COMPARATIVE DISSOLUTION STUDIES OF WARFARIN SODIUM TABLETS: INFLUENCE OF AGITATION RATE, DISSOLUTION MEDIUM, AND USP APPARATUS

Objective: The aim of this study was to carry out comparative dissolution studies with warfarin sodium reference tablets under the hydrodynamic environments generated by the USP basket and paddle apparatus and flow-through cell using different agitation rates and dissolution media. Methods: Dissolution profiles were obtained with the USP basket and paddle apparatus at 50, 75, and 100 rpm and 900 ml of water as dissolution medium. After this, dissolution profiles of warfarin sodium were obtained with the USP paddle apparatus and flow-through cell method using 0.1 N hydrochloric acid, acetate buffer pH 4.5, phosphate buffer pH 6.8, and water. Spectrophotometric determination at 308 nm was carried out during 30 min. Dissolution profiles were compared with model-independent and model-dependent approaches. Results: Significant differences were found with mean dissolution time and dissolution efficiency at 50 and 75 rpm (*P<0.05). Makoid-Banakar was the best-fit model used to describe the in vitro release performance of warfarin sodium with 50-100 rpm and the USP basket and paddle apparatuses. Significant differences in all calculated parameters were found (*P<0.05) excepting percent dissolved at 30 min with 0.1 N hydrochloric acid and phosphate buffer pH 6.8. Conclusion: More research is necessary to identify the in vitro release performance of poorly soluble drugs under available USP apparatuses considering factors as agitation rate and kind of dissolution media. The knowledge of the in vitro release performance of reference drug products is important for the design of better generic formulation

Silencing Expression of the Defensin, Varisin, in Male Dermacentor variabilis by RNA Interference Results in Reduced Anaplasma Marginale Infections

Antimicrobial peptides, including defensins, are components of the innate immune system in ticks that have been shown to provide protection against both gram-negative and gram-positive bacteria. Varisin, one of the defensins identified in Dermacentor variabilis, was shown to be produced primarily in hemocytes but transcript levels were also expressed in midguts and other tick cells. In this research, we studied the role of varisin in the immunity of ticks to the gram-negative cattle pathogen, Anaplasma marginale. Expression of the varisin gene was silenced by RNA interference (RNAi) in which male ticks were injected with varisin dsRNA and then allowed to feed and acquire A. marginale infection on an experimentally-infected calf. Silencing expression of varisin in hemocytes, midguts and salivary glands was confirmed by real time RT-PCR. We expected that silencing of varisin would increase A. marginale infections in ticks, but the results demonstrated that bacterial numbers, as determined by an A. marginale msp4 quantitative PCR, were significantly reduced in the varisin-silenced ticks. Furthermore, colonies of A. marginale in ticks used for RNAi were morphologically abnormal from those seen in elution buffer injected control ticks. The colony shape was irregular and in some cases the A. marginale appeared to be free in the cytoplasm of midgut cells. Some ticks were found to be systemically infected with a microbe that may have been related to the silencing of varisin. This appears to be the first report of the silencing of expression of a defensin in ticks by RNAi that resulted in reduced A. marginale infections

Explosive percolation yields highly-conductive polymer nanocomposites

Explosive percolation is an experimentally-elusive phenomenon where network connectivity coincides with onset of an additional modification of the system; materials with correlated localisation of percolating particles and emergent conductive paths can realise sharp transitions and high conductivities characteristic of the explosively-grown network. Nanocomposites present a structurally- and chemically-varied playground to realise explosive percolation in practically-applicable systems but this is yet to be exploited by design. Herein, we demonstrate composites of graphene oxide and synthetic polymer latex which form segregated networks, leading to low percolation threshold and localisation of conductive pathways. In situ reduction of the graphene oxide at temperatures of <150 °C drives chemical modification of the polymer matrix to produce species with phenolic groups, which are known crosslinking agents. This leads to conductivities exceeding those of dense-packed networks of reduced graphene oxide, illustrating the potential of explosive percolation by design to realise low-loading composites with dramatically-enhanced electrical transport properties

ELSI -- An open infrastructure for electronic structure solvers

Routine applications of electronic structure theory to molecules and periodic systems need to compute the electron density from given Hamiltonian and, in case of non-orthogonal basis sets, overlap matrices. System sizes can range from few to thousands or, in some examples, millions of atoms. Different discretization schemes (basis sets) and different system geometries (finite non-periodic vs. infinite periodic boundary conditions) yield matrices with different structures. The ELectronic Structure Infrastructure (ELSI) project provides an open-source software interface to facilitate the implementation and optimal use of high-performance solver libraries covering cubic scaling eigensolvers, linear scaling density-matrix-based algorithms, and other reduced scaling methods in between. In this paper, we present recent improvements and developments inside ELSI, mainly covering (1) new solvers connected to the interface, (2) matrix layout and communication adapted for parallel calculations of periodic and/or spin-polarized systems, (3) routines for density matrix extrapolation in geometry optimization and molecular dynamics calculations, and (4) general utilities such as parallel matrix I/O and JSON output. The ELSI interface has been integrated into four electronic structure code projects (DFTB+, DGDFT, FHI-aims, SIESTA), allowing us to rigorously benchmark the performance of the solvers on an equal footing. Based on results of a systematic set of large-scale benchmarks performed with Kohn–Sham density-functional theory and density-functional tight-binding theory, we identify factors that strongly affect the efficiency of the solvers, and propose a decision layer that assists with the solver selection process. Finally, we describe a reverse communication interface encoding matrix-free iterative solver strategies that are amenable, e.g., for use with planewave basis sets. Program summary: Program title: ELSI Interface CPC Library link to program files: http://dx.doi.org/10.17632/473mbbznrs.1 Licensing provisions: BSD 3-clause Programming language: Fortran 2003, with interface to C/C++ External routines/libraries: BLACS, BLAS, BSEPACK (optional), EigenExa (optional), ELPA, FortJSON, LAPACK, libOMM, MPI, MAGMA (optional), MUMPS (optional), NTPoly, ParMETIS (optional), PETSc (optional), PEXSI, PT-SCOTCH (optional), ScaLAPACK, SLEPc (optional), SuperLU_DIST Nature of problem: Solving the electronic structure from given Hamiltonian and overlap matrices in electronic structure calculations. Solution method: ELSI provides a unified software interface to facilitate the use of various electronic structure solvers including cubic scaling dense eigensolvers, linear scaling density matrix methods, and other approaches

J-PLUS: Detecting and studying extragalactic globular clusters. The case of NGC 1023.

Open Access article, published by EDP Sciences, under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Context. Extragalactic globular clusters (GCs) are key objects in studies of galactic histories. The advent of wide-field surveys, such as the Javalambre Photometric Local Universe Survey (J-PLUS), offers new possibilities for the study of these systems. Aims. We performed the first study of GCs in J-PLUS to recover information on the history of NGC 1023, taking advantage of wide-field images and 12 filters. Methods. We developed the semiautomatic pipeline GCFinder for detecting GC candidates in J-PLUS images, which can also be adapted to similar surveys. We studied the stellar population properties of a sub-sample of GC candidates using spectral energy distribution (SED) fitting. Results. We found 523 GC candidates in NGC 1023, about 300 of which are new. We identified subpopulations of GC candidates, where age and metallicity distributions have multiple peaks. By comparing our results with the simulations, we report a possible broad age-metallicity relation, supporting the notion that NGC 1023 has experienced accretion events in the past. With a dominating age peak at 1010 yr, we report a correlation between masses and ages that suggests that massive GC candidates are more likely to survive the turbulent history of the host galaxy. Modeling the light of NGC 1023, we find two spiral-like arms and detect a displacement of the galaxy’s photometric center with respect to the outer isophotes and center of GC distribution (~700pc and ~1600pc, respectively), which could be the result of ongoing interactions between NGC 1023 and NGC 1023A. Conclusions. By studying the GC system of NGC 1023 with J-PLUS, we showcase the power of multi-band surveys for these kinds of studies and we find evidence to support the complex accretion history of the host galaxy. © D. de Brito Silva et al. 2022.D.B.S. also acknowledges Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) process number 2017J00204-6 for the financial support provided for the development of this project. P.C. acknowledges support from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) under grant 310041/2018-0 and from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) process number 2018J05392-8. A.C.S. acknowledges funding from CNPq and the Rio Grande do Sul Research Foundation (FAPERGS) through grants CNPq-403580/2016-1, CNPq-11153/2018-6, PqG/FAPERGS-17/2551-0001, FAPERGS/CAPES 19/2551-0000696-9 and L’Oréal UNESCO ABC Para Mulheres na Ciência and the Chinese Academy of Sciences (CAS) President’s International Fellowship Initiative (PIFI) through grant E085201009. G.B. acknowledges financial support from the National Autonomous University of México (UNAM) through grant DGAPA/PAPIIT IG100319 and from CONACyT through grant CB2015-252364. J.V. acknowledges the technical members of the UPAD for their invaluable work: Juan Castillo, Tamara Civera, Javier Hernández, Ángel López, Alberto Moreno, and David Muniesa. J.A.H.J. acknowledges Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), process number 2021J08920-8. A.E. acknowledges the financial support from the Spanish Ministry of Science and Innovation and the European Union – NextGenerationEU through the Recovery and Resilience Facility project ICTS-MRR-2021-03-CEFCA and from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) under grant 313285/2020-9 D.A.F. thanks the ARC for financial assistance via DP170102344. Y.J.-T has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No 898633. Y.J-T. also acknowledges financial support from the State Agency for Research of the Spanish MCIU through the “Center of Excellence Severo Ochoa” award to the Instituto de Astrofísica de Andalucía (SEV-2017-0709). Based on observations made with the JAST80 telescope telescope/s at the Observatorio Astrofísico de Javalambre, in Teruel, owned, managed, and operated by the Centro de Estudios de Física del Cosmos de Aragón. We thank the Centro de Estudios de Física del Cosmos de Aragón for the allocation of the Director’s Discretionary Time to this program. We thank the OAJ Data Processing and Archiving Unit (UPAD) for reducing and calibrating the OAJ data used in this work. Funding for the J-PLUS Project has been provided by the Governments of Spain and Aragón through the Fondo de Inversiones de Teruel; the Aragón Government through the Research Groups E96, E103, and E16_17R; the Spanish Ministry of Science, Innovation, and Universities (MCIU/AEI/FEDER, UE) with grants PGC2018-097585-B-C21 and PGC2018-097585-B-C22; the Spanish Ministry of Economy and Competitiveness (MINECO) under AYA2015-66211-C2-1-P, AYA2015-66211-C2-2, AYA2012-30789, and ICTS-2009-14; and European FEDER funding (FCDD10-4E-867, FCDD13-4E-2685). The Brazilian agencies FINEP, FAPESP, and the National Observatory of Brazil have also contributed to this project. This work has made use of the computing facilities of the Laboratory of Astroinformatics (IAG/USP, NAT/Unicsul), whose purchase was made possible by the Brazilian agency FAPESP (grant 2009/54006-4) and the INCT-A.Peer reviewe

Hitos Demográficos del Siglo XXI: Migración Internacional

La migración ha sido una constante en la historia mundial. Sin embargo, las migraciones que han tenido lugar desde principios del siglo XXI no tienen precedentes, ya que recientemente éstas han alcanzado su mayor volumen en la historia y presentan características que las diferencian de las observadas en periodos anteriores, lo que ha propiciado una nueva conceptualización del fenómeno, enmarcada en lo que algunos estudiosos llaman “la nueva era” de las migraciones internacionales (Arango, 2003, mencionado por Fernández, 2005). Este nuevo ciclo se caracteriza por una profusa re-configuración del mapa migratorio mundial, el cual parece dar cuenta hoy, de una auténtica mundialización migratoria, con una fuerte tendencia a la diversificación de rutas y conexiones origen-destino. El nuevo mapa es el correlato de un escenario de globalización económica, cultural e informacional, que estimula que segmentos amplios de la población respondan cada vez más rápidamente a informaciones y oportunidades que se originan más allá de las fronteras nacionales (CONAPO, 2009). De esta forma la nueva era de la globalización, se ha convertido en un asunto de especial trascendencia. Por un lado, la mejora y expansión de los sistemas de comunicación y transporte y la significativa reducción del tiempo y coste de desplazamiento, así como las disparidades económicas y la existencia de situaciones sociales y políticas extremas han propiciado el crecimiento de los movimientos transnacionales de personas y la intensificación de las presiones migratorias. En este sentido, España nunca ha sido ajena al fenómeno de las corrientes migratorias. Así por ejemplo, en los últimos años y durante la primera mitad del siglo XX y parte de la segunda, grandes contingentes de españoles emigraron hacia diferentes puntos de América Latina y Europa en busca de un empleo y mejor calidad de vida. Pero fue a finales del siglo pasado cuando España, impulsada por el acelerado ritmo de crecimiento económico adoptado en parte gracias a su integración económica en Europa, pasó de ser una economía emisora de emigrantes a una receptora de inmigrantes. Sin embargo, el fenómeno de la inmigración en España cobró verdadera importancia hasta principios del siglo XXI, cuando las fuertes oleadas masivas de personas provenientes de países en vías de desarrollo se dejaron sentir en su estructura poblacional y actividad laboral; de ésta manera, durante el primer quinquenio de este siglo si al 1 de enero del año 2000 los residentes extranjeros en España eran 0.9 millones (que representaban 2.3 por ciento de las personas empadronadas) al 1 de enero de 2005 ya eran 3.7 millones, es decir, 8.5 por ciento de la población residente en el país, habiéndose por tanto cuadriplicado el efectivo de extranjeros en tan sólo cinco años (González, 2006: 2-3; Gil, 2007: 1). Con base en lo anterior, el objetivo del presente trabajo consistió en analizar las características de los flujos de inmigración actuales en España procedentes de países latinoamericanos, enmarcados en la nueva re-configuración del mapa migratorio mundial

Exploring Cosmic Origins with CORE: Cosmological Parameters

We forecast the main cosmological parameter constraints achievable with theCORE space mission which is dedicated to mapping the polarisation of the CosmicMicrowave Background (CMB). CORE was recently submitted in response to ESA'sfifth call for medium-sized mission proposals (M5). Here we report the resultsfrom our pre-submission study of the impact of various instrumental options, inparticular the telescope size and sensitivity level, and review the great,transformative potential of the mission as proposed. Specifically, we assessthe impact on a broad range of fundamental parameters of our Universe as afunction of the expected CMB characteristics, with other papers in the seriesfocusing on controlling astrophysical and instrumental residual systematics. Inthis paper, we assume that only a few central CORE frequency channels areusable for our purpose, all others being devoted to the cleaning ofastrophysical contaminants. On the theoretical side, we assume LCDM as ourgeneral framework and quantify the improvement provided by CORE over thecurrent constraints from the Planck 2015 release. We also study the jointsensitivity of CORE and of future Baryon Acoustic Oscillation and Large ScaleStructure experiments like DESI and Euclid. Specific constraints on the physicsof inflation are presented in another paper of the series. In addition to thesix parameters of the base LCDM, which describe the matter content of aspatially flat universe with adiabatic and scalar primordial fluctuations frominflation, we derive the precision achievable on parameters like thosedescribing curvature, neutrino physics, extra light relics, primordial heliumabundance, dark matter annihilation, recombination physics, variation offundamental constants, dark energy, modified gravity, reionization and cosmicbirefringence. (ABRIDGED

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

ECMO for COVID-19 patients in Europe and Israel

Since March 15th, 2020, 177 centres from Europe and Israel have joined the study, routinely reporting on the ECMO support they provide to COVID-19 patients. The mean annual number of cases treated with ECMO in the participating centres before the pandemic (2019) was 55. The number of COVID-19 patients has increased rapidly each week reaching 1531 treated patients as of September 14th. The greatest number of cases has been reported from France (n = 385), UK (n = 193), Germany (n = 176), Spain (n = 166), and Italy (n = 136) .The mean age of treated patients was 52.6 years (range 16–80), 79% were male. The ECMO configuration used was VV in 91% of cases, VA in 5% and other in 4%. The mean PaO2 before ECMO implantation was 65 mmHg. The mean duration of ECMO support thus far has been 18 days and the mean ICU length of stay of these patients was 33 days. As of the 14th September, overall 841 patients have been weaned from ECMO support, 601 died during ECMO support, 71 died after withdrawal of ECMO, 79 are still receiving ECMO support and for 10 patients status n.a. . Our preliminary data suggest that patients placed on ECMO with severe refractory respiratory or cardiac failure secondary to COVID-19 have a reasonable (55%) chance of survival. Further extensive data analysis is expected to provide invaluable information on the demographics, severity of illness, indications and different ECMO management strategies in these patients

Effect of aliskiren on post-discharge outcomes among diabetic and non-diabetic patients hospitalized for heart failure: insights from the ASTRONAUT trial

Aims The objective of the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) was to determine whether aliskiren, a direct renin inhibitor, would improve post-discharge outcomes in patients with hospitalization for heart failure (HHF) with reduced ejection fraction. Pre-specified subgroup analyses suggested potential heterogeneity in post-discharge outcomes with aliskiren in patients with and without baseline diabetes mellitus (DM). Methods and results ASTRONAUT included 953 patients without DM (aliskiren 489; placebo 464) and 662 patients with DM (aliskiren 319; placebo 343) (as reported by study investigators). Study endpoints included the first occurrence of cardiovascular death or HHF within 6 and 12 months, all-cause death within 6 and 12 months, and change from baseline in N-terminal pro-B-type natriuretic peptide (NT-proBNP) at 1, 6, and 12 months. Data regarding risk of hyperkalaemia, renal impairment, and hypotension, and changes in additional serum biomarkers were collected. The effect of aliskiren on cardiovascular death or HHF within 6 months (primary endpoint) did not significantly differ by baseline DM status (P = 0.08 for interaction), but reached statistical significance at 12 months (non-DM: HR: 0.80, 95% CI: 0.64-0.99; DM: HR: 1.16, 95% CI: 0.91-1.47; P = 0.03 for interaction). Risk of 12-month all-cause death with aliskiren significantly differed by the presence of baseline DM (non-DM: HR: 0.69, 95% CI: 0.50-0.94; DM: HR: 1.64, 95% CI: 1.15-2.33; P < 0.01 for interaction). Among non-diabetics, aliskiren significantly reduced NT-proBNP through 6 months and plasma troponin I and aldosterone through 12 months, as compared to placebo. Among diabetic patients, aliskiren reduced plasma troponin I and aldosterone relative to placebo through 1 month only. There was a trend towards differing risk of post-baseline potassium ≥6 mmol/L with aliskiren by underlying DM status (non-DM: HR: 1.17, 95% CI: 0.71-1.93; DM: HR: 2.39, 95% CI: 1.30-4.42; P = 0.07 for interaction). Conclusion This pre-specified subgroup analysis from the ASTRONAUT trial generates the hypothesis that the addition of aliskiren to standard HHF therapy in non-diabetic patients is generally well-tolerated and improves post-discharge outcomes and biomarker profiles. In contrast, diabetic patients receiving aliskiren appear to have worse post-discharge outcomes. Future prospective investigations are needed to confirm potential benefits of renin inhibition in a large cohort of HHF patients without D