Changes on clinical and participatory outcomes in people with severe-to-profound hearing loss after cochlear implantation: protocol of a multicentre prospective observational cohort study - Societal Merit of Intervention on Hearing Loss Evaluation (SMILE).

INTRODUCTION: Cochlear implantation (CI) is a (cost-)effective intervention for people with severe or profound hearing loss. Since its introduction experience increased and the technology evolved, leading to better results and relaxation of CI eligibility criteria. Meanwhile, with national healthcare costs increasing there is a need for evidence of healthcare technology's value. This protocol describes a study to investigate clinical and participatory outcomes after CI for the currently (expanded) eligible hearing impaired population. The study adds to the current evidence base through its multicentre design, long-term follow-up and use of participatory outcomes alongside standard clinical outcomes. METHODS: This multicentre prospective observational cohort study will include at least 156 adult patients with severe-to-profound hearing loss, approximately evenly divided into two groups (1, ages 18-65 years and 2, age >65 years). The measurements consist of audiometry, cognition tests, listening effort tests and multiple generic and disease specific questionnaires. Questionnaires will be administered twice before CI, soon after inclusion at CI referral and shortly before CI surgery, with an annual follow-up of 3 years after CI. The Impact on Participation and Autonomy questionnaire will be used to assess participation. Generalised models (linear, logistic, Poisson) will be used. Mixed effects models will be used to investigate changes over time while exploring differences in subgroups and the influence of covariates. ETHICS AND DISSEMINATION: The study has received ethical approval from the Medical Ethical Committee of all participating centres. The results could provide valuable insights into changes in participatory outcomes of people with severe-to-profound hearing loss after CI. Results will be disseminated through peer-reviewed journals, scientific conferences and professional and patient organisation meetings. TRIAL REGISTRATION NUMBER: NCT05525221.

Follow-up outcomes of Mindfulness-Based Cognitive Therapy (MBCT) for patients with chronic, treatment-resistant depression.

BACKGROUND: Mindfulness-based cognitive therapy (MBCT) is an evidence-based treatment for depression. The current study focused on the long-term outcomes of MBCT for chronically, treatment-resistant depressed patients during a 6-months follow-up period. Additionally, predictors of treatment outcomes were explored. METHOD: The outcomes of MBCT on depressive symptoms, remission rates, quality of life, rumination, mindfulness skills and self-compassion were investigated in a cohort of chronically, treatment-resistant depressed outpatients (N = 106), who had taken part in an RCT comparing MBCT with treatment-as-usual (TAU). Measures were assessed pre-MBCT, post-MBCT, at 3-months follow-up, and at 6-months follow-up. RESULTS: Results of linear mixed effect models and Bayesian repeated measures ANOVA's reveal that depressive symptoms, quality of life, rumination, mindfulness skills and self-compassion consolidated during follow-up. Remission rates even further increased over the course of follow-up. When controlling for symptoms at baseline, higher baseline levels of rumination predicted lower depressive symptoms and quality of life at 6-month follow-up. No other predictors (i.e. duration of current depressive episode, level of treatment-resistance, childhood trauma, mindfulness skills, self-compassion) were found. LIMITATIONS: All participants received MBCT, therefore time or other non-specific effects might have influenced the results and replication studies including a control conditions are needed. CONCLUSIONS: Results indicate that the clinical benefits of MBCT for chronically, treatment-resistant depressed patients persist up to 6 months after completing MBCT. Duration of the current episode, level of treatment-resistance, childhood trauma and baseline levels of mindfulness skills and self-compassion did not predict treatment outcome. When controlling for baseline depressive symptoms participants with high levels of rumination seem to benefit more; however more research is needed. TRIAL REGISTRY: Dutch Trial Registry, number NTR4843.

Dual pathway inhibition as compared to acetylsalicylic acid monotherapy in relation to endothelial function in peripheral artery disease, a phase IV clinical trial.

Objective: Dual pathway inhibition (DPI) by combining acetylsalicylic acid (ASA) with low-dose rivaroxaban has been shown to reduce cardiovascular events in patients with peripheral arterial disease (PAD) when compared to ASA monotherapy. A potential explanation is that inhibition of factor Xa improves endothelial function through crosstalk between coagulation and inflammatory pathways, subsequently attenuating the occurrence of cardiovascular events. We hypothesize that the addition of rivaroxaban to ASA in PAD patients leads to improved endothelial function. Design: An investigator-initiated, multicentre trial investigating the effect of DPI on endothelial function. Methods: Patients, diagnosed with PAD, were enrolled in two cohorts: cohort A (Rutherford I-III) and cohort B (Rutherford IV-VI). Participants received ASA monotherapy for a 4-weeks run-in period, followed by 12 weeks of DPI. Macro- and microvascular endothelial dysfunction were studied by measuring carotid artery reactivity upon sympathetic stimulus and by measuring plasma endothelin-1 concentrations, respectively. All measurements were performed during the use of ASA (baseline) and after 12 weeks of DPI. Results: 159 PAD patients (111 cohort A, 48 cohort B) were enrolled. Twenty patients discontinued study drugs early. Carotid artery constriction upon sympathetic stimulation at baseline (ASA) and after 12 weeks of DPI was similar in the total group, 22.0 vs. 22.7% (p = 1.000), and in the subgroups (Cohort A 22.6 vs. 23.7%, p = 1.000; cohort B 20.5 vs. 20.5%, p = 1.000), respectively. The mean concentration of plasma endothelin-1 at baseline and after 12 weeks of DPI did not differ, 1.70 ± 0.5 vs. 1.66 ± 0.64 pmol/L (p = 0.440) in the total group, 1.69 ± 0.59 vs. 1.62 ± 0.55 pmol/L in cohort A (p = 0.202), and 1.73 ± 0.53 vs. 1.77 ± 0.82 pmol/L in cohort B (p = 0.682), respectively. Conclusion: Macro- and microvascular endothelial dysfunction, as reflected by carotid artery reactivity and plasma endothelin-1 concentrations, are not influenced in PAD patients by addition of low-dose rivaroxaban to ASA monotherapy for 12 weeks. Trial registration: https://clinicaltrials.gov/ct2/show/NCT04218656.

A Head-On Ordinal Comparison of the Composite Time Trade-Off and the Better-Than-Dead Method.

OBJECTIVES: The valuation of health states worse than dead is challenging. Currently used time trade-off methods face problems in (1) detecting time-dependent preferences and (2) insensitivity toward severity for states worse than dead. The better-than-dead (BTD) method has the potential to detect time-dependent preferences. This study compares the BTD and composite time trade-off (cTTO) methods at the ordinal level. METHODS: An experiment was conducted in a convenience sample in which respondents (N = 200) valued the same set of 7 health states in the BTD method and cTTO method. Binary BTD responses were used, with response categories of better than dead and worse than dead. Ternary cTTO responses were used, with the additional equal-to-dead response category. Polychoric correlations were used to determine the agreement between these methods. Consistency and test-retest reliability were assessed within methods. RESULTS: Overall agreement between the cTTO and BTD method equaled 77.1% and differed between health states and respondents. For both methods, there were few inconsistencies, and the test-retest reliability was comparable (88%). Health states were more often considered worse than dead in the BTD method (BTD: 54.7%, cTTO: 37.2%). CONCLUSIONS: The high agreement between both methods and the comparable amount of inconsistencies and test-retest reliability suggest that the methods have similar measurement properties. The BTD method yielded higher frequencies of worse-than-dead responses while essentially asking respondents to make similar choices. This accounts for part of the disagreement between the methods. Several explanations are offered for this difference, yet more research is needed to explain this phenomenon.

Construct Validity of the Observable Movement Quality Scale in Pediatrics: Hypothesis Testing of a Formative Measurement Model.

BACKGROUND: The Observable Movement Quality (OMQ) Scale measures generic movement quality. Each item of the OMQ Scale focuses on a different element; together, the 15 items assess the whole construct of movement quality. OBJECTIVE: The aim of this study was to determine the construct validity of the OMQ Scale using 7 hypotheses defined to conform to the Consensus-Based Standards for the Selection of Health Measurement Instruments. DESIGN: This was an exploratory validation study. METHODS: A pediatric physical therapist assessed motor performance in 101 children using an age-specific motor test and the OMQ Scale. The direction, magnitude, and rationale for 7 hypotheses, which concerned relationships (n = 2), probability of low scores (n = 4), and difference between diagnosis subgroups (n = 1), were defined. RESULTS: The results confirmed 6 of the 7 hypotheses, indicating sufficient construct validity. Significant positive relationships were found between OMQ Scale total scores and the severity of motor disabilities (r = 0.72) and z scores on motor tests (r = 0.60). Probabilities for low scores on OMQ Scale items-exceeding the chi-square critical value-were confirmed for children diagnosed with spasticity, psychomotor retardation, mitochondrial diseases, and ataxia; however, probabilities for low OMQ Scale item scores on strength regulation in children with ataxia were not confirmed. OMQ Scale total scores for children who were not ambulatory because of neurological conditions were significantly different from those for children who were not ambulatory because of fatigue (r = 0.66). LIMITATIONS: The sample of children was based on theoretical assumptions about relevant variations in clinical representations; on the basis of the results, it appears that children with low strength regulation were underrepresented. CONCLUSION: The confirmation of nearly all hypotheses supported the validity of the OMQ Scale for measuring movement quality in clinical practice in addition to standardized age-adequate motor performance tests.

External Validation of Two Models to Predict Delirium in Critically Ill Adults Using Either the Confusion Assessment Method-ICU or the Intensive Care Delirium Screening Checklist for Delirium Assessment.

OBJECTIVES: To externally validate two delirium prediction models (early prediction model for ICU delirium and recalibrated prediction model for ICU delirium) using either the Confusion Assessment Method-ICU or the Intensive Care Delirium Screening Checklist for delirium assessment. DESIGN: Prospective, multinational cohort study. SETTING: Eleven ICUs from seven countries in three continents. PATIENTS: Consecutive, delirium-free adults admitted to the ICU for greater than or equal to 6 hours in whom delirium could be reliably assessed. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The predictors included in each model were collected at the time of ICU admission (early prediction model for ICU delirium) or within 24 hours of ICU admission (recalibrated prediction model for ICU delirium). Delirium was assessed using the Confusion Assessment Method-ICU or the Intensive Care Delirium Screening Checklist. Discrimination was determined using the area under the receiver operating characteristic curve. The predictive performance was determined for the Confusion Assessment Method-ICU and Intensive Care Delirium Screening Checklist cohort, and compared with both prediction models' original reported performance. A total of 1,286 Confusion Assessment Method-ICU-assessed patients and 892 Intensive Care Delirium Screening Checklist-assessed patients were included. Compared with the area under the receiver operating characteristic curve of 0.75 (95% CI, 0.71-0.79) in the original study, the area under the receiver operating characteristic curve of the early prediction model for ICU delirium was 0.67 (95% CI, 0.64-0.71) for delirium as assessed using the Confusion Assessment Method-ICU and 0.70 (95% CI, 0.66-0.74) using the Intensive Care Delirium Screening Checklist. Compared with the original area under the receiver operating characteristic curve of 0.77 (95% CI, 0.74-0.79), the area under the receiver operating characteristic curve of the recalibrated prediction model for ICU delirium was 0.75 (95% CI, 0.72-0.78) for assessing delirium using the Confusion Assessment Method-ICU and 0.71 (95% CI, 0.67-0.75) using the Intensive Care Delirium Screening Checklist. CONCLUSIONS: Both the early prediction model for ICU delirium and recalibrated prediction model for ICU delirium are externally validated using either the Confusion Assessment Method-ICU or the Intensive Care Delirium Screening Checklist for delirium assessment. Per delirium prediction model, both assessment tools showed a similar moderate-to-good statistical performance. These results support the use of either the early prediction model for ICU delirium or recalibrated prediction model for ICU delirium in ICUs around the world regardless of whether delirium is evaluated with the Confusion Assessment Method-ICU or Intensive Care Delirium Screening Checklist.

Cultural Values: Can They Explain Differences in Health Utilities between Countries?

Introduction. Health utilities are widely used in health care. The distributions of utilities differ between countries; some countries more often report worse than dead health states, while mild states are valued more or less the same. We hypothesize that cultural values explain these country-related utility differences. Research Question. What is the effect of sociodemographic background, methodological factors, and cultural values on differences in health utilities? Methods and Analyses. Time tradeoff data from 28 EQ-5D valuation studies were analyzed, together with their sociodemographic variables. The dependent variable was Δu, the utility difference between mild and severe states. Country-specific cultural variables were taken from the World Values Survey. Multilevel models were used to analyze the effect of sociodemographic background, methodology (3L v. 5L), and cultural values on Δu. Intraclass correlation (ICC) for country variation was used to assess the impact of the predicting variables on the variation between countries. Results. Substantial variation in Δu was found between countries. Adding cultural values did not reduce ICCs for country variation. Sociodemographic background variables were only weakly associated with Δu and did not affect the ICC. Δu was 0.118 smaller for EQ-5D-5L studies. Discussion.Δu varies between countries. These differences were not explained by national cultural values. In conclusion, despite correction for various variables, utility differences between countries remain substantial and unexplained. This justifies the use of country-specific value sets for instruments such as the EQ-5D.

Mindfulness-based cognitive therapy v. treatment as usual in adults with ADHD: a multicentre, single-blind, randomised controlled trial.

BACKGROUND: There is a high need for evidence-based psychosocial treatments for adult attention-deficit hyperactivity disorder (ADHD) to offer alongside treatment as usual (TAU). Mindfulness-based cognitive therapy (MBCT) is a promising psychosocial treatment. This trial investigated the efficacy of MBCT + TAU v. TAU in reducing core symptoms in adults with ADHD. METHODS: A multicentre, single-blind, randomised controlled trial (ClinicalTrials.gov: NCT02463396). Participants were randomly assigned to MBCT + TAU (n = 60), an 8-weekly group therapy including meditation exercises, psychoeducation and group discussions, or TAU only (n = 60), which reflected usual treatment in the Netherlands and included pharmacotherapy and/or psychoeducation. Primary outcome was ADHD symptoms rated by blinded clinicians. Secondary outcomes included self-reported ADHD symptoms, executive functioning, mindfulness skills, self-compassion, positive mental health and general functioning. Outcomes were assessed at baseline, post-treatment, 3- and 6-month follow-up. Post-treatment effects at group and individual level, and follow-up effects were examined. RESULTS: In MBCT + TAU patients, a significant reduction of clinician-rated ADHD symptoms was found at post-treatment [M difference = -3.44 (-5.75, -1.11), p = 0.004, d = 0.41]. This effect was maintained until 6-month follow-up. More MBCT + TAU (27%) than TAU participants (4%) showed a ⩾30% reduction of ADHD symptoms (p = 0.001). MBCT + TAU patients compared with TAU patients also reported significant improvements in ADHD symptoms, mindfulness skills, self-compassion and positive mental health at post-treatment, which were maintained until 6-month follow-up. Although patients in MBCT + TAU compared with TAU reported no improvement in executive functioning at post-treatment, they did report improvement at 6-month follow-up. CONCLUSIONS: MBCT might be a valuable treatment option alongside TAU for adult ADHD aimed at alleviating symptoms.

Delirium prediction in the intensive care unit: comparison of two delirium prediction models.

BACKGROUND: Accurate prediction of delirium in the intensive care unit (ICU) may facilitate efficient use of early preventive strategies and stratification of ICU patients by delirium risk in clinical research, but the optimal delirium prediction model to use is unclear. We compared the predictive performance and user convenience of the prediction  model for delirium (PRE-DELIRIC) and early prediction model for delirium (E-PRE-DELIRIC) in ICU patients and determined the value of a two-stage calculation. METHODS: This 7-country, 11-hospital, prospective cohort study evaluated consecutive adults admitted to the ICU who could be reliably assessed for delirium using the Confusion Assessment Method-ICU or the Intensive Care Delirium Screening Checklist. The predictive performance of the models was measured using the area under the receiver operating characteristic curve. Calibration was assessed graphically. A physician questionnaire evaluated user convenience. For the two-stage calculation we used E-PRE-DELIRIC immediately after ICU admission and updated the prediction using PRE-DELIRIC after 24 h. RESULTS: In total 2178 patients were included. The area under the receiver operating characteristic curve was significantly greater for PRE-DELIRIC (0.74 (95% confidence interval 0.71-0.76)) compared to E-PRE-DELIRIC (0.68 (95% confidence interval 0.66-0.71)) (z score of - 2.73 (p < 0.01)). Both models were well-calibrated. The sensitivity improved when using the two-stage calculation in low-risk patients. Compared to PRE-DELIRIC, ICU physicians (n = 68) rated the E-PRE-DELIRIC model more feasible. CONCLUSIONS: While both ICU delirium prediction models have moderate-to-good performance, the PRE-DELIRIC model predicts delirium better. However, ICU physicians rated the user convenience of E-PRE-DELIRIC superior to PRE-DELIRIC. In low-risk patients the delirium prediction further improves after an update with the PRE-DELIRIC model after 24 h. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02518646 . Registered on 21 July 2015.

Cost-effectiveness of longer-term versus shorter-term provision of antibiotics in patients with persistent symptoms attributed to Lyme disease.

BACKGROUND: The treatment of persistent symptoms attributed to Lyme disease remains controversial. Recently, the PLEASE study did not demonstrate any additional clinical benefit of longer-term versus shorter-term antibiotic treatment. However, the economic impact of the antibiotic strategies has not been investigated. METHODS: This prospective economic evaluation, adhering a societal perspective, was performed alongside the PLEASE study, a multicenter, placebo-controlled, double-blind 1:1:1 randomized clinical trial in which all patients received open-label intravenous ceftriaxone for two weeks before the 12-week randomized blinded oral antibiotic regimen (doxycycline, clarithromycin plus hydroxychloroquine, or placebo). Between 2010 and 2013, patients (n = 271) with borreliosis-attributed persistent symptoms were enrolled and followed for one year. Main outcomes were costs, quality-adjusted life years, and incremental net monetary benefit of longer-term versus shorter-term antibiotic therapy. RESULTS: Mean quality-adjusted life years (95% CI) were not significantly different (p = 0.96): 0.82 (0.77-0.88) for ceftriaxone/doxycycline (n = 82), 0.81 (0.76-0.88) for ceftriaxone/clarithromycin-hydroxychloroquine (n = 93), and 0.81 (0.76-0.86) for ceftriaxone/placebo (n = 96). Total societal costs per patient (95% CI) were not significantly different either (p = 0.35): €11,995 (€8,823-€15,670) for ceftriaxone/doxycycline, €12,202 (€9,572-€15,253) for ceftriaxone/clarithromycin-hydroxychloroquine, and €15,249 (€11,294-€19,781) for ceftriaxone/placebo. Incremental net monetary benefit (95% CI) for ceftriaxone/doxycycline compared to ceftriaxone/placebo varied from €3,317 (-€2,199-€8,998) to €4,285 (-€6,085-€14,524) over the willingness-to-pay range, and that of ceftriaxone/clarithromycin-hydroxychloroquine compared to ceftriaxone/placebo from €3,098 (-€888-€7,172) to €3,710 (-€4,254-€11,651). For every willingness-to-pay threshold, the incremental net monetary benefits did not significantly differ from zero. CONCLUSION: The longer-term treatments were similar with regard to costs, effectiveness and cost-effectiveness compared to shorter-term treatment in patients with borreliosis-attributed persistent symptoms after one year of follow-up. Given the results of this study, and taking into account the external costs associated with antibiotic resistance, the shorter-term treatment is the antibiotic regimen of first choice.

Setting Dead at Zero: Applying Scale Properties to the QALY Model.

INTRODUCTION: Scaling severe states can be a difficult task. First, the method of measurement affects whether a health state is considered better or worse than dead. Second, in discrete choice experiments, different models to anchor health states on 0 (dead) and 1 (perfect health) produce varying amounts of health states worse than dead. RESEARCH QUESTION: Within the context of the quality-adjusted life year (QALY) model, this article provides insight into the value assigned to dead and its consequences for decision making. Our research questions are 1) what are the arguments set forth to assign dead the number 0 on the health-utility scale? And 2) what are the effects of the position of dead on the health-utility scale on decision making? METHODS: A literature review was conducted to explore the arguments set forth to assign dead a value of 0 in the QALY model. In addition, scale properties and transformations were considered. RESULTS: The review uncovered several practical and theoretical considerations for setting dead at 0. In the QALY model, indifference between 2 health episodes is not preserved under changes of the origin of the duration scale. Ratio scale properties are needed for the duration scale to preserve indifferences. In combination with preferences and zero conditions for duration and health, it follows that dead should have a value of 0. CONCLUSIONS: The health-utility and duration scales have ratio scale properties, and dead should be assigned the number 0. Furthermore, the position of dead should be carefully established, because it determines how life-saving and life-improving values are weighed in cost-utility analysis.

Development and Validation of an Abbreviated Questionnaire to Easily Measure Cognitive Failure in ICU Survivors: A Multicenter Study.

OBJECTIVES: To develop and validate an abbreviated version of the Cognitive Failure Questionnaire that can be used by patients as part of self-assessment to measure functional cognitive outcome in ICU survivors. DESIGN: A retrospective multicenter observational study. SETTING: The ICUs of two Dutch university hospitals. PATIENTS: Adult ICU survivors. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Cognitive functioning was evaluated between 12 and 24 months after ICU discharge using the full 25-item Cognitive Failure Questionnaire (CFQ-25). Incomplete CFQ-25 questionnaires were excluded from analysis. Forward selection in a linear regression model was used in hospital A to assess which of the CFQ-25 items should be included to prevent a significant loss of correlation between an abbreviated and the full CFQ-25. Subsequently, the performance of an abbreviated Cognitive Failure Questionnaire was determined in hospital B using Pearson's correlation. A Bland-Altman plot was used to examine whether the reduced-item outcome scores of an abbreviated Cognitive Failure Questionnaire were a replacement for the full CFQ-25 outcome scores. Among 1,934 ICU survivors, 1,737 were included, 819 in hospital A, 918 in hospital B. The Pearson's correlation between the abbreviated 14-item Cognitive Failure Questionnaire (CFQ-14) and the CFQ-25 was 0.99. The mean of the difference scores was -0.26, and 95% of the difference scores fell within +5 and -5.5 on a 100-point maximum score. CONCLUSIONS: It is feasible to use the abbreviated CFQ-14 to measure self-reported cognitive failure in ICU survivors as this questionnaire has a similar performance as the full CFQ-25.

A virtual asthma clinic for children: fewer routine outpatient visits, same asthma control.

eHealth is an appealing medium to improve healthcare and its value (in addition to standard care) has been assessed in previous studies. We aimed to assess whether an eHealth intervention could improve asthma control while reducing 50% of routine outpatient visits.In a multicentre, randomised controlled trial with a 16-month follow-up, asthmatic children (6-16 years) treated in eight Dutch hospitals were randomised to usual care (4-monthly outpatient visits) and online care using a virtual asthma clinic (VAC) (8-monthly outpatient visits with monthly web-based monitoring). Outcome measures were the number of symptom-free days in the last 4 weeks of the study, asthma control, forced expiratory volume in 1 s, exhaled nitric oxide fraction, asthma exacerbations, unscheduled outpatient visits, hospital admissions, daily dose of inhaled corticosteroids and courses of systemic corticosteroids.We included 210 children. After follow-up, symptom-free days differed statistically between the usual care and VAC groups (difference of 1.23 days, 95% CI 0.42-2.04; p=0.003) in favour of the VAC. In terms of asthma control, the Childhood Asthma Control Test improved more in the VAC group (difference of 1.17 points, 95% CI 0.09-2.25; p=0.03). No differences were found for other outcome measures.Routine outpatient visits can partly be replaced by monitoring asthmatic children via eHealth.

Minimizing nocebo effects by conditioning with verbal suggestion: A randomized clinical trial in healthy humans.

Nocebo effects, i.e., adverse treatment effects which are induced by patients' expectations, are known to contribute to the experience of physical symptoms such as pain and itch. A better understanding of how to minimize nocebo responses might eventually contribute to enhanced treatment effects. However, little is known about how to reduce nocebo effects. In the current randomized controlled study, we tested whether nocebo effects can be minimized by positive expectation induction with respect to electrical and histaminic itch stimuli. First, negative expectations about electrical itch stimuli were induced by verbal suggestion and conditioning (part 1: induction of nocebo effect). Second, participants were randomized to either the experimental group or one of the control groups (part 2: reversing nocebo effect). In the experimental group, positive expectations were induced by conditioning with verbal suggestion. In the control groups either the negative expectation induction was continued or an extinction procedure was applied. Afterwards, a histamine application test was conducted. Positive expectation induction resulted in a significantly smaller nocebo effect in comparison with both control groups. Mean change itch NRS scores showed that the nocebo effect was even reversed, indicating a placebo effect. Comparable effects were also found for histamine application. This study is the first to demonstrate that nocebo effects can be minimized and even reversed by conditioning with verbal suggestion. The results of the current study indicate that learning via counterconditioning and verbal suggestion represents a promising strategy for diminishing nocebo responses.

Decision aids for second-line palliative chemotherapy: a randomised phase II multicentre trial.

BACKGROUND: There is increasing recognition of the delicate balance between the modest benefits of palliative chemotherapy and the burden of treatment. Decision aids (DAs) can potentially help patients with advanced cancer with these difficult treatment decisions, but providing detailed information could have an adverse impact on patients' well-being. The objective of this randomised phase II study was to evaluate the safety and efficacy of DAs for patients with advanced cancer considering second-line chemotherapy. METHODS: Patients with advanced breast or colorectal cancer considering second-line treatment were randomly assigned to usual care (control group) or usual care plus a DA (intervention group) in a 1:2 ratio. A nurse offered a DA with information on adverse events, tumour response and survival. Outcome measures included patient-reported well-being (primary outcome: anxiety) and quality of the decision-making process and the resulting choice. RESULTS: Of 128 patients randomised, 45 were assigned to the control group and 83 to the intervention group. Median age was 62 years (range 32-81), 63% were female, and 73% had colorectal cancer. The large majority of patients preferred treatment with chemotherapy (87%) and subsequently commenced treatment with chemotherapy (86%). No adverse impact on patients' well-being was found and nurses reported that consultations in which the DAs were offered went well. Being offered the DA was associated with stronger treatment preferences (3.0 vs. 2.5; p=0.030) and increased subjective knowledge (6.7 vs. 6.3; p=0.022). Objective knowledge, risk perception and perceived involvement were comparable between the groups. CONCLUSIONS: DAs containing detailed risk information on second-line palliative treatment could be delivered to patients with advanced cancer without having an adverse impact on patient well-being. Surprisingly, the DAs only marginally improved the quality of the decision-making process. The effectiveness of DAs for palliative treatment decisions needs further exploration. TRIAL REGISTRATION: Netherlands Trial Registry (NTR): NTR1113 (registered on 2 November 2007).

Teacher Competence in Mindfulness-Based Cognitive Therapy for Depression and Its Relation to Treatment Outcome.

As mindfulness-based cognitive therapy (MBCT) becomes an increasingly mainstream approach for recurrent depression, there is a growing need for practitioners who are able to teach MBCT. The requirements for being competent as a mindfulness-based teacher include personal meditation practice and at least a year of additional professional training. This study is the first to investigate the relationship between MBCT teacher competence and several key dimensions of MBCT treatment outcomes. Patients with recurrent depression in remission (N = 241) participated in a multi-centre trial of MBCT, provided by 15 teachers. Teacher competence was assessed using the Mindfulness-Based Interventions: Teaching Assessment Criteria (MBI:TAC) based on two to four randomly selected video-recorded sessions of each of the 15 teachers, evaluated by 16 trained assessors. Results showed that teacher competence was not significantly associated with adherence (number of MBCT sessions attended), possible mechanisms of change (rumination, cognitive reactivity, mindfulness, and self-compassion), or key outcomes (depressive symptoms at post treatment and depressive relapse/recurrence during the 15-month follow-up). Thus, findings from the current study indicate no robust effects of teacher competence, as measured by the MBI:TAC, on possible mediators and outcome variables in MBCT for recurrent depression. Possible explanations are the standardized delivery of MBCT, the strong emphasis on self-reliance within the MBCT learning process, the importance of participant-related factors, the difficulties in assessing teacher competence, the absence of main treatment effects in terms of reducing depressive symptoms, and the relatively small selection of videotapes. Further work is required to systematically investigate these explanations.

Plasma galectin-3 concentrations in patients with primary aldosteronism.

BACKGROUND: The incidence of cardiovascular events is higher in patients with primary aldosteronism than in patients with essential hypertension (EHT), despite similar blood pressure levels. This suggests detrimental cardiovascular effects of aldosterone. Amongst others, it has been suggested that galectin-3 (Gal-3) is a key mediator in aldosterone-induced myocardial fibrosis. OBJECTIVE: We studied whether patients with primary aldosteronism have higher plasma Gal-3 concentrations than patients with EHT and evaluated its reversibility after adrenalectomy. METHODS: In a retrospective cohort from our tertiary referral centre, we measured plasma Gal-3 concentrations in 78 patients with primary aldosteronism, 39 cured primary aldosteronism patients after adrenalectomy and 56 patients with EHT. Paired samples were available in 11 patients (preadrenalectomy and postadrenalectomy). We compared plasma Gal-3 levels by univariate analysis of covariance with correction for cardiovascular risk factors, plasma creatinine concentration, plasma potassium levels and alcohol intake. RESULTS: Adjusted plasma Gal-3 concentrations in patients with primary aldosteronism, patients after adrenalectomy and patients with EHT were 11.39 ±â€Š0.60, 11.64 ±â€Š0.81 and 11.41 ±â€Š0.73 ng/ml, respectively (mean ±â€ŠSD; P = 0.95). In 11 patients of whom paired samples were available, mean Gal-3 concentrations increased from 10.03 ±â€Š1.67 ng/ml preadrenalectomy to 14.36 ±â€Š2.07 ng/ml postadrenalectomy (P < 0.01). CONCLUSION: In patients with primary aldosteronism, plasma Gal-3 concentrations are not elevated when compared with patients with EHT, and levels do not decrease after adrenalectomy. These results are in contrast to previous studies and do not support a pathophysiological role of plasma Gal-3 in the increased cardiovascular risk in patients with primary aldosteronism.

A tailored-guided internet-based cognitive-behavioral intervention for patients with rheumatoid arthritis as an adjunct to standard rheumatological care: results of a randomized controlled trial.

For patients with chronic pain conditions such as rheumatoid arthritis (RA), who experience elevated levels of distress, tailored-guided internet-based cognitive-behavioral treatment may be effective in improving psychological and physical functioning, and reducing the impact of RA on daily life. A multicenter, randomized controlled trial was conducted for RA patients with elevated levels of distress as assessed by a disease-specific measure. The control group (n = 71) received standard care and the intervention group (n = 62) additionally received an internet-based tailored cognitive-behavioral intervention. Main analyses were performed using a linear mixed model estimating differences between the intervention and control groups in scores of psychological functioning, physical functioning, and impact of RA on daily life at preassesment and postassessment, and at 3, 6, 9, and 12 months. Patients who received the internet-based intervention reported a larger improvement in psychological functioning compared with the control group, indicating less depressed mood (P < 0.001, d = 0.54), negative mood (P = 0.01, d = 0.38), and anxiety (P < 0.001, d = 0.48) during the course of the 1-year follow-up period. Regarding physical functioning, a trend was found for the intervention group reporting less fatigue than the control group (P = 0.06, d = 0.24), whereas no effect was found on pain. No effects were found for the impact of RA on daily life, except for the intervention group experiencing fewer role limitations due to emotional problems (P < 0.001, d = 0.53). Offering guided internet-based cognitive-behavioral therapy is a promising development to aid patients with psychological distress particularly in improving psychological functioning. Further research on adherence and specific intervention ingredients is warranted.

Study protocol of the TIRED study: a randomised controlled trial comparing either graded exercise therapy for severe fatigue or cognitive behaviour therapy with usual care in patients with incurable cancer.

BACKGROUND: Fatigue is a common and debilitating symptom for patients with incurable cancer receiving systemic treatment with palliative intent. There is evidence that non-pharmacological interventions such as graded exercise therapy (GET) or cognitive behaviour therapy (CBT) reduce cancer-related fatigue in disease-free cancer patients and in patients receiving treatment with curative intent. These interventions may also result in a reduction of fatigue in patients receiving treatment with palliative intent, by improving physical fitness (GET) or changing fatigue-related cognitions and behaviour (CBT). The primary aim of our study is to assess the efficacy of GET or CBT compared to usual care (UC) in reducing fatigue in patients with incurable cancer. METHODS: The TIRED study is a multicentre three-armed randomised controlled trial (RCT) for incurable cancer patients receiving systemic treatment with palliative intent. Participants will be randomised to GET, CBT, or UC. In addition to UC, the GET group will participate in a 12-week supervised exercise programme. The CBT group will receive a 12-week CBT intervention in addition to UC. Primary and secondary outcome measures will be assessed at baseline, post-intervention (14 weeks), and at follow-up assessments (18 and 26 weeks post-randomisation). The primary outcome measure is fatigue severity (Checklist Individual Strength subscale fatigue severity). Secondary outcome measures are fatigue (EORTC-QLQ-C30 subscale fatigue), functional impairments (Sickness Impact Profile total score, EORTC-QLQ-C30 subscale emotional functioning, subscale physical functioning) and quality of life (EORTC-QLQ-C30 subscale QoL). Outcomes at 14 weeks (primary endpoint) of either treatment arm will be compared to those of UC participants. In addition, outcomes at 18 and 26 weeks (follow-up assessments) of either treatment arm will be compared to those of UC participants. DISCUSSION: To our knowledge, the TIRED study is the first RCT investigating the efficacy of GET and CBT on reducing fatigue during treatment with palliative intent in incurable cancer patients. The results of this study will provide information about the possibility and efficacy of GET and CBT for severely fatigued incurable cancer patients. TRIAL REGISTRATION: NTR3812 ; date of registration: 23/01/2013.