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.

Randomized Trial of Longer-Term Therapy for Symptoms Attributed to Lyme Disease.

BACKGROUND: The treatment of persistent symptoms attributed to Lyme disease remains controversial. We assessed whether longer-term antibiotic treatment of persistent symptoms attributed to Lyme disease leads to better outcomes than does shorter-term treatment. METHODS: In a randomized, double-blind, placebo-controlled trial conducted in Europe, we assigned patients with persistent symptoms attributed to Lyme disease--either related temporally to proven Lyme disease or accompanied by a positive IgG or IgM immunoblot assay for Borrelia burgdorferi--to receive a 12-week oral course of doxycycline, clarithromycin plus hydroxychloroquine, or placebo. All study groups received open-label intravenous ceftriaxone for 2 weeks before initiating the randomized regimen. The primary outcome measure was health-related quality of life, as assessed by the physical-component summary score of the RAND-36 Health Status Inventory (RAND SF-36) (range, 15 to 61, with higher scores indicating better quality of life), at the end of the treatment period at week 14, after the 2-week course of ceftriaxone and the 12-week course of the randomized study drug or placebo had been completed. RESULTS: Of the 281 patients who underwent randomization, 280 were included in the modified intention-to-treat analysis (86 patients in the doxycycline group, 96 in the clarithromycin-hydroxychloroquine group, and 98 in the placebo group). The SF-36 physical-component summary score did not differ significantly among the three study groups at the end of the treatment period, with mean scores of 35.0 (95% confidence interval [CI], 33.5 to 36.5) in the doxycycline group, 35.6 (95% CI, 34.2 to 37.1) in the clarithromycin-hydroxychloroquine group, and 34.8 (95% CI, 33.4 to 36.2) in the placebo group (P=0.69; a difference of 0.2 [95% CI, -2.4 to 2.8] in the doxycycline group vs. the placebo group and a difference of 0.9 [95% CI, -1.6 to 3.3] in the clarithromycin-hydroxychloroquine group vs. the placebo group); the score also did not differ significantly among the groups at subsequent study visits (P=0.35). In all study groups, the SF-36 physical-component summary score increased significantly from baseline to the end of the treatment period (P<0.001). The rates of adverse events were similar among the study groups. Four serious adverse events thought to be related to drug use occurred during the 2-week open-label ceftriaxone phase, and no serious drug-related adverse event occurred during the 12-week randomized phase. CONCLUSIONS: In patients with persistent symptoms attributed to Lyme disease, longer-term antibiotic treatment did not have additional beneficial effects on health-related quality of life beyond those with shorter-term treatment. (Funded by the Netherlands Organization for Health Research and Development ZonMw; PLEASE ClinicalTrials.gov number, NCT01207739.).

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.

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.

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.

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.

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.

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.

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).

Tailored Therapist-Guided Internet-Based Cognitive Behavioral Treatment for Psoriasis: A Randomized Controlled Trial.

OBJECTIVE: Patients with somatic conditions, such as psoriasis, frequently suffer from high burden of their disease in daily life and might benefit from internet-based cognitive behavioral therapy (ICBT) tailored to their adjustment problems. The aim of this multicenter randomized controlled trial was to examine the effects of therapist-guided, individually tailored ICBT in a clinical sample of patients with psoriasis. METHODS: A total of 131 patients with psoriasis, who were screened for a psychological risk profile, were randomized to either care as usual (CAU, n = 66) or ICBT in addition to CAU (n = 65). Participants filled out standardized self-report questionnaires assessing physical and psychological functioning and impact on daily activities at baseline, posttreatment assessment, and 6-month follow-up. RESULTS: In covariate-controlled linear mixed-model analyses, significantly larger improvements in ICBT compared to CAU were found in the primary outcomes physical functioning (p = 0.03, d = 0.36) and impact on daily activities (p = 0.04, d = 0.35), but not in psychological functioning (p = 0.32), up to 6 months after treatment compared to baseline. In explorative analyses, the working alliance measured at the beginning of ICBT treatment predicted improved physical (p = 0.02) and psychological (p < 0.001) outcomes. CONCLUSIONS: Results underline the promise of therapist-guided, individually tailored ICBT to improve physical functioning and reduce the impact of psoriasis on daily activities in patients with a psychological risk profile. Establishing a good therapeutic relationship early on may be an important factor that influences treatment outcomes in personalized ICBT interventions. Further research is needed to evaluate ICBT effectiveness in additional samples and to explore its underlying mechanisms.

Distress in suspected lung cancer patients following rapid and standard diagnostic programs: a prospective observational study.

OBJECTIVE: Timeliness may influence emotional distress during the diagnostic phase of suspected lung cancer patients. We performed a prospective observational study to compare distress and quality of life (QoL) in two medical centres with a Rapid Outpatient Diagnostic Program (RODP) and two using conventional Stepwise Diagnostic Approach (SDA) on the basis of trained nurse-led care. METHODS: Outpatients with radiological suspicion of lung cancer completed the Hospital Anxiety and Depression Scale (HADS), European Organization for Research and Treatment of Cancer 30-item Quality of Life Questionnaire (QLQ-C30) and its 13-item Lung Cancer specific module (QLQ-LC13) upon first visit, 2 days later, thereafter weekly for 5 weeks and after 3 months. RESULTS: The 72 SDA patients and 121 RODP patients had a mean pre-diagnostic HADS-total score of 13.5 (SD 7.6); 63.4% had a score ≥10. Baseline QLQ-C30 global QoL was 61.6 (SD 22.7) exceeding reference values for lung cancer patients. Generalized least square models showed a significant centre by time interaction effect: during the first 6 weeks, HADS-total scores decreased in RODP patients (13.8-11.9) but sustained in SDA patients (13.1-13.6), whereas QoL showed no relevant changes. Times to diagnosis and discussion of therapy plan for RODP patients were 7 and 11 days shorter, respectively. CONCLUSIONS: Suspected lung cancer patients had high baseline distress levels. A decrease over time was found in RODP compared with SDA patients. QoL did not change relevantly. Albeit observational, these data indicate that patients experience less distress in rapid diagnostic programs than in stepwise diagnostic evaluation.

LONG-TERM OUTCOME OF MINDFULNESS-BASED COGNITIVE THERAPY IN RECURRENTLY DEPRESSED PATIENTS WITH AND WITHOUT A DEPRESSIVE EPISODE AT BASELINE.

BACKGROUND: In a previous randomized controlled trial in patients with three or more previous depressive episodes, mindfulness-based cognitive therapy (MBCT) appeared to be equally effective in those who were depressed and those who were in remission at the start of the trial. AIM: The aim of this study is to compare the 1-year outcome of MBCT in 124 remitted and 58 depressed patients who participated in the original trial and who were all offered MBCT either immediately or after a waiting period of 3 months. METHODS: The course of depressive symptoms, rumination, mindfulness skills, and quality of life over the course of treatment and the 1-year follow-up period was analyzed. Linear mixed modeling was used to compare the outcome between remitted and depressed patients at baseline. RESULTS: In the whole sample, levels of depression and rumination decreased and mindfulness and quality of life increased over treatment. Levels of depressive symptoms, mindfulness, and quality of life remained stable over the 1-year follow-up period. Rumination further decreased. Remitted and depressed patients at the start of the trial did not differ in terms of outcome during or after treatment. CONCLUSIONS: Long-term outcome after MBCT in depressed patients was comparable to those who were in remission at the start of the trial. These findings lend further support to the notion that recurrent depressed patients meeting the criteria of a depressive episode do not need to be excluded from MBCT.

Does stress affect the joints? Daily stressors, stress vulnerability, immune and HPA axis activity, and short-term disease and symptom fluctuations in rheumatoid arthritis.

OBJECTIVES: Both stressors and stress vulnerability factors together with immune and hypothalamus-pituitary-adrenal (HPA) axis activity components have been considered to contribute to disease fluctuations of chronic inflammatory diseases, such as rheumatoid arthritis (RA). The aim of the present study was to investigate whether daily stressors and worrying as stress vulnerability factor as well as immune and HPA axis activity markers predict short-term disease activity and symptom fluctuations in patients with RA. METHODS: In a prospective design, daily stressors, worrying, HPA axis (cortisol) and immune system (interleukin (IL)-1ß, IL-6, IL-8, interferon (IFN)-γ, tumour necrosis factor α) markers, clinical and self-reported disease activity (disease activity score in 28 joints, RA disease activity index), and physical symptoms of pain and fatigue were monitored monthly during 6 months in 80 RA patients. RESULTS: Multilevel modelling indicated that daily stressors predicted increased fatigue in the next month and that worrying predicted increased self-reported disease activity, swollen joint count and pain in the next month. In addition, specific cytokines of IL-1ß and IFN-γ predicted increased fatigue 1 month later. Overall, relationships remained relatively unchanged after controlling for medication use, disease duration and demographic variables. No evidence was found for immune and HPA axis activity markers as mediators of the stress-disease relationship. CONCLUSIONS: Daily stressors and the stress-vulnerability factor worrying predict indicators of the short-term course of RA disease activity and fatigue and pain, while specific cytokines predict short-term fluctuations of fatigue. These stress-related variables and immune markers seem to affect different aspects of disease activity or symptom fluctuations independently in RA.

Immune responses to stress in rheumatoid arthritis and psoriasis.

OBJECTIVE: Stress is one of the factors that may exacerbate the progression of chronic inflammatory diseases such as RA and psoriasis. We exploratively compared the effects of acute stress on levels of circulating cytokines involved in disease progression and/or the stress response in patients with RA, patients with psoriasis and healthy subjects. METHODS: Patients with RA, patients with psoriasis and healthy controls underwent a standardized psychosocial stress test (Trier Social Stress Test). Levels of circulating cytokines (IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IFN-γ and TNF-α) were measured before and after the stress test. RESULTS: The baseline levels of all cytokines, except IL-8, were significantly higher in patients with RA. After correction for baseline levels, patients with RA showed higher stress-induced levels of IL-1ß and IL-2 than patients with psoriasis and healthy controls. CONCLUSION: The results suggest that patients with RA have a different immune response to stress than patients with psoriasis or healthy controls. More needs to be learned about the complex interaction between stress, immune parameters and chronic inflammation.

Study protocol of a randomized controlled trial comparing Mindfulness-Based Stress Reduction with treatment as usual in reducing psychological distress in patients with lung cancer and their partners: the MILON study.

BACKGROUND: Lung cancer is the leading cause of cancer death worldwide and characterized by a poor prognosis. It has a major impact on the psychological wellbeing of patients and their partners. Recently, it has been shown that Mindfulness-Based Stress Reduction (MBSR) is effective in reducing anxiety and depressive symptoms in cancer patients. The generalization of these results is limited since most participants were female patients with breast cancer. Moreover, only one study examined the effectiveness of MBSR in partners of cancer patients. Therefore, in the present trial we study the effectiveness of MBSR versus treatment as usual (TAU) in patients with lung cancer and their partners. METHODS/DESIGN: A parallel group, randomized controlled trial is conducted to compare MBSR with TAU. Lung cancer patients who have received or are still under treatment, and their partners are recruited. Assessments will take place at baseline, post intervention and at three-month follow-up. The primary outcome is psychological distress (i.e. anxiety and depressive symptoms). Secondary outcomes are quality of life (only for patients), caregiver appraisal (only for partners), relationship quality and spirituality. In addition, cost-effectiveness ratio (only in patients) and several process variables are assessed. DISCUSSION: This trial will provide information about the clinical and cost-effectiveness of MBSR compared to TAU in patients with lung cancer and their partners.

Using bayesian models to assess the effects of under-reporting of cannabis use on the association with birth defects, national birth defects prevention study, 1997-2005.

BACKGROUND: Studies on associations between periconceptional cannabis exposure and birth defects have mainly relied on self-reported exposure. Therefore, the results may be biased due to under-reporting of the exposure. The aim of this study was to quantify the potential effects of this form of exposure misclassification. METHODS: Using multivariable logistic regression, we re-analysed associations between periconceptional cannabis use and 20 specific birth defects using data from the National Birth Defects Prevention Study from 1997-2005 for 13 859 case infants and 6556 control infants. For seven birth defects, we implemented four Bayesian models based on various assumptions concerning the sensitivity of self-reported cannabis use to estimate odds ratios (ORs), adjusted for confounding and under-reporting of the exposure. We used information on sensitivity of self-reported cannabis use from the literature for prior assumptions. RESULTS: The results unadjusted for under-reporting of the exposure showed an association between cannabis use and anencephaly (posterior OR 1.9 [95% credible interval (CRI) 1.1, 3.2]) which persisted after adjustment for potential exposure misclassification. Initially, no statistically significant associations were observed between cannabis use and the other birth defect categories studied. Although adjustment for under-reporting did not notably change these effect estimates, cannabis use was associated with esophageal atresia (posterior OR 1.7 [95% CRI 1.0, 2.9]), diaphragmatic hernia (posterior OR 1.8 [95% CRI 1.1, 3.0]), and gastroschisis (posterior OR 1.7 [95% CRI 1.2, 2.3]) after correction for exposure misclassification. CONCLUSIONS: Under-reporting of the exposure may have obscured some cannabis-birth defect associations in previous studies. However, the resulting bias is likely to be limited.

Persistent Lyme Empiric Antibiotic Study Europe (PLEASE)--design of a randomized controlled trial of prolonged antibiotic treatment in patients with persistent symptoms attributed to Lyme borreliosis.

BACKGROUND: Lyme borreliosis, a potentially severe tick-borne infection caused by Borrelia burgdorferi, can cause multi-system inflammatory disease. The incidence has been increasing, as has the number of patients with persistent symptoms attributed to Borrelia. These symptoms, also referred to as post-Lyme disease syndrome, may follow an erythema migrans or other Lyme manifestations, and include pain, fatigue, and cognitive disturbances. The optimal duration of treatment for these symptoms is a subject of controversy. The PLEASE study is designed to determine whether prolonged antibiotic treatment leads to better patient outcome than standard treatment. METHODS/DESIGN: The PLEASE study is a double-blind, randomized, placebo-controlled trial. Based on power analysis and compensating for possible loss to follow-up, a minimum of 255 patients with borreliosis-attributed persistent symptoms are included. These symptoms are either (a) temporally related to an erythema migrans or otherwise proven symptomatic borreliosis, or (b) accompanied by a positive B. burgdorferi IgG or IgM immunoblot. All patients receive open-label ceftriaxone for two weeks. Patients are then randomized (ratio 1:1:1) to blinded oral follow-up treatment for 12 weeks with (I) doxycycline, (II) clarithromycin combined with hydroxychloroquine, or (III) placebo. The primary outcome is the physical component summary score (PCS) of the RAND-36 Health Status Inventory (RAND SF-36) at week 14. Secondary outcomes include physical and mental aspects of health-related quality of life (assessed by the subscales of the RAND SF-36), fatigue, neuropsychological evaluation, physical activity, and cost-effectiveness. DISCUSSION: This article describes the background and design issues of the PLEASE study protocol. The results of this study may provide evidence for prescribing or withholding prolonged antibiotic treatment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01207739 , Netherlands Trial Register: NTR2469.

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.

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.