A Blueprint for Multi-use Disease Modeling in Health Economics: Results from Two Expert-Panel Consultations.

BACKGROUND: The current use of health economic decision models in HTA is mostly confined to single use cases, which may be inefficient and result in little consistency over different treatment comparisons, and consequently inconsistent health policy decisions, for the same disorder. Multi-use disease models (MUDMs) (other terms: generic models, whole disease models, disease models) may offer a solution. However, much is uncertain about their definition and application. The current research aimed to develop a blueprint for the application of MUDMs. METHODS: We elicited expert opinion using a two-round modified Delphi process. The panel consisted of experts and stakeholders in health economic modelling from various professional backgrounds. The first questionnaire concerned definition, terminology, potential applications, issues and recommendations for MUDMs and was based on an exploratory scoping review. In the second round, the panel members were asked to reconsider their input, based on feedback regarding first-round results, and to score issues and recommendations for priority. Finally, adding input from external advisors and policy makers in a structured way, an overview of issues and challenges was developed during two team consensus meetings. RESULTS: In total, 54 respondents contributed to the panel results. The term 'multi-use disease models' was proposed and agreed upon, and a definition was provided. The panel prioritized 10 potential applications (with comparing alternative policies and supporting resource allocation decisions as the top 2), while 20 issues (with model transparency and stakeholders' roles as the top 2) were identified as challenges. Opinions on potential features concerning operationalization of multi-use models were given, with 11 of these subsequently receiving high priority scores (regular updates and revalidation after updates were the top 2). CONCLUSIONS: MUDMs would improve on current decision support regarding cost-effectiveness information. Given feasibility challenges, this would be most relevant for diseases with multiple treatments, large burden of disease and requiring more complex models. The current overview offers policy makers a starting point to organize the development, use, and maintenance of MUDMs and to support choices concerning which diseases and policy decisions they will be helpful for.

Disruption of hospital care during the first year of the COVID-19 pandemic impacted socioeconomic groups differently: population based study using routine registration data.

BACKGROUND: During the COVID-19 pandemic, provision of non-COVID healthcare was recurrently severely disrupted. The objective was to determine whether disruption of non-COVID hospital use, either due to cancelled, postponed, or forgone care, during the first pandemic year of COVID-19 impacted socioeconomic groups differently compared with pre-pandemic use. METHODS: National population registry data, individually linked with data of non-COVID hospital use in the Netherlands (2017-2020). in non-institutionalised population of 25-79 years, in standardised household income deciles (1 = low, 10 = high) as proxy for socioeconomic status. Generic outcome measures included patients who received hospital care (dichotomous): outpatient contact, day treatment, inpatient clinic, and surgery. Specific procedures were included as examples of frequently performed elective and acute procedures, e.g.: elective knee/hip replacement and cataract surgery, and acute percutaneous coronary interventions (PCI). Relative risks (RR) for hospital use were reported as outcomes from generalised linear regression models (binomial) with log-link. An interaction term was included to assess whether income differences in hospital use during the pandemic deviated from pre-pandemic use. RESULTS: Hospital use rates declined in 2020 across all income groups. With baseline (2019) higher hospital use rates among lower than higher income groups, relatively stronger declines were found for lower income groups. The lowest income groups experienced a 10% larger decline in surgery received than the highest income group (RR 0.90, 95% CI 0.87 - 0.93). Patterns were similar for inpatient clinic, elective knee/hip replacement and cataract surgery. We found small or no significant income differences for outpatient clinic, day treatment, and acute PCI. CONCLUSIONS: Disruption of non-COVID hospital use in 2020 was substantial across all income groups during the acute phases of the pandemic, but relatively stronger for lower income groups than could be expected compared with pre-pandemic hospital use. Although the pandemic's impact on the health system was unprecedented, healthcare service shortages are here to stay. It is therefore pivotal to realise that lower income groups may be at risk for underuse in times of scarcity.

Cost-effectiveness of low-dose colchicine in patients with chronic coronary disease in the netherlands.

AIMS: Recent trials have shown that low-dose colchicine (0.5 mg once daily) reduces major cardiovascular events in patients with acute and chronic coronary syndromes. We aimed to estimate the cost-effectiveness of low-dose colchicine therapy in patients with chronic coronary disease when added to standard background therapy. METHODS AND RESULTS: This Markov cohort cost-effectiveness model used estimates of therapy effectiveness, transition probabilities, costs and quality of life obtained from the Low-dose Colchicine 2 (LoDoCo2) trial, as well as meta-analyses and public sources. In this trial, Low-dose colchicine was added to standard of care and compared to placebo. The main outcomes were cardiovascular events including myocardial infarction, stroke and coronary revascularisation, quality-adjusted life-year (QALY), the cost per QALY gained (incremental cost-effectiveness ratio), and net monetary benefit. In the model, low-dose colchicine therapy yielded 0.04 additional QALYs compared with standard of care at an incremental cost of €455 from a societal perspective and €729 from a healthcare perspective, resulting in a cost per QALY gained of €12,176/QALY from a societal perspective and €19,499/QALY from a healthcare perspective. Net monetary benefit was €1,414 from a societal perspective and €1,140 from a healthcare perspective. Low-dose colchicine has a 96% and 94% chance of being cost effective, from respectively a societal and healthcare perspective when using a willingness to pay of €50,000/QALY. Net monetary benefit would decrease below zero when annual low-dose colchicine costs would exceed an annual cost of €221 per patient. CONCLUSION: Adding low-dose colchicine to standard of care in patients with chronic coronary disease is cost-effective according to commonly accepted thresholds in Europe and Australia and compares favourably in cost-effectiveness to other drugs used in chronic coronary disease.

Research Priorities to Increase Confidence in and Acceptance of Health Preference Research: What Questions Should be Prioritized Now?

BACKGROUND AND OBJECTIVE: There has been an increase in the study and use of stated-preference methods to inform medicine development decisions. The objective of this study was to identify prioritized topics and questions relating to health preferences based on the perspective of members of the preference research community. METHODS: Preference research stakeholders from industry, academia, consultancy, health technology assessment/regulatory, and patient organizations were recruited using professional networks and preference-targeted e-mail listservs and surveyed about their perspectives on 19 topics and questions for future studies that would increase acceptance of preference methods and their results by decision makers. The online survey consisted of an initial importance prioritization task, a best-worst scaling case 1 instrument, and open-ended questions. Rating counts were used for analysis. The best-worst scaling used a balanced incomplete block design. RESULTS: One hundred and one participants responded to the survey invitation with 66 completing the best-worst scaling. The most important research topics related to the synthesis of preferences across studies, transferability across populations or related diseases, and method topics including comparison of methods and non-discrete choice experiment methods. Prioritization differences were found between respondents whose primary affiliation was academia versus other stakeholders. Academic researchers prioritized methodological/less studied topics; other stakeholders prioritized applied research topics relating to consistency of practice. CONCLUSIONS: As the field of health preference research grows, there is a need to revisit and communicate previous work on preference selection and study design to ensure that new stakeholders are aware of this work and to update these works where necessary. These findings might encourage discussion and alignment among different stakeholders who might hold different research priorities. Research on the application of previous preference research to new contexts will also help increase the acceptance of health preference information by decision makers.

Intended changes in smoking behaviour of Dutch young adults after an increase in excise tax: a cross-sectional survey.

OBJECTIVES: Increasing the price of tobacco is one of the most effective measures to reduce the prevalence of smoking. In the Netherlands, the excise tax on tobacco increased by €1.14 in 2020, raising the price of a standard package of cigarettes to €8.00. This study investigates how young adults intend to change their smoking behaviour in the case of hypothetical price increases of a pack of cigarettes, and which background characteristics are associated with intended behaviour change. DESIGN: A cross-sectional online survey was carried out between September and November 2020. Smokers indicated how they would react to several hypothetical increases in price. Four behavioural options were investigated: smoking less, quitting smoking, switching to another/cheaper product and buying cheaper cigarettes cross-border. PARTICIPANTS: Data were obtained from 776 Dutch smokers between 15 and 25 years. RESULTS: At a hypothetical price of €10 per package, most respondents reported an intention to smoke less (67%), followed by switching to another/cheaper product (61%), quitting smoking (49%) and shopping for cigarettes cross-border (47%). Prior quit attempts, agreeing with the increase in excise tax and the intention to quit smoking in the future increased the odds of changing behaviour. Higher self-efficacy decreased the odds of behavioural change. CONCLUSION: Many young adults intend to change their smoking behaviour in the event of increased prices. Although intended behaviour can deviate significantly from actual behaviour, an increase in excise tax may result in a significant amount of quit attempts and reduced smoking among young adults.

Balancing benefits and risks in lung cancer therapies: patient preferences for lung cancer treatment alternatives.

Background: In the treatment of Non-Small Cell Lung Cancer (NSCLC) the combination of Immuno- Oncotherapy (IO) and chemotherapy (CT) has been found to be superior to IO or CT alone for patients' survival. Patients and clinicians are confronted with a preference sensitive choice between a more aggressive treatment with a greater negative effect on quality of life versus alternatives that are less effective but have fewer side effects. Objectives: The aims of this study were to: (a) quantify patients' preferences for relevant attributes related to Immuno-Oncotherapy treatment alternatives, and (b) evaluate the maximum acceptable risk (MAR)/Minimum acceptable benefit (MAB) that patients would accept for treatment alternatives. Methods: An online preference survey using discrete-choice experiment (DCE) was completed by NSCLC patients from two hospitals in Italy and Belgium. The survey asked patients' preferences for five patient- relevant treatment attributes. The DCE was developed using a Bayesian D-efficient design. DCE analyses were performed using mixed logit models. Information regarding patient demographics, health literacy, locus of control, and quality of life was also collected. Results: 307 patients (158 Italian, 149 Belgian), stage I to IV, completed the survey. Patients preferred treatments with a higher 5-year survival chance as the most important attribute over all the other attributes. Preference heterogeneity for the attribute weights depended on health literacy, patients' age and locus of control. Patients were willing to accept a substantially increased risks of developing side effects in exchange for the slightest increase (1%) in the chance of surviving at least 5 years from the diagnosis of cancer. Similarly, patients were willing to accept a switch in the mode of administration or complete loss of hair to obtain an increase in survival. Conclusion: In this study, the proportion of respondents who systematically preferred survival over all other treatment attributes was particularly high. Age, objective health literacy and locus of control accounted for heterogeneity in patients' preferences. Evidence on how NSCLC patients trade between survival and other NSCLC attributes can support regulators and other stakeholders on assessing clinical trial evidence and protocols, based on patients' conditions and socio-demographic parameters.

Postponed healthcare in The Netherlands during the COVID-19 pandemic and its impact on self-reported health.

Background: Healthcare services have been seriously disrupted during the COVID-19 pandemic. The aim of this study was to examine the extent to which Dutch citizens have experienced postponed healthcare and how this affected their self-reported health. In addition, individual characteristics that were associated with experiencing postponed healthcare and with self-reported negative health effects were investigated. Methods: An online survey about postponed healthcare and its consequences was developed, and sent out to participants of the Dutch LISS (Longitudinal Internet Studies for the Social Sciences) panel (n = 2.043). Data were collected in August 2022. Multivariable logistic regression analyses were carried out to explore characteristics associated with postponed care and self-reported negative health outcomes. Results: Of the total population surveyed, 31% of the panel experienced postponed healthcare, either initiated by the healthcare provider (14%), on their own initiative (12%) or as a combination of both (5%). Postponed healthcare was associated with being female (OR = 1.61; 95% CI = 1.32; 1.96), presence of chronic diseases (OR = 1.55, 95% CI = 1.24; 1.95), high income (OR = 0.62, 95% CI = 0.48; 0.80) and worse self-reported health (poor vs. excellent OR = 2.88, 95% CI = 1.17; 7.11). Overall, 40% experienced temporary or permanent self-reported negative health effects due to postponed care. Negative health effects as a result of postponed care were associated with presence of chronic conditions and low income levels (p < 0.05). More respondents with worse self-reported health and foregone healthcare reported permanent health effects as compared to those with temporary health effects (p < 0.05). Discussion: People with an impaired health status are most likely to experiencing postponed healthcare and negative health consequences as a result. Furthermore, those with negative health consequences decided to forego health by themselves more often. As part of long-term plans to maintain the accessibility of healthcare services, specific attention should be paid to reaching out to people with an impaired health status.

Discrete choice experiment versus swing-weighting: A head-to-head comparison of diabetic patient preferences for glucose-monitoring devices.

INTRODUCTION: Limited evidence exists for how patient preference elicitation methods compare directly. This study compares a discrete choice experiment (DCE) and swing-weighting (SW) by eliciting preferences for glucose-monitoring devices in a population of diabetes patients. METHODS: A sample of Dutch adults with type 1 or 2 diabetes (n = 459) completed an online survey assessing their preferences for glucose-monitoring devices, consisting of both a DCE and a SW exercise. Half the sample completed the DCE first; the other half completed the SW first. For the DCE, the relative importance of the attributes of the devices was determined using a mixed-logit model. For the SW, the relative importance of the attributes was based on ranks and points allocated to the 'swing' from the worst to the best level of the attribute. The preference outcomes and self-reported response burden were directly compared between the two methods. RESULTS: Participants reported they perceived the DCE to be easier to understand and answer compared to the SW. Both methods revealed that cost and precision of the device were the most important attributes. However, the DCE had a 14.9-fold difference between the most and least important attribute, while the SW had a 1.4-fold difference. The weights derived from the SW were almost evenly distributed between all attributes. CONCLUSIONS: The DCE was better received by participants, and generated larger weight differences between each attribute level, making it the more informative method in our case study. This method comparison provides further evidence of the degree of method suitability and trustworthiness.

Impact of physical activity on healthcare costs: a systematic review.

BACKGROUND: This systematic review aims to describe the relation between physical inactivity and healthcare costs, by taking into account healthcare costs of physical-inactivity-related diseases (common practice), including physical-activity-related injuries (new) and costs in life-years gained due to avoiding diseases (new), whenever available. Moreover, the association between physical inactivity and healthcare costs may both be negatively and positively impacted by increased physical activity. METHODS: A systematic review was conducted, including records reporting on physical (in)activity in relation to healthcare costs for a general population. Studies were required to report sufficient information to calculate the percentage of total healthcare costs potentially attributable to physical inactivity. RESULTS: Of the 264 records identified, 25 were included in this review. Included studies showed substantial variation in the assessment methods of physical activity and in type of costs included. Overall, studies showed that physical inactivity is related to higher healthcare costs. Only one study included costs of healthcare resources used in prolonged life when physical-inactivity-related diseases were averted, showing net higher healthcare costs. No study included healthcare costs for physical-activity-related injuries. CONCLUSIONS: Physical inactivity is associated with higher healthcare costs in the general population in the short-term. However, in the long-term aversion of diseases related with physical inactivity may increase longevity and, as a consequence, healthcare costs in life-years gained. Future studies should use a broad definition of costs, including costs in life-years gained and costs related to physical-activity-related injuries.

Use of Utility and Disability Weights in Economic Evaluation of Pediatric Vaccines.

OBJECTIVE: To describe how utility weights and disability weights have been used in the context of quality-adjusted life-years (QALYs) and disability-adjusted life-years (DALYs)-based cost-effectiveness analysis (CEA) of pediatric vaccines for infectious diseases and assess the comparability between weights. METHODS: A systematic review was conducted of CEAs of pediatric vaccines for 16 infectious diseases, published between January 2013 and December 2020 and using QALYs or DALYs as outcome measure. Data on values and sources of weights for the estimation of QALYs and DALYs were extracted from studies and compared across similar health states. Reporting was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. RESULTS: Out of 2154 articles identified, 216 CEAs met our inclusion criteria. Of the included studies, 157 used utility weights and 59 used disability weights in their valuation of health states. In QALY studies, the source, background, who's preferences (adults'/children's) were applied and adjustments made to utility weights were poorly reported. In DALY studies, the Global Burden of Disease study was most often referenced. Valuation weights for similar health states varied within QALY studies and between DALY and QALY studies, but no systematic differences were identified. CONCLUSIONS: This review identified considerable gaps in the way valuation weights are used and reported on in CEA. The nonstandardized use of weights may lead to different conclusions about cost-effectiveness of vaccines and policy decisions.

Physical and mental health outcomes of COVID-19 induced delay in oncological care: A systematic review.

Background: During the COVID-19 pandemic cancer patients might have experienced delays in screening, diagnosis and/or treatment. A systematic review was conducted to give an overview of the effects of COVID-19 induced delays in oncological care on the physical and mental health outcomes of cancer patients. Methods: MEDLINE and EMBASE databases were searched for articles on the effects of COVID-19 induced delays on physical and mental health outcomes. Results: Out of 1333 papers, eighteen observational, and twelve modelling studies were included. In approximately half of the studies, tumor stage distribution differed during the pandemic compared to before the pandemic. Modelling studies predicted that the estimated increase in the number of deaths ranged from -0.04 to 30%, and the estimated reduction in survival ranged from 0.4 to 35%. Varying results on the impact on mental health, e.g. anxiety and depression, were seen. Conclusions: Due to large methodological discrepancies between the studies and the varying results, the effect of COVID-19 induced delays on the physical and mental health outcomes of cancer patients remains uncertain. While modelling studies estimated an increase in mortality, observational studies suggest that mortality might not increase to a large extent. More longitudinal observational data from the pandemic period is needed for more conclusive results.

Comparing Outcomes of a Discrete Choice Experiment and Case 2 Best-Worst Scaling: An Application to Neuromuscular Disease Treatment.

BACKGROUND AND OBJECTIVES: Case 2 best-worst scaling (BWS-2) is an increasingly popular method to elicit patient preferences. Because BWS-2 potentially has a lower cognitive burden compared with discrete choice experiments, the aim of this study was to compare treatment preference weights and relative importance scores. METHODS: Patients with neuromuscular diseases completed an online survey at two different moments in time, completing one method per occasion. Patients were randomly assigned to either first a discrete choice experiment or BWS-2. Attributes included: muscle strength, energy endurance, balance, cognition, chance of blurry vision, and chance of liver damage. Multinomial logit was used to calculate overall relative importance scores and latent class logit was used to estimate heterogeneous preference weights and to calculate the relative importance scores of the attributes for each latent class. RESULTS: A total of 140 patients were included for analyses. Overall relative importance scores showed differences in attribute importance rankings between a discrete choice experiment and BWS-2. Latent class analyses indicated three latent classes for both methods, with a specific class in both the discrete choice experiment and BWS-2 in which (avoiding) liver damage was the most important attribute. Ex-post analyses showed that classes differed in sex, age, level of education, and disease status. The discrete choice experiment was easier to understand compared with BWS-2. CONCLUSIONS: This study showed that using a discrete choice experiment and BWS-2 leads to different outcomes, both in preference weights as well as in relative importance scores, which might have been caused by the different framing of risks in BWS-2. However, a latent class analysis revealed similar latent classes between methods. Careful consideration about method selection is required, while keeping the specific decision context in mind and pilot testing the methods.

Effectiveness of analgesic ear drops as add-on treatment to oral analgesics in children with acute otitis media: study protocol of the OPTIMA pragmatic randomised controlled trial.

INTRODUCTION: Ear pain is the most prominent symptom of childhood acute otitis media (AOM). To control the pain and reduce reliance on antibiotics, evidence of effectiveness for alternative interventions is urgently needed. This trial aims to investigate whether analgesic ear drops added to usual care provide superior ear pain relief over usual care alone in children presenting to primary care with AOM. METHODS AND ANALYSIS: This is a pragmatic, two-arm, individually randomised, open, superiority trial with cost-effectiveness analysis and nested mixed-methods process evaluation in general practices in the Netherlands. We aim to recruit 300 children aged 1-6 years with a general practitioner (GP) diagnosis of AOM and ear pain. Children will be randomly allocated (ratio 1:1) to either (1) lidocaine hydrochloride 5 mg/g ear drops (Otalgan) one to two drops up to six times daily for a maximum of 7 days in addition to usual care (oral analgesics, with/without antibiotics); or (2) usual care. Parents will complete a symptom diary for 4 weeks as well as generic and disease-specific quality of life questionnaires at baseline and 4 weeks. The primary outcome is the parent-reported ear pain score (0-10) over the first 3 days. Secondary outcomes include proportion of children consuming antibiotics, oral analgesic use and overall symptom burden in the first 7 days; number of days with ear pain, number of GP reconsultations and subsequent antibiotic prescribing, adverse events, complications of AOM and cost-effectiveness during 4-week follow-up; generic and disease-specific quality of life at 4 weeks; parents' and GPs' views and experiences with treatment acceptability, usability and satisfaction. ETHICS AND DISSEMINATION: The Medical Research Ethics Committee Utrecht, the Netherlands, has approved the protocol (21-447/G-D). All parents/guardians of participants will provide written informed consent. Study results will be submitted for publication in peer-reviewed medical journals and presented at relevant (inter)national scientific meetings. TRIAL REGISTRATION: The Netherlands Trial Register: NL9500; date of registration: 28 May 2021. At the time of publication of the study protocol paper, we were unable to make any amendments to the trial registration record in the Netherlands Trial Register. The addition of a data sharing plan was required to adhere to the International Committee of Medical Journal Editors guidelines. The trial was therefore reregistered in ClinicalTrials.gov (NCT05651633; date of registration: 15 December 2022). This second registration is for modification purposes only and the Netherlands Trial Register record (NL9500) should be regarded as the primary trial registration.

Diabetes patient preferences for glucose-monitoring technologies: results from a discrete choice experiment in Poland and the Netherlands.

INTRODUCTION: New glucose-monitoring technologies have different cost-benefit profiles compared with traditional finger-prick tests, resulting in a preference-sensitive situation for patients. This study aimed to assess the relative value adults with diabetes assign to device attributes in two countries. RESEARCH DESIGN AND METHODS: Adults with type 1 or 2 diabetes from the Netherlands (n=226) and Poland (n=261) completed an online discrete choice experiment. Respondents choose between hypothetical glucose monitors described using seven attributes: precision, effort to check, number of finger pricks required, risk of skin irritation, information provided, alarm function and out-of-pocket costs. Panel mixed logit models were used to determine attribute relative importance and to calculate expected uptake rates and willingness to pay (WTP). RESULTS: The most important attribute for both countries was monthly out-of-pocket costs. Polish respondents were more likely than Dutch respondents to choose a glucose-monitoring device over a standard finger prick and had higher WTP for a device. Dutch respondents had higher WTP for device improvements in an effort to check and reduce the number of finger pricks a device requires. CONCLUSION: Costs are the primary concern of patients in both countries when choosing a glucose monitor and would likely hamper real-world uptake. The costs-benefit profiles of such devices should be critically reviewed.

The Impact of Video-Based Educational Materials with Voiceovers on Preferences for Glucose Monitoring Technology in Patients with Diabetes: A Randomised Study.

INTRODUCTION: Ensuring patients have enough information about healthcare choices prior to completing a preference study is necessary to support the validity of the findings. Patients are commonly informed using text-based information with supporting graphics. Video-based information may be more engaging for the general patient population. This study aimed to assess (1) the impact that educating patients using video-based educational materials with a voiceover has on patient preferences compared to traditional text, and (2) whether this impact is consistent between two countries. MATERIALS AND METHODS: A video-based educational tool was developed to inform patients prior to completing a discrete choice experiment assessing preferences for glucose monitors. Patients with diabetes from the Netherlands and Poland were recruited through an online research panel. Respondents were randomised to receive information in either a text or a video with animations and a voiceover. Data were analysed using a mixed-logit model. RESULTS: N = 981 completed surveys were analysed from the Netherlands (n = 459) and Poland (n = 522). Differences were found between the countries, but no interpretable pattern of differences was found between the two types of educational materials. Patients spent less time in the educational material than would be necessary to fully review all of the content. CONCLUSIONS: Simply providing educational material in a video with animations and voiceovers does not necessarily lead to better engagement from respondents or different preference outcomes in a sample of diabetes patients when compared to text. Increasing engagement with educational materials should be a topic of future research for those conducting patient preference research as no amount of educational material will be helpful if respondents do not access it.

Estimating the health impact of delayed elective care during the COVID -19 pandemic in the Netherlands.

BACKGROUND: The COVID-19 pandemic had a major impact on the continuity of healthcare provision. Appointments, treatments and surgeries for non-COVID patients were often delayed, with associated health losses for patients involved. OBJECTIVE: To develop a method to quantify the health impact of delayed elective care for non-COVID patients. METHODS: A model was developed that estimated the backlog of surgical procedures in 2020 and 2021 using hospital registry data. Quality-adjusted life years (QALYs) were obtained from the literature to estimate the non-generated QALYs related to the backlog. In sensitivity analyses QALY values were varied by type of patient prioritization. Scenario analyses for future increased surgical capacity were performed. RESULTS: In 2020 and 2021 an estimated total of 305,374 elective surgeries were delayed. These delays corresponded with 319,483 non-generated QALYs. In sensitivity analyses where QALYs varied by type of patient prioritization, non-generated QALYs amounted to 150,973 and 488,195 QALYs respectively. In scenario analyses for future increased surgical capacity in 2022-2026, the non-generated QALYs decreased to 311,220 (2% future capacity increase per year) and 300,710 (5% future capacity increase per year). Large differences exist in the extent to which different treatments contributed to the total health losses. CONCLUSIONS: The method sheds light on the indirect harm related to the COVID-19 pandemic. The results can be used for policy evaluations of COVID-19 responses, in preparations for future waves or other pandemics and in prioritizing the allocation of resources for capacity increases.

Design of a multinational randomized controlled trial to assess the effects of structured and individualized exercise in patients with metastatic breast cancer on fatigue and quality of life: the EFFECT study.

BACKGROUND: Many patients with metastatic breast cancer experience cancer- and treatment-related side effects that impair activities of daily living and negatively affect the quality of life. There is a need for interventions that improve quality of life by alleviating fatigue and other side effects during palliative cancer treatment. Beneficial effects of exercise have been observed in the curative setting, but, to date, comparable evidence in patients with metastatic breast cancer is lacking. The aim of this study is to assess the effects of a structured and individualized 9-month exercise intervention in patients with metastatic breast cancer on quality of life, fatigue, and other cancer- and treatment-related side effects. METHODS: The EFFECT study is a multinational, randomized controlled trial including 350 patients with metastatic breast cancer. Participants are randomly allocated (1:1) to an exercise or control group. The exercise group participates in a 9-month multimodal exercise program, starting with a 6-month period where participants exercise twice a week under the supervision of an exercise professional. After completing this 6-month period, one supervised session is replaced by one unsupervised session for 3 months. In addition, participants are instructed to be physically active for ≥30 min/day on all remaining days of the week, while being supported by an activity tracker and exercise app. Participants allocated to the control group receive standard medical care, general written physical activity advice, and an activity tracker, but no structured exercise program. The primary outcomes are quality of life (EORTC QLQ-C30, summary score) and fatigue (EORTC QLQ-FA12), assessed at baseline, 3, 6 (primary endpoint), and 9 months post-baseline. Secondary outcomes include physical fitness, physical performance, physical activity, anxiety, depression, pain, sleep problems, anthropometric data, body composition, and blood markers. Exploratory outcomes include quality of working life, muscle thickness, urinary incontinence, disease progression, and survival. Additionally, the cost-effectiveness of the exercise program is assessed. Adherence and safety are monitored throughout the intervention period. DISCUSSION: This large randomized controlled trial will provide evidence regarding the (cost-) effectiveness of exercise during treatment of metastatic breast cancer. If proven (cost-)effective, exercise should be offered to patients with metastatic breast cancer as part of standard care. TRIAL REGISTRATION: ClinicalTrials.gov NCT04120298 . Registered on October 9, 2019.

CeRebrUm and CardIac Protection with ALlopurinol in Neonates with Critical Congenital Heart Disease Requiring Cardiac Surgery with Cardiopulmonary Bypass (CRUCIAL): study protocol of a phase III, randomized, quadruple-blinded, placebo-controlled, Dutch multicenter trial.

BACKGROUND: Neonates with critical congenital heart disease (CCHD) undergoing cardiac surgery with cardiopulmonary bypass (CPB) are at risk of brain injury that may result in adverse neurodevelopment. To date, no therapy is available to improve long-term neurodevelopmental outcomes of CCHD neonates. Allopurinol, a xanthine oxidase inhibitor, prevents the formation of reactive oxygen and nitrogen species, thereby limiting cell damage during reperfusion and reoxygenation to the brain and heart. Animal and neonatal studies suggest that allopurinol reduces hypoxic-ischemic brain injury and is cardioprotective and safe. This trial aims to test the hypothesis that allopurinol administration in CCHD neonates will result in a 20% reduction in moderate to severe ischemic and hemorrhagic brain injury. METHODS: This is a phase III, randomized, quadruple-blinded, placebo-controlled, multicenter trial. Neonates with a prenatal or postnatal CCHD diagnosis requiring cardiac surgery with CPB in the first 4 weeks after birth are eligible to participate. Allopurinol or mannitol-placebo will be administered intravenously in 2 doses early postnatally in neonates diagnosed antenatally and 3 doses perioperatively of 20 mg/kg each in all neonates. The primary outcome is a composite endpoint of moderate/severe ischemic or hemorrhagic brain injury on early postoperative MRI, being too unstable for postoperative MRI, or mortality within 1 month following CPB. A total of 236 patients (n = 188 with prenatal diagnosis) is required to demonstrate a reduction of the primary outcome incidence by 20% in the prenatal group and by 9% in the postnatal group (power 80%; overall type 1 error controlled at 5%, two-sided), including 1 interim analysis at n = 118 (n = 94 with prenatal diagnosis) with the option to stop early for efficacy. Secondary outcomes include preoperative and postoperative brain injury severity, white matter injury volume (MRI), and cardiac function (echocardiography); postnatal and postoperative seizure activity (aEEG) and regional cerebral oxygen saturation (NIRS); neurodevelopment at 3 months (general movements); motor, cognitive, and language development and quality of life at 24 months; and safety and cost-effectiveness of allopurinol. DISCUSSION: This trial will investigate whether allopurinol administered directly after birth and around cardiac surgery reduces moderate/severe ischemic and hemorrhagic brain injury and improves cardiac function and neurodevelopmental outcome in CCHD neonates. TRIAL REGISTRATION: EudraCT 2017-004596-31. Registered on November 14, 2017. ClinicalTrials.gov NCT04217421. Registered on January 3, 2020.

Agent-based modeling of urban exposome interventions: prospects, model architectures, and methodological challenges.

With ever more people living in cities worldwide, it becomes increasingly important to understand and improve the impact of the urban habitat on livability, health behaviors, and health outcomes. However, implementing interventions that tackle the exposome in complex urban systems can be costly and have long-term, sometimes unforeseen, impacts. Hence, it is crucial to assess the health impact, cost-effectiveness, and social distributional impacts of possible urban exposome interventions (UEIs) before implementing them. Spatial agent-based modeling (ABM) can capture complex behavior-environment interactions, exposure dynamics, and social outcomes in a spatial context. This article discusses model architectures and methodological challenges for successfully modeling UEIs using spatial ABM. We review the potential and limitations of the method; model components required to capture active and passive exposure and intervention effects; human-environment interactions and their integration into the macro-level health impact assessment and social costs benefit analysis; and strategies for model calibration. Major challenges for a successful application of ABM to UEI assessment are (1) the design of realistic behavioral models that can capture different types of exposure and that respond to urban interventions, (2) the mismatch between the possible granularity of exposure estimates and the evidence for corresponding exposure-response functions, (3) the scalability issues that emerge when aiming to estimate long-term effects such as health and social impacts based on high-resolution models of human-environment interactions, (4) as well as the data- and computational complexity of calibrating the resulting agent-based model. Although challenges exist, strategies are proposed to improve the implementation of ABM in exposome research.

To what extent do citizens support the disinvestment of healthcare interventions? An exploration of the support for four viewpoints on active disinvestment in the Netherlands.

BACKGROUND: Active disinvestment of healthcare interventions (i.e. discontinuing reimbursement by means of a policy decision) has received limited public support in the past. Previous research has identified four viewpoints on active disinvestment among citizens in the Netherlands. However, it remained unclear how strong these viewpoints are supported by society, and by whom. Therefore, the current study aimed to 1) measure the support for these four viewpoints and 2) assess whether support is associated with background characteristics of citizens. METHOD: In an online survey, a representative sample of adult citizens in the Netherlands (n = 1794) was asked to rate their agreement with short narratives of the four viewpoints on a 7-point Likert scale. The survey also included questions on sociodemographic characteristics, health status, healthcare utilization, and opinions about responsibility and costs in the healthcare context. Logistic regression models were estimated for each viewpoint to assess the association between viewpoint support and these characteristics. RESULTS: The support for the different viewpoints varied between 46.8% and 57.7% of the sample. Viewpoint support was associated with participants' age, gender, educational level, financial situation, healthcare utilization, opinion on the responsibility of the government for the health of citizens, and opinion on whether the increase in healthcare expenditure and health insurance premiums is considered a problem. CONCLUSION: Resistance to active disinvestment may partially be explained by the consequences of disinvestment citizens anticipate experiencing themselves. Citizens considering the increase in healthcare expenditure a larger problem were more supportive of disinvestment than those considering it less of a problem.