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Purpose: We assessed clinical cases to investigate the spectrum of indications for ultra-longterm EEG monitoring using a subcutaneous implantable device in adult patients with focal epilepsy., Methods: Electronic charts were reviewed from patients undergoing ultra-longterm recordings at the European Epilepsy centers Barcelona, Freiburg and Vienna. Specific patient settings approached in the three centers were analyzed, and the main clinical question was extracted. Results from recordings were analyzed based on the specific results and information obtained., Results: 24 patients in whom ultra-longterm recordings were available were analyzed. A total of 11 main indications for subcutaneous long-term EEG recordings were identified, including the identification of active epilepsy in patients with low seizure frequency, under- and overreporting of patients, differentiation of non-epileptic from epileptic events, assessment of seizure severity, circadian and multidian rhythms of seizure occurrence, validation of treatment efficacy, improvement of patient-based reporting and medicolegal evidence for seizure freedom. This is reported with patient-specific case vignettes., Conclusion: Ultra-longterm monitoring using subcutaneous implantable EEG devices can provide relevant diagnostic and treatment information in a large spectrum of clinical situations. This is discussed considering the intrinsic limitations of the method related to spatial coverage, sensitivity and validity as a biomarker of ongoing seizures., Competing Interests: Declaration of competing interest Rodrigo Rocamora has received honoraria as a medical advisor and for lectures from UNEEG. Christoph Baumgartner has received personal honoraria for lectures or advice from UNEEG related to the topic. Andreas Schulze-Bonhage has received research funding from UNEEG and from the Epilepsy Foundation and personal honoraria for lectures or advice from UNEEG related to the topic. The other authors have no potential conflicts of interest to disclose., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: Focal seizure symptoms (FSS) and focal interictal epileptiform discharges (IEDs) are common in patients with idiopathic generalized epilepsies (IGEs), but dedicated studies systematically quantifying them both are lacking. We used automatic IED detection and localization algorithms and correlated these EEG findings with clinical FSS for the first time in IGE patients., Methods: 32 patients with IGEs undergoing long-term video EEG monitoring were systematically analyzed regarding focal vs. generalized IEDs using automatic IED detection and localization algorithms. Quantitative EEG findings were correlated with FSS., Results: We observed FSS in 75% of patients, without significant differences between IGE subgroups. Mostly varying/shifting lateralizations of FSS across successive recorded seizures were seen. We detected a total of 81,949 IEDs, whereof 19,513 IEDs were focal (23.8%). Focal IEDs occurred in all patients (median 13% focal IEDs per patient, range 1.1 - 51.1%). Focal IED lateralization and localization predominance had no significant effect on FSS., Conclusions: All included patients with IGE showed focal IEDs and three-quarter had focal seizure symptoms irrespective of the specific IGE subgroup. Focal IED localization had no significant effect on lateralization and localization of FSS., Significance: Our findings may facilitate diagnostic and treatment decisions in patients with suspected IGE and focal signs., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: Cortical spreading depolarization is highly conserved among the species. It is easily detectable in direct cortical surface recordings and has been recorded in the cortex of humans with severe neurological disease. It is considered the pathophysiological correlate of human migraine aura, but direct electrophysiological evidence is still missing. As signatures of cortical spreading depolarization have been recognized in scalp EEG, we investigated typical spontaneous migraine aura, using full band high-density EEG (HD-EEG)., Methods: In this prospective study, patients with migraine with aura were investigated during spontaneous migraine aura and interictally. Time compressed HD-EEG were analyzed for the presence of cortical spreading depolarization characterized by (a) slow potential changes below 0.05 Hz, (b) suppression of faster activity from 0.5 Hz - 45 Hz (c) spreading of these changes to neighboring regions during the aura phase. Further, topographical changes in alpha-power spectral density (8-14 Hz) during aura were analyzed., Results: In total, 26 HD-EEGs were recorded in patients with migraine with aura, thereof 10 HD-EEGs during aura. Eight HD-EEGs were recorded in the same subject. During aura, no slow potentials were recorded, but alpha-power was significantly decreased in parieto-occipito-temporal location on the hemisphere contralateral to visual aura, lasting into the headache phase. Interictal alpha-power in patients with migraine with aura did not differ significantly from age- and sex-matched healthy controls., Conclusions: Unequivocal signatures of spreading depolarization were not recorded with EEG on the intact scalp in migraine. The decrease in alpha-power contralateral to predominant visual symptoms is consistent with focal depression of spontaneous brain activity as a consequence of cortical spreading depolarization but is not specific thereof., Significance: Cortical spreading depolarization is relevant in migraine, other paroxysmal neurological disorders and neurointensive care., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: Pharmacologic thromboprophylaxis (pTPX) might exacerbate the risk of clinically relevant bleeding (CRB) and hospital-acquired anemia (HAA) in older multimorbid inpatients., Objectives: We aimed to evaluate the association of pTPX use with CRB and HAA., Methods: We used data from a prospective cohort study conducted in 3 Swiss university hospitals. Adult patients admitted to internal medicine wards with no therapeutic anticoagulation were included. pTPX use was ascertained during hospitalization. Outcomes were in-hospital CRB and HAA. We calculated incidence rates by status of pTPX. We assessed the association of pTPX with CRB using survival analysis and with HAA using logistic regression, adjusted for infection, length of stay, and the International Medical Prevention Registry on Venous Thromboembolism bleeding risk score., Results: Among 1305 patients (mean age, 63.7 years; 44% women, 90% at low risk of bleeding), 809 (62%) received pTPX. The incidence of CRB was 2.4 per 1000 patient-days and was not significantly higher in patients with pTPX than in those without. We found no significant association between pTPX and CRB. HAA was frequent (20.2%) and higher in patients with pTPX than in those without (23.2% vs 15.3%). The incidence of HAA was 21.2 per 1000 patient-days and did not significantly differ between patients with pTPX and those without. We found an association between pTPX and HAA (adjusted odds ratio, 1.4; 95% CI, 1.0-2.1)., Conclusion: Our study confirmed the safety of pTPX in medical inpatients at low risk of bleeding but identified an association between pTPX and HAA. Adherence to guidelines that recommend administering pTPX to medical inpatients at increased venous thromboembolism risk and low bleeding risk is necessary., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Background: Health-related quality of life (QoL) impairment is common after pulmonary embolism (PE). Whether the severity of the initial PE has an impact on QoL is unknown., Objectives: To evaluate the association between severity of PE and QoL over time., Methods: We prospectively assessed PE-specific QoL using the Pulmonary Embolism Quality of Life (lower scores indicate better QoL) questionnaire and generic QoL using the Short Form 36 (higher scores indicate better QoL) questionnaire at baseline and 3 and 12 months in older patients with acute PE. We examined whether QoL differed by PE severity based on hemodynamic status, simplified Pulmonary Embolism Severity Index (sPESI), right ventricular function, and high-sensitivity troponin T in mixed-effects models, adjusting for known QoL predictors after PE., Results: Among 546 patients with PE (median age, 74 years), severe vs nonsevere PE based on the sPESI was associated with a worse PE-specific (adjusted mean Pulmonary Embolism Quality of Life score difference of 6.1 [95% CI, 2.4-9.8] at baseline, 7.6 [95% CI, 4.0-11.3] at 3 months, and 6.7 [95% CI, 2.9-10.4] at 12 months) and physical generic QoL (adjusted mean Short Form 36 Physical Component Summary score difference of -3.8 [95% CI, -5.5 to -2.1] at baseline, -4.8 [95% CI, -6.4 to -3.1] at 3 months, and -4.1 [95% CI, -5.8 to -2.3] at 12 months). Elevated troponin levels were also associated with lower PE-specific QoL at 3 months and lower physical generic QoL at 3 and 12 months. QoL did not differ by hemodynamic status or right ventricular function., Conclusion: Severe PE based on the sPESI was consistently associated with worse PE-specific and physical generic QoL over time as compared to nonsevere PE., Competing Interests: Declaration of Competing Interests There are no competing interests to disclose.

Objective: Demonstrating a pilot implementation of the Digital Imaging and Communication in Medicine (DICOM) neurophysiology standard published in 2020., Methods: An automated workflow for converting EEG data from a proprietary vendor EEG format to standardized and interoperable DICOM format was developed and tested., Results: Retrieval of proprietary EEG data, associated videos, annotations and metadata from the vendor EEG archive and their subsequent conversion to DICOM EEG was possible without changes to the departmental workflow. To transfer DICOM EEG data to the central radiology DICOM archive, only minor extensions in the parameterization of the archive's DICOM interfaces were necessary. Linkage with the electronic health record (EHR) and display in a DICOM EEG viewer could be demonstrated. A random sample of 88 DICOM EEG studies was compared to the original vendor files and EEG and video file sizes were comparable., Conclusions: Storing and reviewing EEG data in standardized DICOM format is feasible, facilitated by existing DICOM infrastructure, and therefore allows for vendor independent access to EEG data., Significance: We report the first implementation of the DICOM neurophysiology standard, thus promoting standardization in the field of neurophysiology as well as data exchange and access to legacy recordings in an interoperable vendor independent format., (Copyright © 2023 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: We aimed to evaluate the quality of life (QoL), using patient-reported outcome measures (PROMs), in elderly patients with venous thromboembolism (VTE) and to explore whether VTE complications (recurrence, bleeding, or postthrombotic syndrome) had an impact on later QoL., Methods: We used data from the SWIss venous Thromboembolism COhort of older patients(SWITCO65+), a prospective multicenter cohort of patients aged ≥65 years with acute, symptomatic VTE. Primary outcome was changes in QoL up to 24 months, assessed using generic (36-Item Short-Form Health Survey), with physical (PCS) and mental component score (MCS), and disease-specific (Venous Insufficiency Epidemiological and Economic Study [VEINES]-QoL, [VEINES-Sym], and Pulmonary Embolism QoL) PROMs. PROM scores ranged from 0 to 100 points, higher scores indicating a better QoL. Longitudinal latent class analysis was used to group patients with similar PCS trajectories. Repeated-measures linear regression analyses were used to assess effects of VTE complications on changes in QoL scores., Results: In 923 patients (median age, 75; male, 54%), 140 (15%) patients died, 97 (11%) experienced recurrent VTE, and 106 (12%) major bleeding during follow-up. Compared with patients with higher PCS trajectories, patients with lower PCS trajectories were more likely to be older, female, sicker, and less physically active. On average, generic and disease-specific QoL scores improved over time (+11% in PCS, +3% in MCS, +6% in VEINES QoL, and +16% in Pulmonary Embolism QoL at 3 months). VTE complications were always associated with significantly lower QoL scores (for VTE recurrence: PCS adjusted difference -2.57, 95% CI, -4.47 to -0.67)., Conclusion: Although QoL following VTE tended to improve over time, patients with VTE-related complications had lower QoL than patients without complications., Competing Interests: Declaration of competing interest There are no competing interests to disclose., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Background: Health-related quality of life (QoL) impairment is common after pulmonary embolism (PE). Whether severity of the initial PE has an impact on QoL is unknown., Objective: To evaluate the association between severity of PE and QoL over time., Methods: We prospectively assessed PE-specific QoL using the Pulmonary Embolism Quality of Life (PEmb-QoL; lower scores indicate better QoL) and generic QoL using the Short Form 36 (SF-36; higher scores indicate better QoL) questionnaire at baseline, 3, and 12 months in older patients with acute PE. We examined whether QoL differed by PE severity based on hemodynamic status, simplified Pulmonary Embolism Severity Index (sPESI), right-ventricular function, and high-sensitivity (hs)-troponin T in mixed-effects models, adjusting for known QoL predictors after PE., Results: Among 546 patients with PE (median age 74 years), severe vs. non-severe PE based on the sPESI was associated with a worse PE-specific (adjusted mean PEmb-QoL score difference of 6.1 [95%CI 2.4;9.8] at baseline, 7.6 [95%CI 4.0;11.3] at 3 months, and 6.7 [95%CI 2.9;10.4] at 12 months) and physical generic QoL (adjusted mean SF-36 Physical Component Summary score difference -3.8 [95%CI -5.5;-2.1] at baseline; -4.8 [95%CI -6.4;-3.1] at 3 months; -4.1 [95%CI -5.8;-2.3] at 12 months). Elevated troponin was also associated with lower PE-specific QoL at 3 and physical generic QoL at 3 and 12 months. QoL did not differ by hemodynamic status or right-ventricular function., Conclusion: Severe PE based on the sPESI was consistently associated with worse PE-specific and physical generic QoL over time as compared to non-severe PE., (Copyright © 2023. Published by Elsevier Inc.)

Background: Thromboprophylaxis (TPX) prescription is recommended in medical inpatients categorized as high risk of venous thromboembolism (VTE) by validated risk assessment models (RAMs), but how various RAMs differ in categorizing patients in risk groups, and whether the choice of RAM influences estimates of appropriate TPX use is unknown., Objectives: To determine the proportion of medical inpatients categorized as high or low risk according to validated RAMs, and to investigate the appropriateness of TPX prescription., Methods: This is a prospective cohort study of acutely ill medical inpatients from 3 Swiss university hospitals. Participants were categorized as high or low risk of VTE by validated RAMs (ie, the Padua, the International Medical Prevention Registry on Venous Thromboembolism , simplified, and original Geneva scores). We assessed prescription of any TPX at baseline. We considered TPX prescription in high-risk and no TPX prescription in low-risk patients as appropriate., Results: Among 1352 medical inpatients, the proportion categorized as high risk ranged from 29.8% with the International Medical Prevention Registry on Venous Thromboembolism score to 66.1% with the original Geneva score. Overall, 24.6% were consistently categorized as high risk, and 26.3% as low risk by all 4 RAMs. Depending on the RAM used, TPX prescription was appropriate in 58.7% to 63.3% of high-risk (ie, 36.7%-41.3% underuse) and 52.4% to 62.8% of low-risk patients (ie, 37.2%-47.6% overuse)., Conclusion: The proportion of medical inpatients considered as high or low VTE risk varied widely according to different RAMs. Only half of patients were consistently categorized in the same risk group by all RAMs. While TPX remains underused in high-risk patients, overuse in low-risk patients is even more pronounced., (© 2023 The Author(s).)

Serine-threonine kinase (STK11), also known as liver kinase B1 (LKB1), is a regulator of cellular homeostasis through regulating the cellular ATP-to-ADP ratio. LKB1 is classified as a tumor suppressor and functions as the key activator of AMP-activated protein kinase (AMPK) and a family of serine-threonine kinases called AMPK-like proteins. These proteins include novel (nua) kinase family 1 (NUAK1 and 2), salt inducible kinase (SIK1), QIK (known as SIK2), QSK (known as SIK3 kinase), and maternal embryonic leuzine zipper kinase (MELK) on tightly controlled and specific residual sites. LKB1 also regulates brain selective kinases 1 and 2 (BRSK1 and 2), additional members of AMPK-like protein family, which functions are probably less studied. AMPK-like proteins play a role in variety of reproductive physiology functions such as follicular maturation, menopause, embryogenesis, oocyte maturation, and preimplantation development. In addition, dysfunctional activity of AMPK-like proteins contributes to apoptosis blockade in cancer cells and induction of the epithelial-mesenchymal transition required for metastasis. Dysregulation of these proteins occurs in ovarian, endometrial, and cervical cancers. AMPK-like proteins are still undergoing further classification and may represent novel targets for targeted gynecologic cancer therapies. In this chapter, we describe the AMPK-like family of proteins and their roles in reproductive physiology and gynecologic cancers., (Copyright © 2023. Published by Elsevier Inc.)

Objective: We studied the influence of seizure pattern morphology on detection rate and detection delay of an automatic seizure detection system. We correlated seizure pattern morphology with seizure onset zone and assessed the influence of seizure onset zone on the performance of the seizure detection system., Methods: We analyzed 10.000 hours of EEG in 129 patients, 193 seizures in 67 patients were included in the final analysis. Seizure pattern morphologies were classified as rhythmic activity (alpha, theta and delta), paroxysmal fast activity, suppression of activity, repetitive epileptiform and arrhythmic activity. The seizure detection system EpiScan was compared with visual analysis., Results: Detection rates were significantly higher for rhythmic and repetitive epileptiform activities than for paroxysmal fast activity. Seizure patterns significantly correlated with seizure onset zone. Detection rate was significantly higher in temporal lobe (TL) seizures than in frontal lobe (FL) seizures. Detection delay tended to be shorter in seizures with rhythmic alpha or theta activity. TL seizures were significantly more often detected within 10 seconds than FL seizures., Conclusions: Seizure morphology is critical for optimization of automatic seizure detection algorithms., Significance: This study is unique in exploring the influence of seizure pattern morphology on automatic seizure detection and can help future research on seizure detection in epilepsy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objectives: Gamma transcranial alternating current stimulation (gamma tACS) is considered a non-invasive brain stimulation technique for modulation of cognitive performance and for treatment of psychiatric disorders. There is heterogeneous data on its effectiveness in improving working memory., Methods: In this randomized crossover study, we tested 22 patients with major depression and 21 healthy volunteers who received 20 min of active and sham 40 Hz gamma tACS over bilateral dorsolateral prefrontal cortex during a computerized n-back task in a cross-over design., Results: We showed no improvement in reaction time and accuracy of working memory during active or sham stimulation in both groups, and no interaction between cognitive load and stimulation conditions., Conclusion: The present study suggests that a single session of gamma tACS does not affect cognition in depression. However, the bilateral electrode montage and learning or ceiling effects may have affected results. Overall, this study is in line with the heterogeneous results of previous gamma tACS studies, emphasizing that methodologies and study designs should be harmonized., Competing Interests: Conflict of Interest UP has received speaker's honoraria from neuroCareGroup, Munich, Germany and had a private practice with this company. WS has received speaker's honoraria from Mag&More GmbH, Munich, Germany. FP is a member of the European Scientific Advisory Board of Brainsway Inc., Jerusalem, Israel, and has received speaker's honoraria from Mag&More and neuroCareGroup. His-lab has received support with equipment from neuroConn GmbH, Ilmenau, Germany, and Mag&More and Brainsway. AH has been invited to scientific meetings by Lundbeck, Janssen, and Pfizer, and he received paid speakerships from Desitin, Janssen, Otsuka, and Lundbeck. He was member of Roche, Otsuka, Lundbeck, and Janssen advisory boards. The other authors declare no conflict of interest., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Background: Depression and harmful alcohol use are two of the top five leading causes of years of life lost to disability in high-income countries. Integrated treatment targeting both at the same time is often considered more complicated and difficult and, therefore, more expensive. Consequently, integrated internet-based interventions could be a valuable addition to traditional care., Methods: A three-arm randomized controlled trial was conducted comparing the effectiveness of (1) an integrated, minimal-guidance, adherence-focused self-help intervention designed to reduce both alcohol use and depression symptoms (AFGE-AD); (2) a similar intervention designed to reduce alcohol use only (AFGE-AO), and (3) internet access as usual (IAU) as a control condition, in at least moderately depressed alcohol misusers from February 2016-March 2020. We recruited 689 alcohol misusers (51.6 % males, mean age = 42.8 years) with at least moderate depression symptoms not otherwise in treatment from the general population. Six months after baseline, 288 subjects (41.8 %) were reachable for the final assessment., Results: All interventions yielded reduced alcohol-use after six months (AFGE-AD: -16.6; AFGE-AO: -19.8; IAU: -13.2). Those who undertook active-interventions reported significantly fewer standard drinks than controls (AFGE-AD: p = .048, d=0.10; AFGE-AO: p = .004, d=0.20). The two active-intervention groups also reported significantly less severe depression symptoms than controls (AFGE-AD: p = .006, d=0.41; AFGE-AO: p = .008, d=0.43). Testing revealed noninferiority between the two interventions., Conclusions: This study documented sustained effectiveness of the first integrated, fully internet-based self-help intervention developed for the reduction of both alcohol use and depression symptoms in at least moderately depressed adult alcohol misusers recruited from the general population., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To quantify effects of sleep and seizures on the rate of interictal epileptiform discharges (IED) and to classify patients with epilepsy based on IED activation patterns., Methods: We analyzed long-term EEGs from 76 patients with at least one recorded epileptic seizure during monitoring. IEDs were detected with an AI-based algorithm and validated by visual inspection. We then used unsupervised clustering to characterize patient sub-cohorts with similar IED activation patterns regarding circadian rhythms, deep sleep activation, and seizure occurrence., Results: Five sub-cohorts with similar IED activation patterns were found: "Sporadic" (14%, n = 10) without or few IEDs, "Continuous" (32%, n = 23) with weak circadian/deep sleep or seizure modulation, "Nighttime & seizure activation" (23%, n = 17) with high IED rates during normal sleep times and after seizures but without deep sleep modulation, "Deep sleep" (19%, n = 14) with strong IED modulation during deep sleep, and "Seizure deactivation" (12%, n = 9) with deactivation of IEDs after seizures. Patients showing "Deep sleep" IED pattern were diagnosed with temporal lobe epilepsy in 86%, while 80% of the "Sporadic" cluster were extratemporal., Conclusions: Patients with epilepsy can be characterized by using temporal relationships between rates of IEDs, circadian rhythms, deep sleep and seizures., Significance: This work presents the first approach to data-driven classification of epilepsy patients based on their fully validated temporal pattern of IEDs., Competing Interests: Declaration of Competing Interest Franz Fürbass, Manfred Hartmann, and Georg Brandmayr are employees of AIT. Christoph Baumgartner, Sebastian Hafner, and Johannes Koren report no conflict of interest regarding the content of this study., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Purpose: Epilepsy is one of the most common chronic neurological disorders, and long-term treatment with antiseizure medication is often central to its management. The costs of antiseizure medication are more evident than other disease-related costs; thus, we assessed the direct and indirect costs of epilepsy focusing on both drug expenditure and other cost-driving factors., Methods: Outpatient records and questionnaires applied in a tertiary epilepsy centre in Vienna were used in this bottom-up cost-of-illness study to evaluate disease duration, age at onset, epilepsy syndrome, seizure frequency, sex, healthcare utilisation, diagnostic evaluations, antiseizure medication, and occupation. Cost data were clustered in a histogram-based data analysis, and multivariate regressions were performed to identify cost drivers., Results: The average annual costs of 273 patients amounted to €9,256 ($10,459): €4,486 ($5,069) direct costs and €4,770 ($5,390) indirect costs. A histogram of semi-annual costs revealed distinct groups with low costs (< €2,500 = $2,825) and high costs (> €2,500 = $2,825). Seizure-free patients were clustered in the group with low costs; patients with ongoing seizures appeared more frequently in the group with high costs. Working patients were more often found in the group with low costs, whereas unemployed patients were more prevalent in the group with high costs. The regression analysis confirmed worklessness as the main cost driver., Conclusion: Non-productivity and poorly controlled disease with ongoing seizures are associated with higher costs in epilepsy. Providing high-level care and optimal drug treatment that enables patients to remain in work may help reduce the economic burden of epilepsy., (Copyright © 2021 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Objective: Balancing bleeding risk and stroke risk in patients with atrial fibrillation (AF) is a common challenge. Though several bleeding risk scores exist, most have not included patients on direct oral anticoagulants (DOACs). We aimed at developing a novel bleeding risk score for patients with AF on oral anticoagulants (OAC) including both vitamin K antagonists (VKA) and DOACs., Methods: We included patients with AF on OACs from a prospective multicenter cohort study in Switzerland (SWISS-AF). The outcome was time to first bleeding. Bleeding events were defined as major or clinically relevant non-major bleeding. We used backward elimination to identify bleeding risk variables. We derived the score using a point score system based on the β-coefficients from the multivariable model. We used the Brier score for model calibration (<0.25 indicating good calibration), and Harrel's c-statistics for model discrimination., Results: We included 2147 patients with AF on OAC (72.5% male, mean age 73.4 ± 8.2 years), of whom 1209 (56.3%) took DOACs. After a follow-up of 4.4 years, a total of 255 (11.9%) bleeding events occurred. After backward elimination, age > 75 years, history of cancer, prior major hemorrhage, and arterial hypertension remained in the final prediction model. The Brier score was 0.23 (95% confidence interval [CI] 0.19-0.27), the c-statistic at 12 months was 0.71 (95% CI 0.63-0.80)., Conclusion: In this prospective cohort study of AF patients and predominantly DOAC users, we successfully derived a bleeding risk prediction model with good calibration and discrimination., (© 2021 International Society on Thrombosis and Haemostasis.)

Purpose: Accurate characterization and quantification of seizure types are critical for optimal pharmacotherapy in epilepsy patients. Technological advances have made it possible to continuously monitor physiological signals within or outside the hospital setting. This study tested the utility of single-channel surface-electromyography (sEMG) for characterization of motor epileptic seizure semiology., Methods: Seventy-one subjects were prospectively enrolled where vEEG and sEMG were simultaneously recorded. Three epileptologists independently identified and classified seizure events with upper-extremity (UE) motor activity by reviewing vEEG, serving as a clinical standard. Surface EMG recorded during the events identified by the clinical standard were evaluated using automated classification methods and expert review by a second group of three independent epileptologists (blinded to the vEEG data). Surface EMG classification categories included: tonic-clonic (TC), tonic only, clonic only, or other motor seizures. Both automated and expert review of sEMG was compared to the clinical standard., Results: Twenty subjects experienced 47 motor seizures. Automated sEMG event classification methods accurately classified 72 % (95 % CI [0.57, 0.84]) of events (15/18 TC seizures, 5/9 tonic seizures, 1/3 clonic seizures, and 13/17 other seizures). Three independent reviewers' majority-rule analysis of sEMG correctly classified 81 % (95 % CI [0.67, 0.91]) of events (16/18 TC seizures, 8/9 tonic seizures, 1/3 clonic seizures, and 13/17 other manifestations)., Conclusions: Continuous monitoring of sEMG data provides an objective measure to evaluate motor seizure activity. Using sEMG from a wearable monitor recorded from the biceps, automated and expert review may be used to characterize the semiology of events with UE motor activity, particularly TC and tonic seizures., (Copyright © 2021 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

The use of different cardiac imaging modalities such as MRI, CT or ultrasound enables the visualization and interpretation of altered morphological structures and function of the heart. In recent years, there has been an increasing interest in AI and deep learning that take into account spatial and temporal information in medical image analysis. In particular, deep learning tools using temporal information in image processing have not yet found their way into daily clinical practice, despite its presumed high diagnostic and prognostic value. This review aims to synthesize the most relevant deep learning methods and discuss their clinical usability in dynamic cardiac imaging using for example the complete spatiotemporal image information of the heart cycle. Selected articles were categorized according to the following indicators: clinical applications, quality of datasets, preprocessing and annotation, learning methods and training strategy, and test performance. Clinical usability was evaluated based on these criteria by classifying the selected papers into (i) clinical level, (ii) robust candidate and (iii) proof of concept applications. Interestingly, not a single one of the reviewed papers was classified as a "clinical level" study. Almost 39% of the articles achieved a "robust candidate" and as many as 61% a "proof of concept" status. In summary, deep learning in spatiotemporal cardiac imaging is still strongly research-oriented and its implementation in clinical application still requires considerable efforts. Challenges that need to be addressed are the quality of datasets together with clinical verification and validation of the performance achieved by the used method., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: To study hippocampal integration within task-positive and task-negative language networks and the impact of a diseased left and right hippocampus on the language connectome in temporal lobe epilepsy (TLE)., Methods: We used functional magnetic resonance imaging (fMRI) to study a homogenous group of 32 patients with TLE (17 left) and 14 healthy controls during a verb-generation task. We performed functional connectivity analysis and quantified alterations within the language connectome and evaluated disruptions of the functional dissociation along the anterior-posterior axis of the hippocampi., Results: Connectivity analysis revealed significant differences between left and right TLE compared to healthy controls. Left TLE showed widespread impairment of task-positive language networks, while right TLE showed less pronounced alterations. Particularly right TLE showed altered connectivity for cortical regions that were part of the default mode network (DMN). Left TLE showed a disturbed functional dissociation pattern along the left hippocampus to left and right inferior frontal language regions, while left and right TLE revealed an altered dissociation pattern along the right hippocampus to regions associated with the DMN., Conclusions: Our results showed an impaired hippocampal integration into active language and the default mode networks, which both may contribute to language impairment in TLE., Significance: Our results emphasize the direct role of the left hippocampus in language processing, and the potential role of the right hippocampus as a modulator between DMN and task-positive networks., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: To investigate the effect of metamizole on physiologic variables in calves undergoing surgical extirpation of the navel during anaesthesia using xylazine, ketamine and isoflurane., Study Design: Double-blind, randomized trial., Animals: A total of 26 calves., Methods: Calves with uncomplicated umbilical hernias and otherwise clinically healthy were randomly allocated to one of two groups: the control group (CG) and metamizole group (MG). All calves were administered meloxicam (0.5 mg kg -1 ) intravenously (IV) 150 minutes before skin incision (SI). Animals were premedicated with xylazine (0.2 mg kg -1 ) intramuscularly 50 minutes before SI. Anaesthesia was induced with ketamine (2 mg kg -1 ) IV 30 minutes before SI and maintained with isoflurane in oxygen. MG calves were given metamizole (40 mg kg -1 ) IV 60 minutes before SI. CG calves were administered an equivalent volume of saline. Heart rate (HR) and mean arterial blood pressure (MAP) were recorded from 5 minutes before SI until the end of anaesthesia (60 minutes after SI). Blood samples for determination of the plasma cortisol concentration (PCC) were drawn 60 minutes before SI and at 5, 30, 60, 150, and 510 minutes after SI., Results: In both groups, PCC increased during surgery and decreased after surgery. PCC was consistently lower in MG than in CG and was significantly (p = 0.0026) lower at 150 minutes after SI in the MG. Overall, the mean PCC in MG was 10.9 nmol L -1 lower than that in CG (p = 0.01). In both groups, HR decreased during anaesthesia, whereas MAP increased, albeit with no statistically significant (p > 0.05) differences between groups., Conclusions and Clinical Relevance: Our study results suggest that a single preoperative dose of metamizole may have a positive impact on intra- and immediate postoperative analgesia by reducing PCC when used as an indicator of nociception., (Copyright © 2020 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Background: The RIETE-VTE score was derived to risk-stratify patients with cancer-associated venous thromboembolism (CAT)., Objectives: To externally validate the RIETE-VTE score and to compare its prognostic performance with the modified Ottawa score., Patients/methods: We studied 178 elderly patients with CAT in a prospective multicenter cohort and assessed 30-day all-cause mortality, 90-day overall complications (mortality, major bleeding, or venous thromboembolism [VTE] recurrence), and 6-month VTE recurrence. Patients were stratified into RIETE-VTE and modified Ottawa score risk classes (low, intermediate, high). We compared the discriminative power (area under the receiver operating characteristic [ROC] curve) to predict mortality, overall complications, and VTE recurrence., Results: Fifteen patients (8.4%) died within 30 days, 42 (23.6%) experienced an overall complication by day 90, and 6 (3.4%) had recurrent VTE within 6 months. The RIETE-VTE and the modified Ottawa score classified similar proportions of patients as low risk (35.4% versus 31.5%; P = .37). No low-risk patient died within 30 days. Low-risk patients identified by the RIETE-VTE and modified Ottawa score had similar rates of overall complications (7.9% versus 8.9%) and VTE recurrence (1.6% versus 1.8%). The modified Ottawa score and the RIETE-VTE score had similar areas under the ROC curve for predicting all-cause mortality (0.84 versus 0.75; P = .21), overall complications (0.74 versus 0.68; P = .26), and VTE recurrence (0.67 versus 0.64; P = .78)., Conclusions: Both the RIETE-VTE and modified Ottawa score accurately identified elderly patients with CAT who are at low risk for short-term mortality and who are potential candidates for outpatient care., (© 2020 International Society on Thrombosis and Haemostasis.)

Over the last few decades the ILAE classifications for seizures and epilepsies (ILAE-EC) have been updated repeatedly to reflect the substantial progress that has been made in diagnosis and understanding of the etiology of epilepsies and seizures and to correct some of the shortcomings of the terminology used by the original taxonomy from the 1980s. However, these proposals have not been universally accepted or used in routine clinical practice. During the same period, a separate classification known as the "Four-dimensional epilepsy classification" (4D-EC) was developed which includes a seizure classification based exclusively on ictal symptomatology, which has been tested and adapted over the years. The extensive arguments for and against these two classification systems made in the past have mainly focused on the shortcomings of each system, presuming that they are incompatible. As a further more detailed discussion of the differences seemed relatively unproductive, we here review and assess the concordance between these two approaches that has evolved over time, to consider whether a classification incorporating the best aspects of the two approaches is feasible. To facilitate further discussion in this direction we outline a concrete proposal showing how such a compromise could be accomplished, the "Integrated Epilepsy Classification". This consists of five categories derived to different degrees from both of the classification systems: 1) a "Headline" summarizing localization and etiology for the less specialized users, 2) "Seizure type(s)", 3) "Epilepsy type" (focal, generalized or unknown allowing to add the epilepsy syndrome if available), 4) "Etiology", and 5) "Comorbidities & patient preferences"., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest with respect to this manuscript., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: To investigate the influence of ketamine on plasma cortisol concentration (PCC) in calves., Study Design: Prospective, randomized experimental study., Animals: A total of 41 healthy, predominantly cross-bred calves, aged 3-4 months., Methods: Calves were premedicated with intramuscular xylazine (0.2 mg kg -1 ) and randomly divided into four groups. The control group (CONT) received saline (after 10, 20 and 30 minutes), whereas groups K1, K2 and K3 were injected intravenously once, twice or thrice, respectively, with 4 mg kg -1 of ketamine at 10 minute intervals. Blood samples were collected at fixed time points and analysed to determine the PCC; furthermore, the plasma concentrations of ketamine and norketamine were assessed after a single ketamine administration in group K1. The pharmacokinetic parameters of ketamine and norketamine were calculated as plasma concentrations versus time., Results: All groups showed significant (p < 0.0001) increases in PCC compared with the baseline value; however, for the first 60 minutes, PCC was significantly higher in the ketamine-treated groups (time × dose effect; K1: p < 0.0001; K2: p = 0.0008; K3: p = 0.0135) than in the CONT group. The group receiving triple ketamine administration exhibited the greatest increase in PCC compared with the baseline level (121.17 ± 33.25 nmol L -1 ), whereas in the CONT group, the increase in PCC was smaller than the baseline cortisol level (82.67 ± 36.86 nmol L -1 ). The plasma concentration of ketamine decreased with a half-life of approximately 12 minutes, which was longer than the dose interval. The increase in PCC after triplicate administration might, therefore, have resulted from ketamine/norketamine accumulation rather than from the total dosage., Conclusions and Clinical Relevance: Our results showed that ketamine increases the plasma concentration of cortisol in xylazine-treated calves. Thus, the previous treatment of subjects needs to be considered in studies using plasma/serum cortisol concentrations as an indicator of pain., (Copyright © 2018 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Indications for video-EEG monitoring (VEM) include differential diagnosis of paroxysmal events including epileptic seizures, organic nonepileptic seizures, and psychogenic nonepileptic seizures; classification of seizure types and electroclinical syndromes; quantification of seizures and of interictal and ictal epileptiform discharges; and presurgical evaluation in medically refractory epilepsy patients. Standardized questionnaires and examinations should be used on admission to the epilepsy monitoring unit (EMU). Patients should be provided with comprehensive information concerning purpose and procedures during VEM and need to sign informed consents. Staff working in the EMU needs to be properly trained in the management of seizures and periictal testing according to written protocols as well as in cardiopulmonary resuscitation. Minimum staffing ratios of dedicated healthcare professionals to patients have been recommended. Antiepileptic drug tapering/withdrawal needs to be individualized for each patient. EEG recordings have to be performed according to established guidelines. Cardiorespiratory monitoring including continuous ECG monitoring and continuous measurement of oxygen saturation is strongly recommended. Patient safety is of utmost importance during VEM. Indicators for reporting quality and safety have been developed. Standardized ictal testing protocols and standardized computer-based organized reporting should further improve standards of VEM and training of EMU staff, and facilitate data exchange and collaborations between EMUs., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: To test the diagnostic accuracy of a new automatic algorithm for ictal onset source localization (IOSL) during routine presurgical epilepsy evaluation following STARD (Standards for Reporting of Diagnostic Accuracy) criteria., Methods: We included 28 consecutive patients with refractory focal epilepsy (25 patients with temporal lobe epilepsy (TLE) and 3 with extratemporal epilepsy) who underwent resective epilepsy surgery. Ictal EEG patterns were analyzed with a novel automatic IOSL algorithm. IOSL source localizations on a sublobar level were validated by comparison with actual resection sites and seizure free outcome 2 years after surgery., Results: Sensitivity of IOSL was 92.3% (TLE: 92.3%); specificity 60% (TLE: 50%); positive predictive value 66.7% (TLE: 66.7%); and negative predictive value 90% (TLE: 85.7%). The likelihood ratio was more than ten times higher for concordant IOSL results as compared to discordant results (p = 0.013)., Conclusions: We demonstrated the clinical feasibility of our IOSL approach yielding reasonable high performance measures on a sublobar level., Significance: Our IOSL method may contribute to a correct localization of the seizure onset zone in temporal lobe epilepsy and can readily be used in standard epilepsy monitoring settings. Further studies are needed for validation in extratemporal epilepsy., (Copyright © 2018. Published by Elsevier B.V.)

We report a large compilation of the internal validations of the probabilistic genotyping software STRmix™. Thirty one laboratories contributed data resulting in 2825 mixtures comprising three to six donors and a wide range of multiplex, equipment, mixture proportions and templates. Previously reported trends in the LR were confirmed including less discriminatory LRs occurring both for donors and non-donors at low template (for the donor in question) and at high contributor number. We were unable to isolate an effect of allelic sharing. Any apparent effect appears to be largely confounded with increased contributor number., (Copyright © 2018. Published by Elsevier B.V.)

Essentials The immune response is a significant concern in gene therapy. Platelet-targeted gene therapy can restore hemostasis and induce immune tolerance. CD4 T cell compartment is tolerized after platelet gene therapy. Preconditioning regimen affects immune tolerance induction in platelet gene therapy., Summary: Background Immune responses are a major concern in gene therapy. Our previous studies demonstrated that platelet-targeted factor VIII (FVIII) (2bF8) gene therapy together with in vivo drug selection of transduced cells can rescue the bleeding diathesis and induce immune tolerance in FVIII null mice. Objective To investigate whether non-selectable 2bF8 lentiviral vector (LV) for the induction of platelet-FVIII expression is sufficient to induce immune tolerance and how immune tolerance is induced after 2bF8LV gene therapy. Methods Platelet-FVIII expression was introduced by 2bF8LV transduction and transplantation. FVIII assays and tail bleeding tests were used to confirm the success of platelet gene therapy. Animals were challenged with rhF8 to explore if immune tolerance was induced after gene therapy. Treg cell analysis, T-cell proliferation assay and memory B-cell-mediated ELISPOT assay were used to investigate the potential mechanisms of immune tolerance. Results We showed that platelet-FVIII expression was sustained and the bleeding diathesis was restored in FVIII null mice after 2bF8LV gene therapy. None of the transduced recipients developed anti-FVIII inhibitory antibodies in the groups preconditioned with 660 cGy irradiation or busulfan plus ATG treatment even after rhF8 challenge. Treg cells significantly increased in 2bF8LV-transduced recipients and the immune tolerance developed was transferable. CD4 + T cells from treated animals failed to proliferate in response to rhF8 re-stimulation, but memory B cells could differentiate into antibody secreting cells in 2bF8LV-transduced recipients. Conclusion 2bF8LV gene transfer without in vivo selection of manipulated cells can introduce immune tolerance in hemophilia A mice and this immune tolerance is CD4 + T cell mediated., (© 2017 International Society on Thrombosis and Haemostasis.)

Standardized EEG electrode positions are essential for both clinical applications and research. The aim of this guideline is to update and expand the unifying nomenclature and standardized positioning for EEG scalp electrodes. Electrode positions were based on 20% and 10% of standardized measurements from anatomical landmarks on the skull. However, standard recordings do not cover the anterior and basal temporal lobes, which is the most frequent source of epileptogenic activity. Here, we propose a basic array of 25 electrodes including the inferior temporal chain, which should be used for all standard clinical recordings. The nomenclature in the basic array is consistent with the 10-10-system. High-density scalp EEG arrays (64-256 electrodes) allow source imaging with even sub-lobar precision. This supplementary exam should be requested whenever necessary, e.g. search for epileptogenic activity in negative standard EEG or for presurgical evaluation. In the near future, nomenclature for high density electrodes arrays beyond the 10-10 system needs to be defined, to allow comparison and standardized recordings across centers. Contrary to the established belief that smaller heads needs less electrodes, in young children at least as many electrodes as in adults should be applied due to smaller skull thickness and the risk of spatial aliasing., (Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: This study investigated sensitivity and false detection rate of a multimodal automatic seizure detection algorithm and the applicability to reduced electrode montages for long-term seizure documentation in epilepsy patients., Methods: An automatic seizure detection algorithm based on EEG, EMG, and ECG signals was developed. EEG/ECG recordings of 92 patients from two epilepsy monitoring units including 494 seizures were used to assess detection performance. EMG data were extracted by bandpass filtering of EEG signals. Sensitivity and false detection rate were evaluated for each signal modality and for reduced electrode montages., Results: All focal seizures evolving to bilateral tonic-clonic (BTCS, n=50) and 89% of focal seizures (FS, n=139) were detected. Average sensitivity in temporal lobe epilepsy (TLE) patients was 94% and 74% in extratemporal lobe epilepsy (XTLE) patients. Overall detection sensitivity was 86%. Average false detection rate was 12.8 false detections in 24h (FD/24h) for TLE and 22 FD/24h in XTLE patients. Utilization of 8 frontal and temporal electrodes reduced average sensitivity from 86% to 81%., Conclusion: Our automatic multimodal seizure detection algorithm shows high sensitivity with full and reduced electrode montages., Significance: Evaluation of different signal modalities and electrode montages paces the way for semi-automatic seizure documentation systems., (Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: To investigate the effect of systematic electrode reduction from a common 10-20 EEG system on pattern detection sensitivity (SEN)., Methods: Two reviewers rated 17130 one-minute segments of 83 prospectively recorded cEEGs according to the ACNS standardized critical care EEG terminology (CCET), including burst suppression patterns (BS) and unequivocal electrographic seizures. Consensus annotations between reviewers were used as a gold standard to determine pattern detection SEN and specificity (SPE) of a computational algorithm (baseline, 19 electrodes). Electrodes were than reduced one by one in four different variations. SENs and SPEs were calculated to determine the most beneficial assembly with respect to the number and location of electrodes., Results: High automated baseline SENs (84.99-93.39%) and SPEs (90.05-95.6%) were achieved for all patterns. Best overall results in detecting BS and CCET patterns were found using the "hairline+vertex" montage. While the "forehead+behind ear" montage showed an advantage in detecting ictal patterns, reaching a 15% drop of SEN with 10 electrodes, all montages could detect BS sufficiently if at least nine electrodes were available., Conclusion: For the first time an automated approach was used to systematically evaluate the effect of electrode reduction on pattern detection SEN in cEEG., Significance: Prediction of the expected detection SEN of specific EEG patterns with reduced EEG montages in ICU patients., (Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: To assess whether ICU caregivers can correctly read and interpret continuous EEG (cEEG) data displayed with the computer algorithm NeuroTrend (NT) with the main attention on seizure detection and determination of sedation depth., Methods: 120 screenshots of NT (480h of cEEG) were rated by 18 briefly trained nurses and biomedical analysts. Multirater agreements (MRA) as well as interrater agreements (IRA) compared to an expert opinion (EXO) were calculated for items such as pattern type, pattern location, interruption of recording, seizure suspicion, consistency of frequency, seizure tendency and level of sedation., Results: MRA as well as IRA were almost perfect (80-100%) for interruption of recording, spike-and-waves, rhythmic delta activity and burst suppression. A substantial agreement (60-80%) was found for electrographic seizure patterns, periodic discharges and seizure suspicion. Except for pattern localization (70.83-92.26%), items requiring a precondition and especially those who needed interpretation like consistency of frequency (47.47-79.15%) or level of sedation (41.10%) showed lower agreements., Conclusions: The present study demonstrates that NT might be a useful bedside monitor in cases of subclinical seizures. Determination of correct sedation depth by ICU caregivers requires a more detailed training., Significance: Computer algorithms may reduce the workload of cEEG analysis in ICU patients., (Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Essentials Platelet-Factor (F) VIII gene therapy is a promising treatment in hemophilia A. This study aims to evaluate if platelet-FVIII expression would increase the risk for thrombosis. Targeting FVIII expression to platelets does not induce or elevate thrombosis risk. Platelets expressing FVIII are neither hyper-activated nor hyper-responsive., Summary: Background Targeting factor (F) VIII expression to platelets is a promising gene therapy approach for hemophilia A, and is successful even in the presence of inhibitors. It is well known that platelets play important roles not only in hemostasis, but also in thrombosis and inflammation. Objective To evaluate whether platelet-FVIII expression might increase thrombotic risk and thereby compromise the safety of this approach. Methods In this study, platelet-FVIII-expressing transgenic mice were examined either in steady-state conditions or under prothrombotic conditions induced by inflammation or the FV Leiden mutation. Native whole blood thrombin generation assay, rotational thromboelastometry analysis and ferric chloride-induced vessel injury were used to evaluate the hemostatic properties. Various parameters associated with thrombosis risk, including D-dimer, thrombin-antithrombin complexes, fibrinogen, tissue fibrin deposition, platelet activation status and activatability, and platelet-leukocyte aggregates, were assessed. Results We generated a new line of transgenic mice that expressed 30-fold higher levels of platelet-expressed FVIII than are therapeutically required to restore hemostasis in hemophilic mice. Under both steady-state conditions and prothrombotic conditions induced by lipopolysaccharide-mediated inflammation or the FV Leiden mutation, supratherapeutic levels of platelet-expressed FVIII did not appear to be thrombogenic. Furthermore, FVIII-expressing platelets were neither hyperactivated nor hyperactivatable upon agonist activation. Conclusion We conclude that, in mice, more than 30-fold higher levels of platelet-expressed FVIII than are required for therapeutic efficacy in hemophilia A are not associated with a thrombotic predilection., Competing Interests: of Conflict of Interest: The authors state that they have no conflict of interest., (© 2016 International Society on Thrombosis and Haemostasis.)

Background: Various brain stimulation techniques are in use to treat epilepsy. These methods usually require surgical implantation procedures. Transcutaneous vagus nerve stimulation (tVNS) is a non-invasive technique to stimulate the left auricular branch of the vagus nerve at the ear conch., Objective: We performed a randomized, double-blind controlled trial (cMPsE02) to assess efficacy and safety of tVNS vs. control stimulation in patients with drug-resistant epilepsy., Methods: Primary objective was to demonstrate superiority of add-on therapy with tVNS (stimulation frequency 25 Hz, n = 39) versus active control (1 Hz, n = 37) in reducing seizure frequency over 20 weeks. Secondary objectives comprised reduction in seizure frequency from baseline to end of treatment, subgroup analyses and safety evaluation., Results: Treatment adherence was 84% in the 1 Hz group and 88% in the 25 Hz group, respectively. Stimulation intensity significantly differed between the 1 Hz group (1.02 ± 0.83 mA) and the 25 Hz group (0.50 ± 0.47 mA; p = 0.006). Mean seizure reduction per 28 days at end of treatment was -2.9% in the 1 Hz group and 23.4% in the 25 Hz group (p = 0.146). In contrast to controls, we found a significant reduction in seizure frequency in patients of the 25 Hz group who completed the full treatment period (20 weeks; n = 26, 34.2%, p = 0.034). Responder rates (25%, 50%) were similar in both groups. Subgroup analyses for seizure type and baseline seizure frequency revealed no significant differences. Adverse events were usually mild or moderate and comprised headache, ear pain, application site erythema, vertigo, fatigue, and nausea. Four serious adverse events were reported including one sudden unexplained death in epilepsy patients (SUDEP) in the 1 Hz group which was assessed as not treatment-related., Conclusions: tVNS had a high treatment adherence and was well tolerated. Superiority of 25 Hz tVNS over 1 Hz tVNS could not be proven in this relatively small study, which might be attributed to the higher stimulation intensity in the control group. Efficacy data revealed results that justify further trials with larger patient numbers and longer observation periods., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: To develop a computational method to detect and quantify burst suppression patterns (BSP) in the EEGs of critical care patients. A multi-center validation study was performed to assess the detection performance of the method., Methods: The fully automatic method scans the EEG for discontinuous patterns and shows detected BSP and quantitative information on a trending display in real-time. The method is designed to work without setting any patient specific parameters and to be insensitive to EEG artifacts and periodic patterns. For validation a total of 3982 h of EEG from 88 patients were analyzed from three centers. Each EEG was annotated by two reviewers to assess the detection performance and the inter-rater agreement., Results: Average inter-rater agreement between pairs of reviewers was κ=0.69. On average 22% of the review segments included BSP. An average sensitivity of 90% and a specificity of 84% were measured on the consensus annotations of two reviewers. More than 95% of the periodic patterns in the EEGs were correctly suppressed., Conclusion: A fully automatic method to detect burst suppression patterns was assessed in a multi-center study. The method showed high sensitivity and specificity., Significance: Clinically applicable burst suppression detection method validated in a large multi-center study., (Copyright © 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Background: Venous thromboembolism (VTE) and subclinical thyroid dysfunction (SCTD) are both common in elderly patients. SCTD has been related to a hypercoagulable state and an increased thromboembolic risk. However, prospective data on the relationship between SCTD and VTE are lacking., Objectives: To investigate the relationship between SCTD and recurrent VTE (rVTE), all-cause mortality, and thrombophilic biomarkers. Patients Elderly patients with VTE were studied., Methods: In a prospective multicenter cohort, thyroid hormones and thrombophilic biomarkers were measured 1 year after acute VTE, as both may be influenced by acute thrombosis. We defined subclinical hypothyroidism (SHypo) as elevated thyroid-stimulating hormone (TSH) levels (4.50-19.99 mIU L(-1) ), and subclinical hyperthyroidism (SHyper) as TSH levels of < 0.45 mIU L(-1) , both with normal free thyroxine levels. Outcomes were incidence of rVTE and overall mortality during follow-up starting after the 1-year blood sampling., Results: Of 561 participants (58% with anticoagulation), 6% had SHypo and 5% had SHyper. After 20.8 months of mean follow-up, 9% developed rVTE and 10% died. The rVTE incidence rate was 7.2 (95% confidence interval [CI] 2.7-19.2) per 100 patient-years in SHypo participants, 0.0 (95% CI 0.0-7.6) in SHyper participants, and 5.9 (95% CI 4.4-7.8) in euthyroid participants. In multivariate analyses, the sub-hazard ratio for rVTE was 0.00 (95% CI 0.00-0.58) in SHyper participants and 1.50 (95% CI 0.52-4.34) in SHypo participants as compared with euthyroid participants, without increased levels of thrombophilic biomarkers. SHyper (hazard ratio [HR] 0.80, 95% CI 0.23-2.81) and SHypo (HR 0.99, 95% CI 0.30-3.29) were not associated with mortality., Conclusion: In elderly patients, SHyper may be associated with lower rVTE risks. SHypo showed a non-statistically significant pattern of an association with rVTE, without increased mortality or differences in thrombophilic biomarkers., (© 2016 International Society on Thrombosis and Haemostasis.)

Objectives: To study periodic and rhythmic EEG patterns classified according to Standardized Critical Care EEG Terminology (SCCET) of the American Clinical Neurophysiology Society and their relationship to electrographic seizures., Methods: We classified 655 routine EEGs in 371 consecutive critically ill neurological patients into (1) normal EEGs or EEGs with non-specific abnormalities or interictal epileptiform discharges, (2) EEGs containing unequivocal ictal EEG patterns, and (3) EEGs showing rhythmic and periodic EEG patterns of 'ictal-interictal uncertainty' (RPPIIIU) according to SCCET., Results: 313 patients (84.4%) showed normal EEGs, non-specific or interictal abnormalities, 14 patients (3.8%) had EEGs with at least one electrographic seizure, and 44 patients (11.8%) at least one EEG containing RPPIIIU, but no EEG with electrographic seizures. Electrographic seizures occurred in 11 of 55 patients (20%) with RPPIIIU, but only in 3 of 316 patients (0.9%) without RPPIIIU (p⩽0.001). Conversely, we observed RPPIIIU in 11 of 14 patients (78.6%) with electrographic seizures, but only in 44 of 357 patients (12.3%) without electrographic seizures (p⩽0.001)., Conclusions: On routine-EEG in critically ill neurological patients RPPIIIU occur 3 times more frequently than electrographic seizures and are highly predictive for electrographic seizures., Significance: RPPIIIU can serve as an indication for continuous EEG recordings., (Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Background: We have recently developed a successful gene therapy approach for hemophilia A in which factor VIII (FVIII) expression is targeted to platelets by the αIIb promoter. Levels of platelet-expressed FVIII (2bF8) achieved by gene therapy may vary between individuals due to differences in ex vivo transduction and gene expression efficiency. Accurate assays to evaluate 2bF8 efficacy are desirable., Objective: To compare the hemostatic efficacy of 2bF8 with replacement therapy over a wide therapeutic dose range., Methods: Efficacy of 2bF8 was assessed using a new transgenic mouse model expressing high 2bF8 levels (LV18(tg) ). Blood from LV18(tg) mice or FVIII(null) mice infused with recombinant FVIII was mixed with FVIII(null) blood at different ratios ex vivo to achieve several concentrations of 2bF8 or plasma FVIII. Samples were evaluated with a novel native whole blood thrombin generation assay that uses recalcified whole blood without the addition of tissue factor to initiate coagulation., Results: FVIII dose dependency was observed in all five thrombin generation parameters. While the total amount of thrombin generated was similar, 2bF8 significantly accelerated thrombin generation compared with plasma FVIII. Remarkably, a 10-fold lower dose of 2bF8 than plasma FVIII (0.2% vs. 2%) significantly shortened the onset and peak of thrombin generation compared with FVIII(null) blood., Conclusion: Using a new transgenic mouse model, we showed that the novel native whole blood thrombin generation assay established here can be used to monitor platelet targeted FVIII gene therapy. The higher therapeutic efficacy of 2bF8 compared with factor replacement therapy seemed to be due to acceleration of thrombin generation., (© 2015 International Society on Thrombosis and Haemostasis.)

Aims of the Study: Continuous EEG from critical care patients needs to be evaluated time efficiently to maximize the treatment effect. A computational method will be presented that detects rhythmic and periodic patterns according to the critical care EEG terminology (CCET) of the American Clinical Neurophysiology Society (ACNS). The aim is to show that these detected patterns support EEG experts in writing neurophysiological reports., Materials and Methods: First of all, three case reports exemplify the evaluation procedure using graphically presented detections. Second, 187 hours of EEG from 10 critical care patients were used in a comparative trial study. For each patient the result of a review session using the EEG and the visualized pattern detections was compared to the original neurophysiology report., Results: In three out of five patients with reported seizures, all seizures were reported correctly. In two patients, several subtle clinical seizures with unclear EEG correlation were missed. Lateralized periodic patterns (LPD) were correctly found in 2/2 patients and EEG slowing was correctly found in 7/9 patients. In 8/10 patients, additional EEG features were found including LPDs, EEG slowing, and seizures., Conclusion: The use of automatic pattern detection will assist in review of EEG and increase efficiency. The implementation of bedside surveillance devices using our detection algorithm appears to be feasible and remains to be confirmed in further multicenter studies., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Objective: A method for automatic detection of epileptic seizures in long-term scalp-EEG recordings called EpiScan will be presented. EpiScan is used as alarm device to notify medical staff of epilepsy monitoring units (EMUs) in case of a seizure., Methods: A prospective multi-center study was performed in three EMUs including 205 patients. A comparison between EpiScan and the Persyst seizure detector on the prospective data will be presented. In addition, the detection results of EpiScan on retrospective EEG data of 310 patients and the public available CHB-MIT dataset will be shown., Results: A detection sensitivity of 81% was reached for unequivocal electrographic seizures with false alarm rate of only 7 per day. No statistical significant differences in the detection sensitivities could be found between the centers. The comparison to the Persyst seizure detector showed a lower false alarm rate of EpiScan but the difference was not of statistical significance., Conclusions: The automatic seizure detection method EpiScan showed high sensitivity and low false alarm rate in a prospective multi-center study on a large number of patients., Significance: The application as seizure alarm device in EMUs becomes feasible and will raise the efficiency of video-EEG monitoring and the safety levels of patients., (Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Background: Clinical trials yielded conflicting data about the benefit of adding systemic corticosteroids for treatment of community-acquired pneumonia. We assessed whether short-term corticosteroid treatment reduces time to clinical stability in patients admitted to hospital for community-acquired pneumonia., Methods: In this double-blind, multicentre, randomised, placebo-controlled trial, we recruited patients aged 18 years or older with community-acquired pneumonia from seven tertiary care hospitals in Switzerland within 24 h of presentation. Patients were randomly assigned (1:1 ratio) to receive either prednisone 50 mg daily for 7 days or placebo. The computer-generated randomisation was done with variable block sizes of four to six and stratified by study centre. The primary endpoint was time to clinical stability defined as time (days) until stable vital signs for at least 24 h, and analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00973154., Findings: From Dec 1, 2009, to May 21, 2014, of 2911 patients assessed for eligibility, 785 patients were randomly assigned to either the prednisone group (n=392) or the placebo group (n=393). Median time to clinical stability was shorter in the prednisone group (3·0 days, IQR 2·5-3·4) than in the placebo group (4·4 days, 4·0-5·0; hazard ratio [HR] 1·33, 95% CI 1·15-1·50, p<0·0001). Pneumonia-associated complications until day 30 did not differ between groups (11 [3%] in the prednisone group and 22 [6%] in the placebo group; odds ratio [OR] 0·49 [95% CI 0·23-1·02]; p=0·056). The prednisone group had a higher incidence of in-hospital hyperglycaemia needing insulin treatment (76 [19%] vs 43 [11%]; OR 1·96, 95% CI 1·31-2·93, p=0·0010). Other adverse events compatible with corticosteroid use were rare and similar in both groups., Interpretation: Prednisone treatment for 7 days in patients with community-acquired pneumonia admitted to hospital shortens time to clinical stability without an increase in complications. This finding is relevant from a patient perspective and an important determinant of hospital costs and efficiency., Funding: Swiss National Science Foundation, Viollier AG, Nora van Meeuwen Haefliger Stiftung, Julia und Gottfried Bangerter-Rhyner Stiftung., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

New biomarkers are needed to improve the specificity of prostate cancer detection and characterisation of individual tumors. In a proteomics profiling approach using MALDI-MS tissue imaging on frozen tissue sections, we identified discriminating masses. Imaging analysis of cancer, non-malignant benign epithelium and stromal areas of 15 prostatectomy specimens in a test and 10 in a validation set identified characteristic m/z peaks for each tissue type, e.g. m/z 10775 for benign epithelial, m/z 6284 and m/z 6657.5 for cancer and m/z 4965 for stromal tissue. A 10-fold cross-validation analysis showed highest discriminatory ability to separate tissue types for m/z 6284 and m/z 6657.5, both overexpressed in cancer, and a multicomponent mass peak cluster at m/z 10775-10797.4 overexpressed in benign epithelial tissue. ROC AUC values for these three masses ranged from 0.85 to 0.95 in the discrimination of malignant and non-malignant tissue. To identify the underlying proteins, prostate whole tissue extract was separated by nano-HPLC and subjected to MALDI TOF/TOF analysis. Proteins in fractions containing discriminatory m/z masses were identified by MS/MS analysis and candidate marker proteins subsequently validated by immunohistochemistry (IHC). Biliverdin reductase B (BLVRB) turned out to be overexpressed in PCa tissue., Biological Significance: In this study on cryosections of radical prostatectomies of prostate cancer patients, we performed a MALDI-MS tissue imaging analysis and a consecutive protein identification of significant m/z masses by nano-HPLC, MALDI TOF/TOF and MS/MS analysis. We identified BLVRB as a potential biomarker in the discrimination of PCa and benign tissue, also suggesting BVR as a feasible therapeutic target., (© 2013. Published by Elsevier B.V. All rights reserved.)

Purpose: Epilepsy surgery is the most efficacious therapeutic modality for patients with medically refractory focal epilepsies, but surgical failures remain a challenge to the epilepsy treatment team. The aim of present study was to evaluate the postoperative outcome of patients who underwent reoperation after a failed epilepsy surgery on the temporal lobe., Methods: We systematically analyzed the results of comprehensive preoperative evaluations before the first surgery, and before and after reoperation in 17 patients with drug resistant temporal lobe epilepsies., Results: Overall, 13 of 17 patients (76.5%) improved after reoperation: five patients (29.4%) were completely seizure free after reoperation (median duration 60months, range 12-72); six patients (35.3%) were seizure free at least 12month before observation points (median duration 120.5months, range 35-155) and two patients (11.8%) had a decrease in seizure frequency. Four patients (23.5%) remained unchanged with respect to seizure frequency and severity. There was no correlation between the improvement in seizure outcome after reoperation and other clinical data except of the history of traumatic brain injury (TBI). The patients who had no history of TBI improved after reoperation, compared to patients with TBI (p=0.044). The postoperative seizure outcome of patients with incongruent Video-EEG results before the first surgery (p=0.116) and before reoperation (p=0.622) was not poorer compared to patients with congruent Video-EEG results., Conclusions: Reoperation can considerably improve the operative outcome of the first failed epilepsy surgery in patients with drug resistant temporal lobe epilepsies. Epilepsy centres should be encouraged to report the results of failed epilepsy surgeries., (Copyright © 2012 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Objectives: Cigarette smoking is the most demonstrated risk factor for the development of lung cancer, while the related genetic mechanisms are still unclear., Methods: The preprocessed microarray expression dataset was downloaded from Gene Expression Omnibus database. Samples were classified according to the disease state, stage and smoking state. A new computational strategy was applied for the identification and biological interpretation of new candidate genes in lung cancer and smoking by coupling a network-based approach with gene set enrichment analysis., Measurements: Network analysis was performed by pair-wise comparison according to the disease states (tumor or normal), smoking states (current smokers or nonsmokers or former smokers), or the disease stage (stages I-IV). The most activated metabolic pathways were identified by gene set enrichment analysis., Results: Panels of top ranked gene candidates in smoking or cancer development were identified, including genes involved in cell proliferation and drug metabolism like cytochrome P450 and WW domain containing transcription regulator 1. Semaphorin 5A and protein phosphatase 1F are the common genes represented as major hubs in both the smoking and cancer related network. Six pathways, e.g. cell cycle, DNA replication, RNA transport, protein processing in endoplasmic reticulum, vascular smooth muscle contraction and endocytosis were commonly involved in smoking and lung cancer when comparing the top ten selected pathways., Conclusion: New approach of bioinformatics for biomarker identification and validation can probe into deep genetic relationships between cigarette smoking and lung cancer. Our studies indicate that disease-specific network biomarkers, interaction between genes/proteins, or cross-talking of pathways provide more specific values for the development of precision therapies for lung., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The identification and interpretation of metabolic biomarkers is a challenging task. In this context, network-based approaches have become increasingly a key technology in systems biology allowing to capture complex interactions in biological systems. In this work, we introduce a novel network-based method to identify highly predictive biomarker candidates for disease. First, we infer two different types of networks: (i) correlation networks, and (ii) a new type of network called ratio networks. Based on these networks, we introduce scores to prioritize features using topological descriptors of the vertices. To evaluate our method we use an example dataset where quantitative targeted MS/MS analysis was applied to a total of 52 blood samples from 22 persons with obesity (BMI >30) and 30 healthy controls. Using our network-based feature selection approach we identified highly discriminating metabolites for obesity (F-score >0.85, accuracy >85%), some of which could be verified by the literature., (Copyright © 2012 Elsevier Ltd. All rights reserved.)