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The reduction of iron(II) phthalocyanine (Pc(2-)Fe

Bivariate meta-analysis provides a useful framework for combining information across related studies and has been utilized to combine evidence from clinical studies to evaluate treatment efficacy on two outcomes. It has also been used to investigate surrogacy patterns between treatment effects on the surrogate endpoint and the final outcome. Surrogate endpoints play an important role in drug development when they can be used to measure treatment effect early compared to the final outcome and to predict clinical benefit or harm. The standard bivariate meta-analytic approach models the observed treatment effects on the surrogate and the final outcome outcomes jointly, at both the within-study and between-studies levels, using a bivariate normal distribution. For binomial data, a normal approximation on log odds ratio scale can be used. However, this method may lead to biased results when the proportions of events are close to one or zero, affecting the validation of surrogate endpoints. In this article, we explore modeling the two outcomes on the original binomial scale. First, we present a method that uses independent binomial likelihoods to model the within-study variability avoiding to approximate the observed treatment effects. However, the method ignores the within-study association. To overcome this issue, we propose a method using a bivariate copula with binomial marginals, which allows the model to account for the within-study association. We applied the methods to an illustrative example in chronic myeloid leukemia to investigate the surrogate relationship between complete cytogenetic response and event-free-survival.

BackgroundTelomere length is associated with risk of several age–related diseases and cancers. The extent to which telomere length may be modifiable through lifestyle and behaviour and whether this has any clinical consequences is unknown.MethodsIn up to 422,797 participants in UK Biobank, we investigated associations of leucocyte telomere length (LTL) with 117 potentially modifiable traits, as well as two indices of healthy behaviours incorporating smoking, physical activity, diet, maintenance of a healthy body weight and alcohol intake. Associations were interpreted as age–related change in LTL by dividing the trait beta coefficients with the age–coefficient. We used Mendelian Randomisation (MR) to test causality of the observed associations of educational attainment and smoking behaviour with LTL. We investigated whether the associations of LTL with 22 diseases were modified by the number of healthy behaviours and the extent to which the associations of more healthy behaviours with greater life expectancy and lower risk of coronary artery disease (CAD) may be mediated through LTL.Results71 traits showed significant associations with LTL but most were modest, equivalent to ConclusionsSeveral potentially modifiable traits and healthy behaviours have a quantifiable association with LTL, at least some of which are likely to be causal. However, these effects are not of a sufficient magnitude to substantially alter the association between LTL and various diseases or life expectancy.

Funder: Health Data Research UK EU/EFPIA Innovative Medicines Initiative Joint Undertaking BigData@Heart (11607)., Funder: Health Data Research UK, Telomeres, the end fragments of chromosomes, play key roles in cellular proliferation and senescence. Here we characterize the genetic architecture of naturally occurring variation in leukocyte telomere length (LTL) and identify causal links between LTL and biomedical phenotypes in 472,174 well-characterized UK Biobank participants. We identified 197 independent sentinel variants associated with LTL at 138 genomic loci (108 new). Genetically determined differences in LTL were associated with multiple biological traits, ranging from height to bone marrow function, as well as several diseases spanning neoplastic, vascular and inflammatory pathologies. Finally, we estimated that, at the age of 40 years, people with an LTL >1 s.d. shorter than the population mean had a 2.5-year-lower life expectancy compared with the group with ≥1 s.d. longer LDL. Overall, we furnish new insights into the genetic regulation of LTL, reveal wide-ranging influences of LTL on physiological traits, diseases and longevity, and provide a powerful resource available to the global research community.

Surrogate endpoints are very important in regulatory decision-making in healthcare, in particular if they can be measured early compared to the long-term final clinical outcome and act as good predictors of clinical benefit. Bivariate meta-analysis methods can be used to evaluate surrogate endpoints and to predict the treatment effect on the final outcome from the treatment effect measured on a surrogate endpoint. However, candidate surrogate endpoints are often imperfect, and the level of association between the treatment effects on the surrogate and final outcomes may vary between treatments. This imposes a limitation on the pairwise methods which do not differentiate between the treatments. We develop bivariate network meta-analysis (bvNMA) methods which combine data on treatment effects on the surrogate and final outcomes, from trials investigating heterogeneous treatment contrasts. The bvNMA methods estimate the effects on both outcomes for all treatment contrasts individually in a single analysis. At the same time, they allow us to model the surrogacy patterns across multiple trials (different populations) within a treatment contrast and across treatment contrasts, thus enabling predictions of the treatment effect on the final outcome for a new study in a new population or investigating a new treatment. Modelling assumptions about the between-studies heterogeneity and the network consistency, and their impact on predictions, are investigated using simulated data and an illustrative example in advanced colorectal cancer. When the strength of the surrogate relationships varies across treatment contrasts, bvNMA has the advantage of identifying treatments for which surrogacy holds, thus leading to better predictions.

Background Polygenic risk scores (PRSs) can stratify populations into cardiovascular disease (CVD) risk groups. We aimed to quantify the potential advantage of adding information on PRSs to conventional risk factors in the primary prevention of CVD. Methods and findings Using data from UK Biobank on 306,654 individuals without a history of CVD and not on lipid-lowering treatments (mean age [SD]: 56.0 [8.0] years; females: 57%; median follow-up: 8.1 years), we calculated measures of risk discrimination and reclassification upon addition of PRSs to risk factors in a conventional risk prediction model (i.e., age, sex, systolic blood pressure, smoking status, history of diabetes, and total and high-density lipoprotein cholesterol). We then modelled the implications of initiating guideline-recommended statin therapy in a primary care setting using incidence rates from 2.1 million individuals from the Clinical Practice Research Datalink. The C-index, a measure of risk discrimination, was 0.710 (95% CI 0.703–0.717) for a CVD prediction model containing conventional risk predictors alone. Addition of information on PRSs increased the C-index by 0.012 (95% CI 0.009–0.015), and resulted in continuous net reclassification improvements of about 10% and 12% in cases and non-cases, respectively. If a PRS were assessed in the entire UK primary care population aged 40–75 years, assuming that statin therapy would be initiated in accordance with the UK National Institute for Health and Care Excellence guidelines (i.e., for persons with a predicted risk of ≥10% and for those with certain other risk factors, such as diabetes, irrespective of their 10-year predicted risk), then it could help prevent 1 additional CVD event for approximately every 5,750 individuals screened. By contrast, targeted assessment only among people at intermediate (i.e., 5% to, Luanluan Sun and colleagues investigate whether adding polygenic risk scores to conventional risk factors of cardiovascular disease helps predict disease risk., Author summary Why was this study done? Application of polygenic risk scores (PRSs) has opened opportunities to enhance risk stratification and prevention for common diseases. The clinical utility of PRSs in cardiovascular disease (CVD) risk prediction is, however, uncertain. Previous analyses have generally focused only on coronary heart disease (CHD) rather than the composite outcome of CHD and stroke, and have often lacked modelling of clinical implications of initiating guideline-recommended interventions (e.g., statin therapy). What did the researchers do and find? We quantified the incremental predictive gain with PRSs on top of conventional risk factors using data on 306,654 individuals from UK Biobank. We modelled the population health implications of initiating statin therapy as recommended by current guidelines using data from 2.1 million individuals from the Clinical Practice Research Datalink. Addition of information on PRSs to a conventional risk prediction model increased the C-index (a measure of risk discrimination) and improved risk classification of cases and non-cases. We estimated that targeted assessment of PRSs among people at intermediate (i.e., 5% to

Background: \ud Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene.\ud \ud Objectives: \ud This study sought to test the association between the rs9349379 genotype and SCAD.\ud \ud Methods: \ud Results from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD.\ud \ud Results: \ud The previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95% confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89; 95% CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60; 95% CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence.\ud \ud Conclusions: \ud The first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD.

The effect of incorporating a single amide group on the self-assembly of discotic mesogens was examined. Two series of tetraalkoxydibenzophenazines amides were prepared: tertiary diethyl amides, dEt(n) incapable of hydrogen bonding, and secondary amides HBu(n) that can act as both H-bond donors and acceptors. These compounds exhibit markedly different behavior in solution; NMR studies of dEt(n) show no evidence of self-association, whereas HBu(n) strongly associate via H-bonding and π-stacking. Compounds HBu(n) also act as small molecule gelators in a range of solvents, a property not observed for the corresponding tertiary amides. All compounds were found to form Colh liquid crystal phases; variable temperature XRD experiments indicate that each column has a diameter approximately equal to that of a single molecule. A comparison of the phase behavior of HBu(n) and dEt(n) suggests that the columnar phases of the former are stabilized by hydrogen bonding, likely at the expense of local parallel alignment of these molecules. Single crystal X-ray diffraction studies revealed that dEt(6) adopts an antiparallel arrangement in the solid state, in keeping with previous theories of packing within columnar LC phases. These studies highlight the interplay between competing factors, such as hydrogen bonding, π-stacking and dipole-dipole interactions that affect the stability of the LC phases.

In recent years, there has been an increased interest in conceptual blending in physics and mathematics education research as a theoretical framework to study student reasoning. In this paper, we adapt the conceptual blending framework to construct a blending diagram that not only captures the product but also the process of student reasoning when they interpret a mathematical description of a physical system. We describe how to construct a dynamic blending diagram (DBD) and illustrate this using two cases from an interview study. In the interview, we asked pairs of undergraduate physics and mathematics students about the physical meaning of boundary conditions for the heat equation. The selected examples show different aspects of the DBD as an analysis method. We show that by using a DBD, we can judge the degree to which students integrate their understandings of mathematics and physics. The DBD also enables the reader to follow the line of reasoning of the students. Moreover, a DBD can be used to diagnose difficulties in student reasoning.

Organometallic Ru(II)-cymene complexes linked to ferrocene (Fc) via nitrogen heterocycles have been synthesized and studied as cytotoxic agents. These compounds are analogues of Ru(II)-arene piano-stool anticancer complexes such as RAPTA-C. The Ru center was coordinated by pyridine, imidazole, and piperidine with 0-, 1-, or 2-carbon bridges to Fc to give six bimetallic, dinuclear compounds, and the properties of these complexes were compared with their non-Fc-functionalized parent compounds. Crystal structures for five of the compounds, their Ru-cymene parent compounds, and an unusual trinuclear compound were determined. Cyclic voltammetry was used to determine the formal MIII/II potentials of each metal center of the Ru-cymene-Fc complexes, with distinct one-electron waves observed in each case. The Fc-functionalized complexes were found to exhibit good cytotoxicity against HT29 human colon adenocarcinoma cells, whereas the parent compounds were inactive. Similarly, antibacterial activity from the Ru-cymene-Fc compounds was observed against Bacillus subtilis, but not from the unfunctionalized complexes. In both cases, the IC50 values correlated quantitatively with the Fc+/0 reduction potentials. This is consistent with more facile oxidation to give ferrocenium, and subsequent generation of toxic reactive oxygen species, leading to greater cytotoxicity. The antioxidant properties of the complexes were quantified by a 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. EC50 values indicate that linking of the Ru and Fc centers promotes antioxidant activity.

Mendelian randomisation (MR) is a method for establishing causality between a risk factor and an outcome by using genetic variants as instrumental variables. In practice, the association between individual genetic variants and the risk factor is often weak, which may lead to a lack of precision in the MR and even biased MR estimates. Usually, the most significant variant within a genetic region is selected to represent the association with the risk factor, but there is no guarantee that this variant will be causal or that it will capture all of the genetic association within the region. It may be advantageous to use extra variants selected from the same region in the MR. The problem is to decide which variants to select. Rather than selecting a specific set of variants, we investigate the use of Bayesian model averaging (BMA) to average the MR over all possible combinations of genetic variants. Our simulations demonstrate that the BMA version of MR outperforms classical estimation with many dependent variants and performs much better than an MR based on variants selected by penalised regression. In further simulations, we investigate robustness to violations in the model assumptions and demonstrate sensitivity to the inclusion of invalid instruments. The method is illustrated by applying it to an MR of the effect of body mass index on blood pressure using SNPs in the FTO gene.

Sialic acid (N-acetylneuraminic acid) is a carbohydrate that possess a nine carbon backbone, and it is often found at the termini of glycoconjugates in biological systems. Because of this prominence many syntheses have reported routes to sialic acid and many of its derivatives. Most of these compounds retain the endocyclic oxygen atom that becomes part of the ketal glycosidic linkage that joins sialic acid to the penultimate residue in the glycoconjugate. With respect to carba-sialic acid (replacement of the ring oxygen atom with a methylene group) a single synthesis has been reported (Ogawa et al. (Carbohydr. Res., 1995, 269, 53–78) in 30 steps and 0.5% yield. The current report details a robust synthesis of 6a-carba-α- d -sialic acid that involves 18 steps and give a 5% yield using d -quinic acid as the starting material.

Cystic Fibrosis (CF) is a genetic disorder caused by loss-of-function mutations to the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Ivacaftor (1) was the first therapeutic approved for the treatment of CF that is able to restore gating activity to certain CFTR variants although the mechanism of action is poorly understood. Herein we describe the synthesis of a photoaffinity labelling (PAL) probe (2) based on the structure of ivacaftor incorporating a photoreactive diazirine moiety for use in labelling studies designed to identify the binding site for ivacaftor on mutant CFTR. The PAL probe 2 retained potentiation activity, with a potency similar to 1, using a Fluorescent Imaging Plate Reader (FLIPR®) assay measuring ion conductance potentiation of wild type (Wt)-CFTR. Photolabelling experiments with human serum albumin (HSA) as a model protein have shown that probe 2 can label HSA in a manner consistent with observed and predicted binding.

With the aim to prepare hypoxia tumor imaging agents, technetium(I) and rhenium(I) tricarbonyl complexes with dipyridylamine ( L1 = N -{[1-(2,2-dioxido-1,2-benzoxathiin-6-yl)-1 H -1,2,3-triazol-4-yl]methyl}- N -(2-pyridinylmethyl)-2-pyridinemethanamine; L3 = N -{[1-[ N -(4-aminosulfonylphenyl)]-1 H -1,2,3-triazol-4-yl]methyl}- N -(2-pyridinyl-methyl)-2-pyridinemethanamine), and iminodiacetate (H 2 L2 = N -{[1-(2,2-dioxido-1,2-benzoxathiin-6-yl)-1 H -1,2,3-triazole-4-yl]methyl}- N -(carboxy-methyl)-glycine; H 2 L4 = N -{[1-[ N -(4-aminosulfonylphenyl)]-1 H -1,2,3-triazole-4-yl]methyl}- N -(carboxymethyl)-glycine) ligands appended to sulfonamide or sulfocoumarin carbonic anhydrase inhibitors were synthesized. The Re(I) complexes were characterized using 1 H/ 13 C NMR, MS, EA, and in one case the X-ray structure of [Et 3 NH][Re(CO) 3 ( L2 )] was obtained. As expected, the Re coordination geometry is distorted octahedral, with a tridentate iminodiacetate ligand in a fac arrangement dictated by the three strong-field CO ligands. Inhibition studies of human carbonic anhydrases (hCAs) showed that the Re sulfocoumarin derivatives were inactive against hCA-I, -II and -IV, but had moderate affinity for hCA-IX. The Re sulfonamides showed improved affinity against all tested hCAs, with [Re(CO) 3 ( L4 )] − being the most active and selective for the hCA-IX isoform. The corresponding 99m Tc complexes were synthesized from fac -[ 99m Tc(CO) 3 (H 2 O) 3 ] + , purified by HPLC, and obtained with average 41–76% decay-corrected radiochemical yields and with >99% radiochemical purity. Uptake in HT-29 tumors at 1 h post-injection was highest for [ 99m Tc(CO) 3 ( L4 )] − (0.14 ± 0.10%ID/g) in comparison to [ 99m Tc(CO) 3 ( L1 )] + (0.06 ± 0.01%ID/g), [ 99m Tc(CO) 3 ( L2 )] − (0.03 ± 0.00%ID/g), and [ 99m Tc(CO) 3 ( L3 )] + (0.07 ± 0.03%ID/g). The uptake in tumors was further reduced at 4 h post-injection. For potential imaging application with single photon emission computed tomography, further optimization is needed to improve the affinity to hCA-IX and uptake in hCA-IX expressing tumors.

A series of octahedral CoIII salen complexes (where salen represents a N2O2 bis-Schiff-base bis-phenolate framework) were prepared with axial imidazole ligating groups. When using 1-methylimidazole (1-MeIm) axial ligands, the CoIII/CoII reduction potential could be altered by 220 mV via variation of the electron-donating ability of the para-ring substituents (R = H (1), OMe (2), tBu (3), Br (4), NO2 (5), and CF3 (6)). In addition, the irreversibility of the reduction process suggested substantial geometrical changes and axial ligand exchange upon reduction to the more labile CoII oxidation state. Installing an imidazole-coumarin conjugate as the axial ligands resulted in fluorescence quenching when bound to the CoIII centre (R = H (7), OMe (8), and CF3 (9)). The redox properties and fluorescence increase upon ligand release for 7–9 were studied under reducing conditions and in the presence of excess competing ligand (1-MeIm). It was determined that the Lewis acidity of the CoIII centre was the dominant factor in controlling axial ligand exchange for this series of complexes.

New compounds and coordination polymers with highly polarizable metals (M = Hg, Pb) and 2,2′;6′2′-terpyridine (terpy) and 2,6-bis(benzimidazol-2-yl)pyridine (bbp) ligands have been synthesized and characterized for their photo-physical and optical properties. Hg(L)(CN)2(L = terpy, bbp) exhibit π-stacking interactions, which form a supramolecular alignment of the planar terpy and bbp units. Pb(terpy)X2[Hg(CN)2]0.5(X = Cl, Br) generate one-dimensional coordination polymers through bridging Hg(CN)2linkers and hydrogen-bonding interactions. All of the metal centres have very distorted coordination geometries. Hg(L)(CN)2(L = terpy, bbp) and Pb(terpy)Br2[Hg(CN)2]0.5show terpy or bbp based emission. The materials are very birefringent, with Δn ranging from 0.37(2) to 0.45(2). The magnitude of the observed birefringence depends on the orientation of the highly polarizable terpy and bbp units in relation to the viewing axis of the crystals. These materials represent rare examples of multifunctional emissive and birefringent systems.

We describe the formation of a bis-cyclopropane product, a tricyclic[4.1.0.02,4]heptane, that is formed during a Johnson–Corey–Chaykovsky reaction on a cyclopentenone. Two (of four possible) bicyclic products are selectively formed by addition of a COOEt-stabilized sulfur ylide onto the Michael acceptor. The tricyclic product is formed subsequently via a retro Michael elimination of a hindered ether followed by addition of a further cyclopropyl moiety, affecting only one of the two bicyclic products initially formed. The experimental reaction outcome was rationalized using density functional theory (DFT), investigating the different Michael-addition approaches of the sulfur ylide, the transition state (TS) energies for the formation of possible zwitterionic intermediates and subsequent reactions that give rise to cyclopropanation. Selective formation of only two of the four possible products occurs due to the epimerization of unreactive intermediates from the other two pathways, as revealed by energy barr...

Mendelian randomization (MR) requires strong assumptions about the genetic instruments, of which the most difficult to justify relate to pleiotropy. In a two-sample MR, different methods of analysis are available if we are able to assume, M1 : no pleiotropy (fixed effects meta-analysis), M2 : that there may be pleiotropy but that the average pleiotropic effect is zero (random effects meta-analysis), and M3 : that the average pleiotropic effect is nonzero (MR-Egger). In the latter 2 cases, we also require that the size of the pleiotropy is independent of the size of the effect on the exposure. Selecting one of these models without good reason would run the risk of misrepresenting the evidence for causality. The most conservative strategy would be to use M3 in all analyses as this makes the weakest assumptions, but such an analysis gives much less precise estimates and so should be avoided whenever stronger assumptions are credible. We consider the situation of a two-sample design when we are unsure which of these 3 pleiotropy models is appropriate. The analysis is placed within a Bayesian framework and Bayesian model averaging is used. We demonstrate that even large samples of the scale used in genome-wide meta-analysis may be insufficient to distinguish the pleiotropy models based on the data alone. Our simulations show that Bayesian model averaging provides a reasonable trade-off between bias and precision. Bayesian model averaging is recommended whenever there is uncertainty about the nature of the pleiotropy.

A trend towards earlier menarche in women has been associated with childhood factors (e.g. obesity) and hypothesised environmental exposures (e.g. endocrine disruptors present in household products). Observational evidence has shown detrimental effects of early menarche on various health outcomes including adult lung function, but these might represent spurious associations due to confounding. To address this we used Mendelian randomization where genetic variants are used as proxies for age at menarche, since genetic associations are not affected by classical confounding. We estimated the effects of age at menarche on forced vital capacity (FVC), a proxy for restrictive lung impairment, and ratio of forced expiratory volume in one second to FVC (FEV1/FVC), a measure of airway obstruction, in both adulthood and adolescence. We derived SNP-age at menarche association estimates for 122 variants from a published genome-wide meta-analysis (N = 182,416), with SNP-lung function estimates obtained by meta-analysing three studies of adult women (N = 46,944) and two of adolescent girls (N = 3025). We investigated the impact of departures from the assumption of no pleiotropy through sensitivity analyses. In adult women, in line with previous evidence, we found an effect on restrictive lung impairment with a 24.8 mL increase in FVC per year increase in age at menarche (95% CI 1.8–47.9; p = 0.035); evidence was stronger after excluding potential pleiotropic variants (43.6 mL; 17.2–69.9; p = 0.001). In adolescent girls we found an opposite effect (−56.5 mL; −108.3 to −4.7; p = 0.033), suggesting that the detrimental effect in adulthood may be preceded by a short-term post-pubertal benefit. Our secondary analyses showing results in the same direction in men and boys, in whom age at menarche SNPs have also shown association with sexual development, suggest a role for pubertal timing in general rather than menarche specifically. We found no effect on airway obstruction (FEV1/FVC). Electronic supplementary material The online version of this article (doi:10.1007/s10654-017-0272-9) contains supplementary material, which is available to authorized users.

With the aim of improving detection of novel single-nucleotide polymorphisms (SNPs) in genetic association studies, we propose a method of including prior biological information in a Bayesian shrinkage model that jointly estimates SNP effects. We assume that the SNP effects follow a normal distribution centered at zero with variance controlled by a shrinkage hyperparameter. We use biological information to define the amount of shrinkage applied on the SNP effects distribution, so that the effects of SNPs with more biological support are less shrunk toward zero, thus being more likely detected. The performance of the method was tested in a simulation study (1,000 datasets, 500 subjects with ∼200 SNPs in 10 linkage disequilibrium (LD) blocks) using a continuous and a binary outcome. It was further tested in an empirical example on body mass index (continuous) and overweight (binary) in a dataset of 1,829 subjects and 2,614 SNPs from 30 blocks. Biological knowledge was retrieved using the bioinformatics tool Dintor, which queried various databases. The joint Bayesian model with inclusion of prior information outperformed the standard analysis: in the simulation study, the mean ranking of the true LD block was 2.8 for the Bayesian model versus 3.6 for the standard analysis of individual SNPs; in the empirical example, the mean ranking of the six true blocks was 8.5 versus 9.3 in the standard analysis. These results suggest that our method is more powerful than the standard analysis. We expect its performance to improve further as more biological information about SNPs becomes available.

BackgroundThere is debate about the value of adding information on genetic and other molecular markers to conventional cardiovascular disease (CVD) risk predictors.MethodsUsing data on 306,654 individuals without a history of CVD from UK Biobank, we calculated measures of risk-discrimination and reclassification upon addition of polygenic risk scores (PRS) and a panel of 27 clinical biochemistry markers to a conventional risk prediction model (i.e., including age, sex, systolic blood pressure, smoking status, history of diabetes, total cholesterol and HDL cholesterol). We then modelled implications of initiating guideline-recommended statin therapy after the assessment of molecular markers for a UK primary-care setting.FindingsThe C-index was 0.710 (95% CI, 0.703-0.717) for a CVD prediction model containing conventional risk predictors alone. The C-index increased by similar amounts when adding information on PRS or biochemistry markers (0.011 and 0.014, respectively; PInterpretationAdding information on both PRS and selected biochemistry markers moderately enhanced CVD predictive accuracy and could improve primary prevention of CVD. However, our modelling suggested that targeted assessment of molecular markers among individuals at intermediate-risk would be more efficient than blanket approaches.

[This paper is part of the Focused Collection on Quantitative Methods in PER: A Critical Examination.] How data are collected and how they are analyzed is typically described in the literature, but how the data are encoded is often not described in detail. In this paper, we discuss how data typically gathered in PER are encoded and how the choice of encoding plays a role in data analysis. We describe the kinds of data that are found when using short answer, multiple choice, Likert-scale, ranking task, and free response questions in terms of nominal, ordinal, interval, and ratio data. We discuss the mathematical operations that are available for each kind of data and how this affects ways that similarity and difference between student responses can be determined, a topic we discuss in terms of measures of distances and correlation. Finally, we use several papers from the literature to discuss ways in which data have been encoded and analyzed, with examples of normalized gain, factor analysis, model analysis, cluster analysis, and the investigation of epistemological agreement. We highlight both strengths and weaknesses of the data encoding approaches used in these studies. Our goal is not a comprehensive review, but one that is illustrative and can help researchers understand their own and each other’s work more deeply.

A series of Mn(II) halide complexes has been synthesized with 2,6-bis(benzimidazole)-pyridine (BBP), 2,6-bis(N-methyl-benzimidazole)pyridine (MBBP), and 2,6-bis(benzathiazole)-pyridine (BBTP) ligands in solvents capable of acting as hydrogen bonding donors and/or acceptors, resulting in Mn(BBP)(EtOH)X2 (X = Cl, Br), Mn(BBP)Br2·DMF, Mn(BBP)Br2·MeCN, Mn(MBBP)X2 (X = Cl, Br), [Mn(MBBP)(Br)(MeOH)2][Br] and Mn(BBTP)X2 (X = Cl, Br). The crystal structures of these materials were analyzed for the degree of planar packing of the anisotropic ligands. The exchange of hydrogen bonding donor and acceptor solvents (ethanol) for solvents only capable of accepting hydrogen bonds (DMF, acetonitrile) decreased the role of the solvent in the hydrogen bonding networks and also capped the NH groups of BBP, reducing the effectiveness of the BBP to form extended networks. Replacing NH groups in BBP with N-methyl groups (MBBP) and sulfur (BBTP) reduced the number of strong interactions between complexes, leading to a greater te...

The preparation and structural characterization of a series of chromium phthalocyanine complexes with multiple metal and ring oxidation states were achieved using PcCrII (1) (Pc=phthalocyanine) or PcCrII (THF)2 (1⋅THF2 ) as starting materials. The reaction of soluble 1⋅THF2 with Br2 or I2 gave the PcCrIII halide complexes PcCrX(THF) (X=I/I3 , Br; 3, 4, respectively). Treatment of 1 with 0.5 equivalent of PhIO or air generated the dinuclear [PcCr(THF)]2 (μ-O) (5), whereas the addition of one equivalent of AgSbF6 to 1 resulted in oxidation to THF-solvated octahedral [PcCrIII (THF)2 ]SbF6 (6). The reduction of 1 with three sequential equivalents of KEt3 BH resulted in the isolation of [K(DME)4 ][Pc3- CrII ] (7), [K(DME)4 ]2 [Pc4- CrII ] (8) and [K6 (DME)4 ][Pc4- CrI ]2 (9), respectively. The reduced products are deep purple in colour, with visible absorption maxima between 500-580 nm. The ring-reduced complexes 7 and 8 are monomeric, whereas 9 is a 1D chain of dinuclear [PcCr]2 units with intercalated K+ cations and supported by Cr-Cr interactions of 2.988(2) A. Addition of four equivalents of KC8 resulted in the demetallated product PcK2 (DME)4 (10), which has a 1D chain structure. The isolation and structural characterization of new PcCr complexes spanning five oxidation states, including rare examples of crystalline reduced Pc-ring species emphasizes the broad redox activity and stability of phthalocyanine-based complexes.

A series of PbII materials containing the highly anisotropic tridentate ligand 2,6-bis(benzimidazol-2-yl)pyridine (bbp) and [Au(CN)2]–, Hg(CN)2 or halide bridging units, [Pb(bbp)Br2]·2H2O, Pb(bbp)I2, [Pb(bbp)I]2(µ-I)[Au(CN)2], [Pb(bbp)Br]2(µ-Br)[Au(CN)2], [Pb(bbp)Br2][Hg(CN)2], Pb(bbp)Cl[Au(CN)2]·0.25H2O and Pb(H2O)(bbp)2[Au(CN)2]2, have been prepared, structurally characterised and investigated spectroscopically by 207Pb solid-state NMR spectroscopy. Of these, five possess similar coordination geometries, providing an ideal series to investigate structural parameters as indicators for stereochemical activity by correlation with the 207Pb chemical shift span parameter (Ω). The bond length of the substituent opposite to the stereochemically active lone pair and the angle between axial ligands were found to correlate weakly with Ω for these compounds (R2 = 0.85 and 0.66, respectively) and an expanded set of compounds with varying components and structures (R2 = 0.60 and 0.67, respectively), which indicates that these (or similar) structural parameters or Ω can be used to estimate the degree of lone-pair activity. Compounds were also found to be highly birefringent with values ranging from 0.31(5) for Pb(H2O)(bbp)2[Au(CN)2]2 to 0.660(4) for [Pb(bbp)Br2]·2H2O, the latter being amongst the most birefringent compounds reported.

The Ru(III) complexes indazolium [trans-RuCl4(1H-indazole)2] (KP1019) and sodium [trans-RuCl4(1H-indazole)2] (NKP-1339) are leading candidates for the next generation of metal-based chemotherapeutics. Trifluoromethyl derivatives of these compounds and their imidazole and pyridine analogues were synthesized to probe the effect of ligand lipophilicity on the pharmacological properties of these types of complexes. Addition of CF3 groups also provided a spectroscopic handle for (19)F NMR studies of ligand exchange processes and protein interactions. The lipophilicities of the CF3-functionalized compounds and their unsubstituted parent complexes were quantified by the shake-flask method to give the distribution coefficient D at pH 7.4 (log D7.4). The solution behavior of the CF3-functionalized complexes was characterized in phosphate-buffered saline (PBS) using (19)F NMR, electron paramagnetic resonance (EPR), and UV-vis spectroscopies. These techniques, along with fluorescence competition experiments, were also used to characterize interactions with human serum albumin (HSA). From these studies it was determined that increased lipophilicity correlates with reduced solubility in PBS but enhancement of noncoordinate interactions with hydrophobic domains of HSA. These protein interactions improve the solubility of the complexes and inhibit the formation of oligomeric species. EPR measurements also demonstrated the formation of HSA-coordinated species with longer incubation. (19)F NMR spectra show that the trifluoromethyl complexes release axial ligands in PBS and in the presence of HSA. In vitro testing showed that the most lipophilic complexes had the greatest cytotoxic activity. Addition of CF3 groups enhances the activity of the indazole complex against A549 nonsmall cell lung carcinoma cells. Furthermore, in the case of the pyridine complexes, the parent compound was inactive against the HT-29 human colon carcinoma cell line but showed strong cytotoxicity with CF3 functionalization. Overall, these studies demonstrate that lipophilicity may be a determining factor in the anticancer activity and pharmacological behavior of these types of Ru(III) complexes.

A. Palotie on työryhmän Int IBD Genetics Consortium jäsen. One goal of human genetics is to understand the genetic basis of disease, a challenge for diseases of complex inheritance because risk alleles are few relative to the vast set of benign variants. Risk variants are often sought by association studies in which allele frequencies in case subjects are contrasted with those from population-based samples used as control subjects. In an ideal world we would know population-level allele frequencies, releasing researchers to focus on case subjects. We argue this ideal is possible, at least theoretically, and we outline a path to achieving it in reality. If such a resource were to exist, it would yield ample savings and would facilitate the effective use of data repositories by removing administrative and technical barriers. We call this concept the Universal Control Repository Network (UNICORN), a means to perform association analyses without necessitating direct access to individual-level control data. Our approach to UNICORN uses existing genetic resources and various statistical tools to analyze these data, including hierarchical clustering with spectral analysis of ancestry; and empirical Bayesian analysis along with Gaussian spatial processes to estimate ancestry-specific allele frequencies. We demonstrate our approach using tens of thousands of control subjects from studies of Crohn disease, showing how it controls false positives, provides power similar to that achieved when all control data are directly accessible, and enhances power when control data are limiting or even imperfectly matched ancestrally. These results highlight how UNICORN can enable reliable, powerful, and convenient genetic association analyses without access to the individual-level data.

A series of group(II) metal 2,2′;6′2″-terpyridine (terpy) complex-based coordination polymers has been synthesized and characterised for their photo-physical and optical properties. Sr(OH2)(terpy)[Au(CN)2]2 forms a 1D chain through bridging [Au(CN)2]− units, with aurophilic interactions (3.1403(6) and 3.468(6) A) between chains creating a 2D network. Mg(OH2)(terpy)[Pt(CN)4] forms a 1D coordination polymer through bridging [Pt(CN)4]2− linkers, with a 3D structure formed through hydrogen bonds between the unbound N-cyano groups of [Pt(CN)4]2− and the Mg–OH2 units on adjacent chains. M(terpy)[Pt(CN)4] forms an isostructural set for M = Ca, Sr, Ba consisting of a 3D network through bridging [Pt(CN)4]2− linkers. All compounds show terpy-based emission while Sr(OH2)(terpy)[Au(CN)2]2 may also contain aurophilicity-based emission. The materials all show substantial birefringence, with Δ n values ranging from 0.31(3) to 0.46(1), the magnitude of which correlates to the orientation of the terpy units relative to the viewing axis of the crystals.

We report the synthesis and structural and magnetic characterization of poly[(1,10-phenanthroline)tetrakis(imidazolato)diiron(II)], [Fe2(imid)4(phen)]x, 1. The extended structure of 1 is that of a metal organic framework (MOF) involving double layer sheets (bilayers) of alternating tetrahedral and octahedral irons singly bridged by imidazolate ligands. The octahedral iron centers are each additionally coordinated by phenanthroline ligands. Mossbauer spectroscopy confirms the presence of octahedral and tetrahedral metal centers. A combination of DC susceptibility, ZFCM and Mossbauer studies reveals a magnetic phase transition to long-range order at ∼7 K in 1. Magnetic hysteresis is observed at low temperatures, with coersive fields of approximately 360 and 650 G and remnant magnetizations of approximately 450 and 720 cm3 G mol−1 at 5 and 2.5 K respectively.