Let's stop dumping cookstoves in local communities. It's time to get implementation right

We most welcome the comment by Thakur, van Schayck and Boudewijns on our article on the effects and acceptability of implementing improved cookstoves. Adoption rates of improved cookstoves by local communities are often strikingly low. The authors underline the urge to advance cookstove implementation strategies, and reinforce the approach used in the FRESH AIR project. They highlight several important factors to increase adoption success and call for further research on the topic. We want to build on this comment by reflecting on decades of substantial discrepancies between the disappointing adoption rates of improved cookstoves, and the subsequent failure to adapt implementation strategies accordingly. We argue that it is not necessarily the lack of evidence that impedes the success of implementation strategies for improved cookstoves. Moreover, it is the lack of use of the evidence by implementors. We propose several ideas for overcoming this evidence-to-practice gap

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The FRESHAIR4Life study: Global implementation research on non-communicable disease prevention targeting adolescents’ exposure to tobacco and air pollution in disadvantaged populations

The FRESHAIR4Life study aims to reduce the non-communicable disease (NCD) burden by implementing preventive interventions targeting adolescents’ exposure to tobacco use and air pollution (AP) worldwide. This paper presents the FRESHAIR4Life methodology and initial rapid review results. The rapid review, using various databases and PubMed, aimed to guide decision-making on risk factor focus, target areas, and populations. It showed variable NCD mortality rates related to tobacco use and AP across the participating countries, with tobacco as the main risk factor in the Kyrgyz Republic, Greece, and Romania, and AP prevailing in Pakistan and Uganda. Adolescent exposure levels, sources, and correlates varied. The study will continue with an in-depth situational analysis to guide the selection, adaptation, and integration of evidence-based interventions into the FRESHAIR4Life prevention package. This package will be implemented, evaluated, assessed for cost-effectiveness, and iteratively refined. The research places a strong emphasis on co-creation, capacity building, and comprehensive communication and dissemination.<br/

Therapeutic Drug Monitoring of Kinase Inhibitors in Oncology

Although kinase inhibitors (KI) frequently portray large interpatient variability, a 'one size fits all' regimen is still often used. In the meantime, relationships between exposure-response and exposure-toxicity have been established for several KIs, so this regimen could lead to unnecessary toxicity and suboptimal efficacy. Dose adjustments based on measured systemic pharmacokinetic levels-i.e., therapeutic drug monitoring (TDM)-could therefore improve treatment efficacy and reduce the incidence of toxicities. Therefore, the aim of this comprehensive review is to give an overview of the available evidence for TDM for the 77 FDA/EMA kinase inhibitors currently approved (as of July 1st, 2023) used in hematology and oncology. We elaborate on exposure-response and exposure-toxicity relationships for these kinase inhibitors and provide practical recommendations for TDM and discuss corresponding pharmacokinetic targets when possible

Design and statistics of pharmacokinetic drug-drug, herb-drug, and food-drug interaction studies in oncology patients

Polypharmacy is becoming increasingly prevalent in society. Patients with polypharmacy are at greater risk for drug-drug interactions, which can influence the efficacy of treatment. Especially, in oncology this is a concern since neoplasms are increasing prevalent with age, as well as polypharmacy is. Besides drug-drug interactions, also herb-drug and food-drug interactions could be present. Knowledge of these interactions is of great importance for safe and effective anti-cancer treatment, because the therapeutic window of most of these oncologic drugs are small. To study pharmacokinetic interaction effects, a cross-over pharmacokinetic study is a widely used, efficient and scientifically robust design. Yet, several aspects need to be considered when carrying out an interaction study. This includes the knowledge of the advantages and disadvantages of a cross-over design. Furthermore, determination of the end point and research question of interest, calculation of the required sample size, analysis of the generated data with a robust statistical plan and consideration of the logtransformation for some pharmacokinetic parameters are important aspects to consider. Even though some guidelines exist regarding these key issues, no clear overview exists. In this article an overview of these aspects is provided and their effect is discussed

Enhanced Pro-Inflammatory Cytokine Responses following Toll-Like-Receptor Ligation in Schistosoma haematobium-Infected Schoolchildren from Rural Gabon

BACKGROUND: Schistosoma infection is thought to lead to down-regulation of the host's immune response. This has been shown for adaptive immune responses, but the effect on innate immunity, that initiates and shapes the adaptive response, has not been extensively studied. In a first study to characterize these responses, we investigated the effect of Schistosoma haematobium infection on cytokine responses of Gabonese schoolchildren to a number of Toll-like receptor (TLR) ligands. METHODOLOGY: Peripheral blood mononuclear cells (PBMCs) were collected from S. haematobium-infected and uninfected schoolchildren from the rural area of Zile in Gabon. PBMCs were incubated for 24 h and 72 h with various TLR ligands, as well as schistosomal egg antigen (SEA) and adult worm antigen (AWA). Pro-inflammatory TNF-alpha and anti-inflammatory/regulatory IL-10 cytokine concentrations were determined in culture supernatants. PRINCIPAL FINDINGS: Infected children produced higher adaptive IL-10 responses than uninfected children against schistosomal antigens (72 h incubation). On the other hand, infected children had higher TNF-alpha responses than uninfected children and significantly higher TNF-alpha to IL-10 ratios in response to FSL-1 and Pam3, ligands of TLR2/6 and TLR2/1 respectively. A similar trend was observed for the TLR4 ligand LPS while Poly(I:C) (Mda5/TLR3 ligand) did not induce substantial cytokine responses (24 h incubation). CONCLUSIONS: This pilot study shows that Schistosoma-infected children develop a more pro-inflammatory TLR2-mediated response in the face of a more anti-inflammatory adaptive immune response. This suggests that S. haematobium infection does not suppress the host's innate immune system in the context of single TLR ligation

Reasons for non-feasibility of therapeutic drug monitoring of oral targeted therapies in oncology - an analysis of the closed cohorts of a multicentre prospective study

BackgroundTherapeutic drug monitoring (TDM) - performing dose adjustments based on measured drug levels and established pharmacokinetic (PK) targets - could optimise treatment with drugs that show large interpatient variability in exposure. We evaluated the feasibility of TDM for multiple oral targeted therapies. Here we report on drugs for which routine TDM is not feasible.MethodsWe evaluated drug cohorts from the Dutch Pharmacology Oncology Group - TDM study. Based on PK levels taken at pre-specified time points, PK-guided interventions were performed. Feasibility of TDM was evaluated, and based on the success and practicability of TDM, cohorts could be closed.ResultsFor 10 out of 24 cohorts TDM was not feasible and inclusion was closed. A high incidence of adverse events resulted in closing the cabozantinib, dabrafenib/trametinib, everolimus, regorafenib and vismodegib cohort. The enzalutamide and erlotinib cohorts were closed because almost all PK levels were above target. Other, non-pharmacological reasons led to closing the palbociclib, olaparib and tamoxifen cohort.ConclusionsAlthough TDM could help personalising treatment for many drugs, the above-mentioned reasons can influence its feasibility, usefulness and clinical applicability. Therefore, routine TDM is not advised for cabozantinib, dabrafenib/trametinib, enzalutamide, erlotinib, everolimus, regorafenib and vismodegib. Nonetheless, TDM remains valuable for individual clinical decisions