[Digital papillary adenocarcinoma : Four case reports with brief literature review]. / Digitales papilläres Adenokarzinom : Vier Fallberichte mit kurzer Literaturübersicht.

Digital papillary adenocarcinoma is a rare but well characterized carcinoma of the sweat glands, which apart from very few exceptions is localized in acral skin. This type of sweat gland carcinoma tends to recur locally and may cause delayed metastases in a few cases. We describe the clinical findings and the broad histopathologic spectrum of four cases of this rare adnexal carcinoma and give a short summary of the literature.

Bevacizumab plus hypofractionated radiotherapy versus radiotherapy alone in elderly patients with glioblastoma: the randomized, open-label, phase II ARTE trial.

Background: The addition of bevacizumab to temozolomide-based chemoradiotherapy (TMZ/RT â†’ TMZ) did not prolong overall survival (OS) in patients with newly diagnosed glioblastoma in phase III trials. Elderly and frail patients are underrepresented in clinical trials, but early reports suggested preferential benefit in this population. Patients and methods: ARTE was a 2 : 1 randomized, multi-center, open-label, non-comparative phase II trial of hypofractionated RT (40 Gy in 15 fractions) with bevacizumab (10 mg/kg×14 days) (arm A, N = 50) or without bevacizumab (arm B, N = 25) in patients with newly diagnosed glioblastoma aged ≥65 years. The primary objective was to obtain evidence for prolongation of median OS by the addition of bevacizumab to RT. Response was assessed by RANO criteria. Quality of life (QoL) was monitored by the EORTC QLQ-C30/BN20 modules. Exploratory studies included molecular subtyping by 450k whole methylome and gene expression analyses. Results: Median PFS was longer in arm A than in arm B (7.6 and 4.8 months, P = 0.003), but OS was similar (12.1 and 12.2 months, P = 0.77). Clinical deterioration was delayed and more patients came off steroids in arm A. Prolonged PFS in arm A was confined to tumors with the receptor tyrosine kinase (RTK) I methylation subtype (HR 0.25, P = 0.014) and proneural gene expression (HR 0.29, P = 0.025). In a Cox model of OS controlling for established prognostic factors, associations with more favorable outcome were identified for age <70 years (HR 0.52, P = 0.018) and Karnofsky performance score 90%-100% (HR 0.51, P = 0.026). Including molecular subtypes into that model identified an association of the RTK II gene methylation subtype with inferior OS (HR 1.73, P = 0.076). Conclusion: Efficacy outcomes and exploratory analyses of ARTE do not support the hypothesis that the addition of bevacizumab to RT generally prolongs survival in elderly glioblastoma patients. Molecular biomarkers may identify patients with preferential benefit from bevacizumab. Clinical trial registration number: NCT01443676.

FTO genotype and aging: pleiotropic longitudinal effects on adiposity, brain function, impulsivity and diet.

Although overweight and obesity are associated with poor health outcomes in the elderly, the biological bases of obesity-related behaviors during aging are poorly understood. Common variants in the FTO gene are associated with adiposity in children and younger adults as well as with adverse mental health in older individuals. However, it is unclear whether FTO influences longitudinal trajectories of adiposity and other intermediate phenotypes relevant to mental health during aging. We examined whether a commonly carried obesity-risk variant in the FTO gene (rs1421085 single-nucleotide polymorphism) influences adiposity and is associated with changes in brain function in participants within the Baltimore Longitudinal Study of Aging, one of the longest-running longitudinal aging studies in the United States. Our results show that obesity-related risk allele carriers of FTO gene show dose-dependent increments in body mass index during aging. Moreover, the obesity-related risk allele is associated with reduced medial prefrontal cortical function during aging. Consistent with reduced brain function in regions intrinsic to impulse control and taste responsiveness, risk allele carriers of FTO exhibit dose-dependent increments in both impulsivity and intake of fatty foods. We propose that a common neural mechanism may underlie obesity-associated impulsivity and increased consumption of high-calorie foods during aging.

Time-series analysis of Campylobacter incidence in Switzerland.

Campylobacteriosis has been the most common food-associated notifiable infectious disease in Switzerland since 1995. Contact with and ingestion of raw or undercooked broilers are considered the dominant risk factors for infection. In this study, we investigated the temporal relationship between the disease incidence in humans and the prevalence of Campylobacter in broilers in Switzerland from 2008 to 2012. We use a time-series approach to describe the pattern of the disease by incorporating seasonal effects and autocorrelation. The analysis shows that prevalence of Campylobacter in broilers, with a 2-week lag, has a significant impact on disease incidence in humans. Therefore Campylobacter cases in humans can be partly explained by contagion through broiler meat. We also found a strong autoregressive effect in human illness, and a significant increase of illness during Christmas and New Year's holidays. In a final analysis, we corrected for the sampling error of prevalence in broilers and the results gave similar conclusions.

A simulation study on the statistical monitoring of condemnation rates from slaughterhouses for syndromic surveillance: an evaluation based on Swiss data.

Syndromic surveillance (SyS) systems currently exploit various sources of health-related data, most of which are collected for purposes other than surveillance (e.g. economic). Several European SyS systems use data collected during meat inspection for syndromic surveillance of animal health, as some diseases may be more easily detected post-mortem than at their point of origin or during the ante-mortem inspection upon arrival at the slaughterhouse. In this paper we use simulation to evaluate the performance of a quasi-Poisson regression (also known as an improved Farrington) algorithm for the detection of disease outbreaks during post-mortem inspection of slaughtered animals. When parameterizing the algorithm based on the retrospective analyses of 6 years of historic data, the probability of detection was satisfactory for large (range 83-445 cases) outbreaks but poor for small (range 20-177 cases) outbreaks. Varying the amount of historical data used to fit the algorithm can help increasing the probability of detection for small outbreaks. However, while the use of a 0·975 quantile generated a low false-positive rate, in most cases, more than 50% of outbreak cases had already occurred at the time of detection. High variance observed in the whole carcass condemnations time-series, and lack of flexibility in terms of the temporal distribution of simulated outbreaks resulting from low reporting frequency (monthly), constitute major challenges for early detection of outbreaks in the livestock population based on meat inspection data. Reporting frequency should be increased in the future to improve timeliness of the SyS system while increased sensitivity may be achieved by integrating meat inspection data into a multivariate system simultaneously evaluating multiple sources of data on livestock health.

The COVID-19 vaccination campaign in Switzerland and its impact on disease spread.

We analyse infectious disease case surveillance data to estimate COVID-19 spread and gain an understanding of the impact of introducing vaccines to counter the disease in Switzerland. The data used in this work is extensive and detailed and includes information on weekly number of cases and vaccination rates by age and region. Our approach takes into account waning immunity. The statistical analysis allows us to determine the effects of choosing alternative vaccination strategies. Our results indicate greater uptake of vaccine would have led to fewer cases with a particularly large effect on undervaccinated regions. An alternative distribution scheme not targeting specific age groups also leads to fewer cases overall but could lead to more cases among the elderly (a potentially vulnerable population) during the early stage of prophylaxis rollout.

Perspectives on scientific error.

Theoretical arguments and empirical investigations indicate that a high proportion of published findings do not replicate and are likely false. The current position paper provides a broad perspective on scientific error, which may lead to replication failures. This broad perspective focuses on reform history and on opportunities for future reform. We organize our perspective along four main themes: institutional reform, methodological reform, statistical reform and publishing reform. For each theme, we illustrate potential errors by narrating the story of a fictional researcher during the research cycle. We discuss future opportunities for reform. The resulting agenda provides a resource to usher in an era that is marked by a research culture that is less error-prone and a scientific publication landscape with fewer spurious findings.

Outcome of smoking cessation counselling of HIV-positive persons by HIV care physicians.

OBJECTIVES: Smoking is the most prevalent modifiable risk factor for cardiovascular diseases among HIV-positive persons. We assessed the effect on smoking cessation of training HIV care physicians in counselling. METHODS: The Swiss HIV Cohort Study (SHCS) is a multicentre prospective observational database. Our single-centre intervention at the Zurich centre included a half day of standardized training for physicians in counselling and in the pharmacotherapy of smokers, and a physicians' checklist for semi-annual documentation of their counselling. Smoking status was then compared between participants at the Zurich centre and other institutions. We used marginal logistic regression models with exchangeable correlation structure and robust standard errors to estimate the odds of smoking cessation and relapse. RESULTS: Between April 2000 and December 2010, 11 056 SHCS participants had 121 238 semi-annual visits and 64 118 person-years of follow-up. The prevalence of smoking decreased from 60 to 43%. During the intervention at the Zurich centre from November 2007 to December 2009, 1689 participants in this centre had 6068 cohort visits. These participants were more likely to stop smoking [odds ratio (OR) 1.23; 95% confidence interval (CI) 1.07-1.42; P=0.004] and had fewer relapses (OR 0.75; 95% CI 0.61-0.92; P=0.007) than participants at other SHCS institutions. The effect of the intervention was stronger than the calendar time effect (OR 1.19 vs. 1.04 per year, respectively). Middle-aged participants, injecting drug users, and participants with psychiatric problems or with higher alcohol consumption were less likely to stop smoking, whereas persons with a prior cardiovascular event were more likely to stop smoking. CONCLUSIONS: An institution-wide training programme for HIV care physicians in smoking cessation counselling led to increased smoking cessation and fewer relapses.

Open label randomized study comparing 3 months vs. 6 months treatment of actinic keratoses with 3% diclofenac in 2.5% hyaluronic acid gel: a trial of the German Dermatologic Cooperative Oncology Group.

BACKGROUND: Actinic keratoses (AK) are carcinomata in situ with the potential to develop into invasive carcinoma. Several studies have demonstrated that 3% diclofenac in 2.5% hyaluronic acid gel (HA) is effective and well tolerated in the treatment of AK. To date there are no large randomized multicentre trials with treatment durations longer than 90 days and histopathological control of treatment outcome. OBJECTIVE: The aim of this study was to investigate whether a prolonged treatment with diclofenac in HA of 6 vs. 3 months adds to the efficacy in treatment for AK and if this will influence tolerability and quality of life (QoL). METHODS: This was a multicentre, randomized open-label study in which 418 patients with mild to moderate AKs were randomized into two treatment groups. Group A received diclofenac in HA for 3 months and group B for 6 months. Treatment efficacy was assessed by size measurement and a final biopsy of a defined marker AK. Quality of life was measured using the Dermatology Life Quality Index questionnaire. RESULTS: Clinical complete clearance was observed in 40% in group A and in 45% in group B (P = 0.38). Histopathological clearance was confirmed in 30% in group A and in 40% in group B (P = 0.16). Treatment was well tolerated and QoL was significantly improved after treatment in both treatment groups. CONCLUSION: Treatment with diclofenac in HA is effective and well tolerated during a treatment period of 3 months as well as 6 months. Prolongation of the treatment duration did not significantly affect treatment outcome.

Predictive assessment of a non-linear random effects model for multivariate time series of infectious disease counts.

Infectious disease counts from surveillance systems are typically observed in several administrative geographical areas. In this paper, a non-linear model for the analysis of such multiple time series of counts is discussed. To account for heterogeneous incidence levels or varying transmission of a pathogen across regions, region-specific and possibly spatially correlated random effects are introduced. Inference is based on penalized likelihood methodology for mixed models. Since the use of classical model choice criteria such as AIC or BIC can be problematic in the presence of random effects, models are compared by means of one-step-ahead predictions and proper scoring rules. In a case study, the model is applied to monthly counts of meningococcal disease cases in 94 departments of France (excluding Corsica) and weekly counts of influenza cases in 140 administrative districts of Southern Germany. The predictive performance improves if existing heterogeneity is accounted for by random effects.

Heterogeneity in vaccination coverage explains the size and occurrence of measles epidemics in German surveillance data.

The objective of this study was to characterize empirically the association between vaccination coverage and the size and occurrence of measles epidemics in Germany. In order to achieve this we analysed data routinely collected by the Robert Koch Institute, which comprise the weekly number of reported measles cases at all ages as well as estimates of vaccination coverage at the average age of entry into the school system. Coverage levels within each federal state of Germany are incorporated into a multivariate time-series model for infectious disease counts, which captures occasional outbreaks by means of an autoregressive component. The observed incidence pattern of measles for all ages is best described by using the log proportion of unvaccinated school starters in the autoregressive component of the model.

Successful control of methicillin-resistant Staphylococcus aureus outbreak at a university department of dermatology.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is one of the leading strains among multiresistant hospital microflora. In 2003, we noted an increase in the number of MRSA strain 35 among patients at the University of Zurich, Department of Dermatology. At the end of 2003, we implemented additional policies in hospital hygiene, which significantly decreased the number of MRSA infections. METHODS: This is a retrospective study on 65 consecutive patients at the Department of Dermatology, University Hospital of Zurich, in whom MRSA contamination was newly diagnosed during the period of 2003-2008. All isolated strains were genotyped. We implemented additional policies as strict hand hygiene and avoidance of sharing the same ointment pots or tubes amongst patients. As soon as the skin disease was healed, decolonization of MRSA was undertaken by a 5-day topical treatment. RESULTS: Of the 65 MRSA patients, 19 (29%) patients carried a genotypical strain (MRSA 35) that was identified to be specific for the Department of Dermatology. Three health care workers (HCWs) were tested positive. The outlined measures reduced the incidence of new transmissions of this specific strain MRSA 35 significantly (P=0.001) with a complete disappearance of new transmissions of MRSA 35 in the year 2008. Of the 65 patients, 15 (23%) patients became long-term carriers, among all (15/15; 100%) had persisting active skin lesions. CONCLUSIONS: Strict hand hygiene and avoidance of sharing ointments among patients were highly effective measures in controlling an outbreak of MRSA. Complete of near-to-complete remission of the underlying dermatoses, skin lesions or chronic wounds, is a prerequisite for complete decolonization of MRSA carriers.

Immune responsiveness of SM/J mice. Cellular characteristics and genetic analysis of hyperresponsiveness to B cell mitogens.

We tested the proliferative responses of splenocytes from a panel of inbred mouse strains to AVIS, a B cell mitogen from Actinomyces viscosus bacteria. The SM/J strain was found to exhibit severalfold higher responsiveness than any of the other strains. SM/J splenocytes were also hyperresponsive to the B cell mitogens lipopolysaccharide, dextran sulfate, and purified protein derivative of tuberculin, but responsiveness to the T cell mitogen phytohemagglutinin was normal. (B6 X SM)F1 and F1 x B6 backcross mice were tested for AVIS and lipopolysaccharide responsiveness, and it was determined that hyperresponsiveness was under polygenic, autosomal, non-H-2-linked gene control. Genetic control of response to B mitogens in SM/J mice appears to be expressed solely through the B lymphocyte because removal of T lymphocytes or macrophages did not reduce the magnitude of responsiveness in vitro. SM/J mice may provide a useful model for testing questions regarding B cell triggering, differentiation, and function, and to examine the genes involved with B cell proliferation.

A score regression approach to assess calibration of continuous probabilistic predictions.

Calibration, the statistical consistency of forecast distributions and the observations, is a central requirement for probabilistic predictions. Calibration of continuous forecasts is typically assessed using the probability integral transform histogram. In this article, we propose significance tests based on scoring rules to assess calibration of continuous predictive distributions. For an ideal normal forecast we derive the first two moments of two commonly used scoring rules: the logarithmic and the continuous ranked probability score. This naturally leads to the construction of two unconditional tests for normal predictions. More generally, we propose a novel score regression approach, where the individual scores are regressed on suitable functions of the predictive variance. This conditional approach is applicable even for certain nonnormal predictions based on the Dawid-Sebastiani score. Two case studies illustrate that the score regression approach has typically more power in detecting miscalibrated forecasts than the other approaches considered, including a recently proposed technique based on conditional exceedance probability curves.

Bayesian bivariate meta-analysis of diagnostic test studies using integrated nested Laplace approximations.

For bivariate meta-analysis of diagnostic studies, likelihood approaches are very popular. However, they often run into numerical problems with possible non-convergence. In addition, the construction of confidence intervals is controversial. Bayesian methods based on Markov chain Monte Carlo (MCMC) sampling could be used, but are often difficult to implement, and require long running times and diagnostic convergence checks. Recently, a new Bayesian deterministic inference approach for latent Gaussian models using integrated nested Laplace approximations (INLA) has been proposed. With this approach MCMC sampling becomes redundant as the posterior marginal distributions are directly and accurately approximated. By means of a real data set we investigate the influence of the prior information provided and compare the results obtained by INLA, MCMC, and the maximum likelihood procedure SAS PROC NLMIXED. Using a simulation study we further extend the comparison of INLA and SAS PROC NLMIXED by assessing their performance in terms of bias, mean-squared error, coverage probability, and convergence rate. The results indicate that INLA is more stable and gives generally better coverage probabilities for the pooled estimates and less biased estimates of variance parameters. The user-friendliness of INLA is demonstrated by documented R-code.

Clinical relevance of IgG antibodies against food antigens in Crohn's disease: a double-blind cross-over diet intervention study.

BACKGROUND: Environmental factors are thought to play an important role in the development of Crohn's disease (CD). Immune responses against auto-antigens or food antigens may be a reason for the perpetuation of inflammation. METHODS: In a pilot study, 79 CD patients and 20 healthy controls were examined for food immunoglobulin G (IgG). Thereafter, the clinical relevance of these food IgG antibodies was assessed in a double-blind cross-over study with 40 patients. Based on the IgG antibodies, a nutritional intervention was planned. The interferon (IFN)gamma secretion of T cells was measured. Eosinophil-derived neurotoxin was quantified in stool. RESULTS: The pilot study resulted in a significant difference of IgG antibodies in serum between CD patients and healthy controls. In 84 and 83% of the patients, respectively, IgG antibodies against processed cheese and yeast were detected. The daily stool frequency significantly decreased by 11% during a specific diet compared with a sham diet. Abdominal pain reduced and general well-being improved. IFNgamma secretion of T cells increased. No difference for eosinophil-derived neurotoxin in stool was detected. CONCLUSION: A nutritional intervention based on circulating IgG antibodies against food antigens showed effects with respect to stool frequency. The mechanisms by which IgG antibodies might contribute to disease activity remain to be elucidated.

Which pre-hospital triage parameters indicate a need for immediate evaluation and treatment of severely injured patients in the resuscitation area?

PURPOSE: To find ways to reduce the rate of over-triage without drastically increasing the rate of under-triage, we applied a current guideline and identified relevant pre-hospital triage predictors that indicate the need for immediate evaluation and treatment of severely injured patients in the resuscitation area. METHODS: Data for adult trauma patients admitted to our level-1 trauma centre in a one year period were collected. Outpatients were excluded. Correct triage for trauma team activation was identified for patients with an ISS or NISS ≥ 16 or the need for ICU treatment due to trauma sequelae. In this retrospective analysis, patients were assigned to trauma team activation according to the S3 guideline of the German Trauma Society. This assignment was compared to the actual need for activation as defined above. 13 potential predictors were retained. The relevance of the predictors was assessed and 14 models of interest were considered. The performance of these potential triage models to predict the need for trauma team activation was evaluated with leave-one-out cross-validated Brier and logarithmic scores. RESULTS: A total of 1934 inpatients ≥ 16 years were admitted to our trauma department (mean age 48 ± 22 years, 38% female). Sixty-nine per cent (n = 1341) were allocated to the emergency department and 31% (n = 593) were treated in the resuscitation room. The median ISS was 4 (IQR 7) points and the median NISS 4 (IQR 6) points. The mortality rate was 3.5% (n = 67) corresponding to a standardized mortality ratio of 0.73. Under-triage occurred in 1.3% (26/1934) and over-triage in 18% (349/1934). A model with eight predictors was finally selected with under-triage rate of 3.3% (63/1934) and over-triage rate of 10.8% (204/1934). CONCLUSION: The trauma team activation criteria could be reduced to eight predictors without losing its predictive performance. Non-relevant parameters such as EMS provider judgement, endotracheal intubation, suspected paralysis, the presence of burned body surface of > 20% and suspected fractures of two proximal long bones could be excluded for full trauma team activation. The fact that the emergency physicians did a better job in reducing under-triage compared to our final triage model suggests that other variables not present in the S3 guideline may be relevant for prediction.

Reference equations for lung function screening of healthy never-smoking adults aged 18-80 years.

The need for updated spirometric reference values to be used on European populations is widely acknowledged, especially for subjects aged >70 yrs. Their reference values are generally based on extrapolations. The aim of the present study was to calculate reference values for lung function screening of healthy, never-smoking adults aged 18-80 yrs and to compare them with the most widely used reference equations. Results of screening spirometry of 8,684 healthy, never-smoking adults were used to calculate mean values and fifth percentiles of lung function variables. The European Community of Coal and Steel (ECCS) reference equations underestimate forced expiratory volume in one second (FEV(1)) and forced vital capacity (FVC). For example, in 50-yr-old males (height 175 cm), lower limits of normal for FEV(1) are underestimated by 198 mL, and for FVC by 210 mL. In 50-yr-old females (height 165 cm), lower limits of normal for FEV(1) are underestimated by 191 mL, and for FVC by 270 mL. The decline of FVC in elderly subjects is steeper than predicted by the ECCS. Reference equations derived from spirometry data locally collected in a practical setting by well-trained personnel might be more appropriate for everyday use than generally used equations based on data from scientific studies in the distant past.

Multivariate modelling of infectious disease surveillance data.

This paper describes a model-based approach to analyse multivariate time series data on counts of infectious diseases. It extends a method previously described in the literature to deal with possible dependence between disease counts from different pathogens. In a spatio-temporal context it is proposed to include additional information on global dispersal of the pathogen in the model. Two examples are given: the first describes an analysis of weekly influenza and meningococcal disease counts from Germany. The second gives an analysis of the spatio-temporal spread of influenza in the U.S.A., 1996-2006, using air traffic information. Maximum likelihood estimates in this non-standard model class are obtained using general optimization routines, which are integrated in the R package surveillance.