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This trial revisited research conducted about a decade ago that showed a survival benefit with early neuromuscular blockade in patients with acute respiratory distress syndrome. The new trial did not show a benefit with neuromuscular blockade with respect to overall survival or other clinical outcomes.

Expansion and differentiation of antigen-experienced PD-1 + TCF-1 + stem-like CD8 + T cells into effector cells is critical for the success of immunotherapies based on PD-1 blockade 1 – 4 . Hashimoto et al. have shown that, in chronic infections, administration of the cytokine interleukin (IL)-2 triggers an alternative differentiation path of stem-like T cells towards a distinct population of ‘better effector’ CD8 + T cells similar to those generated in an acute infection 5 . IL-2 binding to the IL-2 receptor α-chain (CD25) was essential in triggering this alternative differentiation path and expanding better effectors with distinct transcriptional and epigenetic profiles. However, constitutive expression of CD25 on regulatory T cells and some endothelial cells also contributes to unwanted systemic effects from IL-2 therapy. Therefore, engineered IL-2 receptor β- and γ-chain (IL-2Rβγ)-biased agonists are currently being developed 6 – 10 . Here we show that IL-2Rβγ-biased agonists are unable to preferentially expand better effector T cells in cancer models and describe PD1-IL2v, a new immunocytokine that overcomes the need for CD25 binding by docking in cis to PD-1. Cis binding of PD1-IL2v to PD-1 and IL-2Rβγ on the same cell recovers the ability to differentiate stem-like CD8 + T cells into better effectors in the absence of CD25 binding in both chronic infection and cancer models and provides superior efficacy. By contrast, PD-1- or PD-L1-blocking antibodies alone, or their combination with clinically relevant doses of non-PD-1-targeted IL2v, cannot expand this unique subset of better effector T cells and instead lead to the accumulation of terminally differentiated, exhausted T cells. These findings provide the basis for the development of a new generation of PD-1 cis -targeted IL-2R agonists with enhanced therapeutic potential for the treatment of cancer and chronic infections. Binding of the PD1-IL2v immunocytokine to PD-1 and IL-2Rβγ on the same cell leads to an alternative differentiation of stem-like CD8 + T cells into better effectors rather than exhausted T cells in models of both chronic infection and cancer.

Purpose To investigate whether neuromuscular blocking agents (NMBA) exert beneficial effects in acute respiratory distress syndrome (ARDS) by reason of their action on respiratory mechanics, particularly transpulmonary pressures ( P L ). Methods A prospective randomised controlled study in patients with moderate to severe ARDS within 48 h of the onset of ARDS. All patients were monitored by means of an oesophageal catheter and followed up for 48 h. Moderate ARDS patients were randomised into two groups according to whether they were given a 48-h continuous infusion of cisatracurium besylate or not (control group). Severe ARDS patients did not undergo randomisation and all received cisatracurium besylate per protocol. The changes during the 48-h study period in oxygenation and in respiratory mechanics, including inspiratory and expiratory P L and driving pressure, were assessed and compared. Delta P L (∆ P L ) was defined as inspiratory P L minus expiratory P L . Results Thirty patients were included, 24 with moderate ARDS and 6 with severe ARDS. NMBA infusion was associated with an improvement in oxygenation in both moderate and severe ARDS, accompanied by a decrease in both plateau pressure and total positive end-expiratory pressure. The mean inspiratory and expiratory P L were higher in the moderate ARDS group receiving NMBA than in the control group. In contrast, there was no change in either driving pressure or ∆ P L related to NMBA administration. Conclusions NMBA could exert beneficial effects in patients with moderate ARDS, at least in part, by limiting expiratory efforts.

The investigators induced muscle paralysis in patients with the acute respiratory distress syndrome (ARDS) by administering a neuromuscular blocking agent, cisatracurium besylate. As compared with placebo, cisatracurium resulted in a lower adjusted 90-day mortality without more severe sequelae of neuromuscular blockade. The acute respiratory distress syndrome (ARDS) is characterized by hypoxemic respiratory failure; it affects both medical and surgical patients. 1 Despite rigorous physiological management, 2 in most studies, ARDS has been fatal in 40 to 60% of patients. 3 – 7 Neuromuscular blocking agents are used in a large but highly variable proportion of patients with ARDS. 8 – 12 Current guidelines indicate that neuromuscular blocking agents are appropriate for facilitating mechanical ventilation when sedation alone is inadequate, most notably in patients with severe gas-exchange impairments. 10 In a four-center randomized, controlled trial of gas exchange in 56 patients with ARDS, 13 infusion of a neuromuscular blocking agent . . .

This Letter proposes a combination of target detection and blockmatching 3D filter for despeckling SAR images. The proposed method is able to effectively preserve targets, such as the edges and dots of synthetic aperture radar (SAR) images, whilst removing noises. In the first step of our proposed method, based on despekling results of bilateral filtering and edge detection of a canny operator, some targets are detected and removed from an SAR image. The second step uses BM3D for denoising the targets-removed image. Finally, the removed targets are added to the despeckled targetsremoved image and desirable results can be achieved. [PUBLICATION ABSTRACT]

Proposed is a cooperation scheme for a system with full-duplex relays. The transmission over one frame from the source and the relay nodes is coordinated so that the effective channel matrix at the destination is block circulant. By using the low complexity block discrete Fourier transform the effective channel is transformed into a block diagonal matrix and the additional diversity gains are extracted with significantly lower computational complexity of the spatial processing. The scheme requires additional pilot overhead for the estimation of channel state information and additional time slots for the initial exchange of data between the source, the destination and the relay nodes. [PUBLICATION ABSTRACT]

Typical blocking indices in longitude or both longitude and latitude are compared to demonstrate: (1) the central blocking latitude (CBL) should be any of 40–80° N; (2) reversals of meridional gradients in absolute fields (ABS) about specified CBLs or in combination with time anomalies exceeding a threshold missed blocking patterns or misidentified non-blocking structures. Blocking highs are identified by a new Eddy-ABS index. A large-scale high is represented by a local maximum of zonal eddy anomalies, its immediately surrounding points and subsequent contiguous grids with decreasing anomalies but exceeding the 75th percentile. A high with any ABS reversal is an instantaneous blocking (IB). Maximum overlapping IBs become quasi-stationary when moving less than 10° longitudes per day. Four and more quasi-stationary IBs form a blocking event (BE). This unified index has identified IBs and BEs at vertical levels in the Northern (NH) and Southern Hemispheres (SH) during different seasons. In the NH, BEs exhibit strong seasonality, geographical preference and quasi-barotropicity. The lifetime, maximum intensity, impact area, and moving speed have a log-linear, log-normal, log-normal, and normal distribution, respectively. These features occur similarly in the SH, except for very small occurrences at 200 hPa in JJA and a normal distribution for the maximum intensity. Properties other than the moving speed significantly correlate with the maximum intensity in both hemispheres. The missing and misidentification issues are reasonably well resolved by this new index.

It is assumed that anti-CTLA-4 antibodies cause tumor rejection by blocking negative signaling from B7-CTLA-4 interactions. Surprisingly, at concentrations considerably higher than plasma levels achieved by clinically effective dosing, the anti-CTLA-4 antibody Ipilimumab blocks neither B7 trans-endocytosis by CTLA-4 nor CTLA-4 binding to immobilized or cell-associated B7. Consequently, Ipilimumab does not increase B7 on dendritic cells (DCs) from either CTLA4 gene humanized ( Ctla4 h/h ) or human CD34 + stem cell-reconstituted NSG™ mice. In Ctla4 h/m mice expressing both human and mouse CTLA4 genes, anti-CTLA-4 antibodies that bind to human but not mouse CTLA-4 efficiently induce Treg depletion and Fc receptor-dependent tumor rejection. The blocking antibody L3D10 is comparable to the non-blocking Ipilimumab in causing tumor rejection. Remarkably, L3D10 progenies that lose blocking activity during humanization remain fully competent in inducing Treg depletion and tumor rejection. Anti-B7 antibodies that effectively block CD4 T cell activation and de novo CD8 T cell priming in lymphoid organs do not negatively affect the immunotherapeutic effect of Ipilimumab. Thus, clinically effective anti-CTLA-4 mAb causes tumor rejection by mechanisms that are independent of checkpoint blockade but dependent on the host Fc receptor. Our data call for a reappraisal of the CTLA-4 checkpoint blockade hypothesis and provide new insights for the next generation of safe and effective anti-CTLA-4 mAbs.

Existing studies of risk factors for physical impairments in acute lung injury (ALI) survivors were potentially limited by single-center design or relatively small sample size. To evaluate risk factors for three measures of physical impairments commonly experienced by survivors of ALI in the first year after hospitalization. A prospective, longitudinal study of 6- and 12-month physical outcomes (muscle strength, 6-minute-walk distance, and Short Form [SF]-36 Physical Function score) for 203 survivors of ALI enrolled from 12 hospitals participating in the ARDS Network randomized trials. Multivariable regression analyses evaluated the independent association of critical illness-related variables and intensive care interventions with impairments in each physical outcome measure, after adjusting for patient demographics, comorbidities, and baseline functional status. At 6 and 12 months, respectively, mean (± SD) values for strength (presented as proportion of maximum strength score evaluated using manual muscle testing) was 92% (± 8%) and 93% (± 9%), 6-minute-walk distance (as percent-predicted) was 64% (± 22%) and 67% (± 26%), and SF-36 Physical Function score (as percent-predicted) was 61% (± 36%) and 67% (± 37%). After accounting for patient baseline status, there was significant association and statistical interaction of mean daily dose of corticosteroids and intensive care unit length of stay with impairments in physical outcomes. Patients had substantial impairments, from predicted values, for 6-minute-walk distance and SF-36 Physical Function outcome measures. Minimizing corticosteroid dose and implementing existing evidence-based methods to reduce duration of intensive care unit stay and associated patient immobilization may be important interventions for improving ALI survivors' physical outcomes.

Wintertime Ural blocking (UB) has been shown to play an important role in cold extremes over Eurasia, and thus it is useful to investigate the impact of warming over the Barents–Kara Seas (BKS) on the behavior of Ural blocking. Here the response of UB to stepwise tropospheric warming over the BKS is examined using a dry dynamic core model. Nonlinear responses are found in the frequency and local persistence of UB. The frequency and local persistence of the UB increase with the strength of BKS warming in a less strong range and decrease with the further increase of BKS warming, which is linked to the UB propagation influenced by upstream background atmospheric circulation. For a weak BKS warming, the UB becomes more persistent due to its less westward movement associated with intensified upstream zonal wind and meridional potential vorticity gradient (PVy) in the North Atlantic mid-high latitudes, which corresponds to a negative height response over the North Atlantic high latitudes. When BKS warming is strong, a positive height response appears in the early winter stratosphere, and its subsequent downward propagation leads to a negative NAO response or increased Greenland blocking events, which reduces zonal wind and PVy in the high latitudes from North Atlantic to Europe, thus enhancing the westward propagation of UB and reducing its local persistence. The transition to the negative NAO phase and the retrogression of UB are not found when numerically suppressing the downward influence of weakened stratospheric polar vortex, suggesting a crucial role of the stratospheric pathway in nonlinear responses of UB to the early winter BKS warming.