Asthma Symptoms in Early Childhood: A public health perspective

__Abstract__ This thesis focuses on asthma symptoms in early childhood. From a public health perspective, we aim to improve health and health-related quality of life through the prevention of asthma symptoms and by signaling, counselling or management of children who are at a high risk of developing asthma. The public health approach that we used in this thesis provides a useful framework to study the association between social indicators and asthma symptoms in early childhood and the underlying pathways. This thesis also studies the impact of asthma on the child’s health-related quality of life and evaluates the systematic assessment of asthma symptoms and environmental tobacco smoke exposure at preventive youth healthcare centers. Finally, we developed an asthma risk appraisal tool to assess the risk on asthma at school age in preschool children who present with asthma symptoms at well-child care

The role of early life factors in the development of ethnic differences in growth and overweight in preschool children: A prospective birth cohort

Background: Ethnic differences in childhood and adulthood are known, but ethnic differences in preschool overweight and associated factors are less studied. We assessed ethnic differences in pre-school age overweight, and studied the mediating role of early life factors in this association. Furthermore, we assessed body mass index (BMI) z-score development from birth to age 4 years to study ethnic-specific differences in BMI z-score trajectory. Methods. We used data on 4581 children participating in a birth cohort who were born between 2002 and 2006 in Rotterdam, the Netherlands. Child's ethnicity was defined according to country of birth of the parents. Weight and length/height was repeatedly measured between 1 and 45 months of age. Overweight at age 4 years was defined according to cut-off points for BMI from the international obesity task force. We performed logistic regression to obtain independent estimates of the association between ethnicity and preschool-age overweight, and to assess the mediating role of early

Design of a controlled trial to evaluate the effectiveness of Supportive Parenting ('Stevig Ouderschap'): An intervention to empower parents at increased risk of parenting problems by providing early home visits

__Background:__ In the Netherlands, 15 % of all families with children under the age of 13 years deal with significant parenting problems. Severe parenting problems may lead to adverse physical, cognitive, and psychosocial outcomes for children, both in the short and long run. The intervention Supportive Parenting (in Dutch: "Stevig Ouderschap") is a preventive program, which aims to reduce the risk of (developing) parenting problems among parents at risk of these problems. The intervention consists of six additional home visits by a Youth Health Care nurse during the first 18 months after childbirth and is focusing on the following elements of parental empowerment: activating social networks, increasing parenting skills and supporting parent(s)/caregiver(s) in getting grip on their own life. __Methods and design:__ A controlled trial is performed in two regions in the Netherlands. An intervention group receives the intervention Supportive Parenting, and a control group receives 'care-as-usual'. Parents in both the intervention and control group fill out three questionnaires focusing on various elements of empowerment (social support, parenting skills, self-sufficiency and resilience), behavioral and emotional problems of the child. The effects of the intervention will be evaluated at child age 1-3 months (baseline) and child age 18 months by comparing the outcomes between the intervention group and the control group on the primary outcomes. Additionally, interviews and focus group interviews will be held to identify factors, which hinder or stimulate a wider implementation of the intervention Supportive Parenting. __Discussion:__ It is hypothesized that parents at increased risk of parenting problems who receive the intervention Supportive Parenting during the first 18 months after childbirth, will have enhanced their social support networks and parenting skills, increased their self-sufficiency and strengthened resilience compared to at risk parents receiving care-as-usual. Additionally children of parents from the intervention group will display less parent-reported behavioral and emotional problems

Patient coaching in secondary care:healthcare professionals' views on target group, intervention and coach profile

Background: Not all patients are able to communicate effectively during consultations with medical specialists. Patient coaching has shown to be effective for enhancing communication. Objective: We aimed to get healthcare professionals' views on target groups for patient coaching, on supportive elements in patient coaching and on the necessary qualifications and profile of a patient coach, to further our knowledge on the concept of patient coaching as supportive intervention for patients in consultations with medical specialists. Methods: We chose a qualitative research design and interviewed 18 healthcare professionals (six medical specialists, four family physicians, four community nurses and four nurse specialists/physician assistants) and analysed the verbatim transcripts using Qualitative Analysis Guide of Leuven. After a short introduction of the global concept of patient coaching and presentation of patients' perceived barriers, two interviewers structured the interview around three research questions: which patients could benefit from a patient coach, what should such a coach do and who could act like such a coach? Results: Participants describe patients who could benefit from patient coaching as generally vulnerable (e.g. older age, insufficiently accompanied, lower socioeconomic status, co-morbidity and cognitive problems) but also patients who are situationally vulnerable (e.g. elicited by bad news). Patient coaching should comprise emotional and instrumental support, aiming at reducing stress and improving the processing of medical information. Patient coaching should start from the patient's home and include preparing questions, navigating to and in the hospital, recording information during the consultation, checking understanding and recalling information. Patient coaches should have at least basic medical knowledge and a higher education. Conclusion: Healthcare professionals believe that patient coaching by a trained professional with medical knowledge could be beneficial to patients who are stressed when visiting a medical specialist. Future research should involve the views of patients on patient coaching, focus on investigating to what extent patient coaching is able to reduce stress and support a patient in processing medical information and the preferred patient coach's profile

Socioeconomic and sociodemographic factors associated with asthma related outcomes in early childhood: The generation R study

Rationale: Few studies have analyzed the association of socioeconomic and sociodemographic factors with asthma related outcomes in early childhood, including Fraction of exhaled Nitric Oxide (FeNO) and airway resistance (Rint). We examined the association of socioeconomic and sociodemographic factors with wheezing, asthma, FeNO and Rint at age 6 years. Additionally, the role of potential mediating factors was studied. Methods: The study included 6717 children participating in The Generation R Study, a prospective population-based cohort study. Data on socioeconomic and sociodemographic factors, wheezing and asthma were obtained by questionnaires. FeNO and Rint were measured at the research center. Statistical analyses were performed using logistic and linear regression models. Results: At age 6 years, 9% (456/5084) of the children had wheezing symptoms and 7% (328/4953) had asthma. Children from parents with financial difficulties had an increased risk of wheezing (adjusted Odds Ratio (aOR) = 1.63, 95% Confidence Interval (CI):1.18-2.24). Parental low education, paternal unemployment and child's male sex were associated with asthma, independent of other socioeconomic or sociodemographic factors (aOR = 1.63, 95% CI:1.24-2.15, aOR = 1.85, 95% CI:1.11-3.09, aOR = 1.58, 95% CI:1.24-2.01, respectively). No socioeconomic or gender differences in FeNO were found. The risks of wheezing, asthma, FeNO and Rint measurements differed between ethnic groups (p<0.05). Associations between paternal unemployment, child's sex, ethnicity and asthma related outcomes remained largely unexplained. Conclusions: This study showed differences between the socioeconomic and sociodemographic correlates of wheezing and asthma compared to the correlates of FeNO and Rint at age 6

Large cell neuroendocrine carcinoma with a solitary brain metastasis and low Ki-67:a unique subtype

INTRODUCTION: Stage IV large cell neuroendocrine carcinoma (LCNEC) of the lung generally presents as disseminated and aggressive disease with a Ki-67 proliferation index (PI) 40-80%. LCNEC can be subdivided in two main subtypes: the first harboring TP53/RB1 mutations (small cell lung carcinoma (SCLC)-like), the second with mutations in TP53 and STK11/KEAP1 (non-small cell lung carcinoma (NSCLC)-like). Here we evaluated 11 LCNEC patients with only a solitary brain metastasis and evaluate phenotype, genotype and follow-up. METHODS: Eleven LCNEC patients with solitary brain metastases were analyzed. Clinical characteristics and survival data were retrieved from medical records. Pathological analysis included histomorphological analysis, immunohistochemistry (pRB and Ki-67 PI) and next generation sequencing (TP53, RB1, STK11, KEAP1 and MEN1). RESULTS: All patients had N0 or N1 disease. Median overall survival (OS) was 12 months (95% confidence interval (CI) 5.5-18.5 months). Mean Ki-67 PI was 59% (range 15-100%). In 6/11 LCNEC Ki-67 PI was ≤40%. OS was longer for Ki-67 ≤40% compared to >40% (17 months (95% CI 11-23 months) vs. 5 months (95% CI 0.7-9 months), p=0.007). Two patients were still alive at follow-up after 86 and 103 months, both had Ki-67 ≤40%. 8/11 patients could be subclassified and both SCLC-like (n=6) and NSCLC-like (n=2) subtype were present. No MEN1 mutation was found. CONCLUSION: Stage IV LCNEC with a solitary brain metastasis and N0/N1 disease show in the majority of cases Ki-67 PI ≤40% and prolonged survival, distinguishing them from general LCNEC. This unique subgroup can be both of the SCLC-like and NSCLC-like subtype

Combined CD28 and 4-1BB Costimulation Potentiates Affinity-tuned Chimeric Antigen Receptor-engineered T Cells

Purpose: Targeting nonspecific, tumor-associated antigens (TAA) with chimeric antigen receptors (CAR) requires specific attention to restrict possible detrimental on-target/off-tumor effects. A reduced affinity may direct CAR-engineered T (CART) cells to tumor cells expressing high TAA levels while sparing low expressing normal tissues. However, decreasing the affinity of the CAR-target binding may compromise the overall antitumor effects. Here, we demonstrate the prime importance of the type of intracellular signaling on the function of lowaffinity CAR-T cells. Experimental Design: We used a series of single-chain variable fragments (scFv) with five different affinities targeting the same epitope of the multiple myeloma-associated CD38 antigen. The scFvs were incorporated in three different CAR costimulation designs and we evaluated the antitumor functionality and off-tumor toxicity of the generated CAR-T cells in vitro and in vivo. Results: We show that the inferior cytotoxicity and cytokine secretion mediated by CD38 CARs of very low-affinity (K d < 1.9 × 10 -6 mol/L) bearing a 4-1BB intracellular domain can be significantly improved when a CD28 costimulatory domain is used. Additional 4-1BB signaling mediated by the coexpression of 4-1BBL provided the CD28-based CD38 CAR-T cells with superior proliferative capacity, preservation of a central memory phenotype, and significantly improved in vivo antitumor function, while preserving their ability to discriminate target antigen density. Conclusions: A combinatorial costimulatory design allows the use of very low-affinity binding domains (K d < 1 mmol/L) for the construction of safe but also optimally effective CAR-T cells. Thus, very-low-affinity scFvs empowered by selected costimulatory elements can enhance the clinical potential of TAA-targeting CARs

Evaluation of systematic assessment of asthma-like symptoms and tobacco smoke exposure in early childhood by well-child professionals: A randomised trial

Objectives: This study aimed to evaluate the effectiveness of systematic assessment of asthma-like symptoms and environmental tobacco smoke (ETS) exposure during regular preventive well-child visits between age 1 and 4 years by wellchild professionals. Methods: Sixteen well-child centres in Rotterdam, the Netherlands, were randomised into 8 centres where the brief assessment form regarding asthma-like symptoms and ETS exposure was used and 8 centres that applied usual care. 3596 and 4179 children (born between April 2002 and January 2006) and their parents visited the intervention and control centres, respectively. At child's age 6 years, physician-diagnosed asthma ever, wheezing, fractional exhaled nitric oxide (FeNO), airway resistance (Rint), health-related quality of life (HRQOL) and ETS exposure at home ever were measured. Linear mixed models were applied. Results: No differences in asthma, wheezing, FeNO, Rint or HRQOL measurements between intervention and control group were found using multilevel regression in an intention-to-treat analysis (p>0.05). Children of whom the parents were interviewed by using the brief assessment form at the intervention well-child centres had a decreased risk on ETS exposure at home ever, compared to children who