Discrete element modelling of the packing of spheres and its application to the structure of porous metals made by infiltration of packed beds of NaCl beads

A numerical model, using the discrete element method, has been developed to quantify specific parameters that are pertinent to the packing behaviour of relatively large, spherical NaCl beads and mixtures of beads of different sizes. These parameters have been compared with porosity and connectivity measurements made on porous aluminium castings made by molten metal infiltration into packed beds of such beads, after removal of the NaCl by dissolution. DEM has been found to accurately predict the packing fraction for salt beads with both mono and binary size distributions and from this the pore fractions in castings made by infiltration into packed beds of beads could be predicted. Through simple development of the condition for contacting of neighbouring beads, the number of windows linking neighbouring pores, and their size, could also be predicted across a wide range of small bead additions. The model also enables an insight into the mixing quality and changes in connectivity introduced through the addition of small beads. This work presents significant progress towards the delivery of a simulation based approach to designing preform architectures in order to tailor the resulting porous structures to best suit specific applications

Numerical simulations of granular dynamics II: Particle dynamics in a shaken granular material

Surfaces of planets and small bodies of our Solar System are often covered by a layer of granular material that can range from a fine regolith to a gravel-like structure of varying depths. Therefore, the dynamics of granular materials are involved in many events occurring during planetary and small-body evolution thus contributing to their geological properties. We demonstrate that the new adaptation of the parallel N-body hard-sphere code pkdgrav has the capability to model accurately the key features of the collective motion of bidisperse granular materials in a dense regime as a result of shaking. As a stringent test of the numerical code we investigate the complex collective ordering and motion of granular material by direct comparison with laboratory experiments. We demonstrate that, as experimentally observed, the scale of the collective motion increases with increasing small-particle additive concentration. We then extend our investigations to assess how self-gravity and external gravity affect collective motion. In our reduced-gravity simulations both the gravitational conditions and the frequency of the vibrations roughly match the conditions on asteroids subjected to seismic shaking, though real regolith is likely to be much more heterogeneous and less ordered than in our idealised simulations. We also show that collective motion can occur in a granular material under a wide range of inter-particle gravity conditions and in the absence of an external gravitational field. These investigations demonstrate the great interest of being able to simulate conditions that are to relevant planetary science yet unreachable by Earth-based laboratory experiments

Bioactive bioflavonoids from Platonia insignis (bacuri) residues as added value compounds

Platonia insignis fruit, popularly known as bacuri, is traditionally used in folk medicine for its anti-inflammatory and antioxidant properties. Therefore, this study determined the chemical composition and biological activities of the bacuri’s shell and seeds extracts, considered residues from its consumption and industrial uses. Four biflavonoids (GB-2a, GB-1a, morelloflavone, and volkensiflavone) were identified in the extracts by high-performance liquid chromatography-diode array detection (HPLC-DAD), liquid chromatography tandem mass spectrometry (LC-MS/MS), and liquid chromatography-solid phase extraction-nuclear magnetic resonance (LC-SPE-NMR) techniques. Morelloflavone was identified as the main compound in the shell ethyl acetate extract, being responsible for the high in vitro antioxidant (50% effective concentration (EC50) ranging from 8.0-10.5 µg mL−1 in different protocols), anti-glycant (80%), and moderate inhibition of nitric oxide (1.56 µg mL−1 for > 90% cell viability) activities. This extract showed promising in vivo anti-inflammatory activity evaluated through the paw edema protocol after its incorporation into a liquid-crystalline drug carrier system, reducing the edema by up to 31%. The results demonstrated the potential of the fruit for the development of drugs of natural origin and corroborated to add economic value to these discarded residues

Analytical study of the accuracy of discrete element simulations

The numerical errors in idealised discrete element method (DEM) simulations are investigated analytically by comparing energy balances applied at the beginning and end of one time-step. This study focuses on the second-order velocity-Verlet integration scheme due to its widespread implementation in DEM codes. The commercial DEM software PFC2D was used to verify the correctness of key results. The truncation errors, which are larger than the round-off errors by orders of magnitude, have a superlinear relationship with both the simulation time-step and the interparticle collision speed. This remains the case regardless of simulation details including the chosen contact model, particle size distribution, particle density or stiffness. Hence, the total errors can usually be reduced by choosing a smaller time-step. Increasing the polydispersity in a simulation by including smaller particles necessitates choosing a smaller time-step to maintain simulation stability and reduces the truncation errors in most cases. The truncation errors are increased by the dissipation of energy by frictional sliding or by the inclusion of damping in the system. The number of contacts affects the accuracy and one can deduce that because 2D simulations contain fewer interparticle contacts than the equivalent 3D simulations, they therefore have lower accrued simulation errors

Numerical and experimental study of horizontal pneumatic transportation of spherical and low-aspect-ratio cylindrical particles

The work presented in this paper was carried out as part of the PARDEM project. The overall aim was to quantify the predictive capability of a coupled CFD-DEM approach to simulating the horizontal pneumatic conveying of spherical and low-aspect-ratio non-spherical particles. Carefully controlled experiments were carried out in a 6.5 m long, 0.075 m diameter horizontal conveying line with the aid of the laser Doppler anemometry (LDA). Three different sizes of spherical glass beads, ranging from 0.8 mm to 2 mm and low-aspect-ratio cylindrical shaped particle of size 1 × 1.5 mm were employed. Simulations of the experiments were performed using a two-way coupled computational fluid dynamics and discrete element method (CFD-DEM) implemented in the commercial software FLUENT-EDEM in an Eulerian–Lagrangian framework. Experimental and simulation results of gas and particle velocities for particle laden flow with spherical particles were compared, showing that the CFD-DEM method could capture the experimental trends. However, quantitative discrepancies between simulation and experimental results were observed. Further modelling of low-aspect-ratio cylindrical particles was conducted using a multi-sphere model to represent cylindrical particles in the DEM code. Drag equations were modified in the code to take the effect of particle shape into account. The simulation results of mean axial particle velocity agreed reasonably well with a maximum of 25% discrepancy when compared to experimental measurements using the LDA technique. The discrepancies between simulation and experimental results were attributed to the selected drag model, mesh size and lack of an appropriate mesh interpolation scheme in the selected code

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

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

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 &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;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 &lt;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&lt;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&lt;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