Efficacy and safety of medications for antihistamine-refractory chronic spontaneous urticaria: a systematic review and network meta-analysis

Purpose Most medications for antihistamine-refractory chronic spontaneous urticaria (CSU) have not been compared head-to-head. This systematic review and network meta-analysis evaluates their relative efficacy and safety. Methods Electronic databases were searched until 05 May 2022 for randomized controlled trials investigating systemic medications for antihistamine-refractory CSU. The change in the urticaria activity score over seven days (UAS7) and occurrence of adverse events were compared between treatments using random-effects network meta-analysis models. Results In all, 32 studies with 3641 patients receiving 31 different systemic medical interventions were included. Among currently available drugs, omalizumab 300 mg injected every 4 weeks and cyclosporine 3–5 mg/kg daily per os were most effective in reducing the UAS7 with a reduction of −10.45 (95% confidence interval [CI]: −12.35, −8.55) and of −10.40 (95% CI: −19.4, −1.4) compared to placebo. Similar efficacies were shown by the nonapproved agents ligelizumab 72 mg injected every 4 weeks (−11.67, 95% CI: −16.80, −7.15) and fenebrutinib 400 mg daily per os (−9.50, 95% CI: −17.56, −1.44). The odds ratio for the occurrence of an adverse event with placebo as comparator was 1.09 for omalizumab (95% CI: 0.83, 1.42), 2.16 for cyclosporine (95% CI: 0.77, 6.07: GRADE; moderate certainty), 0.89 for ligelizumab (95% CI: 0.47, 1.69), and 2.14 for fenebrutinib (95% CI: 0.62, 7.38) in the mentioned dosages. Conclusion Omalizumab 300 mg injected every 4 weeks and cyclosporine 3–5 mg/kg daily per os are the most effective currently available drugs for antihistamine-refractory CSU. Cyclosporine shows a relatively less favorable safety profile

Oxygen-Doped PAH Electrochromes: Difurano, Dipyrano, and Furano-Pyrano Containing Naphthalene-Cored Molecules

In this work, we report the synthesis of O-doped naphthalene-based electrochromes. Exploiting the CuO-mediated Pummerer oxidative cycloetherification reaction, a series of 1,4- and 1,5-disubstituted naphthalene-cored dipyrano, difurano, and furano-pyrano polycyclic aromatic hydrocarbons (PAHs) have been prepared. Steady-state UV-Vis absorption and emission investigations showed that the spectroscopic profile strongly depends on the O-doping topology, with the dipyrano and the difurano derivatives demonstrating the most red-shifted and blue-shifted electronic transition, respectively. Computational investigations revealed that the cycloetherification reaction raises the HOMO energy level (while the LUMO remains largely unaffected), with the dipyrano derivatives displaying the highest values. Spectroelectrochemical measurements showed that, depending on the O-topology and the type of O-ring, different electrochromic responses could be obtained with colour transitions featuring high contrasts involving yellow, pink, orange or blue colours

Drug design on quantum computers

Quantum computers promise to impact industrial applications, for which quantum chemical calculations are required, by virtue of their high accuracy. This perspective explores the challenges and opportunities of applying quantum computers to drug design, discusses where they could transform industrial research and elaborates on what is needed to reach this goal

The generality of the GUGA MRCI approach in COLUMBUS for treating complex quantum chemistry

The core part of the program system COLUMBUS allows highly efficient calculations using variational multireference (MR) methods in the framework of configuration interaction with single and double excitations (MR-CISD) and averaged quadratic coupled-cluster calculations (MR-AQCC), based on uncontracted sets of configurations and the graphical unitary group approach (GUGA). The availability of analytic MR-CISD and MR-AQCC energy gradients and analytic nonadiabatic couplings for MR-CISD enables exciting applications including, e.g., investigations of π-conjugated biradicaloid compounds, calculations of multitudes of excited states, development of diabatization procedures, and furnishing the electronic structure information for on-the-fly surface nonadiabatic dynamics. With fully variational uncontracted spin-orbit MRCI, COLUMBUS provides a unique possibility of performing high-level calculations on compounds containing heavy atoms up to lanthanides and actinides. Crucial for carrying out all of these calculations effectively is the availability of an efficient parallel code for the CI step. Configuration spaces of several billion in size now can be treated quite routinely on standard parallel computer clusters. Emerging developments in COLUMBUS, including the all configuration mean energy multiconfiguration self-consistent field method and the graphically contracted function method, promise to allow practically unlimited configuration space dimensions. Spin density based on the GUGA approach, analytic spin-orbit energy gradients, possibilities for local electron correlation MR calculations, development of general interfaces for nonadiabatic dynamics, and MRCI linear vibronic coupling models conclude this overview

The OpenMolcas Web: A Community-Driven Approach to Advancing Computational Chemistry

The developments of the open-source OpenMolcas chemistry software environment since spring 2020 are described, with a focus on novel functionalities accessible in the stable branch of the package or via interfaces with other packages. These developments span a wide range of topics in computational chemistry and are presented in thematic sections: electronic structure theory, electronic spectroscopy simulations, analytic gradients and molecular structure optimizations, ab initio molecular dynamics, and other new features. This report offers an overview of the chemical phenomena and processes OpenMolcas can address, while showing that OpenMolcas is an attractive platform for state-of-the-art atomistic computer simulations

Quantumchemical and quantumdynamical calculations on the vibrational excitation and photodissociation of HNO3 with ultrashort laser pulses.

Titelseite und Inhaltsverzeichnis 1\. Einleitung 2\. Grundlagen der Femtochemie 2.1 Pump-probe-Spektroskopie 2.2 Kontrolle der Moleküldynamik mit ultraschnellen Laserpulsen 2.3 Photodissoziation über schwingungsangeregte Zustände 3\. Grundlagen der Photochemie von HNO3 und Modellentwicklung 3.1 Zur Photochemie von HNO3 3.2 Das zweidimensionale Modell 4\. Zur Theorie der ab-initio-Rechnung 4.1 Die Born-Oppenheimer-Näherung 4.2 Die Hartree-Fock-Näherung 4.3 Das Problem der Elektronenkorrelation 5\. Ergebnisse der quantenchemischen Rechnungen 5.1 Der elektronische Grundzustand in der MP2-Näherung 5.2 Die tiefliegenden angeregten Zustände - CASSCF-Ergebnisse 6\. Schwingungseigenfunktionen 6.1 Die zeitunabängige Schrödingergleichung der Kernbewegung 6.2 Die Schwingungszustände von HNO3 7\. Theoretische Grundlagen der Quantendynamik 7.1 Die zeitabhängige Schrödingergleichung der Kernbewegung 7.2 Die Kopplung mit dem Strahlungsfeld 7.3 Die numerische Lösung - Gitterverfahren und Propagatoren 7.4 Die zeitabhängige Berechnung von Spektren 8\. Ergebnisse der quantendynamischen Rechnungen 8.1 Das UV-Spektrum 8.2 Selektive Präparation gebundener Zustände 8.3 Selektive Präparation von Kontinuumszuständen 9\. Zusammenfassung und Ausblick LiteraturlisteIn dieser Arbeit werden quantenchemische und quantendynamische Simulationen zur zustandsspezifischen Schwingungsanregung und zur Photodissoziation von HNO3 vorgestellt. Der erste Teil beschreibt die Berechnung der ab-initio-Potentialflächen eines zweidimensionalen Modells, welches die OH- und die NO-Einfachbindung explizit behandelt. Dabei werden MP2 und CASSCF Methoden zur Bestimmung des elektronischen Grundzustandes und der ersten drei angeregten Zustände verwendet. Die Rechnungen zeigen eine gute Übereinstimmung mit den experimentellen Daten. Unter Verwendung der ab-initio-Potentialfläche werden die Schwingungseigenfunktionen des elektronischen Grundzustandes berechnet. Diese Funktionen werden mit Hilfe der entkoppelten Einteilchenfunktionen der beiden Freiheitsgrade analysiert, um die Kopplung zwischen den beiden Bindungen zu untersuchen. Im zweiten Teil wird die laserkontrollierte Moleküldynamik mit Hilfe von quantendynamischen Techniken simuliert. Ausgehend von der Nullpunktsschwingung des elektronischen Grundzustandes werden hochangeregte gebundene und im Kontinuum liegende Schwingungszustände durch ultrakurze Laserpulse präpariert. Zusätzlich kann die Länge der NO-Bindung zu jedem beliebigen Zeitpunkt kontrolliert werden, indem man die Phasenbeziehung der IR-Pulse geeignet wählt. Die so präparierten Kontinuumszustände zeigen eine quasi-kohärente Schwingung im dissoziativen Kontinuum des elektronischen Grundzustandes. Das Abtasten dieser Schwingung durch Femtosekunden-pump-probe-Spektroskopie wird mit Hilfe der Wellenpaketpropagation simuliert.This work presents quantumchemical und quantumdynamical simulations on the state specific vibrational excitation and photodissociation of HNO3. The first part deals with the calculation of ab initio potential energy surfaces for a twodimensional model which treats the OH- and the NO-single- bonds explicitly. Both the MP2 and CASSCF methodes are applied to determine the ground and the lowest three excited electronic states, respectively. The calculations yield good agreement with experimental data. Based on the ab initio potential of the electronic ground state, the vibrational eigenfunctions are calculated. These eigenfunctions are investigated by means of zero-order states to examine the coupling between the two degrees of freedom. In the second part, the laser-driven molecular dynamics is simulated using quantum dynamical techniques. Starting from the lowest vibrational eigenfunction of the ground electronic state, highly excited vibrational bound states as well as states lying in the continuum are prepared selectively using using ultrashort IR laser pulses. In addition, the length of NO bound can be controlled at any time by adjusting the phaserelation within the two selective IR laser pulses. The continuum states prepared by a sequence of two ultrashort pulses show a quasi-coherent vibration in the dissociative continuum of the ground electronic state. Monitoring these vibrations by femtosecond IR+UV pump-probe spectroscopy is simulated using molecular wavepacket propagation