Weak Dispersion of Exciton Landé Factor with Band Gap Energy in Lead Halide Perovskites: Approximate Compensation of the Electron and Hole Dependences.

The optical properties of lead halide perovskite semiconductors in vicinity of the bandgap are controlled by excitons, so that investigation of their fundamental properties is of critical importance. The exciton Landé or g-factor gX is the key parameter, determining the exciton Zeeman spin splitting in magnetic fields. The exciton, electron, and hole carrier g-factors provide information on the band structure, including its anisotropy, and the parameters contributing to the electron and hole effective masses. Here, gX is measured by reflectivity in magnetic fields up to 60 T for lead halide perovskite crystals. The materials band gap energies at a liquid helium temperature vary widely across the visible spectral range from 1.520 up to 3.213 eV in hybrid organic-inorganic and fully inorganic perovskites with different cations and halogens: FA0.9Cs0.1PbI2.8Br0.2, MAPbI3, FAPbBr3, CsPbBr3, and MAPb(Br0.05Cl0.95)3. The exciton g-factors are found to be nearly constant, ranging from +2.3 to +2.7. Thus, the strong dependences of the electron and hole g-factors on the bandgap roughly compensate each other when combining to the exciton g-factor. The same is true for the anisotropies of the carrier g-factors, resulting in a nearly isotropic exciton g-factor. The experimental data are compared favorably with model calculation results.

Photocatalyzed Transition-Metal-Free Oxidative Cross-Coupling Reactions of Tetraorganoborates*.

Readily accessible tetraorganoborate salts undergo selective coupling reactions under blue light irradiation in the presence of catalytic amounts of transition-metal-free acridinium photocatalysts to furnish unsymmetrical biaryls, heterobiaryls and arylated olefins. This represents an interesting conceptual approach to forge C-C bonds between aryl, heteroaryl and alkenyl groups under smooth photochemical conditions. Computational studies were conducted to investigate the mechanism of the transformation.

Nonclinical Development of Biologics: Integrating Safety, Pharmacokinetics, and Pharmacodynamics to Create Smarter and More Flexible Nonclinical Safety Programs Optimizing Animal Use.

Safety assessment of biological drugs has its challenges due to the multiple new different modalities, for example, antibody-drug conjugates, bispecifics, nanobodies, fusion proteins and advanced therapy medicinal products (ATMPs), their different pharmacokinetic and pharmacodynamic properties, and their ability to trigger immunogenicity and toxicity. In the public and in the pharmaceutical industry, there is a strong and general desire to reduce the number of animals used in research and development of drugs and in particular reducing the use of nonhuman primates. Important discussions and activities are ongoing investigating the smarter designs of early research and dose range finding studies, reuse of animals, and replacing animal experiments with in vitro studies. Other important challenges include absence of a relevant species and design of studies and developing genetically modified animals for special investigative toxicology studies. Then, the learnings and challenges from the development of the first ATMPs are available providing valuable insights in the development path for these new potentially transformative treatments. Finally, development of strategies for assessment of immunogenicity and prediction of translation of immunogenicity and associated findings to the clinic. On this, the eighth meeting for the European BioSafe members, these challenges served as the basis for the presentations and discussions during the meeting. This article serves as the workshop report reviewing the presentations and discussions at the meeting.

[Nonoperative treatment of isolated fractures of the distal fibula]. / Konservative Therapie bei Frakturen des oberen Sprunggelenks.

Stable ankle fractures can be successfully managed nonoperatively. Unstable fractures on the other hand should be treated surgically as operative management consistently leads to better outcomes. How to define stability in ankle fractures continues to be a controversial issue. Better understanding of the mechanism of injury as well as improved knowledge of ankle biomechanics now enables surgeons to define stability after isolated fractures of the distal fibula with high accuracy. The following article describes commonly used methods to assess ankle stability after isolated fractures of the lateral malleolus, including stress tests and the use of weight-bearing radiographs. By adhering to the described criteria more than 90% of all isolated nondisplaced fractures of the distal fibula can be managed nonoperatively with excellent results.

Trochaic bias overrides stress typicality in English lexical development.

This paper investigates whether typical stress patterns in English nouns and verbs are available as a prosodic cue for categorisation and accelerated word learning during first language acquisition. The stress typicality hypothesis states that left-stressed nouns and right-stressed verbs should be acquired earlier than the reverse configurations if stress effectively signals lexical class membership. In this view, class-typical stress patterns are expected to facilitate learning of novel items. A series of generalized additive models (GAMs) based on a comprehensive set of lexical data (CELEX) as well as a large set of age-of-acquisition (AoA) and concreteness ratings reveals that stress typicality plays a minor role in early acquisition, as it is generally superseded by a preference for left-hand (or 'trochaic') patterns in both nouns and verbs. This may be explained by general cognitive constraints (perceptual salience and recency) or exposure to the dominant pattern in the ambient language.

Electrochemical Synthesis of Biaryls via Oxidative Intramolecular Coupling of Tetra(hetero)arylborates.

We report herein versatile, transition metal-free and additive-free (hetero)aryl-aryl coupling reactions promoted by the oxidative electrocoupling of unsymmetrical tetra(hetero)arylborates (TABs) prepared from ligand-exchange reactions on potassium trifluoroarylborates. Exploiting the power of electrochemical oxidations, this method complements the existing organoboron toolbox. We demonstrate the broad scope, scalability, and robustness of this unconventional catalyst-free transformation, leading to functionalized biaryls and ultimately furnishing drug-like small molecules, as well as late stage derivatization of natural compounds. In addition, the observed selectivity of the oxidative coupling reaction is related to the electronic structure of the TABs through quantum-chemical calculations and experimental investigations.

Electro-Olefination-A Catalyst Free Stereoconvergent Strategy for the Functionalization of Alkenes.

Conventional methods carrying out C(sp2 )-C(sp2 ) bond formations are typically mediated by transition-metal-based catalysts. Herein, we conceptualize a complementary avenue to access such bonds by exploiting the potential of electrochemistry in combination with organoboron chemistry. We demonstrate a transition metal catalyst-free electrocoupling between (hetero)aryls and alkenes through readily available alkenyl-tri(hetero)aryl borate salts (ATBs) in a stereoconvergent fashion. This unprecedented transformation was investigated theoretically and experimentally and led to a library of functionalized alkenes. The concept was then carried further and applied to the synthesis of the natural product pinosylvin and the derivatization of the steroidal dehydroepiandrosterone (DHEA) scaffold.

Thiete Dioxides as Templates Towards Twisted Scaffolds and Macrocyclic Structures.

Thiete dioxide units have been employed as a template for further functionalization through C-H activation strategies. Using simple thiete dioxide building blocks, a new library of axially chiral molecules has been synthesized that owe their stability to electrostatic interactions in the solid state. Similar starting materials were further engaged in the formation of cyclic trimeric structures, opening the pathway to unprecedented macrocyclic ring systems.

Optical Control of Cytokine Production Using Photoswitchable Galactosylceramides.

α-Galactosylceramides are glycosphingolipids that show promise in cancer immunotherapy. After presentation by CD1d, they activate natural killer T cells (NKT), which results in the production of a variety of pro-inflammatory and immunomodulatory cytokines. Herein, we report the synthesis and biological evaluation of photochromic derivatives of KRN-7000, the activity of which can be modulated with light. Based on established structure-activity relationships, we designed photoswitchable analogues of this glycolipid that control the production of pro-inflammatory cytokines, such as IFN-γ. The azobenzene derivative α-GalACer-4 proved to be more potent than KRN-7000 itself when activated with 370 nm light. Photolipids of this type could improve our mechanistic understanding of cytokine production and could open new directions in photoimmunotherapy.

Two-stage weaning strategy using veno-veno-arterial perfusion for patients on extracorporeal membrane oxygenation following cardiogenic shock.

OBJECTIVES: Veno-arterial extracorporeal membrane oxygenation represents the last therapy option in refractory cardiogenic shock. Successful weaning becomes difficult if the myocardial function recovers but pulmonary impairment persists. We present our experience with a new weaning strategy, using a stepwise mode-switch from veno-arterial to veno-veno-arterial and veno-venous extracorporeal membrane oxygenation setting for patients with primary cardiogenic shock and subsequent respiratory failure. METHODS: From 81 patients treated with veno-arterial extracorporeal membrane oxygenation following acute cardiogenic shock between January 2014 and April 2018, eight patients with cardiac and pulmonary failure were identified to be treated using the following protocol: patients were put on veno-arterial extracorporeal membrane oxygenation, a second inflow cannula was inserted via the right jugular vein and cardiac weaning was performed via veno-veno-arterial support. Finally, patients were pulmonary weaned via veno-venous extracorporeal membrane oxygenation mode. RESULTS: In the mode-switch group, etiologies of cardiogenic shock were cardiac arrest (12.5%), myocardial infarction (12.5%) and post-cardiotomic heart failure (75%). Mean time between onset of cardiogenic shock and start of veno-arterial extracorporeal membrane oxygenation was 76 ± 117 min. At implantation, lactate and pH values were 9.5 ± 5.0 mmol/L and 7.2 ± 0.2. Total extracorporeal membrane oxygenation-time was 9.3 ± 4.7 days, with a mode-switch from veno-arterial to veno-veno-arterial after 3.9 ± 2.7 days. The weaning rate in the mode-switch group was 75% (vs. 41% in the entire cohort) and the 30-day survival was 50% (vs 32% in the cohort). 38% of the patients presented a favorable neurological outcome. CONCLUSION: Mode-switch from veno-arterial to veno-veno-arterial and weaning via veno-venous extracorporeal membrane oxygenation mode is feasible for combined cardiac and pulmonary failure, with promising results due to an optimized pre-pulmonary oxygenation.

Regiodivergent Stereoselective Access to Fused Alkylideneazetidines.

Following recent advances in the generalization and simplification of 2H-azetine synthesis, a regiodivergent approach to fused 2- and 3-alkylideneazetines was designed via the intermediate formation of unprecedented vinylazetine structures. Concise sequences to the latter are described from which an expected unsaturated fused ring system was isolated with very high yields and regio- and stereoselectivities by [4 + 2] cycloadditions.

Oxidative Ring Contraction of Cyclobutenes: General Approach to Cyclopropylketones including Mechanistic Insights.

An original oxidative ring contraction of easily accessible cyclobutene derivatives for the selective formation of cyclopropylketones (CPKs) under atmospheric conditions is reported. Comprehensive mechanistic studies are proposed to support this novel, yet unusual, rearrangement. Insights into the mechanism ultimately led to simplification and generalization of the ring contraction of cyclobutenes using mCPBA as an oxidant. This unique and functional group tolerant transformation proceeds under mild conditions at room temperature, providing access to a new library of polyfunctionalized motifs. With CPKs being attractive and privileged pharmacophores, the elaboration of such a simple and straightforward strategy represents a highly valuable tool for drug discovery and medicinal chemistry. Additionally, the described method was employed to generate a pool of bioactive substances and key precursors in a minimum number of steps.

Biotherapeutics in non-clinical development: Strengthening the interface between safety, pharmacokinetics-pharmacodynamics and manufacturing.

Biological drugs comprise a wide field of different modalities with respect to structure, pharmacokinetics and pharmacological function. Considerable non-clinical experience in the development of proteins (e.g. insulin) and antibodies has been accumulated over the past thirty years. In order to improve the efficacy and the safety of these biotherapeutics, Fc modifications (e.g. Fc silent antibody versions), combinations (antibody-drug conjugates, protein-nanoparticle combinations), and new constructs (darpins, fynomers) have been introduced. In the last decade, advanced therapy medicinal products (ATMPs) in research and development have become a considerable and strongly growing part of the biotherapeutic portfolio. ATMPs consisting of gene and cell therapy modalities or even combinations of them, further expand the level of complexity, which already exists in non-clinical development strategies for biological drugs and has thereby led to a further diversification of expertise in safety and PKPD assessment of biological drugs. It is the fundamental rationale of the BioSafe meetings, held yearly in the EU and in the US, to convene experts on a regular basis and foster knowledge exchange and mutual understanding in this fast growing area. In order to reflect at least partially the variety of the biotherapeutics field, the 2016 EU BioSafe meeting addressed the following topics in six sessions: (i) In vitro Meets in vivo to Leverage Biologics Development (ii) New developments and regulatory considerations in the cell and gene therapy field (iii) CMC Challenges with Biologics development (iv) Minipigs in non-clinical safety assessment (v) Opportunities of PKPD Assessment in Less Common Administration Routes In the breakout sessions the following questions were discussed: (i) Cynomolgus monkey as a reprotoxicology Species: Impact of Immunomodulators on Early Pregnancy Maintenance (ii) Safety Risk of Inflammation and Autoimmunity Induced by Immunomodulators (iii) Experience with non-GMP Material in Pivotal Non-clinical Safety Studies to Support First in Man (FiM) Trials (iv) Safety Assessment of Combination Products for Non-oncology.

Unsaturated Four-Membered Rings: Efficient Strategies for the Construction of Cyclobutenes and Alkylidenecyclobutanes.

Our recent studies of the diastereo- and enantioselective formation of strained alkylidenecycloalkanes drove us to more-thoroughly investigate the formation of four-membered rings for which only few efficient methods are described. We first developed a strategy to diversify the saturated part of the four-membered ring and applied it to a highly diastereoselective synthesis of more-elaborate alkylidenecyclobutanes, which completed our precedent studies. In parallel, cyclobutene structures were built employing simple organometallic methods and further functionalized to give a diverse range of new substitution patterns, which consequently enriched the pool of cyclobutene-based building blocks.

Leverage nonclinical development of bispecifics by translational science.

Bispecific antibody constructs (Bispecifics, bsAbs) may have greater functionality compared to established monoclonal antibodies because they bind to 2 different targets or, potentially, to 2 epitopes on the same target (dual targeting). This may result in enhanced binding avidity with preferential binding to cells that express both targets or binding to targets on different cells. However, development of these next-generation biologics, including new formats, creates unique challenges due to their increased complexity. Here we review aspects of bsAbs preclinical development programs that may increase the success rates of bsAbs in clinical development.

Non-clinical Safety Evaluation of Biotherapeutics - Challenges, Opportunities and new Insights.

New challenges and opportunities in nonclinical safety testing of biotherapeutics were presented and discussed at the 5th European BioSafe Annual General Membership meeting in November 2015 in Ludwigshafen. This article summarizes the presentations and discussions from both the main and the breakout sessions. The following topics were covered in six main sessions: The following questions were discussed across 4 breakout sessions (i-iv) and a case-study based general discussion (v).

PEGylated Biopharmaceuticals: Current Experience and Considerations for Nonclinical Development.

PEGylation (the covalent binding of one or more polyethylene glycol molecules to another molecule) is a technology frequently used to improve the half-life and other pharmaceutical or pharmacological properties of proteins, peptides, and aptamers. To date, 11 PEGylated biopharmaceuticals have been approved and there is indication that many more are in nonclinical or clinical development. Adverse effects seen with those in toxicology studies are mostly related to the active part of the drug molecule and not to polyethylene glycol (PEG). In 5 of the 11 approved and 10 of the 17 PEGylated biopharmaceuticals in a 2013 industry survey presented here, cellular vacuolation is histologically observed in toxicology studies in certain organs and tissues. No other effects attributed to PEG alone have been reported. Importantly, vacuolation, which occurs mainly in phagocytes, has not been linked with changes in organ function in these toxicology studies. This article was authored through collaborative efforts of industry toxicologists/nonclinical scientists to address the nonclinical safety of large PEG molecules (>10 kilo Dalton) in PEGylated biopharmaceuticals. The impact of the PEG molecule on overall nonclinical safety assessments of PEGylated biopharmaceuticals is discussed, and toxicological information from a 2013 industry survey on PEGylated biopharmaceuticals under development is summarized. Results will contribute to the database of toxicological information publicly available for PEG and PEGylated biopharmaceuticals.

Nonclinical safety testing of biopharmaceuticals--Addressing current challenges of these novel and emerging therapies.

Non-clinical safety testing of biopharmaceuticals can present significant challenges to human risk assessment with these often innovative and complex drugs. Hot Topics in this field were discussed recently at the 4th Annual European Biosafe General Membership meeting. In this feature article, the presentations and subsequent discussions from the main sessions are summarized. The topics covered include: (i) wanted versus unwanted immune activation, (ii) bi-specific protein scaffolds, (iii) use of Pharmacokinetic (PK)/Pharmacodynamic (PD) data to impact/optimize toxicology study design, (iv) cytokine release and challenges to human translation (v) safety testing of cell and gene therapies including chimeric antigen receptor T (CAR-T) cells and retroviral vectors and (vi) biopharmaceutical development strategies encompassing a range of diverse topics including optimizing entry of monoclonal antibodies (mAbs) into the brain, safety testing of therapeutic vaccines, non-clinical testing of biosimilars, infection in toxicology studies with immunomodulators and challenges to human risk assessment, maternal and infant anti-drug antibody (ADA) development and impact in non-human primate (NHP) developmental toxicity studies, and a summary of an NC3Rs workshop on the future vision for non-clinical safety assessment of biopharmaceuticals.

Weightbearing Radiographs Facilitate Functional Treatment of Ankle Fractures of Uncertain Stability.

The most important determinant in the treatment of malleolar fractures is stability. Stable fractures have an intact deep deltoid ligament and do not displace with functional treatment. If the deep deltoid/medial malleolar complex is disrupted, the talus is at risk of displacement. Weber (2010) showed that weightbearing radiographs predicted stability in patients with undisplaced ankle fractures. We developed clinical criteria for potential instability and applied them to a prospective series of patients. The criteria included a medial clear space of <4 mm; medial tenderness, bruising or swelling; a fibular fracture above the syndesmosis; a bimalleolar or trimalleolar fracture; an open fracture; and a high-energy fracture mechanism. A prospectively documented series of 43 patients chose functional brace treatment of the potentially unstable fractures. Weightbearing radiographs were performed with the patient wearing the brace before treatment and free of the brace at clinical union (6 to 9 weeks for all patients). The patients were encouraged to bear full weight and actively exercise their ankles in the brace. All fractures healed without displacement. The risk of displacement was 0% (95% confidence interval 0% to 9.5%). The results of the present preliminary series give support for the use of weightbearing radiographs to guide treatment of undisplaced ankle fractures.