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Using recently collected high‐resolution seismic data along a dense linear transect across Ohio, West Virginia, and Virginia (called Mid‐Atlantic Geophysical Integrative Collaboration (MAGIC) profile), we analyze P‐to‐S receiver functions to investigate the undulations of the mantle transition zone (MTZ) discontinuities (410‐ and 660‐km) beneath the central Appalachian region. Our results incorporating the effects of local crustal and mantle structures suggest shallowing of both the 410‐ and the 660‐km discontinuities from the northwest (inland) to the southeast (coast) along MAGIC profile. Hydro‐thermal upwelling beneath the eastern U.S. coastal plain due to a hydrated MTZ and hot upwelling return flow associated with the descending lower mantle Farallon slab is consistent with our observations of MTZ structure considering 3D velocity heterogeneity. The inferred hydrous hot upwelling rising into the upper mantle may trigger dehydration melting atop the 410‐km discontinuity, which may help to explain the presence of a low velocity upper mantle anomaly beneath the region today. Plain Language Summary The dynamic and tectonic processes of passive continental margins that do not lie on plate boundaries are poorly understood compared with active continental margins. The mantle flow patterns beneath the eastern North America, a long‐lived passive continental margin, are debated, due to limited local high‐resolution seismic studies. Using a dense seismic array through Ohio, West Virginia, and Virginia (called MAGIC profile) with unprecedented resolution, we investigate the undulations of 410‐ and 660‐km discontinuities (boundaries of the mantle transition zone) beneath the eastern U.S. by analyzing seismic waves that have been converted at these discontinuities. After correcting for local crustal and mantle structures, we identify positively correlated shallowing of the 410‐ and 660‐km discontinuities from the inland to the coast, which are hard to explain by thermal heterogeneity alone. Our findings suggest the existence of hot upwelling return flow associated with the neighboring descending Farallon slab in the lower mantle beneath the eastern U.S. When this passive hot return flow rises through the hydrated transition zone into the upper mantle, dehydration melting atop 410‐km discontinuity may be triggered. The buoyant melt may further rise through the upper mantle, providing a potential explanation for upper mantle velocity anomalies beneath the region. Key Points Seismic receiver functions image mantle transition zone discontinuities from a regional high‐resolution transect across the eastern U.S The results are difficult to reconcile with either thermal or hydration variations alone in the transition zone Local hydro‐thermal upwelling due to hydrated transition zone and hot return flow associated with the descending Farallon slab may exist

Patients with advanced or metastatic urothelial cancer who had had a response to platinum-based chemotherapy were randomly assigned to best supportive care alone or best supportive care plus avelumab (an anti–PD-L1 antibody) every 2 weeks until progression. Patients receiving avelumab had significantly longer overall survival (21 months) than those receiving only best supportive care (14 months).

Irbesartan, a long acting selective angiotensin-1 receptor inhibitor, in Marfan syndrome might reduce aortic dilatation, which is associated with dissection and rupture. We aimed to determine the effects of irbesartan on the rate of aortic dilatation in children and adults with Marfan syndrome. We did a placebo-controlled, double-blind randomised trial at 22 centres in the UK. Individuals aged 6–40 years with clinically confirmed Marfan syndrome were eligible for inclusion. Study participants were all given 75 mg open label irbesartan once daily, then randomly assigned to 150 mg of irbesartan (increased to 300 mg as tolerated) or matching placebo. Aortic diameter was measured by echocardiography at baseline and then annually. All images were analysed by a core laboratory blinded to treatment allocation. The primary endpoint was the rate of aortic root dilatation. This trial is registered with ISRCTN, number ISRCTN90011794. Between March 14, 2012, and May 1, 2015, 192 participants were recruited and randomly assigned to irbesartan (n=104) or placebo (n=88), and all were followed for up to 5 years. Median age at recruitment was 18 years (IQR 12–28), 99 (52%) were female, mean blood pressure was 110/65 mm Hg (SDs 16 and 12), and 108 (56%) were taking β blockers. Mean baseline aortic root diameter was 34·4 mm in the irbesartan group (SD 5·8) and placebo group (5·5). The mean rate of aortic root dilatation was 0·53 mm per year (95% CI 0·39 to 0·67) in the irbesartan group compared with 0·74 mm per year (0·60 to 0·89) in the placebo group, with a difference in means of −0·22 mm per year (−0·41 to −0·02, p=0·030). The rate of change in aortic Z score was also reduced by irbesartan (difference in means −0·10 per year, 95% CI −0·19 to −0·01, p=0·035). Irbesartan was well tolerated with no observed differences in rates of serious adverse events. Irbesartan is associated with a reduction in the rate of aortic dilatation in children and young adults with Marfan syndrome and could reduce the incidence of aortic complications. British Heart Foundation, the UK Marfan Trust, the UK Marfan Association.

The L-type Ca 2+ channel Ca V 1.2 is essential for arterial myocyte excitability, gene expression and contraction. Elevations in extracellular glucose (hyperglycemia) potentiate vascular L-type Ca 2+ channel via PKA, but the underlying mechanisms are unclear. Here, we find that cAMP synthesis in response to elevated glucose and the selective P2Y 11 agonist NF546 is blocked by disruption of A-kinase anchoring protein 5 (AKAP5) function in arterial myocytes. Glucose and NF546-induced potentiation of L-type Ca 2+ channels, vasoconstriction and decreased blood flow are prevented in AKAP5 null arterial myocytes/arteries. These responses are nucleated via the AKAP5-dependent clustering of P2Y 11 / P2Y 11 -like receptors, AC5, PKA and Ca V 1.2 into nanocomplexes at the plasma membrane of human and mouse arterial myocytes. Hence, data reveal an AKAP5 signaling module that regulates L-type Ca 2+ channel activity and vascular reactivity upon elevated glucose. This AKAP5-anchored nanocomplex may contribute to vascular complications during diabetic hyperglycemia. Molecular mechanisms by which glucose modulates L-type Ca 2+ channel activity and vascular reactivity are unclear. Here the authors report a nanocomplex orchestrated by AKAP5 that facilitates local purinergic stimulation of L-type Ca 2+ channels and vasoconstriction during diabetic hyperglycemia.

Poly(ADP-ribose) polymerase (PARP) inhibition (PARPi) is a precision medicine strategy in advanced prostate cancer, with the greatest benefit seen in a subset of patients with homologous recombination repair (HRR) gene alterations. Combination approaches may expand activity beyond HRR-altered disease. We conducted a phase 2 study of the PARP inhibitor olaparib in combination with the anti-PD-L1 antibody durvalumab in an HRR-unselected population of men with metastatic castration-resistant prostate cancer (mCRPC). This is a single-arm, open-label phase 2 trial of olaparib plus durvalumab in men with mCRPC previously treated with abiraterone and/or enzalutamide. Pretreatment biopsies of metastatic lesions were attempted for tumor sequencing. Peripheral blood was collected longitudinally for immune profiling of cell subsets and soluble factors, circulating tumor DNA (ctDNA) analyses, and peripheral blood mononuclear cell (PBMC) gene expression profiling. 61 patients were enrolled; 60 were evaluable. Median age was 65 years (45-88). Median radiographic progression-free survival (rPFS) was 5.0 months (95% CI 4.6 to 7.6) and median overall survival (OS) was 19.1 months (95% CI 15.0 to 29.3 months). 10 patients achieved partial responses, and 17 (28%) had ≥50% prostate-specific antigen declines. Patients with variants experienced longer rPFS (13.2 months; 95% CI 7.7 to 20.2 months) than patients without variants (4.8 months; 95% CI 4.5 to 6.4 months, p=0.0026). Baseline ctDNA fraction was higher in patients with radiographic progression than in those with partial response (p=0.022) and inversely correlated with time-to-progression (ρ=-0.51). Treatment- induced early peripheral immune perturbations included transient inflammatory cytokine increases and expansion of activated/proliferating T cells with concurrent regulatory features. Exploratory PBMC profiling identified as a response-associated transcript, and lower expression was associated with longer OS. Olaparib plus durvalumab demonstrated modest activity in HRR-unselected mCRPC, with clinical benefit enriched in -variant disease. Integrated ctDNA and peripheral immune analyses support ongoing efforts to refine molecular and immune selection strategies and to better define mechanisms of benefit and resistance for combination approaches in mCRPC. NCT02484404.

In a trial involving patients with subarachnoid hemorrhage and anemia, liberal transfusion of red cells did not result in a lower risk of an unfavorable neurologic outcome than a more restrictive strategy.

PurposeThe aim of this Intensive Care Medicine Rapid Practice Guideline (ICM‑RPG) was to formulate evidence‑based guidance for the use of dexmedetomidine for sedation in invasively mechanically ventilated adults in the intensive care unit (ICU).MethodsWe adhered to the methodology for trustworthy clinical practice guidelines, including use of the Grading of Recommendations Assessment, Development, and Evaluation approach to assess the certainty of evidence, and the Evidence-to-Decision framework to generate recommendations. The guideline panel comprised 28 international panelists, including content experts, ICU clinicians, methodologists, and patient representatives. Through teleconferences and web‑based discussions, the panel provided input on the balance and magnitude of the desirable and undesirable effects, the certainty of evidence, patients’ values and preferences, costs and resources, feasibility, acceptability, and research priorities.ResultsThe ICM‑RPG panel issued one weak recommendation (suggestion) based on overall moderate certainty of evidence: \"In invasively mechanically ventilated adult ICU patients, we suggest using dexmedetomidine over other sedative agents, if the desirable effects including a reduction in delirium are valued over the undesirable effects including an increase in hypotension and bradycardia\".ConclusionThis ICM-RPG provides updated evidence-based guidance on the use of dexmedetomidine for sedation in mechanically ventilated adults, and outlines uncertainties and research priorities.

Relatively little is currently known about the spatiotemporal variability of land surface conditions during the North American monsoon, in particular for regions of complex topography. As a result, the role played by land–atmosphere interactions in generating convective rainfall over steep terrain and sustaining monsoon conditions is still poorly understood. In this study, the variation of hydrometeorological conditions along a large-scale topographic transect in northwestern Mexico is described. The transect field experiment consisted of daily sampling at 30 sites selected to represent variations in elevation and ecosystem distribution. Simultaneous soil and atmospheric variables were measured during a 2-week period in early August 2004. Transect observations were supplemented by a network of continuous sampling sites used to analyze the regional hydrometeorological conditions prior to and during the field experiment. Results reveal the strong control exerted by topography on the spatial and temporal variability in soil moisture, with distinct landscape regions experiencing different hydrologic regimes. Reduced variations at the plot and transect scale during a drydown period indicate that homogenization of hydrologic conditions occurred over the landscape. Furthermore, atmospheric variables are clearly linked to surface conditions, indicating that heating and moistening of the boundary layer closely follow spatial and temporal changes in hydrologic properties. Land–atmosphere interactions at the basin scale (~100 km²), obtained via a technique accounting for topographic variability, further reveal the role played by the land surface in sustaining high atmospheric moisture conditions, with implications toward rainfall generation during the North American monsoon.

This paper documents the seventeenth data release (DR17) from the Sloan Digital Sky Surveys; the fifth and final release from the fourth phase (SDSS-IV). DR17 contains the complete release of the Mapping Nearby Galaxies at Apache Point Observatory (MaNGA) survey, which reached its goal of surveying over 10,000 nearby galaxies. The complete release of the MaNGA Stellar Library accompanies this data, providing observations of almost 30,000 stars through the MaNGA instrument during bright time. DR17 also contains the complete release of the Apache Point Observatory Galactic Evolution Experiment 2 survey that publicly releases infrared spectra of over 650,000 stars. The main sample from the Extended Baryon Oscillation Spectroscopic Survey (eBOSS), as well as the subsurvey Time Domain Spectroscopic Survey data were fully released in DR16. New single-fiber optical spectroscopy released in DR17 is from the SPectroscipic IDentification of ERosita Survey subsurvey and the eBOSS-RM program. Along with the primary data sets, DR17 includes 25 new or updated value-added catalogs. This paper concludes the release of SDSS-IV survey data. SDSS continues into its fifth phase with observations already underway for the Milky Way Mapper, Local Volume Mapper, and Black Hole Mapper surveys.

Constraint-based reconstruction and analysis (COBRA) provides a molecular mechanistic framework for integrative analysis of experimental molecular systems biology data and quantitative prediction of physicochemically and biochemically feasible phenotypic states. The COBRA Toolbox is a comprehensive desktop software suite of interoperable COBRA methods. It has found widespread application in biology, biomedicine, and biotechnology because its functions can be flexibly combined to implement tailored COBRA protocols for any biochemical network. This protocol is an update to the COBRA Toolbox v.1.0 and v.2.0. Version 3.0 includes new methods for quality-controlled reconstruction, modeling, topological analysis, strain and experimental design, and network visualization, as well as network integration of chemoinformatic, metabolomic, transcriptomic, proteomic, and thermochemical data. New multi-lingual code integration also enables an expansion in COBRA application scope via high-precision, high-performance, and nonlinear numerical optimization solvers for multi-scale, multi-cellular, and reaction kinetic modeling, respectively. This protocol provides an overview of all these new features and can be adapted to generate and analyze constraint-based models in a wide variety of scenarios. The COBRA Toolbox v.3.0 provides an unparalleled depth of COBRA methods. The COBRA toolbox provides quality-controlled reconstruction, modeling, topological analysis, and network visualization, as well as network integration of chemoinformatic, metabolomic, transcriptomic, proteomic, and thermochemical data.