Consolidation and prediction of long-term treatment effect of group and online mindfulness-based cognitive therapy for distressed cancer patients.

BACKGROUND: Group face-to-face and individual internet-based mindfulness-based cognitive therapy (MBCT and eMBCT) have been demonstrated to reduce psychological distress for distressed cancer patients in a randomized controlled trial (RCT). This study focused on the long-term effects of this RCT during the nine-month follow-up period, and on possible predictors, moderators and working mechanisms. METHODS: Distressed cancer patients (n = 245) were randomized to MBCT or eMBCT. Data were collected at baseline, post-treatment, three- and nine-month follow-up. Data were analyzed with linear mixed effect models and (hierarchical) linear regressions. RESULTS: Analyses revealed long-term reductions in psychological distress and rumination, and long-term increases in positive mental health and mental health-related quality of life (QoL) in both interventions over the course of the nine-month follow-up. Interestingly, patients reported less psychological distress in the follow-up period after eMBCT in comparison to MBCT. Less psychological distress, rumination and neuroticism, and more extraversion and agreeableness at baseline predicted less psychological distress at the nine-month follow-up after both interventions. Less mindful and conscientious patients at baseline benefited more from eMBCT than from MBCT. Regarding working mechanisms, changes in mindfulness skills, fear of cancer recurrence and rumination during both interventions predicted less psychological distress at follow-up. CONCLUSIONS: Our findings suggest most improvements in cancer patients' increase over time after both interventions. Furthermore, patients seemed to benefit more from eMBCT than MBCT based on psychological distress levels, especially those patients with low levels of mindfulness skills and conscientiousness.

Cognitive reactivity as outcome and working mechanism of mindfulness-based cognitive therapy for recurrently depressed patients in remission.

Major depressive disorder is a prevalent condition with high relapse rates. There is evidence that cognitive reactivity is an important vulnerability factor for the recurrence of depression. Mindfulness-based interventions are designed to reduce relapse rates, with cognitive reactivity as one of the proposed working mechanisms. In a randomised controlled trial we compared the effect of mindfulness-based cognitive therapy (MBCT) with treatment-as-usual (TAU) on cognitive reactivity in recurrently depressed patients (N = 115). Depressive symptoms, cognitive reactivity, and mindfulness skills were assessed pre and post treatment. Patients in the MBCT group reported a significantly greater reduction in cognitive reactivity than those in the TAU group (d = .51). The reduction of cognitive reactivity appeared to mediate the association between MBCT/TAU and decrease of depressive symptoms, using pre and post scores. The current study provides evidence that MBCT reduces cognitive reactivity and preliminary evidence that cognitive reactivity is a working mechanism of MBCT.

Predictors of perceived stigmatization in patients with psoriasis.

BACKGROUND: The physical appearance of psoriasis can be cosmetically disfiguring, resulting in a substantial social burden for patients. An important aspect of this burden is the experience of stigmatization. While stigmatization is known to be disabling and stressful for patients, little is known about its correlates, and effective interventions are lacking. OBJECTIVES: To examine predictor variables for perceived stigmatization in psoriasis. METHODS: Questionnaires were administered to 514 patients with psoriasis in a cross-sectional study. Zero-order correlation and multiple-regression analyses were conducted including sociodemographic, disease-related, personality, illness cognitions and social support predictor variables. RESULTS: Stigmatization was experienced by 73% of patients to some degree, and correlated with all five categories of predictor variables. In multiple-regression analyses, stigmatization was associated with higher impact on daily life; lower education; higher disease visibility, severity and duration; higher levels of social inhibition; having a type D personality; and not having a partner. CONCLUSIONS: The results indicate that perceived stigmatization is common in psoriasis, and can be predicted by sociodemographic, disease-related and personality variables. These predictor variables provide indications of which patients are especially vulnerable regarding perceived stigmatization, which might be used in treatment.

Mindfulness-based stress reduction added to care as usual for lung cancer patients and/or their partners: A multicentre randomized controlled trial.

OBJECTIVE: Lung cancer patients report among the highest distress rates of all cancer patients. Partners report similar distress rates. The present study examined the effectiveness of additional mindfulness-based stress reduction (care as usual [CAU] + MBSR) versus solely CAU to reduce psychological distress in lung cancer patients and/or their partners. METHODS: We performed a multicentre, parallel-group, randomized controlled trial. Mindfulness-based stress reduction is an 8-week group-based intervention, including mindfulness practice and teachings on stress. Care as usual included anticancer treatment, medical consultations, and supportive care. The primary outcome was psychological distress. Secondary outcomes included quality of life, caregiver burden, relationship satisfaction, mindfulness skills, self-compassion, rumination, and posttraumatic stress symptoms. Outcomes were assessed at baseline, post-intervention, and 3-month follow-up. Linear mixed modeling was conducted on an intention-to-treat sample. Moderation (gender, disease stage, baseline distress, participation with/without partner) and mediation analyses were performed. RESULTS: A total of 31 patients and 21 partners were randomized to CAU + MBSR and 32 patients and 23 partners to CAU. After CAU + MBSR patients reported significantly less psychological distress (p = .008, d = .69) than after CAU. Baseline distress moderated outcome: those with more distress benefitted most from MBSR. Additionally, after CAU + MBSR patients showed more improvements in quality of life, mindfulness skills, self-compassion, and rumination than after CAU. In partners, no differences were found between groups. CONCLUSION: Our findings suggest that psychological distress in lung cancer patients can be effectively treated with MBSR. No effect was found in partners, possibly because they were more focused on patients' well-being rather than their own.

Uncovering students' misconceptions by assessment of their written questions.

BACKGROUND: Misconceptions are ideas that are inconsistent with current scientific views. They are difficult to detect and refractory to change. Misconceptions can negatively influence how new concepts in science are learned, but are rarely measured in biomedical courses. Early identification of misconceptions is of critical relevance for effective teaching, but presents a difficult task for teachers as they tend to either over- or underestimate students' prior knowledge. A systematic appreciation of the existing misconceptions is desirable. This explorative study was performed to determine whether written questions generated by students can be used to uncover their misconceptions. METHODS: During a small-group work (SGW) session on Tumour Pathology in a (bio)medical bachelor course on General Pathology, students were asked to write down a question about the topic. This concerned a deepening question on disease mechanisms and not mere factual knowledge. Three independent expert pathologists determined whether the content of the questions was compatible with a misconception. Consensus was reached in all cases. Study outcomes were to determine whether misconceptions can be identified in students' written questions, and if so, to measure the frequency of misconceptions that can be encountered, and finally, to determine if the presence of such misconceptions is negatively associated with the students' course formal examination score. A subgroup analysis was performed according to gender and discipline. RESULTS: A total of 242 students participated in the SGW sessions, of whom 221 (91 %) formulated a question. Thirty-six questions did not meet the inclusion criteria. Of the 185 questions rated, 11 % (n = 20) was compatible with a misconception. Misconceptions were only found in medical students' questions, not in biomedical science students' questions. Formal examination score on Tumour Pathology was 5.0 (SD 2.0) in the group with misconceptions and 6.7 (SD 2.4) in the group without misconceptions (p = 0.003). CONCLUSIONS: This study demonstrates that misconceptions can be uncovered in students' written questions. The occurrence of these misconceptions was negatively associated with the formal examination score. Identification of misconceptions creates an opportunity to repair them during the remaining course sessions, in advance of the formal examination.

Limited sampling strategy for prolonged-release tacrolimus in renal transplant patients by use of the dried blood spot technique.

PURPOSE: The aim of this study was to develop a clinically applicable limited sampling strategy for ambulatory Caucasian kidney transplant patients to estimate area under the curve in a 24-h period (AUC0-24) of prolonged-release tacrolimus. METHODS: Twenty six kidney recipients, at least 6 months after transplantation, receiving prolonged-release tacrolimus, were enrolled. In each patient, seven blood samples were collected during a period of 24 h by use of the validated dried blood spot method. Best subset selection multiple linear regression was performed to derive limited sampling strategy (LSS). The equations were constrained to include a maximum of three samples collected within 4 h after the intake to maintain clinical applicability. To assess the predictive performance of LSS, residuals for each patient were calculated based on models fitted to a dataset where that patient was omitted. RESULTS: The prediction formula for the AUC(0-24) using the time points 0, 2, and 4 h after ingestion (C(0h)-C(2h)-C(4h)) provided the highest correlation with the AUC(0-24) (r(2) = 0.95): AUC0-24 = 44.9 + 8.9 × C(0h) + 2.1 × C(2h) + 7.6 × C(4h). Measures for bias and precision, i.e., median percentage prediction error (MPPE) and median absolute prediction error (MAPE), were 0.4 and 4.8%, respectively. For the same patients, the correlation between C(24h) and AUC0-24 was worse (r(2) = 0.77) while MPPE and MAPE were 6.2 and 7.2%, respectively. CONCLUSION: In the outpatient department, a LSS using C(0h)-C(2h)-C(4h) can be used for reliable estimation of the AUC(0-24) of prolonged-release tacrolimus.

Treatment of paediatric scalp psoriasis with calcipotriene/betamethasone dipropionate scalp formulation: effectiveness, safety and influence on children's quality of life in daily practice.

BACKGROUND: Evidence on efficacy and safety of topical treatments for paediatric scalp psoriasis is lacking. OBJECTIVE: This study aims to evaluate the effectiveness and safety of calcipotriene/betamethasone dipropionate scalp formulation for paediatric scalp psoriasis in daily clinical practice. The influence of this formulation on the quality of life (QoL) was assessed as well. METHODS: Data of children treated with the scalp formulation were extracted from a prospective observational daily clinical practice registry of children with psoriasis, called Child-Continuous Assessment of Psoriasis Treatment Use Registry. Severity was expressed by Psoriasis Scalp Severity Index (PSSI) and the impact on the QoL was reflected by the validated Children's Scalpdex in Psoriasis (CSP). RESULTS: Eighty-four treatment episodes were analysed. Significant improvements of PSSI score (18.7 ± 11.8 to 12.7 ± 9.4) were demonstrated in the first 12 weeks and this result was well maintained during 48 weeks of follow-up. Three patients (4.1%) developed striae of the skin (arms, trunk and legs), which are possibly related to the scalp formulation. CSP scores (79.0-46.3) declined significantly after 3 months. CONCLUSION: In a daily clinical practice cohort of children with scalp psoriasis, calcipotriene/betamethasone dipropionate scalp formulation was effective with a 32.1% improvement of PSSI at week 12 and a maintenance of this effect until 48 weeks of follow-up, in combination with improvement of QoL.

Challenging students to formulate written questions: a randomized controlled trial to assess learning effects.

BACKGROUND: Underutilization of dialogue among students during small-group work is a threat to active meaningful learning. To encourage small-group learning, we challenged students to generate written questions during a small-group work session. As gender differences have been shown to affect learning, these were also inventoried. METHODS: Prospective randomized study during a bachelor General Pathology course including 459 (bio) medical students, 315 females and 144 males. The intervention was to individually generate an extra written question on disease mechanisms, followed by a selection, by each student group, of the two questions considered to be most relevant. These selected questions were open for discussion during the subsequent interactive lecture. Outcome measure was the score on tumour pathology (range 1-10) on the course examination; the effect of gender was assessed. RESULTS: The mean score per student was 7.2 (intervention) and 6.9 (control; p = 0.22). Male students in the intervention group scored 0.5 point higher than controls (p = 0.05). In female students, this was only 0.1 point higher (p = 0.75). CONCLUSIONS: Formulating and prioritizing an extra written question during small-group work seems to exert a positive learning effect on male students. This is an interesting approach to improve learning in male students, as they generally tend to perform less well than their female colleagues.

The psychophysiological stress response in psoriasis and rheumatoid arthritis.

BACKGROUND: Psychosocial stress can be a risk factor for the maintenance and exacerbation of chronic inflammatory diseases, such as psoriasis and rheumatoid arthritis (RA). OBJECTIVES: To gain insight into the specificity of the psychophysiological stress response during chronic inflammation, we assessed autonomic and neuroendocrine responses to stress in different chronic inflammatory diseases. METHODS: Thirty patients with psoriasis (nine women, mean age 58·5 years ± 12·4), 34 patients with RA (16 women, mean age 60·8 years ± 9·2) and 25 healthy controls (16 women, mean age 55·6 years ± 8·7) underwent a standardized psychosocial stress task (Trier Social Stress Test). Salivary levels of α-amylase and cortisol and self-reported tension levels were measured before and after the stress test. RESULTS: The cortisol response to stress was heightened in patients with psoriasis compared with patients with RA and healthy controls, whereas there were no differences in the autonomic and self-reported measures. CONCLUSIONS: The altered neuroendocrine stress response in patients with psoriasis suggests that stressful events might have different physiological consequences for specific patient groups with chronic inflammatory conditions, possibly adversely affecting disease status.

Cost-effectiveness of adjuvant systemic therapy in low-risk breast cancer patients with nodal isolated tumor cells or micrometastases.

BACKGROUND: The cost-effectiveness of adjuvant systemic therapy in patients with low-risk breast cancer and nodal isolated tumor cells or micrometastases is unknown. PATIENTS AND METHODS: A cost-effectiveness analysis of adjuvant systemic therapy was carried out using the costs per 1% event prevented after 5 years of follow-up as incremental cost-effectiveness ratio (ICER). Secondary objective was to establish when adjuvant systemic therapy becomes cost saving. Patients included in the MIRROR study with isolated tumor cells or micrometastases who had a complete 5-year follow-up and who either did or did not receive systemic therapy were eligible. Sensitivity analyses were carried out. RESULTS: In the no adjuvant therapy cohort (N = 366), 24.9% of patients had an event within 5 years versus 16.8% of patients in the adjuvant therapy cohort (N = 483) (P < 0.01). The ICER was €363 per 1% event prevented. Beyond 18 years after diagnosis, the extrapolated mean cumulative costs per patient in the no adjuvant therapy cohort exceeded those of the adjuvant therapy cohort. CONCLUSIONS: In this population of breast cancer patients with isolated tumor cells or micrometastases, €36 300 had to be invested to prevent one event in 5 years of follow-up. Adjuvant systemic therapy was cost saving beyond 18 years after diagnosis.

The efficacy of mindfulness-based cognitive therapy in recurrent depressed patients with and without a current depressive episode: a randomized controlled trial.

BACKGROUND: The aim of this study is to examine the efficacy of mindfulness-based cognitive therapy (MBCT) in addition to treatment as usual (TAU) for recurrent depressive patients with and without a current depressive episode. METHOD: A randomized, controlled trial comparing MBCT+TAU (n=102) with TAU alone (n=103). The study population consisted of patients with three or more previous depressive episodes. Primary outcome measure was post-treatment depressive symptoms according to the Hamilton Rating Scale for Depression. Secondary outcome measures included the Beck Depression Inventory, rumination, worry and mindfulness skills. Group comparisons were carried out with linear mixed modelling, controlling for intra-group correlations. Additional mediation analyses were performed. Comparisons were made between patients with and without a current depressive episode. RESULTS: Patients in the MBCT+TAU group reported less depressive symptoms, worry and rumination and increased levels of mindfulness skills compared with patients receiving TAU alone. MBCT resulted in a comparable reduction of depressive symptoms for patients with and without a current depressive episode. Additional analyses suggest that the reduction of depressive symptoms was mediated by decreased levels of rumination and worry. CONCLUSIONS: The study findings suggest that MBCT is as effective for patients with recurrent depression who are currently depressed as for patients who are in remission. Directions towards a better understanding of the mechanisms of action of MBCT are given, although future research is needed to support these hypotheses.

The influence of treatments in daily clinical practice on the Children's Dermatology Life Quality Index in juvenile psoriasis: a longitudinal study from the Child-CAPTURE patient registry.

BACKGROUND: Juvenile psoriasis has a negative effect on the quality of life (QoL). The influence of treatments on QoL of these children has never been investigated before in a prospective observational study. OBJECTIVES: To assess the Children's Dermatology Life Quality Index (CDLQI) in a cohort of patients with juvenile psoriasis and to evaluate the influence of treatments in daily clinical practice on CDLQI. METHODS: We conducted a prospective observational study of children with psoriasis from a registry containing daily clinical practice data. Before and after treatment, QoL was assessed by the CDLQI and disease severity was documented by the Psoriasis Area and Severity Index (PASI). Three clusters of treatments were analysed: topical, dithranol and systemic therapy. RESULTS: In total, 125 patients were enrolled in the registry. Cross-sectionally, a mean ± SD CDLQI score of 7·5 ± 5·0 and a mean ± SD PASI of 7·0 ± 5·8 were recorded. Itching and problems with treatment had the highest impact on the children's QoL. Longitudinally, 85 patients were analysed with a total of 137 treatment episodes. All treatments contributed to a significant decline in total CDLQI score, with the largest decrease seen in dithranol and systemic treatments. A significant correlation was found between ΔCDLQI and ΔPASI for all treatment modalities. The highest positive impact of treatments was found in a decline of itch and sleep disturbance. CONCLUSIONS: In this first prospective observational study on CDLQI in juvenile psoriasis, a positive influence of treatments in daily clinical practice on QoL was demonstrated.

Tailored cognitive-behavioural therapy and exercise training improves the physical fitness of patients with fibromyalgia.

OBJECTIVES: Patients with fibromyalgia have diminished levels of physical fitness, which may lead to functional disability and exacerbating complaints. Multidisciplinary treatment comprising cognitive-behavioural therapy (CBT) and exercise training has been shown to be effective in improving physical fitness. However, due to the high drop-out rates and large variability in patients' functioning, it was proposed that a tailored treatment approach might yield more promising treatment outcomes. METHODS: High-risk fibromyalgia patients were randomly assigned to a waiting list control group (WLC) or a treatment condition (TC), with the treatment consisting of 16 twice-weekly sessions of CBT and exercise training tailored to the patient's cognitive-behavioural pattern. Physical fitness was assessed with two physical tests before and 3 months after treatment and at corresponding intervals in the WLC. Treatment effects were evaluated using linear mixed models. RESULTS: The level of physical fitness had improved significantly in the TC compared with the WLC. Attrition rates were low, effect sizes large and reliable change indices indicated a clinically relevant improvement among the TC. CONCLUSIONS: A tailored multidisciplinary treatment approach for fibromyalgia consisting of CBT and exercise training is well tolerated, yields clinically relevant changes, and appears a promising approach to improve patients' physical fitness. ClinicalTrials.gov ID NCT00268606.

Subarachnoid Hemorrhage in Germany Between 2010 and 2013: Estimated Incidence Rates Based on a Nationwide Hospital Discharge Registry.

BACKGROUND: Nordic countries are the primary source for nationwide data on the incidence of subarachnoid hemorrhage (SAH). Reliable estimates of national incidence rates of SAH in other countries are lacking, yet studies from Nordic countries with exceptional incidence rates are sometimes disregarded because of concerns regarding external validity. Autopsies are rarely performed for sudden deaths; therefore, estimates of the SAH incidence commonly reflect the hospital discharge rates. Our aim was to estimate the nationwide incidence of nontraumatic SAH in Germany using a national hospital discharge register. METHODS: The German federal statistical office provided the number of patients discharged from all German hospitals between 2010 and 2013 with the primary diagnosis of nontraumatic SAH (ICD code I60.0-I60.9) and corresponding age distribution. Age-standardized attack rates of nontraumatic SAH were calculated using the 2011 German demographic distribution. RESULTS: Between 2010 and 2013, the overall age-standardized incidence rate of nontraumatic SAH was 11.3 per 100,000 person-years, and it reached a maximum of 22.1 per 100,000 person-years in the oldest age group. The absolute number of SAHs was highest in the 50-55-year age group. The distribution of intracranial aneurysms displayed a propensity toward the posterior circulation with advancing age (P < 0.001), although in absolute numbers SAH originated mostly from the anterior circulation. CONCLUSIONS: Our estimate of the German nationwide attack rate suggests that the incidence of nontraumatic SAH is more homogeneous than previously assumed. Rejecting the external validity of studies from countries believed to display an exceptional incidence rates may therefore not be justified.

Parental quality of life in complex paediatric neurologic disorders of unknown aetiology.

Complex paediatric neurology (CPN) patients generally present with non-specific symptoms, such as developmental delay, impaired movement and epilepsy. The diagnostic trajectory in these disorders is usually complicated and long-lasting, and may be burdensome to the patients and their parents. Additionally, as caring for a chronically ill child can be stressful and demanding, parents of these patients may experience impaired health-related quality of life (HRQoL). This study aims to assess parental HRQoL and factors related to it in CPN. Physical and mental HRQoL of 120 parents was measured and compared to the general population using the SF-12 questionnaire. Parents also completed this questionnaire for the measurement of patient HRQoL. Additional questionnaires were used to measure parental uncertainty (Visual Analogue Scale) and worry phenomena (Penn State Worry Questionnaire), and to obtain socio-demographic data. A linear mixed model with random effect was used to investigate which of these variables were associated with parental HRQoL. As compared to the general population, HRQoL of these parents appeared diminished. Fathers showed both lowered physical (51.76, p < 0.05) and mental (49.41, p < 0.01) HRQoL, whereas mothers only showed diminished mental (46.46, p < 0.01) HRQoL. Patient HRQoL and parental worry phenomena were significantly correlated with overall and mental parental HRQoL. The reduction in parental mental HRQoL is alarming, also because children strongly rely on their parents and parental mental health is known to influence children's health. Awareness of these problems among clinicians, and supportive care if needed are important to prevent exacerbation of the problems.

Effect of dipyridamole on myocardial reperfusion injury: A double-blind randomized controlled trial in patients undergoing elective coronary artery bypass surgery.

Dipyridamole reduces reperfusion-injury in preclinical trials and may be beneficial in patients undergoing coronary angioplasty, but its effect on patients undergoing coronary artery bypass grafting (CABG) is unknown. We hypothesized that dipyridamole limits myocardial reperfusion-injury in patients undergoing CABG. The trial design was a double-blind trial randomizing between pretreatment with dipyridamole or placebo. In all, 94 patients undergoing elective on-pump CABG were recruited between February 2010 and June 2012. The primary endpoint was plasma high-sensitive (hs-) troponin-I at 6, 12, and 24 hours after reperfusion. Secondary endpoints were the occurrence of bleeding, arrhythmias, need for inotropic support, and intensive care unit length of stay. Finally, 79 patients (33 dipyridamole) were included in the per-protocol analysis. Dipyridamole did not significantly affect postoperative hs-troponin-I (change in plasma hs-troponin I -3% [95% confidence interval -23% to 36%]; P > 0.1). Secondary endpoints did not differ between groups. Dipyridamole prior to CABG does not significantly reduce postoperative hs-troponin release.

Study protocol of a multicenter randomized controlled trial comparing the effectiveness of group and individual internet-based Mindfulness-Based Cognitive Therapy with treatment as usual in reducing psychological distress in cancer patients: the BeMind study.

BACKGROUND: Mindfulness-based interventions have shown to reduce psychological distress in cancer patients. The accessibility of mindfulness-based interventions for cancer patients could be further improved by providing mindfulness using an individual internet-based format. The aim of this study is to test the effectiveness of a Mindfulness-Based Cognitive Therapy (MBCT) group intervention for cancer patients in comparison with individual internet-based MBCT and treatment as usual (TAU). METHODS/DESIGN: A three-armed multicenter randomized controlled trial comparing group-based MBCT to individual internet-based MBCT and TAU in cancer patients who suffer from at least mild psychological distress (Hospital Anxiety and Depression Scale (HADS) ≥ 11). Measurements will be conducted prior to randomization (baseline), post-treatment and at 3 months and 9 months post-treatment. Participants initially allocated to TAU are subsequently randomized to either group- or individual internet-based MBCT and will receive a second baseline measurement after 3 months. Thus, the three-armed comparison will have a time span of approximately 3 months. The two-armed intervention comparison includes a 9-month follow-up and will also consist of participants randomized to the intervention after TAU. Primary outcome will be post-treatment psychological distress (HADS). Secondary outcomes are fear of cancer recurrence (Fear of Cancer Recurrence Inventory), rumination (Rumination and Reflection Questionnaire), positive mental health (Mental Health Continuum - Short Form), and cost-effectiveness (health-related quality of life (EuroQol -5D and Short Form-12) and health care usage (Trimbos and iMTA questionnaire on Costs associated with Psychiatric illness). Potential predictors: DSM-IV-TR mood/anxiety disorders (SCID-I) and neuroticism (NEO-Five Factor Inventory) will be measured. Mediators of treatment effect: mindfulness skills, (Five-Facets of Mindfulness Questionnaire- Short Form), working alliance (Working Alliance Inventory) and group cohesion (Group Cohesion Questionnaire) will also be measured. DISCUSSION: This trial will provide valuable information on the clinical and cost-effectiveness of group versus internet-based MBCT versus TAU for distressed cancer patients. TRIAL REGISTRATION: Clinicaltrials.gov NCT02138513. Registered 6 May 2014.

Ticagrelor Does Not Inhibit Adenosine Transport at Relevant Concentrations: A Randomized Cross-Over Study in Healthy Subjects In Vivo.

BACKGROUND AND PURPOSE: In patients with myocardial infarction, ticagrelor reduces cardiovascular and sepsis-related mortality, and can cause dyspnea. It is suggested that this is caused by adenosine receptor stimulation, because in preclinical studies, ticagrelor blocks the nucleoside transporter and increases cellular ATP release. We now investigated the effects of ticagrelor on the adenosine system in humans in vivo. EXPERIMENTAL APPROACH: In a double-blinded, placebo-controlled cross-over trial in 14 healthy subjects, we have tested whether ticagrelor (180 mg) affects adenosine- and dipyridamole-induced forearm vasodilation, as surrogates of nucleoside uptake inhibition and adenosine formation, respectively. Also, ex vivo uptake of adenosine and uridine in isolated red blood cells was measured. Primary endpoint was adenosine-induced vasodilation. KEY RESULTS: Ticagrelor did not affect adenosine- or dipyridamole-induced forearm vasodilation. Also, ex vivo uptake of adenosine and uridine in isolated red blood cells was not affected by ticagrelor. In vitro, ticagrelor dose-dependently inhibited nucleoside uptake, but only at supra-physiological concentrations. CONCLUSION AND IMPLICATIONS: In conclusion, at relevant plasma concentration, ticagrelor does not affect adenosine transport, nor adenosine formation in healthy subjects. Therefore, it is unlikely that this mechanism is a relevant pleiotropic effect of ticagrelor. TRIAL REGISTRATION: ClinicalTrials.gov NCT01996735.

Multinational development and validation of an early prediction model for delirium in ICU patients.

RATIONALE: Delirium incidence in intensive care unit (ICU) patients is high and associated with poor outcome. Identification of high-risk patients may facilitate its prevention. PURPOSE: To develop and validate a model based on data available at ICU admission to predict delirium development during a patient's complete ICU stay and to determine the predictive value of this model in relation to the time of delirium development. METHODS: Prospective cohort study in 13 ICUs from seven countries. Multiple logistic regression analysis was used to develop the early prediction (E-PRE-DELIRIC) model on data of the first two-thirds and validated on data of the last one-third of the patients from every participating ICU. RESULTS: In total, 2914 patients were included. Delirium incidence was 23.6%. The E-PRE-DELIRIC model consists of nine predictors assessed at ICU admission: age, history of cognitive impairment, history of alcohol abuse, blood urea nitrogen, admission category, urgent admission, mean arterial blood pressure, use of corticosteroids, and respiratory failure. The area under the receiver operating characteristic curve (AUROC) was 0.76 [95% confidence interval (CI) 0.73-0.77] in the development dataset and 0.75 (95% CI 0.71-0.79) in the validation dataset. The model was well calibrated. AUROC increased from 0.70 (95% CI 0.67-0.74), for delirium that developed <2 days, to 0.81 (95% CI 0.78-0.84), for delirium that developed >6 days. CONCLUSION: Patients' delirium risk for the complete ICU length of stay can be predicted at admission using the E-PRE-DELIRIC model, allowing early preventive interventions aimed to reduce incidence and severity of ICU delirium.

External validation is necessary in prediction research: a clinical example.

BACKGROUND AND OBJECTIVES: Prediction models tend to perform better on data on which the model was constructed than on new data. This difference in performance is an indication of the optimism in the apparent performance in the derivation set. For internal model validation, bootstrapping methods are recommended to provide bias-corrected estimates of model performance. Results are often accepted without sufficient regard to the importance of external validation. This report illustrates the limitations of internal validation to determine generalizability of a diagnostic prediction model to future settings. METHODS: A prediction model for the presence of serious bacterial infections in children with fever without source was derived and validated internally using bootstrap resampling techniques. Subsequently, the model was validated externally. RESULTS: In the derivation set (n=376), nine predictors were identified. The apparent area under the receiver operating characteristic curve (95% confidence interval) of the model was 0.83 (0.78-0.87) and 0.76 (0.67-0.85) after bootstrap correction. In the validation set (n=179) the performance was 0.57 (0.47-0.67). CONCLUSION: For relatively small data sets, internal validation of prediction models by bootstrap techniques may not be sufficient and indicative for the model's performance in future patients. External validation is essential before implementing prediction models in clinical practice.