Genomic insights into the origin of farming in the ancient Near East

We report genome-wide ancient DNA from 44 ancient Near Easterners ranging in time between ~12,000 and 1,400 BC, from Natufian hunter–gatherers to Bronze Age farmers. We show that the earliest populations of the Near East derived around half their ancestry from a ‘Basal Eurasian’ lineage that had little if any Neanderthal admixture and that separated from other non-African lineages before their separation from each other. The first farmers of the southern Levant (Israel and Jordan) and Zagros Mountains (Iran) were strongly genetically differentiated, and each descended from local hunter–gatherers. By the time of the Bronze Age, these two populations and Anatolian-related farmers had mixed with each other and with the hunter–gatherers of Europe to greatly reduce genetic differentiation. The impact of the Near Eastern farmers extended beyond the Near East: farmers related to those of Anatolia spread westward into Europe; farmers related to those of the Levant spread southward into East Africa; farmers related to those of Iran spread northward into the Eurasian steppe; and people related to both the early farmers of Iran and to the pastoralists of the Eurasian steppe spread eastward into South Asia

Multiphysics and Thermodynamic Formulations for Equilibrium and Non-equilibrium Interactions: Non-linear Finite Elements Applied to Multi-coupled Active Materials

[EN] Combining several theories this paper presents a general multiphysics framework applied to the study of coupled and active materials, considering mechanical, electric, magnetic and thermal fields. The framework is based on thermodynamic equilibrium and non-equilibrium interactions, both linked by a two-temperature model. The multi-coupled governing equations are obtained from energy, momentum and entropy balances; the total energy is the sum of thermal, mechanical and electromagnetic parts. The momentum balance considers mechanical plus electromagnetic balances; for the latter the Abraham rep- resentation using the Maxwell stress tensor is formulated. This tensor is manipulated to automatically fulfill the angular momentum balance. The entropy balance is for- mulated using the classical Gibbs equation for equilibrium interactions and non-equilibrium thermodynamics. For the non-linear finite element formulations, this equation requires the transformation of thermoelectric coupling and conductivities into tensorial form. The two-way thermoe- lastic Biot term introduces damping: thermomechanical, pyromagnetic and pyroelectric converse electromagnetic dynamic interactions. Ponderomotrix and electromagnetic forces are also considered. The governing equations are converted into a variational formulation with the resulting four-field, multi-coupled formalism implemented and val- idated with two custom-made finite elements in the research code FEAP. Standard first-order isoparametric eight-node elements with seven degrees of freedom (dof) per node (three displacements, voltage and magnetic scalar potentials plus two temperatures) are used. Non-linearities and dynamics are solved with Newton-Raphson and New- mark-b algorithms, respectively. Results of thermoelectric, thermoelastic, thermomagnetic, piezoelectric, piezomag- netic, pyroelectric, pyromagnetic and galvanomagnetic interactions are presented, including non-linear depen- dency on temperature and some second-order interactions.This research was partially supported by grants CSD2008-00037 Canfranc Underground Physics, Polytechnic University of Valencia under programs PAID 02-11-1828 and 05-10-2674. The first author used the grant Generalitat Valenciana BEST/2014/232 for the completion of this work.Pérez-Aparicio, JL.; Palma, R.; Taylor, R. (2016). Multiphysics and Thermodynamic Formulations for Equilibrium and Non-equilibrium Interactions: Non-linear Finite Elements Applied to Multi-coupled Active Materials. Archives of Computational Methods in Engineering. 23:535-583. https://doi.org/10.1007/s11831-015-9149-9S53558323Abraham M (1910) Sull’elettrodinamica di Minkowski. Rend Circ Mat 30:33–46Allik H, Hughes TJR (1970) Finite elment method for piezoelectric vibration. Int J Numer Methods Eng 2:151–157Antonova EE, Looman DC (2005) Finite elements for thermoelectric device analysis in ANSYS. In: International conference on thermoelectricsAtulasimha J, Flatau AB (2011) A review of magnetostrictive iron–gallium alloys. Smart Mater Struct 20:1–15Ballato A (1995) Piezoelectricity: old effect, new thrusts. IEEE Trans Ultrason Ferroelectr Freq Control 42(5):916–926Baoyuan S, Jiantong W, Jun Z, Min Q (2003) A new model describing physical effects in crystals: the diagrammatic and analytic methods for macro-phenomenological theory. J Mater Process Technol 139:444–447Bargmann S, Steinmann P (2005) Finite element approaches to non-classical heat conduction in solids. Comput Model Eng Sci 9(2):133–150Bargmann S, Steinmann P (2006) Theoretical and computational aspects of non-classical thermoelasticity. Comput Methods Appl Mech Eng 196:516–527Bargmann S, Steinmann P (2008) Modeling and simulation of first and second sound in solids. Int J Solids Struct 45:6067–6073Barnett SM (2010) Resolution of the Abraham–Minkowski dilemma. Phys Rev Lett 104:070401Benbouzid MH, Meunier G, Meunier G (1995) Dynamic modelling of giant magnetostriction in Terfenol-D rods by the finite element method. IEEE Trans Magn 31(3):1821–1824Benbouzid MH, Reyne G, Meunier G (1993) Nonlinear finite element modelling of giant magnetostriction. IEEE Trans Magn 29(6):2467–2469Benbouzid MH, Reyne G, Meunier G (1995) Finite elment modelling of magnetostrictive devices: investigations for the design of the magnetic circuit. IEEE Trans Magn 31(3):1813–1816Besbes M, Ren Z, Razek A (1996) Finite element analysis of magneto-mechanical coupled phenomena in magnetostrictive materials. IEEE Trans Magn 32(3):1058–1061Biot MA (1956) Thermoelasticity and irreversible thermodynamics. J Appl Phys 27(3):240–253Bisio G, Cartesegna M, Rubatto G (2001) Thermodynamic analysis of elastic systems. Energy Convers Manag 42:799–812Blun SL (1974) Materials for radiation detection. National Academy of Sciences, WashingtonBonet J, Wood RD (1997) Nonlinear continuum mechanics for finite element analysis. Cambridge University Press, CambridgeBorovik-Romanov AS (1960) Piezomagnetism in the antiferromagnetic fluorides of cobalt and manganese. Sov Phys 11:786Bowyer P (2005) The momentum of light in media: the Abraham–Minkowski controversy. http://bit.ly/1M7wyATBrauer JR, Ruehl JJ, MacNeal BE, Hirtenfelder F (1995) Finite element analysis of Hall effect and magnetoresistance. IEEE Trans Electron Devices 42(2):328–333Bustamante R, Dorfmann A, Ogden RW (2009) On electric body forces and Maxwell stresses in nonlinearly electroelastic solids. Int J Eng Sci 47:1131–1141Callen HB (1948) The application of Onsager’s reciprocal relations to thermoelectric, thermomagnetic, and galvanomagnetic effects. Phys Rev 73(11):1349–1358Callen HB (1985) Thermodynamics and an introduction to thermostatistics. Wiley, New YorkCarter JP, Booker JR (1989) Finite element analysis of coupled thermoelasticity. Comput Struct 31(1):73–80Cattaneo C (1938) Sulla conduzione del calore. Atti Semin Mat Fis Univ Modena 3:83–1013Chaplik AV (2000) Some exact solutions for the classical Hall effect in an inhomogeneous magnetic field. JETP Lett 72:503Chen PJ, Gurtin ME (1968) On a theory of heat conduction involving two temperatures. J Z Angew Math Phys ZAMP 19(4):614–627Chu LJ, Haus HA, Penfield P (1966) The force density in polarizable and magnetizable fluids. In: Proceedings of the IEEEClin Th, Turenne S, Vasilevskiy D, Masut RA (2009) Numerical simulation of the thermomechanical behavior of extruded bismuth telluride alloy module. J Electron Mater 38(7):994–1001Coleman BD (1964) Thermodynamics of materials with memory. Arch Ration Mech Anal 17:1–46de Groot SR (1961) Non-equilibrium themodynamics of systems in an electromagnetic field. J Nucl Energy C Plasma Phys 2:188–194de Groot SR, Mazur P (1984) Non-equilibrium thermodynamics. Dover, MineolaDebye P (1913) On the theory of anomalous dispersion in the region of long-wave electromagnetic radiation. Verh dtsch phys Ges 15:777–793del Castillo LF, García-Colín LS (1986) Thermodynamic basis for dielectric relaxation in complex materials. Phys Rev B 33(7):4944–4951Delves RT (1964) Figure of merit for Ettingshausen cooling. Br J Appl Phys 15:105–106Dorf RC (1997) The electrical engineering handbook. CRC Press, UKEarle R, Richards JFC (1956) Theophrastus: on stones. Ohio State University, ColumbusEbling D, Jaegle M, Bartel M, Jacquot A, Bottner H (2009) Multiphysics simulation of thermoelectric systems for comparison with experimental device performance. J Electron Mater 38(7):1456–1461El-Karamany AS, Ezzat MA (2011) On the two-temperature Green–Naghdi thermoelasticity theories. J Therm Stress 34:1207–1226Eringen AC (1980) Mechanics of continua. Robert E Krieger, MalabarEringen AC, Maugin GA (1990) Electrodynamics of continua I. Springer, New YorkErsoy Y (1984) A new nonlinear constitutive theory for conducting magnetothermoelastic solids. Int J Eng Sci 22(6):683–705Ersoy Y (1986) A new nonlinear constitutive theory of electric and heat conductions for magnetoelastothermo-electrical anisotropic solids. Int J Eng Sci 24(6):867–882Ferrari A, Mittica A (2013) Thermodynamic formulation of the constitutive equations for solids and fluids. Energy Convers Manag 66:77–86Galushko D, Ermakov N, Karpovski M, Palevski A, Ishay JS, Bergman DJ (2005) Electrical, thermoelectric and thermophysical properties of hornet cuticle. Semicond Sci Technol 20:286–289Gao JL, Du QG, Zhang XD, Jiang XQ (2011) Thermal stress analysis and structure parameter selection for a Bi2Te3-based thermoelectric module. J Electron Mater 40(5):884–888Gaudenzi P, Bathe KJ (1995) An iterative finite element procedure for the analysis of piezoelectric continua. J Intell Mater Syst Struct 6:266–273Gavela D, Pérez-Aparicio JL (1998) Peltier pellet analysis with a coupled, non-linear 3D finite element model. In: 4th European workshop on thermoelectricsGoudreau GL, Taylor RL (1972) Evaluation of numerical integration methods in elastodynamics. Comput Methods Appl Mech Eng 2:69–97Griffiths DJ (1999) Introduction to electrodynamics. Prentice-Hall Inc, Upper Saddle RiverGros L, Reyne G, Body C, Meunier G (1998) Strong coupling magneto mechanical methods applied to model heavy magnetostrictive actuators. IEEE Trans Magn 34(5):3150–3153Gurtin ME, Williams WO (1966) On the Clausius–Duhem inequality. J Z Angew Math Phys ZAMP 17(5):626–633Hamader VM, Patil TA, Chovan SH (1987) Free vibration response of two-dimensional magneto-electro-elastic laminated plates. Build Mater Sci 9:249–253Hausler C, Milde G, Balke H, Bahr HA, Gerlach G (2001) 3-D modeling of pyroelectric sensor arrays part I: multiphysics finite-element simulation. IEEE Sens J 8(12):2080–2087He Y (2004) Heat capacity, thermal conductivity and thermal expansion of barium titanate-based ceramics. Thermochimica 419:135–141Hernández-Lemus E, Orgaz E (2002) Hysteresis in nonequilibrium steady states: the role of dissipative couplings. Rev Mex Fís 48:38–45Hinds EA (2009) Momentum exchange between light and a single atom: Abraham or Minkowski? Phys Rev Lett 102:050403Hirsinger L, Billardon R (1995) Magneto-elastic finite element analysis including magnetic forces and magnetostriction effects. IEEE Trans Magn 31(3):1877–1880Huang MJ, Chou PK, Lin MC (2008) An investigation of the thermal stresses induced in a thin-film thermoelectric cooler. J Therm Stress 31:438–454IEEE Standards Board (1988) IEEE standard on piezoelectricity. ANSI/IEEE Std 176-1987. doi: 10.1109/IEEESTD.1988.79638IEEE Standards Board (1991) IEEE standard on magnetostrictive materials: piezomagnetic nomenclature. IEEE Std 319-1990. doi: 10.1109/IEEESTD.1991.101048Ioffe Institute (2013) INSb—indium antimonide. Ioffe Institute. www.ioffe.rssi.ru/SVA/NSM/Semicond/InSb/index.htmlJackson JD (1962) Classical electrodynamics. Wiley, New YorkJaegle M (2008) Multiphysics simulation of thermoelectric systems—modeling of Peltier—cooling and thermoelectric generation. In: Proceedings of the COMSOLJaegle M, Bartel M, Ebling D, Jacquot A, Bottner H (2008) Multiphysics simulation of thermoelectric systems. In: European conference on thermoelectrics ECT2008Jiménez JL, Campos I (1996) Advanced electromagnetism: foundations, theory and applications, chapter The balance equations of energy and momentum in classical electrodynamics. World Scientific Publishing, SingaporeJohnstone S (2008) Is there potential for use of the Hall effect in analytical science? Analyst 133:293–296Jou D, Lebon G (1996) Extended irreversible thermodynamics. Springer, BerlinKaltenbacher M, Kaltenbacher B, Hegewald T, Lerch R (2010) Finite element formulation for ferroelectric hysteresis of piezoelectric materials. J Intell Mater Syst Struct 21:773–785Kaltenbacher M, Meiler M, Ertl M (2009) Physical modeling and numerical computation of magnetostriction. Int J Comput Math Electr Electron Eng 28(4):819–832Kamlah M, Bohle U (2001) Finite element analysis of piezoceramic components taking into account ferroelectric hysteresis behavior. Int J Solids Struct 38:605–633Kannan KS, Dasgupta A (1997) A nonlinear Galerkin finite-element theory for modeling magnetostrictive smart structures. Smart Mater Struct 6:341–350Kiang J, Tong L (2010) Nonlinear magneto-mechanical finite element analysis of Ni–Mn–Ga single crystals. Smart Mater Struct 19:1–17Kinsler P, Favaro A, McCall MW (2009) Four Poynting theorems. Eur J Phys 30:983–993Klinckel S, Linnemann K (2008) A phenomenological constitutive model for magnetostrictive materials and ferroelectric ceramics. Proc Appl Math Mech 8:10507–10508Kosmeier D (2013) Hornets: Gentle Giants! Wikipedia: the free encyclopedia. www.hornissenschutz.de/hornets.htmLahmer T (2008) Forward and inverse problems in piezoelectricity. PhD thesis, Universität Erlangen-NürnbergLandau LD, Lifshitz EM (1982) Mechanics. Butterworth-Heinemann, OxfordLandau LD, Lifshitz EM (1984) Electrodynamics of continuous media. Pergamon Press, OxfordLandis CM (2002) A new finite-element formulation for electromechanical boundary value problems. Int J Numer Methods Eng 55:613–628Díaz Lantada A (2011) Handbook of active materials for medical devices: advances and applications. CRC Press, Boca RatonLebon G, Jou D, Casas-Vázquez J (2008) Understanding non-equilibrium thermodynamics. Springer, BerlinLinnemann K, Klinkel S (2006) A constitutive model for magnetostrictive materials—theory and finite element implementation. Proc Appl Math Mech 6:393–394Linnemann K, Klinkel S, Wagner W (2009) A constitutive model for magnetostrictive and piezoelectric materials. Int J Solids Struct 46:1149–1166Llebot JE, Jou D, Casas-Vázquez J (1983) A thermodynamic approach to heat and electric conduction in solids. Physica 121(A):552–562Lu X, Hanagud V (2004) Extended irreversible thermodynamics modeling for self-heating and dissipation in piezoelectric ceramics. IEEE Trans Ultrason Ferroelectr Freq Control 51(12):1582–1592Lubarda VA (2004) On thermodynamic potentials in linear thermoelasticity. Int J Solids Struct 41:7377–7398Mansuripur M (2012) Trouble with the lorentz law of force: incompatibility with special relativity and momentum conservation. Phys Rev Lett 108:193901Maruszewski B, Lebon G (1986) An extended irreversible thermodynamic description of electrothermoelastic semiconductors. Int J Eng Sci 24(4):583–593McMeeking RM, Landis CM (2005) Electrostatic forces and stored energy for deformable dielectric materials. J Appl Mech 72:581–590McMeeking RM, Landis CM, Jimenez MA (2007) A principle of virtual work for combined electrostatic and mechanical loading of materials. Int J Non Linear Mech 42:831–838MELCOR (2000) Thermoelectric handbook. Melcor, a unit of Laird Technologies. http://www.lairdtech.comMinkowski H (1908) Nachr. ges. wiss. Gottingen 53Naranjo B, Gimzewski JK, Putterman S (2005) Observation of nuclear fusion driven by a pyroelectric crystal. Nature 28(434):1115–1117Nédélec JC (1980) Mixed finite elements in $${R}^3$$ R 3 . Numer Math 35:314–345Nettleton RE, Sobolev SL (1995) Applications of extended thermodynamics to chemical, rheological, and transport processes: a special survey part I. approaches and scalar rate processes. J Non-Equilib Thermodyn 20:205–229Nettleton RE, Sobolev SL (1995) Applications of extended thermodynamics to chemical, rheological, and transport processes: a special survey part II. vector transport processes, shear relaxation and rheology. J Non-Equilib Thermodyn 20:297–331Nettleton RE, Sobolev SL (1996) Applications of extended thermodynamics to chemical, rheological, and transport processes: a special survey part III. wave phenomena. J Non-Equilib Thermodyn 21:1–16Newmark N (1959) A method of computation for structural dynamics. ASCE J Eng Mech 85:67–94Newnham RE (2005) Properties of materials: anisotropy, symmetry, structure. Oxford University Press, OxfordNour AE, Abd-Alla N, Maugin GA (1990) Nonlinear equations for thermoelastic magnetizable conductors. Int J Eng Sci 27(7):589–603Nowacki A (1962) International series of monographs in aeronautics and astronautics. Pergamon Press, OxfordOkumura H, Hasegawa Y, Nakamura H, Yamaguchi S (1999) A computational model of thermoelectric and thermomagnetic semiconductors. In: 18th international conference on thermoelectricsOkumura H, Yamaguchi S, Nakamura H, Ikeda K, Sawada K (1998) Numerical computation of thermoelectric and thermomagnetic effects. In: 17th international conference on thermoelectricsOliver X, Agelet C (2000) Continuum mechanics for engineers. Edicions UPC, Barcelona. http://hdl.handle.net/2099.3/36197Shankar K, Kondaiah P, Ganesan N (2013) Pyroelectric and pyromagnetic effects on multiphase magneto-electro-elastic cylindrical shells for axisymmetric temperature. Smart Mater Struct 22(2):025007Palma R, Pérez-Aparicio JL, Bravo R (2013) Study of hysteretic thermoelectric behavior in photovoltaic materials using the finite element method, extended thermodynamics and inverse problems. Energy Convers Manag 65:557–563Palma R, Pérez-Aparicio JL, Taylor RL (2012) Non-linear finite element formulation applied to thermoelectric materials under hyperbolic heat conduction model. Comput Method Appl Mech Eng 213–216:93–103Palma R, Rus G, Gallego R (2009) Probabilistic inverse problem and system uncertainties for damage detection in piezoelectrics. Mech Mater 41:1000–1016Pérez-Aparicio JL, Gavela D (1998) 3D, non-linear coupled, finite element model of thermoelectricity. In: 4th European workshop on thermoelectricsPérez-Aparicio JL, Palma R, Taylor RL (2012) Finite element analysis and material sensitivity of Peltier thermoelectric cells coolers. Int J Heat Mass Transf 55:1363–1374Pérez-Aparicio JL, Sosa H (2004) A continuum three-dimensional, fully coupled, dynamic, non-linear finite element formulation for magnetostrictive materials. Smart Mater Struct 13:493–502Perez-Aparicio JL, Sosa H, Palma R (2007) Numerical investigations of field-defect interactions in piezoelectric ceramics. Int J Solids Struct 44:4892–4908Pérez-Aparicio JL, Taylor RL, Gavela D (2007) Finite element analysis of nonlinear fully coupled thermoelectric materials. Comput Mech 40:35–45Qi H, Fang D, Yao Z (1997) FEM analysis of electro-mechanical coupling effect of piezoelectric materials. Comput Mater Sci 8:283–290Pérez-Aparicio JL, Palma R, Abouali-Sánchez S (2014) Complete finite element method analysis of galvanomagnetic and thermomagnetic effects. Appl Therm Eng (submitted)Perez-Aparicio JL, Palma R, Moreno-Navarro P (2014) Elasto-thermoelectric non-linear, fully coupled, and dynamic finite element analysis of pulsed thermoelectrics. Appl Therm Eng (submitted)Ramírez F, Heyliger PR, Pan E (2006) Free vibration response of two-dimensional magneto-electro-elastic laminated plates. J Sound Vib 292:626–644Reitz JR, Milford FJ (1960) Foundations of electromagnetic theory. Addison-Wesley, BostonReng Z, Ionescu B, Besbes M, Razek A (1995) Calculation of mechanical deformation of magnetic materials in electromagnetic devices. IEEE Trans Magn 31(3):1873–1876Restuccia L (2010) On a thermodynamic theory for magnetic relaxation phenomena due to n microscopic phenomena described by n internal variables. J Non-Equilib Thermodyn 35:379–413Restuccia L, Kluitenberg GA (1988) On generalizations of the Debye equation for dielectric relaxation. Phys A 154:157–182Restuccia L, Kluitenberg GA (1992) On the heat dissipation function for dielectric relaxation phenomena in anisotropic media. Int J Eng Sci 30(3):305–315Riffat SB, Ma X (2003) Thermoelectrics: a review of present and potential applications. Appl Therm Eng 23:913–935Rinaldi C, Brenner H (2002) Body versus surface forces in continuum mechanics: is the Maxwell stress tensor a physically objective Cauchy stress? Phys Rev E 65:036615Rowe DM (ed) (1995) CRC handbook of thermoelectrics. CRC Press, UKRus G, Palma R, Pérez-Aparicio JL (2009) Optimal measurement setup for damage detection in piezoelectric plates. Int J Eng Sci 47:554–572Rus G, Palma R, Pérez-Aparicio JL (2012) Experimental design of dynamic model-based damage identification in piezoelectric ceramics. Mech Syst Signal Process 26:268–293Sadiku MNO (2001) Numerical techniques in electromagnetics. CRC Press LLC, Boca RatonSemenov AS, Kessler H, Liskowsky A, Balke H (2006) On a vector potential formulation for 3D electromechanical finite element analysis. Commun Numer Methods Eng 22:357–375Serra E, Bonaldi M (2008) A finite element formulation for thermoelastic damping analysis. Int J Numer Methods Eng 78(6):671–691Several. Wikipedia. Wikipedia: The Free Encyclopedia, SeveralSoh AK, Liu JX (2005) On the constitutive equations of magnetoelectroelastic solids. J Intell Mater Syst Struct 16:597–602Stefanescu DM (2011) Handbook of force transducers: principles and components. Springer, BerlinTamma KK, Namburu RR (1992) An effective finite element modeling/analysis approach for dynamic thermoelasticity due to second sound effects. Comput Mech 9:73–84Tang T, Yu W (2009) Micromechanical modeling of the multiphysical behavior of smart materials using the variational asymptotic method. Smart Mater Struct 18:1–14Taylor RL (2010) FEAP a finite element analysis program: user manual. University of California, Berkeley. http://www.ce.berkeley.edu/feapThurston RN (1994) Warren p. Mason (1900–1986) physicist, engineer, inventor, author, teacher. IEEE Trans Ultrason Ferroelectr Freq Control 41(4):425–434Tian X, Shen Y, Chen C, He T (2006) A direct finite element method study of generalized thermoelastic problems. Int J Solids Struct 43:2050–2063Tinder RF (2008) Tensor properties of solids: phenomenological development of the tensor properties of crystals. Morgan and Claypool, San RafaelTruesdell C (1968) Thermodynamics for beginners, in irreversible aspects of continuum mechanics. Springer, BerlinTzou HS, Ye R (1996) Pyroelectric and thermal strain effects of piezoelectric (PVDF and PZT) devices. Mech Syst Signal Process 10(4):459–469Walser R (1972) Application of pyromagnetic phenomena to radiation detection

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Combined deformation and solidification-driven porosity formation in aluminum alloys

In die-casting processes, the high cooling rates and pressures affect the alloy solidification and deformation behavior, and thereby impact the final mechanical properties of cast components. In this study, isothermal semi-solid compression and subsequent cooling of aluminum die-cast alloy specimens were characterized using fast synchrotron tomography. This enabled the investigation and quantification of gas and shrinkage porosity evolution during deformation and solidification. The analysis of the 4D images (3D plus time) revealed two distinct mechanisms by which porosity formed; (i) deformation-induced growth due to the enrichment of local hydrogen content by the advective hydrogen transport, as well as a pressure drop in the dilatant shear bands, and (ii) diffusion-controlled growth during the solidification. The rates of pore growth were quantified throughout the process, and a Gaussian distribution function was found to represent the variation in the pore growth rate in both regimes. Using a one-dimensional diffusion model for hydrogen pore growth, the hydrogen flux required for driving pore growth during these regimes was estimated, providing a new insight into the role of advective transport associated with the deformation in the mushy region

Differences in the Aerobic Capacity of Flight Muscles between Butterfly Populations and Species with Dissimilar Flight Abilities

Habitat loss and climate change are rapidly converting natural habitats and thereby increasing the significance of dispersal capacity for vulnerable species. Flight is necessary for dispersal in many insects, and differences in dispersal capacity may reflect dissimilarities in flight muscle aerobic capacity. In a large metapopulation of the Glanville fritillary butterfly in the Åland Islands in Finland, adults disperse frequently between small local populations. Individuals found in newly established populations have higher flight metabolic rates and field-measured dispersal distances than butterflies in old populations. To assess possible differences in flight muscle aerobic capacity among Glanville fritillary populations, enzyme activities and tissue concentrations of the mitochondrial protein Cytochrome-c Oxidase (CytOx) were measured and compared with four other species of Nymphalid butterflies. Flight muscle structure and mitochondrial density were also examined in the Glanville fritillary and a long-distance migrant, the red admiral. Glanville fritillaries from new populations had significantly higher aerobic capacities than individuals from old populations. Comparing the different species, strong-flying butterfly species had higher flight muscle CytOx content and enzymatic activity than short-distance fliers, and mitochondria were larger and more numerous in the flight muscle of the red admiral than the Glanville fritillary. These results suggest that superior dispersal capacity of butterflies in new populations of the Glanville fritillary is due in part to greater aerobic capacity, though this species has a low aerobic capacity in general when compared with known strong fliers. Low aerobic capacity may limit dispersal ability of the Glanville fritillary.Peer reviewe

Etiological assessment of congenital profound sensorineural hearing loss

Introduction: Congenital profound sensorineural hearing losses are determined by genetic or nongenetic factors. To further evaluate more accurately congenital profound sensorineural hearing losses from etiologic point of view.Methods: Congenital profound sensorineural hearing loss etiological assessment is a critical component in infants and children clinical and paraclinical evaluation. Nongenetic factors might be implied in about 25% of congenital hearing losses, while genetic factors (hereditary) are thought to determine more than 50% of all hearing losses. Evaluation of nongenetic and genetic factors will allow to determine a disease progression pattern and will facilitate associated clinical manifestations and complications monitoring.Results: Implementation of a cost-efficient etiological assessment based on genetic testing, environmental factors, maternal infections (rubella, cytomegalovirus, herpes simplex virus), prematurity, low birth weight, birth injuries, toxins including drugs and alcohol consumed by the mother during pregnancy, complications associated with the Rh factor in the blood/jaundice, maternal diabetes, toxemia during pregnancy, anoxia evaluation. Imaging studies (CT and MRI) are indicated in order to exclude inner ear malformations.Conclusion: In congenital profound sensorineural hearing loss etiological assessment is mandatory a multidisciplinary approach: ENT surgeon, neonatologist, pediatrician, geneticist, radiologist and other specialists, depending on each case.Der Erstautor gibt keinen Interessenkonflikt an