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Introduction: There is only limited quantitative information on the association between intake of sleep disturbing drugs and nocturnal sleep disturbances. Information on sleep disturbing effects of drugs mostly derives from clinical trials with highly selected patient collectives. As these patient collectives[for full text, please go to the a.m. URL], GMDS 2015; 60. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie e.V. (GMDS)

Background and objectives The equivalence of a survival model with a piecewise constant baseline hazard function and a Poisson regression model has been known since decades. As shown in recent studies, this equivalence carries over to clustered survival data: A frailty model with a log-normal frailty term can be interpreted and estimated as a generalized linear mixed model with a binary response, a Poisson likelihood, and a specific offset. Proceeding this way, statistical theory and software for generalized linear mixed models are readily available for fitting frailty models. This gain in flexibility comes at the small price of (1) having to fix the number of pieces for the baseline hazard in advance and (2) having to “explode” the data set by the number of pieces. Methods In this paper we extend the simulations of former studies by using a more realistic baseline hazard (Gompertz) and by comparing the model under consideration with competing models. Furthermore, the SAS macro %PCFrailty is introduced to apply the Poisson generalized linear mixed approach to frailty models. Results The simulations show good results for the shared frailty model. Our new %PCFrailty macro provides proper estimates, especially in case of 4 events per piece. Conclusions The suggested Poisson generalized linear mixed approach for log-normal frailty models based on the %PCFrailty macro provides several advantages in the analysis of clustered survival data with respect to more flexible modelling of fixed and random effects, exact (in the sense of non-approximate) maximum likelihood estimation, and standard errors and different types of confidence intervals for all variance parameters.

The German Institute of Medical Documentation and Information (DIMDI, Deutsches Institut fur Medizinische Dokumentation und Information) was commissioned through the Data Transparency Regulation of 2012 to collect and process data from different areas of routine health care (1). This new data set provides comprehensive routine data from German statutory health insurance funds for the first time. In the case of type 2 diabetes it is known that the prevalence varies among policyholders from different insurance companies. The nationwide, population-based German National Health Interview and Examination Survey for Adults (DEGS1, Studie zur Gesundheit Erwachsener in Deutschland) of the Robert Koch-Institute (RKI) estimated the overall prevalence of type 2 diabetes in the whole population between 18 and 79 years of age at a total of 7.4%, made up of 9.0% for policyholders of the AOK (a large general statutory health insurance fund) and 7.0% for policyholders of substitute health insurance funds (2). Older population groups over 80 years of age and individuals who are in nursing homes or hospitals at the time of investigation, however, are underrepresented in epidemiological studies, with the result that projections for the total population are inaccurate. In fact, according to the census of 2011, around 4.2 million people in Germany were over 80 years of age (3). Routine data, therefore, often provide the only way of depicting the situation of older and hospitalized population groups. By including data from multiple insurance companies as well as in people over 80, the DIMDI data set closes an important data gap for Germany by facilitating more comprehensive estimates of the prevalence of type 2 diabetes. The prevalence of type 1 diabetes can also be determined on the basis of the data provided by DIMDI. Thus, this data set complements registry data from Baden–Wurttemberg, North Rhine–Westphalia and Saxony, which are limited to children and young adults (1, 4). The present study not only calculates the overall prevalence and incidence of diagnosed diabetes mellitus in Germany with a particular focus on type 2 diabetes, but also the age and sex specific prevalence and incidence including the age group of those over 80.

Meta‐analyses are typically used to estimate the overall/mean of an outcome of interest. However, inference about between‐study variability, which is typically modelled using a between‐study variance parameter, is usually an additional aim. The DerSimonian and Laird method, currently widely used by default to estimate the between‐study variance, has been long challenged. Our aim is to identify known methods for estimation of the between‐study variance and its corresponding uncertainty, and to summarise the simulation and empirical evidence that compares them. We identified 16 estimators for the between‐study variance, seven methods to calculate confidence intervals, and several comparative studies. Simulation studies suggest that for both dichotomous and continuous data the estimator proposed by Paule and Mandel and for continuous data the restricted maximum likelihood estimator are better alternatives to estimate the between‐study variance. Based on the scenarios and results presented in the published studies, we recommend the Q‐profile method and the alternative approach based on a ‘generalised Cochran between‐study variance statistic’ to compute corresponding confidence intervals around the resulting estimates. Our recommendations are based on a qualitative evaluation of the existing literature and expert consensus. Evidence‐based recommendations require an extensive simulation study where all methods would be compared under the same scenarios. © 2015 The Authors. Research Synthesis Methods published by John Wiley & Sons Ltd.

End-stage renal disease (ESRD) in diabetes is a life threatening complication resulting in a poor prognosis for patients as well as high medical costs. The aims of this systematic review were (1) to evaluate the incidence of ESRD due to all causes and due to diabetic nephropathy in the diabetic population and differences between incidences of ESRD with respect to sex, ethnicity, age and regions, (2) to compare incidence rates in the diabetic and non-diabetic population, and (3) to investigate time trends. The systematic review was conducted according to the PRISMA group guidelines by performing systematic literature searches in the biomedical databases until January 3rd 2015; thirty-two studies were included. Among patients with incident type 1 diabetes the 30-year cumulative incidence ranged from 3.3% to 7.8%. Among patients with prevalent diabetes, incidence rates of ESRD due to all causes ranged from 132.0 to 167.0 per 100,000 person-years, whereas incidence rates of ESRD due to diabetic nephropathy varied from 38.4 to 804.0 per 100,000 person-years. The incidence of ESRD in the diabetic population was higher compared to the non-diabetic population, and relative risks varied from 6.2 in the white population to 62.0 among Native Americans. The results regarding time trends were inconsistent. The review conducted demonstrates the considerable variation of incidences of ESRD among the diabetic population. Consistent findings included an excess risk when comparing the diabetic to the non-diabetic population and ethnic differences. We recommend that newly designed studies should use standardized methods for the determination of ESRD and population at risk.

Objectives Aim was to examine the relationship between individually perceived changes in psychosocial stressors associated with German reunification and cardiovascular effects. We hypothesised that higher levels of psychosocial stress related to German reunification were associated with an increase in cardiovascular risk factors and cardiovascular diseases (CVDs). Design Cross-sectional data from 2 cohort studies in East Germany were used: Cardiovascular Disease, Living and Ageing in Halle Study (CARLA), and Study of Health in Pomerania (SHIP). Setting 2 populations in East Germany. Participants CARLA study: 1779 participants, aged 45–83 years at baseline (812 women), SHIP study: 4308 participants, aged 20–79 years at baseline (2193 women). Primary and secondary outcome measures Psychosocial stressors related to reunification were operationalised by the Reunification Stress Index (RSI; scale from 0 to 10). This index was composed of questions that were related to individually perceived changes in psychosocial stressors (occupational, financial and personal) after reunification. To examine the associations between the RSI and each stressor separately with cardiovascular risk factors and CVD, regression models were used. Results RSI was associated with CVD in women (RR=1.15, 95% CI 1.00 to 1.33). Cardiovascular risk factors were associated with RSI for both men and women, with strongest associations between RSI and diabetes in women (RR=1.10, 95% CI 1.01 to 1.20) and depressive disorders in men (RR=1.15, 95% CI 1.07 to 2.77). The change in occupational situation related to reunification was the major contributing psychosocial stressor. We observed a strong association with CVD in women who experienced occupational deterioration after reunification (RR=4.04, 95% CI 1.21 to 13.43). Conclusions Individually perceived deterioration of psychosocial stressors (occupational, financial and personal) related to German reunification was associated with cardiovascular risk factors and CVD. The associations were stronger for women than for men. An explanation for these findings could be that women were more often affected by unemployment after reunification. Morbidity and mortality follow-up of both cohorts could enhance the results.

OBJECTIVE: To compare the association between different anthropometric measurements and incident type 2 diabetes mellitus (T2DM) and to assess their predictive ability in different regions of Germany. METHODS: Data of 10 258 participants from 4 prospective population-based cohorts were pooled to assess the association of body weight, body mass index (BMI), waist circumference (WC), waist-to-hip-ratio (WHR) and waist-to-height-ratio (WHtR) with incident T2DM by calculating HRs of the crude, adjusted and standardised markers, as well as providing receiver operator characteristic (ROC) curves. Differences between HRs and ROCs for the different anthropometric markers were calculated to compare their predictive ability. In addition, data of 3105 participants from the nationwide survey were analysed separately using the same methods to provide a nationally representative comparison. RESULTS: Strong associations were found for each anthropometric marker and incidence of T2DM. Among the standardised anthropometric measures, we found the strongest effect on incident T2DM for WC and WHtR in the pooled sample (HR for 1 SD difference in WC 1.97, 95% CI 1.75 to 2.22, HR for WHtR 1.93, 95% CI 1.71 to 2.17 in women) and in female DEGS participants (HR for WC 2.24, 95% CI 1.91 to 2.63, HR for WHtR 2.10, 95% CI 1.81 to 2.44), whereas the strongest association in men was found for WHR among DEGS participants (HR 2.29, 95% CI 1.89 to 2.78). ROC analysis showed WHtR to be the strongest predictor for incident T2DM. Differences in HR and ROCs between the different markers confirmed WC and WHtR to be the best predictors of incident T2DM. Findings were consistent across study regions and age groups (

Objectives Several countries reported a drop in prescription of hormone replacement therapy (HRT) in the 2000s, followed by decreases in breast cancer incidence among postmenopausal women aged 50–69 years. The aim of this study was to provide hormone receptor specific incidence rates of breast cancer in Germany. Methods Breast cancer data were extracted from the cancer registries of the Federal States of Brandenburg and Saarland and the area of Munich for the period from 1998 to 2007. We obtained nationwide data on HRT prescription in 1998–2007 from health insurances. Multiple imputation was used on missing values for the receptor status. Age-standardized (European standard population) and age-specific rates were calculated. Results The age-standardized incidence rates in breast cancer were virtually constant over the entire period in all regions. In particular, no substantial changes over time occurred within the age- and receptor-specific analyses. In the same period we observed a drop in HRT use, starting in 1999 and leveling off in 2004. The incidence trends of carcinoma in situ of the female breast increased during the study period. Conclusions In our data, we did not observe an association between the decline in HRT prescription and breast cancer incidence among women aged from 50 to 69 years. The lack of temporal changes in breast cancer incidence may be explained by introduction of opportunistic and organized mammography screening and low absolute levels of HRT prescription in Germany.

Few studies have examined the age-specific use of hysterectomy by indication. The aim of this study was to provide detailed nationwide age-specific prevalence-corrected hysterectomy rates for several indications in Germany, representing a population of 42 million women.Nationwide population-based diagnosis related group data of the years 2005 and 2006 were used to calculate the prevalence-corrected hysterectomy rates by age and indication group.Prevalence-corrected age-standardized hysterectomy rates (any indication) was 362.9 (295.0 for benign diseases of the genital tract and 44.0 for primary malignant tumors of the genital tract) per 100,000 person-year. Corrected hysterectomy rates become increasingly greater than the uncorrected hysterectomy rates, such that they are about 68 % greater for women in the age groups 75-79, 80-84, and 85-89 years. Age-specific hysterectomy rates showed quite different patterns depending on the indication of hysterectomy. For example, hysterectomy rates closely follow the cancer incidence rates up to age 44 for cervical cancer and age 69 for uterine cancer, diverging noticeably in ages thereafter.The prevalence-corrected hysterectomy rates presented in this study provide a more accurate indication of the use of hysterectomy, which has implications in terms of costs and resource allocation. Understanding the role of hysterectomy in treating selected diseases across the age span is also important for patients and doctors as they consult together about an appropriate course of treatment.

INTRODUCTION:We aimed to identify the validity and robustness of effect estimates for serious rare adverse events in clinical study reports of antidepressant trials, across different meta-analysis methods for rare binary events data (1,2).METHODS:Four serious rare adverse events (all-cause mortality, suicidality, aggressive behaviour and akathisia) were meta-analyzed using different methods (3). The Yusuf-Peto odds ratio (OR), which ignores studies with no events in the treatment arms, was compared with the alternative approaches of generalized linear mixed models (GLMM), conditional logistic regression, a Bayesian approach using Markov Chain Monte Carlo (MCMC) and a beta-binomial regression model.RESULTS:Though the estimates for the four outcomes did not change substantially across the different analysis methods, the Yusuf-Peto method underestimated the treatment harm and overstimated its precision, especially when the estimated odds ratio (OR) deviated greatly from 1. For example the OR for suicidality for children and adolescents was 2.39 (95 percent Confidence Interval, CI 1.32 to 4.33, using the Yusuf-Peto method), but increased to 2.64 (95 percent CI 1.33 to 5.26) using conditional logistic regression, to 2.69 (95 percent CI 1.19 to 6.09) using beta-binomial, to 2.73 (95 percent CI 1.37 to 5.42) using the GLMM and finally to 2.87 (95 percent CI 1.42 to 5.98) using the MCMC approach.CONCLUSIONS:The method used for meta-analysis of rare events data influences the estimates obtained and the exclusion of double zero-event studies can give misleading results. To ensure reduction of bias and erroneous inferences, sensitivity analyses should be performed using different methods and we recommend that the Yusuf-Peto approach should no longer be used. Other methods, in particular the beta-binomial method that was shown to be superior, should be considered instead.

Objective Analyses comparing randomized to nonrandomized clinical trials suffer from the fact that the study populations are usually different. We aimed for a comparison of randomized clinical trials (RCTs) and propensity score (PS) analyses in similar populations. Study Design and Setting In a systematic review, we “meta-matched” RCTs and PS analyses that compared the off- and the on-pump technique in coronary artery bypass grafting. “Meta-confounders” were summarized in a “meta-propensity score” and were used for “meta-matching.” We compared treatment effects between RCTs and PS analyses for 10 previously defined binary clinical outcomes in this “meta-matched” population as differences in “meta-odds ratios.” Results For all clinical outcomes, the estimated differences in “meta-odds ratios” were below an absolute value of 0.15, all confidence intervals included the null. Conclusions In our example, treatment effects of off-pump versus on-pump surgery from RCTs and PS analyses were very similar in a “meta-matched” population of studies, indicating that only a small remaining bias is present in PS analyses.

Berg A., Fleischer S., Kuss O., Unverzagt S. & Langer G. (2012) Timing of dressing removal in the healing of surgical wounds by primary intention: quantitative systematic review protocol. Journal of Advanced Nursing 68(2), 264–270. Abstract Aim. The purpose of this systematic review is to evaluate the efficacy of different lengths of time of postoperative dressing removal in the healing of surgical wounds by primary intention. Background. It is generally practiced and recommended in clinical guidelines to cover surgical incisions which are healing by primary intention postprocedure. However, the timing of dressing removal in relation to the prevention of surgical site infections has not yet been sufficiently examined. Methods. The systematic review and meta-analyses will be performed according to the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions. Randomized controlled trials will be included. Comparisons will be made between different durations of leaving dressings in place, including not dressing the surgical site at all, and covering wounds until suture removal. Primary outcome measure is the rate of surgical site infections. Funding of the review was confirmed in March 2010. Discussion. The results of the review can put the timing of dressing removal for wounds which are healing by primary intention into perspective. Because of the widespread use of surgical dressings, clinical practice could be changed in various settings.

Descriptive epidemiologic features of testicular cancer suggest that the etiologies of seminoma and nonseminoma of the testis differ. To address this, the authors conducted a systematic review of 150 case-control and cohort studies of the etiology of testicular cancer including 1,148 relative risk estimates, stratified by histologic subgroup, reflecting 631 exposures. Their results do not support the hypothesis that seminoma and nonseminoma have different etiologies among adolescents and young men. To date, only descriptive epidemiologic features, including incidence age patterns and incidence time trends of seminoma and nonseminoma, provide evidence suggesting different etiologies, especially among newborns, infants, and elderly men.

Leisure-time physical activity is associated with better health and a reduced risk of all-cause mortality. It is unclear if this association is also present with a high level of physical activity as it is found in professional athletes. In a population-based retrospective cohort study, we compared the survival experience of all soccer players participating for Germany in international matches between 1908 and 2006 to that of the general population. To summarize survival experience, we calculated cumulative relative survival ratios (RSRs) from a life table. We included data of 812 international players, of which 428 (=52.7%) died during follow-up. In all 13 intervals, cumulative observed survival was smaller than cumulative expected survival, resulting in cumulative RSRs being

Ziel dieser Untersuchung war es zu beurteilen, ob durch die Anwendung der Clampless-off-pump(less OPCAB)-Technik Letalitat und Schlaganfallrate sowie andere schwere Komplikationen in der Koronarchirurgie gesenkt werden konnen. Zwischen Juli 2009 und November 2010 erfassten wir die Daten von 1282 Patienten, die sich einer isolierten Bypassoperation unterziehen mussten, prospektiv in einer Datenbank. In 30,8% der Falle wurden die Prozeduren vollstandig ohne Klemmen der Aorta durchgefuhrt. Dabei wurden die zentral venosen Anastomosen entweder mit dem PAS-Port-System automatisch hergestellt, oder es wurde komplett arteriell ohne das Anlegen von zentralen Anastomosen revaskularisiert. Um fur eine Unausgewogenheit zwischen den Gruppen (Selektionsbias) zu korrigieren, wurde auf der Basis von 15 Variablen, die das Risikoprofil der Patienten abbilden, eine Propensity-Score(PS)-Analyse durchgefuhrt. Letalitat, Schlaganfallrate und weitere Komplikationen sowie Ressourcenverbrauch verglichen wir zwischen der Less-OPCAB- und der konventionellen Gruppe (cCABG). Insgesamt konnten 788 Patienten (394 Paare) erfolgreich gematcht werden. Durch die Less-OPCAB-Technik konnten Letalitat (OR: 0,25, 95%-KI: 0,05–1,17) und Schlaganfallrate (OR: 0,35, 95%-KI: 0,12–0,98) signifikant gesenkt werden. Komplikationen wie Low-output-Syndrom, Langzeitbeatmung oder die Rate der Rethorakotomien waren in der Less-OPCAB-Gruppe ebenfalls reduziert. In dieser retrospektiven Propensity-Score-Analyse senkt die Clampless-OPCAB-Technik Letalitat, Schlaganfallrate und andere Morbiditatsfaktoren in einem nicht selektionierten Kollektiv koronarchirurgischer Patienten.

The aim of this study was to provide population-based German-wide hysterectomy rates based on the national hospitalization file and to estimate the rate of conversion from laparoscopical or vaginal hysterectomy to open abdominal hysterectomy. Nationwide population-based DRG (diagnosis related groups) data of the years 2005 and 2006 were used to calculate hysterectomy rates by indication group and type of surgical approach. Overall 305,015 hysterectomies were performed during the study period (4.5 out of 1,000 women aged 20 years or more). The hysterectomy rate for benign diseases of the genital tract among women aged 20 years or more (3.6 out of 1,000 women) is higher than in Sweden but lower than in the US or Australia. Only 6 and 5% of all hysterectomies were performed by laparoscopically assisted vaginal hysterectomy and laparoscopic hysterectomy, respectively. Twenty-six percent of hysterectomies for benign diseases among women aged 50 years or more included bilateral oophorectomy. 10% of laparoscopical hysterectomies and 1% of vaginal hysterectomies necessitated a conversion to an abdominal hysterectomy. For both types of hysterectomies, the conversion rates were highest for primary malignant genital tract cancer and other cancers compared to the other indication groups. Whereas the conversion rate for laparoscopical hysterectomies increased by age, this rate did not change by age for vaginal hysterectomies. Conversion from laparoscopically or vaginal hysterectomy to open abdominal hysterectomy is associated with the indication and type of hysterectomy started with and is considerably higher for laparoscopic than vaginal hysterectomies.

Objective In a German multicenter case–control study of lumbar disc diseases, we calculated risk and rate advancement periods (RAP) for physical workload. Methods Patients aged 25–70 years with clinically and radiologically verified lumbar disc herniation (286 males, 278 females) or symptomatic lumbar disc narrowing (145 males, 206 females) were compared with population control subjects (453 males and 448 females). For this analysis, all manual handling of objects of about ≥5 kg and postures with trunk inclination of ≥20 °, as assessed by technical experts, were included in the calculation of cumulative lumbar load, determined by biomechanical model calculations. Logistic regression analysis was applied to calculate RAP, adjusted for region. Results We found a steep positive dose–response relationship between age and lumbar disc narrowing among men as well as women; however, we did not find a monotonic increase in lumbar disc herniation risk with age. As a monotonic increase in disease risk with age constitutes a fundamental assumption underlying the RAP concept, we restricted our RAP analysis to cases with symptomatic lumbar disc narrowing. Among men, there was a positive dose–response relationship between the cumulative lumbar load and the acceleration of lumbar disc narrowing. In the highest exposure category, a RAP of 28.0 years [95% confidence interval (95% CI) 9.7–46.3 years] was found. Among women, the RAP was 8.8 years (95% CI 2.4–15.2 years) in the highest exposure category. Conclusion This study emphasizes the conceptual importance of risk acceleration – causation not only comprises the occurrence of a disease (that without a specific exposure would not have occurred at all) but also the accelerated occurrence of a disease (that without exposure would have occurred later in life).

Background: As a modification of patch testing, the strip patch test was established to obtain more sensitive and reliable test results. Comparative data on diagnostic accuracy for both tests are missing. Objectives: To compare the diagnostic accuracy of strip patch tests and patch tests in detecting sensitizations in patients with suspected allergic contact dermatitis by using patient history as the reference standard. Patients/methods: In a multicentre, prospective, investigator-blinded study 790 patients were enrolled. The defined reference standard was established prior to patch testing. Patch tests were performed with nickel sulfate, potassium dichromate, and lanolin alcohol. Duplicate tests were simultaneously performed on both sides of the back, of which one randomly chosen side was tape stripped beforehand, according to a standardized procedure. Primary outcome was the difference in sensitivity between strip patch test and patch test. Results: Seven hundred and eighty-seven patients were included in the analysis. Strip patch tests detected considerably more sensitization to nickel sulfate and potassium dichromate than patch tests: differences of sensitivities were 16.4% (95% CI, 8.7–24.1%) for nickel sulfate and 25.0% (95% CI, 8.9–41.0%) for potassium dichromate, both favouring the strip patch test. Conclusions: The standardized strip patch test proved to be accurate and clinically safe and is promising to improve diagnosis of allergic contact dermatitis beyond the patch test.

Since its introduction into the biomedical literature, statistical significance testing (abbreviated as SST) caused much debate. The aim of this perspective article is to review frequent fallacies and misuses of SST in the biomedical field and to review a potential way out of the fallacies and misuses associated with SSTs. Two frequentist schools of statistical inference merged to form SST as it is practised nowadays: the Fisher and the Neyman-Pearson school. The P-value is both reported quantitatively and checked against the alpha-level to produce a qualitative dichotomous measure (significant/nonsignificant). However, a P-value mixes the estimated effect size with its estimated precision. Obviously, it is not possible to measure these two things with one single number. For the valid interpretation of SSTs, a variety of presumptions and requirements have to be met. We point here to four of them: study size, correct statistical model, correct causal model, and absence of bias and confounding. It has been stated that the P-value is perhaps the most misunderstood statistical concept in clinical research. As in the social sciences, the tyranny of SST is still highly prevalent in the biomedical literature even after decades of warnings against SST. The ubiquitous misuse and tyranny of SST threatens scientific discoveries and may even impede scientific progress. In the worst case, misuse of significance testing may even harm patients who eventually are incorrectly treated because of improper handling of P-values. For a proper interpretation of study results, both estimated effect size and estimated precision are necessary ingredients.

Summary Background In occupational fields with exposure to grease, oil, metal particles, coal, black lead or soot, cleansing formulations containing abrasive bodies (e.g. refined walnut shell, corn, wood, plastic or pumice) are used. These may constitute an irritant per se. As an alternative, hydrogenated castor oil (also known as castor wax) beads have been developed as dirt-binding particles. A polar surface contributes to their mechanical cleaning effects in removal of oily grime. Objectives Standardized examination of the in vivo effects upon the skin barrier of castor wax beads in comparison with abrasive bodies and pure detergent. Methods Three cleansing preparations – (i) detergent, (ii) detergent containing castor wax beads, (iii) detergent containing walnut shell powder – were each repetitively applied in vivo (four times daily for 3 weeks), mimicking workplace conditions, in 30 healthy volunteers (15 with and 15 without an atopic skin diathesis) and compared vs. (iv) no treatment. The treatment effects upon the skin barrier were monitored by repeated measurements of functional parameters [transepidermal water loss (TEWL), redness] and surface topography. Results After a 3-week treatment, a significant global treatment effect (P

Background: Gemcitabine, oxaliplatin and 5-fluorouracil (5-FU) are active in biliary tract cancer and have a potentially synergistic mode of action and non-overlapping toxicity. The objective of these trials was to determine response, survival and toxicity separately in patients with bile duct cancer (BDC) and gallbladder cancer (GBC) treated with gemcitabine/oxaliplatin/5-FU chemotherapy. Methods: Eligible patients with histologically proven, advanced or metastatic BDC (n=37) or GBC (n=35) were treated with gemcitabine (900 mg m−2 over 30 min), oxaliplatin (65 mg m−2) and 5-FU (1500 mg m−2 over 24 h) on days 1 and 8 of a 21-day cycle. Tumour response was the primary outcome measure. Results: Response rates were 19% (95% CI: 6–32%) and 23% (95% CI: 9–37%) for BDC and GBC, respectively. Median survivals were 10.0 months (95% CI: 8.6–12.4) and 9.9 months (95% CI: 7.5–12.2) for BDC and GBC, respectively, and 1- and 2-year survival rates were 40 and 23% in BDC and 34 and 6% in GBC (intention-to-treat analysis). Major grade III and IV adverse events were neutropenia, thrombocytopenia, elevated bilirubin and anorexia. Conclusion: Triple-drug chemotherapy achieves comparable results for response and survival to previously reported regimens, but with more toxicity.

Summary Background Tape stripping the skin prior to patch testing (strip patch test, SPT) may enhance percutaneous penetration of test substances and increase skin reactivity to test substances. Objective To evaluate the test sensitivity of SPT in compliance with our recently presented practical method vs. conventional patch test (PT) in nickel- and dichromate-sensitive subjects. Methods Thirty subjects participated in the prospective, randomized, controlled, investigator-blind study. Serial dilution tests of nickel sulphate (10 000–50 ppm aq.) and potassium dichromate (1000–5 ppm aq.) were used. Tests were applied in duplicate to both sides of the upper back of the subject, where one, randomly chosen side was tape stripped. Results According to the estimated test sensitivities, SPT is more sensitive than PT in nickel- and dichromate-sensitive subjects, regardless of the interindividual different numbers of tape strips. The superiority of the SPT grows with diminishing concentrations of the allergens. Conclusion Test sensitivity of SPT vs. PT is increased. If no positive results are obtained by PT, the SPT could help to detect hidden allergens in case of weak sensitization or low concentration and poor percutaneous penetration of the test substances. Conflict of Interest None declared.

Introduction Measures of heart rate variability (HRV) can be divided in time domain and frequency domain parameters. It is frequently ignored that estimation of frequency-domain parameters is a 2-step procedure where statistical error from the first step (spectral estimation) is neglected in subsequent analyses. Methods We performed a simulation study to quantify the statistical error by using frequency domain instead of time domain parameters. We generated tachograms from a stationary AR(1) process for a wide range of parameters and compared the resulting estimation error (in terms of precision and variability) for the standard deviation of normal RR intervals (SDNN) and low frequency (LF), high frequency (HF), and LF/HF power. Results Estimation of frequency domain parameters is associated with (up to 10-fold) increased variability, as compared with the SDNN. Moreover, the SDNN has higher precision. Conclusion Frequency domain parameters should be applied in HRV analysis only if important physiological reasons suggest their use. If used, frequency domain parameters should be interpreted with caution, taking into account the statistical weaknesses of spectral estimation.

In patients with cardiovascular disease or organ failure, elevated plasma concentrations of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) are associated with an increased risk of future cardiovascular events. We aimed to investigate elevated plasma ADMA concentrations as a prospective risk marker for adverse events in patients undergoing noncardiac surgery.Prospective observational study.Two tertiary care centers.Four hundred and two patients scheduled for elective noncardiac surgery.None.Patients were followed for 30 days after surgery for a predefined composite end point (death, myocardial infarction/acute coronary syndrome, acute heart failure, severe arrhythmia, embolism, or thrombosis). Plasma ADMA concentrations at baseline were determined by high-performance liquid chromatography. ADMA was only weakly (-0.2tau0.2) correlated with other risk markers and risk scores. In univariate logistic regression, per 0.1-micromol/L increment in plasma ADMA concentration, the odds ratio to experience the primary end point increased by 1.26 (95% confidence interval 1.10-1.45, p = .001). In a multivariate logistic regression model adjusting for age, gender, current smoking, plasma creatinine, hypertension, diabetes, ischemic heart disease, highly sensitive C-reactive protein, revised cardiac risk index, type of surgery, high-risk surgery, ASA class, and study center, ADMA was found to be an independent risk marker. The odds ratio to experience the primary end point was 1.33 (95% confidence interval 1.12-1.59, p = .001) per 0.1-micromol/L increase in the plasma ADMA concentration.Elevated plasma ADMA concentrations are independently associated with a higher risk for adverse events in the peri- and postoperative periods.

OBJECTIVES Cardiopulmonary bypass (CPB) is associated with a disturbed immune response, e.g., impaired HLA-DR expression on monocytes and the release of pro- and anti-inflammatory cytokines. Cytokine release plays a role in the pathogenesis of postoperative systemic inflammatory response syndrome (SIRS) and immune system deterioration, e.g., impaired monocyte and polymorphonuclear neutrophil (PMN) function, factors that ultimately lead to an increased susceptibility to infections. To gain a further understanding, we investigated HLA-DR expression on monocytes and on B- and T-lymphocytes. In addition, we investigated the IN VITRO effect of the immunostimulating hematopoietic growth factor granulocyte-macrophage colony-stimulating factor (GM-CSF) on HLA-DR expression of these cell types. Neither HLA-DR expression on B- and T-lymphocytes nor the effects of GM-CSF in cardiac surgical patients have been studied before. METHODS In 16 patients undergoing elective cardiac surgery with CPB, counts of circulating leukocyte subsets as well as HLA-DR expression on monocytes, B- and T-lymphocytes were measured by flow cytometry before, immediately after CPB, and on the 2nd and 10th postoperative days. Treatment with GM-CSF was performed IN VITRO in whole blood cultures with 100 ng/ml recombinant human GM-CSF for 20 h. RESULTS Monocyte HLA-DR expression was attenuated immediately after CPB (125 +/- 4 mean channel fluorescence [MCF] vs. 143 +/- 2 MCF preoperatively, mean +/- SEM, P < 0.001). HLA-DR expression further decreased on the 2nd day after CPB and did not normalize until the 10th day after the operation. In contrast, HLA-DR expression on T-cells was unchanged, whereas HLA-DR expression on B-cells did not decrease before the 2nd day after CPB (152 +/- 3 MCF vs. 170 +/- 2 MCF preoperatively, P < 0.001). IN VITRO GM-CSF treatment increased HLA-DR expression on monocytes prepared after CPB to a degree comparable to preoperative values. HLA-DR expression on B-lymphocytes could not be restored by GM-CSF. CONCLUSIONS Immune system suppression after cardiac surgery is reflected in prolonged diminished HLA-DR expression on monocytes and B-lymphocytes. Suppression is not irreversible but can - at least IN VITRO - be overridden by the immunostimulating compound GM-CSF.

Background: Combinations of gemcitabine–oxaliplatin, gemcitabine–5-fluorouracil (5-FU) and 5-FU–oxaliplatin have synergistic activity and nonoverlapping adverse effect profiles. This trial assessed efficacy and safety of the triple combination gemcitabine–oxaliplatin and infusional 5-FU in patients with locally advanced (n = 11) or metastatic (n = 32) pancreatic adenocarcinoma. Patients and methods: A total of 43 eligible patients were treated with intravenous infusions of gemcitabine (900 mg/m2 over 30 min), followed by oxaliplatin (65 mg/m2 over 2 h) and 5-FU (1500 mg/m2 over 24 h) on days 1 and 8 of a 21-day cycle. Results: Among all 43 patients, the tumor response rate was 19% [95% confidence interval 7% to 30%]. Nine patients were nonassessable for response because they did not complete the first two cycles of chemotherapy due to rapid disease progression, early death or treatment refusal. One patient was lost to follow-up. Median time to progression and overall survival were 5.7 and 7.5 months. Principal grade III/IV toxic effects were leucopenia in 11 (2%), thrombocytopenia in 13 (2%), nausea in 13 (0%), anorexia 16 (7%) and sensory neuropathy in 18 (0%) of patients. Unexpected cardiotoxicity was observed in this trial. Conclusion: Response rates and survival of the three-drug combination compare favorably with single-agent gemcitabine, but do not exceed results for doublets.

Summary Objectives : We reintroduce an exact Mantel-Haenszel (MH) procedure for meta-analysis with binary endpoints which is expected to workespeciallywell i sparse data, e.g., in meta-analyses of safety or adverse events. Methods : The performance of the exact MH procedure in terms of empirical size and power is compared to the asymptotic MH and to the two standard procedures (fixed effects and random effects model) in a simulation study. We illustrate the methods with a metaanalysis of postoperative stroke occurrence after offpump or on-pump surgery in coronary artery bypass grafting. Results : We find that in almost all situations the asymptotic MH procedure outperforms its competitors; especially the standard methods yield poor results in terms of power and size. Conclusions : There is no need to use the reintroduced exact MH procedure; the asymptotic MH procedure will be sufficient in most practical situations. The standard methods (fixed effects and random effects model) should not be used in the sparse data situation.

The number needed to treat (NNT) is a popular measure to describe the absolute effect of a new treatment compared with a standard treatment or placebo in clinical trials with binary outcome. For use of NNT measures in epidemiology to compare exposed and unexposed subjects, the terms 'number needed to be exposed' (NNE) and 'exposure impact number' (EIN) have been proposed. Additionally, in the framework of logistic regression a method was derived to perform point and interval estimation of NNT measures with adjustment for confounding by using the adjusted odds ratio (OR approach). In this paper, a new method is proposed which is based upon the average risk difference over the observed confounder values (ARD approach). A decision has to be made, whether the effect of allocating an exposure to unexposed persons or the effect of removing an exposure from exposed persons should be described. We use the term NNE for the first and the term EIN for the second situation. NNE is the average number of unexposed persons needed to be exposed to observe one extra case; EIN is the average number of exposed persons among one case can be attributed to the exposure. By means of simulations it is shown that the ARD approach is better than the OR approach in terms of bias and coverage probability, especially if the confounder distribution is wide. The proposed method is illustrated by application to data of a cohort study investigating the effect of smoking on coronary heart disease.

A low within-country variability and a large between-country variability in cancer incidence may indicate that ecologic factors are involved in the etiology of the disease. The aim of this study is to explore the within- and between-country variability of cancer incidence to motivate high-quality ecologic studies. We extracted age-standardized incidence rate estimates (world standard population) from 135 regions for the ten most frequent invasive cancers in Europe for non-Hispanic white populations from Cancer Incidence in Five Continents, Volume X. We fitted weighted multilevel Poisson regression models with random country effects for each cancer and sex. We estimated intraclass correlation coefficients (ICCs) and 95% confidence intervals (95% CIs). A high ICC indicates a low within- and a high between-country variability of rates. The two cancer sites with the highest ICC among men were prostate cancer (0.96, 95% CI: 0.92-0.99) and skin melanoma (0.78, 0.64-0.93). Among women, high ICCs were observed for lung cancer (0.84, 0.73-0.95) and breast cancer (0.80, 0.69-0.91). The two most prominent sex differences for ICC occurred for cancers of the head and neck (men: 0.70, 0.55-0.85, women: 0.19, 0.08-0.30) and breast cancer (men: 0.04, 0.01-0.07, women: 0.80, 0.69-0.91). ICCs were relatively low for pancreatic cancer (men: 0.23, 0.10-0.35; women: 0.13, 0.04-0.21) and leukemia (men: 0.12, 0.04-0.21; women: 0.08, 0.02-0.14). For cancers with high ICC for which systematic factors of the health care system, screening and diagnostic activities are not plausible explanations for between-country variations in incidence, cross-country sex-specific ecologic studies may be especially promising.

Background Diabetic individuals have a largely increased risk of lower extremity amputation (LEA) compared with non-diabetic patients. Prior systematic reviews of incidence of LEA have some limitations with respect to lack of consensus in the definition of LEA, level of LEA (all, major, minor), and definition of source population (general population or population with diabetes at risk). The purpose of our review is to evaluate the incidence of LEA in the diabetic population and its differences with regard to sex, ethnicity, age, and regions; to compare the incidence rate (IR) in the diabetic and non-diabetic population; and to investigate time trends. Methods/design We will perform a systematic literature search in MEDLINE, Embase, Web of Knowledge, and publisher databases such as Journals@OVID and ScienceDirect. We will develop comprehensive systematic search strategies according to established guidelines for meta-analyses of observational studies in epidemiology (the MOOSE group). Two authors will independently screen abstracts and full text of all references on the basis of inclusion criteria with respect to types of study, types of population, and the main outcome. We will exclude studies if they report solely incidences of LEA among persons with diabetes mellitus when referring to the total population (diabetic and non-diabetic) and not exclusively to the diabetic population. Data extraction and assessment of risk of bias will be undertaken by two review authors working independently. We will assess incidence rate (IR) or cumulative incidence (CumI), relative risk of amputations comparing the diabetic to non-diabetic populations, cause of LEA, and type of diabetes. If we find subsets of studies to be homogeneous enough, we will perform meta-analyses for incidence rates by Poisson generalized linear mixed models (GLMM). Systematic review registration PROSPERO CRD42015017809 Electronic supplementary material The online version of this article (doi:10.1186/s13643-015-0064-9) contains supplementary material, which is available to authorized users.

Regression models for discrete responses with more than two categories are well established in applied statistics nowadays, where the Proportional odds model is mainly used for ordinal and the Multinomial logistic model for nominal responses. Anderson's Stereotype regression model has been used less. It is a mixture of the aforementioned models that has fewer parameters than the Multinomial model and models the assumed ordinality of the response in terms of the covariates. The main reason for the rare application of the Stereotype model might have been the enhanced mathematical complexity due to multiplicative parameters in the linear predictor and the lack of standard software. Two methods are shown that estimate the model with standard software and the SAS system is used for illustration. The first method interprets the Stereotype model as a nonlinear model with a multivariate response, and thus embeds it in a well-known and mature statistical class of models. The second method maximizes the likelihood function directly. An example on occupational hand eczema in the car industry is used to introduce the model and the different possibilities for computation. Results from a small simulation study, inspired by the hand eczema data set, are given which demonstrate that the estimation of the Stereotype model by the two proposed methods indeed yields valid results in terms of empirical size and power.

Background The increasing burden of cardiovascular diseases (CVD) in the ageing population of industrialized nations requires an intensive search for means of reducing this epidemic. In order to improve prevention, detection, therapy and prognosis of cardiovascular diseases on the population level in Eastern Germany, it is necessary to examine reasons for the East-West gradient of CVD morbidity and mortality, potential causal mechanisms and prognostic factors in the elderly. Psychosocial and nutritional factors have previously been discussed as possible causes for the unexplained part of the East-West gradient. A reduced heart rate variability appears to be associated with cardiovascular disease as well as with psychosocial and other cardiovascular risk factors and decreases with age. Nevertheless, there is a lack of population-based data to examine the role of heart rate variability and its interaction with psychosocial and nutritional factors regarding the effect on cardiovascular disease in the ageing population. There also is a paucity of epidemiological data describing the health situation in Eastern Germany. Therefore, we conduct a population-based study to examine the distribution of CVD, heart rate variability and CVD risk factors and their associations in an elderly East German population. This paper describes the design and objectives of the CARLA Study. Methods/design For this study, a random sample of 45–80 year-old inhabitants of the city of Halle (Saale) in Eastern Germany was drawn from the population registry. By the end of the baseline examination (2002–2005), 1750 study participants will have been examined. A multi-step recruitment strategy aims at achieving a 70 % response rate. Detailed information is collected on own and family medical history, socioeconomic, psychosocial, behavioural and biomedical factors. Medical examinations include anthropometric measures, blood pressure of arm and ankle, a 10-second and a 20-minute electrocardiogram, a general physical examination, an echocardiogram, and laboratory analyses of venous blood samples. On 200 participants, a 24-hour electrocardiogram is recorded. A detailed system of quality control ensures high data quality. A follow-up examination is planned. Discussion This study will help to elucidate pathways to CVD involving autonomic dysfunction and lifestyle factors which might be responsible for the CVD epidemic in some populations.

Up to now, evidence about survival of patients with non-small-cell lung cancer treated with radiation therapy alone is only available from clinical studies. The authors analyzed survival experience depending on several prognostic factors from a population-based cancer registry and compared this to survival data from the literature. Between April 1996 and September 1999, 1,696 patients with lung cancer were recruited by the Halle Lung Cancer (HALLUCA) Study. 1,183 patients were diagnosed as having non-small-cell lung cancer, and 188 in clinical stages I–IIIb (15.9%) were treated with radiation therapy alone. The median survival time of all patients was 10.2 months, the 2-year overall survival rate amounted to 15.8%. Besides tumor stage, radiation dose was found to be a statistically significant prognostic factor for survival in univariate analysis. The median survival time was 4.2 months for 66 patients treated with < 50 Gy, 10.7 months for 80 patients treated with 50 to < 60 Gy, and 18.9 months for 42 patients treated with ≥ 60 Gy; the corresponding 2-year overall survival rates were 8.7%, 13.4%, und 35.2%. The significant influence of dose persisted even after adjustment for different confounders in a Cox regression model. Patients treated with 50 to < 60 Gy under a potentially curative therapeutic regimen had a significantly lower survival, compared to patients treated with ≥ 60 Gy. In terms of quality assurance, the large proportion of patients treated with radiation doses below the curative range of ≥ 60 Gy was unexpected.

The dermatologist's procedure was introduced in 1972 as a "procedure of early detection of occupational skin disease" by industrial, agricultural and public-sector employers' liability insurance funds of Germany's statutory occupational accident insurance. To date, it represents the most relevant tool for secondary prevention in industrial dermatology in Germany. According to the intention of this procedure, insured parties who are likely to have an occupational skin disease have to be offered preventive measures and, if necessary, given appropriate treatment to avoid job-loss. In co-operation with the Central Federation of the Industrial Professional Associations, the Task Force on Occupational and Environmental Dermatology of the German Dermatological Society, and the Professional Organisation of German Dermatologists, a study group was constituted in 1999 to improve the traditional dermatologist's procedure. In October 2002 a controlled intervention study was started in North-western Germany to establish the definitive value of the "optimised" dermatologist's procedure. Past, present, and future of this specific procedure are discussed.

Summary Background We have recently engineered recombinant derivatives of the major birch pollen allergen Bet v 1 (rBet v 1 fragments and trimer) with strongly reduced allergenic activity. Objective The aim of this study was the in vivo characterization of potential allergy vaccines based on Al(OH)3-adsorbed genetically modified rBet v 1 derivatives in mice. Methods BALB/c mice were immunized either with courses of nine injections of increasing doses of Al(OH)3-adsorbed rBet v 1 wild-type, rBet v 1 fragments, rBet v 1 trimer or Al(OH)3 alone in weekly intervals or with three high-dose injections applied in intervals of 3 weeks. Humoral immune responses to rBet v 1 wild-type and homologous plant allergens were measured by ELISA and Western blotting, and the ability of mouse antibodies to inhibit the binding of allergic patients IgE to Bet v 1 was studied by ELISA competition experiments. Results In both schemes, hypoallergenic rBet v 1 derivatives induced low IgE but high IgG1 responses against rBet v 1 wild-type. The IgG1 antibodies induced by genetically modified rBet v 1 derivatives cross-reacted with natural Bet v 1 and its homologues from alder (Aln g 1) as well as hazel (Cor a 1) and strongly inhibited the binding of birch pollen allergic patients' IgE to Bet v 1 wild-type. Conclusion Genetically modified hypoallergenic rBet v 1 derivatives induce blocking antibodies in vivo. Their safety and efficacy for the treatment of birch pollen and associated plant allergies can now be evaluated in clinical immunotherapy studies.

Grundgedanke des 1972 eingefuhrten Verfahrens zur Fruherfassung berufsbedingter Hauterkrankungen „Hautarztverfahren“ war es, hauterkrankten Beschaftigten einen Berufsverbleib durch Ausschopfung aller zur Verfugung stehenden berufsdermatologischen Interventionsmasnahmen und eine fruhzeitig eingeleitete adaquate Therapie zu ermoglichen. Das Hautarztverfahren stellt bis heute das fur die Berufsdermatologie wichtigste sekundarpraventive Instrument in der gesetzlichen Unfallversicherung dar. Auf Anregung des Hauptverbandes der gewerblichen Berufsgenossenschaften und mit Beteiligung der Arbeitsgemeinschaft fur Berufs- und Umweltdermatologie und des Berufsverbandes der Deutschen Dermatologen hatte sich 1999 eine Arbeitsgruppe konstituiert, um das bisherige „klassische“ Hautarztverfahren zu optimieren. Im Vordergrund stand dabei das Bemuhen um eine Effizienzsteigerung des Verfahrens. Eine hierzu im Oktober 2002 in Nordwestdeutschland angelaufene kontrollierte Interventionsstudie soll die bessere Umsetzung sekundarer Praventionsmasnahmen durch das „optimierte“ gegenuber dem „klassischen“ Hautarztverfahren belegen. Ziel ist, aus den Studienergebnissen einen konkreten Vorschlag fur die Gestaltung des „optimierten“ Hautarztverfahrens vor seiner bundesweiten Einfuhrung abzuleiten.

Grundgedanke des 1972 eingefuhrten Verfahrens zur Fruherfassung berufsbedingter Hauterkrankungen, des "Hautarztverfahrens", war es, hauterkrankten Beschaftigten einen Berufsverbleib durch 1. Ausschopfung aller zur Verfugung stehenden berufsdermatologischen Interventionsmasnahmen und 2. adaquate Therapie zu ermoglichen. Das Hautarztverfahren stellt bis heute das fur die Berufsdermatologie wichtigste sekundarpraventive Instrument in der gesetzlichen Unfallversicherung dar. Auf Anregung des HVBG und mit Beteiligung der ABD und des BVDD hatte sich 1999 eine Arbeitsgruppe konstituiert, um das bisherige, "klassische" Hautarztverfahren zu optimieren. Im Vordergrund stand dabei das Bemuhen um eine Effizienzsteigerung des Verfahrens. Eine hierzu im Oktober 2002 angelaufene Pilotstudie soll die bessere Umsetzung sekundarer Praventionsmasnahmen durch das "optimierte" gegenuber dem "klassischen" Hautarztverfahren belegen. Es ist das Ziel, aus den Studienergebnissen einen konkreten Vorschlag fur die Gestaltung des "optimierten" Hautarztverfahrens vor seiner bundesweiten Einfuhrung abzuleiten.

Analysis of medical decisions in the differential allocation of traumatic brain injury (TBI) rehabilitation programmes.Medical specialists routinely involved in the treatment and rehabilitation of TBI patients from acute hospitals, rehabilitation centres, and the Medical Services of the Workers' Pension Insurance of Sachsen-Anhalt and Mecklenburg-Vorpommern were included in a systematic survey, in which they had to give their opinions on the individually optimal rehabilitation setting and therapies and probable outcome on the basis of case vignettes. These specialists are crucial for decision-making in rehabilitation resource allocation.Both allocation and prognosis depended mainly on patient characteristics. In a mixed logistic regression model, which takes into account that: (a) patient and physician characteristics may influence each other; and (b) that expert assessments might be correlated, setting preferences were related to chronicity and degree of motor and cognitive impairment, but also to the institutional background of the reviewer. Neuropsychological therapy dominated intervention recommendations, followed by physio- and occupational therapy. A comparatively great demand of psychotherapy and medicosocial assessment was recognized. Preferred rehabilitation setting did not influence the physicians' subjective prognosis. Older, chronic and motorically impaired patients were considered to profit less from rehabilitation. Physician characteristics and recommendations of either rehabilitation setting or therapies did not influence prognostic expectations.Physician characteristics influenced setting preferences. Preferences for type of treatment and ADL-prognosis depended on patients' variables only. Expected effects of rehabilitation were independent on rehabilitation setting and kinds of treatment.

In shock models, induction of endotoxin tolerance (ET) is known to have a protective effect. The present study was designed to explore if ET is effective in protecting lungs from reperfusion injury. Twelve foxhounds were used as experimental animals. After a left thoracotomy, the left hilum was clamped for 3 h, followed by 8 h of reperfusion. In the treatment group (ET, n = 6), dogs were pretreated with incremental daily endotoxin doses of up to 60 μg/kg on day 6. The ischemia and reperfusion experiment was carried out on day 9. Control group animals ( n = 6) were not subjected to endotoxin. After 8 h of observation, functional parameters of the reperfused lung of the ET and the control group were statistically different ( P < 0.05) with respect to Po2[ET vs. control: 172.7 ± 12.9 vs. 66.1 ± 7.2 (SE) mmHg], compliance (16.0 ± 1.2 vs. 8.3 ± 1.0 ml/0.1 kPa), and the wet-to-dry ratio (9.4 ± 0.8 vs. 16.7 ± 1.2). After 3 h of warm ischemia and 8 h of reperfusion, pulmonary function and lung water content improved in the endotoxin-tolerant group.

Objectives. It is commonly accepted that the standard screening tray is an essential diagnostic test in patch testing supporting the diagnosis of contact dermatitis, the most common type of occupational skin disease (OSD). In this study standard patch-test results of employed persons with an initial report of an OSD were analyzed within 24 occupational groups. Methods. An evaluation was made of employed persons recorded in the Register of Occupational Skin Diseases in Northern Bavaria (Berufskrankheitenregister Haut-Nordbayern; BKH-N) between 1990 and 1999, catering for those standard screening tray allergens tested over the 10-year period. Results. Nickel sulfate was the most common sensitizer (29.5%), showing occupational relevance in only 11% of the cases sensitized. Other common sensitizers were cobalt chloride (13.5%), p-phenylenediamine free base (10.7%), potassium dichromate (9.8%), fragrance mix (5.4%), thiuram mix (4.2%), balsam of Peru (4.0%), chloromethylisothiazolinone/methylisothiazolinone (4.0%), and formaldehyde (4.0%). The most occupationally relevant sensitizers were thiuram mix (71%), epoxy resin (67%), p-phenylenediamine free base (59%), p-phenylenediamine-black-rubber mix/N-isopropyl-N'-phenyl-p-phenylenediamine (53%), potassium dichromate (48%), formaldehyde (38%), chloromethylisothiazolinone/methylisothiazolinone (37%), and mercapto-mix/mercaptobenzothiazole (35%). Occupational groups at risk of acquiring delayed-type sensitization were, in particular, electroplaters, tile setters and terrazzo workers, construction and cement workers, solderers, wood processors, and leather and fur processors. Conclusions. The standard series contributes valuable information and asserts its position in clarifying the causes of OSDs. Based on the study results, the rate of occupationally relevant sensitization to each single allergen is demonstrated, and the difficulties in verifying the occupational relevance are discussed.

SummaryBackground It is not known whether distinct anatomical locations will respond with different recovery rates following acute barrier challenges. Objectives To investigate whether barrier parameters differ at five body sites during recovery from acute disruption. Methods Acute barrier disruption was achieved by tape stripping and by acetone extraction of stratum corneum lipids. Transepidermal water loss (to assess barrier function), capacitance (for stratum corneum hydration) and skin surface pH were measured at each of five different body sites in 14 human volunteers. Individual measurements were obtained every 24 h for 96 h. Results Lipid-rich skin areas (e.g. the forehead) were the most vulnerable to barrier disruption by either method. While acetone treatment affected barrier function and decreased stratum corneum hydration, tape stripping similarly altered barrier function but increased capacitance values. Although the effect of barrier disruption on surface pH appeared to vary with location, no significant pattern of variation emerged. Independent of the method used for barrier disruption, the pH normalized within 96 h. Conclusions Skin at different body sites shows distinct patterns of barrier recovery that are likely to be related to structural and physiological differences. Therefore, ‘anatomically specific’ regimens appear possible and relevant for the treatment of cutaneous disorders. In addition, adequate statistical analyses are essential to detect real differences in barrier recovery parameters.

Background The results of numerous studies on the influence of breastfeeding in the prevention of atopic disorders are often contradictory. One of the most important problems is confounding by other lifestyle factors. Objective The aim of the present study was to analyse the effect of any breastfeeding duration on the prevalence of atopic eczema in the first seven years of life taking into account other risk factors. Methods In an observational birth cohort study 1314 infants born in 1990 were followed-up for seven years. At 3, 6, 12, 18, 24 months and every year thereafter, parents were interviewed and filled in questionnaires, children were examined and blood was taken for in vitro allergy tests. Generalized Estimation Equations (GEE)-models were used to model risk factors for the prevalence of atopic eczema and for confounder adjustment Results Breastfeeding was carried out for longer if at least one parent had eczema, the mother was older, did not smoke in pregnancy, and the family had a high social status. The prevalence of atopic eczema in the first seven years increased with each year of age (OR 1.05; 95% CI 1.01-1.09 for each year), with each additional month of breastfeeding (1.03; 1.00-1.06 for each additional month), with a history of parental atopic eczema (2.06; 1.38-3.08), and if other atopic signs and symptoms appeared, especially specific sensitization (1.53; 1.25-1.88), and asthma (1.41; 1.07-1.85). Although breastfeeding should be recommended for all infants, it does not prevent eczema in children with a genetic risk. Conclusion Parental eczema is the major risk factor for eczema. But in this study, each month of breastfeeding also increased the risk.

Irritant contact dermatitis (ICD), provoked by work materials or workflows, is believed to be a frequent cause of occupational skin disease (OSD). Data of incidence rates of ICD within different occupations are inadequate.We conducted a population-based study to identify occupational groups at risk for irritant and allergic contact dermatitis (ACD).The data are based on all workers' compensation claims reported to our register of OSDs in Northern Bavaria [Berufskrankheitenregister Haut-Nordbayern (BKH-N)], Germany.From 1990 to 1999, 5285 patients had their cases completely assessed and recorded by government-employed physicians. We calculated the incidence rates of ICD and ACD in various occupations, divided into 24 occupational groups, in co-operation with the German State Institute of Labor and Occupation; there were a known total number of employees in each of the occupations. In these groups 3097 (59%) patients with OSD were observed, with an overall annual incidence rate of 4.5 patients per 10,000 workers for ICD, compared with 4.1 patients per 10,000 workers for ACD. The highest ICD annual incidence rates were found in hairdressers (46.9 per 10,000 workers per year), bakers (23.5 per 10,000 workers per year), and pastry cooks (16.9 per 10,000 workers per year); at the same time ICD was the main diagnosis of OSD in pastry cooks (76%), cooks (69%), food processing industry workers and butchers (63%), mechanics (60%), and locksmiths and automobile mechanics (59%). The results of a questionnaire showed frequent skin contact with detergents (52%), disinfectants (24%), and acidic and alkaline chemicals (24%) in the workplace.Based on the incidence data of the BKH-N, this study identified occupational groups with a high risk of ICD. Different frequencies of ICD and ACD within a single group are demonstrated. The frequent usage of detergents is being addressed because of the introduction of German legislation of recent date (the Approved Code of Practice 531 on 'wet work').

Analysis of medical decisions in the differential allocation of stroke rehabilitation programmes.Medical specialists routinely involved in the treatment and rehabilitation of stroke patients from acute hospitals, rehabilitation centres, and the Medical Services of the Workers' Pension Funds of Sachsen-Anhalt and Mecklenburg-Vorpommern were included in a systematic survey, in which they had to give their opinions on the individually optimal rehabilitation setting and therapies and probable outcome on the basis of case vignettes. These specialists are crucial for decision-making in rehabilitation resource allocation.Both allocation and prognosis did not depend only on patient but also on physician characteristics. Neurologists tended to prefer outpatient rehabilitation and expected a greater effect of rehabilitation upon ADL-function than specialists from other professions. Preferred rehabilitation setting did not influence the physicians' subjective prognosis. For patients who qualified both for in- and outpatient rehabilitation, the two settings, therapeutic potentials were considered to be equivalent.Differences in setting and treatment preferences between experts concerning optimal treatment cannot be resolved on the basis of available evidence. Further data are required that allow to decide which type of rehabilitation is best suited for a given patient.

The logistic regression model has become the standard analysing tool for binary responses in medical statistics. Methods for assessing goodness-of-fit, however, are less developed where this problem is especially pronounced in performing global goodness-of-fit tests with sparse data, that is, if the data contain only a small numbers of observations for each pattern of covariate values. In this situation it has been known for a long time that the standard goodness-of-fit tests (residual deviance and Pearson chi-square) behave unsatisfactorily if p-values are calculated from the χ2-distribution. As a remedy in this situation the Hosmer–Lemeshow test is frequently recommended; it relies on a new grouping of the observations to avoid sparseness, where this grouping depends on the estimated probabilities from the model. It has been shown, however, that the Hosmer–Lemeshow test also has some deficiencies, for example, it depends heavily on the calculating algorithm and thus different implementations might lead to different conclusions regarding the fit of the model. We present some alternative tests from the statistical literature which should also perform well with sparse data. Results from a simulation study are given which show that there exist some goodness-of-fit tests (for example, the Farrington test) that have good properties regarding size and power and that even outperform the Hosmer–Lemeshow test. We illustrate the various tests with an example from dermatology on occupational hand eczema in hairdressers. Copyright © 2002 John Wiley & Sons, Ltd.

Background Pressure ulcers affect approximately 10% of people in hospitals and older people are at highest risk. A correlation between inadequate nutritional intake and the development of pressure ulcers has been suggested by several studies, but the results have been inconsistent. Objectives To evaluate the effects of enteral and parenteral nutrition on the prevention and treatment of pressure ulcers. Search methods In March 2014, for this first update, we searched The Cochrane Wounds Group Specialised Trials Register, the Cochrane Central register of Controlled Trials (The Cochrane Library), the Database of Abstracts of Reviews of Effects (DARE) (The Cochrane Library), the Health Technology Assessment Database (HTA) (The Cochrane Library), the Cochrane Methodology Register (The Cochrane Library), NHS Economic Evaluation Database (The Cochrane Library), Ovid Medline, Ovid Embase and EBSCO CINAHL. No date, language or publication status limits were applied. Selection criteria Randomised controlled trials (RCTs) evaluating the effects of enteral or parenteral nutrition on the prevention and treatment of pressure ulcers, which measured the incidence of new ulcers, ulcer healing or changes in pressure ulcer severity. There were no restrictions on types of patient, setting, date, publication status or language. Data collection and analysis Two review authors independently screened for inclusion, and disagreement was resolved by discussion. Two review authors independently extracted data and assessed quality using the Cochrane Collaboration tool for assessing risk of bias. Main results We included 23 RCTs, many were small (between 9 and 4023 participants, median 88) and at high risk of bias. Eleven trials compared a combination of nutritional supplements, consisting of a minimum of energy and protein in different dosages, for the prevention of pressure ulcers. A meta-analysis of eight trials (6062 participants) that compared the effects of mixed nutritional supplements with standard hospital diet found no clear evidence of an effect of supplementation on pressure ulcer development (pooled RR 0.86; 95% CI 0.73 to 1.00; P value 0.05; I2 = 13%, random effects). This outcome is at unclear or high risk of bias. Fourteen trials evaluated the effects of nutritional supplements on the healing of existing pressure ulcers: seven trials examined mixed nutritional supplements, three the effects of proteins, two trials examined zinc, and two studies examined ascorbic acid. The included trials were heterogeneous with regard to participants, interventions, comparisons and outcomes and meta-analysis was not appropriate. There was no clear evidence of an improvement in pressure ulcer healing from the nutritional supplements evaluated in any of these individual studies. Authors' conclusions There is currently no clear evidence of a benefit associated with nutritional interventions for either the prevention or treatment of pressure ulcers. Further trials of high methodological quality are necessary.