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Abstract Background Asymptomatic bacteriuria (ASB) – the presence of bacteria in urine without urinary tract infection (UTI) related signs & symptoms (S&S) – is common in the elderly bladder and is not considered pathogenic for UTI. We hypothesise that colonisation with non-uropathogenic bacteria could protect the bladder from invasion of more harmful bacteria. The exact role and dynamics of bacteriuria in the relation to the development of a UTI is still unknown. We aim to provide insight into the course of bacteriuria in the elderly bladder and its relation to UTI in frail older adults. Methods and analysis A prospective observational cohort study is being conducted in Dutch nursing homes (NHs) between February 2024 and December 2025. Urine samples and case report forms (CRF) on UTI-related S&S will be collected from each consenting NH resident every 3 months for a follow-up period of 18 months. Whenever a UTI-suspicion occurs in between the 3 monthly time points, additional data and a urine sample will be collected. Urine samples undergo several urinalyses (e.g. dipstick and bacterial culture). Additional molecular analysis will be conducted on a selection of cultured Escherichia coli (E. coli) for virulence genes. Primary analyses will be conducted between residents with and without ASB at each time point. The primary outcome is UTI incidence during follow-up. In secondary analyses we will also take into account the low versus high presence of virulence genes of the E. coli. Discussion The combination of high ASB prevalence and a reduced ability of frail older adults to express UTI-related S&S may lead to UTI misdiagnosis and inappropriate antibiotic use. To our knowledge, this is the first study to investigate the dynamics and role of bacteriuria in the elderly bladder and their potential protective effect on the development of UTI. The study findings with comprehensive analysis of epidemiological, clinical and molecular data could set the fundamental base for future guidelines and studies, and contribute to improving prevention, diagnosis and treatment of UTI in frail older adults, in addition to contributing to antibiotic stewardship in NHs.

Background The applicability of quantitative flow ratio (QFR), a nonhyperemic, invasive coronary angiography‐derived computation of fractional flow reserve (FFR), has not been studied in coronary artery bypass grafts. We sought to explore the correlation and diagnostic agreement between QFR and FFR in saphenous vein grafts (SVGs). Methods and Results A total of 129 prospectively included patients (mean age 73±8 years, 84% male) with prior coronary artery bypass grafting underwent invasive coronary angiography and pressure‐derived functional assessment in 150 nonoccluded SVGs. QFR dedicated angiography images of the SVGs were acquired and used for offline QFR computation. The diagnostic performance of QFR was compared with 2‐dimensional quantitative coronary angiography, using FFR as a reference. A threshold of ≤0.80 was used to define functional significance. QFR was successfully computed in 140 (93%) SVGs. We found a significant correlation between QFR and FFR (r=0.72, P

Abstract Background Dementia is often associated with Neuropsychiatric Symptoms (NPS) such as agitation, depression, hallucinations, anxiety, that can cause distress for the resident with dementia in long-term care settings and can impose emotional burden on the environment. NPS are often treated with psychotropic drugs, which, however, frequently cause side effects. Alternatively, non-pharmacological interventions can improve well-being and maintain an optimal quality of life (QoL) of those living with dementia. Other QoL related outcomes, such as pain, discomfort and sleep disruption are relevant outcomes in music trials as well. Music therapy is a non-pharmacological intervention that can reduce NPS and improve well-being, and its associated symptoms in dementia. Methods The research will be conducted at eight nursing home facilities of a health care organization in the Netherlands. A sample size of 30 in each group (experimental and control group) is required, totalling 60 residents increased to 80 when considering expected drop out to follow up. The participants in the intervention group receive 30 min of individual music therapy (MT) in their own room by a music therapist twice a week for 12 weeks. The participants in the control group will receive 30 min of individual attention in their own room by a volunteer twice a week for 12 weeks. Assessments will be done at baseline, 6 weeks and 12 weeks. An independent observer, blinded for the intervention or control condition, will assess directly observed well-being (primary outcome) and pain (secondary outcome) before and after the sessions. Nurses will assess other secondary outcomes unblinded, i.e., perceived quality of life and NPS, both assessed with validated scales. The sleep duration will be indirectly assessed by a wrist device called MotionWatch. Information about psychotropic drug use will be derived from electronic medical chart review. Discussion The main purpose of this study is to assess the effects of individual music therapy on directly observed well-being controlled for individual attention in nursing home residents with dementia with NPS. The outcomes refer to both short-term and long-term effects consistent with therapeutic goals of care for a longer term. We hope to overcome limitations of previous study designs such as not blinded designs and music facilitators that were not only music therapists but also occupational therapists and nurses. This study should lead to more focused recommendations for practice and further research into non-pharmacological interventions in dementia such as music therapy. Trial registration The trial is registered at the International Clinical Trials Registry Platform (ICTRP) search portal in the Netherlands Trial Registration number NL7708, registration date 04-05-2019.

Abstract Background Vestibular rehabilitation is a safe and effective exercise-based treatment for patients with chronic vestibular symptoms. However, it is underused in general practice. Internet-based vestibular rehabilitation (Vertigo Training), which has proven to be effective as well, was developed to increase uptake. We now aim to improve the quality of care for patients with vestibular symptoms by carrying out a nationwide implementation of Vertigo Training. We will evaluate the effect of this implementation on primary care. Methods Our implementation study consists of three successive phases: 1) We will perform a retrospective observational cohort study and a qualitative interview study to evaluate the current management of patients with vestibular symptoms in primary care, in particular anti-vertigo drug prescriptions, and identify areas for improvement. We will use the results of this phase to tailor our implementation strategy to the needs of general practitioners (GPs) and patients. 2) This phase entails the implementation of Vertigo Training using a multicomponent implementation strategy, containing: guideline adaptations; marketing strategy; pharmacotherapeutic audit and feedback meetings; education; clinical decision support; and local champions. 3) In this phase, we will evaluate the effect of the implementation in three ways. a. Interrupted time series. We will use routine primary care data from adult patients with vestibular symptoms to compare the number of GP consultations for vestibular symptoms, referrals for vestibular rehabilitation, prescriptions for anti-vertigo drugs, and referrals to physiotherapy and secondary care before and after implementation. b. Prospective observational cohort study. We will extract data from Vertigo Training to investigate the usage and the characteristics of participants. We will also determine whether these characteristics are associated with successful treatment. c. Qualitative interview study. We will conduct interviews with GPs to explore their experiences with the implementation. Discussion This is one of the first studies to evaluate the effect of a nationwide implementation of an innovative treatment on Dutch primary care. Implementation strategies have been researched before, but it remains unclear which ones are the most effective and under what conditions. We therefore expect to gain relevant insights for future projects that aim to implement innovations in primary care.

AbstractIntroductionVincristine 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).MethodsVIPN 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.ResultsForty‐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. Conclusion1‐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.

Abstract Background To enable successful inclusion of electroencephalography (EEG) outcome measures in Alzheimer’s disease (AD) clinical trials, we retrospectively mapped the progression of resting-state EEG measures over time in amyloid-positive patients with mild cognitive impairment (MCI) or dementia due to AD. Methods Resting-state 21-channel EEG was recorded in 148 amyloid-positive AD patients (MCI, n = 88; dementia due to AD, n = 60). Two or more EEG recordings were available for all subjects. We computed whole-brain and regional relative power (i.e., theta (4-8 Hz), alpha1 (8-10 Hz), alpha2 (10-13 Hz), beta (13-30 Hz)), peak frequency, signal variability (i.e., theta permutation entropy), and functional connectivity values (i.e., alpha and beta corrected amplitude envelope correlation, theta phase lag index, weighted symbolic mutual information, inverted joint permutation entropy). Whole-group linear mixed effects models were used to model the development of EEG measures over time. Group-wise analysis was performed to investigate potential differences in change trajectories between the MCI and dementia subgroups. Finally, we estimated the minimum sample size required to detect different treatment effects (i.e., 50% less deterioration, stabilization, or 50% improvement) on the development of EEG measures over time, in hypothetical clinical trials of 1- or 2-year duration. Results Whole-group analysis revealed significant regional and global oscillatory slowing over time (i.e., increased relative theta power, decreased beta power), with strongest effects for temporal and parieto-occipital regions. Disease severity at baseline influenced the EEG measures’ rates of change, with fastest deterioration reported in MCI patients. Only AD dementia patients displayed a significant decrease of the parieto-occipital peak frequency and theta signal variability over time. We estimate that 2-year trials, focusing on amyloid-positive MCI patients, require 36 subjects per arm (2 arms, 1:1 randomization, 80% power) to detect a stabilizing treatment effect on temporal relative theta power. Conclusions Resting-state EEG measures could facilitate early detection of treatment effects on neuronal function in AD patients. Their sensitivity depends on the region-of-interest and disease severity of the study population. Conventional spectral measures, particularly recorded from temporal regions, present sensitive AD treatment monitoring markers.

Abstract Background Comprehensive insight in the longitudinal development of health-related quality of life (HRQOL) after childhood cancer diagnosis could improve quality of care. Thus, we aimed to study the course and biopsychosocial determinants of HRQOL in a unique national cohort of children with cancer. Methods HRQOL of 2154 children with cancer was longitudinally reported (median: 3 reports) between diagnosis and 5 years after, using the pediatric quality of life inventory generic core scales (PedsQL). HRQOL was modelled over time since diagnosis using mixed model analysis for children 2–7 years (caregiver-reports) and ≥ 8 years (self-reports). Differences in the course between hematological, solid and central nervous system malignancies were studied. Additional associations of demographics, disease characteristics (age at diagnosis, relapse, diagnosis after the national centralization of childhood cancer care and treatment components) and caregiver distress (Distress thermometer) were studied. Results Overall, HRQOL improved with time since diagnosis, mostly in the first years. The course of HRQOL differed between diagnostic groups. In children aged 2–7 years, children with a solid tumor had most favorable HRQOL. In children aged ≥ 8 years, those with a hematological malignancy had lower HRQOL around diagnosis, but stronger improvement over time than the other diagnostic groups. In both age-groups, the course of HRQOL of children with a CNS tumor showed little or no improvement. Small to moderate associations (β: 0.18 to 0.67, p

Abstract There is increasing interest in studying retinal biomarkers for various neurodegenerative diseases. Specific protein aggregates associated with neurodegenerative diseases are present in the retina and could be visualised in a non-invasive way. This study aims to assess the specificity and sensitivity of retinal α-synuclein aggregates in neuropathologically characterised α-synucleinopathies, other neurodegenerative diseases and non-neurological controls. Post-mortem eyes (N = 99) were collected prospectively through the Netherlands Brain Bank from donors with Parkinson’s disease (and dementia), dementia with Lewy bodies, multiple system atrophy, Alzheimer’s disease, other neurodegenerative diseases and non-neurological controls. Multiple retinal and optic nerve cross-sections were immunostained with anti-α-synuclein antibodies (LB509, KM51, and anti-pSer129) and assessed for aggregates and inclusions. α-Synuclein was observed as Lewy neurites in the retina and oligodendroglial cytoplasmic inclusions in the optic nerve and was highly associated with Lewy body disease (P

Abstract Aims Problem Management Plus (PM+) has been effective in reducing mental health problems among refugees at three-month follow-up, but there is a lack of research on its long-term effectiveness. This study examined the effectiveness of PM+ in reducing symptoms of common mental disorders at 12-month follow-up among Syrian refugees in the Netherlands. Methods This single-blind, parallel, controlled trial randomised 206 adult Syrians who screened positive for psychological distress and impaired functioning to either PM+ in addition to care as usual (PM+/CAU) or CAU alone. Assessments were at baseline, 1 week and 3 months after the intervention and 12 months after baseline. Outcomes were psychological distress (Hopkins Symptom Checklist [HSCL-25]), depression (HSCL-25 subscale), anxiety (HSCL-25 subscale), posttraumatic stress disorder symptoms (PCL-5), functional impairment (WHODAS 2.0) and self-identified problems (PSYCHLOPS). Results In March 2019–December 2022, 103 participants were assigned to PM+/CAU and 103 to CAU of which 169 (82.0%) were retained at 12 months. Intention-to-treat analyses showed greater reductions in psychological distress at 12 months for PM+/CAU compared to CAU (adjusted mean difference −0.17, 95% CI −0.310 to −0.027; p = 0.01, Cohen’s d = 0.28). Relative to CAU, PM+/CAU participants also showed significant reductions on anxiety (−0.19, 95% CI −0.344 to −0.047; p = 0.01, d = 0.31) but not on any of the other outcomes. Conclusions PM+ is effective in reducing psychological distress and symptoms of anxiety over a period up to 1 year. Additional support such as booster sessions or additional (trauma-focused) modules may be required to prolong and consolidate benefits gained through PM+ on other mental health and psychosocial outcomes.

BackgroundGlioblastomas 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.MethodsHigh-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.ResultsGlioblastoma 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.ConclusionHigh-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 with immunotherapy.

Abstract Background Physical activity (PA) levels might be a simple overall physical function indicator of recovery in acutely hospitalized older adults; however it is unknown which amount and level of PA is associated with recovery. Our objective was to evaluate the amount and level of post discharge PA and its optimum cut-off values associated with recovery among acutely hospitalized older adults and stratified for frailty. Methods We performed a prospective observational cohort study including acutely hospitalized older adults (≥ 70 years). Frailty was assessed using Fried’s criteria. PA was assessed using Fitbit up to one week post discharge and quantified in steps and minutes light, moderate or higher intensity. The primary outcome was recovery at 3-months post discharge. ROC-curve analyses were used to determine cut-off values and area under the curve (AUC), and logistic regression analyses to calculate odds ratios (ORs). Results The analytic sample included 174 participants with a mean (standard deviation) age of 79.2 (6.7) years of whom 84/174 (48%) were frail. At 3-months, 109/174 participants (63%) had recovered of whom 48 were frail. In all participants, determined cut-off values were 1369 steps/day (OR: 2.7, 95% confidence interval [CI]: 1.3–5.9, AUC 0.7) and 76 min/day of light intensity PA (OR: 3.9, 95% CI: 1.8–8.5, AUC 0.73). In frail participants, cut-off values were 1043 steps/day (OR: 5.0, 95% CI: 1.7–14.8, AUC 0.72) and 72 min/day of light intensity PA (OR: 7.2, 95% CI: 2.2–23.1, AUC 0,74). Determined cut-off values were not significantly associated with recovery in non-frail participants. Conclusions Post-discharge PA cut-offs indicate the odds of recovery in older adults, especially in frail individuals, however are not equipped for use as a diagnostic test in daily practice. This is a first step in providing a direction for setting rehabilitation goals in older adults after hospitalization.

Abstract Background To evaluate the effects of a shared decision making (SDM) intervention for older adults with multiple chronic conditions (MCCs). Methods A pragmatic trial evaluated the effects of the SDMMCC intervention, existing of SDM training for nine geriatricians in two hospitals and a preparatory tool for patients. A prospective pre-intervention post-intervention multi-center clinical study was conducted in which an usual care group of older patients with MCC and their informal caregivers was included before the implementation of the intervention and a new cohort of patients and informal caregivers after the implementation of the intervention. SDM was observed using the OPTIONMCC during video-recorded consultations. Patient- and caregivers reported outcomes regarding their role in SDM, involvement, perceived SDM and decisional conflict were measured. The differences between groups regarding the level of observed SDM (OPTIONMCC) were analyzed with a mixed model analysis. Dichotomous patient-reported outcomes were analyzed with a logistic mixed model. Results From two outpatient geriatric clinics 216 patients with MCCs participated. The mean age was 77.3 years, and 56.3% of patients were female. No significant difference was found in the overall level of SDM as measured with the OPTIONMCC or in patient-reported outcomes. However, at item level the items discussing ‘goals’, ‘options’, and ‘decision making’ significantly improved after the intervention. The items discussing ‘partnership’ and ‘evaluating the decision-making process’ showed a significant decrease. Fifty-two percent of the patients completed the preparatory tool, but the results were only discussed in 12% of the consultations. Conclusion This study provides scope for improvement of SDM in geriatrics. Engaging older adults with MCCs and informal caregivers in the decision making process should be an essential part of SDM training for geriatricians, beyond the SDM steps of explaining options, benefits and harms. More attention should be paid to the integration of preparatory work in the consultation.

Background Cost-effective treatments are needed to reduce the burden of depression. One way to improve the cost-effectiveness of psychotherapy might be to increase session frequency, but keep the total number of sessions constant. Aim To evaluate the cost-effectiveness of twice-weekly compared with once-weekly psychotherapy sessions after 12 months, from a societal perspective. Method An economic evaluation was conducted alongside a randomised controlled trial comparing twice-weekly versus once-weekly sessions of psychotherapy (cognitive–behavioural therapy or interpersonal psychotherapy) for depression. Missing data were handled by multiple imputation. Statistical uncertainty was estimated with bootstrapping and presented with cost-effectiveness acceptability curves. Results Differences between the two groups in depressive symptoms, physical and social functioning, and quality-adjusted life-years (QALY) at 12-month follow-up were small and not statistically significant. Total societal costs in the twice-weekly session group were higher, albeit not statistically significantly so, than in the once-weekly session group (mean difference €2065, 95% CI −686 to 5146). The probability that twice-weekly sessions are cost-effective compared with once-weekly sessions was 0.40 at a ceiling ratio of €1000 per point improvement in Beck Depression Inventory-II score, 0.32 at a ceiling ratio of €50 000 per QALY gained, 0.23 at a ceiling ratio of €1000 per point improvement in physical functioning score and 0.62 at a ceiling ratio of €1000 per point improvement in social functioning score. Conclusions Based on the current results, twice-weekly sessions of psychotherapy for depression are not cost-effective over the long term compared with once-weekly sessions.

Abstract Background Confounding is a common issue in epidemiological research. Commonly used confounder-adjustment methods include multivariable regression analysis and propensity score methods. Although it is common practice to assess the linearity assumption for the exposure-outcome effect, most researchers do not assess linearity of the relationship between the confounder and the exposure and between the confounder and the outcome before adjusting for the confounder in the analysis. Failing to take the true non-linear functional form of the confounder-exposure and confounder-outcome associations into account may result in an under- or overestimation of the true exposure effect. Therefore, this paper aims to demonstrate the importance of assessing the linearity assumption for confounder-exposure and confounder-outcome associations and the importance of correctly specifying these associations when the linearity assumption is violated. Methods A Monte Carlo simulation study was used to assess and compare the performance of confounder-adjustment methods when the functional form of the confounder-exposure and confounder-outcome associations were misspecified (i.e., linearity was wrongly assumed) and correctly specified (i.e., linearity was rightly assumed) under multiple sample sizes. An empirical data example was used to illustrate that the misspecification of confounder-exposure and confounder-outcome associations leads to bias. Results The simulation study illustrated that the exposure effect estimate will be biased when for propensity score (PS) methods the confounder-exposure association is misspecified. For methods in which the outcome is regressed on the confounder or the PS, the exposure effect estimate will be biased if the confounder-outcome association is misspecified. In the empirical data example, correct specification of the confounder-exposure and confounder-outcome associations resulted in smaller exposure effect estimates. Conclusion When attempting to remove bias by adjusting for confounding, misspecification of the confounder-exposure and confounder-outcome associations might actually introduce bias. It is therefore important that researchers not only assess the linearity of the exposure-outcome effect, but also of the confounder-exposure or confounder-outcome associations depending on the confounder-adjustment method used.

Abstract Purpose Vincristine (VCR) is a chemotherapeutic agent used in the treatment of pediatric oncology patients, but its main toxicity is VCR‐induced peripheral neuropathy (VIPN). However, whether VIPN has an effect on health‐related quality of life (HR‐QoL) in children during treatment is unknown. Therefore, the aim of our study was to investigate the association between VIPN and HR‐QoL in children starting treatment for cancer. Methods Measurements of VIPN were performed using two tools: Common Terminology Criteria for Adverse Events (CTCAE) and pediatric‐modified Total Neuropathy Score (ped‐mTNS). Assessment of HR‐QoL was done with self‐ and proxy assessment of the Cancer and Generic module of the Pediatric Cancer Quality of Life Inventory™ (PedsQL). Results In total, N = 86 children were included. HR‐QoL of children with VIPN (n = 67%, 76%) was significantly lower in comparison with children without VIPN: estimated Total score of PedsQL Generic (proxy) 84.57; β = −8.96 and 95% confidence interval (CI) −14.48 to −3.43; p = 0.002, estimated PedsQL Generic Total score (self‐reported): 85.16, β = −8.38 (95% CI: −13.76 to −3.00); p = 0.003. Similar results were found in the Pain and Hurt domain of the PedsQL Cancer (pain: estimated score [proxy]: 85.28, β = −9.94 [95%CI: −16.44 to −3.45], p = 0.003; hurt: estimated score [self‐report] 97.57, β = −19.15 [95%CI: −26.82 to −11.48], p

Abstract (1) To evaluate the prevalence of severe and chronic fatigue in subjects with and without chronic disease; (2) to assess to which extent multi-morbidity contributes to severe and chronic fatigue; and (3) to identify predisposing and associated factors for severe and chronic fatigue and whether these are disease-specific, trans-diagnostic, or generic. The Dutch Lifelines cohort was used, including 78,363 subjects with (n = 31,039, 53 ± 12 years, 33% male) and without (n = 47,324, 48 ± 12 years, 46% male) ≥ 1 of 23 chronic diseases. Fatigue was assessed with the Checklist Individual Strength-Fatigue. Compared to participants without a chronic disease, a higher proportion of participants with ≥ 1 chronic disease were severely (23% versus 15%, p

Abstract Background Mediation analysis methodology underwent many advancements throughout the years, with the most recent and important advancement being the development of causal mediation analysis based on the counterfactual framework. However, a previous review showed that for experimental studies the uptake of causal mediation analysis remains low. The aim of this paper is to review the methodological characteristics of mediation analyses performed in observational epidemiologic studies published between 2015 and 2019 and to provide recommendations for the application of mediation analysis in future studies. Methods We searched the MEDLINE and EMBASE databases for observational epidemiologic studies published between 2015 and 2019 in which mediation analysis was applied as one of the primary analysis methods. Information was extracted on the characteristics of the mediation model and the applied mediation analysis method. Results We included 174 studies, most of which applied traditional mediation analysis methods (n = 123, 70.7%). Causal mediation analysis was not often used to analyze more complicated mediation models, such as multiple mediator models. Most studies adjusted their analyses for measured confounders, but did not perform sensitivity analyses for unmeasured confounders and did not assess the presence of an exposure-mediator interaction. Conclusions To ensure a causal interpretation of the effect estimates in the mediation model, we recommend that researchers use causal mediation analysis and assess the plausibility of the causal assumptions. The uptake of causal mediation analysis can be enhanced through tutorial papers that demonstrate the application of causal mediation analysis, and through the development of software packages that facilitate the causal mediation analysis of relatively complicated mediation models.

Abstract Background The incidence of metachronous contralateral inguinal hernia (MCIH) is high in infants with an inguinal hernia (5–30%), with the highest risk in infants aged 6 months or younger. MCIH is associated with the risk of incarceration and necessitates a second operation. This might be avoided by contralateral exploration during primary surgery. However, contralateral exploration may be unnecessary, leads to additional operating time and costs and may result in additional complications of surgery and anaesthesia. Thus, there is no consensus whether contralateral exploration should be performed routinely. Methods The Hernia-Exploration-oR-Not-In-Infants-Analysis (HERNIIA) study is a multicentre randomised controlled trial with an economic evaluation alongside to study the (cost-)effectiveness of contralateral exploration during unilateral hernia repair. Infants aged 6 months or younger who need to undergo primary unilateral hernia repair will be randomised to contralateral exploration or no contralateral exploration (n = 378 patients). Primary endpoint is the proportion of infants that need to undergo a second operation related to inguinal hernia within 1 year after primary repair. Secondary endpoints include (a) total duration of operation(s) (including anaesthesia time) and hospital admission(s); (b) complications of anaesthesia and surgery; and (c) participants’ health-related quality of life and distress and anxiety of their families, all assessed within 1 year after primary hernia repair. Statistical testing will be performed two-sided with α = .05 and according to the intention-to-treat principle. Logistic regression analysis will be performed adjusted for centre and possible confounders. The economic evaluation will be performed from a societal perspective and all relevant costs will be measured, valued and analysed. Discussion This study evaluates the effectiveness and cost-effectiveness of contralateral surgical exploration during unilateral inguinal hernia repair in children younger than 6 months with a unilateral inguinal hernia. Trial registration ClinicalTrials.gov NCT03623893 . Registered on August 9, 2018 Netherlands Trial Register NL7194. Registered on July 24, 2018 Central Committee on Research Involving Human Subjects (CCMO) NL59817.029.18. Registered on July 3, 2018

Background Cognitive therapy and behavioural activation are both widely applied and effective psychotherapies for depression, but it is unclear which works best for whom. Individual participant data (IPD) meta-analysis allows for examining moderators at the participant level and can provide more precise effect estimates than conventional meta-analysis, which is based on study-level data. Aims This article describes the protocol for a systematic review and IPD meta-analysis that aims to compare the efficacy of cognitive therapy and behavioural activation for adults with depression, and to explore moderators of treatment effect. (PROSPERO: CRD42022341602) Method Systematic literature searches will be conducted in PubMed, PsycINFO, EMBASE and the Cochrane Library, to identify randomised clinical trials comparing cognitive therapy and behavioural activation for adult acute-phase depression. Investigators of these trials will be invited to share their participant-level data. One-stage IPD meta-analyses will be conducted with mixed-effects models to assess treatment effects and to examine various available demographic, clinical and psychological participant characteristics as potential moderators. The primary outcome measure will be depressive symptom level at treatment completion. Secondary outcomes will include post-treatment anxiety, interpersonal functioning and quality of life, as well as follow-up outcomes. Conclusions To the best of our knowledge, this will be the first IPD meta-analysis concerning cognitive therapy versus behavioural activation for adult depression. This study has the potential to enhance our knowledge of depression treatment by using state-of-the-art statistical techniques to compare the efficacy of two widely used psychotherapies, and by shedding more light on which of these treatments might work best for whom.

Abstract Background Confounding bias is a common concern in epidemiological research. Its presence is often determined by comparing exposure effects between univariable- and multivariable regression models, using an arbitrary threshold of a 10% difference to indicate confounding bias. However, many clinical researchers are not aware that the use of this change-in-estimate criterion may lead to wrong conclusions when applied to logistic regression coefficients. This is due to a statistical phenomenon called noncollapsibility, which manifests itself in logistic regression models. This paper aims to clarify the role of noncollapsibility in logistic regression and to provide guidance in determining the presence of confounding bias. Methods A Monte Carlo simulation study was designed to uncover patterns of confounding bias and noncollapsibility effects in logistic regression. An empirical data example was used to illustrate the inability of the change-in-estimate criterion to distinguish confounding bias from noncollapsibility effects. Results The simulation study showed that, depending on the sign and magnitude of the confounding bias and the noncollapsibility effect, the difference between the effect estimates from univariable- and multivariable regression models may underestimate or overestimate the magnitude of the confounding bias. Because of the noncollapsibility effect, multivariable regression analysis and inverse probability weighting provided different but valid estimates of the confounder-adjusted exposure effect. In our data example, confounding bias was underestimated by the change in estimate due to the presence of a noncollapsibility effect. Conclusion In logistic regression, the difference between the univariable- and multivariable effect estimate might not only reflect confounding bias but also a noncollapsibility effect. Ideally, the set of confounders is determined at the study design phase and based on subject matter knowledge. To quantify confounding bias, one could compare the unadjusted exposure effect estimate and the estimate from an inverse probability weighted model.

IntroductionResilience incorporates the presence of a positive response to some type of stressor. To properly explore resilience, it is important to systematically identify relevant stressors. We aimed to identify (combinations of) stressors with the strongest relationship with observer-reported and self-reported mood outcomes in older residents of long-term care facilities (LTCFs) in The Netherlands.Materials and MethodsWe included 4,499 older (≥60) residents of 40 LTCFs who participated in the Dutch InterRAI-LTCF cohort between 2005 and 2018. The association of possible stressors (single stressors, number of stressors, and combinations of two stressors) in this population with observer-reported (Depression Rating Scale) and self-reported mood outcomes was analyzed using multilevel tobit models and logistic regressions.ResultsMajor life stressor [“experiences that (threatened to) disrupt(ed) a person's daily routine and imposed some degree of readjustment”] and conflict with other care recipients and/or staff were most strongly associated with both mood outcomes. Furthermore, conflict was a particularly prevalent stressor (24%). Falls, fractures, and hospital visits were more weakly or not associated at all. Overall, the associations were similar for the mood outcomes based on observer-report and self-report, although there were some differences. Multiple stressors were more strongly associated with both mood outcomes than one stressor.ConclusionMajor life stressor and conflict emerged as important stressors for resilience research within the psychological domain in LTCF residents. Further (longitudinal) research is necessary to determine the directionality and relevance of the strong association of conflict with mood for LTCF practice.

Abstract Background Blood donors are at risk for reduced iron stores, because of which donor iron monitoring received increased attention in the last decade. Despite the importance for donor health, international consensus on an appropriate policy for iron monitoring is lacking. Therefore, we conduct a trial to evaluate to what extent ferritin-guided donation intervals are effective in increasing haemoglobin and ferritin levels, decreasing low-haemoglobin deferral, increasing donor return and improving the health of whole blood donors in the Netherlands. Methods Sanquin Blood Bank is implementing ferritin-guided donation intervals to prevent donors from increasing iron loss at repeated donations. Using a stepped wedge cluster randomised trial approach, the design involves a random crossover of 29 clusters of blood collection centres from the existing policy without ferritin measurements to a ferritin-guided donation interval policy. This new policy includes ferritin measurements for all new donors and at every 5th whole blood donation, extending donation intervals to 6 months if ferritin is 15–≤ 30 ng/mL and to 12 months if ferritin is

Abstract Background Foot problems are highly prevalent in patients with rheumatoid arthritis. Treatment of foot problems related to rheumatoid arthritis often consists of custom made foot orthoses. One of the assumed working mechanisms of foot orthoses is redistribution of plantar pressure by creating a larger weight bearing area. Overall, the reported treatment effect of foot orthoses on foot pain in rheumatoid arthritis is small to medium. Therefore, we developed a foot orthoses optimization protocol for evaluation and adaptation of foot orthoses by using the feedback of in-shoe plantar pressure measurements. The objectives of the present study were: 1) to evaluate the 3-months outcomes of foot orthoses developed according to the protocol on pain, physical functioning and forefoot plantar pressure in patients with foot problems related to rheumatoid arthritis, and 2) to determine the relationship between change in forefoot plantar pressure and change in pain and physical functioning. Methods Forty-five patients with foot problems related to rheumatoid arthritis were included and received foot orthoses developed according to the protocol. Outcome measures were assessed at baseline and after three months of wearing foot orthoses in 38 patients. Change scores and effect sizes (ES) were calculated for pain, physical functioning and plantar pressure. In a subgroup of patients with combined forefoot pain and high plantar pressure, the relationship between change in plantar pressure and change in pain and physical functioning was analyzed. Results In the total group of 38 patients, statistically significant changes in pain (ES 0.69), physical functioning (ES 0.82) and forefoot plantar pressure (ES 0.35) were found. In the subgroup (n = 23) no statistically significant relationships were found between change in plantar pressure and change in pain or physical functioning. Conclusion Foot orthoses developed according to a protocol for improving the plantar pressure redistribution properties lead to medium to large improvements in pain and physical functioning. The hypothesis that more pressure reduction would lead to better clinical outcomes could not be proven.

Abstract Background Car driving is a form of passive transportation associated with higher sedentary behaviour, which is associated with morbidity. The decision to drive a car is likely to be influenced by the ‘drivability’ of the built environment, but there is lack of scientific evidence regarding the relative contribution of environmental characteristics of car driving in Europe, compared to individual characteristics. This study aimed to determine which neighbourhood- and individual-level characteristics were associated with car driving in adults of five urban areas across Europe. Second, the study aimed to determine the percentage of variance in car driving explained by individual- and neighbourhood-level characteristics. Methods Neighbourhood environment characteristics potentially related to car use were identified from the literature. These characteristics were subsequently assessed using a Google Street View audit and available GIS databases, in 59 administrative residential neighbourhoods in five European urban areas. Car driving (min/week) and individual level characteristics were self-reported by study participants (analytic sample n = 4258). We used linear multilevel regression analyses to assess cross-sectional associations of individual and neighbourhood-level characteristics with weekly minutes of car driving, and assessed explained variance at each level and for the total model. Results Higher residential density (β:-2.61, 95%CI: − 4.99; -0.22) and higher land-use mix (β:-3.73, 95%CI: − 5.61; -1.86) were significantly associated with fewer weekly minutes of car driving. At the individual level, higher age (β: 1.47, 95%CI: 0.60; 2.33), male sex (β: 43.2, 95%CI:24.7; 61.7), being employed (β:80.1, 95%CI: 53.6; 106.5) and ≥ 3 person household composition (β: 47.4, 95%CI: 20.6; 74.2) were associated with higher weekly minutes of car driving. Individual and neighbourhood characteristics contributed about equally to explained variance in minutes of weekly car driving, with 2 and 3% respectively, but total explained variance remained low. Conclusions Residential density and land-use mix were neighbourhood characteristics consistently associated with minutes of weekly car driving, besides age, sex, employment and household composition. Although total explained variance was low, both individual- and neighbourhood-level characteristics were similarly important in their associations with car use in five European urban areas. This study suggests that more, higher quality, and longitudinal data are needed to increase our understanding of car use and its effects on determinants of health.

Abstract Background Cognitive dysfunction is highly prevalent in Parkinson’s disease (PD) and a large proportion of patients eventually develops PD-related dementia. Currently, no effective treatment is available. Cognitive training is effective in relieving cognitive dysfunctions in several –neurodegenerative– diseases, and earlier small-scale trials have shown positive results for PD. In this randomized controlled trial, we assess the efficacy of online home-based cognitive training, its long-term effects, as well as the underlying neural correlates in a large group of PD patients. Methods In this double-blind randomized controlled trial we will include 140 non-demented patients with idiopathic PD that experience significant subjective cognitive complaints. Participants will be randomized into a cognitive training group and an active control group. In both groups, participants will individually perform an online home-based intervention for eight weeks, three times a week during 45 min. The cognitive training consists of thirteen games that focus on executive functions, attention and processing speed with an adaptive difficulty. The active control comprises three games that keep participants cognitively engaged without a training component. Participants will be subjected to extensive neuropsychological assessments at baseline and after the intervention, and at six months, one year and two years of follow-up. A subset of participants (40 in each treatment condition) will undergo structural and functional magnetic resonance imaging. The primary outcome of this study is the performance on the Tower of London task. Secondary outcomes are objective and subjective cognitive functioning, conversion to PD-related mild cognitive impairment or dementia, functional and structural connectivity and network topological indices measured with magnetic resonance imaging. None of the outcome measures are part of the cognitive training program. Data will be analyzed using multivariate mixed-model analyses and odds ratios. Discussion This study is a large-scale cognitive training study in PD patients that evaluates the efficacy in relieving cognitive dysfunction, and the underlying mechanisms. The strengths of this study are the large sample size, the long follow-up period and the use of neuroimaging in a large subsample. The study is expected to have a low attrition and a high compliance rate given the home-based and easily-accessible intervention in both conditions. Trial registration ClinicalTrials.gov ID NCT02920632. Registered September 30, 2016.

Abstract Background In children physical activity has been shown to be associated with health-related quality of life (HRQoL). This study further explores this association for specific characteristics of sports participation, namely membership of a sports club, frequency of sports participation, performing individual versus team sports, performing indoor versus outdoor sports, while differentiating between specific dimensions in the physical, psychological and social domain of HRQoL. Methods Cross-sectional data were collected from Dutch primary school children aged 10 to 12 years. They completed the Movement and Sports Monitor Questionnaire Youth aged 8 to 12 years (MSMQ) and the KIDSCREEN-52, an HRQoL questionnaire for children and adolescents. The data were examined using linear multilevel analyses because of the clustering of children in schools. Results The questionnaires were completed by 1876 children (response rate 81.3%). Membership of a sports club, moderate or high frequency of sports participation, and performing outdoor sports were all significantly associated with better HRQoL. These associations were largely found in the physical domain of HRQoL, to a lesser degree in the social domain, and to a limited extent in the psychological domain. Conclusion The association between sports participation and HRQoL in children depends on both characteristics of sports participation and the domain of life that is concerned. These differences offer starting points for developing tailor-made sports programs for children.

Abstract Background Logistic regression is often used for mediation analysis with a dichotomous outcome. However, previous studies showed that the indirect effect and proportion mediated are often affected by a change of scales in logistic regression models. To circumvent this, standardization has been proposed. The aim of this study was to show the relative performance of the unstandardized and standardized estimates of the indirect effect and proportion mediated based on multiple regression, structural equation modeling, and the potential outcomes framework for mediation models with a dichotomous outcome. Methods We compared the performance of the effect estimates yielded by the three methods using a simulation study and two real-life data examples from an observational cohort study (n = 360). Results Lowest bias and highest efficiency were observed for the estimates from the potential outcomes framework and for the crude indirect effect ab and the proportion mediated ab/(ab + c’) based on multiple regression and SEM. Conclusions We advise the use of either the potential outcomes framework estimates or the ab estimate of the indirect effect and the ab/(ab + c’) estimate of the proportion mediated based on multiple regression and SEM when mediation analysis is based on logistic regression. Standardization of the coefficients prior to estimating the indirect effect and the proportion mediated may not increase the performance of these estimates.

Background: Few studies have investigated which patients with obsessive-compulsive disorder (OCD) do not recover through regular cognitive behavior therapy or pharmacotherapy and subsequently end up in intensive treatment like day treatment or inpatient treatment. Knowing the predictors of intensive treatment in these patients is significant because it could prevent intensive treatment. This study has identified predictors of intensive treatment in patients with OCD.Methods: Using 6-year longitudinal data of the Netherlands Obsessive Compulsive Disorder Association (NOCDA), potential predictors of intensive treatment were assessed in patients with OCD (n = 419). Intensive treatment was assessed using the Treatment Inventory Costs in Patients with Psychiatric Disorders (TIC-P). Examined potential predictors were: sociodemographics, and clinical and psychosocial characteristics. Logistic Generalized Estimating Equations was used to estimate to what extent the various characteristics (at baseline, 2- and 4-year assessment) predicted intensive treatment in the following 2 years, averaged over the three assessment periods.Results: Being single, more severe comorbid depression, use of psychotropic medication, and a low quality of life predicted intensive treatment in the following 2 years.Conclusions: Therapists should be aware that patients with OCD who are single, who have more severe comorbid depression, who use psychotropic medication, and who have a low quality of life or a drop in quality of life are at risk for intensive treatment. Intensive treatment might be prevented by focusing regular treatment not only on OCD symptoms but also on comorbid depression and on quality of life. Intensive treatment might be improved by providing extra support in treatment or by adjusting treatment to impairments due to comorbid depressive symptoms or a low quality of life.

Background Antidepressant medication and interpersonal psychotherapy (IPT) are both recommended interventions in depression treatment guidelines based on literature reviews and meta-analyses. However, ‘conventional’ meta-analyses comparing their efficacy are limited by their reliance on reported study-level information and a narrow focus on depression outcome measures assessed at treatment completion. Individual participant data (IPD) meta-analysis, considered the gold standard in evidence synthesis, can improve the quality of the analyses when compared with conventional meta-analysis. Aims We describe the protocol for a systematic review and IPD meta-analysis comparing the efficacy of antidepressants and IPT for adult acute-phase depression across a range of outcome measures, including depressive symptom severity as well as functioning and well-being, at both post-treatment and follow-up (PROSPERO: CRD42020219891). Method We will conduct a systematic literature search in PubMed, PsycINFO, Embase and the Cochrane Library to identify randomised clinical trials comparing antidepressants and IPT in the acute-phase treatment of adults with depression. We will invite the authors of these studies to share the participant-level data of their trials. One-stage IPD meta-analyses will be conducted using mixed-effects models to assess treatment effects at post-treatment and follow-up for all outcome measures that are assessed in at least two studies. Conclusions This will be the first IPD meta-analysis examining antidepressants versus IPT efficacy. This study has the potential to enhance our knowledge of depression treatment by comparing the short- and long-term effects of two widely used interventions across a range of outcome measures using state-of-the-art statistical techniques.

Children with a low level of neuromotor fitness are less skilled to participate in sports activities. Moreover, lower levels of neuromotor fitness are related to adiposity, lower cardiovascular health, and poor self-esteem in children. The aim of this paper was to determine neuromotor fitness in 10–12-year-old Dutch children over a 10-year period. Test scores measured in 2015/2017 (N = 533 in 2015, N = 941 in 2017) were compared with scores of same-aged children measured in 2006 (N = 1986). Neuromotor fitness was assessed using the MOPER fitness test battery, including speed and agility, strength, flexibility, and coordination and upper-limb speed. Data were analyzed using multilevel linear regression models and tobit regression analyses in case of skewed distributions with an excess of zeros. Analyses were stratified by age and gender, and adjusted for level of urbanization. Children in 2015/2017 performed significantly worse on speed and agility (β = 0.8 to 1.1 s), significantly better on coordination/upper-limb speed (β = −1.0 to −0.6 s), and–except for 12-year-old girls–significantly worse on flexibility vs. children in 2006 (β = −3.4 to −1.8 cm). Additionally, upper-body strength was significantly worse among 10-year olds (β = −3.2 to −2.5 s) while leg strength was significantly worse among 11-year-olds in 2015/2017 vs. 2006 (β = −1.8 to −1.7 cm). Trunk strength was worse among 11- and 12-year old boys (β = 1.1 to 1.2 s). In line with a previously observed downward trend in neuromotor fitness among children (1980–2006), we found worse scores on speed and agility, and flexibility in 2015/2017 vs. 2006, stressing the need for interventions aimed at improving neuromotor fitness in order to promote physical activity and future health.

Some evidence supports the involvement of the hypothalamic–pituitary–adrenal axis (HPA axis) with multiple sclerosis (MS)-related fatigue. In this study, we determined the relation of HPA-axis function with primary fatigue in MS patients in the longitudinal treating fatigue in a MS cohort. MS patients from the TREeating FAtigue in MS (TREFAMS) research program that consists of three randomized controlled trials to study the effects of aerobic training, energy conservation management, and cognitive behavioral therapy on MS-related fatigue were included. The HPA-axis functioning was determined at baseline, the end of treatment (16 weeks) and after 52 weeks. The cortisol awakening response (CAR) and night-time cortisol levels were analyzed. Fatigue was measured with the fatigue subscale of the Checklist Individual Strength (CIS20r fatigue). There was no relationship between CAR and night-time cortisol parameters with CIS20r fatigue scores. Neither of the treatments influenced CAR and night-time cortisol parameters, with the exception of an effect in the energy conservation management treatment group on the CAR surge increase over 52 weeks (β = −114.8, p = 0.007, 95% CI = −197.6, −31.9). Our data suggest that the diurnal cortisol secretion is not associated with MS-related fatigue. This indicates that MS-related fatigue is not attributed to diurnal cortisol secretion and is likely caused by other disease mechanisms.

Abstract Background It is well known that sports participation is positively associated with psychosocial health in children, but details about this association over time are lacking. This study aimed to explore longitudinal associations between several characteristics of sports participation and three aspects of psychosocial health (internalizing problems, externalizing problems and prosocial behaviour) in Dutch children aged 10–12 years. Methods Data from 695 fourth-grade primary school children were included at baseline; 10–13 months later, 487 children (response rate 70.1%) were retained. At both time points, children reported on their sports participation (Move and Sports Monitor Questionnaire – Youth Aged 8–12 Years) and psychosocial health (Strength and Difficulties Questionnaire). Longitudinal associations between several characteristics of sports participation and the three aspects of psychosocial health were analysed using linear mixed models, both clustering the repeated measures within children and clustering the children within schools. In addition to crude analyses, analyses were performed adjusting for sex, age, BMI, household composition, SES and frequency of sports participation. Results Membership in a sports club, moderate or high frequency of sports participation, performing team sports, performing outdoor sports, performing contact sports and involvement in competition were longitudinally associated with fewer internalizing problems. The longitudinal association of higher frequency of sports participation with fewer internalizing problems was stronger as a child’s BMI increased. The association of performing team sports with fewer internalizing problems was only observed for boys. Membership in a sports club and moderate or high frequency of sports participation were also longitudinally associated with better prosocial behaviour. These associations with prosocial behaviour were stronger for girls. None of the characteristics of sports participation examined were longitudinally associated with externalizing problems. Conclusions This study shows that from a longitudinal perspective, fewer internalizing problems and better prosocial behaviour were seen in children who were active in sports. Fewer internalizing problems were also associated with the kind of sports participation; for example, with performing outdoor sports. No associations were found for externalizing problems. Future research should preferably take the form of an intervention to investigate whether the observed statistical associations are of a causal nature.

Abstract Objective Missing data in longitudinal studies may constitute a source of bias. We suggest three simple missing data indicators for the initial phase of getting an overview of the missingness pattern in a dataset with a high number of follow-ups. Possible use of the indicators is exemplified in two datasets allowing wave nonresponse; a Norwegian dataset of 420 subjects examined at 21 occasions during 6.5 years and a Dutch dataset of 350 subjects with ten repeated measurements over a period of 35 years. Results The indicators Last response (the timing of last response), Retention (the number of responded follow-ups), and Dispersion (the evenness of the distribution of responses) are introduced. The proposed indicators reveal different aspects of the missing data pattern, and may give the researcher a better insight into the pattern of missingness in a study with several follow-ups, as a starting point for analyzing possible bias. Although the indicators are positively correlated to each other, potential predictors of missingness can have a different relationship with different indicators leading to a better understanding of the missing data mechanism in longitudinal studies. These indictors may be useful descriptive tools when starting to look into a longitudinal dataset with many follow-ups.

Abstract Background In literature, not much emphasis has been placed on methods for analyzing repeatedly measured independent variables, even less so for the use in prediction modeling specifically. However, repeated measurements could especially be interesting for the construction of prediction models. Therefore, our objective was to evaluate different methods to model a repeatedly measured independent variable and a long-term fixed outcome variable into a prediction model. Methods Six methods to handle a repeatedly measured predictor were applied to develop prediction models. Methods were evaluated with respect to the models’ predictive quality (explained variance R 2 and the area under the curve (AUC)) and their properties were discussed. The models included overweight and BMI-standard deviation score (BMI-SDS) at age 10 years as outcome and seven BMI-SDS measurements between 0 and 5.5 years as longitudinal predictor. Methods for comparison encompassed developing models including: all measurements; a single (here: the last) measurement; a mean or maximum value of all measurements; changes between subsequent measurements; conditional measurements; and growth curve parameters. Results All methods, except for using the maximum or mean, resulted in prediction models for overweight of similar predictive quality, with adjusted Nagelkerke R 2 ranging between 0.230 and 0.244 and AUC ranging between 0.799 and 0.807. Continuous BMI-SDS prediction showed similar results. Conclusions The choice of method depends on hypothesized predictor-outcome associations, available data, and requirements of the prediction model. Overall, the growth curve method seems to be the most flexible method capable of incorporating longitudinal predictor information without loss in predictive quality.

Abstract Background Work-related stress is highly prevalent in the educational sector. The aim of the current study was to evaluate the effectiveness of an organizational level, participatory intervention on need for recovery and vitality in educational workers. It was hypothesized that the intervention would decrease need for recovery and increase vitality. Methods A quasi-experiment was conducted at two secondary Vocational Education and Training schools (N = 356) with 12- and 24-months follow-up measurements. The intervention consisted of 1) a needs assessment phase, wherein staff and teachers developed actions for happy and healthy working under supervision of a facilitator, and 2) an implementation phase, wherein these actions were implemented by the management teams. Mixed model analysis was applied in order to assess the differences between the intervention and control group on average over time. All analyses were corrected for baseline values and several covariates. Results No effects of the intervention were found on need for recovery, vitality and most of the secondary outcomes. Two small, statistically significant effects were in unfavorable direction: the intervention group scored on average over time significantly lower on absorption (i.e. a subscale of work engagement) and organizational efficacy than the control group. Conclusions Since no beneficial effects of this intervention were found on the primary and most of the secondary outcomes, further implementation of the intervention in its current form is not eligible. We recommend that future organizational level interventions for occupational health 1) incorporate an elaborate implementation strategy, 2) are more specific in relating actions to stressors in the context, and 3) are integrated with secondary preventive, individual focused stress management interventions. Trial registration Netherlands Trial Register NTR3284 (date registered: February 14 2012).

Objective: Brain imaging communities focusing on different diseases have increasingly started to collaborate and to pool data to perform well-powered meta- and mega-analyses. Some methodologists claim that a one-stage individual-participant data (IPD) mega-analysis can be superior to a two-stage aggregated data meta-analysis, since more detailed computations can be performed in a mega-analysis. Before definitive conclusions regarding the performance of either method can be drawn, it is necessary to critically evaluate the methodology of, and results obtained by, meta- and mega-analyses.Methods: Here, we compare the inverse variance weighted random-effect meta-analysis model with a multiple linear regression mega-analysis model, as well as with a linear mixed-effects random-intercept mega-analysis model, using data from 38 cohorts including 3,665 participants of the ENIGMA-OCD consortium. We assessed the effect sizes and standard errors, and the fit of the models, to evaluate the performance of the different methods.Results: The mega-analytical models showed lower standard errors and narrower confidence intervals than the meta-analysis. Similar standard errors and confidence intervals were found for the linear regression and linear mixed-effects random-intercept models. Moreover, the linear mixed-effects random-intercept models showed better fit indices compared to linear regression mega-analytical models.Conclusions: Our findings indicate that results obtained by meta- and mega-analysis differ, in favor of the latter. In multi-center studies with a moderate amount of variation between cohorts, a linear mixed-effects random-intercept mega-analytical framework appears to be the better approach to investigate structural neuroimaging data.

Background: Traditionally, fat mass is estimated using anthropometric models. Air-displacement plethysmography (ADP) is a relatively new technique for determining fat mass. There is limited information on the agreement between these methods in infants and young children. Therefore we aimed to longitudinally compare fat mass percentage values predicted from skinfold thicknesses (SFTs) and ADP in healthy infants and young children. Methods: Anthropometry and body composition were determined at the ages of 1, 4, and 6 months and 2 years. We quantified the agreement between the two methods using the Bland–Altman procedure, linear mixed-model analysis, and intra-class correlation coefficients (ICC). Results: During the first 6 months of life, fat mass% predicted with SFT was significantly different from that measured with ADP in healthy, term-born infants (n = 245). ICCs ranged from 0.33 (at 2 years of age) and 0.47 (at 4 months of age). Although the mean difference (bias) between the methods was low, the Bland–Altman plots showed proportional differences at all ages with wide limits of agreement. Conclusions: There is poor agreement between ADP and SFTs for estimating fat mass in infancy or early childhood. The amount of body fat was found to influence the agreement between the methods.

Several studies have demonstrated an association between polymorphisms in the insulin-like growth factor-1 (IGF-1) gene and IGF-1 serum levels. IGF-1 levels have been associated with cognitive functioning in older persons and growth hormone deficient patients. The present study investigates whether IGF-1 polymorphisms, IGF-1 levels, and cognition are interconnected in healthy adults. Data of 277 participants (mean age: 42.4 years) of the Amsterdam Growth and Health Longitudinal Study on IGF-1 promoter polymorphisms, IGF-1 serum level, spatial working memory (SWM), paired associate learning (PAL), and IQ tests were analyzed. (M)ANOVAs were applied to confirm the associations between IGF-1 polymorphisms and IGF-1 levels and between IGF-1 levels and cognition. Three groups were distinguished based on specific IGF-1 polymorphism alleles: a homozygote 192 bp/192 bp genotype, a heterozygote 192 bp/x genotype, and a noncarrier x/x genotype. Although different IGF-1 levels were found for the three genotypes, performance on all cognitive tasks and IQ measures was similar. Despite the associations between IGF-1 polymorphisms and IGF-1 levels, no association was found between cognition and IGF-1 levels. It seems that IGF-1 does not play a role in the cognitive performance of healthy middle-aged adults. Possible, IGF-1 fulfills a more developmental and protective role in cognition which becomes apparent during childhood, old-age, or disease.