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Intervention integrity or adherence describes qualities of carrying out an intervention plan and in research is fundamentally linked to experimental validity questions addressed by measurement of independent and dependent variables. Integrity has been well described in conceptual writing but has been a continuing thorny subject in research and practice with some possibility of misunderstandings. In consultation practice, in contrast to research, adherence questions may be best viewed as a triage situation in that teams examine risks and costs of decisions and plan for sufficient intervention implementation checks accordingly. Furthermore, in consultation practice the measurement of intervention adherence is not necessarily needed for internal validity arguments if internal validity evidence is a key characteristic of prior research used in problem solving. However, adherence estimates remain critical for many aspects of decision making. As much thought and resources may be dedicated to the measurement of intervention adherence as are dedicated to the measurement of dependent variables or outcome measures for both consultation practice and research depending on the decision purpose.

Drug development for children presents unique challenges and is highly regulated. Novel approaches, such as the use of extrapolation to address, for example, the need to avoid unethical studies, whilst supporting robust evidence generation have been developed in support of benefit/risk considerations by regulatory authorities. This is only one step in the decision-making process towards access, which in Europe also includes health technology assessment (HTA) bodies. Discussions related to evidentiary requirements in small populations using scientific evidence transfer have been identified as a priority action by European Medicines Agency/European Network for Health Technology Assessment 21 (EMA/EUnetHTA 21). We describe the outcome of this work and reflect on the discussions that had taken place on how to leverage prior knowledge through identifying and addressing uncertainties during life cycle management to support regulatory and HTA decision-making. Using examples, we explore the range of applications for evidence generation and offer regulatory and HTA insights on key design considerations for producing better evidence, reflecting our shared ambition. Early interactions with all respective stakeholders, particularly between regulators and HTA bodies are key to optimise data generation and utility in children. In Europe, the HTA regulation will offer opportunities for collaborations, which are important for all development efforts. We collaboratively explored the unique specific challenges relating to paediatric drug development, ethically and in its ability to leverage prior knowledge, as exemplified using extrapolation. Learnings from these offer opportunities to further develop methodology on how to leverage uncertainties across a product's life cycle for small populations generally., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

The integration of semiconductor Josephson junctions (JJs) in superconducting quantum circuits provides a versatile platform for hybrid qubits and offers a powerful way to probe exotic quasiparticle excitations. Recent proposals for using circuit quantum electrodynamics (cQED) to detect topological superconductivity motivate the integration of novel topological materials in such circuits. Here, we report on the realization of superconducting transmon qubits implemented with (Bi 0.06 Sb 0.94 ) 2 Te 3 topological insulator (TI) JJs using ultrahigh vacuum fabrication techniques. Microwave losses on our substrates, which host monolithically integrated hardmasks used for the selective area growth of TI nanostructures, imply microsecond limits to relaxation times and, thus, their compatibility with strong-coupling cQED. We use the cavity-qubit interaction to show that the Josephson energy of TI-based transmons scales with their JJ dimensions and demonstrate qubit control as well as temporal quantum coherence. Our results pave the way for advanced investigations of topological materials in both novel Josephson and topological qubits.

We optically designed and investigated two deterministic light-trapping concepts named "Hutong" (wafer thickness dependent, patch-like arrangement of "V" grooves with alternating orientations) and "VOSTBAT" (one directional "V" grooves at the front and saw-tooth like structures at the back) for the application in emerging thin silicon heterojunction (SHJ) solar cells. Calculated photocurrent density (J ph ) (by weighting the spectrally resolved absorptance with AM1.5g spectrum and integrating over the wavelength) showed that both the Hutong and VOSTBAT structures exceed the Lambertian reference and achieved J ph of 41.72 mA/cm 2 and 41.86 mA/cm 2 , respectively, on 60 µm thin wafers in the case of directional, normal incidence.

The number of effective antituberculotic drugs is strongly limited to four first-line drugs in standard therapy. In case of resistances second-line antibiotics are used with a poor efficacy and tolerability. Therefore, novel antituberculotic drugs are urgently needed. We synthesized novel nonclassical 1,4-dihydropyridines and evaluated their antituberculotic properties depending on substituent effects. Preferred substituents could be identified. As related classical 1,4-dihydropyridines are known as inhibitors of the transmembrane efflux pump ABCB1 in cancer cells, we wondered whether a use of our compounds may be of favour to enhance the antituberculotic drug efficacy of the second-line antituberculotic drug clofazimine, which is a known substrate of ABCB1 by a suggested inhibition of a corresponding efflux pump in Mycobacterium tuberculosis (Mtb). For this, we determined the ABCB1 inhibiting properties of our compounds in a mouse T-lymphoma cell line model and then evaluated the drug-enhancing properties of selected compounds in a co-application with clofazimine in our Mtb strain. We identified novel enhancers of clofazimine toxicity which could prevent clofazimine resistance development mediated by an efflux pump activity.

Transparent passivated contacts (TPCs) using a wide band gap microcrystalline silicon carbide (μc-SiC:H(n)), silicon tunnel oxide (SiO 2 ) stack are an alternative to amorphous silicon-based contacts for the front side of silicon heterojunction solar cells. In a systematic study of the μc-SiC:H(n)/SiO 2 /c-Si contact, we investigated selected wet-chemical oxidation methods for the formation of ultrathin SiO 2 , in order to passivate the silicon surface while ensuring a low contact resistivity. By tuning the SiO 2 properties, implied open-circuit voltages of 714 mV and contact resistivities of 32 mΩ cm 2 were achieved using μc-SiC:H(n)/SiO 2 /c-Si as transparent passivated contacts.

In this work, we have improved the absorption properties of thin film solar cells by introducing light trapping reflectors deposited onto self-assembled nanostructures. The latter consist of a disordered array of nanopillars and are fabricated by polymer blend lithography. Their broadband light scattering properties are exploited to enhance the photocurrent density of thin film devices, here based on hydrogenated amorphous silicon active layers. We demonstrate that these light scattering nanopillars yield a short-circuit current density increase of +33%rel with respect to equivalent solar cells processed on a planar reflector. Moreover, we experimentally show that they outperform randomly textured substrates that are commonly used for achieving efficient light trapping. Complementary optical simulations are conducted on an accurate 3D model to analyze the superior light harvesting properties of the nanopillar array and to derive general design rules. Our approach allows one to easily tune the morphology of the self-assembled nanostructures, is up-scalable and operated at room temperature, and is applicable to other photovoltaic technologies.

The number of effective first-line antibiotics for the treatment of Mycobacterium tuberculosis infection is strongly limited to a few drugs. Due to emerging resistance against those drugs, second- and third-line antibiotics have been established in therapy with certain problems and also increasing mycobacterial resistance. An alternative to such novel drugs or combined therapeutic regimes which may reduce resistance development is finding enhancers of mycobacterial drug effectiveness, especially enhancers that counteract causative resistance mechanisms. Such enhancers may reduce the extracellular drug efflux mediated by bacterial efflux pumps and thus enhance the intracellular drug toxicity. We developed novel 1,4-dihydropyridines (DHPs) as potential efflux pump inhibitors with some determined P-gp affinities. The influence on the antituberculotic drug toxicity has been investigated for three prominent antituberculotic drugs. Exclusive and selective toxicity enhancing effects have been detected for isoniazid (INH) which could be related to certain substituent effects of the 1,4-DHPs. So, structure-dependent activities have been found. Thus, promising enhancers could be identified and a suggested efflux pump inhibition is discussed.

The aim of phase I clinical trials is to obtain reliable information on safety, tolerability, pharmacokinetics (PK), and mechanism of action of drugs with the objective of determining the maximum tolerated dose (MTD). In most phase I studies, dose-finding and PK analysis are done separately and no attempt is made to combine them during dose allocation. In cases such as rare diseases, paediatrics, and studies in a biomarker-defined subgroup of a defined population, the available population size will limit the number of possible clinical trials that can be conducted. Combining dose-finding and PK analyses to allow better estimation of the dose-toxicity curve should then be considered. In this work, we propose, study, and compare methods to incorporate PK measures in the dose allocation process during a phase I clinical trial. These methods do this in different ways, including using PK observations as a covariate, as the dependent variable or in a hierarchical model. We conducted a large simulation study that showed that adding PK measurements as a covariate only does not improve the efficiency of dose-finding trials either in terms of the number of observed dose limiting toxicities or the probability of correct dose selection. However, incorporating PK measures does allow better estimation of the dose-toxicity curve while maintaining the performance in terms of MTD selection compared to dose-finding designs that do not incorporate PK information. In conclusion, using PK information in the dose allocation process enriches the knowledge of the dose-toxicity relationship, facilitating better dose recommendation for subsequent trials., (© 2017 The Authors. Biometrical Journal published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

There is an urgent need for novel drugs for the treatment of tuberculosis (TB) due to the increasing prevalence of antibiotic resistance among Mycobacterium tuberculosis (Mtb) strains against first-line and second-line therapeutics. We developed novel N-phenyl 1,4-dihydropyridines as potential antituberculotic agents. The observed activity depends on the substitution patterns of the aromatic residues. N-unsubstituted 1,4-dihydropyridines are known inhibitors of the cancer-relevant transmembrane efflux pump ABCB1. Based on the similarity of ABCB1 amino acids sequences relevant to 1,4-dihydropyridine binding and the MTb efflux pump Rv0194, we determined ABCB1-inhibitory properties of our compounds in a cell line model. We identified one compound, which substantially increased the activity of two antituberculotic drugs which are substrates of ABCB1. The data indicate that our N-phenyl 1,4-dihydropyridines represent a novel compound class which improves the efficacy of anti-TB drugs by interfering with transmembrane efflux pumps in Mtb., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

A phase I and pharmacokinetic study was carried out with the new ruthenium complex indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019, FFC14A). Seven patients with various types of solid tumours refractory to standard therapy were treated with escalating doses of KP1019 (25-600 mg) twice weekly for 3 weeks. No dose-limiting toxicity occurred. Ruthenium plasma concentration-time profiles after the first dose and under multiple-dose conditions were analysed using a compartmental approach. The pharmacokinetic disposition was characterised by a small volume of distribution, low clearance and long half-life. Only a small fraction of ruthenium was excreted renally. The area under the curve values increased proportionally with dose indicating linear pharmacokinetics.

Hepatic metastases occur in about half of patients with colorectal cancer. Since hepatic metastases are often not accessible for surgery, chemotherapy of metastases is important. The most commonly used chemotherapy drugs for hepatic metastases are fluorouracil, irinotecan, and oxaliplatin. Several enzymes are known to be involved in the catabolism and anabolism of these drugs, and the activity of these enzymes varies greatly between individuals. The causes of this variation include genetic polymorphisms, different regulation between normal and cancer tissue, and the influence of chemotherapy on enzyme expression. The varying enzyme activity may have an important effect on the outcome of chemotherapy. Several studies confirm the influence of the activity of thymidylate synthase, thymidine phosphorylase and dihydropyrimidine dehydrogenase on the outcome of fluorouracil therapy for colorectal cancer, with higher enzyme activities predicting lower treatment efficacy. Although fewer studies are available regarding therapy of hepatic metastases, the same relationship between thymidylate synthase activity and outcome of fluorouracil therapy observed for primary colorectal cancer was found. For the other two enzymes, only a few studies are available, but the results indicate similarly that higher enzyme activity seems to be disadvantageous. The enzymes responsible for the activation, metabolism and mechanism of action of irinotecan, namely carboxylesterase 2, cytochrome P450 (CYP) 3A4, uridine diphosphate glucuronosyltransferase isoform 1A1 (UGT1A1), and topoisomerase-I, also exhibit variable interindividual activity. Thus, there may be an association between enzyme activity and response to therapy. For instance, in patients with colorectal cancer, higher enzyme activity of topoisomerase-I seems to be predictive of a better response to irinotecan. CYP3A4 and UGT1A1 activity levels might be predictive of irinotecan toxicity rather than efficacy. The degradation of oxaliplatin is independent of potentially varying enzyme activity, but for this drug, the DNA repair enzyme ERCC1 may influence the survival time after chemotherapy. Taken together, the available data indicate the importance of the different enzyme activities on the outcome of chemotherapy of hepatic metastases in colorectal cancer. More information is needed, especially for the newer drugs irinotecan and oxaliplatin. However, the existing data are very promising in respect to the potential to guide dose and drug selection for more efficient and less toxic chemotherapy of hepatic metastases.

Recent research has examined the role of vocational-technical training in facilitating the transition from school to work of adolescents with learning disabilities. The present study provided 6-, 12-, and 24-month follow-up data on such students who had attended vocational-technical programs. Matched groups of students without disabilities from vocational-technical programs, as well as randomly selected students without disabilities from regular high schools, were also included for comparisons. Results of the study raised several questions about the value and purpose of vocational-technical training for adolescents with learning disabilities.

Posterolateral segmentary maxillary impaction osteotomy has a role to play in the treatment of gaps between the upper and lower jaws. It has several advantages, especially an uncomplicated postoperative period and the single-maxillary contention it provides. The indication must be established after an articulator assessment in order to take into account the mandibular protrusion caused by autorotation and to prevent a sagittal shift. Associated marginal glossectomy will frequently be required. Similarly, in case of vertical excess, genioplasty for vertical reduction will improve the facial balance. This technique may also be proposed as "pre-prosthetic surgery" in cases of egression in the premolar and molar areas, for which it has shown excellent results.

This analysis of replies to a questionnaire raises three questions: Is surgery indicated in the treatment of this syndrome? What are the factors on which the indication for surgery should be based? If surgery is indicated what type of operation should be performed? Complications of surgery are discussed.