Identifying somatic changes in drug transporters using whole genome and transcriptome sequencing data of advanced tumors

Drug resistance is a perpetual problem in cancer therapy with many underlying mechanisms. Alterations in drug transport over the cancer cell membrane can severely alter intratumoral drug exposure, contributing to resistance. Here, we present the somatic mutational landscape of 48 ATP-binding cassette and 416 solute carrier transporter genes in a cohort (CPCT-02; NCT01855477) of 3290 patients with different types of advanced and metastasized cancer through analysis of whole genome and transcriptome sequencing. In order to identify potential stressor mechanisms, we stratified patients based on previous systemic therapies and subsequently investigated the enrichment of mutations and copy-number alterations of transporter genes. In tumors from patients pretreated with protein kinase inhibitors (PKIs), genes encoding for specific copper (SLC31A1 and SLC31A2, χ2-test adjusted p-values: 6.9e-09 and 2.5e-09) and nucleoside transporters (SLC28A2 and SLC28A3, χ2-test adjusted p-values: 3.5e-06 and 6.8e-07) were deleted significantly more frequently than in patients pretreated with chemotherapy. Moreover, we detected 16 transporters that were differentially expressed at RNA level between these treatment groups. These findings contradict mechanisms of selective pressure, as they would be expected to originate during treatment with chemotherapy rather than with PKIs. Hence, they might constitute primary drug resistance mechanisms and, therefore, warrant further study.</p

COVID-19 response actors navigating multi-dimensional crises in Flanders, Belgium

Funding Information: TK, LWH, TN, SD, KPG, AV, TGV, NV, CV, CG and CVR declare receiving a grant by Fonds Wetenschappelijk Onderzoek (FWO-Research Foundation – Flanders), to conduct social listening of vaccine concerns in Belgium. LWH, NV, TGV, KPG, CG, CVR, SD, and TN declare receiving funds by the Vaccine Confidence Fund to conduct a study on healthcare workers vaccine sentiments and to foster vaccine dialogue in Belgium. HJL reports receiving a grant by MacArthur Foundation to address inequalities in Covid-19 recovery, by J&J to listening to public concerns around Covid-19, from Unicef to carry out social media listening of vaccine concerns in Central and Eastern Europe, and by Merck for research on vaccine hesitancy among health care providers in 15 countries. Publisher Copyright: © 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.The COVID-19 pandemic has disrupted societies globally. Public health institutions were tasked with responding to the pandemic in a dynamic and uncertain context. This paper sheds light on the experiences of COVID-19 response actors as they navigated multi-dimensional crises associated with the pandemic in general and vaccine hesitancy in particular. This research was conducted during the initial phase of the COVID-19 vaccine rollout in Flanders, Belgium. Participants included informants across all levels of the COVID-19 vaccination strategy including but not limited to those producing scientific knowledge, providing policy input, or implementing public health directives locally. ‘Crisis’ was identified as a recurring theme in interviews with informants. The paper highlights multi-dimensional crises experienced by informants such as the: (i) crisis of prioritization, (ii) crisis of communication, (iii) crisis of the changing image of science, (iv) crisis of epistemic agency and autonomy, and (v) crisis of trust.publishersversionpublishe

Embracing context: Lessons from designing a dialogue-based intervention to address vaccine hesitancy.

Dialogue with people who are vaccine hesitant has been recommended as a method to increase vaccination uptake. The process of cultivating dialogue is shaped by the context in which it occurs, yet the development of interventions addressing vaccine hesitancy with dialogue often overlooks the role of context and favors relatively fixed solutions. This reflexive paper shares three key lessons related to context for dialogue-based interventions. These lessons emerged during a participatory research project to develop a pilot intervention to create open dialogue among healthcare workers in Belgium about COVID-19 vaccination concerns. Through a mixed methods study consisting of in-depth interviews, focus group discussions, and surveys, we engaged healthcare workers in the design, testing, and evaluation of a digital platform featuring text-based and video-based (face-to-face) interactions. The lessons are: (1) what dialogue means, entails, and requires can vary for a population and context, (2) inherent tension exists between helping participants voice (and overcome) their concerns and exposing them to others' ideas that may exacerbate those concerns, and (3) interactional exchanges (e.g., with peers or experts) that matter to participants may shape the dialogue in terms of its content and form. We suggest that having a discovery-orientation-meaning to work not only inductively and iteratively but also reflexively-is a necessary part of the development of dialogue-based interventions. Our case also sheds light on the influences between: dialogue topic/content, socio-political landscape, population, intervention aim, dialogue form, ethics, researcher position, and types of interactional exchanges

Doubt at the core: Unspoken vaccine hesitancy among healthcare workers.

Funding Information: CG, KP, SD, TK, TN, CVR, LWH report a grant from Fonds Wetenschappelijk Onderzoek (FWO- Research Foundation – Flanders), to conduct social listening of vaccine concerns in Belgium.publishersversionpublishe

Trade-offs in operating room planning for electives and emergencies: a review

nrpages: 45status: publishe

Trade-offs in operating room planning for electives and emergencies: a review

The planning of the operating rooms (ORs) is a difficult process due to the different stakeholders involved. The real complexity, however, results from various sources of variability. This variability cannot be ignored since it greatly influences the trade-offs between the hospital costs and the patient waiting times. As a result, a need for policies guiding the OR manager in handling the trade-offs arises. Therefore, researchers have investigated different possibilities to incorporate non-elective patients in the schedule with the goal of maximizing both patient- and hospital-related measures. This paper reviews the literature on OR planning where both elective and non-elective patient categories are involved. It shows the various policies, the differences and similarities in the research settings and the resulting outcomes, whether they are beneficial or not. We find that the dedicated and the flexible policy are mostly pursued, but the setting and the assumptions of the reviewed papers vary widely. Decisions on both operational policies as well as on capacity are required to assure timely access and efficiency, which are the two main drivers for the problem at hand. Furthermore, the policy choice impacts the number of schedule disruptions and the OR utilization. However, results on the overtime and the patient waiting time are partly contradicting. The review shows that some policies have already received considerable attention, but the question of which policies are most appropriate is not yet fully answered. Neither has the full spectrum of policies been explored. The paper also addresses the remaining challenges for research in this field.status: publishe

Lean beyond company borders: costs or benefits?

Purpose - This paper brings lean principles outside the walls of the factory and applies them to the overall supply chain with respect to transportation in particular. We present a solution that increases trailer density by transporting components hanging on rails instead of piling them up. Design/method/approach - A calculation model, validated by a case study, illustrates the different cost drivers across the supply chain and reveals the savings and investment expenditures of the new concept. Findings - The results from a case study show that smoothening the flow of products between the different supply chain partners and increasing the trailer density by 25% results in a reduction of 20% in transportation costs. Based on three critical product characteristics, multiple products are researched in a 2³ design to gain insights in the market analysis and the practical use. Practical implications - Looking for innovative ways to transport goods can lead to transportation cost savings, new business models and a smoother flow of products. Originality/value - The model contributes to the literature by increasing the transparency about the drivers that influence the costs of the different players in the supply chain. Moreover, the paper shows the financial impact of innovations in transporting and handling components.nrpages: 21status: publishe

Finding empirical evidence for the impact of surgery sequencing on non-operative time

We explore to what extent the sequencing of surgeries might impact the nonoperative time in the OR, as this might have consequences for surgery scheduling practice to improve performance measures. We report on insights from data of a large Belgian hospital and differentiate between an outpatient and inpatient setting

The impact of scheduling pediatric operating room sessions

The need for specialized anesthesia equipment for pediatric patients and the preference for audiovisual separation of pediatric and adult patients in the hospital can be addressed by separating pediatric surgeries in one or more fully equipped operating rooms (ORs). Although this separation benefits the equipment use, the planning of specialized anesthesiologists and the patient experience, its impact on patient scheduling has barely been studied. The aim of this study is to assess the feasibility of allocating OR sessions to pediatric patients with regards to keeping the access times of both adult and pediatric patients within acceptable limits and with regards to the change in several operational performance measures. Introducing these separate pediatric sessions obviously decreases the scheduling flexibility. The question is whether this decrease is acceptable compared to the benefits the separation offers. We assess several scenarios using a data-driven simulation model, based on a real academic hospital setting. The results show that the percentage of patients that are served within their due time is only slightly affected when looking at adult and pediatric patients together, but this percentage drops by 13 (s = 6.22) percentage points if we isolate the performance of the pediatric patients. This decrease for some disciplines can be as large as 69 percentage points. Therefore, from a planning point of view, it is advised to only organize pediatric sessions for the disciplines whose performance drop is acceptable. Alternatively, for future research, the capacity allocation could be optimized for each discipline individually to account for the discipline’s characteristics. Moreover, studies on the difference in patient experience would complement this study.status: publishe