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This is the post-print version of the following article: "Remarkable differences and similarities between the isomeric Mn(II)-cis- and trans-1,2-diaminocyclohexane-N,N,N′,N′-tetraacetate complexes", which has been published in final form at https://www.sciencedirect.com/science/article/abs/pii/S0020169317306825?via%3Dihub; International audience; Equilibrium, kinetic (solvent exchange and dissociation of the complex) and relaxometric studies (1H and 17O NMR) have been performed with the [M(II)(c-cdta)]2− complexes (c-cdta = cis-1,2-diaminocyclohexane-N,N,N′,N′-tetraacetic acid, M(II) = Mn(II), Zn(II), Cu(II),Ca(II), Mg(II)) and the physico-chemical data are compared to the isomeric complexes with trans-1,2-cdta (t-cdta) with the aim of searching appropriate ligands for Mn(II) complexation for safe MRI contrast agents. The total basicity (Σ log KiH) of the c-cdta ligand appears to be very similar to that of the trans-derivative under the conditions applied (I = 0.15 M NaCl and 25 °C), but the first two protonation constants notably differ. log K1H is 1.5 log units higher, while the log K2H is 0.8 log units lower than those determined for the trans-derivative. Similar basicity of the ligands results in similar complex stability (log K[Mn(L)] values are 14.19(2) and 14.32), whereas the conditional stabilities near to physiological pH are different (pMn values are 7.82 and 8.68) for the [Mn(c-cdta)]2− and the [Mn(t-cdta)]2− derivatives, respectively. Dissociation kinetic studies revealed that the [Mn(c-cdta)]2− dissociates 250 times faster than the [Mn(t-cdta)]2− complex. The water exchange rate (kex298) of [Mn(c-cdta)]2− is ca. 60% higher than that of [Mn(t-cdta)]2−. The differences can likely be attributed to the different distances between the individual donor atoms, and the arrangement of the donor atoms around the metal ions in the cis- and trans- isomers. Interestingly, the relaxivity values of the Mn(II) complexes are very close (r1p = 3.79 mM−1 s−1 and 3.62 mM−1 s−1; 20 MHz, 25 °C for the cis- and trans-isomers, respectively). DFT calculations were used to gain insight into the different properties of the [Mn(c-cdta)]2− and the [Mn(t-cdta)]2− complexes. The results gained in our studies confirm that the trans-1,2-cyclohexanediamine “building block” displays better features for further ligand development.Graphical abstractM(II) complexes formed with c-cdta (cis-1,2-diaminocyclohexane-N,N,N′,N′-tetraacetic acid) chelator have been investigated by pH-potentiometry, UV–vis spectrophotometry, DFT calculations,1H- and 17O-NMR relaxometry. pMn as well as the inertness of the Mn(II) complex formed with c-cdta ligand were found to differ substantially form those found for the trans-derivative while the water exchange rate and the relaxivity do not differ remarkably. Our results confirm, that the t-cdta platform has better potential for further ligand development owing to better dissociation kinetic parameters of its Mn(II) complex.

In 2010-2012 new outpatient service locations were established in poor Hungarian microregions. We exploit this quasi-experiment to estimate the extent of substitution between outpatient and inpatient care. Fixed-effects Poisson models on individual-level panel data for years 2008-2015 show that the number of outpatient visits increased by 19% and the number of inpatient stays decreased by 1.6% as a result, driven by a marked reduction of potentially avoidable hospitalization (PAH) (5%). In our dynamic specification, PAH effects occur in the year after the treatment, whereas non-PAH only decreases with a multi-year lag. The instrumental variable estimates suggest that a one euro increase in outpatient care expenditures produces a 0.6 euro decrease in inpatient care expenditures. Our results (1) strengthen the claim that bringing outpatient care closer to a previously underserved population yields considerable health benefits, and (2) suggest that there is a strong substitution element between outpatient and inpatient care.

In 2010-2012 new outpatient service locations were established in Hungarian micro-regions, which had lacked such capacities before. We exploit this quasi-experiment to estimate the effect of geographical accessibility on outpatient case numbers using both individual-level and semi-aggregate panel data. We find a 24-27 per cent increase of case numbers as a result of the establishments. Our specialty-by-specialty estimates imply that a one-minute reduction of travel time to the nearest outpatient unit increases case numbers e.g. by 0.9 per cent in internal care and 3.1 per cent in rheumatology. The size of the new outpatient capacities has a separate effect, raising the possibility of the presence of supplier-induced demand. By combining a fixed-effects logit and a fixed-effects truncated Poisson estimator, we decompose the effects into increases in the probability of ever visiting a doctor on the one hand and an increase of the frequency of visits on the other. We find that new visits were dominant in the vast majority of specialties, whereas both margins were important e.g. in rheumatology. Finally, we demonstrate the usefulness of the fixed-effects truncated Poisson estimator in modelling count data by examining its robustness by simulations.