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Background: Glioblastomas manipulate the immune system both locally and systemically, yet, glioblastoma-associated changes in peripheral blood immune composition are poorly studied. Age and dexamethasone administration in glioblastoma patients have been hypothesized to limit the effectiveness of immunotherapy, but their effects remain unclear. We compared peripheral blood immune composition in patients with different types of brain tumor to determine the influence of age, dexamethasone treatment, and tumor volume. Methods: High-dimensional mass cytometry was used to characterise peripheral blood mononuclear cells of 169 patients with glioblastoma, lower grade astrocytoma, metastases and meningioma. We used blood from medically-refractory epilepsy patients and healthy controls as control groups. Immune phenotyping was performed using FlowSOM and t-SNE analysis in R followed by supervised annotation of the resulting clusters. We conducted multiple linear regression analysis between intracranial pathology and cell type abundance, corrected for clinical variables. We tested correlations between cell type abundance and survival with Cox-regression analyses. Results: Glioblastoma patients had significantly fewer naive CD4+ T cells, but higher percentages of mature NK cells than controls. Decreases of naive CD8+ T cells and alternative monocytes and an increase of memory B cells in glioblastoma patients were influenced by age and dexamethasone treatment, and only memory B cells by tumor volume. Progression free survival was associated with percentages of CD4+ regulatory T cells and double negative T cells. Conclusion: High-dimensional mass cytometry of peripheral blood in patients with different types of intracranial tumor provides insight into the relation between intracranial pathology and peripheral immune status. Wide immunosuppression associated with age and pre-operative dexamethasone treatment provide further evidence for their deleterious effects on treatment wi

Introduction: Vincristine is an integral component of treatment for children with cancer. Its main dose-limiting side effect is vincristine-induced peripheral neuropathy (VIPN). The VINCA trial was a randomized controlled trial that explored the effect of 1-hour infusion compared with push injection of vincristine on the development of VIPN in children with cancer. The short-term outcomes (median follow-up 9 months) showed that there was no difference in VIPN between the randomization groups. However, 1-hour infusion was less toxic in children who also received azoles. We now report the results of the final analyses (median follow-up 20 months), which includes treatment outcome as a secondary objective (follow-up 3 years). Methods: VIPN was measured 1–7 times per participant using the Common Terminology Criteria for Adverse Events (CTCAE) and the pediatric-modified total neuropathy score. Poisson mixed model and logistic generalized estimating equation analysis for repeated measures were performed.Results: Forty-five participants per randomization group were included. There was no significant effect of 1-hour infusion compared with push injection on VIPN. In participants receiving concurrent azoles, the total CTCAE score was significantly lower in the one-hour group (rate ratio 0.52, 95% confidence interval 0.33–0.80, p = 0.003). Four patients in the one-hour group and one patient in the push group relapsed. Two patients in the one-hour group died. Conclusion:1-hour infusion of vincristine is not protective against VIPN. However, in patients receiving concurrent azoles, 1-hour infusion may be less toxic. The difference in treatment outcome is most likely the result of differences in risk profile.

Purpose: Severe traumatic brain injury is a leading cause of mortality and morbidity, and these patients are frequently intubated in the prehospital setting. Cerebral perfusion and intracranial pressure are influenced by the arterial partial pressure of CO2 and derangements might induce further brain damage. We investigated which lower and upper limits of prehospital end-tidal CO2 levels are associated with increased mortality in patients with severe traumatic brain injury. Methods: The BRAIN-PROTECT study is an observational multicenter study. Patients with severe traumatic brain injury, treated by Dutch Helicopter Emergency Medical Services between February 2012 and December 2017, were included. Follow-up continued for 1 year after inclusion. End-tidal CO2 levels were measured during prehospital care and their association with 30-day mortality was analyzed with multivariable logistic regression. Results: A total of 1776 patients were eligible for analysis. An L-shaped association between end-tidal CO2 levels and 30-day mortality was observed (p = 0.01), with a sharp increase in mortality with values below 35 mmHg. End-tidal CO2 values between 35 and 45 mmHg were associated with better survival rates compared to < 35 mmHg. No association between hypercapnia and mortality was observed. The odds ratio for the association between hypocapnia (< 35 mmHg) and mortality was 1.89 (95% CI 1.53–2.34, p < 0.001) and for hypercapnia (≥ 45 mmHg) 0.83 (0.62–1.11, p = 0.212). Conclusion: A safe zone of 35–45 mmHg for end-tidal CO2 guidance seems reasonable during prehospital care. Particularly, end-tidal partial pressures of less than 35 mmHg were associated with a significantly increased mortality.

Background: Rheumatoid arthritis is a chronic inflammatory disease with a well-recognised female preponderance. In this post-hoc analysis of the NORD-STAR trial, we aimed to examine sex differences in remission rates with three different biological treatments combined with methotrexate versus active conventional treatment over 24 weeks, in patients with early rheumatoid arthritis. Methods: NORD-STAR was a multicentre, investigator-initiated, assessor-blinded, phase 4, randomised, controlled trial of early rheumatoid arthritis, done in Denmark, Finland, Iceland, Norway, Sweden, and the Netherlands. Newly diagnosed patients, naive to disease-modifying antirheumatic drugs, aged 18 years or older with early rheumatoid arthritis and with a symptom duration less than 24 months were randomly assigned (1:1:1:1) to receive active conventional treatment, certolizumab-pegol, abatacept, or tocilizumab. Sex was reported in case report forms by study physicians or by study nurses. Data on gender were not collected. Remission outcomes were analysed with logistic generalised estimating equations (GEE), using a logit link and exchangeable correlation matrix. The model included treatment, time, sex, and the relevant interactions. For this post-hoc analysis, the co-primary outcomes were differences in Clinical Disease Activity Index (CDAI) remission (CDAI score ≤2·8) between sexes over time and at week 24, assessed with interaction terms (men vs women within each treatment comparison) and using active conventional treatment as the reference. We present adjusted average marginal differences in remission rates (risk differences) with 95% CIs. Findings: Between Dec 14, 2012, and Dec 11, 2018, 812 patients were enrolled and randomly assigned; 217 received active conventional treatment, 203 received certolizumab-pegol, 204 received abatacept, and 188 received tocilizumab. All 812 patients were included in this analysis; 561 (69%) were women and 251 (31%) were men. Observed CDAI remissio

Introduction: Cognitive training (CT) has been proposed as a treatment option for cognitive impairment in Parkinson's disease (PD). We aimed to assess the efficacy of adaptive, computerized CT on cognitive function in PD. Methods: In this double-blind, randomized controlled trial we enrolled PD patients that experienced substantial subjective cognitive complaints. Over a period of eight weeks, participants underwent 24 sessions of computerized multi-domain CT or an active control intervention for 45 min each (randomized 1:1). The primary outcome was the accuracy on the Tower of London task; secondary outcomes included effects on other neuropsychological outcomes and subjective cognitive complaints. Outcomes were assessed before and after training and at six-months follow-up, and analyzed with multivariate mixed-model analyses. Results: The intention-to-treat population consisted of 136 participants (n = 68 vs. n = 68, age M: 62.9y, female: 39.7%). Multivariate mixed-model analyses showed no group difference on the Tower of London accuracy corrected for baseline performance (n = 130): B: −0.06, 95% CI: −0.27 to 0.15, p = 0.562. Participants in the CT group were on average 0.30 SD (i.e., 1.5 s) faster on difficulty load 4 of this task (secondary outcome): 95% CI: −0.55 to −0.06, p = 0.015. CT did not reduce subjective cognitive complaints. At follow-up, no group differences were found. Conclusions: This study shows no beneficial effect of eight-week computerized CT on the primary outcome (i.e., planning accuracy) and only minor improvements on secondary outcomes (i.e., processing speed) with limited clinical impact. Personalized or ecologically valid multi-modal intervention methods could be considered to achieve clinically meaningful and lasting effects.

We aimed to obtain reliable reference charts for sleep duration, estimate the prevalence of sleep complaints across the lifespan and identify risk indicators of poor sleep. Studies were identified through systematic literature search in Embase, Medline and Web of Science (9 August 2019) and through personal contacts. Eligible studies had to be published between 2000 and 2017 with data on sleep assessed with questionnaires including ≥100 participants from the general population. We assembled individual participant data from 200,358 people (aged 1–100 years, 55% female) from 36 studies from the Netherlands, 471,759 people (40–69 years, 55.5% female) from the United Kingdom and 409,617 people (≥18 years, 55.8% female) from the United States. One in four people slept less than age-specific recommendations, but only 5.8% slept outside of the ‘acceptable’ sleep duration. Among teenagers, 51.5% reported total sleep times (TST) of less than the recommended 8–10 h and 18% report daytime sleepiness. In adults (≥18 years), poor sleep quality (13.3%) and insomnia symptoms (9.6–19.4%) were more prevalent than short sleep duration (6.5% with TST <6 h). Insomnia symptoms were most frequent in people spending ≥9 h in bed, whereas poor sleep quality was more frequent in those spending

Background: Psychotropic drugs are frequently prescribed to people with dementia in nursing homes although severe adverse events and side effects are common. Less is known about the prevalence and types of psychotropic drug prescription in primary care for people with dementia. Objective: This study examined the prevalence of psychotropic drug prescriptions in primary care among persons with dementia from the year of diagnosis onwards. Methods: A longitudinal observational study using electronic health record (EHR) data was conducted. People with dementia were selected from EHR data of 451 general practices in the Netherlands. Age and gender-adjusted psychotropic drug prescription rates were calculated per 1000 person-years from the year the dementia diagnosis was first recorded in general practice up to 8 years after diagnosis. Results: Data of 15,687 patients were analyzed. The prescription rate of psychotropic drugs (not including antidementia drugs) was 420 per 1000 person-years (95% CI 409; 431) in the first year after the recorded dementia diagnosis, which increased to 801 per 1000 person-years (95% CI 649; 989) in the eighth year. The most frequently prescribed drugs were antidepressants, antipsychotics, and antidementia drugs, followed by anxiolytics, hypnotics, and antiepileptics. Conclusions: After a dementia diagnosis is recorded in general practice, the prevalence of psychotropic drug prescriptions is substantial and increases steadily during the disease trajectory of persons with dementia. Although the (in)appropriateness of prescribing was not assessed, these insights may stimulate primary care clinicians to (re)consider their prescription policy of psychotropics for people with dementia more carefully.

Purpose This study investigated the effects of psychosocial working conditions on mental health-related long-term sickness absence and whether distress, work satisfaction, burnout, engagement, and work ability mediated the associations between psychosocial working conditions and mental health-related long-term sickness absence. Methods This cohort study included 53,833 non-sick listed workers who participated in occupational health surveys between 2010 and 2013. The effects of the individual psychosocial working conditions on mental long-term sickness absence were analyzed using univariable and multivariable logistic regression analyses. Mediation analyses were performed to examine the mediating role of distress, burnout, work satisfaction, engagement, and work ability between psychosocial working conditions and mental long-term sickness absence. The mediation analyses were performed using structural equation modeling. Results Role clarity, cognitive demands, emotional demands, work variety, learning opportunities, and co-worker support were related to mental health-related long-term sickness absence after adjustment for other working conditions. The relationship between emotional demands and mental health-related long-term sickness absence was the strongest, OR 1.304 (p < 0.001, 95% CI 1.135 to 1.498). The relation between psychosocial working conditions and mental health-related long-term sickness absence was mediated by distress, burnout, work satisfaction, engagement, and work ability. Distress was the most important mediator between psychosocial working conditions and mental health-related long-term sickness absence. Conclusions Psychosocial working conditions are related to mental health-related long-term sickness absence. After correction for other working conditions, the association between emotional demands and mental health-related long-term sickness absence was the strongest. Psychosoci

Background: Psychosocial work characteristics are associated with all-cause long-term sickness absence (LTSA). Aims: This study investigated whether psychosocial work characteristics such as higher workload, faster pace of work, less variety in work, lack of performance feedback, and lack of supervisor support are prospectively associated with higher LTSA due to mental disorders. Methods: Cohort study including 4877 workers employed in the distribution and transport sector in The Netherlands. Psychosocial work characteristics were included in a logistic regression model estimating the odds ratios (OR) and 95% confidence intervals (CI) of mental LTSA during 2-year follow-up. The ability of the regression model to discriminate between workers with and without mental LTSA was investigated with the area under the receiver operating characteristic curve (AUC). Results: Tow thousand seven hundred and eighty-two (57%) workers were included in the analysis; 73 (3%) had mental LTSA. Feedback about one’s performance (OR = 0.82; 95% CI 0.70–0.96) was associated with mental LTSA. A prediction model including psychosocial work characteristics poorly discriminated (AUC = 0.65; 95% CI 0.56–0.74) between workers with and without mental LTSA. Conclusions: Feedback about one’s performance is associated with lower rates of mental LTSA, but it is not useful to measure psychosocial work characteristics to identify workers at risk of mental LTSA.

Purpose: We examined the efficacy of adding short-term psychodynamic psychotherapy (STPP) to antidepressants in the treatment of depression by means of a systematic review and meta-analysis of individual participant data, which is currently considered the most reliable method for evidence synthesis. Results: A thorough systematic literature search resulted in 7 studies comparing combined treatment of antidepressants and STPP versus antidepressant mono-therapy (n = 3) or versus antidepressants and brief supportive psychotherapy (n = 4). Individual participant data were obtained for all these studies and totaled 482 participants. Across the total sample of studies, combined treatment of antidepressants and STPP was found significantly more efficacious in terms of depressive symptom levels at both post-treatment (Cohen's d = 0.26, SE = 0.10, p =.01) and follow-up (d = 0.50, SE = 0.10, p <.001). This effect was most apparent at follow-up and in studies examining STPP's specific treatment efficacy. Effects were still apparent in analyses that controlled for risk of bias and STPP quality in the primary studies. Conclusions: These findings support the evidence-base of adding STPP to antidepressants in the treatment of depression. However, further studies are needed, particularly assessing outcome measures other than depression and cost-effectiveness, as well as examining the relative merits of STPP versus other psychotherapies as added to antidepressants.

Background It is unclear what session frequency is most effective in cognitive-behavioural therapy (CBT) and interpersonal psychotherapy (IPT) for depression.Aims Compare the effects of once weekly and twice weekly sessions of CBT and IPT for depression.Method We conducted a multicentre randomised trial from November 2014 through December 2017. We recruited 200 adults with depression across nine specialised mental health centres in the Netherlands. This study used a 2 × 2 factorial design, randomising patients to once or twice weekly sessions of CBT or IPT over 16-24 weeks, up to a maximum of 20 sessions. Main outcome measures were depression severity, measured with the Beck Depression Inventory-II at baseline, before session 1, and 2 weeks, 1, 2, 3, 4, 5 and 6 months after start of the intervention. Intention-to-treat analyses were conducted.Results Compared with patients who received weekly sessions, patients who received twice weekly sessions showed a statistically significant decrease in depressive symptoms (estimated mean difference between weekly and twice weekly sessions at month 6: 3.85 points, difference in effect size d = 0.55), lower attrition rates (n = 16 compared with n = 32) and an increased rate of response (hazard ratio 1.48, 95% CI 1.00-2.18).Conclusions In clinical practice settings, delivery of twice weekly sessions of CBT and IPT for depression is a way to improve depression treatment outcomes.

Background. The time course of cortical activation and its relation with clinical measures may elucidate mechanisms underlying spontaneous neurobiological recovery after stroke. Objective. We aimed to investigate (1) the time course of cortical activation as revealed by EEG-based spectral characteristics during awake rest and (2) the development of these spectral characteristics in relation to global neurological and upper-limb motor recovery in the first 6 months poststroke. Methods. Resting-state EEG was measured serially in 41 patients after a first-ever ischemic stroke, within 3 and at 5, 12, and 26 weeks poststroke. We computed the brain symmetry index (BSI) and directional BSI (BSIdir) over different frequency bands (1-25 Hz, delta, theta) and delta/alpha ratio (DAR). The National Institutes of Health Stroke Scale (NIHSS) and Fugl-Meyer motor assessment of the upper extremity (FM-UE) were determined as clinical reflections of spontaneous neurobiological recovery. Longitudinal changes in spectral characteristics and within- and between-subject associations with NIHSS and FM-UE were analyzed with linear mixed models. Results. Spectral characteristics showed a gradual normalization over time, within and beyond 12 weeks poststroke. Significant within- and between-subject associations with NIHSS were found for DAR of the affected hemisphere (DARAH) and BSIdirdelta. BSIdirdelta also demonstrated significant within- and between-subject associations with FM-UE. Conclusions. Changes in spectral characteristics are not restricted to the time window of recovery of clinical neurological impairments. The present study suggests that decreasing DARAH and BSIdirdelta reflect improvement of global neurological impairments, whereas BSIdirdelta was also specifically associated with upper-limb motor recovery early poststroke.

Background & aims: Protein-energy malnutrition is a health concern among older adults. Improving nutritional status by increasing energy and protein intake likely benefits health. We therefore aimed to investigate effects of nutritional interventions in older adults (at risk of malnutrition) on change in energy intake and body weight, and explore if the intervention effect was modified by study or participants’ characteristics, analysing pooled individual participant data. Methods: We searched for RCTs investigating the effect of dietary counseling, oral nutritional supplements (ONS) or both on energy intake and weight. Principle investigators of eligible studies provided individual participant data. We investigated the effect of nutritional intervention on meaningful increase in energy intake (>250 kcal/day) and meaningful weight gain (>1.0 kg). Logistic generalized estimating equations were performed and ORs with 95% CIs presented. Results: We included data of nine studies with a total of 990 participants, aged 79.2 ± 8.2 years, 64.5% women and mean baseline BMI 23.9 ± 4.7 kg/m2. An non-significant intervention effect was observed for increase in energy intake (OR:1.59; 95% CI 0.95, 2.66) and a significant intervention effect for weight gain (OR:1.58; 95% CI 1.16, 2.17). Stratifying by type of intervention, an intervention effect on increase in energy intake was only observed for dietary counseling in combination with ONS (OR:2.28; 95% CI 1.90, 2.73). The intervention effect on increase in energy intake was greater for women, older participants, and those with lower BMI. Regarding weight gain, an intervention effect was observed for dietary counseling (OR:1.40; 95% CI 1.14, 1.73) and dietary counseling in combination with ONS (OR:2.48; 95% CI 1.92, 3.31). The intervention effect on weight gain was not influenced by participants’ characteristics. Conclusions: Based on pooled data of older adults (at risk of malnutrition), nutritional interve