FOUNTAIN: a modular research platform for integrated real-world evidence generation.

Background: Real-world evidence (RWE) plays a key role in regulatory and healthcare decision-making, but the potentially fragmentated nature of generated evidence may limit its utility for clinical decision-making. Heterogeneity and a lack of reproducibility in RWE resulting from inconsistent application of methodologies across data sources should be minimized through harmonization.

Methods: This paper's aim is to describe and reflect upon a multidisciplinary research platform (FOUNTAIN; FinerenOne mUlti-database NeTwork for evidence generAtIoN) with coordinated studies using diverse RWE generation approaches and explore the platform's strengths and limitations.

Abrupt Change from Ionic to Covalent Bonding in Nickel Halides Accompanied by Ligand Field Inversion.

The electronic configuration of transition metal centers and their ligands is crucial for redox reactions in metal catalysis and electrochemistry. We characterize the electronic structure of gas-phase nickel monohalide cations via nickel L-edge X-ray absorption spectroscopy. Comparison with multiplet charge-transfer simulations and experimental spectra of selectively prepared nickel monocations in both ground- and excited-state configurations are used to facilitate our analysis.

Electronic Structure of the Complete Series of Gas-Phase Manganese Acetylacetonates by X-ray Absorption Spectroscopy.

Metal centers in transition metal-ligand complexes occur in a variety of oxidation states causing their redox activity and therefore making them relevant for applications in physics and chemistry. The electronic state of these complexes can be studied by X-ray absorption spectroscopy, which is, however, due to the complex spectral signature not always straightforward. Here, we study the electronic structure of gas-phase cationic manganese acetylacetonate complexes Mn(acac) using X-ray absorption spectroscopy at the metal center and ligand constituents.

Iron L-edge energy shifts for the full range of possible 3d occupations within the same oxidation state of iron halides.

Oxidation states are integer in number but d configurations of transition metal centers vary continuously in polar bonds. We quantify the shifts of the iron L excitation energy, within the same formal oxidation state, in a systematic L-edge X-ray absorption spectroscopy study of diatomic gas-phase iron(II) halide cations, [FeX],where X = F, Cl, Br, I. These shifts correlate with the electronegativity of the halogen, and are attributed exclusively to a fractional increase in population of 3d-derived orbitals along the series as supported by charge transfer multiplet simulations and density functional theory calculations.

How can we optimise health technology assessment and reimbursement decisions to accelerate access to new cardiovascular medicines?

Regulatory approvals of, and subsequent access to, innovative cardiovascular medications have declined. How much of this decline relates to the final step of gaining reimbursement for new treatments is unknown. Payers and health technology assessment (HTA) bodies look beyond efficacy and safety to assess whether a new drug improves patient outcomes, quality of life, or satisfaction at a cost that is affordable compared to existing treatments.

Intramolecular hydrogen transfer in DNA induced by site-selective resonant core excitation.

We present experimental evidence for soft X-ray induced intramolecular hydrogen transfer in the protonated synthetic tri-oligonucleotide (UAG) in the gas-phase (U: fluorouracil). The trinucleotide cations were stored in a cryogenic ion trap and exposed to monochromatic synchrotron radiation. Photoionization and photofragmentation product ion yields were recorded as a function of photon energy.

X-ray Induced Fragmentation of Protonated Cystine.

We demonstrate site-specific X-ray induced fragmentation across the sulfur L-edge of protonated cystine, the dimer of the amino acid cysteine. Ion yield NEXAFS were performed in the gas phase using electrospray ionization (ESI) in combination with an ion trap. The interpretation of the sulfur L-edge NEXAFS spectrum is supported by Restricted Open-Shell Configuration Interaction (ROCIS) calculations.

Breaking inversion symmetry by protonation: experimental and theoretical NEXAFS study of the diazynium ion, NH.

As an example of symmetry breaking in NEXAFS spectra of protonated species we present a high resolution NEXAFS spectrum of protonated dinitrogen, the diazynium ion NH. By ab initio calculations we show that the spectrum consists of a superposition of two nitrogen 1s absorption spectra, each including a π* band, and a nitrogen 1s to H charge transfer band followed by a weak irregular progression of high energy excitations. Calculations also show that, as an effect of symmetry breaking by protonation, the π* transitions are separated by 0.

Site-selective soft X-ray absorption as a tool to study protonation and electronic structure of gas-phase DNA.

The conformation and the electronic structure of gas-phase oligonucleotides depends strongly on the protonation site. 5'-d(FUAG) can either be protonated at the A-N1 or at the G-N7 position. We have stored protonated 5'-d(FUAG) cations in a cryogenic ion trap held at about 20 K.

The carbon and oxygen K-edge NEXAFS spectra of CO.

We present and analyze high resolution near edge X-ray absorption fine structure (NEXAFS) spectra of CO+ at the carbon and oxygen K-edges. The spectra show a wealth of features that appear very differently at the two K-edges. The analysis of these features can be divided into three parts; (i) repopulation transition to the open shell orbital - here the C(1s) or O(1s) to 5σ transition, where the normal core hole state is reached from a different initial state and different interaction than in X-ray photoelectron spectroscopy; (ii) spin coupled split valence bands corresponding to C(1s) or O(1s) to π* transitions; (iii) remainder weak and long progressions towards the double ionization potentials containing a manifold of peaks.

Probing the oxidation state of transition metal complexes: a case study on how charge and spin densities determine Mn L-edge X-ray absorption energies.

Transition metals in inorganic systems and metalloproteins can occur in different oxidation states, which makes them ideal redox-active catalysts. To gain a mechanistic understanding of the catalytic reactions, knowledge of the oxidation state of the active metals, ideally , is therefore critical. L-edge X-ray absorption spectroscopy (XAS) is a powerful technique that is frequently used to infer the oxidation state a distinct blue shift of L-edge absorption energies with increasing oxidation state.

Soft X-ray Spectroscopy of the Amine Group: Hydrogen Bond Motifs in Alkylamine/Alkylammonium Acid-Base Pairs.

We use N K-edge absorption spectroscopy to explore the electronic structure of the amine group, one of the most prototypical chemical functionalities playing a key role in acid-base chemistry, electron donor-acceptor interactions, and nucleophilic substitution reactions. In this study, we focus on aliphatic amines and make use of the nitrogen 1s core electron excitations to elucidate the roles of N-H σ* and N-C σ* contributions in the unoccupied orbitals. We have measured N K-edge absorption spectra of the ethylamine bases Et NH ( x = 0.

Cr L-Edge X-ray Absorption Spectroscopy of Cr(acac) in Solution with Measured and Calculated Absolute Absorption Cross Sections.

X-ray absorption spectroscopy at the L-edge of 3d transition metals is widely used for probing the valence electronic structure at the metal site via 2p-3d transitions. Assessing the information contained in L-edge absorption spectra requires systematic comparison of experiment and theory. We here investigate the Cr L-edge absorption spectrum of high-spin chromium acetylacetonate Cr(acac) in solution.

X-ray-induced sample damage at the Mn L-edge: a case study for soft X-ray spectroscopy of transition metal complexes in solution.

X-ray induced sample damage can impede electronic and structural investigations of radiation-sensitive samples studied with X-rays. Here we quantify dose-dependent sample damage to the prototypical MnIII(acac)3 complex in solution and at room temperature for the soft X-ray range, using X-ray absorption spectroscopy at the Mn L-edge. We observe the appearance of a reduced MnII species as the X-ray dose is increased.

Direct Determination of Absolute Absorption Cross Sections at the L-Edge of Dilute Mn Complexes in Solution Using a Transmission Flatjet.

The 3d transition metals play a pivotal role in many charge transfer processes in catalysis and biology. X-ray absorption spectroscopy at the L-edge of metal sites probes metal 2p-3d excitations, providing key access to their valence electronic structure, which is crucial for understanding these processes. We report L-edge absorption spectra of Mn(acac) and Mn(acac) complexes in solution, utilizing a liquid flatjet for X-ray absorption spectroscopy in transmission mode.

How to identify DRESS, drug reaction with eosinophilia and systemic symptoms?

DRESS (drug reaction with eosinophilia and systemic symptoms) is a rare, severe multiorgan adverse drug reaction. Antiepileptic age's and antibiotics are the most frequently reported causative agents. Compared with other drug reactions, DRESS demonstrates a long latency period thus complicating recognition and diagnosis.

Soft x-ray absorption spectroscopy of metalloproteins and high-valent metal-complexes at room temperature using free-electron lasers.

X-ray absorption spectroscopy at the L-edge of 3d transition metals provides unique information on the local metal charge and spin states by directly probing 3d-derived molecular orbitals through 2p-3d transitions. However, this soft x-ray technique has been rarely used at synchrotron facilities for mechanistic studies of metalloenzymes due to the difficulties of x-ray-induced sample damage and strong background signals from light elements that can dominate the low metal signal. Here, we combine femtosecond soft x-ray pulses from a free-electron laser with a novel x-ray fluorescence-yield spectrometer to overcome these difficulties.

Glucocorticoids: The mode of action in bullous pemphigoid.

Bullous pemphigoid (BP) is the most common of pemphigoid diseases caused by autoantibodies against the structures of dermoepidermal junction followed by complement activation, innate immune cell infiltration, neutrophil proteinase secretion and subepidermal blister formation. The first-line treatment of BP is topical and systemic glucocorticoids (GC). Regulation of the immune system and inflammatory cells is the main target of GC actions.

Series: Pragmatic trials and real world evidence: Paper 8. Data collection and management.

Pragmatic trials can improve our understanding of how treatments will perform in routine practice. In a series of eight papers, the GetReal Consortium has evaluated the challenges in designing and conducting pragmatic trials and their specific methodological, operational, regulatory, and ethical implications. The present final paper of the series discusses the operational and methodological challenges of data collection in pragmatic trials.

Patients with male gender or greater body weight use smaller amounts of topical therapy in psoriasis.

Objectives And Methods: Topical therapy is the first-line treatment in mild and moderate psoriasis. We performed a real-life study on topical therapies in psoriasis and observed a variation in the amounts of ointment patients applied during the study.

Results: A statistically significant correlation was found between gender and the total amount of ointment used: women used more than men (p = .

Isotretinoin and lymecycline treatments modify the skin microbiota in acne.

Oral retinoids and tetracyclines have a major role in acne treatment. Here, we report for the first time the effect of isotretinoin and lymecycline therapy on the skin microbiota in cheek, back and armpit swab samples of acne vulgaris patients using 16S ribosomal RNA (16S rRNA) gene amplicon sequencing. Propionibacterium acnes was the most common in sebaceous areas of healthy and untreated acne skin and more abundant in back than cheek samples.

Drop-on-demand sample delivery for studying biocatalysts in action at X-ray free-electron lasers.

X-ray crystallography at X-ray free-electron laser sources is a powerful method for studying macromolecules at biologically relevant temperatures. Moreover, when combined with complementary techniques like X-ray emission spectroscopy, both global structures and chemical properties of metalloenzymes can be obtained concurrently, providing insights into the interplay between the protein structure and dynamics and the chemistry at an active site. The implementation of such a multimodal approach can be compromised by conflicting requirements to optimize each individual method.

Structure of photosystem II and substrate binding at room temperature.

Light-induced oxidation of water by photosystem II (PS II) in plants, algae and cyanobacteria has generated most of the dioxygen in the atmosphere. PS II, a membrane-bound multi-subunit pigment protein complex, couples the one-electron photochemistry at the reaction centre with the four-electron redox chemistry of water oxidation at the MnCaO cluster in the oxygen-evolving complex (OEC). Under illumination, the OEC cycles through five intermediate S-states (S to S), in which S is the dark-stable state and S is the last semi-stable state before O-O bond formation and O evolution.

Clinical Efficiency of Topical Calcipotriol/Betamethasone Treatment in Psoriasis Relies on Suppression of the Inflammatory TNFα - IL-23 - IL-17 Axis.

The effects of topical calcipotriol/betamethasone combination therapy and betamethasone monotherapy on inflammatory T-cell numbers and molecular markers were compared in patients with psoriasis. Combination therapy down-regulated the expression of tumour necrosis factor (TNF)-α, interleukin (IL)-23A, IL-17A, S100A7, CCL-20 and interferon (IFN)-γ in skin and TNF-α, IL-6, IL-23A, T-bet and IFN-γ in peripheral blood mononuclear cells (PBMCs). Betamethasone monotherapy had less effect.