer screening: is it ready for prime time?

Low-dose spiral computed tomography (CT) shows promise as a screening test for lung cancer, as it detects many more malignant pulmonary nodules than does standard plain radiography of the chest. Yet until more data are available we need to temper our enthusiasm. No studies have yet determined if using low-dose spiral CT as a screening test will lead to lower mortality rates. This paper reviews the issue of lung cancer screening and low-dose spiral CT.

Aged↗

The routine microbiological screening of central venous catheters in home parenteral nutrition patients.

BACKGROUND & AIMS: Catheter-related bloodstream infection (CRBSI) is a major complication for patients receiving home parenteral nutrition (HTPN). Endoluminal sampling techniques allow the diagnosis of CRBSI without catheter removal and may allow the screening of asymptomatic patients. METHODS: Over a 5-year period, patients receiving HTPN were offered screening on a 3 monthly basis. All patients had tunnelled cuffed Hickman lines. All were asymptomatic at the time of screening, which took the form of either endoluminal brushing or quantitative cultures on through-line blood. RESULTS: Thirty-two patients were suitable for inclusion within the study period (10 male, median age 51 (iqr 46-61)) years with 30 of these having a least one screening performed. Four had positive screening results and underwent appropriate treatment. Of the remainder, 12 presented with at least one clinical episode of CRBSI and 14 had neither clinical CRBSI nor a positive screening result. The combined clinical and screening CRBSI rate was 0.39 episodes per catheter year. CONCLUSION: Although routine microbiological catheter screening can detect subclinical infections in HTPN patients the positive rate is low with the majority of patients still presenting clinical. Identification of higher risk patients and appropriate alterations to screening frequency may improve its value further.

Candidiasis↗

Breast cancer screening; cost-effective in practice?

The main aim of national breast screening is a reduction in breast cancer mortality. The data on the reduction in breast cancer mortality from three (of the five) Swedish trials in particular gave rise to the expectation that the Dutch programme of 2-yearly screening for women aged 50-70 would produce a 16% reduction in the total population. In all likelihood, many of the years of life gained as a result of screening are enjoyed in good health. According to its critics the actual benefit that can be achieved from the national breast cancer screening programmes is overstated. Considerable benefits have recently been demonstrated in England and Wales. However, the fall was so considerable in such a relatively short space of time that screening (started in 1987) was thought to only have played a small part. As far as the Dutch screening programme is concerned it is still too early to reach any conclusions about a possible reduction in mortality. The first short-term results of the screening are favourable and as good as (or better than) expectations. In Swedish regions where mammographic screening was introduced, a 19% reduction in breast cancer mortality can be estimated at population level, and recently a 20% reduction was presented in the UK. In countries where women are expected to make appointments for screening themselves, the attendance figures are significantly lower and the quality of the process as a whole is sometimes poorer. The benefits of breast cancer screening need to be carefully balanced against the burden to women and to the health care system. Mass breast screening requires many resources and will be a costly service. Cost-effectiveness of a breast cancer screening programme can be estimated using a computer model. Published cost-effectiveness ratios may differ tremendously, but are often the result of different types of calculation, time periods considered, including or excluding downstream cost. The approach of simulation and estimation is here the same for all countries. The effects of a breast-screening program depend on many factors, such as the epidemiology of the disease, the health care system, costs of health care, the quality of the screening programme and the attendance rate. The estimated CE-ratio ranges from 2650 euros per life-year gained in Navarra to 9650 in Germany. Although relatively low incidence levels expected, the CE-ratio in Navarra is most favourable probably due to a relatively unfavourable clinical stage distribution before screening and the increasing incidence. The UK has a screening situation that is almost similar with the Netherlands. Therefore, the CE-ratios of both countries are comparable. The differences between countries make it impossible to set up one uniform screening policy. The theoretical outcomes of the benefit that can be achieved are generally from small-scale trials involving a limited number of experts, persons examined, and areas. On a national scale, with hundreds of professional practitioners, it can be expected to be more difficult to attain uniform quality. Continuous quality control, monitoring and evaluation are therefore crucial.

Aged↗

Rapid time-resolved fluoroimmunoassay for the screening of narasin and salinomycin residues in poultry and eggs.

Anticoccidial drugs are extensively used in the poultry industry to control the infection of the single-cell protozoa of the genus Eimeria. The most commonly used coccidiostats in poultry are the polyether ionophores such as narasin and salinomycin. This paper presents a rapid and simple method for the screening of residues of these two coccidiostatic compounds in poultry and eggs. The method is based on time-resolved fluoroimmunoassay. Sample preparation of eggs consists only of one extraction and evaporation step, and a solid phase extraction step is needed only for the muscle sample preparation. Mean recoveries were 91.0% from muscle tissue and 81.1% from eggs for both narasin and salinomycin. The performance of the assay was evaluated only for narasin because salinomycin had a cross-reactivity of 100% in the assay, and the recoveries of the compounds were not significantly different (P >0.05). The limits of detection [mean + 3 x standard deviation (SD)] of narasin were 0.56 and 0.28 microg/kg, and the limits of quantification (mean + 9 x SD) were 1.80 and 0.57 microg/kg for muscle and eggs, respectively. The coefficients of variation (CV) of the interassay precision of the method, evaluated by five replicate analyses of muscle samples spiked with 2 microg/kg of narasin and egg samples spiked with 1 microg/kg of narasin, were 4.1 and 6.4%, respectively. The CVs of intra-assay precision tests, determined by 10 replicate analyses at the above-mentioned concentration levels, were 3.8 and 4.5%, respectively.

Animals↗

Comparison of the performance of four microtube column agglutination systems in the detection of red cell alloantibodies.

BACKGROUND: The purpose of this study was to compare the performance of four currently available microtube column agglutination systems in the detection of red cell alloantibodies to that of the standard tube low-ionic-strength solution (LISS) indirect antiglobulin test (IAT) (tube LISS-IAT). STUDY DESIGN AND METHODS: In a comparative study, 172 sera, previously demonstrated to contain red cell alloantibodies, were tested in parallel by the tube LISS-IAT and three microtube column agglutination techniques (DiaMed-ID, Ortho BioVue, and Sanofi-Pasteur Scangel) and one affinity-adherence test system (Gamma ReACT). Tests were performed simultaneously by a single person on freshly thawed sera that had been frozen at -20 degrees C. RESULTS: The rate of detection of clinically significant alloantibodies (n = 154) in microtube column systems was very similar. One hundred forty-one sera (91.6%) reacted in the DiaMed-ID, 139 (90.3%) in the ReACT, 139 (90.3%) in the BioVue, and 142 (92.2%) in the Scangel. Only 117 (76.0%) of these sera reacted in the tube LISS-IAT. The detection rates for 18 antibodies of minor clinical significance (anti-M, -N, -P1, -Le(a), and -Le(b)) varied among the test systems: DiaMed-ID, 5 (28%); ReACT, 7 (39%); BioVue, 14 (78%); Scangel, 10 (56%); and tube LISS-IAT, 6 (33%). Antibody reactivity as determined by titer and score was very similar in all microtube column systems and higher in these systems than in the tube LISS-IAT. CONCLUSION: The sensitivity of all four microtube column systems in the detection of clinically significant red cell alloantibodies was similar and was markedly superior to that of the tube LISS-IAT. An individual cost-benefit analysis should be performed in every institution to decide whether a microtube column system should be applied. If so, the antibody screen in the microtube column agglutination system should ideally be performed in advance of the crossmatch to provide time to screen for compatible units.

Erythrocytes↗

Overseas screening for tuberculosis in immigrants and refugees to the United States: current status.

The number of reported cases of tuberculosis (TB) in foreign-born persons in the United States during 1995 was 8,042, 36% of the national total. The overseas screening of immigrants and refugee visa applicants, which relies on a chest radiograph and smear microscopy, is designed to identify future U.S. residents who have active TB or who are at high risk for TB. In this commentary, we summarize current policies and review retrospective evaluations of the screening system currently in place. The system appears to detect most persons who have active TB at the time of screening. However, active TB is actually diagnosed in < 15% of persons who are identified by screening as having suspected TB and who are evaluated in the United States. To improve the system, more sensitive and specific techniques as well as improved means of data transmission to state and local health departments are needed.

Emigration and Immigration↗

Discovery of highly selective inhibitors of p38alpha.

The p38 MAP kinases are a family of serine/threonine protein kinases that play a key role in cellular pathways leading to pro-inflammatory responses. We have developed and implemented a method for rapidly identifying and optimizing potent and selective p38alpha inhibitors, which is amenable to other targets and target classes. A diverse library of druggable, purified and quantitated molecules was assembled and standardized enzymatic assays were performed in a microfluidic format that provided very accurate and precise inhibition data allowing for development of SAR directly from the primary HTS. All compounds were screened against a collection of more than 60 enzymes (kinases, proteases and phosphatases), allowing for removal of promiscuous and non-selective inhibitors very early in the discovery process. Follow-up enzymological studies included measurement of concentration of compound in buffer, yielding accurate determination of K(i) and IC50 values, as well as mechanism of action. In addition, active compounds were screened against less desirable properties such as inhibition of the enzyme activity by aggregation, irreversible binding, and time-dependence. Screening of an 88,634-compound library through the above-described process led to the rapid identification of multiple scaffolds (>5 active compounds per scaffold) of potential drug leads for p38alpha that are highly selective against all other enzymes tested, including the three other p38 isoforms. Potency and selectivity data allowed prioritization of the identified scaffolds for optimization. Herein we present results around our 3-thio-1,2,4-triazole lead series of p38- selective inhibitors, including identification, SAR, synthesis, selectivity profile, enzymatic and cellular data in their progression towards drug candidates.

Animals↗

Estimating time and travel costs incurred in clinic based screening: flexible sigmoidoscopy screening for colorectal cancer.

OBJECTIVES: To identify the characteristics of mode of travel to screening clinics; to estimate the time and travel costs incurred in attending; to investigate whether such costs are likely to bias screening compliance. SETTING: Twelve centres in the trial of flexible sigmoidoscopy screening for colorectal cancer, drawn from across Great Britain. METHOD: Analysis of 3525 questionnaires completed by screening subjects while attending clinics. Information supplied included sociodemographic characteristics, modes of travel, expenses, activities foregone owing to attendance, and details of companions. RESULTS: More than 80% of subjects arrived at the clinics by car, and about two thirds were accompanied. On average, the clinic visit involved a 14.4 mile (22.8 km) round trip, requiring 130 minutes. Mean travel costs amounted to 6.10 Pounds per subject. The mean gross direct non-medical and indirect cost per subject amounted to 16.90 Pounds, and the mean overall gross cost per attendance was 22.40 Pounds. Compared with the Great Britain population as a whole, non-manual classes were more strongly represented, and the self employed less strongly represented, among the attendees. CONCLUSIONS: In relation to direct medical costs, the time and travel costs of clinic based screening can be substantial, may influence the overall cost effectiveness of a screening programme, and may deter potential subjects from attending.

Aged↗

Carrier screening for cystic fibrosis, Gaucher disease, and Tay-Sachs disease in the Ashkenazi Jewish population: the first 1000 cases at New York University Medical Center, New York, NY.

BACKGROUND: By late 1993, the genes for cystic fibrosis and Gaucher disease and the mutations common among Ashkenazi Jews had been identified. In response to these advances, heterozygote screening for cystic fibrosis and Gaucher disease was added to the more than 20-year-old Tay-Sachs disease screening program at New York University Medical Center, New York, NY. OBJECTIVE: To review the outcomes from the first 1000 patients screened through this program. METHODS: Patients and their referring physicians were informed about the new carrier tests. At the time of screening, patients could choose their tests (hexosaminidase A by enzyme analysis for Tay-Sachs disease or mutation analysis for cystic fibrosis and Gaucher disease). All partners of Tay-Sachs and cystic fibrosis carriers were tested. Prenatal diagnosis was offered and performed for carrier couples or mixed-marriage couples in whom the Ashkenazi Jewish partner was a carrier of Gaucher disease. Outcomes were measured by: (1) choice of tests, (2) decisions regarding prenatal diagnosis, and (3) phenotypes of children born to patients who underwent screening. RESULTS: The majority of Ashkenazi Jewish patients chose to have testing for all 3 diseases. If they previously underwent screening for Tay-Sachs disease, then they chose to undergo testing for cystic fibrosis and Gaucher disease. All carrier couples for each of these diseases went on to have prenatal testing. All mixed-marriage couples in whom the Jewish partner was found to be a carrier for Gaucher disease chose to have prenatal diagnosis. One fetus was identified as having cystic fibrosis. Since the program was initiated, no Ashkenazi Jewish baby has been born with any of these diseases at New York University Medical Center. CONCLUSIONS: New tests can be readily incorporated into established heterozygote screening programs. The Ashkenazi Jewish population described herein tends to choose testing for all conditions for which heterozygote screening is available.

Cystic Fibrosis↗