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The etio-pathophysiology of obsessive-compulsive disorder (OCD) can be explained using a biopsychosocial model. Little is known about obsessive-compulsive symptoms (OCS) in the context of chromosomal disorders involving the X chromosome.Case studies of two patients with chromosomal disorders involving the X chromosome (Patient 1 with a variant of Turner syndrome and Patient 2 with triple X syndrome).Both patients were treated due to severe OCS. In the research MRI analysis, the most pronounced MRI change in both patients was a gray matter volume loss in the orbitofrontal cortex. Patient 1 additionally showed left mesiotemporal changes. Patient 2 presented with global gray matter volume reduction, slowing in EEG, and a reduced intelligence quotient.OCS could occur in the context of Turner syndrome or triple X syndrome. The detected MRI changes would be compatible with dysfunction of the cortico-striato-thalamo-cortical loops involved in OCD pathophysiology. Further studies with larger patient groups should investigate whether this association can be validated.

Obsessive-compulsive disorder (OCD) can rarely be associated with immunological etiologies, most notably in Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infections and possibly in autoimmune encephalitis. As cerebrospinal fluid (CSF) analysis is a sensitive method for assessing neuroinflammation, this retrospective study analyzed basic CSF parameters and well-characterized as well as novel neuronal autoantibodies in OCD to screen for signs of autoimmunity.Basic CSF findings of 54 adult OCD patients suspected of an organic etiology were retrospectively compared to a control group of mentally healthy patients (N = 39) with idiopathic intracranial hypertension. Further subgroup analysis included testing for well-characterized neuronal IgG autoantibodies and tissue-based assays using indirect immunofluorescence to screen for novel brain autoantibodies.Elevated protein in the CSF of OCD patients compared to the control group (p = 0.043) were identified. Inflammatory markers (pleocytosis/oligoclonal bands/increased IgG-index) were detected in 7% of all patients with OCD. Well-characterized neuronal autoantibodies were not found in any OCD patient, whereas 6/18 (33%) CSF samples showed binding on mouse brain sections in tissue-based assays (binding to neuropil in the basal ganglia/brainstem, cilia of granule cells, blood vessels, nuclear/perinuclear structures).While elevated CSF protein is merely a weak indicator of blood CSF barrier dysfunction, the presence of inflammatory CSF changes and novel brain autoantibodies in CSF may indicate OCD subtypes with inflammatory pathomechanism and supports the hypothesis of a rare 'autoimmune OCD' subtype.

BACKGROUND AND OBJECTIVES: Pathogenic variants in STXBP1 are among the major genetic causes of neurodevelopmental disorders. Despite the increasing number of individuals diagnosed without a history of epilepsy, little is known about the natural history and developmental trajectories in this subgroup and endpoints for future therapeutic studies are limited to seizure control.; METHODS: We performed a cross-sectional retrospective study using standardized questionnaires for clinicians and caregivers of individuals with STXBP1-related disorders capturing medical histories, genetic findings, and developmental outcomes. Motor and language function were assessed using Gross Motor Function Classification System scores (GMFCS) and a speech impairment score and were compared within and across clinically defined subgroups.; RESULTS: We collected data of 71 individuals with STXBP1-related disorders, including 44 previously unreported individuals. Median age at inclusion was 5.3 years (IQR = 3.5-9.3) with the oldest individual aged 43.8 years. Epilepsy was absent in 18/71 (25%) of individuals. The range of developmental outcomes was broad, including two individuals presenting with close to age-appropriate motor development. 29/61 (48%) individuals were able to walk unassisted and 24/69 (35%) were able to speak single words. Individuals without epilepsy presented with a similar onset and spectrum of phenotypic features but had lower GMFCS scores (median 3 vs. 4, p < 0.01) than individuals with epilepsy. Individuals with epileptic spasms were less likely to walk unassisted than individuals with other seizure types (6% vs. 58%, p < 0.01). Individuals with early epilepsy onset had higher speech impairment scores (p = 0.02) than individuals with later epilepsy onset.; DISCUSSION: We expand the spectrum of STXBP1-related disorders and provide clinical features and developmental trajectories in individuals with and without a history of epilepsy. Individuals with epilepsy, in particular epileptic spasms, and neonatal or early-onset, presented with less favorable motor and language functional outcomes compared to individuals without epilepsy. These findings identify children at risk for severe disease and can serve as comparator for future interventional studies in STXBP1-related disorders. © 2023 American Academy of Neurology.

Zusammenfassung Hintergrund Die Häufigkeit von Suizidversuchen ist ein zentraler Indikator der psychischen Gesundheit der Bevölkerung und daher Gegenstand der Mental Health Surveillance am Robert Koch-Institut. Da bisher keine Datenquellen systematisch zur kontinuierlichen Erfassung von psychiatrischen Notfällen – zu denen Suizidversuche zählen – herangezogen werden, wird die Nutzung von Routinedaten aus Notaufnahmen zu diesem Zweck geprüft. Methoden Routinedaten aus 12 Notaufnahmen wurden für den Zeitraum 01.01.2018–28.03.2021 ausgewertet. Syndromdefinitionen für Suizidversuche, psychiatrische Notfälle und psychische Symptomatik wurden als Kombinationen aus Vorstellungsgründen und Diagnosen entwickelt. Fälle wurden alters- und geschlechtsspezifisch sowie im Zeitverlauf dargestellt. Ergebnisse Von insgesamt 1.516.883 Notaufnahmevorstellungen wurden 5133 (0,3 %) als Suizidversuche, 31.085 (2,1 %) als psychiatrische Notfälle und 34.230 (2,3 %) als Fälle mit einer psychischen Symptomatik identifiziert. 16,5 % der psychiatrischen Notfälle wurden so als Suizidversuch eingeschätzt. Unter den Suizidversuchen entfallen 53,4 % auf Männer und insgesamt 20,2 % auf die Altersgruppe der 25- bis 34-Jährigen. Alle 3 Syndromdefinitionen können über den gesamten Beobachtungszeitraum Fälle sowie deren zeitliche Variation abbilden. Fazit Notaufnahmedaten zeigen Potenzial zur syndromischen Surveillance von Suizidversuchen und psychiatrischen Notfällen und bieten damit einen Ausgangspunkt für weitere Validierung und Analyse. Die Abbildung von Veränderungen in Echtzeit erweitert die bisherigen Forschungsmöglichkeiten zu psychiatrischen Notfällen in Deutschland. Eine systematische Surveillance von Suizidversuchen kann zu einer evidenzbasierten Suizidprävention beitragen.

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.

Symptoms of obsessive–compulsive disorder (OCD) may rarely occur in the context of genetic syndromes. So far, an association between obsessive–compulsive symptoms (OCS) and ACTG1-associated Baraitser-Winter cerebrofrontofacial syndrome has not been described as yet. A thoroughly phenotyped patient with OCS and ACTG1-associated Baraitser-Winter cerebrofrontofacial syndrome is presented. The 25-year-old male patient was admitted to in-patient psychiatric care due to OCD. A whole-exome sequencing analysis was initiated as the patient also showed an autistic personality structure, below average intelligence measures, craniofacial dysmorphia signs, sensorineural hearing loss, and sinus cavernoma as well as subtle cardiac and ophthalmological alterations. The diagnosis of Baraitser-Winter cerebrofrontofacial syndrome type 2 was confirmed by the detection of a heterozygous likely pathogenic variant in the ACTG1 gene [c.1003C > T; p.(Arg335Cys), ACMG class 4]. The automated analysis of magnetic resonance imaging (MRI) revealed changes in the orbitofrontal, parietal, and occipital cortex of both sides and in the right mesiotemporal cortex. Electroencephalography (EEG) revealed intermittent rhythmic delta activity in the occipital and right temporal areas. Right mesiotemporal MRI and EEG alterations could be caused by a small brain parenchymal defect with hemosiderin deposits after a cavernomectomy. This paradigmatic case provides evidence of syndromic OCS in ACTG1-associated Baraitser-Winter cerebrofrontofacial syndrome. The MRI findings are compatible with a dysfunction of the cortico-striato-thalamo-cortical loops involved in OCD. If a common pathophysiology is confirmed in future studies, corresponding patients with Baraitser-Winter cerebrofrontofacial syndrome type 2 should be screened for OCS. The association may also contribute to a better understanding of OCD pathophysiology.

Introduction Infectious and immunological theories of schizophrenia have been discussed for over a century. Contradictory results for infectious agents in association with schizophrenia spectrum disorders (SSDs) were reported. The rationale of this study was to investigate intrathecal antibody synthesis of the most frequently discussed neurotropic pathogens using a pathogen-specific antibody index (AI) in patients with SSD in comparison to controls. Methods In 100 patients with SSD and 39 mentally healthy controls with idiopathic intracranial hypertension (IIH), antibodies against the herpesviruses EBV, CMV, and HSV 1/2 as well as the protozoan Toxoplasma gondii, were measured in paired cerebrospinal fluid (CSF) and serum samples with ELISA-kits. From these antibody concentrations the pathogen-specific AIs were determined with the assumption of intrathecal antibody synthesis at values > 1.5. Results No significant difference was detected in the number of SSD patients with elevated pathogen-specific AI compared to the control group. In a subgroup analysis, a significantly higher EBV AI was observed in the group of patients with chronic SSD compared to patients with first-time SSD diagnosis (p = 0.003). In addition, two identified outlier EBV patients showed evidence for polyspecific immune reactions (with more than one increased AI). Conclusions Evidence for the role of intrathecal EBV antibody synthesis was found in patients with chronic SSD compared to those first diagnosed. Apart from a possible infectious factor in SSD pathophysiology, the evidence for polyspecific immune response in outlier patients may also suggest the involvement of further immunological processes in a small subgroup of SSD patients.

Background: The prevalence and intensity of alcohol use varies among subgroups in the population and changes over time. Routine emergency department data provide a potential for monitoring mental health use cases to gather information on frequencies and distri-butions of specified health events in real time. For this purpose, the development of syndrome definitions for the continuous recording and detection of acute changes in alcohol-related visits and acute alcohol intoxications was explored. Methods: Routinely collected data from 18 emergency departments in Germany were analysed. Syndrome definitions were developed by combining chief complaints and diagnoses to portray alcohol-related health events presenting to the emergency department. Identified cases were described by characteristics of their distributions and compared to another data source of inpatient health care. Further, cases were presented over time and by separate time period before and during the COVID-19 pandemic. Results: From a total of 2,123,492 emergency department attandances, 18,270 cases (0.86%) were identified as alcohol-related visits and 14,141 (0.67%) as acute alcohol intoxica-tions for the observation period between 1 January 2018 to 2 May 2021. Among all acute alcohol intoxications, 71.8% were male and most cases presented in the age category of 45-54 years (20.0%). The syndrome definition continuously recorded cases and displayed acute changes due to the COVID-19 pandemic as well as trends in patient characteristics of identified acute alcohol intoxications. Conclusion: The potential and proof of principle for syndromic surveillance of alcohol-related visits, especially acute alcohol intoxications, using emergency department data was demon-strated. The syndrome definition to identify acute alcohol intoxications can be applied for various surveillance purposes. This systematic data collection provides a first foun-dation for timley information on patterns and changes of alcohol consumption to sup-port prevention and intervention efforts in reducing alcohol-related harm.

Seizures are a primary and early disease manifestation of Tuberous Sclerosis Complex (TSC). We aimed to describe the age-stratified patterns of antiseizure drug (ASD) treatments among children, adolescents, and adults with TSC in Germany. Additionally, we reviewed real-world and clinical study evidence regarding ASD utilization in patients with TSC.We evaluated the pattern of routine ASD use and everolimus prescriptions based on a 2019 multicenter survey of 268 individuals with TSC-associated epilepsy. We contextualized the results with a structured review of real-world and clinical study evidence.TSC-associated epilepsy treatment comprises a wide variety of ASDs. In this German sample, the majority of patients were treated with polytherapy, and lamotrigine (34.7%), valproate (32.8%), oxcarbazepine (28.7%), vigabatrin (19.0%), and levetiracetam (17.9%) were identified as the most-commonly used ASDs. In addition, everolimus was used by 32.5% of patients. In adherence to current TSC guidelines, the disease-modifying ASD vigabatrin was widely used in children (58% below the age of 5 years), whereas treatment in adults did not necessarily reflect guideline preference for (partial) GABAergic ASDs.The selection of ASDs for patients with TSC-associated epilepsy follows well-evaluated recommendations, including the guidelines regarding vigabatrin use in children. Several characteristics, such as the comparatively high frequency of valproate use and polytherapy, reflect the severity of TSC-associated epilepsy.

Autoimmune psychosis may be caused by well-characterized anti-neuronal autoantibodies, such as those against the NMDA receptor. However, the presence of additional anti–central nervous system (CNS) autoantibodies in these patients has not been systematically assessed.MethodsSerum and cerebrospinal fluid (CSF) from patients with schizophreniform and affective syndromes were analyzed for immunoglobulin G anti-CNS autoantibodies using tissue-based assays with indirect immunofluorescence on unfixed murine brain tissue as part of an extended routine clinical practice. After an initial assessment of patients with red flags for autoimmune psychosis (n = 30), tissue-based testing was extended to a routine procedure (n = 89).ResultsBased on the findings from all 119 patients, anti-CNS immunoglobulin G autoantibodies against brain tissue were detected in 18% (n = 22) of patients (serum 9%, CSF 18%) following five principal patterns: 1) against vascular structures, most likely endothelial cells (serum 3%, CSF 8%); 2) against granule cells in the cerebellum and/or hippocampus (serum 4%, CSF 6%); 3) against myelinated fibers (serum 2%, CSF 2%); 4) against cerebellar Purkinje cells (serum 0%, CSF 2%); and 5) against astrocytes (serum 1%, CSF 1%). The patients with novel anti-CNS autoantibodies showed increased albumin quotients (p = .026) and white matter changes (p = .020) more frequently than those who tested negative for autoantibodies.ConclusionsThe study demonstrates five novel autoantibody-binding patterns on brain tissue of patients with schizophreniform and affective syndromes. CSF yielded positive findings more frequently than serum analysis. The frequency and spectrum of autoantibodies in these patient groups may be broader than previously thought.

Background Hyponatremia is known to be associated with a worse patient outcome in heart failure. In cardiorenal syndrome (CRS), the prognostic role of concomitant hyponatremia is unclear. We sought to evaluate potential risk factors for hyponatremia in patients with CRS presenting with or without hyponatremia on hospital admission. Methods In a retrospective study, we investigated 262 CRS patients without sepsis admitted to the University Hospital Halle over a course of 4 years. CRS diagnosis was derived from an electronic search of concomitant diagnoses of acute or chronic (NYHA 3–4) heart failure and acute kidney injury (AKIN 1–3) or chronic kidney disease (KDIGO G3-G5nonD). A verification of CRS diagnosis was done based on patient records. Depending on the presence (Na 65%) and not related to the serum sodium concentration on admission. In comparison to non-hyponatremic CRS patients, the hyponatremic patients had a lower serum osmolality, hypovolemia was more prevalent (41.1% versus 16.3%, p

There is an emerging role of autoimmune causes related to severe mental disorders (SMD). The clinical approach in patients with chronic SMD and novel anti-central nervous system antibodies is complex.Two corresponding cumulative cases are presented. Cerebrospinal fluid (CSF) and serum were investigated using tissue-based assays.Both patients suffered from chronic SMD and were negative for well-characterized neuronal antibodies. Patient 1 suffered from a dysexecutive and neurocognitive syndrome with mild abnormalities in automated electroencephalography analysis, elevated CSF protein levels, several serum autoantibodies (including antibodies against endothelial cells), and novel antibodies with a 'dotted/scalloped' binding against cytoplasmic structures in CSF. Patient 2 with obsessive-compulsive disorder had left temporal abnormalities on automated magnetic resonance imaging analysis, an elevated CSF/serum albumin quotient, and novel atypical cytoplasmic 'spotted' antibody staining in the serum. Patient 1 improved with immunotherapy using high-dose steroids, but patient 2 did not improve under the same treatment.The detection of autoantibodies in CSF of chronic SMD may be beneficial in selecting some patients for immunotherapy. The possible impact of novel anti-cytoplasmic antibodies in this context is critically discussed. Further research is needed to establish the underlying pathophysiological processes as well as their diagnostic and therapeutic implications.

Background and ObjectiveThe spectrum of myelin oligodendrocyte glycoprotein (MOG) antibody–associated disorder (MOGAD) comprises monophasic diseases such as acute disseminated encephalomyelitis (ADEM), optic neuritis (ON), and transverse myelitis and relapsing courses of these presentations. Persistently high MOG antibodies (MOG immunoglobulin G [IgG]) are found in patients with a relapsing disease course. Prognostic factors to determine the clinical course of children with a first MOGAD are still lacking. The objective of the study is to assess the clinical and laboratory prognostic parameters for a risk of relapse and the temporal dynamics of MOG‐IgG titers in children with MOGAD in correlation with clinical presentation and disease course.MethodsIn this prospective multicenter hospital-based study, children with a first demyelinating attack and complete data set comprising clinical and radiologic findings, MOG-IgG titer at onset, and clinical and serologic follow-up data were included. Serum samples were analyzed by live cell-based assay, and a titer level of ≥1:160 was classified as MOG-IgG–positive.ResultsOne hundred sixteen children (f:m = 57:59) with MOGAD were included and initially diagnosed with ADEM (n = 59), unilateral ON (n = 12), bilateral ON (n = 16), myelitis (n = 6), neuromyelitis optica spectrum disorder (n = 8) or encephalitis (n = 6). The median follow-up time was 3 years in monophasic and 5 years in relapsing patients. There was no significant association between disease course and MOG-IgG titers at onset, sex, age at presentation, or clinical phenotype. Seroconversion to MOG-IgG–negative within 2 years of the initial event showed a significant risk reduction for a relapsing disease course. Forty-two/one hundred sixteen patients (monophasic n = 26, relapsing n = 16) had serial MOG-IgG testing in years 1 and 2 after the initial event. In contrast to relapsing patients, monophasic patients showed a significant decrease of MOG-IgG titers during the first and second years, often with seroconversion to negative titers. During the follow-up, MOG-IgG titers were persistently higher in relapsing than in monophasic patients. Decrease in MOG-IgG of ≥3 dilution steps after the first and second years was shown to be associated with a decreased risk of relapses. In our cohort, no patient experienced a relapse after seroconversion to MOG-IgG–negative.DiscussionIn this study, patients with declining MOG-IgG titers, particularly those with seroconversion to MOG-IgG–negative, are shown to have a significantly reduced relapse risk.

Additional file 1: Increased CSF/serum IgG ratios for EBV and CMV antibodies.

Additional file 2: Table S1. Clinical and demographic data. Table S2. Cerebrospinal fluid routine diagnostics. Table S3. Number of participants with abnormal cerebrospinal fluid diagnostics. Table S4. Number of magnetic resonance imaging (MRI) and electroencephalography (EEG) alterations in the patient group with schizophrenia spectrum disorders.

SUMO ist ein am Robert Koch-Institut entwickeltes und betriebenes System, welches Gesundheitsdaten f��r Public Health-Surveillance verarbeitet und bereitstellt. Der Notaufnahme-Situationsreport enth��lt Daten der Routinedokumentation aus einer Auswahl deutscher Notaufnahmen und bildet die aktuelle Inanspruchnahme dieser Notaufnahmen ab., SUMO is a system that has been developed and implemented at the Robert Koch Institute. It processes and provides health data for surveillance and public health research. The Emergency Department Situation Report presents data from the routine documentation of selected emergency departments in Germany, and shows the current utilisation of those emergency departments.

Autoimmune obsessive-compulsive disorder (OCD) in the context of pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) has been observed for decades. The first cases of autoimmune OCD in adulthood were recently described. An association between obsessive-compulsive symptoms (OCS) and systemic autoimmune diseases in the form of connective tissue disease has also been reported. However, whether an association exists between OCD and sarcoidosis is unknown.Here, the authors present an end 20-year-old female patient with symptoms of OCD in whom an advanced diagnostic work-up revealed inflammatory cerebrospinal fluid (CSF) changes (elevated IgG index, CSF-specific oligoclonal bands, intrathecal IgG synthesis, and a positive MRZ reaction). In tissue-based assays using unfixed mouse brain sections, both serum and CSF showed a distinct antinuclear antibody pattern with perinuclear staining. Electroencephalography identified frontocentral theta spindles. Upon endobronchial-guided lymph node biopsy demonstrating non-caseating lymph nodes in further work-up, sarcoidosis was diagnosed. Levels of the sarcoidosis parameters IL-2-R and neopterin were increased. Under immunotherapy for sarcoidosis, the OCS seemed to improve.This case study is paradigmatic, as an association between sarcoidosis and OCD has not been previously reported. After exclusion of alternative causes, the inflammatory CSF changes would be compatible with an inflammatory brain involvement of sarcoidosis. Autoimmune OCD may occur more frequently than is thought, probably also in the context of neurosarcoidosis. This could open up new opportunities through immunotherapies in rare cases with OCD.

Objectives:Autoimmune mechanisms are related to disease development in a subgroup of patients with psychosis. The contribution of immunoglobulin G (IgG) antibodies against myelin oligodendrocyte glycoprotein (MOG) is mainly unclear in this context.Methods:Therefore, two patients with psychosis and anti-MOG antibodies – detected in fixed cell-based and live cell-based assays – are presented.Results:Patient 1 suffered from late-onset psychosis with singular white matter lesions in magnetic resonance imaging (MRI) and intermittent electroencephalography (EEG) slowing. Patient 2 suffered from a chronic paranoid–hallucinatory disorder with intermittent confusional states, non-specific white matter alterations on MRI, a disorganised alpha rhythm on EEG, and elevated cerebrospinal fluid protein. Both patients had anti-MOG antibody titres of 1 : 320 in serum (reference < 1 : 20).Conclusions:The arguments for and against a causal role for anti-MOG antibodies are discussed. The antibodies could be relevant, but due to moderate titres, they may have caused a rather ‘subtle clinical picture’ consisting of psychosis instead of ‘classical’ MOG encephalomyelitis.

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.

The occurrence of suicide attempts is a key indicator of the population's mental health and therefore belongs in the domain of Mental Health Surveillance at the Robert Koch Institute. No data source is currently being used systematically for the continuous observation of psychiatric emergencies (including suicide attempts) in Germany. Therefore, the use of routine data from emergency departments will be explored in this work.We included routine data from 12 emergency departments between 1 January 2018 and 28 March 2021. We developed syndrome definitions for suicide attempts, psychiatric emergencies based on combinations of chief complaints, and diagnoses from patients presenting with psychopathological symptoms. A descriptive analysis over time was presented and stratified by age and sex.In total 1,516,883 emergency department attendances were included, among which we identified 5,133 cases (0.3%) as suicide attempts, 31,085 (2.1%) as psychiatric emergencies, and 34,230 (2.3%) as cases with psychiatric symptoms. Among psychiatric emergencies, 16.5% presented because of a suicide attempt. Of cases presenting with a suicide attempt, 53.4% were male and 20.2% were aged between 25 and 34 years. Cases identified by all 3 syndrome definitions and their temporal variations could be displayed over the entire observation period.Syndromic surveillance using emergency department data indicates a potential for continuous surveillance of suicide attempts and psychiatric emergencies and provides a basis for further validation and analysis. The display of changes in real time extends the current research opportunities for psychiatric emergencies in Germany. Systematic surveillance of suicide attempts can contribute to evidence-based suicide prevention.HINTERGRUND: Die Häufigkeit von Suizidversuchen ist ein zentraler Indikator der psychischen Gesundheit der Bevölkerung und daher Gegenstand der Mental Health Surveillance am Robert Koch-Institut. Da bisher keine Datenquellen systematisch zur kontinuierlichen Erfassung von psychiatrischen Notfällen – zu denen Suizidversuche zählen – herangezogen werden, wird die Nutzung von Routinedaten aus Notaufnahmen zu diesem Zweck geprüft.Routinedaten aus 12 Notaufnahmen wurden für den Zeitraum 01.01.2018–28.03.2021 ausgewertet. Syndromdefinitionen für Suizidversuche, psychiatrische Notfälle und psychische Symptomatik wurden als Kombinationen aus Vorstellungsgründen und Diagnosen entwickelt. Fälle wurden alters- und geschlechtsspezifisch sowie im Zeitverlauf dargestellt.Von insgesamt 1.516.883 Notaufnahmevorstellungen wurden 5133 (0,3 %) als Suizidversuche, 31.085 (2,1 %) als psychiatrische Notfälle und 34.230 (2,3 %) als Fälle mit einer psychischen Symptomatik identifiziert. 16,5 % der psychiatrischen Notfälle wurden so als Suizidversuch eingeschätzt. Unter den Suizidversuchen entfallen 53,4 % auf Männer und insgesamt 20,2 % auf die Altersgruppe der 25- bis 34-Jährigen. Alle 3 Syndromdefinitionen können über den gesamten Beobachtungszeitraum Fälle sowie deren zeitliche Variation abbilden.Notaufnahmedaten zeigen Potenzial zur syndromischen Surveillance von Suizidversuchen und psychiatrischen Notfällen und bieten damit einen Ausgangspunkt für weitere Validierung und Analyse. Die Abbildung von Veränderungen in Echtzeit erweitert die bisherigen Forschungsmöglichkeiten zu psychiatrischen Notfällen in Deutschland. Eine systematische Surveillance von Suizidversuchen kann zu einer evidenzbasierten Suizidprävention beitragen.

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.

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. Supplementary Information The online version contains supplementary material available at 10.1186/s13023-021-01899-x.

Additional file 1. Supplementary Table 1. Direct costs related to TSC manifestations.

Background Cardiorenal syndrome (CRS) defined as concurrent acute or chronic heart failure and acute or chronic kidney injury or disease frequently coincides with hyponatremia. We sought to identify potential risk factors for and outcome of hyponatremia in CRS. Methods In this retrospective study, CRS patients being consecutively hospitalized over 4 years (Department of Internal Medicine II, Martin-Luther University Halle-Wittenberg, Germany) were included. Depending on the presence or absence of hyponatremia on admission, they were analyzed for diabetes comorbidity, signs of hypovolemia on admission, need for renal replacement therapy during and after the hospital stay, in-hospital and one-year mortality. Results 262 CRS patients were included in this study, thereof, 90 CRS patients (34.4%) with hyponatremia (Na 65%) and not related to the serum sodium concentration on admission. In comparison to non-hyponatremic CRS patients, the hyponatremic ones had a lower serum osmolality (293 versus 303 mosm/kg, p

Background Until today, classic human astroviruses have not been associated with central nervous system infections in immunocompetent patients. Case presentation A 16-month-old Caucasian girl presented with repetitive generalized seizures with a 4-day history of watery diarrhea, which had already gradually improved. Initially, the prolonged seizures ceased after systemic midazolam treatment and were thought to be fever associated. However, her mental status remained altered, and after seizure recurrence, she was transferred to our pediatric intensive care unit. Seizure control was achieved by a combination of high-dose levetiracetam and phenobarbital, but she remained unconscious. An electroencephalogram at this time revealed generalized high voltage theta activity. All laboratory analyses, including extended blood and cerebrospinal fluid analyses, and a brain magnetic resonance imaging were normal. On day 4, the child gradually became conscious, but was very agitated and not able to walk. Since an electroencephalogram at this time still revealed generalized high voltage theta activity, although she had not received sedative medications for 72 hours, she was diagnosed as having encephalopathy. At that time, results of diagnostic testing of the stool sample were positive for classic astrovirus infection, and we decided to analyze the initially obtained cerebrospinal fluid for astrovirus as well. Cerebrospinal fluid was also found positive for human astrovirus. Sequencing analysis revealed a classic astrovirus genotype 1 with exactly the same nucleotide sequence as in the feces. Clinically, the child gradually improved and was discharged on day 9. Conclusions Whereas the new human astrovirus subtypes have been recently associated with central nervous system infection, this is the first case of encephalitis in an immunocompetent child due to classic human astrovirus. Considering that classic human astroviruses are the third most common etiological agents of viral gastroenteritis in children, we believe that human astroviruses as causative agents for central nervous system infections should be considered more often, especially in children and infants with preceding gastroenteritis.

Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0–49.3 years). While the mean age at symptom onset was 0.8 ± 0.6 years [standard deviation (SD), range 0.2–5.0], the mean age at diagnosis was 10.2 ± 8.5 years (SD, range 0.1–46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 ± 5.1 years, SD) and later tetraplegia (mean age: 16.1 ± 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 ± 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 ± 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an ‘AP-4 deficiency syndrome’. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials.

BackgroundDeciphering the monogenetic causes of neurodevelopmental disorders (NDD) is an important milestone to offer personalized care. But the plausibility of reported candidate genes in exome studies often remains unclear, which slows down progress in the field.MethodsWe performed exome sequencing (ES) in 198 cases of NDD. Cases that remained unresolved (n=135) were re-investigated in a research setting. We established a candidate scoring system (CaSc) based on 12 different parameters reflecting variant and gene attributes as well as current literature to rank and prioritize candidate genes.ResultsIn this cohort, we identified 158 candidate variants in 148 genes with CaSc ranging from 2 to 11.7. Only considering the top 15% of candidates, 14 genes were already published or funneled into promising validation studies.ConclusionsWe promote that in an approach of case by case re-evaluation of primarily negative ES, systematic and standardized scoring of candidate genes can and should be applied. This simple framework enables better comparison, prioritization, and communication of candidate genes within the scientific community. This would represent an enormous benefit if applied to the tens of thousands of negative ES performed in routine diagnostics worldwide and speed up deciphering the monogenetic causes of NDD.

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.

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. CA extern

In den vergangenen Jahren haben sich die Anforderungen an Manager von indirekten Immobilienanlagen (auch Real Estate Investment Manager genannt) von Seiten institutioneller Investoren sowie der Aufsichtsbehorden, aber auch Marktumfeld und Wettbewerb weitreichend verandert. Ein wesentlicher Ausloser dieser Veranderungen ist sicherlich die globale Finanzkrise, die im Jahr 2008 mit der Pleite der Investmentbank Lehman Brothers Ihren Hohepunkt fand und in deren Folge sich nicht nur die Finanzmarktregulierung deutlich erhoht hat, sondern auch Risikobewusstsein und Professionalisierungsgrad institutioneller Investoren gestiegen sind. Das Spannungsfeld zwischen Kunde, Regulierung, Immobilien- und Kapitalmarkt sowie dem Wettbewerb in der Branche, in dem sich Anbieter von Immobilienanlageprodukten seit jeher bewegen, hat dementsprechend an Kraft gewonnen. Dies hat zur Folge, dass sich Fondsmanager in der heutigen Zeit flexibler aufstellen und traditionelle Geschaftsmodelle sich einem tiefgreifenden Wandel unterziehen mussen, um den Anforderungen und im Wettbewerb zu bestehen (vgl. Abb. 12.1).

Bei den Leitbildern der Raumentwicklung handelt es sich um eine gemeinsame Entwicklungsstrategie für die deutschen Städte und Regionen. Sie werden gemäß Raumordnungsgesetz von den Raumordnungsministern von Bund und Ländern erarbeitet und bilden eine wichtige Grundlage für das gemeinsame Handeln der Raumordnung von Bund und Ländern. Die informellen Leitbilder stellen ein übergeordnetes Konzept für die raumbezogenen politischen Ziele, die Festlegungen im Raumordnungsgesetz und in Raumordnungsplänen sowie für die konkreten Umsetzungsmaßnahmen dar. Sie ergänzen somit die gesetzlich festgelegten und verbindlichen Ziele und Grundsätze der Raumordnung und weisen die Aufgabenschwerpunkte der Raumordnung in den kommenden Jahren aus. Im Mittelpunkt der Beiträge auf der Jahrestagung des Jungen Forums 2014 stand die Bedeutung der veränderten aktuellen Rahmenbedingungen für die Raumentwicklung. Ausgangspunkt der Diskussion über Strategien, Handlungskonzepte und Umsetzungsprojekte war der Leitbildentwurf mit dem Stand 2013. In drei Arbeitsgruppen zu den Themen "Demografischer Wandel", "Energiewende und Klimawandel" sowie "Standortkonkurrenzen" präsentierten die Teilnehmerinnen und Teilnehmer laufende Forschungsvorhaben, Dissertationen und Projekte aus der Praxis von Kommunen oder Verbänden. In den fachlichen Diskussionen wurde deutlich, dass die Neuen Leitbilder eine wichtige Grundlage für die künftige Raumentwicklung darstellen. Trotzdem wurden auch Zielkonflikte gesehen, die planerische Herausforderungen für die Zukunft bringen werden. The guiding principles of spatial planning present a common development strategy for German cities and regions. In line with spatial planning legislation, they are drawn up by the German federation and states and create an important basis for joint spatial planning action by the federal and state authorities. The informal guiding principles represent an overall concept for spatially relevant policy goals, stipulations in spatial planning legislation and in spatial plans, and for concrete implementation measures. They thus supplement the statutory and binding goals and fundamental principles of spatial planning and indicate the core spatial planning tasks for the coming years. The papers of the annual meeting of the Junges Forum 2014 focused on the significance of changes to the general parameters for spatial development. The guiding principles drawn up in 2013 formed the starting point for discussion about strategies, concepts for action and implementation projects. Participants presented ongoing research, PhD theses and practical projects conducted in municipalities or associations in three working groups: "Demographic Change", "Energy Transition and Climate Change" and "Locational Competition". It was clear from discussion that the new guiding principles represent an important basis for future spatial development. Nonetheless, conflicting goals that will challenge planning in the future were also identified.

Die Mobilität in Deutschland befindet sich in einer Umbruchphase. In Großstädten wirddas eigene Auto für jüngere Menschen immer unattraktiver und der Fahrradverkehr steigt an.Doch welche Wege geht die Verkehrswende auf dem Land?

Importance The identification and understanding of the monogenic causes of neurodevelopmental disorders are of high importance for personalized treatment and genetic counseling. Objective To identify and characterize novel genes for a specific neurodevelopmental disorder characterized by refractory seizures, respiratory failure, brain abnormalities, and death in the neonatal period; describe the outcome of glutaminase deficiency in humans; and understand the underlying pathological mechanisms. Design, Setting, and Participants We performed exome sequencing of cases of neurodevelopmental disorders without a clear genetic diagnosis, followed by genetic and bioinformatic evaluation of candidate variants and genes. Establishing pathogenicity of the variants was achieved by measuring metabolites in dried blood spots by a hydrophilic interaction liquid chromatography method coupled with tandem mass spectrometry. The participants are 2 families with a total of 4 children who each had lethal, therapy-refractory early neonatal seizures with status epilepticus and suppression bursts, respiratory insufficiency, simplified gyral structures, diffuse volume loss of the brain, and cerebral edema. Data analysis occurred from October 2017 to June 2018. Main Outcomes and Measures Early neonatal epileptic encephalopathy with glutaminase deficiency and lethal outcome. Results A total of 4 infants from 2 unrelated families, each of whom died less than 40 days after birth, were included. We identified a homozygous frameshift variant p.(Asp232Glufs*2) in GLS in the first family, as well as compound heterozygous variants p.(Gln81*) and p.(Arg272Lys) in GLS in the second family. TheGLSgene encodes glutaminase (Enzyme Commission 3.5.1.2), which plays a major role in the conversion of glutamine into glutamate, the main excitatory neurotransmitter of the central nervous system. All 3 variants probably lead to a loss of function and thus glutaminase deficiency. Indeed, glutamine was increased in affected children (availablezscores, 3.2 and 11.7). We theorize that the potential reduction of glutamate and the excess of glutamine were a probable cause of the described physiological and structural abnormalities of the central nervous system. Conclusions and Relevance We identified a novel autosomal recessive neurometabolic disorder of loss of function of glutaminase that leads to lethal early neonatal encephalopathy. This inborn error of metabolism underlines the importance of GLS for appropriate glutamine homeostasis and respiratory regulation, signal transduction, and survival.

Das Problemlösen gilt als eine zentrale prozessbezogene Kompetenz, die Schüler(innen) im Mathematikunterricht erwerben sollen. Daher stellt sich die Frage, inwieweit der Mathematikunterricht mit Blick auf dieses Ziel von Lehrer(innen) strukturiert werden kann und wird. Im Rahmen dieser qualitativen Interviewstudie werden daher empirisch gewonnene Perspektiven von zwölf erfahrenen Gymnasiallehrkräften mit idealtypischen Überlegungen über die fachdidaktische Strukturierung des Mathematikunterrichts zur Entwicklung der Problemlösekompetenz in Beziehung gesetzt. Unterrichtsvignetten, die auf theoretischer Grundlage entwickelt wurden, konnten zeigen, wie die 12 Lehrerinnen und Lehrer auf den fremden Unterricht blickten und wie sie ihren eigenen Unterricht strukturieren würden. Die Ergebnisse der Untersuchung zeigen ein breites Spektrum an Lehrerperspektiven in Hinblick auf sieben verschiedene Strukturierungsdimensionen für Problemlösen im Unterricht. Man kann dieses Potential zur Entwicklung von Elementen für die Lehrerbildung nutzen.

Treacher Collins syndrome (TCS) is the most common and well-known mandibulofacial dysostosis caused by mutations in at least three genes involved in pre-rRNA transcription, the TCOF1, POLR1D and POLR1C genes. We present a severely affected male individual with TCS with a heterozygous de novo frameshift mutation within the TCOF1 gene (c.790_791delAG,p.Ser264GlnfsX7) and compare the clinical findings with three previously unpublished, milder affected individuals from two families with the same mutation. We elucidate typical clinical features of TCS and its clinical implications for the paediatrician and mandibulofacial surgeon, especially in severely affected individuals and give a short review of the literature. Conclusion:The clinical data of these three families illustrate that the phenotype associated with this specific mutation has a wide intra- and interfamilial variability, which confirms that variable expressivity in carriers of TCOF1 mutations is not a simple consequence of the mutation but might be modified by the combination of genetic, environmental and stochastic factors. Being such a highly complex disease treatment of individuals with TCS should be tailored to the specific needs of each individual, preferably by a multidisciplinary team consisting of paediatricians, craniofacial surgeons and geneticists.

Brenner T. and Schlump C. Policy measures and their effects in the different phases of the cluster life cycle, Regional Studies. In recent years, policy measures have frequently been applied to clusters. This paper analyses whether different types of policy measures should be applied in different stages of the cluster life cycle. Two approaches are used to obtain answers to this question. First, insights are gathered from the existing literature on policy measures and evaluated. Second, a mathematical model is set up in order to examine the effects of various policy measures in the different life cycle phases. It is found that the adequate kind of policy measures depends on the cluster's current stage in its life cycle. Brenner T. et Schlump C. Les decisions politiques et leurs effets a diverses phases du cycle de vie du cluster, Regional Studies. Dans les dernieres annees, on a souvent applique les decisions politiques aux clusters. Cet article cherche a analyser si, oui ou non, diverses decisions polit...

Introduction In most countries, hereditary tyrosinemia type 1 is not included in routine newborn screening. Discussion We present the case of a female newborn with prenatal diagnosis of hereditary tyrosinemia type 1 and clear identification of this disorder by succinylacetone measurement in cord blood and peripheral blood immediately after birth. Succinylacetone was 44 μmol/L (norm

Neurological crises do not occur in patients with tyrosinaemia type I treated with NTBC. We report an 8 month-old boy with severe neurological crisis after interruption of NTBC treatment including progressive ascending polyneuropathy and diaphragmatic paralysis, arterial hypertension, respiratory distress requiring mechanical ventilation who later also developed impaired liver function and tubulopathy. After re-introduction of NTBC the patient slowly regained normal neurological functions and recovered completely.

This paper examines regional effects of the InnoRegio program, which was conducted by the German Federal Ministry of Education and Research. The InnoRegio program has been a new tool of innovation policy with the aim to improve innovativeness in East Germany on the basis of prosperous regional networks. Besides the direct support of networks and innovation activities, the program was meant to trigger the regional development in East Germany. While existing studies examine whether the development of networks or cluster was successful, this paper focuses on the investigation of regional economic development. Using regional data, especially on employment and patents, we examine whether the involved industries have developed better in supported regions than in other (East) German regions. Developments are investigated for a time span including years before, during and after the policy measure. We find some positive effects in the regional development that can be assigned to the InnoRegio program.

It has been repeatedly shown that universities and public research institutes contribute to local innovation generation and facilitation. The mechanisms behind this contribution are well discussed in the literature. However, detailed empirical examinations are missing. We analyse the impact of universities and public research on regional innovation output. Thereby we analyse separately 19 technologies and distinguish whether university education and public research are rather innovation generators or innovation facilitators. All analyses are conducted on German data.

Cooperation in innovation processes has become crucial for the competitiveness of many firms. This paper focuses on technology-oriented East German firms and analyses details of their cooperation behaviour by studying the relationships between geographic and social proximity, the importance and frequency of cooperative interaction and the attributes of innovation cooperation partners that influence the importance of cooperation. Data is collected in two questionnaires and analysed by regressions. It is found, among other results, that cooperation that is established via personal contacts is, on average, more helpful and important for firms but involves less frequent interaction.