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Background/objective: The use of natalizumab (NAT) in multiple sclerosis (MS) may be complicated by progressive multifocal leukoencephalopathy (PML), a rare and life-threatening opportunistic brain infection. We aimed to analyze the course of MS after PML recovery together with the long-term outcome of NAT-associated PML (NAT-PML) in Austria. Methods: Retrospective study based on identification of cases in the nationwide Austrian MS treatment registry (AMSTR) and MS centers with review of patient records. The expanded disability status scale (EDSS) was used to measure neurological disability and outcome. Results: As of December 2022, we identified 15 NAT-PML cases in Austria; only 20% occurred after 2016, when increased vigilance commenced. Two patients did not survive acute PML, and an additional patient died five years later, yielding a mortality rate of 20%. Seizures occurred exclusively in patients with pronounced EDSS increase. Gadolinium (Gd)-enhancement on brain magnetic resonance imaging (MRI) on PML suspicion was associated with minor changes of post-PML neurological disability. Long-term follow-up of up to 132 months (median 76 months) was available in 11/15. The overall median EDSS increased from 3.5 at pre-PML to 6.5 at the last assessment. Regarding inflammatory MS-related disease activity during the observation period, one single individual experienced an MS relapse and another patient had two Gd-enhancing brain lesions. Three patients converted to progressive MS within three years from PML and the EDSS further increased in 6/11. Conclusions: The number of NAT-PML cases is decreasing over time. While many patients accumulated severe persistent neurological deficits compared to pre-PML, inflammatory MS-related disease activity after PML recovery was rare. [ABSTRACT FROM AUTHOR]

Rank-based methods are frequently used in the life sciences, and in the empirical sciences in general. Among the best-known examples of nonparametric rank-based tests are the Wilcoxon-Mann-Whitney test and the Kruskal–Wallis test. However, recently, potential pitfalls and paradoxical results pertaining to the use of traditional rank-based procedures for more than two samples have been highlighted, and the so-called pseudo-ranks have been proposed as a remedy for this type of problems. The aim of the present article is twofold: First, we show that pseudo-ranks might also behave counterintuitively when splitting up groups. Second, since the use of pseudo-ranks leads to a slightly different interpretation of the results, we provide some guidance regarding the decision for one or the other approach, in particular with respect to interpretability and generalizability of the findings. It turns out that the choice of the reference distribution, to which the individual groups are compared, is crucial. The practically relevant implications of these aspects are illustrated by a discussion of a dataset from epilepsy research. Summing up, one should decide based on thorough case-by-case considerations whether ranks or pseudo-ranks are appropriate. [ABSTRACT FROM AUTHOR]

When testing for superiority in a parallel-group setting with a continuous outcome, adjusting for covariates is usually recommended. For this purpose, the analysis of covariance is frequently used, and recently several exact and approximate sample size calculation procedures have been proposed. However, in case of multiple covariates, the planning might pose some practical challenges and pitfalls. Therefore, we propose a method, which allows for blinded re-estimation of the sample size during the course of the trial. Simulations confirm that the proposed method provides reliable results in many practically relevant situations, and applicability is illustrated by a real-life data example. [ABSTRACT FROM AUTHOR]

It is well known that the standard F test is severely affected by heteroskedasticity in unbalanced analysis of covariance models. Currently available potential remedies for such a scenario are based on heteroskedasticity-consistent covariance matrix estimation (HCCME). However, the HCCME approach tends to be liberal in small samples. Therefore, in the present paper, we propose a combination of HCCME and a wild bootstrap technique, with the aim of improving the small-sample performance. We precisely state a set of assumptions for the general analysis of covariance model and discuss their practical interpretation in detail, since this issue may have been somewhat neglected in applied research so far. We prove that these assumptions are sufficient to ensure the asymptotic validity of the combined HCCME-wild bootstrap analysis of covariance. The results of our simulation study indicate that our proposed test remedies the problems of the analysis of covariance F test and its heteroskedasticity-consistent alternatives in small to moderate sample size scenarios. Our test only requires very mild conditions, thus being applicable in a broad range of real-life settings, as illustrated by the detailed discussion of a dataset from preclinical research on spinal cord injury. Our proposed method is ready-to-use and allows for valid hypothesis testing in frequently encountered settings (e.g., comparing group means while adjusting for baseline measurements in a randomized controlled clinical trial). [ABSTRACT FROM AUTHOR]

Analyses of the Journal Impact Factor (JIF) have grown to be a major topic in scientometric literature. Despite widespread and justified critique concerning the JIF and its application, the size of a journal as a predictor for its longitudinal variability–or stability–on a long-term level has not yet comprehensively been analyzed. This study aims to provide robust evidence for an association between JIF variability and the size of journals, expressed by the number of published articles (citable items). For this purpose, the complete set of journals included in the Incite Journal Citation Reports (JCR) with an JIF in the 2017 JCR edition (n = 8750) were analyzed for the association between journal size and longitudinal JIF dynamics. Our results, based on n = 4792 journals with a complete JIF data set over the timespan of 12 annual JIF changes show that larger journals publishing more citable items experience smaller annual changes of the JIF than smaller journals, yet with this association being reversed for journals with a very large number of total cites. Consequently and in accordance with the genuine intention of the JIF to serve as a basis for decisions on journal subscriptions, evaluation of current changes of the JIF have to be accompanied by consideration of the journal's size in order to be accurate and sensible. [ABSTRACT FROM AUTHOR]

Aim: Prevalence and incidence of spinal cord injury (SCI) are low. However, sample sizes have not been systematically examined yet, although this might represent useful information for study planning and power considerations. Therefore, our objective was to determine the median sample size in clinical trials on SCI individuals. Moreover, within small‐sample size studies, statistical methods and awareness of potential problems regarding small samples were examined. Methods: We systematically reviewed all studies on human SCI individuals published between 2014 and 2015, where the effect of an intervention on one or more health‐related outcomes was assessed by means of a hypothesis test. If at least one group had a size <20, the study was classified as a small sample size study. PubMed was searched for eligible studies; subsequently, data on sample sizes and statistical methods were extracted and summarized descriptively. Results: Out of 8897 studies 207 were included. Median total sample size was 18 (range 4‐582). Small sample sizes were found in 167/207 (81%) studies, resulting limitations and implications for statistical analyses were mentioned in 109/167 (65%) studies. Conclusions: Although most recent SCI trials have been conducted with small samples, the consequences on statistical analysis methods and the validity of the results are rarely acknowledged. [ABSTRACT FROM AUTHOR]

Summary: Objective: To pool observational data on the routine use of perampanel to obtain information on real‐world outcomes and data in populations typically underrepresented in clinical trials. Methods: Individual‐level data of people with epilepsy treated with perampanel at 45 European centers were merged into a single dataset. Prespecified outcomes were: 1‐year retention rate, 1‐year seizure freedom rate (duration ≥6 months), and incidence of treatment‐emergent adverse events (TEAEs). In addition, relationships were explored with logistic regression analyses. Results: The full analysis set comprised 2396 people: 95% had focal seizures; median epilepsy duration was 27 years; median number of concomitant antiepileptic drugs (AEDs) was 2; and median prior AEDs was 6. One‐year retention rate was 48% (1117/2332; 95% confidence interval [CI] 46‐50%), and 1‐year seizure‐free rate (≥6‐month duration) was 9.2% (74/803; 95% CI 7‐11%). Median treatment duration was 11.3 months (1832 patient‐years); median dose was 8 mg. In 388 individuals with available data at 3, 6, and 12 months, responder rates were 42%, 46%, and 39%, respectively. During the first year, TEAEs were reported in 68% of participants (1317/1497; 95% CI 66‐70%). Logistic regression found higher age at perampanel initiation was associated with higher seizure‐free rate, and higher number of prior AEDs with lower seizure‐free rate and lower rates of somatic TEAEs. In 135 individuals aged ≥65 years, 1‐year retention rate was 48% and seizure‐free rate was 28%. Significance: Across a large, treatment‐resistant population, add‐on perampanel was retained for ≥1 year by 48% of individuals, and 9% were seizure‐free for ≥6 months. TEAEs were in line with previous reports in routine clinical use, and less frequent than in the clinical trial setting. No new or unexpected TEAEs were seen. Despite the limitations of observational studies, our data indicate that some individuals may derive a marked benefit from the use of perampanel. [ABSTRACT FROM AUTHOR]

Objective Studies using relative measures, such as standardized mortality ratios, have shown that patients with epilepsy have an increased mortality. Reports on more direct and absolute measure such as life expectancy are sparse. We report potential years lost and how life expectancy has changed over 40 years in a cohort of patients with newly diagnosed epilepsy. Methods We analyzed life expectancy in a cohort of adult patients diagnosed with definite epilepsy between 1970 and 2010. Those with brain tumor as cause of epilepsy were excluded. By retrospective probabilistic record linkage, living or death status was derived from the national death registry. We estimated life expectancy by a Weibull regression model using gender, age at diagnosis, epilepsy etiology, and year of diagnosis as covariates at time of epilepsy diagnosis, and 5, 10, 15, and 20 years after diagnosis. Results were compared to the general population, and 95% confidence intervals are given. Results There were 249 deaths (105 women, age at death 19.0-104.0 years) in 1,112 patients (11,978.4 person-years, 474 women, 638 men). A substantial decrease in life expectancy was observed for only a few subgroups, strongly depending on epilepsy etiology and time of diagnosis: time of life lost was highest in patients with symptomatic epilepsy diagnosed between 1970 and 1980; the impact declined with increasing time from diagnosis. Over half of the analyzed subgroups did not differ significantly from the general population. This effect was reversed in the later decades, and life expectancy was prolonged in some subgroups, reaching a maximum in those with newly diagnosed idiopathic and cryptogenic epilepsy between 2001 and 2010. Significance Life expectancy is reduced in symptomatic epilepsies. However, in other subgroups, a prolonged life expectancy was found, which has not been reported previously. Reasons may be manifold and call for further study. [ABSTRACT FROM AUTHOR]

We have read with much interest the paper entitled "Statistical Efficiency of Patient Data in Randomized Clinical Trials of Epilepsy Treatments" by Romero and Goldenholz.1 We highly appreciate the editorial decision to publish articles about methodological topics too. STATISTICAL MODELS The efforts of the authors to adequately generate seizure diary data (Sections 2.2 and 2.5) are much appreciated. [Extracted from the article]

Purpose: Risk calculators (RC) aim to improve prebiopsy risk stratification. Their latest versions now include multiparametric magnetic resonance imaging (mpMRI) findings. For their implementation into clinical practice, critical external validations are needed. Methods: We retrospectively analyzed the patient data of 554 men who underwent ultrasound-guided targeted and systematic prostate biopsies at 2 centers. We validated the mpMRI-RCs of Radtke et al. (RC-R) and Alberts et al. (RC-A), previously shown to predict prostate cancer (PCa) and clinically significant PCa (csPCa). We assessed these RCs' prediction accuracy by analyzing the receiver-operating characteristics (ROC) curve and evaluated their clinical utility using Decision Curve Analysis (DCA), including Net-Benefit and Net-Reduction curves. Results: We found that the Area Under the ROC Curve (AUC) for predicting PCa was 0.681 [confidence interval (CI) 95% 0.635–0.727] for RC-A. The AUCs for predicting csPCa were 0.635 (CI 95% 0.583–0.686) for RC-A and 0.676 (CI 95% 0.627–0.725) for RC-R. For example, at a risk threshold of 12%, RC-A needs to assess 334 and RC-R 500 patients to detect one additional true positive PCa or csPCa patient, respectively. At the same risk threshold of 12%, RC-A only needs to assess 6 and RC-R 16 patients to detect one additional true negative PCa or csPCa patient. Conclusion: The mpMRI-RCs, RC-R and RC-A, are robust and valuable tools for patient counseling. Although they do not improve PCa and csPCa detection rates by a clinically meaningful margin, they aid in avoiding unnecessary prostate biopsies. Their implementation could reduce overdiagnosis and reduce PCa screening morbidity. [ABSTRACT FROM AUTHOR]

The concept of stationary scalar subdivision being interpolatory does not always extend immediately to the vector valued case. We introduce the concepts of interpolating and data preserving vector subdivision schemes and discuss how these concepts are related. We also present two examples. [Copyright &y& Elsevier]

A market mechanism is basically driven by a superposition of decisions of many agents optimizing their profit. The macroeconomic price dynamic is a consequence of the cumulated excess demand/supply created on this micro level. The behavior analysis of a small number of agents is well understood through the game theory. In case of a large number of agents one may use the limiting case that an individual agent does not have an influence on the market, which allows the aggregation of agents by statistic methods. In contrast to this restriction, we can omit the assumption of an atomic market structure, if we model the market through a multi-agent approach. The contribution of the mathematical theory of neural networks to the market price formation is mostly seen on the econometric side: neural networks allow the fitting of high dimensional nonlinear dynamic models. Furthermore, in our opinion, there is a close relationship between economics and the modeling ability of neural networks because a neuron can be interpreted as a simple model of decision making. With this in mind, a neural network models the interaction of many decisions and, hence, can be interpreted as the price formation mechanism of a market. [ABSTRACT FROM AUTHOR]

The Schwartz space of rapidly decaying test functions is characterized by the decay of the short-time Fourier transform or cross-Wigner distribution. Then a version of Hardy's theorem is proved for the short-time Fourier transform and for the Wigner distribution. [ABSTRACT FROM AUTHOR]

AbstractBackgroundObjectivesMethodsResultsConclusionUnderstanding the dynamics of SARS-CoV-2 reinfections is crucial for public health policy, vaccine development, and long-term disease management. However, data on reinfections in the general population remains scarce.This study aimed to investigate SARS-CoV-2 antibody dynamics among Austrian blood donors, representing healthy adults, over two years following primary infection and to evaluate the reinfection risk.117,895 blood donations were analysed for SARS-CoV-2 total anti-N levels from June 2020 to December 2023. We examined anti-N and anti-S antibody dynamics and in vitro functionality in 230 study participants at five defined times during 24 months, assessing associations with demographics, vaccination status, and reinfection awareness.The seroprevalence of SARS-CoV-2 infection-derived anti-N antibodies increased over time, reaching 90% by February 2023 and remaining at that level since then. According to serological screenings, we found an 88% reinfection rate, which is in contrast to participants’ reports indicating a reinfection rate of 59%. Our data further reveal that about 26% of reinfections went completely unnoticed. Antibody dynamics were independent of age, sex, and ABO blood group. Interestingly, individuals with multiple reinfections reported symptoms more frequently during their primary infection. Our results further show that vaccination modestly affected reinfection risk and disease course.SARS-CoV-2 reinfections were uncommon until the end of 2021 but became common with the advent of Omicron. This study highlights the underestimation of reinfection rates in healthy adults and underscores the need for continued surveillance, which is an important support for public health policies and intervention strategies. [ABSTRACT FROM AUTHOR]

Background/Objectives: Dental rehabilitation after extended tumour resection and jaw reconstruction is challenging. The present study aimed to report the prosthetic outcome and quality of life (QoL) in patients with head and neck cancer (HNC) after microvascular alveolar ridge reconstruction. Methods: The prosthetic outcomes of all consecutive patients with HNC who underwent microvascular alveolar ridge reconstruction at the University Hospital Salzburg between 2011 and 2018 were investigated. Oral health-related QoL (OHrQoL) and overall QoL were assessed using the validated Oral Health Impact Profile-49 (OHIP-49) and Short Form-36 questionnaires. Results: During the study period, 115 consecutive patients with head and neck cancer underwent microvascular jaw reconstruction. Among them, 23.3% and 27.4% received conventional tissue-borne prostheses and implant-supported prostheses, respectively, while 48.7% did not undergo dental rehabilitation. The prosthetic outcome was not associated with tumour stage (p = 0.32). Oral health-related quality of life (OHrQoL) was best in patients with implant-supported dental rehabilitation (OHIP-49 median score = 7) and worst in those with conventional removable dentures (OHIP-49 median score = 54). The corresponding OHIP-49 median score for patients who could not undergo dental rehabilitation was 30.5. All Short Form-36 subscale scores were equal to or higher than the malignancy norm scores. Conclusions: After microvascular jaw reconstruction, approximately one-third of the HNC patients received adequate implant-supported dental rehabilitation. However, the risk of dental rehabilitation failure was 50%. The different prosthetic outcomes affected OHrQoL, but not overall QoL. [ABSTRACT FROM AUTHOR]

Objective: Status epilepticus (SE) is frequently associated with peri‐ictal magnetic resonance imaging (MRI) abnormalities (PMA). However, the anatomical distribution of these alterations has not been systematically studied. The aim of this study was to assess the localization patterns of PMA in patients with SE. Methods: In this prospective case–control study, we compared the distribution and combinations of diffusion‐restricted PMA to diffusion‐restricted lesions caused by other neurological conditions. All patients of the SE group and the control group underwent MRI including a diffusion‐weighted imaging sequence. Patients with SE were imaged within 48 h after its onset. Results: We enrolled 201 patients (51 with SE and 150 controls). The most frequent locations of PMA in SE were cortex (25/51, 49%), followed by hippocampus (20/51, 39%) and pulvinar of thalamus (10/51, 20%). In the control group, the cortex was involved in 80 of 150 (53%), white matter in 53 of 150 (35%), and basal ganglia in 33 of 150 (22%). In the control group, the pulvinar of thalamus was never affected and hippocampal structures were rarely involved (7/150, 5%). Involvement of the pulvinar of thalamus and the hippocampus had high specificity for SE at 100% (95% confidence interval [CI] = 98–100) and 95% (95% CI = 91–98), respectively. The sensitivity, however, was low for both locations (pulvinar of thalamus: 20%, 95% CI = 10–33; hippocampus: 39%, 95% CI = 26–54). Significance: Diffusion‐restricted MRI lesions observed in the pulvinar of thalamus and hippocampus are strongly associated with SE. These changes may help physicians in diagnosing SE‐related changes on MRI in an acute setting, especially in cases of equivocal clinical and electroencephalographic manifestations of SE. [ABSTRACT FROM AUTHOR]

The spontaneous eye blink rate (EBR) has been linked to different cognitive processes and neurobiological factors. It has also been proposed as a putative index for striatal dopaminergic function. While estradiol is well-known to increase dopamine levels through multiple mechanisms, no study up to date has investigated whether the EBR changes across the menstrual cycle. This question is imperative however, as women have sometimes been excluded from studies using the EBR due to potential effects of their hormonal profile. Fifty-four women were tested for spontaneous EBR at rest in three different phases of their menstrual cycle: during menses (low progesterone and estradiol), in the pre-ovulatory phase (when estradiol levels peak and progesterone is still low), and during the luteal phase (high progesterone and estradiol). No significant differences were observed across the menstrual cycle and Bayes factors show strong support for the null hypothesis. Instead, we observed high intra-individual consistency of the EBR in our female sample. Accordingly, we strongly encourage including female participants in EBR studies, regardless of their cycle phase. [ABSTRACT FROM AUTHOR]

In applied research, it is often sensible to account for one or several covariates when testing for differences between multivariate means of several groups. However, the "classical" parametric multivariate analysis of covariance (MANCOVA) tests (e.g. , Wilks' Lambda) are based on quite restrictive assumptions (homoscedasticity and normality of the errors), which might be difficult to justify. Furthermore, existing potential remedies (e.g. , heteroskedasticity-robust approaches) become inappropriate in cases where the covariance matrices are singular or close to singular. Nevertheless, such scenarios are frequently encountered in the life sciences and other fields, when, for example, in the context of standardized assessments, a summary performance measure as well as its corresponding subscales are analyzed. Moreover, computational issues may also lead to singular covariance structures. In the present manuscript, we consider a general MANCOVA model, allowing for potentially heteroskedastic and even singular covariance matrices as well as non-normal errors. We combine heteroskedasticity-consistent covariance matrix estimation methods with our proposed modified MANCOVA ANOVA-type statistic (MANCATS) and apply two different bootstrap approaches. We provide the proofs of the asymptotic validity of the respective testing procedures as well as the results from an extensive simulation study, which indicate that especially the parametric bootstrap version of the MANCATS outperforms its competitors in most small-sample scenarios, both in terms of type I error rates and power. These considerations are further illustrated and substantiated by examining real-life data from standardized achievement tests. Yet, for large sample sizes, Wald-type approaches are an attractive alternative option. Moreover, the choice between Wald-type and MANCATS-based tests might depend on the particular setting (e.g. , the covariance structure, or the alternative under consideration). [ABSTRACT FROM AUTHOR]

Background: The conduct of rare disease clinical trials is still hampered by methodological problems. The number of patients suffering from a rare condition is variable, but may be very small and unfortunately statistical problems for small and finite populations have received less consideration. This paper describes the outline of the iSTORE project, its ambitions, and its methodological approaches. Methods: In very small populations, methodological challenges exacerbate. iSTORE's ambition is to develop a comprehensive perspective on natural history course modelling through multiple endpoint methodologies, subgroup similarity identification, and improving level of evidence. Results: The methodological approaches cover methods for sound scientific modeling of natural history course data, showing similarity between subgroups, defining, and analyzing multiple endpoints and quantifying the level of evidence in multiple endpoint trials that are often hampered by bias. Conclusion: Through its expected results, iSTORE will contribute to the rare diseases research field by providing an approach to better inform about and thus being able to plan a clinical trial. The methodological derivations can be synchronized and transferability will be outlined. [ABSTRACT FROM AUTHOR]

Background: High-performance time-of-flight (TOF) positron emission tomography (PET) systems have the capability for rapid data acquisition while preserving diagnostic image quality. However, determining a reliable and clinically applicable cut-off of the acquisition time plays an important role in routine practice. This study aimed to assess the diagnostic equivalence of short acquisition time of 57 with routine 75 seconds per bed position (s/BP) of [18F]-fluoro-deoxy-glucose (FDG) PET. Phantom studies applying EARL criteria suggested the feasibility of shortened acquisition time in routine clinical imaging by 3D TOF PET/CT scanners. Ninety-six patients with melanoma, lung or head and neck cancer underwent a standard whole-body, skull base-to-thigh or vertex-to-thigh [18F]-FDG PET/CT examination using the 3D TOF Ingenuity TF PET/CT system (Philips, Cleveland, OH). The [18F]-FDG activity applied was equal to 4MBq per kg body weight. Retrospectively, PET list-mode data were used to calculate a second PET study per patient with a reduced acquisition time of 57 s instead of routine 75 s/BP. PET/CT data were reconstructed using a 3D OSEM TOF algorithm. Blinded patient data were analysed by two nuclear medicine physicians. The number of [18F]-FDG-avid lesions per body region (head&neck, thorax, abdomen, bone, extremity) and image quality (grade 1–5) were evaluated. Semiquantitative analyses were performed by standardized uptake value (SUV) measurements using 3D volume of interests (VOI). The visual and semiquantitative diagnostic equivalence of 214 [18F]-FDG-avid lesions were analysed in the routine standard (75 s/BP) as well as the calculated PET/CT studies with short acquisition time. Statistical analyses were performed by equivalence testing and Bland–Altman plots. Results: Lesion detection rate per patient's body region agreed in > 98% comparing 57 s/BP and 75 s/BP datasets. Overall image quality was determined as equal or superior to 75 s in 80% and 69%, respectively. In the semiquantitative lesion-based analyses, a significant equivalence was found between the 75 s/BP and 57 s/BP PET/CT images both for SUVmax (p = 0.004) and SUVmean (p = 0.003). Conclusion: The results of this study demonstrate significant clinical and semiquantitative equivalence between short acquisition time of 57 s/BP and standard 75 s/BP 3D TOF [18F]-FDG PET/CT scanning, which may improve the patient's workflow in routine practice. [ABSTRACT FROM AUTHOR]

Background: Recommendations for statistical methods in rare disease trials are scarce, especially for cross-over designs. As a result various state-of-the-art methodologies were compared as neutrally as possible using an illustrative data set from epidermolysis bullosa research to build recommendations for count, binary, and ordinal outcome variables. For this purpose, parametric (model averaging), semiparametric (generalized estimating equations type [GEE-like]) and nonparametric (generalized pairwise comparisons [GPC] and a marginal model implemented in the R package nparLD) methods were chosen by an international consortium of statisticians. Results: It was found that there is no uniformly best method for the aforementioned types of outcome variables, but in particular situations, there are methods that perform better than others. Especially if maximizing power is the primary goal, the prioritized unmatched GPC method was able to achieve particularly good results, besides being appropriate for prioritizing clinically relevant time points. Model averaging led to favorable results in some scenarios especially within the binary outcome setting and, like the GEE-like semiparametric method, also allows for considering period and carry-over effects properly. Inference based on the nonparametric marginal model was able to achieve high power, especially in the ordinal outcome scenario, despite small sample sizes due to separate testing of treatment periods, and is suitable when longitudinal and interaction effects have to be considered. Conclusion: Overall, a balance has to be found between achieving high power, accounting for cross-over, period, or carry-over effects, and prioritizing clinically relevant time points. [ABSTRACT FROM AUTHOR]

Objective: Perception and recognition of emotions are fundamental prerequisites of human life. Patients with juvenile myoclonic epilepsy (JME) may have emotional and behavioral impairments that might influence socially desirable interactions. We aimed to investigate perception and recognition of emotions in patients with JME by means of neuropsychological tests and functional magnetic resonance imaging (fMRI). Methods: Sixty‐five patients with JME (median age = 27 years, interquartile range [IQR] = 23–34) were prospectively recruited at the Department of Neurology, Christian Doppler University Hospital, Paracelsus Medical University, Salzburg, Austria. Patients were compared to 68 healthy controls (median age = 24 years, IQR = 21–31), matched for sex, age, and education. All study participants underwent the Networks of Emotion Processing test battery (NEmo), an fMRI paradigm of "dynamic fearful faces," a structured interview for psychiatric and personality disorders, and comprehensive neuropsychological testing. Results: JME patients versus healthy controls demonstrated significant deficits in emotion recognition in facial and verbal tasks of all emotions, especially fear. fMRI revealed decreased amygdala activation in JME patients as compared to healthy controls. Patients were at a higher risk of experiencing psychiatric disorders as compared to healthy controls. Cognitive evaluation revealed impaired attentional and executive functioning, namely psychomotor speed, tonic alertness, divided attention, mental flexibility, and inhibition of automated reactions. Duration of epilepsy correlated negatively with parallel prosodic and facial emotion recognition in NEmo. Deficits in emotion recognition were not associated with psychiatric comorbidities, impaired attention and executive functions, types of seizures, and treatment. Significance: This prospective study demonstrated that as compared to healthy subjects, patients with JME had significant deficits in recognition and perception of emotions as shown by neuropsychological tests and fMRI. The results of this study may have importance for psychological/psychotherapeutic interventions in the management of patients with JME. [ABSTRACT FROM AUTHOR]

To optimize the use of data from a small number of subjects in rare disease trials, an at first sight advantageous design is the repeated measures cross‐over design. However, it is unclear how these within‐treatment period and within‐subject clustered data are best analyzed in small‐sample trials. In a real‐data simulation study based upon a recent epidermolysis bullosa simplex trial using this design, we compare non‐parametric marginal models, generalized pairwise comparison models, GEE‐type models and parametric model averaging for both repeated binary and count data. The recommendation of which methodology to use in rare disease trials with a repeated measures cross‐over design depends on the type of outcome and the number of time points the treatment has an effect on. The non‐parametric marginal model testing the treatment–time‐interaction effect is suitable for detecting between group differences in the shapes of the longitudinal profiles. For binary outcomes with the treatment effect on a single time point, the parametric model averaging method is recommended, while in the other cases the unmatched generalized pairwise comparison methodology is recommended. Both provide an easily interpretable effect size measure, and do not require exclusion of periods or subjects due to incompleteness. [ABSTRACT FROM AUTHOR]

Purpose: Post-COVID-19-Syndrome (PCS) frequently occurs after an infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). However, the understanding of causative mechanisms is still limited. Aim of this study was to determine the PCS rate among SARS-CoV-2 seropositive blood donors as representatives of supposedly healthy adults, who had experienced an asymptomatic or mild COVID-19 disease course, and to examine whether Epstein-Barr virus (EBV) is reactivated in individuals reporting PCS. Methods: The PCS rate was determined using questionnaires that included questions about infection and persistent symptoms. Pre-pandemic blood samples and samples collected at regular, pre-defined times after a SARS-CoV-2 infection were analysed for neopterin, a marker for antiviral immune responses, by an enzyme-linked immunosorbent assay (ELISA). Additionally, we determined the rate of SARS-CoV-2 anti-N total antibodies using an electrochemiluminescence immunoassay (ECLIA). Furthermore, quantitative real-time polymerase chain reaction (qPCR) to detect EBV DNA and ECLIA screening for EBV viral capsid-antigen (VCA) IgM, IgG and EBV nuclear antigen 1 (EBNA) IgG were performed. Results: Our data reveal that 18% of all infections result in PCS, with symptoms lasting for up to one year. In individuals reporting PCS, no elevated levels of neopterin were detected, indicating no persisting pro-inflammatory, antiviral immune response. SARS-CoV-2 antibody levels were declining in all participants in comparable manner over time, pointing to a successful virus clearance. In individuals with PCS, no EBV DNA could be detected. Furthermore, no differences in EBV specific antibody levels could be shown in PCS groups compared to non-PCS groups. Conclusion: Our data suggest that PCS in per se healthy, immunocompetent adults cannot be ascribed to a reactivation of EBV. [ABSTRACT FROM AUTHOR]

Synchronous visuotactile stimulation on the own hidden hand and a visible fake limb can alter bodily self-perception and influence spontaneous neuroplasticity. The rubber hand illusion (RHI) paradigm experimentally produces an illusion of rubber hand ownership and arm shift by simultaneously stroking a rubber hand in view and a participant's visually occluded hand. The aim of this cross-over, placebo-controlled, single-blind study was to assess whether RHI, in combination with high-frequency repetitive transcranial magnetic stimulation (rTMS) given as intermittent (excitatory) theta burst stimulation (iTBS) applied over the hand area of the primary sensory region (S1) can enhance tactile sensation in a group of 21 healthy subjects and one patient with cervical spinal cord injury. Four sessions covered all combinations of real and sham stimulations of the RHI and the TBS: real TBS and real RHI, real TBS and sham RHI, sham TBS and real RHI, and both conditions sham. The condition sham TBS and real RHI shows the greatest effect on the proprioceptive drift (median 2.3 cm, IQR 2) and on the score of RHI questionnaires (median 3, IQR 2) in the control group as well as in the real-real condition (median 2, IQR 2). The sham TBS and real RHI condition also shows the best results in the electrical perception test of the patient (median 1.9 mA). Conversely, the upregulation of the cortical excitability of S1 via TBS seems to impair the effect of the RHI. This might be due to a strengthening of the top-down connection between the central nervous system and the periphery, diminishing the RHI. This finding helps in understanding the mechanisms of top-down and bottom-up mechanisms in healthy subjects and patients with spinal cord injury. The RHI paradigm could represent an interesting therapeutic approach in improving tactile sensation and rTMS techniques could modulate these effects. Yet, further studies are needed, to examine the direction of the interaction effect of TMS and RH. [ABSTRACT FROM AUTHOR]

Early decompression after acute spinal cord injury (SCI) is recommended. Acute care is crucial, but optimal management is unclear. The aim of this study was to investigate the role of preoperative magnetic resonance imaging (MRI) in addition to computed tomography (CT) in surgical decision making for acute cervical SCI. All patients with cervical SCI between 2008 and 2016 who had preoperative CT and MRI (n = 63) at the Trauma Center Murnau, Germany, were included. We administered a survey to 10 experienced spine surgeons (5 neurosurgeons, 5 trauma surgeons) regarding the surgical management. First, the surgeons were shown clinical information and CT scans. Two months later, the survey was repeated with additional MRI. Corresponding percentages of change and agreement were obtained for each rater and survey item. Finally, results from both parts of the survey were compared with the definitive treatment option (i.e., real-world decision). MRI modified surgical timing in a median of 41% of patients (interquartile range 38%–56%). In almost every fifth patient (17%), no surgery would have been indicated with CT alone. The advocated surgical approach was changed in almost half of patients (median 48%, interquartile range 33%–49%). Surgically addressed levels were changed in a median of 57% of patients (interquartile range 56%–60%). MRI led to higher agreement with the real-world decision concerning addressed levels (median 35% vs. 73%), timing (median 51% vs. 57%), and approach (median 44% vs. 65%). Preoperative MRI influenced surgical decision making substantially in our cohort and has become a new standard for patients with cervical SCI in our institution if medically possible. [ABSTRACT FROM AUTHOR]

Mucopolysaccharidosis (MPS) is a group of rare metabolic diseases associated with reduced life expectancy and a substantial unmet medical need. Immunomodulatory drugs could be a relevant treatment approach for MPS patients, although they are not licensed for this population. Therefore, we aim to provide evidence justifying fast access to innovative individual treatment trials (ITTs) with immunomodulators and a high-quality evaluation of drug effects by implementing a risk–benefit model for MPS. The iterative methodology of our developed decision analysis framework (DAF) consists of the following steps: (i) a comprehensive literature analysis on promising treatment targets and immunomodulators for MPS; (ii) a quantitative risk–benefit assessment (RBA) of selected molecules; and (iii) allocation phenotypic profiles and a quantitative assessment. These steps allow for the personalized use of the model and are in accordance with expert and patient representatives. The following four promising immunomodulators were identified: adalimumab, abatacept, anakinra, and cladribine. An improvement in mobility is most likely with adalimumab, while anakinra might be the treatment of choice for patients with neurocognitive involvement. Nevertheless, a RBA should always be completed on an individual basis. Our evidence-based DAF model for ITTs directly addresses the substantial unmet medical need in MPS and characterizes a first approach toward precision medicine with immunomodulatory drugs. [ABSTRACT FROM AUTHOR]

We have read with great interest the paper entitled, "The difficulty of diagnosing NCSE in clinical practice; external validation of the Salzburg criteria" by Goselink et al.[1] We agree on the importance of "careful weighing of both clinical and EEG information on an individual basis,"[1] which we have also emphasized in papers describing the Salzburg criteria for nonconvulsive status epilepticus (NCSE).[[2]] The low sensitivity in this study is not surprising, because the authors analyzed electroencephalographic (EEG) recordings of only 30-60 minutes for each patient.[1] It is well documented that continuous EEG recordings[[5]] and repeated short-duration recordings increase the sensitivity of EEG in NCSE and in comatose patients.[7] Using repeated short-duration recordings (median = 2 per patient, range = 1-15) and continuous EEG recordings (median = 74.8 h, range = 5-142 h), we achieved a sensitivity of 97.7%.[4] GLO:1F8/01nov19:epi16361-fig-0001.jpg PHOTO (COLOR): Salzburg electroencephalographic (EEG) criteria for the diagnosis of nonconvulsive status epilepticus (NCSE). [Extracted from the article]

Convalescent plasma (CP) has been in use for the treatment of numerous infectious diseases for more than a century, recently also for coronavirus disease 2019 (COVID-19). A major challenge for this treatment is identifying suitable donors with sufficient levels of functional antibodies and to determine the optimal time span for CP donation. In this retrospective study, we analyzed 189 CP donations of 66 donors regarding anti-SARS-CoV-2 anti-S IgG antibody levels. We found a significant correlation between the semi-quantitative SARS-CoV-2 IgG ratio values and in vitro antibody functionality. A time-to-event analysis allowed us to predict the optimal time span of COVID-19 CP donor suitability. We found that high IgG ratio values, which significantly correlate with high in vitro antibody functionality, were suitable for CP donation for a median of 134 days after the first CP donation. Donors with lower IgG ratios were suitable for a median of 53 days. Our data support plasma collection centers to determine optimal points in time for CP donation by means of widely used semi-quantitative laboratory IgG ratio values. [ABSTRACT FROM AUTHOR]

Aims: To find out which variables may be associated with comfort of patients in an epilepsy monitoring unit. Design: Exploratory, quantitative study design. Methods: Data were collected from October 2018 to November 2019 in Austria and Southern Germany. A total of 267 patients of 10 epilepsy centres completed the Epilepsy Monitoring Unit Comfort Questionnaire which is based on Kolcaba's General Comfort Questionnaire. Secondary data analysis were conducted by using descriptive statistics and an exploratory model building approach, including different linear regression models and several sensitivity analyses. Results: Total comfort scores ranged from 83 to 235 points. Gender, occupation and centre turned out to be possible influential variables. On average, women had a total comfort score 4.69 points higher than men, and retired persons 28.2 points higher than high school students ≥18 years. Comfort scores of younger patients were lower than those of older patients. However, age did not show a statistically significant effect. The same could be observed in marital status and educational levels. Conclusion: When implementing comfort measures, nurses must be aware of variables which could influence the intervention negatively. Especially, high school students ≥18 years should be supported by epilepsy specialist nurses, in order to reduce uncertainty, anxiety and discomfort. But, since the identified variables account only for a small proportion of the inter‐individual variability in comfort scores, further studies are needed to find out additional relevant aspects and to examine centre‐specific effects more closely. Impact: Nurses ensure patient comfort during a hospital stay. However, there are variables that may impair the effectiveness of the nursing measures. Our study showed that the experience of comfort was highly individual and could be explained by sociodemographic variables only to a limited extent. Nurses must be aware that additional factors, such as the situation in the individual setting, may be relevant. [ABSTRACT FROM AUTHOR]

Background and purpose: Rare diseases affect up to 29 million people in the European Union, and almost 50% of them affect the nervous system or muscles. Delays in diagnosis and treatment onset and insufficient treatment choices are common. Clinical practice guidelines (CPGs) may improve the diagnosis and treatment of patients and optimize care pathways, delivering the best scientific evidence to all clinicians treating these patients. Recommendations are set for developing and reporting high‐quality CPGs on rare neurological diseases (RNDs) within the European Academy of Neurology (EAN), through a consensus procedure. Methods: A group of 27 experts generated an initial list of items that were evaluated through a two‐step Delphi consensus procedure and a face‐to‐face meeting. The final list of items was reviewed by an external review group of 58 members. Results: The consensus procedure yielded 63 final items. Items are listed according to the domains of the AGREE instruments and concern scope and purpose, stakeholder involvement, rigour of development, and applicability. Additional items consider reporting and ethical issues. Recommendations are supported by practical examples derived from published guidelines and are presented in two tables: (1) items specific to RND CPGs, and general guideline items of special importance for RNDs, or often neglected; (2) items for guideline development within the EAN. Conclusions: This guidance aims to provide solutions to the issues specific to RNDs. This consensus document, produced by many experts in various fields, is considered to serve as a starting point for further harmonization and for increasing the quality of CPGs in the field of RNDs. [ABSTRACT FROM AUTHOR]

The article titled "An Innovative Tool for Evidence-Based, Personalized Treatment Trials in Mucopolysaccharidosis" has been retracted by the journal Pharmaceutics. The retraction was made due to concerns about the use of unpublished trial data without permission and potential inaccuracies in the data. The investigation confirmed that the authors did not have appropriate permission to use the trial data and that there were errors in the presentation of the data. The authors of the article have agreed to the retraction. [Extracted from the article]

The developmental course of antibodies produced after a SARS-CoV-2 infection has been insufficiently investigated so far. Therefore, the aim of this study was to investigate the dynamics of SARS-CoV-2 antibody levels against the viral nucleocapsid- and spike-protein among Austrian blood donors as a representative group of a supposedly healthy population within the first year after a SARS-CoV-2 infection. The impact of age, sex, vaccination status, AB0-blood group and awareness about the infection was evaluated. Our study shows that the level of anti-N antibodies is declining, while anti-S antibody levels remain stable. Antibodies detected were functional in vitro. Age, sex and blood group do not influence antibody dynamics. However, blood group AB shows significantly lower antibody levels and in vitro functionality compared to other blood groups. Our data reveal that one out of five individuals was not aware of a previous SARS-CoV-2 infection and that the disease course neither affects the level of antibody production nor the in vitro functionality. We also found that 14% of participants show persisting COVID-19-related symptoms for up to nine months. Our results provide valuable insights into the dynamics of the immune response after a SARS-CoV-2 infection in a representative cohort of adult blood donors in Central Europe. [ABSTRACT FROM AUTHOR]

Abstract: In the Chung–Yao construction of poised nodes for bivariate polynomial interpolation [K.C. Chung, T.H. Yao, On lattices admitting unique Lagrange interpolations, SIAM J. Numer. Anal. 14 (1977) 735–743], the interpolation nodes are intersection points of some lines. The Berzolari–Radon construction [L. Berzolari, Sulla determinazione di una curva o di una superficie algebrica e su alcune questioni di postulazione, Lomb. Ist. Rend. 47 (2) (1914) 556–564; J. Radon, Zur mechanischen Kubatur, Monatsh. Math. 52 (1948) 286–300] seems to be more general, since in this case the nodes of interpolation lie (almost) arbitrarily on some lines. In 1982 Gasca and Maeztu conjectured that every poised set allowing the Chung–Yao construction is of Berzolari–Radon type. So far, this conjecture has been confirmed only for polynomial spaces of small total degree , the result being evident for and not hard to see for . For the case two proofs are known: one of J.R. Busch [J.R. Busch, A note on Lagrange interpolation in , Rev. Un. Mat. Argentina 36 (1990) 33–38], and another of J.M. Carnicer and M. Gasca [J.M. Carnicer, M. Gasca, A conjecture on multivariate polynomial interpolation, Rev. R. Acad. Cienc. Exactas Fís. Nat. (Esp.) Ser. A Mat. 95 (2001) 145–153]. Here we present a third proof which seems to be more geometric in nature and perhaps easier. We also present some results for the case of and for general which might be useful for later consideration of the problem. [Copyright &y& Elsevier]

Adjusting for baseline values and covariates is a recurrent statistical problem in medical science. In particular, variance heteroscedasticity is non‐negligible in experimental designs and ignoring it might result in false conclusions. Approximate inference methods are developed to test null hypotheses formulated in terms of adjusted treatment effects and regression parameters in general analysis of covariance designs with arbitrary numbers of factors. Variance homoscedasticity is not assumed. The distributions of the test statistics are approximated using Box‐type approximation methods. Extensive simulation studies show that the procedures are particularly suitable when sample sizes are rather small. A real data set illustrates the application of the methods. [ABSTRACT FROM AUTHOR]

We study the orthogonal perturbation of various coherent function systems (Gabor systems, Wilson bases, and wavelets) under convolution operators. This problem is of key relevance in the design of modulation signal sets for digital communication over time-invariant channels. Upper and lower bounds on the orthogonal perturbation are formulated in terms of spectral spread and temporal support of the prototype, and by the approximate design of worst-case convolution kernels. Among the considered bases, the Weyl–Heisenberg structure which generates Gabor systems turns out to be optimal whenever the class of convolution operators satisfies typical practical constraints. [Copyright &y& Elsevier]

Concerns regarding the impact of climate change, food price volatility, and weather uncertainty have motivated users of simulation models to consider uncertainty in their simulations. One way to do this is to integrate uncertainty components in the model equations, thus turning the model into a problem of numerical integration. Most of these problems do not have analytical solutions, and researchers, therefore, apply numerical approximation methods. This article presents a novel approach to conducting an uncertainty analysis as an alternative to the computationally burdensome Monte Carlo-based (MC) methods. The developed method is based on the degree three Gaussian quadrature (GQ) formulae and is tested using three large-scale simulation models. While the standard single GQ method often produces low-quality approximations, the results of this study demonstrate that the proposed approach reduces the approximation errors by a factor of nine using only 3.4% of the computational effort required by the MC-based methods in the most computationally demanding model. • Conventional methods of uncertainty/sensitivity analysis suffer from poor computational efficiency. • Gaussian quadrature (GQ) is an efficient method for uncertainty/sensitivity analysis. • The standard single GQ method often produces low-quality approximations. • The proposed novel method, called MRGQ, overcomes the problem of insufficient accuracy of traditional GQ approaches. • The MRGQ method is especially relevant for computationally intensive models. [ABSTRACT FROM AUTHOR]

• The EMUCQ is the first instrument to assess patient comfort in the epilepsy monitoring unit. • The EMUCQ may be considered a valid and reliable instrument. • The EMUCQ enables nurses to offer individualized interventions. [ABSTRACT FROM AUTHOR]

Several emergencies were admitted less frequently to the hospital during the coronavirus disease 2019 (COVID‐19) pandemic. To investigate whether this also occurred with status epilepticus (SE) we compared admissions due to first SE from March to April 2020 ("Time of COVID," TOC) with January to February 2020 ("pre‐COVID," preCOV). We also compared admission numbers in TOC and preCOV with the respective 2‐month periods in 2018 and 2019 in a retrospective cohort analysis. Two investigators independently searched the hospital patient database for various forms of SE. There was no significant change in the 2‐month incidences of first SE in the city of Salzburg from preCOV of 6.1 (95% confidence interval [CI] 2.9‐12.3) to TOC of 6.9/100 000 adults (95% CI 3.4‐13.3). Admission numbers did not differ significantly from previous years. Estimated adjusted incidence was in line with a recent 5‐year epidemiological study in Salzburg. However, a trend toward less‐frequent nonconvulsive SE (NCSE) and loss of female predominance were indirect hints of underdiagnosing SE. In contrast to other medical conditions, SE most often presents clinically with impaired consciousness, which may promote admission to emergency departments even in times of lock‐down. Further research of medical support of women and patients with NCSE during pandemic‐related restrictions is warranted. [ABSTRACT FROM AUTHOR]

Status epilepticus (SE) is a severe neurologic condition associated with high morbidity and mortality. Population-based studies in adults have found a wide range of incidences in various regions in the world. Although the incidence of SE increases almost exponentially in the elderly, data on census-based population statistics in these studies are scarce. This study provides a critical review with an emphasis on census-based population statistics and study characteristics in adults. We performed a systematic search of population-based studies on SE in adults in PubMed using "status epilepticus" in combination with "epidemiology", "population", and "incidence" as search terms, and also screened references. For each identified study, we assessed and extracted the respective population pyramids of study and reference population, and study characteristics. We identified 22 population-based studies (eleven from Europe, six from North America, three from Asia, one from Africa, and one from Australasia). Incidence rates of patients with SE ranged from 1.29 to 73.7/100,000 adults (95% confidence interval (CI): 76.6–80.3) and of SE episodes up to 81.1/100,000 adults (95% CI: 75.8–87.0). The proportions of elderly and very old patients varied by a factor of 2.6 and 8.5, respectively, depending on study period and place. Further major reasons for heterogeneity were retrospective or prospective study design, definition of time to diagnose SE, variable detection of nonconvulsive SE (NCSE), different etiologies, inclusion of children, recurrent episodes, postanoxic patients, exclusion of patients with preexisting epilepsy or patients identified outside the emergency department, and choice of reference population for age- and gender adjustment. The most recent definition and classification of SE by the International League Against Epilepsy (ILAE) 2015 was used in two studies. Four studies (18.2%) reported incidences per ten-year age strata necessary for age adjustment to various reference populations. This critical review reveals a marked heterogeneity among population-based studies on SE in adults. It provides comprehensive details on census-based population statistics in study and reference populations and various study designs and characteristics essential for direct comparisons between studies. Reporting on these essential key features should be improved in population-based studies on SE. • The annual incidence of status epilepticus (SE) in adults varies between 1.29 to 73.7/100,000 (81.1 SE episodes/100,000). • Clarification of terms is essential, e.g. SE patients or SE episodes, first ever SE or recurrent SE, and the term "per 100,000". • Incidences in adults and children should be reported and adjusted separately to avoid bias. • Choice of reference population (RP) is crucial as study data will change as if the study was performed in that RP. • ILAE 2015 diagnostic time criteria T1 for SE are recommended as different types of semiology qualify at different times. [ABSTRACT FROM AUTHOR]

Status epilepticus (SE) is a severe neurologic condition associated with high morbidity and mortality. Population-based studies in adults have found a wide range of incidences in various regions in the world. Although the incidence of SE increases almost exponentially in the elderly, data on census-based population statistics in these studies are scarce. This study provides a critical review with an emphasis on census-based population statistics and study characteristics in adults. We performed a systematic search of population-based studies on SE in adults in PubMed using "status epilepticus" in combination with "epidemiology", "population", and "incidence" as search terms, and also screened references. For each identified study, we assessed and extracted the respective population pyramids of study and reference population, and study characteristics. We identified 22 population-based studies (eleven from Europe, six from North America, three from Asia, one from Africa, and one from Australasia). Incidence rates of patients with SE ranged from 1.29 to 73.7/100,000 adults (95% confidence interval (CI): 76.6–80.3) and of SE episodes up to 81.1/100,000 adults (95% CI: 75.8–87.0). The proportions of elderly and very old patients varied by a factor of 2.6 and 8.5, respectively, depending on study period and place. Further major reasons for heterogeneity were retrospective or prospective study design, definition of time to diagnose SE, variable detection of nonconvulsive SE (NCSE), different etiologies, inclusion of children, recurrent episodes, postanoxic patients, exclusion of patients with preexisting epilepsy or patients identified outside the emergency department, and choice of reference population for age- and gender adjustment. The most recent definition and classification of SE by the International League Against Epilepsy (ILAE) 2015 was used in two studies. Four studies (18.2%) reported incidences per ten-year age strata necessary for age adjustment to various reference populations. This critical review reveals a marked heterogeneity among population-based studies on SE in adults. It provides comprehensive details on census-based population statistics in study and reference populations and various study designs and characteristics essential for direct comparisons between studies. Reporting on these essential key features should be improved in population-based studies on SE. • The annual incidence of status epilepticus (SE) in adults varies between 1.29 to 73.7/100,000 (81.1 SE episodes/100,000). • Clarification of terms is essential, e.g. SE patients or SE episodes, first ever SE or recurrent SE, and the term "per 100,000". • Incidences in adults and children should be reported and adjusted separately to avoid bias. • Choice of reference population (RP) is crucial as study data will change as if the study was performed in that RP. • ILAE 2015 diagnostic time criteria T1 for SE are recommended as different types of semiology qualify at different times. [ABSTRACT FROM AUTHOR]

To assess the prognostic profile, clinical outcome, treatment-associated morbidity, and treatment burden of elderly patients with glioblastoma (GBM) undergoing microsurgical tumor resection as part of contemporary treatment algorithms. We retrospectively identified patients with GBM ≥65 years of age who were treated by resection at 2 neuro-oncology centers. Survival was assessed by Kaplan-Meier analyses; log-rank tests identified prognostic factors. The study population included 160 patients (mean age, 73.1 ± 5.1 years), and the median contrast-enhancing tumor volume was 31.0 cm3. Biomarker analyses revealed O(6)-methylguanine-DNA methyltransferase–promoter methylation in 62.7% and wild-type isocitrate dehydrogenase in 97.5% of tumors. The median extent of resection (EOR) was 92.3%, surgical complications were noted in 10.0% of patients, and the median postoperative hospitalization period was 8 days. Most patients (60.0%) received adjuvant radio-/chemotherapy. The overall treatment-associated morbidity was 30.6%. The median progression-free and overall survival were 5.4 months (95% confidence interval [CI], 4.6–6.4 months) and 10.0 months (95% CI, 7.9–11.7 months). The strongest predictors for favorable outcome were patient age ≤73.0 years (P = 0.0083), preoperative Karnofsky Performance Status Scale score ≥80% (P = 0.0179), postoperative modified Rankin Scale score ≤1 (P < 0.0001), adjuvant treatment (P < 0.0001), and no treatment-associated morbidity (P = 0.0478). Increased EOR did not correlate with survival (P = 0.5046), but correlated significantly with treatment-associated morbidity (P = 0.0031). Clinical outcome for elderly patients with GBM remains limited. Nonetheless, the observed treatment-associated morbidity and treatment burden were moderate in the patients, and patient age and performance status remained the strongest predictors for survival. The risks and benefits of tumor resection in the age of biomarker-adjusted treatment concepts require further prospective evaluation. [ABSTRACT FROM AUTHOR]

Abstract Introduction Severe aortic stenosis (AS) caused by degenerative calcification is the most frequent acquired valvular heart disease worldwide and mortality rates are considerably high. Transcatheter Aortic Valve Implantation (TAVI) is a well-established method for valve replacement in high risk patients with AS. However, there is a lack of reliable predictors for patients undergoing TAVI since commonly used scores were developed for surgical populations. Materials and methods 208 patients subjected to TAVI were included in this study. Plasma samples were obtained before TAVI and were evaluated for IGFBP-2 using commercially available ELISA kits. IGFBP-2 levels were analyzed for their ability for risk prediction after TAVI. Results IGFBP-2 levels measured before TAVI correlated significantly with left ventricular ejection fraction, EUROSCORE and other functional and prognostic parameters like the 6-minute walking test. When patients were retrospectively divided in two groups with a cut-off of serum IGFBP-2 levels of 275 ng/ml, IGFBP-2 was a strong predictor for 30-day and one-year mortality (3% vs. 11%, p = 0.05 and 18.2% vs. 46.2%; p < 0.001 respectively). Compared to an EUROSCORE above 20 or an STS score cut-off above 8, IGFBP-2 plasma levels above 275 ng/ml outperformed the established risk score for prediction of one-year mortality as assessed by NRI (0.65 95% CI 0.37–0.94; p < 0.001 and 0.54 95% CI 0.25–0.82; p < 0.001, respectively). Conclusions Our results indicate that IGFBP-2 could serve as new outcome predictor for patients undergoing TAVI procedure. By providing additional information to the commonly used EUROSCORE, IGFPB-2 analysis could further assist Heart Team decision making. Highlights • Severe aortic stenosis (AS) is the most frequent acquired valvular heart disease worldwide and mortality rates are considerably high. • Transcatheter Aortic Valve Implantation (TAVI) is a well-established method for valve replacement in high risk patients with AS. • There is a lack of reliable predictors for patients undergoing TAVI since commonly used scores were developed for surgical populations. • Here we show that IGFBP-2 could serve as new outcome predictor for patients undergoing TAVI procedure. [ABSTRACT FROM AUTHOR]

Purpose: Changes of lactate concentration over time were reported to be associated with survival in septic patients. We aimed to evaluate delta-lactate (ΔLac) 24 h after admission (Δ24Lac) to an intensive care unit (ICU) in critically ill patients for short- and long-term prognostic relevance.Methods: In total, 26,285 lactate measurements of 2191 patients admitted to a German ICU were analyzed. Inclusion criterion was a lactate concentration at admission above 2.0 mmol/L. Maximum lactate concentrations of day 1 and day 2 were used to calculate Δ24Lac. Follow-up of patients was performed retrospectively. Association of Δ24Lac and both in-hospital and long-term mortality were investigated. An optimal cut-off was calculated by means of the Youden index.Results: Patients with lower Δ24Lac were of similar age, but clinically sicker. As continuous variable, higher Δ24Lac was associated with decreased in-hospital mortality (per 1% Δ24Lac; HR 0.987 95%CI 0.985-0.990; p < 0.001) and an optimal Δ24Lac cut-off was calculated at 19%. Δ24Lac ≤ 19% was associated with both increased in-hospital (15% vs 43%; OR 4.11; 95%CI 3.23-5.21; p < 0.001) and long-term mortality (HR 1.54 95%CI 1.28-1.87; p < 0.001), even after correction for APACHE II, need for catecholamines and intubation. We matched 256 patients with Δ24Lac ≤ 19% to case-controls > 19% corrected for APACHE II scores, baseline lactate level and sex: Δ24Lac ≤ 19% remained associated with lower in-hospital and long-term survival.Conclusions: Lower Δ24Lac was robustly associated with adverse outcome in critically ill patients, even after correction for confounders. Δ24Lac might constitute an independent, easily available and important parameter for risk stratification in the critically ill. [ABSTRACT FROM AUTHOR]

Summary: Objective: In 2015, the International League Against Epilepsy (ILAE) proposed a new definition of status epilepticus (SE): 5 minutes of ongoing seizure activity to diagnose convulsive SE (CSE, ie, bilateral tonic–clonic SE) and 10 minutes for focal SE and absence SE, rather than the earlier criterion of 30 minutes. Based on semiology, several types of SE with prominent motor phenomena at any time (including CSE) were distinguished from those without (ie, nonconvulsive SE, NCSE). We present the first population‐based incidence study applying the new 2015 ILAE definition and classification of SE and report the impact of the evolution of semiology and level of consciousness (LOC) on outcome. Methods: We conducted a retrospective population‐based incidence study of all adult patients with SE residing in the city of Salzburg between January 2011 and December 2015. Patients with hypoxic encephalopathy were excluded. SE was defined and classified according to the ILAE 2015. Results: We identified 221 patients with a median age of 69 years (range 20‐99 years). The age‐ and sex‐adjusted incidence of a first episode of SE, NCSE, and SE with prominent motor phenomena (including CSE) was 36.1 (95% confidence interval [CI] 26.2‐48.5), 12.1 (95% CI 6.8‐20.0), and 24.0 (95% CI 16.0‐34.5; including CSE 15.8 [95% CI 9.4‐24.8]) per 100 000 adults per year, respectively. None of the patients whose SE ended with or consisted of only bilateral tonic–clonic activity died. In all other clinical presentations, case fatality was lower in awake patients (8.2%) compared with patients with impaired consciousness (33%). Significance: This first population‐based study using the ILAE 2015 definition and classification of SE found an increase of incidence of 10% compared to previous definitions. We also provide epidemiologic evidence that different patterns of status evolution and LOCs have strong prognostic implications. [ABSTRACT FROM AUTHOR]

Summary: Objective: The European Union–funded E‐PILEPSY network (now continuing within the European Reference Network for rare and complex epilepsies [EpiCARE]) aims to harmonize and optimize presurgical diagnostic procedures by creating and implementing evidence‐based guidelines across Europe. The present study evaluates the current evidence on the diagnostic accuracy of long‐term video‐electroencephalographic monitoring (LTM) in identifying the epileptogenic zone in epilepsy surgery candidates. Methods: MEDLINE, Embase, CENTRAL, and ClinicalTrials.gov were searched for relevant articles. First, we used random‐effects meta‐analytical models to calculate pooled estimates of sensitivity and specificity with respect to postsurgical seizure freedom. In a second phase, we analyzed individual patient data in an exploratory fashion, assessing diagnostic accuracy within lesional and nonlesional temporal lobe epilepsy (TLE) and extratemporal lobe epilepsy (ETLE) patients. We also evaluated seizure freedom rate in the presence of "localizing" or "nonlocalizing" LTM within each group. The quality of evidence was assessed using the QUADAS‐2 tool and the GRADE approach. Results: Ninety‐four studies were eligible. Forty‐four were included in sensitivity meta‐analysis and 34 in specificity meta‐analysis. Pooled sensitivity was 0.70 (95% confidence interval [CI] = 0.60‐0.80) and specificity was 0.40 (95% CI = 0.27‐0.54). Subgroup analysis was based on individual data of 534 patients (41% men). In lesional TLE patients, sensitivity was 0.85 (95% CI = 0.81‐0.89) and specificity was −0.19 (95% CI = 0.13‐0.28). In lesional ETLE patients, a sensitivity of 0.47 (95% CI = 0.36‐0.58) and specificity of 0.35 (95% CI = 0.21‐0.53) were observed. In lesional TLE, if LTM was localizing and concordant with resection site, the seizure freedom rate was 247 of 333 (74%), whereas in lesional ETLE it was 34 of 56 (61%). The quality of evidence was assigned as "very low." Significance: Long‐term video‐electroencephalographic monitoring is associated with moderate sensitivity and low specificity in identification of the epileptogenic zone. Sensitivity is remarkably higher in lesional TLE compared to lesional ETLE. Substantial heterogeneity across the studies indicates the need for improved design and quality of reporting. [ABSTRACT FROM AUTHOR]

Summary: Objective: The European Union–funded E‐PILEPSY project was launched to develop guidelines and recommendations for epilepsy surgery. In this systematic review, we aimed to assess the diagnostic accuracy of functional magnetic resonance imaging (fMRI), Wada test, magnetoencephalography (MEG), and functional transcranial Doppler sonography (fTCD) for memory and language decline after surgery. Methods: The literature search was conducted using PubMed, Embase, and CENTRAL. The diagnostic accuracy was expressed in terms of sensitivity and specificity for postoperative language or memory decline, as determined by pre‐ and postoperative neuropsychological assessments. If two or more estimates of sensitivity or specificity were extracted from a study, two meta‐analyses were conducted, using the maximum ("best case") and the minimum ("worst case") of the extracted estimates, respectively. Results: Twenty‐eight papers were eligible for data extraction and further analysis. All tests for heterogeneity were highly significant, indicating large between‐study variability (P < 0.001). For memory outcomes, meta‐analyses were conducted for Wada tests (n = 17) using both memory and language laterality quotients. In the best case, meta‐analyses yielded a sensitivity estimate of 0.79 (95% confidence interval [CI] = 0.67‐0.92) and a specificity estimate of 0.65 (95% CI = 0.47‐0.83). For the worst case, meta‐analyses yielded a sensitivity estimate of 0.65 (95% CI = 0.48‐0.82) and a specificity estimate of 0.46 (95% CI = 0.28‐0.65). The overall quality of evidence, which was assessed using Grading of Recommendations Assessment, Development, and Evaluation methodology, was rated as very low. Meta‐analyses concerning diagnostic accuracy of fMRI, fTCD, and MEG were not feasible due to small numbers of studies (fMRI, n = 4; fTCD, n = 1; MEG, n = 0). This also applied to studies concerning language outcomes (Wada test, n = 6; fMRI, n = 2; fTCD, n = 1; MEG, n = 0). Significance: Meta‐analyses could only be conducted in a few subgroups for the Wada test with low‐quality evidence. Thus, more evidence from high‐quality studies and improved data reporting are required. Moreover, the large between‐study heterogeneity underlines the necessity for more homogeneous and thus comparable studies in future research. [ABSTRACT FROM AUTHOR]

Background: Several EEG criteria have been proposed for diagnosis of non-convulsive status epilepticus (NCSE), but none have been clinically validated. We aimed to assess the diagnostic accuracy of the EEG criteria proposed by a panel of experts at the fourth London-Innsbruck Colloquium on Status Epilepticus in Salzburg, 2013 (henceforth called the Salzburg criteria).Methods: We did a retrospective, diagnostic accuracy study using EEG recordings from patients admitted for neurological symptoms or signs to three centres in two countries (Danish Epilepsy Centre, Dianalund, Denmark; Aarhus University Hospital, Aarhus, Denmark; and Paracelsus Medical University, Salzburg, Austria). Participants were included from the Danish centres if they were aged 4 months or older, and from the Austrian centre if aged 18 years or older. Participants were sorted into two groups: consecutive patients under clinical suspicion of having NCSE (the clinical validation group) or consecutive patients with abnormal EEG findings but no clinical suspicion of NCSE (the control group). Two raters blinded to all other patient data retrospectively analysed the EEG recordings and, using the Salzburg criteria, categorised patients as in NCSE or not in NCSE. By comparing with a reference standard inferred from all clinical and para-clinical data, therapeutic response, and the final outcome, we calculated sensitivity, specificity, overall diagnostic accuracy, positive and negative predictive values, and inter-rater agreement for the Salzburg criteria. The reference standard was inferred by two raters who were blinded to the scorings of the Salzburg criteria.Findings: We retrospectively reviewed EEG data from 220 patients. EEGs in the clinical validation group were recorded in 120 patients between Jan 1, and Feb 28, 2014 (Austria), and Aug 1, 2014, and Jan 31, 2015 (Denmark). EEGs in the control group were recorded in 100 patients between Jan 13 and Jan 22, 2014 (Austria) and Jan 12 and Jan 26, 2015 (Denmark). According to the reference standard, 43 (36%) of the 120 patients in the validation group had NCSE. In the validation cohort sensitivity was 97·7% (95% CI 87·9-99·6) and specificity was 89·6% (80·8-94·6); overall accuracy was 92·5% (88·3-97·5). Positive predictive value was 84·0% (95% CI 74·1-91·5) and negative predictive value was 98·6% (94·4-100). Three people in the control group (n=100) fulfilled the Salzburg criteria and were therefore false positives (specificity 97·0%, 95% CI 91·5-99·0; sensitivity not calculable). Inter-rater agreement was high for both the Salzburg criteria (k=0·87) and for the reference standard (k=0·95). Therapeutic changes occurred significantly more often in the group of patients fulfilling Salzburg criteria (42 [84%] of 50 patients) than in those who did not (11 [16%] of 70; p<0·0001).Interpretation: The Salzburg criteria for diagnosis of NCSE have high diagnostic accuracy and excellent inter-rater agreement, making them suitable for implementation in clinical practice.Funding: None. [ABSTRACT FROM AUTHOR]

Objective: The aim was to describe the safety and efficacy of (S)-ketamine [(S)-KET] in a series of patients with refractory and super-refractory status epilepticus (RSE and SRSE) in a specialized neurological intensive care unit (NICU).Methods: We retrospectively analyzed the data of patients with RSE and SRSE treated with (S)-KET in the NICU, Salzburg, Austria, from 2011 to 2015. Data collection included demographic features, clinical presentation, diagnosis, electroencephalogram (EEG) data, anticonvulsant treatment, timing, and duration of treatment with (S)-KET. Outcomes were seizure control and death.Results: A total of 42 patients (14 women) with RSE and SRSE were treated with (S)-KET. The median duration of status epilepticus (SE) was 10 days [first quartile (Q1) 5.0, Q3 21.0]; the median latency from SE onset to the first administration of (S)-KET was 3 days (Q1 2.0, Q3 6.8). Prior to (S)-KET administration, patients had received a median of two (Q1 2.0, Q3 3.0) anesthetics and three (Q1 2.0, Q3 4.0) antiepileptic drugs. Forty percent of patients (17/42) received propofol: 65 % prior to (S)-KET; 35 % at the same time with (S)-KET. Seven patients received a median bolus of (S)-KET of 200 mg (Q1 200, Q3 250) followed by a continuous infusion, while 35 started with a continuous infusion (maximum rate median 2.55 mg/kg/h; Q1 2.09, Q3 3.22). In 64 % of patients (27/42), (S)-KET was the last drug before SE cessation; in five patients, it was given with propofol at the same time. Median duration of administration was 4 days (Q1 2.0, Q3 6.8). Overall (S)-KET treatment was well tolerated, adverse effects were not observed, and overall mortality was 45.2 %.Conclusions: Treatment of SRSE in adult patients with (S)-KET led to resolution of status in 64 %. No adverse events were found, indicating a favorable safety profile. [ABSTRACT FROM AUTHOR]