Transforming Health Care Delivery towards Value-Based Health Care in Germany: A Delphi Survey among Stakeholders.

Value-based healthcare (VBC) represents one strategy to meet growing challenges in healthcare systems. To date, VBC is not implemented broadly in the German healthcare system. A Delphi survey was conducted to explore stakeholders' perspectives on the relevance and feasibility of actions and practices related to the implementation of VBC in the German healthcare system. Panellists were selected using purposive sampling. Two iterative online survey rounds were conducted which were preceded by a literature search and semi-structured interviews. After two survey rounds, a consensus was reached on 95% of the items in terms of relevance and on 89% of the items regarding feasibility. The expert panels' responses were in favor of the presented actions and practices of VBC in 98% of items for which consensus was found (n = 101). Opposition was present regarding the relevance of health care being provided preferably in one location for each indication. Additionally, the panel considered inter-sectoral joint budgets contingent on treatment outcomes achieved as not feasible. When planning the next steps in moving towards a value-based healthcare system, policymakers should take into account this study's results on stakeholders' perceptions of the relative importance and feasibility of VBC components. This ensures that regulatory changes are aligned with stakeholder values, facilitating greater acceptance and more successful implementation.

Munich atopy prediction study (MAPS): protocol for a prospective birth cohort addressing clinical and molecular risk factors for atopic dermatitis in early childhood.

INTRODUCTION: The pathogenesis of atopic diseases is highly complex, and the exact mechanisms leading to atopic dermatitis (AD) onset in infants remain mostly enigmatic. In addition to an interdependent network of components of skin development in young age and skin barrier dysfunction underlying AD development that is only partially understood, a complex interplay between environmental factors and lifestyle habits with skin barrier and immune dysregulation is suspected to contribute to AD onset. This study aims to comprehensively evaluate individual microbiome and immune responses in the context of environmental determinants related the risk of developing AD in the first 4 years of a child's life. METHODS AND ANALYSES: The 'Munich Atopic Prediction Study' is a comprehensive clinical and biological investigation of a prospective birth cohort from Munich, Germany. Information on pregnancy, child development, environmental factors, parental exposures to potential allergens and acute or chronic diseases of children and parents are collected by questionnaires together with a meticulous clinical examination by trained dermatologists focusing on allergies, skin health, and in particular signs of AD at 2 months after birth and then every 6 months. In addition, skin barrier functions are assessed through cutometry, corneometry and transepidermal water loss at every visit. These measurements are completed with allergy diagnostics and extensive microbiome analyses from stool and skin swabs as well as transcriptome analyses using skin microbiopsies.The aim is to assess the relevance of different known and yet unknown risk factors of AD onset and exacerbations in infants and to identify possible accessible and robust biomarkers. ETHICS AND DISSEMINATION: The study is approved by the Ethical Committee of the Medical Faculty of the Technical University of Munich (reference 334/16S). All relevant study results will be presented at national and international conferences and in peer-reviewed journals.

Photo-Responsive Self-Assembly of Plasmonic Magnetic Janus Nanoparticles.

Stimuli-responsive self-assembly of nanoparticles is a versatile approach for the bottom-up fabrication of adaptive and functional nanomaterials. For this purpose, anisotropic building blocks are of particular importance due to the unique shapes and structures that can be obtained upon self-assembly. Here, we demonstrate the photo-responsive self-assembly of plasmonic magnetic "dumbbell" Janus nanoparticles (Au-Fe3O4) via the host-guest interaction of the supramolecular host cyclodextrin and the molecular photoswitch arylazopyrazole. We developed efficient ligand exchange procedures that enable the introduction of functional ligands, respectively, to the surface of the gold or magnetite core of the dumbbell. Our results indicate that distinct nanoparticle superstructures arise in aqueous solutions if nanoparticle aggregation is crosslinker-induced or self-induced and that the reversible formation and fragmentation of the superstructures can be modulated with light.

[Mindfulness in Trainee Psychotherapies with Children and Adolescents]. / Achtsamkeit in Ausbildungspsychotherapien bei Kindern und Jugendlichen.

Mindfulness in Trainee Psychotherapies with Children and Adolescents The implementation of mindfulness-based interventions (MBIs) in cognitive-behavioral therapy has greatly increased over the past few years. However, there is little research about the implementation of MBIs in individual child and adolescent psychotherapy. The present paper gives an overview of current MBIs and their efficacy in children and adolescents. A depiction of the implementation of MBIs in individual therapy and a description of the "Mindfulness and Relaxation Study - Children and Adolescents" (MARS-CA) is given. The study aims to examine the effects of short session-introducing interventions with mindfulness elements on juvenile patients' psychopathological symptomatology and therapeutic alliance. For this reason, the authors compare session-introducing interventions with mindfulness elements with session-introducing relaxation interventions and no session-introducing intervention. Qualitative results of the pre-study show that both interventions with mindfulness elements and relaxation interventions work well with juvenile patients.

Functionalization of Clinically Approved MRI Contrast Agents for the Delivery of VEGF.

In combining the two clinically approved substances ferumoxytol and VEGF-165 via peptide coupling, we propose a straightforward approach to obtain a potentially ready-to-use theranostic contrast agent for specific cardiovascular diseases. Clinical and preclinical magnetic resonance imaging (MRI) studies have shown that intravenously applied superparamagnetic ferumoxytol nanoparticles accumulate in acute ischemic myocardial tissue. On the other hand, growth factors such as VEGF-165 (vascular endothelial growth factor) play a major role during angiogenesis and vasculogenesis. Promising clinical studies with systemic application of VEGF-165 have been performed in the past. However, following untargeted systemic application, the biological half-life of VEGF-165 was too short to develop its full effect. Therefore, we hypothesized that ferumoxytol particles functionalized with VEGF-165 will accumulate in ischemic myocardial regions and can be detected by MRI, while the prolonged retention of VEGF-165 due to ferumoxytol-coupling will help to prevent adverse tissue remodeling. In addition, strategies such as magnetic targeting can be used to enhance targeted local accumulation. As a precondition for further preclinical research, we confirmed the successful coupling between ferumoxytol and VEGF-165 in detail (TEM, XPS, and IR spectroscopy), characterized the functionalized ferumoxytol particles (DLS, TEM, and MRI) and performed in vitro tests that showed their superior effect on cell growth and survival.

A Modular System for the Design of Stimuli-Responsive Multifunctional Nanoparticle Aggregates by Use of Host-Guest Chemistry.

A self-assembly approach for the design of multifunctional nanomaterials consisting of different nanoparticles (gold, iron oxide, and lanthanide-doped LiYF4 ) is developed. This modular system takes advantage of the light-responsive supramolecular host-guest chemistry of ß-cyclodextrin and arylazopyrazole, which enables the dynamic and reversible self-assembly of particles to spherical nanoparticle aggregates in aqueous solution. Due to the magnetic iron oxide nanoparticles, the aggregates can be manipulated by an external magnetic field leading to the formation of linear structures. As a result of the integration of upconversion nanoparticles, the aggregates are additionally responsive to near-infrared light and can be redispersed by use of the upconversion effect. By varying the nanoparticle and linker concentrations the composition, size, shape, and properties of the multifunctional nanoparticle aggregates can be fine-tuned.

Controlling Complex Stability in Photoresponsive Macromolecular Host-Guest Systems: Toward Reversible Capture of DNA by Cyclodextrin Vesicles.

An effective and universal method for delivering structurally diverse biomolecules in vivo would greatly benefit modern drug therapy, but has yet to be discovered. Self-assembled supramolecular complexes containing vesicles of amphiphilic cyclodextrin and linker molecules with an azobenzene guest unit and a charged functionality have been established as nanoscale carriers for proteins and DNA, making use of multivalent electrostatic attraction. However, light-induced cargo release is only feasible up to a maximum net charge of the biomacromolecules. Herein, it is shown that it is possible to fine-tune macromolecular complex stability and size by addition of a competitive guest molecule that acts as a stopper, partly blocking the vesicle surface. The superior performance of arylazopyrazoles in photoisomerization compared to azobenzenes, which enables a lower surface charge density of the vesicles in the photostationary state, is also demonstrated. Both strategies allow reversible supramolecular aggregation of high molecular weight DNA (2 and 4.8 kbp).

Stimulus-Responsive Assembly of Nanoparticles using Host-Guest Interactions of Cyclodextrins.

The design of multifunctional nanomaterials that respond to external stimuli and mimic the capacity of biological materials to respond and adapt to their environment has become a focus of interest in nanotechnology. In this Concept, we describe the development of supramolecular nanoparticle assemblies constructed by use of host-guest interactions between cyclodextrins and suitable guest molecules. The nanoparticle assembly is reversible and can be directed by applying different stimuli that act either on the guest molecules or the nanoparticles. This strategy can be extended to mesoscale assembly of microparticles. We highlight the newest research work in this field of nanochemistry and point out future perspectives and opportunities.

Kinetic control in the temperature-dependent sequential growth of surface-confined supramolecular copolymers.

We report the sequential growth of supramolecular copolymers on gold surfaces, using oppositely charged dendritic peptide amphiphiles. By including water-solubilising thermoresponsive chains in the monomer design, we observed non-linear effects in the temperature-dependent sequential growth. The step-wise copolymerisation process is characterised using temperature dependent SPR and QCM-D measurements. At higher temperatures, dehydration of peripheral oligoethylene glycol chains supports copolymer growth due to more favourable comonomer interactions. Both monomers incorporate methionine amino acids but remarkably, desorption of the copolymers via competing sulphur gold interactions with the initial monomer layer is not observed. The surface-confined supramolecular copolymers remain kinetically trapped on the metal surface at near neutral pH and form viscoelastic films with a tuneable thickness.

Self-assembly of colloidal molecules that respond to light and a magnetic field.

This communication reports a novel method to prepare Janus particles with light-responsive arylazopyrazole (AAP) polymer caps, which can be reversibly cross-linked to chain-like colloidal oligomers in the presence of cyclodextrin (CD) functionalized superparamagnetic nanoparticles. The resulting colloidal molecules are light-responsive and can be controlled by an external magnetic field.

New trends in the functionalization of metallic gold: from organosulfur ligands to N-heterocyclic carbenes.

In this Tutorial Review, we describe the development of new ligands for functionalizing and stabilizing metallic gold in the form of planar gold surfaces and gold nanoparticles (NPs). Starting from the state-of-the-art of organosulfur ligands, we describe the gold-sulfur bond formation and the nature of the resulting interface. In addition, we explain methods to prepare ordered monolayers on planar surfaces and stable ligand shells around NPs, illustrating important pioneering studies and examples of current research. Moreover, we highlight recent advancement in functionalizing gold by N-heterocyclic carbenes (NHCs), a promising alternative ligand class regarding stability and variable design strategies. We discuss the chemistry of the carbene-gold bond and report on advantages of this new ligand. Additionally, selected examples of current research illustrate the formation of ultra-stable self-assembled monolayers of NHCs on gold surfaces as well as the preparation of NHC-stabilized gold NPs.

Near-infrared photoswitching of cyclodextrin-guest complexes using lanthanide-doped LiYF4 upconversion nanoparticles.

This communication reports a new type of supramolecular cyclodextrin-guest complexes using cyclodextrin coated upconversion nanoparticles as hosts and monovalent and divalent azobenzenes and arylazopyrazoles as guests. A potentially biocompatible photocontrol of the interaction by isomerization of the azobenzene or arylazopyrazole was achieved by laser irradiation at 980 nm and a very low light intensity of 0.22 W cm-2.

Role of endosomes in simian virus 40 entry and infection.

After binding to its cell surface receptor ganglioside GM1, simian virus 40 (SV40) is endocytosed by lipid raft-mediated endocytosis and slowly transported to the endoplasmic reticulum, where partial uncoating occurs. We analyzed the intracellular pathway taken by the virus in HeLa and CV-1 cells by using a targeted small interfering RNA (siRNA) silencing screen, electron microscopy, and live-cell imaging as well as by testing a variety of cellular inhibitors and other perturbants. We found that the virus entered early endosomes, late endosomes, and probably endolysosomes before reaching the endoplasmic reticulum and that this pathway was part of the infectious route. The virus was especially sensitive to a variety of perturbations that inhibited endosome acidification and maturation. Contrary to our previous models, which postulated the passage of the virus through caveolin-rich organelles that we called caveosomes, we conclude that SV40 depends on the classical endocytic pathway for infectious entry.

Caveolin-1 is ubiquitinated and targeted to intralumenal vesicles in endolysosomes for degradation.

Caveolae are long-lived plasma membrane microdomains composed of caveolins, cavins, and a cholesterol-rich membrane. Little is known about how caveolae disassemble and how their coat components are degraded. We studied the degradation of caveolin-1 (CAV1), a major caveolar protein, in CV1 cells. CAV1 was degraded very slowly, but turnover could be accelerated by compromising caveolae assembly. Now, CAV1 became detectable in late endosomes (LE) and lysosomes where it was degraded. Targeting to the degradative pathway required ubiquitination and the endosomal sorting complex required for transport (ESCRT) machinery for inclusion into intralumenal vesicles in endosomes. A dual-tag strategy allowed us to monitor exposure of CAV1 to the acidic lumen of individual, maturing LE in living cells. Importantly, we found that "caveosomes," previously described by our group as independent organelles distinct from endosomes, actually correspond to late endosomal compartments modified by the accumulation of overexpressed CAV1 awaiting degradation. The findings led us to a revised model for endocytic trafficking of CAV1.