Explained variation and degrees of necessity and of sufficiency for competing risks survival data.

In this contribution, the Schemper-Henderson measure of explained variation for survival outcomes is extended to accommodate competing events (CEs) in addition to events of interest. The extension is achieved by moving from the unconditional and conditional survival functions of the original measure to unconditional and conditional cumulative incidence functions, the latter obtained, for example, from Fine and Gray models. In the absence of CEs, the original measure is obtained as a special case. We define explained variation on the population level and provide two different types of estimates. Recently, the authors have achieved a multiplicative decomposition of explained variation into degrees of necessity and degrees of sufficiency. These measures are also extended to the case of competing risks survival data. A SAS macro and an R function are provided to facilitate application. Interesting empirical properties of the measures are explored on the population level and by an extensive simulation study. Advantages of the approach are exemplified by an Austrian study of breast cancer with a high proportion of CEs.

Can thiamine substitution restore cognitive function in alcohol use disorder?

AIMS: While clinical consequences of thiamine deficiency in alcohol use disorder (AUD) are severe, evidence-based recommendations on dosage, type of administration and duration of thiamine substitution (TS), and its' target levels remain sparse. This study aimed to compare the effect of two best practice TS regimens on thiamine blood levels (i.e. thiamine pyrophosphate, TPP) and cognitive function. METHODS: In 50 patients undergoing in-patient alcohol-withdrawal treatment, TPP levels were determined at baseline and end of weeks 1, 2 and 8 following administration of oral TS (3 × 100 mg/day for 7 days followed by 1 × 100 mg/day thereafter) either with or without preceding intravenous TS (3 × 100 mg/day for 5 days). An extensive psychiatric assessment was conducted at baseline, including an evaluation of AUD severity and depressive symptoms. Additionally, cognitive function and depressive symptoms were repeatedly evaluated. RESULTS: Relevant increases (mean increase by 100.2 nmol/l [CI 76.5-123.8], P < 0.001) in peripheral blood TPP levels were observed in all patients at the end of weeks 1 and 2. Furthermore, no relevant difference between the intravenous and the oral group was found (average difference between increases: 2.3 nmol/l, P = 0.912). Importantly, an association between the 'extent of the response' to TS and the performance in a memory task was revealed in secondary analyses. CONCLUSION: TS was associated with improving cognitive function in patients with AUD, independently of the substitution regime. Thus, in clinical practice, oral TS might be a sufficient but obligatory medication to prevent cognitive decline in AUD in the absence of Wernicke-Korsakoff Syndrome.

Effects of high-intensity interval training on trajectories of gas-exchange measures and blood lactate concentrations during cardiopulmonary exercise tests in cardiac rehabilitation-A randomized controlled trial.

BACKGROUND: The optimal allocation of training time to different intensities in cardiac rehabilitation is still under debate. The objective of this study was to explore whether in a 12-week cardiac rehabilitation program, replacement of two of four usual continuous endurance training (CET) sessions per week with energy expenditure-matched high-intensity interval training (HIIT) affects the trajectories of cardiopulmonary exercise test (CPET) variables such as ventilatory equivalents for O2 (EqO2 ) and CO2 (EqCO2 ), and blood lactate (BLa) during CPET. METHODS: Eighty-two male patients undergoing outpatient cardiac rehabilitation after an acute coronary syndrome were randomized to CET (age [mean ± SD] 61.7 ± 9.8 years, body mass index [BMI] 28.1 ± 3.4) or HIIT+CET (60.0 ± 9.4 years, BMI 28.5 ± 3.5). CPET was performed at baseline, after 6 and after 12 weeks. HIIT consisted of ten 60-s bouts of cycling at an intensity of 100% of the maximal power output (Pmax ) achieved in an incremental test to exhaustion, interspersed with 60 s at 20% Pmax . CET was performed at 60% Pmax with equal duration. Training intensities were adjusted after 6 weeks to account for the training-induced improvement in cardiorespiratory fitness. The entire functions defining the relationship between EqO2 , EqCO2 , and BLa, with power output were modeled using linear mixed models to assess how these trajectories are affected by HIIT. RESULTS: After 6 and 12 weeks, Pmax increased to 112.9% and 117.5% of baseline after CET, and to 113.9% and 124.7% after HIIT+CET (means). Twelve weeks of HIIT+CET elicited greater reductions of EqO2 and EqCO2 than CET alone (p < 0.0001 each) in a range above 100% baseline Pmax . Specifically, at 100% of baseline Pmax , least squares arithmetic mean EqO2 values of CET and HIIT+CET patients were 36.2 versus 33.5. At 115% and 130% of baseline Pmax , EqO2 values were 41.2 versus 37.1 and 47.2 versus 41.7. Similarly, corresponding EqCO2 values of CET and HIIT+CET patients were 32.4 versus 31.0, 34.3 versus 32.2, and 37.0 versus 34.0. Conversely, mean BLa levels (mM) were not differently affected (p = 0.64). At 100%, 115%, and 130% of baseline Pmax after 12 weeks, BLa levels did not differ to a relevant extent (least squares geometric means, 3.56 vs. 3.63, 5.59 vs. 5.61, 9.27 vs. 9.10). CONCLUSIONS: While HIIT+CET reduced ventilatory equivalents more effectively than CET alone, specifically when patients were approaching their maximal performance during CPET, both training strategies were equally effective in reducing BLa levels.

Eye-tracking during simulation-based echocardiography: a feasibility study.

INTRODUCTION: Due to the technical progress point-of-care ultrasound (POCUS) is increasingly used in critical care medicine. However, optimal training strategies and support for novices have not been thoroughly researched so far. Eye-tracking, which offers insights into the gaze behavior of experts may be a useful tool for better understanding. The aim of this study was to investigate the technical feasibility and usability of eye-tracking during echocardiography as well as to analyze differences of gaze patterns between experts and non-experts. METHODS: Nine experts in echocardiography and six non-experts were equipped with eye-tracking glasses (Tobii, Stockholm, Sweden), while performing six medical cases on a simulator. For each view case specific areas of interests (AOI) were defined by the first three experts depending on the underlying pathology. Technical feasibility, participants' subjective experience on the usability of the eye-tracking glasses as well as the differences of relative dwell time (focus) inside the areas of interest (AOI) between six experts and six non-experts were evaluated. RESULTS: Technical feasibility of eye-tracking during echocardiography was achieved with an accordance of 96% between the visual area orally described by participants and the area marked by the glasses. Experts had longer relative dwell time in the case specific AOI (50.6% versus 38.4%, p = 0.072) and performed ultrasound examinations faster (138 s versus 227 s, p = 0.068). Furthermore, experts fixated earlier in the AOI (5 s versus 10 s, p = 0.033). CONCLUSION: This feasibility study demonstrates that eye-tracking can be used to analyze experts and non-experts gaze patterns during POCUS. Although, in this study the experts had a longer fixation time in the defined AOIs compared to non-experts, further studies are needed to investigate if eye-tracking could improve teaching of POCUS.

Topical imiquimod compared with conization to treat cervical high-grade squamous intraepithelial lesions: Multicenter, randomized controlled trial.

OBJECTIVE: In a previous phase II trial, we showed that topical imiquimod (IMQ) therapy is an efficacious treatment for high-grade squamous intraepithelial lesion (HSIL). Aim of the present study was to investigate the non-inferiority of a 16-week topical, self-applied IMQ therapy compared to large loop excision of the transformation zone (LLETZ) in patients diagnosed with HSIL. METHODS: Phase III randomized, controlled, multicenter, open trial performed by Austrian Gynecologic Oncology group. Patients with histologically proven cervical intraepithelial neoplasia (CIN)2 (30 years and older) or CIN3 (18 years and older) and satisfactory colposcopy were randomized to topical IMQ treatment or LLETZ. Successful treatment was defined as negative HPV high-risk test result 6 months after start of the treatment. Secondary endpoints were histological outcome and HPV clearance rates. RESULTS: Within 3 years 93 patients were randomized, received the allocated treatment and were available for ITT analysis. In the IMQ group negative HPV test at 6 months after treatment start was observed in 22/51 (43.1%) of patients compared to 27/42 (64.3%) in the LLETZ group on ITT analysis (rate difference 21.2%-points, 95% two-sided CI: 0.8 to 39.1). In the IMQ group histologic regression 6 months after treatment was observed in 32/51 (63%) of patients and complete histologic remission was observed in 19/51 (37%) of patients. Complete surgical resection was observed in 84% after LLETZ. CONCLUSION: In women with HSIL, IMQ treatment results in lower HPV clearance rates when compared to LLETZ. LLETZ remains the standard for women with HSIL when treatment is required. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01283763, EudraCT number: 2012-004518-32.

Triptans and vascular comorbidity in persons over fifty: Findings from a nationwide insurance database - A cohort study.

OBJECTIVE: To gather information about prescription of triptans and to evaluate whether vascular comorbidity differs in users and nonusers of triptans over the age of 50 years. BACKGROUND: Beyond the age of 50 years, migraine is still common-yet the incidence of vascular disorders increases. Triptans, medications for treating migraine attacks, are vasoconstrictive drugs and contraindicated in persons with vascular disorders. METHODS: Based on a nationwide insurance database from 2011, we compared the prescription of vascular drugs (identified by Anatomical Therapeutic Chemical codes), vascular diagnoses and hospitalizations, between triptan users greater than 50 years and a matched control group. RESULTS: Of the 3,116,000 persons over 50 years, 13,833 (0.44%) had at least one triptan prescription; 11,202 (81%) were women. Thirty percent of the triptan users (13,833/47,336 persons) were over 50 years. Of those over 50 years, 6832 (49.4%) had at least one vascular drug and 870 (6.3%) had at least one inpatient vascular diagnosis; 15.7% (2166 of 13,833 users) overused triptans. We compared triptan-users to 41,400 nonusers, using a 1:3 match. In triptan-users, prescriptions of cardiac therapies and beta blockers were significantly more common (odds ratio [OR] = 1.35, 95% confidence interval [CI] = 1.24-1.47 and OR = 1.19, 95% CI = 1.14-1.25, respectively); whereas prescriptions of calcium channel blockers and renin/angiotensin inhibitors were significantly less common (OR = 0.82, 95% CI = 0.76-0.88 and OR = 0.75, 95% CI = 0.72-0.79, respectively). The prescriptions of antihypertensive, diuretic, and antilipidemic drugs as well as platelet inhibitors and direct thrombin inhibitors did not differ in users and nonusers. Triptan users had significantly more hospital stays (OR = 1.39, 95% CI = 1.33-1.45); however, the number of days spent in the hospital and more importantly the frequency of inpatient vascular diagnoses did not differ statistically significantly between the two groups. CONCLUSION: In persons over 50 years of age, a prescription of triptans is common. Vascular comorbidity is comparable in users and nonusers of triptans showing that triptans are prescribed despite vascular comorbidity and suggesting that triptan use does not increase vascular risk in patients with migraine over the age of 50 years. Nevertheless, regular evaluation for contraindications against triptans and for vascular risk factors is recommended in this age group.

Degrees of necessity and of sufficiency: Further results and extensions, with an application to covid-19 mortality in Austria.

The purpose of this paper is to extend to ordinal and nominal outcomes the measures of degree of necessity and of sufficiency defined by the authors for dichotomous and survival outcomes in a previous paper. A cause, represented by certain values of prognostic factors, is considered necessary for an event if, without the cause, the event cannot develop. It is considered sufficient for an event if the event is unavoidable in the presence of the cause. The degrees of necessity and sufficiency, ranging from zero to one, are simple, intuitive functions of unconditional and conditional probabilities of an event such as disease or death. These probabilities often will be derived from logistic regression models; the measures, however, do not require any particular model. In addition, we study in detail the relationship between the proposed measures and the related explained variation summary for dichotomous outcomes, which are the common root for the developments for ordinal, nominal, and survival outcomes. We introduce and analyze the Austrian covid-19 data, with the aim of quantifying effects of age and other potentially prognostic factors on covid-19 mortality. This is achieved by standard regression methods but also in terms of the newly proposed measures. It is shown how they complement the toolbox of prognostic factor studies, in particular when comparing the importance of prognostic factors of different types. While the full model's degree of necessity is extremely high (0.933), its low degree of sufficiency (0.179) is responsible for the low proportion of explained variation (0.193).

Hypofractionated stereotactic photon radiotherapy of choroidal melanoma: 20-year experience.

BACKGROUND: To evaluate the long-term results after hypofractionated stereotactic photon radiotherapy (SRT) in patients with choroidal melanoma treated between 1997 and 2016. MATERIAL AND METHODS: A total of 335 patients (183 male and 152 female) with choroidal melanoma unsuitable for ruthenium-106 brachytherapy or local resection were treated with linear accelerator-based SRT at the Medical University of Vienna. All patients received five fractions with either 10, 12 or 14 Gy per fraction. A complete ophthalmic examination including visual acuity and measurement of the tumor base and height using standardized A- and B-scan ultrasonography was performed every 3 months in the first 2 years, every 6 months until 5 years and yearly thereafter. Early and late adverse side effects were assessed at every follow-up visit. RESULTS: The median overall follow-up was 78.6 months (39.1 to 113.7 months). Local tumor control was 95.4% after 10 and 12 years, respectively. Fifty-four patients developed metastatic disease, and 31 died during the follow-up. Mean visual acuity decreased from 0.55 Snellen at baseline to 0.05 Snellen at the last individual follow-up. Ischemic retinopathy (192/335cases) and optic neuropathy (174/335cases) were the most common radiogenic side effects, followed by radiogenic cataract (n = 127), neovascular glaucoma (n = 71) and corneal epithelium defects (n = 49). Enucleation was performed in 54 patients mostly due to neovascular glaucoma (n = 41) or tumor recurrence (n = 10) during the study period. The eye retention rate was 79.7% after 10 and 12 years. CONCLUSION: Hypofractionated stereotactic photon radiotherapy showed a high rate of local tumor control for choroidal melanoma and an acceptable rate of radiogenic side effects.

Influence of socioeconomic status on cognitive outcome after childhood arterial ischemic stroke.

AIM: To determine whether socioeconomic status (SES) is a stronger predictor for cognitive outcome after childhood arterial ischemic stroke compared to clinical factors. METHOD: We investigated perceptual reasoning, executive functions, language, memory, and attention in 18 children and adolescents (12 males, six females, median age at testing 13y 4mo, range 7y-17y 5mo) after arterial ischemic stroke; collected sociodemographic information (education of parents, household income); and used clinical information (initial lesion volume, residual lesion volume, age at stroke, time since stroke). Linear regression models were used to investigate the potential influence of SES and clinical parameters on cognitive abilities. RESULTS: SES had a moderate effect on all cognitive outcome parameters except attention by explaining 41.9%, 37.9%, 38.0%, and 22.5% of variability in perceptual reasoning, executive functions, language, and memory respectively. Initial lesion volume was the only clinical parameter that showed moderate importance on cognitive outcome (33.1% and 25.6% of the variability in perceptual reasoning and memory respectively). Overall, SES was a stronger predictor of cognitive outcome than clinical factors. INTERPRETATION: Future paediatric studies aiming at clinical predictors of cognitive outcome should control their analyses for SES in their study participants. The findings of the present study further point to the need for more attention to the treatment of children with low SES. WHAT THIS PAPER ADDS: Socioeconomic status (SES) explains up to 42% of variance in cognitive outcome after childhood arterial ischemic stroke. SES is a stronger predictor of outcome than clinical factors.

Effects of roflumilast on arterial stiffness in COPD (ELASTIC): A randomized trial.

BACKGROUND AND OBJECTIVE: Cardiovascular risk is substantially increased in patients with COPD and can be quantified via arterial stiffness. The PDE-IV inhibitor roflumilast revealed a potential reduction of COPD-related cardiovascular risk. We aimed to investigate the effects of roflumilast on arterial stiffness by quantification of pulse wave velocity (PWV) in stable COPD. METHODS: In this randomized placebo-controlled trial, 80 COPD patients received roflumilast or placebo for 24 weeks. The primary outcome was the change in cf-PWV. Secondary outcomes comprised markers of vascular function (e.g. Aix and RHI), systemic inflammation (e.g. IL-6 and TNF-α) and clinical characteristics of COPD (e.g. CAT and 6MWT). RESULTS: A total of 33 and 34 patients completed the roflumilast and placebo arm, respectively (age, median (IQR): 64.5 (61-69.5) vs 64.5 (56-72) years; FEV1 , median (IQR): 34.5 (25.5-48.6) vs 35.3 (27-46.8) % predicted; 6MWT, median (IQR): 428 (340-558) vs 456 (364-570) m). Change from baseline PWV did not show a significant difference between roflumilast and placebo (+5.0 (95% CI: -2.0 to +13.0) vs 0.0 (95% CI: -7.0 to +7.0)%, P = 0.268). Roflumilast did not improve markers of vascular function or systemic inflammation. We observed a significant improvement in change from baseline 6MWT with roflumilast versus placebo (+53.0 (95% CI: +19.1 to +86.9) vs -0.92 (95% CI: -35.1 to +33.3) m, P = 0.026). CONCLUSION: Our study revealed no beneficial effects of roflumilast on arterial stiffness. Further studies are needed to test a potential improvement of exercise capacity with roflumilast in COPD.

The role of prescription drugs in female overactive bladder syndrome-A population-wide cohort study.

PURPOSE: Overactive bladder (OAB) syndrome has severe effects on quality of life. Certain drugs are known risk factors for OAB but have not been investigated in a population-wide cohort. The objective of this study was to investigate the role of prescription drugs in the etiology of the OAB. METHODS: Retrospective cohort study using a population-wide database of 4 185 098 OAB-naïve women followed Strengthening the Reporting of Observational Studies in Epidemiology guidelines. We investigated the subscription use of anticholinergic medication and 188 chemical substances, which are suspected triggers for OAB (trigger medications [TMs]). We hypothesized a relationship between the prescription for one or more TM and the prescription for anticholinergic medication against OAB (marker medication [MM]). RESULTS: The use of MM in Austria increased from 2009 to 2012 on average by 0.025 percentage points per year (95% confidence interval [CI]: 0.015-0.036). In December 2012, 1 in 123 women filled a prescription for any MM, equaling an average utilization of 0.84%. The relative risk of filling a prescription for a MM 6 months after filling a prescription for a TM was 2.70 (95% CI: 2.64-2.77). All investigated medication classes showed a higher risk for the prescription for MM. Medication from classes "genitourinary system and sex hormones" and "systemic anti-infectives" caused the highest increase in risk (109% and 89%, respectively). Prescriptions for class "cardiovascular system" caused the lowest increase in the risk (15%). CONCLUSION: Certain prescription medications are a significant risk factor for the need to take anticholinergic medication as a consequence.

Circulating Myostatin Levels Decrease Transiently after Implantation of a Hip Hemi-Arthroplasty.

INTRODUCTION: Muscle and bone metabolism are both important for the healing of fractures and the regeneration of injured muscle tissue. The aim of this investigation was to evaluate myostatin and other regulating factors in patients with hip fractures who underwent hemi-arthroplasty. METHODS: Serum levels of myostatin (MSTN), follistatin (FSTN), dickkopf-1 (Dkk1), and periostin (PSTN) as well as markers of bone turnover were evaluated in patients with hip fractures before surgery and twice in the 2 weeks after surgery. These parameters were also evaluated in age- and gender-matched subjects without major musculoskeletal injury. RESULTS: MSTN was transiently reduced; its opponent FSTN was transiently increased. Dkk1, the negative regulator of bone mass, and PSTN, a marker of subperiosteal bone formation, increased after surgery. With regard to markers of bone turnover, resorption was elevated during the entire period of observation whereas the early bone formation marker N-terminal propeptide of type I collagen was elevated 12 days after surgery. CONCLUSIONS: Unexpectedly, MSTN, a negative regulator of muscle growth, was reduced after surgery compared with before surgery. As musculoskeletal markers are altered during bone healing, they do not reflect general bone metabolism after fracture or joint arthroplasty. This is important because many elderly patients receive treatment for osteoporosis.

Quantifying degrees of necessity and of sufficiency in cause-effect relationships with dichotomous and survival outcomes.

We suggest measures to quantify the degrees of necessity and of sufficiency of prognostic factors for dichotomous and for survival outcomes. A cause, represented by certain values of prognostic factors, is considered necessary for an event if, without the cause, the event cannot develop. It is considered sufficient for an event if the event is unavoidable in the presence of the cause. Necessity and sufficiency can be seen as the two faces of causation, and this symmetry and equal relevance are reflected by the suggested measures. The measures provide an approximate, in some cases an exact, multiplicative decomposition of explained variation as defined by Schemper and Henderson for censored survival and for dichotomous outcomes. The measures, ranging from zero to one, are simple, intuitive functions of unconditional and conditional probabilities of an event such as disease or death. These probabilities often will be derived from logistic or Cox regression models; the measures, however, do not require any particular model. The measures of the degree of necessity implicitly generalize the established attributable fraction or risk for dichotomous prognostic factors and dichotomous outcomes to continuous prognostic factors and to survival outcomes. In a setting with multiple prognostic factors, they provide marginal and partial results akin to marginal and partial odds and hazard ratios from multiple logistic and Cox regression. Properties of the measures are explored by an extensive simulation study. Their application is demonstrated by three typical real data examples.

Explained variation in shared frailty models.

Explained variation measures the relative gain in predictive accuracy when prediction based on prognostic factors replaces unconditional prediction. The factors may be measured on different scales or may be of different types (dichotomous, qualitative, or continuous). Thus, explained variation permits to establish a ranking of the importance of factors, even if predictive accuracy is too low to be helpful in clinical practice. In this contribution, the explained variation measure by Schemper and Henderson (2000) is extended to accommodate random factors, such as center effects in multicenter studies. This permits a direct comparison of the importance of centers and of other prognostic factors. We develop this extension for a shared frailty Cox model and provide an SAS macro and an R function to facilitate its application. Interesting empirical properties of the variation explained by a random factor are explored by a Monte Carlo study. Advantages of the approach are exemplified by an Austrian multicenter study of colon cancer.

An unjustified benefit: immortal time bias in the analysis of time-dependent events.

Immortal time bias is a problem arising from methodologically wrong analyses of time-dependent events in survival analyses. We illustrate the problem by analysis of a kidney transplantation study. Following patients from transplantation to death, groups defined by the occurrence or nonoccurrence of graft failure during follow-up seemingly had equal overall mortality. Such naive analysis assumes that patients were assigned to the two groups at time of transplantation, which actually are a consequence of occurrence of a time-dependent event later during follow-up. We introduce landmark analysis as the method of choice to avoid immortal time bias. Landmark analysis splits the follow-up time at a common, prespecified time point, the so-called landmark. Groups are then defined by time-dependent events having occurred before the landmark, and outcome events are only considered if occurring after the landmark. Landmark analysis can be easily implemented with common statistical software. In our kidney transplantation example, landmark analyses with landmarks set at 30 and 60 months clearly identified graft failure as a risk factor for overall mortality. We give further typical examples from transplantation research and discuss strengths and limitations of landmark analysis and other methods to address immortal time bias such as Cox regression with time-dependent covariables.

Pre-fibrotic/early primary myelofibrosis vs. WHO-defined essential thrombocythemia: The impact of minor clinical diagnostic criteria on the outcome of the disease.

The 2016 revised WHO criteria for the diagnosis of pre-fibrotic/early primary myelofibrosis (pre-PMF) require at least one of the following four borderline expressed minor clinical criteria: anemia, leukocytosis, elevated lactate dehydrogenase and splenomegaly. In this study, we evaluated the relative frequency of these four criteria in a group of 170 pre-PMF patients and compared them to 225 ET cases. More than 91% of pre-PMF cases showed one or more of these features required for diagnosis, by contrast with only 48% of ET patients. According to clinical data the cumulative risk of progression to advanced/overt PMF in pre-PMF was 36.9% after 15 years. After fitting cox regression models to analyze the impact of the minor criteria on overall survival, only leukocytosis remained as a significant predictor of survival in both pre-PMF and ET. Molecular characterization showed differences in survival in pre-PMF but not ET, with CALR being a more favorable mutation than JAK2. The different outcome of pre-PMF versus ET and associated molecular genetic data supports the concept of two different entities, rather than a continuum of the same disease. Although slightly less than 50% of ET patients also show one or more minor clinical criteria, accurate distinction between ET and pre-PMF is possible by following an integrated approach including histomorphological diagnosis and presence of minor clinical criteria.

Two-group comparisons of zero-inflated intensity values: the choice of test statistic matters.

MOTIVATION: A special characteristic of data from molecular biology is the frequent occurrence of zero intensity values which can arise either by true absence of a compound or by a signal that is below a technical limit of detection. RESULTS: While so-called two-part tests compare mixture distributions between groups, one-part tests treat the zero-inflated distributions as left-censored. The left-inflated mixture model combines these two approaches. Both types of distributional assumptions and combinations of both are considered in a simulation study to compare power and estimation of log fold change. We discuss issues of application using an example from peptidomics.The considered tests generally perform best in scenarios satisfying their respective distributional assumptions. In the absence of distributional assumptions, the two-part Wilcoxon test or the empirical likelihood ratio test is recommended. Assuming a log-normal subdistribution the left-inflated mixture model provides estimates for the proportions of the two considered types of zero intensities. AVAILABILITY: R code is available at http://cemsiis.meduniwien.ac.at/en/kb/science-research/software/

First evidence of Beauvais' hypothesis in a plant model.

INTRODUCTION: Beauvais presented the application of a so-called 'quantum-like model of homeopathy' by introducing the idea of a type of randomization/unblinding which he called 'in situ'. He predicted that randomized studies based on this type of randomization/unblinding lead to more pronounced effects in placebo controlled randomized homeopathic trials. We designed an experiment regarding wheat germination and stalk length to investigate Beauvais' idea of 'in situ randomization/unblinding' using a homeopathic dilution of sulphur (LM VI) as compared to placebo as well as to water. AIM AND METHOD: The primary aim of this double-blind randomized controlled experiment was to investigate whether there are differences of 'in situ randomization/unblinding' vs 'central randomization/unblinding' with respect to the effect of a homeopathic substance compared to placebo. The secondary aim of our study was to examine possible differences between the sulphur and the placebo group in the 'in situ' arm regarding germination and/or stalk growth of wheat seedlings measured after a seven days exposure. Wheat was treated either with sulphur LM VI, placebo, or water. The wheat grains were placed on glass lids and treatment was performed following the 'in situ randomization/unblinding' as well as 'central randomization/unblinding' method. Germination was measured and classified into three categories. RESULTS: Under 'in situ' randomization/unblinding the odds of a seed not to germinate is 40% lower if treated with sulphur compared to placebo (p=0.004). In contrast, these odds are practically equal in the 'central' meta-group (OR=1.01, p=0.954). Under 'in situ' randomization/unblinding the odds of a seed to germinate with a length ≥1mm is practically equal if treated with sulphur or with placebo (OR=0.96, p=0.717). In contrast, these odds are 21% higher under sulphur compared to placebo in the 'central' meta-group (OR=1.21, p=0.062). In summary, we found a sulphur effect that is significantly different between 'in situ' and 'central' randomization/unblinding relating to all three stages of germination.

The Austrian Toxoplasmosis Register, 1992-2008.

BACKGROUND: We aimed to determine the incidence of primary gestational infections with Toxoplasma gondii and congenital toxoplasmosis in Austria, a country with a nationwide prenatal serological screening program since 1974. METHODS: We analyzed retrospective data from the Austrian Toxoplasmosis Register of pregnant women with Toxoplasma infection and their offspring with births between 1992 and 2008, identified by the prenatal mandatory screening program. Treatment was administered to women from diagnosis of a Toxoplasma infection until delivery. Infected infants were treated up to 1 year of life routinely. Clinical manifestations in infected infants were monitored at least for 1 year and documented in the register. RESULTS: The Austrian Toxoplasmosis Register included 2147 pregnant women with suspected Toxoplasma infection. Annually, 8.5 per 10 000 women acquired Toxoplasma infection during pregnancy, and 1.0 per 10 000 infants had congenital toxoplasmosis (13% mean transmission rate). Our data showed that women treated according to the Austrian scheme had a 6-fold decrease in the maternofetal transmission rate compared to women without treatment. CONCLUSIONS: Results from the Austrian Toxoplasmosis Register show the efficiency of the prenatal screening program. Our results are of clinical relevance for infants, healthcare systems, and policy makers to consider preventive Toxoplasma screening as a potential tool to reduce the incidence of congenital toxoplasmosis.

Overexpression of uridine diphospho glucuronosyltransferase 2B17 in high-risk chronic lymphocytic leukemia.

Uridine diphospho glucuronosyltransferase 2B17 (UGT2B17) glucuronidates androgens and xenobiotics including certain drugs. The UGT2B17 gene shows a remarkable copy number variation (CNV), which predisposes for solid tumors and influences drug response. Here, we identify a yet undescribed UGT2B17 mRNA overexpression in poor-risk chronic lymphocytic leukemia (CLL). In total, 320 CLL patients and 449 healthy donors were analyzed. High (above median) UGT2B17 expression was associated with established CLL poor prognostic factors and resulted in shorter treatment-free and overall survival (hazard ratio ([death] 2.18; 95% CI 1.18-4.01; P = .013). The prognostic impact of mRNA expression was more significant than that of UGT2B17 CNV. UGT2B17 mRNA levels in primary CLL samples directly correlated with functional glucuronidation activity toward androgens and the anticancer drug vorinostat (R > 0.9, P < .001). After treatment with fludarabine containing regimens UGT2B17 was up-regulated particularly in poor responders (P = .030). We observed an exclusive involvement of the 2B17 isoform within the UGT protein family. Gene expression profiling of a stable UGT2B17 knockdown in the CLL cell line MEC-1 demonstrated a significant involvement in key cellular processes. These findings establish a relevant role of UGT2B17 in CLL with functional consequences and potential therapeutic implications.