Overcoming the Digital Divide for Older Patients With Respiratory Disease: Focus Group Study.

BACKGROUND: The need for and adoption of eHealth programs are growing worldwide. However, access can be limited among patients with low socioeconomic backgrounds, often resulting in a so-called "digital divide" due to a mismatch between eHealth and target populations that can gain benefit. This digital divide can result in unsuccessful eHealth implementations, which is of critical importance to health care. OBJECTIVE: This study evaluated the opinions of elderly patients with asthma and chronic obstructive pulmonary disease (COPD) about an existing pharmacy-based personalized patient web portal that provides medication overview and information on associated diagnoses. The aim was to obtain insights on the common barriers of elderly people when using health-related websites, which can help to improve accessibility. METHODS: This was a cross-sectional qualitative study of a patient panel of the Groningen Research Institute for Asthma and COPD in primary care. Participants were required to be older than 55 years, be Dutch speaking, have no prior experience with the study website, and be diagnosed with a chronic respiratory illness. Two focus groups were created, and they completed a 45-minute session for testing the website and a 120-minute session for semistructured interviews. The focus group sessions were recorded, transcribed verbatim, and analyzed by content analysis. RESULTS: We enrolled 11 patients (9 women) with a mean age of 66 (SD 9) years. Of these, 5 had asthma, 3 had COPD, 2 had asthma-COPD overlap syndrome, and 1 had bronchiectasis. Participants were generally positive about the website, especially the areas providing disease-related information and the medication overview. They appreciated that the website would enable them to share this information with other health care providers. However, some difficulties were reported with navigation, such as opening a new tab, and others reported that the layout of the website was difficult either because of visual impairments or problems with navigation. It was also felt that monitoring would only be relevant if it is also checked by health care professionals as part of a treatment plan. Participants mentioned few privacy or safety concerns. CONCLUSIONS: It is feasible to develop websites for elderly patients; however, developers must take the specific needs and limitations of elderly people into account (eg, navigation problems, poor vision, or poor hand-eye coordination). The provision of information appears to be the most important aspect of the website, and as such, we should endeavor to ensure that the layout and navigation remain basic and accessible. Patients are only motivated to use self-management applications if they are an integrated part of their treatment. The usability of the website can be improved by including older people during development and by implementing design features that can improve accessibility in this group.

Long-Term Effectiveness of an Online Self-help Intervention for People with HIV and Depressive Symptoms.

The aim of this study was to investigate the long-term effectiveness (3-4 years later) of an online intervention that was previously found to effectively reduce depressive symptoms in people with HIV on the short term. Participants were people with HIV who had participated in the large RCT on the short-term effectiveness of the guided online intervention. The primary outcome measure was depressive symptoms [Patient Health Questionnaire-9 (PHQ-9)] and the secondary outcome measure was anxiety symptoms [Generalized Anxiety Disorder-2 (GAD-2) scale]. Forty-seven participants completed the long-term follow-up. PHQ-9 scores, previously found to have been significantly reduced on the short term, remained low on the long term. GAD-2 scores did not decrease significantly on the short term, however, on the long term, a significant decrease was found. The intervention may not only be effective in lowering depressive symptoms on the short term but also retain the results on the long term.Trial registration International Clinical Trials Registry Platform, NL8448, March 3, 2020.

A Pharmacy-Based eHealth Intervention Promoting Correct Use of Medication in Patients With Asthma and COPD: Nonrandomized Pre-Post Study.

BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) affect millions of people worldwide. While medication can control and improve disease symptoms, incorrect use of medication is a common problem. The eHealth intervention SARA (Service Apothecary Respiratory Advice) aims to improve participants' correct use of inhalation medication by providing information and as-needed tailored follow-up support by a pharmacist. OBJECTIVE: The primary aim of this study was to investigate the effect of SARA on exacerbation rates in participants with asthma and COPD. Secondary aims were to investigate its effects in terms of adherence to maintenance medication and antimycotic treatment. METHODS: In this nonrandomized pre-post study, medication dispensing data from 382 Dutch community pharmacies were included. Exacerbation rates were assessed with dispensed short-course oral corticosteroids. Medication adherence between new and chronic users was assessed by calculating the proportion of days covered from dispensed inhalation maintenance medication. Antimycotic treatment was investigated from dispensed oral antimycotics in participants who were also dispensed inhaled corticosteroids (ICS). Outcomes were assessed 1 year before and 1 year after implementation of SARA and were compared between SARA participants and control participants. More specifically, for exacerbation rates and medication adherence, a difference score was calculated (ie, 1 year after SARA minus 1 year before SARA) and was subsequently compared between the study groups with independent-samples t tests. For antimycotics, the relative number of participants who were dispensed antimycotics was calculated and subsequently analyzed with a mixed-effects logistic regression. RESULTS: The study population comprised 9452 participants, of whom 2400 (25.39%) were SARA participants. The mean age of the population was 60.8 (15.0) years, and approximately two-thirds (n=5677, 60.06%) were female. The results showed an increase in mean exacerbation rates over time for both study groups (SARA: 0.05; control: 0.15). However, this increase in exacerbation rates was significantly lower for SARA participants (t9450=3.10, 95% CI 0.04-0.16; P=.002; Cohen d=0.06). Chronic users of inhalation medication in both study groups showed an increase in mean medication adherence over time (SARA: 6.73; control: 4.48); however, this increase was significantly higher for SARA participants (t5886=-2.74, 95% CI -3.86 to -0.84; P=.01; Cohen d=-0.07). Among new users of inhalation medication, results showed no significant difference in medication adherence between SARA and control participants in the year after implementation of SARA (t1434=-1.85, 95% CI -5.60 to 0.16; P=.06; Cohen d=-0.10). Among ICS users, no significant differences between the study groups were found over time in terms of the proportion of participants who were dispensed antimycotics (t5654=0.29, 95% CI -0.40 to 0.54; P=.76; Cohen d=0). CONCLUSIONS: This study provides preliminary evidence that the SARA eHealth intervention might have the potential to decrease exacerbation rates and improve medication adherence among patients with asthma and COPD.

Development and implementation of guidelines for the management of depression: a systematic review.

OBJECTIVE: To evaluate the development and implementation of clinical practice guidelines for the management of depression globally. METHODS: We conducted a systematic review of existing guidelines for the management of depression in adults with major depressive or bipolar disorder. For each identified guideline, we assessed compliance with measures of guideline development quality (such as transparency in guideline development processes and funding, multidisciplinary author group composition, systematic review of comparative efficacy research) and implementation (such as quality indicators). We compared guidelines from low- and middle-income countries with those from high-income countries. FINDINGS: We identified 82 national and 13 international clinical practice guidelines from 83 countries in 27 languages. Guideline development processes and funding sources were explicitly specified in a smaller proportion of guidelines from low- and middle-income countries (8/29; 28%) relative to high-income countries (35/58; 60%). Fewer guidelines (2/29; 7%) from low- and middle-income countries, relative to high-income countries (22/58; 38%), were authored by a multidisciplinary development group. A systematic review of comparative effectiveness was conducted in 31% (9/29) of low- and middle-income country guidelines versus 71% (41/58) of high-income country guidelines. Only 10% (3/29) of low- and middle-income country and 19% (11/58) of high-income country guidelines described plans to assess quality indicators or recommendation adherence. CONCLUSION: Globally, guideline implementation is inadequately planned, reported and measured. Narrowing disparities in the development and implementation of guidelines in low- and middle-income countries is a priority. Future guidelines should present strategies to implement recommendations and measure feasibility, cost-effectiveness and impact on health outcomes.

SERIES: eHealth in primary care. Part 4: Addressing the challenges of implementation.

BACKGROUND: The implementation of eHealth applications in primary care remains challenging. Enhancing knowledge and awareness of implementation determinants is critical to build evidence-based implementation strategies and optimise uptake and sustainability. OBJECTIVES: We consider how evidence-based implementation strategies can be built to support eHealth implementation. DISCUSSION: What implementation strategies to consider depends on (potential) barriers and facilitators to eHealth implementation in a given situation. Therefore, we first discuss key barriers and facilitators following the five domains of the Consolidated Framework for Implementation Research (CFIR). Cost is identified as a critical barrier to eHealth implementation. Privacy, security problems, and a lack of recognised standards for eHealth applications also hinder implementation. Engagement of key stakeholders in the implementation process, planning the implementation of the intervention, and the availability of training and support are important facilitators. To support care professionals and researchers, we provide a stepwise approach to develop and apply evidence-based implementation strategies for eHealth in primary care. It includes the following steps: (1) specify the eHealth application, (2) define problem, (3) specify desired implementation behaviour, and (4) choose and (5) evaluate the implementation strategy. To improve the fit of the implementation strategy with the setting, the stepwise approach considers the phase of the implementation process and the specific context. CONCLUSION: Applying an approach, as provided here, may help to improve the implementation of eHealth applications in primary care.

SERIES: eHealth in primary care. Part 3: eHealth education in primary care.

BACKGROUND: Education is essential to the integration of eHealth into primary care, but eHealth is not yet embedded in medical education. OBJECTIVES: In this opinion article, we aim to support organisers of Continuing Professional Development (CPD) and teachers delivering medical vocational training by providing recommendations for eHealth education. First, we describe what is required to help primary care professionals and trainees learn about eHealth. Second, we elaborate on how eHealth education might be provided. DISCUSSION: We consider four essential topics. First, an understanding of existing evidence-based eHealth applications and conditions for successful development and implementation. Second, required digital competencies of providers and patients. Third, how eHealth changes patient-provider and provider-provider relationships and finally, understanding the handling of digital data. Educational activities to address these topics include eLearning, blended learning, courses, simulation exercises, real-life practice, supervision and reflection, role modelling and community of practice learning. More specifically, a CanMEDS framework aimed at defining curriculum learning goals can support eHealth education by describing roles and required competencies. Alternatively, Kern's conceptual model can be used to design eHealth training programmes that match the educational needs of the stakeholders using eHealth. CONCLUSION: Vocational and CPD training in General Practice needs to build on eHealth capabilities now. We strongly advise the incorporation of eHealth education into vocational training and CPD activities, rather than providing it as a separate single module. How learning goals and activities take shape and how competencies are evaluated clearly requires further practice, evaluation and study.

SERIES: eHealth in primary care. Part 2: Exploring the ethical implications of its application in primary care practice.

Background: eHealth promises to increase self-management and personalised medicine and improve cost-effectiveness in primary care. Paired with these promises are ethical implications, as eHealth will affect patients' and primary care professionals' (PCPs) experiences, values, norms, and relationships.Objectives: We argue what ethical implications related to the impact of eHealth on four vital aspects of primary care could (and should) be anticipated.Discussion: (1) EHealth influences dealing with predictive and diagnostic uncertainty. Machine-learning based clinical decision support systems offer (seemingly) objective, quantified, and personalised outcomes. However, they also introduce new loci of uncertainty and subjectivity. The decision-making process becomes opaque, and algorithms can be invalid, biased, or even discriminatory. This has implications for professional responsibilities and judgments, justice, autonomy, and trust. (2) EHealth affects the roles and responsibilities of patients because it can stimulate self-management and autonomy. However, autonomy can also be compromised, e.g. in cases of persuasive technologies and eHealth can increase existing health disparities. (3) The delegation of tasks to a network of technologies and stakeholders requires attention for responsibility gaps and new responsibilities. (4) The triangulate relationship: patient-eHealth-PCP requires a reconsideration of the role of human interaction and 'humanness' in primary care as well as of shaping Shared Decision Making.Conclusion: Our analysis is an essential first step towards setting up a dedicated ethics research agenda that should be examined in parallel to the development and implementation of eHealth. The ultimate goal is to inspire the development of practice-specific ethical recommendations.

Psychosocial interventions enhance HIV medication adherence: A systematic review and meta-analysis.

About 40 per cent of people living with HIV do not sufficiently adhere to their medication regimen, which adversely affects their health. The current meta-analysis investigated the effect of psychosocial interventions on medication adherence in people living with HIV. Databases were systematically searched, resulting in 43 included randomized controlled trials. Study and intervention characteristics were investigated as moderators. The overall effect size indicates a small to moderate positive effect (Hedges' g = 0.37) of psychosocial interventions on medication adherence in people living with HIV. No evidence for publication bias was found. This meta-analysis study concludes that various psychosocial interventions can improve medication adherence and thereby the health of people living with HIV.

Moderators of the effect of guided online self-help for people with HIV and depressive symptoms.

The goal of the study was to investigate moderators of intervention effect of a guided Internet-based self-help cognitive behavioral intervention for people with HIV and depressive symptoms. This study was part of a randomized controlled trial where the intervention was found to be effective in reducing depressive symptoms, compared to an attention-only control group. Demographic characteristics (e.g., age), HIV characteristics (e.g., duration of HIV), and psychological characteristics (e.g., coping self-efficacy) were investigated as potential moderators of intervention effect. In 2015, 188 people with HIV and depressive symptoms were included in the study: 97 were randomized to the intervention group and 91 to the control group. Two moderators of intervention effect were found: coping self-efficacy and baseline depression severity. Participants with low coping self-efficacy and baseline depression severity improved more in the intervention group than in the control group, and participants with high coping self-efficacy and baseline depression severity improved in both groups. The results indicate that the intervention may be provided to all people with HIV and depressive symptoms. It may be especially important for people with HIV and low coping self-efficacy to start with the intervention since they show less improvement in the control group with only attention. Trial registration: Nederlands Trialregister NTR5407, September 11, 2015.

SERIES: eHealth in primary care. Part 1: Concepts, conditions and challenges.

Primary care is challenged to provide high quality, accessible and affordable care for an increasingly ageing, complex, and multimorbid population. To counter these challenges, primary care professionals need to take up new and innovative practices, including eHealth. eHealth applications hold the promise to overcome some difficulties encountered in the care of people with complex medical and social needs in primary care. However, many unanswered questions regarding (cost) effectiveness, integration with healthcare, and acceptability to patients, caregivers, and professionals remain to be elucidated. What conditions need to be met? What challenges need to be overcome? What downsides must be dealt with? This first paper in a series on eHealth in primary care introduces basic concepts and examines opportunities for the uptake of eHealth in primary care. We illustrate that although the potential of eHealth in primary care is high, several conditions need to be met to ensure that safe and high-quality eHealth is developed for and implemented in primary care. eHealth research needs to be optimized; ensuring evidence-based eHealth is available. Blended care, i.e. combining face-to-face care with remote options, personalized to the individual patient should be considered. Stakeholders need to be involved in the development and implementation of eHealth via co-creation processes, and design should be mindful of vulnerable groups and eHealth illiteracy. Furthermore, a global perspective on eHealth should be adopted, and eHealth ethics, patients' safety and privacy considered.

eHealth for people with COPD in the Netherlands: a scoping review.

Background: In the Netherlands, almost 600,000 people had chronic obstructive pulmonary disease (COPD) in 2017. This decreases quality of life for many and each year, COPD leads to approximately 6,800 deaths and about one billion health care expenditures. It is expected that eHealth may improve access to care and reduce costs. However, there is no conclusive scientific evidence available of the added value of eHealth in COPD care. We conducted a scoping review into the use of eHealth in Dutch COPD care. The aim of the research was to provide an overview of all eHealth applications used in Dutch COPD care and to assess these applications on a number of relevant criteria. Methods: In order to make an overview of all eHealth applications aimed at COPD patients in the Netherlands, literature was searched in the electronic databases PubMed and Google Scholar. In addition, Dutch health care websites were searched for applications that have been evaluated for effectiveness and reliability. The identified eHealth applications were assessed according to five relevant quality criteria, eg, whether research has been conducted on the effectiveness. Results: Thirteen health care programs and patient platforms in COPD care have been found that use eHealth. In addition, 13 self-care and informative websites and 15 mobile apps were found that are available to citizens and patients. Five of 13 care programs and patient platforms were found to be effective in improving quality of life or reducing hospital admissions in small pilot studies. The effectiveness of these and the other eHealth applications should be established in larger studies in the future. Discussion: More research into the effectiveness of eHealth applications for COPD patients is needed. We recommend to develop a nationwide open source platform where well-evaluated eHealth applications can be showcased for patients and health care providers to improve COPD care.

Exploring Mediators of a Guided Web-Based Self-Help Intervention for People With HIV and Depressive Symptoms: Randomized Controlled Trial.

BACKGROUND: Cognitive behavioral therapy (CBT) is frequently used to treat depressive symptoms in people living with HIV. We developed an internet-based cognitive behavioral intervention for people with HIV and depressive symptoms, which was based on an effective self-help booklet. The Web-based intervention was previously found to be effective. OBJECTIVE: The objective of this study was to investigate potential mediators of the Web-based intervention. METHODS: This study was part of a randomized controlled trial, in which the intervention was compared with an attention-only waiting list control condition. Participants were 188 (97 in intervention group and 91 in control group) people with HIV and mild to moderate depressive symptoms recruited in HIV treatment centers in the Netherlands. A total of 22 participants (22/188, 11.7%) in the study were female and 166 (166/188, 88.3%) were male. The average age of the participants was 46.30 years (SD 10.63). The intervention comprised Web-based self-help CBT for 8 weeks, 1 to 2 hours a week, including minimal telephone support from a coach. The participants received Web-based questionnaires at pretest, 3 times during the intervention/or waiting period, and post intervention. The outcome was depressive symptoms. Factors tested as potential mediators were changes in behavioral activation, relaxation, the cognitive coping strategies catastrophizing and positive refocusing, goal re-engagement, and coping self-efficacy. RESULTS: Using multilevel structural equation modeling, changes in behavioral activation (P=.006) and goal re-engagement (P=.009) were found to be significant mediators of the intervention effect. The mediation effect seemed to occur between weeks 3 and 5 for behavioral activation and weeks 1 and 3 for goal re-engagement. Using (bivariate) autoregressive latent trajectory analysis, we found a return effect (from the dependent variable to the mediator) for goal re-engagement but not for behavioral activation, which suggested that the mediation effect of changes in behavioral activation was stronger than that in goal re-engagement. CONCLUSIONS: The results suggest that changes in behavioral activation and goal re-engagement may mediate the effect of the Web-based intervention for people with HIV and depressive symptoms. The results may lead to possible mechanisms of change of the intervention and improvement of therapy outcomes. TRIAL REGISTRATION: Netherlands Trial Register NTR5407; https://www.trialregister.nl/trial/5298.

Cost-utility of a guided Internet-based intervention in comparison with attention only for people with HIV and depressive symptoms: A randomized controlled trial.

OBJECTIVE: The aim of this study was to evaluate the cost-utility of a guided Internet-based intervention for people living with HIV and depressive symptoms, compared to attention only (control condition). It was previously found that the intervention was effective in decreasing depressive symptoms, compared to the control group. METHODS: This economic evaluation was conducted alongside a randomized controlled trial. The control group received attention only and was put on a waiting list. Quality adjusted life years were calculated over six months. The study was conducted from a societal perspective and included intervention costs, healthcare costs, and non-healthcare costs. Participants completed a pretest, a post-test after two to three months, and a second post-test after six months. Cost-utility acceptability curves were constructed and two sensitivity analyses were conducted. RESULTS: No differences between the intervention and the control group were found in quality adjusted life years and total societal costs. The results indicate that the intervention is likely to be cost-effective, compared to attention only. The findings of the sensitivity analyses point in the same direction. CONCLUSION: More research with larger samples is necessary to confirm the findings. The outcomes of this study may inform policy makers to decide which interventions will be included in policies. The guided Internet intervention may improve psychological care for people living with HIV and depressive symptoms, against low costs. TRIAL REGISTRATION: Nederlands Trialregister NTR5407, September 11, 2015.

Guided internet-based intervention for people with HIV and depressive symptoms: a randomised controlled trial in the Netherlands.

BACKGROUND: Many people living with HIV have depressive symptoms, but some individuals do not receive adequate treatment. We developed an online self-help intervention for people with HIV with depressive symptoms on the basis of previous research. The aim of this study was to investigate the effectiveness of the intervention on depressive symptoms in individuals with HIV. METHODS: In this randomised controlled trial, participants recruited from 23 HIV treatment centres in the Netherlands were eligible if they were aged 18 years and older, had been diagnosed with HIV at least 6 months before the study, and had mild to moderate depressive symptoms (Patient Health Questionnaire-9 [PHQ-9] score >4 and <20). Individuals also had to speak English or Dutch and have internet access and an email address. Participants were randomly assigned (1:1) to an internet-based intervention (Living positive with HIV) or an attention-only waiting-list control condition. Randomisation was done using random number tables, with permuted blocks of 12, stratified by treatment centre and sex. Participants, researchers, and coaches were not masked to group allocation. The primary outcome was depressive symptoms assessed with the PHQ-9 and the Center for Epidemiologic Studies Depression Scale (CES-D) at pretest, 8 weeks after baseline, and 3 months after completion of the intervention or control condition (post-test 2). The primary analysis was done by intention to treat. Between group effect size was assessed with Cohen's d. This trial is registered with the Netherlands Trial Registry, number NTR5407. FINDINGS: Between Feb 1, and Dec 31, 2015, we randomly assigned 188 participants to the intervention group (n=97) or the control group (n=91). Mean pretest PHQ-9 score was 11·74 (SD 2·49) in the intervention group and 11·11 (2·37) in the control group; at the post-test visits it was 6·73 (3·00) and 6·62 (3·03) in the intervention group and 8·60 (3·12) and 8·06 (3·17) in the control group. Mean pretest CES-D score was 24·91 (5·93) in the intervention group and 22·94 (6·48) in the control group; at the post-test visits it was 13·94 (6·39) and 15·71 (6·39) in the intervention group and 19·09 (7·05) and 18·43 (7·05) in the control group. The reduction in depressive symptoms was significantly larger in the intervention group than in the control group (d=-0·56 [95% CI -0·85 to -0·27] for PHQ-9 and -0·72 [-1·02 to -0·42] for CES-D at post-test 1; -0·46 [-0·75 to -0·17] for PHQ-9 and -0·47 [-0·76 to -0·18] for CES-D at post-test 2). No adverse events were reported. INTERPRETATION: This guided internet-based intervention might be effective for the treatment of depressive symptoms. Future research should focus on the effectiveness of online psychological interventions for people with HIV who have mental health problems in low-income and middle-income countries. FUNDING: Aids Fonds.

The Benefits of Psychosocial Interventions for Mental Health in People Living with HIV: A Systematic Review and Meta-analysis.

In this systematic review and meta-analysis we investigated the effectiveness of different psychosocial treatments for people living with HIV (PLWH) and mental health problems. Additionally, characteristics that may influence the effectiveness of a treatment (e.g., treatment duration) were studied. PubMed, PsycINFO and Embase were searched for randomized controlled trials on psychosocial interventions for PLWH. Depression, anxiety, quality of life, and psychological well-being were investigated as treatment outcome measures. Sixty-two studies were included in the meta-analysis. It was found that psychosocial interventions for PLWH had a small positive effect on mental health (g = 0.19, 95% CI [0.13, 0.25]). Furthermore, there was evidence for publication bias. Six characteristics influenced the effectiveness of a treatment for depression. For example, larger effects were found for studies with psychologists as treatment providers. To conclude, this systematic review and meta-analysis suggests that psychosocial interventions have a beneficial effect for PLWH with mental health problems.

An Internet-based self-help intervention for people with HIV and depressive symptoms: study protocol for a randomized controlled trial.

BACKGROUND: Many people living with HIV suffer from depressive symptoms. In a previous pilot study, self-help cognitive behavioral therapy (in booklet format) was found to be effective in treating depressive symptoms in people with HIV. We developed an online self-help program in Dutch and English (based on the booklet) for people with HIV and depressive symptoms. Besides the main question regarding the effectiveness of the program aimed at lowering depressive symptoms, sub-questions will focus on the moderators of treatment success (for which patients is the program especially beneficial?) and the mechanisms of change underlying the treatment outcome (which mediators affect the outcome of treatment?). In this paper, the protocol of the study will be described. METHODS/DESIGN: The effectiveness of the program will be investigated by comparing the intervention group with a waiting list-control group in a randomized controlled design, by including a pretest and three post-tests. The self-help program contains four main components: activation, relaxation, changing maladaptive cognitions, and goal attainment. Participants with mild to moderate depressive symptoms will work on the program for 6 to 10 weeks, during which a coach will provide motivational support by telephone once a week. Participants in the control condition will receive weekly minimal support from a coach for 8 weeks, and after the second post-test, they can gain access to the self-help program. Depressive symptoms and possible mediators (e.g., activation, cognitive coping, self-efficacy, and goal adjustment) will be assessed by self-report three times during the intervention/waiting period and at the pretest and first post-test. DISCUSSION: The proposed study aims to evaluate the effectiveness of an online self-help intervention for people with HIV and depressive symptoms. If the intervention is shown to be effective, the program will be implemented. Consequently, many patients with HIV could be reached, and their psychological care may be improved. TRIAL REGISTRATION: Netherlands Trial Register: NTR5407.