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WAS is a multifaceted monogenic disorder with a broad disease spectrum and variable disease severity and a variety of treatment options including allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT). No reliable biomarker exists to predict disease course and outcome for individual patients. A total of 577 patients with a WAS variant from 26 countries and a median follow-up of 8.9 years (0.3-71.1), totaling 6118 patient-years, were included in this international retrospective study. Overall survival (OS) of the cohort (censored at HSCT or GT) was 82% (95% CI 78-87) at 15 years and 70% (61-80) at 30 years of age. The type of variant was predictive of outcome: patients with a missense variant in exons 1 or 2 or with the intronic hotspot variant c.559+5G>A (class I variants) had a 15-year OS of 93% (89-98) and a 30-year OS of 91% (86-97), compared to 71% (62-81) and 48% (34-68) in patients with any other variant (class II; p<0.0001). The cumulative incidence rates of disease-related complications such as severe bleeding (p=0.007), life-threatening infection (p<0.0001), and autoimmunity (p=0.004) occurred significantly later in patients with a class I variant. The cumulative incidence of malignancy (p=0.6) was not different between classes I and II. This study represents the largest cohort of WAS patients studied so far. It confirms the spectrum of disease severity and quantifies the risk for specific disease-related complications. The class of variant is a biomarker to predict the outcome for WAS patients.

Objective: The present study investigates the predictive validity of intra-subject variability (ISV) for ADHD traits in a community-based sample and the stability of the relationship between ISV and fluid intelligence (gf) across the continuum of ADHD traits. Method: Age-residualized data from 426 participants (8-18 years, 6% ADHD) was used to investigate whether ex-Gaussian and DDM parameters derived from simple choice-reaction-time tasks can predict continuously assessed ADHD traits. Multiple-Group-Analyses and Latent-Moderated-Structural-Equations were used to test whether ADHD traits moderate the relationship between ISV and gf. Results: sigma and mu of the ex-Gaussian model as well as DDM parameters drift rate (v) and boundary separation (a) significantly predicted general ADHD traits, while tau predicted attention difficulties specifically. Across the ADHD continuum, sigma and v were significant predictors of gf. Conclusion: The results confirm the link between ISV and ADHD. The relationship between ISV and gf appears stable across the ADHD continuum.

We report the updated classification of inborn errors of immunity, compiled by the International Union of Immunological Societies Expert Committee. This report documents the key clinical and laboratory features of 55 novel monogenic gene defects, and 1 phenocopy due to autoantibodies, that have either been discovered since the previous update (published January 2020) or were characterized earlier but have since been confirmed or expanded in subsequent studies. While variants in additional genes associated with immune diseases have been reported in the literature, this update includes only those that the committee assessed that reached the necessary threshold to represent novel inborn errors of immunity. There are now a total of 485 inborn errors of immunity. These advances in discovering the genetic causes of human immune diseases continue to significantly further our understanding of molecular, cellular, and immunological mechanisms of disease pathogenesis, thereby simultaneously enhancing immunological knowledge and improving patient diagnosis and management. This report is designed to serve as a resource for immunologists and geneticists pursuing the molecular diagnosis of individuals with heritable immunological disorders and for the scientific dissection of cellular and molecular mechanisms underlying monogenic and related human immune diseases.

Background This study examined the connection between two prominent deficits in schizophrenia: the deficit in parasympathetic regulation and the deficit in cognitive inhibitory control, within the framework of the Neurovisceral Integration Model (NIM). Study Design Thirty healthy controls and 30 patients with schizophrenia performed the internationally standardized antisaccade protocol while their electrocardiographic data were recorded. The interaction between the group, the cognitive inhibitory control as measured with error rate (ER) in the antisaccade task and parasympathetic activity as measured with the High Frequency power component of Heart Rate Variability (HF-HRV) was tested. Study Results Findings confirmed that decreased HF-HRV was specifically related to increased ER in patients with schizophrenia. In contrast, patient deficits in other oculomotor function measures such as reaction time and reaction time variability related to volitional movement control and cognitive stability respectively were not linked to the deficit in parasympathetic regulation. Conclusions Our study validates the theory behind NIM proposing that cognitive inhibition has common physiological substrate with parasympathetic regulation. Future research could test this brain-heart link in other mental disorders especially those with a prominent deficit in inhibitory cognitive function.

While Autism Spectrum Disorder (ASD), Attention-Deficit/Hyperactivity Disorder (ADHD) and Schizophrenia (SCZ) differ in many clinically relevant features such as symptomatology and course, they may also share genetic underpinnings, affective problems, deviancies in social interactions, and are all characterized by some kind of cognitive impairment. This situation calls for a joint investigation of the specifics of cognitive (dys-)functions of the three disorders. Such endeavor should focus, among other domains, on the inter-section of processing cognitive, affective and social information that is crucial in effective real-life interactions and can be accomplished when attentional preferences for human facial expressions of emotions is studied. To that end, attention to facial expressions of basic emotions was examined in young adults with ASD, ADHD, or SCZ in the present study. The three clinical groups were compared with an age-matched group of typically-developing participants (TD) during the free contemplation of five different facial emotions presented simultaneously, by varying identities, through the registration of eye movements. We showed, that dwell times and fixation counts differed for the different emotions in TD and in a highly similar way in ADHD. Patients with ASD differed from TD by showing a stronger differentiation between emotions and partially different attentional preferences. In contrast, the SCZ group showed an overall more restricted scanning behavior and a lack of differentiation between emotions. The ADHD group, showed an emotion-specific gazing pattern that was highly similar to that of controls. Thus, by analyzing eye movements, we were able to differentiate three different viewing patterns that allowed us to distinguish between the three clinical groups. This outcome suggests that attention for emotion may not tap into common pathophysiological processes and argues for a multi-dimensional approach to the grouping of disorders with neurod

Paradoxes are a special form of reasoning leading to absurd inferences in contrast to logical reasoning that is used to reach valid conclusions. A functional MRI (fMRI) study was conducted to investigate the neural substrates of paradoxical and deductive reasoning. Twenty-four healthy participants were scanned using fMRI, while they engaged in reasoning tasks based on arguments, which were either Zeno's like paradoxes (paradoxical reasoning) or Aristotelian arguments (deductive reasoning). Clusters of significant activation for paradoxical reasoning were located in bilateral inferior frontal and middle temporal gyrus. Clusters of significant activation for deductive reasoning were located in bilateral superior and inferior parietal lobe, precuneus, and inferior frontal gyrus. These results confirmed that different brain activation patterns are engaged for paradoxical vs. deductive reasoning providing a basis for future studies on human physiological as well as pathological reasoning.

Sensory features in autism spectrum disorder (ASD) have received increasing interest in clinical work and research during the recent years. With the Sensory Perception Quotient (SPQ), Tavasolli and colleagues have produced a self-rating scale for adults with ASD that measures sensory hyper-sensitivity in different sensory modalities, without also tapping cognitive or motivational aspects that precede or follow autistic sensory experiences. Here, we present the results of a translation of the SPQ to German and its short version as well as their validation in samples of autistic or neuro-typical participants. We, furthermore, present the psychometric properties and validities of Tavasolli's original SPQ-short version as well as an alternative short version based on different psychometric item-selection criteria. We can show here that our alternative SPQ-short version, overlapping with the original short-version in 61% of its items, exhibits superior reliabilities, reasonable concurrent validities with other related measures. It, furthermore, exhibits excellent differentiation between autistic and non-autistic samples, underscoring its utility as a screening instrument in research and a clinical instrument to supplement the ASD diagnostic process.

Findings of genetic overlap between Schizophrenia, Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) contributed to a renewed conceptualization of these disorders as laying on a continuum based on aetiological, pathophysiological and neurodevelopmental features. Given that cognitive impairments are core to their pathophysiology, we compared patients with schizophrenia, ADHD, ASD, and controls on ocular-motor and manual-motor tasks, challenging crucial cognitive processes. Group comparisons revealed inhibition deficits common to all disorders, increased intra-subject variability in schizophrenia and, to a lesser extent, ADHD as well as slowed processing in schizophrenia. Patterns of deviancies from controls exhibited strong correlations, along with differences that posited schizophrenia as the most impaired group, followed by ASD and ADHD. While vector correlations point towards a common neurodevelopmental continuum of impairment, vector levels suggest differences in the severity of such impairment. These findings argue towards a dimensional approach to Neurodevelopmental Disorders' pathophysiological mechanisms.

The most recent updated classification of inborn errors of immunity/primary immunodeficiencies, compiled by the International Union of Immunological Societies Expert Committee, was published in January 2020. Within days of completing this report, it was already out of date, evidenced by the frequent publication of genetic variants proposed to cause novel inborn errors of immunity. As the next formal report from the IUIS Expert Committee will not be published until 2022, we felt it important to provide the community with a brief update of recent contributions to the field of inborn errors of immunity. Herein, we highlight studies that have identified 26 additional monogenic gene defects that reach the threshold to represent novel causes of immune defects.

The Human Phenotype Ontology (HPO, https://hpo.jax.org) was launched in 2008 to provide a comprehensive logical standard to describe and computationally analyze phenotypic abnormalities found in human disease. The HPO is now a worldwide standard for phenotype exchange. The HPO has grown steadily since its inception due to considerable contributions from clinical experts and researchers from a diverse range of disciplines. Here, we present recent major extensions of the HPO for neurology, nephrology, immunology, pulmonology, newborn screening, and other areas. For example, the seizure subontology now reflects the International League Against Epilepsy (ILAE) guidelines and these enhancements have already shown clinical validity. We present new efforts to harmonize computational definitions of phenotypic abnormalities across the HPO and multiple phenotype ontologies used for animal models of disease. These efforts will benefit software such as Exomiser by improving the accuracy and scope of cross-species phenotype matching. The computational modeling strategy used by the HPO to define disease entities and phenotypic features and distinguish between them is explained in detail.We also report on recent efforts to translate the HPO into indigenous languages. Finally, we summarize recent advances in the use of HPO in electronic health record systems.

Chronic cannabis use and schizophrenia are both thought to affect reward processing. While behavioural and neural effects on reward processing have been investigated in both conditions, their interaction has not been studied, although chronic cannabis use is common among these patients. In the present study eighty-nine participants divided into four groups (control chronic cannabis users and non-users; schizophrenia patient cannabis users and non-users) performed a two-choice decision task, preceded by monetary cues (high/low reward/punishment or neutral), while being scanned using functional magnetic resonance imaging. Reward and punishment anticipation resulted in activation of regions of interest including the thalamus, striatum, amygdala and insula. Chronic cannabis use and schizophrenia had opposing effects on reward anticipation sensitivity. More specifically control users and patient non-users showed faster behavioural responses and increased activity in anterior/posterior insula for high magnitude cues compared to control non-users and patient users. The same interaction pattern was observed in the activation of the right thalamus for reward versus punishment cues. This study provided evidence for interaction of chronic cannabis use and schizophrenia on reward processing and highlights the need for future research addressing the significance of this interaction for the pathophysiology of these conditions and its clinical consequences.

In recent years, psychiatric research has focused on the evaluation and implementation of biomarkers in the clinical praxis. Oculomotor function deviances are among the most consistent and replicable cognitive deficits in schizophrenia and have been suggested as viable candidates for biomarkers. In this narrative review, we focus on oculomotor function in first-episode psychosis, recent onset schizophrenia as well as individuals at high risk for developing psychosis. We critically discuss the evidence for the possible utilization of oculomotor function measures as diagnostic, susceptibility, predictive, monitoring, and prognostic biomarkers for these conditions. Based on the current state of research we conclude that there are not sufficient data to unequivocally support the use of oculomotor function measures as biomarkers in schizophrenia.

Introduction Transcranial magnetic stimulation (TMS)-evoked potentials (TEPs) allow for probing cortical functions in health and pathology. However, there is uncertainty whether long-latency TMS-evoked potentials reflect functioning of the targeted cortical area. It has been suggested that components such as the TMS-evoked N100 are stereotypical and related to nonspecific sensory processes rather than transcranial effects of the changing magnetic field. In contrast, TEPs that vary according to the targeted brain region and are systematically lateralized toward the stimulated hemisphere can be considered to reflect activity in the stimulated brain region resulting from transcranial electromagnetic induction. Methods TMS with concurrent 64-channel electroencephalography (EEG) was sequentially performed in homologous areas of both hemispheres. One sample of healthy adults received TMS to the dorsolateral prefrontal cortex; another sample received TMS to the temporo-occipital cortex. We analyzed late negative TEP deflections corresponding to the N100 component in motor cortex stimulation. Results TEP topography varied according to the stimulation target site. Long-latency negative TEP deflections were systematically lateralized (higher in ipsilateral compared to contralateral electrodes) in electrodes over the stimulated brain region. A calculation that removes evoked components that are not systematically lateralized relative to the stimulated hemisphere revealed negative maxima located around the respective target sites. Conclusion TEPs contain long-latency negative components that are lateralized toward the stimulated hemisphere and have their topographic maxima at the respective stimulation sites. They can be differentiated from co-occurring components that are invariable across different stimulation sites (probably reflecting coactivation of peripheral sensory afferences) according to their spatiotemporal patterns. Lateralized long-latency TEP components located at

PURPOSE: The MUNICH Preterm and Term Clinical (MUNICH-PreTCl) birth cohort was established to uncover pathological processes contributing to infant/childhood morbidity and mortality. We collected comprehensive medical information of healthy and sick newborns and their families, together with infant blood samples for proteomic analysis. MUNICH-PreTCl aims to identify mechanism-based biomarkers in infant health and disease to deliver more precise diagnostic and predictive information for disease prevention. We particularly focused on risk factors for pregnancy complications, family history of genetically influenced health conditions such as diabetes and paediatric long-term health-all to be further monitored and correlated with proteomics data in the future.PARTICIPANTS: Newborns and their parents were recruited from the Perinatal Center at the LMU University Hospital, Munich, between February 2017 and June 2019. Infants without congenital anomalies, delivered at 23-41 weeks of gestation, were eligible.FINDINGS: Findings to date concern the clinical data and extensive personal patient information. A total of 662 infants were recruited, 44% were female (36% in preterm, 46% in term). 90% of approached families agreed to participate. Neonates were grouped according to gestational age: extremely preterm (<28 weeks, N=28), very preterm (28 to <32 weeks, N=36), late preterm (32 to <37 weeks, N=97) and term infants (>37+0 weeks, N=501). We collected over 450 data points per child-parent set, (family history, demographics, pregnancy, birth and daily follow-ups throughout hospitalisation) and 841 blood samples longitudinally. The completion rates for medical examinations and blood samples were 100% and 95% for the questionnaire.FUTURE PLANS: The correlation of large clinical datasets with proteomic phenotypes, together with the use of medical registries, will enable future investigations aiming to decipher mechanisms of disorders in a system

BACKGROUND: It is important to identify patients with monogenic IBD as management may differ from classical IBD. In this position statement we formulate recommendations for the use of genomics in evaluating potential monogenic causes of IBD across age groups. METHODS: The consensus included paediatric IBD specialists from the Paediatric IBD Porto group of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and specialists from several monogenic IBD research consortia. We defined key topics and performed a systematic literature review to cover indications, technologies (targeted panel, exome and genome sequencing), gene panel setup, cost-effectiveness of genetic screening, and requirements for the clinical care setting. We developed recommendations that were voted upon by all authors and Porto group members (32 voting specialists). RESULTS: We recommend next-generation DNA-sequencing technologies to diagnose monogenic causes of IBD in routine clinical practice embedded in a setting of multidisciplinary patient care. Routine genetic screening is not recommended for all IBD patients. Genetic testing should be considered depending on age of IBD-onset (infantile IBD, very early-onset IBD, paediatric or young adult IBD), and further criteria, such as family history, relevant comorbidities, and extraintestinal manifestations. Genetic testing is also recommended in advance of hematopoietic stem cell transplantation. We developed a diagnostic algorithm that includes a gene panel of 75 monogenic IBD genes. Considerations are provided also for low resource countries. CONCLUSIONS: Genomic technologies should be considered an integral part of patient care to investigate patients at risk for monogenic forms of IBD.

Protein-coding and non-coding genes like miRNAs tightly control hematopoietic differentiation programs. Although miRNAs are frequently located within introns of protein-coding genes, the molecular interplay between intronic miRNAs and their host genes is unclear. By genomic integration site mapping of gamma-retroviral vectors in genetically corrected peripheral blood from gene therapy patients, we identified the EVL/MIR342 gene locus as a hotspot for therapeutic vector insertions indicating its accessibility and expression in human hematopoietic stem and progenitor cells. We therefore asked if and how EVL and its intronic miRNA-342 regulate hematopoiesis. Here we demonstrate that overexpression (OE) of Evl in murine primary Lin- Sca1+ cKit+ cells drives lymphopoiesis whereas miR-342 OE increases myeloid colony formation in vitro and in vivo, going along with a profound upregulation of canonical pathways essential for B-cell development or myelopoietic functions upon Evl or miR-342 OE, respectively. Strikingly, miR-342 counteracts its host gene by targeting lymphoid signaling pathways, resulting in reduced pre-B-cell output. Moreover, EVL overexpression is associated with lymphoid leukemia in patients. In summary, our data show that one common gene locus regulates distinct hematopoietic differentiation programs depending on the gene product expressed, and that the balance between both may determine hematopoietic cell fate decision.

Since 2013, the International Union of Immunological Societies (IUIS) expert committee (EC) on Inborn Errors of Immunity (IEI) has published an updated phenotypic classification of IEI, which accompanies and complements their genotypic classification into ten tables. This phenotypic classification is user-friendly and serves as a resource for clinicians at the bedside. There are now 430 single-gene IEI underlying phenotypes as diverse as infection, malignancy, allergy, autoimmunity, and autoinflammation. We herein report the 2019 phenotypic classification, including the 65 new conditions. The diagnostic algorithms are based on clinical and laboratory phenotypes for each of the ten broad categories of IEI.

We report the updated classification of Inborn Errors of Immunity/Primary Immunodeficiencies, compiled by the International Union of Immunological Societies Expert Committee. This report documents the key clinical and laboratory features of 430 inborn errors of immunity, including 64 gene defects that have either been discovered in the past 2 years since the previous update (published January 2018) or were characterized earlier but have since been confirmed or expanded upon in subsequent studies. The application of next-generation sequencing continues to expedite the rapid identification of novel gene defects, rare or common; broaden the immunological and clinical phenotypes of conditions arising from known gene defects and even known variants; and implement gene-specific therapies. These advances are contributing to greater understanding of the molecular, cellular, and immunological mechanisms of disease, thereby enhancing immunological knowledge while improving the management of patients and their families. This report serves as a valuable resource for the molecular diagnosis of individuals with heritable immunological disorders and also for the scientific dissection of cellular and molecular mechanisms underlying inborn errors of immunity and related human diseases.

Objective: Relationships between sleep, screen-based media, and ADHD symptomatology were investigated using a case- and community-based approach. Method: N = 357 healthy and N = 61 children with ADHD (12.72 +/- 2.83 years) completed a sleep and media questionnaire. To measure ADHD symptomatology, parents filled out the Strengths and Weaknesses of ADHD symptoms and Normal behavior (SWAN) scale. Two samples were formed: a matched (N = 61 patients and N = 61 controls) and a community sample (N = 357 healthy participants and N = 20 patients). Results: Compared with controls, participants with ADHD reported delayed sleep onset and more screen time on school days. Adolescent patients showed more behavior promoting delayed sleep phase. In the community sample, media time, sleep deviation, and circadian rhythm were correlated with ADHD symptomatology. Furthermore, media time, sleep-wake behavior, and sleep deviation were predictive of ADHD symptomatology (variance explained = 4%-15%). Conclusion: Longer media time and inadequate sleep-wake behavior increase the risk of ADHD-like symptoms. However, research using objective assessments is needed to disentangle this distinct association and to provide possible directions for intervention.

Increased Intra-Subject Variability (ISV) is a candidate endophenotype of ADHD. ISV's relationship with response speed is highly relevant for ADHD as patients are highly variable but typically no slower than controls. This brief report addresses the relationship between variability and speed by employing dimensional analyses for differentiated performance measures, with a particular focus on the ex-Gaussian measures, across relevant ADHD studies and in young healthy adults (N = 70). For both patients with ADHD and healthy adults, we found that reaction time standard deviation and mean reaction time were strongly correlated, thus failing to dissociate, but ex-Gaussian tau (tau) shared only little variance with Gaussian mu (mu), thus dissociating slow responses (tau) from response speed or-if given-slow responding (mu). Our results highlight the utility of employing the ex-Gaussian measures to disentangle ISV and speed, particularly for ADHD data as patients make more slow responses but are not overall slower than typical controls.

Social interaction in individuals with Autism Spectrum Disorder (ASD) is characterized by qualitative impairments that highly impact quality of life. Bayesian theories in ASD frame an understanding of underlying mechanisms suggesting atypicalities in the evaluation of probabilistic links within the perceptual environment of the affected individual. To address these theories, the present study explores the applicability of an innovative Bayesian framework on social visual perception in ASD and demonstrates the use of gaze transitions between different parts of social scenes. We applied advanced analyses with Bayesian Hidden Markov Modeling (BHMM) to track gaze movements while presenting real-life scenes to typically developing (TD) children and adolescents (N= 25) and participants with ASD and Attention-Deficit/Hyperactivity Disorder (ASD+ADHD,N= 15) and ASD without comorbidity (ASD,N= 12). Regions of interest (ROIs) were generated by BHMM based both on spatial and temporal gaze behavior. Social visual perception was compared between groups using transition and fixation variables for social (faces, bodies) and non-social ROIs. Transition variables between faces, namely gaze transitions between faces and likelihood of linking faces, were reduced in the ASD+ADHD compared to TD participants. Fixation count to faces was also reduced in this group. The ASD group showed similar performance to TD in the studied variables. There was no difference between groups for non-social ROIs. Our study provides an innovative, interpretable example of applying Bayesian theories of social visual perception in ASD. BHMM analyses and gaze transitions have the potential to reveal fundamental social perception components in ASD, contributing thus to amelioration of social-skill interventions.

Sensory processing deficits and altered long-range connectivity putatively underlie Multisensory Integration (MSI) deficits in Autism Spectrum Disorder (ASD). The present study set out to investigate non-social MSI stimuli and their electrophysiological correlates in young neurotypical adolescents and adolescents with ASD. We report robust MSI effects at behavioural and electrophysiological levels. Both groups demonstrated normal behavioural MSI. However, at the neurophysiological level, the ASD group showed less MSI-related reduction of the visual P100 latency, greater MSI-related slowing of the auditory P200 and an overall temporally delayed and spatially constrained onset of MSI. Given the task design and patient sample, and the age of our participants, we argue that electro-cortical indices of MSI deficits in ASD: (a) can be detected in early-adolescent ASD, (b) occur at early stages of perceptual processing, (c) can possibly be compensated by later attentional processes, (d) thus leading to normal MSI at the behavioural level.

Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) represent two common neurodevelopmental disorders with considerable co-occurrence. Their comorbidity (ASD + ADHD) has been included in the latest diagnostic guidelines (DSM-V, 2013). The present study focuses on social visual attention that i) is a main aspect of social attention reflecting social cognition and ii) its atypicalities have been suggested as a potential biomarker for ASD. Considering the possible shared background of both disorders and their comorbidity, it is important to compare such traits directly. Here, 73 children and adolescents paired for age and IQ diagnosed with ASD (N = 12), ADHD (N = 21), comorbid ASD + ADHD (N = 15), and typically developing (TD) controls (N = 25), were shown static real-life social scenes while their gaze movements were recorded with eye-tracking. Scenes with two levels of social complexity were presented: low complexity (one person depicted) and high (four interacting individuals). Gaze fixation variables were investigated. Fixation duration on faces was significantly reduced only in ASD + ADHD which also required longer time to fixate all faces at least once. Fixation duration on faces in ASD was reduced, compared to TD, only when looking at scenes with high versus low social complexity. ADHD individuals did not differ from TD. Concluding, the observed alterations of social visual attention support the existence of possible dysfunctional particularities differentiating ASD, ADHD, and ASD + ADHD, which can be revealed with the new method of eye-tracking technique. The objective gaze measurements provided contribute to the development of biomarkers enabling early diagnosis, amelioration of care and further interventions specified for each group.

In their seminal treatises Human Action (1949) and Man, Economy and State (1962), Ludwig von Mises and Murray Rothbard deny that the rise in living standards achieved in the 19th and 20th century should be explained by technological progress and the resulting productivity increases. Rather, it is the praxeological category of time preference that allegedly explains in the increase in savings, capital accumulation and economic progress. The pre- sented paper criticizes Mises’s and Rothbard’s dismissive treatment of technol- ogy and argues that time only acquires economic meaning in its reference to objects of choice. As choice implies an understanding of causal relations between means and ends, human action inevitably presupposes knowledge about the use of technology in its capacity to accommodate intertemporal plans. When people thus employ means to pursue ends, the time factor is already embodied in the feasible consumption and production patterns, which are nothing but the outcomes of the prevailing technological possibilities. When human action requires contextualization to acquire meaning, then the ideas of time and time preference cannot exist independently of the particular means- ends-framework., En sus tratados fundamentales La acción humana (1949) y Hombre, economía y Estado (1962), Ludwig von Mises y Murray Rothbard niegan que el aumento del nivel de vida alcanzado en los siglos XIX y XX deba explicarse por el progreso tecnológico y los aumentos de productividad resultantes. Más bien, es la categoría praxeológica de preferencia temporal la que supuesta- mente explica el aumento en el ahorro, la acumulación de capital y el progreso económico. El documento presentado critica el tratamiento despectivo de la tecnología por Mises y Rothbard y argumenta que el tiempo sólo adquiere un significado económico en su referencia a los objetos de selección. Como la selección implica una comprensión de las relaciones causales entre medios y fines, la acción humana presupone inevitablemente el conocimiento sobre el uso de la tecnología en su capacidad de acomodar planes intertemporales. Cuando las personas emplean medios para perseguir fines, el factor tiempo ya está incorporado en los patrones realizables de consumo y producción, que no son más que el resultado de las posibilidades tecnológicas imperantes. Cuando la acción humana requiere contextualización para adquirir significado, enton- ces las ideas de tiempo y preferencia de tiempo no pueden existir independien- temente del marco particular de medios-fines.

The Human Phenotype Ontology (HPO, https://hpo.jax.org) was launched in 2008 to provide a comprehensive logical standard to describe and computationally analyze phenotypic abnormalities found in human disease. The HPO is now a worldwide standard for phenotype exchange. The HPO has grown steadily since its inception due to considerable contributions from clinical experts and researchers from a diverse range of disciplines. Here, we present recent major extensions of the HPO for neurology, nephrology, immunology, pulmonology, newborn screening, and other areas. For example, the seizure subontology now reflects the International League Against Epilepsy (ILAE) guidelines and these enhancements have already shown clinical validity. We present new efforts to harmonize computational definitions of phenotypic abnormalities across the HPO and multiple phenotype ontologies used for animal models of disease. These efforts will benefit software such as Exomiser by improving the accuracy and scope of cross-species phenotype matching. The computational modeling strategy used by the HPO to define disease entities and phenotypic features and distinguish between them is explained in detail.We also report on recent efforts to translate the HPO into indigenous languages. Finally, we summarize recent advances in the use of HPO in electronic health record systems.

The original version of this article unfortunately contained mistakes in reference numbers. The in-text citations and the references were mismatched. The original article has been corrected.

Background: About 2000 children and adolescents under the age of 18 are diagnosed with cancer each year in Germany. Because of current medical treatment methods, a high survival rate can be reached for many types of the disease. Nevertheless, patients face a number of long-term effects related to the treatment. As a result, physical and psychological consequences have increasingly become the focus of research in recent years. Social dimensions of health have received little attention in health services research in oncology so far. Yet, there are no robust results that allow an estimation of whether and to what extent the disease and treatment impair the participation of children and adolescents and which factors mediate this effect. Social participation is of great importance especially because interactions with peers and experiences in different areas of life are essential for the development of children and adolescents. Methods: Data are collected in a longitudinal, prospective, observational multicenter study. For this purpose, all patients and their parents who are being treated for cancer in one of the participating clinics throughout Germany will be interviewed within the first month after diagnosis (t1), after completion of intensive treatment (t2) and half a year after the end of intensive treatment (t3) using standardized questionnaires. Analysis will be done by descriptive and multivariate methods. Discussion: The results can be used to identify children and adolescents in high-risk situations at an early stage in order to be able to initiate interventions tailored to the needs. Such tailored interventions will finally reduce the risk of impairments in the participation of children and adolescents and increase quality of life. Trial registration: ClinicalTrials.gov: NCT04101123.

For the Phase-II Upgrade of the ATLAS Detector, its Inner Detector, consisting of silicon pixel, silicon strip and transition radiation sub-detectors, will be replaced with an all new 100 % silicon tracker, composed of a pixel tracker at inner radii and a strip tracker at outer radii. The future ATLAS strip tracker will include 11,000 silicon sensor modules in the central region (barrel) and 7,000 modules in the forward region (end-caps), which are foreseen to be constructed over a period of 3.5 years. The construction of each module consists of a series of assembly and quality control steps, which were engineered to be identical for all production sites. In order to develop the tooling and procedures for assembly and testing of these modules, two series of major prototyping programs were conducted: an early program using readout chips designed using a 250 nm fabrication process (ABCN-25) and a subsequent program using a follow-up chip set made using 130 nm processing (ABC130 and HCC130 chips). This second generation of readout chips was used for an extensive prototyping program that produced around 100 barrel-type modules and contributed significantly to the development of the final module layout. This paper gives an overview of the components used in ABC130 barrel modules, their assembly procedure and findings resulting from their tests., Comment: 82 pages, 66 figures

Precise procedural planning is crucial to achieve excellent results in patients undergoing Transcatheter aortic valve implantation (TAVI). The aim of this study was to compare the semi-automated 3mensio (3 m) software to the fully-automated HeartNavigator3 (HN) software. We randomly selected 100 patients from our in-house TAVI-registry and compared aortic annulus and perimeter as well as coronary distances between 3m-measurements and post-hoc HN-measurements. Finally, we retrospectively simulated prosthesis choice based on HN-measurements and analyzed the differences compared to routinely used 3 m based strategy. We observed significant differences between the two software packages regarding area (3 m 464 ± 88 mm², HN 482 ± 96 mm², p < 0.001), perimeter (3 m 77 ± 7 mm, HN 79 ± 8 mm, p < 0.001) and coronary distances (LCA: 3 m 13 ± 3 mm, HN 12 ± 3 mm, p < 0.001; RCA: 3 m 16 ± 3 mm, HN 15 ± 3 mm, p < 0.001). Prosthesis choice simulation based on newly obtained HN-measurements would have led to a decision change in 18% of patients, with a further reduction to 4% following manual adjustment of HN-measurements. The fully-automatic HN-software provides higher values for annular metrics and lower annulus-to-coronary-ostia distances compared to 3m-software. Measurement differences did not influence clinical outcome. Both, the HN-software and the 3m-software are sophisticated, reliable and easy to use for the clinician. Manual adjustment of HN-measurements may increase precision in complex aortic annulus anatomy.

BACKGROUND The aim of this study was to evaluate the impact of transcatheter aortic valve implantation (TAVI) on mitral valve geometry and function. METHODS Eighty-four patients underwent TAVI. Forty-four (52%) patients received a balloon-expandable valve and 40 (48%) were implanted with a self-expandable valve. All patients underwent three-dimensional-volumetric transesophageal echocardiography of the mitral valve before and immediately after TAVI. A dedicated software was used for assisted semiautomatic measurement of mitral annular geometry. RESULTS During systole, the anterior to posterior (AP) diameter was significantly reduced after the procedure (3.4 ± 0.5 cm vs 3.2 ± 0.5 cm; P < .05). The mitral annular area (10.8 ± 2.8cm$^{2}$ vs 9.9 ± 2.6cm$^{2}$ ; P < .05) as well as the tenting area (1.6 ± 0.7 cm$^{2}$ vs 1.2 ± 0.6 cm$^{2}$ ; P < .001) measured at mid-systole were reduced after TAVI. Diastolic measures were similar. Patients treated with balloon-expandable valves showed a significantly larger reduction in the AP diameter compared to self-expandable valves (-0.25 cm vs -0.11 cm; P < .05). The reduction of the annular area was higher in the balloon-expandable group (-1.2 ± 1.59 vs -0.22 ± 1.41; P < .05). Grade of mitral regurgitation did improve or remained stable after TAVI. CONCLUSION TAVI significantly impacts the mitral valve and mitral annular geometry and morphology. The choice of the prosthesis (balloon- vs self-expandable) may be relevant for those changes.

Objective: The Strengths and Weaknesses of ADHS–Symptoms and Normal Behavior (SWAN) Scale has been developed to support the dimensional assessment of ADHD symptoms by capturing variance on both poles of the ADHD continuum. The present study provides the first validation of the German version of SWAN (SWAN-DE). Method: Based on a sample of N1 = 343 children from the general population and N2 = 62 children with ADHD, both aged between 8 and 18 years, normality, internal consistency, test–retest reliability, and different validity indices were examined. Results: SWAN was characterized by normally distributed scores, good to excellent reliability, and factorial validity. It showed high diagnostic utility in discriminating between patients with ADHD and healthy controls and significant correlations to related clinical scales and neuropsychological constructs, such as intra-subject variability. Conclusion: The present study reveals the excellent psychometric properties of SWAN-DE, which can now be usefully applied in the German-speaking countries as well as in cross-national studies., Deutsche Forschungsgemeinschaft https://doi.org/10.13039/501100001659, Peer Reviewed

Very early onset inflammatory bowel disease (VEO-IBD) is defined as IBD presenting before 6 years of age. When compared with IBD diagnosed in older children, VEO-IBD has some distinct characteristics such as a higher likelihood of an underlying monogenic etiology or primary immune deficiency. In addition, patients with VEO-IBD have a higher incidence of inflammatory bowel disease unclassified (IBD-U) as compared with older-onset IBD. In some populations, VEO-IBD represents the age group with the fastest growing incidence of IBD. There are contradicting reports on whether VEO-IBD is more resistant to conventional medical interventions. There is a strong need for ongoing research in the field of VEO-IBD to provide optimized management of these complex patients. Here, we provide an approach to diagnosis and management of patients with VEO-IBD. These recommendations are based on expert opinion from members of the VEO-IBD Consortium (www.VEOIBD.org). We highlight the importance of monogenic etiologies, underlying immune deficiencies, and provide a comprehensive description of monogenic etiologies identified to date that are responsible for VEO-IBD.

BackgroundChildren with very early onset inflammatory bowel diseases (VEO-IBD) often have a refractory and severe disease course. A significant number of described VEO-IBD-causing monogenic disorders can be attributed to defects in immune-related genes. The diagnosis of the underlying primary immunodeficiency (PID) often has critical implications for the treatment of patients with IBD-like phenotypes.MethodsTo identify the molecular etiology in 5 patients from 3 unrelated kindred with IBD-like symptoms, we conducted whole exome sequencing. Immune workup confirmed an underlying PID.ResultsWhole exome sequencing revealed 3 novel CARMIL2 loss-of-function mutations in our patients. Immunophenotyping of peripheral blood mononuclear cells showed reduction of regulatory and effector memory T cells and impaired B cell class switching. The T cell proliferation and activation assays confirmed defective responses to CD28 costimulation, consistent with CARMIL2 deficiency.ConclusionOur study highlights that human CARMIL2 deficiency can manifest with IBD-like symptoms. This example illustrates that early diagnosis of underlying PID is crucial for the treatment and prognosis of children with VEO-IBD.

Measuring gaze behaviour is useful to understand the cognitive processes involved in vehicle control and to test new assistance technology. Most of the research on eye movements in vehicle control was conducted in the context of road traffic and will therefore be focused on in this chapter. In the following, we will first introduce the driving task and outline how the eye-tracking methodology can be used to get insights into the cognitive processes that guide driving behaviour. Furthermore, we will highlight important classical findings and recent developments in the field of eye movements in driving. These include eye movements during basic vehicle control tasks like steering, driving manoeuvres and detecting hazards in the road environment. Additionally, factors influencing task performance (e.g., effects of visual distraction, workload, fatigue, driving experience, and aging) that can be observed by applying the eye-tracking method will be introduced. Conducting an eye-tracking study in the driving context often takes place in complex and highly dynamic environments. Therefore, in the last part of this chapter, we will give a practical guideline of what is important in order to study eye movements in the context of vehicle control including an overview of the most commonly used parameters to describe gaze behaviour in the context of driving. We will sum up this introductory chapter with an outline for future research on the topic of eye movements in vehicle control.

Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs. Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata((R)) and Excel. Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1-25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0-88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE-syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%-subcutaneous; 29%-intravenous; 1%-unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy. Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a m