Subaqueous Barchan dunes in turbulent shear flow. Part 2: Fluid flow.

We report an experimental study of the turbulent flow above a barchan dune in a channel, from particle image velocimetry measurements, for Reynolds numbers ranging from 9000, just below the threshold for particle motion, up to 24 000, where the dune moves. Two calculations of the speed-up over the dune are compared, the usual ‘same-elevation’ and the more relevant ‘Lagrangian’, showing that the latter is smaller by a factor of two. The two-layer structure of the flow disturbance – an essentially inviscid outer layer and a turbulent inner layer of thickness δi – is assessed. In the outer layer, streamline curvature is shown to be responsible for half of the Lagrangian speed-up, from the comparison of the velocity measurements with two Bernoulli calculations. In the inner layer, detailed measurements of the velocity and stresses are provided, down to γ+ ≈ 1, and the momentum budget is discussed. The Reynolds shear stress decreases monotonically towards the dune surface, according to the standard mixing-length closure, whereas the total shear stress increases strongly in the viscous sublayer. Along the dune surface, the shear stress increases up to the crest where it reaches twice its unperturbed value. A good estimate of the surface stress is provided by a parabolic fit of the inner velocity profile matching the outer flow at γd ≈ δi. Doubling the Reynolds number, the surface shear stress and the speed-up decrease by ∼30 %. The implications of these results on the dune motion, presented in Part 1 of this study (Franklin & Charru, J. Fluid Mech., vol. 675, 2011, pp. 199–222), are finally discussed

Role of transverse displacements in the formation of subaqueous barchan dunes

Crescentic shape dunes, known as barchan dunes, are formed by the action of a fluid flow on a granular bed. These bedforms are common in many environments, existing under water or in air, and being formed from grains organized in different initial arrangements. Although they are frequently found in nature and industry, details about their development are still to be understood. In a recent paper [C. A. Alvarez and E. M. Franklin, Phys. Rev. E 96, 062906 (2017)], we proposed a timescale for the development and equilibrium of single barchans based on the growth of their horns. In the present Letter, we report measurements of the growth of horns at the grain scale. In our experiments, conical heaps were placed in a closed conduit and individual grains were tracked as each heap, under the action of a water flow, evolved into a barchan dune. We identified the trajectories of the grains that migrated to the growing horns, and found that most of them came from upstream regions on the periphery of the initial heap, with an average displacement of the order of the heap size. In addition, we show that individual grains had transverse displacements by rolling and sliding that are not negligible, with many of them going around the heap. The mechanism of horns formation revealed by our experiments contrasts with the general picture that barchan horns form from the advance of the lateral dune flanks due to the scaling of migration velocity with the inverse of dune size. Our results change the way in which the growth of subaqueous barchan dunes is explained12116CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP140773/2016-9; 400284/2016-22016/13474-9C. A. A. is grateful to SENESCYT (Grant No. 2013- AR2Q2850) and to CNPq (Grant No. 140773/2016-9). E. M. F. is grateful to FAPESP (Grant No. 2016/13474-9), to CNPq (Grant No. 400284/2016-2) and to FAEPEX/ UNICAMP (Grant No. 2210/18) for the financial support provide

Birth of a subaqueous barchan dune

Barchan dunes are crescentic shape dunes with horns pointing downstream. The present paper reports the formation of subaqueous barchan dunes from initially conical heaps in a rectangular channel. Because the most unique feature of a barchan dune is its horns, we associate the time scale for the appearance of horns to the formation of a barchan dune. A granular heap initially conical was placed on the bottom wall of a closed conduit and it was entrained by a water flow in turbulent regime. After a certain time, horns appear and grow, until an equilibrium length is reached. Our results show the existence of the time scales 0.5tc and 2.5tc for the appearance and equilibrium of horns, respectively, where tc is a characteristic time that scales with the grains diameter, gravity acceleration, densities of the fluid and grains, and shear and threshold velocities966CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP140773/2016-9; 400284/2016-22012/19562-6; 2016/13474-9Carlos A. Alvarez is grateful to SENESCYT Grant No. 2013-AR2Q2850) and to CNPq (Grant No. 140773/2016-9). Erick M. Franklin is grateful to FAPESP (Grants No. 2012/19562-6 and No. 2016/13474-9), to CNPq (Grant No. 400284/2016-2), and to FAEPEX/UNICAMP (Grant No. 2210/17) for the financial support provide

Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups

Background: Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without previous cardiovascular disease (primary prevention). Methods: In CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), 4401 participants with type 2 diabetes mellitus and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care. Results: Primary prevention participants (n=2181, 49.6%) were younger (61 versus 65 years), were more often female (37% versus 31%), and had shorter duration of diabetes mellitus (15 years versus 16 years) compared with secondary prevention participants (n=2220, 50.4%). Canagliflozin reduced the risk of major cardiovascular events overall (hazard ratio [HR], 0.80 [95% CI, 0.67-0.95]; P=0.01), with consistent reductions in both the primary (HR, 0.68 [95% CI, 0.49-0.94]) and secondary (HR, 0.85 [95% CI, 0.69-1.06]) prevention groups (P for interaction=0.25). Effects were also similar for the components of the composite including cardiovascular death (HR, 0.78 [95% CI, 0.61-1.00]), nonfatal myocardial infarction (HR, 0.81 [95% CI, 0.59-1.10]), and nonfatal stroke (HR, 0.80 [95% CI, 0.56-1.15]). The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalization for heart failure were also consistently reduced in both the primary and secondary prevention groups (P for interaction >0.5 for each outcome). Conclusions: Canagliflozin significantly reduced major cardiovascular events and kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, including in participants who did not have previous cardiovascular disease

Sex difference and intra-operative tidal volume: Insights from the LAS VEGAS study

BACKGROUND: One key element of lung-protective ventilation is the use of a low tidal volume (VT). A sex difference in use of low tidal volume ventilation (LTVV) has been described in critically ill ICU patients.OBJECTIVES: The aim of this study was to determine whether a sex difference in use of LTVV also exists in operating room patients, and if present what factors drive this difference.DESIGN, PATIENTS AND SETTING: This is a posthoc analysis of LAS VEGAS, a 1-week worldwide observational study in adults requiring intra-operative ventilation during general anaesthesia for surgery in 146 hospitals in 29 countries.MAIN OUTCOME MEASURES: Women and men were compared with respect to use of LTVV, defined as VT of 8 ml kg-1 or less predicted bodyweight (PBW). A VT was deemed 'default' if the set VT was a round number. A mediation analysis assessed which factors may explain the sex difference in use of LTVV during intra-operative ventilation.RESULTS: This analysis includes 9864 patients, of whom 5425 (55%) were women. A default VT was often set, both in women and men; mode VT was 500 ml. Median [IQR] VT was higher in women than in men (8.6 [7.7 to 9.6] vs. 7.6 [6.8 to 8.4] ml kg-1 PBW, P < 0.001). Compared with men, women were twice as likely not to receive LTVV [68.8 vs. 36.0%; relative risk ratio 2.1 (95% CI 1.9 to 2.1), P < 0.001]. In the mediation analysis, patients' height and actual body weight (ABW) explained 81 and 18% of the sex difference in use of LTVV, respectively; it was not explained by the use of a default VT.CONCLUSION: In this worldwide cohort of patients receiving intra-operative ventilation during general anaesthesia for surgery, women received a higher VT than men during intra-operative ventilation. The risk for a female not to receive LTVV during surgery was double that of males. Height and ABW were the two mediators of the sex difference in use of LTVV.TRIAL REGISTRATION: The study was registered at Clinicaltrials.gov, NCT01601223

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Shape evolution of numerically obtained subaqueous barchan dunes

In the realm of granular bedforms, barchan dunes are strong attractors that can be found in rivers, terrestrial deserts, and other planetary environments. These bedforms are characterized by a crescentic shape, which, although robust, presents different scales according to the environment they are in, their length scale varying from the decimeter under water to the kilometer on Mars. In addition to the scales of bedforms, the transport of grains presents significant differences according to the nature of the entraining fluid, so that the growth of barchans is still not fully understood. Given the smaller length and time scales of the aquatic case, subaqueous barchans are the ideal object to study the growth of barchan dunes. In the present paper, we reproduce numerically the experiments of Alvarez and Franklin [Phys. Rev. E 96, 062906 (2017); Phys. Rev. Lett. 121, 164503 (2018)] on the shape evolution of barchans from their initiation until they have reached a stable shape. We computed the bed evolution by using the computational fluid dynamics-discrete element method, where we coupled the discrete element method with large eddy simulation for the same initial and boundary conditions of experiments, performed in a closed-conduit channel where initially conical heaps evolved to single barchans under the action of a water flow in a turbulent regime. Our simulations captured well the evolution of the initial pile toward a barchan dune in both the bedform and grain scales, with the same characteristic time and lengths observed in experiments. In addition, we obtained the local granular flux and the resultant force acting on each grain, the latter not yet previously measured nor computed. This shows that the present method is appropriate for numerical computations of bedforms, opening new possibilities for accessing data that are not available from current experiments1011CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP400284/2016-2; 140773/2016-92018/14981-7C.A.A. is grateful to SENESCYT (Grant No. 2013-AR2Q2850) and to CNPq (Grant No. 140773/2016-9). E.M.F. is grateful to FAPESP (Grant No. 2018/14981-7), to CNPq (Grant No. 400284/2016-2), and to FAEPEX/UNICAMP (Grant No. 2112/19) for the financial support provided. Part of the work was completed while C.A.A. was a visiting graduate student at Western University, Canada, supported through the Emerging Leaders in the Americas Program, Global Affairs Canada. The authors would like to thank J. M. Floryan from Western University, Canada, for helpful discussions. SHARCNET (www.sharcnet.ca) provided part of computational resources used in the projec

Horns of subaqueous barchan dunes : a study at the grain scale

Many complex aspects are involved in the morphodynamics of crescent-shaped dunes, known as barchans. One of them concerns the trajectories of individual grains over the dune and how they affect its shape. In the case of subaqueous barchans, we proposed [C. A. Alvarez and E. M. Franklin, Phys. Rev. Lett. 121, 164503 (2018)] that their extremities, called horns, are formed mainly by grains migrating from upstream regions of the initial pile, and that they exhibit significant transverse displacements. Here, we extend our previous work to address the dynamics of grains migrating to horns after the dune has reached its crescentic shape and present new aspects of the problem. In our experiments, single barchans evolve, under the action of a turbulent water flow, from heaps of conical shape formed from glass beads poured on the bottom wall of a rectangular channel. Both for evolving and for developed barchans, the horns are fed up with grains coming from upstream regions of the bedform and traveling with significant transverse components, differently from the dynamics usually described for the aeolian case. For these grains, irrespective of their size and the strength of the water flow, the distributions of transverse and streamwise components of velocities are well described by exponential functions, with the probability density functions of their magnitudes being similar to results obtained from previous studies on flat beds. Focusing on moving grains whose initial positions were on the horns, we show that their residence time and traveled distance are related following a quasilinear relation. Our results provide new insights into the physical mechanisms underlying the shape of barchan dunes1004CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP140773/2016-9; 400284/2016-22016/13474-9; 2018/14981-7C.A.A. is grateful to SENESCYT (Grant No. 2013-AR2Q2850) and to CNPq (Grant No. 140773/2016-9). E.M.F. is grateful to FAPESP (Grants No. 2016/13474-9 and No. 2018/14981-7), to CNPq (Grant No. 400284/2016-2), and to FAEPEX/UNICAMP (Grants No. 2100/18 and No. 2112/19) for the financial support provide