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The effectiveness of multi-stakeholder initiatives (MSIs) in tackling grand social and environmental challenges depends on productive dialogue among diverse parties. Facilitating such dialogue in turn entails building common ground in form of joint knowledge, beliefs, and suppositions. To explore how such common ground can be built, we study the role of different facilitators and their strategies for bridging the perspectives of competing stakeholder groups in two contrasting MSIs. The German Partnership for Sustainable Textiles was launched in an initially hostile communicative environment, whereas the Fossil Free Sweden Initiative proceeded in a fertile communicative environment. We trace how the facilitators in these initiatives achieved common ground through three bridging strategies—communicative integration, temporal calibration, and process alignment—adapted to the communicative environments of these MSIs. In hostile communicative environments, facilitators achieve common ground by steering diverging stakeholder groups towards 'reconciling' their different language registers, knowledge bases, and meaning systems to 'meet in the middle' on points of agreement and shared interests. In fertile communicative environments characterised by greater mutual trust, facilitators can steer interactants to 'strategically appropriate' to the language, knowledge, and meaning system of a particular stakeholder group to win this group's support. Our analysis contributes to a better understanding of how productive multi-stakeholder dialogue can be facilitated. [ABSTRACT FROM AUTHOR]

Anti-IgLON5 disease is a unique condition that bridges autoimmunity and neurodegeneration. Since its initial description 10 years ago, an increasing number of autopsies has led to the observation of a broader spectrum of neuropathologies underlying a particular constellation of clinical symptoms. In this study, we describe the neuropathological findings in 22 patients with anti-IgLON5 disease from 9 different European centers. In 15 patients (68%), we observed a hypothalamic and brainstem-predominant tauopathy of varying severity in which the original research neuropathological criteria were readily applicable. This pathology was observed in younger patients (median age at onset 61 years) with a long disease duration (median 9 years). In contrast, in 7 (32%) patients, the originally described brainstem tauopathy was nearly absent or only minimal in the form of delicate threads, despite mild-to-moderate neurodegenerative features, consistent clinical symptoms and the presence of anti-IgLON5 antibodies in CSF and serum. These patients were older at onset (median 79 years) and had shorter disease duration (median < 1 year). Overall, about one-third of the patients showed concomitant TDP-43 pathology within the regions affected by tau pathology and/or neurodegeneration. Based on these observations and in view of the spectrum of the tau burden in the core regions involved in the disease, we propose a simple staging system: stage 1 mild neurodegeneration without overt or only minimal tau pathology, stage 2 moderate neurodegeneration and mild/ moderate tauopathy and stage 3 prominent neurodegeneration and tau pathology. This staging intends to reflect a potential (age- and time-dependent) progression of tau pathology, supporting the current notion that tau accumulation is a secondary phenomenon related to the presence of anti-IgLON5 antibodies in the CNS. Finally, we adapt the original research criteria of the anti-IgLON5 disease-related tauopathy to include the spectrum of pathologies observed in this larger postmortem series. [ABSTRACT FROM AUTHOR]

The escalating worldwide prevalence of Crohn's disease (CD) among children and adolescents, coupled with a trend toward earlier onset, presents significant challenges for healthcare systems. Moreover, the chronicity of this condition imposes substantial individual burdens. Consequently, the principal objective of CD treatment revolves around rapid inducing remission. This study scrutinizes the impact of age, gender, initial disease localization, and therapy on the duration to achieve disease activity amelioration. Data from the Saxon Pediatric IBD Registry in Germany were analyzed over a period of 15 years. In addition to descriptive methods, logistic and linear regression analyses were conducted to identify correlations. Furthermore, survival analyses and Cox regressions were utilized to identify factors influencing the time to improvement in disease activity. These effects were expressed as Hazard Ratios (HR) with 95% confidence intervals. Data on the clinical course of 338 children and adolescents with CD were available in the registry. The analyses showed a significant correlation between a young age of onset and the severity of disease activity. It was evident that treatment with anti-TNF (Infliximab) was associated with a more favorable prognosis in terms of the time required for improvement in disease activity. Similarly, favorable outcomes were observed with the combination therapies of infliximab with enteral nutrition therapy and Infliximab with immunosuppressants. Conclusion: Our analysis of data from the Saxon Pediatric IBD Registry revealed that the timeframe for improvement of disease activity in pediatric Crohn's disease is influenced by several factors. Specifically, patient age, treatment modality, and initial site of inflammation were found to be significant factors. The study provides important findings that underline the need for individualized treatment. [ABSTRACT FROM AUTHOR]

In this paper, a new gram scale experiment with well characterised boundary conditions is proposed for pyrolysis experiments. The set-up consists of a tube furnace, based on ISO19700, with a newly designed concept for a balance within the oven, allowing for online mass loss measurements. Samples with a length up to 50 cm can be investigated in this apparatus. The oven allows for experiments at fixed temperatures or at fixed heating rates, under controlled atmosphere, w.r.t. gas composition and flow rate. A thorough characterisation of the set-up is presented, including aspects like reproducibility of the heating rate or the precision of the balance. The functionality of the balance has been demonstrated with calcium carbonate (CaCO 3 ) experiments. This material was chosen because it decomposes in a single reaction, which only releases CO 2 . This allows for comparison between the mass loss rate of the balance and the CO 2 production rate, measured by a gas analyser. Results for two different heating rates: 3 K/min and 5 K/min and for different masses (25 g and 8.5 g) are presented. The two measurement methods are in excellent agreement. Finally, the data obtained from the new experimental set-up is compared to results from thermogravimetric analyser (TGA) experiments. [ABSTRACT FROM AUTHOR]

The permeability of aquifers strongly influences groundwater flow characteristics. Worldwide, coastal groundwater is often the primary freshwater source for coastal communities and ecosystems but is also particularly vulnerable to abstraction since saltwater intrusion may threaten its quality. Thus, understanding coastal permeability is crucial to the sustainable use of coastal groundwater. Here, we present the first global dataset of coastal permeability (CoPerm 1.0), which provides data on coasts' landward, shoreline, and seaward permeability. CoPerm accounts for shoreline characteristics such as cliffs and beaches and contains information on four million segments representing more than two million kilometers of global coastline. Rocky Shores are the most abundant shoreline class, followed by mangroves, beaches, and muddy coasts. Permeability differs between the immediate shoreline (median permeability: 10−12.3 m2), the seaward (median: 10−13.3 m2), and the landward (median: 10−13 m2) sides of the coast. CoPerm provides input data for global coastal groundwater assessments and regional studies of submarine groundwater discharge or saltwater intrusion that can radiate into ecological and economic studies. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the relationship between pre-pandemic objective and subjective cognitive functioning and sustained Internet use during the pandemic among older adults in Switzerland. Data from 1299 respondents of the Survey of Health, Ageing and Retirement in Europe (SHARE) in 2019/2020 and a supplementary technology use questionnaire during the pandemic in 2021 were used. Cognitive functioning was assessed in 2019/2020 through objective measures (delayed and immediate memory, verbal fluency) and self-rated memory. Sustained Internet use was defined as having used the Internet at least once in the past seven days in 2019/2020 and reporting daily or weekly use in 2021. We found that 73.1% of respondents consistently used Internet between 2019/2020 and 2021. Using multivariable probit regression models controlling for sociodemographic and health variables, we found that higher global cognition z-scores, especially in immediate and delayed memory, were associated with a higher likelihood of sustained Internet use. Additionally, respondents with good, very good, or excellent self-rated memory were more likely to sustain their Internet use. These findings highlight the potential critical role of cognitive health in shaping older adults' digital engagement, suggesting that cognitive assessments and training should be further considered in digital literacy initiatives for this population. [ABSTRACT FROM AUTHOR]

The development of reliable joining techniques for ceramics and metals is crucial for energy applications, such as fuel cells, nuclear reactors, and high-temperature sensors, most especially for the sealing of hydrothermal sensors to study multiphase flows. However, during one-step active laser brazing it is a serious problem that a high thermal stress concentration can occur at the joint interfaces or on the ceramic side of the joint due to mismatches between the CTEs (coefficients of thermal expansion) and/or elastic constants. The uncontrolled thermal residual stress can lead to cracks and defects in the brazement. In the present work, an elastoplastic finite element method/numerical model was formulated to study the thermal residual stresses developed in the brazement between ceramics and austenitic stainless steel during cooling in active laser brazing. Calculations and comparison experiments were conducted to validate the simulated stress distribution in un-patterned ceramics. Stress analyses were conducted for planar and cylindrical specimen geometries (lab joints) relevant for miniaturized energy sensors. Laser interface patterning was employed to create micro-scale features on ceramic interfaces that reduce thermal stress concentrations. The optimization of the interface designing parameters including hatch size, structure width, pattern depth and metal/ceramic thickness ratio was performed using the Taguchi method with orthogonal arrays. The study suggests that laser interface structuring can modify thermal residual stresses in ceramic-to-metal brazements, thereby increasing the reliability of active brazing joints. [ABSTRACT FROM AUTHOR]

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Copyright of Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Let X be a smooth p -adic formal scheme. We show that integral crystalline local systems on the generic fiber of X are equivalent to prismatic F -crystals over the analytic locus of the prismatic site of X . As an application, we give a prismatic proof of Fontaine's C crys -conjecture, for general coefficients, in the relative setting, and allowing ramified base fields. Along the way, we also establish various foundational results for the cohomology of prismatic F -crystals, including various comparison theorems, Poincaré duality, and Frobenius isogeny. [ABSTRACT FROM AUTHOR]

The incidence of ulcerative colitis (UC) among children and adolescents is rising globally, albeit with notable discrepancies across countries. This systematic review and meta-analysis aims to provide a comprehensive overview of the incidence rates of pediatric UC in various countries and explore potential influencing factors. A systematic literature search was conducted in PubMed and EMBASE (via OVID) for studies published between January 1, 1970, and December 31, 2019. Additionally, a manual search was performed to identify relevant systematic reviews. Meta-analyses and meta-regressions were employed to determine the overall incidence rate and examine potential factors that may influence it. A total of 66 studies were included in the qualitative analysis, while 65 studies were included in the meta-analysis and 50 studies were meta-regression. The study reports a rising incidence of pediatric UC in several countries but significant differences across geographic regions, with no discernible global temporal trend. In addition, our meta-regression analysis showed that geographic location and socioeconomic factors significantly influenced the incidence of UC. Conclusion: Our findings indicate a rising incidence of pediatric UC in numerous countries since 1970, but with significant geographical variation, potentially presenting challenges for respective healthcare systems. We have identified geographic and socioeconomic factors that contribute to the observed heterogeneity in incidence rates. These findings provide a foundation for future research and health policies, aiming to tackle the growing burden of UC among children and adolescents. What is Known: • The incidence of ulcerative colitis in childhood and adolescence appears to be increasing worldwide and varies internationally. • Environmental and lifestyle factors are suspected as potential causes. What is New: • Our results highlight that the heterogeneity in incidence rates can be attributed to geographic and socio-economic factors. [ABSTRACT FROM AUTHOR]

Introduction: The selective serotonin and norepinephrine reuptake inhibitor venlafaxine is among the most prescribed antidepressant drugs worldwide and, according to guidelines, its dose titration should be guided by drug-level monitoring of its active moiety (AM) which consists of venlafaxine (VEN) plus active metabolite O-desmethylvenlafaxine (ODV). This indication of therapeutic drug monitoring (TDM), however, assumes a clear concentration/effect relationship for a drug, which for VEN has not been systematically explored yet. Objectives: We performed a systematic review and meta-analysis to investigate the relationship between blood levels, efficacy, and adverse reactions in order to suggest an optimal target concentration range for VEN oral formulations for the treatment of depression. Methods: Four databases (MEDLINE (PubMed), PsycINFO, Web of Science Core Collection, and Cochrane Library) were systematically searched in March 2022 for relevant articles according to a previously published protocol. Reviewers independently screened references and performed data extraction and critical appraisal. Results: High-quality randomized controlled trials investigating concentration/efficacy relationships and studies using a placebo lead-in phase were not found. Sixty-eight articles, consisting mostly of naturalistic TDM studies or small noncontrolled studies, met the eligibility criteria. Of them, five cohort studies reported a positive correlation between blood levels and antidepressant effects after VEN treatment. Our meta-analyses showed (i) higher AM and (ii) higher ODV concentrations in patients responding to VEN treatment when compared to non-responders (n = 360, k = 5). AM concentration-dependent occurrence of tremor was reported in one study. We found a linear relationship between daily dose and AM concentration within guideline recommended doses (75–225 mg/day). The population-based concentration ranges (25–75% interquartile) among 11 studies (n = 3200) using flexible dosing were (i) 225–450 ng/ml for the AM and (ii) 144–302 ng/ml for ODV. One PET study reported an occupancy of 80% serotonin transporters for ODV serum levels above 85 ng/ml. Based on our findings, we propose a therapeutic reference range for AM of 140–600 ng/ml. Conclusion: VEN TDM within a range of 140 to 600 ng/ml (AM) will increase the probability of response in nonresponders. A titration within the proposed reference range is recommended in case of non-response at lower drug concentrations as a consequence of VEN's dual mechanism of action via combined serotonin and norepinephrine reuptake inhibition. Drug titration towards higher concentrations will, however, increase the risk for ADRs, in particular with supratherapeutic drug concentrations. [ABSTRACT FROM AUTHOR]

Human induced pluripotent stem cells (hiPSCs) offer opportunities to study human biology where primary cell types are limited. CRISPR technology allows forward genetic screens using engineered Cas9-expressing cells. Here, we sought to generate a CRISPR activation (CRISPRa) hiPSC line to activate endogenous genes during pluripotency and differentiation. We first targeted catalytically inactive Cas9 fused to VP64, p65 and Rta activators (dCas9-VPR) regulated by the constitutive CAG promoter to the AAVS1 safe harbor site. These CRISPRa hiPSC lines effectively activate target genes in pluripotency, however the dCas9-VPR transgene expression is silenced after differentiation into cardiomyocytes and endothelial cells. To understand this silencing, we systematically tested different safe harbor sites and different promoters. Targeting to safe harbor sites hROSA26 and CLYBL loci also yielded hiPSCs that expressed dCas9-VPR in pluripotency but silenced during differentiation. Muscle-specific regulatory cassettes, derived from cardiac troponin T or muscle creatine kinase promoters, were also silent after differentiation when dCas9-VPR was introduced. In contrast, in cell lines where the dCas9-VPR sequence was replaced with cDNAs encoding fluorescent proteins, expression persisted during differentiation in all loci and with all promoters. Promoter DNA was hypermethylated in CRISPRa-engineered lines, and demethylation with 5-azacytidine enhanced dCas9-VPR gene expression. In summary, the dCas9-VPR cDNA is readily expressed from multiple loci during pluripotency but induces silencing in a locus- and promoter-independent manner during differentiation to mesoderm derivatives. Researchers intending to use this CRISPRa strategy during stem cell differentiation should pilot their system to ensure it remains active in their population of interest. [ABSTRACT FROM AUTHOR]

Care—concern for and attending to the needs of the particular other we take responsibility—requires enacting time in a way that clashes with the industrial 'clock time' dominating our lives. Ethicists of care have highlighted the tensions between the temporalities involved in caring as a situated, relational and processual practice and the organization of care work according to standardized clock time. Yet, the practice of care work within bureaucratic work organizations seems to reconcile temporal demands of care and clock time. In this article, we build on Barbara Adam's concept of 'timescape' (Adam, Timewatch: The social analysis of time, Polity, 1995; Adam, Time, Polity, 2004) to inquire how care workers juggle apparently conflicting temporalities. Through a participant observation study of a child protection agency in France, we discover that care workers 'trick' time by carving out care timescapes that resist the clock—time as continuous, non-standardized, and in the present moment—while utilizing the structure of clock time in the form of 'scheduling work' to negotiate for and safeguard the process time they needed to ensure the provision of appropriate, ethical care. Confirming the centrality of time to ethical practices in organizations, our study further evidences and elucidates the intricate relations between clock time and process time in the ethical practice of care. [ABSTRACT FROM AUTHOR]

Purpose: Identification of patients at risk of complicated or more severe COVID-19 is of pivotal importance, since these patients might require monitoring, antiviral treatment, and hospitalization. In this study, we prospectively evaluated the SACOV-19 score for its ability to predict complicated or more severe COVID-19. Methods: In this prospective multicenter study, we included 124 adult patients with acute COVID-19 in three German hospitals, who were diagnosed in an early, uncomplicated stage of COVID-19 within 72 h of inclusion. We determined the SACOV-19 score at baseline and performed a follow-up at 30 days. Results: The SACOV-19 score's AUC was 0.816. At a cutoff of > 3, it predicted deterioration to complicated or more severe COVID-19 with a sensitivity of 94% and a specificity of 55%. It performed significantly better in predicting complicated COVID-19 than the random tree-based SACOV-19 predictive model, the CURB-65, 4C mortality, or qCSI scores. Conclusion: The SACOV-19 score is a feasible tool to aid decision making in acute COVID-19. [ABSTRACT FROM AUTHOR]

Anti-IgLON5 disease is a rare neurological, probably autoimmune, disorder associated in many cases with a specific tauopathy. Only a few post-mortem neuropathological studies have been reported so far. Little is known about the pathogenic mechanisms that result in neurodegeneration. We investigated the neuropathology of anti-IgLON5 disease and characterized cellular and humoral inflammation. We included nine cases (six of them previously published). Median age of patients was 71 years (53–82 years), the median disease duration was 6 years (0.5–13 years), and the female to male ratio was 5:4. Six cases with a median disease duration of 9 years presented a prominent tauopathy. Five of them had a classical anti-IgLON5-related brainstem tauopathy and another presented a prominent neuronal and glial 4-repeat tauopathy, consistent with progressive supranuclear palsy (PSP). Three cases with short disease duration (median 1.25 years) only showed a primary age-related neurofibrillary pathology. Inflammatory infiltrates of T and B cells were mild to moderate and did not significantly differ between anti-IgLON5 disease cases with or without tauopathy. In contrast, we found an extensive neuropil deposition of IgG4 in the tegmentum of the brainstem, olivary nucleus, and cerebellar cortex that was most prominent in two patients with short disease duration without the typical IgLON5-related tauopathy. The IgG4 deposits were particularly prominent in the cerebellar cortex and in these regions accompanied by mild IgG1 deposits. Activated complement deposition (C9neo) was absent. Our study indicates that IgLON5-related tau pathology occurs in later disease stages and may also present a PSP-phenotype with exclusively 4-repeat neuronal and glial tau pathology. The prominent deposition of anti-IgLON5 IgG4 at predilection sites for tau pathology suggests that anti-IgLON5 antibodies precede the tau pathology. Early start of immunotherapy might prevent irreversible neuronal damage and progression of the disease, at least in a subgroup of patients. [ABSTRACT FROM AUTHOR]

This study investigated the anaerobic digestion of an algal–bacterial biofilm grown in artificial wastewater in an Algal Turf Scrubber (ATS). The ATS system was located in a greenhouse (50°54′19ʺN, 6°24′55ʺE, Germany) and was exposed to seasonal conditions during the experiment period. The methane (CH4) potential of untreated algal–bacterial biofilm (UAB) and thermally pretreated biofilm (PAB) using different microbial inocula was determined by anaerobic batch fermentation. Methane productivity of UAB differed significantly between microbial inocula of digested wastepaper, a mixture of manure and maize silage, anaerobic sewage sludge, and percolated green waste. UAB using sewage sludge as inoculum showed the highest methane productivity. The share of methane in biogas was dependent on inoculum. Using PAB, a strong positive impact on methane productivity was identified for the digested wastepaper (116.4%) and a mixture of manure and maize silage (107.4%) inocula. By contrast, the methane yield was significantly reduced for the digested anaerobic sewage sludge (50.6%) and percolated green waste (43.5%) inocula. To further evaluate the potential of algal–bacterial biofilm for biogas production in wastewater treatment and biogas plants in a circular bioeconomy, scale-up calculations were conducted. It was found that a 0.116 km2 ATS would be required in an average municipal wastewater treatment plant which can be viewed as problematic in terms of space consumption. However, a substantial amount of energy surplus (4.7–12.5 MWh a−1) can be gained through the addition of algal–bacterial biomass to the anaerobic digester of a municipal wastewater treatment plant. Wastewater treatment and subsequent energy production through algae show dominancy over conventional technologies. [ABSTRACT FROM AUTHOR]

Cardiac output (CO) is a key parameter in diagnostics and therapy of heart failure (HF). The thermodilution method (TD) as gold standard for CO determination is an invasive procedure with corresponding risks. As an alternative, thoracic bioimpedance (TBI) has gained popularity for CO estimation as it is non-invasive. However, systolic heart failure (HF) itself might worsen its validity. The present study validated TBI against TD. In patients with and without systolic HF (LVEF ≤ 50% or > 50% and NT-pro-BNP < 125 pg/ml, respectively) right heart catheterization including TD was performed. TBI (Task Force Monitor©, CNSystems, Graz, Austria) was conducted semi-simultaneously. 14 patients with and 17 patients without systolic HF were prospectively enrolled in this study. In all participants, TBI was obtainable. Bland-Altman analysis indicated a mean bias of 0.3 L/min (limits of agreement ± 2.0 L/min, percentage error or PE 43.3%) for CO and a bias of -7.3 ml (limits of agreement ± 34 ml) for cardiac stroke volume (SV). PE was markedly higher in patients with compared to patients without systolic HF (54% vs. 35% for CO). Underlying systolic HF substantially decreases the validity of TBI for estimation of CO and SV. In patients with systolic HF, TBI clearly lacks diagnostic accuracy and cannot be recommended for point-of-care decision making. Depending on the definition of an acceptable PE, TBI may be considered sufficient when systolic HF is absent. Trial registration number: DRKS00018964 (German Clinical Trial Register, retrospectively registered) [ABSTRACT FROM AUTHOR]

Background: According to major cognitive accounts of panic disorder, bodily sensations can lead to automatic activation of an associative fear network, potentially triggering a cascade of cognitive, emotional, and physiological responses culminating in a panic attack. However, the evidence for the automatic associations assumed by these models is mixed. This may reflect the heterogeneous nature of panic disorder, in that the relative importance of different bodily sensations and symptoms varies between individuals. The current study aimed to test this possibility via measuring the associations between three different sets of panic symptoms (cognitive, respiratory, cardiac) and scores on three symptom-specific single target implicit association tests (STIATs). Methods: A total of 226 unselected female participants aged 18–35 completed the STIATs as well as questionnaires assessing panic symptoms and related measures in a web-based study. Results: Only limited evidence was found to support the idea of specific associations between STIAT stimuli sets and their related panic symptoms. Exploratory analyses indicated that there were only associations between STIAT scores and panic-relevant questionnaires amongst those participants who had experienced a panic attack in the previous 6 months. Conclusions: The results have implications for measuring panic-relevant associations and understanding their role in panic disorder. [ABSTRACT FROM AUTHOR]

This research note presents two replication studies that were conducted during a research-oriented course at Heidelberg University in summer 2022. The first study, initially conducted by Korell, replicates the findings from Albert's original contribution on rebel governance. Albert conducted an explorative study in analyzing the associations between rebel governance and rebel military capacity. Our replication study indicates support for Albert's argument of the relevance of disaggregating rebel governance, while we also show that the original findings are mainly driven by Albert's explorative model specifications. The second study, initially conducted by Reinecke, tests the robustness of Levin et al.'s study on the democratic peacekeeping hypothesis and expands upon the original study by directly testing the "selectorate-theoretic causal mechanism" for the democratic peacekeeping hypothesis. Overall, the replication studies presented in this research note provide interesting findings regarding empirical conflict studies and contribute to ongoing efforts to promote replication initiatives in the education of future political scientists. [ABSTRACT FROM AUTHOR]

Updating beliefs in changing environments can be driven by gradually adapting expectations or by relying on inferred hidden states (i.e. contexts), and changes therein. Previous work suggests that increased reliance on context could underly fear relapse phenomena that hinder clinical treatment of anxiety disorders. We test whether trait anxiety variations in a healthy population influence how much individuals rely on hidden-state inference. In a Pavlovian learning task, participants observed cues that predicted an upcoming electrical shock with repeatedly changing probability, and were asked to provide expectancy ratings on every trial. We show that trait anxiety is associated with steeper expectation switches after contingency reversals and reduced oddball learning. Furthermore, trait anxiety is related to better fit of a state inference, compared to a gradual learning, model when contingency changes are large. Our findings support previous work suggesting hidden-state inference as a mechanism behind anxiety-related to fear relapse phenomena. Here, the authors show that anxiety-related alterations of aversive learning can be understood in terms of a computational model in which anxious humans mentally represent more hidden states as causes of different levels of threats. [ABSTRACT FROM AUTHOR]

Background: Interpretation biases (IBs) are central in panic disorder, and there is rich evidence showing that these are correlated with and predictive of panic-relevant symptomatology. However, experimental studies are needed to examine the potential causal effects of IBs, as predicted by cognitive models. Methods: Panic-related IBs were manipulated via a sentence-completion Cognitive Bias Modification-Interpretation (CBM-I) training. The sample included N = 112 healthy participants reporting moderate levels of fear of bodily sensations. Participants were randomly allocated to a positive, negative, or control CBM-I condition. To test the trainings' effect on panic-relevant cognitive processing, IBs were assessed via proximal and distal measures. Symptom provocation tasks were applied to test transfer to panic-relevant symptomatology. Results: Results on the proximal measure showed that positive CBM-I led to more positive IBs compared to negative, and control training. Further, positive CBM-I led to more positive IBs on the distal measure as compared to negative CBM-I. However, there were no differential training effects on panic-related symptomatology triggered via the provocation tasks. Conclusion: The findings indicate a limited generalization of the effects of CBM-I on IBs and panic-related symptoms. Potential means to improve generalization, such as applying more nuanced measures and combining CBM-I with psychoeducation are discussed. [ABSTRACT FROM AUTHOR]

Sustainability research has increasingly emphasized the importance of value networks in the design and development of sustainable business models (SBM). This is because SBMs must incorporate economic, environmental and social goals to achieve their desired impacts, hence designing such models requires firms to develop an understanding of value creation from the perspective of all key stakeholders in their networks in order to co-create economic, social and ecological value. To advance our understanding of how value network activities shape SBM development, we conducted a longitudinal case study of RECUP, a born sustainable startup with a circular economy business model that has developed and worked with a broad value network to achieve a major reduction in waste from linear consumption. We identify three sets of value network activities that supported the continuous development of the firm's value proposition and contributed to mutual value creation among stakeholders from business, politics and society: B2B-partnering, political agenda-setting and mobilizing end-consumers. Our contributions to research on SBM innovation and design include demonstrating how value network activities initially emerge through experimentation and consolidate over time through iterative learning processes. Such learning and adaption through dynamic value network activities is especially important, we argue, when value-creating factors are not sufficiently known in advance by startups and/or their stakeholders. [ABSTRACT FROM AUTHOR]

The selective serotonin reuptake inhibitor escitalopram (ESC) is indicated for the treatment of major depressive disorder (MDD) and of generalized anxiety disorder (GAD). Monitoring of blood levels (BLs) is strongly indicated due to ESC's high interindividual pharmacokinetic variability. The aim of this study was to analyse clinical efficacy and pharmacokinetic influences on ESC BLs, in patients with depressive disorder alone and with comorbid alcohol or benzodiazepine use disorder. Data were collected from patients treated under naturalistic conditions for whom Therapeutic Drug Monitoring (TDM) was requested to guide antidepressant drug therapy and analysed retrospectively. Particular emphasis was given to patients with alcohol or benzodiazepine use disorder. Responders according to the clinical global impression (CGI) scale were compared with nonresponders for their ESC blood level (BL). The patient sample included 344 patients from 16 psychiatric hospitals in Germany. Influencing factors that could explain 22% of ESC BLs were dose, sex and age. Variability was high between individuals, and doses up to 40 mg were common in real-world settings. Patients treated with ESC monotherapy who responded showed a trend towards higher BLs compared to nonresponders with a concentration of 15 ng/mL separating both groups. Pathological changes in liver function (indicated by elevated GGT in combination with an AST/ALT ratio ≥ 1) resulted in higher dose-corrected ESC concentrations. Influencing factors that could explain 22% of ESC blood levels were dose, sex, and age. Our findings confirm the currently recommended lower threshold level and support the need for standard TDM analyses in everyday clinical practice. The ICD 10 diagnosis alcohol dependence alone does not lead to pharmacokinetic changes in the metabolism of ESC, but altered liver function does. [ABSTRACT FROM AUTHOR]

Developing vascular networks that integrate with the host circulation and support cells engrafted within engineered tissues remains a key challenge in tissue engineering. Most previous work in this field has focused on developing new methods to build human vascular networks within engineered tissues prior to their implant in vivo, with substantively less attention paid to the role of the host in tissue vascularization and engraftment. Here, we assessed the role that different host animal models and anatomic implant locations play in vascularization and cardiomyocyte survival within engineered tissues. We found major differences in the formation of graft-derived blood vessels and survival of cardiomyocytes after implantation of identical tissues in immunodeficient athymic nude mice versus rats. Athymic mice supported robust guided vascularization of human microvessels carrying host blood but relatively sparse cardiac grafts within engineered tissues, regardless of implant site. Conversely, athymic rats produced substantive inflammatory changes that degraded grafts (abdomen) or disrupted vascular patterning (heart). Despite disrupted vascular patterning, athymic rats supported > 3-fold larger human cardiomyocyte grafts compared to athymic mice. This work demonstrates the critical importance of the host for vascularization and engraftment of engineered tissues, which has broad translational implications across regenerative medicine. [ABSTRACT FROM AUTHOR]

Despite the efficacy, safety, and availability of COVID-19 vaccines, a lack of awareness and trust of vaccine safety research remains an important barrier to public health. The goal of this research was to design and test online meta-summaries—transparent, interactive summaries of the state of relevant studies—to improve people's awareness and opinion of vaccine safety research. We used insights from a set of co-design interviews (n = 22) to develop meta-summaries to highlight metascientific information about vaccine safety research. An experiment with 863 unvaccinated participants showed that our meta-summaries increased participants' perception of the amount, consistency, and direction of vaccine safety research relative to the U.S. Center for Disease Control (CDC) webpage, and that participants found them more trustworthy than the CDC page as well. They were also more likely to discuss it with others in the week following. We conclude that direct summaries of scientific research can be a useful communication tool for controversial scientific topics. [ABSTRACT FROM AUTHOR]

Corporate social responsibility (CSR) aspirations by companies have been identified as a motivating factor for active employee participation in CSR implementation. However, a failure to practise what one preaches can backfire and lead to attribution of hypocrisy. Drawing on a qualitative study of an award-winning sustainability pioneer in the cosmetics sector, we explore the role of moral judgement in how and when employees interpret word–deed misalignment in CSR implementation as hypocritical. First, our case reveals that high CSR aspirations by companies raise employees' moral expectations. Second, we develop a framework that explains variations in employees' hypocrisy interpretations based on consequentialist and deontological forms of moral judgement. Our research advances a contextual view of hypocrisy, not as an objective characteristic of an organisation, but as an outcome of interpretative processes of perceived motives and results in CSR implementation. Our framework thereby explains why even highly committed organisations may face accusations of hypocrisy. [ABSTRACT FROM AUTHOR]

Despite the efficacy, safety, and availability of COVID-19 vaccines, a lack of awareness and trust of vaccine safety research remains an important barrier to public health. The goal of this research was to design and test online meta-summaries—transparent, interactive summaries of the state of relevant studies—to improve people's awareness and opinion of vaccine safety research. We used insights from a set of co-design interviews (n = 22) to develop meta-summaries to highlight metascientific information about vaccine safety research. An experiment with 863 unvaccinated participants showed that our meta-summaries increased participants' perception of the amount, consistency, and direction of vaccine safety research relative to the U.S. Center for Disease Control (CDC) webpage, and that participants found them more trustworthy than the CDC page as well. They were also more likely to discuss it with others in the week following. We conclude that direct summaries of scientific research can be a useful communication tool for controversial scientific topics. [ABSTRACT FROM AUTHOR]

Rationale: While one of the basic axioms of pharmacology postulates that there is a relationship between the concentration and effects of a drug, the value of measuring blood levels is questioned by many clinicians. This is due to the often-missing validation of therapeutic reference ranges. Objectives: Here, we present a prototypical meta-analysis of the relationships between blood levels of aripiprazole, its target engagement in the human brain, and clinical effects and side effects in patients with schizophrenia and related disorders. Methods: The relevant literature was systematically searched and reviewed for aripiprazole oral and injectable formulations. Population-based concentration ranges were computed (N = 3,373) and pharmacokinetic influences investigated. Results: Fifty-three study cohorts met the eligibility criteria. Twenty-nine studies report blood level after oral, 15 after injectable formulations, and nine were positron emission tomography studies. Conflicting evidence for a relationship between concentration, efficacy, and side effects exists (assigned level of evidence low, C; and absent, D). Population-based reference ranges are well in-line with findings from neuroimaging data and individual efficacy studies. We suggest a therapeutic reference range of 120–270 ng/ml and 180–380 ng/ml, respectively, for aripiprazole and its active moiety for the treatment of schizophrenia and related disorders. Conclusions: High interindividual variability and the influence of CYP2D6 genotypes gives a special indication for Therapeutic Drug Monitoring of oral and long-acting aripiprazole. A starting dose of 10 mg will in most patients result in effective concentrations in blood and brain. 5 mg will be sufficient for known poor metabolizers. [ABSTRACT FROM AUTHOR]

A social network intervention is a process of intentionally altering a social network to achieve an objective. The objective in question may concern accelerating behaviour change or improving organisational performance. In this work we propose a novel model of social network interventions which considers topological properties of relationships existing between communities. Broadly speaking, topological properties of such relationships include properties described by natural language descriptions such as contains, partial overlap and disjoint. The proposed model provides an abstraction which in many cases is useful for solving problems involving social network interventions. We demonstrate this by simulating interventions on a number of hypothetical and real social networks in the domains of health and security. [ABSTRACT FROM AUTHOR]

Purpose: Concern is growing about long-term side effects of differentiated thyroid cancer treatment, most notably radioactive iodine (RAI) therapy. However, published studies on the subject have had heterogeneous cohorts and conflicting results. This review seeks to provide an updated evaluation of published evidence, and to elucidate the risk of second primary malignancies (SPMs), especially secondary hematologic malignancies (SHMs), attributable to RAI therapy. Methods: An extensive literature search was performed in Ovid MEDLINE, Ovid MEDLINE and In-Process & Other Non-Indexed Citations, Ovid MEDLINE Epub Ahead of Print, Cochrane Central Register of Controlled Trials (CENTRAL) and PubMed. Studies regarding RAI-induced SPMs or a dose–response relationship between RAI therapy and SPMs were identified, 10 of which were eligible for the analysis. We evaluated risk of bias in each study and judged quality of evidence (QOE) across all studies using the Grading of Recommendations, Assessment, Development and Evaluations approach. Results: For the outcome "SPM", the relative effect (relative risk, hazard ratio, or odds ratio) of RAI vs. no RAI ranged from 1.14 to 1.84 across studies, but most results were not statistically significant. For the outcome "SHM", reported relative effects ranged from 1.30 to 2.50, with 2/3 of the studies presenting statistically significant results. In 7/8 of the studies, increased risk for SPM was shown with increasing cumulative RAI activity. QOE was "very low" regarding SPM after RAI and regarding a dose–response relationship, and "low" for SHM after RAI. Conclusion: Based on low quality evidence, an excess risk for the development of SPM cannot be excluded but is expected to be small. [ABSTRACT FROM AUTHOR]

The present study investigates the processing of presuppositions across the life span and extends the findings of the only available study on presupposition processing and typical aging by Domaneschi and Di Paola (J Pragmat 140:70–87, 2019). In an online and offline task, we investigate the impact of cognitive load during the processing and recovery of two presupposition triggers—definite descriptions and change-of-state verbs—comparing a group of younger adults with a group of older adults. The collected experimental data show that (1) presupposition recovery declines during normal aging, (2) presupposition recovery of change-of-state verbs is more cognitively demanding for older adults than the recovery of definite descriptions, and lastly (3) presupposition recovery for the change-of-state verb begin is more demanding than the change-of-state verb stop. As of today, few works have directly investigated presupposition processing across the life span. To the best of our knowledge, this is the first work revealing that cognitive load directly impacts the recovery of presuppositions across the life span, which in turn suggests an involvement of verbal working memory. [ABSTRACT FROM AUTHOR]

Background: When treating patients with epileptic seizures in the emergency room (ER), it is of paramount importance to rapidly assess whether the seizure was acute symptomatic or unprovoked as the former points to a potentially life-threatening underlying condition. In this study, we seek to identify predictors and analyze characteristics of acute symptomatic seizures (ASS). Methods: Data from patients presenting with seizures to highly frequented ERs of two sites of a university hospital were analyzed retrospectively. Seizures were classified as acute symptomatic or unprovoked according to definitions of the International League Against Epilepsy. Univariate and multivariate analysis were conducted to identify predictors; furthermore, characteristics of ASS were assessed. Results: Finally, 695 patients were included, 24.5% presented with ASS. Variables independently associated with ASS comprised male sex (OR 3.173, 95% CI 1.972–5.104), no prior diagnosis of epilepsy (OR 11.235, 95% CI 7.195–17.537), and bilateral/generalized tonic–clonic seizure semiology (OR 2.982, 95% CI 1.172–7.588). Alcohol withdrawal was the most common cause of ASS (74.1%), with hemorrhagic stroke being the second most prevalent etiology. Neuroimaging was performed more often in patients with the final diagnosis of ASS than in those with unprovoked seizures (82.9% vs. 67.2%, p < 0.001). Patients with ASS were more likely to receive acute antiseizure medication in the ER (55.9% vs. 30.3%, p < 0.001). Conclusions: In one quarter of patients presenting to the ER after an epileptic fit, the seizure had an acute symptomatic genesis. The independently associated variables may help to early identify ASS and initiate management of the underlying condition. [ABSTRACT FROM AUTHOR]

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Background: Brain metastases represent a severe complication in many gastrointestinal malignancies especially those arising from the upper gastrointestinal tract, including cancer of the esophagus, gastroesophageal junction, and stomach (GEC). However, there is little knowledge about the onset or potential risk factors for brain metastases (BRMs) in upper gastrointestinal cancers resulting in a lack of screening guidelines for BRMs. Methods: We analyzed 827 patients from our cancer registry suffering from gastroesophageal cancer (GEC) and treated at the University Medical Center Göttingen between January 2013 and December 2019 for the presence of BRMs. Results: From 827 patients with GEC we found 54 patients with BRMs, resulting in an incidence of 6.5%. BRMs are more frequent in male patients (90.74% vs 9.26%, p = 0.0051) and in adenocarcinomas (90.74% vs 9.26%, p = 0.0117). Mean duration for the onset of BRMs from initial cancer diagnoses was 20.9 months in limited disease (curative approach) and 9.3 months in advanced disease (palliative approach) (p = 0.0026). However, early detection of BRMs is a prognostic factor since patients with successful resection of BRMs have a better prognosis compared to those with unresectable BRMs (5.93 vs 2.07 months, p = 0.0091). Conclusion: In this single-center retrospective study, brain metastases (BRMs) occur with a high frequency (6.5%) in gastroesophageal cancer (GEC), significantly more often in male patients and adenocarcinomas. Since survival of these patients considerably correlates with successful BRMs resection, our observations propose further prospective trails to validate our hypothesis and ultimately the implementation of routine screening procedures to detect asymptomatic brain metastases. [ABSTRACT FROM AUTHOR]

This study investigated pretreatment variables associated with depression severity in adolescents following maintenance treatment for major depressive disorder (MDD). Data was derived from the Treatment for Adolescents with Depression Study (TADS). Participants received one of three treatments: cognitive behavioral therapy (CBT), fluoxetine (FLX), or combined CBT and fluoxetine (COMB). Participants received 12 weeks of acute treatment, 6 weeks of consolidation treatment, and 18 weeks of maintenance treatment (N = 327, M age = 14.62 yrs). Outcome was measured by the Children's Depression Rating Scale-Revised. Results showed adolescents with shorter depressive episodes, better global functioning, less suicidal ideation, better health/social functioning, and greater expectancy of positive treatment response were more likely to have lower depression severity following 36 weeks of treatment, regardless of modality. Adolescents with lower initial depression demonstrated lower depression severity if treated with CBT. FLX was more effective in reducing depression severity in adolescents with severe baseline depression than for those with mild or moderate depression. Adolescents with higher family incomes were more likely to have lower depression severity if they received CBT only. In conclusion, adolescents with shorter depressive episodes, better health, social, and global functioning, less suicidal ideation, and greater expectancy for treatment at baseline respond equally well to CBT, fluoxetine, and combined treatment. Adolescents who are more severely depressed at baseline may have a better treatment response if they are treated with FLX; whereas adolescents of higher income are more likely to have a better response if they receive CBT only. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular morbidity and mortality are closely linked to chronic kidney disease (CKD). Sex-specific long-term outcome data of patients with coronary artery disease (CAD) and CKD are scarce. Methods: In the prospective observational multicenter Coronary Artery Disease and REnal Failure (CAD-REF) Registry, 773 (23.1%) women and 2,579 (76.9%) men with angiographically documented CAD and different stages of CKD were consecutively enrolled and followed for up to 8 years. Long-term outcome was evaluated using survival analysis and multivariable Cox-regression models. Results: At enrollment, women were significantly older than men, and suffered from more comorbidities like CKD, hypertension, diabetes mellitus, and multivessel coronary disease. Regarding long-term mortality, no sex-specific differences were observed (Kaplan–Meier survival estimates: 69% in women vs. 69% in men, plog-rank = 0.7). Survival rates decreased from 89% for patients without CKD at enrollment to 72% for patients with CKD stages 1–2 at enrollment and 49% for patients with CKD stages 3–5 at enrollment (plog-rank < 0.001). Cox-regression analysis revealed that sex or multivessel coronary disease were no independent predictors of long-term mortality, while age, CKD stages 3–5, albumin/creatinine ratio, diabetes, valvular heart disease, peripheral artery disease, and left-ventricular ejection fraction were predictors of long-term mortality. Conclusions: Sex differences in CAD patients mainly exist in the cardiovascular risk profile and the extent of CAD. Long-term mortality was not depended on sex or multivessel disease. More attention should be given to treatment of comorbidities such as CKD and peripheral artery disease being independent predictors of death. Clinical Trail Registration ClinicalTrials.gov Identifier: NCT00679419 [ABSTRACT FROM AUTHOR]

Optical investigations of the dynamics of concentrated suspensions, such as in blood flows (Fitzgibbon et al. in Biophys J 108(10):2601–2608, 2015. http://doi/org/10.1016/j.bpj.2015.04.013) or slurry flows (Li et al. in Ocean Eng 163(October 2017):691–705, 2018. http://doi/org/10.1016/j.oceaneng.2018.06.046), are challenging due to reduced optical accessibility. Furthermore, the suspension particle image size can strongly deviate from the optimal particle image size for PIV measurements. Optical accessibility can be achieved by refractive index matching of surface labelled suspension particles. This results in particle images that are transparent in the particle image centre, but fluoresce at the particle image rim, resulting in ring-shaped particle images. In the present study, the influence of the particle image size on the cross-correlation result of such ring-shaped particle images is compared with Gaussian and plateau-shaped particle images. Particles of Gaussian image shape result from fully labelled particles with small image diameters and are commonly used in PIV measurements. Such particles are also utilized for the determination of the continuous phase velocities in the experimental part of the present study. With increasing image diameter, fully labelled particles are observed to assume plateau-shaped particle images. Monte Carlo simulations of synthetically generated images show that ring-shaped particle images have a superior behaviour, i.e. they assume a reduced displacement estimation error for noisy as well as for noise-free image data, compared to Gaussian and plateau-shaped particle images. This is also true for large particle image diameters when particle images are intersected at interrogation window borders or when different values of nonzero particle image displacements are considered. The detectability is similar for all three particle image shapes as long as particles do not intersect with the interrogation window border. Interestingly, for intersected particles of large image diameter, ring-shaped particle images show a slightly improved detectability compared to particle images of Gaussian and plateau shape. Furthermore, the detectability is insensitive against a nonzero particle image displacement. The usage of refractive index matched, ring-shaped particle images results in a good optical accessibility of the suspension. This allows to perform simultaneous cross-correlation evaluations on large ring-shaped particle images and fluid tracers with Gaussian particle images that are two orders of magnitude smaller compared to suspension particle images. Velocity measurements are taken on a suspension containing 5 vol% surface labelled, refractive index matched 60 μ m polymethylmethacrylate (PMMA) particles. Simultaneously, μ PIV measurements of the carrier liquid flow are performed utilizing 1.19 μ m fluorescent polystyrene (PS) particles. Measurement results reveal a parabolic shape of the velocity profiles of both phases with a mean slip velocity of 7.4% at the position of maximum streamwise velocity in a 580 μ m high trapezoidal channel. An error analysis confirms the presence of these slip velocities within a 68.5% confidence interval. A measurement uncertainty in the order of magnitude of O (10 - 1 px) is reached for both fluid tracers and suspension particles. Overall, the present study demonstrates theoretically and experimentally that the usage of suspension particles with ring-shaped images is superior compared to Gaussian and plateau-shaped particle images of the same size. Additionally, the present study demonstrates that the usage of ring-shaped particle images allows to investigate suspension bulk dynamics by measuring velocity fields of both the suspended and the continuous phase simultaneously and with an overall uncertainty that is in the same order of magnitude as for standard μ PIV measurements. [ABSTRACT FROM AUTHOR]

Copyright of Herz is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Buprenorphine is a partial μ-opioid agonist widely used for opioid maintenance therapy (OMT). It is mainly metabolized to pharmacologically active norbuprenorphine by the cytochrome P450 (CYP) isozyme 3A4. This may give rise to drug–drug interactions under combinations with inhibitors or inducers of CYP3A4. Cannabis is a potential inhibitor of CYP3A4, and there is a large degree of concomitant cannabis use among OMT patients. We performed a retrospective analysis on liver healthy OMT patients substituted with buprenorphine, either with (n = 15) or without (n = 17) concomitant use of cannabis. Patients with additional illicit drugs or medications affecting CYP3A were excluded. Measured blood concentrations of buprenorphine and norbuprenorphine were compared between the two groups. Cannabis users and non-users received similar doses, but users had 2.7-fold higher concentrations of buprenorphine (p < 0.01) and 1.4-fold for norbuprenorphine (1.4-fold, p = 0.07). Moreover, the metabolite-to-parent drug ratio was 0.98 in non-users and 0.38 in users (p = 0.02). Female gender did not produce significant effects. These findings indicate that cannabis use decreases the formation of norbuprenorphine and elevates buprenorphine and norbuprenorphine concentrations in blood most probably by inhibition of CYP3A4. The pharmacokinetic interaction may give rise to enhanced or altered opioid activity and risk of intoxications. Physicians should inform patients about this risk and supervise cannabis users by regular control of buprenorphine blood levels, i.e., by therapeutic drug monitoring. [ABSTRACT FROM AUTHOR]

The Siberian mammoth steppe ecosystem changed dramatically with the disappearance of large grazers in the Holocene. The concept of Pleistocene rewilding is based on the idea that large herbivore grazing significantly alters plant communities and can be employed to recreate lost ecosystems. On the other hand, modern rangeland ecology emphasizes the often overriding importance of harsh climates. We visited two rewilding projects and three rangeland regions, sampling a total of 210 vegetation relevés in steppe and surrounding vegetation (grasslands, shrublands and forests) along an extensive climatic gradient across Yakutia, Russia. We analyzed species composition, plant traits, diversity indices and vegetation productivity, using partial canonical correspondence and redundancy analysis. Macroclimate was most important for vegetation composition, and microclimate for the occurrence of extrazonal steppes. Macroclimate and soil conditions mainly determined productivity of vegetation. Bison grazing was responsible for small-scale changes in vegetation through trampling, wallowing and debarking, thus creating more open and disturbed plant communities, soil compaction and xerophytization. However, the magnitude of effects depended on density and type of grazers as well as on interactions with climate and site conditions. Effects of bison grazing were strongest in the continental climate of Central Yakutia, and steppes were generally less affected than meadows. We conclude that contemporary grazing overall has rather limited effects on vegetation in northeastern Siberia. Current rewilding practices are still far from recreating a mammoth steppe, although large herbivores like bison can create more open and drier vegetation and increase nutrient availability in particular in the more continental Central Yakutian Plain. [ABSTRACT FROM AUTHOR]

The emergence and global spread of SARS-CoV-2 has resulted in the urgent need for an in-depth understanding of molecular functions of viral proteins and their interactions with the host proteome. Several individual omics studies have extended our knowledge of COVID-19 pathophysiology1–10. Integration of such datasets to obtain a holistic view of virus–host interactions and to define the pathogenic properties of SARS-CoV-2 is limited by the heterogeneity of the experimental systems. Here we report a concurrent multi-omics study of SARS-CoV-2 and SARS-CoV. Using state-of-the-art proteomics, we profiled the interactomes of both viruses, as well as their influence on the transcriptome, proteome, ubiquitinome and phosphoproteome of a lung-derived human cell line. Projecting these data onto the global network of cellular interactions revealed crosstalk between the perturbations taking place upon infection with SARS-CoV-2 and SARS-CoV at different levels and enabled identification of distinct and common molecular mechanisms of these closely related coronaviruses. The TGF-β pathway, known for its involvement in tissue fibrosis, was specifically dysregulated by SARS-CoV-2 ORF8 and autophagy was specifically dysregulated by SARS-CoV-2 ORF3. The extensive dataset (available at ) highlights many hotspots that could be targeted by existing drugs and may be used to guide rational design of virus- and host-directed therapies, which we exemplify by identifying inhibitors of kinases and matrix metalloproteases with potent antiviral effects against SARS-CoV-2.Multi-omics profiling of effects of SARS-CoV-2 and SARS-CoV on A549, a lung-derived human cell line, produces a dataset enabling identification of common and virus-specific mechanisms of infection. [ABSTRACT FROM AUTHOR]