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Chronic inflammatory disease of the gastrointestinal (GI) tract is defined by several pathophysiological characteristics, such as dysbiosis of the microbiota, epithelial barrier hyperpermeability, systemic dissemination of endotoxins and chronic inflammation. In addition to well-reported environmental factors in non-communicable disease, such as smoking, diet, and exercise, humans are frequently exposed to myriads more environmental factors, from pesticides to food additives. Such factors are ubiquitous across both our diet and indoor/outdoor environments. A major route of human exposure to these factors is ingestion, which frequently occurs due to their intentional addition (intentional food additives) and/or unintentional contamination (unintentional food contaminants) of food products-often linked to environmental pollution. Understanding how this persistent, diverse exposure impacts GI health is of paramount importance, as deterioration of the GI barrier is proposed to be the first step towards systemic inflammation and chronic disease. Therefore, we aim to evaluate the impact of ingestion of environmental factors on inflammatory processes in the GI tract. In this review, we highlight human exposure to intentional food additives (e.g. emulsifiers, bulking agents) and unintentional food contaminants (e.g. persistent organic pollutants, pesticides, microplastics), then present evidence for their association with chronic disease, modification of the GI microbiota, increased permeability of the GI barrier, systemic dissemination of endotoxins, local (and distal) pro-inflammatory signalling, and induction of oxidative stress and/or endoplasmic reticulum stress. We also propose a link to NLRP3-inflammasome activation. These findings highlight the contribution of common environmental factors towards deterioration of GI health and the induction of pathophysiology associated with onset and maintenance of chronic inflammation in the GI tract.

Lankhorst, K, Takken, T, Zwinkels, M, van Gaalen, L, Velde, St, Backx, F, Verschuren, O, Wittink, H, and de Groot, J. Sports participation, physical activity, and health-related fitness in youth with chronic diseases or physical disabilities: the health in adapted youth sports study. J Strength Cond Res 35(8): 2327-2337, 2021-Youth with chronic diseases or physical disabilities (CDPD) often show reduced fitness and physical activity (PA) levels and participate less in organized sports compared with healthy peers. The purpose of this study was to examine the associations between participation in sports and health-related fitness and PA in youth with CDPD. A total of 163 subjects (mean age 14 years; range 8-19 years) with CDPD were included in this cross-sectional study, with 81 participating in organized sports and 82 not. Subjects were recruited between October 2014 and November 2016. Aerobic and anaerobic fitness, agility, and muscle strength were assessed in the laboratory, whereas PA was monitored in daily life using accelerometry during 1 week. Linear regression analyses were used to assess the associations of sports participation (independent variable) with health-related fitness and PA (dependent variables). Results show that youth with CDPD participating in organized sports 2 times a week performed better on all outcome measures. They reached a higher peak oxygen uptake (difference of 4.9 ml O2·kg-1·min-1, P = 0.001) compared with their peers not participating in sports. Also, anaerobic fitness, agility, muscle strength, and PA were all positively associated with sports participation. Moreover, the association between sports participation and aerobic fitness was mediated by PA for 31% (P = 0.045). In conclusion, participation in sports is associated with both higher levels of PA and health-related fitness in youth with CDPD. Promotion and stimulation of participation in sports seems a good way to promote health-related fitness as well as a healthy active lifestyle in youth with CDPD.

Background SP140 is a bromodomain-containing protein expressed predominantly in immune cells. Genetic polymorphisms and epigenetic modifications in the SP140 locus have been linked to Crohn’s disease (CD), suggesting a role in inflammation. Results We report the development of the first small molecule SP140 inhibitor (GSK761) and utilize this to elucidate SP140 function in macrophages. We show that SP140 is highly expressed in CD mucosal macrophages and in in vitro-generated inflammatory macrophages. SP140 inhibition through GSK761 reduced monocyte-to-inflammatory macrophage differentiation and lipopolysaccharide (LPS)-induced inflammatory activation, while inducing the generation of CD206+ regulatory macrophages that were shown to associate with a therapeutic response to anti-TNF in CD patients. SP140 preferentially occupies transcriptional start sites in inflammatory macrophages, with enrichment at gene loci encoding pro-inflammatory cytokines/chemokines and inflammatory pathways. GSK761 specifically reduces SP140 chromatin binding and thereby expression of SP140-regulated genes. GSK761 inhibits the expression of cytokines, including TNF, by CD14+ macrophages isolated from CD intestinal mucosa. Conclusions This study identifies SP140 as a druggable epigenetic therapeutic target for CD.

Objective: Vascular calcification contributes to the cause of cardiovascular disease. The calciprotein particle maturation time (T 50 ) in serum, a measure of calcification propensity, has been linked with adverse outcomes in patients with chronic kidney disease, but its role in the general population is unclear. We investigated whether serum T 50 is associated with cardiovascular mortality in a large general population-based cohort. Approach and Results: The relationship between serum T 50 and cardiovascular mortality was studied in 6231 participants of the PREVEND (Prevention of Renal and Vascular End-Stage Disease) cohort. All-cause mortality was the secondary outcome. Mean (±SD) age was 53±12 years, 50% were male, and mean serum T 50 was 329±58 minutes. A shorter serum T 50 is indicative of a higher calcification propensity. Serum T 50 was inversely associated with circulating phosphate, age, estimated glomerular filtration rate, and alcohol consumption, whereas plasma magnesium was positively associated with serum T 50 ( P R 2 =0.281). During median (interquartile range) follow-up for 8.3 (7.8–8.9) years, 364 patients died (5.8%), of whom 95 (26.1%) died from a cardiovascular cause. In multivariable Cox proportional hazard models, each 60 minutes decrease in serum T 50 was independently associated with a higher risk of cardiovascular mortality (fully adjusted hazard ratio [95% CI], 1.22 [1.04–1.36], P =0.021). This association was modified by diabetes mellitus; stratified analysis indicated a more pronounced association in individuals with diabetes mellitus. Conclusions: Serum T 50 is independently associated with an increased risk of cardiovascular mortality in the general population and thus may be an early and potentially modifiable risk marker for cardiovascular mortality.

Contains fulltext : 252064.pdf (Publisher’s version ) (Open Access) PURPOSE: Describe the differences in characteristics and outcomes between COVID-19 and other viral pneumonia patients admitted to Dutch ICUs. MATERIALS AND METHODS: Data from the National-Intensive-Care-Evaluation-registry of COVID-19 patients admitted between February 15th and January 1th 2021 and other viral pneumonia patients admitted between January 1st 2017 and January 1st 2020 were used. Patients' characteristics, the unadjusted, and adjusted in-hospital mortality were compared. RESULTS: 6343 COVID-19 and 2256 other viral pneumonia patients from 79 ICUs were included. The COVID-19 patients included more male (71.3 vs 49.8%), had a higher Body-Mass-Index (28.1 vs 25.5), less comorbidities (42.2 vs 72.7%), and a prolonged hospital length of stay (19 vs 9 days). The COVID-19 patients had a significantly higher crude in-hospital mortality rate (Odds ratio (OR) = 1.80), after adjustment for patient characteristics and ICU occupancy rate the OR was respectively 3.62 and 3.58. CONCLUSION: Higher mortality among COVID-19 patients could not be explained by patient characteristics and higher ICU occupancy rates, indicating that COVID-19 is more severe compared to other viral pneumonia. Our findings confirm earlier warnings of a high need of ICU capacity and high mortality rates among relatively healthy COVID-19 patients as this may lead to a higher mental workload for the staff.

BACKGROUND AND OBJECTIVE Bobath therapy, or neurodevelopmental therapy (NDT) is widely practiced despite evidence other interventions are more effective in cerebral palsy (CP). The objective is to determine the efficacy of NDT in children and infants with CP or high risk of CP. METHODS Cumulative Index to Nursing and Allied Health Literature, Cochrane Library, Embase, and Medline were searched through March 2021. Randomized controlled trials comparing NDT with any or no intervention were included. Meta-analysis was conducted with standardized mean differences calculated. Quality was assessed by using Cochrane Risk of Bias tool-2 and certainty by using Grading of Recommendations Assessment, Development, and Evaluation. RESULTS Of 667 records screened, 34 studies (in 35 publications, 1332 participants) met inclusion. Four meta-analyses were conducted assessing motor function. We found no effect between NDT and control (pooled effect size 0.13 [−0.20 to 0.46]), a moderate effect favoring activity-based approaches (0.76 [0.12 to 1.40]) and body function and structures (0.77 [0.19 to 1.35]) over NDT and no effect between higher- and lower-dose NDT (0.32 [−0.11 to 0.75]). A strong recommendation against the use of NDT at any dose was made. Studies were not all Consolidated Standards of Reporting Trials-compliant. NDT versus activity-based comparator had considerable heterogeneity (I2 = 80%) reflecting varied measures. CONCLUSIONS We found that activity-based and body structure and function interventions are more effective than NDT for improving motor function, NDT is no more effective than control, and higher-dose NDT is not more effective than lower-dose. Deimplementation of NDT in CP is required.

In 2020, three articles were published on a protein that can activate the immune system by binding to macrophage-inducible C-type lectin receptor (Mincle). In the articles, the protein was referred to as ‘SAP130, a subunit of the histone deacetylase complex.’ However, the Mincle ligand the authors aimed to investigate is splicing factor 3b subunit 3 (SF3B3). This splicing factor is unrelated to SAP130 (Sin3A associated protein 130, a subunit of the histone deacetylase-dependent Sin3A corepressor complex). The conclusions in the three articles were formulated for SF3B3, while the researchers used qPCR primers and antibodies against SAP130. We retraced the origins of the ambiguity about the two proteins and found that Online Mendelian Inheritance in Man (OMIM) added a Nature publication on SF3B3 as a reference for Sin3A associated protein 130 in 2016. Subsequently, companies such as Abcam referred to OMIM and the Nature article in their products for both SF3B3 and SAP130. In turn, the mistake by OMIM followed in the persistent and confusing use of ‘SAP130′ (spliceosome-associated protein 130) as an alternative symbol for SF3B3. With this report, we aim to eliminate the persistent confusion and separate the literature regarding the two proteins.

A nutritional intervention, exclusive enteral nutrition (EEN) can induce remission in patients with pediatric Crohn’s disease (CD). We characterized changes in the fecal microbiota and metabolome to identify the mechanism of EEN. Feces of 43 children were collected prior, during and after EEN. Microbiota and metabolites were analyzed by 16S rRNA gene amplicon sequencing and NMR. Selected metabolites were evaluated in relevant model systems. Microbiota and metabolome of patients with CD and controls were different at all time points. Amino acids, primary bile salts, trimethylamine and cadaverine were elevated in patients with CD. Microbiota and metabolome differed between responders and non-responders prior to EEN. EEN decreased microbiota diversity and reduced amino acids, trimethylamine and cadaverine towards control levels. Patients with CD had reduced microbial metabolism of bile acids that partially normalized during EEN. Trimethylamine and cadaverine inhibited intestinal cell growth. TMA and cadaverine inhibited LPS-stimulated TNF-alpha and IL-6 secretion by primary human monocytes. A diet rich in free amino acids worsened inflammation in the DSS model of intestinal inflammation. Trimethylamine, cadaverine, bile salts and amino acids could play a role in the mechanism by which EEN induces remission. Prior to EEN, microbiota and metabolome are different between responders and non-responders.

Supplemental Digital Content is available in the text., Background. Galectin-3 may play a causal role in kidney inflammation and fibrosis, which may also be involved in the development of kidney graft failure. With novel galectin-3-targeted pharmacological therapies increasingly coming available, we aimed to investigate whether galectin-3 is associated with risk of late graft failure in kidney transplant recipients (KTR). Methods. We studied adult KTR who participated in TransplantLines Insulin Resistance and Inflammation Biobank and Cohort Study, recruited in a university setting (2001–2003). Follow-up was performed for a median of 9.5 (interquartile range, 6.2–10.2) years. Overall and stratified (Pinteraction < 0.05) multivariable-adjusted Cox proportional-hazards regression analyses were performed to study the association of galectin-3 with risk of graft failure (restart of dialysis or retransplantation). Results. Among 561 KTR (age 52 ± 12 y; 54% males), baseline median galectin-3 was 21.1 (interquartile range, 17.0–27.2) ng/mL. During follow-up, 72 KTR developed graft failure (13, 18, and 44 events over increasing tertiles of galectin-3). Independent of adjustment for donor, recipient, and transplant characteristics, galectin-3-associated with increased risk of graft failure (hazard ratios [HR] per 1 SD change, 2.12; 95% confidence interval [CI], 1.63-2.75; P < 0.001), particularly among KTR with systolic blood pressure ≥140 mmHg (HR, 2.29; 95% CI, 1.80-2.92; P < 0.001; Pinteraction = 0.01) or smoking history (HR, 2.56; 95% CI, 1.95-3.37; P < 0.001; Pinteraction = 0.03). Similarly, patients in the highest tertile of galectin-3 were consistently at increased risk of graft failure. Conclusions. Serum galectin-3 levels are elevated in KTR, and independently associated with increased risk of late graft failure. Whether galectin-3-targeted therapies may represent novel opportunities to decrease the long-standing high burden of late graft failure in stable KTR warrants further studies.

Chronic kidney disease mineral and bone disorders (CKD-MBD) and vascular calcification are often seen in kidney transplantation recipients (KTR). This study focused on the bone-vascular axis hypothesis, the pathophysiological mechanisms driving both bone loss and vascular calcification, supported by an association between lower bone mineral density (BMD) and higher risk of vascular calcification.KTR referred for a dual-energy X-ray absorptiometry procedure within 6 mo after transplantation were included in a cross-sectional study (2004-2014). Areal BMD was measured at the proximal femur, and abdominal aortic calcification (AAC) was quantified (8-points score) from lateral single-energy images of the lumbar spine. Patients were divided into 3 AAC categories (negative-AAC: AAC 0; low-AAC: AAC 1-3; and high-AAC: AAC 4-8). Multivariable-adjusted multinomial logistic regression models were performed to study the association between BMD and AAC.We included 678 KTR (51 ± 13 y old, 58% males), 366 (54%) had BMD disorders, and 266 (39%) had detectable calcification. High-AAC was observed in 9%, 11%, and 25% of KTR with normal BMD, osteopenia, and osteoporosis, respectively (P 0.001). Higher BMD (T-score, continuous) was associated with a lower risk of high-AAC (odds ratio 0.61, 95% confidence interval 0.42-0.88; P = 0.008), independent of age, sex, body mass index, estimated glomerular filtration rate, and immunosuppressive therapy. KTR with normal BMD were less likely to have high-AAC (odds ratio 0.24, 95% confidence interval 0.08-0.72; P = 0.01).BMD disorders are highly prevalent in KTR. The independent inverse association between BMD and AAC may provide evidence to point toward the existence, while highlighting the clinical and epidemiological relevance, of a bone-vascular axis after kidney transplantation.

SARS-CoV-2 might directly activate NLRP3 inflammasome resulting in an endogenous adjuvant activity necessary to mount a proper adaptive immune response against the virus. Heterogeneous response of COVID-19 patients could be attributed to differences in not being able to properly downregulate NLRP3 inflammasome activation. This relates to the fitness of the immune system of the individual challenged by the virus. Patients with a reduced immune fitness can demonstrate a dysregulated NLRP3 inflammasome activity resulting in severe COVID-19 with tissue damage and a cytokine storm. We sketch the outlines of five possible scenarios for COVID-19 in medical practice and provide potential treatment options targeting dysregulated endogenous adjuvant activity in severe COVID-19 patients.

Contains fulltext : 206793.pdf (Publisher’s version ) (Open Access) Dietary plant sterols and stanols as present in our diet and in functional foods are well-known for their inhibitory effects on intestinal cholesterol absorption, which translates into lower low-density lipoprotein cholesterol concentrations. However, emerging evidence suggests that plant sterols and stanols have numerous additional health effects, which are largely unnoticed in the current scientific literature. Therefore, in this review we pose the intriguing question "What would have occurred if plant sterols and stanols had been discovered and embraced by disciplines such as immunology, hepatology, pulmonology or gastroenterology before being positioned as cholesterol-lowering molecules?" What would then have been the main benefits and fields of application of plant sterols and stanols today? We here discuss potential effects ranging from its presence and function intrauterine and in breast milk towards a potential role in the development of non-alcoholic steatohepatitis (NASH), cardiovascular disease (CVD), inflammatory bowel diseases (IBD) and allergic asthma. Interestingly, effects clearly depend on the route of entrance as observed in intestinal-failure associated liver disease (IFALD) during parenteral nutrition regimens. It is only until recently that effects beyond lowering of cholesterol concentrations are being explored systematically. Thus, there is a clear need to understand the full health effects of plant sterols and stanols.

To link data from a large maternal perinatal trial with the Australian Cerebral Palsy Register (ACPR) to identify children with cerebral palsy (CP).Deidentified data from the Australasian Collaborative Trial of Magnesium Sulphate (ACTOMgSOWe included 913 children (492 males, 421 females; mean gestational age at birth 27.8wks [standard deviation 2.1wks]; range 23.0-40.0wks). Eighty-four children received a CP diagnosis: 35 by the ACTOMgSOLinking deidentified perinatal trial data with the ACPR was achieved. Limitations of both strategies for identifying children with CP in this era (late 1990s and early 2000s) probably explain many of the differences observed, and inform future linkage studies and evaluations of CP-preventive interventions.Randomized trial data were linked with the Australian Cerebral Palsy Register. Trial (2y) and register (up to 5y) diagnoses of cerebral palsy (CP) differed. States with long-standing registers were more likely to include children with CP.Vincular los datos de un gran estudio perinatal materno con el Registro Australiano de Parálisis Cerebral (ACPR) para identificar a niños con parálisis cerebral (PC). MÉTODO: Se identificaron datos no identificados del Ensayo de colaboración australiano de sulfato de magnesio (ACTOMgSO4) y el ACPR. Se incluyeron niños nacidos entre 1996 y 2000 en hospitales australianos que sobrevivieron y tuvieron evaluaciones pediátricas de 2 años. Los niños identificados con PC en: (1) tanto el ACTOMgSO4 (2y) como el ACPR (5y), (2) solo el ACTOMgSO4 y (3) solo se compararon el ACPR.Se incluyeron 913 niños (492 varones, 421 mujeres; edad gestacional media al nacer 27.8 semanas [desviación estándar 2.1 semanas]; rango 23.0-40.0 semanas). Ochenta y cuatro niños recibieron un diagnóstico de PC: 35 por ACTOMgSO4 y ACPR, 29 solo por ACTOMgSO4 y 20 solo por ACPR. El ACTOMgSO4 diagnosticó el 76,2% (intervalo de confianza [IC] del 95%: 65,9-84,1) y el ACPR identificó el 65,5% (IC del 95%: 54,7-74,9). Los niños nacidos en estados / territorios con registros de larga data versus registros establecidos más recientemente tenían más probabilidades de ser incluidos en el ACPR (p0.05). INTERPRETACIÓN: Se logró vincular los datos de estudios perinatales desidentificados con el ACPR. Las limitaciones de ambas estrategias para identificar a los niños con PC en esta época (finales de los 90 y principios de los 2000) probablemente explican muchas de las diferencias observadas e informan futuros estudios de vinculación y evaluaciones de intervenciones preventivas de la PC.Ligar os dados de um grande estudo maternal perinatal com o Registro Australiano de Paralisia Cerebral (RAPC) para identificar crianças com paralisia cerebral (PC). MÉTODO: Dados não identificados do Estudo Australasiano Colaborativo sobre Sulfato de Magnésio (ACTOMgSOIncluímos 913 crianças (492 do sexo masculino, 421 do sexo feminino; idade gestacional média ao nascimento de 27,8 semanas [desvio padrão 2,1semanas]; variação 23,0-40,0 semanas). Oitenta e quarto crianças receberam diagnóstico de PC: 35 no ACTOMgSO

This study aims to assess the prevalence of different modes of commuting to school and work for 10–12 year-olds and their parents; to assess the associations with demographic variables (country, sex, parental education and ethnicity) and with weight status in eight European countries. As part of the ENERGY project a cross-sectional survey was conducted in 2010 in which modes of commuting and socio-demographic variables for children (N = 7903) and one of their parents (n = 6455) were measured by questionnaires. Children's weight and height were objectively measured; parents self-reported their weight and height. Logistic multilevel regression analyses assessed the associations between mode of commuting and overweight. Differences between countries and differences in mode of commuting according to demographic variables were tested using χ2-test and Marascuilo's Post-hoc analysis. There were marked differences between countries, especially regarding cycling to school, which was common in The Netherlands and Norway and rare in Greece and Spain. Demographic variables were associated with mode of commuting in children and parents. Mode of commuting was not associated with being overweight in children, after adjustment for demographic variables. Bicycling to work, but not other modes of commuting, was significantly inversely associated with being overweight among parents (OR = 0.74 (95%CI 0.57–0.97)). Interventions targeting active commuting may promote cycling, and should take into account the differences regarding demographic variables.

Purpose of ReviewCerebral palsy is the most common physical disability of childhood, but the rate is falling, and severity is lessening. We conducted a systematic overview of best available evidence (2012–2019), appraising evidence using GRADE and the Evidence Alert Traffic Light System and then aggregated the new findings with our previous 2013 findings. This article summarizes the best available evidence interventions for preventing and managing cerebral palsy in 2019.Recent FindingsEffective prevention strategies include antenatal corticosteroids, magnesium sulfate, caffeine, and neonatal hypothermia. Effective allied health interventions include acceptance and commitment therapy, action observations, bimanual training, casting, constraint-induced movement therapy, environmental enrichment, fitness training, goal-directed training, hippotherapy, home programs, literacy interventions, mobility training, oral sensorimotor, oral sensorimotor plus electrical stimulation, pressure care, stepping stones triple P, strength training, task-specific training, treadmill training, partial body weight support treadmill training, and weight-bearing. Effective medical and surgical interventions include anti-convulsants, bisphosphonates, botulinum toxin, botulinum toxin plus occupational therapy, botulinum toxin plus casting, diazepam, dentistry, hip surveillance, intrathecal baclofen, scoliosis correction, selective dorsal rhizotomy, and umbilical cord blood cell therapy.SummaryWe have provided guidance about what works and what does not to inform decision-making, and highlighted areas for more research.

Item does not contain fulltext PURPOSE: Previous studies indicate that patients with a more negative perception of their illness tend to respond less favorably to treatment, but little is known about whether illness perceptions differ based on the type of hand or wrist conditions. Therefore, we compared illness perceptions between patients scheduled to undergo surgery for 4 illnesses in hand surgery: carpometacarpal osteoarthritis (CMC OA), Dupuytren disease, carpal tunnel syndrome (CTS), and trigger finger syndrome (TFS). We hypothesized there would be differences in illness perception between these patient groups. METHODS: Before surgery, patients were asked to complete the Brief Illness Perception Questionnaire (Brief-IPQ) as part of routine outcome measurement in a specialized hand and wrist surgery clinic. The Brief-IPQ is a validated questionnaire to rapidly assess the cognitive and emotional representation of illness. Differences in illness perception between the 4 diagnostic groups, corrected for age, sex, hand dominance, and work type, were examined. Cohen D effect sizes were calculated for the between-group differences. RESULTS: We included 514 patients in the analyses: 87 with CMC OA, 146 with Dupuytren disease, 129 with CTS, and 152 with TFS. On a scale ranging from 0 (most positive perception) to 80 (most negative perception) the Brief-IPQ sum scores for these subgroups were 42.0, 28.2, 38.8, and 33.3, respectively. Corrected for age, sex, hand dominance, and work type, patients with Dupuytren disease had a more positive perception of their illness than patients with CMC OA and CTS. Compared with CMC OA patients, the effect sizes for Dupuytren, CTS, and TFS patients were, respectively, 1.28, 0.32, and 0.81. CONCLUSIONS: In these patients with various hand/wrist disorders, differences were found in their preoperative perceptions of illness. Interventions that directly target negative illness perceptions might improve treatment outcomes for CMC OA and CTS. CLINICAL RELEVANCE: These differences should be considered during preoperative medical consultations and/or when investigating surgical outcomes.

PURPOSE: Youth with physical disabilities have lower psychosocial health and attention compared to their typically developing peers. Recent research has shown positive associations between sports participation and these outcomes. The purpose of the current study was to explore whether a school-based sports program affects psychosocial health and attention in youth with physical disabilities. METHODS: Seventy children and adolescents (mean age (SD) 13.8 (2.9) years, aged 8–19 years, 54% boys) with physical disabilities were included in this quasi-experimental study from schools for special education. The sports group (n = 31) followed a school-based sports program (45 min/week) for six months. The control group followed the regular curriculum. Psychosocial health was assessed with self-perception (Self-Perception Profile for Children) and quality of life (DISABKIDS Chronic Generic Measure, DCGM-37). Attention was measured with experimental tasks on search efficiency, sustained attention, and distractibility. RESULTS: Linear regression analyses revealed no differences between the sports and control group for self-perception, quality of life, and attention. CONCLUSION: A school-based sports program seems to have no effect on psychosocial health and attention in youth with physical disabilities. Research into the important factors influencing these variables is needed before further resources can be given to improve sports participation for increasing psychosocial health and attention.

IntroductionCycling for transport could integrate physical activity (PA) into daily routines and potentially increase total PA levels. However, for parents with young children, most factors affecting transport mode choice tend to facilitate car use. Greater insight is necessary into reasons for (not) using sustainable transport modes in parents with young children. Therefore, the objective of this study was to explore the experiences, including motives, perceptions, attitudes, and norms, of parents of young children by using an e-bike, a longtail bike, and a traditional bike for everyday travel to the workplace, kindergarten, and the grocery store during the autumn, winter, and spring, in nine months.MethodsSemistructured focus group interviews were conducted with 18 parents of young children residing in southern Norway. Parents were recruited through Facebook announcements and direct contact with kindergartens, selected organisations, and companies in the Kristiansand municipality. Data were analysed by systematic text condensation by using NVivo V.11.ResultsParticipants' experiences were summarised by three main themes: 'cycling is cumbersome', 'cycling reflects the desirable me', and 'breaking the cycling code'. Time use, planning, logistics, wet and cold weather, long distances, and no cycling habit were frequently mentioned barriers, and the most notable facilitator was the children's attitude towards cycling. In general, children loved to cycle and preferred cycling to driving. Additionally, the freedom and independence of cycling were emphasised and valued.ConclusionIn challenging weather conditions, parents of young children may experience cycling as cumbersome but desirable, and bike access could increase the feasibility of daily cycling.

Conveying a diagnosis of a disability to the parents of young children is difficult both for the parent and the clinician, however there is an ethical and medical imperative to do so. However, the process and manner of disclosure needs to be done well. When communication between parent and clinicians fails, parental mental health can be adversely affected. This paper adapts and explains how to use the SPIKES protocol to deliver "bad news" about a developmental disability diagnosis with families of infants

Background Immune regulated pathways influence both breast cancer (BrC) development and response to (neo)adjuvant chemotherapy. The sentinel lymph node (SLN), as the first metastatic site, is also the first site where BrC-induced suppression of immune effector subsets occurs. Since intricate knowledge of the phenotypic and functional status of these immune effector subsets is lacking, we set out to map the immune landscape of BrC SLN. Methods Viable LN cells from BrC SLN (n = 58) were used for detailed flowcytometry-assisted mapping of the immune landscape of BrC SLN in a comparative analysis with healthy (i.e. prophylactic mastectomy-derived) axillary lymph nodes (HLN, n = 17). Findings were related to clinicopathological characteristics. Results Our data show that BrC-induced immune suppression in tumor-involved SLN, as evidenced by increased Treg and MDSC rates as well as by a generalized state of T cell anergy, coincides with hampered activation of LN-resident (LNR) dendritic cell (DC) subsets rather than of migratory DC subsets. Importantly, suppression of these LN-resident DC subsets preceded profoundly disabled T cell effector functions in tumor-involved SLN. Furthermore, we provide evidence that the suppressed state of LNR-cDC is not only related to nodal involvement but is also related to high-risk breast cancer subtypes that lack expression of hormone receptors and may be a negative predictor of disease-free survival. Conclusion These data thus provide new insights in the mechanisms underlying loco-regional immune suppression induced by BrC and how these relate to clinical outcome. They identify the LNR-cDC subset as a pivotal regulatory node in cellular immune suppressive pathways and therefore as a promising therapeutic target to combat immune suppression and secure the induction of effective antitumor immunity, e.g. in combination with neo-adjuvant chemotherapy. Electronic supplementary material The online version of this article (10.1186/s40425-019-0605-1) contains supplementary material, which is available to authorized users.

STUDY QUESTION: How can we predict chances of natural conception at various time points in couples diagnosed with unexplained subfertility?SUMMARY ANSWER: We developed a dynamic prediction model that can make repeated predictions over time for couples with unexplained subfertility that underwent a fertility workup at a fertility clinic.WHAT IS KNOWN ALREADY: The most frequently used prediction model for natural conception (the 'Hunault model') estimates the probability of natural conception only once per couple, that is, after completion of the fertility workup. This model cannot be used for a second or third time for couples who wish to know their renewed chances after a certain period of expectant management.STUDY DESIGN, SIZE, DURATION: A prospective cohort studying the long-term follow-up of subfertile couples included in 38 centres in the Netherlands between January 2002 and February 2004. Couples with bilateral tubal occlusion, anovulation or a total motile sperm count PARTICIPANTS/MATERIALS, SETTING, METHODS: The primary endpoint was time to natural conception, leading to an ongoing pregnancy. Follow-up time was censored at the start of treatment or at the last date of contact. In developing the new dynamic prediction model, we used the same predictors as the Hunault model, i.e. female age, duration of subfertility, female subfertility being primary or secondary, sperm motility and referral status. The performance of the model was evaluated in terms of calibration and discrimination. Additionally, we assessed the utility of the model in terms of the variability of the calculated predictions.MAIN RESULTS AND THE ROLE OF CHANCE: Of the 4999 couples in the cohort, 1053 (21%) women reached a natural conception leading to an ongoing pregnancy within a mean follow-up of 8 months (5th and 95th percentile: 1-21). Our newly developed dynamic prediction model estimated the median probability of conceiving in the first year after the completion of the fertility workup at 27%. For couples not yet pregnant after half a year, after one year and after one and a half years of expectant management, the median probability of conceiving over the next year was estimated at 20, 15 and 13%, respectively. The model performed fair in an internal validation. The prediction ranges were sufficiently broad to aid in counselling couples for at least two years after their fertility workup.LIMITATIONS, REASONS FOR CAUTION: The dynamic prediction model needs to be validated in an external population.WIDER IMPLICATIONS OF THE FINDINGS: This dynamic prediction model allows reassessment of natural conception chances after various periods of unsuccessful expectant management. This gives valuable information to counsel couples with unexplained subfertility that are seen for a fertility workup.STUDY FUNDING/COMPETING INTERESTS: This study was facilitated by grant 945/12/002 from ZonMW, The Netherlands Organization for Health Research and Development, The Hague, The Netherlands. No competing interests.

Introduction This study aims to assess (i) the prevalence of having regular family breakfast, lunch, dinner (i.e. 5–7 days/week together with their family) among 10–12 year olds in Europe, (ii) the association between family meals and child weight status, and (iii) potential differences in having family meals according to country of residence, gender, ethnicity and parental levels of education. Methods 7716 children (mean age: 11.5 ± 0.7 years, 52% girls) in eight European countries (Belgium, Greece, Hungary, The Netherlands, Norway, Slovenia, Spain, Switzerland) participated in a cross-sectional school-based survey in 2010. Data on family meals were self-reported by the parents and children's height and weight were objectively measured to determine overweight status. Binary regression analyses assessed the associations of having regular family meals (adjusted for potential confounders) with children's overweight/obesity and to assess potential differences in having family meals according to gender, ethnicity and parental education, in the total sample and for each country respectively. Results The prevalence of regular family meals was 35%, 37% and 76% for breakfast, lunch and dinner respectively. Having regular family breakfast, but not lunch or dinner, was inversely associated with overweight (OR = 0.78 (95% CI 0.67–0.91)). Children of higher educated parents were more likely to have regular family breakfast (1.63 (95% CI 1.42–1.86)) and less likely to have regular family lunch (0.72 (95% CI 0.63–0.82)) compared to children of lower educated parents. Conclusion This study showed that having regular family breakfast – but not other family meals- was inversely associated with children's weight status., Highlights • Having regular family breakfast, but not other family meals, was inversely associated with children's overweight. • Having regular family breakfast was associated with high parental education. • Having regular family lunch was inversely associated with high parental education.

Objectives Preterm birth is the leading pregnancy outcome associated with perinatal morbidity and mortality and remains difficult to prevent. There is evidence that some modifiable maternal health characteristics may influence the risk of preterm birth. Our aim was to investigate the relationships of self-reported maternal health behaviour and psychological characteristics in nulliparous women with spontaneous preterm birth in prenatal primary care. Methods The data of our prospective study was obtained from the nationwide DELIVER multicentre cohort study (September 2009–March 2011), which was designed to examine perinatal primary care in the Netherlands. In our study, consisting of 2768 nulliparous women, we estimated the relationships of various self-reported health behaviours (smoking, alcohol consumption, folic acid supplementation, daily fruit, daily fresh vegetables, daily hot meal and daily breakfast consumption) and psychological characteristics (anxious/depressed mood and health control beliefs) with spontaneous preterm birth as a dichotomous outcome. Due to the clustering of clients within midwife practices, Generalized Estimating Equations was used for these analyses. Results Low health control beliefs was the sole characteristic significantly associated with spontaneous preterm birth (odds ratio 2.26; 95 % confidence interval 1.51, 3.39) after being adjusted for socio-demographics, anthropometrics and the remaining health behaviour and psychological characteristics. The other characteristics were not significantly associated with spontaneous preterm birth. Conclusions for Practice Maternal low health control beliefs need to be explored further as a possible marker for women at risk for preterm birth, and as a potentially modifiable characteristic to be used in interventions which are designed to reduce the risk of spontaneous preterm birth.

Summary This literature review assesses the current knowledge about the immunological aspects of the vermiform appendix in health and disease. An essential part of its immunological function is the interaction with the intestinal bacteria, a trait shown to be preserved during its evolution. The existence of the appendiceal biofilm in particular has proved to have a beneficial effect for the entire gut. In assessing the influence of acute appendicitis and the importance of a normally functioning gut flora, however, multiple immunological aspects point towards the appendix as a priming site for ulcerative colitis. Describing the immunological and microbiotical changes in the appendix during acute and chronic inflammation of the appendix, this review suggests that this association becomes increasingly plausible. Sustained by the distinct composition of cells, molecules and microbiota, as well as by the ever more likely negative correlation between the appendix and ulcerative colitis, the idea of the appendix being a vestigial organ should therefore be discarded.

MiR-511-3p is embedded in intron 5 of the CD206/MRC1 gene Mrc1, expressed by macrophage and dendritic cell populations. CD206 and miR-511-3p expression are co-regulated, and their contribution to intestinal inflammation is unclear. We investigated their roles in intestinal inflammation in both mouse and human systems. Colons of CD206-deficient mice displayed normal numbers of monocytes, macrophage, and dendritic cells. In experimental colitis, CD206-deficient mice had attenuated inflammation compared with wild-type (WT) mice. However, neither a CD206 antagonist nor a blocking antibody reproduced this phenotype, suggesting that CD206 was not involved in this response. Macrophages isolated from CD206-deficient mice had reduced levels of miR-511-3p and Tlr4 compared with WT, which was associated with reduced pro-inflammatory cytokine production upon lipopolysaccharides (LPS) and fecal supernatant stimulation. Macrophages overexpressing miR-511-3p showed 50% increase of Tlr4 mRNA, whereas knockdown of miR-511-3p reduced Tlr4 mRNA levels by 60%, compared with scrambled microRNA (miRNA)-transduced cells. Response to anti-tumor necrosis factor (TNF) treatment has been associated with elevated macrophage CD206 expression in the mucosa. However, in colon biopsies no statistically significant change in miR-511-3p was detected. Taken together, our data show that miR-511-3p controls macrophage-mediated microbial responses and is involved in the regulation of intestinal inflammation.

Peritoneal dissemination is diagnosed in 10-25 % of colorectal cancer patients. Selected patients are treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. For these patients, earlier diagnosis, optimised selection criteria and a personalised approach are warranted. Biomarkers could play a crucial role here. However, little is known about possible candidates. Considering tumour cell adhesion as a key step in peritoneal dissemination, we aim to provide an overview of the functional importance of adhesion molecules in peritoneal dissemination and discuss the prognostic, diagnostic and therapeutic options of these candidate biomarkers. A systematic literature search was conducted according to the PRISMA guidelines. In 132 in vitro, ex vivo and in vivo studies published between 1995 and 2013, we identified twelve possibly relevant adhesion molecules in various cancers that disseminate peritoneally. The most studied molecules in tumour cell adhesion are integrin α2β1, CD44 s and MUC16. Furthermore, L1CAM, EpCAM, MUC1, sLe(x) and Le(x), chemokine receptors, Betaig-H3 and uPAR might be of clinical importance. ICAM1 was found to be less relevant in tumour cell adhesion in the context of peritoneal metastases. Based on currently available data, sLe(a) and MUC16 are the most promising prognostic biomarkers for colorectal peritoneal metastases that may help improve patient selection. Different adhesion molecules appear expressed in haematogenous and transcoelomic spread, indicating two different attachment processes. However, our extensive assessment of available literature reveals that knowledge on metastasis-specific genes and their possible candidates is far from complete.

Background:The school environment can play an important role in the prevention of childhood overweight and obesity. Photos of the school environment may contribute to more adequate measurement of the school environment, as photos can be rated by different assessors. We aimed to examine the interrater reliability for rating characteristics of primary school environments related to physical activity and eating.Methods:Photos taken at 172 primary schools in 7 European countries were rated according to a standardized protocol. Briefly, after categorizing all photos in subsections of physical activity or eating opportunities, 2 researchers independently rated aspects of safety, functionality, aesthetics, type of food/drinks advertised, type/variety of foods provided. Interrater reliability was assessed using the intraclass correlation coefficient (ICC) and Cohen’s kappa.Results:Six subsections of the photo-rating instrument showed excellent (ICC or Cohen’s kappa ≥0.81) or good (ICC or Cohen’s kappa 0.61 to 0.80) interrater reliability. Outdoor physical activity facilities (ICC = 0.54) showed moderate, and school canteens (Cohen’s kappa = 0.05) and vending machines showed poor (Cohen’s kappa = 0.16) interrater reliability.Conclusion:Interrater reliability of the ENERGY (EuropeaN Energy balance Research to prevent excessive weight Gain among Youth) photo-rating instrument was good-to-excellent for 6 out of 9 characteristics of primary school environment components related to physical activity and eating.

IntroductionWe aimed to investigate whether providing parents with children in kindergarten with access to different bicycle types could influence (i) travel behavior and cycling amount, and (ii) intrinsic motivation for cycling and psychological constructs related to car use.MethodsA randomized, controlled trial was conducted in Southern Norway from September 2017 to June 2018. In total 36 parents were recruited and randomly drawn into an intervention (n = 18) or control group (n = 18). The intervention group was in random order equipped with an e-bike with trailer (n = 6), a cargo (longtail) bike (n = 6) and a traditional bike with trailer (n = 6).ResultsAt follow-up, more participants from the intervention group (vs. the control group) were classified as cyclists to the workplace (n = 7 (38.9%) vs. n = 1 (5.9%), p = 0.04), but not to the kindergarten (n = 6 (33.3%) vs. n = 2 (11.8%), p = 0.23) or to the grocery store (n = 2 (11.1%) vs. n = 0 (0%), p = 0.49). A significant (p = ≤0.05) increase in cycling frequency (0.1 to 2.0 days/week) from baseline to follow-up was found in the intervention group for all destinations and seasons, except to the grocery store during winter (p = 0.16). A decrease in frequency of car driving (-0.2 to -1.7 days/week) was found to be apparent in terms of travelling to the workplace and the kindergarten for all seasons, yet not to the grocery store for any season (p = 0.15-0.49). The intervention group (vs. the control group) reported significantly higher "intrinsic regulation" for cycling (p = 0.01) at follow-up.ConclusionAccess to different bike types for parents with children attending kindergarten resulted in overall increased cycling, decreased car use and higher intrinsic motivation for cycling. E-bikes obtained the greatest cycling amount in total, with the smallest sample variability. Hence, providing parents with children in kindergarten with access to e-bikes might result in increased and sustained cycling, also during the winter season.

The intake of fruit and vegetables is associated with beneficial health outcomes, and studies aimed at increasing fruit and vegetable intake lack long-term follow-up. The primary objective of this study was to evaluate the long-term (14-year) effects of a multicomponent school-based educational intervention targeted to increase fruit and vegetable intake in children. The secondary objective was to evaluate the potential synergistic effect between free school fruit and the educational program. A cluster randomized school-based intervention was initiated in 2001 in Norway, known as the Fruit and Vegetable Make the Marks study. In total, 38 schools were randomized; for the intervention (n = 18) and as control schools (n = 20). A subsample of the intervention schools (n = 9) were additionally given free school fruit, resulting in two intervention groups - one with and one without free fruit. Participants completed questionnaires in September 2001 (baseline, mean age 11.8), May 2002 (at the end of the intervention), May 2003, May 2005, September 2009 and throughout 2016 (mean age 26.5). Of 1950 participants, 982 (50.4%) completed the 14-year follow-up and were considered as the current study sample. Analysis yielded no 14-year effects of the educational program on fruit and vegetable intake. A synergistic effect between the educational program and free fruit was not observed either. Future studies might benefit from increased focus on more extensive parental involvement, increased home availability, and a longer intervention period. However, more long-term studies are needed to evaluate the effects of school-based interventions into adulthood. Trial registration number: Ethical approval and research clearance was obtained from The National Committees for Research Ethics in Norway (file number S-01076) and The Norwegian Centre for Research Data (file number 12395).

Objectives Synovial mast cells contain IL-17A, a key driver of tissue inflammation in SpA. A recent in vitro study showed that tissue-derived mast cells can capture and release exogenous IL-17A. The present study aimed to investigate if this mechanism could contribute to tissue inflammation in SpA. Methods Potential activation of mast cells by IL-17A was assessed by gene expression analysis of the Laboratory of Allergic Diseases 2 (LAD2) mast cell line. The presence of IL-17A-positive mast cells was assessed by immunohistochemistry in synovial tissue obtained before and after secukinumab treatment, as well as in skin and gut tissues from SpA-related conditions. Results IL-17A did not induce a pro-inflammatory response in human LAD2 mast cells according to the canonical IL-17A signalling pathway. In SpA synovial tissue, the percentage of IL-17A-positive mast cells increased upon treatment with secukinumab. IL-17A-positive mast cells were also readily detectable in non-inflamed barrier tissues such as skin and gut. In non-inflamed dermis and gut submucosa, IL-17A-positive mast cells are the most prevalent IL-17A-positive cells in situ. Compared with non-inflamed tissues, both total mast cells and IL-17A-positive mast cells were increased in psoriatic skin dermis and in submucosa from inflammatory bowel disease gut. In contrast, the proportion of IL-17A-positive mast cells was strikingly lower in the inflamed compared with non-inflamed gut lamina propria. Conclusion IL-17A-positive mast cells are present across SpA target tissues and correlate inversely with inflammation, indicating that their IL-17A content can be regulated. Tissue-resident mast cells may act as IL-17A-loaded sentinel cells, which release IL-17A to amplify tissue inflammation.

Background The rationale for promoting increased consumption of fruit and vegetables (FV) at an early age is based on results from previous tracking-studies, indicating that dietary habits learned in childhood sustain into adulthood. Previous tracking studies have several limitations (e.g. low study sample, few repeated measurements and/or short a follow-up period). In addition, to our knowledge, no study has shown that a dietary intervention initiated in childhood affects tracking of dietary behaviour. The main objectives in this study were therefore to assess tracking of FV and unhealthy snacks in a large sample with multiple follow-up surveys over 15-years, and whether exposure to free school fruit for one school year modified tracking. Method The longitudinal cohort-study, Fruit and Vegetables Make the Marks, included 38 randomly drawn schools in Norway; nine intervention schools received free fruit (or vegetable) in the school year 2001/2002 and 29 schools severed as control. The baseline sample included 1950 subjects, and 16–92% participated at five follow-up surveys (2002–2016). FV consumption and unhealthy snacks were measured by FFQ. Mixed models were applied to estimate overall tracking coefficients, and to assess whether the intervention modified tracking ((from baseline, from follow-up one (while intervention was running) and from follow-up two (after end of intervention)). Results Overall tracking coefficients were 0.33 for fruit, 0.36 for vegetables and differed by sex for unhealthy snacks: 0.46 males and 0.39 for females (interaction p = 0.065). Most analyses showed no significant difference in tracking between the intervention group and control group. However, from follow-up one, tracking coefficients were different for unhealthy snacks, 0.46 vs. 0.38 (interaction p = 0.036), and from follow-up two for vegetables, 0.35 vs 0.48 (p = 0.036), in the intervention group and control group, respectively. Conclusion Our results indicate low to moderate tracking of FV and unhealthy snacks from childhood to adulthood. We found little evidence that the free fruit intervention modified tracking of fruit, vegetables or unhealthy snacks. More research is needed on if or how we can influence the tracking of fruit, vegetables and unhealthy snacks consumption to improve public health.

Formerly considered as a passive process, the resolution of acute inflammation is now recognized as an active host response, with a cascade of coordinated cellular and molecular events that promotes termination of the inflammatory response and initiates tissue repair and healing. In a state of immune fitness, the resolution of inflammation is contained in time and space enabling the restoration of tissue homeostasis. There is increasing evidence that poor and/or inappropriate resolution of inflammation participates in the pathogenesis of chronic inflammatory diseases, extending in time the actions of pro-inflammatory mechanisms, and responsible in the long run for excessive tissue damage and pathology. In this review, we will focus on how resolution can be the target for therapy in "Th1/Th17 cell-driven" immune diseases and "Th2 cell-driven" immune diseases, with inflammatory bowel diseases (IBD) and asthma, as relevant examples. We describe the main cells and mediators stimulating the resolution of inflammation and discuss how pharmacological and dietary interventions but also life style factors, physical and psychological conditions, might influence the resolution phase. A better understanding of the impact of endogenous and exogenous factors on the resolution of inflammation might open a whole area in the development of personalized therapies in non-resolving chronic inflammatory diseases.

Real‐time assessment of excised tissue may help to improve surgical results in breast tumor surgeries. Here, as a step towards this purpose, the potential of second and third harmonic generation (SHG, THG) microscopy is explored. SHG and THG are nonlinear optical microscopic techniques that do not require labeling of tissue to generate 3D images with intrinsic depth‐sectioning at sub‐cellular resolution. Until now, this technique had been applied on fixated breast tissue or to visualize the stroma only, whereas most tumors start in the lobules and ducts. Here, SHG/THG images of freshly excised unprocessed healthy human tissue are shown to reveal key breast components—lobules, ducts, fat tissue, connective tissue and blood vessels, in good agreement with hematoxylin and eosin histology. DNA staining of fresh unprocessed mouse breast tissue was performed to aid in the identification of cell nuclei in label‐free THG images. Furthermore, 2‐ and 3‐photon excited auto‐fluorescence images of mouse and human tissue are collected for comparison. The SHG/THG imaging modalities generate high quality images of freshly excised tissue in less than a minute with an information content comparable to that of the gold standard, histopathology. Therefore, SHG/THG microscopy is a promising tool for real‐time assessment of excised tissue during surgery., Most breast cancers are carcinomas, a type of cancer that is derived from epithelial cells, aligning ducts and lobules. This study shows that second and third harmonic generation (SHG/THG) microscopy reveals the morphology of those key structures in freshly excised, unprocessed human breast tissue, including their cells and cell nuclei. The SHG/THG images have an information content comparable to that of the gold standard, (H&E histology) but are generated much faster, in less than a minute.

BACKGROUND: Initiating and maintaining a healthy lifestyle -including healthy eating and sufficient physical activity- is key for cardiometabolic health. A health-promoting environment can facilitate a healthy lifestyle, and may be especially helpful to reach individuals with a lower socio-economic status (SES). In the Supreme Nudge project, we will study the effects of pricing and nudging strategies in the supermarket - one of the most important point-of-choice settings for food choices - and of a context-specific mobile physical activity promotion app. This paper describes the stepwise and theory-based design of Supreme Nudge, which aims to develop, implement and evaluate environmental changes for a sustained impact on lifestyle behaviours and cardiometabolic health in low SES adults.METHODS: Supreme Nudge uses a multi-disciplinary and mixed methods approach, integrating participatory action research, qualitative interviews, experimental pilot studies, and a randomized controlled trial in a real-life (supermarket) setting. First, we will identify the needs, characteristics and preferences of the target group as well as of the participating supermarket chain. Second, we will conduct a series of pilot studies to test novel, promising and feasible intervention components. Third, a final selection of intervention components will be implemented in a full-scale randomised controlled supermarket trial. Approximately 1000 low SES adults will be recruited across 8-12 supermarkets and randomised at supermarket level to receive 1) no intervention (control); 2) environmental nudges such as food product placement or promotion; 3) nudges and a tailored physical activity app that provides time- and context specific feedback; 4) pricing interventions, nudges, and the physical activity app. The effects on dietary behaviours and physical activity will be evaluated at 3, 6 and 12 months, and on cardiometabolic health at 6 and 12 months. Finally, we will evaluate the Reach, Effectiveness, Adoption, Implementation and Maintenance (RE-AIM) of the intervention, and we will use insights from System Innovation and Transition Management theories to define the best strategies for implementation and upscaling beyond the study period.DISCUSSION: The Supreme Nudge project is likely to generate thorough evidence relevant for policy and practice on the effects of a mixed method and multi-disciplinary intervention targeting dietary behaviours and physical activity.TRIAL REGISTRATION: The real-life trial has been registered on 30 May 2018, NTR7302 .

The human appendix has long been considered as a vestigial organ, an organ that has lost its function during evolution. In recent years, however, reports have emerged that link the appendix to numerous immunological functions in humans. Evidence has been presented for an important role of the appendix in maintaining intestinal health. This theory suggests that the appendix may be a reservoir or 'safe house' from which the commensal gut flora can rapidly be reestablished if it is eradicated from the colon. However, the appendix may also have a role in the development of inflammatory bowel disease (IBD). Several large epidemiological cohort studies have demonstrated the preventive effect of appendectomy on the development of ulcerative colitis, a finding that has been confirmed in murine colitis models. In addition, current studies are examining the possible therapeutic effect of an appendectomy to modulate disease course in patients with ulcerative colitis. This literature review assesses the current knowledge about the clinical and immunological aspects of the vermiform appendix in IBD and suggests that the idea of the appendix as a vestigial remnant should be discarded.

Background and Aims: Ciclosporin A [CsA] and infliximab [IFX] are similarly effective in preventing short-term colectomy in ulcerative colitis [UC] patients, but long-term data are scarce. We aimed to compare short- and long-term efficacy of CsA and IFX by analysing colectomy rates and failure of remission-induction treatment as outcome parameters for treatment success. Methods: We retrospectively studied hospitalised UC patients who received CsA or IFX for moderate-to-severe UC, between January 2000 and April 2014. The primary endpoint was time to colectomy, and treatment failure [defined as colectomy or another remission-induction treatment with corticosteroids, CsA, or IFX] was used as secondary endpoint. Variables possibly affecting colectomy outcomes were analysed. Results: A total of 55 patients were studied for colectomy outcome and 58 patients for treatment failure. A significantly longer follow-up duration was available for CsA-treated patients [ p < 0.001, both subcohorts]. Patients showed comparable patient- and disease-specific characteristics. Colectomy rates did not differ significantly at 3, 12, and 36 months: 36% versus 29%, 58% versus 48%, and 64% versus 67% for CsA- and IFX-treated patients, respectively. Multivariate Cox regression analysis revealed the lowest hazard ratio [HR] for colectomy in patients concomitantly using thiopurines: HR 0.28 (confidence interval [CI] 0.13–0.64), p = 0.002. Treatment failure rates were not significantly different at 3, 12 and 36 months: 35% versus 48%, 51% versus 68%, and 62% versus 83% for CsA- and IFX-treated patients, respectively. Conclusions: Treatment with CsA and IFX is similarly effective in preventing short- and long-term colectomy in hospitalised UC patients. Furthermore, failure rates of these remission-induction treatments were comparable.

T regulatory cells (Tregs) play an important role in the regulation of autoimmunity, autoinflammation, allergic diseases, infection, and the tumor environment. Different subsets are characterized that use a number of regulatory mechanisms. Tregs can influence the progression of inflammatory bowel disease and the development of colorectal cancer. Knowledge of Tregs and their regulatory mechanisms can provide new targets for therapeutic intervention.

BACKGROUND AND AIMS: We have recently shown that the mode of action of IgG1 anti-tumour necrosis factor [TNF] antibodies in inflammatory bowel disease [IBD] requires Fcγ-receptor [FcγR] engagement on macrophages. Here we examine the effect of Fcγ-receptor signalling by anti-TNF on macrophage IL-12/IL-23 secretion. METHODS: Cytokine production by human inflammatory macrophages was assessed at the level of RNA and protein. TNF-anti-TNF immune complex formation was determined by size-exclusion chromatography and signalling visualized by immunofluorescence. IL-12/IL-23p40 was measured in CD14+ lamina propria cells from IBD patients. RESULTS: Infliximab and adalimumab potently suppressed IL-12/IL-23 production by inflammatory macrophages, but Fab' fragment certolizumab did not. IL-12/IL-23 suppression depended on Syk activity and was mediated at the level of IL-12/IL-23p40 mRNA. Etanercept, a soluble TNF receptor fused to an Fc-region, did not inhibit IL-12/L-23 secretion, suggesting that the presence of an Fc-region was not sufficient. Infliximab and adalimumab formed immune complexes with soluble TNF whereas etanercept did not, suggesting that FcγR-mediated suppression of IL-12/IL-23 required the formation of immune complexes. Indeed, non-specific IgG1 immune complexes, but not uncomplexed IgG1, similarly suppressed IL-12/IL-23 secretion. Finally, infliximab significantly decreased IL-12/IL-23p40 production in myeloid cells isolated from the lamina propria of IBD patients. CONCLUSIONS: TNF-anti-TNF antibody immune complexes potently inhibit IL-12/IL-23 expression by inflammatory macrophages. Our data suggest that anti-TNFs and antibodies against IL-12/IL-23 may therefore have partially overlapping modes of action in patients with IBD. ispartof: JOURNAL OF CROHNS & COLITIS vol:12 issue:9 pages:1122-1130 ispartof: location:England status: published

Background: The obesity epidemic presents a major public health challenge, and a poor diet quality has been identified as one of the most important contributing factors. Whereas a sufficient fruit and vegetable consumption has been associated with several positive health outcomes, the long-term effect on overweight and obesity is unclear. Thus, the aims of this study were to investigate if one year with free school fruit had any effect on weight status 14 years later, and if it affected the birth weight of the participants’ children. Methods: In 2001, 10 -12-year old Norwegian children, received one year of free school fruit in the intervention study “Fruits and Vegetables Make the Marks” (FVMM) and in 2016, a total of 1081 participants of 2049 eligible responded to a follow-up survey. Multilevel logistic regression was used to investigate if one year of free school fruit was associated with weight status and with birthweight status of the offspring. The analyses were adjusted for gender, educational level, and the offspring analysis also for parents’ weight status, and the nested design (child/parent). Results: The odds ratios of being overweight (OR: 0.93, 95% CI: 0.70, 1.24) or having a child with high or low birth weight (OR: 0.52, 95% CI: 0.21, 1.30) in the intervention group compared to the control group were not statistically significant, 14 years after the intervention period. Conclusions: One year of free school fruit did not have an effect on weight status on the participants or birth weight of their offspring, 14 years after the intervention period. Although, results from the present study contribute to fill the knowledge gaps concerning long-term effects of public health efforts on weight status, more follow-up studies with larger samples are warranted.

BackgroundThe chronic remitting and relapsing intestinal inflammation characteristic of Crohn's disease frequently leads to fibrosis and subsequent stenosis of the inflamed region. Approximately a third of all Crohn's disease patients require resection at some stage in their disease course. As the pathogenesis of Crohn's disease associated fibrosis is largely unknown, a strong necessity exists to better understand the pathophysiology thereof.MethodsIn this study, we investigated changes of the DNA methylome and transcriptome of ileum-derived fibroblasts associated to the occurrence of Crohn's disease associated fibrosis. Eighteen samples were included in a DNA methylation array and twenty-one samples were used for RNA sequencing.ResultsMost differentially methylated regions and differentially expressed genes were observed when comparing stenotic with non-inflamed samples. By contrast, few differences were observed when comparing Crohn's disease with non-Crohn's disease, or inflamed with non-inflamed tissue. Integrative methylation and gene expression analyses revealed dysregulation of genes associated to the PRKACA and E2F1 network, which is involved in cell cycle progression, angiogenesis, epithelial to mesenchymal transition, and bile metabolism.ConclusionOur research provides evidence that the methylome and the transcriptome are systematically dysregulated in stenosis-associated fibroblasts.

Aim Various types of cholinergic receptors are expressed on intestinal epithelia. Their function is not completely understood. We hypothesize that cholinergic receptor activation on epithelium may serve a protective function in cytokine-induced barrier dysfunction. Methods The effect of cholinergic receptor activation on cellular barrier function in epithelial cells was assessed by measuring electrical impedance, and by determining para-cellular transport in transwell experiments. Cell lysates treated with cytokine and/or cholinergic agonists were analysed for cyto- and chemokine production, and tight junction (TJ) protein rearrangement was assessed. Primary colonic epithelial cells were isolated from surgically resected colon tissue of patients with inflammatory bowel disease. Results IL-1β induced production of chemokines (CXCL-1, CXCL-10, IL-8, CCL-7) and led to a rearrangement of TJ proteins (occludin and ZO-1). This response was inhibited by pre-treatment with muscarinic, rather than nicotinic, acetylcholine receptor agonists. Treatment with IL-1β enhanced paracellular permeability (4kD dextran) and reduced impedance across the monolayer, which was counteracted by pre-incubation with acetylcholine, or muscarinic receptor agonist bethanechol. The protective effect of acetylcholine was antagonized by atropine, underscoring muscarinic receptor involvement. IL-1β induced transcription of myosin light chain kinase and phosphorylation of myosin light chain, and this cytokine-induced phosphorylation of MLC was inhibited by muscarinic receptor agonists. Furthermore, in epithelial cells from resection material of patients with Crohn's disease and ulcerative colitis, high expression of CXCL-8 was associated with a reduced choline acetyl transferase expression, suggesting an aberrant epithelial production of ACh in inflammatory context. Conclusion Acetylcholine acts on muscarinic receptors on epithelial cells to maintain epithelial barrier function under inflammatory conditions.

Aims and objectives: To gain insight into cancer survivors' needs towards an eHealth application monitoring quality of life and targeting personalised access to supportive care. Background: Supportive care in cancer addresses survivors' concerns and needs. However, many survivors are not taking advantage of supportive care provided. To enable cancer survivors to benefit, survivors' needs must be identified timely and effectively. An eHealth application could be a solution to meet patients' individual supportive care needs. Design: A qualitative approach. Methods: Thirty cancer survivors (15 head and neck and 15 breast cancer survivors) participated. The majority were female (n = 20·67%). The mean age was 60 (SD 8·8) years. Mean time interval since treatment was 13·5 months (SD 10·5). All interviews were audio-recorded and transcribed verbatim. During the interviews, participants were asked about their unmet needs during follow-up care and a potential eHealth application. Data were analyzed independently by two coders and coded into key issues and themes. Results: Cancer survivors commented that they felt unprepared for the post-treatment period and that their symptoms often remained unknown to care providers. Survivors also mentioned a suboptimal referral pattern to supportive care services. Mentioned advantages of an eHealth application were as follows: insight into the course of symptoms by monitoring, availability of information among follow-up appointments, receiving personalised advice and tailored supportive care. Conclusions: Cancer survivors identified several unmet needs during follow-up care. Most survivors were positive towards the proposed eHealth application and expressed that it could be a valuable addition to follow-up cancer care. Relevance to clinical practice: Study results provide care providers with insight into barriers that impede survivors from obtaining optimal supportive care. This study also provides insight into the characteristics needed to design, build and implement an eHealth application targeting personalised access to supportive care from the survivors' perspective. Future studies should address the viewpoints of care providers, and investigate the usability of the eHealth application prototype to facilitate implementation.

The association of vitamin D status with bone mineral density (BMD) and Quantitative Ultrasound measurements (QUS) has been inconsistent in previous studies, probably caused by moderating effects. This study explored (1) the association of vitamin D status with QUS and BMD, and (2) whether these associations were modified by body mass index (BMI), age, gender, or physical activity. Two-independent cohorts of the Longitudinal Aging Study Amsterdam (LASA-I, 1995/1996, aged a parts per thousand yen65; LASA-II, 2008/2009, aged 61-71) and baseline measurement of the B-vitamins for the prevention of osteoporotic fractures (B-PROOF) study (2008-2011, aged 65+) were used. QUS measurements [broadband ultrasound attenuation (BUA) and speed of sound (SOS)] were performed at the calcaneus in all three cohorts (N = 1,235, N = 365, N = 1319); BMD was measured by Dual X-ray absorptiometry (DXA) in B-PROOF (N = 1,162 and 1,192 for specific sites) and LASA-I (N = 492 and 503). The associations of vitamin D status with BUA and BMD were modified by BMI. Only in persons with low-to-normal BMI (< 25 kg/m(2)) and serum 25(OH)D < 25 nmol/L was associated with lower BUA as compared to the reference group (a parts per thousand yen50 nmol/L) in LASA-I and B-PROOF. Furthermore, in LASA-I, these individuals had lower BMD at the hip and lumbar spine. In LASA-II, no associations with BUA were observed. Vitamin D status was not associated with SOS, and these associations were not modified by the effect modifiers tested. The association between vitamin D status and BUA and BMD was modified by BMI in the older-aged cohorts: there was only an association in individuals with BMI < 25 kg/m(2).

Background: Patients with peritoneal metastases (PMs) originating from colorectal carcinoma (CRC) are curatively treated by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin C (MMC). We aim to improve patient selection for HIPEC by predicting MMC sensitivity. Methods: The MMC sensitivity was determined for 12 CRC cell lines and correlated to mRNA expression of 37 genes related to the Fanconi anaemia (FA)–BRCA pathway, ATM–ATR pathway and enzymatic activation of MMC. Functionality of the FA–BRCA pathway in cell lines was assessed using a chromosomal breakage assay and western blot for key protein FANCD2. Bloom syndrome protein (BLM) was further analysed by staining for the corresponding protein with immunohistochemistry (IHC) on both CRC cell lines (n=12) and patient material (n=20). Results: High sensitivity correlated with a low BLM (P=0.01) and BRCA2 (P=0.02) at mRNA expression level. However, FA–BRCA pathway functionality demonstrated no correlation to MMC sensitivity. In cell lines, weak intensity staining of BLM by IHC correlated to high sensitivity (P=0.04) to MMC. Low BLM protein expression was significantly associated with an improved survival in patients after CRS and HIPEC (P=0.04). Conclusions: Low BLM levels are associated with high MMC sensitivity and an improved survival after HIPEC.

Objective We assessed whether differences in children's sports participation and television time according to parental education were mediated by parental modeling. Moreover, we explored the differences between parental and child reports on parental sports participation and television time as potential mediators. Methods 5729 children and 5183 parents participating in the EuropeaN Energy balance Research to prevent excessive weight Gain among Youth (ENERGY-project) during 2010 in seven European countries provided information on sports participation and television time using validated self-report questionnaires. Multilevel country-specific mediation models analyzed the potential mediation effect of parental self-reports and child-reports on parental sports participation and television time. Results Significant mediation effect was found for parental self-reported television time in four countries (Greece, Hungary, The Netherlands and Slovenia), with the highest proportion for Slovenia (40%) and the lowest for Greece (21%). Child-reported parental television time showed mediation effect in Greece only. Parental self-reported sports participation showed significant mediation effect only in Greece. With child-reported parental sports participation, significant mediation was observed in Greece and Norway. Conclusions Parental behaviors appear to be important in explaining parental educational differences in children's sports participation and television time. However, child reports on parental behavior appear to be more relevant than parents' self-reports as correlates of children's own sports participation and television time.

Reliable methods of contraception were introduced in the1960s and enabled women to postpone childbearing and to prevent the birth of not-yet-wanted children. This allowed women to delay the start of their family. However, with increasing female age (>30 years and especially >35 years), there is increased risk of aneuploidy and either miscarriage or a deformed baby. The availability of in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) methods allows embryo selection prior to implantation in these women and birth of healthy babies. This allows older women to delay their first pregnancy and plan to have more than 1 child. As a result, the mean age of women at first childbirth increased by 4 to 5 years since the 1970s in most European countries, and the proportion who have their first child at older than 30 years has increased from about 8% to 40%. Both the treatment-independent and treatment-dependent (IVF/ICSI) chances of pregnancy decline with female age. Research on the age-dependent effects has focused on the chance of a first pregnancy and not on having more than 1 child. This study was designed to estimate at what age couples can wait to start a family without compromising their chances of realizing the desired number of children (a 1-, 2-, or 3-child family). The investigators used an established computer simulation model of fertility to simulate a cohort of 10,000 couples in order to assess the chances of realizing a 1-, 2-, or 3-child family. The model used treatment-independent pregnancy chances and pregnancy chances after IVF/ICSI updated with recent IVF success rates. Three levels of importance a couple attaches to achieving a desired family size were singled out: (i) The extremely important level is aimed for at least a 90% success chance; (ii) important (but not at all costs) is aimed at a 75% success chance; and (iii) good to have children (parenthood is not essential) is aimed at a 50% success chance. Based on the computer model, couples who wish to have at least a 90% chance to realize a 1-child family, the age for the female partner to start trying to conceive using IVF should be 35 years or younger. For those desiring 2 children using IVF, the latest starting age should be 31 years, and for 3 children, 28 years. Without IVF, couples who desire a 90% chance should start no later than age 32 years for a 1-child family, at 27 years for a 2-child family, and at 23 years for 3 children. If a 75% or lower chance is acceptable for couples attempting to conceive naturally, they can start 4 to 11 years later for a 1-, 2-, or 3-child family (at 37, 34, and 31 years of age, respectively). Use of IVF has the greatest impact on the starting age for the couples wishing a 90% chance of conceiving. For a 50% or 75% chance at older ages of realizing a 2- or 3-child family, there was little improvement for couples using IVF. The data appeared to be robust for plausible changes in model assumptions. The latest female age at which a couple should start trying to become pregnant is strongly dependent on the importance they attach to achieving a desired family size and on whether IVF is an acceptable option if no natural pregnancy occurs. In the absence of large-scale prospective studies (which would provide more conclusive data), this evidence-based simulation study is the next best option. With continuing improvements in IVF technology, the assumptions on success chances with IVF run the risk of becoming outdated. Therefore, simulations should be updated every 5 to 10 years with new evidence. These findings are important for prospective parents in family planning and for preconception counseling. This information is also useful for inclusion in educational courses in human biology and for increasing public awareness on possibilities and limitations of human reproduction.

Background and aims Crohn's disease is a chronic inflammatory disorder of the intestine and often leads to fibrosis, characterized by excess extracellular matrix [ECM] deposition, increased tissue stiffness, and stricture formation. Here we evaluated the contribution of myofibroblast-ECM interactions to the development of intestinal fibrosis in Crohn's disease. Methods Matched primary human myofibroblasts were isolated from stenotic, inflamed and normal-appearing small intestine within the same Crohn's disease patient [n = 10]. Cells were analyzed by gene expression profiling, microscopy and functional assays, including matrix metalloproteinase [MMP] production and ECM contraction. Results We demonstrated that myofibroblasts isolated from stenotic intestine differed both in phenotype and function from those isolated from purely inflammatory or normal-appearing intestine of the same patient. Stenotic myofibroblasts displayed increased expression of genes associated with ECM modulation and collagen deposition. Upon culture in a fibrotic environment, normal myofibroblasts increased expression of MMPs to counteract the mechanical force exerted by the matrix. Interestingly, stenotic myofibroblasts showed a paradoxical response with decreased expression of MMP3. In addition, stenotic myofibroblasts expressed increased levels of the collagen crosslinking enzyme lysyl oxidase [LOX] and induced significantly more ECM contraction than both normal and inflamed myofibroblasts. Importantly, LOX inhibition completely restored MMP3 activity in stenotic myofibroblasts grown in a fibrotic environment, and prevented excessive ECM contraction. Conclusions Together these data indicate aberrancies in the myofibroblast-ECM interaction in Crohn's disease, and identify LOX inhibition as a potential anti-fibrotic agent in this condition.

Published version of an article in the journal: PLoS One. Also available from the publisher: http://dx.doi.org/10.1371/journal.pone.0111775 Open Acces Objective: To design interventions that target energy balance-related behaviours, knowledge of primary schoolchildren’s perceptions regarding soft drink intake, fruit juice intake, breakfast consumption, TV viewing and physical activity (PA) is essential. The current study describes personal beliefs and attitudes, home- and friend-related variables regarding these behaviours across Europe. Design: Cross-sectional study in which personal, family and friend -related variables were assessed by validated questionnaires, and dichotomized as favourable versus unfavourable answers. Logistic regression analyses were conducted to estimate proportions of children giving unfavourable answers and test between-country differences. Setting: A survey in eight European countries. Subjects: A total of 7903 10–12 year old primary schoolchildren. Results: A majority of the children reported unfavourable attitudes, preferences and subjective norms regarding soft drink, fruit juice intake and TV viewing accompanied with high availability and accessibility at home. Few children reported unfavourable attitudes and preferences regarding breakfast consumption and PA. Many children reported unfavourable health beliefs regarding breakfast consumption and TV viewing. Substantial differences between countries were observed, especially for variables regarding soft drink intake, breakfast consumption and TV viewing. Conclusion: The surveyed children demonstrated favourable attitudes to some healthy behaviours (PA, breakfast intake) as well as to some unhealthy behaviours (soft drink consumption, TV viewing). Additionally, many children across Europe have personal beliefs and are exposed to social environments that are not supportive to engagement in healthy behaviours. Moreover, the large differences in personal, family and friend-related variables across Europe argue for implementing different strategies in the different European countries.

BackgroundIt is well known that the prevalence of overweight and obesity is considerably higher among youth from lower socio-economic families, but there is little information about the role of some energy balance-related behaviors in the association between socio-economic status and childhood overweight and obesity. The objective of this paper was to assess the possible mediation role of energy balance-related behaviors in the association between parental education and children’s body composition.MethodsData were obtained from the cross sectional study of the “EuropeaN Energy balance Research to prevent excessive weight Gain among Youth” (ENERGY) project. 2121 boys and 2516 girls aged 10 to 12 from Belgium, Greece, Hungary, the Netherlands, Norway, Slovenia and Spain were included in the analyses. Data were obtained via questionnaires assessing obesity related dietary, physical activity and sedentary behaviors and basic anthropometric objectively measured indicators (weight, height, waist circumference). The possible mediating effect of sugared drinks intake, breakfast consumption, active transportation to school, sports participation, TV viewing, computer use and sleep duration in the association between parental education and children’s body composition was explored via MacKinnon’s product-of-coefficients test in single and multiple mediation models. Two different body composition indicators were included in the models, namely Body Mass Index and waist circumference.ResultsThe association between parental education and children’s body composition was partially mediated by breakfast consumption, sports participation, TV viewing and computer use. Additionally, a suppression effect was found for sugared drinks intake. No mediation effect was found for active transportation and sleep duration. The significant mediators explained a higher proportion of the association between parental education and waist circumference compared to the association between parental education and BMI.ConclusionsTailored overweight and obesity prevention strategies in low SES preadolescent populations should incorporate specific messages focusing on the importance of encouraging daily breakfast consumption, increasing sports participation and decreasing TV viewing and computer use. However, longitudinal research to support these findings is needed.