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Severe SARS-CoV-2 infection1 has been associated with highly inflammatory immune activation since the earliest days of the COVID-19 pandemic2–5. More recently, these responses have been associated with the emergence of self-reactive antibodies with pathologic potential6–10, although their origins and resolution have remained unclear11. Previously, we and others have identified extrafollicular B cell activation, a pathway associated with the formation of new autoreactive antibodies in chronic autoimmunity12,13, as a dominant feature of severe and critical COVID-19 (refs. 14–18). Here, using single-cell B cell repertoire analysis of patients with mild and severe disease, we identify the expansion of a naive-derived, low-mutation IgG1 population of antibody-secreting cells (ASCs) reflecting features of low selective pressure. These features correlate with progressive, broad, clinically relevant autoreactivity, particularly directed against nuclear antigens and carbamylated proteins, emerging 10–15 days after the onset of symptoms. Detailed analysis of the low-selection compartment shows a high frequency of clonotypes specific for both SARS-CoV-2 and autoantigens, including pathogenic autoantibodies against the glomerular basement membrane. We further identify the contraction of this pathway on recovery, re-establishment of tolerance standards and concomitant loss of acute-derived ASCs irrespective of antigen specificity. However, serological autoreactivity persists in a subset of patients with postacute sequelae, raising important questions as to the contribution of emerging autoreactivity to continuing symptomology on recovery. In summary, this study demonstrates the origins, breadth and resolution of autoreactivity in severe COVID-19, with implications for early intervention and the treatment of patients with post-COVID sequelae.

Introduction: Esophagectomy is the mainstay of esophageal cancer treatment, but anastomotic insufficiency related morbidity and mortality remain challenging for patient outcome. Therefore, the objective of this work was to optimize anastomotic technique and gastric conduit perfusion with hyperspectral imaging (HSI) for total minimally invasive esophagectomy (MIE) with linear stapled anastomosis. Material and methods: A live porcine model (n = 58) for MIE was used with gastric conduit formation and simulation of linear stapled side-to-side esophagogastrostomy. Four main experimental groups differed in stapling length (3 vs. 6 cm) and simulation of anastomotic position on the conduit (cranial vs. caudal). Tissue oxygenation around the anastomotic simulation site was evaluated using HSI and was validated with histopathology. Results: The tissue oxygenation (ΔStO₂) after the anastomotic simulation remained constant only for the short stapler in caudal position (−0.4 ± 4.4%, n.s.) while it was impaired markedly in the other groups (short-cranial: −15.6 ± 11.5%, p = 0.0002; long-cranial: −20.4 ± 7.6%, p = 0.0126; long-caudal: −16.1 ± 9.4%, p < 0.0001). Tissue samples from avascular stomach as measured by HSI showed correspondent eosinophilic pre-necrotic changes in 35.7 ± 9.7% of the surface area. Conclusion: Tissue oxygenation at the site of anastomotic simulation of the gastric conduit during MIE is influenced by stapling technique. Optimal oxygenation was achieved with a short stapler (3 cm) and sufficient distance of the simulated anastomosis to the cranial end of the gastric conduit. HSI tissue deoxygenation corresponded to histopathologic necrotic tissue changes. The experimental model with HSI and ML allow for systematic optimization of gastric conduit perfusion and anastomotic technique while clinical translation will have to be proven. in press

Dry reforming of methane (DRM) is considered to be one of the most promising key technologies in the context of a successful carbon dioxide management, since CO2 and CH4 can effectively be utilised to obtain a syngas with a low H2/CO ratio. CO-rich syngas mixtures are an important feedstock for various petrochemical products, such as formic acid, acetic acid, polycarbonates, phosgene, dimethyl ether and oxo products. However, the high endothermicity of the DRM process and the strong deactivation tendency of the DRM catalysts under industrially relevant reaction conditions, mainly driven by sintering and coking, make the industrial large-scale realisation of the DRM process challenging. To overcome these issues, research focussed on catalyst design strategies to prevent coking and sintering, either by targeting the design of the environment of active metal species or by the modification of specific properties of the support material.

From preoperative medications to intraoperative needs to postoperative thromboprophylaxis, anticoagulants are encountered throughout the perioperative period. This review focuses on coagulation testing clinicians utilize to monitor the effects of these medications.

Background Tachycardia-induced cardiomyopathy (TCM) is a reversible and likely underrecognized form of heart failure. Thus, a better understanding of the TCM-pathophysiology is warranted as the underlying early mechanisms that mediate the progression of TCM remain unclear. Purpose This study aimed to identify the cellular mechanisms of TCM. Methods and results Human induced pluripotent stem cell cardiomyocytes (iPSC-CM) were utilized as a translational human-based model. We performed chronic tachycardic (120 bpm) or normofrequent (control, 60bpm) cell culture pacing to study cellular changes during TCM progression. Already after 24h of tachycardic stimulation of iPSC-CM, we detected a decrease in Ca transient amplitude compared to control (Fura-2, n=49/44 cells/9 differentiations). Diastolic Ca levels and cytosolic Ca elimination were not affected after 24h of tachycardia (n=49/44/9). We detected no difference in sarcoplasmic reticulum (SR) Ca load (assessed via caffeine application) or SERCA activity (Ksys-Kcaff) after 24h of tachycardia (n=13/15/5). However, demonstrating the progress of TCM, 7d of tachycardia resulted in progressive decline of Ca transient amplitude together with an impaired Ca elimination, while diastolic Ca concentration was unchanged (n=73/66/8). These changes may underlie the reduced systolic force and impaired relaxation in TCM. We could explain these results by a significantly reduced SR Ca load and a diminished SERCA activity after 7d tachycardia (n=13/7 vs. 13/4). Using confocal microscopy (Fluo-4) we detected no difference in SR Ca spark frequency after 24h of tachycardia (n=82/66/8), while 7d of tachycardia caused an increase of Ca spark frequency (n=76/79/7), which is a typical hallmark of maladaptive remodeling in HF and likely underlie the reduced SR Ca load. Voltage clamp data of late Na current (INaL) showed no difference in INaL after 24h of stimulation (n=17/6 vs. 19/7), whereas INaL was increased after 7d of tachycardia (n=26/7 vs. 19/6). Accordingly, whole-cell current clamp experiments revealed a prolongation of the action potential after 7d of tachycardia compared to control (n=21/6 vs. 19/5), while no difference of action potential duration could be detected after 24h (n=37/31/8). Resting membrane potential and action potential amplitude were not changed. Finally, we investigated tachycardia-mediated effects on explanted human failing hearts. 8h of tachycardic stimulation (120 bpm) of human failing ventricular trabeculae already compromised systolic force, and diastolic tension and relaxation time were markedly increased compared to control (60bpm, n=8/6 trabeculae /7/6 human hearts). Conclusion This study demonstrates that persistent tachycardia adversely alters cardiomyocyte excitation-contraction coupling via electrophysiological cellular remodeling. Our translational investigation in human myocardium may help to understand the pathophysiology of an underrated but prevalent disease. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Else Kröner-Fresenius-Stiftung (EKFS)Deutsche Gesellschaft für Innere Medizin

Background Heart failure with preserved ejection fraction (HFpEF) is a major health problem associated with substantial morbidity and mortality. However, the underlying pathophysiological mechanisms are poorly understood, and effective treatment strategies are scarce. Importantly, SGLT2i, which have been suggested to improve cellular Na and Ca homeostasis in HFrEF, have recently been shown to also improve clinical outcomes in patients with HFpEF. Interestingly, post-hoc analyses of clinical data suggest an involvement of anti-arrhythmic effects of SGLT2i. Purpose We tested, if isolated human atrial cardiomyocytes from patients with HFpEF exhibit an increased Na influx that is responsive to treatment with the SGLT2i empagliflozin (Empa) and if Empa has anti-arrhythmic properties in human atrial trabeculae. Methods Atrial biopsies were obtained from 101 patients undergoing elective cardiac surgery. Na influx was measured as increase in [Na]i during Na/K-ATPase inhibition in isolated cardiomyocytes loaded with the Na-sensitive fluorescence dye Asante Natrium Green–2 AM (ANG-2). Western Blot and HDAC4 pulldown assay were used to investigate NaV1.5 expression/phosphorylation as well as CaMKII expression/autophosphorylation and activity. Anti-arrhythmic effects of Empa were evaluated as the reduction in premature atrial complexes (PACs), which were induced in electrically field-stimulated (1Hz) human atrial trabeculae by superfusion with isoproterenol (100 nM) and high Ca (3.5 mM). Results Compared to patients without heart failure (NF), Na influx was almost doubled in HFpEF patients (NF vs HFpEF: 0.21±0.02 vs 0.38±0.04 mmol/L/min (N=7 vs 18); p=0.005) (Fig. 1D, E). CaMKII expression, CaMKII autophosphorylation, CaMKII activity, and CaMKII-dependent NaV1.5 phosphorylation were significantly increased in atrial biopsies of HFpEF patients, whereas NaV1.5 protein abundance remained unchanged (Fig. 1A–C). Consistent with these results, the increased Na influx was significantly reduced by treatment with the specific CaMKII inhibitor autocamtide-2 related inhibitory peptide (AIP) and the late INa inhibitor tetrodotoxin (TTX) (Fig. 1D, E). Importantly, Empa also abolished the increased Na influx in HFpEF cardiomyocytes (Fig. 1D, E). Multivariate linear regression analysis, adjusting for clinical co-variates, revealed HFpEF to be an independent predictor of cardiomyocyte Na handling. In line with Empa-mediated inhibition of Na influx, the frequency of PACs in human atrial trabeculae was significantly reduced by Empa (Fig. 1F, G). Conclusion This is the first study to demonstrate increased Na influx in human cardiomyocytes from HFpEF patients potentially by an increased CaMKII-dependent NaV1.5 phosphorylation. Excitingly, treatment with Empa decreases this Na influx in HFpEF cardiomyocytes and reduces isoproterenol-induced arrhythmic activity in human atrial trabeculae, which could contribute to the cardioprotective effects of this drug in patients with HFpEF. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Else Kröner-Fresenius-Stiftung,Deutsche Forschungsgemeinschaft

BackgroundPlatelet function testing to monitor antiplatelet therapy is important for reducing thromboembolic complications, yet variability across testing methods remains challenging. Here we evaluated the agreement of four different testing platforms used to monitor antiplatelet effects of aspirin (ASA) or P2Y12 inhibitors (P2Y12-I).MethodsBlood and urine specimens from 20 patients receiving dual antiplatelet therapy were analyzed by light transmission aggregometry (LTA), whole blood aggregometry (WBA), VerifyNow PRUTest and AspirinWorks. Result interpretation based on pre-defined cutoff values was used to calculate raw agreement indices, and Pearson's correlation coefficient determined using individual units of measure.ResultsAgreement between LTA and WBA for P2Y12-I-response was 60% (r = 0.65, high-dose ADP; r = 0.75, low-dose ADP). VerifyNow agreed with LTA in 75% (r = 0.86, high-dose ADP; r = 0.75, low-dose ADP) and WBA in 55% (r = 0.57) of cases. Agreement between LTA and WBA for ASA-response was 45% (r = 0.09, high-dose collagen WBA; r = 0.19, low-dose collagen WBA). AspirinWorks agreed with LTA in 60% (r = 0.32) and WBA in 35% (r = 0.02, high-dose collagen WBA; r = 0.08, low-dose collagen WBA) of cases.ConclusionsOverall agreement varied from 35 to 75%. LTA and VerifyNow demonstrated the highest agreement for P2Y12-I-response, followed by moderate agreement between LTA and WBA. LTA and AspirinWorks showed moderate agreement for aspirin response, while WBA showed the weakest agreement with both LTA and AspirinWorks. The results from this study support the continued use of LTA for monitoring dual antiplatelet therapy, with VerifyNow as an appropriate alternative for P2Y12-I-response. Integration of results obtained from these varied testing platforms with patient outcomes remains paramount for future studies.

Introduction: Observational studies have found an increased risk of hemorrhagic transformation and worse functional outcomes in patients with higher systolic blood pressure variability (BPV). However, the time-varying behavior of BPV after endovascular thrombectomy (EVT) and its effects on functional outcome have not been well characterized. Patients and methods: We analyzed data from an international cohort of patients with large-vessel occlusion stroke who underwent EVT at 11 centers across North America, Europe, and Asia. Repeated time-stamped blood pressure data were recorded for the first 72 h after thrombectomy. Parameters of BPV were calculated in 12-h epochs using five established methodologies. Systolic BPV trajectories were generated using group-based trajectory modeling, which separates heterogeneous longitudinal data into groups with similar patterns. Results: Of the 2041 patients (age 69 ± 14, 51.4% male, NIHSS 15 ± 7, mean number of BP measurements 50 ± 28) included in our analysis, 1293 (63.4%) had a poor 90-day outcome (mRS ⩾ 3) or a poor discharge outcome (mRS ⩾ 3). We identified three distinct SBP trajectories: low (25%), moderate (64%), and high (11%). Compared to patients with low BPV, those in the highest trajectory group had a significantly greater risk of a poor functional outcome after adjusting for relevant confounders (OR 2.2; 95% CI 1.2–3.9; p = 0.008). In addition, patients with poor outcomes had significantly higher systolic BPV during the epochs that define the first 24 h after EVT ( p Discussion and conclusions: Acute ischemic stroke patients demonstrate three unique systolic BPV trajectories that differ in their association with functional outcome. Further research is needed to rapidly identify individuals with high-risk BPV trajectories and to develop treatment strategies for targeting high BPV.

Background While convalescent plasma (CP) may benefit patients with COVID‐19, fundamental questions remain regarding its efficacy, including the components of CP that may contribute to its therapeutic effect. Most current serological evaluation of CP relies on examination of total immunoglobulin or IgG‐specific anti‐SARS‐CoV‐2 antibody levels. However, IgA antibodies, which also circulate and are secreted along the respiratory mucosa, represent a relatively uncharacterized component of CP. Study design and methods Residual samples from patients and CP donors were assessed for IgM, IgG, and IgA anti‐SARS‐CoV‐2 antibody titers against the receptor‐binding domain responsible for viral entry. Symptom onset was obtained by chart review. Results Increased IgA anti‐SARS‐CoV‐2 antibody levels correlated with clinical improvement and viral clearance in an infant with COVID‐19, prompting a broader examination of IgA levels among CP donors and hospitalized patients. Significant heterogeneity in IgA levels was observed among CP donors, which correlated weakly with IgG levels or the results of a commonly employed serological test. Unlike IgG and IgM, IgA levels were also more likely to be variable in hospitalized patients and this variability persisted in some patients >14 days following symptom onset. IgA levels were also less likely to be sustained than IgG levels following subsequent CP donation. Conclusions IgA levels can be very heterogenous among CP donors and hospitalized patients and do not necessarily correlate with commonly employed testing platforms. Examining isotype levels in CP and COVID‐19 patients may allow for a tailored approach when seeking to fill specific gaps in humoral immunity.

Patients critically ill with COVID-19 are at risk for thrombotic events despite prophylactic anticoagulation. Impaired fibrinolysis has been proposed as an underlying mechanism. Our objective was to determine if fibrinolysis stimulated by tissue plasminogen activator (tPA) differed between COVID patients and controls. Plasma from 14 COVID patients on prophylactic heparin therapy was obtained and compared with heparinized plasma from 14 different healthy donors to act as controls. Kaolin activated thromboelastography with heparinase was utilized to obtain baseline measurements and then repeated with the addition of 4 nM tPA. Baseline fibrinogen levels were higher in COVID plasma as measured by maximum clot amplitude (43.6 ± 6.9 mm vs. 23.2 ± 5.5 mm, p

BACKGROUND AND PURPOSE: EmboTrap II is a novel stent retriever with a dual-layer design and distal mesh designed for acute ischemic stroke emergent large-vessel occlusions. We present the first postmarket prospective multicenter experience with the EmboTrap II stent retriever. MATERIALS AND METHODS: A prospective registry of patients treated with EmboTrap II at 7 centers following FDA approval was maintained with baseline patient characteristics, treatment details, and clinical/radiographic follow-up. RESULTS: Seventy patients were treated with EmboTrap II (mean age, 69.9 years; 48.6% women). Intravenous thrombolysis was given in 34.3%, and emergent large-vessel occlusions were located in the ICA (n = 18), M1 (n = 38), M2 or M3 (n = 13), and basilar artery (n = 1). The 5 × 33 mm device was used in 88% of cases. TICI ≥ 2b recanalization was achieved in 95.7% (82.3% in EmboTrap II–only cases), and first-pass efficacy was achieved in 35.7%. The NIHSS score improved from a preoperative average of 16.3 to 12.1 postprocedure and to 10.5 at discharge. An average of 2.5 [SD, 1.8] passes was recorded per treatment, including non-EmboTrap attempts. Definitive treatment was performed with an alternative device (aspiration or stent retriever) in 9 cases (12.9%). Some hemorrhagic conversion was noted in 22.9% of cases, of which 4.3% were symptomatic. There were no device-related complications. CONCLUSIONS: Initial postmarket results with the EmboTrap II stent retriever are favorable and comparable with those of other commercially available stent retrievers. Compared with EmboTrap II, the first-generation EmboTrap may have a higher first-pass efficacy; however, data are limited by retrospective case analysis, incomplete clinical follow-up, and small sample size, necessitating future trials.

The #MeToo movement promotes awareness of the prevalence of sexual victimization, but it has been criticized for overlooking some survivors. The purpose of this qualitative research is to explore 41 U.S. rape victim advocates’ perceptions of the #MeToo movement’s inclusion of or impact on survivors who identify as men. Results indicate that advocates perceive that men are not encouraged to disclose their experiences or become involved in the #MeToo movement. This reflects differences in general societal responses to rape survivors based on gender. Advocates’ perceptions inform the #MeToo movement’s future and possibly the anti-rape movement’s future. The movement’s efforts to recognize the prevalence of sexual victimization and create change through social media activism may fall short without recognition of the experiences of all survivors.

Background Studies of COVID-19 have shown that African Americans have been affected by the virus at a higher rate compared to other races. This cohort study investigated comorbidities and clinical outcomes by race among COVID-19 patients admitted to the intensive care unit. Methods This is a case series of critically ill patients admitted with COVID-19 to an academic healthcare system in Atlanta, Georgia. The study included all critically ill hospitalized patients between March 6, 2020, and May 5, 2020. Clinical outcomes during hospitalization included mechanical ventilation, renal replacement therapy, and mortality stratified by race. Results Of 288 patients included (mean age, 63 ± 16 years; 45% female), 210 (73%) were African American. African Americans had significantly higher rates of comorbidities compared to other races, including hypertension (80% vs 59%, P = 0.001), diabetes (49% vs 34%, P = 0.026), and mean BMI (33 kg/m2 vs 28 kg/m2, P

Given the breath of subspecialties within Clinical Pathology (CP), creating a curriculum with adequate exposure to all areas is challenging. Immunology, coagulation, and HLA rotations have been cited repeatedly by pathology trainees at our institution as targets for improvement. To address these concerns, a combined immunology/ HLA/ coagulation rotation was implemented wherein trainees spend a month exploring testing methods and their interpretations in each of these three different specialized laboratory sections. Herein, we describe the experience of the first 7 trainees (approximately the size of one residency class in our institution) who completed the newly implemented rotation. The rotation combines didactic lectures, assigned reading, time at the bench (to observe procedures), online modules, and case study discussions in each of the areas. The goal was to compare and contrast related concepts/techniques across lab sections. The month is divided so that residents spend the mornings of the first two weeks in HLA, the mornings of the third week in coagulation, and the mornings of the fourth week in immunology. Residents spend afternoons completing assignments and providing narrative interpretations for coagulation tests (such as the Lupus Anticoagulant/Antiphospholipid Antibody test) that they then review with attending physicians. Residents were assessed at the beginning and end of the rotation for their medical knowledge in each area. Additionally, they were provided the opportunity to share their expectations and evaluations of the rotation at its onset and completion, respectively. There was a significant increase in average scores when comparing pre- and post-rotation assessments (46% compared to 78%; p < 0.01) of medical knowledge. Overall, trainees ranked the rotation 4.25 in a Likert scale of 5 and favored the asynchronous eLearning modules (4.7) over discussions in signout (4.29), in person case review (4.43), and assigned reading (4.0). Residents were also asked to rank their comfort in generating reports within each section; they felt more confident with Coagulation profiles (2.86 in a Likert scale out of 3) compared to ANA patterns (2.29) or interpreting HLA results (1.86). Residents described the rotation as “very useful” and “challenging.” Learners cited signing out coagulation cases and exposure to the HLA lab as highlights of the rotation. Coordinating individual schedules across three lab sections was a persistent challenge for trainees. In conclusion, we implemented a new CP rotation combining Coagulation, HLA, and Immunology topics into one month-long rotation. Evaluation of trainees to-date demonstrated an increase in medical knowledge post-rotation compared to pre-rotation, and an overall satisfaction with the rotation based on their feedback. HLA learning modules were restructured in response to limited confidence in HLA report interpretation. Based on the success of the combined rotation, it will become a permanent component of the CP curriculum for all residents.

INTRODUCTION: Frequent and severe bleeding events (SBE) in patients with inherited qualitative platelet disorders Bernard-Soulier Syndrome (BSS) and Glanzmann Thrombasthenia (GT) can lead to secondary iron deficiency anemia (IDA). SBE are primarily treated with platelet transfusions or recombinant activated factor VII (rFVIIa) infusions. The impact of IDA on bleeding management and disease outcomes is understudied. AIM: To evaluate bleeding management, outcomes, and any association with IDA in pediatric patients with BSS and GT. METHODS: Retrospective chart-review of pediatric patients with BSS or GT followed at a single hemophilia treatment center between 2007 and 2019. RESULTS: We identified 14 patients with BSS (n = 2) or GT (n = 12). Patients received rFVIIa (7%), platelet transfusions (7%), or a combination of both (57%) for SBE. Eleven patients (79%) had IDA requiring oral and/or intravenous iron replacement and 50% required red blood cell transfusions. Due to recurrent SBE and refractory IDA, three patients (21%) received rFVIIa prophylaxis at 90 μg/kilogram 2–3 times/week for ≥15 months. Patients initiated on rFVIIa prophylaxis had a median baseline hemoglobin of 9.8 g/dL (min-max: 8.0–10.7 g/dL) compared to 11.7 g/dL (8.4–13.8 g/dL) for patients treated on-demand. Following initiation of rFVIIa prophylaxis, median hemoglobin and ferritin increased by 1.3 g/dL (0.7–2.5 g/dL) and 14.6 ng/mL (0.2–42.9 ng/mL), respectively, and bleeding rates were reduced by 7–78%. CONCLUSION: IDA is a known complication of recurrent bleeding events in individuals with inherited bleeding disorders. Routine monitoring for IDA may help improve bleeding management and reduce bleed burden in BSS/GT.

The coronavirus disease (COVID-19) pandemic has threatened millions of lives worldwide with severe systemic inflammation, organ dysfunction, and thromboembolic disease. Within our institution, many critically ill COVID-19 positive patients suffered major thrombotic events, prompting our clinicians to evaluate hypercoagulability outside of traditional coagulation testing.We determined the prevalence of fibrinolysis shutdown via rotational thromboelastometry (ROTEM, Instrumentation Laboratories, Bedford, MA) in patients admitted to the intensive care unit (ICU) over a period of 3 weeks. In 21 patients who had a ROTEM test, we found that eleven (52.4%) met the criteria for fibrinolysis shutdown. Nine patients (42.9%) were diagnosed with venous thromboembolic (VTE) events during their admission. Eight of 9 (89%) of the VTE patients met criteria for fibrinolysis shutdown.Given the high rate of fibrinolysis shutdown in these patients, our data support using viscoelastic testing to evaluate for the presence of impaired fibrinolysis. This may help identify patient subsets who might benefit from the administration of fibrinolytics.

Catalina Basin, located within the southern California Inner Continental Borderland (ICB), United States, is traversed by two active submerged fault systems that are part of the broader North America–Pacific plate boundary: the San Clemente fault (along with a prominent splay, the Kimki fault) and the Catalina fault. Previous studies have suggested that the San Clemente fault (SCF) may be accommodating up to half of the ∼8 mm/yr right-lateral slip distributed across the ICB between San Clemente Island and the mainland coast, and that the Catalina fault (CF) acts as a significant restraining bend in the larger transform system. Here, we provide new high-resolution geophysical constraints on the seabed morphology, deformation history, and kinematics of the active faults in and on the margins of Catalina Basin. We significantly revise SCF mapping and describe a discrete releasing bend that corresponds with lows in gravity and magnetic anomalies, as well as a connection between the SCF and the Santa Cruz fault to the north. Subsurface seismic-reflection data show evidence for a vertical SCF with significant lateral offsets, while the CF exhibits lesser cumulative deformation with a vertical component indicated by folding adjacent to the CF. Geodetic data are consistent with SCF right-lateral slip rates as high as ∼3.6 mm/yr and transpressional convergence of

Background The targeted use of endovascular therapy (EVT), with or without intravenous thrombolysis (IVT) in acute large cerebral vessel occlusion stroke (LVOS) has been proven to be superior compared to IVT alone. Despite favorable functional outcome, many patients complain about cognitive decline after EVT. If IVT in addition to EVT has positive effects on cognitive function is unclear. Methods We analyzed data from the German Stroke Registry (GSR, an open, multicenter and prospective observational study) and compared cognitive function 90 days after index ischemic stroke using MoCA in patients with independent (mRS ≤ 2 pts) and excellent (mRS = 0 pts) functional outcome receiving combined EVT and IVT (EVT + IVT) vs. EVT alone (EVT-IVT). Results Of the 2636 GSR patients, we included 166 patients with mRS ≤ 2 at 90 days in our analysis. Of these, 103 patients (62%) received EVT + IVT, 63 patients (38%) were treated with EVT alone. There was no difference in reperfusion status between groups (mTICI ≥ 2b in both groups at 95%, p = 0.65). Median MoCA score in the EVT + IVT group was 20 pts. (18–25 IQR) vs. 18 pts. (16–21 IQR) in the EVT-IVT group (p = 0.014). There were more patients with cognitive impairment (defined as MoCA p = 0.033, B = 2.39; mRS = 0: p = 0.021, B = 4.38). Conclusions In Patients with good functional outcome after LVOS, rates of cognitive impairment are lower with combined EVT and IVT compared to EVT alone. Trial registration ClinicalTrials.gov Identifier: NCT03356392.

New high-resolution datasets across La Jolla submarine fan, offshore California, illuminate low-relief, down-dip widening conduits emanating from a deep-sea channel that deposited a combination of laterally extensive sand strata seemingly crisscrossed by distributary patterns. Extensive coverage of this sector of the seafloor shows submarine-fan architecture and morphologies essentially different than distributary channelized patterns characteristic of subaerial systems and previous conceptual models of submarine fans. The main La Jolla channel, connected to La Jolla Canyon, loses confinement by widening, decreasing in relief, and developing scoured margins across kilometers-long down-slope and lateral distances. Two scales of distributary patterns are associated with sand-rich deposits down-system from, and outside of, fully formed channels. A larger-scale distributary pattern is identified in backscatter and bathymetry from trains of preferential erosion associated with laterally continuous repetitive steps that extend for kilometers outside channel confinement and may represent net erosional upper-flow-regime transitional bedforms. Smaller-scale distributary backscatter patterns in unconfined sand-rich deposits originate from the wide, low-relief channel. We suggest that the newly imaged La Jolla seascape displays sedimentary features that may be common on deep-sea fans but missed in previous lower resolution studies of submarine fans. Thus, La Jolla provides the basis for integrating previously enigmatic and (or) incomplete images of submarine fans. High-resolution seafloor, subsurface, and sample datasets highlight the importance of channel widening, headward erosion, and unconfined flows in La Jolla submarine-fan development, and may be relevant to other sandy submarine fan systems.

This research examines how college students’ fear of crime and perception of safety at a university relates to prior victimization, knowledge of others’ victimization, perception of likelihood of v...

Supplemental Digital Content is available in the text., OBJECTIVES: Body temperature trajectories of infected patients are associated with specific immune profiles and survival. We determined the association between temperature trajectories and distinct manifestations of coronavirus disease 2019. DESIGN: Retrospective observational study. SETTING: Four hospitals within an academic healthcare system from March 2020 to February 2021. PATIENTS: All adult patients hospitalized with coronavirus disease 2019. INTERVENTIONS: Using a validated group-based trajectory model, we classified patients into four previously defined temperature trajectory subphenotypes using oral temperature measurements from the first 72 hours of hospitalization. Clinical characteristics, biomarkers, and outcomes were compared between subphenotypes. MEASUREMENTS AND MAIN RESULTS: The 5,903 hospitalized coronavirus disease 2019 patients were classified into four subphenotypes: hyperthermic slow resolvers (n = 1,452, 25%), hyperthermic fast resolvers (1,469, 25%), normothermics (2,126, 36%), and hypothermics (856, 15%). Hypothermics had abnormal coagulation markers, with the highest d-dimer and fibrin monomers (p < 0.001) and the highest prevalence of cerebrovascular accidents (10%, p = 0.001). The prevalence of venous thromboembolism was significantly different between subphenotypes (p = 0.005), with the highest rate in hypothermics (8.5%) and lowest in hyperthermic slow resolvers (5.1%). Hyperthermic slow resolvers had abnormal inflammatory markers, with the highest C-reactive protein, ferritin, and interleukin-6 (p < 0.001). Hyperthermic slow resolvers had increased odds of mechanical ventilation, vasopressors, and 30-day inpatient mortality (odds ratio, 1.58; 95% CI, 1.13–2.19) compared with hyperthermic fast resolvers. Over the course of the pandemic, we observed a drastic decrease in the prevalence of hyperthermic slow resolvers, from representing 53% of admissions in March 2020 to less than 15% by 2021. We found that dexamethasone use was associated with significant reduction in probability of hyperthermic slow resolvers membership (27% reduction; 95% CI, 23–31%; p < 0.001). CONCLUSIONS: Hypothermics had abnormal coagulation markers, suggesting a hypercoagulable subphenotype. Hyperthermic slow resolvers had elevated inflammatory markers and the highest odds of mortality, suggesting a hyperinflammatory subphenotype. Future work should investigate whether temperature subphenotypes benefit from targeted antithrombotic and anti-inflammatory strategies.

The near-bed section of submarine gravity flows travels at the highest and most destructive speeds making direct measurements of this region of the flow difficult. Here results are presented from “boulder-like” Benthic Event Detectors (BEDs) that measured their own rotation, depth and temperature while carried within the near-bed region of gravity flows. BEDs were deployed in Monterey Canyon from 200 to 500 m water depth for 18 months (2016–2017) during the Coordinated Canyon Experiment. BEDs moved in 10 out of 14 gravity flows that transited the upper canyon. BEDs moved within the body of the flow because the initial velocities of the BEDs were 66 ± 16% (1 SD) of the flow transit velocities. BEDs rotated freely during most of their first moves and gained depth faster than in later moves, when their motion was more random and wobblier. The differences in BED motions between first and later moves suggest BEDs moved at different depths within the flow. The inferred near-bed flow structure is strongly stratified with a fast, less-dense layer moving above a slower and denser layer. Coherent changes between pressure and acceleration indicate that BEDs rode a crescent shaped bedform (CSB) morphology that persisted throughout flow events. The variability in BED speeds while riding the CSB morphology indicates a fluid-like nature of the near-bed layer. BED motions ended after being caught in the trough of a CSB. Based on recorded temperature decay rates after flow events, the thickness of redeposited sediment is 2–3 m.

Contains fulltext : 249977.pdf (Publisher’s version ) (Closed access) BACKGROUND: It is important to evaluate whether a new treatment for heart failure with reduced ejection fraction (HFrEF) provides additive benefit to background foundational treatments. As such, we aimed to evaluate the efficacy and safety of empagliflozin in patients with HFrEF in addition to baseline treatment with specific doses and combinations of disease-modifying therapies. METHODS: We performed a post-hoc analysis of the EMPEROR-Reduced randomised, double-blind, parallel-group trial, which took place in 520 centres (hospitals and medical clinics) in 20 countries in Asia, Australia, Europe, North America, and South America. Patients with New York Heart Association (NYHA) classification II-IV with an ejection fraction of 40% or less were randomly assigned (1:1) to receive the addition of either oral empagliflozin 10 mg per day or placebo to background therapy. The primary composite outcome was cardiovascular death and heart failure hospitalisation; the secondary outcome was total heart failure hospital admissions. An extended composite outcome consisted of inpatient and outpatient HFrEF events was also evaluated. Outcomes were analysed according to background use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) or angiotensin receptor neprilysin inhibitors (ARNIs), as well as β blockers and mineralocorticoid receptor antagonists (MRAs) at less than 50% or 50% or more of target doses and in various combinations. This study is registered with ClinicalTrials.gov, NCT03057977. FINDINGS: In this post-hoc analysis of 3730 patients (mean age 66·8 years [SD 11·0], 893 [23·9%] women; 1863 [49·9%] in the empagliflozin group, 1867 [50·1%] in the placebo group) assessed between March 6, 2017, and May 28, 2020, empagliflozin reduced the risk of the primary outcome (361 in 1863 participants in the empagliflozin group and 462 of 1867 in the placebo group; HR 0·75 [95% CI 0·65-0·86]) regardless of background therapy or its target doses for ACE inhibitors or ARBs at doses of less than 50% of the target dose (HR 0·85 [0·69-1·06]) and for doses of 50% or more of the target dose (HR 0·67 [0·52-0·88]; p(interaction)=0·18). A similar result was seen for β blockers at doses of less than 50% of the target dose (HR 0·66 [0·54-0·80]) and for doses of 50% or more of the target dose (HR 0·81 [0·66-1·00]; p(interaction)=0·15). Empagliflozin also reduced the risk of the primary outcome irrespective of background use of triple therapy with an ACE inhibitor, ARB, or ARNI plus β blocker plus MRA (given combination HR 0·73 [0·61-0·88]; not given combination HR 0·76 [0·62-0·94]; p(interaction)=0·77). Similar patterns of benefit were observed for the secondary and extended composite outcomes. Empagliflozin was well tolerated and rates of hypotension, symptomatic hypotension, and hyperkalaemia were similar across all subgroups. INTERPRETATION: Empagliflozin reduced serious heart failure outcomes across doses and combinations of disease-modifying therapies for HFrEF. Clinically, these data suggest that empagliflozin might be considered as a foundational therapy in patients with HFrEF regardless of their existing background therapy. FUNDING: Boehringer Ingelheim and Eli Lilly and Company.