Background: Prolonged exposure (PE) is an effective treatment for post-traumatic stress disorder (PTSD).Objective: This study aimed to analyse the cost-effectiveness of three exposure-based... Show moreBackground: Prolonged exposure (PE) is an effective treatment for post-traumatic stress disorder (PTSD).Objective: This study aimed to analyse the cost-effectiveness of three exposure-based treatments in patients with childhood abuse-related PTSD.Method: A net–benefit analysis was conducted alongside a pragmatic randomized controlled trial with participants (N = 149) randomized to three conditions: PE (n = 48), intensified PE (i-PE, n = 51), and phase-based PE [Skills Training in Affective and Interpersonal Regulation (STAIR) + PE, n = 50]. Assessments took place at baseline (T0), post-treatment (T3), 6 month follow-up (T4), and 12 month follow-up (T5). Costs stemming from healthcare utilization and productivity losses were estimated using the Trimbos/iMTA questionnaire for Costs associated with Psychiatric Illness. Quality-adjusted life-years (QALYs) were based on the 5-level EuroQoL 5 Dimensions (EQ-5D-5L) using the Dutch tariff. Missing values of costs and utilities were multiply imputed. To compare i-PE to PE and STAIR + PE to PE, pair-wise unequal-variance t-tests were conducted. Net–benefit analysis was used to relate costs to QALYs and to draw acceptability curves.Results: Intervention costs did not differ across the three treatment conditions. Total medical costs, productivity losses, total societal costs, and EQ-5D-5L-based QALYs did not differ between treatment conditions either (all p > .10). At the relevant €50,000/QALY threshold, the probability of one treatment being more cost-effective than another was 32%, 28%, and 40% for PE, i-PE, and STAIR-PE, respectively.Conclusion: Three equally effective treatments were compared and no differences in cost-effectiveness between treatments were found. Therefore, we advocate the implementation and adoption of any of the treatments and endorse shared decision making. Show less
Mutations in the DMD gene are causative for Duchenne muscular dystrophy (DMD). Antisense oligonucleotide (AON) mediated exon skipping to restore disrupted dystrophin reading frame is a therapeutic... Show moreMutations in the DMD gene are causative for Duchenne muscular dystrophy (DMD). Antisense oligonucleotide (AON) mediated exon skipping to restore disrupted dystrophin reading frame is a therapeutic approach that allows production of a shorter but functional protein. As DMD causing mutations can affect most of the 79 exons encoding dystrophin, a wide variety of AONs are needed to treat the patient population. Design of AONs is largely guided by trial-and-error, and it is yet unclear what defines the skippability of an exon. Here, we use a library of phosphorodiamidate morpholino oligomer (PMOs) AONs of similar physical properties to test the skippability of a large number of DMD exons. The DMD transcript is non-sequentially spliced, meaning that certain introns are retained longer in the transcript than downstream introns. We tested whether the relative intron retention time has a significant effect on AON efficiency, and found that targeting an out-of-frame exon flanked at its 5'-end by an intron that is retained in the transcript longer ('slow' intron) leads to overall higher exon skipping efficiency than when the 5'-end flanking intron is 'fast'. Regardless of splicing speed of flanking introns, we find that positioning an AON closer to the 5'-end of the target exon leads to higher exon skipping efficiency opposed to targeting an exons 3'-end. The data enclosed herein can be of use to guide future target selection and preferential AON binding sites for both DMD and other disease amenable by exon skipping therapies. Show less
During the COVID-19 pandemic the number of hospital admissions due to chronic obstructive pulmonary disease (COPD) exacerbations was significantly reduced. The reason for this decline is not fully... Show moreDuring the COVID-19 pandemic the number of hospital admissions due to chronic obstructive pulmonary disease (COPD) exacerbations was significantly reduced. The reason for this decline is not fully understood. Governmental non-pharmaceutical interventions (NPI's), an increase in community treated exacerbations, or healthcare avoidance by patients, are potential reasons. For the current study, the impact of Dutch governmental NPI's on the COPD exacerbations and respiratory infections rate in patients with severe alpha-1 antitrypsin deficiency (AATD) was analyzed. The patients participated in the NCT04204252 study, a randomized controlled trial evaluating the efficacy and safety of inhaled alpha-1 antitrypsin. Data collected in the time-period from March 2020 until February 2022 was analyzed. In this period the Dutch government imposed variable NPI's to contain the spread of SARS-CoV-2. Patients were required to document their daily symptoms in an electronic diary. The strictness of the governmental NPI's was measured by the COVID-19 Stringency Index. 19 patients participated in this study during the analysis period. A total of 40 respiratory infections and COPD exacerbations occurred. The Spearman's correlation coefficient of the monthly average COVID-19 Stringency Index and respiratory infections and COPD exacerbations rate was -0.316 (p = 0.132). When months known for a low respiratory infection rate were excluded, the correlation coefficient was -0.625 (p = 0.010). This study showed a significant negative correlation between the COPD exacerbations and respiratory infection rate and the COVID-19 Stringency Index in patients with AATD related COPD in the autumn-winter months. Show less
Borm, F.J.; Smit, J.; Bakker, J.; Wondergem, M.; Smit, E.F.; Langen, A.J. de; Gruijl, T.D. de 2023
Better biomarkers for programmed death - (ligand) 1 (PD-(L)1) checkpoint blockade in non-small cell lung cancer (NSCLC) are needed. We explored the predictive value of early response evaluation... Show moreBetter biomarkers for programmed death - (ligand) 1 (PD-(L)1) checkpoint blockade in non-small cell lung cancer (NSCLC) are needed. We explored the predictive value of early response evaluation using Fluor-18-deoxyglucose positron emission tomography and pre- and on-treatment flowcytometric T-cell profiling in peripheral blood and tumor-draining lymph nodes (TDLN). The on-treatment evaluation was performed 7–14 days after the start of PD-1 blockade in NSCLC patients. These data were related to (pathological) tumor response, progression-free survival, and overall survival (OS). We found that increases in total lesion glycolysis (TLG) had a strong reverse correlation with OS (r = −0.93, p = 0.022). Additionally, responders showed decreased and progressors increased Treg frequencies on-treatment. Frequencies of detectable PD-1-expressing CD8+ T cells decreased in responders but remained stable in progressors. This was especially found in the TDLN. Changes in activated Treg rates in TDLN were strongly but, due to low numbers of data points, non-significantly correlated with ΔTLG and reversely correlated with OS. Show less
Vlegel-Brouwer, W. van der; Eelderink, M.; Bussemaker, J. 2023
Introduction: Ignited by the persistent health inequalities many cities and neighbourhoods, the ‘Healthy and Happy The Hague’ network in the Netherlands wanted to gain insight in how prevention and... Show moreIntroduction: Ignited by the persistent health inequalities many cities and neighbourhoods, the ‘Healthy and Happy The Hague’ network in the Netherlands wanted to gain insight in how prevention and health promotion could become successful in one deprived neighbourhood, Moerwijk. Methods: The cycle of Look-Think-Act of Participatory Action Research was used in which both citizens and professionals got involved from the start. Besides interviews, field notes were analysed, visualised and discussed in several rounds of focus groups. Results: Thematic analysis yielded seven themes: Healthy Eating and Exercise, Healthy Money, Healthy Mind, Healthy Relationships, Growing up healthy, Healthy Environment and Healthy Collaboration. During sessions around combination of themes, eight initiatives were co-created by citizens and professionals together, improving the feeling of ownership and interconnectedness. Discussion and conclusion: This PAR sheds a light on the mismatch between the system world’s solutions for individuals and the living world’s needs for solutions for the collective. Findings provides a better insight into the social, political, and cultural mechanisms and processes that influence clustering and interaction of health conditions. PAR is a promising process of citizens and professionals working together is an excellent way to learn about the conditions under which people experience health inequalities, and how to combat these inequalities. Show less
Background Lifestyle intervention programmes target behavioural risk factors that contribute to cardiovascular diseases (CVDs). Unfortunately, sustainable implementation of these programmes can be... Show moreBackground Lifestyle intervention programmes target behavioural risk factors that contribute to cardiovascular diseases (CVDs). Unfortunately, sustainable implementation of these programmes can be challenging. Gaining insights into the barriers and facilitators for successful implementation is important for maximising public health impact of these interventions. The Healthy Heart (HH) programme is an example of a combined lifestyle intervention programme.Aim To analyse the reach, adoption, and implementation of the HH programme.Design & setting A mixed-methods study conducted in a general practice setting in The Netherlands.Method Quantitative data were collected from the Healthy Heart study (HH study), a non-randomised cluster stepped-wedge trial to assess the effect of the HH programme on patients at high risk of developing CVDs at practice level. Qualitative data were obtained through focus groups.Results Out of 73 approached general practices, 55 implemented the HH programme. A total of 1082 patients agreed to participate in the HH study, of whom 64 patients were referred to the HH programme and 41 patients participated. Several barriers for participation were identified such as time investment, lack of risk perception, and being confident in changing lifestyle on their own. Important barriers for healthcare providers (HCPs) to refer a patient were time investment, lack of information to sufficiently inform patients, and preconceived notions regarding which patients the programme was suitable for.Conclusion This study has offered insights from a patient and HCP perspective regarding barriers and facilitators for implementation of the group-based lifestyle intervention programme. The identified barriers and facilitators, and the suggested improvements, can be used by others who wish to implement a similar programme. Show less
Rakers, M.; Vijver, S. van de; Bossio, P.; Moens, N.; Rauws, M.; Orera, M.; ... ; Villalobos-Quesada, M. 2023
Background: eHealth offers opportunities to improve health and healthcare systems and overcome primary care challenges in low-resource settings (LRS). LRS has been typically associated with low-... Show moreBackground: eHealth offers opportunities to improve health and healthcare systems and overcome primary care challenges in low-resource settings (LRS). LRS has been typically associated with low- and middle-income countries (LMIC), but they can be found in high-income countries (HIC) when human, physical or financial resources are constrained. Adopting a concept of LRS that applies to LMIC and HIC can facilitate knowledge interchange between eHealth initiatives while improving healthcare provision for socioeconomically disadvantaged groups across the globe.Objectives: To outline the contributions and challenges of eHealth in low-resource primary care settings.Strategy: We adopt a socio-ecological understanding of LRS, making LRS relevant to LMIC and HIC. To assess the potential of eHealth in primary care settings, we discuss four case studies according to the WHO 'building blocks for strengthening healthcare systems'.Results and discussion: The case studies illustrate eHealth's potential to improve the provision of healthcare by i) improving the delivery of healthcare (using AI-generated chats); ii) supporting the workforce (using telemedicine platforms); iii) strengthening the healthcare information system (through patient-centred healthcare information systems), and iv) improving system-related elements of healthcare (through a mobile health financing platform). Nevertheless, we found that development and implementation are hindered by user-related, technical, financial, regulatory and evaluation challenges. We formulated six recommendations to help anticipate or overcome these challenges: 1) evaluate eHealth's appropriateness, 2) know the end users, 3) establish evaluation methods, 4) prioritise the human component, 5) profit from collaborations, ensure sustainable financing and local ownership, 6) and contextualise and evaluate the implementation strategies. Show less
Holzer, A.K.; Dreser, N.; Pallocca, G.; Mangerich, A.; Stacey, G.; Dipalo, M.; ... ; Leist, M. 2023
Every test procedure, scientific and non-scientific, has inherent uncertainties, even when performed according to a standard operating procedure (SOP). In addition, it is prone to errors, defects,... Show moreEvery test procedure, scientific and non-scientific, has inherent uncertainties, even when performed according to a standard operating procedure (SOP). In addition, it is prone to errors, defects, and mistakes introduced by operators, laboratory equipment, or materials used. Adherence to an SOP and comprehensive validation of the test method cannot guarantee that each test run produces data within the acceptable range of variability and with the precision and accuracy determined during the method validation. We illustrate here (part I) why controlling the validity of each test run is an important element of experimental design. The definition and application of acceptance criteria (AC) for the validity of test runs is important for the setup and use of test methods, particularly for the use of new approach methods (NAM) in toxicity testing. AC can be used for decision rules on how to handle data, e.g., to accept the data for further use (AC fulfilled) or to reject the data (AC not fulfilled). The adherence to AC has important requirements and consequences that may seem surprising at first sight: (i) AC depend on a test method's objectives, e.g., on the types/concentrations of chemicals tested, the regulatory context, the desired throughput; (ii) AC are applied and documented at each test run, while validation of a method (including the definition of AC) is only performed once; (iii) if AC are altered, then the set of data produced by a method can change. AC, if missing, are the blind spot of quality assurance: Test results may not be reliable and comparable. The establishment and uses of AC will be further detailed in part II of this series. Show less
Scheuplein, M.; Vermeulen, S.; van Harmelen, A.L.; Alink, L. 2023
It is estimated that up to 25% of all children growing up worldwide experience child maltreatment, making it a global emergency with substantial individual and public health consequences. This... Show moreIt is estimated that up to 25% of all children growing up worldwide experience child maltreatment, making it a global emergency with substantial individual and public health consequences. This chapter addresses one of the most societally pervasive consequences of child maltreatment which is known as the "cycle of victimization." This concept depicts the increased risk of maltreated individuals to victimize others later in life, both within and outside the family environment. To understand the architecture of this victimization cycle, the chapter further sheds light on neurocognitive mechanisms aiding different forms of victimization and the buffering role of social support that could help break the cycle of victimization. Advancing our understanding of these complex and interrelated mechanisms will ultimately facilitate the design and implementation of more targeted early treatments and (preventive) interventions and support a move toward a safer society. Show less
The role of Italian vernacular varieties in the history of communication in the Mediterranean world has only occasionally been investigated (see Baglioni 2010). In this research are brought to... Show moreThe role of Italian vernacular varieties in the history of communication in the Mediterranean world has only occasionally been investigated (see Baglioni 2010). In this research are brought to attention some letters exchanged between the States General of the United Provinces and the Ottoman Empire between the sixteenth and seventeenth centuries. They contribute to framing the spread of the Venetian variety as a lingua franca in diplomatic correspondence between the Mediterranean and Northern European worlds. Show less
Villalobos-Quesada, M.; Ho, K.D.; Chavannes, N.H.; Talboom-Kamp, E.P.W.A. 2023
BackgroundDiagnostics are increasingly shifting to patients’ home environment, facilitated by new digital technologies. Digital diagnostics (diagnostic services enabled by digital technologies) can... Show moreBackgroundDiagnostics are increasingly shifting to patients’ home environment, facilitated by new digital technologies. Digital diagnostics (diagnostic services enabled by digital technologies) can be a tool to better respond to the challenges faced by primary care systems while aligning with patients’ and healthcare professionals’ needs. However, it needs to be clarified how to determine the success of these interventions.ObjectivesWe aim to provide practical guidance to facilitate the adequate development and implementation of digital diagnostics.StrategyHere, we propose the quadruple aim (better patient experiences, health outcomes and professional satisfaction at lower costs) as a framework to determine the contribution of digital diagnostics in primary care. Using this framework, we critically analyse the advantages and challenges of digital diagnostics in primary care using scientific literature and relevant casuistry.ResultsTwo use cases address the development process and implementation in the Netherlands: a patient portal for reporting laboratory results and digital diagnostics as part of hybrid care, respectively. The third use case addresses digital diagnostics for sexually transmitted diseases from an international perspective.ConclusionsWe conclude that although evidence is gathering, the often-expected value of digital diagnostics needs adequate scientific evidence. We propose striving for evidence-based ‘responsible digital diagnostics’ (sustainable, ethically acceptable, and socially desirable digital diagnostics). Finally, we provide a set of conditions necessary to achieve it. The analysis and actionable guidance provided can improve the chance of success of digital diagnostics interventions and overall, the positive impact of this rapidly developing field. Show less
Background and Aims: The Pharmacovigilance Risk Assessment Committee (PRAC) proposed measures to address severe side effects linked to Janus kinase inhibitors (JAKi) in immune-mediated inflammatory... Show moreBackground and Aims: The Pharmacovigilance Risk Assessment Committee (PRAC) proposed measures to address severe side effects linked to Janus kinase inhibitors (JAKi) in immune-mediated inflammatory diseases (IMID). Use of these medications in individuals aged 65 and older, those at high cardiovascular risk, active or former long-term smokers, and those with increased cancer risk should be considered only if no alternatives exist. Caution is advised when administering JAKi to patients at risk of venous thromboembolism. We aim to implement recommendations from regulatory guidelines based on areas of uncertainty identified. Methods: A two-round modified Research and Development/University of California Los Angeles appropriateness methodology study was conducted. A panel of 21 gastroenterologists, dermatologists and rheumatologists used a 9-point Likert scale to rate the appropriateness of administering a JAKi for each proposed clinical scenario. Scores for appropriateness were categorized as appropriate, uncertain, or inappropriate. Two rounds were performed, each with online surveys and a virtual meeting to enable discussion and rating of each best practice. Results: Round 1 involved participants rating JAKi appropriateness and suggesting descriptors to reduce uncertainty. Survey results were discussed in a virtual meeting, identifying areas of disagreement. In round 2, participants rated their agreement with descriptors from round 1, and the level of uncertainty and disagreement reduced. Age flexibility is recommended in the absence of other risk factors. Active counseling on modifiable risks (e.g., overweight, mild hyperlipidemia and hypertension) and smoking cessation is advised. Uncertainty persists regarding cancer risk due to various factors. Conclusions: We outlined regulatory guidance without a personalized evaluation of the patient's risk profile might lead to uncertainty and become an arid technicality. Therefore, we identified gaps and implemented PRAC recommendations to help health professionals in clinical practice. Show less
Arvidsson, R.; Svanström, M.; Sandén, B.A.; Thonemann, N.; Steubing, B.R.P.; Cucurachi, S. 2023
PurposeSome future-oriented life cycle assessment (LCA) terms, particularly prospective and ex-ante, show notable increase in use in publications over the last decade. However, scholars have... Show morePurposeSome future-oriented life cycle assessment (LCA) terms, particularly prospective and ex-ante, show notable increase in use in publications over the last decade. However, scholars have pointed out that it is currently unclear exactly what these terms mean and how they are related. This paper aims to explain defining differences between future-oriented LCA terms and provide terminology recommendations.MethodsExisting definitions of future-oriented LCA terms were reviewed and analyzed. Workshops were held where defining differences of future-oriented LCA terms were discussed.ResultsTemporal positionality and technology maturity appear to be two critical aspects of future-oriented LCA. Prospective and ex-ante LCA are similar, with the possible difference that ex-ante LCA always involves an increase in technology maturity in the future. Considering the notable similarities, it seems reasonable to converge terms to mitigate field fragmentation and avoid terminology confusion.ConclusionsTo denote LCA studies with a future temporal positionality, we recommend using the term prospective LCA, defined as “LCA that models the product system at a future point in time relative to the time at which the study is conducted”. Furthermore, since technology maturity is clearly a critical aspect for prospective LCA, we recommend prospective LCA studies to clearly define the maturity of the technologies modeled in the production system. Show less
