Showing papers by "University of Freiburg published in 2020"

The ATLAS Experiment at the CERN Large Hadron Collider

Abstract: The ATLAS detector as installed in its experimental cavern at point 1 at CERN is described in this paper. A brief overview of the expected performance of the detector when the Large Hadron Collider begins operation is also presented.

Evolutionary classification of CRISPR-Cas systems: a burst of class 2 and derived variants.

Abstract: The number and diversity of known CRISPR-Cas systems have substantially increased in recent years. Here, we provide an updated evolutionary classification of CRISPR-Cas systems and cas genes, with an emphasis on the major developments that have occurred since the publication of the latest classification, in 2015. The new classification includes 2 classes, 6 types and 33 subtypes, compared with 5 types and 16 subtypes in 2015. A key development is the ongoing discovery of multiple, novel class 2 CRISPR-Cas systems, which now include 3 types and 17 subtypes. A second major novelty is the discovery of numerous derived CRISPR-Cas variants, often associated with mobile genetic elements that lack the nucleases required for interference. Some of these variants are involved in RNA-guided transposition, whereas others are predicted to perform functions distinct from adaptive immunity that remain to be characterized experimentally. The third highlight is the discovery of numerous families of ancillary CRISPR-linked genes, often implicated in signal transduction. Together, these findings substantially clarify the functional diversity and evolutionary history of CRISPR-Cas.

TRY plant trait database : Enhanced coverage and open access

Abstract: Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives.

Neuropathology of patients with COVID-19 in Germany: a post-mortem case series.

Abstract: Summary Background Prominent clinical symptoms of COVID-19 include CNS manifestations. However, it is unclear whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, gains access to the CNS and whether it causes neuropathological changes. We investigated the brain tissue of patients who died from COVID-19 for glial responses, inflammatory changes, and the presence of SARS-CoV-2 in the CNS. Methods In this post-mortem case series, we investigated the neuropathological features in the brains of patients who died between March 13 and April 24, 2020, in Hamburg, Germany. Inclusion criteria comprised a positive test for SARS-CoV-2 by quantitative RT-PCR (qRT-PCR) and availability of adequate samples. We did a neuropathological workup including histological staining and immunohistochemical staining for activated astrocytes, activated microglia, and cytotoxic T lymphocytes in the olfactory bulb, basal ganglia, brainstem, and cerebellum. Additionally, we investigated the presence and localisation of SARS-CoV-2 by qRT-PCR and by immunohistochemistry in selected patients and brain regions. Findings 43 patients were included in our study. Patients died in hospitals, nursing homes, or at home, and were aged between 51 years and 94 years (median 76 years [IQR 70–86]). We detected fresh territorial ischaemic lesions in six (14%) patients. 37 (86%) patients had astrogliosis in all assessed regions. Activation of microglia and infiltration by cytotoxic T lymphocytes was most pronounced in the brainstem and cerebellum, and meningeal cytotoxic T lymphocyte infiltration was seen in 34 (79%) patients. SARS-CoV-2 could be detected in the brains of 21 (53%) of 40 examined patients, with SARS-CoV-2 viral proteins found in cranial nerves originating from the lower brainstem and in isolated cells of the brainstem. The presence of SARS-CoV-2 in the CNS was not associated with the severity of neuropathological changes. Interpretation In general, neuropathological changes in patients with COVID-19 seem to be mild, with pronounced neuroinflammatory changes in the brainstem being the most common finding. There was no evidence for CNS damage directly caused by SARS-CoV-2. The generalisability of these findings needs to be validated in future studies as the number of cases and availability of clinical data were low and no age-matched and sex-matched controls were included. Funding German Research Foundation, Federal State of Hamburg, EU (eRARE), German Center for Infection Research (DZIF).

Automated Machine Learning

Abstract: This open access book presents the first comprehensive overview of general methods in Automated Machine Learning (AutoML), collects descriptions of existing systems based on these methods, and discusses the first series of international challenges of AutoML systems. The recent success of commercial ML applications and the rapid growth of the field has created a high demand for off-the-shelf ML methods that can be used easily and without expert knowledge. However, many of the recent machine learning successes crucially rely on human experts, who manually select appropriate ML architectures (deep learning architectures or more traditional ML workflows) and their hyperparameters. To overcome this problem, the field of AutoML targets a progressive automation of machine learning, based on principles from optimization and machine learning itself. This book serves as a point of entry into this quickly-developing field for researchers and advanced students alike, as well as providing a reference for practitioners aiming to use AutoML in their work.

Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity.

Abstract: The papain-like protease PLpro is an essential coronavirus enzyme that is required for processing viral polyproteins to generate a functional replicase complex and enable viral spread1,2. PLpro is also implicated in cleaving proteinaceous post-translational modifications on host proteins as an evasion mechanism against host antiviral immune responses3-5. Here we perform biochemical, structural and functional characterization of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PLpro (SCoV2-PLpro) and outline differences with SARS-CoV PLpro (SCoV-PLpro) in regulation of host interferon and NF-κB pathways. SCoV2-PLpro and SCoV-PLpro share 83% sequence identity but exhibit different host substrate preferences; SCoV2-PLpro preferentially cleaves the ubiquitin-like interferon-stimulated gene 15 protein (ISG15), whereas SCoV-PLpro predominantly targets ubiquitin chains. The crystal structure of SCoV2-PLpro in complex with ISG15 reveals distinctive interactions with the amino-terminal ubiquitin-like domain of ISG15, highlighting the high affinity and specificity of these interactions. Furthermore, upon infection, SCoV2-PLpro contributes to the cleavage of ISG15 from interferon responsive factor 3 (IRF3) and attenuates type I interferon responses. Notably, inhibition of SCoV2-PLpro with GRL-0617 impairs the virus-induced cytopathogenic effect, maintains the antiviral interferon pathway and reduces viral replication in infected cells. These results highlight a potential dual therapeutic strategy in which targeting of SCoV2-PLpro can suppress SARS-CoV-2 infection and promote antiviral immunity.

Dealing with sleep problems during home confinement due to the COVID-19 outbreak: Practical recommendations from a task force of the European CBT-I Academy.

Abstract: In the current global home confinement situation due to the COVID-19 outbreak, most individuals are exposed to an unprecedented stressful situation of unknown duration. This may not only increase daytime stress, anxiety and depression levels, but also disrupt sleep. Importantly, because of the fundamental role that sleep plays in emotion regulation, sleep disturbance can have direct consequences upon next day emotional functioning. In this paper, we summarize what is known about the stress-sleep link and confinement as well as effective insomnia treatment. We discuss those effects of the current home confinement situation that can disrupt sleep but also those that could benefit sleep quality. We suggest adaptions of cognitive behavioural therapy elements that are feasible to implement for those facing changed work schedules and requirements, those with health anxiety and those handling childcare and home-schooling, whilst also recognizing the general limitations imposed on physical exercise and social interaction. Managing sleep problems as best as possible during home confinement can limit stress and possibly prevent disruptions of social relationships.

Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms.

Abstract: The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a grave threat to public health and the global economy. SARS-CoV-2 is closely related to the more lethal but less transmissible coronaviruses SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV). Here, we have carried out comparative viral-human protein-protein interaction and viral protein localization analyses for all three viruses. Subsequent functional genetic screening identified host factors that functionally impinge on coronavirus proliferation, including Tom70, a mitochondrial chaperone protein that interacts with both SARS-CoV-1 and SARS-CoV-2 ORF9b, an interaction we structurally characterized using cryo-electron microscopy. Combining genetically validated host factors with both COVID-19 patient genetic data and medical billing records identified molecular mechanisms and potential drug treatments that merit further molecular and clinical study.

Excess electronic recoil events in XENON1T

Abstract: We report results from searches for new physics with low-energy electronic recoil data recorded with the XENON1T detector. With an exposure of 0.65 tonne-years and an unprecedentedly low background rate of 76±2stat events/(tonne×year×keV) between 1 and 30 keV, the data enable one of the most sensitive searches for solar axions, an enhanced neutrino magnetic moment using solar neutrinos, and bosonic dark matter. An excess over known backgrounds is observed at low energies and most prominent between 2 and 3 keV. The solar axion model has a 3.4σ significance, and a three-dimensional 90% confidence surface is reported for axion couplings to electrons, photons, and nucleons. This surface is inscribed in the cuboid defined by gae<3.8×10-12, gaeganeff<4.8×10-18, and gaegaγ<7.7×10-22 GeV-1, and excludes either gae=0 or gaegaγ=gaeganeff=0. The neutrino magnetic moment signal is similarly favored over background at 3.2σ, and a confidence interval of μν∈(1.4,2.9)×10-11 μB (90% C.L.) is reported. Both results are in strong tension with stellar constraints. The excess can also be explained by β decays of tritium at 3.2σ significance with a corresponding tritium concentration in xenon of (6.2±2.0)×10-25 mol/mol. Such a trace amount can neither be confirmed nor excluded with current knowledge of its production and reduction mechanisms. The significances of the solar axion and neutrino magnetic moment hypotheses are decreased to 2.0σ and 0.9σ, respectively, if an unconstrained tritium component is included in the fitting. With respect to bosonic dark matter, the excess favors a monoenergetic peak at (2.3±0.2) keV (68% C.L.) with a 3.0σ global (4.0σ local) significance over background. This analysis sets the most restrictive direct constraints to date on pseudoscalar and vector bosonic dark matter for most masses between 1 and 210 keV/c2. We also consider the possibility that Ar37 may be present in the detector, yielding a 2.82 keV peak from electron capture. Contrary to tritium, the Ar37 concentration can be tightly constrained and is found to be negligible.

Care of patients with liver disease during the COVID-19 pandemic: EASL-ESCMID position paper

Abstract: The coronavirus disease 2019 (COVID-19) pandemic poses an enormous challenge to healthcare systems in affected communities. Older patients and those with pre-existing medical conditions have been identified as populations at risk of a severe disease course. It remains unclear at this point to what extent chronic liver diseases should be considered as risk factors, due to a shortage of appropriate studies. However, patients with advanced liver disease and those after liver transplantation represent vulnerable patient cohorts with an increased risk of infection and/or a severe course of COVID-19. In addition, the current pandemic requires unusual allocation of healthcare resources which may negatively impact the care of patients with chronic liver disease that continue to require medical attention. Thus, the challenge hepatologists are facing is to promote telemedicine in the outpatient setting, prioritise outpatient contacts, avoid nosocomial dissemination of the virus to patients and healthcare providers, and at the same time maintain standard care for patients who require immediate medical attention.

Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease

Abstract: Background Acute graft-versus-host disease (GVHD) remains a major limitation of allogeneic stem-cell transplantation; not all patients have a response to standard glucocorticoid treatment....

Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility

Abstract: Background: Several new genes and clinical subtypes have been identified since the publication in 2014 of the report of the last International Consensus Meeting on Epidermolysis Bullosa (EB). Objectives: We sought to reclassify disorders with skin fragility, with a focus on EB, based on new clinical and molecular data. Methods: This was a consensus expert review. Results: In this latest consensus report, we introduce the concept of genetic disorders with skin fragility, of which classical EB represents the prototype. Other disorders with skin fragility, where blisters are a minor part of the clinical picture or are not seen because skin cleavage is very superficial, are classified as separate categories. These include peeling skin disorders, erosive disorders, hyperkeratotic disorders, and connective tissue disorders with skin fragility. Because of the common manifestation of skin fragility, these ‘EB-related’ disorders should be considered under the EB umbrella in terms of medical and socioeconomic provision of care. Conclusions: The proposed classification scheme should be of value both to clinicians and researchers, emphasizing both clinical and genetic features of EB. What is already known about this topic?. Epidermolysis bullosa (EB) is a group of genetic disorders with skin blistering. The last updated recommendations on diagnosis and classification were published in 2014. What does this study add?. We introduce the concept of genetic disorders with skin fragility, of which classical EB represents the prototype. Clinical and genetic aspects, genotype–phenotype correlations, disease-modifying factors and natural history of EB are reviewed. Other disorders with skin fragility, e.g. peeling skin disorders, erosive disorders, hyperkeratotic disorders, and connective tissue disorders with skin fragility are classified as separate categories; these ‘EB-related’ disorders should be considered under the EB umbrella in terms of medical and socioeconomic provision of care. Linked Comment: Pope. Br J Dermatol 2020; 183:603.

Treatment of Nontuberculous Mycobacterial Pulmonary Disease: An Official ATS/ERS/ESCMID/IDSA Clinical Practice Guideline.

Abstract: Nontuberculous mycobacteria (NTM) represent over 190 species and subspecies, some of which can produce disease in humans of all ages and can affect both pulmonary and extrapulmonary sites. This guideline focuses on pulmonary disease in adults (without cystic fibrosis or human immunodeficiency virus infection) caused by the most common NTM pathogens such as Mycobacterium avium complex, Mycobacterium kansasii, and Mycobacterium xenopi among the slowly growing NTM and Mycobacterium abscessus among the rapidly growing NTM. A panel of experts was carefully selected by leading international respiratory medicine and infectious diseases societies (ATS, ERS, ESCMID, IDSA) and included specialists in pulmonary medicine, infectious diseases and clinical microbiology, laboratory medicine, and patient advocacy. Systematic reviews were conducted around each of 22 PICO (Population, Intervention, Comparator, Outcome) questions and the recommendations were formulated, written, and graded using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. Thirty-one evidence-based recommendations about treatment of NTM pulmonary disease are provided. This guideline is intended for use by healthcare professionals who care for patients with NTM pulmonary disease, including specialists in infectious diseases and pulmonary diseases.

A standard protocol for reporting species distribution models

Abstract: Species distribution models (SDMs) constitute the most common class of models across ecology, evolution and conservation. The advent of ready-to-use software pack - ages and increasing availability of digital geoinformation have considerably assisted the application of SDMs in the past decade, greatly enabling their broader use for informing conservation and management, and for quantifying impacts from global change. However, models must be fit for purpose, with all important aspects of their development and applications properly considered. Despite the widespread use of SDMs, standardisation and documentation of modelling protocols remain limited, which makes it hard to assess whether development steps are appropriate for end use. To address these issues, we propose a standard protocol for reporting SDMs, with an emphasis on describing how a study’s objective is achieved through a series of model - ing decisions. We call this the ODMAP (Overview, Data, Model, Assessment and Prediction) protocol, as its components reflect the main steps involved in building SDMs and other empirically-based biodiversity models. The ODMAP protocol serves two main purposes. First, it provides a checklist for authors, detailing key steps for model building and analyses, and thus represents a quick guide and generic workflow for modern SDMs. Second, it introduces a structured format for documenting and communicating the models, ensuring transparency and reproducibility, facilitating peer review and expert evaluation of model quality, as well as meta-analyses. We detail all elements of ODMAP, and explain how it can be used for different model objectives and applications, and how it complements efforts to store associated metadata and define modelling standards. We illustrate its utility by revisiting nine previously published case studies, and provide an interactive web-based application to facilitate its use. We plan to advance ODMAP by encouraging its further refinement and adoption by the scientific community.

Treatment of nontuberculous mycobacterial pulmonary disease: an official ATS/ERS/ESCMID/IDSA clinical practice guideline

Abstract: Nontuberculous mycobacteria (NTM) represent over 190 species and subspecies, some of which can produce disease in humans of all ages and can affect both pulmonary and extrapulmonary sites. This guideline focuses on pulmonary disease in adults (without cystic fibrosis or human immunodeficiency virus infection) caused by the most common NTM pathogens such as Mycobacterium avium complex, Mycobacterium kansasii, and Mycobacterium xenopi among the slowly growing NTM and Mycobacterium abscessus among the rapidly growing NTM. A panel of experts was carefully selected by leading international respiratory medicine and infectious diseases societies (ATS, ERS, ESCMID, IDSA) and included specialists in pulmonary medicine, infectious diseases and clinical microbiology, laboratory medicine, and patient advocacy. Systematic reviews were conducted around each of 22 PICO (Population, Intervention, Comparator, Outcome) questions and the recommendations were formulated, written, and graded using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. Thirty-one evidence-based recommendations about treatment of NTM pulmonary disease are provided. This guideline is intended for use by healthcare professionals who care for patients with NTM pulmonary disease, including specialists in infectious diseases and pulmonary diseases.

Search for electroweak production of charginos and sleptons decaying into final states with two leptons and missing transverse momentum in √s = 13 TeV pp collisions using the ATLAS detector

Abstract: A search for the electroweak production of charginos and sleptons decaying into final states with two electrons or muons is presented. The analysis is based on 139 fb$^{-1}$ of proton–proton collisions recorded by the ATLAS detector at the Large Hadron Collider at $\sqrt{s}=13$ $\text {TeV}$. Three R-parity-conserving scenarios where the lightest neutralino is the lightest supersymmetric particle are considered: the production of chargino pairs with decays via either W bosons or sleptons, and the direct production of slepton pairs. The analysis is optimised for the first of these scenarios, but the results are also interpreted in the others. No significant deviations from the Standard Model expectations are observed and limits at 95% confidence level are set on the masses of relevant supersymmetric particles in each of the scenarios. For a massless lightest neutralino, masses up to 420 $\text {Ge}\text {V}$ are excluded for the production of the lightest-chargino pairs assuming W-boson-mediated decays and up to 1 $\text {TeV}$ for slepton-mediated decays, whereas for slepton-pair production masses up to 700 $\text {Ge}\text {V}$ are excluded assuming three generations of mass-degenerate sleptons.

Single cell RNA sequencing of human microglia uncovers a subset associated with Alzheimer’s disease

Abstract: The extent of microglial heterogeneity in humans remains a central yet poorly explored question in light of the development of therapies targeting this cell type. Here, we investigate the population structure of live microglia purified from human cerebral cortex samples obtained at autopsy and during neurosurgical procedures. Using single cell RNA sequencing, we find that some subsets are enriched for disease-related genes and RNA signatures. We confirm the presence of four of these microglial subpopulations histologically and illustrate the utility of our data by characterizing further microglial cluster 7, enriched for genes depleted in the cortex of individuals with Alzheimer's disease (AD). Histologically, these cluster 7 microglia are reduced in frequency in AD tissue, and we validate this observation in an independent set of single nucleus data. Thus, our live human microglia identify a range of subtypes, and we prioritize one of these as being altered in AD.

Electrical recognition of the twenty proteinogenic amino acids using an aerolysin nanopore.

Abstract: Efforts to sequence single protein molecules in nanopores1-5 have been hampered by the lack of techniques with sufficient sensitivity to discern the subtle molecular differences among all twenty amino acids. Here we report ionic current detection of all twenty proteinogenic amino acids in an aerolysin nanopore with the help of a short polycationic carrier. Application of molecular dynamics simulations revealed that the aerolysin nanopore has a built-in single-molecule trap that fully confines a polycationic carrier-bound amino acid inside the sensing region of the aerolysin. This structural feature means that each amino acid spends sufficient time in the pore for sensitive measurement of the excluded volume of the amino acid. We show that distinct current blockades in wild-type aerolysin can be used to identify 13 of the 20 natural amino acids. Furthermore, we show that chemical modifications, instrumentation advances and nanopore engineering offer a route toward identification of the remaining seven amino acids. These findings may pave the way to nanopore protein sequencing.

Understanding and Robustifying Differentiable Architecture Search

Abstract: Differentiable Architecture Search (DARTS) has attracted a lot of attention due to its simplicity and small search costs achieved by a continuous relaxation and an approximation of the resulting bi-level optimization problem. However, DARTS does not work robustly for new problems: we identify a wide range of search spaces for which DARTS yields degenerate architectures with very poor test performance. We study this failure mode and show that, while DARTS successfully minimizes validation loss, the found solutions generalize poorly when they coincide with high validation loss curvature in the architecture space. We show that by adding one of various types of regularization we can robustify DARTS to find solutions with less curvature and better generalization properties. Based on these observations, we propose several simple variations of DARTS that perform substantially more robustly in practice. Our observations are robust across five search spaces on three image classification tasks and also hold for the very different domains of disparity estimation (a dense regression task) and language modelling.

Linking the Remote Sensing of Geodiversity and Traits Relevant to Biodiversity—Part II: Geomorphology, Terrain and Surfaces

Abstract: The status, changes, and disturbances in geomorphological regimes can be regarded as controlling and regulating factors for biodiversity. Therefore, monitoring geomorphology at local, regional, and global scales is not only necessary to conserve geodiversity, but also to preserve biodiversity, as well as to improve biodiversity conservation and ecosystem management. Numerous remote sensing (RS) approaches and platforms have been used in the past to enable a cost-effective, increasingly freely available, comprehensive, repetitive, standardized, and objective monitoring of geomorphological characteristics and their traits. This contribution provides a state-of-the-art review for the RS-based monitoring of these characteristics and traits, by presenting examples of aeolian, fluvial, and coastal landforms. Different examples for monitoring geomorphology as a crucial discipline of geodiversity using RS are provided, discussing the implementation of RS technologies such as LiDAR, RADAR, as well as multi-spectral and hyperspectral sensor technologies. Furthermore, data products and RS technologies that could be used in the future for monitoring geomorphology are introduced. The use of spectral traits (ST) and spectral trait variation (STV) approaches with RS enable the status, changes, and disturbances of geomorphic diversity to be monitored. We focus on the requirements for future geomorphology monitoring specifically aimed at overcoming some key limitations of ecological modeling, namely: the implementation and linking of in-situ, close-range, air- and spaceborne RS technologies, geomorphic traits, and data science approaches as crucial components for a better understanding of the geomorphic impacts on complex ecosystems. This paper aims to impart multidimensional geomorphic information obtained by RS for improved utilization in biodiversity monitoring.

Spatial validation reveals poor predictive performance of large-scale ecological mapping models.

Abstract: Mapping aboveground forest biomass is central for assessing the global carbon balance. However, current large-scale maps show strong disparities, despite good validation statistics of their underlying models. Here, we attribute this contradiction to a flaw in the validation methods, which ignore spatial autocorrelation (SAC) in data, leading to overoptimistic assessment of model predictive power. To illustrate this issue, we reproduce the approach of large-scale mapping studies using a massive forest inventory dataset of 11.8 million trees in central Africa to train and validate a random forest model based on multispectral and environmental variables. A standard nonspatial validation method suggests that the model predicts more than half of the forest biomass variation, while spatial validation methods accounting for SAC reveal quasi-null predictive power. This study underscores how a common practice in big data mapping studies shows an apparent high predictive power, even when predictors have poor relationships with the ecological variable of interest, thus possibly leading to erroneous maps and interpretations. Mapping ecological variables using machine-learning algorithms based on remote-sensing data has become a widespread practice in ecology. Here, the authors use forest biomass mapping as a study case to show that the most common model validation approach, which ignores data spatial structure, leads to overoptimistic assessment of model predictive power.

Quantitative prediction of human pharmacokinetic responses to drugs via fluidically coupled vascularized organ chips.

Abstract: Analyses of drug pharmacokinetics (PKs) and pharmacodynamics (PDs) performed in animals are often not predictive of drug PKs and PDs in humans, and in vitro PK and PD modelling does not provide quantitative PK parameters. Here, we show that physiological PK modelling of first-pass drug absorption, metabolism and excretion in humans-using computationally scaled data from multiple fluidically linked two-channel organ chips-predicts PK parameters for orally administered nicotine (using gut, liver and kidney chips) and for intravenously injected cisplatin (using coupled bone marrow, liver and kidney chips). The chips are linked through sequential robotic liquid transfers of a common blood substitute by their endothelium-lined channels (as reported by Novak et al. in an associated Article) and share an arteriovenous fluid-mixing reservoir. We also show that predictions of cisplatin PDs match previously reported patient data. The quantitative in-vitro-to-in-vivo translation of PK and PD parameters and the prediction of drug absorption, distribution, metabolism, excretion and toxicity through fluidically coupled organ chips may improve the design of drug-administration regimens for phase-I clinical trials.

Prevention of Psychosis: Advances in Detection, Prognosis, and Intervention

Abstract: Importance Detection, prognosis, and indicated interventions in individuals at clinical high risk for psychosis (CHR-P) are key components of preventive psychiatry. Objective To provide a comprehensive, evidence-based systematic appraisal of the advancements and limitations of detection, prognosis, and interventions for CHR-P individuals and to formulate updated recommendations. Evidence Review Web of Science, Cochrane Central Register of Reviews, and Ovid/PsychINFO were searched for articles published from January 1, 2013, to June 30, 2019, to identify meta-analyses conducted in CHR-P individuals. MEDLINE was used to search the reference lists of retrieved articles. Data obtained from each article included first author, year of publication, topic investigated, type of publication, study design and number, sample size of CHR-P population and comparison group, type of comparison group, age and sex of CHR-P individuals, type of prognostic assessment, interventions, quality assessment (using AMSTAR [Assessing the Methodological Quality of Systematic Reviews]), and key findings with their effect sizes. Findings In total, 42 meta-analyses published in the past 6 years and encompassing 81 outcomes were included. For the detection component, CHR-P individuals were young (mean [SD] age, 20.6 [3.2] years), were more frequently male (58%), and predominantly presented with attenuated psychotic symptoms lasting for more than 1 year before their presentation at specialized services. CHR-P individuals accumulated several sociodemographic risk factors compared with control participants. Substance use (33% tobacco use and 27% cannabis use), comorbid mental disorders (41% with depressive disorders and 15% with anxiety disorders), suicidal ideation (66%), and self-harm (49%) were also frequently seen in CHR-P individuals. CHR-P individuals showed impairments in work (Cohend = 0.57) or educational functioning (Cohend = 0.21), social functioning (Cohend = 1.25), and quality of life (Cohend = 1.75). Several neurobiological and neurocognitive alterations were confirmed in this study. For the prognosis component, the prognostic accuracy of CHR-P instruments was good, provided they were used in clinical samples. Overall, risk of psychosis was 22% at 3 years, and the risk was the highest in the brief and limited intermittent psychotic symptoms subgroup (38%). Baseline severity of attenuated psychotic (Cohend = 0.35) and negative symptoms (Cohend = 0.39) as well as low functioning (Cohend = 0.29) were associated with an increased risk of psychosis. Controlling risk enrichment and implementing sequential risk assessments can optimize prognostic accuracy. For the intervention component, no robust evidence yet exists to favor any indicated intervention over another (including needs-based interventions and control conditions) for preventing psychosis or ameliorating any other outcome in CHR-P individuals. However, because the uncertainty of this evidence is high, needs-based and psychological interventions should still be offered. Conclusions and Relevance This review confirmed recent substantial advancements in the detection and prognosis of CHR-P individuals while suggesting that effective indicated interventions need to be identified. This evidence suggests a need for specialized services to detect CHR-P individuals in primary and secondary care settings, to formulate a prognosis with validated psychometric instruments, and to offer needs-based and psychological interventions.

Higgs Boson studies at future particle colliders

Abstract: This document aims to provide an assessment of the potential of future colliding beam facilities to perform Higgs boson studies. The analysis builds on the submissions made by the proponents of future colliders to the European Strategy Update process, and takes as its point of departure the results expected at the completion of the HL-LHC program. This report presents quantitative results on many aspects of Higgs physics for future collider projects of sufficient maturity using uniform methodologies.