Several studies suggest that HPV testing is more sensitive than cytology in primary cervical screening. These studies had different designs and were reported in different ways. Individual patient data were collected for all European and North American studies in which cytology was routinely performed and HPV testing was included as an additional parallel test. More than 60,000 women were included. The sensitivity and specificity of HPV testing were compared with routine cytology, both overall and for ages <35, 35-49 and 501. The age-specific prevalence of high risk HPV (hr-HPV) was also analysed. HPV testing was substantially more sensitive in detecting CIN21 than cytology (96.1% vs. 53.0%) but less specific (90.7% vs. 96.3%). The sensitivity of HPV testing was similar in all studies carried out in different areas of Europe and North America, whereas the sensitivity of cytology was highly variable. HPV sensitivity was uniformly high at all ages, whereas the sensitivity of cytology was substantially better in women over the age of 50 than in younger women (79.3% vs. 59.6%). The specificity of both tests increased with age. Positivity rates for HPV testing in women without high-grade CIN were region dependent. These results support the use of HPV testing as the sole primary screening test, with cytology reserved for women who test HPV positive. Large demonstration projects are needed to fully evaluate this strategy. ' 2006 Wiley-Liss, Inc.Key words: HPV testing; cervical screening; sensitivity; specificity; primary screening Currently in Europe and North America, cervical cancer screening is based on exfoliative cytology performed at intervals ranging between 1 and 5 years. Although there has been a marked reduction in incidence and mortality rates of squamous cell carcinoma of the cervix in countries with established cytology screening programmes, 1-3 Sasieni et al. (1996) reported that 47% of women in the UK who developed stage 1B1 or worse invasive cervical cancer before the age of 70 had had an adequate previous screening history. 2 The weaknesses in cytology are 3-fold. First, results are dependent on the high quality sample being collected during examination. Second, the test requires the identification of morphological changes within cells, whose interpretation is highly subjective. Last, this method of screening is particularly repetitive, which can lead to a greater number of interpretive errors. False negative cytology has major medical, economic and legal implications, and this is reflected in high malpractice litigation costs in the US associated with misreading cervical smears.Interest in the use of HPV testing as a screening test is based on the finding that HPV DNA is present in almost all cervical cancers, 4 and the availability of easily performed tests, which have demonstrated higher sensitivity for high grade CIN (CIN21) than that achieved by cytology in several studies. This higher sensitivity offers several potential advantages, including reduced cancer rates and longer screening intervals, ...

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OBJECTIVE—Stimulation of the retina with flickering light increases retinal vessel diameters in humans. Nitric oxide is a mediator of the retinal vasodilation to flicker. The reduction of vasodilation is considered an endothelial dysfunction. We investigated the response of retinal vessels to flickering light in diabetic patients in different stages of diabetic retinopathy. RESEARCH DESIGN AND METHODS—We studied 53 healthy volunteers, 68 type 1 diabetic patients, and 172 type 2 diabetic patients. The diameter of retinal vessels was measured continuously online with the Dynamic Vessel Analyzer (DVA). Diabetic retinopathy was classified using Early Treatment Diabetic Retinopathy Study criteria. Changes in vasodilation are expressed as percent change over baseline values. RESULTS—After adjustments for age, sex, and antihypertensive treatment, the response of retinal arterioles to diffuse luminance flicker was significantly diminished in patients with type 1 diabetes compared with healthy volunteers. The vasodilation of retinal arterioles and venules decreased continuously with increasing stages of diabetic retinopathy. The retinal arterial diameter change was 3.6 ± 2.1% in the control group, 2.6 ± 2.5% in the no diabetic retinopathy group, 2.0 ± 2.7% in the mild nonproliferative diabetic retinopathy (NPDR) group, 1.6 ± 2.2% in the moderate NPDR group, 1.8 ± 1.9% in severe NPDR group, and 0.8 ± 1.6% in proliferative diabetic retinopathy group. CONCLUSIONS—Flicker responses of retinal vessels are abnormally reduced in diabetic patients. This decreased response deteriorated with increasing stages of retinopathy. The response was already reduced before clinical appearance of retinopathy. The noninvasive testing of retinal autoregulation with DVA might prove to be of value in early detection of diabetic vessel pathological changes.

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IntroductionCurrent sepsis guidelines recommend antimicrobial treatment (AT) within one hour after onset of sepsis-related organ dysfunction (OD) and surgical source control within 12 hours. The objective of this study was to explore the association between initial infection management according to sepsis treatment recommendations and patient outcome.MethodsIn a prospective observational multi-center cohort study in 44 German ICUs, we studied 1,011 patients with severe sepsis or septic shock regarding times to AT, source control, and adequacy of AT. Primary outcome was 28-day mortality.ResultsMedian time to AT was 2.1 (IQR 0.8 – 6.0) hours and 3 hours (-0.1 – 13.7) to surgical source control. Only 370 (36.6%) patients received AT within one hour after OD in compliance with recommendation. Among 422 patients receiving surgical or interventional source control, those who received source control later than 6 hours after onset of OD had a significantly higher 28-day mortality than patients with earlier source control (42.9% versus 26.7%, P <0.001). Time to AT was significantly longer in ICU and hospital non-survivors; no linear relationship was found between time to AT and 28-day mortality. Regardless of timing, 28-day mortality rate was lower in patients with adequate than non-adequate AT (30.3% versus 40.9%, P < 0.001).ConclusionsA delay in source control beyond 6 hours may have a major impact on patient mortality. Adequate AT is associated with improved patient outcome but compliance with guideline recommendation requires improvement. There was only indirect evidence about the impact of timing of AT on sepsis mortality.

OBJECTIVES: To examine the prevalence and changes in the prevalence of overweight and obesity among school children in Jena (Germany) in the last twenty years and to identify factors associated with childhood overweight. DESIGN: Cross-sectional surveys in 1975Cross-sectional surveys in , 1985Cross-sectional surveys in , 1995 and a household questionnaire in 1995. SUBJECTS: Children from schools in Jena, aged 7 ± 14 y, participated (1975 : 1002 boys and 1000 girls; 1985 : 781 boys and 753 girls; 1995 : 989 boys and 912 girls). MEASUREMENTS: Prevalence of overweight or obesity based on the 90th or 97th age ± and sex ± speci®c percentile of the body mass index (BMI) developed for French children. In 1995 factors examined in relation to overweight included birth weight, birth length, age ± class, number of children in household, occupation of the father, education of the mother and size of¯at (apartment). RESULTS: In boys the prevalence of overweight increased from 10.0 to 16.3% and in girls from 11.7 to 20.7% between 1975 and 1995. The prevalence of obesity increased from 5.3 to 8.2% in boys and from 4.7 to 9.9% in girls between 1975 and 1995. However, the peak in the increase of overweight as well as of obesity lie for both sexes between 1985 and 1995. Using logistic regression, statistically signi®cant associations with overweight were found for occupation of the father, birth weight in both sexes and additionally, for size of¯at in girls. CONCLUSIONS: Overweight and obesity are incresing health problems among Jena children. Further investigations are needed to explore the in¯uence of factors such as feeding pattern, food habits and physical activity on overweight. Special attention should be paid to the further social development in the society and to the link between low social class and overweight. Through such investigations effective preventive strategies could be developed.

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High-risk human papillomavirus (hrHPV)-DNA testing is frequently performed parallel to cytology for the detection of high-grade dysplasia and cervical cancer particularly in women above 30 years of age. Although highly sensitive, hrHPV testing cannot distinguish between HPV-positive women with or without clinically relevant lesions. However, in principle discrimination is possible on the basis of DNA methylation markers.In order to identify novel DNA regions which allow an effective triage of hrHPV-positive cases, hypermethylated DNA enriched from cervical cancers was compared with that from cervical scrapes of HPV16-positive cases with no evidence for disease by CpG island microarray hybridization. The most promising marker regions were validated by quantitative methylation-specific PCR (qMSP) using DNA from archived cervical tissues and cervical scrapes. The performance of these markers was then determined in an independent set of 217 hrHPV-positive cervical scrapes from outpatients with histopathological verification.A methylation signature comprising the 5′ regions of the genes DLX1, ITGA4, RXFP3, SOX17 and ZNF671 specific for CIN3 and cervical cancer (termed CIN3+) was identified and validated. A high detection rate of CIN3+ was obtained if at least 2 of the 5 markers were methylated. In the subsequent cross-sectional study all cervical carcinomas (n = 19) and 56% (13/23) of CIN3 were identified by this algorithm. Only 10% (11/105) of hrHPV-positive women without histological evidence of cervical disease were scored positive by the methylation assay. Of note is that the detection rate of CIN3 differed between age groups. Eight of nine CIN3 were detected among women ≥30 years of age but only five of fourteen among <30 year old group (p = 0.03). The specificity for CIN3+ in the older age group was 76.6% (95% CI 65.6–85.5%). Clinical validation studies are required to determine the usefulness of these novel markers for triage after primary hrHPV testing in a cervical cancer screening setting.