Metabolische Epilepsien mit spezifischen Therapieoptionen: Diagnostischer Leitfaden

Zusammenfassung: Bei therapieresistenten Anfällen müssen, unabhängig vom jeweiligen Lebensalter, angeborene Stoffwechselerkrankungen erwogen werden. Nur selten liegen hierbei erkennbare Epilepsiesyndrome mit typischem EEG-Muster (EEG: Elektroenzephalographie) oder wegweisende Begleitbefunde in Klinik oder kranialer Bildgebung vor. Für zahlreiche metabolisch bedingte Epilepsien existiert ein kausaler Therapieansatz, z.B. durch gezielte Substitution von Vitaminen, Aminosäuren oder alternativen Energieträgern. Dabei entscheidet ein früher Therapiebeginn wesentlich über das Langzeit-Outcome. Der vorliegende Beitrag soll durch die Beschreibung des klinischen Phänotyps, der Anfallssemiologie sowie der diagnostischen Biomarker und Enzymdefekte einen Leitfaden für die Früherkennung behandelbarer metabolischer Epilepsien im Klinikalltag biete

Causal Fairness for Outcome Control

As society transitions towards an AI-based decision-making infrastructure, an ever-increasing number of decisions once under control of humans are now delegated to automated systems. Even though such developments make various parts of society more efficient, a large body of evidence suggests that a great deal of care needs to be taken to make such automated decision-making systems fair and equitable, namely, taking into account sensitive attributes such as gender, race, and religion. In this paper, we study a specific decision-making task called outcome control in which an automated system aims to optimize an outcome variable $Y$ while being fair and equitable. The interest in such a setting ranges from interventions related to criminal justice and welfare, all the way to clinical decision-making and public health. In this paper, we first analyze through causal lenses the notion of benefit, which captures how much a specific individual would benefit from a positive decision, counterfactually speaking, when contrasted with an alternative, negative one. We introduce the notion of benefit fairness, which can be seen as the minimal fairness requirement in decision-making, and develop an algorithm for satisfying it. We then note that the benefit itself may be influenced by the protected attribute, and propose causal tools which can be used to analyze this. Finally, if some of the variations of the protected attribute in the benefit are considered as discriminatory, the notion of benefit fairness may need to be strengthened, which leads us to articulating a notion of causal benefit fairness. Using this notion, we develop a new optimization procedure capable of maximizing $Y$ while ascertaining causal fairness in the decision process

A Causal Framework for Decomposing Spurious Variations

One of the fundamental challenges found throughout the data sciences is to explain why things happen in specific ways, or through which mechanisms a certain variable $X$ exerts influences over another variable $Y$. In statistics and machine learning, significant efforts have been put into developing machinery to estimate correlations across variables efficiently. In causal inference, a large body of literature is concerned with the decomposition of causal effects under the rubric of mediation analysis. However, many variations are spurious in nature, including different phenomena throughout the applied sciences. Despite the statistical power to estimate correlations and the identification power to decompose causal effects, there is still little understanding of the properties of spurious associations and how they can be decomposed in terms of the underlying causal mechanisms. In this manuscript, we develop formal tools for decomposing spurious variations in both Markovian and Semi-Markovian models. We prove the first results that allow a non-parametric decomposition of spurious effects and provide sufficient conditions for the identification of such decompositions. The described approach has several applications, ranging from explainable and fair AI to questions in epidemiology and medicine, and we empirically demonstrate its use on a real-world dataset

Reconciling Predictive and Statistical Parity: A Causal Approach

Since the rise of fair machine learning as a critical field of inquiry, many different notions on how to quantify and measure discrimination have been proposed in the literature. Some of these notions, however, were shown to be mutually incompatible. Such findings make it appear that numerous different kinds of fairness exist, thereby making a consensus on the appropriate measure of fairness harder to reach, hindering the applications of these tools in practice. In this paper, we investigate one of these key impossibility results that relates the notions of statistical and predictive parity. Specifically, we derive a new causal decomposition formula for the fairness measures associated with predictive parity, and obtain a novel insight into how this criterion is related to statistical parity through the legal doctrines of disparate treatment, disparate impact, and the notion of business necessity. Our results show that through a more careful causal analysis, the notions of statistical and predictive parity are not really mutually exclusive, but complementary and spanning a spectrum of fairness notions through the concept of business necessity. Finally, we demonstrate the importance of our findings on a real-world example

Das psychotherapeutische Gerichtsgutachten. Annäherungen an die Tätigkeit des Gerichtssachverständigen.

In einer Rezension gibt es keinen Abstract.An abstract does not exist in the Book Review

Mycoplasma genitalium: Clinical Significance and Diagnosis

Mycoplasma genitalium is considered the smallest self-replicating cell. It was first isolated in 1981, from 2 of 13 men with urethritis. Mycoplasma genitalium causes urethrtis, cervicitis and pelvic inflammatory disease. Because of difficulties in cultivation, the diagnosis is based exclusively on PCR methodology. The recommended therapy for Mycoplasma genitalium infections is azithromycin or doxycycline. Developement of macrolide resistance was shown to correlate with treatment failure. Key words: Mycoplasma genitalium,urethritis, molecular diagnosis, therapy </span

Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency)

Pyridoxine-dependent epilepsy was recently shown to be due to mutations in the ALDH7A1 gene, which encodes antiquitin, an enzyme that catalyses the nicotinamide adenine dinucleotide-dependent dehydrogenation of L-{alpha}-aminoadipic semialdehyde/L-{Delta}1-piperideine 6-carboxylate. However, whilst this is a highly treatable disorder, there is general uncertainty about when to consider this diagnosis and how to test for it. This study aimed to evaluate the use of measurement of urine L-{alpha}-aminoadipic semialdehyde/creatinine ratio and mutation analysis of ALDH7A1 (antiquitin) in investigation of patients with suspected or clinically proven pyridoxine-dependent epilepsy and to characterize further the phenotypic spectrum of antiquitin deficiency. Urinary L-{alpha}-aminoadipic semialdehyde concentration was determined by liquid chromatography tandem mass spectrometry. When this was above the normal range, DNA sequencing of the ALDH7A1 gene was performed. Clinicians were asked to complete questionnaires on clinical, biochemical, magnetic resonance imaging and electroencephalography features of patients. The clinical spectrum of antiquitin deficiency extended from ventriculomegaly detected on foetal ultrasound, through abnormal foetal movements and a multisystem neonatal disorder, to the onset of seizures and autistic features after the first year of life. Our relatively large series suggested that clinical diagnosis of pyridoxine dependent epilepsy can be challenging because: (i) there may be some response to antiepileptic drugs; (ii) in infants with multisystem pathology, the response to pyridoxine may not be instant and obvious; and (iii) structural brain abnormalities may co-exist and be considered sufficient cause of epilepsy, whereas the fits may be a consequence of antiquitin deficiency and are then responsive to pyridoxine. These findings support the use of biochemical and DNA tests for antiquitin deficiency and a clinical trial of pyridoxine in infants and children with epilepsy across a broad range of clinical scenarios

Metabolomics analysis of antiquitin deficiency in cultured human cells and plasma: Relevance to pyridoxine-dependent epilepsy

Deficiency of antiquitin (α-aminoadipic semialdehyde dehydrogenase), an enzyme involved in lysine degradation and encoded by ALDH7A1, is the major cause of vitamin B6-dependent epilepsy (PDE-ALDH7A1). Despite seizure control with high dose pyridoxine (PN), developmental delay still occurs in approximately 70% of patients. We aimed to investigate metabolic perturbations due to possible previously unidentified roles of antiquitin, which may contribute to developmental delay, as well as metabolic effects of high dose pyridoxine supplementation reflecting the high doses used for seizure control in patients with PDE-ALDH7A1. Untargeted metabolomics by high resolution mass spectrometry (HRMS) was used to analyze plasma of patients with PDE-ALDH7A1 and two independently generated lines of cultured ReNcell CX human neuronal progenitor cells (NPCs) with CRISPR/Cas mediated antiquitin deficiency. Accumulation of lysine pathway metabolites in antiquitin-deficient NPCs and western-blot analysis confirmed knockdown of ALDH7A1. Metabolomics analysis of antiquitin-deficient NPCs in conditions of lysine restriction and PN supplementation identified changes in metabolites related to the transmethylation and transsulfuration pathways and osmolytes, indicating a possible unrecognized role of antiquitin outside the lysine degradation pathway. Analysis of plasma samples of PN treated patients with PDE-ALDH7A1 and antiquitin-deficient NPCs cultured in conditions comparable to the patient plasma samples demonstrated perturbation of metabolites of the gamma-glutamyl cycle, suggesting potential oxidative stress-related effects in PN-treated patients with PDE-ALDH7A1. We postulate that a model of human NPCs with CRISPR/Cas mediated antiquitin deficiency is well suited to characterize previously unreported roles of antiquitin, relevant to this most prevalent form of pyridoxine-dependent epilepsy

Displaced 3- and 4-part proximal humeral fractures: Evaluation and management with an intramedullary nail within 48 h, in the emergency department

Abstract Objective To investigate if a locking intramedullary nail could be useful in the treatment of fractures of the humeral head in 3 and 4-fragments operated within 48 h from the trauma. Methods During the period of February 2011–May 2013, we performed 21 cases of humeral fractures treated with the Polarus intramedullary nail (Acumed). We considered parameters such as age, sex, time of radiological healing and functional outcome, which were assessed by Constant shoulder score, University of California at Los Angeles shoulder score, Oxford shoulder score and Dash score. The study was designed as a prospective cohort study. Results Clinical and radiographic follow-up of patients was performed at 1, 2, 3, 6, 12, and 24 months after surgery. Evidence of radiographic bone healing occurred at an average of 2.42 months post-surgery (range: 1–6 months, median 2). There were no cases of avascular necrosis of the humeral head or failure of the synthesis. The functional outcome was excellent in 6 out of 21 cases (Constant score > 86%); good in 11 out of 21 cases (Constant score 71–85); satisfactory in 3 out of 21 cases (Constant score 56–70); only in one case we recorded poor outcome (Constant score = 55). Conclusions The nail utilized is provided with locking and multiplanar proximal screws and could be applied through a mini-invasive anterolateral approach. This enables the reduction of the fracture fragments, while preserving vascularization of the scapulo-humeral joint. Our results confirm that the indication of endomedullary nail could be extended to the treatment of complex proximal humeral fractures with 3 and 4 fragments (level of evidence IV, according to the Oxford Centre for Evidence Based Medicine Levels of Evidence Working Group)

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