Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Autocatalytic cathodic dehalogenation triggered by dissociative electron transfer through a C−H⋯OC-H\cdots O hydrogen bond

A combined action of the $C-H\cdots O_{alkoxide}$ hydrogen bonding and $Cl\cdots\pi_{pyrazolyl}$ dispersive interactions facilitates intramolecular electron transfer (ET) in the transient $\{Mo^{I}(NO)(Tp^{Me2})(O_{alkoxide})\}^{\cdot}-\cdots HCCl_3$ adduct $([Tp^{Me2}]^{-} = K^{3}$-hydrotris(3,5-dimethylpyrazol-1-yl)borate), setting off a radical autocatalytic process, eventually leading to chloroform degradation. In the voltammetric curve, this astonishingly fast process is seen as an almost vertical drop-down. The potential at which it occurs is favorably shifted by ca. 1 V in comparison with uncatalyzed reduction. As predicted by DFT calculations, crucial in the initial step is a close and prolonged contact between the electron donor $(Mo^{I}$4d-based SOMO) and acceptor $(\sigma ^{\ast }_{C-Cl}$-based LUMO). This occurs owing to the exceptionally short $(d_{H\cdots O} = 1.82 Å)$ and nearly linear $C-H\cdots O_{alkoxide}$ bonding, which is reflected by a large $Δν_{C-H}$ red-shift of 380 $cm^{-1}$ and a noticeable reorganization of electronic density along the H-bond axis. The advantageous noncovalent interactions inside the cavity formed by two pyrazolyl (pz) rings are strengthened during the C–Cl bond elongation coupled with the ET, giving rise to possible transition state stabilization. After the initial period, the reaction proceeds as a series of consecutive alternating direct or $Mo^{II/I}$-mediated electron and proton transfers. Alcohols inhibit the electrocatalysis by binding with the $\{{Mo^{I-O}}_{alkoxide}\}^{\cdot-}$ active site, and olefins by trapping transient radicals. The proximity and stabilization effects, and competitive inhibition in the studied system may be viewed as analogous to those operating in enzymatic catalysis

Comprehensive support for chemistry computations in PL-Grid infrastructure

InSilicoLab for Chemistry with its experiments and QC Advisor are the tools assisting PL-Grid users in chemistry computations on grid infrastructure. The tools are designed to help the user at all stages of calculations – from the software choice and input data preparation, through job submission and monitoring to the retrieval of output files and analysis of results. General Quantum Chemistry experiment helps in launching QC computations on PL-Grid. A specialized tool – Trajectory Sculptor – is designed for manipulations with Molecular Dynamics trajectories and large sets of molecular structures in sequential computational experiments. QC Advisor collects information about availability of different computational methods in quantum-chemical programs and supports preparation of input files for the most popular software. The main idea behind the tools described in the paper is to reduce the effort needed to set-up the calculations, allowing users to focus on scientific content of their work

On the role of noncovalent interactions in electrocatalysis : two cases of mediated reductive dehalogenation

Two cases of mediated electron transfer are presented: chloroform reduction catalysed by MoII/I alkoxy scorpionates and debromination of hexabromocyclododecane (HBCD) in the presence of free-base tetraphenylporphyrin (H2TPP). Although H2TPP should act as a typical outer-sphere mediator, it is not active towards analogous dehalogenation of 1,2-dibromocyclododecane. The observed phenomena can be rationalised by considering the catalytically relevant transient adducts formed owing to noncovalent interactions (Csingle bondH hydrogen bonds and dispersive Csingle bondhalogen⋯π interactions or directional halogen bonding), which warrants the close and prolonged contact between the catalyst and its substrate, thus increases the probability of electron transfer, and decisively accelerates the reaction. Crucial for this action is thermodynamic stability of the adducts, which can only be explained if dispersive van der Waals interactions are properly accounted for, e.g., as by dispersion-corrected density functional theory (DFT-D) calculations. The structures involving strong and anisotropic interactions, like the surprisingly short Csingle bondH⋯Oalkoxide H-bonding in the MoI–chloroform adduct, may be reasonably well described by standard DFT calculations and the energy needs only be corrected for dispersion without the need for structure re-optimisation at the DFT-D level. The latter is, however, a method of choice for the prediction of supramolecular structures chiefly controlled by weak non-directional van der Waals forces

The effect of C−H···O bonding and Cl···π interactions in electrocatalytic dehalogenation of C2C_2 chlorides containing an acidic hydrogen

A tungsten alkoxy scorpionate shows activity in the electrocatalytic reductive dehalogenation of pentachloroethane and trichloroethylene owing to the formation of hydrogen and halogen bonded adducts with the substrates, which is further reinforced by dispersive interactions. The ensuing proximity between the substrate molecule and the metal centre promotes dechlorination in a concerted process. Two-electron reduction of pentachloroethane yields trichloroethylene that undergoes further, non-catalysed, reactions that ultimately give acetylenes. Interestingly, pentachloroethane proved to be a highly efficient proton donor for the transient anions, in extremely exothermic and rapid proton transfer concerted with chloride anion abstraction, which yields perchloroethylene. The total process and the mechanism thereof were verified based on DFT and coupled cluster (CC) calculations. The calculations evaluated feasibility of various pathways in the mechanism. Standard redox potentials for the environmentally relevant species, participating in the studied reactions, were accurately computed employing the explicitly correlated CCSD(T)-F12 method that provides an improved C-Cl bond energy, of essential importance to the dissociative potentials

Munchausen syndrome – forgotten but dangerous disease. Diagnostic challenges in female patient

According to the International Statistical Classification of Diseases and Related Health Problems ICD-10, Munchausen syndrome is a mental disorder classified as an F68.1 diagnosis code – “Intentional production or feigning of symptoms or disabilities, either physical or psychological [factitious disorder]”. In contrast to people consciously simulating ailments for specific benefits, patients with suspected Munchausen syndrome persistently contacting health care providers are not aware of their inner motives (social gratification, need for control, high levels of self-harm), exposing themselves to a long diagnostic process. OBJECTIVE: To present the difficulties associated with differentiation, diagnosis and appropriate treatment of Munchausen syndrome. The presented case study concerns a young patient repeatedly hospitalized due to numerous somatic complaints. Despite many physical examinations, including imaging and treatment no diagnosis could be made which would explain all of the symptoms. Only psychiatric hospitalization, with full analysis of the patient’s medical history, made it possible to diagnose the Munchausen syndrome and to treat the patient accordingly. Paradoxically, that diagnosis might have contributed to undermining subsequent problems reported by the patient that emerged because of an expanding brain tumor. COMMENT: Proper understanding of the symptoms presented by the patient could have lead to a faster diagnosis. However, the later fatal symptoms show that one cannot focus on only one diagnosis. Properly planned imaging seems to play a huge role.Według Międzynarodowej Klasyfikacji Chorób i Problemów Zdrowotnych ICD-10, zespół Münchhausena jest zaburzeniem psychicznym, zaliczanym do kategorii diagnostycznej F68.1 „Zamierzone wytwarzanie lub naśladowanie objawów czy niewydolności fizycznych lub psychicznych (zaburzenia pozorowane)”. W przeciwieństwie do osób świadomie symulujących dolegliwości w celu uzyskania konkretnych korzyści, chorzy z podejrzeniem zespołu Münchhausena zgłaszając się kolejny raz do placówek służby zdrowia nie są świadomi swoich wewnętrznych motywów (społeczna gratyfikacja, potrzeba kontroli, wysoki poziom autoagresji), narażając się na długi proces diagnostyczny. CEL PRACY: Przedstawienie trudności związanych z różnicowaniem, rozpoznawaniem i odpowiednim leczeniem zespołu Münchhausena. Przedstawiony opis przypadku dotyczy młodej pacjentki, wielokrotnie hospitalizowanej z powodu licznych dolegliwości somatycznych, u której mimo wielu przeprowadzonych badań, w tym obrazowych i zabiegowych, nie można było postawić żadnego, tłumaczącego występujące objawy, rozpoznania. Dopiero hospitalizacja psychiatryczna, z pełną analizą dotychczasowej historii chorobowej pacjentki, pozwoliła na postawienie diagnozy zespołu Münchhausena i podjęcie właściwego leczenia. Paradoksalnie rozpoznanie to mogło przyczynić się do umniejszania zgłaszanych przez pacjentkę w późniejszym okresie dolegliwości, które pojawiły się w związku z rozrastającym się guzem mózgu. KOMENTARZ: Właściwe rozumienie prezentowanych przez chorą objawów mogło doprowadzić do znacznie szybszego postawienia diagnozy. Późniejsze, tragiczne w skutkach objawy pokazują, iż nie można zamykać się w obrębie jednego rozpoznania. Istotną rolę zdają się odgrywać właściwie zaplanowane badania obrazowe

PRACE research infrastructure offer for Polish R\&D community

The mission of the PRACE Research Infrastructure is to enable high impactscientific discovery and engineering research and development across all disciplines to enhance European competitiveness for the benefit of society. The paper presents the current state of the computational infrastructure, which is unique on the European level and procedures helping with the seamless access to the European HPC infrastructure: supercomputers, applications,storage. Several Polish computational grants have been called in the paper in order to present examples of the Polish domestic scientific engagement

Designing Affordable Housing out of Shipping Containers for Ciudad Juarez, Mexico and Chicago, Illinois (Semester Unknown) IPRO 339: Designing Affordable Housing out of Shipping Containers for Ciudad Juarez, Mexico IPRO 339 Poster Su08

Currently there are several countries throughout the world that have a large need for affordable housing. Our IPRO is currently dealing with solutions for Juarez, Mexico and Chicago, Illinois. These two places are very different in climate, culture, as well as economy. Our IPRO this semester will focus on applying the prototype from last semester to these two regions, while making adjustments as needed. We will continue the research into systems which will be advantageous to each situation and develop them accordingly. Once we get a better understanding as to how we can apply our prototype to these situations we will be better able to apply the prototype to various other countries throughout the world.Deliverable

Designing Affordable Housing out of Shipping Containers for Ciudad Juarez, Mexico and Chicago, Illinois (Semester Unknown) IPRO 339: Designing Affordable Housing out of Shipping Containers for Ciudad Juarez, Mexico IPRO 339 Project Plan Su08

Currently there are several countries throughout the world that have a large need for affordable housing. Our IPRO is currently dealing with solutions for Juarez, Mexico and Chicago, Illinois. These two places are very different in climate, culture, as well as economy. Our IPRO this semester will focus on applying the prototype from last semester to these two regions, while making adjustments as needed. We will continue the research into systems which will be advantageous to each situation and develop them accordingly. Once we get a better understanding as to how we can apply our prototype to these situations we will be better able to apply the prototype to various other countries throughout the world.Deliverable