Non-stationary Gaussian Process Surrogates

We provide a survey of non-stationary surrogate models which utilize Gaussian processes (GPs) or variations thereof, including non-stationary kernel adaptations, partition and local GPs, and spatial warpings through deep Gaussian processes. We also overview publicly available software implementations and conclude with a bake-off involving an 8-dimensional satellite drag computer experiment. Code for this example is provided in a public git repository.Comment: 13 pages, 5 figure

Vecchia-approximated Deep Gaussian Processes for Computer Experiments

Deep Gaussian processes (DGPs) upgrade ordinary GPs through functional composition, in which intermediate GP layers warp the original inputs, providing flexibility to model non-stationary dynamics. Two DGP regimes have emerged in recent literature. A “big data” regime, prevalent in machine learning, favors approximate, optimization-based inference for fast, high-fidelity prediction. A “small data” regime, preferred for computer surrogate modeling, deploys posterior integration for enhanced uncertainty quantification (UQ). We aim to bridge this gap by expanding the capabilities of Bayesian DGP posterior inference through the incorporation of the Vecchia approximation, allowing linear computational scaling without compromising accuracy or UQ. We are motivated by surrogate modeling of simulation campaigns with upwards of 100,000 runs – a size too large for previous fully-Bayesian implementations – and demonstrate prediction and UQ superior to that of “big data” competitors. All methods are implemented in the deepgp package on CRAN.</p

The Effect of Transoesophageal Echocardiography on Treatment Change in a High-Volume Stroke Unit

Background and purpose—current guidelines recommend the use of transesophageal echocardiography (TEE) in relation to cardio-embolic sources of stroke. Methods—by using an hospital-based cohort, we retrospectively analyzed consecutive patients with acute ischemic stroke (AIS), acute hemorrhagic stroke (AHS) and transient ischemic attack (TIA) who were admitted in Strasbourg Stroke Center, France between November 2017 to December 2018. TEE reports were screened for detection of potential cardiac sources of embolism and the subsequent change in medical management. We performed univariate and multivariate analyses to identify predictors of relevant TEE findings. Results-out of the 990 patients admitted with confirmed stroke, 432 patients (42.6%) underwent TEE. Patients with TEE were younger (62.8 ± 14.8 vs. 73.8, p p Rankin Scale (1 IQR (0–1) vs. 1 (0–3), p p p = 0.01), previous TIA (HR: 7.830, CI 95% 2214 to 27,689; p = 0.001) and superficial middle cerebral artery territory infarction (HR: 2.774, CI 95% 1.168–6.589; p = 0.021) were strong independent predictors with change in medical management following TEE. Conclusions—additional TEE changed the medical course of stroke patients in 7.1% in a French high-volume stroke unit

Life-threatening arrhythmias in anterior ST-segment elevation myocardial infarction patients treated by percutaneous coronary intervention: adverse impact of morphine

International audienceAims: Important controversies remain concerning the determinants of life-threatening arrhythmias during ST-segment elevation myocardial infarction (STEMI) and their impact on late adverse events. This study sought to investigate which factors might facilitate ventricular tachycardia (VT) and ventricular fibrillation (VF), in a homogeneous population of anterior STEMI patients defined by abrupt left anterior descending coronary artery (LAD) occlusion and no collateral flow.Methods and results: The 967 patients, who entered into the CIRCUS (Does Cyclosporine ImpRove Clinical oUtcome in ST elevation myocardial infarction patients) study, were assessed for further analysis. Acute VT/VF was defined as VT (run of tachycardia >30 s either self-terminated or requiring electrical/pharmacological cardioversion) or VF documented by electrocardiogram or cardiac monitoring, during transportation to the cathlab or initial hospitalization. VT/VF was documented in 136 patients (14.1%). Patients with VT/VF were younger and had shorter time from symptom onset to hospital arrival. Site of LAD occlusion, thrombus burden, area at risk, pre-percutaneous coronary intervention Thrombolysis in Myocardial Infarction flow, and ST-segment resolution were similar to that of patients without VT/VF. There was no impact of VT/VF on left ventricular remodelling or clinical outcomes. By multivariate analysis, the use of morphine (odds ratio 1.71; 95% confidence interval (1.13-2.60); P = 0.012) was the sole independent predictor of VT/VF occurrence.Conclusions: In STEMI patients with LAD occlusion, our findings support the view that morphine could favour severe ventricular arrhythmias

5 '-AMP impacts lymphocyte recirculation through activation of A(2B) receptors

<p>Natural hibernation consists of torpid phases with metabolic suppression alternating with euthermic periods. Induction of torpor holds substantial promise in various medical conditions, including trauma, major surgery, and transplantation. Torpor in mice can be induced pharmacologically by 5-AMP. Previously, we showed that during natural torpor, the reduction in body temperature results in lymphopenia via a reduction in plasma S1P. Here, we show that during torpor induced by 5-AMP, there is a similar reduction in the number of circulating lymphocytes that is a result of their retention in secondary lymphoid organs. This lymphopenia could be mimicked by engagement of A(2B)Rs by a selective A(2B)R agonist (LUF6210) in the absence of changes in temperature and prevented by A(2B)R antagonists during 5-AMP-induced torpor. In addition, forced cooling of mice led to peripheral blood lymphopenia, independent of A(2B)R signaling. The induction of torpor using 5-AMP impacted the migration of lymphocytes within and between secondary lymphoid organs. During torpor, the homing into LNs was impaired, and two-photon intravital microscopy revealed that cell motility was decreased significantly and rapidly upon 5-AMP administration. Furthermore, the S1P plasma concentration was reduced by 5-AMP but not by LUF6210. S1P plasma levels restored upon arousal. Likely, the reduced migration in LNs combined with the reduced S1P plasma level substantially reduces lymphocyte egress after injection of 5-AMP. In conclusion, 5-AMP induces a state of pharmacological torpor in mice, during which, lymphopenia is governed primarily by body temperature-independent suppression of lymphocyte egress from LNs.</p>

Phase 1 clinical trial of CRISPR-engineered CAR19 universal T cells for treatment of children with refractory B cell leukemia

Copyright © 2022 The Authors, some rights reserved.Genome editing of allogeneic T cells can provide “off-the-shelf” alternatives to autologous chimeric antigen receptor (CAR) T cell therapies. Disruption of T cell receptor α chain (TRAC) to prevent graft-versus-host disease (GVHD) and removal of CD52 (cluster of differentiation 52) for a survival advantage in the presence of alemtuzumab have previously been investigated using transcription activator–like effector nuclease (TALEN)-mediated knockout. Here, we deployed next-generation CRISPR-Cas9 editing and linked CAR expression to multiplexed DNA editing of TRAC and CD52 through incorporation of self-duplicating CRISPR guide RNA expression cassettes within the 3’ long terminal repeat of a CAR19 lentiviral vector. Three cell banks of TT52CAR19 T cells were generated and cryopreserved. A phase 1, open-label, non-randomized clinical trial was conducted and treated six children with relapsed/refractory CD19-positive B cell acute lymphoblastic leukemia (B-ALL) (NCT04557436). Lymphodepletion included fludarabine, cyclophosphamide, and alemtuzumab and was followed by a single infusion of 0.8 × 106 to 2.0 × 106 CAR19 T cells per kilogram with no immediate toxicities. Four of six patients infused with TT52CAR19 T cells exhibited cell expansion, achieved flow cytometric remission, and then proceeded to receive allogeneic stem cell transplantation. Two patients required biological intervention for grade II cytokine release syndrome, one patient developed transient grade IV neurotoxicity, and one patient developed skin GVHD, which resolved after transplant conditioning. Other complications were within expectations, and primary safety objectives were met. This study provides a demonstration of the feasibility, safety, and therapeutic potential of CRISPR-engineered immunotherapy.11Nsciescopu