Real-World Evidence Study on the Long-Term Safety of Everolimus in Patients With Tuberous Sclerosis Complex: Final Analysis Results

Everolimus; Post-authorization safety study; Tuberous sclerosis complexEverolimus; Estudio de seguridad posautorización; Complejo de esclerosis tuberosaEverolimus; Estudi de seguretat posterior a l'autorització; Complex d'esclerosi tuberosaThe TuberOus SClerosis registry to increase disease Awareness (TOSCA) Post-Authorization Safety Study (PASS) was a non-interventional, multicenter, safety substudy that assessed the long-term safety of everolimus in patients with tuberous sclerosis complex (TSC) receiving everolimus for its licensed indications in the European Union (EU). This substudy also aimed to address TSC-associated neuropsychiatric disorders (TAND), sexual development, and male infertility. Eligible patients were enrolled from 39 sites across 11 countries in the EU. Outcomes of interest included the incidence of adverse events (AEs), serious adverse events (SAEs), treatment-related AEs (TRAEs), AEs leading to everolimus discontinuation, AEs of special interest (AESIs), the observed relationship between everolimus blood levels and incidence of AESIs, TAND, and reproductive clinical features. Herein, we present the final analysis results from this substudy (data cutoff date: 22 January 2020). At data cutoff, 179 patients were enrolled (female, 59.2%; age ≥18 years, 65.9%), of which the majority completed the study (76%). Overall, 121 patients (67.6%) had AEs regardless of causality. The most frequent TRAEs (≥5%) were stomatitis (7.8%), aphthous ulcer (6.7%), and hypercholesterolemia (6.1%). The most common treatment-related SAEs (>1%) were pneumonia (3.4%), influenza, pyelonephritis, aphthous ulcer, stomatitis, dyslipidemia, and hypercholesterolemia (1.1% each). Ten patients (5.6%) reported AEs leading to everolimus discontinuation. The common psychiatric disorders (N = 179) were autism spectrum disorder (21.8%), anxiety disorder (12.8%), “other” psychiatric disorders (8.9%), attention-deficit hyperactivity disorder, and depressive disorder (7.8% each). Of 179 patients, 88 (49.2%) had ≥1 behavioral problem. Of these (n = 88), the most common (>20%) were sleep difficulties (47.7%), anxiety (43.2%), mood swings (37.5%), depression mood (35.2%), impulsivity (30.7%), severe aggression (23.9%), and overactivity (22.7%). Of 179 patients, four (2.2%) reported abnormal puberty onset, and three (1.7%) reported other reproductive disorders. Of 106 females, 23 (21.7%) reported menstrual cycle disorders and 10 (9.4%) reported amenorrhea. Available data did not show delays in sexual maturation or an association between sexual development and infertility. The results demonstrate that everolimus has a manageable long-term safety profile in the TSC treatment setting. No new safety signals emerged. This substudy also contributed to the mapping of TAND and reproductive clinical features in patients with TSC.This study was funded by Novartis Pharmaceuticals Corporation

Changes in the Cerebrospinal Fluid and Plasma Lipidome in Patients with Rett Syndrome

Rett syndrome (RTT) is defined as a rare disease caused by mutations of the methyl-CpG binding protein 2 (MECP2). It is one of the most common causes of genetic mental retardation in girls, characterized by normal early psychomotor development, followed by severe neurologic regression. Hitherto, RTT lacks a specific biomarker, but altered lipid homeostasis has been found in RTT model mice as well as in RTT patients. We performed LC-MS/MS lipidomics analysis to investigate the cerebrospinal fluid (CSF) and plasma composition of patients with RTT for biochemical variations compared to healthy controls. In all seven RTT patients, we found decreased CSF cholesterol levels compared to age-matched controls (n = 13), whereas plasma cholesterol levels were within the normal range in all 13 RTT patients compared to 18 controls. Levels of phospholipid (PL) and sphingomyelin (SM) species were decreased in CSF of RTT patients, whereas the lipidomics profile of plasma samples was unaltered in RTT patients compared to healthy controls. This study shows that the CSF lipidomics profile is altered in RTT, which is the basis for future (functional) studies to validate selected lipid species as CSF biomarkers for RTT

A new model for fatty acid hydroxylase-associated neurodegeneration reveals mitochondrial and autophagy abnormalities

Fatty acid hydroxylase-associated neurodegeneration (FAHN) is a rare disease that exhibits brain modifications and motor dysfunctions in early childhood. The condition is caused by a homozygous or compound heterozygous mutation in fatty acid 2 hydroxylase (FA2H), whose encoded protein synthesizes 2-hydroxysphingolipids and 2-hydroxyglycosphingolipids and is therefore involved in sphingolipid metabolism. A few FAHN model organisms have already been established and give the first insight into symptomatic effects. However, they fail to establish the underlying cellular mechanism of FAHN so far. Drosophila is an excellent model for many neurodegenerative disorders; hence, here, we have characterized and validated the first FAHN Drosophila model. The investigation of loss of dfa2h lines revealed behavioral abnormalities, including motor impairment and flying disability, in addition to a shortened lifespan. Furthermore, alterations in mitochondrial dynamics, and autophagy were identified. Analyses of patient-derived fibroblasts, and rescue experiments with human FA2H, indicated that these defects are evolutionarily conserved. We thus present a FAHN Drosophila model organism that provides new insights into the cellular mechanism of FAHN

Safety and efficacy of mTOR inhibitor treatment in patients with tuberous sclerosis complex under 2 years of age – a multicenter retrospective study

Background: Tuberous sclerosis complex (TSC) is a multisystem disease with prominent neurologic manifestations such as epilepsy, cognitive impairment and autism spectrum disorder. mTOR inhibitors have successfully been used to treat TSC-related manifestations in older children and adults. However, data on their safety and efficacy in infants and young children are scarce. The objective of this study is to assess the utility and safety of mTOR inhibitor treatment in TSC patients under the age of 2 years. Results: A total of 17 children (median age at study inclusion 2.4 years, range 0–6; 12 males, 5 females) with TSC who received early mTOR inhibitor therapy were studied. mTOR inhibitor treatment was started at a median age of 5 months (range 0–19 months). Reasons for initiation of treatment were cardiac rhabdomyomas (6 cases), subependymal giant cell astrocytomas (SEGA, 5 cases), combination of cardiac rhabdomyomas and SEGA (1 case), refractory epilepsy (4 cases) and disabling congenital focal lymphedema (1 case). In all cases everolimus was used. Everolimus therapy was overall well tolerated. Adverse events were classified according to the Common Terminology Criteria of Adverse Events (CTCAE, Version 5.0). Grade 1–2 adverse events occurred in 12 patients and included mild transient stomatitis (2 cases), worsening of infantile acne (1 case), increases of serum cholesterol and triglycerides (4 cases), changes in serum phosphate levels (2 cases), increase of cholinesterase (2 cases), transient neutropenia (2 cases), transient anemia (1 case), transient lymphopenia (1 case) and recurrent infections (7 cases). No grade 3–4 adverse events were reported. Treatment is currently continued in 13/17 patients. Benefits were reported in 14/17 patients and included decrease of cardiac rhabdomyoma size and improvement of arrhythmia, decrease of SEGA size, reduction of seizure frequency and regression of congenital focal lymphedema. Despite everolimus therapy, two patients treated for intractable epilepsy are still experiencing seizures and another one treated for SEGA showed no volume reduction. Conclusion: This retrospective multicenter study demonstrates that mTOR inhibitor treatment with everolimus is safe in TSC patients under the age of 2 years and shows beneficial effects on cardiac manifestations, SEGA size and early epilepsy

Clinical spectrum in three families with familial hemiplegic migraine type 2 including a novel mutation in the ATP1A2 gene

Introduction Familial hemiplegic migraine (FHM) is a rare subtype of migraine with transient hemiplegic aura. Patients and methods We describe three unrelated families with familial hemiplegic migraine type II (FHM2). Retrospectively, information on 47 family members could be obtained, 15 by personal examination and 32 by indirect anamnesis from relatives. Genetic analyses were performed in 13 patients. Results One family had a novel missense mutation in the ATP1A2 gene (c.659C>T, p.Ser220Leu) that segregated with the phenotype in three generations. Two further unrelated families with different ethnic backgrounds (one from Germany and one from Russia) had a missense mutation that has not been described as yet in FHM, but occurred in only a single patient with sporadic hemiplegic migraine (c.2723G>A, p.Arg908Gln). Clinically the patients had severe attacks lasting up to several weeks as well as epileptic seizures. Three patients with a proven mutation in the ATP1A2 gene clinically presented without hemiparesis. Furthermore, there was a possible relation of FHM2 to mental retardation in another two patients. Conclusion Clinical symptoms may last for several weeks in some patients. Patients with FHM2 may also present without hemiplegia. Therefore, the full family history has to be taken into account to establish the diagnosis of FHM

Treatment of Flax Fabric with AP-DBD in Parallel Plane Configuration

For the use of natural fibers in composite materials it is often necessary to improve the compatibility between fiber (sizing) and polymer matrix systems, e.g., by increasing the number of functional groups on the fiber surfaces. In this work, a dielectric barrier discharge (DBD) source in plane configuration is used to treat flax fabrics in ambient air. It is examined whether it is possible to increase the functionality on both fabric sides, which is achieved by simple changes in the DBD setup. After evaluating the treatment homogeneity of the filamentary plasma, an explanation for the treatment mechanism on the fiber surfaces is developed. It is shown that waxy substances, which naturally occur on natural fibers, play an important role in the wettability of the fabric

On the Edge of Buying:A Targeting Approach for Indecisive Buyers Based on Willingness-to-Pay Ranges

Targeting the “right” consumers is a core part of marketing. Whereas existing techniques to identify these consumers use demographic or psychographic variables or behaviors such as response probabilities, a proposed new targeting approach builds on consumers’ incremental responses to identify them by their willingness-to-pay (WTP) ranges. These WTP ranges reveal a consumer as a definite buyer, a definite non-buyer, or an indecisive buyer. The proposed theoretical framework indicates that indecisive buyers offer the highest incremental responses to targeted marketing mix activities and thus should be the most preferred targeting group. A sequence of three laboratory experimental studies validates the proposed approach for targeted price discounts and non-price tactics. In addition, a large-scale field experiment involving a consumer engagement campaign that includes observed purchase behavior demonstrates the high external validity and applicability of this approach

Early Development of Spinal Deformities in Children Severely Affected with Spinal Muscular Atrophy after Gene Therapy with Onasemnogene Abeparvovec—Preliminary Results

Spinal muscular atrophy (SMA) is a rare genetic disorder, with the most common form being 5q SMA. Survival of children with severe SMA is poor, yet major advances have been made in recent years in pharmaceutical treatment, such as gene-therapy, which has improved patient survival. Therefore, clinical problems, such as the development of spinal deformities in these genetically treated SMA children represent an unknown challenge in clinical work. In a retrospective case series, the development of spinal deformities was analyzed in 16 SMA children (9 male, 7 female) treated with onasemnogene abeparvovec in two institutions during the years 2020 to 2022. Ten out of sixteen patients had a significant kyphosis, and nine out of sixteen patients had significant scoliosis, with the mean curvature angles of 24 ± 27° for scoliosis, and 69 ± 15° for kyphosis. Based on these preliminary data, it can be assumed that early-onset kyphosis presents a clinical challenge in gene-therapy-treated SMA children. Larger datasets with longer follow-up times need to be collected in order to verify these preliminary observations

Job-related stress and work ability of dispatchers in a metropolitan fire department

Background Our aim was to assess psychomental stress and strain among dispatchers in fire departments, particularly during emergency instructions by phone and to evaluate their work ability. Methods 27 dispatchers and 20 controls were examined. In a protocol, participants recorded 1. phone instructions causing mental stress (event) 2. working time without phone instructions (non-event) 3. breaks. Continuous heart rate (variability), urine catecholamine, salivary cortisol and lymphocytes were measured. To assess the job-related burden, the Work Ability Index (WAI) was applied. Results Dispatchers demonstrated significantly higher heart rates and reduced standard deviation of all NN (heartbeat-to-heartbeat) intervals (SDNN) than the controls in all phases. WAI of dispatchers was significantly lower than that of the controls. Within the dispatchers, there was a significantly higher rate of inability to work during the past year. Conclusions The increased heart rate and reduced SDNN of examined dispatchers indicate chronic stress effects as a possible preliminary stage of a health disorder. In respect of the reduced work ability among dispatchers preventive measures are required to reduce the stress situation during their job-performance

Atmospheric pressure plasma activation of natural fibres for improved matrix interaction: Abstrac presented at 16th International Conference on Plasma Surface Engineering, 17.-21.09.2018, Garmisch-Partenkirchen

Several investigations have shown that plasma activation is a suitable, environmental friendly method to modify fibre materials. Depending on the plasma chemistry, the surface energy and also the topography of fibres can be significantly changed which can lead to an improved wettability and surface chemistry. This is of particular interest during subsequent processing steps if fibres are implemented into fibre-reinforced polymers (FRPs).The processing of natural fibres is particularly difficult because their surface chemistry and topography are highly inhomogeneous and depend on the natural growth of the fibres. Additionally, the chemistry of cellulose, hemicellulose, pectin and lignin is not compatible with a lot of matrix systems. One possibility to improve the adhesion between natural fibres and matrix systems is to treat the fibres with cold plasma at atmospheric pressure. Hereby, beside a gentle surface cleaning, functional groups are formed on the fibre surfaces. Usually, the matrix material is often heated to lower its viscosity before impregnating the fibres. Therefore, it is important to know if the functional groups sustain the heat influence and still allow for a better impregnation. In this work surfaces of natural fibres were activated by a cold atmospheric pressure plasma source that offers a high treatment width and can be easily integrated into processing chains with regard to industrial applications. After activation the fibres were characterized by SEM, XPS, tensile testing and adapted wetting measurements by a Wilhelmy balance. Additionally, fibres were heated under defined atmospheres to simulate the temperature effects during the injection process. The results show an increase of oxygen containing groups and surface energy of the fibres after the plasma treatment. However, these activation effects were highly reduced after heating of the fibres. Thereby, the level of remaining activation effects depended on different plasma treatment parameters