Prospective, longitudinal, multicenter study on the provision of information regarding sudden unexpected death in epilepsy to adults with epilepsy.

OBJECTIVE: Despite increased awareness of the serious epilepsy complication sudden unexpected death in epilepsy (SUDEP), a substantial population of people with epilepsy (PWE) remain poorly informed. Physicians indicate concern that SUDEP information may adversely affect patients' health and quality of life. We examined SUDEP awareness and the immediate and long-term effects of providing SUDEP information to PWE. METHODS: Baseline knowledge and behaviors among PWE and behavioral adjustments following the provision of SUDEP information were evaluated in a prospective, multicenter survey using the following validated scales: Neurological Disorders Depression Inventory for Epilepsy for depression symptoms, the EuroQoL five-dimension scale for health-related quality of life (HRQoL), a visual analog scale for overall health, the revised Epilepsy Stigma Scale for perceived stigma, and the Seizure Worry Scale for seizure-related worries. The prospective study collected data through semiquantitative interviews before (baseline), immediately after, and 3 months after the provision of SUDEP information. RESULTS: In total, 236 participants (mean age = 39.3 years, range = 18-77 years, 51.7% women) were enrolled, and 205 (86.9%) completed long-term, 3-month follow-up. One patient died from SUDEP before follow-up. No worsening symptoms from baseline to 3-month follow-up were observed on any scale. At baseline, 27.5% of participants were aware of SUDEP. More than 85% of participants were satisfied with receiving SUDEP information. Three quarters of participants were not concerned by the information, and >80% of participants recommended the provision of SUDEP information to all PWE. Although most patients reported no behavioral adjustments, 24.8% reported strong behavioral adjustments at 3-month follow-up. SIGNIFICANCE: The provision of SUDEP information has no adverse effects on overall health, HRQoL, depressive symptoms, stigma, or seizure worry among PWE, who appreciate receiving information. SUDEP information provision might improve compliance among PWE and reduce but not eliminate the increased mortality risk.

Reliability of probing depth assessments at healthy implant sites and natural teeth.

AIM: To evaluate the intra- and inter-examiner reliability in the assessment of probing depth (PD) measurements at healthy dental implant sites and periodontally healthy natural teeth. MATERIALS AND METHODS: Five patients exhibiting 21 dental implants were enrolled in the study. Eight experienced examiners performed duplicate PD measurements at six sites of all implants and of preselected natural teeth. Intra-examiner accuracy was estimated using intra-examiner correlation coefficients (ICCs) with 95% confidence intervals (CI). A gold standard (GS) examiner was set. Inter-examiner accuracy compared to the GS examiner was assessed using pairwise inter-examiner ICCs. RESULTS: The intra-examiner ICC ranged from 0.759 (95% CI, 0.692-0.812) to 0.863 (95% CI, 0.826-0.892) for the measurements at teeth and from 0.712 (95% CI, 0.580-0.800) to 0.841 (95% CI, 0.774-0.888) for the PDs assessed at implants. The inter-examiner ICCs for tooth measurements varied from 0.197 (95% CI, - 0.280 to 0.511) to 0.791 (95% CI, 0.560-0.892). The corresponding values for the assessments at implants varied from 0.576 (95% CI, 0.286-0.734) to 0.794 (95% CI, 0.708-0.855). CONCLUSIONS: The intra- and inter-examiner reproducibility of repeated PD measurements assessed by experienced examiners tended to be higher for the measurements at periodontally healthy teeth compared to healthy dental implant sites. CLINICAL RELEVANCE: Experienced examiners demonstrated a higher degree of reliability of probing measurements around teeth compared to dental implants.

Use of Health-Related Apps and Telehealth in Adults with Epilepsy in Germany: A Multicenter Cohort Study.

Background: Telehealth can improve the treatment of chronic disorders, such as epilepsy. Telehealth prevalence and use increased during the coronavirus disease 2019 (COVID-19) pandemic. However, familiarity with and use of telehealth and health-related mobile applications (apps) by persons with epilepsy remain unknown. Methods: We investigated telehealth use, demographics, and clinical variables within the multicenter Epi2020 cross-sectional study. Between October and December 2020, adults with epilepsy completed a validated questionnaire, including individual questions regarding knowledge and use of apps and telehealth. Results: Of 476 included individuals (58.2% women; mean age 40.2 ± 15.4 years), 41.6% reported using health-related apps. Health apps were used more frequently (pedometer 32.1%, exercise app 17.6%) than medical apps (health insurance 15.1%, menstrual apps 12.2%) or apps designed for epilepsy (medication reminders 10.3%, seizure calendars 4.6%). Few used seizure detectors (i.e., apps as medical devices 1.9%) or mobile health devices (fitness bracelet 11.3%). A majority (60.9%) had heard the term telehealth, 78.6% of whom had a positive view. However, only 28.6% had a concrete idea of telehealth, and only 16.6% reported personal experience with telehealth. A majority (55%) would attend a teleconsultation follow-up, and 41.2% would in a medical emergency. Data privacy and availability were considered equally important by 50.8%, 21.8% considered data privacy more important, and 20.2% considered data availability more important. Current health-related app use was independently associated with younger age (p = 0.003), higher education (p < 0.001), and subjective COVID-19-related challenges (p = 0.002). Persistent seizure occurrence (vs. seizure freedom ≥12 months) did not affect willingness to use teleconsultations on multivariable logistic regression analysis. Conclusions: Despite positive telehealth views, few persons with epilepsy in Germany are familiar with specific apps or services. Socioeconomic factors influence telehealth use more than baseline epilepsy characteristics. Telehealth education and services should target socioeconomically disadvantaged individuals to reduce the digital care gap. German Clinical Trials Register (DRKS00022024; Universal Trial Number: U1111-1252-5331).

Dissecting Rubella Placental Infection in an In Vitro Trophoblast Model.

Vertical transmission of rubella virus (RuV) occurs at a high rate during the first trimester of pregnancy. The modes of vertical transmission including the response of trophoblasts to RuV are not well understood. Here, RuV-trophoblast interaction was studied in the BeWo trophoblast cell line. Analysis included early and late time-point kinetics of virus infection rate and the antiviral innate immune response at mRNA and protein level. BeWo characteristics were addressed through metabolic activity by extracellular flux analysis and syncytiotrophoblast formation through incubation with forskolin. We found that RuV infection of BeWo led to profuse type III interferon (IFN) production. Transfecting trophoblast cells with dsRNA analog induced an increase in the production of type I IFN-ß and type III IFNs; however, this did not occur in RuV-infected BeWo trophoblasts. IFN-ß and to a lesser extent type III IFN-λ1 were inhibitory to RuV. While no significant metabolic alteration was detected, RuV infection reduced the cell number in the monolayer culture in comparison to the mock control and resulted in detached and floating cells. Syncytia formation restricted RuV infection. The use of BeWo as a relevant cell culture model for infection of trophoblasts highlights cytopathogenicity in the absence of a type I IFN response as a pathogenic alteration by RuV.

Multicenter, cross-sectional study of the costs of illness and cost-driving factors in adult patients with epilepsy.

OBJECTIVE: This study was undertaken to quantify epilepsy-related costs of illness (COI) in Germany and identify cost-driving factors. METHODS: COI were calculated among adults with epilepsy of different etiologies and severities. Multiple regression analysis was applied to determine any epilepsy-related and sociodemographic factors that serve as cost-driving factors. RESULTS: In total, 486 patients were included, with a mean age of 40.5 ± 15.5 years (range = 18-83 years, 58.2% women). Mean 3-month COI were estimated at €4911, €2782, and €2598 for focal, genetic generalized, and unclassified epilepsy, respectively. The mean COI for patients with drug-refractory epilepsy (DRE; €7850) were higher than those for patients with non-DRE (€4720), patients with occasional seizures (€3596), or patients with seizures in remission for >1 year (€2409). Identified cost-driving factors for total COI included relevant disability (unstandardized regression coefficient b = €2218), poorer education (b = €2114), living alone (b = €2612), DRE (b = €1831), and frequent seizures (b = €2385). Younger age groups of 18-24 years (b = -€2945) and 25-34 years (b = -€1418) were found to have lower overall expenditures. A relevant disability (b = €441), DRE (b = €1253), frequent seizures (b = €735), and the need for specialized daycare (b = €749) were associated with higher direct COI, and poorer education (b = €1969), living alone (b = €2612), the presence of a relevant disability (b = €1809), DRE (b = €1831), and frequent seizures (b = €2385) were associated with higher indirect COI. SIGNIFICANCE: This analysis provides up-to-date COI data for use in further health economics analyses, highlighting the high economic impacts associated with disease severity, disability, and disease-related loss of productivity among adult patients with epilepsy. The identified cost drivers could be used as therapeutic and socioeconomic targets for future cost-containment strategies.

Trends in resource utilization and cost of illness in patients with active epilepsy in Germany from 2003 to 2020.

OBJECTIVE: This study was undertaken to calculate epilepsy-related direct, indirect, and total costs in adult patients with active epilepsy (ongoing unprovoked seizures) in Germany and to analyze cost components and dynamics compared to previous studies from 2003, 2008, and 2013. This analysis was part of the Epi2020 study. METHODS: Direct and indirect costs related to epilepsy were calculated with a multicenter survey using an established and validated questionnaire with a bottom-up design and human capital approach over a 3-month period in late 2020. Epilepsy-specific costs in the German health care sector from 2003, 2008, and 2013 were corrected for inflation to allow for a valid comparison. RESULTS: Data on the disease-specific costs for 253 patients in 2020 were analyzed. The mean total costs were calculated at €5551 (±€5805, median = €2611, range = €274-€21 667) per 3 months, comprising mean direct costs of €1861 (±€1905, median = €1276, range = €327-€13 158) and mean indirect costs of €3690 (±€5298, median = €0, range = €0-€11 925). The main direct cost components were hospitalization (42.4%), antiseizure medication (42.2%), and outpatient care (6.2%). Productivity losses due to early retirement (53.6%), part-time work or unemployment (30.8%), and seizure-related off-days (15.6%) were the main reasons for indirect costs. However, compared to 2013, there was no significant increase of direct costs (-10.0%), and indirect costs significantly increased (p < .028, +35.1%), resulting in a significant increase in total epilepsy-related costs (p < .047, +20.2%). Compared to the 2013 study population, a significant increase of cost of illness could be observed (p = .047). SIGNIFICANCE: The present study shows that disease-related costs in adult patients with active epilepsy increased from 2013 to 2020. As direct costs have remained constant, this increase is attributable to an increase in indirect costs. These findings highlight the impact of productivity loss caused by early retirement, unemployment, working time reduction, and seizure-related days off.

Gender differences in concerns about planning to have children and child-rearing among patients with epilepsy: A prospective, multicenter study with 477 patients from Germany.

OBJECTIVE: To analyze the concerns and worries about planning to have children and being a parent as a person with epilepsy and investigate gender differences in these perceptions. METHODS: The Epi2020 study was a large multicenter study focusing on different healthcare aspects of adult patients with epilepsy in Germany. In addition to basic clinical and demographic characteristics, patients were asked to answer a questionnaire regarding their plan to have children, if they had children, and concerns about their children's health. Data were analyzed to detect differences between men and women with epilepsy according to age group. RESULTS: In total, 477 patients with epilepsy with a mean age of 40.5 years (SD = 15.5, range: 18-83 years) participated in this study; 280 (58.7%) were female and 197 (41.3%) were male. Both women and men frequently reported concerns and worries about having children: In the age group below 45 years of age, 72.5% of women and 58.2% of men described being worried to some extent that their children may also suffer from epilepsy (p = .006). Furthermore, 67.3% of women and 54.2% of men below the age of 45 years reported being worried that their children may be disabled (p = .003). Women were more likely to have family members who are reluctant to support their desire to have children (p = .048). CONCLUSION: Women with epilepsy of childbearing age are significantly more likely to report major concerns that their children might be disabled or also have epilepsy than men with epilepsy and, therefore, express more concerns about choosing to have a child. However, men also report frequent concerns and worries, and this should be addressed not only on request but should be included in the provision of general information on epilepsy.

Trends in antiseizure medication prescription patterns among all adults, women, and older adults with epilepsy: A German longitudinal analysis from 2008 to 2020.

INTRODUCTION: The prescription patterns of antiseizure medication (ASM) are subject to new scientific evidence and sociodemographic and practical aspects. This study analyzed trends in ASM prescription patterns among all adults with epilepsy, with special consideration for women of childbearing potential (WOCBP) and older adult (≥65 years old) patients. METHODS: Data from four questionnaire-based cohort studies, conducted in 2008, 2013, 2016, and 2020, were analyzed for ASM prescription frequencies and common mono- and dual therapy regimens. Statistical comparisons were performed with the Chi-square test and one-way analysis of variance. RESULTS: Overall, the individual prescription patterns among 1,642 adult patients with epilepsy were analyzed. A significant increase in the prescription frequency of third-generation ASMs, from 59.3% to 84.2% (p = 0.004), was accompanied by a decrease in the frequency of first- and second-generation ASMs (5.4% to 2.1% and 34.9% to 12.6%, respectively). This trend was accompanied by a significant decrease in the use of enzyme-inducing ASMs, from 23.9% to 4.6% (p = 0.004). Among frequently prescribed ASMs, prescriptions of carbamazepine (18.6% to 3.1%, p = 0.004) and valproate (15.4% to 8.7%, p = 0.004) decreased, whereas prescriptions of levetiracetam (18.0% up to 32.4%, p = 0.004) increased significantly. The prescription frequency of lamotrigine remained largely constant at approximately 20% (p = 0.859). Among WOCBP, the prescription frequencies of carbamazepine (11.4% to 2.0%, p = 0.004) and valproate (16.1% to 6.1%, p = 0.004) decreased significantly. Levetiracetam monotherapy prescriptions increased significantly (6.6% to 30.4%, p = 0.004) for WOCBP, whereas lamotrigine prescriptions remained consistent (37.7% to 44.9%, p = 0.911). Among older adult patients, a significant decrease in carbamazepine prescriptions (30.1% to 7.8%, p = 0.025) was the only relevant change in ASM regimens between 2008 and 2020. In patients with genetic generalized epilepsies, levetiracetam was frequently used as an off-label monotherapy (25.0% to 35.3%). CONCLUSION: These results show a clear trend toward the use of newer and less interacting third-generation ASMs, with lamotrigine, levetiracetam, and lacosamide representing the current ASMs of choice, displacing valproate and carbamazepine over the last decade. In WOCBP, prescription patterns shifted to minimize teratogenic effects, whereas, among older adults, the decrease in carbamazepine use may reflect the avoidance of hyponatremia risks and attempts to reduce the interaction potential with other drugs and ASMs. Levetiracetam is frequently used off-label as a monotherapy in patients with genetic generalized epilepsy.

Long-term efficacy, tolerability, and retention of brivaracetam in epilepsy treatment: A longitudinal multicenter study with up to 5 years of follow-up.

OBJECTIVE: This study was undertaken to evaluate the long-term efficacy, retention, and tolerability of add-on brivaracetam (BRV) in clinical practice. METHODS: A multicenter, retrospective cohort study recruited all patients who initiated BRV between February and November 2016, with observation until February 2021. RESULTS: Long-term data for 262 patients (mean age = 40 years, range = 5-81 years, 129 men) were analyzed, including 227 (87%) diagnosed with focal epilepsy, 19 (7%) with genetic generalized epilepsy, and 16 (6%) with other or unclassified epilepsy syndromes. Only 26 (10%) patients had never received levetiracetam (LEV), whereas 133 (50.8%) were switched from LEV. The length of BRV exposure ranged from 1 day to 5 years, with a median retention time of 1.6 years, resulting in a total BRV exposure time of 6829 months (569 years). The retention rate was 61.1% at 12 months, with a reported efficacy of 33.1% (79/239; 50% responder rate, 23 patients lost-to-follow-up), including 10.9% reported as seizure-free. The retention rate for the entire study period was 50.8%, and at last follow-up, 133 patients were receiving BRV at a mean dose of 222 ± 104 mg (median = 200, range = 25-400), including 52 (39.1%) who exceeded the recommended upper dose of 200 mg. Fewer concomitant antiseizure medications and switching from LEV to BRV correlated with better short-term responses, but no investigated parameters correlated with positive long-term outcomes. BRV was discontinued in 63 (24%) patients due to insufficient efficacy, in 29 (11%) for psychobehavioral adverse events, in 25 (10%) for other adverse events, and in 24 (9%) for other reasons. SIGNIFICANCE: BRV showed a clinically useful 50% responder rate of 33% at 12 months and overall retention of >50%, despite 90% of included patients having previous LEV exposure. BRV was well tolerated; however, psychobehavioral adverse events occurred in one out of 10 patients. Although we identified short-term response and retention predictors, we could not identify significant predictors for long-term outcomes.

Patients' knowledge about epilepsy-related risks, morbidity, and mortality: A multicenter cohort study from Germany.

INTRODUCTION: Patient education is a central component of quality care. Enhancing patient knowledge can improve patients' quality of life and facilitate successful self-management. We sought to identify patients' knowledge levels and knowledge gaps regarding epilepsy-related risks, morbidity, and mortality. METHODS: Adult patients with epilepsy presenting to the university hospitals in Frankfurt, Greifswald, and Marburg between February 2018 and May 2020 were asked to participate in this questionnaire-based study. RESULTS: A total of 238 patients (52% women), with a mean age of 39.2 years (range: 18-77 years), participated in this study. Spontaneously, the majority of patients (51.3%) named driving a car, and other traffic-related accidents as possible causes of morbidity and mortality, and 23.9% of patients reported various causes of premature death, such as suffocation, drowning, and respiratory or cardiac arrest due to seizures. Falls due to epilepsy (19.7%) and injuries in general (17.6%) were named as further causes of morbidity and mortality. The vast majority were aware that alcohol (87.4%), sleep deprivation (86.6%), and risky activities in daily life (80.3%) increased the risk of seizure occurrence or increased morbidity and mortality. Regarding overall mortality, 52.1% thought that people with epilepsy were at greater risk of premature death, whereas 46.2% denied this fact to be true. Only 29.4% were aware of status epilepticus, and 27.3% were aware of sudden unexpected death in epilepsy (SUDEP). Driving ability, working ability, and seizure risk were named as major or moderate concerns among patients, but the risk of premature mortality was not a major concern. One-quarter of all patients (26.9%) indicated that they were not counseled about any risk factors or causes of morbidity or mortality by their physicians. CONCLUSIONS: A lack of knowledge concerning premature mortality, SUDEP, and status epilepticus exists among adult patients with epilepsy. A substantial number of patients indicated that these issues were not discussed adequately by their physicians.

Counseling and social work for people with epilepsy in Germany: A cross-sectional multicenter study on demand, frequent content, patient satisfaction, and burden-of-disease.

BACKGROUND: The diagnosis of epilepsy is accompanied by relevant personal, interpersonal, and professional restrictions for patients and their caregivers. Specialized epilepsy counseling services (ECS) have been introduced to inform, advise, and support patients with disease-related problems. AIM AND SCOPE: The objective of this cross-sectional, multicenter study was to determine the demand, typical content, and outcomes of ECS in children, adolescents, and adults in two adjacent German regions of Hessen and Lower Franconia. All ECS sites in these regions participated in 2014 and 2015, offering a total population of 7.5 million inhabitants. RESULTS: A total number of 435 patients [323 adults (74.3%), 51.7% female, mean age: 40.3 ±â€¯14.7 years and 112 children/adolescents (25.7%), 52.7% female, mean age: 9.4 ±â€¯4.6 years] were enrolled at six ECS sites. The most common reasons for counseling were general information needs (n = 304; 69.9%), administrative help (n = 208; 47.8%), problems with education or work (n = 176; 40.5%), and recreational activities (n = 119; 27.3%). In addition, 6.2% reported epilepsy-related questions on family planning as a specific reason for desiring counseling. Recommendation by the treating physicians was the most frequent reason for receiving counseling through ECS (62.5%), and most patients preferred to receive a personal consultation (73.1%). Patient satisfaction as measured by the ZUF-8 client satisfaction score was high with a mean of 29.7 points (standard deviation: ±2.7 points, median: 29.9 points), and 83.9% of patients said they would recommend ECS. Disease-related job loss or change in school was avoided in 72% of 82 patients. Suggestions for improvement of ECS included an extension of service hours (58.6%) and a better availability of more sites located nearby (32.8%). CONCLUSION: Epilepsy counseling services are necessary, valued, and effective institutions for people with epilepsy complementing outpatient and inpatient care. To improve the care for people with epilepsy, access to and availability of ECS should be improved.

Secreted frizzled-related protein 5 serum levels in human periodontitis-A nested case-control study.

AIM: Recombinant secreted frizzled-related protein 5 (sFRP5) improved periodontal status in mice. Thus, this study aimed to investigate this finding in human periodontitis using an epidemiological approach. MATERIALS AND METHODS: sFRP5 and wnt5a concentrations were determined in human serum from the Food Chain Plus cohort using ELISAs. A total of 128 patients with periodontitis and tooth loss and 245 patients with periodontitis without tooth loss were compared to 373 sex-, smoker-, age- and BMI-matched individuals in a nested case-control design. RESULTS: Systemic sFRP5 serum levels were significantly lower in patients with periodontitis and tooth loss (2.5 [0.0-10.4] ng/ml, median [IQR]) compared to patients with periodontitis without tooth loss (6.0 [2.5-15.8] ng/ml, median [IQR], p = 0.04] and matched controls (7.0 [2.5-18.3] ng/ml, median [IQR], p = 0.02). No significant differences in sFRP5 serum levels were found among patients with periodontitis without tooth loss (6.0 [2.5-15.8] ng/ml, median [IQR]) and controls (3.1 [0.0-10.6] ng/ml, median [IQR], p = 0.06). CONCLUSIONS: sFRP5 might serve as a novel biomarker for periodontitis severity. Modulating the inflammatory background of severe forms of periodontitis, in the time of precision medicine, needs to be revealed in further studies.

[Acceptance, demand, reasons for consultation and outcome of counseling on epilepsy in Hesse and Lower Franconia]. / Akzeptanz, Bedarf, Konsultationsgründe und Beratungsoutcome von Epilepsieberatung in Hessen und Unterfranken.

BACKGROUND AND AIM: The diagnosis of epilepsy is often accompanied by relevant restrictions for patients, which may result in disease-specific daily problems that need targeted and professional counseling. Specialized epilepsy counseling services (ECS) were introduced in some German states since 1996 to provide an additional and independent service for epilepsy-related problems. The objective of this prospective, multicenter cohort study at six ECS was to determine and analyze the acceptance, demand and frequent reasons for consultation in Hesse and Lower Franconia. RESULTS: A total of 435 clients were enrolled during the 12-month observation period (June 2014-May 2015) of which 74.3% were adults (n = 323, mean age 40.3 ± 14.7 years, range 18-76 years, 51.7% female) and 25.7% children and adolescents (n = 112, mean age 9.4 ± 4.8 years, range 1-17 years, 52.7% female). The mean number of outpatient consultations per year was 2.5 (median 2.0, SD ± 2.8, range 1-20), whereby a general counseling on dealing with epilepsy (adults 55.7%, children and adolescents 51.8%), clarification and information about the disease (43.7% and 41.1%, respectively) and assistance in applying for support (39.0% and 46.4%, respectively) were the most frequent issues. The distance from the place of residence to the ECS was significantly shorter in Lower Franconia compared to Hesse (p < 0.002). Client satisfaction was high with a mean patient satisfaction questionnaire (ZUF-8) score of 29.0 (maximum score 32). Overall 96.4% of the clients rated the quality of counseling as good or very good and 96.6% would consider consulting the ECS again in case of new problems. In cases of threatened workplace, training position or situation at school, counseling helped to avoid negative consequences in 72.0% of cases. CONCLUSION: The ECS are frequently used, appreciated and effective institutions for adults and children with epilepsy as well as for their caregivers. The ECS complements the existing comprehensive specialized outpatient and inpatient care for epilepsy in Germany; however, in view of their limited numbers and inhomogeneous allocation, the number and the availability of ECS should be expanded on the national level.

Inferring causal metabolic signals that regulate the dynamic TORC1-dependent transcriptome.

Cells react to nutritional cues in changing environments via the integrated action of signaling, transcriptional, and metabolic networks. Mechanistic insight into signaling processes is often complicated because ubiquitous feedback loops obscure causal relationships. Consequently, the endogenous inputs of many nutrient signaling pathways remain unknown. Recent advances for system-wide experimental data generation have facilitated the quantification of signaling systems, but the integration of multi-level dynamic data remains challenging. Here, we co-designed dynamic experiments and a probabilistic, model-based method to infer causal relationships between metabolism, signaling, and gene regulation. We analyzed the dynamic regulation of nitrogen metabolism by the target of rapamycin complex 1 (TORC1) pathway in budding yeast. Dynamic transcriptomic, proteomic, and metabolomic measurements along shifts in nitrogen quality yielded a consistent dataset that demonstrated extensive re-wiring of cellular networks during adaptation. Our inference method identified putative downstream targets of TORC1 and putative metabolic inputs of TORC1, including the hypothesized glutamine signal. The work provides a basis for further mechanistic studies of nitrogen metabolism and a general computational framework to study cellular processes.

Predictors for and use of rescue medication in adults with epilepsy: A multicentre cross-sectional study from Germany.

BACKGROUND: Seizure clusters, prolonged seizures, and status epilepticus are life-threatening neurological emergencies leading to irreversible neuronal damage. Benzodiazepines are current evidence-based rescue therapy options; however, recent investigations indicated the prescription of mainly unsuitable benzodiazepines and inappropriate use of rescue medication. OBJECTIVE: To examine current use, satisfaction, and adverse events concerning rescue medication in patients with epilepsy in Germany. PATIENTS AND METHODS: The study was conducted at epilepsy centres in Frankfurt am Main, Greifswald, Marburg, and Münster between 10/2020 and 12/2020. Patients with an epilepsy diagnosis were assessed based on a questionnaire examining a 12-month period. RESULTS: In total, 486 patients (mean age: 40.5, range 18-83, 58.2 % female) participated in this study, of which 125 (25.7 %) reported the use of rescue medication. The most frequently prescribed rescue medications were lorazepam tablets (56.8 %, n = 71 out of 125), buccal midazolam (19.2 %, n = 24), and rectal diazepam (10.4 %, n = 13). Seizures continuing for over several minutes (43.2 %, n = 54), seizure clusters (28.0 %, n = 35), and epileptic auras (28.0 %, n = 35) were named as indications, while 28.0 % (n = 35) stated they administered the rescue medication for every seizure. Of those continuing to have seizures, 46.0 % did not receive rescue medication. On average, rescue medication prescription occurred 7.1 years (SD 12.7, range 0-66) after an epilepsy diagnosis. CONCLUSIONS: Unsuitable oral benzodiazepines remain widely prescribed for epilepsy patients as rescue medication. Patients also reported inappropriate use of medication. A substantial proportion of patients who were not seizure-free did not receive rescue medication prescriptions. Offering each patient at risk for prolonged seizures or clusters of seizures an individual rescue treatment with instructions on using it may decrease mortality and morbidity and increase quality of life. .

Association of spermidine blood levels with microstructure of sleep-implications from a population-based study.

Deteriorations in slow wave sleep (SWS) have been linked to brain aging and Alzheimer's disease (AD), possibly due to its key role in clearance of amyloid-beta and tau (Aß/tau), two pathogenic hallmarks of AD. Spermidine administration has been shown to improve sleep quality in animal models. So far, the association between spermidine levels in humans and parameters of SWS physiology are unknown but may be valuable for therapeutic strategies. Data from 216 participants (age range 50-81 years) of the population-based Study of Health in Pomerania TREND were included in our analysis. We investigated associations between spermidine plasma levels, key parameters of sleep macroarchitecture and microarchitecture that were previously associated with AD pathology, and brain health measured via a marker of structural brain atrophy (AD score). Higher spermidine levels were significantly associated with lower coupling between slow oscillations and spindle activity. No association was evident for SWS, slow oscillatory, and spindle activity throughout non-rapid eye movement sleep. Furthermore, elevated spermidine blood levels were significantly associated with a higher AD score, while sleep markers revealed no association with AD score. The association between higher spermidine levels and brain health was not mediated by coupling between slow oscillations and spindle activity. We report that higher spermidine blood levels are associated not only with deteriorated brain health but also with less advantageous markers of sleep quality in older adults. Future studies need to evaluate whether sleep, spermidine, and Aß/tau deposition are interrelated and whether sleep may play a mediating role.

Counseling and social work for persons with epilepsy: observational study on demand and issues in Hessen, Germany.

The goal of the social management of epilepsy is to decrease the physical, psychological, and social consequences for persons with epilepsy (PWEs). The objective of this observational study was to determine the needs and issues of PWEs in the utilization of epilepsy counseling services between 2008 and 2012 in the German state of Hessen. Sociodemographic data, employment status, counseling issues, and characteristics were collected at first and follow-up visits. An average of 492 (272 males, 55.3%) PWEs presented at counseling services per year. These were mainly children or adolescents below the age of 20years (22.4%) and PWEs in working age between 20 and 65years (73.6%). The majority of PWEs seeking counseling were employed (44.4%, annual average: 219 PWEs, SD: 39). However, a substantial part (114/219, 52.1%) of these employed PWEs reported problems or difficulties at their workplace associated with the diagnosis of epilepsy. We could identify four major issues addressed by the PWEs as 1) diagnosis of epilepsy, 2) employment, 3) family-related matters, and 4) social or medical aids linked with public authorities. This study demonstrated the continuous demand for epilepsy counseling with at least one out of twenty (5.8%) PWEs in need of counseling per year. Further studies are warranted to answer questions on outcome and long-term course. Epilepsy counseling should be available to all PWEs on a national level and may be helpful in preventing long-term unemployment and early retirement while maintaining quality of care for PWEs.

The preoperative use of navigated transcranial magnetic stimulation facilitates early resection of suspected low-grade gliomas in the motor cortex.

BACKGROUND: Resection is recommended for low-grade gliomas, but often it is not performed if the tumor is suspected of invading the primary motor cortex. The study aim is to assess what influence preoperative navigated transcranial magnetic stimulation (nTMS) has on the treatment strategy and clinical outcome for suspected low-grade gliomas in presumed motor eloquent location. METHODS: This paper reports on all our patients with gliomas in the primary motor cortex that were non-enhancing on MRI, since we began using nTMS (n = 11). For the comparison group, we identified the 11 most recent such patients just before we started using nTMS. RESULTS: Exact delineation of motor functional versus non-functional cortical tissue was provided by nTMS in all cases, also within the area of altered FLAIR signal. In 6 out of 11 cases, the nTMS mapping result changed the treatment plan towards early and more extensive resection. Only one nTMS patient had another seizure within the follow-up period, whereas four patients in the comparison group had further seizures. In the nTMS group, 1 of 4 patients with pre-op neurological deficits improved by one year; whereas the comparison group had increased neurological deficits in 3 of the 8 patients not having surgery. The median (range) change of tumor volume from baseline to 1 year was -83 % (-67 % to -100 %) in the nTMS group, but +12 % (+40 % to -56 %) in the comparison group (p < 0.001). CONCLUSIONS: nTMS provides accurate motor mapping results also in infiltrative gliomas and enables more frequent and more extensive surgical resection of non-enhancing gliomas in or near the primary motor cortex. The substantial differences observed here in neurological and oncological outcomes suggest that further comparative research is warranted.

The reliability of topographic measurements from navigated transcranial magnetic stimulation in healthy volunteers and tumor patients.

BACKGROUND: Navigated transcranial magnetic stimulation (nTMS) is increasingly being used for preoperative mapping of the motor cortex. Any new technology should undergo rigorous validation before being widely adopted in routine clinical practice. The aim of this experimental study was to assess the intraexaminer and interexaminer reliability of topographic mapping with nTMS. METHODS: nTMS mapping of the motor cortex for the first dorsal interosseous (FDI) muscle was performed by an expert and a novice examiner, twice in ten healthy volunteers and once in ten tumor patients. The distances between the centers-of-gravity and hotspots were calculated, as were coefficients of variation. This study also compared orthogonal versus variable orientation of the stimulation coil. RESULTS: The mean (range) distance between centers-of-gravity for the expert examiner in the test-retest protocol with healthy volunteers was 4.40 (1.86-7.68) mm. The mean (range) distance between centers-of-gravity for the expert vs. novice examiner was 4.89 (2.39-9.22) mm. There were no significant differences in this result between healthy volunteers and tumor patients. CONCLUSIONS: nTMS is sufficiently reliable for clinical use, but examiners should make efforts to minimize sources of error. The reliability of nTMS in tumor patients appears comparable to healthy subjects.