Stroke risk estimation across nine European countries in the MORGAM project.

Previous tools for stroke risk assessment have either been developed for specific populations or lack data on non-fatal events or uniform data collection. The purpose of this study was to develop a stepwise model for the estimation of 10 year risk of stroke in nine different countries across Europe.Using data from the MOnica Risk, Genetics, Archiving and Monograph (MORGAM) Project, sex-specific models estimating 10 year risk of stroke were developed using a Cox regression model stratified by country and including modelling of competing risks. Models were developed in a stepwise manner first using only data from questionnaires, and then adding data from physical examinations and finally data from blood samples.During 1,176,296 years of observation, 2928 incident fatal and non-fatal events of stroke were registered. The developed model showed good calibration and accuracy of prediction. The discrimination of the model varied between sex and country but increased with increasing number of variables used (area under the receiver operating characteristic curve between 0.77 and 0.79 in men and between 0.75 and 0.80 in women).The present study shows that using a large multicountry cohort from nine European countries it is possible to develop a stepwise risk estimation model for 10 year risk of stroke tailored to different availability of risk factors and still obtain valid measures of risk even in the simplest form of the model, with increasing performance of the model following increasing complexity. The methods chosen which separate this model from previous models (competing risk and stepwise approach) should be considered for future risk estimation models

Gauge-origin independent magneto-optical activity within coupled-cluster response theory

We present a gauge-origin independent formulation of the Faraday B term of magnetic circular dichroism and of the Verdet constant of magneto-optical rotation, in terms of first derivatives with respect to the magnetic field strength of gauge invariant coupled cluster response functionals [1]. Gauge invariance is ensured by the derivative formulation in connection with the use of a magnetic field dependent basis of atomic orbitals, the so-called London orbitals. To our knowledge this represent the first application of London atomic orbitals to the calculation of frequency dependent quadratic response properties. The approach can easily be extended to other wavefunction models, and to any other frequency dependent property which can be formulated as total derivative of a (frequency-dependent) functional with respect to the field strengths of a static magnetic perturbation. In other words, any properties for which the frequency dependence is not associated with the magnetic field. This is for example the case for the hypermagnetizabilities in the Cotton-Moutton effect. The implementation of the derived equations is currently undertaken for a CCSD wavefunction on a local version of the Dalton program. [1] S. Coriani, C. H\ue4ttig, P. J\uf8rgensen, T. Helgake

Accurate geometries from ab initio calculations: systems containing second-row atoms and transition metals

The performance of the standard hierarchies of ab initio models HF, MP2, CCSD and CCSD(T) and of correlation consistent basis sets is analyzed in determining bond lengths and bond angles on a set of 32 closed-shell molecules containing second-row elements. The importance of core correlation is assessed using hierarchies of correlation consistent valence and core-valence basis sets, the former used in connection with the frozen-core approximation and the latter freezing only the 1s orbital on the second row atom. Results of the geometry optimization of ferrocene in the eclipsed and staggered conformational forms at the MP2, CCSD and CCSD(T) levels in a TZV2P+f basis set and with 66 valence electrons correlated are also presented

Comparison of standard and damped response formulations of magnetic circular dichroism

We apply damped response theory to the phenomenon of magnetic circular dichroism (MCD), and we investigate how the numerical instability associated with the simulation of the MCD spectrum from individually calculated A and B terms for close lying states can be remedied by the use of damped response theory. We also present a method for calculating the Faraday A term, formulated as a double residue of the quadratic response function

An atomic-orbital based Lagrangian approach for calculating geometric gradients of linear response properties

We present a Lagrangian approach for the calculation of molecular (quadratic) response properties that can be expressed as geometric gradients of a generic linear response function, its poles, and its residues. The approach is implemented within an atomic-orbital-based formalism suitable for linear scaling at the level of self-consistent time-dependent Hartree 12Fock and density functional theory. Among the properties that can be obtained using this formalism are the gradient of the frequency-dependent polarizability (e.g., Raman intensities) and that of the one-photon transition dipole moment (entering the Herzberg 12Teller factors), in addition to the excited-state molecular forces required for excited-state geometry optimizations. Geometric derivatives of ground-state first-order properties (e.g., IR intensities) and excited-state first-order property expressions are also reported as byproducts of our implementation. The one-photon transition moment gradient is the first analytic implementation of the one-photon transition moment derivative at the DFT level of theory. Besides offering a simple solution to overcome phase (hence, sign) uncertainties connected to the determination of the Herzberg 12Teller corrections by numerical derivatives techniques based on independent calculations, our approach also opens the possibility to determine, for example by a mixed analytic 12numerical approach, the one-photon transition dipole Hessian, and thus to investigate vibronic effects beyond the linear Herzberg 12Teller approximation. As an illustrative application, we report a DFT study of the vibronic fine structure of the one-photon (1A1g) 12 (1B2u) transition in the absorption spectrum of benzene, which is Franck 12Condon-forbidden in the electric dipole approximation and hence determined by the Herzberg 12Teller integrals and electronic transition dipole-moment derivatives

The prebiotic molecular inventory of Serpens SMM1: I. An investigation of the isomers CH3NCO and HOCH2CN

Aims. Methyl isocyanate (CH3NCO) and glycolonitrile (HOCH2CN) are isomers and prebiotic molecules that are involved in the formation of peptide structures and the nucleobase adenine, respectively. These two species are investigated to study the interstellar chemistry of cyanides (CN) and isocyanates (NCO) and to gain insight into the reservoir of interstellar prebiotic molecules. Methods. ALMA observations of the intermediate-mass Class 0 protostar Serpens SMM1-a and ALMA-PILS data of the low-mass Class 0 protostar IRAS 16293B are used. Spectra are analysed with the CASSIS line analysis software package in order to identify and characterise molecules. Results. CH3NCO, HOCH2CN, and various other molecules are detected towards SMM1-a. HOCH2CN is identified in the PILS data towards IRAS 16293B in a spectrum extracted at a half-beam offset position from the peak continuum. CH3NCO and HOCH2CN are equally abundant in SMM1-a at [X]/[CH3OH] of 5.3 7 10-4 and 6.2 7 10-4, respectively. A comparison between SMM1-a and IRAS 16293B shows that HOCH2CN and HNCO are more abundant in the former source, but CH3NCO abundances do not differ significantly. Data from other sources are used to show that the [CH3NCO]/[HNCO] ratio is similar in all these sources within ~10%.Conclusions. The new detections of CH3NCO and HOCH2CN are additional evidence for a large interstellar reservoir of prebiotic molecules that can contribute to the formation of biomolecules on planets. The equal abundances of these molecules in SMM1-a indicate that their formation is driven by kinetic processes instead of thermodynamic equilibrium, which would drive the chemistry to one product. HOCH2CN is found to be much more abundant in SMM1-a than in IRAS 16293B. From the observational data, it is difficult to indicate a formation pathway for HOCH2CN, but the thermal Strecker-like reaction of CN- with H2CO is a possibility. The similar [CH3NCO]/[HNCO] ratios found in the available sample of studied interstellar sources indicate that these two species are either chemically related or their formation is affected by physical conditions in the same way. Both species likely form early during star formation, presumably via ice mantle reactions taking place in the dark cloud or when ice mantles are being heated in the hot core. The relatively high abundances of HOCH2CN and HNCO in SMM1-a may be explained by a prolonged stage of relatively warm ice mantles, where thermal and energetic processing of HCN in the ice results in the efficient formation of both species

The ALMA-PILS survey: Detection of CH3NCO toward the low-mass protostar IRAS 16293-2422 and laboratory constraints on its formation

Methyl isocyanate (CH3NCO) belongs to a select group of interstellar moleculesconsidered to be relevant precursors in the formation of larger organic compounds, including those with peptide bonds. The molecule has only been detected in a couple of high-mass protostars and potentially on comets. A formation route on icy grains has been postulated for this molecule but experimental evidence is lacking. Here we ex- tend the range of environments where methyl isocyanate is found, and unambiguously identify CH3NCO through the detection of 43 unblended transitions in the ALMA Protostellar Interferometric Line Survey (PILS) of the low mass solar-type protostel- lar binary IRAS 16293-2422. The molecule is detected toward both components of the binary with a ratio HNCO/CH3NCO ∼4–12. The isomers CH3CNO and CH3OCN are not identified, resulting in upper abundance ratios of CH3NCO/CH3CNO > 100 and CH3NCO/CH3OCN > 10. The resulting abundance ratios compare well with those found for related N-containing species toward high-mass protostars. To constrain its formation, a set of cryogenic UHV experiments is performed. VUV irradiation of CH4:HNCO mixtures at 20 K strongly indicate that methyl isocyanate can be formed in the solid-state through CH3 and (H)NCO recombinations. Combined with gas-grain models that include this reaction, the solid-state route is found to be a plausible sce- nario to explain the methyl isocyanate abundances found in IRAS 16293-2422.Ke

Management of fracture risk in CKD : traditional and novel approaches

The coexistence of osteoporosis and chronic kidney disease (CKD) is an evolving healthcare challenge in the face of increasingly aging populations. Globally, accelerating fracture incidence causes disability, impaired quality of life and increased mortality. Consequently, several novel diagnostic and therapeutic tools have been introduced for treatment and prevention of fragility fractures. Despite an especially high fracture risk in CKD, these patients are commonly excluded from interventional trials and clinical guidelines. While management of fracture risk in CKD has been discussed in recent opinion-based reviews and consensus papers in the nephrology literature, many patients with CKD stages 3–5D and osteoporosis are still underdiagnosed and untreated. The current review addresses this potential treatment nihilism by discussing established and novel approaches to diagnosis and prevention of fracture risk in patients with CKD stages 3–5D. Skeletal disorders are common in CKD. A wide variety of underlying pathophysiological processes have been identified, including premature aging, chronic wasting, and disturbances in vitamin D and mineral metabolism, which may impact bone fragility beyond established osteoporosis. We discuss current and emerging concepts of CKD–mineral and bone disorders (CKD-MBD) and integrate management of osteoporosis in CKD with current recommendations for management of CKD-MBD. While many diagnostic and therapeutic approaches to osteoporosis can be applied to patients with CKD, some limitations and caveats need to be considered. Consequently, clinical trials are needed that specifically study fracture prevention strategies in patients with CKD stages 3–5D

Sex Differences and Similarities in Atrial Fibrillation Epidemiology, Risk Factors, and Mortality in Community Cohorts: Results From the BiomarCaRE Consortium (Biomarker for Cardiovascular Risk Assessment in Europe)

BACKGROUND: Atrial fibrillation (AF) is a common cardiac disease in aging populations with high comorbidity and mortality. Sex differences in AF epidemiology are insufficiently understood. METHODS: In N=79\u2009793 individuals without AF diagnosis at baseline (median age, 49.6 years; age range, 24.1-97.6 years; 51.7% women) from 4 community-based European studies (FINRISK, DanMONICA, Moli-sani Northern Sweden) of the BiomarCaRE consortium (Biomarker for Cardiovascular Risk Assessment in Europe), we examined AF incidence, its association with mortality, common risk factors, biomarkers, and prevalent cardiovascular disease, and their attributable risk by sex. Median follow-up time was 12.6 (to a maximum of 28.2) years. RESULTS: Fewer AF cases were observed in women (N=1796; 4.4%), than in men (N=2465; 6.4%). Cardiovascular risk factor distribution and lipid profile at baseline were less beneficial in men than in women, and cardiovascular disease was more prevalent in men. Cumulative incidence increased markedly after the age of 50 years in men and after 60 years in women. The lifetime risk was similar (>30%) for both sexes. Subjects with incident AF had a 3.5-fold risk of death in comparison with those without AF. Multivariable-adjusted models showed sex differences for the association of body mass index and AF (hazard ratio per standard deviation increase, 1.18; 95% confidence interval [CI], 1.12-1.23 in women versus 1.31; 95% CI 1.25-1.38 in men; interaction P value of 0.001). Total cholesterol was inversely associated with incident AF with a greater risk reduction in women (hazard ratio per SD, 0.86; 95% CI, 0.81-0.90 versus 0.92; 95% CI, 0.88-0.97 in men; interaction P value of 0.023). No sex differences were seen for C-reactive protein and N-terminal pro B-type natriuretic peptide. The population-attributable risk of all risk factors combined was 41.9% in women and 46.0% in men. About 20% of the risk was observed for body mass index. CONCLUSIONS: Lifetime risk of AF was high, and AF was strongly associated with increased mortality both in women and men. Body mass index explained the largest proportion of AF risk. Observed sex differences in the association of body mass index and total cholesterol with AF need to be evaluated for underlying pathophysiology and relevance to sex-specific prevention strategies