Societal costs of subclinical depressive symptoms in Dutch adolescents: a cost‐of‐illness study

Background: Subclinical depressive symptoms are highly prevalent among adolescents and are associated with negative consequences, which may pose an economic burden for society. We conducted a prevalence-based cost-of-illness study using a societal perspective to investigate the cost-of-illness of subclinical depressive symptoms among adolescents. Methods: Using a bottom-up approach, cost questionnaires were assessed to measure costs from 237 Dutch families with an adolescent aged 11–18 with subclinical depressive symptoms (of which 34 met the criteria of a depressive disorder). The study is registered in the Dutch Trial Register (Trial NL5584/NTR6176; www.trialregister.nl/trial/5584). Results: Our calculations show that adolescents with subclinical depressive symptoms cost the Dutch society more than €42 million annually, expressed in costs related to depressive symptoms. Secondary analyses were performed to test the reliability and stability of the costs. When costs related to psychological problems were considered, the annual costs amounted to €67 million. The total societal costs related to physical problems amounted to approximately €126 million. All costs combined (depressive, psychological, behavioural and physical problems and other reasons) amounted to a €243 million. Total costs were highest for physical-related problems of the adolescent (52% of the total costs), followed by psychological (28%), depressive (17%) and behavioural problems (1%). Using an international prevalence rate, societal costs related to depressive symptoms resulted in €54 million a year. Conclusions: Cost-effective prevention programmes seem warranted given the high societal costs and risk of future costs as subclinical depressive symptoms could be a precursor of clinical depression later in life

Pretransplant sequential hypo- and normothermic machine perfusion of suboptimal livers donated after circulatory death using a hemoglobin-based oxygen carrier perfusion solution

Ex situ dual hypothermic oxygenated machine perfusion (DHOPE) and normothermic machine perfusion (NMP) of donor livers may have a complementary effect when applied sequentially. While DHOPE resuscitates the mitochondria and increases hepatic adenosine triphosphate (ATP) content, NMP enables hepatobiliary viability assessment prior to transplantation. In contrast to DHOPE, NMP requires a perfusion solution with an oxygen carrier, for which red blood cells (RBC) have been used in most series. RBC, however, have limitations and cannot be used cold. We, therefore, established a protocol of sequential DHOPE, controlled oxygenated rewarming (COR), and NMP using a new hemoglobin-based oxygen carrier (HBOC)-based perfusion fluid (DHOPE-COR-NMP trial, NTR5972). Seven livers from donation after circulatory death (DCD) donors, which were initially declined for transplantation nationwide, underwent DHOPE-COR-NMP. Livers were considered transplantable if perfusate pH and lactate normalized, bile production was >= 10 mL and biliary pH > 7.45 within 150 minutes of NMP. Based on these criteria five livers were transplanted. The primary endpoint, 3-month graft survival, was a 100%. In conclusion, sequential DHOPE-COR-NMP using an HBOC-based perfusion fluid offers a novel method of liver machine perfusion for combined resuscitation and viability testing of suboptimal livers prior to transplantation

Proton Pump Inhibitor Use, Fatigue, and Health-Related Quality of Life in Kidney Transplant Recipients:Results From the TransplantLines Biobank and Cohort Study

Rationale &amp; Objective: Prior studies report that the use of proton pump inhibitors (PPIs) can adversely affect gut microbiota and gastrointestinal uptake of micronutrients, in particular iron and magnesium, and are used frequently by kidney transplant recipients. Altered gut microbiota, iron deficiency, and magnesium deficiency have been implicated in the pathogenesis of chronic fatigue. Therefore, we hypothesized that PPI use may be an important and underappreciated cause of fatigue and reduced health-related quality of life (HRQoL) in this population. Study Design: Cross-sectional study. Setting &amp; Participants: Kidney transplant recipients (≥1 year after transplantation) enrolled in the TransplantLines Biobank and Cohort Study. Exposure: PPI use, PPI type, PPI dosage, and duration of PPI use. Outcome: Fatigue and HRQoL, assessed using the validated Checklist Individual Strength 20 Revised questionnaire and Short Form-36 questionnaire. Analytical Approach: Logistic and linear regression. Results: We included 937 kidney transplant recipients (mean age 56 ± 13 years, 39% female) at a median of 3 (1-10) years after transplantation. PPI use was associated with fatigue severity (regression coefficient 4.02, 95% CI, 2.18 to 5.85, P &lt; 0.001), a higher risk of severe fatigue (OR 2.05, 95% CI, 1.48 to 2.84, P &lt; 0.001), lower physical HRQoL (regression coefficient −8.54, 95% CI, −11.54 to −5.54, P &lt; 0.001), and lower mental HRQoL (regression coefficient −4.66, 95% CI, −7.15 to −2.17, P &lt; 0.001). These associations were independent of potential confounders including age, time since transplantation, history of upper gastrointestinal disease, antiplatelet therapy, and the total number of medications. They were present among all individually assessed PPI types and were dose dependent. Duration of PPI exposure was only associated with fatigue severity. Limitations: Residual confounding and inability to assess causal relationships. Conclusions: PPI use is independently associated with fatigue and lower HRQoL among kidney transplant recipients. PPI use might be an easily accessible target for alleviating fatigue and improving HRQoL among kidney transplant recipients. Further studies examining the effect of PPI exposure in this population are warranted. Plain-Language Summary: In this observational study, we investigated the association of proton pump inhibitors with fatigue and health-related quality of life among kidney transplant recipients. Our data showed that proton pump inhibitors were independently associated with fatigue severity, severe fatigue, and lower physical and mental health-related quality of life. These associations were present among all individually assessed proton pump inhibitor types and were dose dependent. While we await future studies on this topic, proton pump inhibitor use might be an easily accessible target for alleviating fatigue and improving health-related quality of life among kidney transplant recipients.</p

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors

Subcortical volumes across the lifespan: Data from 18,605 healthy individuals aged 3–90 years

Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta‐Analysis (ENIGMA) Consortium to examine age‐related trajectories inferred from cross‐sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3–90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter‐individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age‐related morphometric patterns

Cortical thickness across the lifespan: Data from 17,075 healthy individuals aged 3-90 years

Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large‐scale studies. In response, we used cross‐sectional data from 17,075 individuals aged 3–90 years from the Enhancing Neuroimaging Genetics through Meta‐Analysis (ENIGMA) Consortium to infer age‐related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta‐analysis and one‐way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes

Dismantling the relative effectiveness of core components of cognitive behavioural therapy in preventing depression in adolescents: protocol of a cluster randomized microtrial

Background: Both depressive disorder and subclinical depressive symptoms during adolescence are a major public health concern. Therefore, it is important that depression is detected at an early stage and is treated preventively. Prevention based on the principles of Cognitive Behavioural Therapy (CBT) has proven to be the most effective, however research has mainly focused on the effectiveness of “prevention packages” consisting of multiple CBT-components, rather than on the distinct CBT-components. This study will evaluate the relative effectiveness of four core components of CBT (cognitive restructuring (CR), behavioural activation (BA), problem solving (PS) and relaxation (RE)). In addition the relative (cost-)effectiveness of four different sequences of these components will be evaluated: (1) CR – BA – RE – PS, (2) BA – CR – RE – PS, (3) PS – GA – CR – RE and (4) RE – PS – BA – CR. Methods: We will perform a non-blinded multisite cluster randomized prevention microtrial with four parallel conditions consisting of the four sequences. The four sequences of components will be offered in groups of high school students with elevated depressive symptoms. For each CBT-component a module of three sessions is developed. Assessments will be conducted at baseline, after each CBT-component, prior to each session, at post-intervention and at 6-month followup. Potential moderators and mediators will be evaluated exploratively to shed light on for whom the (sequences of) CBT-components are most effective and how effects are mediated. Discussion: The potential value of the study is insight in the relative effectiveness of the four most commonly used CBT-components and four different sequences, and possible moderators and mediators in the prevention of depression among adolescents. This knowledge can be used to optimize and personalize CBT-programs. Trial registration: The study is registered in the Dutch Trial Register (Trial NL5584 / NTR6176) on October 13, 2016. Keywords: Prevention, Depression, Adolescents, Cognitive behavioural therapy, Comparative effectiveness research, Cost effectivenes

Coping with stressful life events: Cognitive emotion regulation profiles and depressive symptoms in adolescents

Cognitive strategies that adolescents use to cope with negative emotions might show distinct profiles of cognitive emotion regulation strategies, which could be differentially associated with depressive symptoms. In total, 411 Dutch adolescents who had experienced at least one stressful life event that required some coping strategy participated in this study, including 334 nonclinical and 77 clinically depressed adolescents (12–21 years). A person-centered approach with Latent Profile Analysis was used to identify underlying profiles of cognitive emotion regulation based on the adolescents’ reports of their use of cognitive emotion regulation strategies when they were confronted with stressful life events. Nine different strategies, five adaptive and four maladaptive, were used as indicators. Four profiles with distinct features were found in the nonclinical sample, as well as in the combined sample of nonclinical and clinically depressed adolescents: Low Regulators, High Regulators, Maladaptive Regulators, and Adaptive Regulators. In both samples, the High Regulators profile was most commonly used, followed by the Adaptive, Maladaptive, and Low Regulators profile. Maladaptive Regulators endorsed higher levels of depressive symptoms relative to Low, High, and Adaptive Regulators. The findings underscore the utility of using a person-centered approach in order to identify patterns of cognitive emotion regulation deficits in psychopathology

Dismantling the relative effectiveness of core components of cognitive behavioural therapy in preventing depression in adolescents: protocol of a cluster randomized microtrial

Background Both depressive disorder and subclinical depressive symptoms during adolescence are a major public health concern. Therefore, it is important that depression is detected at an early stage and is treated preventively. Prevention based on the principles of Cognitive Behavioural Therapy (CBT) has proven to be the most effective, however research has mainly focused on the effectiveness of “prevention packages” consisting of multiple CBT-components, rather than on the distinct CBT-components. This study will evaluate the relative effectiveness of four core components of CBT (cognitive restructuring (CR), behavioural activation (BA), problem solving (PS) and relaxation (RE)). In addition the relative (cost-)effectiveness of four different sequences of these components will be evaluated: (1) CR – BA – RE – PS, (2) BA – CR – RE – PS, (3) PS – GA – CR – RE and (4) RE – PS – BA – CR. Methods We will perform a non-blinded multisite cluster randomized prevention microtrial with four parallel conditions consisting of the four sequences. The four sequences of components will be offered in groups of high school students with elevated depressive symptoms. For each CBT-component a module of three sessions is developed. Assessments will be conducted at baseline, after each CBT-component, prior to each session, at post-intervention and at 6-month follow-up. Potential moderators and mediators will be evaluated exploratively to shed light on for whom the (sequences of) CBT-components are most effective and how effects are mediated. Discussion The potential value of the study is insight in the relative effectiveness of the four most commonly used CBT-components and four different sequences, and possible moderators and mediators in the prevention of depression among adolescents. This knowledge can be used to optimize and personalize CBT-programs. Trial registration The study is registered in the Dutch Trial Register (Trial NL5584 / NTR6176) on October 13, 2016

Societal costs of subclinical depressive symptoms in Dutch adolescents: a cost‐of‐illness study

Background: Subclinical depressive symptoms are highly prevalent among adolescents and are associated with negative consequences, which may pose an economic burden for society. We conducted a prevalence-based cost-of-illness study using a societal perspective to investigate the cost-of-illness of subclinical depressive symptoms among adolescents. Methods: Using a bottom-up approach, cost questionnaires were assessed to measure costs from 237 Dutch families with an adolescent aged 11–18 with subclinical depressive symptoms (of which 34 met the criteria of a depressive disorder). The study is registered in the Dutch Trial Register (Trial NL5584/NTR6176; www.trialregister.nl/trial/5584). Results: Our calculations show that adolescents with subclinical depressive symptoms cost the Dutch society more than €42 million annually, expressed in costs related to depressive symptoms. Secondary analyses were performed to test the reliability and stability of the costs. When costs related to psychological problems were considered, the annual costs amounted to €67 million. The total societal costs related to physical problems amounted to approximately €126 million. All costs combined (depressive, psychological, behavioural and physical problems and other reasons) amounted to a €243 million. Total costs were highest for physical-related problems of the adolescent (52% of the total costs), followed by psychological (28%), depressive (17%) and behavioural problems (1%). Using an international prevalence rate, societal costs related to depressive symptoms resulted in €54 million a year. Conclusions: Cost-effective prevention programmes seem warranted given the high societal costs and risk of future costs as subclinical depressive symptoms could be a precursor of clinical depression later in life