Functions and mechanism of thyroid hormone receptor action during amphibian development.

Thyroid hormones and their receptors (TRs) play critical roles during vertebrate development. One of the most dramatic developmental processes regulated by thyroid hormones is frog metamorphosis, which mimics the postembryonic (perinatal) period in mammals. Here, we review some of the findings on the developmental functions of thyroid hormones and TRs as well as their associated mechanisms of action obtained from this model system. Over two decades ago, a dual function model was proposed for TR in anuran development. During larval development, unliganded receptors recruits corepressors to repress thyroid hormone response genes to prevent premature metamorphic changes. Subsequently, when thyroid hormone levels rise, liganded receptors recruit coactivators to activate thyroid hormone response genes, leading to metamorphic changes. Over the years, molecular and genetic approaches have provided strong support for this model and shown that it is applicable to mammalian development as well as understanding the diverse effects of thyroid hormones in normal physiology and diseases caused by thyroid hormone signaling dysfunction.

Testing the sensitivity of the medaka Transgenic Eleuthero-embryonic THYroid-Specific assay (TETHYS) to different mechanisms of action.

There are many concerns about the impacts of Endocrine-Disrupting Chemicals on both wildlife and human populations. A plethora of chemicals have been shown to interfere with the Hypothalamic-Pituitary-Thyroid (HPT) axis in vertebrates. Disruption of the HPT axis is one of main endocrine criteria considered for the regulation of chemicals, along with the estrogen axis, androgen axis and steroidogenesis (EATS). In response to these concerns, the Organization for Economic Cooperation and Development (OECD) initiated the validation of test guidelines (TGs) covering the EATS modalities. Regarding thyroid activity and/or disruption assessment, three OECD TGs are validated, all of them using amphibians. To date, no OECD TGs based on fish are available for the detection of Thyroid Active Chemicals (TACs). To fill this gap, we developed a new test for the detection of TACs, the TETHYS assay (Transgenic Eleuthero-embryonic THYroid-Specific assay). This assay uses a medaka (Oryzias latipes) transgenic line Tg(tg:eGFP) expressing Green Fluorescent Protein in the thyroid follicles, under the control of the thyroglobulin promoter. This assay is performed at eleuthero-embryonic life-stages with an exposure length of 72 h. In the present study, the following reference chemicals with known thyroid hormone system mechanism of action have been tested: methimazole, sodium perchlorate, sodium tetrafluoroborate, diclofenac, iopanoic acid, sobetirome, NH-3 and 1-850. Except for the thyroid receptor antagonists, all chemicals tested were identified as thyroid active, modifying the total fluorescence and the size of the thyroid follicles. To investigate the test specificity, we tested three chemicals presumed to be inert on the HPT axis: cefuroxime, abamectin and 17α-ethinylestradiol. All were found to be inactive in the TETHYS assay. This promising New Approach Methodology can serve as a foundation for the development of a new OECD TG in the frame of regulatory assessment of chemicals for thyroid activity.

Higher doses of fluconazole are needed to ensure target attainment in critically ill adults on continuous Veno-venous hemodialysis.

BACKGROUND: Critically ill patients undergoing Continuous Renal Replacement Therapy (CRRT) are treated with higher doses of fluconazole based on the literature recommendations. However, clinical follow-up data demonstrating the effectiveness of this approach are lacking. PURPOSE: A retrospective cohort study was conducted to evaluate whether target attainment was achieved with higher doses of fluconazole. Additionally, the study focused on identifying factors that may contribute to variability in fluconazole exposure in these patients. METHODS: Critically ill patients undergoing Continuous Veno-Venous Hemodialysis (CVVHD) who received either standard or higher doses of intravenous fluconazole were included. Evaluation of target attainment was conducted for each dose regimen. RESULTS: Administering higher doses resulted in target attainment in 100 % of the patients, indicating that starting with at least 400 mg twice daily is an adequate dosing guideline. In this study, only the dose of fluconazole was found to significantly influence target attainment (p < 0.001), with no other predefined factors identified as having a significant impact. CONCLUSION: According to the results of the study, increasing the fluconazole dose to at least 400 mg twice daily is sufficient to reach the desired target in critically ill patients undergoing CVVHD.

Lithium and endocrine disruption: A concern for human health?

Lithium is a key medication for the treatment of psychiatric disorders and is also used in various industrial applications (including battery production and recycling). Here, we review published data on the endocrine-disrupting potential of lithium, with a particular focus on the thyroid hormone system. To this end, we used PubMed and Scopus databases to search for, select and review primary research addressing human and animal health endpoints during or after lithium exposure at non-teratogenic doses. Given the key role of thyroid hormones in neurodevelopmental processes, we focused at studies of the neural effects of developmental exposure to lithium in humans and animals. Our results show that lithium meets the World Health Organization's definition of a thyroid hormone system disruptor - particularly when used at therapeutic doses. When combined with knowledge of adverse outcome pathways linking molecular initiating events targeting thyroid function and neurodevelopmental outcomes, the neurodevelopmental data reported in animal experiments prompt us to suggest that lithium influences neurodevelopment. However, we cannot rule out the involvement of additional modes of action (i.e. unrelated to the thyroid hormone system) in the described neural effects. Given the increasing use of lithium salts in new technologies, attention must be paid to this emerging pollutant - particularly with regard to its potential effects at environmental doses on the thyroid hormone system and potential consequences on the developing nervous system.

A multicenter, matched case-control analysis comparing burden of illness among patients with tuberous sclerosis complex related epilepsy, generalized idiopathic epilepsy, and focal epilepsy in Germany.

BACKGROUND: Depending on the underlying etiology and epilepsy type, the burden of disease for patients with seizures can vary significantly. This analysis aimed to compare direct and indirect costs and quality of life (QoL) among adults with tuberous sclerosis complex (TSC) related with epilepsy, idiopathic generalized epilepsy (IGE), and focal epilepsy (FE) in Germany. METHODS: Questionnaire responses from 92 patients with TSC and epilepsy were matched by age and gender, with responses from 92 patients with IGE and 92 patients with FE collected in independent studies. Comparisons were made across the main QoL components, direct costs (patient visits, medication usage, medical equipment, diagnostic procedures, ancillary treatments, and transport costs), indirect costs (employment, reduced working hours, missed days), and care level costs. RESULTS: Across all three cohorts, mean total direct costs (TSC: €7602 [median €2620]; IGE: €1919 [median €446], P < 0.001; FE: €2598 [median €892], P < 0.001) and mean total indirect costs due to lost productivity over 3 months (TSC: €7185 [median €11,925]; IGE: €3599 [median €0], P < 0.001; FE: €5082 [median €2981], P = 0.03) were highest among patients with TSC. The proportion of patients with TSC who were unemployed (60%) was significantly larger than the proportions of patients with IGE (23%, P < 0.001) or FE (34%, P = P < 0.001) who were unemployed. Index scores for the EuroQuol Scale with 5 dimensions and 3 levels were significantly lower for patients with TSC (time-trade-off [TTO]: 0.705, visual analog scale [VAS]: 0.577) than for patients with IGE (TTO: 0.897, VAS: 0.813; P < 0.001) or FE (TTO: 0.879, VAS: 0.769; P < 0.001). Revised Epilepsy Stigma Scale scores were also significantly higher for patients with TSC (3.97) than for patients with IGE (1.48, P < 0.001) or FE (2.45, P < 0.001). Overall Quality of Life in Epilepsy Inventory-31 items scores was significantly lower among patients with TSC (57.7) and FE (57.6) than among patients with IGE (66.6, P = 0.004 in both comparisons). Significant differences between patients with TSC and IGE were also determined for Neurological Disorder Depression Inventory for Epilepsy (TSC: 13.1; IGE: 11.2, P = 0.009) and Liverpool Adverse Events Profile scores (TSC: 42.7; IGE: 37.5, P = 0.017) with higher score and worse results for TSC patients in both questionnaires. CONCLUSIONS: This study is the first to compare patients with TSC, IGE, and FE in Germany and underlines the excessive QoL burden and both direct and indirect cost burdens experienced by patients with TSC.

Xenopus tropicalis osteoblast-specific open chromatin regions reveal promoters and enhancers involved in human skeletal phenotypes and shed light on early vertebrate evolution.

While understanding the genetic underpinnings of osteogenesis has far-reaching implications for skeletal diseases and evolution, a comprehensive characterization of the osteoblastic regulatory landscape in non-mammalian vertebrates is still lacking. Here, we compared the ATAC-Seq profile of Xenopus tropicalis (Xt) osteoblasts to a variety of non mineralizing control tissues, and identified osteoblast-specific nucleosome free regions (NFRs) at 527 promoters and 6747 distal regions. Sequence analyses, Gene Ontology, RNA-Seq and ChIP-Seq against four key histone marks confirmed that the distal regions correspond to bona fide osteogenic transcriptional enhancers exhibiting a shared regulatory logic with mammals. We report 425 regulatory regions conserved with human and globally associated to skeletogenic genes. Of these, 35 regions have been shown to impact human skeletal phenotypes by GWAS, including one trps1 enhancer and the runx2 promoter, two genes which are respectively involved in trichorhinophalangeal syndrome type I and cleidocranial dysplasia. Intriguingly, 60 osteoblastic NFRs also align to the genome of the elephant shark, a species lacking osteoblasts and bone tissue. To tackle this paradox, we chose to focus on dlx5 because its conserved promoter, known to integrate regulatory inputs during mammalian osteogenesis, harbours an osteoblast-specific NFR in both frog and human. Hence, we show that dlx5 is expressed in Xt and elephant shark odontoblasts, supporting a common cellular and genetic origin of bone and dentine. Taken together, our work (i) unravels the Xt osteogenic regulatory landscape, (ii) illustrates how cross-species comparisons harvest data relevant to human biology and (iii) reveals that a set of genes including bnc2, dlx5, ebf3, mir199a, nfia, runx2 and zfhx4 drove the development of a primitive form of mineralized skeletal tissue deep in the vertebrate lineage.

Real World Data from Catheter Ablation of Ventricular Tachycardias and Premature Ventricular Complexes in a Tertiary Care Center.

Background: Catheter ablation in patients with ventricular arrhythmias (VA), such as ventricular tachycardias (VT) or frequent premature ventricular complexes (PVC), is increasingly considered an effective and safe therapy when performed in experienced centers. This study sought to determine acute success rates and complication rates of ablation procedures for patients with VA in a Swiss tertiary care center. Methods: All patients who underwent ablation therapy for VT and PVC at the University Heart Center in Zurich, Switzerland, between March 2012 and April 2017 were included in this analysis. Results: A total of 120 patients underwent catheter ablation for VT and PVC (69 and 51, respectively). Seventy percent of patients were male, and the mean age was 55.3 years. The most common indication for ablation was high PVC burden (47.5%), followed by paroxysmal VT (38.3%), ICD shocks (23.3%), incessant VT (12.5%), electrical storm (7.5%), and syncope (3.3%). Acute success rates for VT and PVC ablations were 94.2% and 92.2%, respectively. Rates for complications (including major and minor) for VT and PVC were 10.1% and 7.8%, respectively. Complications occurred only in patients with structural heart disease; no complications were noted in structurally normal hearts. Conclusions: Our results suggest that catheter ablation for VT and PVC has high acute success rates with a reasonable risk for complications in the setting of tertiary care centers, comparable to those reported in other studies.

Overlapping action of T3 and T4 during Xenopus laevis development.

Thyroid hormones are involved in many biological processes such as neurogenesis, metabolism, and development. However, compounds called endocrine disruptors can alter thyroid hormone signaling and induce unwanted effects on human and ecosystems health. Regulatory tests have been developed to detect these compounds but need to be significantly improved by proposing novel endpoints and key events. The Xenopus Eleutheroembryonic Thyroid Assay (XETA, OECD test guideline no. 248) is one such test. It is based on Xenopus laevis tadpoles, a particularly sensitive model system for studying the physiology and disruption of thyroid hormone signaling: amphibian metamorphosis is a spectacular (thus easy to monitor) life cycle transition governed by thyroid hormones. With a long-term objective of providing novel molecular markers under XETA settings, we propose first to describe the differential effects of thyroid hormones on gene expression, which, surprisingly, are not known. After thyroid hormones exposure (T3 or T4), whole tadpole RNAs were subjected to transcriptomic analysis. By using standard approaches coupled to system biology, we found similar effects of the two thyroid hormones. They impact the cell cycle and promote the expression of genes involves in cell proliferation. At the level of the whole tadpole, the immune system is also a prime target of thyroid hormone action.

Multifractal Multiscale Analysis of Human Movements during Cognitive Tasks.

Continuous adaptations of the movement system to changing environments or task demands rely on superposed fractal processes exhibiting power laws, that is, multifractality. The estimators of the multifractal spectrum potentially reflect the adaptive use of perception, cognition, and action. To observe time-specific behavior in multifractal dynamics, a multiscale multifractal analysis based on DFA (MFMS-DFA) has been recently proposed and applied to cardiovascular dynamics. Here we aimed at evaluating whether MFMS-DFA allows identifying multiscale structures in the dynamics of human movements. Thirty-six (12 females) participants pedaled freely, after a metronomic initiation of the cadence at 60 rpm, against a light workload for 10 min: in reference to cycling (C), cycling while playing "Tetris" on a computer, alone (CT) or collaboratively (CTC) with another pedaling participant. Pedal revolution periods (PRP) series were examined with MFMS-DFA and compared to linearized surrogates, which attested to a presence of multifractality at almost all scales. A marked alteration in multifractality when playing Tetris was evidenced at two scales, τ ≈ 16 and τ ≈ 64 s, yet less marked at τ ≈ 16 s when playing collaboratively. Playing Tetris in collaboration attenuated these alterations, especially in the best Tetris players. This observation suggests the high sensitivity to cognitive demand of MFMS-DFA estimators, extending to the assessment of skill/demand interplay from individual behavior. So, by identifying scale-dependent multifractal structures in movement dynamics, MFMS-DFA has obvious potential for examining brain-movement coordinative structures, likely with sufficient sensitivity to find echo in diagnosing disorders and monitoring the progress of diseases that affect cognition and movement control.

Conserved chromatin and repetitive patterns reveal slow genome evolution in frogs.

Frogs are an ecologically diverse and phylogenetically ancient group of anuran amphibians that include important vertebrate cell and developmental model systems, notably the genus Xenopus. Here we report a high-quality reference genome sequence for the western clawed frog, Xenopus tropicalis, along with draft chromosome-scale sequences of three distantly related emerging model frog species, Eleutherodactylus coqui, Engystomops pustulosus, and Hymenochirus boettgeri. Frog chromosomes have remained remarkably stable since the Mesozoic Era, with limited Robertsonian (i.e., arm-preserving) translocations and end-to-end fusions found among the smaller chromosomes. Conservation of synteny includes conservation of centromere locations, marked by centromeric tandem repeats associated with Cenp-a binding surrounded by pericentromeric LINE/L1 elements. This work explores the structure of chromosomes across frogs, using a dense meiotic linkage map for X. tropicalis and chromatin conformation capture (Hi-C) data for all species. Abundant satellite repeats occupy the unusually long (~20 megabase) terminal regions of each chromosome that coincide with high rates of recombination. Both embryonic and differentiated cells show reproducible associations of centromeric chromatin and of telomeres, reflecting a Rabl-like configuration. Our comparative analyses reveal 13 conserved ancestral anuran chromosomes from which contemporary frog genomes were constructed.

A Novel Transgenic Model to Study Thyroid Axis Activity in Early Life Stage Medaka.

Identifying endocrine disrupting chemicals in order to limit their usage is a priority and required according to the European Regulation. There are no Organization for Economic Co-operation and Development (OECD) test guidelines based on fish available for the detection of Thyroid axis Active Chemicals (TACs). This study aimed to fill this gap by developing an assay at eleuthero-embryonic life stages in a novel medaka (Oryzias latipes) transgenic line. This transgenic line expresses green fluorescent protein (GFP) in thyrocytes, under the control of the medaka thyroglobulin gene promoter. The fluorescence expressed in the thyrocytes is inversely proportional to the thyroid axis activity. When exposed for 72 h to activators (triiodothyronine (T3) and thyroxine (T4)) or inhibitors (6-N-propylthiouracil (PTU), Tetrabromobisphenol A (TBBPA)) of the thyroid axis, the thyrocytes can change their size and express lower or higher levels of fluorescence, respectively. This reflects the regulation of thyroglobulin by the negative feedback loop of the Hypothalamic-Pituitary-Thyroid axis. T3, T4, PTU, and TBBPA induced fluorescence changes with the lowest observable effect concentrations (LOECs) of 5 µg/L, 1 µg/L, 8 mg/L, and 5 mg/L, respectively. This promising tool could be used as a rapid screening assay and also to help decipher the mechanisms by which TACs can disrupt the thyroid axis in medaka.

The impact of referring patients with drug-resistant focal epilepsy to an epilepsy center for presurgical diagnosis.

BACKGROUND: Epilepsy surgery is an established treatment for drug-resistant focal epilepsy (DRFE) that results in seizure freedom in about 60% of patients. Correctly identifying an epileptogenic lesion in magnetic resonance imaging (MRI) is challenging but highly relevant since it improves the likelihood of being referred for presurgical diagnosis. The epileptogenic lesion's etiology directly relates to the surgical intervention's indication and outcome. Therefore, it is vital to correctly identify epileptogenic lesions and their etiology presurgically. METHODS: We compared the final histopathological diagnoses of all patients with DRFE undergoing epilepsy surgery at our center between 2015 and 2021 with their MRI diagnoses before and after presurgical diagnosis at our epilepsy center, including MRI evaluations by expert epilepsy neuroradiologists. Additionally, we analyzed the outcome of different subgroups. RESULTS: This study included 132 patients. The discordance between histopathology and MRI diagnoses significantly decreased from 61.3% for non-expert MRI evaluations (NEMRIs) to 22.1% for epilepsy center MRI evaluations (ECMRIs; p < 0.0001). The MRI-sensitivity improved significantly from 68.6% for NEMRIs to 97.7% for ECMRIs (p < 0.0001). Identifying focal cortical dysplasia (FCD) and amygdala dysplasia was the most challenging for both subgroups. 65.5% of patients with negative NEMRI were seizure-free 12 months postoperatively, no patient with negative ECMRI achieved seizure-freedom. The mean duration of epilepsy until surgical intervention was 13.6 years in patients with an initial negative NEMRI and 9.5 years in patients with a recognized lesion in NEMRI. CONCLUSIONS: This study provides evidence that for patients with DRFE-especially those with initial negative findings in a non-expert MRI-an early consultation at an epilepsy center, including an ECMRI, is important for identifying candidates for epilepsy surgery. NEMRI-negative findings preoperatively do not preclude seizure freedom postoperatively. Therefore, patients with DRFE that remain MRI-negative after initial NEMRI should be referred to an epilepsy center for presurgical evaluation. Nonreferral based on NEMRI negativity may harm such patients and delay surgical intervention. However, ECMRI-negative patients have a reduced chance of becoming seizure-free after epilepsy surgery. Further improvements in MRI technique and evaluation are needed and should be directed towards improving sensitivity for FCDs and amygdala dysplasias.

Trends and Differences in Status Epilepticus Treatment of Children and Adults Over 10 Years: A Comparative Study of Medical Records (2012-2021) from a University Hospital in Germany.

BACKGROUND AND OBJECTIVES: Over the last decade, significant advancements have been made in status epilepticus (SE) management, influenced by landmark trials such as ESETT and RAMPART. The objectives of this study were to explore the evolution of drug treatments for patients with SE, to investigate its association with outcomes and mortality, and to evaluate differences in treatment patterns between adults and children for a potential shift in medication trends due to the above mentioned trials. METHODS: The medical records of patients with SE treated at University Hospital Frankfurt between 2012 and 2021 were evaluated for medication trends and outcomes. Children and adults were analyzed separately and jointly. RESULTS: This study included 1151 SE episodes in 1021 patients (mean age = 53.3 ± 28.3 years; 52.5 % female [n = 533]). The overall percentage of patients with SE treated prehospital was stable over the last decade. More than half (53.6 %) of children were treated prehospital, compared with less than one-third (26.7 %) of adults. Prehospital midazolam use increased over time, while diazepam use decreased. Lorazepam was the most commonly used benzodiazepine in hospitals in 2012-2013, used in 40.8 % of all episodes. However, its use declined to 27.2 % in 2020-2021, while midazolam use increased to 44.0 %. While the use of older antiseizure medications (ASMs) such as phenobarbital (p = 0.02), phenytoin (p < 0.001), and valproate (p < 0.001) decreased, the use of newer ASMs such as levetiracetam and lacosamide significantly increased (p < 0.001). Propofol and continuous midazolam infusion remained the most used third-line therapy drugs. Overall mortality was 16.5 % at discharge and 18.9 % at 30 days. Mortality rates did not change between 2012 and 2021. CONCLUSION: Midazolam has become the preferred benzodiazepine in pre- and in-hospital settings, both in children and adults. The same applies to the increased use of levetiracetam and lacosamide over time in children and adults, while phenobarbital, phenytoin, and valproate use decreased. Continuous midazolam infusion and propofol remain the most frequently used anesthetic drugs. Mortality and outcome remain stable despite changes in medication patterns.

Autoantibody subclass predominance is not driven by aberrant class switching or impaired B cell development.

A subset of autoimmune diseases is characterized by predominant pathogenic IgG4 autoantibodies (IgG4-AID). Why IgG4 predominates in these disorders is unknown. We hypothesized that dysregulated B cell maturation or aberrant class switching causes overrepresentation of IgG4+ B cells and plasma cells. Therefore, we compared the B cell compartment of patients from four different IgG4-AID with two IgG1-3-AID and healthy donors, using flow cytometry. Relative subset abundance at all maturation stages was normal, except for a, possibly treatment-related, reduction in immature and naïve CD5+ cells. IgG4+ B cell and plasma cell numbers were normal in IgG4-AID patients, however they had a (sub)class-independent 8-fold increase in circulating CD20-CD138+ cells. No autoreactivity was found in this subset. These results argue against aberrant B cell development and rather suggest the autoantibody subclass predominance to be antigen-driven. The similarities between IgG4-AID suggest that, despite displaying variable clinical phenotypes, they share a similar underlying immune profile.

Breast cancer time to treatment in Martinique: predictive factors and effect on survival.

BACKGROUND: Martinique is the second French Region with the lowest physician-to-population ratio, which may affect waiting times for access to care. OBJECTIVES: To assess (i) factors influencing waiting times from diagnosis to cancer-related treatments in breast cancer women in Martinique, and (ii) the impact of waiting times on patients' survival. STUDY DESIGN: Retrospective observational study. METHODS: Data on women diagnosed with invasive breast cancer between 1st January 2013 and 31st December 2017 and initially treated by surgery were extracted from the Martinique population-based registry. A cox model was performed to find predictive factors for waiting times. A log-rank test was used to compare time-to-treatment between groups. RESULTS: In total, 713 patients were included (mean age: 58 ± 13). Median time from diagnosis to surgery was 40 [25-60] days. Age at diagnosis was found to predict variations in waiting times. Patients > 75 had longer waiting time to surgery than those < 40 or [40-50] (P = 0.016 and P < 0.001, respectively). Women with a time-to-treatment ≥ 4 months had a significant lower survival (P < 0.01). CONCLUSIONS: Specific interventions are needed to improve waiting time from diagnosis to initial treatment, as they are longer than recommended and affect survival time.

Prognostic value of comorbidities in older patients with cancer: the ELCAPA cohort study.

BACKGROUND: In older patients, comorbidities competed with cancer for mortality risk. We assessed the prognostic value of comorbidities in older patients with cancer. PATIENTS AND METHODS: We analysed all patients >70 years of age with colorectal, breast, prostate, or lung cancer included in the prospective ELCAPA cohort. The Cumulative Illness Rating Scale-Geriatrics (CIRS-G) score was used to assess comorbidities. The primary endpoint was overall survival (OS) at 3, 12, and 36 months. The adjusted difference in the restricted mean survival time (RMST) was used to assess the strength of the relationship between comorbidities and survival. RESULTS: Of the 1551 patients included (median age 82 years; interquartile range 78-86 years), 502 (32%), 575 (38%), 283 (18%), and 191 (12%) had colorectal, breast, prostate, and lung cancer, respectively, and 50% had metastatic disease. Hypertension, kidney failure, and cognitive impairment were the most common comorbidities (67%, 38%, and 29% of the patients, respectively). A CIRS-G score >17, two or more severe comorbidities, more than seven comorbidities, heart failure, and cognitive impairment were independently associated with shorter OS. The greatest effect size was observed for CIRS-G >17 (versus CIRS-G <11): at 36 months, the adjusted differences in the RMST (95% confidence interval) were -6.0 months (-9.3 to -2.6 months) for colorectal cancer, -9.1 months (-13.2 to -4.9 months) for breast cancer, -8.3 months (-12.8 to -3.9 months) for prostate cancer, and -5.5 months (-9.9 to -1.1 months) for lung cancer (P < 0.05 for all). CONCLUSIONS: Comorbidities' type, number, and severity were independently associated with shorter OS. A 17-point cut-off over 56 for the total CIRS-G score could be considered in clinical practice.

Entropy-Based Multifractal Testing of Heart Rate Variability during Cognitive-Autonomic Interplay.

Entropy-based and fractal-based metrics derived from heart rate variability (HRV) have enriched the way cardiovascular dynamics can be described in terms of complexity. The most commonly used multifractal testing, a method using q moments to explore a range of fractal scaling in small-sized and large-sized fluctuations, is based on detrended fluctuation analysis, which examines the power-law relationship of standard deviation with the timescale in the measured signal. A more direct testing of a multifractal structure exists based on the Shannon entropy of bin (signal subparts) proportion. This work aims to reanalyze HRV during cognitive tasks to obtain new markers of HRV complexity provided by entropy-based multifractal spectra using the method proposed by Chhabra and Jensen in 1989. Inter-beat interval durations (RR) time series were obtained in 28 students comparatively in baseline (viewing a video) and during three cognitive tasks: Stroop color and word task, stop-signal, and go/no-go. The new HRV estimators were extracted from the f/α singularity spectrum of the RR magnitude increment series, established from q-weighted stable (log-log linear) power laws, namely: (i) the whole spectrum width (MF) calculated as αmax - αmin; the specific width representing large-sized fluctuations (MFlarge) calculated as α0 - αq+; and small-sized fluctuations (MFsmall) calculated as αq- - α0. As the main results, cardiovascular dynamics during Stroop had a specific MF signature while MFlarge was rather specific to go/no-go. The way these new HRV markers could represent different aspects of a complete picture of the cognitive-autonomic interplay is discussed, based on previously used entropy- and fractal-based markers, and the introduction of distribution entropy (DistEn), as a marker recently associated specifically with complexity in the cardiovascular control.

Determinants of quality of life in adults with epilepsy: a multicenter, cross-sectional study from Germany.

BACKGROUND: Assessment of quality of life (QoL) has become an important indicator for chronic neurological diseases. While these conditions often limit personal independence and autonomy, they are also associated with treatment-related problems and reduced life expectancy. Epilepsy has a tremendous impact on the QoL of patients and their families, which is often underestimated by practitioners. The aim of this work was to identify relevant factors affecting QoL in adults with epilepsy. METHODS: This cross-sectional, multicenter study was conducted at four specialized epilepsy centers in Germany. Patients diagnosed with epilepsy completed a standardized questionnaire focusing on QoL and aspects of healthcare in epilepsy. Univariate regression analyses and pairwise comparisons were performed to identify variables of decreased QoL represented by the overall Quality of Life in Epilepsy Inventory (QOLIE-31) score. The variables were then considered in a multivariate regression analysis after multicollinearity analysis. RESULTS: Complete datasets for the QOLIE-31 were available for 476 patients (279 [58.6%] female, 197 [41.4%] male, mean age 40.3 years [range 18-83 years]). Multivariate regression analysis revealed significant associations between low QoL and a high score on the Liverpool Adverse Events Profile (LAEP; beta=-0.28, p < 0.001), Hospital Anxiety and Depression Scale - depression subscale (HADS-D; beta=-0.27, p < 0.001), Neurological Disorders Depression Inventory in Epilepsy (NDDI-E; beta=-0.19, p < 0.001), revised Epilepsy Stigma Scale (beta=-0.09, p = 0.027), or Seizure Worry Scale (beta=-0.18, p < 0.001) and high seizure frequency (beta = 0.14, p < 0.001). CONCLUSION: Epilepsy patients had reduced QoL, with a variety of associated factors. In addition to disease severity, as measured by seizure frequency, the patient's tolerability of anti-seizure medications and the presence of depression, stigma, and worry about new seizures were strongly associated with poor QoL. Diagnosed comorbid depression was underrepresented in the cohort; therefore, therapeutic decisions should always consider individual psychobehavioral and disease-specific aspects. Signs of drug-related adverse events, depression, fear, or stigmatization should be actively sought to ensure that patients receive personalized and optimized treatment. TRIAL REGISTRATION: German Clinical Trials Register (DRKS00022024; Universal Trial Number: U1111-1252-5331).

The Long-Term Use of Diagnostic Subdural Electroencephalogram Electrodes and Subdural Hematoma: A Prospective Cohort Study.

OBJECTIVES: Seizures and status epilepticus (SE) are frequent complications of acute subdural hematoma (aSDH) associated with increased morbidity and mortality. Therefore, we aimed to evaluate whether invasive subdural electroencephalogram recording leads to earlier seizure detection and treatment initiation in patients with aSDH. DESIGN: Prospective, single-center, cohort trial. SETTING: Neurologic and neurosurgical ICUs of one academic hospital in Germany. PATIENTS: Patients with aSDH undergoing surgical treatment. In total, 76 patients were enrolled in this study, 31 patients (40.8%) were assigned to the invasive electroencephalogram (iEEG) monitoring group and 45 patients (59.2%) to control group. INTERVENTIONS: The electrode group was implanted with a subdural strip electrode providing up to 7 days of real-time electroencephalogram recording in the neurointensive care unit, whereas the control group received regular normal surface electroencephalograms during the 7-day period. The primary outcomes were the prevalence and time to seizures and SE occurrence. Secondary outcomes included neurologic outcomes assessed using the Glasgow Outcome Scale (GOS) at discharge and 6-month follow-up and the prevalence of focal structural epilepsy within 2 years after discharge. MEASUREMENTS AND MAIN RESULTS: The trial was stopped after a study committee meeting when the prespecified criteria were met. The iEEG and control groups were well-matched for clinical characteristics at admission. Frequencies of seizures and SE detection were significantly higher in the iEEG group than in the control group (61% vs 15.6%; p < 0.001 and 38.7% vs 11.1%; p = 0.005). Time to seizure and SE detection was significantly earlier (median 29.2 vs 83.8 hr; p = 0.018 and 17.2 vs 83.8 hr; p = 0.033) in the iEEG group than in the control group. Favorable outcomes (GOS 4-5) were more frequently achieved in the iEEG group than in the control group (58% vs 31%; p = 0.065). No significant differences were detected in long-term mortality or post-traumatic epilepsy. CONCLUSIONS: Invasive subdural electroencephalogram monitoring is valuable and safe for early seizure/SE detection and treatment and might improve outcomes in the neurocritical care of patients with aSDH.