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Background Thrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19. Methods In this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care–level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. The primary outcome was organ support–free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of −1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d -dimer level. Results The trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support–free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d -dimer cohort, 92.9% in the low d -dimer cohort, and 97.3% in the unknown d -dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagulation and in 0.9% of those receiving thromboprophylaxis. Conclusions In noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis. (ATTACC, ACTIV-4a, and REMAP-CAP ClinicalTrials.gov numbers, NCT04372589 , NCT04505774 , NCT04359277 , and NCT02735707 .)

The PTEN tumor suppressor gene is frequently inactivated in human prostate cancers, particularly in more advanced cancers, suggesting that the AKT/protein kinase B (PKB) kinase, which is negatively regulated by PTEN, may be involved in human prostate cancer progression. We now show that AKT activation and activity are markedly increased in androgen-independent, prostate-specific antigen-positive prostate cancer cells (LNAI cells) established from xenograft tumors of the androgen-dependent LNCaP cell line. These LNAI cells show increased expression of integrin-linked kinase, which is putatively responsible for AKT activation/Ser-473 phosphorylation, as well as for increased phosphorylation of the AKT target protein, BAD. Furthermore, expression of the p27 Kip1 cell cycle regulator was diminished in LNAI cells, consistent with the notion that AKT directly inhibits AFX/Forkhead-mediated transcription of p27 Kip1 . To assess directly the impact of increased AKT activity on prostate cancer progression, an activated hAKT1 mutant was overexpressed in LNCaP cells, resulting in a 6-fold increase in xenograft tumor growth. Like LNAI cells, these transfectants showed dramatically reduced p27 Kip1 expression. Together, these data implicate increased AKT activity in prostate tumor progression and androgen independence and suggest that diminished p27Kip1 expression, which has been repeatedly associated with prostate cancer progression, may be a consequence of increased AKT activity.

We present novel measurements of the primary instabilities of thin liquid films flowing down an incline. A fluorescence imaging method allows accurate measurements of film thickness h(x, y, t) in real time with a sensitivity of several microns, and laser beam deflection yields local measurements with a sensitivity of less than one micron. We locate the instability with good accuracy despite the fact that it occurs (asymptotically) at zero wavenumber, and determine the critical Reynolds number Rc for the onset of waves as a function of angle β. The measurements of Rc(β) are found to be in good agreement with calculations, as are the growth rates and wave velocities. We show experimentally that the initial instability is convective and that the waves are noisesustained. This means that the waveform and its amplitude are strongly affected by external noise at the source. We investigate the role of noise by varying the level of periodic external forcing. The nonlinear evolution of the waves depends strongly on the initial wavenumber (or the frequency f). A new phase boundary f*s(R) is measured, which separates the regimes of saturated finite amplitude waves (at high f) from multipeaked solitary waves (at low f). This boundary probably corresponds approximately to the sign reversal of the third Landau coefficient in weakly nonlinear theory. Finally, we show that periodic waves are unstable over a wide frequency band with respect to a convective subharmonic instability. This instability leads to disordered two-dimensional waves.

Rationale: Pulmonary arterial hypertension (PAH) is a proliferative arteriopathy associated with glucose transporter-1 (Glut1) up-regulation and a glycolytic shift in lung metabolism. Glycolytic metabolism can be detected with the positron emission tomography (PET) tracer 18 F-fluorodeoxyglucose (FDG).Objectives: The precise cell type in which glycolytic abnormalities occur in PAH is unknown. Moreover, whether FDG-PET is sufficiently sensitive to monitor PAH progression and detect therapeutic regression is untested. We hypothesized that increased lung FDG-PET reflects enhanced glycolysis in vascular cells and is reversible in response to effective therapies. Methods: PAH was induced in Sprague-Dawley rats by monocrotaline or chronic hypoxia (10% oxygen) in combination with Sugen 5416. Monocrotaline rats were treated with oral dichloroacetate or daily imatinib injections. FDG-PET scans and pulmonary artery acceleration times were obtained weekly. The origin of the PET signal was assessed by laser capture microdissection of airway versus vascular tissue. Metabolism was measured in pulmonary artery smooth muscle cell (PASMC) cultures, using a Seahorse extracellular flux analyzer. Measurements and Main Results: Lung FDG increases 1-2 weeks after monocrotaline (when PAH is mild) and is normalized by dichloroacetate and imatinib, which both also regress medial hypertrophy. Glut1 mRNA is up-regulated in both endothelium and PASMCs, but not airway cells or macrophages. PASMCs from monocrotaline rats are hyperproliferative and display normoxic activation of hypoxia-inducible factor-1a (HIF-1a), which underlies their glycolytic phenotype. Conclusions: HIF-1a-mediated Glut1 up-regulation in proliferating vascular cells in PAH accounts for increased lung FDG-PET uptake. FDG-PET is sensitive to mild PAH and can monitor therapeutic changes in the vasculature.Keywords: hypoxia-inducible factor-1a (HIF-1a); glucose transporter-1 (Glut1); glycolysis; imatinib; Sugen 5416Pulmonary arterial hypertension (PAH) is a syndrome in which the mean pulmonary artery pressure exceeds 25 mm Hg because of obstruction and constriction of precapillary pulmonary resistance arteries. An important aspect of the pathophysiology of PAH is increased proliferation and reduced apoptosis of pulmonary arterial endothelial and smooth muscle cells (PASMCs) (1-8), leading to plexiform lesions and increased muscularization, respectively.Publications describe impaired glucose oxidation and/or a shift to glycolytic metabolism in PASMCs in rodents with experimental PAH (9), in endothelial cells of patients with PAH (10, 11), and in the pulmonary arteries of rats (12) and mice (13) exposed to chronic hypoxia. Aerobic glycolysis is also known as the Warburg effect and was shown to confer a growth advantage to proliferating cells (14). A crucial determinant of whether cells generate energy through glycolysis or aerobic mitochondrial respiration is the activity of pyruvate dehydrogenase complex (PDH). PDH catalyzes the conversion of pyruvate into acetyl coenzyme A...

Granulocyte colony-stimulating factor administration to CAD patients mobilizes cells with endothelial progenitor potential from bone marrow, but without objective evidence of cardiac benefit and with the potential for adverse outcomes in some patients.

Objective— Endothelial progenitor cells (EPCs) that may repair vascular injury are reduced in patients with coronary artery disease (CAD). We reasoned that EPC number and function may be increased by granulocyte colony-stimulating factor (G-CSF) used to mobilize hematopoietic progenitor cells in healthy donors. Methods and Results— Sixteen CAD patients had reduced CD34 + /CD133 + (0.0224±0.0063% versus 0.121±0.038% mononuclear cells [MNCs], P <0.01) and CD133 + /VEGFR-2 + cells, consistent with EPC phenotype (0.00033±0.00015% versus 0.0017±0.0006% MNCs, P <0.01), compared with 7 healthy controls. Patients also had fewer clusters of cells in culture, with out-growth consistent with mature endothelial phenotype (2±1/well) compared with 16 healthy subjects at high risk (13±4/well, P <0.05) or 14 at low risk (22±3/well, P <0.001) for CAD. G-CSF 10 μg/kg per day for 5 days increased CD34 + /CD133 + cells from 0.5±0.2/μL to 59.5±10.6/μL and CD133 + / VEGFR-2 + cells from 0.007±0.004/μL to 1.9±0.6/μL (both P <0.001). Also increased were CD133 + cells that coexpressed the homing receptor CXCR4 (30.4±8.3/μL, P <0.05). Endothelial cell-forming clusters in 10 patients increased to 27±9/well after treatment ( P <0.05), with a decline to 9±4/well at 2 weeks ( P =0.06). Conclusions— Despite reduced EPCs compared with healthy controls, patients with CAD respond to G-CSF with increases in EPC number and homing receptor expression in the circulation and endothelial out-growth in culture.

Key Points:• We invert large sets of longitudinal river profiles. Fits to data are excellent • Our history of uplift is consistent with independent geological calibration • We have reconstructed the evolution of dynamic topography in Africa since 50 Ma Abstract It is generally accepted that Cenozoic epeirogeny of the African continent is moderated by convective circulation of the mantle. Nevertheless, the spatial and temporal evolution of Africa's "basin-and-swell" physiography is not well known. Here we show how continental drainage networks can be used to place broad constraints on the pattern of uplift through space and time. First, we assemble an inventory of 710 longitudinal river profiles that includes major tributaries of the 10 largest catchments. River profiles have been jointly inverted to determine the pattern of uplift rate as a function of space and time.Our inverse model assumes that shapes of river profiles are controlled by uplift rate history and modulated by erosional processes, which can be calibrated using independent geologic evidence (e.g., marine terraces, volcanism and thermochronologic data). Our results suggest that modern African topography started to develop ∼30 Myr ago when volcanic swells appeared in North and East Africa. During the last 15-20 Myr, subequatorial Africa was rapidly elevated, culminating in the appearance of three large swells that straddle southern and western coasts. Our results enable patterns of sedimentary flux at major deltas to be predicted and tested. We suggest that the evolution of drainage networks is dominated by rapid upstream advection of signals produced by a changing pattern of regional uplift. An important corollary is that, with careful independent calibration, these networks might act as useful tape recorders of otherwise inaccessible mantle processes. Finally, we note that there are substantial discrepancies between our results and published dynamic topographic predictions.