The impact of direct oral anticoagulants on viscoelastic testing – A systematic review

Background: In case of bleeding patients and in acute care, the assessment of residual direct oral anticoagulant (DOAC) activity is essential for evaluating the potential impact on hemostasis, especially when a timely decision on urgent surgery or intervention is required. Viscoelastic tests are crucial in a modern goal-directed coagulation management to assess patients' coagulation status. However, the role of viscoelastic test to detect and quantify residual DOAC plasma levels is controversially discussed. The aim of this review was to systematically summarize the evidence of viscoelastic tests for the assessment of residual DOAC activity. Method: PubMed, Embase, Scopus, and the Cochrane Library were searched for original articles investigating the effect of rivaroxaban, apixaban, edoxaban, or dabigatran plasma levels on different viscoelastic tests of the adult population from database inception to December 31, 2021. Results: We included 53 studies from which 31 assessed rivaroxaban, 22 apixaban, six edoxaban, and 29 dabigatran. The performance of viscoelastic tests varied across DOACs and assays. DOAC specific assays are more sensitive than unspecific assays. The plasma concentration of rivaroxaban and dabigatran correlates strongly with the ROTEM EXTEM, ClotPro RVV-test or ECA-test clotting time (CT) and TEG 6s anti-factor Xa (AFXa) or direct thrombin inhibitor (DTI) channel reaction time (R). Results of clotting time (CT) and reaction time (R) within the normal range do not reliable exclude relevant residual DOAC plasma levels limiting the clinical utility of viscoelastic assays in this context. Conclusion: Viscoelastic test assays can provide fast and essential point-of-care information regarding DOAC activity, especially DOAC specific assays. The identification and quantification of residual DOAC plasma concentration with DOAC unspecific viscoelastic assays are not sensitive enough, compared to recommended anti-Xa activity laboratory measurements. Systematic review registration: [https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=320629], identifier [CRD42022320629]. Keywords: ClotPro; DOAC; FII inhibitor; FXa inhibitor; ROTEM; TEG; point-of-car

Prevalence of cognitive impairments and strengths in the early course of psychosis and depression.

BACKGROUND Studies investigating cognitive impairments in psychosis and depression have typically compared the average performance of the clinical group against healthy controls (HC), and do not report on the actual prevalence of cognitive impairments or strengths within these clinical groups. This information is essential so that clinical services can provide adequate resources to supporting cognitive functioning. Thus, we investigated this prevalence in individuals in the early course of psychosis or depression. METHODS A comprehensive cognitive test battery comprising 12 tests was completed by 1286 individuals aged 15-41 (mean age 25.07, s.d. 5.88) from the PRONIA study at baseline: HC (N = 454), clinical high risk for psychosis (CHR; N = 270), recent-onset depression (ROD; N = 267), and recent-onset psychosis (ROP; N = 295). Z-scores were calculated to estimate the prevalence of moderate or severe deficits or strengths (>2 s.d. or 1-2 s.d. below or above HC, respectively) for each cognitive test. RESULTS Impairment in at least two cognitive tests was as follows: ROP (88.3% moderately, 45.1% severely impaired), CHR (71.2% moderately, 22.4% severely impaired), ROD (61.6% moderately, 16.2% severely impaired). Across clinical groups, impairments were most prevalent in tests of working memory, processing speed, and verbal learning. Above average performance (>1 s.d.) in at least two tests was present for 40.5% ROD, 36.1% CHR, 16.1% ROP, and was >2 SDs in 1.8% ROD, 1.4% CHR, and 0% ROP. CONCLUSIONS These findings suggest that interventions should be tailored to the individual, with working memory, processing speed, and verbal learning likely to be important transdiagnostic targets

Effects of crystallographic anisotropy on fracture development and acoustic emission in quartz

Transgranular microcracking is fundamental for the initiation and propagation of all fractures in rocks. The geometry of these microcracks is primarily controlled by the interaction of the imposed stress field with the mineral elastic properties. However, the effects of anisotropic elastic properties of minerals on brittle fracture are not well understood. This study examines the effects of elastic anisotropy of quartz on the geometry of brittle fracture and related acoustic emissions (AE) developed during indentation experiments on single crystals at ambient pressure and temperature. A Hertzian cone crack developed during blunt indentation of a single crystal of flawless Brazilian quartz parallel to the c axis shows geometric deviation away from predictions based on the isotropic case, consistent with trigonal symmetry. The visible cone crack penetration depth varies from 3 to 5 mm and apical angle from 53 to 40. Electron backscatter diffraction (EBSD) mapping of the crack tip shows that fracturing initiates along a ~40 μm wide process zone, comprising damage along overlapping en echelon high-index crystallographic planes, shown by discrete bands of reduced electron backscatter pattern (EBSP) quality (band contrast).Coalescence of these surfaces results in a stepped fracture morphology. Monitoring of AE during indentation reveals that the elastic anisotropy of quartz has a significant effect on AE location and focal mechanisms. Ninety-four AE events were recorded during indentation and show an increasing frequency with increasing load. They correspond to the development of subsidiary concentric cracks peripheral to the main cone crack. The strong and complex anisotropy in seismic velocity (~28% Vp, ~43% Vs with trigonal symmetry) resulted in inaccurate and high uncertainty in AE locations using Geiger location routine with an isotropic velocity model. This problem was overcome by using a relative (master event) location algorithm that only requires a priori knowledge of the velocity structure within the source volume. The AE location results correlate reasonably well to the extent of the observed cone crack. Decomposition of AE source mechanisms of the Geiger relocated events shows dominantly end-member behavior between tensile and compressive vector dipole events, with some double-couple-dominated events and no purely tensile or compressive events. The same events located by the master event algorithm yield greater percentage of vector dipole components and no double-couple events, indicating that AE source mechanism solutions can depend on AE location accuracy, and therefore, relocation routine that is utilized. Calculations show that the crystallographic anisotropy of quartz causes apparent deviation of the moment tensors away from double-couple and pure tensile/compressive sources consistent with the observations. Preliminary modeling of calcite anisotropy shows a response distinct from quartz, indicating that the effects of anisotropy on interpreting AE are complex and require detailed further study

Neurobiologically Based Stratification of Recent Onset Depression and Psychosis: Identification of Two Distinct Transdiagnostic Phenotypes

Background Identifying neurobiologically based transdiagnostic categories of depression and psychosis may elucidate heterogeneity, and provide better candidates for predictive modelling. We aimed to identify clusters across patients with recent onset depression (ROD) and recent onset psychosis (ROP) based on structural neuroimaging data. We hypothesized that these transdiagnostic clusters would identify patients with poor outcome and allow more accurate prediction of symptomatic remission than traditional diagnostic structures. Methods HYDRA (HeterogeneitY through DiscRiminant Analysis) was trained on whole brain volumetric measures from 577 participants from the discovery sample of the multi-site PRONIA study to identify neurobiologically driven clusters which were then externally validated in the PRONIA replication sample (n=404) and three datasets of chronic samples (COBRE, n=146; MCIC, n=202; MUC, n=470). Results The optimal clustering solution was two transdiagnostic clusters (Cluster 1, n=153, 67 ROP, 86 ROD and Cluster 2, n=149, 88 ROP, 61 ROD; ARI=.618). The two clusters contained both ROP and ROD. One cluster had widespread GMV deficits, more positive, negative, and functional deficits (impaired cluster) and one cluster revealed a more preserved neuroanatomical signature and more ‘core’ depressive symptomatology (preserved cluster). The clustering solution was internally and externally validated and assessed for clinical utility in predicting 9-month symptomatic remission -outperforming traditional diagnostic structures. Conclusions We identified two transdiagnostic neuroanatomically informed clusters which are clinically and biologically distinct, challenging current diagnostic boundaries in recent onset mental health disorders. These results may aid understanding of aetiology of poor outcome patients transdiagnostically and improve development of stratified treatments

Microseismic Full Waveform Modeling in Anisotropic Media with Moment Tensor Implementation

Seismic anisotropy which is common in shale and fractured rocks will cause travel-time and amplitude discrepancy in different propagation directions. For microseismic monitoring which is often implemented in shale or fractured rocks, seismic anisotropy needs to be carefully accounted for in source location and mechanism determination. We have developed an efficient finite-difference full waveform modeling tool with an arbitrary moment tensor source. The modeling tool is suitable for simulating wave propagation in anisotropic media for microseismic monitoring. As both dislocation and non-double-couple source are often observed in microseismic monitoring, an arbitrary moment tensor source is implemented in our forward modeling tool. The increments of shear stress are equally distributed on the staggered grid to implement an accurate and symmetric moment tensor source. Our modeling tool provides an efficient way to obtain the Green’s function in anisotropic media, which is the key of anisotropic moment tensor inversion and source mechanism characterization in microseismic monitoring. In our research, wavefields in anisotropic media have been carefully simulated and analyzed in both surface array and downhole array. The variation characteristics of travel-time and amplitude of direct P- and S-wave in vertical transverse isotropic media and horizontal transverse isotropic media are distinct, thus providing a feasible way to distinguish and identify the anisotropic type of the subsurface. Analyzing the travel-times and amplitudes of the microseismic data is a feasible way to estimate the orientation and density of the induced cracks in hydraulic fracturing. Our anisotropic modeling tool can be used to generate and analyze microseismic full wavefield with full moment tensor source in anisotropic media, which can help promote the anisotropic interpretation and inversion of field data

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Dopamine-Induced Dysconnectivity Between Salience Network and Auditory Cortex in Subjects With Psychotic-like Experiences: A Randomized Double-Blind Placebo-Controlled Study

Dopamine is involved in the pathophysiology of schizophrenia. Disrupted salience processing by the salience network (SN) may be a central link between dysregulated dopamine function and psychotic symptoms. However, dopaminergic influence on the SN and its presumed influence on psychotic and subpsychotic symptoms or psychotic-like experiences in healthy individuals remain unclear. Therefore, we investigated dopamine-induced changes in functional connectivity of the right anterior insula (rAI), a central SN hub, and their association with psychotic-like experiences. We enrolled 54 healthy, right-handed male subjects in a randomized, double-blind, cross-sectional placebo-controlled experiment. Psychotic-like experiences were assessed using the revised Exceptional Experiences Questionnaire (PAGE-R). They then received either placebo (n = 32) or 200 mg L-DOPA (n = 33), a dopamine precursor, orally and underwent resting-state functional magnetic resonance imaging. In a seed-to-voxel approach, we analyzed dopamine-induced changes in functional connectivity of the rAI and assessed the relationship between functional connectivity changes and PAGE-R score. L-DOPA reduced functional connectivity between the rAI and the left auditory cortex planum polare. In the placebo group, we found a strong negative correlation between PAGE-R score and rAI to planum polare functional connectivity; in the L-DOPA group, there was a strong positive correlation between PAGE-R score and functional connectivity between rAI and planum polare. The PAGE-R score explained about 30% of the functional connectivity variation between rAI and planum polare in the two groups. Our findings suggest that psychotic-like experiences are associated with dopamine-induced disruption of auditory input to the SN, which may lead to aberrant attribution of salience

Dopamine-Induced Dysconnectivity Between Salience Network and Auditory Cortex in Subjects With Psychotic-like Experiences: A Randomized Double-Blind Placebo-Controlled Study

Dopamine is involved in the pathophysiology of schizophrenia. Disrupted salience processing by the salience network (SN) may be a central link between dysregulated dopamine function and psychotic symptoms. However, dopaminergic influence on the SN and its presumed influence on psychotic and subpsychotic symptoms or psychotic-like experiences in healthy individuals remain unclear. Therefore, we investigated dopamine-induced changes in functional connectivity of the right anterior insula (rAI), a central SN hub, and their association with psychotic-like experiences. We enrolled 54 healthy, right-handed male subjects in a randomized, double-blind, cross-sectional placebo-controlled experiment. Psychotic-like experiences were assessed using the revised Exceptional Experiences Questionnaire (PAGE-R). They then received either placebo (n = 32) or 200 mg L-DOPA (n = 33), a dopamine precursor, orally and underwent resting-state functional magnetic resonance imaging. In a seed-to-voxel approach, we analyzed dopamine-induced changes in functional connectivity of the rAI and assessed the relationship between functional connectivity changes and PAGE-R score. L-DOPA reduced functional connectivity between the rAI and the left auditory cortex planum polare. In the placebo group, we found a strong negative correlation between PAGE-R score and rAI to planum polare functional connectivity; in the L-DOPA group, there was a strong positive correlation between PAGE-R score and functional connectivity between rAI and planum polare. The PAGE-R score explained about 30% of the functional connectivity variation between rAI and planum polare in the two groups. Our findings suggest that psychotic-like experiences are associated with dopamine-induced disruption of auditory input to the SN, which may lead to aberrant attribution of salience.ISSN:0586-7614ISSN:1745-170

Schizotypal traits are linked to dopamine-induced striato-cortical decoupling: a randomized double-blind placebo-controlled study

The dopamine hypothesis of schizophrenia implies that alterations in the dopamine system cause functional abnormalities in the brain that may converge to aberrant salience attribution and eventually lead to psychosis. Indeed, widespread brain disconnectivity across the psychotic spectrum has been revealed by resting-state functional magnetic resonance imaging (rs-fMRI). However, the dopaminergic involvement in intrinsic functional connectivity (iFC) and its putative relationship to the development of psychotic spectrum disorders remains partly unclear-in particular at the low-end of the psychosis continuum. Therefore, we investigated dopamine-induced changes in striatal iFC and their modulation by psychometrically assessed schizotypy. Our randomized, double-blind placebo-controlled study design included 54 healthy, right-handed male participants. Each participant was assessed with the Schizotypal Personality Questionnaire (SPQ) and underwent 10 minutes of rs-fMRI scanning. Participants then received either a placebo or 200 mg of L-DOPA, a dopamine precursor. We analyzed iFC of 6 striatal seeds that are known to evoke modulation of dopamine-related networks. The main effect of L-DOPA was a significant functional decoupling from the right ventral caudate to both occipital fusiform gyri. This dopamine-induced decoupling emerged primarily in participants with low SPQ scores, while participants with high positive SPQ scores showed decoupling indifferently of the L-DOPA challenge. Taken together, these findings demonstrate that schizotypal traits may be the result of dopamine-induced striato-occipital decoupling