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.

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.

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.

Adverse Event Profiles of Antiseizure Medications and the Impact of Coadministration on Drug Tolerability in Adults with Epilepsy.

BACKGROUND: Antiseizure medication (ASM) as monotherapy or in combination is the treatment of choice for most patients with epilepsy. Therefore, knowledge about the typical adverse events (AEs) for ASMs and other coadministered drugs (CDs) is essential for practitioners and patients. Due to frequent polypharmacy, it is often difficult to clinically assess the AE profiles of ASMs and differentiate the influence of CDs. OBJECTIVE: This retrospective analysis aimed to determine typical AE profiles for ASMs and assess the impact of CDs on AEs in clinical practice. METHODS: The Liverpool AE Profile (LAEP) and its domains were used to identify the AE profiles of ASMs based on data from a large German multicenter study (Epi2020). Following established classifications, drugs were grouped according to their mode of action (ASMs) or clinical indication (CDs). Bivariate correlation, multivariate ordinal regression (MORA), and artificial neural network (ANNA) analyses were performed. Bivariate correlation with Fisher's z-transformation was used to compare the correlation strength of LAEP with the Hospital Anxiety and Depression Scale (HADS) and Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) to avoid LAEP bias in the context of antidepressant therapy. RESULTS: Data from 486 patients were analyzed. The AE profiles of ASM categories and single ASMs matched those reported in the literature. Synaptic vesicle glycoprotein 2A (SV2A) and voltage-gated sodium channel (VGSC) modulators had favorable AE profiles, while brivaracetam was superior to levetiracetam regarding psychobehavioral AEs. MORA revealed that, in addition to seizure frequency, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) modulators and antidepressants were the only independent predictors of high LAEP values. After Fisher's z-transformation, correlations were significantly lower between LAEP and antidepressants than between LAEP and HADS or NDDI-E. Therefore, a bias in the results toward over interpreting the impact of antidepressants on LAEP was presumed. In the ANNA, perampanel, zonisamide, topiramate, and valproic acid were important nodes in the network, while VGSC and SV2A modulators had low relevance for predicting relevant AEs. Similarly, cardiovascular agents, analgesics, and antipsychotics were important CDs in the ANNA model. CONCLUSION: ASMs have characteristic AE profiles that are highly reproducible and must be considered in therapeutic decision-making. Therapy using perampanel as an AMPA modulator should be considered cautiously due to its relatively high AE profile. Drugs acting via VGSCs and SV2A receptors are significantly better tolerated than other ASM categories or substances (e.g., topiramate, zonisamide, and valproate). Switching to brivaracetam is advisable in patients with psychobehavioral AEs who take levetiracetam. Because CDs frequently pharmacokinetically interact with ASMs, the cumulative AE profile must be considered. TRIAL REGISTRATION: DRKS00022024, U1111-1252-5331.

The neurovasculature as a target in temporal lobe epilepsy.

The blood-brain barrier (BBB) is a physiological barrier maintaining a specialized brain micromilieu that is necessary for proper neuronal function. Endothelial tight junctions and specific transcellular/efflux transport systems provide a protective barrier against toxins, pathogens, and immune cells. The barrier function is critically supported by other cell types of the neurovascular unit, including pericytes, astrocytes, microglia, and interneurons. The dysfunctionality of the BBB is a hallmark of neurological diseases, such as ischemia, brain tumors, neurodegenerative diseases, infections, and autoimmune neuroinflammatory disorders. Moreover, BBB dysfunction is critically involved in epilepsy, a brain disorder characterized by spontaneously occurring seizures because of abnormally synchronized neuronal activity. While resistance to antiseizure drugs that aim to reduce neuronal hyperexcitability remains a clinical challenge, drugs targeting the neurovasculature in epilepsy patients have not been explored. The use of novel imaging techniques permits early detection of BBB leakage in epilepsy; however, the detailed mechanistic understanding of causes and consequences of BBB compromise remains unknown. Here, we discuss the current knowledge of BBB involvement in temporal lobe epilepsy with the emphasis on the neurovasculature as a therapeutic target.

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

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

Seizure related injuries - Frequent injury patterns, hospitalization and therapeutic aspects.

PURPOSE: Epileptic seizures frequently result in distinct physical injuries, fractures, traumatic brain injuries and minor trauma. The aim of this study was to retrospectively determine the frequent injury patterns due to seizure episode and to analyze consecutive acute medical care. METHODS: This retrospective mono-center study was conducted at Frankfurt University Hospital, Frankfurt am Main, Germany between January 2007 and December 2017. Epilepsy patients with seizure-related fractures admitted to the emergency department were identified via a retrospective systematic query in the hospital information system using the ICD-10 German modification codes G40.0-G40.9. Patients with an unclear diagnosis of epilepsy were excluded. Sociodemographic as well as disease specific aspects were analyzed. Descriptive and Kruskal-Wallis one-way analysis of variance were used for statistical analysis. RESULTS: A total number of 62 epilepsy patients were included. The mean age was 58.1 years. Fractures concerned the upper extremity most frequently (43.5%, n = 20), and 70.0% (14/20) were humerus fractures. Admission to intensive care unit for acute trauma care was necessary in 29.0% patients (n = 18), and surgery in 45.2% patients (n = 28). Twenty-five patients (26.6%) showed clinical or radiological signs of traumatic brain injury. Provoking factors were identified in 20 patients (32.3%), i.e., acute withdrawal or excess of alcohol (n = 15), relevant sleep deprivation (n = 2), and intoxication or withdrawal of other illegal drugs or trivial infect (n = 1 for each) and non-compliance with anti-seizure drugs (n = 1). A decreased T-score (-1.04 ± 1.15) and Z-score (-0.84 ± 0.75) compared to healthy subjects were found. CONCLUSION: Fractures in upper extremities, trunk and craniocerebral trauma occur frequently as seizure-induced injuries. Alcohol excess and withdrawal are important provoking factors and should be targeted with preventive measurements to avoid seizure related injuries and accidents.

Type of treatment, symptoms and patient satisfaction play an important role in primary care contact during prostate cancer follow-up: results from the population-based PROFILES registry.

BACKGROUND: With the increasing attention for the role of General Practitioners (GPs) after cancer treatment, it is important to better understand the involvement of GPs following prostate cancer treatment. This study investigates factors associated with GP contact during follow-up of prostate cancer survivors, such as patient, treatment and symptom variables, and satisfaction with, trust in, and appraised knowledge of GPs. METHODS: Of 787 prostate cancer survivors diagnosed between 2007 and 2013, and selected from the Netherlands Cancer Registry, 557 (71%) responded to the invitation to complete a questionnaire. Multivariable logistic regression analyses were performed to investigate which variables were associated with GP contact during follow- up. RESULTS: In total, 200 (42%) prostate cancer survivors had contact with their GP during follow-up, and 76 (16%) survivors preferred more contact. Survivors who had an intermediate versus low educational level (OR = 2.0) were more likely to have had contact with their GP during follow-up. Survivors treated with surgery (OR = 2.8) or hormonal therapy (OR = 3.5) were also more likely to seek follow-up care from their GP compared to survivors who were treated with active surveillance. Patient reported bowel symptoms (OR = 1.4), hormonal symptoms (OR = 1.4), use of incontinence aids (OR = 1.6), and being satisfied with their GP (OR = 9.5) were also significantly associated with GP contact during follow-up. CONCLUSIONS: Education, treatment, symptoms and patient satisfaction were associated with GP contact during prostate cancer follow-up. These findings highlight the potential for adverse side-effects to be managed in primary care. In light of future changes in cancer care, evaluating prostate cancer follow-up in primary care remains important.

Health-related quality of life in children and adolescents with tuberous sclerosis complex and their caregivers: A multicentre cohort study from Germany.

OBJECTIVE: This study aimed to measure health-related quality of life (HRQOL) in children and adolescents with tuberous sclerosis complex (TSC) and quality of life (QOL) and depressive symptoms among caregivers. METHODS: Adequate metrics were used to assess HRQOL in children and adolescents with TSC (4-18 years, KINDLR) as well as QOL (EQ-5D) and symptoms of depression (BDI-II) among caregivers. Predictors for reduced HRQOL and depressive symptoms were identified by variance analysis, ordinal regression, and bivariate correlation. RESULTS: The mean HRQOL score was 67.9 ± 12.7, and significantly lower values were associated with increasing age, attending special needs education, TSC-associated psychiatric symptoms, and drug-related adverse events. The mean QOL of caregivers was 85.4 ± 15.7, and caregiver's sex, TSC mutation locus, familial TSC clustering, special needs education, degree of disability, care dependency, presence of TSC-associated psychiatric symptoms, and TSC severity were significant predictors of lower QOL. Depressive symptoms were identified in 45.7% of caregivers, associated with female sex of the caregiver, familial TSC clustering, special needs education, and presence of TSC-associated psychiatric symptoms of the child. Multivariate regression analysis revealed adolescence and drug-related adverse events as significant predictors for lower HRQOL in TSC children, and TSC2 variants predicted lower QOL and depressive symptoms in caregivers. CONCLUSION: Compared with other chronic diseases, such as headache, diabetes or obesity, children with TSC have significantly lower HRQOL, which further decreases during adolescence. A decreased HRQOL of patients correlates with a lower QOL and increased symptoms of depression of their caregivers. These results may improve the comprehensive therapy and care of children and adolescents with TSC and their families and caregivers. TRIAL REGISTRATION: DRKS, DRKS00016045. Registered 01 March 2019, http://www.drks.de/DRKS00016045.

Efficacy and Safety of Bevacizumab Biosimilar FKB238 Versus Originator Bevacizumab: Results from AVANA, a Phase III Trial in Patients with Non-Squamous Non-Small-Cell Lung Cancer (non-sq-NSCLC).

BACKGROUND: Bevacizumab is an antiangiogenic recombinant humanized monoclonal antibody that inhibits tumor growth. FKB238, a bevacizumab biosimilar, has analytical pharmacokinetic and safety profiles similar to those of bevacizumab. OBJECTIVE: This phase III trial (NCT02810457) compared the efficacy and safety of FKB238 with that of bevacizumab in patients with advanced/recurrent non-squamous non-small-cell lung cancer (non-sq-NSCLC). METHODS: This global, multicenter, double-blind, parallel, randomized, comparative clinical trial enrolled and randomized patients with advanced/recurrent non-sq-NSCLC to receive intravenous infusions of either FKB238 15 mg/kg or bevacizumab 15 mg/kg. All patients received intravenous infusions of paclitaxel 200 mg/m2 and carboplatin (area under the curve 6.0) immediately prior to investigational products for 4-6 cycles. FKB238 and bevacizumab were administered on day 1 of each 21-day cycle until objective progressive disease by RECIST version 1.1 or other discontinuation criteria were met. The primary efficacy endpoint was overall response rate (ORR), including complete and partial response and based on blinded independent central review assessment. Other efficacy determinations included progression-free survival (PFS), overall survival (OS), and immunogenicity. Adverse events and severity were reported. RESULTS: The ORR for the intent-to-treat (ITT) population (N = 731) was 51.6% in the FKB238 arm (N = 364) and 53.7% in the bevacizumab arm (N = 367). The FKB238:bevacizumab ORR ratio (ITT population) was 0.96 (90% confidence interval [CI] 0.86-1.08), and the difference in ORR (per-protocol set) between FKB238 and bevacizumab was - 0.02 (95% CI - 0.09 to 0.06). Both CIs fell within the prespecified equivalence margins. Estimated median PFS was 7.72 and 7.62 months in the FKB238 and bevacizumab arms, respectively (hazard ratio 0.97; 95% CI 0.82-1.16). Treatment-emergent adverse events (TEAEs) were reported for 94.2% and 95.1% of patients in the FKB238 and bevacizumab arms, respectively. Grade 3 or higher TEAEs were reported for 53.6% and 55.5% of patients in the FKB238 and bevacizumab arms, respectively. Serious TEAEs were reported for 25.1% and 26.0% of patients treated with FKB238 and bevacizumab, respectively. CONCLUSIONS: Efficacy equivalence was demonstrated between the two drugs, and safety profiles were similar. There were no meaningful differences in efficacy and safety between FKB238 or bevacizumab in patients with non-sq-NSCLC. TRIAL REGISTRATION NUMBER: NCT02810457.

Efficacy, Retention and Tolerability of Everolimus in Patients with Tuberous Sclerosis Complex: A Survey-Based Study on Patients' Perspectives.

BACKGROUND: The approval of everolimus (EVE) for the treatment of angiomyolipoma (2013), subependymal giant cell astrocytoma (2013) and drug-refractory epilepsy (2017) in patients with tuberous sclerosis complex (TSC) represents the first disease-modifying treatment option available for this rare and complex genetic disorder. OBJECTIVE: The objective of this study was to analyse the use, efficacy, tolerability and treatment retention of EVE in patients with TSC in Germany from the patient's perspective. METHODS: A structured cross-age survey was conducted at 26 specialised TSC centres in Germany and by the German TSC patient advocacy group between February and July 2019, enrolling children, adolescents and adult patients with TSC. RESULTS: Of 365 participants, 36.7% (n = 134) reported the current or past intake of EVE, including 31.5% (n = 115) who were taking EVE at study entry. The mean EVE dosage was 6.1 ± 2.9 mg/m2 (median: 5.6 mg/m2, range 2.0-15.1 mg/m2) in children and adolescents and 4 ± 2.1 mg/m2 (median: 3.7 mg/m2, range 0.8-10.1 mg/m2) in adult patients. An early diagnosis of TSC, the presence of angiomyolipoma, drug-refractory epilepsy, neuropsychiatric manifestations, subependymal giant cell astrocytoma, cardiac rhabdomyoma and overall multi-organ involvement were associated with the use of EVE as a disease-modifying treatment. The reported efficacy was 64.0% for angiomyolipoma (75% in adult patients), 66.2% for drug-refractory epilepsy, and 54.4% for subependymal giant cell astrocytoma. The overall retention rate for EVE was 85.8%. The retention rates after 12 months of EVE therapy were higher among adults (93.7%) than among children and adolescents (88.7%; 90.5% vs 77.4% after 24 months; 87.3% vs 77.4% after 36 months). Tolerability was acceptable, with 70.9% of patients overall reporting adverse events, including stomatitis (47.0%), acne-like rash (7.7%), increased susceptibility to common infections and lymphoedema (each 6.0%), which were the most frequently reported symptoms. With a total score of 41.7 compared with 36.8 among patients not taking EVE, patients currently being treated with EVE showed an increased Liverpool Adverse Event Profile. Noticeable deviations in the sub-items 'tiredness', 'skin problems' and 'mouth/gum problems', which are likely related to EVE-typical adverse effects, were more frequently reported among patients taking EVE. CONCLUSIONS: From the patients' perspective, EVE is an effective and relatively well-tolerated disease-modifying treatment option for children, adolescents and adults with TSC, associated with a high long-term retention rate that can be individually considered for each patient. Everolimus therapy should ideally be supervised by a centre experienced in the use of mechanistic target of rapamycin inhibitors, and adverse effects should be monitored on a regular basis.

Direct and indirect costs and cost-driving factors of Tuberous sclerosis complex in children, adolescents, and caregivers: a multicenter cohort study.

BACKGROUND: Tuberous sclerosis complex (TSC), a multisystem genetic disorder, affects many organs and systems, characterized by benign growths. This German multicenter study estimated the disease-specific costs and cost-driving factors associated with various organ manifestations in TSC patients. METHODS: A validated, three-month, retrospective questionnaire was administered to assess the sociodemographic and clinical characteristics, organ manifestations, direct, indirect, out-of-pocket, and nursing care-level costs, completed by caregivers of patients with TSC throughout Germany. RESULTS: The caregivers of 184 patients (mean age 9.8 ± 5.3 years, range 0.7-21.8 years) submitted questionnaires. The reported TSC disease manifestations included epilepsy (92%), skin disorders (86%), structural brain disorders (83%), heart and circulatory system disorders (67%), kidney and urinary tract disorders (53%), and psychiatric disorders (51%). Genetic variations in TSC2 were reported in 46% of patients, whereas 14% were reported in TSC1. Mean total direct health care costs were EUR 4949 [95% confidence interval (95% CI) EUR 4088-5863, median EUR 2062] per patient over three months. Medication costs represented the largest direct cost category (54% of total direct costs, mean EUR 2658), with mechanistic target of rapamycin (mTOR) inhibitors representing the largest share (47%, EUR 2309). The cost of anti-seizure drugs (ASDs) accounted for a mean of only EUR 260 (5%). Inpatient costs (21%, EUR 1027) and ancillary therapy costs (8%, EUR 407) were also important direct cost components. The mean nursing care-level costs were EUR 1163 (95% CI EUR 1027-1314, median EUR 1635) over three months. Total indirect costs totaled a mean of EUR 2813 (95% CI EUR 2221-3394, median EUR 215) for mothers and EUR 372 (95% CI EUR 193-586, median EUR 0) for fathers. Multiple regression analyses revealed polytherapy with two or more ASDs and the use of mTOR inhibitors as independent cost-driving factors of total direct costs. Disability and psychiatric disease were independent cost-driving factors for total indirect costs as well as for nursing care-level costs. CONCLUSIONS: This study revealed substantial direct (including medication), nursing care-level, and indirect costs associated with TSC over three months, highlighting the spectrum of organ manifestations and their treatment needs in the German healthcare setting. TRIAL REGISTRATION: DRKS, DRKS00016045. Registered 01 March 2019, http://www.drks.de/DRKS00016045.

Pressure measurement in gas flows using laser-induced grating lifetime.

Optical diagnostics of gas-phase pressure are relatively unusual. In this work, we demonstrate a novel, rapid, and robust method to use laser-induced grating scattering (LIGS) to derive this property in real time. Previous pressure measurements with LIGS have employed a signal fitting method, but this is relatively time-consuming and requires specialist understanding. In this paper, we directly measure a decay lifetime from a LIGS signal and then employ a calibration surface constructed using a physics-based model to convert this value to pressure. This method was applied to an optically accessible single-cylinder internal combustion engine, yielding an accuracy of better than 10% at all tested conditions above atmospheric pressure. This new approach complements the existing strength of LIGS in precisely and accurately deriving temperature with a simple analysis method, by adding pressure information with a similarly simple method.

Comparison of frame-less robotic versus frame-based stereotactic biopsy of intracranial lesions.

OBJECTIVE: Robotic guidance might be an alternative to classic stereotaxy for biopsies of intracranial lesions. Both methods were compared regarding time efficacy, histopathological results and complications. METHODS: A retrospective analysis enrolling all patients undergoing robotic- or stereotactic biopsies between 01/2015 and 12/2018 was conducted. Trajectory planning was performed on magnetic resonance imaging (MRI). With the Robotic Surgery Assistant (ROSA), patient registration was accomplished using a facial laser scan in the operating room (OR), immediately followed by biopsy. In stereotaxy, patients were transported to the CT for Leksell Frame registration, followed by biopsy in the OR. RESULTS: The average overall procedure time amounted in robotics to 169 min and in stereotaxy to 179 min (p = 0.005). The difference was greatest for temporal targets, amounting in robotics to 161 min and in stereotaxy to 188 min (p = 0,0007). However, the average time spent purely in the OR amounted in robotics to 140 min and in stereotaxy to 113 min (p < 0.001). In 150 robotic biopsies, diagnostic yield amounted to 98%, in 266 stereotactic biopsies to 91%. Symptomatic postoperative hemorrhages were observed in 3 patients (2%) in robotic biopsy and 7 patients (2,7%) in stereotactic biopsy. CONCLUSION: Robotics showed a shorter overall procedure time as there is no need for a transport to the CT whereas the pure OR time was shorter in stereotaxy due to skipping the laser registration process. Diagnostic yield was higher in robotics, most likely due to case selection, complication rates were equal.

Quality of life and its predictors in adults with tuberous sclerosis complex (TSC): a multicentre cohort study from Germany.

BACKGROUND: Tuberous sclerosis complex (TSC) is a monogenetic, multisystemic disease characterised by the formation of benign tumours that can affect almost all organs, caused by pathogenic variations in TSC1 or TSC2. In this multicentre study from Germany, we investigated the influence of sociodemographic, clinical, and therapeutic factors on quality of life (QoL) among individuals with TSC. METHODS: We assessed sociodemographic and clinical characteristics and QoL among adults with TSC throughout Germany using a validated, three-month, retrospective questionnaire. We examined predictors of health-related QoL (HRQoL) using multiple linear regression analysis and compared the QoL among patients with TSC with QoL among patients with other chronic neurological disorders. RESULTS: We enrolled 121 adults with TSC (mean age: 31.0 ± 10.5 years; range: 18-61 years, 45.5% [n = 55] women). Unemployment, a higher grade of disability, a higher number of organ manifestations, the presence of neuropsychiatric manifestations or active epilepsy, and a higher burden of therapy-related adverse events were associated with worse QoL, as measured by two QoL instruments (EuroQoL-5 dimensions [EQ-5D] and Quality of Life in Epilepsy Patients [QOLIE-31]). Neuropsychiatric and structural nervous system manifestations, the number of affected organs, and therapy-related adverse events were also associated with higher depression, as measured by the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E). In multiple regression analysis, more severe therapy-related adverse events (large effect, p < 0.001), active epilepsy (large effect, p < 0.001), and neuropsychiatric manifestations (medium effect, p = 0.003) were independently associated with worse HRQoL, explaining 65% of the variance (p < 0.001). The HRQoL among patients with active TSC-associated epilepsy was worse than that among patients with drug-refractory mesial temporal lobe epilepsy (p < 0.001), and the generic QoL among patients with more than three TSC organ manifestations was similar to those of patients with severe migraine and uncontrolled asthma. CONCLUSIONS: Active epilepsy, neuropsychiatric manifestations (such as anxiety and depression), and therapy-related adverse events are important independent predictors of worse quality of life among adults with TSC. Generic quality of life in TSC with several manifestations is similar to uncontrolled severe chronic diseases and significantly negatively correlates with TSC severity. TRIAL REGISTRATION: DRKS, DRKS00016045 . Registered 01 March 2019.

Direct and indirect costs and cost-driving factors in adults with tuberous sclerosis complex: a multicenter cohort study and a review of the literature.

BACKGROUND: Tuberous sclerosis complex (TSC) is a monogenetic, multisystem disorder characterized by benign growths due to TSC1 or TSC2 mutations. This German multicenter study estimated the costs and related cost drivers associated with organ manifestations in adults with TSC. METHODS: A validated, three-month, retrospective questionnaire assessed the sociodemographic and clinical characteristics, organ manifestations, direct, indirect, out-of-pocket (OOP), and nursing care-level costs among adult individuals with TSC throughout Germany from a societal perspective (costing year: 2019). RESULTS: We enrolled 192 adults with TSC (mean age: 33.4 ± 12.7 years; range: 18-78 years, 51.6% [n = 99] women). Reported TSC disease manifestations included skin (94.8%) and kidney and urinary tract (74%) disorders, epilepsy (72.9%), structural brain defects (67.2%), psychiatric disorders (50.5%), heart and circulatory system disorders (50.5%), and lymphangioleiomyomatosis (11.5%). TSC1 and TSC2 mutations were reported in 16.7% and 25% of respondents, respectively. Mean direct health care costs totaled EUR 6452 (median EUR 1920; 95% confidence interval [CI] EUR 5533-7422) per patient over three months. Medication costs represented the major direct cost category (77% of total direct costs; mean EUR 4953), and mechanistic target of rapamycin (mTOR) inhibitors represented the largest share (68%, EUR 4358). Mean antiseizure drug (ASD) costs were only EUR 415 (6%). Inpatient costs (8%, EUR 518) and outpatient treatment costs (7%; EUR 467) were important further direct cost components. The mean care grade allowance as an approximator of informal nursing care costs was EUR 929 (median EUR 0; 95% CI EUR 780-1083) over three months. Mean indirect costs totaled EUR 3174 (median EUR 0; 95% CI EUR 2503-3840) among working-age individuals (< 67 years in Germany). Multiple regression analyses revealed mTOR inhibitor use and persistent seizures as independent cost-driving factors for total direct costs. Older age and disability were independent cost-driving factors for total indirect costs, whereas epilepsy, psychiatric disease, and disability were independent cost-driving factors for nursing care costs. CONCLUSIONS: This three-month study revealed substantial direct healthcare, indirect healthcare, and medication costs associated with TSC in Germany. This study highlights the spectrum of organ manifestations and their associated treatment needs in the German healthcare setting. TRIAL REGISTRATION: DRKS, DRKS00016045. Registered 01 March 2019, http://www.drks.de/DRKS00016045 .

Benefits, safety and outcomes of long-term video EEG monitoring in pediatric patients.

OBJECTIVE: To investigate benefits of in-hospital, long-term video EEG monitoring (LVEM) for pediatric patients, from a therapeutic perspective and from the perspectives of patients and their families. METHODS: A monocentric retrospective cohort study was conducted. Patients aged 0-18 years who underwent LVEM for epilepsy surgery eligibility, epilepsy syndrome clarification, or medication adjustment were evaluated regarding paroxysmal event type, change in seizure frequency and patients' benefits using a standardized evaluation protocol. RESULTS: A total of 163 (88 boys and 75 girls, mean age 10.9 years) pediatric patients underwent 178 LVEM sessions, with a mean duration of 5.4 days. The rate of habitual event detection was 69.1%. Epilepsy diagnosis was confirmed in 147 patients and excluded in 16 patients (9.8%). LVEM results altered the diagnosis of 37.4% of patients. Diagnosis remained unchanged in 49.1% of patients and was specified in 13.5% of patients. Epilepsy surgery was performed in 32 patients, and 64% of epilepsy patients deemed ineligible for epilepsy surgery underwent medication adjustments. Patients or their families found LVEM helpful in 75% of cases. Significant seizure reductions and improvements in the disease course were reported by 45% of epilepsy patients. Three episodes of non-convulsive status epilepticus occurred, representing 1.7% of admissions and 1.9% of patients diagnosed with epilepsy, while no injuries were observed. CONCLUSIONS: LVEM is beneficial for pediatric patients from both a medical perspective and from the perspective of patients and their families, even if patients are ineligible for epilepsy surgery. LVEM is well-tolerated with a low risk of status epilepticus and injuries.

Fractures in Parkinson's Disease: injury patterns, hospitalization, and therapeutic aspects.

AIM: The primary aim of this study was to analyze the frequency and characteristic patterns of fall-related fractures as well as consecutive hospitalization and management relating to such fractures. In addition, important pathognomonic and therapeutic aspects are discussed. METHODS: This retrospective mono-center study was conducted at the University Hospital Frankfurt am Main, Germany. Between 2007 and 2017, a total of 145 PD patients with fall-related fractures were identified via a retrospective systematic query in the hospital information system using the ICD-10 German modification codes G20.0-G20.9. Patients with unclear or falsely coded PD were strictly excluded. RESULTS: The mean age of the cohort was 77.7 years (± 7.5, median 77.) and 57.9% of the cohort were females (n = 84). A total number of 151 fractures were reported, with 140 patients (96.6%) suffering from one, four patients from two (2.8%), and one patient from three fractures (0.6%) at a time. For 43.9% (n = 65) of the cohort, fractures concerned lower extremities (LE) followed by trunk (38.1%, n = 58) and upper extremities (UE, 17.9%, n = 27). Most common fracture types in LE were femoral neck fractures (52.3%, n = 34). Mean length of hospital stay (LOS) was 13.6 days (95% CI 12.4-14.7). In 43.4% (n = 63) of cases, an interim admission to an intensive-care unit (ICU) was necessary. Mean ICU LOS was 2.3 days (95% CI 1.5-3.0), and mean LOS for normal care unit was 10.5 days (95% CI 10.3-12.4). Surgical treatment was necessary in 75.9% of the cases (n = 110). Patients undergoing surgical treatment showed significantly longer LOS compared to conservatively treated patients (p < 0.001). Moreover, fractures of the LE (p = 0.018) and UE (p = 0.010) were associated with a significant longer LOS. CONCLUSION: Fall-related fractures are a common and relevant complication in PD patients leading to increased immobility, frequent hospitalization, and immediate surgical care. Fractures of the lower extremities and trunk were the most common in the cohort for this study. A PD patient presenting to the emergency room or at the general practitioner with a fracture should always be checked for osteoporosis and a fall-related injury should be seen as a red flag for reviewing a patient's individual therapeutic regime.

Increased occurrence of status epilepticus in patients with brain metastases and checkpoint inhibition.

Integration of immune checkpoint inhibitors (ICIs) has improved the efficacy of treatment regimens for various cancers. The array of potential side effects keeps evolving and includes neurological complications. An increased risk of seizures and status epilepticus (SE) has been discussed and appears likely. In this report, we present clinical data from brain metastases patients undergoing ICI treatment revealing, for what we believe is the first time, SE as a serious adverse effect of ICI treatment. In our cohort of 3202 patients with brain metastases, we observed an increasing incidence of SE since the approval of ICIs in 2014 (16 patients in 2008-2013 vs. 36 patients in 2014-2019). Almost half of the patients treated in 2014-2019 received ICIs during the course of their disease, and in more than 80% of cases last dose of ICIs was given less than 30 days before SE. These findings suggest that ICIs may lead to an increased rate of SE in patients with brain metastases. Additional mechanistic research and prospective trials are necessary to elucidate the pathomechanism causing SE in patients treated with ICIs.