Men with erectile dysfunction (ED) should be screened for cardiovascular risk factors - Cost-benefit considerations in Swiss men.

Background: Current evidence indicates that erectile dysfunction (ED) is an independent risk factor for future cardiovascular events. This study aimed to estimate the cost-effectiveness of screening and subsequent preventive treatment for cardiovascular risk factors among men newly diagnosed with ED from the Swiss healthcare system perspective. Methods: Based on known data on ED and cardiovascular disease (CVD) prevalence and incidence costs and effects of a screening intervention for cardiovascular risk including corresponding cardiovascular prevention in men with ED were calculated for the Swiss population over a period of 10 years. Results: Screening and cardiovascular prevention over a period of 10 years in Swiss men with ED of all seriousness degrees, moderate and severe ED only, or severe ED only can probably avoid 41,564, 35,627, or 21,206 acute CVD events, respectively. Number needed to screen (NNS) to prevent one acute CVD event is 30, 23, and 10, respectively. Costs for the screening intervention are expected to be covered at the seventh, the fifth, and the first year, respectively. Conclusion: Screening and intervention for cardiovascular risk factors in men suffering from ED is a cost-effective tool not only to strengthen prevention and early detection of cardiovascular diseases but also to avoid future cardiovascular events.

The population-attributable fraction for time-dependent exposures and competing risks-A discussion on estimands.

The population-attributable fraction (PAF) quantifies the public health impact of a harmful exposure. Despite being a measure of significant importance, an estimand accommodating complicated time-to-event data is not clearly defined. We discuss current estimands of the PAF used to quantify the public health impact of an internal time-dependent exposure for data subject to competing outcomes. To overcome some limitations, we proposed a novel estimand that is based on dynamic prediction by landmarking. In a profound simulation study, we discuss interpretation and performance of the various estimands and their estimators. The methods are applied to a large French database to estimate the health impact of ventilator-associated pneumonia for patients in intensive care.

A simulation approach for power calculation in large cohort studies based on multistate models.

Realistic power calculations for large cohort studies and nested case control studies are essential for successfully answering important and complex research questions in epidemiology and clinical medicine. For this, we provide a methodical framework for general realistic power calculations via simulations that we put into practice by means of an R-based template. We consider staggered recruitment and individual hazard rates, competing risks, interaction effects, and the misclassification of covariates. The study cohort is assembled with respect to given age-, gender-, and community distributions. Nested case-control analyses with a varying number of controls enable comparisons of power with a full cohort analysis. Time-to-event generation under competing risks, including delayed study-entry times, is realized on the basis of a six-state Markov model. Incidence rates, prevalence of risk factors and prefixed hazard ratios allow for the assignment of age-dependent transition rates given in the form of Cox models. These provide the basis for a central simulation-algorithm, which is used for the generation of sample paths of the underlying time-inhomogeneous Markov processes. With the inclusion of frailty terms into the Cox models the Markov property is specifically biased. An "individual Markov process given frailty" creates some unobserved heterogeneity between individuals. Different left-truncation- and right-censoring patterns call for the use of Cox models for data analysis. p-values are recorded over repeated simulation runs to allow for the desired power calculations. For illustration, we consider scenarios with a "testing" character as well as realistic scenarios. This enables the validation of a correct implementation of theoretical concepts and concrete sample size recommendations against an actual epidemiological background, here given with possible substudy designs within the German National Cohort.

The health and economic burden of bloodstream infections caused by antimicrobial-susceptible and non-susceptible Enterobacteriaceae and Staphylococcus aureus in European hospitals, 2010 and 2011: a multicentre retrospective cohort study.

We performed a multicentre retrospective cohort study including 606,649 acute inpatient episodes at 10 European hospitals in 2010 and 2011 to estimate the impact of antimicrobial resistance on hospital mortality, excess length of stay (LOS) and cost. Bloodstream infections (BSI) caused by third-generation cephalosporin-resistant Enterobacteriaceae (3GCRE), meticillin-susceptible (MSSA) and -resistant Staphylococcus aureus (MRSA) increased the daily risk of hospital death (adjusted hazard ratio (HR) = 1.80; 95% confidence interval (CI): 1.34-2.42, HR = 1.81; 95% CI: 1.49-2.20 and HR = 2.42; 95% CI: 1.66-3.51, respectively) and prolonged LOS (9.3 days; 95% CI: 9.2-9.4, 11.5 days; 95% CI: 11.5-11.6 and 13.3 days; 95% CI: 13.2-13.4, respectively). BSI with third-generation cephalosporin-susceptible Enterobacteriaceae (3GCSE) significantly increased LOS (5.9 days; 95% CI: 5.8-5.9) but not hazard of death (1.16; 95% CI: 0.98-1.36). 3GCRE significantly increased the hazard of death (1.63; 95% CI: 1.13-2.35), excess LOS (4.9 days; 95% CI: 1.1-8.7) and cost compared with susceptible strains, whereas meticillin resistance did not. The annual cost of 3GCRE BSI was higher than of MRSA BSI. While BSI with S. aureus had greater impact on mortality, excess LOS and cost than Enterobacteriaceae per infection, the impact of antimicrobial resistance was greater for Enterobacteriaceae.

Geriatric assessment in multiple myeloma patients: validation of the International Myeloma Working Group (IMWG) score and comparison with other common comorbidity scores.

This first validation of the International Myeloma Working Group geriatric assessment in 125 newly diagnosed multiple myeloma patients was performed using the International Myeloma Working Group score based on age, the Charlson Comorbidity Index and cognitive and physical conditions (Activities of Daily Living / Instrumental Activities of Daily Living) to classify patients as fit, intermediate-fit or frail. We verified the International Myeloma Working Group score's impact on outcome, and whether additional tools complement it. Since our prior analyses determined renal, lung and Karnofsky performance impairment as multivariate risks, and the inclusion of frailty, age and cytogenetics complements this, we included the revised myeloma comorbidity index, the Charlson Comorbidity Index, the Hematopoietic Cell Transplantation-Comorbidity Index and the Kaplan-Feinstein Index in this assessment. Multivariate analysis confirmed cytogenetics, Activities of Daily Living, Instrumental Activities of Daily Living and the Charlson Comorbidity Index as risks: 3-year overall survival for fit, intermediate-fit and frail patients was 91%, 77% and 47%, respectively. Using the Charlson Comorbidity Index, the Hematopoietic Cell Transplantation-Comorbidity Index, the Kaplan-Feinstein Index and the revised Myeloma Comorbidity Index allowed us to define fit and frail patients with distinct progression-free and overall survival rates, with the most pronounced differences evidenced via the International Myeloma Working Group score, the Charlson Comorbidity Index and the revised Myeloma Comorbidity Index. Since the Charlson Comorbidity Index is included in the International Myeloma Working Group score, we propose the latter and the revised Myeloma Comorbidity Index for future frailty measurements. Both are useful instruments for identifying myeloma patients with a geriatric risk profile and have a strong prognostic value for functional decline and overall survival. The study was registered as: (clinicaltrials.gov Identifier: 00003686).

From hypertension control to global cardiovascular risk management: an educational intervention in a cluster-randomised controlled trial.

BACKGROUND: Guidelines on hypertension management recommend adjusting therapeutic efforts in accordance with global cardiovascular risk (CVR) rather than by blood pressure levels alone. However, this paradigm change has not yet arrived in German General Practice. We have evaluated the effect of an educational outreach visit with general practitioners (GPs), encouraging them to consider CVR in treatment decisions for patients with hypertension. METHODS: Prospective cluster-randomised trial comprising 3443 patients with known hypertension treated by 87 GPs. Practices were randomly assigned to complex (A) or simple (B) intervention. Both groups received a guideline by mail; group A also received complex peer intervention promoting the concept of global CVR. Clinical data were collected at baseline and 6-9 months after intervention. Main outcome was improvement of calculated CVR in the predefined subpopulation of patients with a high CVR (10-year mortality ≥5%), but no manifest cardiovascular disease. RESULTS: Adjusted for baseline the follow-up CVR were 13.1% (95% CI 12.6%-13.6%) (A) and 12.6% (95% CI 12.2%-13.1%) (B) with a group difference (A vs. B) of 0.5% (-0.2%-1.1%), p = 0.179. The group difference was -0.05% in patients of GPs familiar with global CVR and 1.1% in patients of GPs not familiar with with global CVR. However, this effect modification was not significant (p = 0.165). Pooled over groups, the absolute CVR reduction from baseline was 1.0%, p < 0.001. The ICC was 0.026 (p = 0.002). Hypertension control (BP <140/90 mmHg) improved in the same subpopulation from 38.1 to 45.9% in the complex intervention group, and from 35.6 to 46.5% in the simple intervention group, with adjusted follow-up control rates of 46.7% (95% CI 40.4%-53.1%) (A) and 46.9% (95% CI 40.3%-53.5% (B) and an adjusted odds ratio (A vs B) of 0.99 (95% CI 0.68-1.45), p = 0.966. CONCLUSIONS: Our complex educational intervention, including a clinical outreach visit, had no significant effect on CVR of patients with known hypertension at high risk compared to a simple postal intervention. TRIAL REGISTRATION: ISRCTN44478543 .

Assessment of the "case-chaos" design as an adjunct to the case-control design.

In 2012, a novel case series method dubbed the "case-chaos" design was proposed as an alternative to case-control studies, whereby controls are artificially created by permutating the exposure information of the cases. Our aim in the current work was to further evaluate the case-chaos method. Using a theoretical example of 2 risk factors, we demonstrated that the case-chaos design yields risk estimations for which the odds ratios obtained for every risk factor are in the same ascending order as the risk factors' exposure prevalences in the case group. Applying the method to data from the European Study of Severe Cutaneous Adverse Reactions (EuroSCAR; 1997-2001), we were not able to obtain sensible results but instead produced results as predicted by our theoretical assessment. We therefore claim that the method is equivalent to declaring risk solely on the basis of prevalences obtained in cases. While the proposers of the case-chaos method view it as a useful adjunct, we show that it cannot produce sensible estimates.

Application of multistate models in hospital epidemiology: advances and challenges.

Survival analysis has established itself as a major statistical technique in medical research. Applications in hospital epidemiology, however, are only beginning to emerge. One reason for this delay is that usually complete follow-up of patients in hospital is feasible. This overview discusses where survival techniques provide additional insight into hospital epidemiology, and where they are, in fact, needed even in the absence of right-censoring.

Valproate-induced metabolic changes in patients with epilepsy: assessment with H-MRS.

PURPOSE: Valproate (VPA) interferes with mitochondrial metabolism causing hyperammonemia, thereby shifting the balance reaction of glutamine (Gln)/glutamate (Glu) toward Gln. In this study we wanted to determine whether metabolic changes could be reproduced in VPA-treated patients with epilepsy and whether the results differed from those known in chronic hepatic encephalopathy (CHE). METHODS: Seven patients with epilepsy pretreated with VPA and seven healthy volunteers were investigated on a 3T-scanner. We performed proton magnetic resonance spectroscopy ((1)H-MRS) using a short echo time point-resolved spectroscopy (PRESS) in the parietal and occipital lobe, respectively. Spectral analysis was performed by LCModel, allowing a separation of Glu and Gln at 3T. Absolute values of myo-Inositol (mI), choline (Cho), creatine (Cr), N-acetyl-aspartate (NAA), glutamine (Gln), glutamate (Glu), and the sum of Gln and Glu (Glx) were calculated. RESULTS: In the parietal lobe, mI was significantly decreased in the patients' group compared to the healthy volunteers. After separation of the signals of Gln and Glu, a significant increase of Gln was observed in the parietal lobe in the patients' group. No significant differences in the occipital spectra could be observed between the groups. DISCUSSION: In VPA-treated patients the alteration of the Glu/Gln ratio differs from that in patients with CHE, where Glx is markedly increased because of an increase in Gln. The expected shift from the biochemical balance reaction of Gln/Glu induced by VPA could be reproduced for the parietal lobe. Significantly reduced mI in the parietal lobe of VPA-treated patients most likely reflects an osmolytic compensation for high Gln.

Assessment of survival prediction models based on microarray data.

MOTIVATION: In the process of developing risk prediction models, various steps of model building and model selection are involved. If this process is not adequately controlled, overfitting may result in serious overoptimism leading to potentially erroneous conclusions. METHODS: For right censored time-to-event data, we estimate the prediction error for assessing the performance of a risk prediction model (Gerds and Schumacher, 2006; Graf et al., 1999). Furthermore, resampling methods are used to detect overfitting and resulting overoptimism and to adjust the estimates of prediction error (Gerds and Schumacher, 2007). RESULTS: We show how and to what extent the methodology can be used in situations characterized by a large number of potential predictor variables where overfitting may be expected to be overwhelming. This is illustrated by estimating the prediction error of some recently proposed techniques for fitting a multivariate Cox regression model applied to the data of a prognostic study in patients with diffuse large-B-cell lymphoma (DLBCL). AVAILABILITY: Resampling-based estimation of prediction error curves is implemented in an R package called pec available from the authors.

Economic impact of community-acquired and nosocomial lower respiratory tract infections in young children in Germany.

Data on the economic burden of lower respiratory tract infections (LRTI) in young children are lacking in Germany. The objective of the cost-of-illness study was to estimate the economic impact of community-acquired LRTI and nosocomial LRTI as well as of infections due to respiratory syncytial virus (RSV), parainfluenza viruses (PIV) and influenza viruses (IV). The economic analysis is part of the PRIDE study, a prospective, multi-centre, population-based epidemiological study on the impact of LRTI in children aged 0 to 36 months in Germany. The analysis includes children with community-acquired infections (1329 cases treated as outpatients, 2039 cases treated as inpatients) and nosocomial infections (90 cases). Medical services consumed were generated by chart abstraction and parental expenses data by telephone interviews within four weeks after physician visit or hospitalisation. Costs were evaluated from following perspectives: third party payer, parent and society. Total costs for outpatient treatment are Euro 123 per LRTI case. Stratified by virus type, total costs per case are Euro 163 (RSV), Euro 100 (PIV) and Euro 223 (IV). Total costs per hospitalised LRTI case amount to Euro 2579. Stratified by virus type, total costs per case are Euro 2772 (RSV), Euro 2374 (PIV) and Euro 2597 (IV). Total costs per nosocomial case are Euro 2814. Economic burden due to LRTI is Euro 213 million annually. It is concluded that treatment of LRTI in children up to age three causes a considerable economic burden in Germany. Presented results are the first data describing the economic burden of LRTI in young children assessed by means of the incidence data for Germany. This cost-of-illness study provides basic data for further decision-making, focusing on the economic assessment of preventive strategies for RSV, PIV and IV infections.

Valproate-induced encephalopathy: assessment with MR imaging and 1H MR spectroscopy.

The anticonvulsant agent valproate (VPA) may cause hyperammonemic encephalopathy. Magnetic resonance imaging (MRI) and proton MR spectroscopic (MRS) findings in a patient with VPA-induced hyperammonemic encephalopathy are described. MRI showed a metabolic-toxic lesion pattern with bilateral T2-hyperintense lesions in the cerebellar white matter and in the globus pallidus. MR spectroscopic findings were indistinguishable from hepatic encephalopathy with severe depletion of myoinositol and choline and with glutamine excess. N-Acetylaspartate levels were moderately decreased. Quantitative MRS gave detailed insight into alterations of brain metabolism in VPA-induced encephalopathy.

Comparison of three-dimensional rotational angiography with digital subtraction angiography in the assessment of ruptured cerebral aneurysms.

BACKGROUND AND PURPOSE: Rotational angiography (RA) and digital subtraction angiography (DSA) together may depict more intracranial aneurysms than DSA alone. We compared the diagnostic value of 3D RA and biplanar DSA in detecting, classifying, and planning treatment for ruptured intracranial aneurysms. METHODS: A total of 53 patients with acute subarachnoid hemorrhage (Hunt and Hess grades I-V) underwent angiography with both methods. DSA was performed in two to six standard projections in every vascular territory. Three-dimensional RA datasets were evaluated by using surface-shaded display and maximum intensity projection. The usefulness of DSA images and 3D datasets in detecting aneurysms (number, configuration) and treatment planning were retrospectively analyzed in a blinded manner. RESULTS: In 42 patients, 56 aneurysms were detected, (one to five per patient; size, 0.6-20.4 mm); no aneurysm was found in 11 patients. RA revealed seven aneurysms not seen at conventional DSA. RA failed to depict one aneurysm visible only in a compression series. Delineation of the aneurysmal neck improved with RA in 71% of cases; the parent vessel and its relationship to adjacent vessels was demonstrated better with RA than with DSA in 45% and 50%, respectively. Endovascular treatment was proposed in nine patients; microsurgical therapy, in 26. In seven patients, both options were rated as being equal. Actual treatment consisted of eight endovascular procedures and 30 neurosurgical operations. Four patients died before therapy. CONCLUSION: Compared with DSA, 3D RA allows more exact depiction of anatomic details that are important in planning surgery and interventional therapy for intracranial aneurysms. RA depicted more aneurysms.