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Introduction: A major knowledge gap in the treatment of complicated Staphylococcus aureus bacteraemia (SAB) is the optimal duration of antibiotic therapy. Safe shortening of antibiotic therapy has the potential to reduce adverse drug events, length of hospital stay and costs. The objective of the SAFE trial is to evaluate whether 4 weeks of antibiotic therapy is non-inferior to 6 weeks in patients with complicated SAB., Methods and Analysis: The SAFE-trial is a multicentre, non-inferiority, open-label, parallel group, randomised controlled trial evaluating 4 versus 6 weeks of antibiotic therapy for complicated SAB. The study is performed in 15 university hospitals and general hospitals in the Netherlands. Eligible patients are adults with methicillin-susceptible SAB with evidence of deep-seated or metastatic infection and/or predictors of complicated SAB. Only patients with a satisfactory clinical response to initial antibiotic treatment are included. Patients with infected prosthetic material or an undrained abscess of 5 cm or more at day 14 of adequate antibiotic treatment are excluded. Primary outcome is success of therapy after 180 days, a combined endpoint of survival without evidence of microbiologically confirmed disease relapse. Assuming a primary endpoint occurrence of 90% in the 6 weeks group, a non-inferiority margin of 7.5% is used. Enrolment of 396 patients in total is required to demonstrate non-inferiority of shorter antibiotic therapy with a power of 80%. Currently, 152 patients are enrolled in the study., Ethics and Dissemination: This is the first randomised controlled trial evaluating duration of antibiotic therapy for complicated SAB. Non-inferiority of 4 weeks of treatment would allow shortening of treatment duration in selected patients with complicated SAB. This study is approved by the Medical Ethics Committee VUmc (Amsterdam, the Netherlands) and registered under NL8347 (the Netherlands Trial Register). Results of the study will be published in a peer-reviewed journal., Trial Registration Number: NL8347 (the Netherlands Trial Register)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The aim of this article was to perform a scoping review of methods available for dealing with confounding when analyzing the effect of health care treatments with single-point exposure in observational data. We aim to provide an overview of methods and their performance assessed by simulation studies indexed in PubMed. We searched PubMed for simulation studies published until January 2021. Our search was restricted to studies evaluating binary treatments and binary and/or continuous outcomes. Information was extracted on the methods' assumptions, performance, and technical properties. Of 28,548 identified references, 127 studies were eligible for inclusion. Of them, 84 assessed 14 different methods (ie, groups of estimators that share assumptions and implementation) for dealing with measured confounding, and 43 assessed 10 different methods for dealing with unmeasured confounding. Results suggest that there are large differences in performance between methods and that the performance of a specific method is highly dependent on the estimator. Furthermore, the methods' assumptions regarding the specific data features also substantially influence the methods' performance. Finally, the methods result in different estimands (ie, target of inference), which can even vary within methods. In conclusion, when choosing a method to adjust for measured or unmeasured confounding it is important to choose the most appropriate estimand, while considering the population of interest, data structure, and whether the plausibility of the methods' required assumptions hold., (© 2022 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd.)

Background: Major depression is a highly prevalent disorder causing severe personal distress, and high societal costs. Patients with depression often have comorbid insomnia disorder (ID) leading to even worse personal distress and worse treatment outcomes. Recent results from a non-randomised pilot study with internet-delivered Cognitive Behavioural Therapy (CBTi) for Insomnia (I-Sleep) added to regular depression care were promising regarding feasibility and initial effects on insomnia complaints and depression. However, no randomised controlled trial (RCT) has been performed yet to access the (cost-) effectiveness of I-Sleep for depression. Therefore, this protocol article presents the design of an RCT aimed to assess the (cost-) effectiveness of I-Sleep in addition to usual care for depression compared to usual care alone in depressed patients with a comorbid Insomnia Disorder (ID) treated at outpatient clinics for mood disorders.  METHODS /DESIGN: This is a multi-centre RCT with measurements at baseline and at 3, 6, 9, and 12 months of follow-up. Patients with depression and an ID are randomised to either I-Sleep treatment followed by regular depression care or to regular depression care alone. Our aim is to recruit one hundred and seventy-five patients from multiple outpatient clinics for mood disorders. The primary outcome is the change in depressive symptoms over 12 months of follow-up measured with the Patient Health Questionnaire (PHQ-9). Secondary outcomes are recovery from depression (PHQ-9), insomnia severity (Insomnia Severity Index, ISI), daily functioning (Work and Social Adjustment Scale, WSAS), general quality of life (EuroQol 5-level version, EQ-5D-5L), and societal costs (Adapted versions of the iMTA Productivity Cost Questionnaire, iPCQ and iMTA Medical Cost Questionnaire, iMCQ)., Discussion: We hypothesize that the addition of I-Sleep to usual care will result in a significant improvement in depression treatment outcomes and quality of life as well as a decrease in healthcare and societal costs compared to usual care alone. This study is the first pragmatic RCT evaluating the effectiveness and cost-effectiveness of adding CBTi to usual care for depression., Trial Registration: Netherlands Trial Register (NL8955). Registered on October 6 th 2020. https://trialsearch.who.int/Trial2.aspx?TrialID=NL8955., (© 2023. The Author(s).)

Introduction: Effective non-pharmacological treatment options for depression in older adults are lacking., Objective: The effectiveness of behavioural activation (BA) by mental health nurses (MHNs) for depressed older adults in primary care compared with treatment as usual (TAU) was evaluated., Methods: In this multicentre cluster-randomised controlled trial, 59 primary care centres (PCCs) were randomised to BA and TAU. Consenting older (≥65 years) adults (n = 161) with clinically relevant symptoms of depression (PHQ-9 ≥ 10) participated. Interventions were an 8-week individual MHN-led BA programme and unrestricted TAU in which general practitioners followed national guidelines. The primary outcome was self-reported depression (QIDS-SR16) at 9 weeks and 3, 6, 9, and 12-month follow-up., Results: Data of 96 participants from 21 PCCs in BA and 65 participants from 16 PCCs in TAU, recruited between July 4, 2016, and September 21, 2020, were included in the intention-to-treat analyses. At post-treatment, BA participants reported significantly lower severity of depressive symptoms than TAU participants (QIDS-SR16 difference = -2.77, 95% CI = -4.19 to -1.35), p < 0.001; between-group effect size = 0.90; 95% CI = 0.42-1.38). This difference persisted up to the 3-month follow-up (QIDS-SR16 difference = -1.53, 95% CI = -2.81 to -0.26, p = 0.02; between-group effect size = 0.50; 95% CI = 0.07-0.92) but not up to the 12-month follow-up [QIDS-SR16 difference = -0.89 (-2.49 to 0.71)], p = 0.28; between-group effect size = 0.29 (95% CI = -0.82 to 0.24)., Conclusions: BA led to a greater symptom reduction of depressive symptoms in older adults, compared to TAU in primary care, at post-treatment and 3-month follow-up, but not at 6- to 12-month follow-up., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

The statistical quality of trial-based economic evaluations is often suboptimal, while a comprehensive overview of available statistical methods is lacking. Therefore, this review summarized and critically appraised available statistical methods for trial-based economic evaluations. A literature search was performed to identify studies on statistical methods for dealing with baseline imbalances, skewed costs and/or effects, correlated costs and effects, clustered data, longitudinal data, missing data and censoring in trial-based economic evaluations. Data was extracted on the statistical methods described, their advantages, disadvantages, relative performance and recommendations of the study. Sixty-eight studies were included. Of them, 27 (40%) assessed methods for baseline imbalances, 39 (57%) assessed methods for skewed costs and/or effects, 27 (40%) assessed methods for correlated costs and effects, 18 (26%) assessed methods for clustered data, 7 (10%) assessed methods for longitudinal data, 26 (38%) assessed methods for missing data and 10 (15%) assessed methods for censoring. All identified methods were narratively described. This review provides a comprehensive overview of available statistical methods for dealing with the most common statistical complexities in trial-based economic evaluations. Herewith, it can provide valuable input for researchers when deciding which statistical methods to use in a trial-based economic evaluation., (© 2022 The Authors. Health Economics published by John Wiley & Sons Ltd.)

Objectives: C-reactive protein point-of-care testing (CRP POCT) is a promising diagnostic tool to guide antibiotic prescribing for lower respiratory tract infections (LRTI) in nursing home residents. This study aimed to evaluate cost-effectiveness and return-on-investment (ROI) of CRP POCT compared with usual care for nursing home residents with suspected LRTI from a healthcare perspective., Design: Economic evaluation alongside a cluster randomised, controlled trial., Setting: 11 Dutch nursing homes., Participants: 241 nursing home residents with a newly suspected LRTI., Intervention: Nursing home access to CRP POCT (POCT-guided care) was compared with usual care without CRP POCT (usual care)., Main Outcome Measures: The primary outcome measure for the cost-effectiveness analysis was antibiotic prescribing at initial consultation, and the secondary outcome was full recovery at 3 weeks. ROI analyses included intervention costs, and benefits related to antibiotic prescribing. Three ROI metrics were calculated: Net Benefits, Benefit-Cost-Ratio and Return-On-Investment., Results: In POCT-guided care, total costs were on average €32 higher per patient, the proportion of avoided antibiotic prescribing was higher (0.47 vs 0.18; 0.30, 95% CI 0.17 to 0.42) and the proportion of fully recovered patients statistically non-significantly lower (0.86 vs 0.91; -0.05, 95% CI -0.14 to 0.05) compared with usual care. On average, an avoided antibiotic prescription was associated with an investment of €137 in POCT-guided care compared with usual care. Sensitivity analyses showed that results were relatively robust. Taking the ROI metrics together, the probability of financial return was 0.65., Conclusion: POCT-guided care effectively reduces antibiotic prescribing compared with usual care without significant effects on recovery rates, but requires an investment. Future studies should take into account potential beneficial effects of POCT-guided care on costs and health outcomes related to antibiotic resistance., Trial Registration Number: NL5054., Competing Interests: Competing interests: The authors declare: LWvB, TMB, MEA, JB and CMPMH report a grant from The Netherlands Organisation for Health Research and Development (ZonMw), for the conduct of the current study. RH receives no support from any organisation for the submitted work. MWvT reports grants from The Netherlands Organisation for Health Research and Development (ZonMw), outside the submitted work. TJMV reports grants from Abbott, Becton Dickinson, Biomerieux, European Commission; grants from European Commission, Orion, during the conduct of the study; grants from European Commission, Janssen Pharmaceuticals; and grants from ZonMw, outside the submitted work., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The growing number of people living with dementia will result in increased costs of dementia worldwide. The e-Health intervention 'Exergaming' may improve health and quality of life of people with dementia, but the cost-effectiveness is unknown. We assessed the cost-effectiveness of exergaming compared to regular activities from a societal perspective in day-care centres (DCC) for people with dementia and their informal caregivers (IC) alongside a cluster randomised controlled trial. We included 112 dyads (person with dementia and IC) from 20 psychogeriatric DCCs (11 exergaming, 9 control) across the Netherlands. Exergaming consisted of interactive cycling at least twice a week for 6 months. Measurements were conducted at baseline (T0), after 3 (T1) and 6 (T2) months. Primary outcomes were minutes of physical activity, mobility of the participants with dementia (Short Physical Performances Battery, SPPB), and Quality-Adjusted Life-Years (QALYs) of participants with dementia and ICs. ICs filled out cost diaries to measure healthcare and informal care utilisation during the study. There were no statistically significant differences in outcomes or costs between the groups at the level of participants with dementia, the ICs or the dyad. With regard to QALYs and SPPB, the probability that exergaming is cost-effective compared to control was low for all possible willingness-to-pay (WTP) thresholds. However, for physical activity at WTP thresholds of 0, 50 and 250 Euros per additional minute of physical activity, the probability of cost-effectiveness is 0.46, 0.84 and 0.87, respectively. Exergaming in DCC was not cost-effective compared to usual activities. However, considering the small sample size and the large number of missing observations, findings should be interpreted with caution. Future studies with larger samples are recommended to obtain definitive answers on the cost-effectiveness of exergaming. This trial was registered in the Netherlands Trial Register (NTR5537/NL5420)., (© 2021 The Authors. Health and Social Care in the Community published by John Wiley & Sons Ltd.)

Background: Physical activity may be both a risk and protective factor for falls and fall-related fractures. Despite its positive effects on muscle and bone health, physical activity also increases exposure to situations where falls and fractures occur. This paradox could possibly be explained by frailty status. Therefore, the aim of this study was to investigate the associations between physical activity and both falls and fractures, and to determine whether frailty modifies the association of physical activity with falls, and fractures., Methods: Data of 311 community-dwelling participants aged 75 years or older from the Longitudinal Aging Study Amsterdam, who participated in a three-year longitudinal study with five nine-monthly measurements between 2015/2016 and 2018/2019. Their mean age was 81.1 (SD 4.8) years and frailty was present in 30.9% of the participants. Physical activity in minutes per day was objectively assessed with an inertial sensor (Actigraph) for seven consecutive days. Falls and fractures were assessed every nine months using self-report during an interview over a follow-up period of three years. Frailty was determined at baseline using the frailty index. Associations were estimated using longitudinal logistic regression analyses based on generalized estimating equations., Results: No association between physical activity and falls was found (OR = 1.00, 95% CI: 0.99-1.00). Fall risk was higher in frail compared to non-frail adults (OR = 2.21, 95% CI: 1.33-3.68), but no effect modification was seen of frailty on the association between physical activity and falls. Also no relation between physical activity and fractures was found (OR = 1.00, 95% CI: 0.99-1.01). Fracture risk was higher in frail compared to non-frail adults (OR = 2.81, 95% CI: 1.02-7.75), but also no effect modification of frailty was present in the association between physical activity and fractures., Conclusions: No association between physical activity and neither falls nor fractures was found, and frailty appeared not to be an effect modifier. However, frailty was a risk factor for falls and fractures in this population of older adults. Our findings suggest that physical activity can be safely recommended in non-frail and frail populations for general health benefits, without increasing the risk of falls., (© 2022. The Author(s).)

Background: Cognitive side-effects are an important reason for the limited use of electroconvulsive therapy (ECT). Cognitive side-effects are heterogeneous and occur frequently in older persons. To date, insight into these side-effects is hampered due to inconsistencies in study designs and small sample sizes. Among all cognitive side-effects, confusion and delirious states are especially troublesome for patients, relatives and clinicians. In particular inter-ictal delirium-like states are worrisome, since they may lead to premature treatment discontinuation. Besides a need for further insight into determinants of cognitive side-effects of ECT, there is a great need for treatment options., Methods and Design: The Rivastigmine for ECT-induced Cognitive Adverse effects in Late Life depression (RECALL) study combines a multicenter, prospective cohort study on older patients with depression, treated with ECT, with an embedded randomized, placebo-controlled cross-over trial to examine the effect of rivastigmine on inter-ictal delirium. Patients are recruited in four centers across the Netherlands and Belgium. We aim to include 150 patients into the cohort study, in order to be able to subsequently include 30 patients into the trial. Patients are included in the trial when inter-ictal delirium, assessed by the Confusion Assessment method (CAM), or a drop in Mini Mental State Examination (MMSE) score of ≥4 during ECT, develops. In the cohort study, comprehensive measurements of ECT-related cognitive side-effects-and their putative determinants-are done at baseline and during the ECT-course. The primary outcome of the clinical trial is the effectiveness of rivastigmine on inter-ictal delirium-severity, assessed with a change in the Delirium Rating Scale-Revised-98. Secondary outcomes of the clinical trial are several ECT-characteristics and side-effects of rivastigmine., Discussion: This study is the first clinical trial with a focus on ECT-induced, inter-ictal delirium. The cohort provides the basis for recruitment of patients for the cross-over trial and additionally provides an excellent opportunity to unravel cognitive side-effects of ECT and identify putative determinants. This paper describes the rationale and study protocol., Clinical Trial Registration: EudraCT 2014-003385-24., (Copyright © 2022 Henstra, Feenstra, Kok, Spaans, van Exel, Dols, Oudega, Vergouwen, van der Loo, Bet, Loer, Eikelenboom, Sienaert, Lambrichts, Bouckaert, Bosmans, van der Velde, Beekman, Stek and Rhebergen.)

Purpose: To assess whether regression modeling can be used to predict EQ-5D-3L utility values from the Oswestry Disability Index (ODI) in low back pain (LBP) patients for use in cost-effectiveness analysis., Methods: EQ-5D-3L utility values of LBP patients were estimated using their ODI scores as independent variables using regression analyses, while adjusting for case-mix variables. Six different models were estimated: (1) Ordinary Least Squares (OLS) regression, with total ODI score, (2) OLS, with ODI item scores as continuous variables, (3) OLS, with ODI item scores as ordinal variables, (4) Tobit model, with total ODI score, (5) Tobit model, with ODI item scores as continuous variables, and (6) Tobit model, with ODI item scores as ordinal variables. The models' performance was assessed using explained variance (R 2 ) and root mean squared error (RMSE). The potential impact of using predicted instead of observed EQ-5D-3L utility values on cost-effectiveness outcomes was evaluated in two empirical cost-effectiveness analysis., Results: Complete individual patient data of 18,692 low back pain patients were analyzed. All models had a more or less similar R 2 (range 45-52%) and RMSE (range 0.21-0.22). The two best performing models produced similar probabilities of cost-effectiveness for a range of willingness-to-pay (WTP) values compared to those based on the observed EQ-5D-3L values. For example, the difference in probabilities ranged from 2 to 5% at a WTP of 50,000 €/QALY gained., Conclusion: Results suggest that the ODI can be validly used to predict low back pain patients' EQ-5D-3L utility values and QALYs for use in cost-effectiveness analyses., (© 2022. The Author(s).)

Background: It is estimated that between 12 to 25% of women who undergo an endometrial ablation for heavy menstrual bleeding (HMB) are dissatisfied after two years because of recurrent menstrual bleeding and/or cyclical pelvic pain, with around 15% of these women ultimately having a hysterectomy. The insertion of a levonorgestrel-releasing intrauterine system (LNG-IUS) immediately after endometrial ablation may inactivate residual untreated endometrium and/or inhibit the regeneration of endometrial tissue. Furthermore, the LNG-IUS may prevent agglutination of the uterine walls preventing intrauterine adhesion formation associated with endometrial ablation. In these ways, insertion of an LNG-IUS immediately after endometrial ablation might prevent subsequent hysterectomies because of persisting uterine bleeding and cyclical pelvic pain or pain that arises de novo. Hence, we evaluate if the combination of endometrial ablation and an LNG-IUS is superior to endometrial ablation alone in terms of reducing subsequent rates of hysterectomy at two years following the initial ablative procedure., Methods/design: We perform a multicentre randomised controlled trial in 35 hospitals in the Netherlands. Women with heavy menstrual bleeding, who opt for treatment with endometrial ablation and without contraindication for an LNG-IUS are eligible. After informed consent, participants are randomly allocated to either endometrial ablation plus LNG-IUS or endometrial ablation alone. The primary outcome is the hysterectomy rate at 24 months following endometrial ablation. Secondary outcomes include women's satisfaction, reinterventions, complications, side effects, menstrual bleeding patterns, quality of life, societal costs., Discussion: The results of this study will help clinicians inform women with HMB who opt for treatment with endometrial ablation about whether concomitant use of the LNG-IUS is beneficial for reducing the need for hysterectomy due to ongoing bleeding and/or pain symptoms. Trial registration Dutch Trial registration: NL7817. Registered 20 June 2019, https://www.trialregister.nl/trial/7817 ., (© 2022. The Author(s).)

Background: Because of the expected increase in the number of people with dementia, and the associated social and economic costs, there is an urgent need to develop effective and cost-effective care for people with dementia and their caregivers. The intervention proposed here combines two approaches to caregiver support that have shown to be effective in empowering caregivers, i.e., multiple components for caregiver support and actively engaging caregivers to involve the person with dementia in activities at home. The aim is to investigate whether the intervention is effective in improving quality of life in the caregiver and the person with dementia. A further aim will be to investigate whether this intervention can improve caregivers' feeling of competence, experience of caregiving, and mood., Methods: The study design is a pragmatic, cluster randomised controlled trial with cost-effectiveness analysis. The study participants are informal caregivers and home-living persons with dementia for whom they care, recruited in various regions in the Netherlands. The trial will compare outcomes in two groups of participants: 85 dyads who receive the intervention, and 85 dyads who receive care as usual. The intervention is a caregiver support training that is manual based and consists of 6 group sessions over 2 months. Training takes place in small groups of caregivers led by a health care professional presented at dementia day care centres. Randomisation occurs at the level of the day care centre. Participants are assessed on the outcome measures at baseline, prior to the intervention, and at 3 and 6 months after baseline., Discussion: The study will provide insight into effectiveness and cost-effectiveness of an intervention that has not previously been evaluated or implemented in the Netherlands. The intervention potentially adds to the effective support options for informal caregivers of people with dementia without greatly increasing the workload for health- or social care professionals., Trial Registration: The trial is registered at the Dutch Trial Register at NTR6643 ; August 22 nd , 2017., (© 2022. The Author(s).)

Routine third trimester ultrasonography is increasingly used to screen for fetal growth restriction. However, evidence regarding its cost-effectiveness is lacking. We aimed to evaluate the cost-effectiveness of routine third trimester ultrasonography to reduce adverse perinatal outcomes compared to usual care (selective ultrasonography). An economic evaluation alongside a stepped-wedge cluster-randomized trial was conducted. Via 60 midwifery practices 12,974 Dutch women aged ≥16 years with low-risk pregnancies were enrolled at 22.8 (SD = 2.4) weeks' gestation. All practices provided usual care. At 3, 7, and 10 months a third of the practices were randomized to the intervention strategy providing routine ultrasonography at 28-30 and 34-36 weeks' gestation and usual care. The primary clinical outcome was a dichotomous composite measure of 12 severe adverse perinatal outcomes (SAPO) up to one week postpartum. Information on perinatal care and societal costs was derived from Netherlands Perinatal Registry, hospital records and a survey. Cost-effectiveness analyses revealed no significant differences in SAPO and healthcare and societal costs between the intervention strategy ( n = 7026) and usual care ( n = 5948). Cost-effectiveness acceptability curves showed that the probability of cost-effectiveness was never higher than 0.6 for all possible ceiling ratios. Adding routine third trimester ultrasonography to usual care is not cost-effective in reducing SAPO.

Study Objectives: Clinical guidelines recommend cognitive-behavioral therapy for insomnia (CBT-I) as first-line treatment. However, provision of CBT-I is limited due to insufficient time and expertise. Internet-delivered CBT-I might bridge this gap. This study aimed to estimate the cost-effectiveness of guided, internet-delivered CBT-I (i-Sleep) compared to care-as-usual for insomnia patients in general practice over 26 weeks from a societal perspective., Methods: Primary outcomes were the Insomnia Severity Index (ISI, continuous score and clinically relevant response), and Quality-Adjusted Life Years (QALYs). Societal costs were assessed at baseline, and at 8 and 26 weeks. Missing data were imputed using multiple imputation. Statistical uncertainty around cost and effect differences was estimated using bootstrapping, and presented in cost-effectiveness planes and acceptability curves., Results: The difference in societal costs between i-Sleep and care-as-usual was not statistically significant (-€318; 95% CI -1282 to 645). Cost-effectiveness analyses revealed a 95% probability of i-Sleep being cost-effective compared to care-as-usual at ceiling ratios of €450/extra point of improvement in ISI score and €7,000/additional response to treatment, respectively. Cost-utility analysis showed a 67% probability of cost-effectiveness for i-Sleep compared to care-as-usual at a ceiling ratio of 20,000 €/QALY gained., Conclusions: The internet-delivered intervention may be considered cost-effective for insomnia severity in comparison with care-as-usual from the societal perspective. However, the improvement in insomnia severity symptoms did not result in similar improvements in QALYs.

Purpose: To examine the cost effectiveness of dietary advice to increase protein intake on 6-month change in physical functioning among older adults., Methods: In this multicenter randomized controlled trial, 276 community-dwelling older adults with a habitual protein intake < 1.0 g/kg adjusted body weight (aBW)/d were randomly assigned to either Intervention 1; advice to increase protein intake to ≥ 1.2 g/kg aBW/d (PROT, n = 96), Intervention 2; similar advice and in addition advice to consume protein (en)rich(ed) foods within half an hour after usual physical activity (PROT + TIMING, n = 89), or continue the habitual diet with no advice (CON, n = 91). Primary outcome was 6-month change in 400-m walk time. Secondary outcomes were 6-month change in physical performance, leg extension strength, grip strength, body composition, self-reported mobility limitations and quality of life. We evaluated cost effectiveness from a societal perspective., Results: Compared to CON, a positive effect on walk time was observed for PROT;  - 12.4 s (95%CI,  - 21.8 to  - 2.9), and for PROT + TIMING;  - 4.9 s (95%CI,  - 14.5 to 4.7). Leg extension strength significantly increased in PROT (+ 32.6 N (95%CI, 10.6-54.5)) and PROT + TIMING (+ 24.3 N (95%CI, 0.2-48.5)) compared to CON. No significant intervention effects were observed for the other secondary outcomes. From a societal perspective, PROT was cost effective compared to CON., Conclusion: Dietary advice to increase protein intake to ≥ 1.2 g/kg aBW/d improved 400-m walk time and leg strength among older adults with a lower habitual protein intake. From a societal perspective, PROT was considered cost-effective compared to CON. These findings support the need for re-evaluating the protein RDA of 0.8 g/kg BW/d for older adults., Trial Registration: The trial has been registered at ClinicalTrials.gov (NCT03712306). Date of registration: October 2018. Registry name: The (Cost) Effectiveness of Increasing Protein Intake on Physical Functioning in Older Adults. Trial Identifier: NCT03712306., (© 2021. The Author(s).)

Objective: To evaluate the cost-effectiveness of the Cardiac Care Bridge (CCB) nurse-led transitional care program in older (≥70 years) cardiac patients compared to usual care., Methods: The intervention group (n = 153) received the CCB program consisting of case management, disease management and home-based cardiac rehabilitation in the transition from hospital to home on top of usual care and was compared with the usual care group (n = 153). Outcomes included a composite measure of first all-cause unplanned hospital readmission or mortality, Quality Adjusted Life Years (QALYs) and societal costs within six months follow-up. Missing data were imputed using multiple imputation. Statistical uncertainty surrounding Incremental Cost-Effectiveness Ratios (ICERs) was estimated by using bootstrapped seemingly unrelated regression., Results: No significant between group differences in the composite outcome of readmission or mortality nor in societal costs were observed. QALYs were statistically significantly lower in the intervention group, mean difference -0.03 (95% CI: -0.07; -0.02). Cost-effectiveness acceptability curves showed that the maximum probability of the intervention being cost-effective was 0.31 at a Willingness To Pay (WTP) of €0,00 and 0.14 at a WTP of €50,000 per composite outcome prevented and 0.32 and 0.21, respectively per QALY gained., Conclusion: The CCB program was on average more expensive and less effective compared to usual care, indicating that the CCB program is dominated by usual care. Therefore, the CCB program cannot be considered cost-effective compared to usual care., Competing Interests: The authors have declared that no competing interests exist.

Background: Bladder cancer imposes a significant public health burden on the European Union. There is a need for cost-effective treatment and follow-up regimens., Objective: To assess the cost-effectiveness of immediate mitomycin C (MMC) instillation within 1 d after surgery compared to delayed MMC instillation within 2 wk after surgery with further adjuvant treatment, depending on the patient's risk group., Design Setting and Participants: This economic evaluation was based on a randomized controlled trial among 2243 Dutch patients with non-muscle-invasive bladder cancer (NMIBC) patients from a health care perspective over a 3-yr time period., Outcome Measurements and Statistical Analysis: The treatment effect was measured as time to recurrence and recurrence-free survival. Missing effect data were imputed with multiple imputation. Health care utilization and related costs were estimated on the basis of treatment protocols for NMIBC patients in the Netherlands. Statistical uncertainty was estimated using bootstrapping and is graphically presented using cost-effectiveness planes and cost-effectiveness acceptability curves., Results and Limitations: Time to recurrence was significantly longer for immediate MMC instillation (27.31 mo) than for delayed MMC instillation (24.97 mo), with an adjusted mean difference of 2.21 mo (95% confidence interval [CI] 1.58-2.84). The proportion of patients with recurrence-free survival was significantly higher after immediate MMC instillation (0.65) than after delayed MMC instillation (0.56), with an adjusted mean difference of 0.08 (95% CI 0.06-0.11). Total mean health care costs per patient were significantly lower for immediate MMC instillation (€22 959) than for delayed MMC instillation (€24 624), with an adjusted mean difference of -€1350 (95% CI -€1799 to -€900). The study is limited by the retrospective estimation of costs., Conclusions: This trial-based cost-effectiveness analysis shows that from a health care perspective, immediate MMC instillation is more effective and less expensive compared to delayed MMC instillation., Patient Summary: We assessed the cost-effectiveness of immediate bladder instillation of mitomycin C after surgery to reduce the risk of recurrence after removal of the bladder tumor as compared to delayed instillation in a large Dutch population of patients with non-muscle-invasive bladder cancer. We found that immediate instillation was more effective and less expensive than delayed instillation. We conclude that immediate mitomycin C instillation is a cost-effective treatment for non-muscle-invasive bladder cancer., (© 2021 The Author(s).)

Background: Surgery for pelvic organ prolapse (POP) is associated with high recurrence rates. The costs associated with the treatment of recurrent POP are huge, and the burden from women who encounter recurrent POP, negatively impacts their quality of life. Estrogen therapy might improve surgical outcome for POP due to its potential beneficial effects. It is thought that vaginal estrogen therapy improves healing and long-term maintenance of connective tissue integrity. Hence, this study aims to evaluate the cost-effectiveness of perioperative vaginal estrogen therapy in postmenopausal women undergoing POP surgery., Methods: The EVA trial is a multi-center double-blind randomized placebo-controlled trial conducted in the Netherlands comparing the effectiveness and costs-effectiveness of vaginal estrogen therapy. This will be studied in 300 postmenopausal women undergoing primary POP surgery, with a POP-Q stage of ≥ 2. After randomization, participants administer vaginal estrogen cream or placebo cream from 4 to 6 weeks preoperative until 12 months postoperative. The primary outcome is subjective improvement of POP symptoms at 1 year follow-up, measured with the Patient Global Impression of Improvement (PGI-I) scale. Secondary outcomes are POP-Q anatomy in all compartments, re-interventions, surgery related complications, general and disease specific quality of life, sexual function, signs and complaints of vaginal atrophy, vaginal pH, adverse events, costs, and adherence to treatment. Follow up is scheduled at 6 weeks, 6 months and 12 months postoperative. Data will be collected using validated questionnaires and out-patient visits including gynecological examination performed by an independent gynecologist., Discussion: This study investigates whether perioperative vaginal estrogen will be cost-effective in the surgical treatment of POP in postmenopausal women. It is hypothesized that estrogen therapy will show a reduction in recurrent POP symptoms and a reduction in reoperations for POP, with subsequent improved quality of life among women and cost savings. Trial registrationNetherlands Trial Registry: NL6853; registered 19-02-2018, https://www.trialregister.nl/trial/6853 . EudraCT: 2017-003144-21; registered: 24-07-2017., (© 2021. The Author(s).)

Background: As resources for healthcare are scarce, decision-makers increasingly rely on economic evaluations when making reimbursement decisions about new health technologies, such as drugs, procedures, devices, and equipment. Economic evaluations compare the costs and effects of two or more interventions. Musculoskeletal disorders have a high prevalence and result in high levels of disability and high costs worldwide. Because physical therapy interventions are usually the first line of treatment for musculoskeletal disorders, economic evaluations of such interventions are becoming increasingly important for stakeholders in the field of physical therapy, including physical therapists, decision-makers, and reseachers. However, economic evaluations are relatively difficult to interpret for the majority of stakeholders., Objective: To support physical therapists, decision-makers, and researchers in the field of physical therapy interpreting trial-based economic evaluations and translating the results of such studies to clinical practice., Methods: The design, analysis, and interpretation of economic evaluations performed alongside randomized controlled trials are discussed. To further illustrate and explain these concepts, we use a case study assessing the cost-effectiveness of exercise therapy compared to standard advice in patients with musculoskeletal disorders., Conclusions: Economic evaluations are increasingly being used in healthcare decision-making. Therefore, it is of utmost importance that their design, conduct, and analysis are state-of-the-art and that their interpretation is adequate. This masterclass will help physical therapists, decision-makers, and researchers in the field of physical therapy to critically appraise the quality and results of trial-based economic evaluations and to apply the results of such studies to their own clinical practice and setting., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2021 Associação Brasileira de Pesquisa e Pós-Graduação em Fisioterapia. Publicado por Elsevier España, S.L.U. All rights reserved.)

Abstract: Nonpharmacological interventions are recommended for the treatment of fibromyalgia, but there is a lack of knowledge about the cost-effectiveness of these interventions. The aim of this study was to systematically review economic evaluations of educational, physical, and psychological interventions for the treatment of fibromyalgia. The search was performed in PUBMED, EMBASE, CINAHL, Cochrane Library, Physiotherapy Evidence Database, PsycINFO, EconLit, National Health Service Economic Evaluation Database, and Health Technology Assessment. Economic evaluations of educational, physical, and psychological interventions for adult patients with fibromyalgia were included. Primary outcomes were healthcare and societal costs, and quality-adjusted life-years, and secondary outcomes were any disease-specific clinical outcome. Costs and effects were pooled in a meta-analysis, when possible. Eleven studies were included, of which 7 compared a psychological intervention with another intervention or usual care/control. Over a 6-month time horizon, healthcare and societal costs of the psychological intervention were significantly lower than usual care (mean difference: $-2087, 95% confidence interval [CI]: -3061 to -1112; mean difference: $-2411, 95% CI: -3582 to -1240, respectively), and healthcare costs were significantly lower for the psychological intervention compared with a pharmacological intervention (mean difference: $-1443, 95% CI: -2165 to -721). Over a 12-month time horizon, healthcare costs for the psychological intervention were significantly lower than for usual care (mean difference: $-538, 95% CI: -917 to -158). Incremental cost-effectiveness ratios for quality-adjusted life-years and impact of fibromyalgia showed that the psychological intervention was cost-effective compared with other interventions and control conditions. There is a need of more economic evaluations conducted alongside randomized controlled trials with interventions recommended for the treatment of fibromyalgia, such as physical exercise., (Copyright © 2021 International Association for the Study of Pain.)

Background: Patients with diabetes mellitus type 2 (DM2) and/or coronary heart disease (CHD) are at high risk to develop major depression. Preventing incident major depression may be an important tool in reducing the personal and societal burden of depression. The aim of the current study was to assess the cost-effectiveness of a stepped care program to prevent major depression (Step-Dep) in diabetes mellitus type 2 and/or coronary heart disease patients with subthreshold depression in comparison with usual care., Methods: An economic evaluation with 12 months follow-up was conducted alongside a pragmatic cluster-randomized controlled trial from a societal perspective. Participants received care as usual (n = 140) or Step-Dep (n = 96) which consisted of four sequential treatment steps: watchful waiting, guided self-help, problem solving treatment and referral to a general practitioner. Primary outcomes were quality-adjusted life years (QALYs) and cumulative incidence of major depression. Costs were measured every 3 months. Missing data was imputed using multiple imputation. Uncertainty around cost-effectiveness outcomes was estimated using bootstrapping and presented in cost-effectiveness planes and acceptability curves., Results: There were no significant differences in QALYs or depression incidence between treatment groups. Secondary care costs (mean difference €1644, 95% CI €344; €3370) and informal care costs (mean difference €1930, 95% CI €528; €4089) were significantly higher in the Step-Dep group than in the usual care group. The difference in total societal costs (€1001, 95% CI €-3975; €6409) was not statistically significant. The probability of the Step-Dep intervention being cost-effective was low, with a maximum of 0.41 at a ceiling ratio of €30,000 per QALY gained and 0.32 at a ceiling ratio of €0 per prevented case of major depression., Conclusions: The Step-Dep intervention is not cost-effective compared to usual care in a population of patients with DM2/CHD and subthreshold depression. Therefore, widespread implementation cannot be recommended., Trial Registration: The trial was registered in the Netherlands Trial Register ( NTR3715 )., (© 2021. The Author(s).)

Objective: To evaluate the cost-effectiveness of double-layer compared with single-layer uterine closure after a first caesarean section (CS) from a societal and healthcare perspective., Design: Economic evaluation alongside a multicentre, double-blind, randomised controlled trial., Setting: 32 hospitals in the Netherlands, 2016-2018., Participants: 2292 women ≥18 years undergoing a first CS were randomly assigned (1:1). Exclusion criteria were: inability for counselling, previous uterine surgery, known menstrual disorder, placenta increta or percreta, pregnant with three or more fetuses. 1144 women were assigned to single-layer and 1148 to double-layer closure. We included 1620 women with a menstrual cycle in the main analysis., Interventions: Single-layer unlocked uterine closure and double-layer unlocked uterine closure with the second layer imbricating the first., Main Outcome Measures: Spotting days, quality-adjusted life-years (QALYs), and societal costs at 9 months of follow-up. Missing data were imputed using multiple imputation., Results: No significant differences were found between single-layer versus double-layer closure in mean spotting days (1.44 and 1.39 days; mean difference (md) -0.056, 95% CI -0.374 to 0.263), QALYs (0.663 and 0.658; md -0.005, 95% CI -0.015 to 0.005), total healthcare costs (€744 and €727; md €-17, 95% CI -273 to 143), and total societal costs (€5689 and €5927; md €238, 95% CI -624 to 1108). The probability of the intervention being cost-effective at willingness-to-pay of €0, €10 000 and €20 000/QALY gained was 0.30, 0.27 and 0.25, respectively, (societal perspective), and 0.55, 0.41 and 0.32, respectively, (healthcare perspective)., Conclusion: Double-layer uterine closure is not cost-effective compared with single-layer uterine closure from both perspectives. If this is confirmed by our long-term reproductive follow-up, we suggest to adjust uterine closure technique guidelines., Trial Registration Number: NTR5480/NL5380., Competing Interests: Competing interests: JH received grants from ZonMw, during the conduct of the study; and reports grants from Samsung, grants from PlantTec Medical, and received a fee from Olympus, all outside the submitted work. CdG received a grant from ZonMw outside the submitted work., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Background: Falls and fall-related injuries among older adults are a serious threat to the quality of life and result in high healthcare and societal costs. Despite evidence that falls can be prevented by fall prevention programmes, practical barriers may challenge the implementation of these programmes. In this study, we will investigate the effectiveness and cost-effectiveness of In Balance, a fourteen-week, low-cost group fall prevention intervention, that is widely implemented in community-dwelling older adults with an increased fall risk in the Netherlands. Moreover, we will be the first to include cost-effectiveness for this intervention. Based on previous evidence of the In Balance intervention in pre-frail older adults, we expect this intervention to be (cost-)effective after implementation-related adjustments on the target population and duration of the intervention., Methods: This study is a single-blinded, multicenter randomized controlled trial. The target sample will consist of 256 community-dwelling non-frail and pre-frail adults of 65 years or older with an increased risk of falls. The intervention group receives the In Balance intervention as it is currently widely implemented in Dutch healthcare, which includes an educational component and physical exercises. The physical exercises are based on Tai Chi principles and focus on balance and strength. The control group receives general written physical activity recommendations. Primary outcomes are the number of falls and fall-related injuries over 12 months follow-up. Secondary outcomes consist of physical performance measures, physical activity, confidence, health status, quality of life, process evaluation and societal costs. Mixed model analyses will be conducted for both primary and secondary outcomes and will be stratified for non-frail and pre-frail adults., Discussion: This trial will provide insight into the clinical and societal impact of an implemented Dutch fall prevention intervention and will have major benefits for older adults, society and health insurance companies. In addition, results of this study will inform healthcare professionals and policy makers about timely and (cost-)effective prevention of falls in older adults., Trial Registration: Netherlands Trial Register: NL9248 (registered February 13, 2021).

This study aims to benchmark mean societal costs per client in different home care models and to describe characteristics of home care models with the lowest societal costs. In this prospective longitudinal study in 6 European countries, 6-month societal costs of resource utilization of 2060 older home care clients were estimated. Three care models were identified and compared based on level of patient-centered care (PCC), availability of specialized professionals (ASP) and level of monitoring of care performance (MCP). Differences in costs between care models were analyzed using linear regression while adjusting for case mix differences. Societal costs incurred in care model 2 (low ASP; high PCC & MCP) were significantly higher than in care model 1 (high ASP, PCC & MCP, mean difference €2230 (10%)) and in care model 3 (low ASP & PCC; high MCP, mean difference €2552 (12%)). Organizations within both models with the lowest societal costs, systematically monitor their care performance. However, organizations within one model arranged their care with a low focus on patient-centered care, and employed mainly generalist care professionals, while organizations in the other model arranged their care delivery with a strong focus on patient-centered care combined with a high availability of specialized care professionals., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Background: Baseline imbalances, skewed costs, the correlation between costs and effects, and missing data are statistical challenges that are often not adequately accounted for in the analysis of cost-effectiveness data. This study aims to illustrate the impact of accounting for these statistical challenges in trial-based economic evaluations., Methods: Data from two trial-based economic evaluations, the REALISE and HypoAware studies, were used. In total, 14 full cost-effectiveness analyses were performed per study, in which the four statistical challenges in trial-based economic evaluations were taken into account step-by-step. Statistical approaches were compared in terms of the resulting cost and effect differences, ICERs, and probabilities of cost-effectiveness., Results: In the REALISE study and HypoAware study, the ICER ranged from 636,744€/QALY and 90,989€/QALY when ignoring all statistical challenges to - 7502€/QALY and 46,592€/QALY when accounting for all statistical challenges, respectively. The probabilities of the intervention being cost-effective at 0€/ QALY gained were 0.67 and 0.59 when ignoring all statistical challenges, and 0.54 and 0.27 when all of the statistical challenges were taken into account for the REALISE study and HypoAware study, respectively., Conclusions: Not accounting for baseline imbalances, skewed costs, correlated costs and effects, and missing data in trial-based economic evaluations may notably impact results. Therefore, when conducting trial-based economic evaluations, it is important to align the statistical approach with the identified statistical challenges in cost-effectiveness data. To facilitate researchers in handling statistical challenges in trial-based economic evaluations, software code is provided.

Objectives: Fibroids are the most common benign tumours found in the uterus and can cause various symptoms. In 20-50 % of the women, an intervention is required. When conservative options fail, invasive options such as hysterectomy, uterine artery embolization or myomectomy are eligible options. Ulipristal acetate (UPA) was launched as the sole available long term pharmaceutical treatment, with the potential to avoid surgery. It is suggested that UPA improves quality of life, reduces symptoms and fibroid volumes. However, UPA is an expensive medicine, is possibly associated with liver injury and has never been directly compared to surgical treatment. The aim of this trial is to compare UPA to surgical treatment on both effectiveness and cost-effectiveness. Primary outcome is the reduction in symptom severity scores (part of the Uterine Fibroid Symptom and Quality of Life questionnaire) at 24 months of follow-up compared to baseline. Secondary outcomes include quality of life, societal costs, societal participation, liver function variation, patient satisfaction and preference. Outcomes will be analysed according to intention-to-treat principle., Study Design: The MYOMEX-2 trial is an open-label, multicentre, non-inferiority randomized controlled trial. Patients are pre-menopausal women with symptomatic fibroids eligible for surgical treatment (hysterectomy, myomectomy or UAE). Fibroid symptoms may comprise (but are not limited to) heavy menstrual bleeding, bulk symptoms or pain. Patients are randomised 2:1 in a parallel group design between two treatment arms: 119 patients in the UPA group and 60 patients in the surgery group. Follow up comprises of online questionnaires, outpatient visits and phone appointments on several follow up moments, up to 24 months after surgery or start UPA., Registration Details: MYOMEX-2 trial; protocol version 4, date 22-02-2019; NTR6860; NL62638.029.18. All items from the World Health Organization Trial Registration Data Set are provided in the online supplementary file (Appendix-B)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: To assess the impact of EQ-5D country-specific value sets on cost-utility outcomes., Methods: Data from 2 randomized controlled trials on low back pain (LBP) and depression were used. 3L value sets were identified from the EuroQol Web site. A nonparametric crosswalk was employed for each tariff to obtain the likely 5L values. Differences in quality-adjusted life years (QALYs) between countries were tested using paired t tests, with United Kingdom as reference. Cost-utility outcomes were estimated for both studies and both EQ-5D versions, including differences in QALYs and cost-effectiveness acceptability curves., Results: For the 3L, QALYs ranged between 0.650 (Taiwan) and 0.892 (United States) in the LBP study and between 0.619 (Taiwan) and 0.879 (United States) in the depression study. In both studies, most country-specific QALY estimates differed statistically significantly from that of the United Kingdom. Incremental cost-effectiveness ratios ranged between &OV0556;2044/QALY (Taiwan) and &OV0556;5897/QALY (Zimbabwe) in the LBP study and between &OV0556;38,287/QALY (Singapore) and &OV0556;96,550/QALY (Japan) in the depression study. At the NICE threshold of &OV0556;23,300/QALY (≈£20,000/QALY), the intervention's probability of being cost-effective versus control ranged between 0.751 (Zimbabwe) and 0.952 (Taiwan) and between 0.230 (Canada) and 0.396 (Singapore) in the LBP study and depression study, respectively. Similar results were found for the 5L, with extensive differences in ICERs and moderate differences in the probability of cost-effectiveness., Conclusions: This study indicates that the use of different EQ-5D country-specific value sets impacts on cost-utility outcomes. Therefore, to account for the fact that health state preferences are affected by sociocultural differences, relevant country-specific value sets should be used.

This study aims to develop and validate a prediction model of societal costs during a period of 6-months in older community care-recipients across multiple European countries. Participants were older community care-recipients from 5 European countries. The outcome measure was mean 6-months total societal costs of resource utilisation (healthcare and informal care). Potential predictors included sociodemographic characteristics, functional limitations, clinical conditions, and diseases/disorders. The model was developed by performing Linear Mixed Models with a random intercept for the effect of country and validated by an internal-external validation procedure. Living alone, caregiver distress, (I)ADL impairment, required level of care support, health instability, presence of pain, behavioural problems, urinary incontinence and multimorbidity significantly predicted societal costs during 6 months. The model explained 32% of the variation within societal costs and showed good calibration in Iceland, Finland and Germany. Minor model adaptations improved model performance in The Netherland and Italy. The results can provide a valuable orientation for policymakers to better understand cost development among older community care-recipients. Despite substantial differences of countries' care systems, a validated cross-national set of key predictors could be identified., Competing Interests: Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article., (© The Author(s) 2020.)

Introduction: This study assesses the cost-effectiveness (CE) of a multidisciplinary pain rehabilitation program (treatment as usual [TAU]) with and without psychomotor therapy (PMT) for chronic pain patients., Methods: Chronic pain patients were assigned to TAU + PMT or TAU using cluster randomization. Clinical outcomes measured were health-related quality of life (HRQOL), pain-related disability, and quality-adjusted life years (QALYs). Costs were measured from a societal perspective. Multiple imputation was used for missing data. Uncertainty surrounding incremental CE ratios was estimated using bootstrapping and presented in CE planes and CE acceptability curves., Results: Ninety-four chronic pain patients (n = 49 TAU + PMT and n = 45 TAU) were included. There were no significant differences in HRQOL, Pain Disability Index, and QALYs between TAU + PMT and TAU. Direct costs in TAU + PMT were significantly higher than in TAU (mean difference €3327, 95% confidence interval [CI] 1329; 5506). However, total societal costs in TAU + PMT were not significantly higher than in TAU (mean difference €642, 95% CI -3323; 4373). CE analyses showed that TAU + PMT was not cost-effective in comparison with TAU., Conclusions: Adding PMT to a multidisciplinary pain rehabilitation program is not considered cost-effective in comparison with a multidisciplinary pain rehabilitation program alone. The results of this study should be interpreted with caution because of the small sample size and high drop-out rate., Competing Interests: Conflict of interest: The authors declare that there is no conflict of interest., (Copyright © 2020, The Authors.)

Introduction: Short-term metabolic and observational studies suggest that protein intake above the recommended dietary allowance of 0.83 g/kg body weight (BW)/day may support preservation of lean body mass and physical function in old age, but evidence from randomised controlled trials is inconclusive., Methods and Analysis: The PRevention Of Malnutrition In Senior Subjects in the EU (PROMISS) trial examines the effect of personalised dietary advice aiming at increasing protein intake with or without advice regarding timing of protein intake to close proximity of usual physical activity, on change in physical functioning after 6 months among community-dwelling older adults (≥65 years) with a habitual protein intake of <1.0 g/kg adjusted (a)BW/day. Participants (n=264) will be recruited in Finland and the Netherlands, and will be randomised into three groups; two intervention groups and one control group. Intervention group 1 (n=88) receives personalised dietary advice and protein-enriched food products in order to increase their protein intake to at least 1.2 g/kg aBW/day. Intervention group 2 (n=88) receives the same advice as described for intervention group 1, and in addition advice to consume 7.5-10 g protein through protein-(en)rich(ed) foods within half an hour after performing usual physical activity. The control group (n=88) receives no intervention. All participants will be invited to attend lectures not related to health. The primary outcome is a 6-month change in physical functioning measured by change in walk time using a 400 m walk test. Secondary outcomes are: 6-month change in the Short Physical Performance Battery score, muscle strength, body composition, self-reported mobility limitations, quality of life, incidence of frailty, incidence of sarcopenia risk and incidence of malnutrition. We also investigate cost-effectiveness by change in healthcare costs., Discussion: The PROMISS trial will provide evidence whether increasing protein intake, and additionally optimising the timing of protein intake, has a positive effect on the course of physical functioning after 6 months among community-dwelling older adults with a habitual protein intake of <1.0 g/kg aBW/day., Ethics and Dissemination: The study has been approved by the Ethics Committee of the Helsinki University Central Hospital, Finland (ID of the approval: HUS/1530/2018) and The Medical Ethical Committee of the Amsterdam UMC, location VUmc, Amsterdam, the Netherlands (ID of the approval: 2018.399). All participants provided written informed consent prior to being enrolled onto the study. Results will be submitted for publication in peer-reviewed journals and will be made available to stakeholders (ie, older adults, healthcare professionals and industry)., Trial Registration Number: ClinicalTrials.gov Registry (NCT03712306)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Objective: To assess the cost-effectiveness of a brief cognitive behavioural intervention for patients with medically unexplained physical symptoms (MUPS) provided by a mental health nurse practitioner (MHNP) in primary care in comparison with usual care., Methods: We performed an economic evaluation from a societal perspective alongside a cluster randomised controlled trial with 12 months follow-up. The primary outcome was quality-adjusted life-years (QALYs). Secondary outcomes were the RAND-36 physical component summary score (PCS), somatic symptom severity (Patient Health Questionnaire (PHQ-15), and anxiety and depression symptoms (Hospital Anxiety and Depression Scale (HADS)). Missing data were imputed using multiple imputation. We used non-parametric bootstrapping to estimate statistical uncertainty. The bootstrapped cost-effect pairs were used to estimate cost-effectiveness planes and cost-effectiveness acceptability curves., Results: Mean total costs in the intervention group were significantly lower than in the usual care group (mean difference - 2300€, 95% CI -3257 to -134). The mean difference in QALYs was 0.01 (95% CI -0.01 to 0.04), in PCS 2.46 (95% CI 1.44 to 3.47), in PHQ-15 -0.26 (95% CI -0.81 to 0.28), and in HADS -0.07 (-0.81 to 0.67). At a willingness to pay of 0 € per additional unit of effect, the probability of the intervention being cost-effective was 0.93 for QALYs and 0.92 for PCS, PHQ-15 and HADS scores., Conclusion: Our intervention is cost-effective compared to usual care for patients with MUPS. Implementation of the intervention has the potential to result in a significant decline in costs. However, large scale implementation would require increased deployment of MHNPs., Competing Interests: Declaration of Competing Interest The authors have no competing interests to report., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to assess the performance and impact of multilevel modelling (MLM) compared with ordinary least squares (OLS) regression in trial-based economic evaluations with clustered data., Methods: Three thousand datasets with balanced and unbalanced clusters were simulated with correlation coefficients between costs and effects of - 0.5, 0, and 0.5, and intraclass correlation coefficients (ICCs) varying between 0.05 and 0.30. Each scenario was analyzed using both MLM and OLS. Statistical uncertainty around MLM and OLS estimates was estimated using bootstrapping. Performance measures were estimated and compared between approaches, including bias, root mean squared error (RMSE) and coverage probability. Cost and effect differences, and their corresponding confidence intervals and standard errors, incremental cost-effectiveness ratios, incremental net-monetary benefits and cost-effectiveness acceptability curves were compared., Results: Cost-effectiveness outcomes were similar between OLS and MLM. MLM produced larger statistical uncertainty and coverage probabilities closer to nominal levels than OLS. The higher the ICC, the larger the effect on statistical uncertainty between MLM and OLS. Significant cost-effectiveness outcomes as estimated by OLS became non-significant when estimated by MLM. At all ICCs, MLM resulted in lower probabilities of cost effectiveness than OLS, and this difference became larger with increasing ICCs. Performance measures and cost-effectiveness outcomes were similar across scenarios with varying correlation coefficients between costs and effects., Conclusions: Although OLS produced similar cost-effectiveness outcomes, it substantially underestimated the amount of variation in the data compared with MLM. To prevent suboptimal conclusions and a possible waste of scarce resources, it is important to use MLM in trial-based economic evaluations when data are clustered.

Objectives: To evaluate the cost-effectiveness of stand-alone and blended internet-based vestibular rehabilitation (VR) in comparison with usual care (UC) for chronic vestibular syndromes in general practice., Design: Economic evaluation alongside a three-armed, individually randomised controlled trial., Setting: 59 Dutch general practices., Participants: 322 adults, aged 50 years and older with a chronic vestibular syndrome., Interventions: Stand-alone VR consisted of a 6-week, internet-based intervention with weekly online sessions and daily exercises. In blended VR, this intervention was supplemented with face-to-face physiotherapy support. UC group participants received usual general practice care without restrictions., Main Outcome Measures: Societal costs, quality-adjusted life years (QALYs), Vertigo Symptom Scale-Short Form (VSS-SF), clinically relevant response (≥3 points VSS-SF improvement)., Results: Mean societal costs in both the stand-alone and blended VR groups were statistically non-significantly higher than in the UC group (mean difference (MD) €504, 95% CI -1082 to 2268; and €916, 95% CI -663 to 2596). Both stand-alone and blended VR groups reported non-significantly more QALYs than the UC group (MD 0.02, 95% CI -0.00 to 0.04; and 0.01, 95% CI -0.01 to 0.03), and significantly better VSS-SF Scores (MD 3.8 points, 95% CI 1.7 to 6.0; and 3.3 points, 95% CI 1.3 to 5.2). For stand-alone VR compared with UC, the probability of cost-effectiveness was 0.95 at a willingness-to-pay ratio of €24 161/QALY, €600/point improvement in VSS-SF and €8000/clinically relevant responder in VSS-SF. For blended VR versus UC, the probability of cost-effectiveness was 0.95 at a willingness-to-pay ratio of €123 335/QALY, €900/point improvement in VSS-SF and €24 000/clinically relevant responder in VSS-SF., Conclusion: Stand-alone and blended internet-based VR non-significantly increased QALYs and significantly reduced vestibular symptoms compared with UC, while costs in both groups were non-significantly higher. Stand-alone VR has the highest probability to be cost-effective compared with UC., Trial Registration Number: The Netherlands Trial Register NTR5712., Competing Interests: Competing interests: All authors have completed the Unified Competing Interest form (available on request from the corresponding author) and declare: support from The Netherlands Organisation for Health Research and Development (ZonMw); no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: Dementia is a progressive disease that decreases quality of life of persons with dementia and is associated with high societal costs. The burden of caring for persons with dementia also decreases the quality of life of family caregivers. The objective of this study was to assess the societal cost-effectiveness of Namaste Care Family program in comparison with usual care in nursing home residents with advanced dementia., Methods: Nursing homes were randomized to either Namaste Care Family program or usual care. Outcome measures of the cluster-randomized trial in 231 residents included Quality of Life in Late-Stage Dementia (QUALID) and the Gain in Alzheimer Care Instrument (GAIN) for family caregivers over 12 months of follow-up. Health states were measured using the EQ-5D-3L questionnaire which were translated into utilities. QALYs were calculated by multiplying the amount of time a participant spent in a specific health state with the utility score associated with that health state. Healthcare utilization costs were estimated using standard unit costs, while intervention costs were estimated using a bottom-up approach. Missing cost and effect data were imputed using multiple imputation. Bootstrapped multilevel models were used after multiple imputation. Cost-effectiveness acceptability curves were estimated., Results: The Namaste Care Family program was more effective than usual care in terms of QUALID (- 0.062, 95%CI: - 0.40 to 0.28), QALY (0.0017, 95%CI: - 0.059 to 0.063) and GAIN (0.075, 95%CI: - 0.20 to 0.35). Total societal costs were lower for the Namaste Care Family program as compared to usual care (- 552 €, 95%CI: - 2920 to 1903). However, these differences were not statistically significant. The probability of cost-effectiveness at a ceiling ratio of 0 €/unit of effect extra was 0.70 for the QUALID, QALY and GAIN., Conclusions: The Namaste Care Family program is dominant over usual care and, thus, cost-effective, although statistical uncertainty was considerable., Trial Registration: Netherlands Trial Register ( http://www.trialregister.nl/trialreg/index.asp , identifier: NL5570, date of registration: 2016/03/23).

Objective: The aim of this study was to compare the effect of ulipristal acetate (UPA) and gonadotropin-releasing hormone agonists (GnRHa) before laparoscopic myomectomy on long term secondary outcomes of the MYOMEX-trial, regarding quality of life, ultrasound characteristics, hemoglobin levels 6 weeks post-operative, sexual function and menstrual bleeding control. A cost-analysis was also performed. Short-term primary and secondary outcomes are reported elsewhere., Study Design: A double-blind, randomized, controlled, non-inferiority trial in nine hospitals in the Netherlands. Participants were randomized in a 1:1 ratio (block size of four, stratified per hospital) to either UPA or GnRHa pre-treatment. Additional placebo injections containing saline, respectively daily placebo tablets were given to both groups to ensure double-blinding. Surgery was performed within a month after the last tablet. Women were followed up until six months post-surgery., Results: A total of 55 participants were randomized: 30 to the UPA- and 25 to the GnRHa-group between May 2015 and July 2017. Uterine volume at six weeks post-operative did not differ significantly between both pre-treatment groups with 170.1 cm 3 (106.8-243.5; N = 29) vs. 152.8 cm 3 (92.3-205.6; N = 23) for the UPA- and GnRHa-group respectively (p = 0.423). Hemoglobin levels six weeks post-operatively recovered back to baseline and were not significantly different between groups with 7.7 mmol/L for the UPA- vs. 8.1 mmol/L for the GnRHa-group (p = 0.157; mean difference -0.4 (CI -0.9, 0.2). Menstrual bleeding pattern, quality of life, effects on general and sexual health showed a significant improvement compared to baseline in both groups without any differences between the treatment groups. Symptom severity scores also decreased significantly at 6 week post-operatively compared to baseline, but did not differ between the treatment groups. Fibroid characteristics at baseline (e.g. mean diameter of largest fibroid) appeared not to be a confounding factor. An exploratory cost analysis showed no significant differences in absenteeism costs, total healthcare and societal costs, after adjustment for confounding factors., Conclusion: Pre-treatment prior to laparoscopic myomectomy with UPA compared to GnRHa has similar effects on bleeding pattern, menopausal symptoms, sexual functioning, symptom severity and quality of life from baseline up to six months post-operative. Due to the small sample size, these findings should be interpreted with caution. Also, no firm conclusions on costs could be made., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: To assess the cost-effectiveness and return-on-investment (ROI) of the Dynamic Work (DW) Intervention, a worksite intervention aimed at reducing sitting time among office workers., Methods: In total, 244 workers were randomized to the intervention or control group. Overall sitting time, standing time, step counts, quality-adjusted life years (QALYs), and costs were measured over 12 months. The cost-effectiveness analysis was performed from the societal perspective and the ROI analysis from the employers' perspective., Results: No significant differences in effects and societal costs were observed between groups. Presenteeism costs were significantly lower in the intervention group. The probability of the intervention being cost-effective was 0.90 at a willingness-to-pay of 20,000&OV0556;/QALY. The probability of financial savings was 0.86., Conclusion: The intervention may be considered cost-effective from the societal perspective depending on the willingness-to-pay. From the employer perspective, the intervention seems cost-beneficial.

Background: Psychological distress is highly prevalent among patients with metastatic colorectal cancer., Aims: To perform an economic evaluation of a combined screening and treatment program targeting psychological distress in patients with metastatic colorectal cancer in comparison with usual care., Design: Societal costs were collected alongside a cluster randomized controlled trial for 48 weeks. A total of 349 participants were included., Setting: Participants were recruited from oncology departments at 16 participating hospitals in the Netherlands., Methods: Outcome measures were the Hospital Anxiety and Depression Scale and quality-adjusted life-years. Missing data were imputed using multiple imputation. Uncertainty was estimated using bootstrapping. Cost-effectiveness planes and cost-effectiveness acceptability curves were estimated to show uncertainty surrounding the cost-effectiveness estimates. Sensitivity analyses were performed to check robustness of results., Results: Between treatment arms, no significant differences were found in Hospital Anxiety and Depression Scale score (mean difference: -0.058; 95% confidence interval: -0.13 to 0.011), quality-adjusted life-years (mean difference: 0.042; 95% confidence interval: -0.015 to 0.099), and societal costs (mean difference: -1152; 95% confidence interval: -5058 to 2214). Cost-effectiveness acceptability curves showed that the probability of cost-effectiveness was 0.64 and 0.74 at willingness-to-pay values of €0 and €10,000 per point improvement on the Hospital Anxiety and Depression Scale, respectively. The probability that the intervention was cost-effective compared to usual care for quality-adjusted life-years was 0.64 and 0.79 at willingness-to-pay values of €0 and €20,000 per quality-adjusted life-year, respectively., Conclusion: The intervention is dominant over usual care, primarily due to lower costs in the intervention group. However, there were no statistically significant differences in clinical effects and the uptake of the intervention was quite low. Therefore, widespread implementation cannot be recommended.

Objective: To investigate the effectiveness of spinal manipulation combined with myofascial release compared with spinal manipulation alone, in individuals with chronic non-specific low back pain (CNLBP)., Design: Randomized controlled trial with three months follow-up., Setting: Rehabilitation clinic., Participants: Seventy-two individuals (between 18 and 50 years of age; CNLBP ≥12 consecutive weeks) were enrolled and randomly allocated to one of two groups: (1) Spinal manipulation and myofascial release - SMMRG; n=36) or (2) Spinal manipulation alone (SMG; n=36)., Interventions: Combined spinal manipulation (characterized by high velocity/low amplitude thrusts) of the sacroiliac and lumbar spine and myofascial release of lumbar and sacroiliac muscles vs manipulation of the sacroiliac and lumbar spine alone, twice a week, for three weeks., Main Outcome Measures: Assessments were performed at baseline, three weeks post intervention and three months follow-up. Primary outcomes were pain intensity and disability. Secondary outcomes were quality of life, pressure pain-threshold and dynamic balance., Results: No significant differences were found between SMMRG vs SMG in pain intensity and disability post intervention and at follow-up. We found an overall significant difference between-groups for CNLBP disability (SMG-SMMRG: mean difference of 5.0; 95% confidence interval of difference 9.9; -0.1), though this effect was not clinically important and was not sustained at follow-up., Conclusions: We demonstrated that spinal manipulation combined with myofascial release was not more effective compared to spinal manipulation alone for patients with CNLBP., Clinical Trial Registration Number: NCT03113292., (Copyright © 2019 Chartered Society of Physiotherapy. Published by Elsevier Ltd. All rights reserved.)

This study compares the five-level EuroQol five-dimension questionnaire (EQ-5D-5L) crosswalks and the 5L value sets for England, the Netherlands, and Spain and explores the implication of using one or the other for the results of cost-utility analyses. Data from two randomized controlled trials in depression and diabetes were used. Utility value distributions were compared, and mean differences in utility values between the EQ-5D-5L crosswalk and the 5L value set were described by country. Quality-adjusted life years (QALYs) were calculated using the area-under-the-curve method. Incremental cost-effectiveness ratios (ICERs) were calculated, and uncertainty around ICERs was estimated using bootstrapping and graphically shown in cost-effectiveness acceptability curves. For all countries investigated, utility value distributions differed between the EQ-5D-5L crosswalk and 5L value set. In both case studies, mean utility values were lower for the EQ-5D-5L crosswalk compared with the 5L value set in England and Spain, but higher in the Netherlands. However, these differences in utility values did not translate into relevant differences across utility estimation methods in incremental QALYs and the interventions' probability of cost-effectiveness. Thus, our results suggest that EQ-5D-5L crosswalks and 5L value sets can be used interchangeably in patients affected by mild or moderate conditions. Further research is needed to establish whether these findings are generalizable to economic evaluations among severely ill patients., (© 2020 John Wiley & Sons, Ltd.)

Objective: Prolonged sitting, which is highly prevalent in office workers, has been associated with several health risks. The aim of this study was to evaluate the Dynamic Work intervention by determining its effect on total sitting time at the 8-month follow-up in comparison to the control., Methods: This two-arm pragmatic cluster randomised controlled trial included 244 office workers from 14 different departments of a large, Dutch insurance company. The Dynamic Work intervention was a real-life, worksite intervention that included environmental components (i.e. sit-stand workstations), organisational components (i.e. group sessions), and individual components (e.g. activity/sitting trackers). Outcomes were assessed at baseline, 4-month follow-up, and 8-month follow-up. The primary outcome was total sitting time per day, objectively assessed using the activPAL activity monitor at 8-month follow-up. Secondary outcomes included other total and occupational movement behaviour outcomes, health-related outcomes, and work-related outcomes. Data analyses were performed using linear and logistic mixed models., Results: Total sitting time did not differ between the intervention and control group at the 8-month follow-up. Secondary outcomes also showed no difference between the intervention and control group at either the 4-month or at 8-month follow-up, with the exception of number of occupational steps, which showed a statistically significant effect at 4-month follow-up (but not at 8-month follow-up) of 913 (95% CI = 381-1445) steps/8-h working day., Conclusions: This study evaluated the effectiveness of a real-life worksite intervention to reduce sitting time and showed little to no effect. This may be due to the relatively low intensity of the intervention, i.e. that it only involved the replacement of 25% of sitting workstations with sit-stand workstations. Future research should focus on the evaluation of more intensive real-life worksite interventions that are still feasible for implementation in daily practice. CLINICALTRIALS., Gov, Registration Number: NCT03115645., Competing Interests: Declaration of competing interests The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors declare no conflicts of interest. This work was supported by Achmea, Interne Diensten N.V. (Handelsweg 2 Zeist, The Netherlands), which also provided the study population and co-developed the Dynamic Work intervention with the research team. Achmea had no influence on or role in the study design, data collection, analyses and interpretation of the data, the writing of this paper, and the decision to submit the paper for publication., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Low Back Pain (LBP) is associated with an increase in disability-adjusted life years, and increased risk of disability retirement and greater absenteeism in Brazil. Hence, evidence on healthcare and lost productivity costs due to LBP is of utmost importance to inform decision-makers., Methods: Cost-of-illness study with top-down approach, and societal perspective. We extracted data from National databases, considering the period 2012-2016. Outpatient expenses included clinical, surgical, diagnosis, orthosis/prosthetics, and complementary actions. Inpatient care expenses included hospital and professional services, intensive care unit, and companion stay. For productivity losses, duration of work absence and associated information (work-related and non-work-related; value of the sickness absence benefit; age; gender; and economic activity) were analyzed. Lost productivity costs were calculated multiplying the absence from work (days) by the daily-benefit., Results: The societal costs amounted to US$ 2.2 billion, and productivity losses represented 79% of the costs. Total healthcare expenses were estimated to US$ 460 million. We found more than 880,000 diagnostic images. Individuals with LBP were in total 59 million days absent from work between 2012-2016. The mean lost days absent from work per person, for each year investigated was, respectively, 88; 84; 83; 87; and 100. Men were more days absent from work than women. In addition, rural workers presented greater absence from work compared to other professional activities., Conclusion: Healthcare expenses and lost productivity costs due to LBP were substantial, hence, there is a need for improvement of health services and policies to deal with this increasing burden of illness. We found an extensive use of diagnostic imaging, which is rather discouraged by clinical guidelines. We assume that men were experiencing high levels of back pain disability compared with women, as they presented greater absenteeism and higher lost productivity costs., Competing Interests: The authors have declared that no competing interests exist.

Objective: To compare success rates, associated risks and cost-effectiveness between intrauterine insemination (IUI) and in vitro fertilisation (IVF)., Design: Retrospective observational study., Setting: The UK from 2012 to 2016., Participants: Data from Human Fertilisation and Embryology Authority's freedom of information request for 2012-2016 for IVF/ICSI (intracytoplasmic sperm injection)and IUI as practiced in 319 105 IVF/ICSI and 30 669 IUI cycles. Direct-cost calculations for maternal and neonatal expenditure per live birth (LB) was constructed using the cost of multiple birth model, with inflation-adjusted Bank of England index-linked data. A second direct-cost analysis evaluating the incremental cost-effective ratio (ICER) was modelled using the 2016 national mean (baseline) IVF and IUI success rates., Outcome Measures: LB, risks from IVF and IUI, and costs to gain 1 LB., Results: This largest comprehensive analysis integrating success, risks and costs at a national level shows IUI is safer and more cost-effective than IVF treatment.IVF LB/cycle success was significantly better than IUI at 26.96% versus 11.49% (p<0.001) but the IUI success is much closer to IVF at 2.35:1, than previously considered. IVF remains a significant source of multiple gestation pregnancy (MGP) compared with IUI (RR (Relative Risk): 1.45 (1.31 to 1.60), p<0.001) as was the rate of twins (RR: 1.58, p<0.001).In 2016, IVF maternal and neonatal cost was £115 082 017 compared with £2 940 196 for IUI and this MGP-related perinatal cost is absorbed by the National Health Services. At baseline tariffs and success rates IUI was £42 558 cheaper than IVF to deliver 1LB with enhanced benefits with small improvements in IUI. Reliable levels of IVF-related MGP, OHSS (ovarian hyperstimulation syndrome), fetal reductions and terminations are revealed., Conclusion: IUI success rates are much closer to IVF than previously reported, more cost-effective in delivering 1 LB, and associated with lower risk of complications for maternal and neonatal complications. It is prudent to offer IUI before IVF nationally., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Increasing physical activity reduces the risk of chronic illness including Type 2 diabetes, cardiovascular disease and certain types of cancer. Lifestyle interventions can increase physical activity but few successfully engage men. This study aims to investigate the 5 year cost-effectiveness of EuroFIT, a program to improve physical activity tailored specifically for male football (soccer) fans compared to a no intervention comparison group., Methods: We developed a Markov cohort model in which the impact of improving physical activity on five chronic health conditions (colorectal cancer, Type 2 diabetes, coronary heart disease, stroke and depression) and mortality was modelled. We estimated costs from a societal perspective and expressed benefits as quality adjusted life years (QALYs). We obtained data from a 4-country (England, Netherlands, Portugal and Norway) pragmatic randomised controlled trial evaluating EuroFIT, epidemiological and cohort studies, and meta-analyses. We performed deterministic and probabilistic sensitivity analyses to assess the impact of uncertainty in the model's parameter values on the cost-effectiveness results. We used Monte Carlo simulations to estimate uncertainty and presented this using cost-effectiveness acceptability curves (CEACs). We tested the robustness of the base case analysis using five scenario analyses., Results: Average costs over 5 years per person receiving EuroFIT were €14,663 and per person receiving no intervention €14,598. Mean QALYs over 5 years were 4.05 per person for EuroFIT and 4.04 for no intervention. Thus, the average incremental cost per person receiving EuroFIT was €65 compared to no intervention, while the average QALY gain was 0.01. This resulted in an ICER of €5206 per QALY gained. CEACs show that the probability of EuroFIT being cost-effective compared to no intervention is 0.53, 0.56 and 0.58 at thresholds of €10,000, €22,000 and €34,000 per QALY gained, respectively. When using a time horizon of 10 years, the results suggest that EuroFIT is more effective and less expensive compared to (i.e. dominant over) no intervention with a probability of cost-effectiveness of 0.63 at a threshold of €22,000 per QALY gained., Conclusions: We conclude the EuroFIT intervention is not cost-effective compared to no intervention over a period of 5 years from a societal perspective, but is more effective and less expensive (i.e. dominant) after 10 years. We thus suggest that EuroFIT can potentially improve public health in a cost-effective manner in the long term.

Study Questions: The objective of this study is to evaluate the effectiveness and cost-effectiveness of surgical treatment of women suffering from pain due to an ovarian endometrioma when compared to treatment with medication (analgesia and/or hormones). The primary outcome is defined as successful pain reduction (-30% reduction of pain) measured by the numeric rating scale (NRS) after 6 months. Secondary outcomes include successful pain reduction after 12 and 18 months, quality of life, affective symptoms, cost-effectiveness, recurrence rate, need of adjuvant medication after surgery, ovarian reserve, adjuvant surgery and budget impact., What Is Known Already: Evidence suggests that both medication and surgical treatment of an ovarian endometrioma are effective in reducing pain and improving quality of life. However, there are no randomised studies that compare surgery to treatment with medication., Study Design Size Duration: This study will be performed in a research network of university and teaching hospitals in the Netherlands. A multicentre randomised controlled trial and parallel prospective cohort study in patients with an ovarian endometrioma, with the exclusion of patients with deep endometriosis, will be conducted. After obtaining informed consent, eligible patients will be randomly allocated to either treatment arm (medication or surgery) by using web-based block randomisation stratified per centre. A successful pain reduction is set at a 30% decrease on the NRS at 6 months after randomisation. Based on a power of 80% and an alpha of 5% and using a continuity correction, a sample size of 69 patients in each treatment arm is needed. Accounting for a drop-out rate of 25% (i.e. loss to follow up), we need to include 92 patients in each treatment arm, i.e. 184 in total. Simultaneously, a cohort study will be performed for eligible patients who are not willing to be randomised because of a distinct preference for one of the two treatment arms. We intend to include 100 women in each treatment arm to enable standardization by inverse probability weighting, which means 200 patients in total. The expected inclusion period is 24 months with a follow-up of 18 months., Participants/materials Setting Methods: Premenopausal women (age ≥ 18 years) with pain (dysmenorrhoea, pelvic pain or dyspareunia) and an ovarian endometrioma (cyst diameter ≥ 3 cm) who visit the outpatient clinic will make up the study population. Patients with signs of deep endometriosis will be excluded. The primary outcome is successful pain reduction, which is defined as a 30% decrease of pain on the NRS at 6 months after randomisation. Secondary outcomes include successful pain reduction after 12 and 18 months, quality of life and affective symptoms, cost-effectiveness (from a healthcare and societal perspective), number of participants needing additional surgery, need of adjuvant medication after surgery, ovarian reserve and recurrence rate of endometriomas. Measurements will be performed at baseline, 6 weeks and 6, 12 and 18 months after randomisation., Study Funding/competing Interests: This study is funded by ZonMw, a Dutch organization for Health Research and Development, project number 80-85200-98-91041. The Department of Reproductive Medicine of the Amsterdam UMC location VUmc has received several research and educational grants from Guerbet, Merck KGaA and Ferring not related to the submitted work. B.W.J. Mol is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for ObsEva, Merck KGaA and Guerbet. V. Mijatovic reports grants from Guerbet, grants from Merck and grants from Ferring outside the submitted work. All authors declare that they have no competing interests concerning this publication., Trial Registration Number: Dutch Trial Register (NTR 7447, http://www.trialregister.nl)., Trial Registration Date: 2 January 2019., Date of First Patient’s Enrolment: First inclusion in randomised controlled trial October 4, 2019. First inclusion in cohort May 22, 2019., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.)

Introduction : The statistical quality of many trial-based economic evaluations is poor. When conducting trial-based economic evaluations, researchers often turn to national pharmacoeconomic guidelines for guidance. Therefore, this study reviewed which recommendations are currently given by national pharmacoeconomic guidelines on the statistical analysis of trial-based economic evaluations. Areas covered : 40 national pharmacoeconomic guidelines were identified. Data were extracted on the guidelines' recommendations on how to deal with baseline imbalances, skewed costs, correlated costs and effects, clustering of data, longitudinal data, and missing data in trial-based economic evaluations. Four guidelines (10%) were found to include recommendations on how to deal with baseline imbalances, five (13%) on how to deal with skewed costs, and seven (18%) on how to deal with missing data. Recommendations were very general in nature and recommendations on dealing with correlated costs and effects, clustering of data, and longitudinal data were lacking. Expert opinion : Current national pharmacoeconomic guidelines provide little to no guidance on how to deal with the statistical challenges to trial-based economic evaluations. Since the use of suboptimal statistical methods may lead to biased results, and, therefore, possibly to a waste of scarce resources, national agencies are advised to include more statistical guidance in their pharmacoeconomic guidelines.

Introduction: Guidelines recommend cognitive behavioral therapy for insomnia (CBT-I) as the first line of treatment for insomnia in general practice, but CBT-I is rarely available. Nurse-guided Internet-delivered CBT-I might be a solution to improve access to care., Objective: We aimed to determine the effectiveness of nurse-guided Internet-delivered CBT-I (I-CBT-I) on insomnia severity experienced by patients in general practice., Methods: Nurse-guided I-CBT-I ("i-Sleep") was compared to care-as-usual (and I-CBT-I after 6 months) in 15 participating general practices among 134 patients (≥18 years old) with clinical insomnia symptoms. Assessments took place at 8, 26 and 52 weeks. Primary outcome was self-reported insomnia severity (Insomnia Severity Index) at 8 weeks. Secondary outcomes were sleep diary indices, depression and anxiety symptoms (Hospital Anxiety and Depression Scale), fatigue, daytime consequences of insomnia, sleep medication and adverse events., Results: Two thirds of the 69 intervention patients (n = 47; 68%) completed the whole intervention. At the posttest examination, there were large significant effects for insomnia severity (Cohen's d =1.66), several sleep diary variables (wake after sleep onset, number of awakenings, terminal wakefulness, sleep efficiency, sleep quality) and depression. At 26 weeks there were still significant effects on insomnia severity (d = 1.02) and on total sleep time and sleep efficiency. No significant effects were observed for anxiety, fatigue, daily functioning or sleep medication. No adverse events were reported., Conclusions: Nurse-guided I-CBT-I effectively reduces insomnia severity among general practice patients. I-CBT-I enables general practitioners to offer effective insomnia care in accordance with the clinical guidelines., (© 2020 The Author(s) Published by S. Karger AG, Basel.)

Background: Utility values can be obtained from different respondent groups, including patients and members of the general public. Evidence suggests that patient values are typically higher than general public values. This study explores whether the magnitude of disagreement between both values can be explained by socio-demographic characteristics and/or health status., Methods: Data of 5037 chronic low back pain patients were used. Self-reported EQ-VAS was employed as a proxy of patients' preference for their own health state. General public values for the patients' EQ-5D-3L health states were obtained using the Dutch VAS-based tariff. The difference between patient and general public values was assessed using a paired t-test. Subsequently, this difference was used as a dependent variable and regressed upon dummy variables of socio-demographic and health status characteristics. Coefficients represented age, gender, education level, social support, back pain intensity, leg pain intensity, functional status, comorbidities, catastrophizing, and treatment expectations., Results: Patient values were higher than general public values (0.069; 95%CI:0.063-0.076). The magnitude of disagreement between both values was associated with age, gender, education level, social support, functional status, and comorbidities, but not with back pain intensity, leg pain intensity, catastrophizing, and treatment expectations., Conclusions: Patients were found to value their own health status higher than members of the general public. The magnitude of disagreement between both values was found to differ by various socio-demographic and/or health status characteristics. This suggest that patient characteristics account for a relevant fraction of the identified disagreements between patient and general public values, and that mechanisms thought to be responsible for these disagreements, such as adaptation and response shift, have a differential impact across patient sub-groups.

Background: This study aimed to identify subgroups for whom supported self-help preventive cognitive therapy (S-PCT) is more (cost)effective than treatment as usual (TAU) in preventing relapse and recurrence of major depression., Methods: We conducted a randomized controlled trial in which 248 remitted, recurrently depressed participants were randomized to S-PCT (n = 124) or TAU (n = 124). Clinical outcome was relapse or recurrence of major depressive disorder (SCID-I). We tested the moderating effects on relapse or recurrence of age, gender, education level, residual depressive symptoms, number of previous episodes, age of onset, antidepressant medication, somatization, and self-efficacy with logistic regression analyses adjusted for baseline values of depressive symptoms. We examined moderating effects on costs using linear regression analyses adjusted for baseline costs. A stratified cost-effectiveness analysis was performed to tease out differences in cost-effectiveness between subgroups., Results: We found no moderating effect on relapse or recurrence for any of the potential moderators. For costs, the number of previous depressive episodes was identified as a moderator. At a willingness-to-pay of 16,000€, the probability that S-PCT was cost-effective compared to TAU was 95% for participants with 2-3 episodes and 11% for participants with ≥4 episodes., Limitations: Participants and counselors were not blinded. The study was primarily designed to assess the (cost)effectiveness of S-PCT and not to conduct moderation analyses., Conclusions: S-PCT was effective in preventing relapse or recurrence of depressive disorders in a broad range of participants, but is more likely to be cost-effective in participants with 2-3 episodes than ≥4 episodes. This indicates that S-PCT can best be offered to participants with fewer previous depressive episodes., (Copyright © 2019. Published by Elsevier B.V.)

Objective: Evaluate the cost-effectiveness of laparoscopic ileocaecal resection compared with infliximab in patients with ileocaecal Crohn's disease failing conventional therapy., Design: A multicentre randomised controlled trial was performed in 29 centres in The Netherlands and the UK. Adult patients with Crohn's disease of the terminal ileum who failed >3 months of conventional immunomodulators or steroids without signs of critical strictures were randomised to laparoscopic ileocaecal resection or infliximab. Outcome measures included quality-adjusted life-years (QALYs) based on the EuroQol (EQ) 5D-3L Questionnaire and the Inflammatory Bowel Disease Questionnaire (IBDQ). Costs were measured from a societal perspective. Analyses were performed according to the intention-to-treat principle. Missing cost and effect data were imputed using multiple imputation. Cost-effectiveness planes and cost-effectiveness acceptability curves were estimated to show uncertainty., Results: In total, 143 patients were randomised. Mean Crohn's disease total direct healthcare costs per patient at 1 year were lower in the resection group compared with the infliximab group (mean difference €-8931; 95% CI €-12 087 to €-5097). Total societal costs in the resection group were lower than in the infliximab group, however not statistically significant (mean difference €-5729, 95% CI €-10 606 to €172). The probability of resection being cost-effective compared with infliximab was 0.96 at a willingness to pay (WTP) of €0 per QALY gained and per point improvement in IBDQ Score. This probability increased to 0.98 at a WTP of €20 000/QALY gained and 0.99 at a WTP of €500/point of improvement in IBDQ Score., Conclusion: Laparoscopic ileocaecal resection is a cost-effective treatment option compared with infliximab., Clinical Trial Registration Number: Dutch Trial Registry NTR1150; EudraCT number 2007-005042-20 (closed on 14 October 2015)., Competing Interests: Competing interests: EJdG, TS, JEB, HvD, EJE, TJG, BM, CB, PCFS and WAB declare no conflict of interest. CYP declares a grant from Takeda, Dr Falk Pharma and Abbvie, advisory board fees from Takeda and GSK, as well as speaker’s fees from Takeda, Abbvie, Ferring, MSD and Dr. Falk Pharma. GRAMD’H has served as advisor for Abbvie, Ablynx, Amakem, AM Pharma, Avaxia, Biogen, Bristol Meiers Squibb, Boerhinger Ingelheim, Celgene, Celltrion, Cosmo, Covidien/Medtronics, Ferring, DrFalk Pharma, Engene, Galapagos, Genentech/Roche, Gilead, Glaxo Smith Kline, Hospira, Immunic, Johnson and Johnson, Lycera, Medimetrics, Millenium/Takeda, Mitsubishi Pharma, Merck Sharp Dome, Mundipharma, Novonordisk, Otsuka, Pfizer, Prometheus laboratories/Nestle, Protagonist, Receptos, Robarts Clinical Trials, Salix, Sandoz, Setpoint, Shire, Teva, Tigenix, Tillotts, Topivert, Versant and Vifor and received speaker fees from Abbvie, Biogen, Ferring, Johnson and Johnson, Merck Sharp Dome, Mundipharma, Norgine, Pfizer, Shire, Millenium/Takeda, Tillotts and Vifor. AH declares an advisory board fee from MSD., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)