Daily Physical Activity Patterns and Their Associations with Cardiometabolic Biomarkers: The Maastricht Study.

PURPOSE: This study aimed to identify physical activity patterns and examine their association with cardiometabolic biomarkers in a cross-sectional design. METHODS: Overall 6072 participants (mean age, 60.2 yr; SD 8.6 yr, 50% women) from The Maastricht Study provided daily physical activity data collected with thigh-worn activPAL3 accelerometers. The patterns of daily physical activity over weekdays and weekend days were identified by using Group Based Trajectory Modeling. Cardiometabolic biomarkers included body mass index, waist circumference, office blood pressure, glucose, HbA1c, and cholesterol levels. Associations between the physical activity patterns and cardiometabolic outcomes were examined using the analyses of covariance adjusted for sex, age, education, smoking, and diet. Because of statistically significant interaction, the analyses were stratified by type 2 diabetes status. RESULTS: Overall, seven physical activity patterns were identified: consistently inactive (21% of participants), consistently low active (41%), active on weekdays (15%), early birds (2%), consistently moderately active (7%), weekend warriors (8%), and consistently highly active (6%). The consistently inactive and low active patterns had higher body mass index, waist, and glucose levels compared with the consistently moderately and highly active patterns, and these associations were more pronounced for participants with type 2 diabetes. The more irregular patterns accumulated moderate daily total activity levels but had rather similar cardiometabolic profiles compared with the consistently active groups. CONCLUSIONS: The cardiometabolic profile was most favorable in the consistently highly active group. All patterns accumulating moderate to high levels of daily total physical activity had similar health profile suggesting that the amount of daily physical activity rather than the pattern is more important for cardiometabolic health.

Effect, economic and process-evaluation of a generic function focused care program for long-term care; study protocol of a multicenter cluster-randomized trial.

BACKGROUND: Nurses are in a key position to stimulate older people to maximize their functional activity and independence. However, nurses still often work in a task-oriented manner and tend to take over tasks unnecessarily. It is evident to support nurses to focus on the capabilities of older people and provide care assistance only when required. Function-Focused Care (FFC) is a holistic care-philosophy aiming to support nurses to deliver care in which functioning and independence of older people is optimized. Dutch and internationally developed FFC-based interventions often lack effectiveness in changing nurses' and client's behavior. Process-evaluations have yielded lessons and implications resulting in the development of an advanced generic FFC-program: the 'SELF-program'. The SELF-program aims to improve activity stimulation behavior of nurses in long-term care services, and with that optimize levels of self-reliance in activities of daily living (ADL) in geriatric clients. The innovative character of the SELF-program lies for example in the application of extended behavior change theory, its interactive nature, and tailoring its components to setting-specific elements and needs of its participants. This paper describes the outline, content and theoretical background of the SELF-program. Subsequently, this paper describes a protocol for the assessment of the program's effect, economic and process-evaluation in a two-arm (SELF-program vs care as usual) multicenter cluster-randomized trial (CRT). METHOD: The proposed CRT has three objectives, including getting insight into the program's: (1) effectiveness regarding activity stimulation behavior of nurses and self-reliance in ADL of geriatric clients, and (2) cost-effectiveness from a societal perspective including assessments of quality of life and health-care use. Measurements will take place prior to program implementation (baseline), directly after (T1), and in long-term (T2). Parallel to the CRT, a process evaluation will be conducted to provide insight into the program's: (3) feasibility regarding implementation, mechanisms of impact and contextual factors. DISCUSSION: The SELF-program was developed following the Medical Research Council framework, which addresses the systematic development, feasibility testing, evaluation and implementation of complex interventions. The program has been subjected to a feasibility study before and results of studies described in this protocol are expected to be available from end 2022 onwards. TRIAL-REGISTRATION: The study is registered in the Dutch Trial Register ( NL9189 ), as of December 22 2020.

Children's sunburn exposed: identification of sun exposure and parental sun protection patterns.

Preventing sunburn in childhood is imperative in the light of skin cancer prevention. To provide directions for targeted interventions, a better understanding of children's sunburn and associated parental behaviours is necessary. To explore sun exposure and parent-for-child sun protection patterns and their relationship with sunburn experienced in children. An online survey was conducted among parents (n = 1,299) of children (4 to 12 years). Latent class analysis (LCA) was performed to identify parental subgroups for children's sunburn, sun exposure and several sun protection behaviours (i.e. applying sunscreen, clothing, seeking shade) in two sun exposure settings (i.e. planned versus incidental). LCA results were validated by assessing predictions of class membership through several socio-demographic characteristics. Reported sunburn in the previous year was frequent (>40%). Four latent classes of sunburn-exposure-protection were identified. Overall, the majority of parents reported fair sun protection behaviours. While a low level of protection behaviour was not strongly reflected in lower sunburn rates among the classes, a high level of planned exposure (e.g. going to the beach) seemed to correspond with higher sunburn risk. Parents of younger children and those with more sensitive skin reported sun protection measures more frequently. Older children and those with more sensitive skin experienced more sunburn. This study contributes to current insight into children's sunburn, based on parent-proxy reports. Although a clear differentiation in sunburn risk was not found, several variables, relevant for future interventions, were indicated. By further understanding the complexity of children's sunburn, further research may be directed accordingly.

Effectiveness of a reablement training program for homecare staff on older adults' sedentary behavior: A cluster randomized controlled trial.

BACKGROUND/OBJECTIVES: Homecare staff often take over activities instead of "doing activities with" clients, thereby hampering clients from remaining active in daily life. Training and supporting staff to integrate reablement into their working practices may reduce clients' sedentary behavior and improve their independence. This study evaluated the effectiveness of the "Stay Active at Home" (SAaH) reablement training program for homecare staff on older homecare clients' sedentary behavior. DESIGN: Cluster randomized controlled trial (c-RCT). SETTING: Dutch homecare (10 nursing teams comprising a total of 313 staff members). PARTICIPANTS: 264 clients (aged ≥65 years). INTERVENTION: SAaH seeks to equip staff with knowledge, attitude, and skills on reablement, and to provide social and organizational support to implement reablement in homecare practice. SAaH consists of program meetings, practical assignments, and weekly newsletters over a 9-month period. The control group received no additional training and delivered care as usual. MEASUREMENTS: Sedentary behavior (primary outcome) was measured using tri-axial wrist-worn accelerometers. Secondary outcomes included daily functioning (GARS), physical functioning (SPPB), psychological functioning (PHQ-9), and falls. Data were collected at baseline and at 12 months; data on falls were also collected at 6 months. Intention-to-treat analyses using mixed-effects linear and logistic regression were performed. RESULTS: We found no statistically significant differences between the study groups for sedentary time expressed as daily minutes (adjusted mean difference: ß 18.5 (95% confidence interval [CI] -22.4, 59.3), p = 0.374) and as proportion of wake/wear time (ß 0.6 [95% CI -1.5, 2.6], p = 0.589) or for most secondary outcomes. CONCLUSION: Our c-RCT showed no evidence for the effectiveness of SAaH for all client outcomes. Refining SAaH, by adding components that intervene directly on homecare clients, may optimize the program and require further research. Additional research should explore the effectiveness of SAaH on behavioral determinants of clients and staff and cost-effectiveness.

Validation of the Dutch Version of the M.D. Anderson Dysphagia Inventory for Neurogenic Patients.

BACKGROUND/AIM: The aim of this study was to validate the Dutch-language version of the M.D. Anderson Dysphagia Inventory (MDADI) for patients with neurogenic oropharyngeal dysphagia (OD). METHODS: One hundred and seventy-eight patients with neurogenic OD and 92 healthy control subjects completed the MDADI and the Dutch version of the Swallowing Quality-of-Life Questionnaire (SWAL-QOL-NL). Exclusion criteria were: suffering from a concurrent head-and-neck oncological disease, scoring below 23 on a Mini Mental State Examination, being older than 85 years, and being illiterate or blind. None of the patients was in a palliative state of disease. Floor and ceiling effects, known-groups validity, internal consistency, construct validity, and criterion validity were assessed. RESULTS: The MDADI total score showed no floor or ceiling effects for the patient group. Known-groups validity was confirmed by group differences in score distributions between patients and healthy control subjects. The internal consistency showed Cronbach's α-values ranging from 0.77 to 0.92. Correlations between the MDADI subscales and SWAL-QOL-NL domains were moderate to strong: 0.71, 0.70, and 0.62 (convergent construct validity). Correlations between the MDADI scores and the SWAL-QOL-NL domains general burden, food selection, eating duration, communication, mental health, social functioning, and frequency of symptoms were moderate to strong, ranging from 0.41 to 0.75. Weak correlations (<0.4) were found between the MDADI scores and the SWAL-QOL-NL domains eating desire, sleep, and fatigue. CONCLUSION: The results of this study show that the Dutch translation of the MDADI is a psychometrically validated and suitable dysphagia-specific quality-of-life questionnaire for patients with neurogenic OD.

Phenotyping the shoulder patient based on ultrasound-detected pathologies: a cross-sectional study in general practice.

BACKGROUND: Shoulder complaints arise from a single pathology or a combination of different underlying pathologies that are hard to differentiate in general practice. Subgroups of pathologies have been identified on the basis of ultrasound imaging that might affect treatment outcomes. OBJECTIVE: Our aim was to validate the existence of different subgroups of patients with shoulder complaints, based on ultrasound-detected pathology, and compare clinical features among them. Profiling shoulder patients into distinct shoulder pathology phenotypes could help designing tailored treatment trials. METHODS: This was a cross-sectional study in general practice. Data were extracted from 840 first visit patient records at a single diagnostic centre in the Netherlands. Exclusion criteria were age <18 years and previous shoulder surgery. Latent class analysis was used to uncover cross-combinations of ultrasound detected pathologies, yielding subgroups of shoulder patients. The uncovered subgroups were compared for demographic and clinical characteristics. RESULTS: We uncovered four distinct subgroups of patients with shoulder complaints: (i) Frozen shoulder group (11%), (ii) Limited pathology group (44%), (iii) Degenerative pathology group (31%) and (iv) Calcifying tendinopathy group (15%). Group comparisons showed significant differences in demographic and clinical characteristics among subgroups, consistent with the literature. CONCLUSION: In a general practice population, we uncovered four different phenotypes of shoulder patients on the basis of ultrasound detected pathology. These phenotypes can be used designing tailored treatment trials in patients with shoulder complaints.

Highways to Ageing - Linking life course SEP to multivariate trajectories of health outcomes in older adults.

OBJECTIVES: Ageing is a temporal, multi-faceted process subject to interacting factors. In this study, we used life course and multidimensional approaches to elucidate the association between socioeconomic forces across a lifetime and the developmental origins in health and disease of the Mexican elderly. METHODS: Data stemmed from the Mexican Health and Ageing Study, constituting a sample of older adults (N= 5169, ≥50 years). With retrospective information on early, intermediary and contemporaneous socioeconomic indicators, life course typologies of socioeconomic position were identified using Latent Class Analysis. Based on prospective data of functional mobility, number of chronic conditions and self-rated health, multivariate trajectories of health outcomes were uncovered with Group Based Trajectory Model. Links between the extracted SEP and multivariate health latent constructs were explored with multinomial logistic regression. RESULTS: Life course SEP classes were heterogeneous, yet a large proportion of subjects was characterized by persistent socioeconomic adversity throughout life. The health outcomes' patterns of co-evolution were diverse too, shedding light on the nature of their developmental links, while revealing variable synchronicity in their temporal decline. A graded association was observed between the life course SEP classes and ageing trajectories. CONCLUSION: The results primarily backed the cumulative advantage/disadvantage life course framework, while finding some indication for age as a leveller hypothesis. Variability in patterns of dynamic co-action among the health outcomes depicts ageing as a naturally variable process of interconnected changes. Life course evidence for the ways socio-economic forces are differentially linked to distinct developmental profiles of ageing is provided.

An overview of mixture modelling for latent evolutions in longitudinal data: Modelling approaches, fit statistics and software.

The use of finite mixture modelling (FMM) is becoming increasingly popular for the analysis of longitudinal repeated measures data. FMMs assist in identifying latent classes following similar paths of temporal development. This paper aims to address the confusion experienced by practitioners new to these methods by introducing the various available techniques, which includes an overview of their interrelatedness and applicability. Our focus will be on the commonly used model-based approaches which comprise latent class growth analysis (LCGA), group-based trajectory models (GBTM), and growth mixture modelling (GMM). We discuss criteria for model selection, highlight often encountered challenges and unresolved issues in model fitting, showcase model availability in software, and illustrate a model selection strategy using an applied example.

Dynamic, data-driven typologies of long-term smoking, cessation, and their correlates: Findings from the International Tobacco Control (ITC) Netherlands Survey.

RATIONALE: Efforts towards tobacco control are numerous, but relapse rates for smoking cessations remain high. Behavioral changes necessary for continuous cessation appear complex, variable and subject to social, biological, psychological and environmental determinants. Currently, most cessation studies concentrate on short-to midterm behavioral changes. Besides, they use fixed typologies, thereby failing to capture the temporal changes in smoking/cessation behaviors, and its determinants. OBJECTIVE: To obtain long-term, data-driven longitudinal patterns or profiles of smoking, cessation, and related determinants in a cohort of adult smokers, and to investigate their dynamic links. METHODS: The dataset originated from the International Tobacco Control (ITC) Netherlands Project, waves 2008 to 2016. Temporal dynamics of smoking/cessation, psychosocial constructs, and time-varying determinants of smoking were extracted with Group-Based Trajectory Modeling technique. Their associations were investigated via multiple regression models. RESULTS: Substantial heterogeneity of smoking and cessation behaviors was unveiled. Most respondents were classified as persistent smokers, albeit with distinct levels of consumption. For a minority, cessation could be sustained between 1 and 8 years, while others showed relapsing or fluctuating smoking behavior. Links between smoking/cessation trajectories with those of psychosocial and sociodemographic variables were diverse. Notably, changes in two variables were aligned to behavioral changes towards cessation: decreasing number of smoking peers and attaining a higher self-perceived control. CONCLUSION: The unveiled heterogeneity of smoking behavior over time and the varied cross-dependencies between smoking data-driven typologies and those of underlying risk factors underscore the need of individually tailored approaches for motivational quitting.

Adding Speckle-Tracking Echocardiography to Visual Assessment of Systolic Wall Motion Abnormalities Improves the Detection of Myocardial Infarction.

BACKGROUND: The aim of this study was to investigate whether speckle-tracking echocardiography (STE) improves the detection of myocardial infarction (MI) over visual assessment of systolic wall motion abnormalities (SWMAs) using delayed enhancement cardiac magnetic resonance imaging as a reference. METHODS: Transthoracic echocardiography was performed in 95 patients with first ST segment elevation MI 110 days (interquartile range, 97-171 days) after MI and in 48 healthy control subjects. Two experienced observers independently assessed SWMAs. Separately, longitudinal peak negative, peak systolic, end-systolic, global strain, and strain rate were measured and averaged for the American Heart Association-recommended coronary artery perfusion territories. Receiver operating characteristic analysis was used to determine a single optimal cutoff value for each strain parameter. The diagnostic accuracy of an algorithm combining visual assessment and STE was evaluated. RESULTS: Median infarct size and transmurality were 15% (interquartile range, 7%-24%) and 64% (interquartile range, 46%-78%), respectively. Sensitivity, specificity, and accuracy of visual assessment to detect MI were 74% (95% CI, 63%-82%), 85% (95% CI, 72%-93%), and 78% (95% CI, 70%-84%), respectively. Among the strain parameters, SR had the highest diagnostic accuracy (area under the curve, 0.88; 95% CI, 0.83-0.94; cutoff value, -0.97 sec-1). The combination with STE improved sensitivity compared with visual assessment alone (94%; 95% CI, 86%-97%; P < .001), minimally affecting specificity (79%; 95% CI, 65%-89%; P = .607). Overall accuracy improved to 89% (95% CI, 82%-93%; P = .011). Multivariate analysis accounting for age and sex demonstrated that SR was independently associated with MI (odds ratio, 2.0; 95% CI, 1.6-2.7). CONCLUSIONS: The sensitivity and diagnostic accuracy of visually detecting chronic MI by assessing SWMAs are moderate but substantially improve when adding STE.

Uncovering the heterogeneity of disease impact in axial spondyloarthritis: bivariate trajectories of disease activity and quality of life.

OBJECTIVE: The goal of managing axial spondyloarthritis (axSpA) is to improve and maintain patients' health-related quality of life (HRQoL), mainly through targeting towards low disease activity. Here, we aim to gain insight into the joint evolution of HRQoL and disease activity by identifying and characterising latent subgroups of patients with longstanding disease displaying similar trajectories throughout 8 years of follow-up. METHODS: Data from Outcome in Ankylosing Spondylitis (AS) International Study (n=161) and Groningen Leeuwarden AS cohort (n=264) were used. Biennially, HRQoL was assessed by AS Quality of Life (ASQoL) and disease activity by AS Disease Activity Score-C reactive protein (ASDAS-CRP). Bivariate trajectories of these outcomes were estimated by group-based trajectory modelling. Next, trajectories were profiled by comparing the latent groups with respect to baseline factors using analysis of variance and χ² test. RESULTS: Five bivariate trajectories were distinguished, in which ASQoL and ASDAS-CRP were tightly linked: (t1) low impact of disease; (t2) moderate impact; (t3) high impact with major improvement; (t4) high impact with some improvement; (t5) very high impact. Profiling revealed, for example, that (t1) was characterised by male gender and Human Leucocyte Antigen B27 positivity; (t3) by younger age, shorter symptom duration and biological intake and (t5) by the highest proportion of females. CONCLUSIONS: We identified five bivariate trajectories of HRQoL and disease activity demonstrating a clear mutual relationship. The profiles revealed that both individual-related and disease-related features define the type of disease course in respect to HRQoL and disease activity in axSpA. This may provide clinicians insight into the differences among patients and help in the management of the disease.

At the heart of the problem - A person-centred, developmental perspective on the link between alcohol consumption and cardio-vascular events.

INTRODUCTION: The cardio-protective effect of alcohol has been the subject of a long-standing scientific controversy. Emerging evidence remains equivocal, as the validity of the dose-dependent J-shape association is tainted by conceptual, theoretical and methodological problems. A major impediment for a resolution on the matter is the lack of a life-long developmental approach to pinpoint alcohol's specific impact on the risk for cardio-vascular events (CVE). OBJECTIVE: Using retrospective and prospective individual-level data of alcohol consumption (AC) we applied a model-based clustering technique to uncover life-course trajectories of AC and explored their links to CVE. METHODS: Data stemmed from a random sub-cohort of a large-scale, longitudinal study conducted in the Netherlands (N=2288). Group Based Trajectory Model (GBTM) was applied to extract distinct progressions of AC over time. Stratified by sex, the association between the developmental trajectories and CVE was examined with multiple logistic regression models, with adjustment for traditional risk factors. RESULTS: GBTM analysis laid bare the heterogeneity of AC dynamics over the life-course, reiterating sex differences in drinking habits and CVE risk. AC temporal behaviors during adolescence and adulthood were diverse, but showed relative stability in in middle-age and elderly years. For males, adjusted odds for CVE differed among the uncovered developmental classes. CONCLUSIONS: The findings elicited supportive evidence for a J-shape, but with a new twist. Besides moderation the results indicate that onset, timing, duration and stability of AC over the life-course are major aspects to be accounted for when attempting to elucidate alcohol's cardio-vascular role.

Introducing the fit-criteria assessment plot - A visualisation tool to assist class enumeration in group-based trajectory modelling.

Background and objective Group-based trajectory modelling is a model-based clustering technique applied for the identification of latent patterns of temporal changes. Despite its manifold applications in clinical and health sciences, potential problems of the model selection procedure are often overlooked. The choice of the number of latent trajectories (class-enumeration), for instance, is to a large degree based on statistical criteria that are not fail-safe. Moreover, the process as a whole is not transparent. To facilitate class enumeration, we introduce a graphical summary display of several fit and model adequacy criteria, the fit-criteria assessment plot. Methods An R-code that accepts universal data input is presented. The programme condenses relevant group-based trajectory modelling output information of model fit indices in automated graphical displays. Examples based on real and simulated data are provided to illustrate, assess and validate fit-criteria assessment plot's utility. Results Fit-criteria assessment plot provides an overview of fit criteria on a single page, placing users in an informed position to make a decision. Fit-criteria assessment plot does not automatically select the most appropriate model but eases the model assessment procedure. Conclusions Fit-criteria assessment plot is an exploratory, visualisation tool that can be employed to assist decisions in the initial and decisive phase of group-based trajectory modelling analysis. Considering group-based trajectory modelling's widespread resonance in medical and epidemiological sciences, a more comprehensive, easily interpretable and transparent display of the iterative process of class enumeration may foster group-based trajectory modelling's adequate use.

Characteristics of daily arm activities in patients with COPD.

Arm activities are required for maintenance of self-care and independent living. This study aimed to investigate whether and to what extent arm activities of daily living (ADL) in chronic obstructive pulmonary disease (COPD) patients differ compared to healthy controls and the extent to which they perform arm ADL at a relatively higher upper limb muscle effort. Daily arm and leg activities were assessed using accelerometers in the home environment (COPD: n=21, healthy: n=24; part 1). The relative efforts of the trapezius, deltoid and biceps muscles were studied using electromyography during domestic arm ADL in a laboratory setting (COPD: n=17, healthy: n=15; part 2). After correction for walking time, the time spent on arm ADL was similar between COPD patients and healthy control subjects (p=0.52), while the intensity of arm activities was lower in COPD patients (p=0.041). In the laboratory setting, arm ADL were performed at a lower intensity by COPD patients, while the trapezius muscle effort was significantly higher during several arm ADL compared to healthy control subjects (p<0.05). COPD patients have a similar duration of arm ADL compared to healthy subjects after correction for walking time, but perform arm activities at a lower intensity. Moreover, patients perform some arm ADL at a relatively higher muscle effort.

Lower leg muscle strengthening does not redistribute plantar load in diabetic polyneuropathy: a randomised controlled trial.

BACKGROUND: Higher plantar pressures play an important role in the development of plantar foot ulceration in diabetic polyneuropathy and earlier studies suggest that higher pressures under the forefoot may be related to a decrease in lower leg muscle strength. Therefore, in this randomised controlled trial we evaluated whether lower-extremity strength training can reduce plantar pressures in diabetic polyneuropathy. METHODS: This study was embedded in an unblinded randomised controlled trial. Participants had diabetes and polyneuropathy and were randomly assigned to the intervention group (n = 48) receiving strength training during 24 weeks, or the control group (n = 46) receiving no intervention. Plantar pressures were measured in both groups at 0, 12, 24 and 52 weeks. A random intercept model was applied to evaluate the effects of the intervention on peak pressures and pressure-time-integrals, displacement of center-of-pressure and the forefoot to rearfoot pressure-time-integral-ratio. RESULTS: Plantar pressure patterns were not affected by the strength training. In both the intervention and control groups the peak pressure and the pressure-time-integral under the forefoot increased by 55.7 kPa (95% CI: 14.7, 96.8) and 2.0 kPa.s (95% CI: 0.9, 3.2) over 52 weeks, respectively. Both groups experienced a high number of drop-outs, mainly due to deterioration of health status and lower-extremity disabilities. CONCLUSIONS: Plantar pressures under the forefoot increase progressively over time in people with diabetic polyneuropathy, but in this study were not affected by strength training. Future intervention studies should take this increase of plantar pressure into account and alternative interventions should be developed to reduce the progressive lower extremity problems in these patients. TRIAL REGISTRATION: This study was embedded in a clinical trial with trial number NCT00759265.

Systemic G-CSF attenuates cerebral inflammation and hypomyelination but does not reduce seizure burden in preterm sheep exposed to global hypoxia-ischemia.

Hypoxic-ischemic encephalopathy (HIE) is common in preterm infants, but currently no curative therapy is available. Cell-based therapy has a great potential in the treatment of hypoxic-ischemic preterm brain injury. Granulocyte-colony stimulating factor (G-CSF) is known to mobilize endogenous hematopoietic stem cells (HSC) and promotes proliferation of endogenous neural stem cells. On these grounds, we hypothesized that systemic G-CSF would be neuroprotective in a large translational animal model of hypoxic-ischemic injury in the preterm brain. Global hypoxia-ischemia (HI) was induced by transient umbilical cord occlusion in instrumented preterm sheep. G-CSF treatment (100µg/kg intravenously, during five consecutive days) was started one day before the global HI insult to ascertain mobilization of endogenous stem cells within the acute phase after global HI. Mobilization of HSC and neutrophils was studied by flow cytometry. Brain sections were stained for microglia (IBA-1), myelin basic protein (MBP) and myeloperoxidase (MPO) to study microglial proliferation, white matter injury and neutrophil invasion respectively. Electrographic seizure activity was analyzed using amplitude-integrated electroencephalogram (aEEG). G-CSF effectively mobilized CD34-positive HSC in the preterm sheep. In addition, G-CSF caused marked mobilization of neutrophils, but did not influence enhanced invasion of neutrophils into the preterm brain after global HI. Microglial proliferation and hypomyelination following global HI were reduced as a result of G-CSF treatment. G-CSF did not cause a reduction of the electrographic seizure activity after global HI. In conclusion, G-CSF induced mobilization of endogenous stem cells which was associated with modulation of the cerebral inflammatory response and reduced white matter injury in an ovine model of preterm brain injury after global HI. G-CSF treatment did not improve neuronal function as shown by seizure analysis. Our study shows that G-CSF treatment has neuroprotective potential following hypoxic-ischemic injury in the preterm brain.

Mesenchymal stem cells induce T-cell tolerance and protect the preterm brain after global hypoxia-ischemia.

Hypoxic-ischemic encephalopathy (HIE) in preterm infants is a severe disease for which no curative treatment is available. Cerebral inflammation and invasion of activated peripheral immune cells have been shown to play a pivotal role in the etiology of white matter injury, which is the clinical hallmark of HIE in preterm infants. The objective of this study was to assess the neuroprotective and anti-inflammatory effects of intravenously delivered mesenchymal stem cells (MSC) in an ovine model of HIE. In this translational animal model, global hypoxia-ischemia (HI) was induced in instrumented preterm sheep by transient umbilical cord occlusion, which closely mimics the clinical insult. Intravenous administration of 2 x 10(6) MSC/kg reduced microglial proliferation, diminished loss of oligodendrocytes and reduced demyelination, as determined by histology and Diffusion Tensor Imaging (DTI), in the preterm brain after global HI. These anti-inflammatory and neuroprotective effects of MSC were paralleled by reduced electrographic seizure activity in the ischemic preterm brain. Furthermore, we showed that MSC induced persistent peripheral T-cell tolerance in vivo and reduced invasion of T-cells into the preterm brain following global HI. These findings show in a preclinical animal model that intravenously administered MSC reduced cerebral inflammation, protected against white matter injury and established functional improvement in the preterm brain following global HI. Moreover, we provide evidence that induction of T-cell tolerance by MSC might play an important role in the neuroprotective effects of MSC in HIE. This is the first study to describe a marked neuroprotective effect of MSC in a translational animal model of HIE.

Exhaled breath profiling in diagnosing wheezy preschool children.

Although wheeze is common in preschool children, the underlying pathophysiology has not yet been disentangled. Volatile organic compounds (VOCs) in exhaled breath may serve as noninvasive markers of early wheeze. We aimed to assess the feasibility of VOC collection in preschool children, and to study whether a VOC profile can differentiate between children with and without recurrent wheeze. We included children (mean (range) age 3.3 (1.9-4.5) yrs) with (n=202) and without (n=50) recurrent wheeze. Exhaled VOCs were analysed by gas chromatography-time-of-flight mass spectrometry. VOC profiles were generated by ANOVA simultaneous component analysis (ASCA) and sparse logistic regression (SLR). Exhaled breath collection was possible in 98% of the children. In total, 913 different VOCs were detected. The signal-to-noise ratio improved after correction for age, sex and season using ASCA pre-processing. An SLR model with 28 VOCs correctly classified 83% of the children (84% sensitivity, 80% specificity). After six-fold cross-validation, 73% were correctly classified (79% sensitivity, 50% specificity). Assessment of VOCs in exhaled breath is feasible in young children. VOC profiles are able to distinguish children with and without recurrent wheeze with a reasonable accuracy. This proof of principle paves the way for additional research on VOCs in preschool wheezing.

Cerebral inflammation and mobilization of the peripheral immune system following global hypoxia-ischemia in preterm sheep.

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) is one of the most important causes of brain injury in preterm infants. Preterm HIE is predominantly caused by global hypoxia-ischemia (HI). In contrast, focal ischemia is most common in the adult brain and known to result in cerebral inflammation and activation of the peripheral immune system. These inflammatory responses are considered to play an important role in the adverse outcomes following brain ischemia. In this study, we hypothesize that cerebral and peripheral immune activation is also involved in preterm brain injury after global HI. METHODS: Preterm instrumented fetal sheep were exposed to 25 minutes of umbilical cord occlusion (UCO) (n = 8) at 0.7 gestation. Sham-treated animals (n = 8) were used as a control group. Brain sections were stained for ionized calcium binding adaptor molecule 1 (IBA-1) to investigate microglial proliferation and activation. The peripheral immune system was studied by assessment of circulating white blood cell counts, cellular changes of the spleen and influx of peripheral immune cells (MPO-positive neutrophils) into the brain. Pre-oligodendrocytes (preOLs) and myelin basic protein (MBP) were detected to determine white matter injury. Electro-encephalography (EEG) was recorded to assess functional impairment by interburst interval (IBI) length analysis. RESULTS: Global HI resulted in profound activation and proliferation of microglia in the hippocampus, periventricular and subcortical white matter. In addition, non-preferential mobilization of white blood cells into the circulation was observed within 1 day after global HI and a significant influx of neutrophils into the brain was detected 7 days after the global HI insult. Furthermore, global HI resulted in marked involution of the spleen, which could not be explained by increased splenic apoptosis. In concordance with cerebral inflammation, global HI induced severe brain atrophy, region-specific preOL vulnerability, hypomyelination and persistent suppressed brain function. CONCLUSIONS: Our data provided evidence that global HI in preterm ovine fetuses resulted in profound cerebral inflammation and mobilization of the peripheral innate immune system. These inflammatory responses were paralleled by marked injury and functional loss of the preterm brain. Further understanding of the interplay between preterm brain inflammation and activation of the peripheral immune system following global HI will contribute to the development of future therapeutic interventions in preterm HIE.

Histologic chorioamnionitis, fetal involvement, and antenatal steroids: effects on neonatal outcome in preterm infants.

OBJECTIVE: The objective of the study was to study the effects of histologic chorioamnionitis (HC) with or without fetal involvement and antenatal steroid (AS) exposure on neonatal outcome in a prospective cohort of preterm infants. STUDY DESIGN: The clinical characteristics and placental histology were prospectively collected in 301 infants born at a gestational age 32.0 weeks or less in the Erasmus University Medical Center. RESULTS: In univariable analyses, HC without fetal involvement (n=53) was associated with decreased severe respiratory distress syndrome (RDS) (11% vs 28%; P<.05), whereas HC with fetal involvement infants (n=68) had more necrotizing enterocolitis (9% vs 2%; P<.05), intraventricular hemorrhage (IVH) (25% vs 12%; P<.05), and neonatal mortality (19% vs 9%; P<.05). In HC without fetal involvement infants, AS reduced the incidences of RDS (43% vs 85%; P<.05) and IVH (5% vs 39%; P<.01). In multivariable analyses, HC without fetal involvement was associated with decreased severe RDS (odds ratio, 0.22; 95% confidence interval, 0.05-0.93; P<.05) and increased early-onset sepsis (odds ratio, 2.22; 95% confidence interval, 1.02-4.83; P<.05). CONCLUSION: In a prospective cohort of preterm infants, multivariable analyses reveal only a modest association between histologic chorioamnionitis and neonatal outcome.