Previous publications

Background: Chikungunya is a viral disease caused by a mosquito-borne alphavirus. The acute phase of the disease includes symptoms such as fever and arthralgia and lasts 7–10 days. However, debilitating symptoms can persist for months or years. Despite the substantial impact of this disease, a comprehensive assessment of its clinical picture is currently lacking.

Methods: We conducted a systematic literature review on the clinical manifestations of chikungunya, their prevalence and duration, and related hospitalization. Embase and MEDLINE were searched with no time restrictions. Subsequently, meta-analyses were conducted to quantify pooled estimates on clinical outcomes, the symptomatic rate, the mortality rate, and the hospitalization rate. The pooling of effects was conducted using the inverse-variance weighting methods and generalized linear mixed effects models, with measures of heterogeneity reported.

Results: The systematic literature review identified 316 articles. Out of the 28 outcomes of interest, we were able to conduct 11 meta-analyses. The most prevalent symptoms during the acute phase included arthralgia in 90% of cases (95% CI: 83–94%), and fever in 88% of cases (95% CI: 85–90%). Upon employing broader inclusion criteria, the overall symptomatic rate was 75% (95% CI: 63–84%), the chronicity rate was 44% (95% CI: 31–57%), and the mortality rate was 0.3% (95% CI: 0.1–0.7%). The heterogeneity between subpopulations was more than 92% for most outcomes. We were not able to estimate all predefined outcomes, highlighting the existing data gap.

Conclusion: Chikungunya is an emerging public health concern. Consequently, a thorough understanding of the clinical burden of this disease is necessary. Our study highlighted the substantial clinical burden of chikungunya in the acute phase and a potentially long-lasting chronic phase. Understanding this enables health authorities and healthcare professionals to effectively recognize and address the associated symptoms and raise awareness in society.

Objectives: Type-2 Diabetes mellitus (T2DM) increases both the patient risk of cardiovascular disease (CVD) and renal outcomes, such as chronic kidney disease (CKD). Recent clinical trials of the glucose-lowering drug-class of sodium-glucose co-transporter-2 inhibitors (SGLT2is) have shown benefits in preventing CVD events and progression of CKD, leading to an update of the Dutch T2DM treatment guideline for patients at risk. The aim of this study is to assess the health and economic impact of the guideline-recommended utilization of SGLT2is in the Netherlands.

Methods: The patient population at risk was determined by multiplying Dutch T2DM prevalence rates with the total numbers of inhabitants of the Netherlands in 2020. Subsequently, two analyses, comparing a treatment setting before and after implementation of the new guideline for SGLT2is, were conducted. Clinical and adverse event rates in both settings as well as direct healthcare costs were sourced from the literature. Total costs were calculated by multiplying disease prevalence, event rates and costs associated to outcomes. One-time disutilities per event were included to estimate the health impact. The potential health and economic impact of implementing the updated guideline was calculated.

Results: Using a 5-year time horizon, the guideline-suggested utilization of SGLT2is resulted in a health impact equal to 4835 quality adjusted life years gained (0.0031 per patient per year) and €461 million cost-savings. The costs of treatment with SGLT2is were €813 million. Hence the net budget impact was €352 million for the total Dutch T2DM population, which translated to €0,57 per patient per day.

Conclusion: SGLT2is offer an option to reduce the number of CVD and CKD related events and associated healthcare costs and health losses in the Netherlands. Further research is needed to include the benefits of improved T2DM management options from a broader societal perspective.

Highlights: The glucose-lowering drug-class of sodium-glucose co-transporter-2 inhibitors (SGLT2is) has shown benefits in preventing cardiovascular events and progression of kidney disease in patients with type-2 diabetes leading to a revision of the respective Dutch treatment guideline. The 5-year budget impact of the adoption of SGLT2is in the new treatment guideline was equal to €352 million or €0.57 per patient per day, with a total of 4385 quality adjusted life years gained. The introduction of SGLT2is for Dutch type-2 diabetes patients has the potential to substantially reduce the number of cardiovascular as well as renal disease events and related healthcare costs while also delivering a health benefit.

Background: Evidence-based reassurances addressing vaccine-related concerns are crucial to promoting primary vaccination, completion of the primary series, and booster vaccination. By summarizing and comparing the reactogenicity of COVID-19 vaccines authorized by the European Medicines Agency, this analysis aims to support in-formed decision-making by the lay public and help overcome vaccine hesitancy.

Research design and methods: A systematic literature review identified 24 records reporting solicited adverse events for AZD1222, BNT162b2, mRNA-1273, NVX-Cov2373, and VLA2001 in individuals aged 16 or older. Network meta-analyses were conducted for each solicited adverse events reported for at least two vaccines that were not compared head-to-head but could be connected through a common comparator.

Results: A total of 56 adverse events were investigated through network meta-analyses within a Bayesian framework with random-effects models. Overall, the two mRNA vaccines were found to be the most reactogenic vaccines. VLA2001 had the highest likelihood of being the least reactogenic vaccine after the first and second vaccine dose, especially for systemic adverse events after the first dose.

Conclusions: The reduced chance of experiencing an adverse event with some COVID-19 vaccines may help to overcome vaccine hesitancy in population groups with concerns about the side effects of vaccines.

Purpose: To give a comprehensive literature overview of alterations in regional cerebral glucose metabolism, measured using [18F]FDG PET, in conditions associated with hyperkinetic movement disorders and ataxia. In addition, correlations between glucose metabolism and clinical variables as well as the effect of treatment on glucose metabolism are discussed.

Methods: A systematic literature search was performed according to PRISMA guidelines. Studies concerning tremors, tics, dystonia, ataxia, chorea, myoclonus, functional movement disorders, or mixed movement disorders due to autoimmune or metabolic aetiologies were eligible for inclusion. A PubMed search was performed up to November 2021.

Results: Of 1240 studies retrieved in the original search, 104 articles were included. Most articles concerned patients with chorea (n = 27), followed by ataxia (n = 25), dystonia (n = 20), tremor (n = 8), metabolic disease (n = 7), myoclonus (n = 6), tics (n = 6), and autoimmune disorders (n = 5). No papers on functional movement disorders were included. Altered glucose metabolism was detected in various brain regions in all movement disorders, with dystonia-related hypermetabolism of the lentiform nuclei and both hyper- and hypometabolism of the cerebellum; pronounced cerebellar hypometabolism in ataxia; and striatal hypometabolism in chorea (dominated by Huntington disease). Correlations between clinical characteristics and glucose metabolism were often described. [18F]FDG PET-showed normalization of metabolic alterations after treatment in tremors, ataxia, and chorea.

Conclusion: In all conditions with hyperkinetic movement disorders, hypo- or hypermetabolism was found in multiple, partly overlapping brain regions, and clinical characteristics often correlated with glucose metabolism. For some movement disorders, [18F]FDG PET metabolic changes reflected the effect of treatment.

Background: In the Netherlands, more than one million patients have type 2 diabetes (T2D), and approximately 36% of these patients have chronic kidney disease (CKD). Yearly medical costs related to T2D and CKD account for approximately €1.3 billion and €805 million, respectively. The FIDELIO-DKD trial showed that the addition of finerenone to the standard of care (SoC) lowers the risk of CKD progression and cardiovascular (CV) events in patients with CKD stages 2–4 associated with T2D. This study investigates the cost-effectiveness of adding finerenone to the SoC of patients with advanced CKD and T2D compared to SoC monotherapy.

Methods: The validated FINE-CKD model is a Markov cohort model which simulates the disease pathway of patients over a lifetime time horizon. The model was adapted to reflect the Dutch societal perspective. The model estimated the incremental costs, utilities, and incremental cost-effectiveness ratio (ICER). Sensitivity and scenario analyses were performed to assess the effect of parameter uncertainty on model robustness.

Results: When used in conjunction with SoC, finerenone extended time free of CV events and renal replacement therapy by respectively 0.30 and 0.31 life years compared to SoC alone, resulting in an extension of 0.20 quality-adjusted life years (QALYs). The reduction in renal and CV events led to a €6136 decrease in total lifetime costs per patient compared to SoC alone, establishing finerenone as a dominant treatment option. Finerenone in addition to SoC had a 83% probability of being dominant and a 93% probability of being cost-effective at a willingness-to-pay threshold of €20,000.

Conclusion: By reducing the risk of CKD progression and CV events, finerenone saves costs to society while gaining QALYs in patients with T2D and advanced CKD in the Netherlands.

Objectives: The aim of this study was to evaluate the cost-effectiveness of ravulizumab compared with eculizumab for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH) in the Netherlands.

Methods: A cost-effectiveness analysis was conducted based on a Markov cohort model simulating the course of patients with PNH with clinical symptom(s) indicative of high disease activity, or who are clinically stable after having been treated with eculizumab for at least the past six months. Costs, quality of life, and the incremental cost-effectiveness ratio (ICER) were estimated over a lifetime horizon from a Dutch societal perspective. Several additional analyses were performed, including a one-way sensitivity analysis, a probabilistic sensitivity analysis, and scenario analysis.

Results: When compared with eculizumab, ravulizumab saves €266,833 and 1.57 quality adjusted life years (QALYs) are gained, resulting in a dominant ICER. Drug costs account for the majority of the total costs in both intervention groups. Cost savings were driven by the difference in total treatment costs of ravulizumab compared with eculizumab caused by the reduced administration frequency, accounting for 98% of the total cost savings. The QALY gain with ravulizumab is largely attributable to the improved quality of life associated with less frequent infusions and BTH events. At a willingness-to-pay threshold of €20,000/QALY, there is a 76.6% probability that ravulizumab would be cost-effective.

Conclusions: The cost reduction and QALY gain associated with the lower rates of BTH and less frequent administration make ravulizumab a cost-saving and clinically beneficial substitute for eculizumab for adults with PNH in the Netherlands.

Objective: The radiopharmaceuticals radium-223 and the pharmacy preparation 177 Lu-PSMA-I&T are reimbursed in the Netherlands for metastatic castration-resistant prostate cancer (mCRPC) treatment. Although shown to be life-prolonging in patients with mCRPC, the treatment procedures associated with these radiopharmaceuticals can be challenging for both patients and hospitals. This study investigates the costs of mCRPC treatment in Dutch hospitals for currently reimbursed radiopharmaceuticals with a demonstrated overall survival benefit.

Methods: A cost model that calculated the direct medical per-patient costs of radium-223 and 177 Lu-PSMA-I&T was developed, following clinical trial regimens. The model considered six 4-weekly administrations (i.e. ALSYMPCA regimen) of radium-223. Regarding 177 Lu-PSMA-I&T, the model used both the VISION regimen (i.e. five 6-weekly administrations) and the SPLASH regimen (i.e. four 8-weekly administrations). Based on health insurance claims, we also estimated the coverage a hospital would receive for providing treatment. No fitting health insurance claim for 177 Lu-PSMA-I&T is currently available; therefore, we calculated a break-even value for a potential health insurance claim that would exactly counterbalance the per-patient costs and coverage.

Results: Radium-223 administration is associated with per-patient costs of e30,905, and these costs are fully covered by the coverage a hospital receives. The per-patient costs of 177 Lu-PSMA-I&T range between e35,866 and e47,546 per administration period, depending on the regimen. Current health-care insurance claims do not fully cover the costs of providing 177 Lu-PSMA-I&T: hospitals must paye4,414–e4,922 for each patient out of their own budget. The break-even value for the potential insurance claim covering 177 Lu-PSMA-I&T administration with a VISION (SPLASH) regimen is e1,073(e1,215).

Conclusion: This study shows that, without consideration of the treatment effect, radium-223 treatment for mCRPC leads to lower per-patient costs than treatment with 177 Lu-PSMA-I&T. The detailedoverview of the costs associated with radiopharmaceutical treatment provided by this study is relevantfor both hospitals and healthcare insurers.

Background: In older adults, the burden of respiratory syncytial virus (RSV) resembles that of influenza and may even be considered worse due to the lack of preventive interventions. This study was performed to identify the available literature on RSV infection in older adults, and to provide updated exploratory results of the cost-effectiveness of a hypothetical RSV vaccine in the Netherlands and the United Kingdom.

Methods: A literature search was performed in Medline and EMBASE on 11 November 2019, which served as input for a static decision-tree model that was used to estimate the EJP, for an RSV vaccine applying different willingness-to-pay (WTP) thresholds. WTP thresholds applied were €20 000 and €50 000 per quality-adjusted life-year for the Netherlands, and £20 000 and £30 000 per quality-adjusted life-year for the United Kingdom. Analyses were—in line with country-specific guidelines—conducted from a societal perspective for the Netherlands and a third-party payer perspective for the United Kingdom. The robustness of the cost-effectiveness results was tested in sensitivity analysis.

Results: After screening the literature, 3 studies for the Netherlands and 6 for the United Kingdom remained to populate the country-specific models. In the base case analysis for the Netherlands (mean RSV incidence, 3.32%), justifiable vaccine prices of €16.38 and €50.03 were found, based on applying the lower and higher WTP thresholds, respectively. Similarly, for the United Kingdom (mean incidence, 7.13%), vaccine prices of £72.29 and £109.74 were found, respectively.

Conclusion: RSV vaccination may well be cost-effective in both the Netherlands and the United Kingdom, depending on the exact RSV incidence, vaccine effectiveness and price. However, sensitivity analysis showed that the results were robust based on varying the different parameter estimates and assumptions. With RSV vaccines reaching the final stages of development, a strong need exists for cost-effectiveness studies to understand economically justifiable pricing of the vaccine.

Objectives: National health technology assessments (HTAs) across Europe show differences in evidentiary requirements from assessments by the European Medicines Agency (EMA), affecting time to patient access for drugs after marketing authorization. This article analyzes the differences between EMA and HTA bodies’ evidentiary requirements for oncology drugs and provides recommendations on potential further alignment to minimize and optimally manage the remaining differences.

Methods: Interviews were performed with representatives and drug assessment experts from EMA and HTA bodies to identify evidentiary requirements for several subdomains and collect recommendations for potentially more efficiently addressing differences. A comparative analysis of acceptability of the evidence by EMA and the HTA bodies and for potential further alignment between both authorities was conducted.

Results: Acceptability of available evidence was higher for EMA than HTA bodies. HTA bodies and EMA were aligned on evidentiary requirements in most cases. The subdomains showing notable differences concerned the acceptance of limitation of the target population and extrapolation of target populations, progression-free survival and (other) surrogate endpoints as outcomes, cross-over designs, short trial duration, and clinical relevance of the effect size. Recommendations for reducing or optimally managing differences included joint early dialogues, joint relative effectiveness assessments, and the use of managed entry agreements.

Conclusions: Differences between assessments of EMA and HTA bodies were identified in important areas of evidentiary requirements. Increased alignment between EMA and HTA bodies is suggested and recommendations for realization are discussed.

Background: Patients suffering from functional neurological disorder (FND) experience disabling neurological symptoms not caused by an underlying classical neurological disease (such as stroke or multiple sclerosis). The diagnosis is made based on reliable positive clinical signs, but clinicians often require additional time- and cost consuming medical tests and examinations. Resting-state functional connectivity (RS FC) showed its potential as an imaging-based adjunctive biomarker to help distinguish patients from healthy controls and could represent a “rule-in” procedure to assist in the diagnostic process. However, the use of RS FC depends on its applicability in a multi-centre setting, which is particularly susceptible to inter-scanner variability. The aim of this study was to test the robustness of a classification approach based on RS FC in a multi-centre setting.

Methods: This study aimed to distinguish 86 FND patients from 86 healthy controls acquired in four different centres using a multivariate machine learning approach based on whole-brain resting-state functional connectivity. First, previously published results were replicated in each centre individually (intra-centre cross- validation) and its robustness across inter-scanner variability was assessed by pooling all the data (pooled cross-validation). Second, we evaluated the generalizability of the method by using data from each centre once as a test set, and the data from the remaining centres as a training set (inter-centre cross-validation).

Results: FND patients were successfully distinguished from healthy controls in the replication step (accuracy of 74%) as well as in each individual additional centre (accuracies of 73%, 71% and 70%). The pooled cross validation confirmed that the classifier was robust with an accuracy of 72%. The results survived post-hoc adjustment for anxiety, depression, psychotropic medication intake, and symptom severity. The most discriminant features involved the angular- and supramarginal gyri, sensorimotor cortex, cingular- and insular cortex, and hippocampal regions. The inter-centre validation step did not exceed chance level (accuracy below 50%).

Conclusions: The results demonstrate the applicability of RS FC to correctly distinguish FND patients from healthy controls in different centres and its robustness against inter-scanner variability. In order to generalize its use across different centres and aim for clinical application, future studies should work towards optimization of acquisition parameters and include neurological and psychiatric control groups presenting with similar symptoms.

The study aimed to determine the associations of Peak Inspiratory Flow (PIF), inhalation technique and adherence with health status and exacerbations in participants with COPD using DPI maintenance therapy. This cross-sectional multi-country observational real-world study included COPD participants aged ≥40 years using a DPI for maintenance therapy. PIF was measured three times with the In-Check DIAL G16: (1) typical PIF at resistance of participant’s inhaler, (2) maximal PIF at resistance of participant’s inhaler, (3) maximal PIF at low resistance. Suboptimal PIF (sPIF) was defined as PIF lower than required for the device. Participants completed questionnaires on health status (Clinical COPD Questionnaire (CCQ)), adherence (Test of Adherence to Inhalers (TAI)) and exacerbations. Inhalation technique was assessed by standardised evaluation of video recordings. Complete data were available from 1434 participants (50.1% female, mean age 69.2 years). GOLD stage was available for 801 participants: GOLD stage I (23.6%), II (54.9%), III (17.4%) and IV (4.1%)). Of all participants, 29% had a sPIF, and 16% were shown able to generate an optimal PIF but failed to do so. sPIF was significantly associated with worse health status (0.226 (95% CI 0.107–0.346), worse units on CCQ; p=0.001). The errors ‘teeth and lips sealed around mouthpiece’, ‘breathe in’, and ‘breathe out calmly after inhalation’ were related to health status. Adherence was not associated with health status. After correcting for multiple testing, no significant association was found with moderate or severe exacerbations in the last 12 months. To conclude, sPIF is associated with poorer health status. This study demonstrates the importance of PIF assessment in DPI inhalation therapy. Healthcare professionals should consider selecting appropriate inhalers in cases of sPIF.

Objectives: Spinal muscular atrophy (SMA) is a rare genetic disorder that causes progressive muscle weakness and paralysis. In its most common and severe form, the majority of untreated infants die before 2 years of age. Early detection and treatment, ideally before symptom onset, maximize survival and achievement of age-appropriate motor milestones, with potentially substantial impact on health-related quality of life. Therefore, SMA is an ideal candidate for inclusion in newborn screening (NBS) programs. We evaluated the cost-effectiveness of including SMA in the NBS program in The Netherlands.

Methods: We developed a cost-utility model to estimate lifetime health effects and costs of NBS for SMA and subsequent treatment versus a treatment pathway without NBS (ie, diagnosis and treatment after presentation with overt symptoms). Model inputs were based on literature, local data, and expert opinion. Sensitivity and scenario analyses were conducted to assess model robustness and validity of results.

Results: After detection of SMA by NBS in 17 patients, the number of quality-adjusted life-years gained per annual birth cohort was estimated at 320 with NBS followed by treatment compared with treatment after clinical SMA diagnosis. Total healthcare costs, including screening, diagnostics, treatment, and other healthcare resource use, were estimated to be V12014949 lower for patients identified by NBS.

Conclusions: NBS for early identification and treatment of SMA versus later symptomatic treatment after clinical diagnosis improves health outcomes and is less costly and, therefore, is a cost-effective use of resources. Results were robust in sensitivity and scenario analyses.

Objectives: Going beyond their initial use as antidiabetic agents, sodium-glucose cotransporter-2 (SGLT2) inhibitors have certified their roles in the treatment of other chronic diseases independent from diabetes. We aim to demonstrate how the positions of SGLT2 inhibitors have changed in the treatment algorithms of type 2 diabetes (T2DM), heart failure (HF), and chronic kidney disease (CKD), and which opportunities lie in the future.

Methods: A targeted review was performed. International guidelines for T2DM, HF, and CKD published from 2012 onward were included for the analysis of positioning. An advanced search on clinicaltrials.gov was conducted to identify recently published and ongoing trials of SGLT2 inhibitors in related diseases to analyse their possible positions in the future.

Results: Established evidence of cardiorenal protective benefits of these drugs has placed SGLT2 inhibitors as first-line monotherapy agents in T2DM patients with related comorbidities. Both dapagliflozin and empagliflozin are recommended in the combined therapy of chronic HF due to their clinical efficacy and cost-effectiveness. While dapagliflozin already has proven its place in the treatment algorithm of CKD, empagliflozin might share a similar position based on the early termination of the EMPA-KIDNEY trial due to clear positive results in patients with CKD. Furthermore, the cardiorenal benefits of SGLT2 inhibitors regardless of diabetic status are being investigated in ongoing trials looking at the efficacy and safety in patients with acute HF, myocardial infarction, and severe CKD, including dialysis and kidney transplantation.

Conclusions: Despite emerging evidence however, prescriptions of SGLT2 inhibitors are lagging. Their limited usage within T2DM at present and potentially slow adaptation in HF and CKD hinders treatment and protection in these patients, resulting in potential losses in health benefits, measured by quality adjusted life years. This suggests that policy makers should be attentive to their uptake among eligible patients since their protective evidence has already been established.

Background/Objectives: Smoking is the leading risk factor for many chronic diseases. The quantitative analysis of potential health gains from reduced smoking is important for establishing priorities in Mongolia’s health policy. This study quantifies the effect of tobacco-tax increases on future smoking prevalence and the associated smoking-related burden of disease in Mongolia.

Methods: The dynamic model for health impact assessment (DYNAMO-HIA) tool was used. The most recent data were used as input for evaluating tobacco-taxation scenarios. Demographic data were taken from the Mongolian Statistical Information Services. Smoking data came from a representative population-based STEPS survey, and smoking-related disease data were obtained from the health-information database of Mongolia’s National Health Center. Simulation was used to evaluate various levels of one-time price increases on tobacco products (25% and 75%) in Mongolia. Conservative interpretation suggests that the population will eventually adjust to the higher tobacco price and return to baseline smoking behaviors.

Results: Over a three-year period, smoking prevalence would be reduced by 1.2% points, corresponding to almost 40 thousand smokers at the population level for a price increase of 75%, compared to the baseline scenario. Projected health benefits of this scenario suggest that more than 137 thousand quality adjusted of life years would be gained by avoiding smoking-related diseases within a population of three million over a 30-year period.

Discussion: Prevention through effective tobacco-control policy could yield considerable gains in population health in Mongolia. Compared to current policy, tax increases must be higher to have a significant effect on population health.

Implications: Tobacco taxation is an effective policy for reducing the harm of tobacco smoking, while benefiting population health in countries where the tobacco epidemic is still in an early stage. Smoking prevalence and smoking behaviors in these countries differ from those in Western countries. Reducing the uptake of smoking among young people could be a particularly worthwhile benefit of tobacco-tax increases.

Purpose: Although intraocular anti-vascular endothelial growth factors (anti-VEGFs) are effective as treatment of neovascular age-related macular degeneration (nAMD), the (economic) burden on the healthcare system is considerable. A treat-andextend (T&E) regimen is associated with a lower number of injections without compromising the effectiveness and can therefore help optimise nAMD treatment. This study investigates the per-patient costs associated with nAMD treatment, when using aflibercept, bevacizumab, or ranibizumab with a T&E regimen.

Methods: In this cost-minimisation model, the per-patient costs in the Netherlands were modelled using a healthcare payers’ perspective over a 3-year time horizon with the assumption that efficacy of treatments is similar. Additionally, the break-even price of the different anti-VEGFs was calculated relative to the cheapest option and injection frequency.

Results: The injection frequency varied from 14.2 for aflibercept to 27.4 for bevacizumab in 3 years. Nonetheless, bevacizumab remains the cheapest treatment option (€14,215), followed by aflibercept (€18,202) and ranibizumab (€31,048). The medication covers the majority of the per-patient costs for aflibercept and ranibizumab, while administration covers the majority of the per-patient costs for bevacizumab. The break-even prices of aflibercept and ranibizumab are respectively €507 and €60.58 per injection. Brolucizumab was included in the scenario analysis and was more expensive than aflibercept (€20,446). Brolucizumab should reduce to 13.8 injections over 3 years to be as costly as aflibercept.

Conclusion: Bevacizumab is the cheapest anti-VEGF treatment. The list prices of all anti-VEGFs should reduce to be as costly as bevacizumab. Aflibercept is the second-choice treatment and so far brolucizumab is not.

Background: This study aimed to assess the association between multimorbidity and exit from paid employment, and which combinations of chronic health conditions (CHCs) have the strongest association with exit from paid employment.

Methods: Data from 111 208 workers aged 18–64years from Lifelines were enriched with monthly employment data from Statistics Netherlands. Exit from paid employment during follow-up was defined as a change from paid employment to unemployment, disability benefits, economic inactivity or early retirement. CHCs included cardiovascular diseases (CVD), chronic obstructive pulmonary disease (COPD), rheumatoid arthritis (RA), type 2 diabetes (T2DM) and depression. Cox-proportional hazards models were used to examine the impact of multimorbidity and combinations of CHCs on exit from paid employment.

Results: Multimorbidity increased the risk of exiting paid employment compared with workers without CHCs (hazard ratio (HR): 1.52; 95% confidence interval (CI): 1.35–1.71) or one CHC (HR: 1.14; 95% CI: 1.01–1.28). The risk for exit from paid employment increased among workers with COPD if they additionally had CVD(HR: 1.39; 95% CI: 1.03–1.88), depression (HR: 1.46; 95% CI: 1.10–1.93) or RA (HR: 1.44; 95% CI: 1.08–1.91), for workers with T2DM if they additionally had CVD (HR: 1.43; 95% CI: 1.07–1.91) or depression (HR: 2.09; 95% CI: 1.51–2.91) and for workers with depression who also had T2DM (HR: 1.68; 95% CI: 1.21–2.32).

Conclusion: This study showed that workers with multimorbidity, especially having a combination of COPD and depression or T2DM and depression, have a higher risk for early exit from paid employment and, therefore, may need tailored support at the workplace.

Aims: Valid health economic models are essential to inform the adoption and reimbursement of therapies for diabetes mellitus. Often existing health economic models are applied in other countries and settings than those where they were developed. This practice requires assessing the transferability of a model developed from one setting to another. We evaluate the transferability of the MICADO model, developed for the Dutch 2007 setting, in two different settings using a range of adjustment steps. MICADO predicts micro- and macrovascular events at the population level.

Methods: MICADO simulation results were compared to observed events in an Italian 2000–2015 cohort (Casale Monferrato Survey [CMS]) and in a Dutch 2008–2019 (Hoorn Diabetes Care Center [DCS]) cohort after adjusting the demographic characteristics. Additional adjustments were performed to: (1) risk factors prevalence at baseline, (2) prevalence of complications, and (3) all-cause mortality risks by age and sex. Model validity was assessed by mean average percentage error (MAPE) of cumulative incidences over 10 years of follow-up, where lower values mean better accuracy.

Results: For mortality, MAPE was lower for CMS compared to DCS (0.38 vs. 0.70 following demographic adjustment) and adjustment step 3 improved it to 0.20 in CMS, whereas step 2 showed best results in DCS (0.65). MAPE for heart failure and stroke in DCS were 0.11 and 0.22, respectively, while for CMS was 0.42 and 0.41.

Conclusions: The transferability of the MICADO model varied by event and per cohort. Additional adjustments improved prediction of events for MICADO. To ensure a valid model in a new setting it is imperative to assess the impact of adjustments in terms of model accuracy, even when this involves the same country, but a new time period.

Objectives: Chikungunya virus (CHIKV) is a re-emerging arbovirus with infection characterized by an acute phase commonly presenting with fever, severe polyarthralgia, and myalgia, which can progress to chronic sequelae resulting in productivity losses and a significant reduction in health-related quality-of-life (HRQoL). To investigate the available evidence on the disease burden associated with CHIKV, we conducted a systematic literature review (SLR) of the clinical evidence and a targeted literature review (TLR) on the burden of CHIKV.

Methods: The SLR of clinical evidence was conducted in Medline and Embase databases (no date restriction) and congress abstract repositories (2019–2021). The search adhered to Preferred Reporting Item for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A TLR of burden evidence was also performed.

Results: Of 13,285 records identified, 246 studies were included in the SLR of which 17 (6.91%) were interventional studies. The TLR included 101 studies. The acute and chronic polyarthralgia and myalgia associated with CHIKV infection was found to cause substantial physical incapacity impacting the daily functioning and HRQoL of patients. In addition, mental health is significantly affected, with patients experiencing pain, mental, mood, and sleep disorders. CHIKV infection may lead to long-term disability due to neurocognitive and psychological sequelae associated with a reduction in HRQoL. Population shifts, increased travel, and climate change are contributing to the increased spread of emerging and re-emerging CHIKV infections, yet effective preventive measures or treatments are lacking.

Conclusions: CHIKV is a serious threat to global public health and causes significant disease burden worldwide. The tools available to prevent and treat CHIKV infection are limited; vector control measures are suboptimal and challenging, and only symptomatic treatment currently exists for chikungunya. Due to the unpredictable nature of CHIKV spread and lack of treatment options for chikungunya, there is an immediate need for effective preventive measures such as vaccines.

Background: Sub-Saharan Africa (SSA) has the world's highest maternal and neonatal morbidity and mortality and has shown the slowest progress in reducing them. In addition, there is substantial inequality in terms of maternal and neonatal morbidity and mortality in the region. Geospatial studies can help prioritize scarce resources by pinpointing priority areas for implementation. This systematic review was conducted to explore the application of geospatial analysis to maternal and neonatal morbidity and mortality in SSA.

Methods: A systematic search of PubMed, SCOPUS, EMBASE, and Web of Science databases was performed. All observational and qualitative studies that reported on maternal or neonatal health outcomes were included if they used a spatial analysis technique and were conducted in a SSA country. After removing duplicates, two reviewers independently reviewed each study's abstract and full text for inclusion. Furthermore, the quality of the studies was assessed using the Joanna Briggs Institute (JBI) critical appraisal checklists. Finally, due to the heterogeneity of studies, narrative synthesis was used to summarize the main findings, and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was strictly followed to report the review results. A total of 56 studies were included in the review.

Results: We found that geospatial analysis was used to identify inequalities in maternal and neonatal morbidity, mortality, and health care utilization and to identify gaps in the availability and geographic accessibility of maternal health facilities. In addition, we identified a few studies that used geospatial analysis for modelling intervention areas. We also detected challenges and shortcomings, such as unrealistic assumptions used by geospatial models and a shortage of reliable, up-to-date, small-scale georeferenced data.

Conclusions: The use of geospatial analysis for maternal and neonatal health in SSA is still limited, and more detailed spatial data are required to exploit the potential of geospatial technologies fully.

Objectives: Studies in clinical settings showed a potential relationship between socioeconomic status (SES) and lifestyle factors with COVID-19, but it is still unknown whether this holds in the general population. In this study, we investigated the associations of SES with self- reported, tested and diagnosed COVID-19 status in the general population.

Design, setting, participants and outcome measures: Participants were 49 474 men and women (46±12 years) residing in the Northern Netherlands from the Lifelines cohort study. SES indicators and lifestyle factors (i.e., smoking status, physical activity, alcohol intake, diet quality, sleep time and TV watching time) were assessed by questionnaire from the Lifelines Biobank. Self- reported, tested and diagnosed COVID-19 status was obtained from the Lifelines COVID-19 questionnaire.

Results: There were 4711 participants who self- reported having had a COVID-19 infection, 2883 participants tested for COVID-19, and 123 positive cases were diagnosed in this study population. After adjustment for age, sex, lifestyle factors, body mass index and ethnicity, we found that participants with low education or low income were less likely to self- report a COVID-19 infection (OR [95% CI]: low education 0.78 [0.71 to 0.86]; low income 0.86 [0.79 to 0.93]) and be tested for COVID-19 (OR [95% CI]: low education 0.58 [0.52 to 0.66]; low income 0.86 [0.78 to 0.95]) compared with high education or high income groups, respectively.

Conclusion: Our findings suggest that the low SES group was the most vulnerable population to self- reported and tested COVID-19 status in the general population.

Poor prognosis caused by type 2 diabetes mellitus (T2DM) in women with breast cancer is conferred, while the association between T2DM and breast tumor aggressiveness is still a matter of debate. This study aimed to clarify the differences in breast cancer characteristics, including stage, size, lymph node status, grade, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (Her2), between patients with and without pre-existing T2DM. PubMed, Embase, and Web of Science were searched for studies from 1 January 2010 to 2 July 2021. Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were pooled by using a random effects model. T2DM was significantly associated with tumor stages III/IV versus cancers in situ and stages I/II (pooled ORs (pOR), 95% CI: 1.19; 1.04–1.36, p = 0.012), tumor size >20 versus 20 mm (pOR, 95% CI: 1.18; 1.04–1.35, p = 0.013), and lymph node invasion versus no involvement (pOR, 95% CI: 1.26; 1.05–1.51, p = 0.013). These findings suggest that women with T2DM are at a higher risk of late-stage tumors, large tumor sizes, and invasive lymph nodes at breast cancer diagnosis.

In this study, we estimated the benefits of rotavirus vaccination for infants had the rotavirus vaccine been introduced in the Netherlands as of its market authorization in 2006. An age-structured, deterministic cohort model was developed to simulate different birth cohorts over a period of 15 years from 2006 until 2021, comparing both universal and targeted high-risk group vaccination to no vaccination. Different scenarios for the duration of protection (5 or 7 years) and herd immunity (only for universal vaccination) were analyzed. All birth cohorts together included 2.6 million infants, of which 7.9% were high-risk individuals, and an additional 13.2 million children between 1-15 years born prior to the first cohort in 2006. The costs and health outcomes associated with rotavirus vaccination were calculated per model scenario and discounted at 4% and 1.5%, respectively. Our analysis reveals that, had rotavirus vaccination been implemented in 2006, it would have prevented 356,800 (51% decrease) and 32,200 (5% decrease) cases of rotavirus gastroenteritis after universal and targeted vaccination, respectively. Over the last 15 years, this would have led to significant avoided costs and quality-adjusted life year losses for either vaccination strategy with the most favorable outcomes for universal vaccination. Clearly, an opportunity has been lost.

Objectives: As of 2019, quadrivalent influenza vaccine (QIV) has replaced trivalent influenza vaccine (TIV) in the national immunization program in The Netherlands. Target groups are individuals of 601 years of age and those with chronic diseases. The objective was to estimate the incremental break-even price of QIV over TIV at a threshold of EUR20.000 per quality-adjusted life-year (QALY).

Methods: An age-structured compartmental dynamic model was adapted for The Netherlands to assess health outcomes and associated costs of vaccinating all individuals at higher risk for influenza with QIV instead of TIV over the seasons 2010 to 2018. Influenza incidence rates were derived from a global database. Other parameters (probabilities, QALYs and costs) were extracted from the literature and applied according to Dutch guidelines. A threshold of EUR20.000 per QALY was applied to estimate the incremental break-even prices of QIV versus TIV. Sensitivity analyses were performed to test the robustness of the model outcomes.

Results: Retrospectively, vaccination with QIV instead of TIV could have prevented on average 9500 symptomatic influenza cases, 2130 outpatient visits, 84 hospitalizations, and 38 deaths per year over the seasons 2010 to 2018. This translates into 385 QALYs and 398 life-years potentially gained. On average, totals of EUR431.527 direct and EUR2.388.810 indirect costs could have been saved each year.

Conclusion: Using QIV over TIV during the influenza seasons 2010 to 2018 would have been cost-effective at an incremental price of maximally EUR3.81 (95% confidence interval, EUR3.26-4.31). Sensitivity analysis showed consistent findings on the incremental break-even price in the same range.

Background: HER2+ tumors make up approximately 20% of MBCs. The survival outcomes for HER2+ MBC patients improved significantly in the last decade due to the development of HER2-targeted therapies. The objective of this SLR was to assess recent evidence on the burden of HER2+ MBC.

Methods: A SLR was conducted in MEDLINE and EMBASE databases (2010-2020) and congress abstract repositories (2018-2020). The search adhered to Preferred Reporting Item for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A total of 8,115 records were identified, of which 6,549 were retrieved upon deduplication. Two reviewers independently screened titles and abstracts for eligibility. Fulltext review of 571 articles was then carried out.

Results: 260 studies met the inclusion criteria. Seven sources of which compared HER2+ mBC patients to the general and BC populations reporting impaired health utility scores and moderate or worse health status. This was assessed using a variety of tools, such as EQ-5D-5L, FACT-B and EORTC QLQ-C30. In addition to lower Quality of Life (QoL), the disease is associated with impairment of work- and daily activity, negative body image perception, and mental disorders. The symptoms, comorbidities and treatment adverse events most frequently reported by HER2+ mBC patients include tiredness, decreased sexual interest, lack of energy, sore muscles, worry, difficulty sleeping and joint pain. Due to the longer treatment duration and high treatment costs of anti-HER2 treatments, HER2+ MBC leads to greater costs than other types of mBC. In Europe, overall-per-patient costs of HER2+ mBC per patient were V235,238-V269,749, of which V37,431-53,950 were annual treatment costs. Costs are primarily driven by treatment and hospitalization costs, and accumulatively increase by line of treatment.

Conclusions: With improvements in disease management being made in recent years, the SLR demonstrated that a substantial burden of HER2+ MBC on patients’ QoL and on the healthcare systems still exists, highlighting the need for more cost-effective treatment options.

Functional neurological disorder (FND) was of great interest to early clinical neuroscience leaders. During the 20th century, neurology and psychiatry grew apart – leaving FND a borderland condition. Fortunately, a renaissance has occurred in the last two decades, fostered by increased recognition that FND is prevalent and diagnosed using “rule-in” examination signs. The parallel use of scientific tools to bridge brain structure - function relationships has helped refine an integrated biopsychosocial framework through which to conceptualize FND. In particular, a growing number of quality neuroimaging studies using a variety of methodologies have shed light on the emerging pathophysiology of FND. This renewed scientific interest has occurred in parallel with enhanced interdisciplinary collaborations, as illustrated by new care models combining psychological and physical therapies and the creation of a new multidisciplinary FND society supporting knowledge dissemination in the field. Within this context, this article summarizes the output of the first International FND Neuroimaging Workgroup meeting, held virtually, on June 17th, 2020 to appraise the state of neuroimaging research in the f ield and to catalyze large-scale collaborations. We first briefly summarize neural circuit models of FND, and then detail the research approaches used to date in FND within core content areas: cohort characterization; control group considerations; task-based functional neuroimaging; resting-state networks; structural neuroimaging; biomarkers of symptom severity and risk of illness; and predictors of treatment response and prognosis. Lastly, we outline a neuroimaging-focused research agenda to elucidate the pathophysiology of FND and aid the development of novel biologically and psychologically-informed treatments.

Aim: To externally validate the UK Prospective Diabetes Study Outcomes Model version 2 (UKPDS-OM2) by comparing the predicted and observed outcomes in two European population-based cohorts of people with type 2 diabetes.

Materials and methods: We used data from the Casale Monferrato Survey (CMS; n = 1931) and a subgroup of the Hoorn Diabetes Care System (DCS) cohort (n = 5188). The following outcomes were analysed: all-cause mortality, myocardial infarction (MI), ischaemic heart disease (IHD), stroke, and congestive heart failure (CHF). Model performance was assessed by comparing predictions with observed cumulative incidences in each cohort during follow-up.

Results: All-cause mortality was overestimated by the UKPDS-OM2 in both the cohorts, with a bias of 0.05 in the CMS and 0.12 in the DCS at 10 years of follow-up. For MI, predictions were consistently higher than observed incidence over the entire follow-up in both cohorts (10 years bias 0.07 for CMS and 0.10 for DCS). The model performed well for stroke and IHD outcomes in both cohorts. CHF incidence was predicted well for the DCS (5 years bias -0.001), but underestimated for the CMS cohort.

Conclusions: The UKPDS-OM2 consistently overpredicted the risk of mortality and MI in both cohorts during follow-up. Period effects may partially explain the differences. Results indicate that transferability is not satisfactory for all outcomes, and new or adjusted risk equations may be needed before applying the model to the Italian or Dutch settings.

Introduction: Progression of amnestic mild cognitive impairment (aMCI) to Alzheimer’s disease (AD) is a clinical event with highly variable progression rates varying from 10–15% up to 30–34%. Functional connectivity (FC), the temporal similarity between spatially remote neurophysiological events, has previously been reported to differ between aMCI patients who progress to AD (pMCI) and those who do not (i.e., remain stable; sMCI). However, these reports had a short-term follow-up and do not provide insight into long-term AD progression.

Methods: Seventy-nine participants with a baseline and 78 with a 12-month, 51 with a 24-month, and 22 with a +48-month follow-up resting-state fMRI with aMCI diagnosis from the Alzheimer’s Disease Neuroimaging Initiative database were included. FC was assessed using the CONN toolbox. Local correlation and group independent component analysis were utilized to compare regional functional coupling and between-network FC, respectively, between sMCI and pMCI groups. Two-sample t tests were used to test for statistically significant differences between groups, and paired t-tests were used to assess cognitive changes over time.

Results: All participants (i.e., 66 sMCI and 19 pMCI) had a baseline and a year follow-up fMRI scan. Progression from aMCI to AD occurred in 19 patients (10 at 12 months, 5 at 24 months, and 4 at >48 months), while 73 MCI patients remained cognitively stable (sMCI). The pMCI and sMCI cognitive profiles were different. More between-network FC than regional functional coupling differences were present between sMCI and pMCI patients. Activation in the salience network (SN) and the default mode network (DMN) was consistently different between sMCI and pMCI patients across time.

Discussion: sMCI and pMCI patients have different cognitive and FC profiles. Only pMCI patients showed cognitive differences across time. The DMN and SN showed local correlation and between-network FC differences between the sMCI and pMCI patient groups at multiple moments in time.

Objective: To explore changes in resting-state networks in patients with jerky and tremulous functional movement disorders (JT-FMD).

Methods: Resting-state functional magnetic resonance imaging data from seventeen patients with JT-FMD and seventeen age-, sex-, and education-matched healthy controls (HC) were investigated. Independent component analysis was used to examine the central executive network (CEN), salience network, and default mode network (DMN). Frequency distribution of network signal fluctuations and intra- and internetwork functional connectivity were investigated. Symptom severity was measured using the Clinical Global Impression-Severity scale. Beck Depression Inventory and Beck Anxiety Inventory scores were collected to measure depression and anxiety in FMD, respectively.

Results: Compared with HC, patients with JT-FMD had significantly decreased power of lower range (0.01–0.10Hz) frequency fluctuations in a precuneus and posterior cingulate cortex component of the DMN and in the dorsal attention network (DAN) component of the CEN (false discovery rate-corrected p<0.05). No significant group differences were found for intra- and internetwork functional connectivity. In patients with JT-FMD, symptom severity was not significantly correlated with network measures. Depression scores were weakly correlated with intranetwork functional connectivity in the medial prefrontal cortex, while anxiety was not found to be related to network connectivity.

Conclusions: Given the changes in the posterodorsal components of the DMN and DAN, we postulate that the JT-FMD-related functional alterations found in these regions could provide support for the concept that particularly attentional dysregulation is a fundamental disturbance in these patients.

Background: Schizophrenia Spectrum Disorder (SSD) is characterized by its chronic, episodic nature. The clear definition of such episodes is essential for various clinical and research purposes. Most current definitions of episodes in SSD are based on either hospitalizations or on symptom scales. Both have drawbacks; symptom scales are measured infrequently, while hospitalization rates are often affected by policy. This study presents an approach for defining episodes in healthcare data that does not suffer such drawbacks.

Methods: Healthcare use of 13,155 SSD patients in the Northern Netherlands with up to 12 years of follow-up was available. Patient-level structural changes in the trend of healthcare use costs were determined using Exponentially Weighted Moving Average (EWMA) control charts. Control charts restart with updated parameters after a detected structural change. Episodes were defined using these structural changes. The resulting episodes were validated by investigating their association with the Global Assessment of Functioning (GAF) scale.

Results: The mean number of episodes was 0.61 (sd: 0.60) per patient per year. For the sub-group without hospitalizations this was 0.51 (sd: 0.71). Average episode duration of the sub-group (147 days, sd: 309.4) was similar to that of the full sample (150 days, sd: 305.5). A significant inverse association was identified between GAF scores and the episode-state indicator.

Conclusions: The repeated application of EWMA control charts based on healthcare-intensity is a feasible and promising tool for quantifying patient-level healthcare episodes. The validation using GAF scores indicates that our episode indicator is associated with lower levels of global functioning. Results for individuals without hospitalizations indicate that the method is robust with regard to changes in healthcare policy.

Aims: Rifaximin-a as an adjunct to lactulose is reimbursed in the Netherlands for prevention of the third and subsequent episodes of overt Hepatic Encephalopathy (HE) in cirrhotic patients. However, use of rifaximin-a remains limited. This study evaluates the clinical and economic impact of treating all patients eligible under Dutch reimbursement conditions with rifaximin-a as an adjunct to lactulose for the prevention of overt HE in the Netherlands from a hospital and healthcare payer’s perspective.

Materials and methods: A budget impact analysis was performed following national and international guidelines. Resource use was based on Dutch real-world data. HE-related cost inputs were based on the declaration codes, Dutch cost manual, and actual drug list prices. Several sensitivity and scenario analyses were conducted to assess model robustness.

Results: Treating eligible HE patients with rifaximin-a in addition to lactulose saves e4,487 and costse249 per patient over a 5-year period compared with lactulose monotherapy from hospital and health-care payer’s perspectives, respectively. In the Netherlands, an estimated 38% of the 2,567 eligiblepatients are currently being treated with rifaximin-a. Optimizing rifaximin-a use by treating all eligiblepatients with the rifaximin-a þ lactulose could save more than 3,000 hospital admissions, almost15,000 hospital bed days, and 300 deaths over a 5-year period. Despite increased drug costs, treat-ment is estimated to result in potential cost savings over a 5-year period of 7.2 million euros from aDutch hospital perspective. The budget impact is 397,770 euros from a healthcare payer’s perspective.

Conclusions: Next to a clinical perspective, also from an economic perspective, wider prescription ofrifaximin-a adhering to guidelines could be beneficial to reduce costs from a hospital perspective. From a healthcare payer’s perspective, costs increase with addition of rifaximin-a due to relative better survival causing relatively higher drug and liver transplantation-related costs.

Purpose: Cognitive biases and factors affecting decision making in critical care can potentially lead to life threatening errors. We aimed to examine the existing evidence on the influence of cognitive biases and factors on decision making in critical care.

Materials and methods: We conducted a scoping review by searching MEDLINE for articles from 2004 to November 2020. We included studies conducted in physicians that described cognitive biases or factors associated with decision making. During the study process we decided on the method to summarize the evidence, and based on the obtained studies a descriptive summary of findings was the best fit.

Results: Thirty heterogenous studies were included. Four main biases or factors were observed, e.g. cognitive biases, personal factors, environmental factors, and patient factors. Six (20%) studies reported biases associated with decision making comprising omission-, status quo-, implicit-, explicit-, outcome-, and overconfidence bias. Nineteen (63%) studies described personal factors, twenty-two (73%) studies described environmental factors, and sixteen (53%) studies described patient factors.

Conclusions: The current evidence on cognitive biases and factors is heterogenous, but shows they influence clinical decision. Future studies should investigate the prevalence of cognitive biases and factors in clinical practice and their impact on clinical outcomes.